CA2431151A1 - Heterocyclic ether substituted imidazoquinolines - Google Patents
Heterocyclic ether substituted imidazoquinolines Download PDFInfo
- Publication number
- CA2431151A1 CA2431151A1 CA002431151A CA2431151A CA2431151A1 CA 2431151 A1 CA2431151 A1 CA 2431151A1 CA 002431151 A CA002431151 A CA 002431151A CA 2431151 A CA2431151 A CA 2431151A CA 2431151 A1 CA2431151 A1 CA 2431151A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- imidazo
- heteroaryl
- amine
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biotechnology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- AIDS & HIV (AREA)
- Gastroenterology & Hepatology (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Transplantation (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
Abstract
Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and heterocyclyl or heteroaryl functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.
Description
Heterocyclic Ether Substituted Imidazoquinolines Field of the Invention This invention relates to imidazoquinoline compounds that have ether and heterocycle or heteroaryl functionality at the 1-position, and to pharmaceutical compositions containing such compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
Background of the Invention The first reliable report on the 1H imidazo[4,5-c]quinoline ring system, Backman et al., J. Or . Chern. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H imidazo[4,5-c]
quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J.
Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Certain 1H imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Patent Nos.
4,689,338;
4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference.
There continues to be interest in the imidazoquinoline ring system. Certain 1H-imidazo[4,5-c] naphthyridine-4-amines, 1H-imidazo [4,5-c] pyridin-4-amines, and 1H-imidazo[4,5-c] quinolin-4-amines having an ether containing substituent at the 1 position are known. These are described in U.S. Patent Nos. 5,268,376; 5,389,640;
5,494,916; and WO 99/29693.
There is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
Summary of the Invention We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides imidazo[4, 5-c]quinoline-4-amine and tetrahydroimidazo[4, 5-c]quinoline-4-amine compounds that have an ether containing substituent at the 1-position. The compounds are described by Formulas (I), (II), (III) and (IV), which are defined in more detail irafi~a. These compounds share the IO general structural formula NHZ
Ni N
~~ Rz N
~- ~- R1 Rn wherein X, R1, R2, and R are as defined herein for each class of compounds having Formulas (I), (II), (III) and (IV).
The compounds of Formulas (I), (II), (III), and (IV) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful.in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytolcine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I), (II), (III), or (IV) to the animal.
In addition, the invention provides methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of these compounds.
Background of the Invention The first reliable report on the 1H imidazo[4,5-c]quinoline ring system, Backman et al., J. Or . Chern. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H imidazo[4,5-c]
quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J.
Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Certain 1H imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Patent Nos.
4,689,338;
4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference.
There continues to be interest in the imidazoquinoline ring system. Certain 1H-imidazo[4,5-c] naphthyridine-4-amines, 1H-imidazo [4,5-c] pyridin-4-amines, and 1H-imidazo[4,5-c] quinolin-4-amines having an ether containing substituent at the 1 position are known. These are described in U.S. Patent Nos. 5,268,376; 5,389,640;
5,494,916; and WO 99/29693.
There is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
Summary of the Invention We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides imidazo[4, 5-c]quinoline-4-amine and tetrahydroimidazo[4, 5-c]quinoline-4-amine compounds that have an ether containing substituent at the 1-position. The compounds are described by Formulas (I), (II), (III) and (IV), which are defined in more detail irafi~a. These compounds share the IO general structural formula NHZ
Ni N
~~ Rz N
~- ~- R1 Rn wherein X, R1, R2, and R are as defined herein for each class of compounds having Formulas (I), (II), (III) and (IV).
The compounds of Formulas (I), (II), (III), and (IV) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful.in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytolcine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I), (II), (III), or (IV) to the animal.
In addition, the invention provides methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of these compounds.
Detailed Description of the Invention As mentioned earlier, we have found certain compounds that metuce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulas (I), (II), (III), and (IV), as shown below.
Imidazoquinoline compounds of the invention, which have ether and heterocyclyl or heteroaryl functionality at the I-position are represented by Formula (I):
N i N
N
/ X-O-Ri Rn (I) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)z;
-CO-N(R3)z;
-CO-C1_lo alkyl;
-CO-O-C~_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or CI-io alkyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, Ci-to alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also provides imidazoquinoline compounds that contain ether functionality at the 1-position, where the ether containing substituent also contains an alkynyl group and a heterocyclyl or heteroaryl group. These compounds are represented by Formula (II):
Imidazoquinoline compounds of the invention, which have ether and heterocyclyl or heteroaryl functionality at the I-position are represented by Formula (I):
N i N
N
/ X-O-Ri Rn (I) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)z;
-CO-N(R3)z;
-CO-C1_lo alkyl;
-CO-O-C~_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or CI-io alkyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, Ci-to alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also provides imidazoquinoline compounds that contain ether functionality at the 1-position, where the ether containing substituent also contains an alkynyl group and a heterocyclyl or heteroaryl group. These compounds are represented by Formula (II):
N~
N
X- O-(CH2)i-1 o-C- C-Rlo (II) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rlo is selected from the group consisting of heteroaryl and heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)a;
-CO-N~R3)2;
-CO-C1_10 alkyl;
-CO-O-Cl_lo alkyl;
-N3;
-aryl;
-heteroaryl;
N
X- O-(CH2)i-1 o-C- C-Rlo (II) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rlo is selected from the group consisting of heteroaryl and heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)a;
-CO-N~R3)2;
-CO-C1_10 alkyl;
-CO-O-Cl_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
nisOto4;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_2-; and each R present is independently selected from the group consisting of C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also includes tetrahydroimidazoquinoline compounds that bear an ether and heterocyclyl or heteroaryl containing substituent at the 1-position.
Such tetrahydroimidazoquinoline compounds axe represented by Formula (III):
NHz N~
Rz ~ N
I
R"
(III) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
2 S -alkyl;
-alkenyl;
-aryl;
-CO-aryl; and -CO-heteroaryl;
nisOto4;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_2-; and each R present is independently selected from the group consisting of C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also includes tetrahydroimidazoquinoline compounds that bear an ether and heterocyclyl or heteroaryl containing substituent at the 1-position.
Such tetrahydroimidazoquinoline compounds axe represented by Formula (III):
NHz N~
Rz ~ N
I
R"
(III) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
2 S -alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of -OH;
-halogen;
-N(R3)z;
-CO-N(R3)z;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R~ is alkyl or alkenyl, which may be interrupted by one or more -0-groups;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-to alkyl, CI_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of -OH;
-halogen;
-N(R3)z;
-CO-N(R3)z;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R~ is alkyl or alkenyl, which may be interrupted by one or more -0-groups;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-to alkyl, CI_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
An additional class of immune response modifying compounds of the invention are tetrahydroimidazoquinoline compounds that have an ether containing substituent at the 1-position, where the ether containing substituent also contains an alkynyl group and a heterocyclyl or heteroaryl group. These compounds are represented by Formula (IV):
NHS
N~
N
I
X-O-(CHZ)i-io-C=CRIo (IV) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rlo is selected from the group consisting of heteroaryl and heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)Zi -CO-N(R3)z;
-CO-C1_IO alkyl;
-CO-O-C1_lo alkyl;
NHS
N~
N
I
X-O-(CHZ)i-io-C=CRIo (IV) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rlo is selected from the group consisting of heteroaryl and heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)Zi -CO-N(R3)z;
-CO-C1_IO alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_2-;
n is 0 to 4; and each R present is independently selected from the group consisting of Cl_io alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Preparation of the Compounds Compounds of the invention can be prepared according to Reaction Scheme I
where R, RZ, X and n are as defined above and Rl l is alkyl substituted by a heteroaryl group wherein the heteroaryl group may be unsubstituted or may be substituted as defined iyafi~a or R~ 1 is substituted heteroaryl as defined infYa With the proviso that if Rl ~ is substituted heteroaryl at least one substituent is a strong electron withdrawing group located of°tlzo or para to the ether bond.
In Reaction Scheme I a 4-amino-1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula X is allcylated with a halide of Formula XI to provide a 1H
imidazo[4,5-c]quinolin-4-amine of Formula XII which is a subgenus of Formula I. The alcohol of Formula X is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The halide is then added to the reaction mixture.
The reaction can be carried out at ambient temperature or with gentle heating (~50°C) if desired. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Many compounds of Formula X are known, see for example Gerster, U.S. Patent No. 4,689,338 and Gerster et. al., U.S. Patent No. 5,605,899, the disclosures of which are incorporated by reference herein; others can readily be prepared using known synthetic routes, see for example, Andre et. al, U.S. Patent No. 5,578,727; Gerster, U.S. Patent No.
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_2-;
n is 0 to 4; and each R present is independently selected from the group consisting of Cl_io alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Preparation of the Compounds Compounds of the invention can be prepared according to Reaction Scheme I
where R, RZ, X and n are as defined above and Rl l is alkyl substituted by a heteroaryl group wherein the heteroaryl group may be unsubstituted or may be substituted as defined iyafi~a or R~ 1 is substituted heteroaryl as defined infYa With the proviso that if Rl ~ is substituted heteroaryl at least one substituent is a strong electron withdrawing group located of°tlzo or para to the ether bond.
In Reaction Scheme I a 4-amino-1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula X is allcylated with a halide of Formula XI to provide a 1H
imidazo[4,5-c]quinolin-4-amine of Formula XII which is a subgenus of Formula I. The alcohol of Formula X is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The halide is then added to the reaction mixture.
The reaction can be carried out at ambient temperature or with gentle heating (~50°C) if desired. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Many compounds of Formula X are known, see for example Gerster, U.S. Patent No. 4,689,338 and Gerster et. al., U.S. Patent No. 5,605,899, the disclosures of which are incorporated by reference herein; others can readily be prepared using known synthetic routes, see for example, Andre et. al, U.S. Patent No. 5,578,727; Gerster, U.S. Patent No.
5,175,296; Nikolaides et al., U.S. Patent No. 5,395,937; and Gerster et. aL, U.S. Patent No.
5,741,908, the disclosures of whzch are incorporated by reference herein. Many halides of Formula XI are commercially available; others can be readily prepared using known synthetic methods.
Reaction Scheme I
N
~>---Rz + Hal-R~~ ~ N \ N>---RZ
/ N / N
Rn / ~X Rn / ~X
OH Q
X XI XI I
Compounds of the invention can also be prepared according to Reaction Scheme II
where R, RZ, R11, X and n are as defined above.
In step (1) of Reaction Scheme II the hydroxy group of a 1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is protected with a benzyl group. The alcohol of Formula XIII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The alkoxide is then alkylated with benzyl bromide to provide a compound of Formula XIV. The reaction can be carried out at ambient temperature. Many compounds of Formula XIII are known, see for example, Gerster, U.S. Patent 4,689,338; others can readily be prepared using known synthetic routes, see for example, Gerster et al., U.S. Patent No. 5,605,899 and Gerster, U.S. Patent No.5,175,296.
In step (2) of Reaction Scheme II a compound of Formula XIV is oxidized to provide a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XV using a conventional oxidizing agent capable of forming N-oxides . Preferably a solution of a compound of Formula XIV in a suitable solvent such as chloroform or dichloromethane is oxidized using 3-chloroperoxybenzoic acid at ambient temperature.
In step (3) of Reaction Scheme II a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XV is chlorinated to provide a 4-chloro-1H imidazo[4,5-c]quinoline of Formula XVI. Preferably a solution of a compound of Formula XV in a suitable solvent such as toluene is treated with phosphorous oxychloride at ambient temperature.
In step (4) of Reaction Scheme II a 4-chloro-1H imidazo[4,5-c]quinoline of Formula XVI is reacted with phenol to provide a 4-phenoxy-1H imidazo[4,5-c]quinoline of Formula XVII. The phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form a phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XVI.
In step (5) of Reaction Scheme II the benzyl protecting gxoup is removed from a compound of Formula XVII to provide a 4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XVIII. The reaction is preferably carried out by adding triflic acid in a controlled fashion to a solution of a compound of Formula XVII in a suitable solvent such as dichloromethane at ambient temperature.
In step (6) of Reaction Scheme II a 4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XVIII is alkylated with halide Hal-RI l to provide a 4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XIX. The alkoxide of a compound of Formula XVIII is formed by adding the alcohol to a biphasic mixture of aqueous 50%
sodium hydroxide and an inert solvent such as dichloromethane in the presence of a phase transfer catalyst such as benzyltrimethlammonium chloride. The alkoxide is then alkylated. The reaction can be carried out at ambient temperature.
In step (7) of Reaction Scheme II a 4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl ether of Formula XIX is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XII which is a subgenus of Formula I. The reaction can be carried out by combining a compound of Formula XIX with ammonium acetate and heating the resulting mixture at 150°C. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme II
N ~ N~R ( ~ ) N ~ N~ (~ O. N+ ~ N~ R
/ ~ z / N R2 ~ N
R" / X R" / X R" / IX
OH O O
XIII XIV XV
(3) \ ~ \
0 o c1 N~'Rz E (5) N / N~'R ~ N , N)-R
N N z N a R" V / IX R" / IX R" / X
OH O O
XVI I I XVI I XVI
(6) / N~ R~ ~ N / N~ R2 'N
Rn / X R" / X
O O
XIX R~1 XII
Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme III where R, R2, R11, X and n are as defined above.
In Reaction Scheme III a 4-amino-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-yl alcohol of Formula XX is alkylated with a halide of Formula XI to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XXI which is a subgenus of Formula III. The alcohol of Formula XX is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The alkoxide is then combined with the halide. The reaction can be carned out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Many tetrahydro-1H imidazo[4,5-c]quinolines of Formula XX are known, see for example, Nikolaides et al., U.S. Patent No. 5,352,784; others can be prepared using known synthetic methods, see for example, Lindstrom, U.S. Patent No. 5,693,811; the disclosures of which are incorporated by reference herein.
Reaction Scheme III
NHZ NHz N
N ~ \~Rz + Hal-R~~ ~- N \ N~-Rz N / N
R° ~X Rn ~X
OH O
XX XI XXI R~~
Compounds of the invention can be prepared according to Reaction Scheme IV
where R, R2, X and n are as defined above and R12 is a heteroaryl group which may be unsubstituted or substituted as defined infra.
In step (1) of Reaction Scheme IV a 1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is alkylated with a halide of Formula XXII to provide a 1H
imidazo[4,5-c]quinolin-1-yl ether of Formula XXIII. The compound of Formula XIII and the halide of Formula XXII are combined in a biphasic mixture of 50% aqueous sodium hydroxide and a suitable solvent such as dichloromethane in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride. The reaction can be run at ambient temperature.
In step (2) of Reaction Scheme IV a 1H imidazo[4,5-c]quinoline of Formula XXIII
is oxidized using the method of step (2) of Reaction Scheme II to provide a 1H
imidazo[4,5-c]quinoline-SN-oxide of Formula XXIV.
In step (3) of Reaction Scheme IV a 1H imidazoj4,5-c]quinoline-SN-oxide of Formula XXIV is reacted with trichloroacetyl isocyanate to provide a 1H
imidazo[4,5-c]quinolin-4-yl acetamide of Formula XXV. Preferably the isocyanate is added in a controlled fashion at ambient temperature to a solution of the SN-oxide in a suitable solvent such as dichloromethane.
In step (4) of Reaction Scheme IV a 1H imidazo[4,5-c]quinolin-4-yl acetamide of Formula XXV is hydrolyzed to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI. The hydrolysis can be carried out by conventional methods preferably by treating a solution of a compound of Formula XXV in methanol with sodium methoxide.
In step (5) of Reaction Scheme IV 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI is coupled with a halide of formula Hal-Rlz using a transition metal catalyst to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II. Preferably a compound of Formula XXVI is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile. The reaction is preferably carried out at an elevated temperature (60-80°C). The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
N~Rz '~' Hal-(CHz)1-1o- (~~~ N ~ N>-Rz / N / N
R° / ~H Rn /
XIII XXII XXIII
(CHz) CI CI (2) ~CI
NHz HN O
N W N _ (4) N W N (3) O.N+ ~ N
/ ~ Rz ~ ~ i' N~ Rz E ~ / N~ Rz ~N
Rn / X Rn / X Rn / X
O O O
XXVI (CHz)1-1o XXV (CHz)1-1o XXIV (CHz)1-1o Hal -R~z NHz N
N / \~ Rz ~N
i Rn /
O
(CHz) R~z Compounds of the invention can be prepared according to Reaction Scheme V
where R, R2, R12, X and n are as defined above and BOC is tent-butoxycarbonyl.
IS
In step (1) of Reaction Scheme V the amino group of a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI is protected with tef~t-butoxycarbonyl groups. A
compound of Formula XXVI is combined with di-tef~t-butyl dicarbonate in a suitable solvent such as N,N-dimethylformamide in the presence of 4-(dimethylamino)pyridine and triethylamine.
The reaction is carried out at an elevated temperature (80-85°C).
In step (2) of Reaction Scheme V a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVIII is coupled with a halide of formula Hal-R12 using a transition metal catalyst to provide a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XXIX.
Preferably a compound of Formula XXVIII is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile. The reaction can be carried out at ambient temperature or at an elevated temperature (40-80°C).
In step (3) of Reaction Scheme V the protecting groups are removed by hydrolysis under acidic conditions to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II. Preferably a compound of Formula XXIX
is treated with trifluoroacetic acid in a suitable solvent such as dichloromethane. The reaction can be run at ambient temperature or at a reduced temperature (0°C). The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (4) of Reaction Scheme V the alkyne bond of a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XXIX is reduced to provide a protected 1H
imidazo[4,5-c]quinolin-4-amine of Formula XXX. Preferably, the reduction is carried out using a conventional heterogeneous hydxogentation catalyst such as platinum oxide, platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol.
In step (5) of Reaction Scheme V the protecting groups of a compound of Formula XXX are removed in the same manner as in step (3) to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXXI which is a subgenus of Formula I. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme V
NHz N(BOC)z N(BOC)z N / N>-.Rz (1~ N ~ N~R (-~ N ~ N~Rz z N / N / N
X
Rn / O Rn / O Rn / O
XXVI (CHz)1-1o XXVlI! (CHz)1-1o SIX (CHz)1-1o R~z (4) (3) NH N(BOC)z NHz z N~R E (5) N ~ N N \ N~R
/ N z ~ / ~Rz / N z 'N
i Rn / p R° / x Rn / O
O
XXX! (CHz)s-12 ~( (CHz) XXVI! (CHz)1-1o R~z R~z , R~z Compounds of the invention can be prepared according to Reaction Scheme VI
where R, RZ, R~2, X and n are as defined above and CBZ is benzyloxycarbonyl.
In step (1) of Reaction Scheme VI the amino group of a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI is protected with benzyloxycarbonyl groups.
A
compound of Formula XXVI is combined with dibenzyl dicarbonate in a suitable solvent such as N,N-dimethylformamide. The reaction can be carried out at ambient temperature or with mild heating (40°C).
In step (2) of Reaction Scheme VI a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula ~;XXII is coupled with a halide of formula Hal-R12 using a transition metal catalyst to provide a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XX~~III.
Preferably a compound of Formula XX~~II is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile. The reaction can be carried out at ambient temperature ox at an elevated temperature (40-80°C).
In step (3) of Reaction Scheme VI the protecting groups are removed by hydrolysis to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II. Preferably a compound of Formula XX~~III is treated with sodium methoxide in a suitable solvent such as methanol. The reaction can be run at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (4) of Reaction Scheme VI the protecting groups of a compound of Formula X~~XIII are removed by hydrogenolysis and the alkyne bond is reduced to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XX~~I which is a subgenus of Formula I. Preferably, the hydrogenolysislreduction is carried out using palladium hydroxide on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VT
NHz N(CBZ)z N(CBZ)z N~' Rz (~ N \ N~ R (~ N \ N~ R
z 2 ,N / N / N
Rn / O Rn / O Rn / O
XXVI (CHz)~-~o XXXII (CHz)~-~o XXXIII (CHz) III
R~z (4) (3) NHz NHz N N
~ ~
N N
~' y' Rz R
I I
/ N z /
'N
Rn Rn / X
/
O O
XXXI
(CHz) XXVII
3-12 (CHz) q-'o R~z R~z Compounds of the invention can~be prepared according to Reaction Scheme VII
where R, Rl, R2, X and n are as defined above.
In step (1) of Reaction Scheme VII a 2,4-dichloro-3-nitroquinoline of Formula XXXIV is reacted with an amine of Formula Rl-O-X-NHZ to provide a 2-chloro-3-nitroquinolin-4-amine of Formula XXXV. The reaction can be carried out by adding the amine to a solution of a compound of Formula XXXIV in a suitable solvent such as chloroform or dichloromethane and optionally heating. Many quinolines of Formula XXXIV are known or can be prepared using known synthetic methods (see for example, Andre et al., U.S. Patent No. 4,988,815 and references cited therein).
In step (2) of Reaction Scheme VII a 2-chloro-3-nitroquinolin-4-amine of Formula XX~~V is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula XX~~~VI.
Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be caxried out on a Parr apparatus in a suitable solvent. such as isopropyl alcohol ox toluene.
In step (3) of Reaction Scheme VII a 2-chloroquinoline-3,4-diamine of Formula XXXVI is is reacted with a carboxylic acid or an equivalent thereof to provide a 4-chloro-1H-irnidazo[4,5-c]quinoline of Formula XXXVII. Suitable equivalents to carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XXXVII. For example, triethyl orthofonnate will provide a compound where R2 is hydrogen and triethyl orthoacetate will provide a compound where RZ is methyl.
The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction. Optionally a catalyst such as pyridine hydrochloxide can be included.
Alternatively, step (3) can be carried out by (i) reacting the diamine of Formula XXXVI with an acyl halide of Formula RZC(O)Cl and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of the diamine in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. In part (ii) the product of part (i) is heated in an alcoholic solvent in the pxesence of a base.
Preferably the product of part (i) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia. Alternatively, if step (i) has been run in pyridine, step (ii) can be carried out by heating the reaction mixture after analysis indicates that step (i) is complete.
In step (4) of Reaction Scheme VII a 4-chloro-1H imidazo[4,5-c]quinoline of Formula ~~XXVII is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula I. The reaction is tamed out by heating (e.g.,125-175°C) a compound of Formula XXXVII under pressure in a sealed reactor in the presence of a solution of ammonia in an alkanol. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VII
CI O ~ CI O CI
n* n*
N ~ N.O- (~ ) ' N ~ N.O- (2) N ~ NHz I / CI I / NH I / NH
n / n / x ~ /
O O
XXXIV ~ R X~(VI I
(3) NHz CI
N / N)-- Rz E (4) N / N~- R
z ~N
Rn / X Rn / X
O O
Compounds of the invention can be prepared according to Reaction Scheme VIII
where R, Rl, R2, X and n are as defined above.
In Reaction Scheme VTII a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXXVITI is alkylated with a halide of Formula XXXIX to provide a 1H
imidazo[4,5-c]quinolin-4-amine of Formula I. The compound of Formula XXXVIII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide. The halide is then added to the reaction mixture. The reaction can be carned out at an elevated temperature 0100°C). Allcylation occurs at both the Nl and the N3 nitrogens;
however, the desired 1-isomer can be readily separated from the 3-isomer using conventional teclmliques such as column chromatography and recrystallization.
Many 1H imidazo[4,5-c]quinolin-4-amines of Formula XXXVIII are known;
others may be prepared using known synthetic methods, sae for example, Gerster, U.S.
Patent No. 5,756,747 and the references cited therein.
Reaction Scheme VIII
N>---.RZ + Hal-X-O-R~ ~ ~j / N~--Rz 'H N
R" ~ R" ~ X
O
XXXVIII XXXIX I R~
Compounds of the invention can be prepared according to Reaction Scheme IX
where R, Rl R2, X and n are as defined above.
In step (1) of Reaction Scheme IX a 4-nitrotetrazolo[1,5-a]quinolin-5-of of Formula XL is chlorinated to provide a 5-chloro-4-nitrotetrazolo[1,5-a]quinoline of Formula XLI. Conventional chlorinating agents can be used. Preferably the reaction is carried out using phosphorus oxychloride in a suitable solvent such as N,N-dimethylformamide. 4-Nitrotetrazolo[1,5-a]quinolin-5-ols of Formula XL are known or can be prepared using known synthetic methods (see for example, Gerster, et al., U.S.
Patent No. 5,741,905 and references cited therein).
In step (2) of Reaction Scheme IX a 5-chloro-4-nitrotetrazolo[1,5-a]quinoline of Formula XLI is reacted with an amine of Formula RI-O-X-NHZ to provide a 4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula XLII. The reaction can be carried out by adding the amine to a solution of a compound of Formula XLI in a suitable solvent such as dichloromethane in the presence of triethylamine.
In step (3) of Reaction Scheme IX a 4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula XLII is reduced using the method of step (2) in Reaction Scheme VII to provide a tetrazolo[1,5-a]quinolin-4,5-diamine of Formula XLIII.
In step (4 ) of Reaction Scheme IX a tetrazolo[1,5-a]quinolin-4,5-diamine of Formula XLIII is cyclized using the method of step (3) in Reaction Scheme VII
to provide a 6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline of Formula XLIV.
In step (5) of Reaction Scheme IX a 6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline of Formula XLIV is reduced to provide a 1H imidazo[4,5-a]quinolin- 4-amine of Formula I.
Step (5) involves (i) reacting a compound of Formula XLIV with triphenylphosphine and then (ii) hydrolyzing. Part (i) can be carried out by combining a compound of Formula XLIV with triphenylphosphine in a suitable solvent such as 1,2-dichlorobenzene and heating. Part (ii) involves hydrolysis of the product from part (i). The hydrolysis can be carried out by conventional methods such as heating in the presence of water or a lower alkanol optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide. The product or a pharniaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IX
NN_N O+ NN_N O+ ~N_N O+
N.O- (~ N l N.O=(2~ N,N N,0_ ~OH ~ ~C! ~ NH
R~ / R~ / Rn / X
O
XL XLI XLII
(3) NHZ ,N-N ,N-N
N ~ N~R E (5) N,N ~ I N~R E (4) N,N ~ I NHS
/ ~ 2 NH
Rn / O R~ / O R~ / X
O
I R~ XLIV R~ XL R~
III
Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme X where R, R2, R12, X and n are as defined above.
In step (1) of Reaction Scheme X a 4-amino-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XX is alkylated using the method of Reaction Scheme III with a halide of formula Hal-(CHZ)i-io-CH=CH to provide a 6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine of Formula XLV.
In step (2) of Reaction Scheme X a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XLV is coupled using the method of step (5) of Reaction Scheme IV
with a halide of Formula Hal-Rl2 to provide a 6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine of Formula XLIV which is a subgenus of Formula IV. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme X
NHz NHz NHz N \ N C7 ) N \ N C2) \ N
~Rz ~ ~~Rz ~ N ~~Rz ,N / N ~ N
X
Rn OH R" p R" O' XX XLV ~ I H2)1-10 XLVI t I Ha)1-10 R~z Compounds of the invention can be prepared according to Reaction Scheme XI
where R, Rj, R2, X and n are as defined above.
In step (1) of Reaction Scheme XI a 2,4-dihydroxy-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula XLVII is chlorinated to provide a 2,4-dichloro-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula XLVIII. Conventional chlorinating agents can be used. Preferably the reaction is carned out by combining a compound of Formula XLVII
with phosphorous oxychloride and then heating (55-65°C). Compounds of Formula XLVII are known or can be prepared using known synthetic methods (see for example Nikolaides et al,. U.S. Patent 5,352,784 and references cited therein).
In step (2) of Reaction Scheme XI a 2,4-dichloro-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula XLVIII is reacted with an amine of Formula Rl-O-X-NHZ to provide a 2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula XLIX.
The reaction can be carried out by adding the amine to a solution of a compound of Formula XLVIII in a suitable solvent such as N,N-dimethylformamide and heating (55-65°C).
In step (3) of Reaction Scheme XI a 2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula XLIX is reacted with phenol using the method of step (4) of Reaction Scheme II to provide a 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula L.
hi step (4) of Reaction Scheme XI a 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula L is reduced using the method of step (2) of Reaction Scheme VII to provide a 2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of Formula LI.
In step (5) of Reaction Scheme XI a 2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of Formula LI is cyclized using the method of step (3) of Reaction Scheme VII to provide a 4-phenoxy-6,7,8,9-tetTahydro-1H imidazo[4,5-c]quinoline of Formula LII.
In step (6) of Reaction Scheme XI a 4-phenoxy-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinoline of Formula LII is aminated using the method of step (7) of Reaction Scheme II to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula III.
Reaction Scheme XI
OH O+ CI O+ CI O\
N ~ N.O- (~) N ~ N.O- (2) N ~ O_ -~ I , I ~ OH I ~ CI NH
Rn Rn n X
O
XLVII XLVIII XLIX
R~
(3) \ / \ / ~ /
NH "+
N ~ N~R E (5) N ~ 2E (4) N ~ N.O_ / I
~N ~NH ~ NH
Rn X R" X R" X
O O
LII R LI R L OI
I ~ Ra (6) NHS
N
N ~ y R2 ,N
R" X
O
III R~
The invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formulas (I), (II), (III), and (IV). These intermediate compounds have the structural Formulas (V) - (IX) and (XLIV) described in more detail below.
One class of intermediate compounds has Formula (V):
N~ N
~~ R2 N
X-O-Rl (V) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
Z 0 -R4- heteroaryl;
-R4-heterocyclyl; and -(CHZ)i-io-C=C-Rio RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)Zp -CO-N(R3)a;
-CO-Cl_lo alkyl;
-CO-O-C1_~o alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_lo alkyl;
Rlo is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)o_Z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Another class of intermediates are imidazoquinoline-4-phenoxy compounds of Formula (VI):
O
Ni N
I ~>---RZ
N
I X-O-Rl Rn wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl;
-R4-heterocyclyl; and -(CHZ)i-io-C=C-Rlo;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)z;
-CO-N(R3)z;
-CO-C~_IO alkyl;
-CO-O-C1_io alkyl;
-N3~
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_IO alkyl;
Rlo is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-to alkyl, CI_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Another class of intermediate compounds is represented by Formula (VII):
~N_N
N, 1 Z
N
NH
Rn / X
O
R
(VII) wherein: Z is NHz or NOZ;
X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_lo alkyl;
n is 0 to 4; and each R present is independently selected from the group consisting of C~_~o alkyl, C1-to alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Another class of intermediate compounds has the Formula (XLIV):
~N_N
'N ~ ~~R2 'N
R~ / X
O
"1 (XLIV) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of-.
-OH;
-halogen;
-N(R3)z~
-CO-N(R3)a;
-CO-C1_lo alkyl;
-CO-O-C1_IO alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Rd is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-to alkyl;
each Y is independently -O- or -S(O)o_2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_~o alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
An additional class of intermediate compounds has the Formula (VIII):
N-(COOR7)2 N, N
( ~~ Ra N
X-O-Rl (VIII) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting o~
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(Rs)a~
-CO-N(R3)2;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C~_lo alkyl;
each Y is independently -O- or -S(O)o_2-;
nisOto4;
each R present is independently selected from the group consisting of C1_Io alkyl, C ~ _I O alkoxy, hydroxy, halogen and trifluoromethyl; and R~ is test-butyl or benzyl;
or a pharmaceutically acceptable salt thereof.
A further class of intermediates are imidazoquinoline-4-chloro compounds of the Formula (IX) >-R~
(IX) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(Rs)z;
-CO-N(R3)z;
-CO-Ci_io alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Rø is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of CI_Io alkyl, Ci_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
As used herein, the terms "alkyl", "allcenyl" and the prefix "allc-" are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e.
cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl.
In addition, the alkyl and alkenyl portions of -X- groups can be unsubstituted or substituted by one or more substituents, which substituents are selected from the group consisting of allcyl, alkenyl, aryl, heteroaxyl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylallcyl.
The term "haloalkyl" is inclusive of groups that ai-a substituted by one or more halogen atoms, including perfluorinated groups. This is also true of groups that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.
Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, quinazolinyl, purinyl, and so on.
"Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N) and includes the fully saturated and partially unsaturated derivatives of any of the above mentioned heteroaryl groups.
Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiornorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.
The aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, allcylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, aroyloxy, aroylthio, aroylamino, alkylarninosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, alkylenesulfonylamino, arylsulfonylamino, arylalkylsulfonylamino,heteroarylsulfonylamino, heteroalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonyl, heteroarylaminocarbonylamino, herteroarylalkylaminocarbonylamino, but, in the case of heterocyclyl, alkylcarbonyl, alkenylcarbonyl, haloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, heteroarylcarbonyl, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl are not permitted.
If any other groups are identified as being "substituted" or "optionally substituted", then those groups can also be substituted by one or more of the above enumerated substituents.
Certain substituents are generally preferred. For example, preferred heteroaryl groups include 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, and 5-pyrimidine.
Preferably no R substituents are present (i.e., n is 0). Preferred RZ groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl.
One or more of these preferred substituents, if present, can be present in the compounds of the invention in any combination.
1 S The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers.
Pharmaceutical Compositions and Biological Activity Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.
The term "a therapeutically effective amount" means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg, of the compound to the subject. Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc.
The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon-a (IFN-a) and/or tumor necrosis factor-a (TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN-a, TNF-a, IL-I, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
Certain compounds of the invention have been found to preferentially induce the expression of IFN-a in a population of hematopoietic cells such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.
In addition to the ability to induce the production of cytokines, the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. The compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
Compounds of the invention also have an effect on the acquired immune response.
For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Thl) cytokine IFN-y is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds. This activity means that the compounds are useful in the treatment of diseases where upregulation of the Thl response and/or downregulation of the Th2 response is desired. In view of the ability of compounds of the invention to inhibit the Th2 immune response, the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
The immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN-a and/or TNF-a, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum;
variola, particularly variola major; rhinovirus; adenovirus; influenza; pare-influenza; HIV;
CMV; VZV; intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g. candida, aspergillus, and cryptococcal meningitis; neoplastic diseases, e.g., basal cell carcinoma, hairy cell leukemia, I~aposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases, e.g. pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis; and bacterial infections, e.g., tuberculosis, and mycobacterium avium.
Additional diseases or conditions that can be treated using the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocythaemia;
leprosy;
multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis; alopecia areata; the inhibition of keloid formation after surgery and other types of post-surgical scars. In addition, these compounds could enhance or stimulate the healing of wounds, including chronic wounds. The compounds may be useful for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV
patients.
An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-a, TNF-a,, IL-l, IL-6, IL-10 and IL-12 that is increased over the background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/lcg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mglkg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, xate of virus production, and mortality as compared to untreated control animals. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg. An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/leg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg.
The invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.
In the examples below some of the compounds were purified using semi-preparative HPLC. Two different methods were used and they are described below. Both methods used a A-100 Gilson-6 equipped with 900 Series Intelligent Interface.
The semi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriate fractions were combined and lyophilized to provide the trifluoroacetate salt of the desired compound.
Method A
Column: column Microsorb C18, 21.4 x 250 mm, 8 micron particle size, 60~ pore;
flow rata: 10 mL/min.; gradient elution from 2-95% B in 25 min., hold at 95% B
for 5 min., where A=0.1 % trifluoroacetic acid/water and B=0.1 % trifluoroacetic acid/acetonitrile; peak detection at 254 nm for triggering fraction collection.
Method B
Column: Phenomenex Capcell PakCl8, 35 x 20 mm, 5 micron particle size; flow rate: 20 mL/min.; gradient elution from 5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1 % trifluoroacetic acid/water and B=0.1 % trifluoroacetic acid/acetonitrile;
peak detection at 254 nm for triggering fraction collection.
Example 1 1-(2-{[3-(Isoquinolin-4-yl)-2-propynyl]oxy~ethyl)-1H imidazo[4,5-c]quinolin-4-amine N H~
N
N j 'N
O
N
Part A
2-(1H Imidazo[4,5-c]quinolin-1-yl)-1-ethanol (28.5 g, 0.133 mol) was added in portions over a period of 1 hour to a mixture of sodium hydroxide (240 mL of 50%), dichloromethane (240 mL), propargyl bromide (39.6 g of 80%, 0.266 mol) and benzyltrimethylammonium chloride (2.46 g, 0.013 mmol). The resulting reaction mixture was allowed to stir at ambient temperature for 16 hours at which time the reaction mixture was homogeneous. The layers were separated. The aqueous fraction was extracted with additional dichloromethane. The organic fractions were combined, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was combined with diethyl ether and the mixture was allowed to stir. An orange solid was isolated by filtration. This material was recrystallized from ethyl acetate to provide 19.8 g of 2-(1H imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether as a yellow crystalline solid, m.p. 124-126°C.
Analysis. Calculated for ClSHisN30: %C, 71.70; %H, 5.21; %N, 16.72. Found: %C, 71.85; %H, 5.25; %N, 16.90 S IH NMR (300 MHz, DMSO) 8 9.21 (s, 1 H), 8.44 (m, 1 H), 8.36 (s, 1H), 8.18 (m, 1 H), 7.71 (m, 2 H), 4.93 (t, J = 5.1 Hz, 2 H), 4.14 (d, J = 2.4 Hz, 2 H), 3.98 (t, J = S.1 Hz, 2 H), 3 .3 S (t, J = 2.2 Hz, 1 H) HRMS(ESI) calcd for C15H14N3O (MH+) 252.1137, found 252.1141 Part B
2-(1H Imidazo[4,5-c]quinolin-I-yl)ethyl (2-propynyl) ether (19.7 g, 78.4 mmol) and chloroform were combined and then cooled to 0°C. 3-Chloroperoxybenzoic acid (15.7 g of S7-86%) was added and the mixture was allowed to stir for 0.5 hour. The mixture was allowed to warm to ambient temperature by which time all material was in solution.
Analysis by thin Layer chromatography (TLC) indicated that some starting material was 1 S still present so more 3-chloroperoxybenzoic acid (two separate 4 g portions) was added.
About O.S hour after the second portion was added, TLC showed no starting material. The reaction solution was extracted with 10% sodium hydroxide. The aqueous fraction was then extracted multiple times with dichloromethane. The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide 18.5 g of I-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide as a yellow oil.
HRMS(ESI) calcd for C15Hi4N30a (MH+) 268.1086, found 268.1098 Part C
Under a nitrogen atmosphere trichloroacetyl isocyanate (15.5 g, 82.2 mmol) was added dropwise to a mixture of I-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (18.3 g, 68.5 mmol) and dichloromethane (300 mL). Vigorous carbon dioxide evolution was observed. After about 0.5 hour all of the material was in solution. The reaction solution was allowed to stir for about 1 hour at which time analysis by TLC
indicated the presence of a small amount of starting material. More tl-ichloroacetyl isocyanate (4.S g) was added. After 1 hour, TLC analysis indicated that the reaction was complete. The volatiles were removed under reduced pressure to provide N-{1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamide as a pale yellow solid.
Part D
Dichloromethane (150 mL) was added to a mixture of the solid from Part C and methanol (200 mL) and all of the material went into solution. Sodium methoxide (50 g of 25% in methanol) was added and the solution was allowed to stir at ambient temperature overnight. The resulting precipitate was isolated by filtration. The filtrate was concentrated to a volume of approximately 100 mL and a second crop of precipitate was isolated by filtration. The two crops were combined and dried in a vacuum oven at 60°C
for 16 hours to provide 16.4 g of 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. 225-227°C.
Analysis. Calculated for CISH14N4O (HZO)va~ %C, 66.53; %H, 5.40; %N, 20.69.
Found:
%C, 66.33; %H, S.I8; %N, 21.12 'H NMR (300 MHz, DMSO) 8 8.I3 (s, 1 H), 8.08 (br d, J = 7.8 Hz, 1 H), 7.62 (br d, J =
8.3 Hz, 1 H), 7.44 (br t, J = 7.6 Hz, 1 H), 7.24 (br t, J = 7.5 Hz, 1 H), 6.54 (s, 2 H), 4.81 (t, J = 5.4 Hz, 2 H), 4.14 (d, J = 2.4 Hz, 2 H), 3.93 (t, J = 5.1 Hz, 2 H), 3.38 (t, J = 2.4 Hz, 1 H) HRMS(ESI) calcd for CISHisN4O (MH+) 267.1246, found 267.1253 Part E
Under a nitrogen atmosphere 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (16 g, 60.1 mmol), di-tert-butyl dicarbonate (32.7 g, 150 mmol), triethylamine (21 mL, 150 mol), N,N-dimethylformamide (150 mL) and 4-(dimethylamino)pyridine (0.1 g) were combined and heated to 80-85°C.
After about 1 hour the mixture became homogeneous and TLC analysis indicated that very little starting material remained. The solution was heated for an additional hour. The solution was diluted with ethyl acetate and water. The layers were separated and the aqueous fraction was extracted with ethyl acetate. The organic fractions were combined, washed with water and then with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a pale orange-yellow solid. This material was triturated with diethyl ether to provide 22.6 g of N,N-(bis tent-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. 139-142°C.
Analysis. Calculated for CZSH3oN4Os: %C, 64.36; %H, 6.48; %N, 12.01. Found:
%C, 64.40; %H, 6.43; %N, 12.06 1H NMR (300 MHz, DMSO) 8 8.44 (m, 1 H), 8.35 (s, 1 H), 8.08 (m, 1 H), 7.73 (m, 2 H), 4.94 (t, J = 4.9 Hz, 2 H), 4.12 (d, J = 2.4 Hz, 2 H), 3.98 (t, J = 5.1 Hz, 2 H), 3.31 (t, J = 2.4 Hz, 1 H), 1.34 (s, 18 H) HRMS(ESI) calcd for Cz5H3~N4Os (MHO) 467.2294, found 467.2307 Part F
Under a nitrogen atmosphere N,N-(bis test-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.14 nnmol), triethylamine (0.8 mL, 5.56 mmol) and N,N-dimethylformamide (25 mL) were combined and the resulting solution was heated to 80-85°C.
Dichlorobis(triphenylphosphine)palladium(II) (0.08 g, 0.11 mol), copper(I) iodide (0.04 g, 0.21 mmol) and 4-bromoisoquinoline (0.49 g, 2.35 mmol) were added. After 3 hours analysis by high performance liquid chromatography (reverse phase with an acetonitrile/water gradient) indicated that the reaction was complete. The reaction solution was slowly poured into water with vigorous stirring. A cream colored precipitate was isolated by filtration, washed with water and then dried in a vacuum oven (<40°C) for 16 hours to provide 1.21 g of N,N-(bis tert-butoxycarbonyl)-1-(2-{[3-(isoquinolin-4-yl)-2-propynyl]oxy)ethyl)-1H
imidazo[4,5-c] quinolin-4-amine.
HRMS(EI) calcd for C34H3sNs~s (M+) 594.2716, found 594.2732 Part G
Under a nitrogen atmosphere, the material from Part F was added in portions to a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The resulting solution was allowed to stir at ambient temperature for 2 hours at which time TLC
indicated the reaction was complete. The solvents were removed under reduced pressure. The residue was diluted with dichloromethane/methanol (~4/1) and 20% sodium hydroxide. The layers were separated. The aqueous fraction was extracted with dichloromethane/methanol (~4/1). The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography to provide 0.15 g of 1-(2- f [3-(isoquinolin-4-yl)-2-propynyl]oxy~ethyl)-1H imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. dec >
205°.
'H NMR (300 MHz, DMSO) S 9.30 (s, 1 H), 8.43 (s, 1 H), 8.35 (s, 1 H), 8.19 (m, 2 H), 7.88 (br d, J = 8.0 Hz, 1 H), 7.65 - 7.80 (m, 4 H), 7.60 (d, J = 8.3 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 4.93 (t, J = 4.9 Hz, 2 H), 4.57 (s, 2 H), 4.14 (t, J = 5.1 Hz, 2 H) HRMS(ESI) calcd for Cz4Hi9Ns0 (MH+) 394.1668, found 394.1669 Example 2 1-(2-{[3-(1,3-Thiazol-2-yl)-2-propynyl]oxy}ethyl) 1H imidazo[4,5-c]quinolin-4-amine N
N
'N
O
Ni_S
Part A
Using the general method of Example 1 Part F, N,N-(bis tent-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.14 rnmol) was reacted with 2-bromothiazole to provide 0.97 g of N,N-(bis tej°t-butoxycarbonyl)-1-(2-{[3-(1,3-thiazol-2-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine as a glassy yellow solid.
MS (CI) 550, 450, 350 Part B
Using the general method of Example 1 Part G, the material from Part B Was hydrolyzed to provide 0.11 g of 1-(2-{[3-(1,3-thiazol-2-yl)-2-propynyl]oxy}ethyl)-1H
imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 157-159°C.
Analysis. Calculated for C18H~SNSOS ~ (HZO)l4: %C, 61.09; %H, 4.42; %N, 19.79.
Found:
%C, 61.06; %H, 4.37; %N, 19.53 'H NMR (500 MHz, DMSO) 8 8.18 (s, 1 H), 8.11 (d, J = 7.9 Hz, 1 H), 7.89 (dd, J
= 17.7, 2.9 Hz, 1 H), 7.62 (d, J = 7.9 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.23 (t, J
= 7.5 Hz, 1 H), 6.64 (s, 2 H), 4.83 (m, 2 H), 4.50 (s, 2 H), 4.01 (m, 2 H) HRMS(EI) calcd for CI$H~SNSOS (M''~ 349.0997, found 349.0988 Example 3 1-{2-[3-(1H Pyrazol-4-yl)propoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine N
N j 'N
O
N-N
H
Part A
N,N-(bis tent-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (2.25 g, 4.82 mmol), triethylamine (1.34 mL, 9.64 mmol), 4-iodopyrazole (1.02 g, 5.30 mmol) and anhydrous acetonitrile (40 mL) were combined.
Nitrogen was bubbled through the resulting solution for 10 minutes.
Dichlorobis(triphenylphosphine)palladium(II) (68 mg, 0.096 mol) and copper(I) iodide (37 mg, 0.192 mmol) were added and the solution was heated to 40°C.
After 1 hour analysis by HPLC (reverse phase) indicated that no reaction had taken place.
The reaction solution was heated to about 90°C. After 4 hours analysis by HPLC
indicated that the reaction was complete. The volatiles were removed under reduced pressure. The residue was purified by flash chromatography (9l1 dichloromethane/methanol) to provide 1.2 g of N,N-(bis tent-butoxycarbonyl)-1-(2- f [3-(1H pyrazol-4-yl)-2-propynyl]oxy}ethyl)-1H
imidazo[4,5-c]quinolin-4-amine as a white solid.
Part B
The material from Part A was combined with methanol (~20 rnL) and catalyst (0.25 g of 10% palladium on carbon). The mixture was hydrogenated for 4 hours at which time analysis by reverse phase LC-MS indicated reduction to the alkene and the alkane.
More catalyst (0.25 g) was added and the mixture was hydrogenated for 2 days at which time LC-MS indicated one product with no starting material or alkene. The mixture was filtered and the filtrate Was washed with methanol. The solution was concentrated to give a solid. This material was puxified by flash chromatography (9/1 dichloromethane/methanol) to provide 0.9 g of N,N-(bis text-butoxycarbonyl)-1-{2-[3-(1H pyrazol-4-yl)propoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a white solid.
1H NMR (300 MHz, DMSO) 512.43 (br s, I H), 8.48 (br d, J = 7.1 Hz, I H), 8.37 (s, 1H), 8.08 (br d, J = 7.3 Hz, 1 H), 7.72 (m, 2 H), 7.30 (br s, 1 H), 7.14 (br s, 1 H), 4.92 (t, J = 4.9 Hz, 2 H), 3.88 (t, J = 4.9 Hz, 2 H), 2.22 (t, J = 7.8 Hz, 2 H), 1.56 (m, 2 H), 1.31 (s, 18 H) MS (EI) 537, 437, 337 Part C
Under a nitrogen atmosphere trifluoroacetic acid was added to a mixture of N,N-(bis test-butoxycarbonyl)-1-{2-[3-(1H pyrazol-4-yl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 0.93 mmol) and dichloromethane (5 mL). The resulting solution was allowed to stir for 16 hours at which time analysis by LC-MS
indicated that the reaction was complete. The solvents were removed under reduced pressure.
The residue was dissolved in ethyl acetate (~10 mL) and triethylamine (2 mL) was added. A
precipitate formed and the reaction mixture was allowed to stir for 2 hours.
The solid was isolated by filtration and then it was purred by flash chromatography (9/1 to dichloromethane/methanol) to provide 0.18 g of 1- f 2-[3-(1H pyrazo-4-lyl)propoxy]ethyl}-1H imidazo[4,5-a]quinolin-4-amine as a white solid, m.p.
163-169°C.
Analysis. Calculated for ClBHZON60 ~ (CF3COZH)o,15 %C, 62.18; %H, 5.75; %F, 2.42; %N, 23.77. Found: %C, 61.86; %H, 5.70; %F, 2.52; %N, 23.44 1H NMR (300 MHz, DMSO) 8 12.50 (br s, 1 H), 8.20 (s, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.15 - 7.40 (br ' s, 2 H), 7.00 (br s, 2 H), 4.81 (t, J = 4.6 Hz, 2 H), 3.84 (t, J = 4.6 Hz, 2 H), 3.34 (t, J = 6.1 Hz, 2 H), 2.27 (t, J = 7.6 Hz, 2 H), 1.60 (m, 2 H) Example 4 1-[2-(3-Pyrimidin-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine N
N
N
~\
Part A
Under a nitrogen atmosphere dibenzyl Bicarbonate (50 g, 174 mmol) was added to a mixture of 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (16.4 g, 61.6 mmol) and anhydrous N,N-dimethylformamide (200 mL). The reaction mixture was allowed to stir at ambient temperature for 16 hours and the reaction mixture turned homogeneous. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted with ethyl acetate. The organic fractions were combined, washed with water, washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a semisolid. This material was triturated with diethyl ether to provide 27.4 g of N,N-(bis benzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a white solid.
Part B
N,N-(Bis benzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.00 g, 1.87 mmol), anhydrous acetonitrile (10 mL), triethylamine (0.68 mL, 4.86 mmol), and 2-bromopyrimidine (0.327 g, 2.06 mmol) were combined.
Under a nitrogen atmosphere copper (I) iodide (0.014 g) and dichlorobis(triphenylphosphine)palladium(II) (0.026 g) were added. The reaction mixture was maintained at ambient temperature for 15 minutes and then heated to 80°C for 1.5 hours. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was separated and then extracted with ethyl acetate until no UV materials remained in the aqueous layer. The organic fractions were combined, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtexed and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with 98/2 ethyl acetate/methanol to provide 0.68 g of a mixture of the mono and di benzyloxycarbonyl protected 1- f 2-[(3-pyrimidin-2-ylprop-2-ynyl)oxy]ethyl}-1H
imidazo [4, 5-c] quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) 8 8.78 (d, J= 4.9 Hz, 2 H), 8.49 (m, 1 H), 8.45 (s, 1 H), 8.12 (m, 1 H), 7.73-7.78 (m, 2 H), 7.50 (t, J= 4.9 Hz, 1 H), 7.23-7.28 (m, 6 H), 7.14-7.17 (m, 4 H), 5.20 (s, 4 H), 5.02 (t, J= 5.0 Hz, 2 H), 4.51 (s, 2 H), 4.10 (t, J=
5.0 Hz, 2 H), MS (CI) for C35Hz8N505 m/z 613 (MHO), 569, 461, 345 Part C
The material from Part B, palladium~hydroxide (0.25 g of 20% on carbon) and methanol (25 rnL) were combined and hydrogenated at 47 psi (3.3 Kglcmz) for 3 hours at ambient temperature. The reaction mixture was allowed to stand over the weekend at which time analysis indicated the presence of some product with protected amine groups.
The reaction mixture was filtered to remove the catalyst and the filtrate was treated with sodium methoxide (1 mL of 25% in methanol) for about 16 hours to remove the protecting groups. The reaction mixture was concentrated under reduced pressure. 'The residue was purified by column chromatography eluting with 1/1/1 ethyl acetate/methanol/hexane to provide 0.235 g of a solid. This material was stirred with hot toluene and then filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure. The residue was triturated with isopropanol and ethyl acetate to provide 61 mg of 1-[2-(3-pyrimidin-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 126-127°C.
Analysis. Calculated for Cl9HzoN60: %C, 65.5; %H, 5.79; %N, 24.12. Found: %C, 65.65; %H, 5.78; %N, 24.15 IH NMR (300 MHz, DMSO-d6) b 8.66 (d, J= 4.7 Hz, 2 H), 8.14 (s, 1 H), 8.08 (d, J= 8.0 Hz, 1 H), 7.62 (d, J= 8.2 Hz, 1 H), 7.45 (t, J= 7.0 Hz, 1 H), 7.24-7.31 (m, 2 H), 6.58 (s, 2 H), 4.77 (t, J = 4.7 Hz, 2 H), 3 . 84 (t, J = 4. 5 Hz, 2 H), 3 .42 (t, J = 6.2 Hz, 2 H), 2. 82 (t, J =
7.5 Hz, 2 H), 1.89 (rn, 2H) IR (KBr) 3302, 3187, 2868, 1637, 1561, 1418, 1139 cm 1 HRMS (EI) calcd for Cl~HzoN~O (M+) 348.1699, found 348.1700.
Example 5 1-[2-(3-Pyridin-4-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHZ
N
N
O
N
Part A
Using the general method of Example 4 Part B N,N-(bis benzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (2.00 g, 3.74 mmol) was reacted with 4-bromopyridine (0.8 g, 4.12 mmol) to provide 1.47 g of a mixture of mono and di benzyloxycarbonyl protected 1-{2-[(3-pyridin-4-ylprop-2-ynyl)oxy]ethyl}-imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) 8 8.46 (m, 3 H), 8.43 (s, 1 H), 8.12 (m, 1 H), 7.72-7.76 (m, 2 H), 722-7.28 (m, 5 H), 7.14-7.17 (m, 6 H), 5.18 (s, 4 H), 5.00 (t, J=
5.0 Hz, 2 H), 4.45 (s, 2 H), 4.12 (t, J= 4.0 Hz, 2 H) MS (CI) for C36H29NSO5 m/z 612 (MH+), 568, 344 Part B
Palladium hydroxide (0.57 g of 20% on carbon) was added to a solution of the material from Part A in methanol (~10 mL). The mixture was hydrogenated at 50 psi (3.5 I~g/cm2) for 5 hours. More catalyst (0.07 g) was added and the hydrogenation was continued for another hour. The reaction mixture was filtered to remove catalyst and the filter cake was thoroughly washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 6/3/1 ethyl acetate/methanol/hexane and then triturated with diethyl ether to provide a solid.
This material was further purified by column chromatography eluting with 9/1 dichloromethane/methanol with ammonium hydroxide to provide 0.20 g of 1-[2-(3-pyridin-4-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p.
162°C.
Analysis. Calculated for CZOH21N50: %C, 69.14; %H, 6.09; %N, 20.16. Found: %C, 69.17; %H, 6.09; %N, 19.79 1H NMR (300 MHz, DMSO-d6) 8 8.29 (dd, J= 2.6, 1.8 Hz, 2 H), 8.18 (s, 1 H), 8.11 (d, J
= 8.2 Hz, 1 H), 7.62 (dd, J= 7.1, 1.4 Hz, 1 H), 7.45 (dt, J= 6.9, 1.7 Hz, 1 H), 7.23 (dt, J=
6.7, 1.3 Hz, 1 H), 6.91 (dd, J= 4.4, 1.3 Hz, 2 H), 6.62 (s, 2 H), 4.81 (t, J=
5.0 Hz, 2 H), 3.82 (t, J= 5.0 Hz, 2 H), 2.38 (t, J= 7.6 Hz, 2 H), 3.28 (t, J= 6.1 Hz, 2 H), 1.64 (m, 2 H) IR (KBr) 3418, 3100, 1698, 1595, 1531, 1094, 767 cm 1 HRMS (EI) calcd for C2oHz1N50 (M+) 347.1746, found 347.1747 Example 6 1-[2-(3-Pyridin-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHa N
N / y O
N
Part A
Under a nitrogen atmosphere N,N-(bisbenzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-IH imidazo[4,5-c]quinolin-4-amine (2.5 g, 4.68 mmol), anhydrous acetonitrile (20 mL), triethylamine (1.7 mL, 12.2 mmol), and 2-bromopyridine (0.5 mL, 5.14 mmol) were combined and the resulting homogeneous mixture was heated to 40°C.
Copper (I) iodide (0.036 g) and dichlorobis(triphenylphosphine)palladium(II) (0.066 g) were added. After 18.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic fraction was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with 1/9 hexane/ethyl acetate to provide 0.9 g of a mixture of mono and di benzyloxycarbonyl protected 1-{2-[(3-pyridin-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) & 8.50-8.54 (m, 2 H), 8.44 (s, 1H), 8.12 (m, 1 H), 7.71-7.77 (m, 3 H), 7.34-7.39 (m, 1 H), 7.23-7.29 (m, 7 H), 7.14-7.17 (m, 4 H), 5.19 (s, 4 H), 5.01 (t, J = 4.6 Hz, 2 H), 4.46 (s, 2 H), 4.10 (t, J = 4.8 Hz, 2 H) MS (CI) for C36H29N5~5 m/Z 612 (MH+), 568, 460 Part B
Palladium hydroxide (0.776 g of 20% on carbon) was added to a solution of the material from Part A in methanol. The mixture was hydrogenated at 45 psi (3.2 Kg/cm2) for 2.5 hours. The reaction mixture was filtered to remove catalyst and the filter cake was thoroughly washed with methanol. The filtrate was concentrated under reduced pressure to provide a glassy solid. This material was triturated with diethyl ether and hexane containing a small amount of toluene. The resulting powder was isolated by filtration and dried at 78°C overnight in a vacuum oven. This material was further purified by column chromatography eluting with 9/1 dichloromethane/methanol with a few drops of ammonium hydroxide to provide 25 mg of 1-[2-(3-pyridin-2-ylpropoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 138-140°C.
Analysis. Calculated for C2oHz1Ns0~(Hz0)ls: %C, 68.43; %H, 6.15; %N, 19.95.
Found:
%C, 68.47; %H, 5.95; %N, 19.63 'H NMR (300 MHz, DMSO-d6) 8 8.41 (d, J= 4.4 Hz, 1 H), 8.16 (s, 1 H), 8.10 (d, J= 7.7 Hz, 1 H), 7.63 (d, J= 8.4 Hz, 1 H), 7.54 (dt, J= 9.7, 1.7 Hz, 1 H), 7.43 (t, J= 7.3 Hz, 1 H), 7.24 (t, J= 7.5 Hz, 1 H), 7.13 (t, J= 5.5 Hz, 1 H), 6.93 (d, J= 7.6 Hz, 1 H), 6.59 (s, 2 H), 4.77 (t, J= 5.1 Hz, 2 H), 3.82 (t, J= 5.5 Hz, 2 H), 3.34 (t, J= 6.3 Hz, 2 H), 2.57 (t, J=
7.3 Hz, 2 H), 1.75 (m, 2 H) IR (KBr) 3361, 3302, 3188, 1638, 1526, 1119, 751 cm 1 HRMS (EI) calcd for CZOH21N50 (M+) 347.1746, found 347.1747.
Example 7 1-{2-[3-(1,3-Thiazol-2-yl)propoxy]ethyl}-1H irnidazo[4,5-c]quinolin-4-amine NHa N
N ~ N
O
Ni S
Part A
Under a nitrogen atmosphere N,N-(Bisbenzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (3.25 g, 6.08 mmol), anhydrous N,N-dimethylformamide (15 mL), triethylamine (2.2 mL, 15.8 mmol) and 2-bromothiazole (0.6 mL, 6.69 mmol) were combined and heated to 80°C.
Copper (I) iodide (0.046 g) and dichlorobis(triphenylphosphine)palladium (II) (0.085 g) were added. After 2 hours the reaction was stopped and the solvent was removed. The crude product was purifted by column chromatography eluting with 8/2 ethyl acetate/hexane to provide ~2 g of a mixture of mono and di benzyloxycarbonyl protected 1-(2-{[3-(1,3-thiazol-2-yl)prop-2-ynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) 8 8.47-8.50 (m, 1 H), 8.44 (s, 1 H), 8.11 (m, 1 H), 7.89 (d, J= 3.2 Hz, 1 H), 7.85 (d, J= 3.3 Hz, 1 H), 7.31-7.77 (m, 2 H), 7.23-7.28 (m, 6 H), 7.14-7.17 (m, 4 H), 5.20 (s, 4 H), 5.00 (t, J= 5.0 Hz, 2 H), 4.52 (s, 2 H), 4.09 (t, J= 5.5 Hz, 2 H) MS (CI) for C24H2~NSOSS m/z 618 (MH+), 475, 466 Part B
Palladium hydroxide (~2 g of 20% on carbon) was added to a solution of the material from Part A in methanol. The mixture was hydrogenated at 45 psi (3.2 Kg/cm2) for 3 hours. More catalyst (0.3 g) was added twice and the hydrogenation was continued for a total of ~25 houxs. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to provide 1.3 g of mono benzyloxycarbonyl protected 1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H
imidazo[4,5-c]quinolin-4-amine. This material was combined with methanol (5 mL) and sodium methoxide (25 mL of 25% in methanol). The resulting mixture was stirred for 3 days.
The reaction mixture was concentrated under reduced pressure and then purified by column chromatography. The resulting material was triturated with diethyl ether and dried to provide 0.28 g of 1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 134-135°C.
Analysis. Calculated for C18HI9NSOS: %C, 61.17; %H, 5.42; %N, 19.81. Found:
%C, 61.20; %H, 5.23; N, %I9.51 1H NMR (300 MHz, DMSO-d6) 8 8.16 (s, 1 H), 8.10 (d, J= 8.4 Hz, 1 H), 7.63 (m, 2 H), 7.51 (d, J= 3.3 Hz, 1 H), 7.43 (t, J= 7.1 Hz, 1 H), 7.23 (t, J= 8.0 Hz, 1 H), 6.58 (s, 2 H), 4.79 (t, J= 4.7 Hz, 2 H), 3.84 (t, J= 4.8 Hz, 2 H), 3.4 (t, J= 6.0 Hz, 2 H), 2.86 (t, J= 7.8 Hz, 2 H), 1.83 (m, 2 H) IR (KBr) 3458, 3358, 3295, 3191, 1640, 1538, 1121, 752 cm 1 HRMS (EI) calcd for CI$H1~NSOS (M+) 353.1310, found 353.1308.
Example 8 1-[2-(3-Pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine Bis(trifluoroacetate) N
N
'N
O
N
Part A
Under a nitrogen atmosphere N,N-(bis text-butyoxycabonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.75 g, 3.75 mmol), 3-iodopyridine (0.85 g, 4.13 mmol), triethylamine (1.4 mL) and acetonitrile (15 mL) were combined and then heated to 60°C. Copper (I) iodide (0.03 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.05 g, 0.075 mmol) were added.
The reaction was complete after 30 minutes. The solvents were removed under reduced pressure. The crude product was purified by column chromatography (silica gel eluting first with dichloromethane and then with 98/2 dichloromethane/methanol) to provide 1.26 g of a mixture of di-BOC protected and unprotected 1-{2-[(3-pyridin-3-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) b 8.54 (bs, 1 H), 8.44-8.48 (m, 2 H), 8.4 (s, 1 H), 8.06 (m, 1 H), 7.69-7.73 (m, 2 H), 7.54 (d, J= 7.6 Hz, 1 H), 7.35 (m, 1 H), 4.99 (t, J= 4.8 Hz, 2 H), 4.40 (s, 2 H), 4.09 (t, J= 5.0 Hz, 2 H), 1.31 (s, 18 H), MS (CI) for C3pH33N505 ~z 544 (MH+), 444, 344 Part B
A solution of the material from Part A in methanol was combined with catalyst (0.7 g of 10% palladium on carbon) and the mixture was hydrogenated at 45 psi (3.2 Kg/cm2) for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide 0.67 g of a mixture of di-BOC
protected and unprotected 1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine.
iH NMR (300 MHz, DMSO-d6) ~ 8.50 (d, J= 7.3 Hz, 1 H), 8.39-8.486 (m, 2 H), 8.29 (s, 1 H), 8.07 (d, J= 8.4 Hz, 1 H), 7.71-7.75 (m, 2 H), 7.46 (d, J= 8.5 Hz, 1 H), 7.31 (m, 1 H), 4. 94 (t, J = 4. 6 Hz, 2 H), 3 . 8 8 (t, J = 5 . 0 Hz, 2 H), 3 . 3 2 (t, J
= 5 . 9 Hz, 2 H), 2. 3 8 (t, J =
7.5 Hz, 2 H), 1.63 (m, 2 H), 1.30 (s, 18 H), MS (CI) for C3oH3~N505 m/z 548 (MH+), 448, 348 Part C
Under a nitrogen atmosphere the material from Part B was combined with anhydrous dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at ambient temperature for 1 hr. The solvents were removed under reduced pressure. The residue was triturated with diethyl ether, isolated by filtration and then dried in a vacuum oven to provide a tan solid. This material was recrystallized first from isopropyl alcohol and then from dichloromethane/methanol to provide 0.40 g of 1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine bis(trifluoroacetate), m.p.
134-136°C.
Analysis. Calculated for CZpH21N5~~(C2~'3~2)2~(H2~)1/2~ %C, 50.08; %H, 4.23;
%N, 12.03. Found: %C, 49.87; %H, 3.82; %N, 12.16 1H NMR (300 MHz, DMSO-d6) b 9.00-9.25 (bs, 2 H), 8.50 (s, 2 H), 8.37 (d, J=
7.7 Hz, 1 H), 7.82 (d, J= 7.4 Hz, 1 H), 7.73-7.75 (m, 2 H), 7.55-7.58 (m, 2 H), 4.90 (t, J= 4.9 Hz, 2 H), 3.86 (t, J= 4.8 Hz, 2 H), 3.35 (t, J= 6.1 Hz, 2 H), 2.49 (t, J= 7.0 Hz, 2 H), 1.67 (m, 2 H) IR (KBr) 3421, 3212, 2885, 1699, 1199, 1120, 720 cm 1 HRMS (EI) calcd fox CZOHaiNsO (M~ 347.1746, found 347.1743.
Example 9 1-[2-(3-Pyrimidin-5-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine N
N
'N
O
(~ \
NON
Part A
Using the general method of Example 8 Part A, except that the reaction temperature was raised to 80°C, N,N-(bis tef°t-butyoxycabonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (2.5 g, 5.36 mmol) was coupled with 5-bromopyrimidine (0.94 g, 5.89mmo1) to provide 1.59 g of N,N-(bis tert-butoxycarbonyl)-1-{2-[(3-pyrimidin-5-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c] quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) ~ 9.19 (s, 1 H), 8.64 (s, 2 H), 8.44-8.47 (m, 1 H), 8.40 (s, 1 H), 8.02-8.06 (m, 1 H), 7.68-7.72 (m, 2 H), 4.99 (t, J= 5.0 Hz, 2 H), 4.43 (s, 2 H), 4.10 (t, J= 5.2 Hz, 2 H), 1.32 (s, 18 H) MS (CI) for C29H32N(OS m/z 545 (MH+), 445, 345 Part B
A methanol solution of the material from Part A was combined with catalyst ( 5%
platinum on carbon, palladium hydroxide and 10% palladium on carbon were used in succession) and hydrogenated to provide 0.60 g of N,N-(bis tent-butoxycarbonyl)-1-[2-(3-pyrimidin-5-ylpropoxy)ethyl]-1H irnidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) S 8.98 (s, 1 H), 8.48-8.52 (m, 1 H), 8.45 (s, 2 H), 8.40 (s, 1 H), 8.06-8.09 (m, 1 H), 7.70-7.74 (m, 2 H), 4.94 (t, J= 5.1 Hz, 2 H), 3.89 (t, J= 5.0 Hz, 2 H), 3.34 (m, 2 H), 2.34 (t, J= 7.3 Hz, 2 H), 1.64 (m, 2 H), 1.29 (s, 18 H) MS (CI) for C29H36N6Os m/z 549 (MH+), 449, 349 Part C
Using the general method of Example 8 Part C, the material from Part B was hydrolyzed to provide 0.14 g of 1-[2-(3-pyrimidin-5-ylpropoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine, m.p. 159-161°C.
Analysis. Calculated for C]9H20N6~~(C2HF3O2)1/10~(H20)1/4~ %C, 63.27; %H, 5.70; %N, 23.06. Found: %C, 63.47; %H, 5.35; %N, 22.88 1H NMR (300 MHz, DMSO-d6) 8 8.98 (s, 1 H), 8.48 (s, 2 H), 8.19 (s, 1 H), 8.15 (d, J=
8.0 Hz, 1 H), 7.63 (d, J= 8.6 Hz, 1 H), 7.46 (t, J= 6.0 Hz, 1 H), 7.28 (t, J=
8.4 Hz, 1 H), 6.79 (s, 2 H), 4. 81 (t, J = 4. 8 Hz, 2 H), 3. 84 (t, J = 5.1 Hz, 2 H), 3.3 5 (t, J = 6.0 Hz, 2 H), 2.43 (t, J= 7.4 Hz, 2 H), 1.69 (m, 2 H) IR (KBr) 3310, 3132, 1647, 1582, 1531, 1403, 1117 crri 1 HRMS (EI) calcd for CI~HZON60 (M+) 348.1699, found 348.1695 Example 10 1-{2-[(1-Benzyl-1H 1,2,3-triazol-4-yl)methoxy]ethyl}-1H irnidazo[4,5-c]quinoline-4-amine hydrochloride 1-{2-[(1-Benzyl-1H 1,2,3-triazol-5-yl)methoxy]ethyl}-1H imidazo[4,5-c]quinoline-4-amine hydrochloride NHS NN~
N
N + N
N / N~ / N
'N-N N'N
Part A
N,N-(Bis benzyloxycaxbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.5 g, 2.81 mmol), anhydrous toluene (30 mL) and benzyl azide (1.3 mL, 9.12 mmol) were combined and heated in an oil bath at 100°C for 28 hours. The reaction mixture was concentrated under reduced pressure to provide crude product as a brown oil.
Part B
Sodium methoxide (2.19 mL of 25% in methanol, 9.52 mmol) was added to a mixture of the material from Part A and methanol (20 mL). The reaction mixture was allowed to stir at ambient temperature overnight and then it was concentrated under reduced pressure to provide a dark oil. The oil was purified by column chromatography eluting with 5% methanol in dichloromethane to provide a light yellow oil. The oil was treated with 1.0 M hydrogen chloride to provide a pink solid. This solid was recrystallized twice from acetonitrile and the resulting product was dried in a vacuum oven at 80°C for 2 hours to provide 0.12 g of a mixture of the regio isomers of the desired product i.e. a mixture containing both 1-{2-[(1-benzyl-1H 1,2,3-triazol-4-yl)methoxy]ethyl}-imidazo[4,5-c]quinoline-4-amine hydrochloride and 1-{2-[(1-benzyl-1H 1,2,3-triazol-5-yl)methoxy]ethyl}-1H imidazo[4,S-c]quinoline-4-amine hydrochloride, as a light pink crystalline solid, m.p. 209-211 °C.
Analysis: Calculated for CZZHZIN~O ~ 0.951 HCl ~ 0.615 HZO: %C, S9.3S; %H, S.2S; %N, 22.02; Found: %C, 59.46; %H, 5.16; %N, 22.0S.
S IH-NMR (300 MHz, DMSO-d6) ~ 9.00 (br s, 2 H), 8.46 (s, 1 H), 8.28 (d, J=7.8 Hz, 1 H), 7.98 (s, 1 H), 7.83 (br d, J=7.8 Hz, 1 H), 7.71 (br t, J=7.8 Hz, 1 H), 7.50 (br t, J=7.7 Hz, 1 H) 7.20-7.40 (rn, 5 H), S.S2 (s, 1.88 H), 5.39 (s, 0.12 H), 4.88 (t, J=4.9 Hz, 2 H), 4.52 (s, 2 H), 3.95 (t, J=4.9 Hz, 1.88 H), 3.87 (t, J=S.1 Hz, 0.12 H) IR (KBr) 3152, 2638, 1672, 1605, 1126 cm 1 HRMS (EI) calcd for C22H21N7O (M+) 399.1808, found 399.1802.
Example 11 1-[2-({1-[(Phenylsulfanyl)methyl]-1H 1,2,3-triazol-4-yl}methoxy)ethyl]-1H
imidazo[4,S-c]quinoline-4-amine 1S 1-[2-({1-[(Phenylsulfanyl)methyl]-1H 1,2,3-triazol-S-yl}methoxy)ethyl]-1H
imidazo[4,S-c]quinoline-4-amine NHa NHz N
N ~ N~ + N
i N ~ N
/ N
N
,NINA N;N S
S
l~
Part A
Under a nitrogen atmosphere, anhydrous toluene (20 mL), N,N-(bis ter~t-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,S-c]quinolin-4-amine (1.0 g, 2.1 mmol) and azidomethyl phenylsulfide (0.61 mL, 4.3 mmol) were combined and heated at reflux for 72 hours. The reaction mixture was allowed to cool to ambient temperature and then it was concentrated under reduced pressure to provide a brown oil.
This material was purified by column chromatography eluting with 80/20 ethyl acetate/hexane to provide 0.95 g of product as a clear oil.
MS (CI) for C32H3~N~OSS mlZ 632 (MH+), 532, 458, 432 Part B
A solution of the material from Part A in anhydrous dichloromethane (15 mL) was added to a mixture of trifluoroacetic acid (7.4 mL) and anhydrous dichloromethane (6 mL) which had been chilled to 0°C. The reaction mixture was kept in an ice bath for 2 hours and then allowed to warm to ambient temperature. After 6 hours the reaction mixture was washed with 20% sodium hydroxide. The aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a green oil. The oil was purified by column chromatography eluting with 5%
methanol in dichloromethane to provide a green crystalline solid. This material was xecrystallized from isopropanol to provide 0.12 g of a mixture of the regio isomers of the desired product i.e. a mixture containing both 1-[2-({1-[(phenylsulfanyl)methyl]-1H 1,2,3-triazol-4-yl]methoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine and 1-[2-( f 1-[(phenylsulfanyl)rnethyl]-1H 1,2,3-triazol-5-yl}methoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine, as an off white solid, m.p. 182-184°C.
Analysis: Calculated for CZZHZ1N~OS: %C, 61.24; %H, 4.91; %N, 22.72; Found:
%C, 60.94; %H, 4.94; %N, 22.3 8.
1H-NMR (300 MHz, DMSO-d6) 8 8.00-8.20 (m, 2 H), 7.87 (s, 0.8 H), 7.60-7.65 (m, 1 H), 7.52 (s, 0.2 H), 7.40-7.50 (m, 1 H), 7.20-7.40 (m, 6 H), 6.65 (s, 2 H), 5.87 (s, 1.6 H), 5.65 (s, 0.4 H), 4.83 (br t, J=4.6 Hz, 0.4 H), 4.78 (br t, J=4.9 Hz, 1.6 H), 4.49 (s, 1.6 H), 4.42 (s, 0.4 H), 3.80-3.90 (m, 2H) IR (KBr) 3322, 3205, 1643, 1527, 1095 cm 1 HRMS (EI) calcd for CZZHaiN70S (M~ 431.1528, found 431.1522.
Example 12 1-[2-(Benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHS
N
N
'N
O
~O
Part A
Benzyltrimethylammonium chloride (0.436 g) and propargyl bromide (6.07 mL of 80%) were added with stirring to a mixture of dichloromethane (185 mL) and aqueous sodium hydroxide (60 mL of 50%). 2-(1H Imidazo[4,5-c]quinolin-1-yl)ethanol (10.0 g, 46.9 mmol) was added to the resulting solution. The reaction mixture was stirred at ambient temperature for 21 hours at which time analysis by HPLC showed that starting material remained. An additional equivalent of propargyl bromide was added and the reaction mixture was stirred for an additional 46 hours. Water was added to the reaction mixture and the layers were separated. The aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water and with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark brown solid. This material was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane) to provide 7.0 g of 1-[2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline as a brownish solid.
Part B
Under a nitrogen atmosphere, 1-[2-(propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline (1.0 g, 4.21 rnmol), triethylamine (1.53 mL, 10.96 mmol) and anhydrous acetonitrile (20 mL) were combined and then heated to 60°C. 2-Iodophenol (1.02 g, 4.63 mmol), copper (I) iodide (0.08 g) and dichlorobis(triphenylphosphine)palladium(II) (0.148 g) were added. After 4 hours analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was filtered through a layer of CeIite~ filter aid to remove the catalysts. The filtrate was concentrated under reduced pressure to provide an oil. This material was purified by flash chromatography (silica gel eluting with 3% methanol in dichloromethane) to provide 0.91 g of 1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazoj4,5-c]quinoline as a yellow oil.
Part C
3-Chloroperoxybenzoic acid (0.65 g) was added in portions over a period of 5 minutes to a solution of the material from Part B in chloroform (15 mL). The progress of the reaction was monitored by TLC. More 3-chloroperoxybenzoic acid (2 X 0.2 g) was added. After 1.5 hr the reaction mixture was washed twice with aqueous sodium bicarbonate, back extracted with chloroform, washed with brine and then concentrated under reduced pressure to provide 1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H
imidazo[4,5-c]quinoline-SN-oxide. The material was stored under nitrogen at a reduced temperature over the weekend.
Part D
Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.60 g, 3.18 mmol) was slowly added via a syringe to a solution of the N-oxide from Part C in dichloromethane (15 mL). The volatiles were removed under reduced pressure to provide 2,2,2-trichloro-{1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-yl}acetamide as a tan solid. This material was dissolved in methanol (15 mL). Sodium methoxide (2.04 mL, 9.01 mmol) was added and the resulting solution was allowed to stir for 48 hours. A white precipitate was isolated by filtration and then recrystallized from acetonitrile to provide 0.22 g of 1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine as off white needles, m.p. 201-203°C.
Analysis: Calculated for CZIH1gN402: %C, 70.38; %H, 5.06; %N, 15.63; Found:
%C, 70.36; %H, 4.80; %N 15.51.
1H-NMR (300 MHz, DMSO-d6) 8 8.16 (s, 1H), 8.06 (d, J= 7.8 Hz, 1H), 7.49-7.62 (m, 3H), 7.42 (m, 1H), 7.16-7.31 (m, 3H), 6.76 (s, 1H), 6.58 (br s, 2H), 4.83 (t, J= 5.4 Hz, 2H), 4.61 (s, 2H), 3.97 (t, J = 5.1 Hz, 2H) IR (KBr) 3455, 3069, 1583, 1530, 1397, 1254, 1088 HRMS (EI) calcd for CZ1HI$N4O2 (M+) 358.1430, found 358.1428.
Example 13 1-[2-(Pyridin-3-ylmethoxy)ethylj-1H imidazo[4,5-c]quinolin-4-amine Hydrochloride N
N
'N
O
N
Part A
Under a nitrogen atmosphere, sodium hydride (16.88 g of 60% in mineral oil, mmol) was added in portions to a solution of 2-(1H imidazo[4,5-c]quinolin-1-yl)ethanol (60.0 g, 281 mmol) in anhydrous N,N-dimethylformamide (600 mL). The alkoxide was allowed to stir for about 1.5 hours. Benzyl bromide (50.2 mL, 422 mmol) was slowly added over a period of about 30 minutes. The reaction mixture was allowed to stir at ambient temperature overnight. Solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed several times with water, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1-[2-(benzyloxy)ethyl]-1H imidazo[4,5-c]quinoline as a dark oil.
1H-NMR (300 MHz, DMSO-d6) S 9.22 (s, 1H), 8.42 (s, 1H), 8.40 (s, 1H), 8.17 (m, 1H), 7.69 (m, 2H), 7.10-7.22 (m, 5H), 4.95 (t, J= 5.1 Hz, 2H), 4.45 (s, 2H), 3.93 (t, J= 5.1 Hz, 2H) MS (CI) for C19H17N3O IT1~Z 304 (MH+), 214 Part B
3-Chloroperoxybenzoic acid (69.36 g of 77% maximum) was added in portions over a period of 15 minutes to a solution of 1-[2-(benzyloxy)ethyl]-1H
imidazo[4,5-c]quinoline (85.36 g, 281 mmol) in chloroform (800 mL). After 1 hour analysis by TLC
(10% methanol in dichloromethane) showed that the reaction was complete. The reaction mixture was washed with saturated sodium bicarbonate (twice), washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a solid.
The solid was slurried with diethyl ether and then isolated by ftltration to provide 1-[2 (benzyloxy)ethyl]-1H imidazo[4,5-c]quinoline-5N-oxide as a dark yellow solid.
Part C
Phosphorous oxychloride (12.84 mL, 138 mmol) was slowly added to a mixture of 1-[2-(benzyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (40.0 g, 125 mmol) and anhydrous toluene (600 mL). The reaction mixture was allowed to stir for about minutes and then the volatiles were removed under reduced pressure. The resulting red oil was dissolved in dichloromethane, washed twice with saturated sodium bicarbonate, and then concentrated under reduced pressure. An attempt to recrystallize the residue from ethyl acetate resulted in a gum. The material was taken up in ethyl acetate (500 mL) and then combined with triethylamine (25.34 g, 250 mmol). The solution was chilled in an ice bath and the precipitate was isolated by filtration. The material changed back into an oil shortly after filtration. The oil was taken up in dichloromethane, combined with the filtrate and then concentrated under reduced pressure to provide an oil. This material was partitioned between dichloromethane and 15% sodium hydroxide. The organic fraction was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide an oil. This oil was further purified by flash chromatography (silica geI eluting fixst with dichloromethane, then with 2% methanol in dichloromethane and then with 5% methanol in dichloromethane) to provide ~21 g of 1-[2-(benzyloxy)ethyl]-4-chloro-1H imidazo[4,5-c]quinoline.
1H-NMR (300 MHz, DMSO-d6) ~ 8.47 (s, 1H), 8.42 (dd, J= 8.3, 1.5 Hz, 1H), 8.08 (dd, J
= 8.3, 1.5 Hz, 1H), 7.72 (m, 2H), 7.04-7.17 (m, SH), 4.96 (t, J= 5.1 Hz, 2H), 4.44 (s, 2H), 3.92 (t, J= 5.1 Hz, 2H) MS (CI) for Cl~Hi6C1N30 m/z 338 (MH+), 309, 248, 214 Part D
Phenol (6.21 g, 66 mmol) was added in portions to a chilled suspension of sodium hydride (2.79 g of 60% in mineral oil, 69.7 mmol) in diglyrne (25 mL). When bubbling had subsided, a solution of the material from Part C in diglyme (10 mL) was added in a single portion. The resulting solution was heated to 110°C and stirred overnight. Analysis by TLC (3% methanol in dichloromethane) indicated that the reaction was complete. The solution was cooled to 0°C and a brown precipitate formed. The diglyme was decanted off. The solid was slurried with hexane and then isolated by filtration. The solid was then slurned with water, isolated by filtration and dried in an oven overnight. The solid was recrystallized from isopropanol to provide 19.3 g of 1-[2-(benzyloxy)ethyl]-4-phenoxy-1H imidazo[4,5-c]quinoline as a solid.
1H-NMR (300 MHz, DMSO-d6) 8 8.39 (s, 1H), 8.32 (dd, J= 8.3, 1.5 Hz, 1H), 7.69 (dd, J
= 8.3, 1.5 Hz, 1H), 7.46-7.59 (m, 4H), 7.12-7.33 (m, 8H), 4.93 (t, J= 5.1 Hz, 2H), 4.47 (s, 2H), 3.94 (t, J= 5.1 Hz, 2H) MS (CI) for C25H21N302 m/z 396 (MH+), 306, 288 Part E
Under a nitrogen atmosphere, triflic acid (29.0 g) was added dropwise to a solution of 1-[2-(benzyloxy)ethyl]-4-phenoxy-1H imidazo[4,5-c]quinoline (7.65 g) in anhydrous dichloromethane (200 mL). When analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete, the reaction mixture was concentrated under reduced pressure to provide an oil. This material was dissolved in ethyl acetate and then combined with triethylamine (10 eq.). The solution was diluted with additional ethyl acetate, washed with water, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The xesidue was recrystallized from ethyl acetate to provide ~4.8 g of 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol as a white fluffy solid.
iH-NMR (300 MHz, DMSO-d6) 8 8.34 (m, 1H), 8.32 (rn, 1H), 7.70 (m, 1H), 7.46-7.60 (m, 4H), 7.25-7.31 (m, 3H), 5.06 (t, J= 5.4 Hz, 1H), 4.76 (t, J= 5.4 Hz, 2H), 3.90 (q, J=
5.4 Hz, 2H) Part F
3-(Bromomethyl)pyridine hydrobromide (0.638 g, 2.52 mmol) was added in a single portion with stirring to a solution containing 2-(4-phenoxy-1H
imidazo[4,5-c]quinolin-1-yl)ethanol (0.7 g, 2.29 mmol), benzyltrimethylammonium chloride 00.03 g), sodium hydroxide (28 mL of 50%) and dichloromethane (28 mL). After 3 houxs analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was diluted with water (100 mL) and dichloromethane (100 mL).
The layers were separated and the aqueous fraction was extracted with dichloromethane (100 mL). The organic fractions were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark yellow solid. This material was purified by flash chromatography (silica gel eluting with 5%
methanol in dichloromethane) to provide 0.74 g of 4-phenoxy-1-[2-(pyridin-3-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline as a bright yellow solid.
'H-NMR (300 MHz, DMSO-d6) 8.42 (dd, J= 4.9, 2.0 Hz, 1H), 8.38 (s, 2H), 8.33 (dd, J=
8.3, 1.5 Hz, 1H), 7.70 (dd, J= 8.3, 2.0 Hz, 1H), 7.46-7.59 (m, SH), 7.22-7.33 (m, 4H), 4.96 (t, J= 4.9 Hz, 2H), 4.52 (s, 2H), 3.98 (t, J= 4.9 Hz, 2H) MS (CI) for C24HzoNaOa mlz 397 (MH+), 306, 288, 212, 110 Part G
4-Phenoxy-1-[2-(pyridin-3-yhnethoxy)ethyl]-1H irnidazo[4,5-c]quinoline (0.67 g, 1.69 mmol) and ammonium acetate (1.30 g, 16.9 mmol) were combined and heated to 150°C. After 5 hours analysis by TLC (10% methanol in dichloromethane) showed starting material. More ammonium acetate (5 g) was added. After 1 hour TLC
indicated that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature overnight. The resulting brown oil was combined with water (100 mL) and made basic (pH 9) with sodium bicarbonate. The product was extracted into dichloromethane (2 X 100 mL). The extracts were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide an off white gummy solid. This material was purified by flash chromatography (silica gel eluting with 10% methanol in dichloromethane) to provide 0.40 g of a gummy white solid.
This material was dissolved in methanol (10 mL). Hydrogen chloride/diethyl ether (5 eq) was added dropwise and the mixture was allowed to stir for 1 hour. The resulting precipitate was isolated by filtration, rinsed with diethyl ether and dried in a vacuum oven to provide 0.358 g of 1-[2-(pyridin-3-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine hydrochloride as a light yellow solid, m.p. 229-231°C.
Analysis: Calculated for CIgHl~N50 ~ 2.75 HCl ~ 0.4 HZO: %C, 50.62; %H, 4.85;
%N, 16.40; Found: %C, 50.44; %H, 4.96; %N, 16.19.
'H-NMR (300 MHz, DMSO-d6) b 8.78 (d, J= 5.4 Hz, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.34 (d, J= 8.3 Hz, 1H), 8.26 (d, J= 7.8 Hz, 1H), 7.90 (dd, J= 7.8, 5.9 Hz, 1H), 7.84 (d, J
= 8. 3 Hz, 1 H), 7.72 (t, J = 7. 8 Hz, 1 H), 7.54 (t, J = 7. 8 Hz, 1 H), 4.9 8 (t, J = 4.9 Hz, 2H), 4.69 (s, 2H), 4.04 (t, J= 4.9 Hz, 2H) MS (CI) for C18H1~N50 ~ HCly 1i4~ ~ HZO~zis~ m/z 321 (MH+), 229.
Example 14 1-[2-(Pyridin-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHS
N
N i N
O
N
Part A
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol (0.9 g, 2.95 mmol) was reacted with 2-picolyl chloride hydrogen chloride (0.53 g, 3.24 mmol) and the product purified to provide 0.65 g of 4-phenoxy-1-[2-(pyridin-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline.
1H-NMR (300 MHz, DMSO-d6) 8.41 (m, 2H), 8.34 (dd, J= 8.3, 1.5 Hz, 1H), 7.70 (dd, J
= 8.3, 1.5 Hz, 2H), 7.46-7.66 (m, 5H), 7.18-7.33 (m, 4H), 7.30 (d, J= 7.8 Hz, 1H), 4.98 (t, J=4.9 Hz, 2H), 4.55 (s, 2H), 4.04 (t, J= 4.9 Hz, 2H) Part B
The material from Part A and ammonium acetate were combined and heated to 150°C. After 5 hours analysis by TLC (10% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature, then it was combined with water (100 mL) and made basic (pH 9) with sodium bicarbonate. The resulting white precipitate was isolated by filtration and then slurried with diethyl ether. The resulting white solid was isolated by filtration and then recrystallized from acetonitrile to provide 0.18 g of 1-[2-(pyridin-2-ylmethoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 196-198°C.
Analysis: Calculated for C18H1~N50: %C, 67.70; %H, 5.37; %N, 21.93; Found: %C, 67.86; %H, 5.31; %N, 22.13.
'H-NMR (300 MHz, DMSO-d6) b 8.43 (d, J= 4.9 Hz, 2H), 8.20 (s, 1H), 8.09 (d, J=
6.8 Hz, 1H), 7.63 (dt, J= 8.3, 1.5 Hz, 2H), 7.43 (dt, J= 8.3, 1.5 Hz, 1H), 7.19-7.24 (m, 2H), 7.12 (d, J=7.8 Hz, 1H), 6.53 (hr s, 2H), 4.87 (t, J= 5.1 Hz, 2H), 4.54 (s, 2H), 3.99 (t, J=
5.1 Hz, 2H) MS (CI) for C18HI~N50 mlz 320 (MH+), 229, 211.
Example 15 I-[2-(Pyridin-4-ylmethoxy)ethyl]-IH imidazo[4,5-c]quinolin-4-amine N
N / y O
N
Part A
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol (1.1 g, 3.61 mmol) was reacted with 4-picolyl chloride hydrogen chloride (0.649 g, 3.96 mmol) and the product purified to provide ~0.3 g of 4-phenoxy-1-[2-(pyridin-4-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline.
IH-NMR (300 MHz, DMSO-d6) b 8.41 (s, 1H), 8.39 (s, 1H), 8.34 (dd, J= 7.8, 1.5 Hz, 2H), 7.70 (dd, J= 7.8, 1.5 Hz, 1H), 7.46-7.60 (m, 4H), 7.25-7.33 (m, 3H), 7.10 (d, J= 5.9 Hz, 2H), 5.00 (t, J= 4.9 Hz, 2H), 4.53 (s, 2H), 4.00 (t, J= 4.9 Hz, 2H) MS (CI) for C24HzQN~O2 m/z 397 (MH+), 306, 288, 212, 110 Part B
Using the general method of Example 14 Part B, 4-phenoxy-1-[2-(pyridin-4-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline (0.25 g) was aminated to provide 0.14 g of 1-[2-(pyridin-4-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 159-161°C.
Analysis: Calculated for CIBHI~N50: %C, 67.70; %H, 5.37; %N, 21.93; Found: %C, 67.37; %H, 5.31; %N, 22.49.
~H-NMR (300 MHz, DMSO-d6) 8 8.40 (dd, J= 4.4, 1.5 Hz, 2H), 8.20 (s, 1H), 8.09 (d, J=
8.3 Hz, 1 H), 7. 62 (d, J = 8.3 Hz, 1 H), 7.43 (m, 1 H), 7.21 (m, 1 H), 7.10 (d, J =5 .4 Hz, 1 H), 6.54 (br s, 2H), 4.87 (t, J= 5.1 Hz, 2H), 4.51 (s, 2H), 3.94 (t, J= 5.1 Hz, 2H) MS (CI) for C18H1~N50 m/z 320 (MH+), 229, 136 Example 16 1-{2-[(3,5-Dimethylisoxazol-4-yl)methoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine NHZ
N
N
O
I
O-N
Part A
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol (0.82 g, 2.69 mmol) was reacted with 4-(chloromethyl)-3,5-dimethylisoxazole (0.43 g, 2.95 mmol) and purified to provide 0.59 g of 1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-4-phenoxy-1H imidazo[4,5-c]quinoline as a white foamy solid.
1H-NMR (300 MHz, DMSO-d6) 8 8.29-8.32 (m, 2H), 7.70 (dd, J= 7.8, 1.5 Hz, 1H), 7.46-7.60 (m, 4H), 7.25-7.32 (m, 3H) 4.89 (t, J=5.1 Hz, 2H), 4.24 (s, 2H), 3.89 (t, J= 4.9 Hz, 2H), 2.16 (s, 3H), 1.93 (s, 3H) MS (CI) for CZøHz2N4O3 ln/Z 415 (MH+), 306, 212, 112 Part B
Using the general method of Example 14 Part B, the material from Part A was aminated to provide 0.39 g of 1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-IH
imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 213-215°C.
Analysis: Calculated for C18H19N502: %C, 64.08; %H, 5.68; %N, 20.76; Found:
%C, 64.02; %H, 5.53; %N, 21.01.
1H-NMR (300 MHz, DMSO-d6) 8 8.12 (s, 1H), 8.05 (dd, J= 8.3, 1.0 Hz, 1H), 7.61 (dd, J
= 8.3, 1.0 Hz, 1H), 7.43 (m, 1H), 7.21 (m, 1H), 6.52 (br s, 2H), 4.79 (t, J=
5.1 Hz, 2H), 4.23 (s, 2H), 3.85 (t, J= 5.1 Hz, 2H), 2.20 (s, 3H), 1.97 (s, 3H) MS (CI) for C18HI9N502 m/z 338 (MH~, 229, 112 Example 17 1-(2- f [3-(Pyrimidin-2-yl)-2-propynyl]oxy}ethyl) 1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate N
N
'N
O
N
' \\
Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.7 mmol), triethylamine (1.0 g, 9.7 mmol) and anhydrous N,N-dimethylformamide (20 mL) were combined. The resulting solution was heated to 65°C . Copper (I) iodide (0.07 g, 0.4 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.13 g, 0.2 mmol) and 2-bromopyrimidine (0.65 g, 4.1 mmol) were added and the reaction mixture was stirred at 65°C overnight. The N,N-dimethylformamide was removed under reduced pressure to provide crude product as a tar. This tar was purified first by column chromatography (silica gel eluting with dichloromethane) and then by semi-preparative HPLC using Method A to provide 0.05 g of 1-(2-{[3-(pyrimidin-2-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a spongy white solid, m.p. 214-215°C.
Analysis: Calculated for C19H16N6O ' 1.S CZHF3O2 ~ 0.3 H20: %C, 50.67; %H, 3.51; %N, 16.12; Found: %C, 50.67; %H, 3.1 l; %N, 16.14.
1H-NMR (300 MHz; DMSO-d6) 8 (ppm) 9.169(s,lH), 8.646(s,2H), 8.497(s,lH), 8.328(d,J=8.3Hz,lH), 7.773(d,J=6.9Hz,lH), 7.703(t,J=6.7Hz,lH), 7.558(t,J=7.2Hz,lH), 4.942(t,J=4.8Hz,2H), 4.447(s,2H), 4.073(t,J=4.9Hz,2H).
Example 18 1-(2- {[3-(Pyrid-4-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine bis(trifluoroacetate) NHZ
N
N
~N
O
N
Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5 c]quinolin-4-amine (0.5 g, 1.9 mmol), triethylamine (0.5 g, 4.9 mmol), copper (I) iodide (0.036 g, 0.2 mmol), 4-bromopyridine (0.51 g, 2.6 mmol) and acetonitrile (20 mL) were combined and stirred at ambient temperature.
Dichlorobis(triphenylphosphine)palladium(II) (0.066 g, 0.1 mmol) was added.
The reaction mixture was heated at reflux overnight. The acetonitrile was removed under reduced pressure. The residue was taken up in dichloromethane and methanol and then put through a basic alumina column. The fractions were combined and concentrated under reduced pressure. The residue was triturated with acetonitrile. The resulting solid was isolated by filtration and then purified by semi-preparative HPLC using Method A to provide 0.1 g of 1-(2-{[3-(pyrid-4-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine bis(trifluoroacetate) as a gray fluffy solid, m.p. 135°C
(dec.).
Analysis: Calculated for CZOH1~N50 ~ 2.0 CZHF30z ~ 0.5 HZO: %C, 49.66; %H, 3.47; %N, 12.06; Found: %C, 49.59; %H, 3.51; %N, 12.22.
1H-NMR (300 MHz; DMSO-d6) 8 (ppxn) 9.063(bs,2H), 8.551(d,J=5.2Hz,2H), 8.498(s,lH), 8.335(d,J=7.7Hz,lH), 7.795(d,J=6.9Hz,lH), 7.727(t,J=8.3Hz,lH), 7.564(t,J=8.3Hz,lH), 7.139(d,J=5.7Hz,2H), 4.942(t,J=4.8Hz,2H), 4.427(s,2H), 4.056(t,J=4.8Hz,2H).
Example 19 1-(2-{[3-(Fur-3-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate N
N
'N
O
y Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol), triethylamine (0.5 g, 4.9 mmol), copper (I) iodide (0.036 g, 0.2 mmol), 3-bromofuran (0.38 g, 2.6 mmol) and anhydrous N,N-dimethylformamide (20 mL) v~ere combined and stirred at ambient temperature.
Dichlorobis(triphenylphosphine)palladium(II) (0.066 g, 0.1 mmol) was added.
The reaction mixture was heated at 80°C overnight. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with dichloromethane. The resulting fine brown precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved into a minimum amount of N,N-dimethylformamide and put through a silica gel column. The appropriate fractions were combined and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC
using Method A to provide 0.1 g of 1-(2-{[3-(fur-3-yl)-2-propynyl]oxy}ethyl)-imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a fluffy ivory solid, m.p.
160-162°C.
Analysis: Calculated for C19H16N402 ' C2HF3O2 ' 0.25 HZO: %C, 55.94; %H, 3.91;
%N, 12.42; Found: %C, 55.57; %H, 3.43; %N, 12.45.
1H-NMR (300 MHz; DMSO-d~) 8 (ppm) 8.859(bs,2H), 8.473(s,lH), 8.32(d,J=8.3Hz,lH), 7.849(s,lH), 7.813(d,J=7.3Hz,lH), 7.714(t,J=8.SHz,lH), 7.697(d,J=2Hz,lH), 7.551(t,J=6.8Hz,lH), 6.409(d,J=l.9Hz,lH), 4.919(t,J=S.SHz,2H), 4.337(s,2H), 4.002(t,J=4.8Hz,2H).
Example 20 4-{3-[2-(4-Amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]-propyn-1-yl}
thiophen-2-ylcarboxaldehyde trifluoroacetate N
N
'N
O
S H
O
Using the general method of Example 20, 1-[2-(2-propynyloxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol) was reacted with 3-bromo-2-thiophenecarboxaldehyde (0.5 g, 2.6 mmol) and the crude product purified by semi-preparative HPLC using Method A to provide 0.13 g of 4-{3-[2-(4-amino-1H
imidazo[4, 5-c] quinolin-1-yl)ethoxy]-propyn-1-yl } -thiophen-2-ylcarboxaldehyde trifluoroaeetate as a fluffy ivory solid, m.p. 195°C.
Analysis: Calculated for CZOH16N40aS ' CzHF30z: %C, 53.88; %H, 3.49; %N, 11.42;
Found: %C, 54.16; %H, 3.21; %N, 11.36.
1H-NMR (300 MHz; DMSO-d6) d (ppm) 9.874(s,lH), 8.972(bs,2H), 8.483(s,lH), 8,.322(d,J=7.9Hz,lH), 8.076(s,lH), 7.771(d,J=8.3Hz,lH), 7.736(s,lH), 7.71(t,J=8.4Hz,lH), 7.555(t,J=6.9Hz,lH), 4.928(t,J=5.3Hz,2H), 4.371(s,2H), 4.043(t,J=4.8Hz,2H).
Example 21 1-(2-~[3-(Pyrid-2-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate NHa N
N
'N
O
~~N
Using the general method of Example 19, 1-[2-(2-propynyloxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol) was reacted with 2-bromopyridine (0.51 g, 2.6 mmol) and the crude product purified by semi-preparative HPLC
using Method A to provide 0.1 g of 1-(2-{[3-(pyrid-2-yl)-2-propynyl]oxy~ethyl)-1H
imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a gray fluffy solid, m.p.
129-131°C.
Analysis: Calculated for C20H1~Ns0 ~ 1.75 CZHF302 ~ 0.25 H20: %C, 51.56; %H, 3.55;
%N, 12:80; Found: %C, 51.80; %H, 3.20; %N, 13.11.
1H-NMR (300 MHz; DMSO-d6) 8 (ppm) 9.013(bs,2H), 8.516(s,lH), 8.495(s,lH), 8.331(d,J=8.2Hz,lH), 7.75(m,3H), 7.553(t,J=8.2Hz,lH), 7.375(dd,J=7.8;4.9Hz,lH), 7.23(d,J=7.8Hz,lH), 4.944(t,J=5.4Hz,2H), 4.418(s,2H), 4.059(t,J=4.8Hz,2H).
Examples 22 - 26 The compounds in the table below were prepared according to the synthetic method of Reaction Scheme I above using the following general method.
The 4-amino-1H imidazo[4,5-c]quinolin-1-yl alcohol (25 mg) was placed in a 2 dram (7.4 mL) vial. Sodium hydride (1.2 eq of 60% in mineral oil) and N,N-dimethylformamide (1 nnL,) were added. The vial was placed on a sonicator for about 15 to 30 minutes at ambient temperature to allow the alkoxide to form. The halide (1.2 eq) was added and the vial was placed back on the sonicator for about 15 to 120 minutes at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The reaction mixture was purified by semi-preparative HPLC. The semi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriate fractions were combined and lyophilized to provide the trifluoroacetate salt of the desired product,which was confirmed by accurate mass and 1H NMR
spectroscopy.
The table below shows the structure of the free base, the theoretical mass (TM), and the measured mass (MM) or nominal mass (NM).
Example Structure of the Free Base Purification Mass Measurement # Method (Da.) 22 NHS A TM = 326.1743 N ~ N~ MM = 326.1739 N
O
~0 23 NHS A TM = 392.1597 N ~ N~ MM = 392.1584 i N O; N~
O
N
24 NH2 A TM = 450.1281 N~ MM = 450.1285 N
O
CI
S
25 NH2 A TM = 422.0968 N~ MM = 422.0966 N
O
~ CI
S
Example Structure of the Free PurificationMass Measurement # Base Method (Da.) 26 NH2 A TM = 364 N ~ N> NM [M+H]+i = 365 r N
O N~
O
+ I /
. N
O
Example 27 1- f 2-Methyl-1-[(pyrid-2-yloxy)methyl]propyl)-1H imidazo[4,S-c]quinoline-4-amine trifluoroacetate NHS
N
N
'N
N, O
f Using the general method of Examples 22 - 26 above, 2-(4-amino-1H
imidazo[4,5-c]quinolin-1-yl)-3-methylbutan-1-of was reacted with 2-(trifluoromethylsulfonyloxy)pyridine and the crude product purified via semi-preparative HPLC using Method A to provide 1- f 2-methyl-1-[(pyrid-2-yloxy)methyl]propyl}-imidazo[4,5-c]quinoline-4-amine as the trifluoroacetate salt. TM = 347.1746, MM =
347.1740 Example 28 1- f 1-[(pyrid-2-yloxy)methyl]propyl}-1H imidazo[4,5-c]quinoline-4-amine trifluoroacetate NHS
N
N /
~N
N
O
Using the general method of Examples 22 - 26 above 2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)-3-methylbutan-1-oI was reacted with 2-(trifluoromethylsulfonyloxy)pyridine and the crude product purified via semi-preparative HPLC using Method B to provide 1-{1-[(pyrid-2-yloxy)methyl]propyl}-1H
imidazo[4,5-c]quinoline-4-amine as the trifluoroacetate salt. TM = 333.1590, MM = 333.1598 Example 29 1-[2-(9H carbazol-3-yloxy)propyl]-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate NHZ
N
N
'N
i O
HN
A 1 mL portion of a solution prepared by dissolving 0.5 g of 1-(4-amino-1H
imidazo[4,5-c]quinolin-1-yl)propan-2-of in N,N-dimethylformamide (20 mL) was added to a 2 dram (7.4 mL) glass vial containing 2-hydroxycarbazole (38 mg, 2 eq.).
Triphenylphosphine (54 mg, 2 eq.) dissolved in N,N-dimethylformamide (1 mL) was added to the vial. The resulting slurry was sonicated to dissolve the phenol.
Diethyl azidocarboxylate (36 mg, 2 eq.) was added neat. The reaction mixture was sonicated for about 30 minutes and then shaken overnight at ambient temperature. The solvent was removed and the residue was purified by semi-preparative HPLC using Method A.
The compound was provided as the trifluoroacetate salt. TM = 407, NM[M + H]+1 =
408.
Example 30 1-{2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine NHZ
N w N
N
O
S
i Part A
Using the general method of Example 1 Part B, 2-(1H imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether was oxidized to provide 67.5 g of 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide as a tan solid.
MS (CI) for C15H14N3Oz m/z 268 (MH+), 252, 214.
Part B
A dried round bottom flask was charged with a stir bar, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (57.5 g, 215.1 mmol), anhydrous toluene (200 mL) and anhydrous dimethyl formamide (400 mL) under a nitrogen atmosphere. Phosphorus oxychloride (23 mL, 247.4 mmol) was added dropwise over 20 minutes to this mixture leading to a modest exotherm (~ 40 °C).
The reaction was judged complete after 1.25 hours at ambient temperature. The volatiles were removed under reduced pressure and the resulting solid was partitioned between chloroform and 10% aqueous sodium carbonate. The aqueous layer was extracted with chloroform;
the organic fractions were combined, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown solid was dried at 60 °C, under vacuum, for 4 hours to obtain 36.6 g of 4-chloro-1-[2-(prop-2-ynyloxy)ethyl]-imidazo[4,5-c]quinoline as a powder.
MS (CI) for ClSHizCIN3O m/Z 286 (MH+), 246, 204.
Part C
A dried round bottom flask was charged with a stir bar, sodium hydride (8.15 g, 203.9 rnmol) and anhydrous 2-methoxylethyl ether (diglyme, 100 mL) while under a nitrogen atmosphere and at ambient temperature. Phenol (20.7 g, 220.2 mmol) was added in several portions as a solid and the resulting solution stirred under a nitrogen atmosphere until gas evolution ceased. 4-chloro-1-[2-(prop-2-ynyloxy)ethyl]-1H
imidazo[4,5-c]quinoline (46.6 g, 163.1 mmol) was added neat and the solution was heated to 110 °C.
After 15.5 hours, a preformed solution of sodium phenoxide (phenol 5 g, 53.1 mmol and sodium hydride 1.91 g, 47.8 mmol) in diglyme (20 mL) was added to the reaction solution and heating was increased to 165 °C. The reaction was judged complete after 1 hour at 165 °C. After cooling to less than 70 °C, the volatiles were removed under reduced pressure and the resulting brown solid was partitioned between chloroform and saturated aqueous sodium carbonate. The aqueous fraction was extracted with chloroform;
the combined organic fractions were dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile with a small amount of dimethyl formamide to provide 25 g of 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H imidazo[4,5-c]quinoline as a crystalline solid.
MS (CI) for CZ1H1~N302 m/z 344 (MH+), 306, 288.
Part D
Using the general method of Example 3 Part A, 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H imidazo[4,5-c]quinoline (10 g, 29.4 mmol) was reacted with 2-iodothiophene (3.6 mL, 32.3 mmol). The glassy solid obtained from purification by chromatography over silica gel (98/2 dichloromethane/methanol) was triturated with ether to provide 5.3 g of 4-phenoxy-1- f 2-[(3-thien-3-ylprop-2-ynyl)oxy]ethyl}-1H
imidazo[4,5-c]quinoline as a gray powder.
MS (CI) for C25H19N302S r~Z 426 (MH+), 306, 288.
Part E
4-Phenoxy-1-{2-[(3-thien-3-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinoline (3.2 g, 7.52 mmol) and ammonium acetate (32 g, 415 mmol) were melted together in a dried round bottom heated to 150 °C under a nitrogen atmosphere. After 2 hrs additional ammonium acetate (10 g, 129 mmol) was added. The reaction was judged complete after a total of 4 hours. The melted solids were cooled to ambient temperature and basified with 1N aqueous potassium hydroxide to a pH of~l3. The aqueous mixture was extracted with dichloromethane (3x); the combined organic fractions were washed with brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting solid was purified by chromatography over silica gel (98/2 dichloromethane/methanol), then triturated with ether to provide 0.812 g of 1-~2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a white powder, m.p.
148-150 °C.
Analysis. Calculated for C19H16N4OS: %C, 65.50; %H, 4.63; %N, 16.08. Found:
%C, 65.42; %H, 4.65; %N, 16.11 IH NMR (300 MHz, DMSO) 8 8.16 (s, 1 H), 8.11 (d, J = 6.8 Hz, 1 H), 7.60 (m, 2 H), 7.43 (t, J = 6.8 Hz, 1 H), 7.20-7.25 (m, 2 H), 7.04 (dd, J = 4.9, 3.9 Hz, 1 H), 6.58 (s, 2 H), 4.84 (t, J = 5.4, 2 H), 4.41 (s, 2 H), 3.99 (t, J = 5.4, 2 H) MS (CI) for C1~H16N40S m/z 349 (MHO), 229, 185.
Example 31 1- f 2-[(1-methyl-1H indol-2-yl)methoxy]ethyl}
1H imidazo[4,5-c]quinolin-4-amine NHS
N ~ N
N
O
/ N~
Part A
Using the general method of Example 30 Part D, 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H imidazo[4,5-c]quinoline (3.16 g, 9.20 mmol) was reacted with 2-iodo-N,N-dimethylaniline (2.5 g, 10.1 mmol) to provide a 1.0 g of 1- f 2-[(1-methyl-1H indol-2-yl)methoxy]ethyl}-4-phenoxy-1H imidazo[4,5-c]quinoline as a pale yellow crystalline solid.
MS (CI) for C28H24N4O2 m/z 449 (MH+), 306, 186.
Part B
1- f 2-[(1-Methyl-IH indol-2-yl)methoxy]ethyl}-4-phenoxy-1H imidazo[4,5-c]quinoline (0.78 g, 1.74 mmol) was partially converted to the desired product by exposure to ammonia, (7% in methanol, 20 mL) for 52 hours at 160 °C in a bomb. The volatiles were removed under reduced pressure and the material was reacted with more ammonia (7% in methanol, 20 mL) for 80 hours at 160 °C to completely consume the starting material. The solid was removed by filtration and the filtrate was concentrated under reduced vacuum. The resulting material was purified by chromatography over silica gel (9/1 dichloromethane/methanol). The resulting solid was recrystallized from dimethyl formamide to provide 0.121 g of 1-{2-[(1-methyl-1H indol-2-yl)methoxy]ethyl}-imidazo[4,5-c]quinolin-4-amine as white, flat crystals, m.p. 243-245 °C.
Analysis. Calculated for CZZHziNsO ' (C3H~ON)o,20: %C, 70.50; %H, 5.81; %N, 18.75.
Found: %C, 70.72; %H, 5.70; %N, 18.36 1H NMR (300 MHz, DMSO) 8 8.13 (s, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.60 (d, J
= 9.3, 1 H), 7.36-7.47 (m, 3 H), 7.10-7.20 (m, 2 H), 6.98 (t, J = 7.3 Hz, 1 H), 6.58 (brs, 2 H), 6.36 (s, 1 H), 4.82 (t, J = 4.9, 2 H), 4.64 (s, 2 H), 3.92 (t, J = 4.9, 2 H), 3.52 (s, 3 H) MS (CI) for CZZHZiNsO m/z 372 (MH+), 229, 144.
Example 32 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine N ~ N
N
O
Part A
A dried round bottom flask was charged with a stir bar, 2-(1H imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether (11.78 g, 46.88 mmol), anhydrous triethylamine (14 mL, 121.9 mmol), 2-iodothiophene (5.7 rnL, 51.57 mmol) and anhydrous dimethyl formamide(130 mL) under a nitrogen atmosphere and heated to 80 °C.
After 5 minutes dichlorobis(triphenylphosphine)palladium(II) (0.658 g, 0.937 mol) and copper(I) iodide (0.357 g, 1.875 mmol) were added neat to the solution. The reaction was judged complete after 50 minutes. The volatiles were removed under reduced pressure and the resulting solid partitioned between dichloromethane and 0.5N aqueous potassium hydroxide. The aqueous fraction was extracted with dichloromethane (3x); the combined organic fractions were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide a brown solid. The glassy solid obtained from purification by chromatography over silica gel (98/2 dichloromethane/methanol) was triturated with ether to provide 9.5 g of 1- f 2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinoline as a tan solid.
MS (CI) for Cl9HisNsOS m/z 334 (MH+), 290, 214.
Part B
Using the general method of Example 3 Part B, 1- f 2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl-1H imidazo[4,5-c]quinoline (9.5 g, 28.49 mmol) was reduced with palladium on carbon (10%, 1 g) in methanol (25 mL) to provide 9.1 g of 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline as a brown oil.
MS (CI) for C19H19N3OS 111/Z 338 (MH+), 214.
Part C
Using the general method of Example 1 Part B, 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline was oxidized to provide 4.4 g of 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide as an unpurified tan solid.
MS (CI) for C19H19N3O2s Tn/Z 354 (MH+), 338, 214.
Part D
Using the general method of Example 1 Part C, 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (4.4 g, 12.45 mmol) was reacted with trichloroacetyl isocyanate (1.8 mL, 14.9 mmol) to provide 2,2,2-trichloro-N {1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-yl}acetamide as an unpurified glassy solid.
Part E
A dried round bottom flask Was charged with a stir bar, 2,2,2-trichloro-N { 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-ylJacetamide and sodium methoxide (25% in methanol, 11 mL, 49.8 mmol) at ambient temperature. The reaction was judged complete after 30 hours. The volatiles were removed under reduced pressure.
The resulting oil was purified with chromatography over silica gel (95/5 dichloromethane/methanol), semi-preparative HPLC using method A, and recrystallization from ethyl acetate/hexane to provide 43 mg of 1-[2-(3-thien-2-ylpropoxy)ethyl]-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid. m.p. 130.1-131.6 °C.
Analysis. Calculated for Cl9HZON40S ' (HZO)o,3o: %C, 63.77; %H, 5.80; %N, 15.66.
Found: %C, 63.84; %H, 5.79; %N, 15.57 IH NMR (300 MHz, DMSO) 8 8.16 (s, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 7.62 (d, J
= 8.3 Hz, 1 H), 7.43 (t, J = 7.3 Hz, 1 H), 7.20-7.26 (m, 2 H), 6.84 (dd, J = 4.9, 3.4 Hz, 1 H), 6.62 (d, J = 2.4 Hz, 1 H) 6.58 (s, 2 H), 4.79 (t, J = 5.4 Hz, 2 H), 3.83 (t, J = 5.4 Hz, 2 H), 3.35 (t, J
= 6.4, 2 H), 2.64 (t, J = 7.8 Hz, 2 H), 1.69 (p, J = 6.8, 6.3 Hz, 2 H).
MS (CI) for Cl~HzoN40S m/z 353 (MH+), 211, 185.
Example 33 1-[2-(3-Pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHZ
N
'N
O
N
Part A
Under a nitrogen atmosphere, a solution of 2-aminobenzoic acid (100.0 g, 0.73 mol) in acetic anhydride (400 ml, 4.2 mol) was heated to reflux for 2 hours.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in glacial acetic acid (500 ml) and NaN3 (49.77 g, 0.77 mol) was added. The mixture was stirred overnight at room temperature followed by concentration of the acetic acid in vacuo. The residue was dissolved in 10% NaOH (500 ml) solution and heated to reflux for 3.5 hours. The reaction was cooled to room temperature and then poured over a mixture of ice water (2 L) and HCl (150 ml). A white solid precipitated and was collected by vacuum filtration. The solid was dried in vacuo to yield 130.5 g of 2-(5-methyl-1H
tetrazol-1-yl)benzoic acid.
1H NMR (300 MHz, DMSO-d~) 8 8.12 (d, J = 7.2 Hz, 1H), 7.91-7.78 (m, 2H), 7.72 (d, J =
7.4 Hz, 1H), 2.37 (s, 3H);
MS (CI) m/e 205 (MH+), 162 (M - N3).
Part B
Under a nitrogen atmosphere, 2-(5-methyl-1H tetrazol-1-yl)benzoic acid (89.7 g, 0.44 mol) was dissolved in acetone (1 L) and cesium carbonate (214.7 g, 0.66 mol) was added with vigorous stirring. Ethyl iodide (70.3 ml, 0.88 mol) was added dropwise and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature and filtered. The acetone was removed in vacuo to yield a yellow solid which was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate (200 ml). The organic fraction was dried (Na2S04), ftltered, and concentrated to yield 92.7 g of ethyl 2-(S-methyl-1H tetrazol-1-yl)benzoate as a light yellow solid.
1H NMR (300 MHz, DMSO-d6) 8 8.14 (d, J = 7.8 Hz, 1H), 7.89 (m, 2H), 7.79 (d, J
= 7.9 Hz, 1 H), 4.08 (q, J = 7.4 Hz, 2H), 2.40 (s, 3H), 1.04 (t, J = 6.9 Hz, 3H);
MS (CI) m/e 233 (MHO), 1 S9.
Part C
Under a nitrogen atmosphere, ethyl 2-(S-methyl-1H tetrazol-1-yl)benzoate (92.7 g, 0.34 mol) was dissolved in N,N-dimethylformamide (600m1) and the solution was chilled in an ice water bath. Potassium ethoxide (67.2 g, 0.80 mol) was added slowly to the solution. After a few minutes, the ice water bath was removed and the reaction was stirred at room temperature for 3 hours. The reaction was treated with 100 ml of water and approximately 300-400 ml of solvent was removed in vacuo. The remainder of the reaction was poured over a solution of glacial acetic acid (125 ml) in ice water (2 L). A
precipitate formed and the mixture was diluted with additional water (3 L).
The solid was 1S collected by vacuum filtration to yield 63.25 g of tetrazolo[1,5-a]quinolin-S-of as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) 8 8.54 (d, J = 8.4 Hz, 1H). 8.27 (d, J = 8.1 Hz, 1H), 7.99 (t, J = 7.4 Hz, 1 H), 7.80 (t, J = 7.2 Hz, 1 H), 7.04 (s, 1 H);
MS (CI) m/e 187 (MH+), 159.
Part D
Tetrazolo[1,5-a]quinolin-5-of (63.25 g, 0.34 mol) was added to glacial acetic acid (630 ml) to form a thick off white suspension. The mixture was vigorously stirred while nitric acid (23.6 ml, 0.37 mol, 70% solution) was slowly added. The reaction was then heated from 25 to 80 °C over a period of 1 S minutes. A yellow precipitate formed and the reaction was maintained at 80 °C for 5 minutes. The mixture was slowly cooled to 0 °C.
The solid was collected by filtration and then dried in vacuo to yield 60.0 g of 4-nitro-tetrazolo[1,5-a]quinolin-5-of as a yellow solid.
IH-NMR (300 MHz, DMSO-d6) 8 8.35 (d, J = 3.9 Hz, 1H); 8.32 (d, J = 3.2 Hz, 1H), 7.90 (t, J = 7.3 Hz, 1 H), 7.68 (t, J = 8.2 Hz, 1 H);
MS (CI) m/e 232 (MH+), 204.
Part E
Under a nitrogen atmosphere, POC13 (16.42 ml, 0.17 mol) was slowly added to a chilled (0 °C) flask containing N,N-dimethylformamide (100 ml). The resulting solution was slowly warmed to room temperature and then added dropwise to a suspension of 4-nitro-tetrazolo[1,5-a]quinolin-5-of in N,N-dimethylformamide (300 ml). The reaction was heated to 100 °C for 30 minutes. The orange/red solution was quenched by pouring over 1 liter of ice water. A yellow precipitate formed and was collected by filtration, redissolved in chloroform (approx. 750 ml), dried (Na2S04), filtered, and concentrated iya vacuo to yield 33.74 g of 5-chloro-4-nitrotetrazolo[1,5-a]quinoline as a yellow solid.
'H NMR (300 MHz, DMSO-d~) 8 8.78 (d, J = 8.2 Hz, 1H); 8.57 (d, J = 8.3 Hz, 1H), 8.29-8.22 (m, 1H), 8.09-8.03 (m, 1H);
MS (CI) m/e 250 (MH+).
Part F
5-Chloro-4-nitrotetrazolo[1,5-a]quinoline (28.86 g, 0.11 mol), dichloromethane (600 ml), and triethylamine (21.14 ml, 0.11 mol) were combined and the resulting solution was chilled to 0 °C. 2-(3-Pyridin-3-ylpropoxy)ethylamine (22.9 g, 0.13 mol) was added dropwise. The reaction was allowed to slowly warm to room temperature, then stirred at room temperature for 1 hour and finally at reflux for 2 hours. The reaction was cooled to room temperature and then quenched with water (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (3 x SOmI).
The combined organic fractions were washed with brine (100 ml), dried (NaZS04), filtered and concentrated to yield a yellow solid. The solid was slurried in ethanol ( 150 ml) and filtered to provide 34.3 g of 4-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a] quinolin-5-amine.
'H NMR (300 MHz, DMSO-d6) 8 10.27 (bs, 1H), 8.69 (d, J = 8.3 Hz, 1H), 8.54 (d, J =
8.3 Hz, 1H), 8.37 (bs, 2H), 8.08 (t, J = 7.7 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.57 (d, J =
7.3 Hz, 1H), 7.27 (dd, J = 7.9, 5.0 Hz, 1H), 3.92 (m, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 1.82 (m, 2H);
MS (CI) m/e 394 (MH+), 366.
Part G
4-Nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinolin-5-amine (34.3 g, 87.2 mmol) was added to a 3 liter stainless steel pressure flask containing ethanol (1.25 L, absolute). Platinum on carbon (3.00 g, 5% w/w) was added and the flask was placed on a Parr hydrogenation apparatus. The reaction was shaken under 45 psi (3.15 Kg/cmz) of hydrogen for 24 hours. The catalyst was removed by filtration through CeliteTM
and the Celite pad was washed with several portions of ethanol. The filtrate was concentrated in vacuo to provide 30.8 g of NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,S-a]quinoline-4,S-diamine as an orangelred oil. MS (CI) m/e 364 (MH+), 336.
Part H
Triethyl orthoformate (21.1m1, 127mmo1) was added to a solution of NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,S-a]quinoline-4,S-diamine (30.8 g, 84.7 mmol) in 1,2-dichloroethane (7S0 ml) and the reaction was heated to reflux for 3 hours.
The reaction was cooled to room temperature and diluted with saturated sodium bicarbonate (200 ml).
The phases were separated and the aqueous layer was extracted with dichloromethane (3 x7Sm1). The combined organic fractions were washed with brine (200 ml), dried (NaZS04) and concentrated to provide an orange solid. The solid was triturated with diethyl ether and then filtered to yield 28.7 g of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H
imidazo[4,S-c]tetrazolo[1,S-a]quinoline as a tan/orange solid.
1H-NMR (300 MHz, CDC13) 8 8.71 (dd, J = 8.1, 1.3 Hz, 1H), 8.38 (dd, J = 4.8, 1.S Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 8.07 (s, 1H), 7.73 (m, 2H), 7.32 (dt, 1 S J = 7.8, 1.9 Hz, 1 H), 7.13 (dd, J = 7.7, 4.8 Hz, 1H), 4.81 (t, J = S.1 Hz, 2H), 3.96 (t, J = S.1 Hz, 2H), 3.42 (t, J = 6.2 Hz, 2H), 2.52 (t, J = 7.S Hz, 2H), 1.82-1.74 (m, 2H);
MS (CI) m/e 374 (MH+).
Part I
Triphenylphosphine (27.0g, 1 l Smmol) was added to a solution of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,S-c]tetrazolo[l,S-a]quinoline (28.7 g, 76.9 mmol) in 1,2-dichlorobenzene (1 L). The reaction was heated at reflux temperature overnight. The dark red solution was cooled to room temperature and treated with 1N HCl (22S
ml). A
tan precipitate formed. The resulting mixture was concentrated in. vacuo to yield a dark red/brown solid. This material was treated with S00 ml water and vigorously stirred.
2S Excess triphenylphosphine and triphenylphosphine oxide formed as precipitates and were removed by vacuum filtration. The solid was washed with several portions of water followed by a final wash with dilute HCl (1:S, 1N HCl:water). The red/brown filtrate was collected, washed with ether (3 x 1 SOmI), and treated with 10% NaOH solution until the pH reached 12. The crude product formed as a tan precipitate and was collected by filtration. Purification of the crude material was accomplished by treatment (2X) with activated charcoal (Darco-G60) in refluxing methanol. The charcoal was removed by filtration. The desired product formed as a precipitate during concentration of the filtrate.
The solid was collected by vacuum filtration washed with diethyl ether, and dried under vacuum to provide 17 g of 1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a tan solid, m.p. 125.0-128.0 °C.
1H NMR (300 MHz, DMSO-d6) 8 8.33 (d, J = 4.8 Hz, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 6.8 Hz, 1H), 7.33-7.21 (m, 2H), 7.16 (dd, J = 7.7, 4.8 Hz, 1H), 6.62 (s, 2H), 4.80 (t, J = 4.8 Hz, 2H), 3.82 (t, J = 4.9 Hz, 2H), 3.30 (t, J = 6.3 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.64 (m, 2H);
MS (CI) m/e 348 (MH+);
Anal calcd for CzoHzlNsO*0.08 H20: C, 68.89; H, 6.11; N, 20.09. Found: C, 68.49; H, 5.95; N, 20.08.
Example 34 2-Methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine Part A
Under an atmosphere of nitrogen, Ns-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (0.70 g, 1.92 mmol) was dissolved in 1,2-dichloroethane (15 ml). Triethyl orthoacetate (0.53 ml, 2.88 mmol) was added via syringe and the reaction was heated to reflux fox 3 hours. Analysis by thin layer chromatography (9515 chloroform/methanol) showed complete consumption of the diamine. The reaction was quenched by the addition of water (15 ml). The phases were separated and the aqueous fraction was extracted with dichloromethane (3 x 10 ml). The combined organic fractions were washed with brine (15 ml), dried (NazS04), filtered and concentrated in vacuo to yield 0.73 g of 5-methyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H
imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a red oil. This material was used without further purification.
MS (CI) m/e 388 (M + H).
Part B
Under an atmosphere of nitrogen, 5-methyl-6-[2-(3=pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline (0.73 g, 1.89 mmol) and triphenylphosphine (0.64 g, 2.84 mmol) were dissolved in 1,2-dichlorobenzene (15 ml). The reaction was heated at reflux for 18 hours. After cooling to ambient temperature, the solvent was removed ih vacuo. The resulting residue was treated with 1N HCl/water (30 ml) and vigorous stirring produced an off white suspension. The solid was removed by filtration leaving a yellow ftltrate. The filtrate was treated with 10 % sodium hydroxide/water until pH 11 was reached. The filtrate was extracted with dichloromethane (3 x 25 ml). The combined organic fractions were washed with brine (25 ml), dried (NaZS04), filtered and concentrated in vacuo to yield an orange oil. The oil was dissolved in a minimum amount of dichloromethane and diluted with ether to produce a precipitate. The solid was recrystallized from n-propyl acetate to yield 0.16 g of 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine as a tan solid, m.p. 145.0-146Ø
1H NMR (300 MHz, CDC13) 8 8.40 (d, J = 4.9 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.93 (d, J
= 7.4 Hz, 1 H), 7. 84 (d, J = 8.4 Hz, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.31 (t, J = 6.6 Hz, 1 H), 7.22 (d, J = 7.8 Hz, 1H), 7.09 (dd, J = 4.8, 7.8 Hz, 1H), 5.46 (bs, 2H), 4.67 (t, J = 5.3 Hz, 2H), 3.90 (t, J = 5.3 Hz, 2H), 3.34 (t, J = 6.2 Hz, 2H), 2.70 (s, 3H), 2.52 (t, J = 8.0 Hz, 2H), 1.76 (m, 2H);
MS (CI) m/e 362 (M + H);
Anal calcd for CZIHasNsO: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.40; H, 6.38; N, 19.00.
Example 35 2-Butyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine Part A
Under an atmosphere of nitrogen, NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (2.48 g, 6.82 mmol) was dissolved in toluene (40 ml). Trimethyl orthovalerate (1.29 ml, 7.51 mmol) was added via syringe.
A catalytic amount of pyridine hydrochloride was added to the reaction and the flask was fitted with a Dean-Stark trap. The reaction was heated to reflux and the volatiles were collected in the trap. After 4 hours, the reaction was cooled to room temperature and quenched by the addition of water (30 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 15 ml). The combined organic fractions were washed with brine (25 ml), dried (Na2SO4), filtered and concentrated iya vacuo to provide a red/brown oil. The material was purified by flash column chromatography (silica gel, 2/1 to 95/5 ethyl acetate/hexane gradient) to yield 1.98 g of 2-butyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline as an orange oil.
1H NMR (300 MHz, DMSO-d6) 8 8.53 (d, J = 8.2 Hz, 1 H), 8.41 (d, J = 7.9 Hz, 1 H), 8.37 (d, J = 5.0 Hz, 1 H), 8.31 (d, J = 1.9 Hz, 1 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.75 (t, J = 7.5 Hz, 1 H), 7.48 (d, J = 7.9 Hz, 1 H), 7.23 (dd, J = 7.8, 4.9 Hz, 1 H), 3.63 (t, J =
5.0 Hz, 2 H), 3 .5 6 (t, J = 4.9 Hz, 2 H), 3 .3 6 (t, J = 6.3 Hz, 2 H), 2. 51 (m, 2H), 2.12 (t, J = 7. 7 Hz, 2 H), 1.73 (pentet, J = 7.4 Hz, 2 H), 1.45 (pentet, J = 7.7 Hz, 2 H), 1.12 (m, 2 H), 0.68 (t, J = 7.4 Hz, 3 H);
MS (CI) m/e 430 (M + H).
Part B
2-Butyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline (1.98 g, 4.61 mmol) was treated following the general procedure described in Example 35. Recrystallization from isopropyl alcohol gave 1.09 g of 2-butyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine as a beige solid.
1H NMR (300 MHz, DMSO-d6) 8 8.33 (d, J = 4.3 Hz, 1 H), 8.24 (s, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.30 - 7.20 (m, 2 H), 7.1.5 (dd, J = 7.4, 4.8 Hz, 1 H), 6.44 (bs, 2 H), 4.74 (t, J = 5.4 Hz, 2 H), 3.82 (t, J = 5.3 Hz, 2 H), 3.27 (t, J = 5.9 Hz, 2 H), 2.97 (t, J = 7.4 Hz, 2 H), 2.41 (t, J = 7.5 Hz, 2 H), 1.84 (p~ntet, J
= 7.4 Hz, 2 H), 1.64 (pentet, J = 7.2 Hz, 2 H), 1.46 (m, 2 H), 0.95 (t, J =
7.3 Hz, 3 H);
MS (CI) m/e 404 (M + H);
Anal calcd for Cz4HZgN50: C, 71.44; H, 7.24; N, 17.36. Found: C, 71.23; H, 6.98; N, 17.05.
Example 36 2-(2-Methoxyethyl)-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine N ~ Nr' Om '~ N
O
N
Part A
Under a nitrogen atmosphere, NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetraazolo[1,5-a]quinoline-4,5-diamine (2.48 g, 6.82 mmol), 1,2-dichloroethane (30 ml), and triethylamine (1.14 ml, 8.2 mmol) were combined and the resulting solution was chilled in an ice water bath. 3-methoxypropionyl chloride (0.92 g, 7.5 mmol) was added dropwise to the solution. The cooling bath was removed and the reaction was stirred for an additional 18 hours. The solution was quenched by the addition of water (30 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 ml). The combined organic fractions were washed with brine (20 ml), dried (Na2S04), filtered and concentrated to yield 3.16 g of an orange syrup. LCMS analysis of the crude product showed a mixture of mono- and di-acylated product. The material was used without further purification.
Part B
Under a nitrogen atmosphere, the product from part A (3.16 g), toluene (40 ml), and pyridine hydrochloride (50 mg, 0,4 mmol) were combined and the resulting mixture was heated at reflux temperature for 4 hours. The volatiles were collected in a Dean-Stark trap. The reaction was cooled to ambient temperature and then diluted with water (30 ml).
The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (20 ml), dried (Na2S04), filtered and concentrated to yield an orange foam. The material was purified by column chromatography (silica gel, 99:1 CHCI3:MeOH gradient to 9:1) and then recrystallized from 2-propanol to yield 0.35 g of 5-(2-methoxyethyl)-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetraazolo[1,5-a]quinoline as a beige solid.
Part C
5-(2-rnethoxyethyl)-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,S-c]tetraazolo[1,5-a]quinoline (0.35 g, 0.80 mmol) was treated with triphenylphosphine (0.28 g, 1.20 mmol) using the general procedure described in Part B of example 35. The crude product was crystallized from ether to yield 90 mg of 2-(2-methoxyethyl)-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as off white crystals.
1H NMR (300 MHz, CDC13) 8 8.39 (dd, J = 4.8, 1.5 Hz, 1 H), 8.33 (d, J = 1.8 Hz, 1 H), 7.94 (d, J = 7.4 Hz, 1 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.52-7.47 (m, 1 H), 7.32-7.21 (m, 2 H), 7.09 (dd, J = 7.0, 4.8 Hz, 1 H), 5.59 (bs, 2 H), 4.74 (t, J = 5.4 Hz, 2 H), 3.90 (t, J = 6.6 Hz, 2 H), 3.87 (t, J = 5.4 Hz, 2 H), 3.38 (s, 3 H), 3.33 (t, J = 6.1 Hz, 2 H), 3.28 (t, J = 6.6 Hz, 2 H), 2.51 (t, J = 7.4 Hz, 2 H), 1.81-1.71 (m, 2 H);
13C NMR (75 MHz, CDC13) 8 152.4, 151.6, 150.2, 147.8, 145,2, 137.1, 136.2, 133.7, 127.7, 127.4, 123.6, 122.5, 120.0, 115.9, 71.2, 70.6, 69.6, 59.4, 46.1, 31.1, 29.6, 28.7;
MS(CI) m/e 406.2242 calcd for (406.2243 C23H28N502, M+H).
Example 37 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H imidazo[4,5 c]quinolin-4-amine NHZ
N~ \ N
N
O
s N
Part A
A 200 mL round bottom flask was charged with 3-nitro-5,6,7,8-tetrahydroquinoline-2,4-diol (10 g, 0.048 mol.) and phosphorous oxychloride (100 mL, 1.07 mol., 22 equivalents). The reaction mixture was heated to 80°C and maintained, with stirnng for six hours. The reaction was quenched by slowly adding the reaction mixture to water (1500 mL). The reaction mixture was extracted with dichloromethane (4 x mL). The dichloromethane fractions were combined, dried over magnesium sulfate and concentrated to provide 2,4-dichloro-3-vitro-5,6,7,8-tetrahydroquinoline as a tan solid (10.6 g, 91 %). m.p. 63-64°C. TLC (10% MeOH/CH2CL2, Rf--0.84).
Part B
A 200 ml round bottom flask was charged with 2,4-dichloro-3-vitro-5,6,7,8-tetrahydroquinoline (10 g, 0.04 mol), triethylamine (6.1g, 0.06 mol, 1.5 equivalents) and anhydrous N,N-dimethylformamide (100 mL). To this solution was added 2-(3-pynidin-3-ylpropoxy)ethanamine (7.3 g, 0.04 mol). The reaction mixture was heated to 55°C and maintained overnight with stirring. The reaction was quenched by pouring into water (1000 mL). The reaction mixture was then extracted with a 1:1 solution of hexane/ethyl acetate (4 x 200 mL). The organics were combined, washed with brine (300 mL) and concentrated to provide 2-chloro-3-vitro-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine as an orange syrup (14.8 g, 94%). TLC (10%
MeOH/CH2CL2, R~0.84).
Part C
A 200 mL round bottom flask was charged with 60% sodium hydride (2.5 g, 0.06 mol, 1.7 equivalents) and washed with hexane (50 mL). A solution of phenol (5.7 g, 0.06 mol, 1.6 equivalents) in diglyrne (25 mL) was then slowly added to the sodium hydride.
The reaction was maintained with stirring at room temperature for 1.5 hours.
To the phenol anion solution was slowly added a solution of 2-chloro-3-nitro-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine (14.8 g, 0.04 mol) in diglyme (25 mL). The stirred reaction mixture was heated to 60°C and maintained overnight. The reaction was quenched by pouring onto ice (1000 mL). The product oiled out of solution.
The mixture was extracted with dichloromethane (4 x1 00 mL). The combined extracts were concentrated to dryness. The residue was taken up in 1:1 hexane/ethyl acetate (250 mL) and washed with water (2 x 50 mL). The organic layer was concentrated to dryness.
The residue was found to contain excess phenol. The phenol was removed by taking the residue up in diethyl ether (500 mL) and stirring over 10% sodium hydroxide (250 mL) overnight. The layers were separated. The ether layer was concentrated to provide 3-nitro-2-phenoxy-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydxoquinolin-4-amine as a pale orange syrup (12.0 g, 71%). TLC=(10% MeOH/CH2C12, Rf--0.58).
Part D
A 500 mL Parr bottle was charged with a solution of 3-nitro-2-phenoxy-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine in toluene (150 mL) and 5% Pt/C catalyst (l .l g), placed on Parr apparatus and charged with hydrogen (~54 psi, 3.8 Kg/cm2). The reaction was allowed to shake for 4 hours, at which time the reaction was monitored by HPLC. The reaction was not complete. An additional 1.0 g 5% PtIC
catalyst was added to the Parr bottle, it was recharged with hydrogen and shaken overnight. The reaction was then complete. The mixture was filtered through Celite and washed with toluene (500 mL). The filtrate was concentrated to provide 2-phenoxy-1V4-[2 (3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine as a yellow syrup (8.2 g, 74%). TLC (10% MeOH/CH2C12, R~0.48). Mass-spec M+1=419.2 Part E
A 200 ml round bottom flask was charged with 2-phenoxy-1V4-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine (4.1 g, 0.0098 mol.) and pyridine (40 mL) at room temperature. To this solution was slowly added acetyl chloride (0.8 g, 0.011 mol., 1.1 equivalents). The reaction was maintained with stirring at room temperature. After two hours the reaction was monitored and found to only contain the amide intermediate. The reaction mixture was then heated to reflux and maintained overnight. The reaction mixture was concentrated to provide a dark amber syrup. The syrup was taken up in ethyl acetate (300 mL) and washed with water (2 x 100 mL). The ethyl acetate layer was concentrated to provide 2-methyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinoline as an orange syrup (3.8 g, 88%). TLC (10%MeOH/CH2C12, Rf--0.34). Mass-spec M+1=443.2 Part F
A 200 ml round bottom flask was charged with 2-methyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline (3.7 g, 0.0084 mol.) and ammonium acetate (37 g, 0.48 mol, 57 equivalents) and then heated to 150°C.
Within 20 minutes the reaction mixture was homogeneous. The reaction mixture was maintained with stirring at 150°C overnight. The reaction was monitored after 24 hours and found to be incomplete. The reaction mixture was maintained over the weekend. The reaction mixture was cooled and then taken up in 1N HCl (250 mL) and washed with diethyl ether (200 mL). The aqueous layer was then adjusted to pHl 1 with sodium hydroxide and extracted with dichloromethane (3 x 100 mL). The combined organics were concentrated to provide an orange syrup, The syrup was purified by column chromatography (10% MeOH/CH2Cl2). The appropriate fractions were combined and concentrated to provide a pale orange syrup. The syrup was found to be a mixture of the desired product and N-acetylated product. The mixture was treated with refluxing 1N HCl for 1 hour. The mixture was cooled, adjusted to pH 11 and then extracted with dichloromethane. The organics were concentrated to dryness. The residua was purified by column chromatography to provide 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine as a pale gold solid (0.07 g, 2%). TLC
(10% MeOH/CH2Cl2 R~0.05). m.p. 140-141°C.
CYTOI~INE INDUCTION 1N HUMAN CELLS
An in vitro human blood cell system is used to assess cytokine induction.
Activity is based on the measurement of interferon and tumor necrosis factor (a) (IFN
and TNF, respectively) secreted into culture media as described by Testerman et. al. In "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
Blood Cell Preparation for Culture Whole blood from healthy human donors is collected by venipuncture into EDTA
vacutainer tubes. Peripheral blood mononuclear cells (PBMCs) are separated from whole blood by density gradient centrifugation using Histopaque~-1077. The PBMCs are washed twice with Hanlc's Balanced Salts Solution and then are suspended at 3-4 x 106 cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
Compound Preparation The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO
concentration should not exceed a final concentration of 1% for addition to the culture wells Incubation The solution of test compound is added at 60 ~M to the first well containing RPMI
complete and serial 3 fold dilutions are made in the wells. The PBMC
suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (0.12 to 30 ~M). The final concentration of PBMC suspension is 1.5-2 X
106 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
Se aration Following incubation the plates are centrifuged for 5-10 minutes at 1000 rpm 0200 x g) at 4°C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to sterile polypropylene tubes. Samples are maintained at -30 to -70°C until analysis. The samples are analyzed for interferon (a) and for tumor necrosis factor (a) by ELISA.
Interferon (a) and Tumor Necrosis Factor (a) Analysis by ELISA
Interferon (a) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL.
Tumor necrosis factor (a) (TNF)concentration is determined using ELISA kits available from Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Pharmingen, San Diego, CA. Results are expressed in pg/mL.
The table below lists the lowest concentration found to induce interferon and the lowest concentration found to induce tumor necrosis factor for each compound.
A "*"
indicates that no induction was seen at any of the tested concentrations;
generally the highest tested concentration was 10 or 30 ~,M.
Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Number Interferon Tumor Necrosis Factor 1 0.12 3.33 2 0.37 10 3 0.04 *
4 3.33 5 0.04 0.37 6 0.12 1.11 7 0.37 8 0.04 0.12 9 0.12 3.33 IO 1.11 1.I1 11 1.11 0.04 12 I.11 13 0.37 1.11 14 0.12 0.37 1.11 3.33 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Numbex Interferon Tumor Necrosis Factor 16 3.33 10 17 0.37 0.37 18 0.37 10 19 0.12 3.33 20 0.12 3.33 21 1.11 10 22 1.11 10 23 1.11 24 * *
26 I.Il 27 1.11 *
29 1.11 30 0.37 3.33 31 3.33 3.33 32 0.01 1.11 33 0.04 0,12 34 0.01 0.04 35 0.01 0.12
5,741,908, the disclosures of whzch are incorporated by reference herein. Many halides of Formula XI are commercially available; others can be readily prepared using known synthetic methods.
Reaction Scheme I
N
~>---Rz + Hal-R~~ ~ N \ N>---RZ
/ N / N
Rn / ~X Rn / ~X
OH Q
X XI XI I
Compounds of the invention can also be prepared according to Reaction Scheme II
where R, RZ, R11, X and n are as defined above.
In step (1) of Reaction Scheme II the hydroxy group of a 1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is protected with a benzyl group. The alcohol of Formula XIII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The alkoxide is then alkylated with benzyl bromide to provide a compound of Formula XIV. The reaction can be carried out at ambient temperature. Many compounds of Formula XIII are known, see for example, Gerster, U.S. Patent 4,689,338; others can readily be prepared using known synthetic routes, see for example, Gerster et al., U.S. Patent No. 5,605,899 and Gerster, U.S. Patent No.5,175,296.
In step (2) of Reaction Scheme II a compound of Formula XIV is oxidized to provide a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XV using a conventional oxidizing agent capable of forming N-oxides . Preferably a solution of a compound of Formula XIV in a suitable solvent such as chloroform or dichloromethane is oxidized using 3-chloroperoxybenzoic acid at ambient temperature.
In step (3) of Reaction Scheme II a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XV is chlorinated to provide a 4-chloro-1H imidazo[4,5-c]quinoline of Formula XVI. Preferably a solution of a compound of Formula XV in a suitable solvent such as toluene is treated with phosphorous oxychloride at ambient temperature.
In step (4) of Reaction Scheme II a 4-chloro-1H imidazo[4,5-c]quinoline of Formula XVI is reacted with phenol to provide a 4-phenoxy-1H imidazo[4,5-c]quinoline of Formula XVII. The phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form a phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XVI.
In step (5) of Reaction Scheme II the benzyl protecting gxoup is removed from a compound of Formula XVII to provide a 4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XVIII. The reaction is preferably carried out by adding triflic acid in a controlled fashion to a solution of a compound of Formula XVII in a suitable solvent such as dichloromethane at ambient temperature.
In step (6) of Reaction Scheme II a 4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XVIII is alkylated with halide Hal-RI l to provide a 4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XIX. The alkoxide of a compound of Formula XVIII is formed by adding the alcohol to a biphasic mixture of aqueous 50%
sodium hydroxide and an inert solvent such as dichloromethane in the presence of a phase transfer catalyst such as benzyltrimethlammonium chloride. The alkoxide is then alkylated. The reaction can be carried out at ambient temperature.
In step (7) of Reaction Scheme II a 4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl ether of Formula XIX is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XII which is a subgenus of Formula I. The reaction can be carried out by combining a compound of Formula XIX with ammonium acetate and heating the resulting mixture at 150°C. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme II
N ~ N~R ( ~ ) N ~ N~ (~ O. N+ ~ N~ R
/ ~ z / N R2 ~ N
R" / X R" / X R" / IX
OH O O
XIII XIV XV
(3) \ ~ \
0 o c1 N~'Rz E (5) N / N~'R ~ N , N)-R
N N z N a R" V / IX R" / IX R" / X
OH O O
XVI I I XVI I XVI
(6) / N~ R~ ~ N / N~ R2 'N
Rn / X R" / X
O O
XIX R~1 XII
Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme III where R, R2, R11, X and n are as defined above.
In Reaction Scheme III a 4-amino-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-yl alcohol of Formula XX is alkylated with a halide of Formula XI to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XXI which is a subgenus of Formula III. The alcohol of Formula XX is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The alkoxide is then combined with the halide. The reaction can be carned out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Many tetrahydro-1H imidazo[4,5-c]quinolines of Formula XX are known, see for example, Nikolaides et al., U.S. Patent No. 5,352,784; others can be prepared using known synthetic methods, see for example, Lindstrom, U.S. Patent No. 5,693,811; the disclosures of which are incorporated by reference herein.
Reaction Scheme III
NHZ NHz N
N ~ \~Rz + Hal-R~~ ~- N \ N~-Rz N / N
R° ~X Rn ~X
OH O
XX XI XXI R~~
Compounds of the invention can be prepared according to Reaction Scheme IV
where R, R2, X and n are as defined above and R12 is a heteroaryl group which may be unsubstituted or substituted as defined infra.
In step (1) of Reaction Scheme IV a 1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is alkylated with a halide of Formula XXII to provide a 1H
imidazo[4,5-c]quinolin-1-yl ether of Formula XXIII. The compound of Formula XIII and the halide of Formula XXII are combined in a biphasic mixture of 50% aqueous sodium hydroxide and a suitable solvent such as dichloromethane in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride. The reaction can be run at ambient temperature.
In step (2) of Reaction Scheme IV a 1H imidazo[4,5-c]quinoline of Formula XXIII
is oxidized using the method of step (2) of Reaction Scheme II to provide a 1H
imidazo[4,5-c]quinoline-SN-oxide of Formula XXIV.
In step (3) of Reaction Scheme IV a 1H imidazoj4,5-c]quinoline-SN-oxide of Formula XXIV is reacted with trichloroacetyl isocyanate to provide a 1H
imidazo[4,5-c]quinolin-4-yl acetamide of Formula XXV. Preferably the isocyanate is added in a controlled fashion at ambient temperature to a solution of the SN-oxide in a suitable solvent such as dichloromethane.
In step (4) of Reaction Scheme IV a 1H imidazo[4,5-c]quinolin-4-yl acetamide of Formula XXV is hydrolyzed to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI. The hydrolysis can be carried out by conventional methods preferably by treating a solution of a compound of Formula XXV in methanol with sodium methoxide.
In step (5) of Reaction Scheme IV 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI is coupled with a halide of formula Hal-Rlz using a transition metal catalyst to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II. Preferably a compound of Formula XXVI is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile. The reaction is preferably carried out at an elevated temperature (60-80°C). The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
N~Rz '~' Hal-(CHz)1-1o- (~~~ N ~ N>-Rz / N / N
R° / ~H Rn /
XIII XXII XXIII
(CHz) CI CI (2) ~CI
NHz HN O
N W N _ (4) N W N (3) O.N+ ~ N
/ ~ Rz ~ ~ i' N~ Rz E ~ / N~ Rz ~N
Rn / X Rn / X Rn / X
O O O
XXVI (CHz)1-1o XXV (CHz)1-1o XXIV (CHz)1-1o Hal -R~z NHz N
N / \~ Rz ~N
i Rn /
O
(CHz) R~z Compounds of the invention can be prepared according to Reaction Scheme V
where R, R2, R12, X and n are as defined above and BOC is tent-butoxycarbonyl.
IS
In step (1) of Reaction Scheme V the amino group of a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI is protected with tef~t-butoxycarbonyl groups. A
compound of Formula XXVI is combined with di-tef~t-butyl dicarbonate in a suitable solvent such as N,N-dimethylformamide in the presence of 4-(dimethylamino)pyridine and triethylamine.
The reaction is carried out at an elevated temperature (80-85°C).
In step (2) of Reaction Scheme V a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVIII is coupled with a halide of formula Hal-R12 using a transition metal catalyst to provide a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XXIX.
Preferably a compound of Formula XXVIII is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile. The reaction can be carried out at ambient temperature or at an elevated temperature (40-80°C).
In step (3) of Reaction Scheme V the protecting groups are removed by hydrolysis under acidic conditions to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II. Preferably a compound of Formula XXIX
is treated with trifluoroacetic acid in a suitable solvent such as dichloromethane. The reaction can be run at ambient temperature or at a reduced temperature (0°C). The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (4) of Reaction Scheme V the alkyne bond of a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XXIX is reduced to provide a protected 1H
imidazo[4,5-c]quinolin-4-amine of Formula XXX. Preferably, the reduction is carried out using a conventional heterogeneous hydxogentation catalyst such as platinum oxide, platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol.
In step (5) of Reaction Scheme V the protecting groups of a compound of Formula XXX are removed in the same manner as in step (3) to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXXI which is a subgenus of Formula I. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme V
NHz N(BOC)z N(BOC)z N / N>-.Rz (1~ N ~ N~R (-~ N ~ N~Rz z N / N / N
X
Rn / O Rn / O Rn / O
XXVI (CHz)1-1o XXVlI! (CHz)1-1o SIX (CHz)1-1o R~z (4) (3) NH N(BOC)z NHz z N~R E (5) N ~ N N \ N~R
/ N z ~ / ~Rz / N z 'N
i Rn / p R° / x Rn / O
O
XXX! (CHz)s-12 ~( (CHz) XXVI! (CHz)1-1o R~z R~z , R~z Compounds of the invention can be prepared according to Reaction Scheme VI
where R, RZ, R~2, X and n are as defined above and CBZ is benzyloxycarbonyl.
In step (1) of Reaction Scheme VI the amino group of a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVI is protected with benzyloxycarbonyl groups.
A
compound of Formula XXVI is combined with dibenzyl dicarbonate in a suitable solvent such as N,N-dimethylformamide. The reaction can be carried out at ambient temperature or with mild heating (40°C).
In step (2) of Reaction Scheme VI a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula ~;XXII is coupled with a halide of formula Hal-R12 using a transition metal catalyst to provide a protected 1H imidazo[4,5-c]quinolin-4-amine of Formula XX~~III.
Preferably a compound of Formula XX~~II is combined with the halide in the presence of copper (I) iodide, dichlorobis(triphenylphosphine)palladium(II), and excess triethylamine in a suitable solvent such as N,N-dimethylformamide or acetonitrile. The reaction can be carried out at ambient temperature ox at an elevated temperature (40-80°C).
In step (3) of Reaction Scheme VI the protecting groups are removed by hydrolysis to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXVII which is a subgenus of Formula II. Preferably a compound of Formula XX~~III is treated with sodium methoxide in a suitable solvent such as methanol. The reaction can be run at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (4) of Reaction Scheme VI the protecting groups of a compound of Formula X~~XIII are removed by hydrogenolysis and the alkyne bond is reduced to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XX~~I which is a subgenus of Formula I. Preferably, the hydrogenolysislreduction is carried out using palladium hydroxide on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VT
NHz N(CBZ)z N(CBZ)z N~' Rz (~ N \ N~ R (~ N \ N~ R
z 2 ,N / N / N
Rn / O Rn / O Rn / O
XXVI (CHz)~-~o XXXII (CHz)~-~o XXXIII (CHz) III
R~z (4) (3) NHz NHz N N
~ ~
N N
~' y' Rz R
I I
/ N z /
'N
Rn Rn / X
/
O O
XXXI
(CHz) XXVII
3-12 (CHz) q-'o R~z R~z Compounds of the invention can~be prepared according to Reaction Scheme VII
where R, Rl, R2, X and n are as defined above.
In step (1) of Reaction Scheme VII a 2,4-dichloro-3-nitroquinoline of Formula XXXIV is reacted with an amine of Formula Rl-O-X-NHZ to provide a 2-chloro-3-nitroquinolin-4-amine of Formula XXXV. The reaction can be carried out by adding the amine to a solution of a compound of Formula XXXIV in a suitable solvent such as chloroform or dichloromethane and optionally heating. Many quinolines of Formula XXXIV are known or can be prepared using known synthetic methods (see for example, Andre et al., U.S. Patent No. 4,988,815 and references cited therein).
In step (2) of Reaction Scheme VII a 2-chloro-3-nitroquinolin-4-amine of Formula XX~~V is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula XX~~~VI.
Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be caxried out on a Parr apparatus in a suitable solvent. such as isopropyl alcohol ox toluene.
In step (3) of Reaction Scheme VII a 2-chloroquinoline-3,4-diamine of Formula XXXVI is is reacted with a carboxylic acid or an equivalent thereof to provide a 4-chloro-1H-irnidazo[4,5-c]quinoline of Formula XXXVII. Suitable equivalents to carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XXXVII. For example, triethyl orthofonnate will provide a compound where R2 is hydrogen and triethyl orthoacetate will provide a compound where RZ is methyl.
The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction. Optionally a catalyst such as pyridine hydrochloxide can be included.
Alternatively, step (3) can be carried out by (i) reacting the diamine of Formula XXXVI with an acyl halide of Formula RZC(O)Cl and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of the diamine in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. In part (ii) the product of part (i) is heated in an alcoholic solvent in the pxesence of a base.
Preferably the product of part (i) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia. Alternatively, if step (i) has been run in pyridine, step (ii) can be carried out by heating the reaction mixture after analysis indicates that step (i) is complete.
In step (4) of Reaction Scheme VII a 4-chloro-1H imidazo[4,5-c]quinoline of Formula ~~XXVII is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula I. The reaction is tamed out by heating (e.g.,125-175°C) a compound of Formula XXXVII under pressure in a sealed reactor in the presence of a solution of ammonia in an alkanol. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VII
CI O ~ CI O CI
n* n*
N ~ N.O- (~ ) ' N ~ N.O- (2) N ~ NHz I / CI I / NH I / NH
n / n / x ~ /
O O
XXXIV ~ R X~(VI I
(3) NHz CI
N / N)-- Rz E (4) N / N~- R
z ~N
Rn / X Rn / X
O O
Compounds of the invention can be prepared according to Reaction Scheme VIII
where R, Rl, R2, X and n are as defined above.
In Reaction Scheme VTII a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXXVITI is alkylated with a halide of Formula XXXIX to provide a 1H
imidazo[4,5-c]quinolin-4-amine of Formula I. The compound of Formula XXXVIII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide. The halide is then added to the reaction mixture. The reaction can be carned out at an elevated temperature 0100°C). Allcylation occurs at both the Nl and the N3 nitrogens;
however, the desired 1-isomer can be readily separated from the 3-isomer using conventional teclmliques such as column chromatography and recrystallization.
Many 1H imidazo[4,5-c]quinolin-4-amines of Formula XXXVIII are known;
others may be prepared using known synthetic methods, sae for example, Gerster, U.S.
Patent No. 5,756,747 and the references cited therein.
Reaction Scheme VIII
N>---.RZ + Hal-X-O-R~ ~ ~j / N~--Rz 'H N
R" ~ R" ~ X
O
XXXVIII XXXIX I R~
Compounds of the invention can be prepared according to Reaction Scheme IX
where R, Rl R2, X and n are as defined above.
In step (1) of Reaction Scheme IX a 4-nitrotetrazolo[1,5-a]quinolin-5-of of Formula XL is chlorinated to provide a 5-chloro-4-nitrotetrazolo[1,5-a]quinoline of Formula XLI. Conventional chlorinating agents can be used. Preferably the reaction is carried out using phosphorus oxychloride in a suitable solvent such as N,N-dimethylformamide. 4-Nitrotetrazolo[1,5-a]quinolin-5-ols of Formula XL are known or can be prepared using known synthetic methods (see for example, Gerster, et al., U.S.
Patent No. 5,741,905 and references cited therein).
In step (2) of Reaction Scheme IX a 5-chloro-4-nitrotetrazolo[1,5-a]quinoline of Formula XLI is reacted with an amine of Formula RI-O-X-NHZ to provide a 4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula XLII. The reaction can be carried out by adding the amine to a solution of a compound of Formula XLI in a suitable solvent such as dichloromethane in the presence of triethylamine.
In step (3) of Reaction Scheme IX a 4-nitrotetrazolo[1,5-a]quinolin-5-amine of Formula XLII is reduced using the method of step (2) in Reaction Scheme VII to provide a tetrazolo[1,5-a]quinolin-4,5-diamine of Formula XLIII.
In step (4 ) of Reaction Scheme IX a tetrazolo[1,5-a]quinolin-4,5-diamine of Formula XLIII is cyclized using the method of step (3) in Reaction Scheme VII
to provide a 6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline of Formula XLIV.
In step (5) of Reaction Scheme IX a 6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline of Formula XLIV is reduced to provide a 1H imidazo[4,5-a]quinolin- 4-amine of Formula I.
Step (5) involves (i) reacting a compound of Formula XLIV with triphenylphosphine and then (ii) hydrolyzing. Part (i) can be carried out by combining a compound of Formula XLIV with triphenylphosphine in a suitable solvent such as 1,2-dichlorobenzene and heating. Part (ii) involves hydrolysis of the product from part (i). The hydrolysis can be carried out by conventional methods such as heating in the presence of water or a lower alkanol optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide. The product or a pharniaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IX
NN_N O+ NN_N O+ ~N_N O+
N.O- (~ N l N.O=(2~ N,N N,0_ ~OH ~ ~C! ~ NH
R~ / R~ / Rn / X
O
XL XLI XLII
(3) NHZ ,N-N ,N-N
N ~ N~R E (5) N,N ~ I N~R E (4) N,N ~ I NHS
/ ~ 2 NH
Rn / O R~ / O R~ / X
O
I R~ XLIV R~ XL R~
III
Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme X where R, R2, R12, X and n are as defined above.
In step (1) of Reaction Scheme X a 4-amino-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XX is alkylated using the method of Reaction Scheme III with a halide of formula Hal-(CHZ)i-io-CH=CH to provide a 6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine of Formula XLV.
In step (2) of Reaction Scheme X a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XLV is coupled using the method of step (5) of Reaction Scheme IV
with a halide of Formula Hal-Rl2 to provide a 6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine of Formula XLIV which is a subgenus of Formula IV. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme X
NHz NHz NHz N \ N C7 ) N \ N C2) \ N
~Rz ~ ~~Rz ~ N ~~Rz ,N / N ~ N
X
Rn OH R" p R" O' XX XLV ~ I H2)1-10 XLVI t I Ha)1-10 R~z Compounds of the invention can be prepared according to Reaction Scheme XI
where R, Rj, R2, X and n are as defined above.
In step (1) of Reaction Scheme XI a 2,4-dihydroxy-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula XLVII is chlorinated to provide a 2,4-dichloro-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula XLVIII. Conventional chlorinating agents can be used. Preferably the reaction is carned out by combining a compound of Formula XLVII
with phosphorous oxychloride and then heating (55-65°C). Compounds of Formula XLVII are known or can be prepared using known synthetic methods (see for example Nikolaides et al,. U.S. Patent 5,352,784 and references cited therein).
In step (2) of Reaction Scheme XI a 2,4-dichloro-3-nitro-6,7,8,9-tetrayhydroquinoline of Formula XLVIII is reacted with an amine of Formula Rl-O-X-NHZ to provide a 2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula XLIX.
The reaction can be carried out by adding the amine to a solution of a compound of Formula XLVIII in a suitable solvent such as N,N-dimethylformamide and heating (55-65°C).
In step (3) of Reaction Scheme XI a 2-chloro-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula XLIX is reacted with phenol using the method of step (4) of Reaction Scheme II to provide a 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula L.
hi step (4) of Reaction Scheme XI a 2-phenoxy-3-nitro-6,7,8,9-tetrahydroquinolin-4-amine of Formula L is reduced using the method of step (2) of Reaction Scheme VII to provide a 2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of Formula LI.
In step (5) of Reaction Scheme XI a 2-phenoxy-6,7,8,9-tetrahydroquinolin-3,4-diamine of Formula LI is cyclized using the method of step (3) of Reaction Scheme VII to provide a 4-phenoxy-6,7,8,9-tetTahydro-1H imidazo[4,5-c]quinoline of Formula LII.
In step (6) of Reaction Scheme XI a 4-phenoxy-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinoline of Formula LII is aminated using the method of step (7) of Reaction Scheme II to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula III.
Reaction Scheme XI
OH O+ CI O+ CI O\
N ~ N.O- (~) N ~ N.O- (2) N ~ O_ -~ I , I ~ OH I ~ CI NH
Rn Rn n X
O
XLVII XLVIII XLIX
R~
(3) \ / \ / ~ /
NH "+
N ~ N~R E (5) N ~ 2E (4) N ~ N.O_ / I
~N ~NH ~ NH
Rn X R" X R" X
O O
LII R LI R L OI
I ~ Ra (6) NHS
N
N ~ y R2 ,N
R" X
O
III R~
The invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formulas (I), (II), (III), and (IV). These intermediate compounds have the structural Formulas (V) - (IX) and (XLIV) described in more detail below.
One class of intermediate compounds has Formula (V):
N~ N
~~ R2 N
X-O-Rl (V) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
Z 0 -R4- heteroaryl;
-R4-heterocyclyl; and -(CHZ)i-io-C=C-Rio RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)Zp -CO-N(R3)a;
-CO-Cl_lo alkyl;
-CO-O-C1_~o alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_lo alkyl;
Rlo is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)o_Z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Another class of intermediates are imidazoquinoline-4-phenoxy compounds of Formula (VI):
O
Ni N
I ~>---RZ
N
I X-O-Rl Rn wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl;
-R4-heterocyclyl; and -(CHZ)i-io-C=C-Rlo;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)z;
-CO-N(R3)z;
-CO-C~_IO alkyl;
-CO-O-C1_io alkyl;
-N3~
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_IO alkyl;
Rlo is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-to alkyl, CI_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Another class of intermediate compounds is represented by Formula (VII):
~N_N
N, 1 Z
N
NH
Rn / X
O
R
(VII) wherein: Z is NHz or NOZ;
X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_lo alkyl;
n is 0 to 4; and each R present is independently selected from the group consisting of C~_~o alkyl, C1-to alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Another class of intermediate compounds has the Formula (XLIV):
~N_N
'N ~ ~~R2 'N
R~ / X
O
"1 (XLIV) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of-.
-OH;
-halogen;
-N(R3)z~
-CO-N(R3)a;
-CO-C1_lo alkyl;
-CO-O-C1_IO alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Rd is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-to alkyl;
each Y is independently -O- or -S(O)o_2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_~o alkyl, C1_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
An additional class of intermediate compounds has the Formula (VIII):
N-(COOR7)2 N, N
( ~~ Ra N
X-O-Rl (VIII) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting o~
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(Rs)a~
-CO-N(R3)2;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C~_lo alkyl;
each Y is independently -O- or -S(O)o_2-;
nisOto4;
each R present is independently selected from the group consisting of C1_Io alkyl, C ~ _I O alkoxy, hydroxy, halogen and trifluoromethyl; and R~ is test-butyl or benzyl;
or a pharmaceutically acceptable salt thereof.
A further class of intermediates are imidazoquinoline-4-chloro compounds of the Formula (IX) >-R~
(IX) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Rl is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(Rs)z;
-CO-N(R3)z;
-CO-Ci_io alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Rø is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_z-;
n is 0 to 4; and each R present is independently selected from the group consisting of CI_Io alkyl, Ci_lo alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
As used herein, the terms "alkyl", "allcenyl" and the prefix "allc-" are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e.
cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl.
In addition, the alkyl and alkenyl portions of -X- groups can be unsubstituted or substituted by one or more substituents, which substituents are selected from the group consisting of allcyl, alkenyl, aryl, heteroaxyl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylallcyl.
The term "haloalkyl" is inclusive of groups that ai-a substituted by one or more halogen atoms, including perfluorinated groups. This is also true of groups that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.
Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, quinazolinyl, purinyl, and so on.
"Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N) and includes the fully saturated and partially unsaturated derivatives of any of the above mentioned heteroaryl groups.
Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiornorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.
The aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, allcylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, aroyloxy, aroylthio, aroylamino, alkylarninosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, alkylenesulfonylamino, arylsulfonylamino, arylalkylsulfonylamino,heteroarylsulfonylamino, heteroalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonyl, heteroarylaminocarbonylamino, herteroarylalkylaminocarbonylamino, but, in the case of heterocyclyl, alkylcarbonyl, alkenylcarbonyl, haloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, heteroarylcarbonyl, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl are not permitted.
If any other groups are identified as being "substituted" or "optionally substituted", then those groups can also be substituted by one or more of the above enumerated substituents.
Certain substituents are generally preferred. For example, preferred heteroaryl groups include 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, and 5-pyrimidine.
Preferably no R substituents are present (i.e., n is 0). Preferred RZ groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl.
One or more of these preferred substituents, if present, can be present in the compounds of the invention in any combination.
1 S The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers.
Pharmaceutical Compositions and Biological Activity Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.
The term "a therapeutically effective amount" means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg, of the compound to the subject. Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc.
The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon-a (IFN-a) and/or tumor necrosis factor-a (TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN-a, TNF-a, IL-I, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
Certain compounds of the invention have been found to preferentially induce the expression of IFN-a in a population of hematopoietic cells such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.
In addition to the ability to induce the production of cytokines, the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. The compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
Compounds of the invention also have an effect on the acquired immune response.
For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Thl) cytokine IFN-y is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds. This activity means that the compounds are useful in the treatment of diseases where upregulation of the Thl response and/or downregulation of the Th2 response is desired. In view of the ability of compounds of the invention to inhibit the Th2 immune response, the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
The immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN-a and/or TNF-a, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum;
variola, particularly variola major; rhinovirus; adenovirus; influenza; pare-influenza; HIV;
CMV; VZV; intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g. candida, aspergillus, and cryptococcal meningitis; neoplastic diseases, e.g., basal cell carcinoma, hairy cell leukemia, I~aposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases, e.g. pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis; and bacterial infections, e.g., tuberculosis, and mycobacterium avium.
Additional diseases or conditions that can be treated using the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocythaemia;
leprosy;
multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis; alopecia areata; the inhibition of keloid formation after surgery and other types of post-surgical scars. In addition, these compounds could enhance or stimulate the healing of wounds, including chronic wounds. The compounds may be useful for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV
patients.
An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-a, TNF-a,, IL-l, IL-6, IL-10 and IL-12 that is increased over the background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/lcg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mglkg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, xate of virus production, and mortality as compared to untreated control animals. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg. An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/leg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg.
The invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.
In the examples below some of the compounds were purified using semi-preparative HPLC. Two different methods were used and they are described below. Both methods used a A-100 Gilson-6 equipped with 900 Series Intelligent Interface.
The semi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriate fractions were combined and lyophilized to provide the trifluoroacetate salt of the desired compound.
Method A
Column: column Microsorb C18, 21.4 x 250 mm, 8 micron particle size, 60~ pore;
flow rata: 10 mL/min.; gradient elution from 2-95% B in 25 min., hold at 95% B
for 5 min., where A=0.1 % trifluoroacetic acid/water and B=0.1 % trifluoroacetic acid/acetonitrile; peak detection at 254 nm for triggering fraction collection.
Method B
Column: Phenomenex Capcell PakCl8, 35 x 20 mm, 5 micron particle size; flow rate: 20 mL/min.; gradient elution from 5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1 % trifluoroacetic acid/water and B=0.1 % trifluoroacetic acid/acetonitrile;
peak detection at 254 nm for triggering fraction collection.
Example 1 1-(2-{[3-(Isoquinolin-4-yl)-2-propynyl]oxy~ethyl)-1H imidazo[4,5-c]quinolin-4-amine N H~
N
N j 'N
O
N
Part A
2-(1H Imidazo[4,5-c]quinolin-1-yl)-1-ethanol (28.5 g, 0.133 mol) was added in portions over a period of 1 hour to a mixture of sodium hydroxide (240 mL of 50%), dichloromethane (240 mL), propargyl bromide (39.6 g of 80%, 0.266 mol) and benzyltrimethylammonium chloride (2.46 g, 0.013 mmol). The resulting reaction mixture was allowed to stir at ambient temperature for 16 hours at which time the reaction mixture was homogeneous. The layers were separated. The aqueous fraction was extracted with additional dichloromethane. The organic fractions were combined, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was combined with diethyl ether and the mixture was allowed to stir. An orange solid was isolated by filtration. This material was recrystallized from ethyl acetate to provide 19.8 g of 2-(1H imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether as a yellow crystalline solid, m.p. 124-126°C.
Analysis. Calculated for ClSHisN30: %C, 71.70; %H, 5.21; %N, 16.72. Found: %C, 71.85; %H, 5.25; %N, 16.90 S IH NMR (300 MHz, DMSO) 8 9.21 (s, 1 H), 8.44 (m, 1 H), 8.36 (s, 1H), 8.18 (m, 1 H), 7.71 (m, 2 H), 4.93 (t, J = 5.1 Hz, 2 H), 4.14 (d, J = 2.4 Hz, 2 H), 3.98 (t, J = S.1 Hz, 2 H), 3 .3 S (t, J = 2.2 Hz, 1 H) HRMS(ESI) calcd for C15H14N3O (MH+) 252.1137, found 252.1141 Part B
2-(1H Imidazo[4,5-c]quinolin-I-yl)ethyl (2-propynyl) ether (19.7 g, 78.4 mmol) and chloroform were combined and then cooled to 0°C. 3-Chloroperoxybenzoic acid (15.7 g of S7-86%) was added and the mixture was allowed to stir for 0.5 hour. The mixture was allowed to warm to ambient temperature by which time all material was in solution.
Analysis by thin Layer chromatography (TLC) indicated that some starting material was 1 S still present so more 3-chloroperoxybenzoic acid (two separate 4 g portions) was added.
About O.S hour after the second portion was added, TLC showed no starting material. The reaction solution was extracted with 10% sodium hydroxide. The aqueous fraction was then extracted multiple times with dichloromethane. The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide 18.5 g of I-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide as a yellow oil.
HRMS(ESI) calcd for C15Hi4N30a (MH+) 268.1086, found 268.1098 Part C
Under a nitrogen atmosphere trichloroacetyl isocyanate (15.5 g, 82.2 mmol) was added dropwise to a mixture of I-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (18.3 g, 68.5 mmol) and dichloromethane (300 mL). Vigorous carbon dioxide evolution was observed. After about 0.5 hour all of the material was in solution. The reaction solution was allowed to stir for about 1 hour at which time analysis by TLC
indicated the presence of a small amount of starting material. More tl-ichloroacetyl isocyanate (4.S g) was added. After 1 hour, TLC analysis indicated that the reaction was complete. The volatiles were removed under reduced pressure to provide N-{1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamide as a pale yellow solid.
Part D
Dichloromethane (150 mL) was added to a mixture of the solid from Part C and methanol (200 mL) and all of the material went into solution. Sodium methoxide (50 g of 25% in methanol) was added and the solution was allowed to stir at ambient temperature overnight. The resulting precipitate was isolated by filtration. The filtrate was concentrated to a volume of approximately 100 mL and a second crop of precipitate was isolated by filtration. The two crops were combined and dried in a vacuum oven at 60°C
for 16 hours to provide 16.4 g of 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. 225-227°C.
Analysis. Calculated for CISH14N4O (HZO)va~ %C, 66.53; %H, 5.40; %N, 20.69.
Found:
%C, 66.33; %H, S.I8; %N, 21.12 'H NMR (300 MHz, DMSO) 8 8.I3 (s, 1 H), 8.08 (br d, J = 7.8 Hz, 1 H), 7.62 (br d, J =
8.3 Hz, 1 H), 7.44 (br t, J = 7.6 Hz, 1 H), 7.24 (br t, J = 7.5 Hz, 1 H), 6.54 (s, 2 H), 4.81 (t, J = 5.4 Hz, 2 H), 4.14 (d, J = 2.4 Hz, 2 H), 3.93 (t, J = 5.1 Hz, 2 H), 3.38 (t, J = 2.4 Hz, 1 H) HRMS(ESI) calcd for CISHisN4O (MH+) 267.1246, found 267.1253 Part E
Under a nitrogen atmosphere 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (16 g, 60.1 mmol), di-tert-butyl dicarbonate (32.7 g, 150 mmol), triethylamine (21 mL, 150 mol), N,N-dimethylformamide (150 mL) and 4-(dimethylamino)pyridine (0.1 g) were combined and heated to 80-85°C.
After about 1 hour the mixture became homogeneous and TLC analysis indicated that very little starting material remained. The solution was heated for an additional hour. The solution was diluted with ethyl acetate and water. The layers were separated and the aqueous fraction was extracted with ethyl acetate. The organic fractions were combined, washed with water and then with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a pale orange-yellow solid. This material was triturated with diethyl ether to provide 22.6 g of N,N-(bis tent-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. 139-142°C.
Analysis. Calculated for CZSH3oN4Os: %C, 64.36; %H, 6.48; %N, 12.01. Found:
%C, 64.40; %H, 6.43; %N, 12.06 1H NMR (300 MHz, DMSO) 8 8.44 (m, 1 H), 8.35 (s, 1 H), 8.08 (m, 1 H), 7.73 (m, 2 H), 4.94 (t, J = 4.9 Hz, 2 H), 4.12 (d, J = 2.4 Hz, 2 H), 3.98 (t, J = 5.1 Hz, 2 H), 3.31 (t, J = 2.4 Hz, 1 H), 1.34 (s, 18 H) HRMS(ESI) calcd for Cz5H3~N4Os (MHO) 467.2294, found 467.2307 Part F
Under a nitrogen atmosphere N,N-(bis test-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.14 nnmol), triethylamine (0.8 mL, 5.56 mmol) and N,N-dimethylformamide (25 mL) were combined and the resulting solution was heated to 80-85°C.
Dichlorobis(triphenylphosphine)palladium(II) (0.08 g, 0.11 mol), copper(I) iodide (0.04 g, 0.21 mmol) and 4-bromoisoquinoline (0.49 g, 2.35 mmol) were added. After 3 hours analysis by high performance liquid chromatography (reverse phase with an acetonitrile/water gradient) indicated that the reaction was complete. The reaction solution was slowly poured into water with vigorous stirring. A cream colored precipitate was isolated by filtration, washed with water and then dried in a vacuum oven (<40°C) for 16 hours to provide 1.21 g of N,N-(bis tert-butoxycarbonyl)-1-(2-{[3-(isoquinolin-4-yl)-2-propynyl]oxy)ethyl)-1H
imidazo[4,5-c] quinolin-4-amine.
HRMS(EI) calcd for C34H3sNs~s (M+) 594.2716, found 594.2732 Part G
Under a nitrogen atmosphere, the material from Part F was added in portions to a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The resulting solution was allowed to stir at ambient temperature for 2 hours at which time TLC
indicated the reaction was complete. The solvents were removed under reduced pressure. The residue was diluted with dichloromethane/methanol (~4/1) and 20% sodium hydroxide. The layers were separated. The aqueous fraction was extracted with dichloromethane/methanol (~4/1). The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography to provide 0.15 g of 1-(2- f [3-(isoquinolin-4-yl)-2-propynyl]oxy~ethyl)-1H imidazo[4,5-c]quinolin-4-amine as an off white solid, m.p. dec >
205°.
'H NMR (300 MHz, DMSO) S 9.30 (s, 1 H), 8.43 (s, 1 H), 8.35 (s, 1 H), 8.19 (m, 2 H), 7.88 (br d, J = 8.0 Hz, 1 H), 7.65 - 7.80 (m, 4 H), 7.60 (d, J = 8.3 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 4.93 (t, J = 4.9 Hz, 2 H), 4.57 (s, 2 H), 4.14 (t, J = 5.1 Hz, 2 H) HRMS(ESI) calcd for Cz4Hi9Ns0 (MH+) 394.1668, found 394.1669 Example 2 1-(2-{[3-(1,3-Thiazol-2-yl)-2-propynyl]oxy}ethyl) 1H imidazo[4,5-c]quinolin-4-amine N
N
'N
O
Ni_S
Part A
Using the general method of Example 1 Part F, N,N-(bis tent-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.14 rnmol) was reacted with 2-bromothiazole to provide 0.97 g of N,N-(bis tej°t-butoxycarbonyl)-1-(2-{[3-(1,3-thiazol-2-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine as a glassy yellow solid.
MS (CI) 550, 450, 350 Part B
Using the general method of Example 1 Part G, the material from Part B Was hydrolyzed to provide 0.11 g of 1-(2-{[3-(1,3-thiazol-2-yl)-2-propynyl]oxy}ethyl)-1H
imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 157-159°C.
Analysis. Calculated for C18H~SNSOS ~ (HZO)l4: %C, 61.09; %H, 4.42; %N, 19.79.
Found:
%C, 61.06; %H, 4.37; %N, 19.53 'H NMR (500 MHz, DMSO) 8 8.18 (s, 1 H), 8.11 (d, J = 7.9 Hz, 1 H), 7.89 (dd, J
= 17.7, 2.9 Hz, 1 H), 7.62 (d, J = 7.9 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.23 (t, J
= 7.5 Hz, 1 H), 6.64 (s, 2 H), 4.83 (m, 2 H), 4.50 (s, 2 H), 4.01 (m, 2 H) HRMS(EI) calcd for CI$H~SNSOS (M''~ 349.0997, found 349.0988 Example 3 1-{2-[3-(1H Pyrazol-4-yl)propoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine N
N j 'N
O
N-N
H
Part A
N,N-(bis tent-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (2.25 g, 4.82 mmol), triethylamine (1.34 mL, 9.64 mmol), 4-iodopyrazole (1.02 g, 5.30 mmol) and anhydrous acetonitrile (40 mL) were combined.
Nitrogen was bubbled through the resulting solution for 10 minutes.
Dichlorobis(triphenylphosphine)palladium(II) (68 mg, 0.096 mol) and copper(I) iodide (37 mg, 0.192 mmol) were added and the solution was heated to 40°C.
After 1 hour analysis by HPLC (reverse phase) indicated that no reaction had taken place.
The reaction solution was heated to about 90°C. After 4 hours analysis by HPLC
indicated that the reaction was complete. The volatiles were removed under reduced pressure. The residue was purified by flash chromatography (9l1 dichloromethane/methanol) to provide 1.2 g of N,N-(bis tent-butoxycarbonyl)-1-(2- f [3-(1H pyrazol-4-yl)-2-propynyl]oxy}ethyl)-1H
imidazo[4,5-c]quinolin-4-amine as a white solid.
Part B
The material from Part A was combined with methanol (~20 rnL) and catalyst (0.25 g of 10% palladium on carbon). The mixture was hydrogenated for 4 hours at which time analysis by reverse phase LC-MS indicated reduction to the alkene and the alkane.
More catalyst (0.25 g) was added and the mixture was hydrogenated for 2 days at which time LC-MS indicated one product with no starting material or alkene. The mixture was filtered and the filtrate Was washed with methanol. The solution was concentrated to give a solid. This material was puxified by flash chromatography (9/1 dichloromethane/methanol) to provide 0.9 g of N,N-(bis text-butoxycarbonyl)-1-{2-[3-(1H pyrazol-4-yl)propoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a white solid.
1H NMR (300 MHz, DMSO) 512.43 (br s, I H), 8.48 (br d, J = 7.1 Hz, I H), 8.37 (s, 1H), 8.08 (br d, J = 7.3 Hz, 1 H), 7.72 (m, 2 H), 7.30 (br s, 1 H), 7.14 (br s, 1 H), 4.92 (t, J = 4.9 Hz, 2 H), 3.88 (t, J = 4.9 Hz, 2 H), 2.22 (t, J = 7.8 Hz, 2 H), 1.56 (m, 2 H), 1.31 (s, 18 H) MS (EI) 537, 437, 337 Part C
Under a nitrogen atmosphere trifluoroacetic acid was added to a mixture of N,N-(bis test-butoxycarbonyl)-1-{2-[3-(1H pyrazol-4-yl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 0.93 mmol) and dichloromethane (5 mL). The resulting solution was allowed to stir for 16 hours at which time analysis by LC-MS
indicated that the reaction was complete. The solvents were removed under reduced pressure.
The residue was dissolved in ethyl acetate (~10 mL) and triethylamine (2 mL) was added. A
precipitate formed and the reaction mixture was allowed to stir for 2 hours.
The solid was isolated by filtration and then it was purred by flash chromatography (9/1 to dichloromethane/methanol) to provide 0.18 g of 1- f 2-[3-(1H pyrazo-4-lyl)propoxy]ethyl}-1H imidazo[4,5-a]quinolin-4-amine as a white solid, m.p.
163-169°C.
Analysis. Calculated for ClBHZON60 ~ (CF3COZH)o,15 %C, 62.18; %H, 5.75; %F, 2.42; %N, 23.77. Found: %C, 61.86; %H, 5.70; %F, 2.52; %N, 23.44 1H NMR (300 MHz, DMSO) 8 12.50 (br s, 1 H), 8.20 (s, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.15 - 7.40 (br ' s, 2 H), 7.00 (br s, 2 H), 4.81 (t, J = 4.6 Hz, 2 H), 3.84 (t, J = 4.6 Hz, 2 H), 3.34 (t, J = 6.1 Hz, 2 H), 2.27 (t, J = 7.6 Hz, 2 H), 1.60 (m, 2 H) Example 4 1-[2-(3-Pyrimidin-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine N
N
N
~\
Part A
Under a nitrogen atmosphere dibenzyl Bicarbonate (50 g, 174 mmol) was added to a mixture of 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (16.4 g, 61.6 mmol) and anhydrous N,N-dimethylformamide (200 mL). The reaction mixture was allowed to stir at ambient temperature for 16 hours and the reaction mixture turned homogeneous. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted with ethyl acetate. The organic fractions were combined, washed with water, washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a semisolid. This material was triturated with diethyl ether to provide 27.4 g of N,N-(bis benzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a white solid.
Part B
N,N-(Bis benzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.00 g, 1.87 mmol), anhydrous acetonitrile (10 mL), triethylamine (0.68 mL, 4.86 mmol), and 2-bromopyrimidine (0.327 g, 2.06 mmol) were combined.
Under a nitrogen atmosphere copper (I) iodide (0.014 g) and dichlorobis(triphenylphosphine)palladium(II) (0.026 g) were added. The reaction mixture was maintained at ambient temperature for 15 minutes and then heated to 80°C for 1.5 hours. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was separated and then extracted with ethyl acetate until no UV materials remained in the aqueous layer. The organic fractions were combined, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtexed and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with 98/2 ethyl acetate/methanol to provide 0.68 g of a mixture of the mono and di benzyloxycarbonyl protected 1- f 2-[(3-pyrimidin-2-ylprop-2-ynyl)oxy]ethyl}-1H
imidazo [4, 5-c] quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) 8 8.78 (d, J= 4.9 Hz, 2 H), 8.49 (m, 1 H), 8.45 (s, 1 H), 8.12 (m, 1 H), 7.73-7.78 (m, 2 H), 7.50 (t, J= 4.9 Hz, 1 H), 7.23-7.28 (m, 6 H), 7.14-7.17 (m, 4 H), 5.20 (s, 4 H), 5.02 (t, J= 5.0 Hz, 2 H), 4.51 (s, 2 H), 4.10 (t, J=
5.0 Hz, 2 H), MS (CI) for C35Hz8N505 m/z 613 (MHO), 569, 461, 345 Part C
The material from Part B, palladium~hydroxide (0.25 g of 20% on carbon) and methanol (25 rnL) were combined and hydrogenated at 47 psi (3.3 Kglcmz) for 3 hours at ambient temperature. The reaction mixture was allowed to stand over the weekend at which time analysis indicated the presence of some product with protected amine groups.
The reaction mixture was filtered to remove the catalyst and the filtrate was treated with sodium methoxide (1 mL of 25% in methanol) for about 16 hours to remove the protecting groups. The reaction mixture was concentrated under reduced pressure. 'The residue was purified by column chromatography eluting with 1/1/1 ethyl acetate/methanol/hexane to provide 0.235 g of a solid. This material was stirred with hot toluene and then filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure. The residue was triturated with isopropanol and ethyl acetate to provide 61 mg of 1-[2-(3-pyrimidin-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 126-127°C.
Analysis. Calculated for Cl9HzoN60: %C, 65.5; %H, 5.79; %N, 24.12. Found: %C, 65.65; %H, 5.78; %N, 24.15 IH NMR (300 MHz, DMSO-d6) b 8.66 (d, J= 4.7 Hz, 2 H), 8.14 (s, 1 H), 8.08 (d, J= 8.0 Hz, 1 H), 7.62 (d, J= 8.2 Hz, 1 H), 7.45 (t, J= 7.0 Hz, 1 H), 7.24-7.31 (m, 2 H), 6.58 (s, 2 H), 4.77 (t, J = 4.7 Hz, 2 H), 3 . 84 (t, J = 4. 5 Hz, 2 H), 3 .42 (t, J = 6.2 Hz, 2 H), 2. 82 (t, J =
7.5 Hz, 2 H), 1.89 (rn, 2H) IR (KBr) 3302, 3187, 2868, 1637, 1561, 1418, 1139 cm 1 HRMS (EI) calcd for Cl~HzoN~O (M+) 348.1699, found 348.1700.
Example 5 1-[2-(3-Pyridin-4-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHZ
N
N
O
N
Part A
Using the general method of Example 4 Part B N,N-(bis benzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (2.00 g, 3.74 mmol) was reacted with 4-bromopyridine (0.8 g, 4.12 mmol) to provide 1.47 g of a mixture of mono and di benzyloxycarbonyl protected 1-{2-[(3-pyridin-4-ylprop-2-ynyl)oxy]ethyl}-imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) 8 8.46 (m, 3 H), 8.43 (s, 1 H), 8.12 (m, 1 H), 7.72-7.76 (m, 2 H), 722-7.28 (m, 5 H), 7.14-7.17 (m, 6 H), 5.18 (s, 4 H), 5.00 (t, J=
5.0 Hz, 2 H), 4.45 (s, 2 H), 4.12 (t, J= 4.0 Hz, 2 H) MS (CI) for C36H29NSO5 m/z 612 (MH+), 568, 344 Part B
Palladium hydroxide (0.57 g of 20% on carbon) was added to a solution of the material from Part A in methanol (~10 mL). The mixture was hydrogenated at 50 psi (3.5 I~g/cm2) for 5 hours. More catalyst (0.07 g) was added and the hydrogenation was continued for another hour. The reaction mixture was filtered to remove catalyst and the filter cake was thoroughly washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 6/3/1 ethyl acetate/methanol/hexane and then triturated with diethyl ether to provide a solid.
This material was further purified by column chromatography eluting with 9/1 dichloromethane/methanol with ammonium hydroxide to provide 0.20 g of 1-[2-(3-pyridin-4-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p.
162°C.
Analysis. Calculated for CZOH21N50: %C, 69.14; %H, 6.09; %N, 20.16. Found: %C, 69.17; %H, 6.09; %N, 19.79 1H NMR (300 MHz, DMSO-d6) 8 8.29 (dd, J= 2.6, 1.8 Hz, 2 H), 8.18 (s, 1 H), 8.11 (d, J
= 8.2 Hz, 1 H), 7.62 (dd, J= 7.1, 1.4 Hz, 1 H), 7.45 (dt, J= 6.9, 1.7 Hz, 1 H), 7.23 (dt, J=
6.7, 1.3 Hz, 1 H), 6.91 (dd, J= 4.4, 1.3 Hz, 2 H), 6.62 (s, 2 H), 4.81 (t, J=
5.0 Hz, 2 H), 3.82 (t, J= 5.0 Hz, 2 H), 2.38 (t, J= 7.6 Hz, 2 H), 3.28 (t, J= 6.1 Hz, 2 H), 1.64 (m, 2 H) IR (KBr) 3418, 3100, 1698, 1595, 1531, 1094, 767 cm 1 HRMS (EI) calcd for C2oHz1N50 (M+) 347.1746, found 347.1747 Example 6 1-[2-(3-Pyridin-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHa N
N / y O
N
Part A
Under a nitrogen atmosphere N,N-(bisbenzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-IH imidazo[4,5-c]quinolin-4-amine (2.5 g, 4.68 mmol), anhydrous acetonitrile (20 mL), triethylamine (1.7 mL, 12.2 mmol), and 2-bromopyridine (0.5 mL, 5.14 mmol) were combined and the resulting homogeneous mixture was heated to 40°C.
Copper (I) iodide (0.036 g) and dichlorobis(triphenylphosphine)palladium(II) (0.066 g) were added. After 18.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic fraction was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with 1/9 hexane/ethyl acetate to provide 0.9 g of a mixture of mono and di benzyloxycarbonyl protected 1-{2-[(3-pyridin-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) & 8.50-8.54 (m, 2 H), 8.44 (s, 1H), 8.12 (m, 1 H), 7.71-7.77 (m, 3 H), 7.34-7.39 (m, 1 H), 7.23-7.29 (m, 7 H), 7.14-7.17 (m, 4 H), 5.19 (s, 4 H), 5.01 (t, J = 4.6 Hz, 2 H), 4.46 (s, 2 H), 4.10 (t, J = 4.8 Hz, 2 H) MS (CI) for C36H29N5~5 m/Z 612 (MH+), 568, 460 Part B
Palladium hydroxide (0.776 g of 20% on carbon) was added to a solution of the material from Part A in methanol. The mixture was hydrogenated at 45 psi (3.2 Kg/cm2) for 2.5 hours. The reaction mixture was filtered to remove catalyst and the filter cake was thoroughly washed with methanol. The filtrate was concentrated under reduced pressure to provide a glassy solid. This material was triturated with diethyl ether and hexane containing a small amount of toluene. The resulting powder was isolated by filtration and dried at 78°C overnight in a vacuum oven. This material was further purified by column chromatography eluting with 9/1 dichloromethane/methanol with a few drops of ammonium hydroxide to provide 25 mg of 1-[2-(3-pyridin-2-ylpropoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 138-140°C.
Analysis. Calculated for C2oHz1Ns0~(Hz0)ls: %C, 68.43; %H, 6.15; %N, 19.95.
Found:
%C, 68.47; %H, 5.95; %N, 19.63 'H NMR (300 MHz, DMSO-d6) 8 8.41 (d, J= 4.4 Hz, 1 H), 8.16 (s, 1 H), 8.10 (d, J= 7.7 Hz, 1 H), 7.63 (d, J= 8.4 Hz, 1 H), 7.54 (dt, J= 9.7, 1.7 Hz, 1 H), 7.43 (t, J= 7.3 Hz, 1 H), 7.24 (t, J= 7.5 Hz, 1 H), 7.13 (t, J= 5.5 Hz, 1 H), 6.93 (d, J= 7.6 Hz, 1 H), 6.59 (s, 2 H), 4.77 (t, J= 5.1 Hz, 2 H), 3.82 (t, J= 5.5 Hz, 2 H), 3.34 (t, J= 6.3 Hz, 2 H), 2.57 (t, J=
7.3 Hz, 2 H), 1.75 (m, 2 H) IR (KBr) 3361, 3302, 3188, 1638, 1526, 1119, 751 cm 1 HRMS (EI) calcd for CZOH21N50 (M+) 347.1746, found 347.1747.
Example 7 1-{2-[3-(1,3-Thiazol-2-yl)propoxy]ethyl}-1H irnidazo[4,5-c]quinolin-4-amine NHa N
N ~ N
O
Ni S
Part A
Under a nitrogen atmosphere N,N-(Bisbenzyloxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (3.25 g, 6.08 mmol), anhydrous N,N-dimethylformamide (15 mL), triethylamine (2.2 mL, 15.8 mmol) and 2-bromothiazole (0.6 mL, 6.69 mmol) were combined and heated to 80°C.
Copper (I) iodide (0.046 g) and dichlorobis(triphenylphosphine)palladium (II) (0.085 g) were added. After 2 hours the reaction was stopped and the solvent was removed. The crude product was purifted by column chromatography eluting with 8/2 ethyl acetate/hexane to provide ~2 g of a mixture of mono and di benzyloxycarbonyl protected 1-(2-{[3-(1,3-thiazol-2-yl)prop-2-ynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) 8 8.47-8.50 (m, 1 H), 8.44 (s, 1 H), 8.11 (m, 1 H), 7.89 (d, J= 3.2 Hz, 1 H), 7.85 (d, J= 3.3 Hz, 1 H), 7.31-7.77 (m, 2 H), 7.23-7.28 (m, 6 H), 7.14-7.17 (m, 4 H), 5.20 (s, 4 H), 5.00 (t, J= 5.0 Hz, 2 H), 4.52 (s, 2 H), 4.09 (t, J= 5.5 Hz, 2 H) MS (CI) for C24H2~NSOSS m/z 618 (MH+), 475, 466 Part B
Palladium hydroxide (~2 g of 20% on carbon) was added to a solution of the material from Part A in methanol. The mixture was hydrogenated at 45 psi (3.2 Kg/cm2) for 3 hours. More catalyst (0.3 g) was added twice and the hydrogenation was continued for a total of ~25 houxs. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to provide 1.3 g of mono benzyloxycarbonyl protected 1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H
imidazo[4,5-c]quinolin-4-amine. This material was combined with methanol (5 mL) and sodium methoxide (25 mL of 25% in methanol). The resulting mixture was stirred for 3 days.
The reaction mixture was concentrated under reduced pressure and then purified by column chromatography. The resulting material was triturated with diethyl ether and dried to provide 0.28 g of 1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 134-135°C.
Analysis. Calculated for C18HI9NSOS: %C, 61.17; %H, 5.42; %N, 19.81. Found:
%C, 61.20; %H, 5.23; N, %I9.51 1H NMR (300 MHz, DMSO-d6) 8 8.16 (s, 1 H), 8.10 (d, J= 8.4 Hz, 1 H), 7.63 (m, 2 H), 7.51 (d, J= 3.3 Hz, 1 H), 7.43 (t, J= 7.1 Hz, 1 H), 7.23 (t, J= 8.0 Hz, 1 H), 6.58 (s, 2 H), 4.79 (t, J= 4.7 Hz, 2 H), 3.84 (t, J= 4.8 Hz, 2 H), 3.4 (t, J= 6.0 Hz, 2 H), 2.86 (t, J= 7.8 Hz, 2 H), 1.83 (m, 2 H) IR (KBr) 3458, 3358, 3295, 3191, 1640, 1538, 1121, 752 cm 1 HRMS (EI) calcd for CI$H1~NSOS (M+) 353.1310, found 353.1308.
Example 8 1-[2-(3-Pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine Bis(trifluoroacetate) N
N
'N
O
N
Part A
Under a nitrogen atmosphere N,N-(bis text-butyoxycabonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.75 g, 3.75 mmol), 3-iodopyridine (0.85 g, 4.13 mmol), triethylamine (1.4 mL) and acetonitrile (15 mL) were combined and then heated to 60°C. Copper (I) iodide (0.03 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.05 g, 0.075 mmol) were added.
The reaction was complete after 30 minutes. The solvents were removed under reduced pressure. The crude product was purified by column chromatography (silica gel eluting first with dichloromethane and then with 98/2 dichloromethane/methanol) to provide 1.26 g of a mixture of di-BOC protected and unprotected 1-{2-[(3-pyridin-3-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) b 8.54 (bs, 1 H), 8.44-8.48 (m, 2 H), 8.4 (s, 1 H), 8.06 (m, 1 H), 7.69-7.73 (m, 2 H), 7.54 (d, J= 7.6 Hz, 1 H), 7.35 (m, 1 H), 4.99 (t, J= 4.8 Hz, 2 H), 4.40 (s, 2 H), 4.09 (t, J= 5.0 Hz, 2 H), 1.31 (s, 18 H), MS (CI) for C3pH33N505 ~z 544 (MH+), 444, 344 Part B
A solution of the material from Part A in methanol was combined with catalyst (0.7 g of 10% palladium on carbon) and the mixture was hydrogenated at 45 psi (3.2 Kg/cm2) for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide 0.67 g of a mixture of di-BOC
protected and unprotected 1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine.
iH NMR (300 MHz, DMSO-d6) ~ 8.50 (d, J= 7.3 Hz, 1 H), 8.39-8.486 (m, 2 H), 8.29 (s, 1 H), 8.07 (d, J= 8.4 Hz, 1 H), 7.71-7.75 (m, 2 H), 7.46 (d, J= 8.5 Hz, 1 H), 7.31 (m, 1 H), 4. 94 (t, J = 4. 6 Hz, 2 H), 3 . 8 8 (t, J = 5 . 0 Hz, 2 H), 3 . 3 2 (t, J
= 5 . 9 Hz, 2 H), 2. 3 8 (t, J =
7.5 Hz, 2 H), 1.63 (m, 2 H), 1.30 (s, 18 H), MS (CI) for C3oH3~N505 m/z 548 (MH+), 448, 348 Part C
Under a nitrogen atmosphere the material from Part B was combined with anhydrous dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at ambient temperature for 1 hr. The solvents were removed under reduced pressure. The residue was triturated with diethyl ether, isolated by filtration and then dried in a vacuum oven to provide a tan solid. This material was recrystallized first from isopropyl alcohol and then from dichloromethane/methanol to provide 0.40 g of 1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine bis(trifluoroacetate), m.p.
134-136°C.
Analysis. Calculated for CZpH21N5~~(C2~'3~2)2~(H2~)1/2~ %C, 50.08; %H, 4.23;
%N, 12.03. Found: %C, 49.87; %H, 3.82; %N, 12.16 1H NMR (300 MHz, DMSO-d6) b 9.00-9.25 (bs, 2 H), 8.50 (s, 2 H), 8.37 (d, J=
7.7 Hz, 1 H), 7.82 (d, J= 7.4 Hz, 1 H), 7.73-7.75 (m, 2 H), 7.55-7.58 (m, 2 H), 4.90 (t, J= 4.9 Hz, 2 H), 3.86 (t, J= 4.8 Hz, 2 H), 3.35 (t, J= 6.1 Hz, 2 H), 2.49 (t, J= 7.0 Hz, 2 H), 1.67 (m, 2 H) IR (KBr) 3421, 3212, 2885, 1699, 1199, 1120, 720 cm 1 HRMS (EI) calcd fox CZOHaiNsO (M~ 347.1746, found 347.1743.
Example 9 1-[2-(3-Pyrimidin-5-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine N
N
'N
O
(~ \
NON
Part A
Using the general method of Example 8 Part A, except that the reaction temperature was raised to 80°C, N,N-(bis tef°t-butyoxycabonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (2.5 g, 5.36 mmol) was coupled with 5-bromopyrimidine (0.94 g, 5.89mmo1) to provide 1.59 g of N,N-(bis tert-butoxycarbonyl)-1-{2-[(3-pyrimidin-5-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c] quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) ~ 9.19 (s, 1 H), 8.64 (s, 2 H), 8.44-8.47 (m, 1 H), 8.40 (s, 1 H), 8.02-8.06 (m, 1 H), 7.68-7.72 (m, 2 H), 4.99 (t, J= 5.0 Hz, 2 H), 4.43 (s, 2 H), 4.10 (t, J= 5.2 Hz, 2 H), 1.32 (s, 18 H) MS (CI) for C29H32N(OS m/z 545 (MH+), 445, 345 Part B
A methanol solution of the material from Part A was combined with catalyst ( 5%
platinum on carbon, palladium hydroxide and 10% palladium on carbon were used in succession) and hydrogenated to provide 0.60 g of N,N-(bis tent-butoxycarbonyl)-1-[2-(3-pyrimidin-5-ylpropoxy)ethyl]-1H irnidazo[4,5-c]quinolin-4-amine.
1H NMR (300 MHz, DMSO-d6) S 8.98 (s, 1 H), 8.48-8.52 (m, 1 H), 8.45 (s, 2 H), 8.40 (s, 1 H), 8.06-8.09 (m, 1 H), 7.70-7.74 (m, 2 H), 4.94 (t, J= 5.1 Hz, 2 H), 3.89 (t, J= 5.0 Hz, 2 H), 3.34 (m, 2 H), 2.34 (t, J= 7.3 Hz, 2 H), 1.64 (m, 2 H), 1.29 (s, 18 H) MS (CI) for C29H36N6Os m/z 549 (MH+), 449, 349 Part C
Using the general method of Example 8 Part C, the material from Part B was hydrolyzed to provide 0.14 g of 1-[2-(3-pyrimidin-5-ylpropoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine, m.p. 159-161°C.
Analysis. Calculated for C]9H20N6~~(C2HF3O2)1/10~(H20)1/4~ %C, 63.27; %H, 5.70; %N, 23.06. Found: %C, 63.47; %H, 5.35; %N, 22.88 1H NMR (300 MHz, DMSO-d6) 8 8.98 (s, 1 H), 8.48 (s, 2 H), 8.19 (s, 1 H), 8.15 (d, J=
8.0 Hz, 1 H), 7.63 (d, J= 8.6 Hz, 1 H), 7.46 (t, J= 6.0 Hz, 1 H), 7.28 (t, J=
8.4 Hz, 1 H), 6.79 (s, 2 H), 4. 81 (t, J = 4. 8 Hz, 2 H), 3. 84 (t, J = 5.1 Hz, 2 H), 3.3 5 (t, J = 6.0 Hz, 2 H), 2.43 (t, J= 7.4 Hz, 2 H), 1.69 (m, 2 H) IR (KBr) 3310, 3132, 1647, 1582, 1531, 1403, 1117 crri 1 HRMS (EI) calcd for CI~HZON60 (M+) 348.1699, found 348.1695 Example 10 1-{2-[(1-Benzyl-1H 1,2,3-triazol-4-yl)methoxy]ethyl}-1H irnidazo[4,5-c]quinoline-4-amine hydrochloride 1-{2-[(1-Benzyl-1H 1,2,3-triazol-5-yl)methoxy]ethyl}-1H imidazo[4,5-c]quinoline-4-amine hydrochloride NHS NN~
N
N + N
N / N~ / N
'N-N N'N
Part A
N,N-(Bis benzyloxycaxbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.5 g, 2.81 mmol), anhydrous toluene (30 mL) and benzyl azide (1.3 mL, 9.12 mmol) were combined and heated in an oil bath at 100°C for 28 hours. The reaction mixture was concentrated under reduced pressure to provide crude product as a brown oil.
Part B
Sodium methoxide (2.19 mL of 25% in methanol, 9.52 mmol) was added to a mixture of the material from Part A and methanol (20 mL). The reaction mixture was allowed to stir at ambient temperature overnight and then it was concentrated under reduced pressure to provide a dark oil. The oil was purified by column chromatography eluting with 5% methanol in dichloromethane to provide a light yellow oil. The oil was treated with 1.0 M hydrogen chloride to provide a pink solid. This solid was recrystallized twice from acetonitrile and the resulting product was dried in a vacuum oven at 80°C for 2 hours to provide 0.12 g of a mixture of the regio isomers of the desired product i.e. a mixture containing both 1-{2-[(1-benzyl-1H 1,2,3-triazol-4-yl)methoxy]ethyl}-imidazo[4,5-c]quinoline-4-amine hydrochloride and 1-{2-[(1-benzyl-1H 1,2,3-triazol-5-yl)methoxy]ethyl}-1H imidazo[4,S-c]quinoline-4-amine hydrochloride, as a light pink crystalline solid, m.p. 209-211 °C.
Analysis: Calculated for CZZHZIN~O ~ 0.951 HCl ~ 0.615 HZO: %C, S9.3S; %H, S.2S; %N, 22.02; Found: %C, 59.46; %H, 5.16; %N, 22.0S.
S IH-NMR (300 MHz, DMSO-d6) ~ 9.00 (br s, 2 H), 8.46 (s, 1 H), 8.28 (d, J=7.8 Hz, 1 H), 7.98 (s, 1 H), 7.83 (br d, J=7.8 Hz, 1 H), 7.71 (br t, J=7.8 Hz, 1 H), 7.50 (br t, J=7.7 Hz, 1 H) 7.20-7.40 (rn, 5 H), S.S2 (s, 1.88 H), 5.39 (s, 0.12 H), 4.88 (t, J=4.9 Hz, 2 H), 4.52 (s, 2 H), 3.95 (t, J=4.9 Hz, 1.88 H), 3.87 (t, J=S.1 Hz, 0.12 H) IR (KBr) 3152, 2638, 1672, 1605, 1126 cm 1 HRMS (EI) calcd for C22H21N7O (M+) 399.1808, found 399.1802.
Example 11 1-[2-({1-[(Phenylsulfanyl)methyl]-1H 1,2,3-triazol-4-yl}methoxy)ethyl]-1H
imidazo[4,S-c]quinoline-4-amine 1S 1-[2-({1-[(Phenylsulfanyl)methyl]-1H 1,2,3-triazol-S-yl}methoxy)ethyl]-1H
imidazo[4,S-c]quinoline-4-amine NHa NHz N
N ~ N~ + N
i N ~ N
/ N
N
,NINA N;N S
S
l~
Part A
Under a nitrogen atmosphere, anhydrous toluene (20 mL), N,N-(bis ter~t-butoxycarbonyl)-1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,S-c]quinolin-4-amine (1.0 g, 2.1 mmol) and azidomethyl phenylsulfide (0.61 mL, 4.3 mmol) were combined and heated at reflux for 72 hours. The reaction mixture was allowed to cool to ambient temperature and then it was concentrated under reduced pressure to provide a brown oil.
This material was purified by column chromatography eluting with 80/20 ethyl acetate/hexane to provide 0.95 g of product as a clear oil.
MS (CI) for C32H3~N~OSS mlZ 632 (MH+), 532, 458, 432 Part B
A solution of the material from Part A in anhydrous dichloromethane (15 mL) was added to a mixture of trifluoroacetic acid (7.4 mL) and anhydrous dichloromethane (6 mL) which had been chilled to 0°C. The reaction mixture was kept in an ice bath for 2 hours and then allowed to warm to ambient temperature. After 6 hours the reaction mixture was washed with 20% sodium hydroxide. The aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a green oil. The oil was purified by column chromatography eluting with 5%
methanol in dichloromethane to provide a green crystalline solid. This material was xecrystallized from isopropanol to provide 0.12 g of a mixture of the regio isomers of the desired product i.e. a mixture containing both 1-[2-({1-[(phenylsulfanyl)methyl]-1H 1,2,3-triazol-4-yl]methoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine and 1-[2-( f 1-[(phenylsulfanyl)rnethyl]-1H 1,2,3-triazol-5-yl}methoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine, as an off white solid, m.p. 182-184°C.
Analysis: Calculated for CZZHZ1N~OS: %C, 61.24; %H, 4.91; %N, 22.72; Found:
%C, 60.94; %H, 4.94; %N, 22.3 8.
1H-NMR (300 MHz, DMSO-d6) 8 8.00-8.20 (m, 2 H), 7.87 (s, 0.8 H), 7.60-7.65 (m, 1 H), 7.52 (s, 0.2 H), 7.40-7.50 (m, 1 H), 7.20-7.40 (m, 6 H), 6.65 (s, 2 H), 5.87 (s, 1.6 H), 5.65 (s, 0.4 H), 4.83 (br t, J=4.6 Hz, 0.4 H), 4.78 (br t, J=4.9 Hz, 1.6 H), 4.49 (s, 1.6 H), 4.42 (s, 0.4 H), 3.80-3.90 (m, 2H) IR (KBr) 3322, 3205, 1643, 1527, 1095 cm 1 HRMS (EI) calcd for CZZHaiN70S (M~ 431.1528, found 431.1522.
Example 12 1-[2-(Benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHS
N
N
'N
O
~O
Part A
Benzyltrimethylammonium chloride (0.436 g) and propargyl bromide (6.07 mL of 80%) were added with stirring to a mixture of dichloromethane (185 mL) and aqueous sodium hydroxide (60 mL of 50%). 2-(1H Imidazo[4,5-c]quinolin-1-yl)ethanol (10.0 g, 46.9 mmol) was added to the resulting solution. The reaction mixture was stirred at ambient temperature for 21 hours at which time analysis by HPLC showed that starting material remained. An additional equivalent of propargyl bromide was added and the reaction mixture was stirred for an additional 46 hours. Water was added to the reaction mixture and the layers were separated. The aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water and with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark brown solid. This material was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane) to provide 7.0 g of 1-[2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline as a brownish solid.
Part B
Under a nitrogen atmosphere, 1-[2-(propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline (1.0 g, 4.21 rnmol), triethylamine (1.53 mL, 10.96 mmol) and anhydrous acetonitrile (20 mL) were combined and then heated to 60°C. 2-Iodophenol (1.02 g, 4.63 mmol), copper (I) iodide (0.08 g) and dichlorobis(triphenylphosphine)palladium(II) (0.148 g) were added. After 4 hours analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was filtered through a layer of CeIite~ filter aid to remove the catalysts. The filtrate was concentrated under reduced pressure to provide an oil. This material was purified by flash chromatography (silica gel eluting with 3% methanol in dichloromethane) to provide 0.91 g of 1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazoj4,5-c]quinoline as a yellow oil.
Part C
3-Chloroperoxybenzoic acid (0.65 g) was added in portions over a period of 5 minutes to a solution of the material from Part B in chloroform (15 mL). The progress of the reaction was monitored by TLC. More 3-chloroperoxybenzoic acid (2 X 0.2 g) was added. After 1.5 hr the reaction mixture was washed twice with aqueous sodium bicarbonate, back extracted with chloroform, washed with brine and then concentrated under reduced pressure to provide 1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H
imidazo[4,5-c]quinoline-SN-oxide. The material was stored under nitrogen at a reduced temperature over the weekend.
Part D
Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.60 g, 3.18 mmol) was slowly added via a syringe to a solution of the N-oxide from Part C in dichloromethane (15 mL). The volatiles were removed under reduced pressure to provide 2,2,2-trichloro-{1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-yl}acetamide as a tan solid. This material was dissolved in methanol (15 mL). Sodium methoxide (2.04 mL, 9.01 mmol) was added and the resulting solution was allowed to stir for 48 hours. A white precipitate was isolated by filtration and then recrystallized from acetonitrile to provide 0.22 g of 1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine as off white needles, m.p. 201-203°C.
Analysis: Calculated for CZIH1gN402: %C, 70.38; %H, 5.06; %N, 15.63; Found:
%C, 70.36; %H, 4.80; %N 15.51.
1H-NMR (300 MHz, DMSO-d6) 8 8.16 (s, 1H), 8.06 (d, J= 7.8 Hz, 1H), 7.49-7.62 (m, 3H), 7.42 (m, 1H), 7.16-7.31 (m, 3H), 6.76 (s, 1H), 6.58 (br s, 2H), 4.83 (t, J= 5.4 Hz, 2H), 4.61 (s, 2H), 3.97 (t, J = 5.1 Hz, 2H) IR (KBr) 3455, 3069, 1583, 1530, 1397, 1254, 1088 HRMS (EI) calcd for CZ1HI$N4O2 (M+) 358.1430, found 358.1428.
Example 13 1-[2-(Pyridin-3-ylmethoxy)ethylj-1H imidazo[4,5-c]quinolin-4-amine Hydrochloride N
N
'N
O
N
Part A
Under a nitrogen atmosphere, sodium hydride (16.88 g of 60% in mineral oil, mmol) was added in portions to a solution of 2-(1H imidazo[4,5-c]quinolin-1-yl)ethanol (60.0 g, 281 mmol) in anhydrous N,N-dimethylformamide (600 mL). The alkoxide was allowed to stir for about 1.5 hours. Benzyl bromide (50.2 mL, 422 mmol) was slowly added over a period of about 30 minutes. The reaction mixture was allowed to stir at ambient temperature overnight. Solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed several times with water, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1-[2-(benzyloxy)ethyl]-1H imidazo[4,5-c]quinoline as a dark oil.
1H-NMR (300 MHz, DMSO-d6) S 9.22 (s, 1H), 8.42 (s, 1H), 8.40 (s, 1H), 8.17 (m, 1H), 7.69 (m, 2H), 7.10-7.22 (m, 5H), 4.95 (t, J= 5.1 Hz, 2H), 4.45 (s, 2H), 3.93 (t, J= 5.1 Hz, 2H) MS (CI) for C19H17N3O IT1~Z 304 (MH+), 214 Part B
3-Chloroperoxybenzoic acid (69.36 g of 77% maximum) was added in portions over a period of 15 minutes to a solution of 1-[2-(benzyloxy)ethyl]-1H
imidazo[4,5-c]quinoline (85.36 g, 281 mmol) in chloroform (800 mL). After 1 hour analysis by TLC
(10% methanol in dichloromethane) showed that the reaction was complete. The reaction mixture was washed with saturated sodium bicarbonate (twice), washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a solid.
The solid was slurried with diethyl ether and then isolated by ftltration to provide 1-[2 (benzyloxy)ethyl]-1H imidazo[4,5-c]quinoline-5N-oxide as a dark yellow solid.
Part C
Phosphorous oxychloride (12.84 mL, 138 mmol) was slowly added to a mixture of 1-[2-(benzyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (40.0 g, 125 mmol) and anhydrous toluene (600 mL). The reaction mixture was allowed to stir for about minutes and then the volatiles were removed under reduced pressure. The resulting red oil was dissolved in dichloromethane, washed twice with saturated sodium bicarbonate, and then concentrated under reduced pressure. An attempt to recrystallize the residue from ethyl acetate resulted in a gum. The material was taken up in ethyl acetate (500 mL) and then combined with triethylamine (25.34 g, 250 mmol). The solution was chilled in an ice bath and the precipitate was isolated by filtration. The material changed back into an oil shortly after filtration. The oil was taken up in dichloromethane, combined with the filtrate and then concentrated under reduced pressure to provide an oil. This material was partitioned between dichloromethane and 15% sodium hydroxide. The organic fraction was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide an oil. This oil was further purified by flash chromatography (silica geI eluting fixst with dichloromethane, then with 2% methanol in dichloromethane and then with 5% methanol in dichloromethane) to provide ~21 g of 1-[2-(benzyloxy)ethyl]-4-chloro-1H imidazo[4,5-c]quinoline.
1H-NMR (300 MHz, DMSO-d6) ~ 8.47 (s, 1H), 8.42 (dd, J= 8.3, 1.5 Hz, 1H), 8.08 (dd, J
= 8.3, 1.5 Hz, 1H), 7.72 (m, 2H), 7.04-7.17 (m, SH), 4.96 (t, J= 5.1 Hz, 2H), 4.44 (s, 2H), 3.92 (t, J= 5.1 Hz, 2H) MS (CI) for Cl~Hi6C1N30 m/z 338 (MH+), 309, 248, 214 Part D
Phenol (6.21 g, 66 mmol) was added in portions to a chilled suspension of sodium hydride (2.79 g of 60% in mineral oil, 69.7 mmol) in diglyrne (25 mL). When bubbling had subsided, a solution of the material from Part C in diglyme (10 mL) was added in a single portion. The resulting solution was heated to 110°C and stirred overnight. Analysis by TLC (3% methanol in dichloromethane) indicated that the reaction was complete. The solution was cooled to 0°C and a brown precipitate formed. The diglyme was decanted off. The solid was slurried with hexane and then isolated by filtration. The solid was then slurned with water, isolated by filtration and dried in an oven overnight. The solid was recrystallized from isopropanol to provide 19.3 g of 1-[2-(benzyloxy)ethyl]-4-phenoxy-1H imidazo[4,5-c]quinoline as a solid.
1H-NMR (300 MHz, DMSO-d6) 8 8.39 (s, 1H), 8.32 (dd, J= 8.3, 1.5 Hz, 1H), 7.69 (dd, J
= 8.3, 1.5 Hz, 1H), 7.46-7.59 (m, 4H), 7.12-7.33 (m, 8H), 4.93 (t, J= 5.1 Hz, 2H), 4.47 (s, 2H), 3.94 (t, J= 5.1 Hz, 2H) MS (CI) for C25H21N302 m/z 396 (MH+), 306, 288 Part E
Under a nitrogen atmosphere, triflic acid (29.0 g) was added dropwise to a solution of 1-[2-(benzyloxy)ethyl]-4-phenoxy-1H imidazo[4,5-c]quinoline (7.65 g) in anhydrous dichloromethane (200 mL). When analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete, the reaction mixture was concentrated under reduced pressure to provide an oil. This material was dissolved in ethyl acetate and then combined with triethylamine (10 eq.). The solution was diluted with additional ethyl acetate, washed with water, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The xesidue was recrystallized from ethyl acetate to provide ~4.8 g of 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol as a white fluffy solid.
iH-NMR (300 MHz, DMSO-d6) 8 8.34 (m, 1H), 8.32 (rn, 1H), 7.70 (m, 1H), 7.46-7.60 (m, 4H), 7.25-7.31 (m, 3H), 5.06 (t, J= 5.4 Hz, 1H), 4.76 (t, J= 5.4 Hz, 2H), 3.90 (q, J=
5.4 Hz, 2H) Part F
3-(Bromomethyl)pyridine hydrobromide (0.638 g, 2.52 mmol) was added in a single portion with stirring to a solution containing 2-(4-phenoxy-1H
imidazo[4,5-c]quinolin-1-yl)ethanol (0.7 g, 2.29 mmol), benzyltrimethylammonium chloride 00.03 g), sodium hydroxide (28 mL of 50%) and dichloromethane (28 mL). After 3 houxs analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was diluted with water (100 mL) and dichloromethane (100 mL).
The layers were separated and the aqueous fraction was extracted with dichloromethane (100 mL). The organic fractions were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark yellow solid. This material was purified by flash chromatography (silica gel eluting with 5%
methanol in dichloromethane) to provide 0.74 g of 4-phenoxy-1-[2-(pyridin-3-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline as a bright yellow solid.
'H-NMR (300 MHz, DMSO-d6) 8.42 (dd, J= 4.9, 2.0 Hz, 1H), 8.38 (s, 2H), 8.33 (dd, J=
8.3, 1.5 Hz, 1H), 7.70 (dd, J= 8.3, 2.0 Hz, 1H), 7.46-7.59 (m, SH), 7.22-7.33 (m, 4H), 4.96 (t, J= 4.9 Hz, 2H), 4.52 (s, 2H), 3.98 (t, J= 4.9 Hz, 2H) MS (CI) for C24HzoNaOa mlz 397 (MH+), 306, 288, 212, 110 Part G
4-Phenoxy-1-[2-(pyridin-3-yhnethoxy)ethyl]-1H irnidazo[4,5-c]quinoline (0.67 g, 1.69 mmol) and ammonium acetate (1.30 g, 16.9 mmol) were combined and heated to 150°C. After 5 hours analysis by TLC (10% methanol in dichloromethane) showed starting material. More ammonium acetate (5 g) was added. After 1 hour TLC
indicated that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature overnight. The resulting brown oil was combined with water (100 mL) and made basic (pH 9) with sodium bicarbonate. The product was extracted into dichloromethane (2 X 100 mL). The extracts were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide an off white gummy solid. This material was purified by flash chromatography (silica gel eluting with 10% methanol in dichloromethane) to provide 0.40 g of a gummy white solid.
This material was dissolved in methanol (10 mL). Hydrogen chloride/diethyl ether (5 eq) was added dropwise and the mixture was allowed to stir for 1 hour. The resulting precipitate was isolated by filtration, rinsed with diethyl ether and dried in a vacuum oven to provide 0.358 g of 1-[2-(pyridin-3-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine hydrochloride as a light yellow solid, m.p. 229-231°C.
Analysis: Calculated for CIgHl~N50 ~ 2.75 HCl ~ 0.4 HZO: %C, 50.62; %H, 4.85;
%N, 16.40; Found: %C, 50.44; %H, 4.96; %N, 16.19.
'H-NMR (300 MHz, DMSO-d6) b 8.78 (d, J= 5.4 Hz, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.34 (d, J= 8.3 Hz, 1H), 8.26 (d, J= 7.8 Hz, 1H), 7.90 (dd, J= 7.8, 5.9 Hz, 1H), 7.84 (d, J
= 8. 3 Hz, 1 H), 7.72 (t, J = 7. 8 Hz, 1 H), 7.54 (t, J = 7. 8 Hz, 1 H), 4.9 8 (t, J = 4.9 Hz, 2H), 4.69 (s, 2H), 4.04 (t, J= 4.9 Hz, 2H) MS (CI) for C18H1~N50 ~ HCly 1i4~ ~ HZO~zis~ m/z 321 (MH+), 229.
Example 14 1-[2-(Pyridin-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHS
N
N i N
O
N
Part A
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol (0.9 g, 2.95 mmol) was reacted with 2-picolyl chloride hydrogen chloride (0.53 g, 3.24 mmol) and the product purified to provide 0.65 g of 4-phenoxy-1-[2-(pyridin-2-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline.
1H-NMR (300 MHz, DMSO-d6) 8.41 (m, 2H), 8.34 (dd, J= 8.3, 1.5 Hz, 1H), 7.70 (dd, J
= 8.3, 1.5 Hz, 2H), 7.46-7.66 (m, 5H), 7.18-7.33 (m, 4H), 7.30 (d, J= 7.8 Hz, 1H), 4.98 (t, J=4.9 Hz, 2H), 4.55 (s, 2H), 4.04 (t, J= 4.9 Hz, 2H) Part B
The material from Part A and ammonium acetate were combined and heated to 150°C. After 5 hours analysis by TLC (10% methanol in dichloromethane) indicated that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature, then it was combined with water (100 mL) and made basic (pH 9) with sodium bicarbonate. The resulting white precipitate was isolated by filtration and then slurried with diethyl ether. The resulting white solid was isolated by filtration and then recrystallized from acetonitrile to provide 0.18 g of 1-[2-(pyridin-2-ylmethoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 196-198°C.
Analysis: Calculated for C18H1~N50: %C, 67.70; %H, 5.37; %N, 21.93; Found: %C, 67.86; %H, 5.31; %N, 22.13.
'H-NMR (300 MHz, DMSO-d6) b 8.43 (d, J= 4.9 Hz, 2H), 8.20 (s, 1H), 8.09 (d, J=
6.8 Hz, 1H), 7.63 (dt, J= 8.3, 1.5 Hz, 2H), 7.43 (dt, J= 8.3, 1.5 Hz, 1H), 7.19-7.24 (m, 2H), 7.12 (d, J=7.8 Hz, 1H), 6.53 (hr s, 2H), 4.87 (t, J= 5.1 Hz, 2H), 4.54 (s, 2H), 3.99 (t, J=
5.1 Hz, 2H) MS (CI) for C18HI~N50 mlz 320 (MH+), 229, 211.
Example 15 I-[2-(Pyridin-4-ylmethoxy)ethyl]-IH imidazo[4,5-c]quinolin-4-amine N
N / y O
N
Part A
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol (1.1 g, 3.61 mmol) was reacted with 4-picolyl chloride hydrogen chloride (0.649 g, 3.96 mmol) and the product purified to provide ~0.3 g of 4-phenoxy-1-[2-(pyridin-4-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline.
IH-NMR (300 MHz, DMSO-d6) b 8.41 (s, 1H), 8.39 (s, 1H), 8.34 (dd, J= 7.8, 1.5 Hz, 2H), 7.70 (dd, J= 7.8, 1.5 Hz, 1H), 7.46-7.60 (m, 4H), 7.25-7.33 (m, 3H), 7.10 (d, J= 5.9 Hz, 2H), 5.00 (t, J= 4.9 Hz, 2H), 4.53 (s, 2H), 4.00 (t, J= 4.9 Hz, 2H) MS (CI) for C24HzQN~O2 m/z 397 (MH+), 306, 288, 212, 110 Part B
Using the general method of Example 14 Part B, 4-phenoxy-1-[2-(pyridin-4-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinoline (0.25 g) was aminated to provide 0.14 g of 1-[2-(pyridin-4-ylmethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 159-161°C.
Analysis: Calculated for CIBHI~N50: %C, 67.70; %H, 5.37; %N, 21.93; Found: %C, 67.37; %H, 5.31; %N, 22.49.
~H-NMR (300 MHz, DMSO-d6) 8 8.40 (dd, J= 4.4, 1.5 Hz, 2H), 8.20 (s, 1H), 8.09 (d, J=
8.3 Hz, 1 H), 7. 62 (d, J = 8.3 Hz, 1 H), 7.43 (m, 1 H), 7.21 (m, 1 H), 7.10 (d, J =5 .4 Hz, 1 H), 6.54 (br s, 2H), 4.87 (t, J= 5.1 Hz, 2H), 4.51 (s, 2H), 3.94 (t, J= 5.1 Hz, 2H) MS (CI) for C18H1~N50 m/z 320 (MH+), 229, 136 Example 16 1-{2-[(3,5-Dimethylisoxazol-4-yl)methoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine NHZ
N
N
O
I
O-N
Part A
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H imidazo[4,5-c]quinolin-1-yl)ethanol (0.82 g, 2.69 mmol) was reacted with 4-(chloromethyl)-3,5-dimethylisoxazole (0.43 g, 2.95 mmol) and purified to provide 0.59 g of 1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-4-phenoxy-1H imidazo[4,5-c]quinoline as a white foamy solid.
1H-NMR (300 MHz, DMSO-d6) 8 8.29-8.32 (m, 2H), 7.70 (dd, J= 7.8, 1.5 Hz, 1H), 7.46-7.60 (m, 4H), 7.25-7.32 (m, 3H) 4.89 (t, J=5.1 Hz, 2H), 4.24 (s, 2H), 3.89 (t, J= 4.9 Hz, 2H), 2.16 (s, 3H), 1.93 (s, 3H) MS (CI) for CZøHz2N4O3 ln/Z 415 (MH+), 306, 212, 112 Part B
Using the general method of Example 14 Part B, the material from Part A was aminated to provide 0.39 g of 1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-IH
imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 213-215°C.
Analysis: Calculated for C18H19N502: %C, 64.08; %H, 5.68; %N, 20.76; Found:
%C, 64.02; %H, 5.53; %N, 21.01.
1H-NMR (300 MHz, DMSO-d6) 8 8.12 (s, 1H), 8.05 (dd, J= 8.3, 1.0 Hz, 1H), 7.61 (dd, J
= 8.3, 1.0 Hz, 1H), 7.43 (m, 1H), 7.21 (m, 1H), 6.52 (br s, 2H), 4.79 (t, J=
5.1 Hz, 2H), 4.23 (s, 2H), 3.85 (t, J= 5.1 Hz, 2H), 2.20 (s, 3H), 1.97 (s, 3H) MS (CI) for C18HI9N502 m/z 338 (MH~, 229, 112 Example 17 1-(2- f [3-(Pyrimidin-2-yl)-2-propynyl]oxy}ethyl) 1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate N
N
'N
O
N
' \\
Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.7 mmol), triethylamine (1.0 g, 9.7 mmol) and anhydrous N,N-dimethylformamide (20 mL) were combined. The resulting solution was heated to 65°C . Copper (I) iodide (0.07 g, 0.4 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.13 g, 0.2 mmol) and 2-bromopyrimidine (0.65 g, 4.1 mmol) were added and the reaction mixture was stirred at 65°C overnight. The N,N-dimethylformamide was removed under reduced pressure to provide crude product as a tar. This tar was purified first by column chromatography (silica gel eluting with dichloromethane) and then by semi-preparative HPLC using Method A to provide 0.05 g of 1-(2-{[3-(pyrimidin-2-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a spongy white solid, m.p. 214-215°C.
Analysis: Calculated for C19H16N6O ' 1.S CZHF3O2 ~ 0.3 H20: %C, 50.67; %H, 3.51; %N, 16.12; Found: %C, 50.67; %H, 3.1 l; %N, 16.14.
1H-NMR (300 MHz; DMSO-d6) 8 (ppm) 9.169(s,lH), 8.646(s,2H), 8.497(s,lH), 8.328(d,J=8.3Hz,lH), 7.773(d,J=6.9Hz,lH), 7.703(t,J=6.7Hz,lH), 7.558(t,J=7.2Hz,lH), 4.942(t,J=4.8Hz,2H), 4.447(s,2H), 4.073(t,J=4.9Hz,2H).
Example 18 1-(2- {[3-(Pyrid-4-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine bis(trifluoroacetate) NHZ
N
N
~N
O
N
Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5 c]quinolin-4-amine (0.5 g, 1.9 mmol), triethylamine (0.5 g, 4.9 mmol), copper (I) iodide (0.036 g, 0.2 mmol), 4-bromopyridine (0.51 g, 2.6 mmol) and acetonitrile (20 mL) were combined and stirred at ambient temperature.
Dichlorobis(triphenylphosphine)palladium(II) (0.066 g, 0.1 mmol) was added.
The reaction mixture was heated at reflux overnight. The acetonitrile was removed under reduced pressure. The residue was taken up in dichloromethane and methanol and then put through a basic alumina column. The fractions were combined and concentrated under reduced pressure. The residue was triturated with acetonitrile. The resulting solid was isolated by filtration and then purified by semi-preparative HPLC using Method A to provide 0.1 g of 1-(2-{[3-(pyrid-4-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine bis(trifluoroacetate) as a gray fluffy solid, m.p. 135°C
(dec.).
Analysis: Calculated for CZOH1~N50 ~ 2.0 CZHF30z ~ 0.5 HZO: %C, 49.66; %H, 3.47; %N, 12.06; Found: %C, 49.59; %H, 3.51; %N, 12.22.
1H-NMR (300 MHz; DMSO-d6) 8 (ppxn) 9.063(bs,2H), 8.551(d,J=5.2Hz,2H), 8.498(s,lH), 8.335(d,J=7.7Hz,lH), 7.795(d,J=6.9Hz,lH), 7.727(t,J=8.3Hz,lH), 7.564(t,J=8.3Hz,lH), 7.139(d,J=5.7Hz,2H), 4.942(t,J=4.8Hz,2H), 4.427(s,2H), 4.056(t,J=4.8Hz,2H).
Example 19 1-(2-{[3-(Fur-3-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate N
N
'N
O
y Under a nitrogen atmosphere, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol), triethylamine (0.5 g, 4.9 mmol), copper (I) iodide (0.036 g, 0.2 mmol), 3-bromofuran (0.38 g, 2.6 mmol) and anhydrous N,N-dimethylformamide (20 mL) v~ere combined and stirred at ambient temperature.
Dichlorobis(triphenylphosphine)palladium(II) (0.066 g, 0.1 mmol) was added.
The reaction mixture was heated at 80°C overnight. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with dichloromethane. The resulting fine brown precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved into a minimum amount of N,N-dimethylformamide and put through a silica gel column. The appropriate fractions were combined and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC
using Method A to provide 0.1 g of 1-(2-{[3-(fur-3-yl)-2-propynyl]oxy}ethyl)-imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a fluffy ivory solid, m.p.
160-162°C.
Analysis: Calculated for C19H16N402 ' C2HF3O2 ' 0.25 HZO: %C, 55.94; %H, 3.91;
%N, 12.42; Found: %C, 55.57; %H, 3.43; %N, 12.45.
1H-NMR (300 MHz; DMSO-d~) 8 (ppm) 8.859(bs,2H), 8.473(s,lH), 8.32(d,J=8.3Hz,lH), 7.849(s,lH), 7.813(d,J=7.3Hz,lH), 7.714(t,J=8.SHz,lH), 7.697(d,J=2Hz,lH), 7.551(t,J=6.8Hz,lH), 6.409(d,J=l.9Hz,lH), 4.919(t,J=S.SHz,2H), 4.337(s,2H), 4.002(t,J=4.8Hz,2H).
Example 20 4-{3-[2-(4-Amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]-propyn-1-yl}
thiophen-2-ylcarboxaldehyde trifluoroacetate N
N
'N
O
S H
O
Using the general method of Example 20, 1-[2-(2-propynyloxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol) was reacted with 3-bromo-2-thiophenecarboxaldehyde (0.5 g, 2.6 mmol) and the crude product purified by semi-preparative HPLC using Method A to provide 0.13 g of 4-{3-[2-(4-amino-1H
imidazo[4, 5-c] quinolin-1-yl)ethoxy]-propyn-1-yl } -thiophen-2-ylcarboxaldehyde trifluoroaeetate as a fluffy ivory solid, m.p. 195°C.
Analysis: Calculated for CZOH16N40aS ' CzHF30z: %C, 53.88; %H, 3.49; %N, 11.42;
Found: %C, 54.16; %H, 3.21; %N, 11.36.
1H-NMR (300 MHz; DMSO-d6) d (ppm) 9.874(s,lH), 8.972(bs,2H), 8.483(s,lH), 8,.322(d,J=7.9Hz,lH), 8.076(s,lH), 7.771(d,J=8.3Hz,lH), 7.736(s,lH), 7.71(t,J=8.4Hz,lH), 7.555(t,J=6.9Hz,lH), 4.928(t,J=5.3Hz,2H), 4.371(s,2H), 4.043(t,J=4.8Hz,2H).
Example 21 1-(2-~[3-(Pyrid-2-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate NHa N
N
'N
O
~~N
Using the general method of Example 19, 1-[2-(2-propynyloxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.9 mmol) was reacted with 2-bromopyridine (0.51 g, 2.6 mmol) and the crude product purified by semi-preparative HPLC
using Method A to provide 0.1 g of 1-(2-{[3-(pyrid-2-yl)-2-propynyl]oxy~ethyl)-1H
imidazo[4,5-c]quinolin-4-amine trifluoroacetate as a gray fluffy solid, m.p.
129-131°C.
Analysis: Calculated for C20H1~Ns0 ~ 1.75 CZHF302 ~ 0.25 H20: %C, 51.56; %H, 3.55;
%N, 12:80; Found: %C, 51.80; %H, 3.20; %N, 13.11.
1H-NMR (300 MHz; DMSO-d6) 8 (ppm) 9.013(bs,2H), 8.516(s,lH), 8.495(s,lH), 8.331(d,J=8.2Hz,lH), 7.75(m,3H), 7.553(t,J=8.2Hz,lH), 7.375(dd,J=7.8;4.9Hz,lH), 7.23(d,J=7.8Hz,lH), 4.944(t,J=5.4Hz,2H), 4.418(s,2H), 4.059(t,J=4.8Hz,2H).
Examples 22 - 26 The compounds in the table below were prepared according to the synthetic method of Reaction Scheme I above using the following general method.
The 4-amino-1H imidazo[4,5-c]quinolin-1-yl alcohol (25 mg) was placed in a 2 dram (7.4 mL) vial. Sodium hydride (1.2 eq of 60% in mineral oil) and N,N-dimethylformamide (1 nnL,) were added. The vial was placed on a sonicator for about 15 to 30 minutes at ambient temperature to allow the alkoxide to form. The halide (1.2 eq) was added and the vial was placed back on the sonicator for about 15 to 120 minutes at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The reaction mixture was purified by semi-preparative HPLC. The semi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriate fractions were combined and lyophilized to provide the trifluoroacetate salt of the desired product,which was confirmed by accurate mass and 1H NMR
spectroscopy.
The table below shows the structure of the free base, the theoretical mass (TM), and the measured mass (MM) or nominal mass (NM).
Example Structure of the Free Base Purification Mass Measurement # Method (Da.) 22 NHS A TM = 326.1743 N ~ N~ MM = 326.1739 N
O
~0 23 NHS A TM = 392.1597 N ~ N~ MM = 392.1584 i N O; N~
O
N
24 NH2 A TM = 450.1281 N~ MM = 450.1285 N
O
CI
S
25 NH2 A TM = 422.0968 N~ MM = 422.0966 N
O
~ CI
S
Example Structure of the Free PurificationMass Measurement # Base Method (Da.) 26 NH2 A TM = 364 N ~ N> NM [M+H]+i = 365 r N
O N~
O
+ I /
. N
O
Example 27 1- f 2-Methyl-1-[(pyrid-2-yloxy)methyl]propyl)-1H imidazo[4,S-c]quinoline-4-amine trifluoroacetate NHS
N
N
'N
N, O
f Using the general method of Examples 22 - 26 above, 2-(4-amino-1H
imidazo[4,5-c]quinolin-1-yl)-3-methylbutan-1-of was reacted with 2-(trifluoromethylsulfonyloxy)pyridine and the crude product purified via semi-preparative HPLC using Method A to provide 1- f 2-methyl-1-[(pyrid-2-yloxy)methyl]propyl}-imidazo[4,5-c]quinoline-4-amine as the trifluoroacetate salt. TM = 347.1746, MM =
347.1740 Example 28 1- f 1-[(pyrid-2-yloxy)methyl]propyl}-1H imidazo[4,5-c]quinoline-4-amine trifluoroacetate NHS
N
N /
~N
N
O
Using the general method of Examples 22 - 26 above 2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)-3-methylbutan-1-oI was reacted with 2-(trifluoromethylsulfonyloxy)pyridine and the crude product purified via semi-preparative HPLC using Method B to provide 1-{1-[(pyrid-2-yloxy)methyl]propyl}-1H
imidazo[4,5-c]quinoline-4-amine as the trifluoroacetate salt. TM = 333.1590, MM = 333.1598 Example 29 1-[2-(9H carbazol-3-yloxy)propyl]-1H imidazo[4,5-c]quinolin-4-amine trifluoroacetate NHZ
N
N
'N
i O
HN
A 1 mL portion of a solution prepared by dissolving 0.5 g of 1-(4-amino-1H
imidazo[4,5-c]quinolin-1-yl)propan-2-of in N,N-dimethylformamide (20 mL) was added to a 2 dram (7.4 mL) glass vial containing 2-hydroxycarbazole (38 mg, 2 eq.).
Triphenylphosphine (54 mg, 2 eq.) dissolved in N,N-dimethylformamide (1 mL) was added to the vial. The resulting slurry was sonicated to dissolve the phenol.
Diethyl azidocarboxylate (36 mg, 2 eq.) was added neat. The reaction mixture was sonicated for about 30 minutes and then shaken overnight at ambient temperature. The solvent was removed and the residue was purified by semi-preparative HPLC using Method A.
The compound was provided as the trifluoroacetate salt. TM = 407, NM[M + H]+1 =
408.
Example 30 1-{2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine NHZ
N w N
N
O
S
i Part A
Using the general method of Example 1 Part B, 2-(1H imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether was oxidized to provide 67.5 g of 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide as a tan solid.
MS (CI) for C15H14N3Oz m/z 268 (MH+), 252, 214.
Part B
A dried round bottom flask was charged with a stir bar, 1-[2-(2-propynyloxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (57.5 g, 215.1 mmol), anhydrous toluene (200 mL) and anhydrous dimethyl formamide (400 mL) under a nitrogen atmosphere. Phosphorus oxychloride (23 mL, 247.4 mmol) was added dropwise over 20 minutes to this mixture leading to a modest exotherm (~ 40 °C).
The reaction was judged complete after 1.25 hours at ambient temperature. The volatiles were removed under reduced pressure and the resulting solid was partitioned between chloroform and 10% aqueous sodium carbonate. The aqueous layer was extracted with chloroform;
the organic fractions were combined, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown solid was dried at 60 °C, under vacuum, for 4 hours to obtain 36.6 g of 4-chloro-1-[2-(prop-2-ynyloxy)ethyl]-imidazo[4,5-c]quinoline as a powder.
MS (CI) for ClSHizCIN3O m/Z 286 (MH+), 246, 204.
Part C
A dried round bottom flask was charged with a stir bar, sodium hydride (8.15 g, 203.9 rnmol) and anhydrous 2-methoxylethyl ether (diglyme, 100 mL) while under a nitrogen atmosphere and at ambient temperature. Phenol (20.7 g, 220.2 mmol) was added in several portions as a solid and the resulting solution stirred under a nitrogen atmosphere until gas evolution ceased. 4-chloro-1-[2-(prop-2-ynyloxy)ethyl]-1H
imidazo[4,5-c]quinoline (46.6 g, 163.1 mmol) was added neat and the solution was heated to 110 °C.
After 15.5 hours, a preformed solution of sodium phenoxide (phenol 5 g, 53.1 mmol and sodium hydride 1.91 g, 47.8 mmol) in diglyme (20 mL) was added to the reaction solution and heating was increased to 165 °C. The reaction was judged complete after 1 hour at 165 °C. After cooling to less than 70 °C, the volatiles were removed under reduced pressure and the resulting brown solid was partitioned between chloroform and saturated aqueous sodium carbonate. The aqueous fraction was extracted with chloroform;
the combined organic fractions were dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile with a small amount of dimethyl formamide to provide 25 g of 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H imidazo[4,5-c]quinoline as a crystalline solid.
MS (CI) for CZ1H1~N302 m/z 344 (MH+), 306, 288.
Part D
Using the general method of Example 3 Part A, 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H imidazo[4,5-c]quinoline (10 g, 29.4 mmol) was reacted with 2-iodothiophene (3.6 mL, 32.3 mmol). The glassy solid obtained from purification by chromatography over silica gel (98/2 dichloromethane/methanol) was triturated with ether to provide 5.3 g of 4-phenoxy-1- f 2-[(3-thien-3-ylprop-2-ynyl)oxy]ethyl}-1H
imidazo[4,5-c]quinoline as a gray powder.
MS (CI) for C25H19N302S r~Z 426 (MH+), 306, 288.
Part E
4-Phenoxy-1-{2-[(3-thien-3-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinoline (3.2 g, 7.52 mmol) and ammonium acetate (32 g, 415 mmol) were melted together in a dried round bottom heated to 150 °C under a nitrogen atmosphere. After 2 hrs additional ammonium acetate (10 g, 129 mmol) was added. The reaction was judged complete after a total of 4 hours. The melted solids were cooled to ambient temperature and basified with 1N aqueous potassium hydroxide to a pH of~l3. The aqueous mixture was extracted with dichloromethane (3x); the combined organic fractions were washed with brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting solid was purified by chromatography over silica gel (98/2 dichloromethane/methanol), then triturated with ether to provide 0.812 g of 1-~2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a white powder, m.p.
148-150 °C.
Analysis. Calculated for C19H16N4OS: %C, 65.50; %H, 4.63; %N, 16.08. Found:
%C, 65.42; %H, 4.65; %N, 16.11 IH NMR (300 MHz, DMSO) 8 8.16 (s, 1 H), 8.11 (d, J = 6.8 Hz, 1 H), 7.60 (m, 2 H), 7.43 (t, J = 6.8 Hz, 1 H), 7.20-7.25 (m, 2 H), 7.04 (dd, J = 4.9, 3.9 Hz, 1 H), 6.58 (s, 2 H), 4.84 (t, J = 5.4, 2 H), 4.41 (s, 2 H), 3.99 (t, J = 5.4, 2 H) MS (CI) for C1~H16N40S m/z 349 (MHO), 229, 185.
Example 31 1- f 2-[(1-methyl-1H indol-2-yl)methoxy]ethyl}
1H imidazo[4,5-c]quinolin-4-amine NHS
N ~ N
N
O
/ N~
Part A
Using the general method of Example 30 Part D, 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H imidazo[4,5-c]quinoline (3.16 g, 9.20 mmol) was reacted with 2-iodo-N,N-dimethylaniline (2.5 g, 10.1 mmol) to provide a 1.0 g of 1- f 2-[(1-methyl-1H indol-2-yl)methoxy]ethyl}-4-phenoxy-1H imidazo[4,5-c]quinoline as a pale yellow crystalline solid.
MS (CI) for C28H24N4O2 m/z 449 (MH+), 306, 186.
Part B
1- f 2-[(1-Methyl-IH indol-2-yl)methoxy]ethyl}-4-phenoxy-1H imidazo[4,5-c]quinoline (0.78 g, 1.74 mmol) was partially converted to the desired product by exposure to ammonia, (7% in methanol, 20 mL) for 52 hours at 160 °C in a bomb. The volatiles were removed under reduced pressure and the material was reacted with more ammonia (7% in methanol, 20 mL) for 80 hours at 160 °C to completely consume the starting material. The solid was removed by filtration and the filtrate was concentrated under reduced vacuum. The resulting material was purified by chromatography over silica gel (9/1 dichloromethane/methanol). The resulting solid was recrystallized from dimethyl formamide to provide 0.121 g of 1-{2-[(1-methyl-1H indol-2-yl)methoxy]ethyl}-imidazo[4,5-c]quinolin-4-amine as white, flat crystals, m.p. 243-245 °C.
Analysis. Calculated for CZZHziNsO ' (C3H~ON)o,20: %C, 70.50; %H, 5.81; %N, 18.75.
Found: %C, 70.72; %H, 5.70; %N, 18.36 1H NMR (300 MHz, DMSO) 8 8.13 (s, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.60 (d, J
= 9.3, 1 H), 7.36-7.47 (m, 3 H), 7.10-7.20 (m, 2 H), 6.98 (t, J = 7.3 Hz, 1 H), 6.58 (brs, 2 H), 6.36 (s, 1 H), 4.82 (t, J = 4.9, 2 H), 4.64 (s, 2 H), 3.92 (t, J = 4.9, 2 H), 3.52 (s, 3 H) MS (CI) for CZZHZiNsO m/z 372 (MH+), 229, 144.
Example 32 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine N ~ N
N
O
Part A
A dried round bottom flask was charged with a stir bar, 2-(1H imidazo[4,5-c]quinolin-1-yl)ethyl (2-propynyl) ether (11.78 g, 46.88 mmol), anhydrous triethylamine (14 mL, 121.9 mmol), 2-iodothiophene (5.7 rnL, 51.57 mmol) and anhydrous dimethyl formamide(130 mL) under a nitrogen atmosphere and heated to 80 °C.
After 5 minutes dichlorobis(triphenylphosphine)palladium(II) (0.658 g, 0.937 mol) and copper(I) iodide (0.357 g, 1.875 mmol) were added neat to the solution. The reaction was judged complete after 50 minutes. The volatiles were removed under reduced pressure and the resulting solid partitioned between dichloromethane and 0.5N aqueous potassium hydroxide. The aqueous fraction was extracted with dichloromethane (3x); the combined organic fractions were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide a brown solid. The glassy solid obtained from purification by chromatography over silica gel (98/2 dichloromethane/methanol) was triturated with ether to provide 9.5 g of 1- f 2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H imidazo[4,5-c]quinoline as a tan solid.
MS (CI) for Cl9HisNsOS m/z 334 (MH+), 290, 214.
Part B
Using the general method of Example 3 Part B, 1- f 2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl-1H imidazo[4,5-c]quinoline (9.5 g, 28.49 mmol) was reduced with palladium on carbon (10%, 1 g) in methanol (25 mL) to provide 9.1 g of 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline as a brown oil.
MS (CI) for C19H19N3OS 111/Z 338 (MH+), 214.
Part C
Using the general method of Example 1 Part B, 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline was oxidized to provide 4.4 g of 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide as an unpurified tan solid.
MS (CI) for C19H19N3O2s Tn/Z 354 (MH+), 338, 214.
Part D
Using the general method of Example 1 Part C, 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-SN-oxide (4.4 g, 12.45 mmol) was reacted with trichloroacetyl isocyanate (1.8 mL, 14.9 mmol) to provide 2,2,2-trichloro-N {1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-yl}acetamide as an unpurified glassy solid.
Part E
A dried round bottom flask Was charged with a stir bar, 2,2,2-trichloro-N { 1-[2-(3-thien-2-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-ylJacetamide and sodium methoxide (25% in methanol, 11 mL, 49.8 mmol) at ambient temperature. The reaction was judged complete after 30 hours. The volatiles were removed under reduced pressure.
The resulting oil was purified with chromatography over silica gel (95/5 dichloromethane/methanol), semi-preparative HPLC using method A, and recrystallization from ethyl acetate/hexane to provide 43 mg of 1-[2-(3-thien-2-ylpropoxy)ethyl]-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid. m.p. 130.1-131.6 °C.
Analysis. Calculated for Cl9HZON40S ' (HZO)o,3o: %C, 63.77; %H, 5.80; %N, 15.66.
Found: %C, 63.84; %H, 5.79; %N, 15.57 IH NMR (300 MHz, DMSO) 8 8.16 (s, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 7.62 (d, J
= 8.3 Hz, 1 H), 7.43 (t, J = 7.3 Hz, 1 H), 7.20-7.26 (m, 2 H), 6.84 (dd, J = 4.9, 3.4 Hz, 1 H), 6.62 (d, J = 2.4 Hz, 1 H) 6.58 (s, 2 H), 4.79 (t, J = 5.4 Hz, 2 H), 3.83 (t, J = 5.4 Hz, 2 H), 3.35 (t, J
= 6.4, 2 H), 2.64 (t, J = 7.8 Hz, 2 H), 1.69 (p, J = 6.8, 6.3 Hz, 2 H).
MS (CI) for Cl~HzoN40S m/z 353 (MH+), 211, 185.
Example 33 1-[2-(3-Pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine NHZ
N
'N
O
N
Part A
Under a nitrogen atmosphere, a solution of 2-aminobenzoic acid (100.0 g, 0.73 mol) in acetic anhydride (400 ml, 4.2 mol) was heated to reflux for 2 hours.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in glacial acetic acid (500 ml) and NaN3 (49.77 g, 0.77 mol) was added. The mixture was stirred overnight at room temperature followed by concentration of the acetic acid in vacuo. The residue was dissolved in 10% NaOH (500 ml) solution and heated to reflux for 3.5 hours. The reaction was cooled to room temperature and then poured over a mixture of ice water (2 L) and HCl (150 ml). A white solid precipitated and was collected by vacuum filtration. The solid was dried in vacuo to yield 130.5 g of 2-(5-methyl-1H
tetrazol-1-yl)benzoic acid.
1H NMR (300 MHz, DMSO-d~) 8 8.12 (d, J = 7.2 Hz, 1H), 7.91-7.78 (m, 2H), 7.72 (d, J =
7.4 Hz, 1H), 2.37 (s, 3H);
MS (CI) m/e 205 (MH+), 162 (M - N3).
Part B
Under a nitrogen atmosphere, 2-(5-methyl-1H tetrazol-1-yl)benzoic acid (89.7 g, 0.44 mol) was dissolved in acetone (1 L) and cesium carbonate (214.7 g, 0.66 mol) was added with vigorous stirring. Ethyl iodide (70.3 ml, 0.88 mol) was added dropwise and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature and filtered. The acetone was removed in vacuo to yield a yellow solid which was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate (200 ml). The organic fraction was dried (Na2S04), ftltered, and concentrated to yield 92.7 g of ethyl 2-(S-methyl-1H tetrazol-1-yl)benzoate as a light yellow solid.
1H NMR (300 MHz, DMSO-d6) 8 8.14 (d, J = 7.8 Hz, 1H), 7.89 (m, 2H), 7.79 (d, J
= 7.9 Hz, 1 H), 4.08 (q, J = 7.4 Hz, 2H), 2.40 (s, 3H), 1.04 (t, J = 6.9 Hz, 3H);
MS (CI) m/e 233 (MHO), 1 S9.
Part C
Under a nitrogen atmosphere, ethyl 2-(S-methyl-1H tetrazol-1-yl)benzoate (92.7 g, 0.34 mol) was dissolved in N,N-dimethylformamide (600m1) and the solution was chilled in an ice water bath. Potassium ethoxide (67.2 g, 0.80 mol) was added slowly to the solution. After a few minutes, the ice water bath was removed and the reaction was stirred at room temperature for 3 hours. The reaction was treated with 100 ml of water and approximately 300-400 ml of solvent was removed in vacuo. The remainder of the reaction was poured over a solution of glacial acetic acid (125 ml) in ice water (2 L). A
precipitate formed and the mixture was diluted with additional water (3 L).
The solid was 1S collected by vacuum filtration to yield 63.25 g of tetrazolo[1,5-a]quinolin-S-of as a yellow solid.
1H-NMR (300 MHz, DMSO-d6) 8 8.54 (d, J = 8.4 Hz, 1H). 8.27 (d, J = 8.1 Hz, 1H), 7.99 (t, J = 7.4 Hz, 1 H), 7.80 (t, J = 7.2 Hz, 1 H), 7.04 (s, 1 H);
MS (CI) m/e 187 (MH+), 159.
Part D
Tetrazolo[1,5-a]quinolin-5-of (63.25 g, 0.34 mol) was added to glacial acetic acid (630 ml) to form a thick off white suspension. The mixture was vigorously stirred while nitric acid (23.6 ml, 0.37 mol, 70% solution) was slowly added. The reaction was then heated from 25 to 80 °C over a period of 1 S minutes. A yellow precipitate formed and the reaction was maintained at 80 °C for 5 minutes. The mixture was slowly cooled to 0 °C.
The solid was collected by filtration and then dried in vacuo to yield 60.0 g of 4-nitro-tetrazolo[1,5-a]quinolin-5-of as a yellow solid.
IH-NMR (300 MHz, DMSO-d6) 8 8.35 (d, J = 3.9 Hz, 1H); 8.32 (d, J = 3.2 Hz, 1H), 7.90 (t, J = 7.3 Hz, 1 H), 7.68 (t, J = 8.2 Hz, 1 H);
MS (CI) m/e 232 (MH+), 204.
Part E
Under a nitrogen atmosphere, POC13 (16.42 ml, 0.17 mol) was slowly added to a chilled (0 °C) flask containing N,N-dimethylformamide (100 ml). The resulting solution was slowly warmed to room temperature and then added dropwise to a suspension of 4-nitro-tetrazolo[1,5-a]quinolin-5-of in N,N-dimethylformamide (300 ml). The reaction was heated to 100 °C for 30 minutes. The orange/red solution was quenched by pouring over 1 liter of ice water. A yellow precipitate formed and was collected by filtration, redissolved in chloroform (approx. 750 ml), dried (Na2S04), filtered, and concentrated iya vacuo to yield 33.74 g of 5-chloro-4-nitrotetrazolo[1,5-a]quinoline as a yellow solid.
'H NMR (300 MHz, DMSO-d~) 8 8.78 (d, J = 8.2 Hz, 1H); 8.57 (d, J = 8.3 Hz, 1H), 8.29-8.22 (m, 1H), 8.09-8.03 (m, 1H);
MS (CI) m/e 250 (MH+).
Part F
5-Chloro-4-nitrotetrazolo[1,5-a]quinoline (28.86 g, 0.11 mol), dichloromethane (600 ml), and triethylamine (21.14 ml, 0.11 mol) were combined and the resulting solution was chilled to 0 °C. 2-(3-Pyridin-3-ylpropoxy)ethylamine (22.9 g, 0.13 mol) was added dropwise. The reaction was allowed to slowly warm to room temperature, then stirred at room temperature for 1 hour and finally at reflux for 2 hours. The reaction was cooled to room temperature and then quenched with water (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (3 x SOmI).
The combined organic fractions were washed with brine (100 ml), dried (NaZS04), filtered and concentrated to yield a yellow solid. The solid was slurried in ethanol ( 150 ml) and filtered to provide 34.3 g of 4-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a] quinolin-5-amine.
'H NMR (300 MHz, DMSO-d6) 8 10.27 (bs, 1H), 8.69 (d, J = 8.3 Hz, 1H), 8.54 (d, J =
8.3 Hz, 1H), 8.37 (bs, 2H), 8.08 (t, J = 7.7 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.57 (d, J =
7.3 Hz, 1H), 7.27 (dd, J = 7.9, 5.0 Hz, 1H), 3.92 (m, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 1.82 (m, 2H);
MS (CI) m/e 394 (MH+), 366.
Part G
4-Nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinolin-5-amine (34.3 g, 87.2 mmol) was added to a 3 liter stainless steel pressure flask containing ethanol (1.25 L, absolute). Platinum on carbon (3.00 g, 5% w/w) was added and the flask was placed on a Parr hydrogenation apparatus. The reaction was shaken under 45 psi (3.15 Kg/cmz) of hydrogen for 24 hours. The catalyst was removed by filtration through CeliteTM
and the Celite pad was washed with several portions of ethanol. The filtrate was concentrated in vacuo to provide 30.8 g of NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,S-a]quinoline-4,S-diamine as an orangelred oil. MS (CI) m/e 364 (MH+), 336.
Part H
Triethyl orthoformate (21.1m1, 127mmo1) was added to a solution of NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,S-a]quinoline-4,S-diamine (30.8 g, 84.7 mmol) in 1,2-dichloroethane (7S0 ml) and the reaction was heated to reflux for 3 hours.
The reaction was cooled to room temperature and diluted with saturated sodium bicarbonate (200 ml).
The phases were separated and the aqueous layer was extracted with dichloromethane (3 x7Sm1). The combined organic fractions were washed with brine (200 ml), dried (NaZS04) and concentrated to provide an orange solid. The solid was triturated with diethyl ether and then filtered to yield 28.7 g of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H
imidazo[4,S-c]tetrazolo[1,S-a]quinoline as a tan/orange solid.
1H-NMR (300 MHz, CDC13) 8 8.71 (dd, J = 8.1, 1.3 Hz, 1H), 8.38 (dd, J = 4.8, 1.S Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 8.07 (s, 1H), 7.73 (m, 2H), 7.32 (dt, 1 S J = 7.8, 1.9 Hz, 1 H), 7.13 (dd, J = 7.7, 4.8 Hz, 1H), 4.81 (t, J = S.1 Hz, 2H), 3.96 (t, J = S.1 Hz, 2H), 3.42 (t, J = 6.2 Hz, 2H), 2.52 (t, J = 7.S Hz, 2H), 1.82-1.74 (m, 2H);
MS (CI) m/e 374 (MH+).
Part I
Triphenylphosphine (27.0g, 1 l Smmol) was added to a solution of 6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,S-c]tetrazolo[l,S-a]quinoline (28.7 g, 76.9 mmol) in 1,2-dichlorobenzene (1 L). The reaction was heated at reflux temperature overnight. The dark red solution was cooled to room temperature and treated with 1N HCl (22S
ml). A
tan precipitate formed. The resulting mixture was concentrated in. vacuo to yield a dark red/brown solid. This material was treated with S00 ml water and vigorously stirred.
2S Excess triphenylphosphine and triphenylphosphine oxide formed as precipitates and were removed by vacuum filtration. The solid was washed with several portions of water followed by a final wash with dilute HCl (1:S, 1N HCl:water). The red/brown filtrate was collected, washed with ether (3 x 1 SOmI), and treated with 10% NaOH solution until the pH reached 12. The crude product formed as a tan precipitate and was collected by filtration. Purification of the crude material was accomplished by treatment (2X) with activated charcoal (Darco-G60) in refluxing methanol. The charcoal was removed by filtration. The desired product formed as a precipitate during concentration of the filtrate.
The solid was collected by vacuum filtration washed with diethyl ether, and dried under vacuum to provide 17 g of 1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a tan solid, m.p. 125.0-128.0 °C.
1H NMR (300 MHz, DMSO-d6) 8 8.33 (d, J = 4.8 Hz, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 6.8 Hz, 1H), 7.33-7.21 (m, 2H), 7.16 (dd, J = 7.7, 4.8 Hz, 1H), 6.62 (s, 2H), 4.80 (t, J = 4.8 Hz, 2H), 3.82 (t, J = 4.9 Hz, 2H), 3.30 (t, J = 6.3 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.64 (m, 2H);
MS (CI) m/e 348 (MH+);
Anal calcd for CzoHzlNsO*0.08 H20: C, 68.89; H, 6.11; N, 20.09. Found: C, 68.49; H, 5.95; N, 20.08.
Example 34 2-Methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine Part A
Under an atmosphere of nitrogen, Ns-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (0.70 g, 1.92 mmol) was dissolved in 1,2-dichloroethane (15 ml). Triethyl orthoacetate (0.53 ml, 2.88 mmol) was added via syringe and the reaction was heated to reflux fox 3 hours. Analysis by thin layer chromatography (9515 chloroform/methanol) showed complete consumption of the diamine. The reaction was quenched by the addition of water (15 ml). The phases were separated and the aqueous fraction was extracted with dichloromethane (3 x 10 ml). The combined organic fractions were washed with brine (15 ml), dried (NazS04), filtered and concentrated in vacuo to yield 0.73 g of 5-methyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H
imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a red oil. This material was used without further purification.
MS (CI) m/e 388 (M + H).
Part B
Under an atmosphere of nitrogen, 5-methyl-6-[2-(3=pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline (0.73 g, 1.89 mmol) and triphenylphosphine (0.64 g, 2.84 mmol) were dissolved in 1,2-dichlorobenzene (15 ml). The reaction was heated at reflux for 18 hours. After cooling to ambient temperature, the solvent was removed ih vacuo. The resulting residue was treated with 1N HCl/water (30 ml) and vigorous stirring produced an off white suspension. The solid was removed by filtration leaving a yellow ftltrate. The filtrate was treated with 10 % sodium hydroxide/water until pH 11 was reached. The filtrate was extracted with dichloromethane (3 x 25 ml). The combined organic fractions were washed with brine (25 ml), dried (NaZS04), filtered and concentrated in vacuo to yield an orange oil. The oil was dissolved in a minimum amount of dichloromethane and diluted with ether to produce a precipitate. The solid was recrystallized from n-propyl acetate to yield 0.16 g of 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine as a tan solid, m.p. 145.0-146Ø
1H NMR (300 MHz, CDC13) 8 8.40 (d, J = 4.9 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.93 (d, J
= 7.4 Hz, 1 H), 7. 84 (d, J = 8.4 Hz, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.31 (t, J = 6.6 Hz, 1 H), 7.22 (d, J = 7.8 Hz, 1H), 7.09 (dd, J = 4.8, 7.8 Hz, 1H), 5.46 (bs, 2H), 4.67 (t, J = 5.3 Hz, 2H), 3.90 (t, J = 5.3 Hz, 2H), 3.34 (t, J = 6.2 Hz, 2H), 2.70 (s, 3H), 2.52 (t, J = 8.0 Hz, 2H), 1.76 (m, 2H);
MS (CI) m/e 362 (M + H);
Anal calcd for CZIHasNsO: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.40; H, 6.38; N, 19.00.
Example 35 2-Butyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine Part A
Under an atmosphere of nitrogen, NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (2.48 g, 6.82 mmol) was dissolved in toluene (40 ml). Trimethyl orthovalerate (1.29 ml, 7.51 mmol) was added via syringe.
A catalytic amount of pyridine hydrochloride was added to the reaction and the flask was fitted with a Dean-Stark trap. The reaction was heated to reflux and the volatiles were collected in the trap. After 4 hours, the reaction was cooled to room temperature and quenched by the addition of water (30 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 15 ml). The combined organic fractions were washed with brine (25 ml), dried (Na2SO4), filtered and concentrated iya vacuo to provide a red/brown oil. The material was purified by flash column chromatography (silica gel, 2/1 to 95/5 ethyl acetate/hexane gradient) to yield 1.98 g of 2-butyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline as an orange oil.
1H NMR (300 MHz, DMSO-d6) 8 8.53 (d, J = 8.2 Hz, 1 H), 8.41 (d, J = 7.9 Hz, 1 H), 8.37 (d, J = 5.0 Hz, 1 H), 8.31 (d, J = 1.9 Hz, 1 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.75 (t, J = 7.5 Hz, 1 H), 7.48 (d, J = 7.9 Hz, 1 H), 7.23 (dd, J = 7.8, 4.9 Hz, 1 H), 3.63 (t, J =
5.0 Hz, 2 H), 3 .5 6 (t, J = 4.9 Hz, 2 H), 3 .3 6 (t, J = 6.3 Hz, 2 H), 2. 51 (m, 2H), 2.12 (t, J = 7. 7 Hz, 2 H), 1.73 (pentet, J = 7.4 Hz, 2 H), 1.45 (pentet, J = 7.7 Hz, 2 H), 1.12 (m, 2 H), 0.68 (t, J = 7.4 Hz, 3 H);
MS (CI) m/e 430 (M + H).
Part B
2-Butyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetrazolo[1,5-a]quinoline (1.98 g, 4.61 mmol) was treated following the general procedure described in Example 35. Recrystallization from isopropyl alcohol gave 1.09 g of 2-butyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinoline-4-amine as a beige solid.
1H NMR (300 MHz, DMSO-d6) 8 8.33 (d, J = 4.3 Hz, 1 H), 8.24 (s, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.30 - 7.20 (m, 2 H), 7.1.5 (dd, J = 7.4, 4.8 Hz, 1 H), 6.44 (bs, 2 H), 4.74 (t, J = 5.4 Hz, 2 H), 3.82 (t, J = 5.3 Hz, 2 H), 3.27 (t, J = 5.9 Hz, 2 H), 2.97 (t, J = 7.4 Hz, 2 H), 2.41 (t, J = 7.5 Hz, 2 H), 1.84 (p~ntet, J
= 7.4 Hz, 2 H), 1.64 (pentet, J = 7.2 Hz, 2 H), 1.46 (m, 2 H), 0.95 (t, J =
7.3 Hz, 3 H);
MS (CI) m/e 404 (M + H);
Anal calcd for Cz4HZgN50: C, 71.44; H, 7.24; N, 17.36. Found: C, 71.23; H, 6.98; N, 17.05.
Example 36 2-(2-Methoxyethyl)-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H
imidazo[4,5-c]quinolin-4-amine N ~ Nr' Om '~ N
O
N
Part A
Under a nitrogen atmosphere, NS-[2-(3-pyridin-3-ylpropoxy)ethyl]tetraazolo[1,5-a]quinoline-4,5-diamine (2.48 g, 6.82 mmol), 1,2-dichloroethane (30 ml), and triethylamine (1.14 ml, 8.2 mmol) were combined and the resulting solution was chilled in an ice water bath. 3-methoxypropionyl chloride (0.92 g, 7.5 mmol) was added dropwise to the solution. The cooling bath was removed and the reaction was stirred for an additional 18 hours. The solution was quenched by the addition of water (30 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 ml). The combined organic fractions were washed with brine (20 ml), dried (Na2S04), filtered and concentrated to yield 3.16 g of an orange syrup. LCMS analysis of the crude product showed a mixture of mono- and di-acylated product. The material was used without further purification.
Part B
Under a nitrogen atmosphere, the product from part A (3.16 g), toluene (40 ml), and pyridine hydrochloride (50 mg, 0,4 mmol) were combined and the resulting mixture was heated at reflux temperature for 4 hours. The volatiles were collected in a Dean-Stark trap. The reaction was cooled to ambient temperature and then diluted with water (30 ml).
The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (20 ml), dried (Na2S04), filtered and concentrated to yield an orange foam. The material was purified by column chromatography (silica gel, 99:1 CHCI3:MeOH gradient to 9:1) and then recrystallized from 2-propanol to yield 0.35 g of 5-(2-methoxyethyl)-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,5-c]tetraazolo[1,5-a]quinoline as a beige solid.
Part C
5-(2-rnethoxyethyl)-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H imidazo[4,S-c]tetraazolo[1,5-a]quinoline (0.35 g, 0.80 mmol) was treated with triphenylphosphine (0.28 g, 1.20 mmol) using the general procedure described in Part B of example 35. The crude product was crystallized from ether to yield 90 mg of 2-(2-methoxyethyl)-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as off white crystals.
1H NMR (300 MHz, CDC13) 8 8.39 (dd, J = 4.8, 1.5 Hz, 1 H), 8.33 (d, J = 1.8 Hz, 1 H), 7.94 (d, J = 7.4 Hz, 1 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.52-7.47 (m, 1 H), 7.32-7.21 (m, 2 H), 7.09 (dd, J = 7.0, 4.8 Hz, 1 H), 5.59 (bs, 2 H), 4.74 (t, J = 5.4 Hz, 2 H), 3.90 (t, J = 6.6 Hz, 2 H), 3.87 (t, J = 5.4 Hz, 2 H), 3.38 (s, 3 H), 3.33 (t, J = 6.1 Hz, 2 H), 3.28 (t, J = 6.6 Hz, 2 H), 2.51 (t, J = 7.4 Hz, 2 H), 1.81-1.71 (m, 2 H);
13C NMR (75 MHz, CDC13) 8 152.4, 151.6, 150.2, 147.8, 145,2, 137.1, 136.2, 133.7, 127.7, 127.4, 123.6, 122.5, 120.0, 115.9, 71.2, 70.6, 69.6, 59.4, 46.1, 31.1, 29.6, 28.7;
MS(CI) m/e 406.2242 calcd for (406.2243 C23H28N502, M+H).
Example 37 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H imidazo[4,5 c]quinolin-4-amine NHZ
N~ \ N
N
O
s N
Part A
A 200 mL round bottom flask was charged with 3-nitro-5,6,7,8-tetrahydroquinoline-2,4-diol (10 g, 0.048 mol.) and phosphorous oxychloride (100 mL, 1.07 mol., 22 equivalents). The reaction mixture was heated to 80°C and maintained, with stirnng for six hours. The reaction was quenched by slowly adding the reaction mixture to water (1500 mL). The reaction mixture was extracted with dichloromethane (4 x mL). The dichloromethane fractions were combined, dried over magnesium sulfate and concentrated to provide 2,4-dichloro-3-vitro-5,6,7,8-tetrahydroquinoline as a tan solid (10.6 g, 91 %). m.p. 63-64°C. TLC (10% MeOH/CH2CL2, Rf--0.84).
Part B
A 200 ml round bottom flask was charged with 2,4-dichloro-3-vitro-5,6,7,8-tetrahydroquinoline (10 g, 0.04 mol), triethylamine (6.1g, 0.06 mol, 1.5 equivalents) and anhydrous N,N-dimethylformamide (100 mL). To this solution was added 2-(3-pynidin-3-ylpropoxy)ethanamine (7.3 g, 0.04 mol). The reaction mixture was heated to 55°C and maintained overnight with stirring. The reaction was quenched by pouring into water (1000 mL). The reaction mixture was then extracted with a 1:1 solution of hexane/ethyl acetate (4 x 200 mL). The organics were combined, washed with brine (300 mL) and concentrated to provide 2-chloro-3-vitro-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine as an orange syrup (14.8 g, 94%). TLC (10%
MeOH/CH2CL2, R~0.84).
Part C
A 200 mL round bottom flask was charged with 60% sodium hydride (2.5 g, 0.06 mol, 1.7 equivalents) and washed with hexane (50 mL). A solution of phenol (5.7 g, 0.06 mol, 1.6 equivalents) in diglyrne (25 mL) was then slowly added to the sodium hydride.
The reaction was maintained with stirring at room temperature for 1.5 hours.
To the phenol anion solution was slowly added a solution of 2-chloro-3-nitro-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine (14.8 g, 0.04 mol) in diglyme (25 mL). The stirred reaction mixture was heated to 60°C and maintained overnight. The reaction was quenched by pouring onto ice (1000 mL). The product oiled out of solution.
The mixture was extracted with dichloromethane (4 x1 00 mL). The combined extracts were concentrated to dryness. The residue was taken up in 1:1 hexane/ethyl acetate (250 mL) and washed with water (2 x 50 mL). The organic layer was concentrated to dryness.
The residue was found to contain excess phenol. The phenol was removed by taking the residue up in diethyl ether (500 mL) and stirring over 10% sodium hydroxide (250 mL) overnight. The layers were separated. The ether layer was concentrated to provide 3-nitro-2-phenoxy-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydxoquinolin-4-amine as a pale orange syrup (12.0 g, 71%). TLC=(10% MeOH/CH2C12, Rf--0.58).
Part D
A 500 mL Parr bottle was charged with a solution of 3-nitro-2-phenoxy-N [2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine in toluene (150 mL) and 5% Pt/C catalyst (l .l g), placed on Parr apparatus and charged with hydrogen (~54 psi, 3.8 Kg/cm2). The reaction was allowed to shake for 4 hours, at which time the reaction was monitored by HPLC. The reaction was not complete. An additional 1.0 g 5% PtIC
catalyst was added to the Parr bottle, it was recharged with hydrogen and shaken overnight. The reaction was then complete. The mixture was filtered through Celite and washed with toluene (500 mL). The filtrate was concentrated to provide 2-phenoxy-1V4-[2 (3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine as a yellow syrup (8.2 g, 74%). TLC (10% MeOH/CH2C12, R~0.48). Mass-spec M+1=419.2 Part E
A 200 ml round bottom flask was charged with 2-phenoxy-1V4-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine (4.1 g, 0.0098 mol.) and pyridine (40 mL) at room temperature. To this solution was slowly added acetyl chloride (0.8 g, 0.011 mol., 1.1 equivalents). The reaction was maintained with stirring at room temperature. After two hours the reaction was monitored and found to only contain the amide intermediate. The reaction mixture was then heated to reflux and maintained overnight. The reaction mixture was concentrated to provide a dark amber syrup. The syrup was taken up in ethyl acetate (300 mL) and washed with water (2 x 100 mL). The ethyl acetate layer was concentrated to provide 2-methyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinoline as an orange syrup (3.8 g, 88%). TLC (10%MeOH/CH2C12, Rf--0.34). Mass-spec M+1=443.2 Part F
A 200 ml round bottom flask was charged with 2-methyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline (3.7 g, 0.0084 mol.) and ammonium acetate (37 g, 0.48 mol, 57 equivalents) and then heated to 150°C.
Within 20 minutes the reaction mixture was homogeneous. The reaction mixture was maintained with stirring at 150°C overnight. The reaction was monitored after 24 hours and found to be incomplete. The reaction mixture was maintained over the weekend. The reaction mixture was cooled and then taken up in 1N HCl (250 mL) and washed with diethyl ether (200 mL). The aqueous layer was then adjusted to pHl 1 with sodium hydroxide and extracted with dichloromethane (3 x 100 mL). The combined organics were concentrated to provide an orange syrup, The syrup was purified by column chromatography (10% MeOH/CH2Cl2). The appropriate fractions were combined and concentrated to provide a pale orange syrup. The syrup was found to be a mixture of the desired product and N-acetylated product. The mixture was treated with refluxing 1N HCl for 1 hour. The mixture was cooled, adjusted to pH 11 and then extracted with dichloromethane. The organics were concentrated to dryness. The residua was purified by column chromatography to provide 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine as a pale gold solid (0.07 g, 2%). TLC
(10% MeOH/CH2Cl2 R~0.05). m.p. 140-141°C.
CYTOI~INE INDUCTION 1N HUMAN CELLS
An in vitro human blood cell system is used to assess cytokine induction.
Activity is based on the measurement of interferon and tumor necrosis factor (a) (IFN
and TNF, respectively) secreted into culture media as described by Testerman et. al. In "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
Blood Cell Preparation for Culture Whole blood from healthy human donors is collected by venipuncture into EDTA
vacutainer tubes. Peripheral blood mononuclear cells (PBMCs) are separated from whole blood by density gradient centrifugation using Histopaque~-1077. The PBMCs are washed twice with Hanlc's Balanced Salts Solution and then are suspended at 3-4 x 106 cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
Compound Preparation The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO
concentration should not exceed a final concentration of 1% for addition to the culture wells Incubation The solution of test compound is added at 60 ~M to the first well containing RPMI
complete and serial 3 fold dilutions are made in the wells. The PBMC
suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (0.12 to 30 ~M). The final concentration of PBMC suspension is 1.5-2 X
106 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
Se aration Following incubation the plates are centrifuged for 5-10 minutes at 1000 rpm 0200 x g) at 4°C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to sterile polypropylene tubes. Samples are maintained at -30 to -70°C until analysis. The samples are analyzed for interferon (a) and for tumor necrosis factor (a) by ELISA.
Interferon (a) and Tumor Necrosis Factor (a) Analysis by ELISA
Interferon (a) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL.
Tumor necrosis factor (a) (TNF)concentration is determined using ELISA kits available from Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Pharmingen, San Diego, CA. Results are expressed in pg/mL.
The table below lists the lowest concentration found to induce interferon and the lowest concentration found to induce tumor necrosis factor for each compound.
A "*"
indicates that no induction was seen at any of the tested concentrations;
generally the highest tested concentration was 10 or 30 ~,M.
Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Number Interferon Tumor Necrosis Factor 1 0.12 3.33 2 0.37 10 3 0.04 *
4 3.33 5 0.04 0.37 6 0.12 1.11 7 0.37 8 0.04 0.12 9 0.12 3.33 IO 1.11 1.I1 11 1.11 0.04 12 I.11 13 0.37 1.11 14 0.12 0.37 1.11 3.33 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Numbex Interferon Tumor Necrosis Factor 16 3.33 10 17 0.37 0.37 18 0.37 10 19 0.12 3.33 20 0.12 3.33 21 1.11 10 22 1.11 10 23 1.11 24 * *
26 I.Il 27 1.11 *
29 1.11 30 0.37 3.33 31 3.33 3.33 32 0.01 1.11 33 0.04 0,12 34 0.01 0.04 35 0.01 0.12
Claims (52)
1. A compound of the formula (I):
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
2. A compound or salt of claim 1 wherein R1 is -(CH2)0-3-heteroaryl.
3. A compound or salt of claim 2 wherein the heteroaryl is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 4-triazolyl, 2-benzofuranyl, 2-indolyl, 3-carbazolyl, 2-furanyl, 4-isoquinolinyl, 4-isoxazolyl, and 4-pyrazolyl
4. A compound or salt of claim 1 wherein X is -CH(alkyl)(alkyl)- wherein the alkyl groups can be the same or different.
5. A compound or salt of claim 1 wherein X is -CH2-CH2-
6. A compound or salt of claim 1 wherein X is -CH(C2H5)(CH2)-.
7. A compound or salt of claim 1 wherein R2 is H.
8. A compound or salt of claim 1 wherein R2 is alkyl.
9. A compound or salt of claim 1 wherein R2 is -alkyl-O-alkyl.
10. A compound of the formula (II) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R10 is selected from the group consisting of heteroaryl and heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-1o alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
n is 0 to 4;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
R10 is selected from the group consisting of heteroaryl and heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-1o alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
n is 0 to 4;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
11. A compound or salt of claim 10 wherein R10 is selected from the group consisting of heteroaryl and substituted heteroaryl.
12. A compound of claim 11 wherein the heteroaryl is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-pyrazolyl, 3-furanyl, 2-thienyl, and 2-pyrimidinyl.
13. A compound or salt of claim 10 wherein X is -CH(alkyl)(alkyl)-, wherein the alkyl groups can be the same or different.
14. A compound or salt of claim 10 wherein X is -CH2-CH2-.
15. A compound or salt of claim 10 wherein X is -CH(C2H5)(CH2)-.
16. A compound or salt of claim 10 wherein R2 is H, alkyl, or alkyl-O-alkyl.
17. A compound selected from the group consisting of:
1-(2-{[3-(isoquinolin-4-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(1,3-thiazol-2-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[3-(1H-4-pyrazolyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyrimidin-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyridin-4-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyridin-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyrimidin-5-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-{2-[(1-benzyl-1H-1,2,3-triazol-5-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-[2-({1-[(phenylsulfanyl)methyl]-1H-1,2,3-triazol-4-yl}methoxy)ethyl]-1H
imidazo[4,5-c]quinoline-4-amine;
1-[2-({1-[(phenylsulfanyl)methyl]-1H-1,2,3-triazol-5-yl}methoxy)ethyl]-1H
imidazo[4,5-c]quinoline-4-amine;
1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(pyridin-3-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(pyridin-2-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(pyrimidin-2-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(pyrid-4-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(fur-3-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
4-{3-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]-propyn-1-yl}
thiophen-2-ylcarboxaldehyde;
1-(2-{[3-(pyrid-2-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-methyl-1-[(pyrid-2-yloxy)methyl]propyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-{1-[(pyrid-2-yloxy)methyl]propyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-[2-(9H-carbazol-3-yloxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(1-methyl-1H-indol-2-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-thien-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;
2-butyl-1-[2,-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;
1-[2-(tetrahydrofuran-2-ylmethoxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(5-chloro-1-benzothien-3-yl)methoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(3-nitropyridin-2-yl)oxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-methyl-1-{[(3-nitropyridin-2-yl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-(1-{[(5-chloro-1-benzothien-3-yl)methoxy]methyl}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine;
2-(2-methoxyethyl)-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine; and 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;
or a pharmaceutically acceptable salt thereof.
1-(2-{[3-(isoquinolin-4-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(1,3-thiazol-2-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[3-(1H-4-pyrazolyl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyrimidin-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyridin-4-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyridin-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-pyrimidin-5-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-{2-[(1-benzyl-1H-1,2,3-triazol-5-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-[2-({1-[(phenylsulfanyl)methyl]-1H-1,2,3-triazol-4-yl}methoxy)ethyl]-1H
imidazo[4,5-c]quinoline-4-amine;
1-[2-({1-[(phenylsulfanyl)methyl]-1H-1,2,3-triazol-5-yl}methoxy)ethyl]-1H
imidazo[4,5-c]quinoline-4-amine;
1-[2-(benzo[b]furan-2-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(pyridin-3-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(pyridin-2-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(pyridin-4-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(pyrimidin-2-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(pyrid-4-yl)-2-propynyl]oxy}ethyl)-1H imidazo[4,5-c]quinolin-4-amine;
1-(2-{[3-(fur-3-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
4-{3-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]-propyn-1-yl}
thiophen-2-ylcarboxaldehyde;
1-(2-{[3-(pyrid-2-yl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-methyl-1-[(pyrid-2-yloxy)methyl]propyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-{1-[(pyrid-2-yloxy)methyl]propyl}-1H-imidazo[4,5-c]quinoline-4-amine;
1-[2-(9H-carbazol-3-yloxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(3-thien-2-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(1-methyl-1H-indol-2-yl)methoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-[2-(3-thien-2-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine;
2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;
2-butyl-1-[2,-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinoline-4-amine;
1-[2-(tetrahydrofuran-2-ylmethoxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(5-chloro-1-benzothien-3-yl)methoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-{2-[(3-nitropyridin-2-yl)oxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine;
1-(2-methyl-1-{[(3-nitropyridin-2-yl)oxy]methyl}propyl)-1H-imidazo[4,5-c]quinolin-4-amine;
1-(1-{[(5-chloro-1-benzothien-3-yl)methoxy]methyl}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine;
2-(2-methoxyethyl)-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine; and 2-methyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine;
or a pharmaceutically acceptable salt thereof.
18. A compound of the formula (III) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
19. A compound or salt of claim 18 wherein R2 is H or alkyl.
20. A compound or salt of claim 18 wherein R2 is -alkyl-O-alkyl.
21. A compound of the formula (IV):
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R10 is selected from the group consisting of heteroaryl and heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R10 is selected from the group consisting of heteroaryl and heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
23. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 10 and a pharmaceutically acceptable carrier.
24. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 17 and a pharmaceutically acceptable carrier.
25. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
26. The method of claim 25 wherein the cytokine is IFN-.alpha..
27. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 10 to the animal.
28. The method of claim 27 wherein the cytokine is IFN-.alpha..
29. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
30. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
31. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 10 to the animal.
32. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 10 to the animal.
33. A method of inducing cytokine biosynthesis in an animal comprising administering a theraputically effective amount of a compound or salt of claim 17 to the animal.
34. The method of claim 33 wherein the cytokine is IFN-.alpha..
35. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 17 to the animal.
36. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 17 to the animal.
37. A compound of the formula (V):
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl;
-R4-heterocyclyl; and -(CH2)1-10-C=C-R10;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
R10 is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl;
-R4-heterocyclyl; and -(CH2)1-10-C=C-R10;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
R10 is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
38. A compound of the formula (VI):
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4-heteroaryl;
-R4-heterocyclyl; and -(CH2)1-10-C.ident.C-R10;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
R10 is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4-heteroaryl;
-R4-heterocyclyl; and -(CH2)1-10-C.ident.C-R10;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
R10 is heteroaryl or heterocyclyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
39. A compound of the formula (VIII):
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4-heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4;
each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl; and R7 is tert-butyl or benzyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4-heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently -O- or -S(O)0-2-;
n is 0 to 4;
each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl; and R7 is tert-butyl or benzyl;
or a pharmaceutically acceptable salt thereof.
40. A compound of the formula (IX) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more ~O~
groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently ~O~ or ~S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4- heteroaryl; and -R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more ~O~
groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently ~O~ or ~S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim, 18 and a pharmaceutically acceptable carrier.
42. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 18 to the animal.
43. The method of claim 42 wherein the cytokine is IFN-.alpha..
44. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 18 to the animal.
45. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 18 to the animal.
46. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 21 and a pharmaceutically acceptable carrier.
47. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 21 to the animal.
48. The method of claim 47 wherein the cytokine is IFN-.alpha..
49. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 21 to the animal.
50. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 21 to the animal.
51. A compound of the formula (VII):
wherein: Z is NH2 or NO2;
X is ~CHR3-, -CHR3-alkyl-, or ~CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4~ heteroaryl; and -R4~heterocyclyl;
R4 is alkyl or alkenyl, which may be interrupted by one or more ~O~
groups;
each R3 is independently H or C1-10 alkyl;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: Z is NH2 or NO2;
X is ~CHR3-, -CHR3-alkyl-, or ~CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4~ heteroaryl; and -R4~heterocyclyl;
R4 is alkyl or alkenyl, which may be interrupted by one or more ~O~
groups;
each R3 is independently H or C1-10 alkyl;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
52. A compound of the formula (XLIV):
wherein: X is ~CHR3-, -CHR3-alkyl-, or ~CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4~ heteroaryl; and -R4~heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more ~O~
groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently ~O~ or ~S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is ~CHR3-, -CHR3-alkyl-, or ~CHR3-alkenyl-;
R1 is selected from the group consisting of:
-heteroaryl;
-heterocyclyl;
-R4~ heteroaryl; and -R4~heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R4 is alkyl or alkenyl, which may be interrupted by one or more ~O~
groups;
each R3 is independently H or C1-10 alkyl;
each Y is independently ~O~ or ~S(O)0-2-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25421800P | 2000-12-08 | 2000-12-08 | |
US60/254,218 | 2000-12-08 | ||
PCT/US2001/046704 WO2002046193A2 (en) | 2000-12-08 | 2001-12-06 | Heterocyclic ether substituted imidazoquinolines |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2431151A1 true CA2431151A1 (en) | 2002-06-13 |
Family
ID=22963391
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002430844A Withdrawn CA2430844A1 (en) | 2000-12-08 | 2001-12-06 | Aryl ether substituted imidazoquinolines |
CA2436980A Expired - Fee Related CA2436980C (en) | 2000-12-08 | 2001-12-06 | Amido ether substituted imidazoquinolines |
CA002431151A Withdrawn CA2431151A1 (en) | 2000-12-08 | 2001-12-06 | Heterocyclic ether substituted imidazoquinolines |
CA002436984A Abandoned CA2436984A1 (en) | 2000-12-08 | 2001-12-06 | Urea substituted imidazoquinoline ethers |
CA002436983A Abandoned CA2436983A1 (en) | 2000-12-08 | 2001-12-06 | Sulfonamido ether substituted imidazoquinolines |
CA2436846A Expired - Fee Related CA2436846C (en) | 2000-12-08 | 2001-12-06 | Thioether substituted imidazoquinolines |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002430844A Withdrawn CA2430844A1 (en) | 2000-12-08 | 2001-12-06 | Aryl ether substituted imidazoquinolines |
CA2436980A Expired - Fee Related CA2436980C (en) | 2000-12-08 | 2001-12-06 | Amido ether substituted imidazoquinolines |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002436984A Abandoned CA2436984A1 (en) | 2000-12-08 | 2001-12-06 | Urea substituted imidazoquinoline ethers |
CA002436983A Abandoned CA2436983A1 (en) | 2000-12-08 | 2001-12-06 | Sulfonamido ether substituted imidazoquinolines |
CA2436846A Expired - Fee Related CA2436846C (en) | 2000-12-08 | 2001-12-06 | Thioether substituted imidazoquinolines |
Country Status (32)
Country | Link |
---|---|
US (8) | US6670372B2 (en) |
EP (6) | EP1343784B1 (en) |
JP (7) | JP2004515501A (en) |
KR (6) | KR20040047733A (en) |
CN (6) | CN1247575C (en) |
AR (6) | AR035669A1 (en) |
AT (3) | ATE296301T1 (en) |
AU (12) | AU2002232482B2 (en) |
BR (6) | BR0116470A (en) |
CA (6) | CA2430844A1 (en) |
CY (2) | CY1105586T1 (en) |
CZ (6) | CZ20031562A3 (en) |
DE (3) | DE60126645T2 (en) |
DK (3) | DK1341791T3 (en) |
EE (6) | EE200300271A (en) |
ES (3) | ES2260323T3 (en) |
HK (3) | HK1064383A1 (en) |
HR (6) | HRP20030466A2 (en) |
HU (6) | HUP0400710A2 (en) |
IL (6) | IL155950A0 (en) |
MX (6) | MXPA03005012A (en) |
NO (6) | NO20032449D0 (en) |
NZ (6) | NZ526106A (en) |
PL (7) | PL392462A1 (en) |
PT (2) | PT1341790E (en) |
RU (6) | RU2315049C2 (en) |
SI (1) | SI1341790T1 (en) |
SK (6) | SK6842003A3 (en) |
TW (3) | TWI222972B (en) |
UA (2) | UA74852C2 (en) |
WO (6) | WO2002046188A2 (en) |
ZA (6) | ZA200305270B (en) |
Families Citing this family (206)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5741908A (en) | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
UA67760C2 (en) * | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines |
US6331539B1 (en) * | 1999-06-10 | 2001-12-18 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
US6756382B2 (en) | 1999-06-10 | 2004-06-29 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6573273B1 (en) | 1999-06-10 | 2003-06-03 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6541485B1 (en) | 1999-06-10 | 2003-04-01 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6916925B1 (en) | 1999-11-05 | 2005-07-12 | 3M Innovative Properties Co. | Dye labeled imidazoquinoline compounds |
JP3436512B2 (en) * | 1999-12-28 | 2003-08-11 | 株式会社デンソー | Accelerator device |
US6545017B1 (en) * | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Urea substituted imidazopyridines |
US6660735B2 (en) | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Urea substituted imidazoquinoline ethers |
US6545016B1 (en) * | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Amide substituted imidazopyridines |
US6677348B2 (en) | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Aryl ether substituted imidazoquinolines |
US6677347B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamido ether substituted imidazoquinolines |
UA74852C2 (en) | 2000-12-08 | 2006-02-15 | 3M Innovative Properties Co | Urea-substituted imidazoquinoline ethers |
US6660747B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6667312B2 (en) * | 2000-12-08 | 2003-12-23 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6664265B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6664264B2 (en) | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6525064B1 (en) | 2000-12-08 | 2003-02-25 | 3M Innovative Properties Company | Sulfonamido substituted imidazopyridines |
US7226928B2 (en) * | 2001-06-15 | 2007-06-05 | 3M Innovative Properties Company | Methods for the treatment of periodontal disease |
EP1450804B9 (en) * | 2001-11-29 | 2009-04-01 | 3M Innovative Properties Company | Pharmaceutical formulations comprising an immune response modifier |
WO2004080430A2 (en) * | 2003-03-13 | 2004-09-23 | 3M Innovative Properties Company | Methods of improving skin quality |
CA2365732A1 (en) | 2001-12-20 | 2003-06-20 | Ibm Canada Limited-Ibm Canada Limitee | Testing measurements |
US6677349B1 (en) | 2001-12-21 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
IL147953A (en) | 2002-02-01 | 2008-04-13 | Meir Bialer | Derivatives and pharmaceutical compositions of n-hydroxymethyl tetramethylcyclopropyl- |
EP1478327B1 (en) * | 2002-02-22 | 2015-04-29 | Meda AB | Method of reducing and treating uvb-induced immunosuppression |
GB0211649D0 (en) | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
AU2003237386A1 (en) * | 2002-06-07 | 2003-12-22 | 3M Innovative Properties Company | Ether substituted imidazopyridines |
AU2003281340B2 (en) | 2002-07-02 | 2009-04-09 | Southern Research Institute | Inhibitors of FtsZ and uses thereof |
ATE488246T1 (en) | 2002-08-15 | 2010-12-15 | 3M Innovative Properties Co | IMMUNO-STIMULATORY COMPOSITIONS AND METHODS FOR STIMULATING AN IMMUNE RESPONSE |
JP2006503068A (en) | 2002-09-26 | 2006-01-26 | スリーエム イノベイティブ プロパティズ カンパニー | 1H-Imidazo dimer |
AU2003301052A1 (en) | 2002-12-20 | 2004-07-22 | 3M Innovative Properties Company | Aryl / hetaryl substituted imidazoquinolines |
EP2572715A1 (en) | 2002-12-30 | 2013-03-27 | 3M Innovative Properties Company | Immunostimulatory Combinations |
WO2004071459A2 (en) | 2003-02-13 | 2004-08-26 | 3M Innovative Properties Company | Methods and compositions related to irm compounds and toll-like receptor 8 |
EP1599726A4 (en) | 2003-02-27 | 2009-07-22 | 3M Innovative Properties Co | Selective modulation of tlr-mediated biological activity |
AU2004218349A1 (en) | 2003-03-04 | 2004-09-16 | 3M Innovative Properties Company | Prophylactic treatment of UV-induced epidermal neoplasia |
AU2004220534A1 (en) * | 2003-03-07 | 2004-09-23 | 3M Innovative Properties Company | 1-amino 1H-imidazoquinolines |
US7163947B2 (en) * | 2003-03-07 | 2007-01-16 | 3M Innovative Properties Company | 1-Amino 1H-imidazoquinolines |
JP2006523212A (en) * | 2003-03-13 | 2006-10-12 | スリーエム イノベイティブ プロパティズ カンパニー | Diagnosis method of skin lesion |
JP2006520245A (en) | 2003-03-13 | 2006-09-07 | スリーエム イノベイティブ プロパティズ カンパニー | How to remove a tattoo |
US20040192585A1 (en) | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
US20040265351A1 (en) * | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
CA2521682A1 (en) * | 2003-04-10 | 2004-12-16 | 3M Innovative Properties Company | Delivery of immune response modifier compounds using metal-containing particulate support materials |
WO2004096144A2 (en) * | 2003-04-28 | 2004-11-11 | 3M Innovative Properties Company | Compositions and methods for induction of opioid receptors |
WO2004110992A2 (en) * | 2003-06-06 | 2004-12-23 | 3M Innovative Properties Company | Process for imidazo[4,5-c] pyridin-4-amines |
WO2004110991A2 (en) * | 2003-06-06 | 2004-12-23 | 3M Innovative Properties Company | PROCESS FOR IMIDAZO[4,5-c]PYRIDIN-4-AMINES |
JP2007501252A (en) * | 2003-08-05 | 2007-01-25 | スリーエム イノベイティブ プロパティズ カンパニー | Formulation containing immune response modifier |
AR045260A1 (en) * | 2003-08-12 | 2005-10-19 | 3M Innovative Properties Co | COMPOUNDS CONTAINING IMIDAZO-OXIMA REPLACED |
EP2939693A1 (en) * | 2003-08-14 | 2015-11-04 | 3M Innovative Properties Company | Lipid-modified immune response modifiers |
ES2545826T3 (en) * | 2003-08-14 | 2015-09-16 | 3M Innovative Properties Company | Lipid Modified Immune Response Modifiers |
WO2005020912A2 (en) * | 2003-08-25 | 2005-03-10 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
WO2005018574A2 (en) * | 2003-08-25 | 2005-03-03 | 3M Innovative Properties Company | Immunostimulatory combinations and treatments |
AR045529A1 (en) | 2003-08-27 | 2005-11-02 | 3M Innovative Properties Co | IMIDAZOQUINOLINAS REPLACED WITH ARILOXI OR ARILALQUILENOXI GROUPS |
US20060216333A1 (en) * | 2003-09-02 | 2006-09-28 | Miller Richard L | Methods related to the treatment of mucosal associated conditions |
US20050054665A1 (en) * | 2003-09-05 | 2005-03-10 | 3M Innovative Properties Company | Treatment for CD5+ B cell lymphoma |
JP2007505629A (en) * | 2003-09-17 | 2007-03-15 | スリーエム イノベイティブ プロパティズ カンパニー | Selective regulation of TLR gene expression |
US20090075980A1 (en) * | 2003-10-03 | 2009-03-19 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and Analogs Thereof |
SG149829A1 (en) | 2003-10-03 | 2009-02-27 | 3M Innovative Properties Co | Pyrazolopyridines and analogs thereof |
US7544697B2 (en) * | 2003-10-03 | 2009-06-09 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and analogs thereof |
CN1897948A (en) * | 2003-10-03 | 2007-01-17 | 3M创新有限公司 | Alkoxy substituted imidazoquinolines |
WO2005041891A2 (en) * | 2003-10-31 | 2005-05-12 | 3M Innovative Properties Company | Neutrophil activation by immune response modifier compounds |
US8598192B2 (en) | 2003-11-14 | 2013-12-03 | 3M Innovative Properties Company | Hydroxylamine substituted imidazoquinolines |
EP1685129A4 (en) * | 2003-11-14 | 2008-10-22 | 3M Innovative Properties Co | Oxime substituted imidazo ring compounds |
PL1687305T3 (en) * | 2003-11-21 | 2008-12-31 | Novartis Ag | 1h-imidazoquinoline derivatives as protein kinase inhibitors |
AR046845A1 (en) * | 2003-11-21 | 2005-12-28 | Novartis Ag | DERIVATIVES OF 1H-IMIDAZO [4,5-C] QUINOLINE FOR THE TREATMENT OF PROTEIN-KINASE DEPENDENT DISEASES |
JP4891088B2 (en) | 2003-11-25 | 2012-03-07 | スリーエム イノベイティブ プロパティズ カンパニー | Substituted imidazo ring systems and methods |
US8778963B2 (en) * | 2003-11-25 | 2014-07-15 | 3M Innovative Properties Company | Hydroxylamine and oxime substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
US8940755B2 (en) * | 2003-12-02 | 2015-01-27 | 3M Innovative Properties Company | Therapeutic combinations and methods including IRM compounds |
CN1914203A (en) * | 2003-12-04 | 2007-02-14 | 3M创新有限公司 | Sulfone substituted imidazo ring ethers |
US7888349B2 (en) * | 2003-12-29 | 2011-02-15 | 3M Innovative Properties Company | Piperazine, [1,4]Diazepane, [1,4]Diazocane, and [1,5]Diazocane fused imidazo ring compounds |
JP2007517035A (en) * | 2003-12-29 | 2007-06-28 | スリーエム イノベイティブ プロパティズ カンパニー | Arylalkenyl and arylalkynyl substituted imidazoquinolines |
EP1699398A4 (en) * | 2003-12-30 | 2007-10-17 | 3M Innovative Properties Co | Enhancement of immune responses |
US8735421B2 (en) | 2003-12-30 | 2014-05-27 | 3M Innovative Properties Company | Imidazoquinolinyl sulfonamides |
US20050158325A1 (en) * | 2003-12-30 | 2005-07-21 | 3M Innovative Properties Company | Immunomodulatory combinations |
JP4991520B2 (en) * | 2004-03-15 | 2012-08-01 | スリーエム イノベイティブ プロパティズ カンパニー | Immune response modulator formulation and method |
EP1730143A2 (en) | 2004-03-24 | 2006-12-13 | 3M Innovative Properties Company | Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines |
EP1735010A4 (en) * | 2004-04-09 | 2008-08-27 | 3M Innovative Properties Co | Methods, compositions, and preparations for delivery of immune response modifiers |
US20050267145A1 (en) * | 2004-05-28 | 2005-12-01 | Merrill Bryon A | Treatment for lung cancer |
US20080015184A1 (en) * | 2004-06-14 | 2008-01-17 | 3M Innovative Properties Company | Urea Substituted Imidazopyridines, Imidazoquinolines, and Imidazonaphthyridines |
WO2005123080A2 (en) | 2004-06-15 | 2005-12-29 | 3M Innovative Properties Company | Nitrogen-containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines |
WO2006009826A1 (en) | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines |
WO2006065280A2 (en) | 2004-06-18 | 2006-06-22 | 3M Innovative Properties Company | Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and methods |
WO2006038923A2 (en) | 2004-06-18 | 2006-04-13 | 3M Innovative Properties Company | Aryl substituted imidazonaphthyridines |
EP1765348B1 (en) * | 2004-06-18 | 2016-08-03 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
US8541438B2 (en) | 2004-06-18 | 2013-09-24 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
WO2006009832A1 (en) * | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Substituted imidazo ring systems and methods |
AU2005282726B2 (en) * | 2004-09-02 | 2011-06-02 | 3M Innovative Properties Company | 1-alkoxy 1H-imidazo ring systems and methods |
WO2006029115A2 (en) | 2004-09-02 | 2006-03-16 | 3M Innovative Properties Company | 2-amino 1h imidazo ring systems and methods |
US20090270443A1 (en) * | 2004-09-02 | 2009-10-29 | Doris Stoermer | 1-amino imidazo-containing compounds and methods |
WO2006029223A2 (en) * | 2004-09-08 | 2006-03-16 | Children's Medical Center Corporation | Method for stimulating the immune response of newborns |
WO2006031878A2 (en) * | 2004-09-14 | 2006-03-23 | Novartis Vaccines And Diagnostics Inc. | Imidazoquinoline compounds |
EP1804583A4 (en) * | 2004-10-08 | 2009-05-20 | 3M Innovative Properties Co | Adjuvant for dna vaccines |
WO2006063072A2 (en) * | 2004-12-08 | 2006-06-15 | 3M Innovative Properties Company | Immunomodulatory compositions, combinations and methods |
US8080560B2 (en) * | 2004-12-17 | 2011-12-20 | 3M Innovative Properties Company | Immune response modifier formulations containing oleic acid and methods |
EP1831226B1 (en) * | 2004-12-30 | 2012-08-08 | 3M Innovative Properties Company | Chiral tetracyclic compounds inducing interferon biosynthesis |
US8034938B2 (en) | 2004-12-30 | 2011-10-11 | 3M Innovative Properties Company | Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds |
US8436176B2 (en) * | 2004-12-30 | 2013-05-07 | Medicis Pharmaceutical Corporation | Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine |
CA2592897A1 (en) * | 2004-12-30 | 2006-07-13 | Takeda Pharmaceutical Company Limited | 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate and 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate |
CA2594253C (en) | 2004-12-30 | 2015-08-11 | 3M Innovative Properties Company | Treatment for cutaneous metastases |
WO2006084251A2 (en) | 2005-02-04 | 2006-08-10 | Coley Pharmaceutical Group, Inc. | Aqueous gel formulations containing immune reponse modifiers |
WO2007120121A2 (en) | 2005-02-09 | 2007-10-25 | Coley Pharmaceutical Group, Inc. | Oxime and hydroxylamine substituted thiazolo[4,5-c] ring compounds and methods |
ES2475728T3 (en) | 2005-02-09 | 2014-07-11 | 3M Innovative Properties Company | Thiazoloquinolines and alkoxy substituted thiazolonaphthyridines |
WO2006086634A2 (en) | 2005-02-11 | 2006-08-17 | Coley Pharmaceutical Group, Inc. | Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods |
CA2597446A1 (en) | 2005-02-11 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Substituted imidazoquinolines and imidazonaphthyridines |
CN101203529A (en) | 2005-02-18 | 2008-06-18 | 诺华疫苗和诊断公司 | Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli |
ES2595363T3 (en) | 2005-02-18 | 2016-12-29 | J. Craig Venter Institute, Inc. | Sepsis associated with meningitis proteins and nucleic acids / Escherichia coli |
US8343993B2 (en) | 2005-02-23 | 2013-01-01 | 3M Innovative Properties Company | Hydroxyalkyl substituted imidazonaphthyridines |
CA2598437A1 (en) * | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Method of preferentially inducing the biosynthesis of interferon |
AU2006216798A1 (en) | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazoquinoline compounds and methods |
EP1851224A2 (en) | 2005-02-23 | 2007-11-07 | 3M Innovative Properties Company | Hydroxyalkyl substituted imidazoquinolines |
JP2008533148A (en) | 2005-03-14 | 2008-08-21 | スリーエム イノベイティブ プロパティズ カンパニー | Treatment method for actinic keratosis |
AU2006232375A1 (en) | 2005-04-01 | 2006-10-12 | Coley Pharmaceutical Group, Inc. | 1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases |
CA2602683A1 (en) | 2005-04-01 | 2006-10-12 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridine-1,4-diamines and analogs thereof |
US20080193474A1 (en) * | 2005-04-25 | 2008-08-14 | Griesgraber George W | Immunostimulatory Compositions |
CA2615626A1 (en) | 2005-07-18 | 2007-01-25 | Novartis Ag | Small animal model for hcv replication |
ZA200803029B (en) | 2005-09-09 | 2009-02-25 | Coley Pharm Group Inc | Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods |
JP2009507856A (en) | 2005-09-09 | 2009-02-26 | コーリー ファーマシューティカル グループ,インコーポレイテッド | Amide and carbamate derivatives of N- {2- [4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -1,1-dimethylethyl} methanesulfonamide and Method |
US8889154B2 (en) | 2005-09-15 | 2014-11-18 | Medicis Pharmaceutical Corporation | Packaging for 1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-4-amine-containing formulation |
AU2006310163B2 (en) | 2005-11-04 | 2011-09-15 | Seqirus UK Limited | Influenza vaccine with reduced amount of oil-in-water emulsion as adjuvant |
PT2368572T (en) | 2005-11-04 | 2020-06-16 | Seqirus Uk Ltd | Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture |
EP1948173B1 (en) | 2005-11-04 | 2013-07-17 | 3M Innovative Properties Company | Hydroxy and alkoxy substituted 1h-imidazoquinolines and methods |
US8697087B2 (en) | 2005-11-04 | 2014-04-15 | Novartis Ag | Influenza vaccines including combinations of particulate adjuvants and immunopotentiators |
EP2377551A3 (en) | 2005-11-04 | 2013-04-24 | Novartis Vaccines and Diagnostics S.r.l. | Adjuvanted influenza vaccines including cytokine-inducing agents |
ES2619160T7 (en) | 2006-01-27 | 2020-07-29 | Seqirus Uk Ltd | Flu vaccines containing hemagglutinin and matrix proteins |
US8951528B2 (en) | 2006-02-22 | 2015-02-10 | 3M Innovative Properties Company | Immune response modifier conjugates |
WO2007106854A2 (en) | 2006-03-15 | 2007-09-20 | Coley Pharmaceutical Group, Inc. | Hydroxy and alkoxy substituted 1h-imidazonaphthyridines and methods |
ES2536426T3 (en) | 2006-03-23 | 2015-05-25 | Novartis Ag | Imidazoquinoxaline compounds as immunomodulators |
EP2010530A2 (en) * | 2006-03-23 | 2009-01-07 | Novartis AG | Methods for the preparation of imidazole-containing compounds |
ES2388556T3 (en) * | 2006-03-23 | 2012-10-16 | Novartis Ag | Immunopotentiating compounds |
JP2009534303A (en) | 2006-03-24 | 2009-09-24 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス ゲーエムベーハー アンド カンパニー カーゲー | Preserving influenza vaccines that are not refrigerated |
SG173336A1 (en) | 2006-03-31 | 2011-08-29 | Novartis Ag | Combined mucosal and parenteral immunization against hiv |
DK2054431T3 (en) | 2006-06-09 | 2012-01-02 | Novartis Ag | Conformers of bacterial adhesins |
US7906506B2 (en) | 2006-07-12 | 2011-03-15 | 3M Innovative Properties Company | Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods |
GB0614460D0 (en) | 2006-07-20 | 2006-08-30 | Novartis Ag | Vaccines |
EP2064230A2 (en) | 2006-08-16 | 2009-06-03 | Novartis AG | Immunogens from uropathogenic escherichia coli |
WO2008030511A2 (en) | 2006-09-06 | 2008-03-13 | Coley Pharmaceuticial Group, Inc. | Substituted 3,4,6,7-tetrahydro-5h, 1,2a,4a,8-tetraazacyclopenta[cd]phenalenes |
CA3016948A1 (en) | 2006-09-11 | 2008-03-20 | Seqirus UK Limited | Making influenza virus vaccines without using eggs |
EA200900784A1 (en) | 2006-12-06 | 2009-12-30 | Новартис Аг | VACCINES INCLUDING ANTIGENS FROM FOUR STRAINS OF THE INFLUENZA VIRUS |
US20080149123A1 (en) * | 2006-12-22 | 2008-06-26 | Mckay William D | Particulate material dispensing hairbrush with combination bristles |
GB0700562D0 (en) | 2007-01-11 | 2007-02-21 | Novartis Vaccines & Diagnostic | Modified Saccharides |
PL2185191T3 (en) | 2007-06-27 | 2013-02-28 | Novartis Ag | Low-additive influenza vaccines |
GB0714963D0 (en) | 2007-08-01 | 2007-09-12 | Novartis Ag | Compositions comprising antigens |
GB0810305D0 (en) | 2008-06-05 | 2008-07-09 | Novartis Ag | Influenza vaccination |
GB0818453D0 (en) | 2008-10-08 | 2008-11-12 | Novartis Ag | Fermentation processes for cultivating streptococci and purification processes for obtaining cps therefrom |
AU2008347400B2 (en) * | 2008-01-15 | 2014-12-11 | Meda Ab | Treatment of colon diseases or prevention of colorectal carcinoma with imidazoquinoline derivatives |
NZ588191A (en) | 2008-03-03 | 2012-06-29 | Irm Llc | Compounds and compositions as tlr activity modulators |
EP2889042A3 (en) | 2008-03-18 | 2015-10-14 | Novartis AG | Improvements in preparation of influenza virus vaccine antigens |
EP3549602A1 (en) | 2009-03-06 | 2019-10-09 | GlaxoSmithKline Biologicals S.A. | Chlamydia antigens |
MX2011010050A (en) | 2009-03-25 | 2011-12-14 | Univ Texas | Compositions for stimulation of mammalian innate immune resistance to pathogens. |
EP2510947B1 (en) | 2009-04-14 | 2016-02-10 | GlaxoSmithKline Biologicals SA | Compositions for immunising against Staphylococcus aureus |
CN102548577A (en) | 2009-04-27 | 2012-07-04 | 诺华有限公司 | Adjuvanted vaccines for protecting against influenza |
AU2013203591B2 (en) * | 2009-05-01 | 2017-01-19 | University Court Of The University Of Dundee | Treatment or prophylaxis of proliferative conditions |
GB0907551D0 (en) * | 2009-05-01 | 2009-06-10 | Univ Dundee | Treatment or prophylaxis of proliferative conditions |
CN105214080A (en) | 2009-07-15 | 2016-01-06 | 诺华股份有限公司 | RSV F protein compositions and its manufacture method |
PL2464658T3 (en) | 2009-07-16 | 2015-03-31 | Novartis Ag | Detoxified escherichia coli immunogens |
GB0918392D0 (en) | 2009-10-20 | 2009-12-02 | Novartis Ag | Diagnostic and therapeutic methods |
GB0919690D0 (en) | 2009-11-10 | 2009-12-23 | Guy S And St Thomas S Nhs Foun | compositions for immunising against staphylococcus aureus |
GB201009861D0 (en) | 2010-06-11 | 2010-07-21 | Novartis Ag | OMV vaccines |
RS55819B1 (en) | 2010-08-17 | 2017-08-31 | 3M Innovative Properties Co | Lipidated immune response modifier compound compositions, formulations, and methods |
EP2651937B8 (en) | 2010-12-16 | 2016-07-13 | Sumitomo Dainippon Pharma Co., Ltd. | Imidazo[4,5-c]quinolin-1-yl derivative useful in therapy |
EP2667892B1 (en) | 2011-01-26 | 2019-03-27 | GlaxoSmithKline Biologicals SA | Rsv immunization regimen |
PT3275892T (en) | 2011-05-13 | 2020-04-08 | Glaxosmithkline Biologicals Sa | Pre-fusion rsv f antigens |
US8728486B2 (en) | 2011-05-18 | 2014-05-20 | University Of Kansas | Toll-like receptor-7 and -8 modulatory 1H imidazoquinoline derived compounds |
CA2838158C (en) | 2011-06-03 | 2019-07-16 | 3M Innovative Properties Company | Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom |
BR112013031039B1 (en) | 2011-06-03 | 2020-04-28 | 3M Innovative Properties Co | hydrazine compounds 1h-imidazoquinoline-4-amines, conjugates made from these compounds, composition and pharmaceutical composition comprising said compounds and conjugates, uses thereof and method of manufacturing the conjugate |
US20130023736A1 (en) | 2011-07-21 | 2013-01-24 | Stanley Dale Harpstead | Systems for drug delivery and monitoring |
CA2854934A1 (en) | 2011-11-07 | 2013-05-16 | Novartis Ag | Carrier molecule comprising a spr0096 and a spr2021 antigen |
WO2013108272A2 (en) | 2012-01-20 | 2013-07-25 | International Centre For Genetic Engineering And Biotechnology | Blood stage malaria vaccine |
CN103566377A (en) | 2012-07-18 | 2014-02-12 | 上海博笛生物科技有限公司 | Targeted immunotherapy for cancer |
LT2941233T (en) | 2013-01-07 | 2020-10-26 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treating cutaneous t cell lymphoma |
EP3632458A1 (en) | 2013-07-26 | 2020-04-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of bacterial infections |
EP3065741B1 (en) | 2013-11-05 | 2021-09-22 | 3M Innovative Properties Company | Sesame oil based injection formulations |
EP2870974A1 (en) | 2013-11-08 | 2015-05-13 | Novartis AG | Salmonella conjugate vaccines |
JP2017503803A (en) | 2014-01-10 | 2017-02-02 | シャンハイ バーディー バイオテック インコーポレイテッド | Compounds and compositions for treating EGFR expressing tumors |
KR20160132109A (en) | 2014-03-26 | 2016-11-16 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | Mutant staphylococcal antigens |
CN105233291A (en) | 2014-07-09 | 2016-01-13 | 博笛生物科技有限公司 | Combined therapy composition and combined therapy method for treating cancers |
CN105440135A (en) | 2014-09-01 | 2016-03-30 | 博笛生物科技有限公司 | Anti-PD-L1 conjugate for treating tumors |
WO2016004876A1 (en) | 2014-07-09 | 2016-01-14 | Shanghai Birdie Biotech, Inc. | Anti-pd-l1 combinations for treating tumors |
CN105461767B (en) * | 2014-08-07 | 2019-03-12 | 富力 | A kind of chemical synthesis process of forsythin |
US10286065B2 (en) | 2014-09-19 | 2019-05-14 | Board Of Regents, The University Of Texas System | Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds |
RU2722149C1 (en) * | 2015-09-14 | 2020-05-27 | Пфайзер Инк. | New derivatives of imidazo [4,5-c] quinolines and imidazo [4,5-c] [1,5] naphthyridines as lrrk2 inhibitors |
JP2018531318A (en) * | 2015-09-29 | 2018-10-25 | ザ・ユニバーシティ・オブ・シカゴThe University Of Chicago | Polymer conjugate vaccine |
WO2017059280A1 (en) | 2015-10-02 | 2017-04-06 | The University Of North Carolina At Chapel Hill | Novel pan-tam inhibitors and mer/axl dual inhibitors |
CN106943598A (en) | 2016-01-07 | 2017-07-14 | 博笛生物科技(北京)有限公司 | Anti- HER2 for treating tumour is combined |
CN115554406A (en) | 2016-01-07 | 2023-01-03 | 博笛生物科技有限公司 | anti-CD 20 combinations for the treatment of tumors |
CN115252792A (en) | 2016-01-07 | 2022-11-01 | 博笛生物科技有限公司 | anti-EGFR combinations for the treatment of tumors |
CN110234401B (en) | 2016-11-09 | 2024-03-01 | 德克萨斯大学系统董事会 | Methods and compositions for adaptive immunomodulation |
CN108794467A (en) | 2017-04-27 | 2018-11-13 | 博笛生物科技有限公司 | 2- amino-quinoline derivatives |
JP7080501B2 (en) | 2017-06-23 | 2022-06-06 | バーディー バイオファーマシューティカルズ インコーポレイテッド | Pharmaceutical composition |
EP3728255B1 (en) | 2017-12-20 | 2022-01-26 | 3M Innovative Properties Company | Amide substituted imidazo[4,5-c]quinoline compounds with a branched chain linking group for use as an immune response modifier |
JP2021512953A (en) | 2018-02-02 | 2021-05-20 | メイベリックス オンコロジー インコーポレイテッド | Small molecule drug conjugate of gemcitabine monophosphate |
SG11202007518RA (en) | 2018-02-28 | 2020-09-29 | Pfizer | Il-15 variants and uses thereof |
US11370788B2 (en) * | 2018-02-28 | 2022-06-28 | 3M Innovative Properties Company | Substituted imidazo[4,5-c]quinoline compounds with an N-1 branched group |
WO2019224716A2 (en) | 2018-05-23 | 2019-11-28 | Pfizer Inc. | Antibodies specific for gucy2c and uses thereof |
KR102602329B1 (en) | 2018-05-23 | 2023-11-16 | 화이자 인코포레이티드 | Antibodies specific for CD3 and their uses |
CA3101277A1 (en) * | 2018-05-24 | 2019-11-28 | 3M Innovative Properties Company | N-1 branched cycloalkyl substituted imidazo[4,5-c]quinoline compounds, compositions, and methods |
US20210213010A1 (en) * | 2018-07-24 | 2021-07-15 | Torque Therapeutics, Inc. | Tlr7/8 agonists and liposome compositions |
EP3887369A1 (en) * | 2018-11-26 | 2021-10-06 | 3M Innovative Properties Company | N-1 branched alkyl ether substituted imidazo[4,5-c]quinoline compounds, compositions, and methods |
WO2020128893A1 (en) | 2018-12-21 | 2020-06-25 | Pfizer Inc. | Combination treatments of cancer comprising a tlr agonist |
EP3921322A4 (en) * | 2019-02-07 | 2022-07-20 | Canwell Biotech Limited | Phosphorus imidazoquinoline amine derivatives, pharmaceutical compositions and therapeutic methods thereof |
KR20210136014A (en) | 2019-02-12 | 2021-11-16 | 암브룩스, 인코포레이티드 | Compositions, methods and uses thereof containing antibody-TLR agonist conjugates |
CN114599360A (en) * | 2019-10-29 | 2022-06-07 | 骏达贸易有限公司 | 4-amino-imidazoquinoline compounds and uses thereof |
WO2021116420A1 (en) | 2019-12-13 | 2021-06-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of tlr7 and/or tlr8 agonists for the treatment of leptospirosis |
AU2020410410A1 (en) | 2019-12-17 | 2022-06-09 | Pfizer Inc. | Antibodies specific for CD47, PD-L1, and uses thereof |
CN116323668A (en) | 2020-07-17 | 2023-06-23 | 辉瑞公司 | Therapeutic antibodies and uses thereof |
CA3190606A1 (en) | 2020-08-20 | 2022-02-24 | Ambrx, Inc. | Antibody-tlr agonist conjugates, methods and uses thereof |
Family Cites Families (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2135210A (en) * | 1937-03-13 | 1938-11-01 | John R Farrar | Golf ball |
US3314941A (en) | 1964-06-23 | 1967-04-18 | American Cyanamid Co | Novel substituted pyridodiazepins |
US3692907A (en) * | 1970-10-27 | 1972-09-19 | Richardson Merrell Inc | Treating viral infections with bis-basic ethers and thioethers of fluorenone and fluorene and pharmaceutical compositons of the same |
US3819190A (en) * | 1972-10-02 | 1974-06-25 | D Nepela | Golf ball |
US4284276A (en) * | 1980-02-13 | 1981-08-18 | Worst Joseph C | Grooved golf ball |
ZA848968B (en) | 1983-11-18 | 1986-06-25 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinolines and 1h-imidazo(4,5-c)quinolin-4-amines |
IL73534A (en) * | 1983-11-18 | 1990-12-23 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds |
US4880779A (en) * | 1987-07-31 | 1989-11-14 | Research Corporation Technologies, Inc. | Method of prevention or treatment of AIDS by inhibition of human immunodeficiency virus |
US5238944A (en) | 1988-12-15 | 1993-08-24 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine |
US5756747A (en) | 1989-02-27 | 1998-05-26 | Riker Laboratories, Inc. | 1H-imidazo 4,5-c!quinolin-4-amines |
US5037986A (en) | 1989-03-23 | 1991-08-06 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo[4,5-c]quinolin-4-amines |
US4929624A (en) | 1989-03-23 | 1990-05-29 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo(4,5-c)quinolin-4-amines |
NZ232740A (en) | 1989-04-20 | 1992-06-25 | Riker Laboratories Inc | Solution for parenteral administration comprising a 1h-imidazo(4,5-c) quinolin-4-amine derivative, an acid and a tonicity adjuster |
US4988815A (en) * | 1989-10-26 | 1991-01-29 | Riker Laboratories, Inc. | 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines |
US5054153A (en) * | 1989-12-01 | 1991-10-08 | Silliman Paul D | Golf club cleaner |
WO1992006093A1 (en) * | 1990-10-05 | 1992-04-16 | Minnesota Mining And Manufacturing Company | Process for the preparation of imidazo[4,5-c]quinolin-4-amines |
US5389640A (en) | 1991-03-01 | 1995-02-14 | Minnesota Mining And Manufacturing Company | 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
SG46492A1 (en) * | 1991-03-01 | 1998-02-20 | Minnesota Mining & Mfg | 1-Substituted 2-substituted 1H-imidazo [4,5-c] quinolin-4-amines |
US5175296A (en) * | 1991-03-01 | 1992-12-29 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]quinolin-4-amines and processes for their preparation |
US5268376A (en) | 1991-09-04 | 1993-12-07 | Minnesota Mining And Manufacturing Company | 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
US5266575A (en) * | 1991-11-06 | 1993-11-30 | Minnesota Mining And Manufacturing Company | 2-ethyl 1H-imidazo[4,5-ciquinolin-4-amines |
IL105325A (en) | 1992-04-16 | 1996-11-14 | Minnesota Mining & Mfg | Immunogen/vaccine adjuvant composition |
FR2692159B1 (en) * | 1992-06-10 | 1996-10-11 | Vartan Berberian | BALL FOR BALL GAMES AND METHODS OF OBTAINING SUCH A BALL. |
US5395937A (en) * | 1993-01-29 | 1995-03-07 | Minnesota Mining And Manufacturing Company | Process for preparing quinoline amines |
US5648516A (en) | 1994-07-20 | 1997-07-15 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
ATE195735T1 (en) | 1993-07-15 | 2000-09-15 | Minnesota Mining & Mfg | IMIDAZO (4,5-C)PYRIDINE-4-AMINE |
US5352784A (en) * | 1993-07-15 | 1994-10-04 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
US5644063A (en) | 1994-09-08 | 1997-07-01 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]pyridin-4-amine intermediates |
US5482936A (en) | 1995-01-12 | 1996-01-09 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-C]quinoline amines |
JPH09116911A (en) * | 1995-10-20 | 1997-05-02 | Canon Inc | Image pickup system |
JPH09208584A (en) | 1996-01-29 | 1997-08-12 | Terumo Corp | Amide derivative, pharmaceutical preparation containing the same, and intermediate for synthesizing the same |
JPH09255926A (en) | 1996-03-26 | 1997-09-30 | Diatex Co Ltd | Pressure-sensitive tape |
US5693811A (en) * | 1996-06-21 | 1997-12-02 | Minnesota Mining And Manufacturing Company | Process for preparing tetrahdroimidazoquinolinamines |
US5741908A (en) * | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
US5759109A (en) * | 1996-09-09 | 1998-06-02 | Martini; Byron Rocco | Simulated golf ball instructional device |
EP0938315B9 (en) * | 1996-10-25 | 2008-02-20 | Minnesota Mining And Manufacturing Company | Immune response modifier compounds for treatment of th2 mediated and related diseases |
US5939090A (en) | 1996-12-03 | 1999-08-17 | 3M Innovative Properties Company | Gel formulations for topical drug delivery |
US6069149A (en) * | 1997-01-09 | 2000-05-30 | Terumo Kabushiki Kaisha | Amide derivatives and intermediates for the synthesis thereof |
UA67760C2 (en) * | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines |
JPH11222432A (en) | 1998-02-03 | 1999-08-17 | Terumo Corp | Preparation for external use containing amide derivative inducing interferon |
JPH11255926A (en) | 1998-03-13 | 1999-09-21 | Toray Ind Inc | Silicone molding and its production |
US6239965B1 (en) * | 1998-05-22 | 2001-05-29 | Matsushita Electric Industrial Co., Ltd. | Electrolytic capacitor and method of producing the same |
US6110929A (en) | 1998-07-28 | 2000-08-29 | 3M Innovative Properties Company | Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof |
JP2000119271A (en) * | 1998-08-12 | 2000-04-25 | Hokuriku Seiyaku Co Ltd | 1h-imidazopyridine derivative |
US20020058674A1 (en) * | 1999-01-08 | 2002-05-16 | Hedenstrom John C. | Systems and methods for treating a mucosal surface |
CA2361936C (en) * | 1999-01-08 | 2009-06-16 | 3M Innovative Properties Company | Formulations comprising imiquimod or other immune response modifiers for treating mucosal conditions |
US6558951B1 (en) * | 1999-02-11 | 2003-05-06 | 3M Innovative Properties Company | Maturation of dendritic cells with immune response modifying compounds |
JP2000247884A (en) | 1999-03-01 | 2000-09-12 | Sumitomo Pharmaceut Co Ltd | Arachidonic acid-induced skin disease-treating agent |
US6756382B2 (en) | 1999-06-10 | 2004-06-29 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6541485B1 (en) | 1999-06-10 | 2003-04-01 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6451810B1 (en) * | 1999-06-10 | 2002-09-17 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6331539B1 (en) | 1999-06-10 | 2001-12-18 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
US6573273B1 (en) * | 1999-06-10 | 2003-06-03 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6376669B1 (en) * | 1999-11-05 | 2002-04-23 | 3M Innovative Properties Company | Dye labeled imidazoquinoline compounds |
US6894060B2 (en) | 2000-03-30 | 2005-05-17 | 3M Innovative Properties Company | Method for the treatment of dermal lesions caused by envenomation |
US20020055517A1 (en) * | 2000-09-15 | 2002-05-09 | 3M Innovative Properties Company | Methods for delaying recurrence of herpes virus symptoms |
JP2002145777A (en) | 2000-11-06 | 2002-05-22 | Sumitomo Pharmaceut Co Ltd | Therapeutic agent for arachidonic acid-induced dermatosis |
US6677348B2 (en) | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Aryl ether substituted imidazoquinolines |
US6664265B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6660735B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Urea substituted imidazoquinoline ethers |
US6545017B1 (en) * | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Urea substituted imidazopyridines |
US6677347B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamido ether substituted imidazoquinolines |
US6545016B1 (en) * | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Amide substituted imidazopyridines |
US6664260B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Heterocyclic ether substituted imidazoquinolines |
US6664264B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6667312B2 (en) * | 2000-12-08 | 2003-12-23 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
CA2430206A1 (en) | 2000-12-08 | 2002-06-13 | 3M Innovative Properties Company | Screening method for identifying compounds that selectively induce interferon alpha |
UA74852C2 (en) | 2000-12-08 | 2006-02-15 | 3M Innovative Properties Co | Urea-substituted imidazoquinoline ethers |
US6525064B1 (en) * | 2000-12-08 | 2003-02-25 | 3M Innovative Properties Company | Sulfonamido substituted imidazopyridines |
UA74593C2 (en) | 2000-12-08 | 2006-01-16 | 3M Innovative Properties Co | Substituted imidazopyridines |
US6660747B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
EP1401437A1 (en) | 2001-06-15 | 2004-03-31 | 3M Innovative Properties Company | Immune response modifiers for the treatment of periodontal disease |
CA2458876A1 (en) | 2001-08-30 | 2003-03-13 | 3M Innovative Properties Company | Methods of maturing plasmacytoid dendritic cells using immune response modifier molecules |
US20030139364A1 (en) | 2001-10-12 | 2003-07-24 | University Of Iowa Research Foundation | Methods and products for enhancing immune responses using imidazoquinoline compounds |
US20040014779A1 (en) | 2001-11-16 | 2004-01-22 | 3M Innovative Properties Company | Methods and compositions related to IRM compounds and toll-like recptor pathways |
WO2004080430A2 (en) | 2003-03-13 | 2004-09-23 | 3M Innovative Properties Company | Methods of improving skin quality |
EP1450804B9 (en) | 2001-11-29 | 2009-04-01 | 3M Innovative Properties Company | Pharmaceutical formulations comprising an immune response modifier |
US6677349B1 (en) | 2001-12-21 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
EP1478327B1 (en) | 2002-02-22 | 2015-04-29 | Meda AB | Method of reducing and treating uvb-induced immunosuppression |
GB0211649D0 (en) | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
EP1511746A2 (en) | 2002-05-29 | 2005-03-09 | 3M Innovative Properties Company | Process for imidazo[4,5-c]pyridin-4-amines |
AU2003237386A1 (en) | 2002-06-07 | 2003-12-22 | 3M Innovative Properties Company | Ether substituted imidazopyridines |
ATE488246T1 (en) | 2002-08-15 | 2010-12-15 | 3M Innovative Properties Co | IMMUNO-STIMULATORY COMPOSITIONS AND METHODS FOR STIMULATING AN IMMUNE RESPONSE |
JP2006503068A (en) | 2002-09-26 | 2006-01-26 | スリーエム イノベイティブ プロパティズ カンパニー | 1H-Imidazo dimer |
WO2004053057A2 (en) | 2002-12-11 | 2004-06-24 | 3M Innovative Properties Company | Gene expression systems and recombinant cell lines |
WO2004053452A2 (en) | 2002-12-11 | 2004-06-24 | 3M Innovative Properties Company | Assays relating to toll-like receptor activity |
AU2003301052A1 (en) * | 2002-12-20 | 2004-07-22 | 3M Innovative Properties Company | Aryl / hetaryl substituted imidazoquinolines |
EP2572715A1 (en) | 2002-12-30 | 2013-03-27 | 3M Innovative Properties Company | Immunostimulatory Combinations |
WO2004071459A2 (en) | 2003-02-13 | 2004-08-26 | 3M Innovative Properties Company | Methods and compositions related to irm compounds and toll-like receptor 8 |
EP1599726A4 (en) | 2003-02-27 | 2009-07-22 | 3M Innovative Properties Co | Selective modulation of tlr-mediated biological activity |
AU2004218349A1 (en) | 2003-03-04 | 2004-09-16 | 3M Innovative Properties Company | Prophylactic treatment of UV-induced epidermal neoplasia |
AU2004220534A1 (en) | 2003-03-07 | 2004-09-23 | 3M Innovative Properties Company | 1-amino 1H-imidazoquinolines |
JP2006523212A (en) | 2003-03-13 | 2006-10-12 | スリーエム イノベイティブ プロパティズ カンパニー | Diagnosis method of skin lesion |
JP2006520245A (en) | 2003-03-13 | 2006-09-07 | スリーエム イノベイティブ プロパティズ カンパニー | How to remove a tattoo |
JP2006523452A (en) | 2003-03-25 | 2006-10-19 | スリーエム イノベイティブ プロパティズ カンパニー | Selective activation of cellular activity mediated through a common Toll-like receptor |
US20040192585A1 (en) | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
CA2521682A1 (en) | 2003-04-10 | 2004-12-16 | 3M Innovative Properties Company | Delivery of immune response modifier compounds using metal-containing particulate support materials |
EA200600540A1 (en) | 2003-09-05 | 2006-08-25 | Анадис Фармасьютикалз, Инк. | INTRODUCTION OF TLR7 LIGANDS AND THEIR TREATMENTS FOR THE TREATMENT OF HEPATITIS C VIRUS INFECTION |
-
2001
- 2001-06-12 UA UA2003065275A patent/UA74852C2/en unknown
- 2001-06-12 UA UA2003065277A patent/UA75622C2/en unknown
- 2001-12-06 MX MXPA03005012A patent/MXPA03005012A/en active IP Right Grant
- 2001-12-06 EP EP01992018A patent/EP1343784B1/en not_active Expired - Lifetime
- 2001-12-06 SK SK684-2003A patent/SK6842003A3/en not_active Application Discontinuation
- 2001-12-06 DE DE60126645T patent/DE60126645T2/en not_active Expired - Fee Related
- 2001-12-06 IL IL15595001A patent/IL155950A0/en unknown
- 2001-12-06 BR BR0116470-8A patent/BR0116470A/en not_active IP Right Cessation
- 2001-12-06 PT PT01987283T patent/PT1341790E/en unknown
- 2001-12-06 AU AU2002232482A patent/AU2002232482B2/en not_active Ceased
- 2001-12-06 DK DK01987297T patent/DK1341791T3/en active
- 2001-12-06 KR KR10-2003-7007539A patent/KR20040047733A/en not_active Application Discontinuation
- 2001-12-06 KR KR10-2003-7007538A patent/KR20040028691A/en not_active Application Discontinuation
- 2001-12-06 AU AU3951602A patent/AU3951602A/en active Pending
- 2001-12-06 AU AU3951702A patent/AU3951702A/en active Pending
- 2001-12-06 DE DE60117859T patent/DE60117859T2/en not_active Expired - Fee Related
- 2001-12-06 DE DE60111076T patent/DE60111076T2/en not_active Expired - Lifetime
- 2001-12-06 WO PCT/US2001/046359 patent/WO2002046188A2/en active IP Right Grant
- 2001-12-06 BR BRPI0116464-3A patent/BR0116464A/en not_active IP Right Cessation
- 2001-12-06 WO PCT/US2001/046696 patent/WO2002046191A2/en active IP Right Grant
- 2001-12-06 PL PL392462A patent/PL392462A1/en unknown
- 2001-12-06 EP EP01987282A patent/EP1341789A2/en not_active Ceased
- 2001-12-06 CZ CZ20031562A patent/CZ20031562A3/en unknown
- 2001-12-06 ES ES01992018T patent/ES2260323T3/en not_active Expired - Lifetime
- 2001-12-06 IL IL15604401A patent/IL156044A0/en unknown
- 2001-12-06 JP JP2002547930A patent/JP2004515501A/en active Pending
- 2001-12-06 KR KR10-2003-7007537A patent/KR20030070050A/en not_active Application Discontinuation
- 2001-12-06 PL PL01365995A patent/PL365995A1/en unknown
- 2001-12-06 AT AT01987297T patent/ATE296301T1/en active
- 2001-12-06 BR BR0116026-5A patent/BR0116026A/en not_active IP Right Cessation
- 2001-12-06 WO PCT/US2001/046582 patent/WO2002046190A2/en active IP Right Grant
- 2001-12-06 HU HU0400710A patent/HUP0400710A2/en unknown
- 2001-12-06 SK SK711-2003A patent/SK7112003A3/en unknown
- 2001-12-06 MX MXPA03004975A patent/MXPA03004975A/en active IP Right Grant
- 2001-12-06 AU AU2002239517A patent/AU2002239517B2/en not_active Ceased
- 2001-12-06 EE EEP200300271A patent/EE200300271A/en unknown
- 2001-12-06 CN CNB018201598A patent/CN1247575C/en not_active Expired - Fee Related
- 2001-12-06 JP JP2002547928A patent/JP2004521092A/en not_active Ceased
- 2001-12-06 JP JP2002547929A patent/JP2004515500A/en not_active Withdrawn
- 2001-12-06 CA CA002430844A patent/CA2430844A1/en not_active Withdrawn
- 2001-12-06 RU RU2003116061/04A patent/RU2315049C2/en not_active IP Right Cessation
- 2001-12-06 CA CA2436980A patent/CA2436980C/en not_active Expired - Fee Related
- 2001-12-06 EE EEP200300275A patent/EE200300275A/en unknown
- 2001-12-06 US US10/013,202 patent/US6670372B2/en not_active Expired - Fee Related
- 2001-12-06 CN CNA018201687A patent/CN1479739A/en active Pending
- 2001-12-06 EP EP01987297A patent/EP1341791B1/en not_active Expired - Lifetime
- 2001-12-06 SK SK713-2003A patent/SK287732B6/en not_active IP Right Cessation
- 2001-12-06 EE EEP200300274A patent/EE200300274A/en unknown
- 2001-12-06 AU AU2002239516A patent/AU2002239516B2/en not_active Ceased
- 2001-12-06 IL IL15604301A patent/IL156043A0/en unknown
- 2001-12-06 PL PL366330A patent/PL207340B1/en not_active IP Right Cessation
- 2001-12-06 AU AU3248202A patent/AU3248202A/en active Pending
- 2001-12-06 NZ NZ526106A patent/NZ526106A/en not_active IP Right Cessation
- 2001-12-06 KR KR10-2003-7007535A patent/KR20040028690A/en not_active Application Discontinuation
- 2001-12-06 AU AU3953002A patent/AU3953002A/en active Pending
- 2001-12-06 MX MXPA03004973A patent/MXPA03004973A/en not_active Application Discontinuation
- 2001-12-06 HU HU0700062A patent/HUP0700062A2/en active IP Right Revival
- 2001-12-06 AU AU3061802A patent/AU3061802A/en active Pending
- 2001-12-06 JP JP2002547925A patent/JP4437189B2/en not_active Expired - Fee Related
- 2001-12-06 EE EEP200300268A patent/EE200300268A/en unknown
- 2001-12-06 CZ CZ20031591A patent/CZ20031591A3/en unknown
- 2001-12-06 MX MXPA03005011A patent/MXPA03005011A/en active IP Right Grant
- 2001-12-06 CN CNB018199070A patent/CN1252070C/en not_active Expired - Fee Related
- 2001-12-06 EP EP01987283A patent/EP1341790B1/en not_active Expired - Lifetime
- 2001-12-06 KR KR10-2003-7007534A patent/KR20030070049A/en active IP Right Grant
- 2001-12-06 HU HU0400704A patent/HUP0400704A2/en unknown
- 2001-12-06 AT AT01987283T patent/ATE353895T1/en not_active IP Right Cessation
- 2001-12-06 CZ CZ20031560A patent/CZ295848B6/en not_active IP Right Cessation
- 2001-12-06 AU AU2002230618A patent/AU2002230618B2/en not_active Ceased
- 2001-12-06 IL IL15590301A patent/IL155903A0/en unknown
- 2001-12-06 CA CA002431151A patent/CA2431151A1/en not_active Withdrawn
- 2001-12-06 PL PL01366115A patent/PL366115A1/en not_active Application Discontinuation
- 2001-12-06 SK SK712-2003A patent/SK7122003A3/en unknown
- 2001-12-06 KR KR10-2003-7007532A patent/KR20040023576A/en not_active Application Discontinuation
- 2001-12-06 NZ NZ526105A patent/NZ526105A/en unknown
- 2001-12-06 RU RU2003116123/04A patent/RU2003116123A/en not_active Application Discontinuation
- 2001-12-06 WO PCT/US2001/046581 patent/WO2002046189A2/en active IP Right Grant
- 2001-12-06 PL PL01361948A patent/PL361948A1/en not_active Application Discontinuation
- 2001-12-06 DK DK01987283T patent/DK1341790T3/en active
- 2001-12-06 PL PL01365883A patent/PL365883A1/en not_active Application Discontinuation
- 2001-12-06 AU AU2002232497A patent/AU2002232497B2/en not_active Ceased
- 2001-12-06 CZ CZ20031563A patent/CZ20031563A3/en unknown
- 2001-12-06 SK SK710-2003A patent/SK287264B6/en not_active IP Right Cessation
- 2001-12-06 RU RU2003116649/04A patent/RU2351598C2/en not_active IP Right Cessation
- 2001-12-06 CN CNA018201725A patent/CN1894244A/en active Pending
- 2001-12-06 MX MXPA03004972A patent/MXPA03004972A/en active IP Right Grant
- 2001-12-06 HU HU0600600A patent/HUP0600600A2/en unknown
- 2001-12-06 AU AU3249702A patent/AU3249702A/en active Pending
- 2001-12-06 SK SK715-2003A patent/SK7152003A3/en unknown
- 2001-12-06 BR BR0116047-8A patent/BR0116047A/en not_active IP Right Cessation
- 2001-12-06 IL IL15588401A patent/IL155884A0/en unknown
- 2001-12-06 MX MXPA03004974A patent/MXPA03004974A/en active IP Right Grant
- 2001-12-06 EP EP01990852A patent/EP1339715A2/en not_active Withdrawn
- 2001-12-06 AU AU2002239530A patent/AU2002239530B2/en not_active Ceased
- 2001-12-06 WO PCT/US2001/046704 patent/WO2002046193A2/en active IP Right Grant
- 2001-12-06 BR BRPI0116032-0A patent/BR0116032A/en not_active IP Right Cessation
- 2001-12-06 PL PL01365907A patent/PL365907A1/en not_active Application Discontinuation
- 2001-12-06 RU RU2003116060/04A patent/RU2302418C2/en active
- 2001-12-06 NZ NZ526088A patent/NZ526088A/en unknown
- 2001-12-06 EE EEP200300272A patent/EE200300272A/en unknown
- 2001-12-06 RU RU2003116059/04A patent/RU2308456C2/en not_active IP Right Cessation
- 2001-12-06 HU HU0600338A patent/HUP0600338A2/en active IP Right Revival
- 2001-12-06 JP JP2002547927A patent/JP2004529078A/en active Pending
- 2001-12-06 EE EEP200300270A patent/EE200300270A/en unknown
- 2001-12-06 CA CA002436984A patent/CA2436984A1/en not_active Abandoned
- 2001-12-06 PT PT01987297T patent/PT1341791E/en unknown
- 2001-12-06 US US10/012,599 patent/US6683088B2/en not_active Expired - Fee Related
- 2001-12-06 CA CA002436983A patent/CA2436983A1/en not_active Abandoned
- 2001-12-06 HU HU0600605A patent/HUP0600605A2/en unknown
- 2001-12-06 EP EP01992005A patent/EP1341792A2/en not_active Withdrawn
- 2001-12-06 SI SI200130720T patent/SI1341790T1/en unknown
- 2001-12-06 CN CNB018201679A patent/CN1297554C/en not_active Expired - Fee Related
- 2001-12-06 NZ NZ526087A patent/NZ526087A/en unknown
- 2001-12-06 NZ NZ526089A patent/NZ526089A/en unknown
- 2001-12-06 AT AT01992018T patent/ATE319711T1/en not_active IP Right Cessation
- 2001-12-06 DK DK01992018T patent/DK1343784T3/en active
- 2001-12-06 RU RU2003116063/04A patent/RU2003116063A/en not_active Application Discontinuation
- 2001-12-06 ES ES01987297T patent/ES2242782T3/en not_active Expired - Lifetime
- 2001-12-06 CZ CZ20031561A patent/CZ20031561A3/en unknown
- 2001-12-06 CZ CZ20031592A patent/CZ303462B6/en not_active IP Right Cessation
- 2001-12-06 NZ NZ526086A patent/NZ526086A/en unknown
- 2001-12-06 CN CNB01820161XA patent/CN1253452C/en not_active Expired - Fee Related
- 2001-12-06 BR BRPI0116052-4A patent/BR0116052A/en not_active Application Discontinuation
- 2001-12-06 WO PCT/US2001/046697 patent/WO2002046192A2/en active IP Right Grant
- 2001-12-06 ES ES01987283T patent/ES2281456T3/en not_active Expired - Lifetime
- 2001-12-06 JP JP2002547926A patent/JP2004523498A/en active Pending
- 2001-12-06 US US10/013,060 patent/US6656938B2/en not_active Expired - Fee Related
- 2001-12-06 CA CA2436846A patent/CA2436846C/en not_active Expired - Fee Related
- 2001-12-06 IL IL15590401A patent/IL155904A0/en unknown
- 2001-12-07 TW TW090130402A patent/TWI222972B/en active
- 2001-12-07 TW TW090130401A patent/TW584633B/en not_active IP Right Cessation
- 2001-12-07 TW TW090130404A patent/TWI293300B/en active
- 2001-12-10 AR ARP010105731A patent/AR035669A1/en unknown
- 2001-12-10 AR ARP010105730A patent/AR035668A1/en unknown
- 2001-12-10 AR ARP010105728A patent/AR035666A1/en unknown
- 2001-12-10 AR ARP010105726A patent/AR035664A1/en active IP Right Grant
- 2001-12-10 AR ARP010105729A patent/AR035667A1/en unknown
- 2001-12-10 AR ARP010105727A patent/AR035665A1/en unknown
-
2003
- 2003-05-28 NO NO20032449A patent/NO20032449D0/en not_active Application Discontinuation
- 2003-05-28 NO NO20032452A patent/NO20032452L/en not_active Application Discontinuation
- 2003-05-28 NO NO20032451A patent/NO20032451L/en not_active Application Discontinuation
- 2003-05-30 NO NO20032473A patent/NO326159B1/en not_active IP Right Cessation
- 2003-06-06 NO NO20032596A patent/NO20032596D0/en not_active Application Discontinuation
- 2003-06-06 HR HR20030466A patent/HRP20030466A2/en not_active Application Discontinuation
- 2003-06-06 HR HR20030461A patent/HRP20030461A2/en not_active Application Discontinuation
- 2003-06-06 NO NO20032595A patent/NO20032595D0/en not_active Application Discontinuation
- 2003-06-06 HR HR20030462A patent/HRP20030462A2/en not_active Application Discontinuation
- 2003-06-06 HR HR20030464A patent/HRP20030464A2/en not_active Application Discontinuation
- 2003-06-06 HR HR20030463A patent/HRP20030463A2/en not_active Application Discontinuation
- 2003-06-06 HR HR20030467A patent/HRP20030467B1/en not_active IP Right Cessation
- 2003-07-08 ZA ZA200305270A patent/ZA200305270B/en unknown
- 2003-07-08 ZA ZA200305273A patent/ZA200305273B/en unknown
- 2003-07-08 ZA ZA200305274A patent/ZA200305274B/en unknown
- 2003-07-08 ZA ZA200305271A patent/ZA200305271B/en unknown
- 2003-07-08 ZA ZA200305275A patent/ZA200305275B/en unknown
- 2003-07-08 ZA ZA2003/05272A patent/ZA200305272B/en unknown
- 2003-10-07 US US10/680,989 patent/US7049439B2/en not_active Expired - Fee Related
- 2003-10-29 US US10/696,476 patent/US20040092545A1/en not_active Abandoned
- 2003-10-29 US US10/696,753 patent/US6953804B2/en not_active Expired - Fee Related
-
2004
- 2004-09-20 HK HK04107230A patent/HK1064383A1/en not_active IP Right Cessation
- 2004-11-11 HK HK04108904A patent/HK1066005A1/en not_active IP Right Cessation
-
2005
- 2005-01-25 HK HK05100647A patent/HK1069166A1/en not_active IP Right Cessation
- 2005-02-28 US US11/069,033 patent/US7132429B2/en not_active Expired - Fee Related
- 2005-05-19 US US11/132,900 patent/US7612083B2/en not_active Expired - Fee Related
- 2005-08-24 CY CY20051101024T patent/CY1105586T1/en unknown
-
2007
- 2007-05-09 CY CY20071100621T patent/CY1106569T1/en unknown
-
2009
- 2009-11-06 JP JP2009255040A patent/JP2010031040A/en not_active Ceased
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6664260B2 (en) | Heterocyclic ether substituted imidazoquinolines | |
AU2002230618B2 (en) | Heterocyclic ether substituted imidazoquinolines | |
AU2002230618A1 (en) | Heterocyclic ether substituted imidazoquinolines | |
US6969722B2 (en) | Amide substituted imidazopyridines | |
AU773113B2 (en) | Amide substituted imidazoquinolines | |
US8598192B2 (en) | Hydroxylamine substituted imidazoquinolines | |
US7897767B2 (en) | Oxime substituted imidazoquinolines | |
US6696465B2 (en) | Sulfonamido substituted imidazopyridines | |
KR20040105695A (en) | Amide Substituted Imidazopyridines | |
AU2002239516A1 (en) | Aryl ether substituted imidazoquinolines | |
JP2004525868A (en) | Substituted imidazopyridines | |
MXPA06001674A (en) | Hydroxylamine substituted imidazo-containing compounds. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
AZWI | Withdrawn application |