CA2436984A1 - Urea substituted imidazoquinoline ethers - Google Patents
Urea substituted imidazoquinoline ethers Download PDFInfo
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- CA2436984A1 CA2436984A1 CA002436984A CA2436984A CA2436984A1 CA 2436984 A1 CA2436984 A1 CA 2436984A1 CA 002436984 A CA002436984 A CA 002436984A CA 2436984 A CA2436984 A CA 2436984A CA 2436984 A1 CA2436984 A1 CA 2436984A1
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- alkyl
- alkenyl
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- heteroaryl
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- 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
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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Abstract
Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and urea 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
Urea Substituted Imidazoquinoline Ethers Field of the Invention This invention relates to imidazoquinoline compounds that have ether and urea 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 cytolcine 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 . Chem. 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-e]
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, iyater 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.
Despite these attempts to identify compounds that are useful as immune response modifiers, 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 imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-amine compounds that have an ether and urea containing substituent at the 1-position. The compounds are defined by Formulas (I) and (II), which are defined in more detail infra. These compounds share the general structural formula:
NHS
Ra wherein X, Rl, R2, and R are as defined herein for each class of compounds having Formulas (I) and (II).
The compounds of Formulas (I) and (II) 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.
Background of the Invention The first reliable report on the 1H imidazo[4,5-c]quinoline ring system, Backman et al., J. Or . Chem. 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-e]
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, iyater 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.
Despite these attempts to identify compounds that are useful as immune response modifiers, 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 imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-amine compounds that have an ether and urea containing substituent at the 1-position. The compounds are defined by Formulas (I) and (II), which are defined in more detail infra. These compounds share the general structural formula:
NHS
Ra wherein X, Rl, R2, and R are as defined herein for each class of compounds having Formulas (I) and (II).
The compounds of Formulas (I) and (II) 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.
2 The invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytokine 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) or (II) to the animal.
In addition, the invention provides methods of synthesizing the compounds of the invention and novel intermediates useful in the synthesis of these compounds.
Detailed Description of the Invention As mentioned earlier, we have found certain compounds that induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulas (I) and (II), as shown below.
Imidazoquinoline compounds of the invention, which have ether and urea functionality at the I-position are represented by Formula (I):
N~
\ R2 N
/ X-o-Ri Rn (I) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
_R4-NRs-CR3-NRs_Z-R6_alkyl;
-R4-NRs-CR3-NRs Z-R~-alkenyl;
-R4-NRs-CR3-NRS-Z-R6-aryl;
-R4-NRa- CR3-NRS-Z-R6-heteroaryl;
-R4-NRs- CR3-NRS-Z-R6-heterocyclyl;
-R4-NRs-CR3-NRsR~;
-Rq-NRs-CR3-NR9-Z-R6-alkyl;
In addition, the invention provides methods of synthesizing the compounds of the invention and novel intermediates useful in the synthesis of these compounds.
Detailed Description of the Invention As mentioned earlier, we have found certain compounds that induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulas (I) and (II), as shown below.
Imidazoquinoline compounds of the invention, which have ether and urea functionality at the I-position are represented by Formula (I):
N~
\ R2 N
/ X-o-Ri Rn (I) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
_R4-NRs-CR3-NRs_Z-R6_alkyl;
-R4-NRs-CR3-NRs Z-R~-alkenyl;
-R4-NRs-CR3-NRS-Z-R6-aryl;
-R4-NRa- CR3-NRS-Z-R6-heteroaryl;
-R4-NRs- CR3-NRS-Z-R6-heterocyclyl;
-R4-NRs-CR3-NRsR~;
-Rq-NRs-CR3-NR9-Z-R6-alkyl;
3 -R4-NR$-CR3-NR9-Z-R~-alkenyl;
-R4-NRg-CR3-NR9-Z-R6-aryl;
-R4-NR$- CR3-NR9-Z-R6 heteroaryl; and -R4-NR$- CR3-NR9-Z-R6-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(RS)z;
-CO-N(Rs)z -CO-C1_io alkyl;
-CO-O-C1_io alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each RS is independently H or C1-to alkyl;
-R4-NRg-CR3-NR9-Z-R6-aryl;
-R4-NR$- CR3-NR9-Z-R6 heteroaryl; and -R4-NR$- CR3-NR9-Z-R6-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(RS)z;
-CO-N(Rs)z -CO-C1_io alkyl;
-CO-O-C1_io alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each RS is independently H or C1-to alkyl;
4 R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is H or C1_lo alkyl which may be interrupted by a hetero atom, or R~ can j oin with RS to form a ring;
S R8 is H, C1-to alkyl, or arylalkyl; or R4 and R$ can join together to form a ring;
R9 is Cl_lo alkyl which can join with R$ to form a ring;
each Y is independently -O- or -S(O)o_z-;
Z is a bond, -CO-, or -SOZ-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_io 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 urea containing substituent at the 1-position. Such tetrahydroimidazoquinoline compounds are represented by Formula (II):
N~
Ra N
I
(II) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
-R4-NR$-CR3-NRS-Z-R6-alkyl;
-R.4-NR$-CR3-NRS-Z-R6-alkenyl;
-R4-NR$-CR3-NRS-Z-R6-aryl;
-R4-NR$- CR3-NRS-Z-R6-heteroaryl;
-R4-NR8- CR3-NRS-Z-R6-heterocyclyl;
R~ is H or C1_lo alkyl which may be interrupted by a hetero atom, or R~ can j oin with RS to form a ring;
S R8 is H, C1-to alkyl, or arylalkyl; or R4 and R$ can join together to form a ring;
R9 is Cl_lo alkyl which can join with R$ to form a ring;
each Y is independently -O- or -S(O)o_z-;
Z is a bond, -CO-, or -SOZ-;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_io 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 urea containing substituent at the 1-position. Such tetrahydroimidazoquinoline compounds are represented by Formula (II):
N~
Ra N
I
(II) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
-R4-NR$-CR3-NRS-Z-R6-alkyl;
-R.4-NR$-CR3-NRS-Z-R6-alkenyl;
-R4-NR$-CR3-NRS-Z-R6-aryl;
-R4-NR$- CR3-NRS-Z-R6-heteroaryl;
-R4-NR8- CR3-NRS-Z-R6-heterocyclyl;
5 -Ra.-NRa-"CR3-NRSR~;
-R4-NRs-CR3-NR9-Z-R6-alkyl;
-R4-NR$-CR3-NR~-Z-R6-alkenyl;
-Rq-NRs-CR3-NR9-Z-R~-aryl;
-R4-NRs- CR3-NR9-Z-R6-heteroaryl; and -R4-NRs- CR3-NR9 Z-R6-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(Rs)z;
-CO-N(Rs)2;
-CO-C1_io alkyl;
-CO-O-CI_lo alkyl;
-N3~
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
-R4-NRs-CR3-NR9-Z-R6-alkyl;
-R4-NR$-CR3-NR~-Z-R6-alkenyl;
-Rq-NRs-CR3-NR9-Z-R~-aryl;
-R4-NRs- CR3-NR9-Z-R6-heteroaryl; and -R4-NRs- CR3-NR9 Z-R6-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(Rs)2;
-CO-C1_io alkyl;
-CO-O-CI_lo alkyl;
-N3~
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
6 each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each RS is independently H or C1_lo alkyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is H or C1_io alkyl which may be interrupted by a hetero atom, or R~ can j oin with RS to form a ring;
R$ is H, C1_IO alkyl, or arylalkyl; or R4 and R8 can join together to form a ring;
R9 is C1_lo alkyl which can join together with R$ to form a ring;
each Y is independently -O- or -S(O)o_2-;
Z is a bond, -CO-, or -SOZ-;
n is 0 to 4; and each R present is independently selected from the group consisting of CI_lo alkyl, C1_~o 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, R~, R3, R4, Rs, R8, X and n are as defined above, BOC is test-butoxycarbonyl and RI1 is -Z-R6-alkyl, -Z-R6-alkenyl, -Z-R6-aryl, -Z-R6-heteroaryl, -Z-R6-heterocyclyl or Rl 1 is R~ where R6, R~ and Z are as defined above.
In step (1) of Reaction Scheme I the amino group of an aminoalcohol of Formula X is protected with a text-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula X are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme I a protected aminoalcohol of Formula XI is converted to an iodide of Formula XII. Iodine is added to a solution of triphenylphosphine and imidazole in dichloromethane; then a solution of a protected aminoalcohol of Formula XI in dichlorornethane is added. The reaction is carried out at ambient temperature.
In step (3) of Reaction Scheme I a 1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is alkylated with an iodide of Formula XII to provide a 1H
imidazo[4,5-
each RS is independently H or C1_lo alkyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is H or C1_io alkyl which may be interrupted by a hetero atom, or R~ can j oin with RS to form a ring;
R$ is H, C1_IO alkyl, or arylalkyl; or R4 and R8 can join together to form a ring;
R9 is C1_lo alkyl which can join together with R$ to form a ring;
each Y is independently -O- or -S(O)o_2-;
Z is a bond, -CO-, or -SOZ-;
n is 0 to 4; and each R present is independently selected from the group consisting of CI_lo alkyl, C1_~o 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, R~, R3, R4, Rs, R8, X and n are as defined above, BOC is test-butoxycarbonyl and RI1 is -Z-R6-alkyl, -Z-R6-alkenyl, -Z-R6-aryl, -Z-R6-heteroaryl, -Z-R6-heterocyclyl or Rl 1 is R~ where R6, R~ and Z are as defined above.
In step (1) of Reaction Scheme I the amino group of an aminoalcohol of Formula X is protected with a text-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula X are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme I a protected aminoalcohol of Formula XI is converted to an iodide of Formula XII. Iodine is added to a solution of triphenylphosphine and imidazole in dichloromethane; then a solution of a protected aminoalcohol of Formula XI in dichlorornethane is added. The reaction is carried out at ambient temperature.
In step (3) of Reaction Scheme I a 1H imidazo[4,5-c]quinolin-1-yl alcohol of Formula XIII is alkylated with an iodide of Formula XII to provide a 1H
imidazo[4,5-
7 c]quinolin-1-yl ether of Formula XIV. The alcohol of Formula XIII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide.
The iodide is added to the alkoxide solution at ambient temperature. After the addition is complete the reaction is stirred at an elevated temperature 0100°C).
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 (4) of Reaction Scheme I a 1H imidazo[4,5-c]quinolin-1-yl ether 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 chloroform is oxidized using 3-chloroperoxybenzoic acid at ambient temperature.
In step (5) of Reaction Scheme I a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XV is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVI. Step (5) involves (i) reacting a compound of Formula XV with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (5) involves reacting an N-oxide of Formula XV with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.
Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (5) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of Formula XV in an inert solvent such as dichloromethane or 1,2-dichloroethane with heating if necessary, adding the aminating agent to the solution, and then slowly adding the acylating agent. Optionally the reaction can be carried out in a sealed pressure vessel at an elevated temperature (85-100°).
In step (6) of Reaction Scheme I the protecting group is removed by hydrolysis under acidic conditions to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVII.
Preferably the compound of Formula XVI is treated with hydrochloric acid/ethanol at ambient temperature or with gentle heating.
The iodide is added to the alkoxide solution at ambient temperature. After the addition is complete the reaction is stirred at an elevated temperature 0100°C).
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 (4) of Reaction Scheme I a 1H imidazo[4,5-c]quinolin-1-yl ether 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 chloroform is oxidized using 3-chloroperoxybenzoic acid at ambient temperature.
In step (5) of Reaction Scheme I a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XV is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVI. Step (5) involves (i) reacting a compound of Formula XV with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (5) involves reacting an N-oxide of Formula XV with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.
Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (5) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of Formula XV in an inert solvent such as dichloromethane or 1,2-dichloroethane with heating if necessary, adding the aminating agent to the solution, and then slowly adding the acylating agent. Optionally the reaction can be carried out in a sealed pressure vessel at an elevated temperature (85-100°).
In step (6) of Reaction Scheme I the protecting group is removed by hydrolysis under acidic conditions to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVII.
Preferably the compound of Formula XVI is treated with hydrochloric acid/ethanol at ambient temperature or with gentle heating.
8 In step (7) of Reaction Scheme I a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVII is converted to a urea or thiourea of Formula XVIII using conventional synthetic methods. For example, a compound of Formula XVII can be reacted with an isocyanate of formula R12-N=C=O where R12 is -R6-alkyl, -R~-alkenyl, -R6-aryl, -R~-heteroaryl or -R6-heterocyclyl. The reaction can be carried out by adding a solution of the isocyanate in a suitable solvent such as dichloromethane or 1-methyl-2-pyrrolidinone to a solution of a compound of Formula XVII at ambient temperature. Alternatively, a compound of Formula XVII can be reacted with a thioisocyanate of formula R12-N=C=S, an acyl isocyanate of formula R12-C(O)-N=C=O, a sulfonyl isocyanate of formula -RIZ-S(Oa)-N=C=O or a carbamoyl chloride of formula R~3-N-C(O)Cl where RI3 is R~2 or R~.
The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
9 Reaction Scheme I
H (~ ) ,BOC (2) BOC
HO-R4 N ~. HO-R4 N --~ I-R N~
~e \R a \
X XI 8 ~ XII Ra N
N ~ ~~ Rz (3) . / N
Rn / X
OH
NHz ~ XIII
N w NCR E (s> OwN \ N E (4> N ~ N
/ N z I / ~ Rz I / ~~ Rz i ,N N
Rn / X Rn / X Rn / X
O
,BOC ~ ,BOC BOC
_ I _ i XVI R4 ~ XV R4 N XIV R4 N
a Rs Ra (6) NHz NHz N ~ N~ ~ N ~ N~ R
/ N Rz / N z Rn / X Rn / X
O O
XVII R4 N R4 N-CR3 NR5 R~~
Ra XVIII R
Compounds of the invention can be prepared according to Reaction Scheme II
where R, R2, R3, R4, R5, Rs, Rl l, X and n are as defined above and BOC is tert-butoxycarbonyl.
In step (1) of Reaction Scheme II the amino group of an aminoalcohol of Formula XIX is protected with a tef-t-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-teYt-butyl dicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula XIX are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme II a protected amino alcohol of Formula XX is converted to a methanesulfonate of Formula XXI. A solution of a compound of Formula XX in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of a base such as triethylamine. The reaction can be carried out at a reduced temperature (0°C).
In step (3a) of Reaction Scheme II a methanesulfonate of Formula YXI is converted to an azide of Formula XXII. Sodium azide is added to a solution of a compound of Formula XXI in a suitable solvent such as N,N-dimethylformamide.
The reaction can be carried out at an elevated temperature (80 - 100°C).
In step (3b) of Reaction Scheme II a compound of Formula XXII is alkylated with a halide of formula Hal-R$ to provide a compound of Formula XXIII. In compounds where R$ is hydrogen this step is omitted. The compound of Formula XXII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran to form the anion and then combined with the halide. The reaction can be carried out at ambient temperature.
In step (4) of Reaction Scheme II an azide of Formula XXII or XXIII is reduced to provide an amine of Formula XXIV. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon.
The reaction can conveniently be carned out on a Parr apparatus in a suitable solvent such as methanol or isopropanol.
In step (5) of Reaction Scheme II a 4-chloro-3-nitroquinoline of Formula XXV
is reacted with an amine of Formula XXIV to provide a 3-nitroquinoline of Formula XXVI.
The reaction can be carned out by adding an amine of Formula XXIV to a solution of a compound of Formula XXV in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. Many quinolines of Formula YXV are known compounds or can be prepared using known synthetic methods, see for example, Gerster, U.S. Patent 4,689,338 and references cited therein.
In step (6) of Reaction Scheme II a 3-nitroquinoline of Formula XXVI is reduced to provide a 3-aminoquinoline of Formula XXVII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon.
The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene.
In step (7) of Reaction Scheme II a compound of Formula XXVII is reacted with a carboxylic acid or an equivalent thereof to provide a 1H imidazo[4,5-c]quinoline of Formula XIV. 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 XIV. For example, triethyl orthoformate will provide a compound where RZ is hydrogen and triethyl orthovalerate will provide a compound where R2 is butyl. 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 catalytic amount of pyridine hydrochloride can be included.
Alternatively, step (7) can be carried out by (i) reacting a compound of Formula XXVII 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 a compound of Formula XXVII in an inert solvent such as acetonitrile or dichloromethane. The reaction can be carried out at ambient temperature or at a reduced temperature. In part (ii) the product of part (i) is heated in an alcoholic solvent in the presence 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.
Steps (8), (9), (10) and (11) are carried out in the same manner as steps (4), (5), (6) and (7) of Reaction Scheme I.
Reaction Scheme II
HO-X-O-R4 NHz (--~ HO-X-O-R4 ~~gOC
XIX
N3 X-O-R4 ~ BOCE (3a) -~_ O-X-O-R ~ BOC
(3b) ~ 0 a XXII ~(4) XXI
BOC (4) BOC
Ns X_O-Ra N ---~ HzN_X-O-Ra Ni XXIII R8 XXIV \R8 O
l+
N ~ N.O_ I /
(5) Rn 'CI
XXV
O
N ~ N~R E (~) N ~ NHz N \ N;O_ (6) / z I / E I
~N 'NH /
Rn I NH
n / X / X Rn / X
I
XIV R4 N~BOC R-N~gOC IO ~BOC
\R8 XXVII 4 \R XXVI RQ N
R
a (8) O + ~ NHz NHz N\ R (9) N ~ N (10) N
/ N 2~ I \~Rz~ N\ ~~R
I / N / N z Rn / O Rn / X Rn / X
XV R4 N~BOC ~ sBOC 0 \R XVI R4 N R
a R8 XVII 4 \R
(11 ) i NHz N
N / y Rz ~N
I
Rn / X
O
13 VIII R4 R CR3--NR5 R~~
Compounds of the invention can be prepared according to Reaction Scheme III
where R, R2, R3, R4, RS, R8, Rl l, X and n are as defined above.
In step (1) of Reaction Scheme III a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVII is reduced to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XXVIII. Preferably the reduction is tamed out by suspending or dissolving a compound of Formula XVII in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then hydrogenating. The reaction can be conveniently carried out in a Parr apparatus.
Step (2) is carried out in the same manner as step (7) of Reaction Scheme I to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XXIX. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme III
N / N~ Rz C 1~ N ~ N~ R2 y N / N~ R
N
N
Rn / X Rn X Rn X
O
I H
I H
Ra N Ra N Ra. ~Ra XVII R$ XXVIII ~R$ XXIX
"11 Compounds of the invention can also be prepared according to Reaction Scheme IV where R, Rt, R2, X and n are as defined above.
In step (1) of Reaction Scheme IV a 4-chloro-3-nitroquinoline of Formula XXV
is reacted with an amine of formula RI-0-X-NHZ to provide a 3-nitroquinolin-4-amine of Formula XXX. The reaction can be tamed out by adding the amine to a solution of a compound of Formula XXV in a suitable solvent such as chloroform or dichloromethane and optionally heating. Many quinolines of Formula XXV are known compounds, see for example, Gerster, U.S. Patent 4,689,338 and references cited therein.
In step (2) of Reaction Scheme IV a 3-nitroquinolin-4-amine of Formula XXX
is reduced using the method of step (6) of Reaction Scheme II to provide a quinoline-3~4-diamine of Formula XXXI.
In step (3) of Reaction Scheme IV a quinoline-3,4-diamine of Formula XXXI is cyclized using the method of step (7) of Reaction Scheme II to provide a 1H
imidazo[4,5-cJquinoline of Formula XX~~II.
In step (4) of Reaction Scheme IV a 1H imidazo[4,5-c]quinoline of Formula XXXII is oxidized using the method of step (4) of Reaction Scheme I to provide a 1H
imidazo[4,5-c]quinoline-SN-oxide of Formula XXXIII.
In step (5) of Reaction Scheme IV a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XXXIII is aminated using the method of step (5) of Reaction Scheme I
to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula I. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
O
"+ O
N. - n+
/ O ~ N ~ N.O- (~~ N ~ NH2 CI /
-NH ~NH
R~ / ' Rn / X R~ / X
XXV XXX ~ XXXI O
R~ R~
(3) NHZ
/ N~R~ E (5) O'N+ \ N~Rz E (4) N \ N~Ra ~N / N / N.
R'n ~/ X Rn / X Rn / X
O p O
I
R~ XXXIII R~ XXXII R~
Compounds of the invention can be prepared according to Reaction Scheme V
where R, R2, R3, R4, R5, R8, Rl l, X and n are as defined above.
In step (1) of Reaction Scheme V the BOC group is removed from a compound of Formula XIV using the method of step (6) of Reaction Scheme I to provide a 1H
imidazo[4,5-c]quinoline of Formula XX~~IV.
In step (2) of Reaction Scheme V a 1H imidazo[4,5-c]quinoline of Formula X~~XIV is converted to a urea or thiourea of Formula XXXV using the method of step (7) of Reaction Scheme I.
In step (3) of Reaction Scheme V a 1H imidazo[4,5-c]quinoline of Formula XXXV is oxidized using the method of step (4) of Reaction Scheme I to provide a 1H
imidazo[4,5-c]quinolin-SN-oxide of Formula XXXVI.
In step (4) of Reaction Scheme V a 1H imidazo[4,5-c]quinolin-SN-oxide of Formula ~~XXVI is aminated using the method of step (5) of Reaction Scheme I
to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVIII. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme V
N>-- Rz (~ N \ ~ R (~ N \ N
N / N z I , ~-Rz Rn / X X N
O n / ~ n ~
iBOC ~ H O
XIV R4 NR XXXIV R4 ~ XXXV R4~N~R8 Rs R~~
(3) N Hz N \ N (4) O\.~ \ N
I / N~ Rz I / y Rz i 'N
, n / O n /
O
R . iR
XVIII 4 i a XXXVI R4~N~R$
Rs CRs R~' R11 The invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formulas (I) and (II). These intermediate compounds have the structural Formulas (III) and (IV), described in more detail below.
One class of intermediate compounds has formula (III):
Ni N
~~' RZ
N
X-O-Rl (III) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
-R4-NR$-CR3-NRS-Z-R6-alkyl;
-R4.-NR8-CR3-NRS-Z-R6-alkenyl;
-R4-NR$-CR3-NRS-Z-R6-aryl;
-R4-NR8- CR3-NRS-Z-R6-heteroaryl;
-R4.-NR$- CR3-NRS-Z-RG--heterocyclyl; and -R4-NR8-CR3-NRSR~;
-R4-NRa-CR3-NR9-Z-R6-alkyl;
-R4-NRg-CR3-NR9-Z-R~-alkenyl;
-R4-NR$-CR3-NR9-Z-R6-aryl;
-R4-NRg- CR3-NR9-Z-R6-heteroaryl; and -R4-NR$- CR3-NR9-Z-R6-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
S -N(Rs)z~
-CO-N(Rs)z;
-CO-C1_lo alkyl;
-CO-O-CI_IO alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each RS is independently H or C1_io alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is H or C~_IO alkyl which may be interrupted by a hetero atom, or R~ can j oin with Rs to form a ring;
R8 is H, C~_IO alkyl, or arylalkyl; or R4 and R$ can join to form a ring;
R9 is C1_lo alkyl which can join together with R$ to form a ring;
2S each Y is independently -O- or -S(O)o_z-;
Z is a bond, -CO-, or -SOz-;
nisOto4;and each R present is independently selected from the group consisting of C1_lo alkyl, CI_IO alkoxy, hydroxy, halogen and trifluoromethyl;
30 or a pharmaceutically acceptable salt thereof.
Another class of intermediate compounds are the imidazoquinoline-N-oxide compounds of Formula (IV):
O
~N i N
N
X-O-Rl (IV) wherein X is -CHRs-, -CHRs-alkylene-, or-CHRs-alkenylene-;
Rl is selected from the group consisting of:
-R4-NR$-CR3-NRs-Z-R6-alkyl;
-R4-NR8-CR3-NRs-Z-R6-alkenyl;
-R4-NR8-CR3-NRs-Z-R6-aryl;
-Ra: NR$- CR3-NRs-Z-R6-heteroaryl;
-R4-NR$-C R3-NRs-Z-R6-heterocyclyl;
-~-NRs-CR3-NRsR~
_R4-NRs-CR3-NR9-Z-R6-alkyl;
-R4-NR$-CR3-NR9-Z-R6-alkenyl;
-R4-NR$-CR3-NR9-Z-R6-aryl; .
-Ra.-NR$- CR3-NR9-Z-R6-heteroaryl; and -R4-NR$- CR3-NR9-Z-R6-heterocyclyl;
each Y is independently -O- or -S(O)o_2-;
Z is a bond, -CO-, or-SOZ-;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each RS is independently H or C1_io alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is H or C1_lo alkyl which may be interrupted by a hetero atom, or R~ can join with Rs to form a ring;
R8 is H, C1_lo alkyl, or arylalkyl; or R4 and R8 can join to form a ring;
R9 is C1_IO alkyl which can join together with R$ to form a ring;
nisOto4;and each R present is independently selected from the group consisting of C1-to alkyl, CI_lo alkoxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
As used herein, the terms "alkyl", "alkenyl" and the prefix "alk-" 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, cyclopropylmethyl, cyclopentyl, cyclohexyl 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 groups consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl.
The term "haloalkyl" is inclusive of groups that are 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, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, 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 all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 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, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylaminocarbonylamino and, in the case of I heterocyclyl, oxo. 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 R~ groups include -R4-NR$-CR3-NRS-Z-R6-alkyl and -R4-NR$-CR3-NRS-Z-R6-aryl, wherein the alkyl and aryl groups can be unsubstituted or substituted; and R4 is preferably ethylene or n-butylene or Ra and R$ join to form a ring. 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. For substituted groups such as substituted alkyl or substituted aryl groups, preferred substituents include halogen, nitrite, methoxy, methylthio, trifluoromethyl, and trifluoromethoxy. One or more of these preferred substituents, if present, can be present in the compounds of the invention in any combination.
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, andlor 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 nglkg 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-1, IL-6, IL-
H (~ ) ,BOC (2) BOC
HO-R4 N ~. HO-R4 N --~ I-R N~
~e \R a \
X XI 8 ~ XII Ra N
N ~ ~~ Rz (3) . / N
Rn / X
OH
NHz ~ XIII
N w NCR E (s> OwN \ N E (4> N ~ N
/ N z I / ~ Rz I / ~~ Rz i ,N N
Rn / X Rn / X Rn / X
O
,BOC ~ ,BOC BOC
_ I _ i XVI R4 ~ XV R4 N XIV R4 N
a Rs Ra (6) NHz NHz N ~ N~ ~ N ~ N~ R
/ N Rz / N z Rn / X Rn / X
O O
XVII R4 N R4 N-CR3 NR5 R~~
Ra XVIII R
Compounds of the invention can be prepared according to Reaction Scheme II
where R, R2, R3, R4, R5, Rs, Rl l, X and n are as defined above and BOC is tert-butoxycarbonyl.
In step (1) of Reaction Scheme II the amino group of an aminoalcohol of Formula XIX is protected with a tef-t-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-teYt-butyl dicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula XIX are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme II a protected amino alcohol of Formula XX is converted to a methanesulfonate of Formula XXI. A solution of a compound of Formula XX in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of a base such as triethylamine. The reaction can be carried out at a reduced temperature (0°C).
In step (3a) of Reaction Scheme II a methanesulfonate of Formula YXI is converted to an azide of Formula XXII. Sodium azide is added to a solution of a compound of Formula XXI in a suitable solvent such as N,N-dimethylformamide.
The reaction can be carried out at an elevated temperature (80 - 100°C).
In step (3b) of Reaction Scheme II a compound of Formula XXII is alkylated with a halide of formula Hal-R$ to provide a compound of Formula XXIII. In compounds where R$ is hydrogen this step is omitted. The compound of Formula XXII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran to form the anion and then combined with the halide. The reaction can be carried out at ambient temperature.
In step (4) of Reaction Scheme II an azide of Formula XXII or XXIII is reduced to provide an amine of Formula XXIV. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon.
The reaction can conveniently be carned out on a Parr apparatus in a suitable solvent such as methanol or isopropanol.
In step (5) of Reaction Scheme II a 4-chloro-3-nitroquinoline of Formula XXV
is reacted with an amine of Formula XXIV to provide a 3-nitroquinoline of Formula XXVI.
The reaction can be carned out by adding an amine of Formula XXIV to a solution of a compound of Formula XXV in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. Many quinolines of Formula YXV are known compounds or can be prepared using known synthetic methods, see for example, Gerster, U.S. Patent 4,689,338 and references cited therein.
In step (6) of Reaction Scheme II a 3-nitroquinoline of Formula XXVI is reduced to provide a 3-aminoquinoline of Formula XXVII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon.
The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene.
In step (7) of Reaction Scheme II a compound of Formula XXVII is reacted with a carboxylic acid or an equivalent thereof to provide a 1H imidazo[4,5-c]quinoline of Formula XIV. 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 XIV. For example, triethyl orthoformate will provide a compound where RZ is hydrogen and triethyl orthovalerate will provide a compound where R2 is butyl. 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 catalytic amount of pyridine hydrochloride can be included.
Alternatively, step (7) can be carried out by (i) reacting a compound of Formula XXVII 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 a compound of Formula XXVII in an inert solvent such as acetonitrile or dichloromethane. The reaction can be carried out at ambient temperature or at a reduced temperature. In part (ii) the product of part (i) is heated in an alcoholic solvent in the presence 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.
Steps (8), (9), (10) and (11) are carried out in the same manner as steps (4), (5), (6) and (7) of Reaction Scheme I.
Reaction Scheme II
HO-X-O-R4 NHz (--~ HO-X-O-R4 ~~gOC
XIX
N3 X-O-R4 ~ BOCE (3a) -~_ O-X-O-R ~ BOC
(3b) ~ 0 a XXII ~(4) XXI
BOC (4) BOC
Ns X_O-Ra N ---~ HzN_X-O-Ra Ni XXIII R8 XXIV \R8 O
l+
N ~ N.O_ I /
(5) Rn 'CI
XXV
O
N ~ N~R E (~) N ~ NHz N \ N;O_ (6) / z I / E I
~N 'NH /
Rn I NH
n / X / X Rn / X
I
XIV R4 N~BOC R-N~gOC IO ~BOC
\R8 XXVII 4 \R XXVI RQ N
R
a (8) O + ~ NHz NHz N\ R (9) N ~ N (10) N
/ N 2~ I \~Rz~ N\ ~~R
I / N / N z Rn / O Rn / X Rn / X
XV R4 N~BOC ~ sBOC 0 \R XVI R4 N R
a R8 XVII 4 \R
(11 ) i NHz N
N / y Rz ~N
I
Rn / X
O
13 VIII R4 R CR3--NR5 R~~
Compounds of the invention can be prepared according to Reaction Scheme III
where R, R2, R3, R4, RS, R8, Rl l, X and n are as defined above.
In step (1) of Reaction Scheme III a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVII is reduced to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XXVIII. Preferably the reduction is tamed out by suspending or dissolving a compound of Formula XVII in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then hydrogenating. The reaction can be conveniently carried out in a Parr apparatus.
Step (2) is carried out in the same manner as step (7) of Reaction Scheme I to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine of Formula XXIX. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme III
N / N~ Rz C 1~ N ~ N~ R2 y N / N~ R
N
N
Rn / X Rn X Rn X
O
I H
I H
Ra N Ra N Ra. ~Ra XVII R$ XXVIII ~R$ XXIX
"11 Compounds of the invention can also be prepared according to Reaction Scheme IV where R, Rt, R2, X and n are as defined above.
In step (1) of Reaction Scheme IV a 4-chloro-3-nitroquinoline of Formula XXV
is reacted with an amine of formula RI-0-X-NHZ to provide a 3-nitroquinolin-4-amine of Formula XXX. The reaction can be tamed out by adding the amine to a solution of a compound of Formula XXV in a suitable solvent such as chloroform or dichloromethane and optionally heating. Many quinolines of Formula XXV are known compounds, see for example, Gerster, U.S. Patent 4,689,338 and references cited therein.
In step (2) of Reaction Scheme IV a 3-nitroquinolin-4-amine of Formula XXX
is reduced using the method of step (6) of Reaction Scheme II to provide a quinoline-3~4-diamine of Formula XXXI.
In step (3) of Reaction Scheme IV a quinoline-3,4-diamine of Formula XXXI is cyclized using the method of step (7) of Reaction Scheme II to provide a 1H
imidazo[4,5-cJquinoline of Formula XX~~II.
In step (4) of Reaction Scheme IV a 1H imidazo[4,5-c]quinoline of Formula XXXII is oxidized using the method of step (4) of Reaction Scheme I to provide a 1H
imidazo[4,5-c]quinoline-SN-oxide of Formula XXXIII.
In step (5) of Reaction Scheme IV a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XXXIII is aminated using the method of step (5) of Reaction Scheme I
to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula I. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
O
"+ O
N. - n+
/ O ~ N ~ N.O- (~~ N ~ NH2 CI /
-NH ~NH
R~ / ' Rn / X R~ / X
XXV XXX ~ XXXI O
R~ R~
(3) NHZ
/ N~R~ E (5) O'N+ \ N~Rz E (4) N \ N~Ra ~N / N / N.
R'n ~/ X Rn / X Rn / X
O p O
I
R~ XXXIII R~ XXXII R~
Compounds of the invention can be prepared according to Reaction Scheme V
where R, R2, R3, R4, R5, R8, Rl l, X and n are as defined above.
In step (1) of Reaction Scheme V the BOC group is removed from a compound of Formula XIV using the method of step (6) of Reaction Scheme I to provide a 1H
imidazo[4,5-c]quinoline of Formula XX~~IV.
In step (2) of Reaction Scheme V a 1H imidazo[4,5-c]quinoline of Formula X~~XIV is converted to a urea or thiourea of Formula XXXV using the method of step (7) of Reaction Scheme I.
In step (3) of Reaction Scheme V a 1H imidazo[4,5-c]quinoline of Formula XXXV is oxidized using the method of step (4) of Reaction Scheme I to provide a 1H
imidazo[4,5-c]quinolin-SN-oxide of Formula XXXVI.
In step (4) of Reaction Scheme V a 1H imidazo[4,5-c]quinolin-SN-oxide of Formula ~~XXVI is aminated using the method of step (5) of Reaction Scheme I
to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XVIII. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme V
N>-- Rz (~ N \ ~ R (~ N \ N
N / N z I , ~-Rz Rn / X X N
O n / ~ n ~
iBOC ~ H O
XIV R4 NR XXXIV R4 ~ XXXV R4~N~R8 Rs R~~
(3) N Hz N \ N (4) O\.~ \ N
I / N~ Rz I / y Rz i 'N
, n / O n /
O
R . iR
XVIII 4 i a XXXVI R4~N~R$
Rs CRs R~' R11 The invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formulas (I) and (II). These intermediate compounds have the structural Formulas (III) and (IV), described in more detail below.
One class of intermediate compounds has formula (III):
Ni N
~~' RZ
N
X-O-Rl (III) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
-R4-NR$-CR3-NRS-Z-R6-alkyl;
-R4.-NR8-CR3-NRS-Z-R6-alkenyl;
-R4-NR$-CR3-NRS-Z-R6-aryl;
-R4-NR8- CR3-NRS-Z-R6-heteroaryl;
-R4.-NR$- CR3-NRS-Z-RG--heterocyclyl; and -R4-NR8-CR3-NRSR~;
-R4-NRa-CR3-NR9-Z-R6-alkyl;
-R4-NRg-CR3-NR9-Z-R~-alkenyl;
-R4-NR$-CR3-NR9-Z-R6-aryl;
-R4-NRg- CR3-NR9-Z-R6-heteroaryl; and -R4-NR$- CR3-NR9-Z-R6-heterocyclyl;
RZ is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
S -N(Rs)z~
-CO-N(Rs)z;
-CO-C1_lo alkyl;
-CO-O-CI_IO alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each RS is independently H or C1_io alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is H or C~_IO alkyl which may be interrupted by a hetero atom, or R~ can j oin with Rs to form a ring;
R8 is H, C~_IO alkyl, or arylalkyl; or R4 and R$ can join to form a ring;
R9 is C1_lo alkyl which can join together with R$ to form a ring;
2S each Y is independently -O- or -S(O)o_z-;
Z is a bond, -CO-, or -SOz-;
nisOto4;and each R present is independently selected from the group consisting of C1_lo alkyl, CI_IO alkoxy, hydroxy, halogen and trifluoromethyl;
30 or a pharmaceutically acceptable salt thereof.
Another class of intermediate compounds are the imidazoquinoline-N-oxide compounds of Formula (IV):
O
~N i N
N
X-O-Rl (IV) wherein X is -CHRs-, -CHRs-alkylene-, or-CHRs-alkenylene-;
Rl is selected from the group consisting of:
-R4-NR$-CR3-NRs-Z-R6-alkyl;
-R4-NR8-CR3-NRs-Z-R6-alkenyl;
-R4-NR8-CR3-NRs-Z-R6-aryl;
-Ra: NR$- CR3-NRs-Z-R6-heteroaryl;
-R4-NR$-C R3-NRs-Z-R6-heterocyclyl;
-~-NRs-CR3-NRsR~
_R4-NRs-CR3-NR9-Z-R6-alkyl;
-R4-NR$-CR3-NR9-Z-R6-alkenyl;
-R4-NR$-CR3-NR9-Z-R6-aryl; .
-Ra.-NR$- CR3-NR9-Z-R6-heteroaryl; and -R4-NR$- CR3-NR9-Z-R6-heterocyclyl;
each Y is independently -O- or -S(O)o_2-;
Z is a bond, -CO-, or-SOZ-;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each RS is independently H or C1_io alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is H or C1_lo alkyl which may be interrupted by a hetero atom, or R~ can join with Rs to form a ring;
R8 is H, C1_lo alkyl, or arylalkyl; or R4 and R8 can join to form a ring;
R9 is C1_IO alkyl which can join together with R$ to form a ring;
nisOto4;and each R present is independently selected from the group consisting of C1-to alkyl, CI_lo alkoxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
As used herein, the terms "alkyl", "alkenyl" and the prefix "alk-" 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, cyclopropylmethyl, cyclopentyl, cyclohexyl 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 groups consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl.
The term "haloalkyl" is inclusive of groups that are 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, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, 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 all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 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, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylaminocarbonylamino and, in the case of I heterocyclyl, oxo. 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 R~ groups include -R4-NR$-CR3-NRS-Z-R6-alkyl and -R4-NR$-CR3-NRS-Z-R6-aryl, wherein the alkyl and aryl groups can be unsubstituted or substituted; and R4 is preferably ethylene or n-butylene or Ra and R$ join to form a ring. 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. For substituted groups such as substituted alkyl or substituted aryl groups, preferred substituents include halogen, nitrite, methoxy, methylthio, trifluoromethyl, and trifluoromethoxy. One or more of these preferred substituents, if present, can be present in the compounds of the invention in any combination.
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, andlor 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 nglkg 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-1, 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-cc 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; HIV; CMV; VZV; rhinovirus; adenovirus;
influenza;
and para-influenza; 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, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myelorna, 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-1, 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/kg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg. 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, rate 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 100ng/kg to about SOmg/kg, preferably about 10~g/kg to about Smg/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/kg to about 50 mg/kg, preferably about 10 p,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. A Waters Fraction Lynx automated purification system was used. The semi-prep HPLC fractions were analyzed using a Micromass LC-TOFMS and the appropriate fractions were combined and centrifuge evaporated to provide the trifluoroacetate salt of the desired compound. The structures were confirmed by 1H NMR.
Column: Phenomenex Luna C18(2), 10 x 50 mm, 5 micron particle size, 100A
pore; flow rate: 25 mL/min.; gradient elution from 5-65% B in 4 min., then 65 to 95 % B
in 0.1 min, then hold at 95% B for 0.4 min., where A=0.05 % trifluoroacetic acid/water and B=0.05% trifluoroacetic acid/acetonitrile; fraction collection by mass-selective triggering.
w Example 1 N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-phenylurea NHz \ N
yOw N
O
H
N
O~NH
Part A
A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol) in 180 mL of tetrahydrofuran (THF), under Nz, was cooled to 0°C and treated with 140 mL of 2N NaOH
solution. A solution of di-tart-butyl dicarbonate (60.2 g, 0.276 mol) in 180 mL of THF
was then added dropwise over 1 h to the rapidly stirred solution. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 18 h.
The THF
was then removed under reduced pressure and the remaining aqueous slurry was brought to pH 3 by addition of 150 mL of 1M H2S04 solution. This was then extracted with ethyl acetate (300 mL, 100 mL) and the combined organic layers were washed with H20 (2X) and brine. The organic portion was dried over NaZS04 and concentrated to give tart-butyl 2-(2-hydroxyethoxy)ethylcarbamate as a colorless oil (47.1 g).
Part B
A rapidly stirred solution of tent-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CHZC12 was cooled to 0°C under NZ and treated with triethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 22 h. The reaction was quenched by addition of 500 mL saturated NaHC03 solution and the organic layer was separated. The organic phase was then washed with HZO (3 X 500 mL) and brine. The organic portion was dried over Na2S04 and concentrated to give 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g).
Part C
A stirred solution of 2-{2-[(tent-butoxycarbonyl)amino]ethoxy]ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90°C under NZ. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold H20. The reaction mixture was then extracted with Et20 (3 X 300 mL). The combined organic extracts were washed with HZO (4 X 100 mL) and brine (2 X 100 mL).
The organic portion was dried over MgS04 and concentrated to give 52.0 g of tart-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil.
Part D
A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under HZ (3 I~g/cm2) for 24 h. The solution was then ftltered through a Celite pad and concentrated to give 35.3 g of crude tent-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
Part E
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL
of anhydrous CHZC12, under N2, was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with H20 (2 X 300 mL) and brine (300 mL). The organic portion was dried over Na2S04 and concentrated to give a bright yellow solid.
Recrystallization from ethyl acetate/hexanes gave 43.6 g of tent-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy]ethylcarbamate as bright yellow crystals.
Part F
A solution of tart-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shaken under HZ (3 I~g/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.92 g of crude tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy]ethylcarbamate as a yellow syrup.
Part G
A solution of tei°t-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5 mmol) in 250 mL of anhydrous CHZCl2 was cooled to 0 °C and treated with triethylamine (4.18 mL, 30.0 mmol).
Methoxypropionyl chloride (3.30 mL, 30.3 mmol) was then added dropwise over 5 min.
The reaction was then warmed to room temperature and stirring was continued for 1 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 250 mL of EtOH and 12.5 mL of triethylamine was added.
The mixture was heated to reflux and stirred under NZ overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et20. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. The solid was dissolved in 200 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 11.1 g of tent-butyl 2- f 2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow syrup.
Part H
A solution of ter°t-butyl 2- f 2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethylcarbamate (10.22 g, 24.7 mmol) in 250 mL of CHC13 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). After stirring 30 min, the reaction mixture was washed with 1% Na2C03 solution (2 X 75 mL) and brine. The organic layer was then dried over Na2S04 and concentrated to give 10.6 g of test-butyl 2-f 2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethylcarbamate as an orange foam that was used without further purification.
Part I
A solution of tef~t-butyl 2- f 2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60°C and treated with 10 mL of concentrated NH40H
solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHCl3. The reaction mixture was then washed with HzO, 1 % NaZC03 solution (2X) and brine. The organic portion was dried over NaaS04 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Part J
Text-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) was treated with 75 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 1.5 h, the reaction mixture was cooled and ftltered to give a gummy solid. The solid was washed EtOH and Et20 and dried under vacuum to give the hydrochloride salt as a light brown solid. The free base was made by dissolving the hydrochloride salt in 50 mL of HZO and treating with 10%
NaOH solution. The aqueous suspension was then concentrated to dryness and the residue was treated with CHCl3. The resulting salts were removed by filtration and the filtrate was concentrated to give 3.82 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 330 (M + H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.10 (d, J = 8.1 Hz, 1 H); 7.66 (d, J = 8.2 Hz, 1 H);
7.40 (m, 1 H); 7.25 (m, 1 H); 6.88 (br s, 2 H); 4.78 (t, J = 5.4 Hz, 2 H);
3.89 (t, J = 4.8 Hz, 2 H); 3 .84 (t, J = 6.9 Hz, 2 H); 3.54 (t, J = 5.4 Hz, 2 H); 3.31 (s, 3 H); 3 .23 (t, J = 6.6 Hz, 2 H); 2.88 (t, J = 5.3 Hz, 2 H).
Part K
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CHZCh and cooled to 0 °C under N2. The reaction mixture was then treated with phenyl isocyanate (247 p.L, 2.28 mmol) and Et3N (0.64 mL, 4.56 mmol) and allowed to warm slowly to room temperature.
After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to yield a yellow solid. The yellow solid was dissolved in a minimum amount of CH~,Cl2 and EtOAc was added until the solution became turbid. The mixture was placed in a freezer overnight and white crystal formed. The crystals were isolated by filtration and were dried under vacuum to give 126 mg of N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-phenylurea. mp 171.0-174.0 °C ;
MS 449 (M + H)+;
'H NMR (300 MHz, DMSO-d6) 8 8.50 (s, 1 H); 8.05 (d, J = 7.7 Hz, 1 H); 7.62 (d, J = 8.8 Hz, 1 H); 7.44-7.18 (rn, 3 H); 7.27-7.18 (m, 3 H); 6.88 (t, J = 7.3 Hz, 1 H);
6.54 (s, 2 H);
6.12 (t, J = 5.5 Hz, 2 H); 4.76 (t, J = 4.8 Hz, 2 H); 3.88 (t, J = 5.3 Hz, 2 H); 3.81 (t, J =
6.7 Hz, 2 H); 3.40 (t, J = 6.0 Hz, 2 H); 3.28 (s, 3 H); 3.25-3.14 (m, 4 H);
'3C (75 MHz, DMSO-d6) S 155.5, 152.0, 144.9, 140.8, 132.7, 129.0, 126.8, 126.5, 121.5, 121.4, 120.5, 117.9, 115.1, 70.5, 69.4, 58.4, 45.5, 27.6;
Anal. Calcd for C~4H2gN6O3 ~ 0.21 H20: %C, 63.73, %H, 6.33, %N, 18.58. Found:
%C, 63.33, %H, 6.28, %N, 18.67.
Example 2 N (2-~2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H irnidazo[4,5-c]quinolin-1-yl]ethoxy~ethyl)-N'-phenylurea N
N ~~0~
N
O
H
N
O' -NH
~i Part A
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with Pt02 (1.0 g). The reaction mixture was shaken under HZ (3 I~g/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d.
The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 200 mL of H20 then made basic (pH~l 1) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5 X 75 mL) and the combined organic layers were dried over NaZS04 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,S-c]quinolin-4-amine as a tan solid.
MS 334 (M + H)+;
S ~H NMR (300 MHz, CDCl3) 8 5.19 (s, 2 H); 4.49 (t, J = S.4 Hz, 2 H); 3.84 (t, J = 6.6 Hz, 2 H); 3 . 71 (t, J = 5.4 Hz, 2 H), 3 .3 6 (t, J = 5.2 Hz, 2 H); 3 . S 1 (s, 3 H); 3 .1 S (t, J = 6.6 Hz, 2 H); 2.95 (m, 2 H); 2.82 (m, 2 H); 2.76 (t, J = S.1 Hz, 2 H); 1.84 (m, 4 H), 1.47 (br s, 2 H).
Part B
I -[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6, 7, 8,9-tetrahydro-1 H
imidazo[4,S-c]quinolin-4-amine (919 mg, 2.76 rnmol) was dissolved in 30 mL of anhydrous CHZC12 and cooled to 0 °C under NZ. The reaction mixture was then treated with phenyl isocyanate (300 ~.L, 2.76 mmol) and Et3N (0.77 mL, S.S1 mmol) and allowed to warm slowly to room temperature. After stirring overnight, the reaction mixture was 1 S then quenched by addition of saturated NaHC03 solution (30 mL). The organic layer was separated and washed with H20 and brine, dried over NaZS04 and concentrated under reduced pressure to give a yellow solid. The solid was trituxated with Et20 (30 mL) and a few drops of MeOH. The solid was isolated by filtration and dried under vacuum to give 460 mg of N-(2- f 2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,S-c]quinolin-1-yl]ethoxy}ethyl)-N'-phenylurea as a white powder. m.p. 180-182 °C;
MS 4S3 (M + H)+;IH NMR (300 MHz, DMSO-d6) 8 8.51 (s, 1 H); 7.37 (d, J= 7.7 Hz, H); 7.19 (t, J = 8.2 Hz, 2 H); 6.86 (t, J = 7.7 Hz, 1 H); 6.11 (t, J = 5.S Hz, 2 H); 5.70 (s, 2 H); 4.43 (t, J = S.l Hz, 2 H); 3.78-3.69 (m, 4 H); 3.39 (t, J = S.6 Hz, 2 H);
3.25 (s, 3 H);
3.19 (m, 2 H); 3.10 (t, J = 6.8 Hz, 2 H); 2.91 (m, 2 H); 2.64 (m, 2 H); 1.72 (m, 4 H);
'3C (75 MHz, DMSO-d6) S ISS.S, 151.3, 149.3, 146.3, 140.8, 138.5, I29.0, 125.0, 121.4, 118.0, 10S.6, 70.6, 70.5, 70.4, 58.4, 44.6, 39.2, 32.7, 27.6, 23.8, 23.1, 23.0; Anal. Calcd fox C24H32N6~3~ %C, 63.70, %H, 7.13, %N, 18.57. Found: %C, 63.33, %H, 7.16, %N, 18.66.
Example 3 N (2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methyl-N'-phenylurea N H~
N \ N~O~
N
O
N~
O~NH
\
Part A
Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placed in a round bottom flask and washed with hexanes (3X) under NZ. The dried sodium hydride was treated with 800 mL of anhydrous THF. A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added to the stirred sodium hydride solution over 40 min. After addition was complete, the reaction was stirred an additional 20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). After stirring overnight, the reaction was quenched with 300 mL of saturated NaHC03 solution. The reaction mixture was then treated with 200 mL of H20 and 1 L of Et20. The organic phase was separated and washed with H20 and brine. The organic portion was then dried over MgS04 and concentrated under reduced pressure to give 41.9 g of text-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.
Part B
A solution test-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate (41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken under H2 (3 Kg/cmz) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 37.2 g of crude text-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellow liquid.
Part C
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL
of anhydrous CHZC12, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tent-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with HZO (2 X 300 mL) and brine (300 mL).
The organic portion was dried over Na2S04 and concentrated to give a brown oil. Column chromatography (Si02, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tent-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy]ethyl)carbamate as a yellow solid.
Part D
A solution of test-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxyJethyl)carbamate (6.56 g, 16.8 mmol) in 75 mL of toluene was treated with 0.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.8 g of crude test-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate as an orange syrup which was carned on without further purification.
Part E
A solution of tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy]ethyl(methyl)carbamate (6.05 g, 16.8 mmol) in 200 mL of anhydrous CH2C12 was cooled to 0°C and treated with triethylamine (2.40 mL, 17.2 mmol).
Methoxypropionyl chloride (1.72 mL, 17.2 mmol) was then added dropwise over 5 min.
The reaction was then warmed to room temperature and stirring was continued for 3 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 200 mL of EtOH and 7.2 mL of triethylamine was added.
The mixture was heated to reflux and stirred under NZ overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et20. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. This was dissolved in 300 mL of CHZC12 and washed with HZO and brine.
The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 100 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 7.20 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxyJethyl(methyl)carbamate as a yellow syrup.
Part F
A solution of tent-butyl 2- f 2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-yl]ethoxy}ethyl(methyl)carbamate (7.20 g, 16.8 mmol) in 200 mL of CHZC12 was treated with MCPBA (77%, 4.32 g, 19.3 mmol). After stirring 6 h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with HZO and brine then dried over NaZS04 and concentrated to give 7.05 g of test-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a light brown solid.
Part G
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80°C and treated with 5 mL of concentrated solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CHZC12. The reaction mixture was then washed with H20, 1% NaZC03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 6.50 g of tef-t-butyl 2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil.
Part H
Test-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (6.50 g, 14.7 mmol) was dissolved in 100 mL
of EtOH
and treated with 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 6 h, the reaction mixture was cooled and filtered to give a gummy solid.
The solid was washed with EtOH and EtzO and dried under vacuum to give the hydrochloride salt as a lightbrown powder. The free base was made by dissolving the hydrochloride salt in 50 mL of H20 and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHZCl2 (5 X 50 mL). The combined organic layers were dried over Na2S04 and concentrated to give 3.93 g of 2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 344 (M + H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.07 (d, J = 7.7 Hz, 1 H); 7.62 (dd, J = 1.0, 8.3 Hz, 1 H); 7.42 (ddd, J= 1.0, 7.1, 8.2 Hz, 1 H); 7.22 (ddd, J= 1.l, 7.1, 8.2 Hz, 1 H); 6.49 (s, 2 H); 4.75 (t, J = 5.1 Hz, 2 H); 3.83 (t, J = 6.8 Hz, 4 H); 3.35 (t, J = 5.6 Hz, 2 H); 3.30 (s, 3 H); 3.21 (t, J = 6.9 Hz, 2 H); 2.45 (t, J = 5.6 Hz, 2 H); 2.12 (s, 3 H).
Part I
2-(2-Methoxyethyl)-1-~2-[2-(methylamino)ethoxy]ethyl-1H irnidazo[4,5-c]quinolin-4-amine (929 mg, 2.71 mmol) was dissolved in 30 mL of anhydrous CHZCl2 and treated with phenyl isocyanate (300 ~L, 2.76 mmol). After stirring under NZ
overnight, the reaction mixture was concentrated under reduced pressure.
Purification by column chromatography (Si02, 3% MeOH/CHC13 saturated with aqueous NH40H) gave the product as a white solid. Crystallization from HZO and MeOH gave 610 mg of N (2-f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methyl-N'-phenylurea as a flakey white crystals. m.p. 184.8-185.8 °C ;
MS 463 (M + H)+;
IH NMR (300 MHz, DMSO-d6) 8 8.16 (s, 1 H); 8.06 (d, J= 7.7 Hz, 1 H); 7.61 (dd, J=
1.0, 8.3 Hz, 1 H); 7.43-7.38 (m, 3 H); 7.25-7.17 (m, 3 H); 6.91 (t, J = 7.3 Hz, 1 H); 6.47 (s, 2 H); 4.76 (t, J = 5.0 Hz, 2 H); 3.88 (t, J = 5.1 Hz, 2 H); 3.78 (t, J =
6.8 Hz, 2 H); 3.48 (t, J = 5.2 Hz, 2 H); 3.39 (t, J = 5.4 Hz, 2 H); 3.27 (s, 3 H); 3.20 (t, J =
6.8 Hz, 2 H); 2.82 (s, 3 H);
13C NMR (75 MHz, DMSO-d6) 8 155.6, 152.0, 151.9, 145.1, 140.9, 132.7, 128.5, 126.7, 126.6, 122.0, 121.4, 120.5, 120.1, 115.1, 70.5, 69.6, 69.4, 58.4, 47.7, 45.5, 35.4, 27.6.
Anal. Calcd for CZSHsoN60s~0.12 H20: %C, 64.62; %H, 6.56; %N, 18.08. Found:
%C, 64.69; %H, 6.65; %N, 18.09.
Example 4 N (2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl)-N methyl-N-phenylurea NHZ
N
N yOw N
O
N~
O~NH
Part A
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid and treated with PtO2 (0.5 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of Pt02 was added and hydrogenation was continued for an additional 3 d. The reaction was then filtered through Celite and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 50 mL
of H20 and extracted with 50 mL of CHCl3. The organic portion was removed and discarded.
The aqueous portion was then made basic (pH~l2) by addition of 10% NaOH solution.
This was then extracted with CHCl3 (6 X 50 mL) and the combined organic layers were dried over NaZS04 and concentrated to a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 g of activated charcoal. The hot solution was filtered through Celite and concentrated to dryness. The resulting gummy solid was concentrated several times with Et20 to give 3.19 g of 2-(2-methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine as an off white powder.
MS 348 (M + H)+;
'H NMR (300 MHz, CDCl3) 8 4.84 (s, 2 H); 4.48 (t, J = 5.7 Hz, 2 H); 3.84 (t, J
= 6.7 Hz, 2 H); 3.70 (t, J = 5.7 Hz, 2 H); 3.46 (t, J = 5.1 Hz, 2 H); 3.36 (s, 3 H);
3.14 (t, J = 6.7 Hz, 2 H); 2.96 (m, 2 H); 2.83 (m, 2 H); 2.65 (t, J = 5.1 Hz, 2 H); 2.36 (s, 3 H);
1.85 (m, 4 H).
Part B
2-(2-Methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine (750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CHZC1Z and treated with phenyl isocyanate (239 p,L, 2.20 mmol).
After stirring under NZ overnight, the reaction mixture was concentrated under reduced pressure.
Crystallization from EtOAc and CHZC12 gave 170 mg of N (2- f 2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methyl-N'-phenylurea as fluffy white crystals. m.p. 167.7-170.0 °C ;
MS 467 (M + H)+;
1H NMR (300 MHz, DMSO-d6) ~ 8.17 (s, 1 H); 7.43 (d, J = 7.6 Hz, 2 H); 7.21 (t, J = 7.9 Hz, 2 H); 6.91 (t, J = 7.3 Hz, 1 H); 5.65 (s, 2 H); 4.43 (t, J = 5.0 Hz, 2 H);
3.72 (t, J = 7.0 Hz, 2 H); 3.70 (t, J = 5.2 Hz, 2 H); 3.46-3.41 (m, 4 H); 3.24 (s, 3 H); 3.07 (t, J = 6.9 Hz, 2 H); 2.92 (m, 2 H); 2.85 (s, 3 H); 2.64 (m, 2 H); 1.72 (m, 4 H);
i3C NMR (75 MHz, DMSO-d6) 8 155.6, 151.2, 149.3, 146.3, 140.9, 138.4, 128.5, 124.9, 122.0, 120.1, 105.5, 70.7, 70.5, 69.5, 58.4, 48.0, 44.6, 35.5, 32.8, 27.6, 23.8, 23.1, 23Ø
Anal. Calcd for CZSH34N6~3~ %C, 64.36; %H, 7.35; %N, 18.01. Found: %C, 64.04;
%H, 7.38; %N, 18.02.
Example 5 N-(2-~2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide NHZ
N ~ N~ O
I
N
O
N
~O
O
Under a nitrogen atmosphere, 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H
imidazo[4,5-c]quinolin-4-amine (0.75 g, 2.3 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (0.64 mL, 4.6 mmol) using mild heat and vigorous stirring. The solution was chilled in an ice-water bath and 4-morpholinecarbonyl chloride (0.27 mL, 2.3 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for an additional 4 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (25 mL). The phases were separated and the organic layer was washed with water (3 ae 25 ml), brine (25 mL), dried (NaZS04), filtered and concentrated to yield a yellow foam. The product was recrystallized from dichloromethane and ethyl acetate. The crystals were triturated with ether (2 x 5 mL) to remove residual solvent.
The final product was dried in a vacuum oven to provide 200 mg of N-(2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl)morpholine-4-carboxamide as a tan crystalline solid, m.p. 164-166 °C.
'H NMR (300 MHz, DMSO-d6) 8 8.06 (d, J = 8.1 Hz, 1 H), 7.61 (d, J = 7.3 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 6.51 (s, 2 H), 6.33 (t, J =
5.0 Hz, 1 H), 4.74 (t, J = 4.3 Hz, 2 H), 3.85-3.81 (m, 4 H), 3.49 (t, J = 4.3 Hz, 4 H), 3.33 (t, J = 5.9 Hz, 2 H), 3.30 (s, 3 H), 3.21 (t, J = 6.8 Hz, 2 H), 3.14 (t, J = 4.5 Hz, 4 H), 3.08 (t, J = 6.0 Hz, 2 H);
'3C NMR (75 MHz, DMSO-d6) 8 157.8, 151.9, 145.0, 132.7, 126.7, 126.6, 121.4, 120.5, 115.1, 70.4, 70.2, 69.2, 58.4, 45.5, 44.0, 27.6;
Anal. Calcd for CZZH3oN6O4: %C, 59.71, %H, 6.83, %N, 18.99. Found: %C, 59.71, %H, 6.80,% N, 18.78;
MS(CI) m/e 443 (M+H) Example 6 N-(2- f 2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl) N-methylmorpholine-4-carboxamide.
NHz N ~ N~O~
N
/O/
N
N
JO
2-(2-Methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (802 mg, 2.34 mmol) was dissolved in 30 mL of anhydrous CHZCl2 and cooled to 0 °C under NZ. To the stirred solution were added Et3N
(0.65 mL, 4.68 mmol) and morpholinecarbonyl chloride (273 ~L, 2.34 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL) and CHZCl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (SiO~,, 2-5%
MeOH/CHC13 saturated with aqueous NH40H) gave the product as a colorless foam.
Crystallization from EtOAc gave 640 mg of N-(2-(2-[4-amino-2-(2-methoxyethyl)-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmorpholine-4-carboxamide as white crystals. Mp = 121.8-122.3 °C.
MS 457 (M + H)+;
'H NMR (500 MHz, DMSO-d6) b 8.06 (dd, J = 0.9, 8.3 Hz, 1 H); 7.61 (dd, J = 1.
l, 8.3 Hz, 1 H); 7.41 (ddd, J = 1.2, 7.0, 8.3 Hz, 1 H); 7.22 (ddd, J = 1.3, 7.0, 8.1 Hz, 1 H); 6.44 (s, 2 H); 4.74 (t, J= 5.2 Hz, 2 H); 3.84 (t, J= 5.2 Hz, 2 H); 3.82 (t, J= 6.9 Hz, 2 H); 3.50-3.43 (m, 6 H); 3.30 (s, 3 H); 3.20 (t, J = 6.9 Hz, 2 H); 3.16 (t, J = 5.5 Hz, 2 H); 2.88 (t, J
= 4.7 Hz, 4 H); 2.59 (s, 3 H);
~3C NMR (75 MHz, DMSO-d6) 8 163.8, 152.0, 151.8, 145.2, 132.7, 126.7, 121.3, 120.6, 115.1, 70.4, 69.4, 68.9, 66.1, 58.5, 49.1, 47.3, 45.5, 36.9, 27.7.
Anal. Calcd for C23H32N6O4: %C, 60.51; %H, 7.07; %N, 18.41. Found: %C, 60.56;
%H, 6.85; %N, 18.19.
Examples 7 -21 Part A
A solution of tart-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy~ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 50 mL of CHzCl2 and washed with saturated NaHC03, and brine. The organic portion was dried over Na2S04 and concetrated to give a green oil.
The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal.
The hot solution was filtered and concentrated to give 4.12 g of tart-butyl 2-[2-(2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbarnate as a yellow oil.
Part B
A solution of tart-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12 g, 10.0 mmol) in 50 mL of CHZCl2 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirring for 5 h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over Na2S04 and concentrated to give 3.68 g of tart-butyl 2-[2-(2-butyl-5-oxido-1H
imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(2-butyl-5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH4OH solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (1.87 g, 9.81 mmol) over a 10 min period. The reaction mixture was then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHZC12. The reaction mixture was then washed with H20, 1% NaZC03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 3.68 g of tert-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Text-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) was suspended in 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction mixture '~='~
was concentrated to give a solid. The solid was triturated with hot EtOH (50 mL) and filtered to give 2.90 g of the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of HZO and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CH2C1~ (3 X 50 mL). The combined organic layers were dried over NaZS04 and concentrated to give 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 328 (M + H)+;
1H NMR (300 MHz, CDC13) S 7.95 (d, J = 8.3 Hz, 1 H); 7.83 (d, J = 8.4 Hz, 1 H); 7.50 (m, 1 H); 7.30 (m, 1 H); 5.41 (s, 2 H); 4.69 (t, J = 5.6 Hz, 2 H); 3.93 (t, J
= 5.6 Hz, 2 H);
3.39 (t, J = 5.1 Hz, 2 H); 2.97 (t, J = 7.9 Hz, 2 H); 2.76 (t, J = 5.1 Hz, 2 H); 1.89 (m, 2 H);
1.52 (m, 2 H); 1.26 (br s, 2 H); 1.0l (t, J = 7.3 Hz, 3 H).
Part E
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme I above using the following general method.
The isocyanate (84 ~mol.) was added to a test tube containing a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H imidazo[4,5-c]quinolin-4-amine (25 mg, 76 ~mol) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC using the method described above. The table below shows the structure of the free base and the observed accurate mass (M +
H).
Example Accurate Mass Number S~cture of Free Base obs.
NHz CH3 N~ \ N
N
7 413.2644 ~N
~N
O ~
~CH3 N
!\~/\
8 O 427.2841 N
N \ N
\\
/ N
°~ 427.2823 °
N~ \ N
/ N
°~ 447.2496 N
O
U
Example Accurate Mass Number S~cture of Free Base obs.
I \ N
Y\
N
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-cc 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; HIV; CMV; VZV; rhinovirus; adenovirus;
influenza;
and para-influenza; 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, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myelorna, 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-1, 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/kg to about 50 mg/kg, preferably about 10 ~g/kg to about 5 mg/kg. 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, rate 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 100ng/kg to about SOmg/kg, preferably about 10~g/kg to about Smg/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/kg to about 50 mg/kg, preferably about 10 p,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. A Waters Fraction Lynx automated purification system was used. The semi-prep HPLC fractions were analyzed using a Micromass LC-TOFMS and the appropriate fractions were combined and centrifuge evaporated to provide the trifluoroacetate salt of the desired compound. The structures were confirmed by 1H NMR.
Column: Phenomenex Luna C18(2), 10 x 50 mm, 5 micron particle size, 100A
pore; flow rate: 25 mL/min.; gradient elution from 5-65% B in 4 min., then 65 to 95 % B
in 0.1 min, then hold at 95% B for 0.4 min., where A=0.05 % trifluoroacetic acid/water and B=0.05% trifluoroacetic acid/acetonitrile; fraction collection by mass-selective triggering.
w Example 1 N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-phenylurea NHz \ N
yOw N
O
H
N
O~NH
Part A
A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol) in 180 mL of tetrahydrofuran (THF), under Nz, was cooled to 0°C and treated with 140 mL of 2N NaOH
solution. A solution of di-tart-butyl dicarbonate (60.2 g, 0.276 mol) in 180 mL of THF
was then added dropwise over 1 h to the rapidly stirred solution. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 18 h.
The THF
was then removed under reduced pressure and the remaining aqueous slurry was brought to pH 3 by addition of 150 mL of 1M H2S04 solution. This was then extracted with ethyl acetate (300 mL, 100 mL) and the combined organic layers were washed with H20 (2X) and brine. The organic portion was dried over NaZS04 and concentrated to give tart-butyl 2-(2-hydroxyethoxy)ethylcarbamate as a colorless oil (47.1 g).
Part B
A rapidly stirred solution of tent-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CHZC12 was cooled to 0°C under NZ and treated with triethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 22 h. The reaction was quenched by addition of 500 mL saturated NaHC03 solution and the organic layer was separated. The organic phase was then washed with HZO (3 X 500 mL) and brine. The organic portion was dried over Na2S04 and concentrated to give 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g).
Part C
A stirred solution of 2-{2-[(tent-butoxycarbonyl)amino]ethoxy]ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90°C under NZ. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold H20. The reaction mixture was then extracted with Et20 (3 X 300 mL). The combined organic extracts were washed with HZO (4 X 100 mL) and brine (2 X 100 mL).
The organic portion was dried over MgS04 and concentrated to give 52.0 g of tart-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil.
Part D
A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under HZ (3 I~g/cm2) for 24 h. The solution was then ftltered through a Celite pad and concentrated to give 35.3 g of crude tent-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
Part E
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL
of anhydrous CHZC12, under N2, was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with H20 (2 X 300 mL) and brine (300 mL). The organic portion was dried over Na2S04 and concentrated to give a bright yellow solid.
Recrystallization from ethyl acetate/hexanes gave 43.6 g of tent-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy]ethylcarbamate as bright yellow crystals.
Part F
A solution of tart-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shaken under HZ (3 I~g/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.92 g of crude tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy]ethylcarbamate as a yellow syrup.
Part G
A solution of tei°t-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5 mmol) in 250 mL of anhydrous CHZCl2 was cooled to 0 °C and treated with triethylamine (4.18 mL, 30.0 mmol).
Methoxypropionyl chloride (3.30 mL, 30.3 mmol) was then added dropwise over 5 min.
The reaction was then warmed to room temperature and stirring was continued for 1 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 250 mL of EtOH and 12.5 mL of triethylamine was added.
The mixture was heated to reflux and stirred under NZ overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et20. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. The solid was dissolved in 200 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 11.1 g of tent-butyl 2- f 2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow syrup.
Part H
A solution of ter°t-butyl 2- f 2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethylcarbamate (10.22 g, 24.7 mmol) in 250 mL of CHC13 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). After stirring 30 min, the reaction mixture was washed with 1% Na2C03 solution (2 X 75 mL) and brine. The organic layer was then dried over Na2S04 and concentrated to give 10.6 g of test-butyl 2-f 2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethylcarbamate as an orange foam that was used without further purification.
Part I
A solution of tef~t-butyl 2- f 2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60°C and treated with 10 mL of concentrated NH40H
solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHCl3. The reaction mixture was then washed with HzO, 1 % NaZC03 solution (2X) and brine. The organic portion was dried over NaaS04 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Part J
Text-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) was treated with 75 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 1.5 h, the reaction mixture was cooled and ftltered to give a gummy solid. The solid was washed EtOH and Et20 and dried under vacuum to give the hydrochloride salt as a light brown solid. The free base was made by dissolving the hydrochloride salt in 50 mL of HZO and treating with 10%
NaOH solution. The aqueous suspension was then concentrated to dryness and the residue was treated with CHCl3. The resulting salts were removed by filtration and the filtrate was concentrated to give 3.82 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 330 (M + H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.10 (d, J = 8.1 Hz, 1 H); 7.66 (d, J = 8.2 Hz, 1 H);
7.40 (m, 1 H); 7.25 (m, 1 H); 6.88 (br s, 2 H); 4.78 (t, J = 5.4 Hz, 2 H);
3.89 (t, J = 4.8 Hz, 2 H); 3 .84 (t, J = 6.9 Hz, 2 H); 3.54 (t, J = 5.4 Hz, 2 H); 3.31 (s, 3 H); 3 .23 (t, J = 6.6 Hz, 2 H); 2.88 (t, J = 5.3 Hz, 2 H).
Part K
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CHZCh and cooled to 0 °C under N2. The reaction mixture was then treated with phenyl isocyanate (247 p.L, 2.28 mmol) and Et3N (0.64 mL, 4.56 mmol) and allowed to warm slowly to room temperature.
After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to yield a yellow solid. The yellow solid was dissolved in a minimum amount of CH~,Cl2 and EtOAc was added until the solution became turbid. The mixture was placed in a freezer overnight and white crystal formed. The crystals were isolated by filtration and were dried under vacuum to give 126 mg of N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-phenylurea. mp 171.0-174.0 °C ;
MS 449 (M + H)+;
'H NMR (300 MHz, DMSO-d6) 8 8.50 (s, 1 H); 8.05 (d, J = 7.7 Hz, 1 H); 7.62 (d, J = 8.8 Hz, 1 H); 7.44-7.18 (rn, 3 H); 7.27-7.18 (m, 3 H); 6.88 (t, J = 7.3 Hz, 1 H);
6.54 (s, 2 H);
6.12 (t, J = 5.5 Hz, 2 H); 4.76 (t, J = 4.8 Hz, 2 H); 3.88 (t, J = 5.3 Hz, 2 H); 3.81 (t, J =
6.7 Hz, 2 H); 3.40 (t, J = 6.0 Hz, 2 H); 3.28 (s, 3 H); 3.25-3.14 (m, 4 H);
'3C (75 MHz, DMSO-d6) S 155.5, 152.0, 144.9, 140.8, 132.7, 129.0, 126.8, 126.5, 121.5, 121.4, 120.5, 117.9, 115.1, 70.5, 69.4, 58.4, 45.5, 27.6;
Anal. Calcd for C~4H2gN6O3 ~ 0.21 H20: %C, 63.73, %H, 6.33, %N, 18.58. Found:
%C, 63.33, %H, 6.28, %N, 18.67.
Example 2 N (2-~2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H irnidazo[4,5-c]quinolin-1-yl]ethoxy~ethyl)-N'-phenylurea N
N ~~0~
N
O
H
N
O' -NH
~i Part A
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with Pt02 (1.0 g). The reaction mixture was shaken under HZ (3 I~g/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d.
The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 200 mL of H20 then made basic (pH~l 1) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5 X 75 mL) and the combined organic layers were dried over NaZS04 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,S-c]quinolin-4-amine as a tan solid.
MS 334 (M + H)+;
S ~H NMR (300 MHz, CDCl3) 8 5.19 (s, 2 H); 4.49 (t, J = S.4 Hz, 2 H); 3.84 (t, J = 6.6 Hz, 2 H); 3 . 71 (t, J = 5.4 Hz, 2 H), 3 .3 6 (t, J = 5.2 Hz, 2 H); 3 . S 1 (s, 3 H); 3 .1 S (t, J = 6.6 Hz, 2 H); 2.95 (m, 2 H); 2.82 (m, 2 H); 2.76 (t, J = S.1 Hz, 2 H); 1.84 (m, 4 H), 1.47 (br s, 2 H).
Part B
I -[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6, 7, 8,9-tetrahydro-1 H
imidazo[4,S-c]quinolin-4-amine (919 mg, 2.76 rnmol) was dissolved in 30 mL of anhydrous CHZC12 and cooled to 0 °C under NZ. The reaction mixture was then treated with phenyl isocyanate (300 ~.L, 2.76 mmol) and Et3N (0.77 mL, S.S1 mmol) and allowed to warm slowly to room temperature. After stirring overnight, the reaction mixture was 1 S then quenched by addition of saturated NaHC03 solution (30 mL). The organic layer was separated and washed with H20 and brine, dried over NaZS04 and concentrated under reduced pressure to give a yellow solid. The solid was trituxated with Et20 (30 mL) and a few drops of MeOH. The solid was isolated by filtration and dried under vacuum to give 460 mg of N-(2- f 2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,S-c]quinolin-1-yl]ethoxy}ethyl)-N'-phenylurea as a white powder. m.p. 180-182 °C;
MS 4S3 (M + H)+;IH NMR (300 MHz, DMSO-d6) 8 8.51 (s, 1 H); 7.37 (d, J= 7.7 Hz, H); 7.19 (t, J = 8.2 Hz, 2 H); 6.86 (t, J = 7.7 Hz, 1 H); 6.11 (t, J = 5.S Hz, 2 H); 5.70 (s, 2 H); 4.43 (t, J = S.l Hz, 2 H); 3.78-3.69 (m, 4 H); 3.39 (t, J = S.6 Hz, 2 H);
3.25 (s, 3 H);
3.19 (m, 2 H); 3.10 (t, J = 6.8 Hz, 2 H); 2.91 (m, 2 H); 2.64 (m, 2 H); 1.72 (m, 4 H);
'3C (75 MHz, DMSO-d6) S ISS.S, 151.3, 149.3, 146.3, 140.8, 138.5, I29.0, 125.0, 121.4, 118.0, 10S.6, 70.6, 70.5, 70.4, 58.4, 44.6, 39.2, 32.7, 27.6, 23.8, 23.1, 23.0; Anal. Calcd fox C24H32N6~3~ %C, 63.70, %H, 7.13, %N, 18.57. Found: %C, 63.33, %H, 7.16, %N, 18.66.
Example 3 N (2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methyl-N'-phenylurea N H~
N \ N~O~
N
O
N~
O~NH
\
Part A
Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placed in a round bottom flask and washed with hexanes (3X) under NZ. The dried sodium hydride was treated with 800 mL of anhydrous THF. A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added to the stirred sodium hydride solution over 40 min. After addition was complete, the reaction was stirred an additional 20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). After stirring overnight, the reaction was quenched with 300 mL of saturated NaHC03 solution. The reaction mixture was then treated with 200 mL of H20 and 1 L of Et20. The organic phase was separated and washed with H20 and brine. The organic portion was then dried over MgS04 and concentrated under reduced pressure to give 41.9 g of text-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.
Part B
A solution test-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate (41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken under H2 (3 Kg/cmz) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 37.2 g of crude text-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellow liquid.
Part C
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL
of anhydrous CHZC12, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tent-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with HZO (2 X 300 mL) and brine (300 mL).
The organic portion was dried over Na2S04 and concentrated to give a brown oil. Column chromatography (Si02, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tent-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy]ethyl)carbamate as a yellow solid.
Part D
A solution of test-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxyJethyl)carbamate (6.56 g, 16.8 mmol) in 75 mL of toluene was treated with 0.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.8 g of crude test-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate as an orange syrup which was carned on without further purification.
Part E
A solution of tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy]ethyl(methyl)carbamate (6.05 g, 16.8 mmol) in 200 mL of anhydrous CH2C12 was cooled to 0°C and treated with triethylamine (2.40 mL, 17.2 mmol).
Methoxypropionyl chloride (1.72 mL, 17.2 mmol) was then added dropwise over 5 min.
The reaction was then warmed to room temperature and stirring was continued for 3 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 200 mL of EtOH and 7.2 mL of triethylamine was added.
The mixture was heated to reflux and stirred under NZ overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et20. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. This was dissolved in 300 mL of CHZC12 and washed with HZO and brine.
The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 100 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 7.20 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxyJethyl(methyl)carbamate as a yellow syrup.
Part F
A solution of tent-butyl 2- f 2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-yl]ethoxy}ethyl(methyl)carbamate (7.20 g, 16.8 mmol) in 200 mL of CHZC12 was treated with MCPBA (77%, 4.32 g, 19.3 mmol). After stirring 6 h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with HZO and brine then dried over NaZS04 and concentrated to give 7.05 g of test-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a light brown solid.
Part G
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80°C and treated with 5 mL of concentrated solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CHZC12. The reaction mixture was then washed with H20, 1% NaZC03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 6.50 g of tef-t-butyl 2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil.
Part H
Test-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (6.50 g, 14.7 mmol) was dissolved in 100 mL
of EtOH
and treated with 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 6 h, the reaction mixture was cooled and filtered to give a gummy solid.
The solid was washed with EtOH and EtzO and dried under vacuum to give the hydrochloride salt as a lightbrown powder. The free base was made by dissolving the hydrochloride salt in 50 mL of H20 and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHZCl2 (5 X 50 mL). The combined organic layers were dried over Na2S04 and concentrated to give 3.93 g of 2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 344 (M + H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.07 (d, J = 7.7 Hz, 1 H); 7.62 (dd, J = 1.0, 8.3 Hz, 1 H); 7.42 (ddd, J= 1.0, 7.1, 8.2 Hz, 1 H); 7.22 (ddd, J= 1.l, 7.1, 8.2 Hz, 1 H); 6.49 (s, 2 H); 4.75 (t, J = 5.1 Hz, 2 H); 3.83 (t, J = 6.8 Hz, 4 H); 3.35 (t, J = 5.6 Hz, 2 H); 3.30 (s, 3 H); 3.21 (t, J = 6.9 Hz, 2 H); 2.45 (t, J = 5.6 Hz, 2 H); 2.12 (s, 3 H).
Part I
2-(2-Methoxyethyl)-1-~2-[2-(methylamino)ethoxy]ethyl-1H irnidazo[4,5-c]quinolin-4-amine (929 mg, 2.71 mmol) was dissolved in 30 mL of anhydrous CHZCl2 and treated with phenyl isocyanate (300 ~L, 2.76 mmol). After stirring under NZ
overnight, the reaction mixture was concentrated under reduced pressure.
Purification by column chromatography (Si02, 3% MeOH/CHC13 saturated with aqueous NH40H) gave the product as a white solid. Crystallization from HZO and MeOH gave 610 mg of N (2-f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methyl-N'-phenylurea as a flakey white crystals. m.p. 184.8-185.8 °C ;
MS 463 (M + H)+;
IH NMR (300 MHz, DMSO-d6) 8 8.16 (s, 1 H); 8.06 (d, J= 7.7 Hz, 1 H); 7.61 (dd, J=
1.0, 8.3 Hz, 1 H); 7.43-7.38 (m, 3 H); 7.25-7.17 (m, 3 H); 6.91 (t, J = 7.3 Hz, 1 H); 6.47 (s, 2 H); 4.76 (t, J = 5.0 Hz, 2 H); 3.88 (t, J = 5.1 Hz, 2 H); 3.78 (t, J =
6.8 Hz, 2 H); 3.48 (t, J = 5.2 Hz, 2 H); 3.39 (t, J = 5.4 Hz, 2 H); 3.27 (s, 3 H); 3.20 (t, J =
6.8 Hz, 2 H); 2.82 (s, 3 H);
13C NMR (75 MHz, DMSO-d6) 8 155.6, 152.0, 151.9, 145.1, 140.9, 132.7, 128.5, 126.7, 126.6, 122.0, 121.4, 120.5, 120.1, 115.1, 70.5, 69.6, 69.4, 58.4, 47.7, 45.5, 35.4, 27.6.
Anal. Calcd for CZSHsoN60s~0.12 H20: %C, 64.62; %H, 6.56; %N, 18.08. Found:
%C, 64.69; %H, 6.65; %N, 18.09.
Example 4 N (2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl)-N methyl-N-phenylurea NHZ
N
N yOw N
O
N~
O~NH
Part A
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid and treated with PtO2 (0.5 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of Pt02 was added and hydrogenation was continued for an additional 3 d. The reaction was then filtered through Celite and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 50 mL
of H20 and extracted with 50 mL of CHCl3. The organic portion was removed and discarded.
The aqueous portion was then made basic (pH~l2) by addition of 10% NaOH solution.
This was then extracted with CHCl3 (6 X 50 mL) and the combined organic layers were dried over NaZS04 and concentrated to a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 g of activated charcoal. The hot solution was filtered through Celite and concentrated to dryness. The resulting gummy solid was concentrated several times with Et20 to give 3.19 g of 2-(2-methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine as an off white powder.
MS 348 (M + H)+;
'H NMR (300 MHz, CDCl3) 8 4.84 (s, 2 H); 4.48 (t, J = 5.7 Hz, 2 H); 3.84 (t, J
= 6.7 Hz, 2 H); 3.70 (t, J = 5.7 Hz, 2 H); 3.46 (t, J = 5.1 Hz, 2 H); 3.36 (s, 3 H);
3.14 (t, J = 6.7 Hz, 2 H); 2.96 (m, 2 H); 2.83 (m, 2 H); 2.65 (t, J = 5.1 Hz, 2 H); 2.36 (s, 3 H);
1.85 (m, 4 H).
Part B
2-(2-Methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine (750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CHZC1Z and treated with phenyl isocyanate (239 p,L, 2.20 mmol).
After stirring under NZ overnight, the reaction mixture was concentrated under reduced pressure.
Crystallization from EtOAc and CHZC12 gave 170 mg of N (2- f 2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methyl-N'-phenylurea as fluffy white crystals. m.p. 167.7-170.0 °C ;
MS 467 (M + H)+;
1H NMR (300 MHz, DMSO-d6) ~ 8.17 (s, 1 H); 7.43 (d, J = 7.6 Hz, 2 H); 7.21 (t, J = 7.9 Hz, 2 H); 6.91 (t, J = 7.3 Hz, 1 H); 5.65 (s, 2 H); 4.43 (t, J = 5.0 Hz, 2 H);
3.72 (t, J = 7.0 Hz, 2 H); 3.70 (t, J = 5.2 Hz, 2 H); 3.46-3.41 (m, 4 H); 3.24 (s, 3 H); 3.07 (t, J = 6.9 Hz, 2 H); 2.92 (m, 2 H); 2.85 (s, 3 H); 2.64 (m, 2 H); 1.72 (m, 4 H);
i3C NMR (75 MHz, DMSO-d6) 8 155.6, 151.2, 149.3, 146.3, 140.9, 138.4, 128.5, 124.9, 122.0, 120.1, 105.5, 70.7, 70.5, 69.5, 58.4, 48.0, 44.6, 35.5, 32.8, 27.6, 23.8, 23.1, 23Ø
Anal. Calcd for CZSH34N6~3~ %C, 64.36; %H, 7.35; %N, 18.01. Found: %C, 64.04;
%H, 7.38; %N, 18.02.
Example 5 N-(2-~2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide NHZ
N ~ N~ O
I
N
O
N
~O
O
Under a nitrogen atmosphere, 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H
imidazo[4,5-c]quinolin-4-amine (0.75 g, 2.3 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (0.64 mL, 4.6 mmol) using mild heat and vigorous stirring. The solution was chilled in an ice-water bath and 4-morpholinecarbonyl chloride (0.27 mL, 2.3 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for an additional 4 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution (25 mL). The phases were separated and the organic layer was washed with water (3 ae 25 ml), brine (25 mL), dried (NaZS04), filtered and concentrated to yield a yellow foam. The product was recrystallized from dichloromethane and ethyl acetate. The crystals were triturated with ether (2 x 5 mL) to remove residual solvent.
The final product was dried in a vacuum oven to provide 200 mg of N-(2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl)morpholine-4-carboxamide as a tan crystalline solid, m.p. 164-166 °C.
'H NMR (300 MHz, DMSO-d6) 8 8.06 (d, J = 8.1 Hz, 1 H), 7.61 (d, J = 7.3 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 6.51 (s, 2 H), 6.33 (t, J =
5.0 Hz, 1 H), 4.74 (t, J = 4.3 Hz, 2 H), 3.85-3.81 (m, 4 H), 3.49 (t, J = 4.3 Hz, 4 H), 3.33 (t, J = 5.9 Hz, 2 H), 3.30 (s, 3 H), 3.21 (t, J = 6.8 Hz, 2 H), 3.14 (t, J = 4.5 Hz, 4 H), 3.08 (t, J = 6.0 Hz, 2 H);
'3C NMR (75 MHz, DMSO-d6) 8 157.8, 151.9, 145.0, 132.7, 126.7, 126.6, 121.4, 120.5, 115.1, 70.4, 70.2, 69.2, 58.4, 45.5, 44.0, 27.6;
Anal. Calcd for CZZH3oN6O4: %C, 59.71, %H, 6.83, %N, 18.99. Found: %C, 59.71, %H, 6.80,% N, 18.78;
MS(CI) m/e 443 (M+H) Example 6 N-(2- f 2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl) N-methylmorpholine-4-carboxamide.
NHz N ~ N~O~
N
/O/
N
N
JO
2-(2-Methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (802 mg, 2.34 mmol) was dissolved in 30 mL of anhydrous CHZCl2 and cooled to 0 °C under NZ. To the stirred solution were added Et3N
(0.65 mL, 4.68 mmol) and morpholinecarbonyl chloride (273 ~L, 2.34 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL) and CHZCl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (SiO~,, 2-5%
MeOH/CHC13 saturated with aqueous NH40H) gave the product as a colorless foam.
Crystallization from EtOAc gave 640 mg of N-(2-(2-[4-amino-2-(2-methoxyethyl)-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmorpholine-4-carboxamide as white crystals. Mp = 121.8-122.3 °C.
MS 457 (M + H)+;
'H NMR (500 MHz, DMSO-d6) b 8.06 (dd, J = 0.9, 8.3 Hz, 1 H); 7.61 (dd, J = 1.
l, 8.3 Hz, 1 H); 7.41 (ddd, J = 1.2, 7.0, 8.3 Hz, 1 H); 7.22 (ddd, J = 1.3, 7.0, 8.1 Hz, 1 H); 6.44 (s, 2 H); 4.74 (t, J= 5.2 Hz, 2 H); 3.84 (t, J= 5.2 Hz, 2 H); 3.82 (t, J= 6.9 Hz, 2 H); 3.50-3.43 (m, 6 H); 3.30 (s, 3 H); 3.20 (t, J = 6.9 Hz, 2 H); 3.16 (t, J = 5.5 Hz, 2 H); 2.88 (t, J
= 4.7 Hz, 4 H); 2.59 (s, 3 H);
~3C NMR (75 MHz, DMSO-d6) 8 163.8, 152.0, 151.8, 145.2, 132.7, 126.7, 121.3, 120.6, 115.1, 70.4, 69.4, 68.9, 66.1, 58.5, 49.1, 47.3, 45.5, 36.9, 27.7.
Anal. Calcd for C23H32N6O4: %C, 60.51; %H, 7.07; %N, 18.41. Found: %C, 60.56;
%H, 6.85; %N, 18.19.
Examples 7 -21 Part A
A solution of tart-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy~ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 50 mL of CHzCl2 and washed with saturated NaHC03, and brine. The organic portion was dried over Na2S04 and concetrated to give a green oil.
The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal.
The hot solution was filtered and concentrated to give 4.12 g of tart-butyl 2-[2-(2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbarnate as a yellow oil.
Part B
A solution of tart-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12 g, 10.0 mmol) in 50 mL of CHZCl2 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirring for 5 h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over Na2S04 and concentrated to give 3.68 g of tart-butyl 2-[2-(2-butyl-5-oxido-1H
imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(2-butyl-5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH4OH solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (1.87 g, 9.81 mmol) over a 10 min period. The reaction mixture was then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHZC12. The reaction mixture was then washed with H20, 1% NaZC03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 3.68 g of tert-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Text-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) was suspended in 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction mixture '~='~
was concentrated to give a solid. The solid was triturated with hot EtOH (50 mL) and filtered to give 2.90 g of the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of HZO and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CH2C1~ (3 X 50 mL). The combined organic layers were dried over NaZS04 and concentrated to give 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 328 (M + H)+;
1H NMR (300 MHz, CDC13) S 7.95 (d, J = 8.3 Hz, 1 H); 7.83 (d, J = 8.4 Hz, 1 H); 7.50 (m, 1 H); 7.30 (m, 1 H); 5.41 (s, 2 H); 4.69 (t, J = 5.6 Hz, 2 H); 3.93 (t, J
= 5.6 Hz, 2 H);
3.39 (t, J = 5.1 Hz, 2 H); 2.97 (t, J = 7.9 Hz, 2 H); 2.76 (t, J = 5.1 Hz, 2 H); 1.89 (m, 2 H);
1.52 (m, 2 H); 1.26 (br s, 2 H); 1.0l (t, J = 7.3 Hz, 3 H).
Part E
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme I above using the following general method.
The isocyanate (84 ~mol.) was added to a test tube containing a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H imidazo[4,5-c]quinolin-4-amine (25 mg, 76 ~mol) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC using the method described above. The table below shows the structure of the free base and the observed accurate mass (M +
H).
Example Accurate Mass Number S~cture of Free Base obs.
NHz CH3 N~ \ N
N
7 413.2644 ~N
~N
O ~
~CH3 N
!\~/\
8 O 427.2841 N
N \ N
\\
/ N
°~ 427.2823 °
N~ \ N
/ N
°~ 447.2496 N
O
U
Example Accurate Mass Number S~cture of Free Base obs.
I \ N
Y\
N
11 ~ 441.2638 ~N
O~ ~O
N~ \ N
O~ ~O
N~ \ N
12 453.2980 N
O
NHZ ~CH
N~ ~ N
N
O
NHZ ~CH
N~ ~ N
N
13 ~ 472.2457 N
NHZ ~CH
N~ ~ N
N
I
NHZ ~CH
N~ ~ N
N
I
14 477.2611 N
O
H3C,0 Example Accurate Mass Number Structure of Free Base (obs.) I \ N
!!U\
N
O
H3C,0 Example Accurate Mass Number Structure of Free Base (obs.) I \ N
!!U\
N
15 487.2804 ~N
~-N ~ ~
v NHz ~CHJ
~ \
/
~-N ~ ~
v NHz ~CHJ
~ \
/
16 ~~ 490.2919 \ ~ _ tw ~C NCH, NHz ~OHa i \ N
/ N
/
/ N
/
17 °~ 493.2386 N
NHZ ~CH, ~ N
/
NHZ ~CH, ~ N
/
18 ~N 207.2741 ~N
O
O / \
HOC
O~CH~
Example s~cture of Free Base Accurate Mass Number obs.
~ N
N
O
O / \
HOC
O~CH~
Example s~cture of Free Base Accurate Mass Number obs.
~ N
N
19 / 511.2120 N o\~S o ~N~
O
N~ \ N
N
O
N~ \ N
N
20 0~ 525.2280 ~\~So N~
NHS ~~H3 N~ \ \
s
NHS ~~H3 N~ \ \
s
21 ~ 545.1758 o ~ ,o o-a Examples 22 - 36 Part A
Using the general method of Part A of Examples 7 - 21, 4-piperidine ethanol (10 g, 77.4 mmol) was reacted with di-tei°t-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tent-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear oil.
Part B
Iodine (7.97 g) was added in three portions to a solution of imidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1 mmol) in dichloromethane (350 mL).
After minutes a solution of the material from Part A in dichloromethane (70 mL) was added.
The reaction mixture was stirred at ambient temperature overnight. More iodine (7.97 g) was added and the reaction was stirred at ambient temperature for 1 hr. The reaction mixture was washed with saturated sodium thiosulfate (2X) and brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide an oily residue.
The residue was purified by column chromatography (silica gel eluting with 20%
ethyl acetate in hexanes) to provide 15.52 g of tef-t-butyl 4-(2-iodoethyl)piperidine-1-carboxylate as a pale yellow oil.
Part C
Under a nitrogen atmosphere, 2-(1H imidazo[4,5-c]quinolin-1-yl)butan-1-of (6.5 g, 26.9 mmol) was added in three portions to a suspension of sodium hydride (1.4 g of 60%, 35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction mixture was allowed to stir for 45 minutes by which time gas evolution had ceased. Tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was allowed to stir at ambient temperature for 2.5 hrs; then it was heated to 100°C and stirred overnight. Analysis by HPLC showed that the reaction was about 35% complete. Saturated ammonium chloride solution was added, the resulting mixture was allowed to stir for 20 minutes and then it was extracted with ethyl acetate (2X). The ethyl acetate extracts were washed with water (2X) and then with brine, combined, dried over sodium sulfate, Eltered and then concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography (silica gel eluting sequentially with 30% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, and ethyl acetate) to provide 2.2 g of test-butyl 4- f 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)butoxy] ethyl ] piperidine-1-c arboxylate.
Part D
Using the general method of Examples 7 - 21 Part H, the material from Part C
was oxidized to provide test-butyl 4- f 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl~piperidine-1-carboxylate as an oil.
Part E
Ammonium hydroxide solution (20 mL) was added to a solution of the material from Part D in dichloromethane (20 mL). A solution of tosyl chloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was added over a period of 5 minutes. The resulting biphasic reaction mixture was allowed to stir overnight. The reaction mixture was diluted with chloroform and saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried over sodium sulfate, ftltered and then concentrated under reduced pressure to provide a brown glass. This material was purified by column chromatography (silica gel eluting ftrst with 50% ethyl acetate in hexanes and then with ethyl acetate) to provide 1.0 g of text-butyl 4- f 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate as pale yellow glassy foam.
Part F
Under a nitrogen atmosphere, tent-butyl 4- f 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate (1.00 g, 2.1 mmol) and ethanolic hydrochloric acid (10 ml, 20 mmol) were combined and the solution was stirred at ambient temperature for 14 hours. The solvent was removed ih vacuo and the resulting tan solid was dissolved in water. Saturated aqueous sodium carbonate was added until the pH reached 10. After extraction with dichloromethane (3X), the organic fractions were combined, washed with brine, dried (Na2S04), filtered, and the majority of the solvent was removed iia vacuo. Hexane was added to form a precipitate. Vacuum filtration yielded 0.5 g of 1- f 1-[(2-piperidin-4-ylethoxy)methyl]propyl~-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
IH-NMR (300MHz, DMSO-d6) : b 8.34 (bs, 1H), 8.19 (d, J = 8.49Hz, 1H), 7.61 (dd, J =
8.31, 1.13Hz, 1H), 7.45-7.39 (m, 1H), 7.25-7.19 (m, 1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H), 3.5-3.3 (m, 2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H), 2.09-1.99 (m, 2H), 1.8-1.63 (bs, 1H), 1.37-1.0 (m, SH), 0.95-0.7 (m, SH);
'3C-NMR (75MHz, DMSO-d6): 8 152.8, 145.8, 140.6, 133.0, 127.8, 127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1, 58.4, 46.1, 36.3, 33.1, 32.7, 24.5, 9.9;
MS (CI) m/e 368.2459 (368.2450 calcd for CZIH3oN50).
Part G
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme I above using the following general method.
The isocyanate or isothiocyanate (75 ~,mol.) was added to a test tube containing a solution of 1- f 1-[(2-piperidin-4-ylethoxy)methyl]propyl]-1H imidazo[4,5-c]quinolin-4-amine (25 mg, 68 pmol) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purred by semi-preparative HPLC using the method described above. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Stucture of Free Base Accurate Mass Number obs.
NHS
N \ N
\
N
Using the general method of Part A of Examples 7 - 21, 4-piperidine ethanol (10 g, 77.4 mmol) was reacted with di-tei°t-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tent-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear oil.
Part B
Iodine (7.97 g) was added in three portions to a solution of imidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1 mmol) in dichloromethane (350 mL).
After minutes a solution of the material from Part A in dichloromethane (70 mL) was added.
The reaction mixture was stirred at ambient temperature overnight. More iodine (7.97 g) was added and the reaction was stirred at ambient temperature for 1 hr. The reaction mixture was washed with saturated sodium thiosulfate (2X) and brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide an oily residue.
The residue was purified by column chromatography (silica gel eluting with 20%
ethyl acetate in hexanes) to provide 15.52 g of tef-t-butyl 4-(2-iodoethyl)piperidine-1-carboxylate as a pale yellow oil.
Part C
Under a nitrogen atmosphere, 2-(1H imidazo[4,5-c]quinolin-1-yl)butan-1-of (6.5 g, 26.9 mmol) was added in three portions to a suspension of sodium hydride (1.4 g of 60%, 35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction mixture was allowed to stir for 45 minutes by which time gas evolution had ceased. Tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was allowed to stir at ambient temperature for 2.5 hrs; then it was heated to 100°C and stirred overnight. Analysis by HPLC showed that the reaction was about 35% complete. Saturated ammonium chloride solution was added, the resulting mixture was allowed to stir for 20 minutes and then it was extracted with ethyl acetate (2X). The ethyl acetate extracts were washed with water (2X) and then with brine, combined, dried over sodium sulfate, Eltered and then concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography (silica gel eluting sequentially with 30% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, and ethyl acetate) to provide 2.2 g of test-butyl 4- f 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)butoxy] ethyl ] piperidine-1-c arboxylate.
Part D
Using the general method of Examples 7 - 21 Part H, the material from Part C
was oxidized to provide test-butyl 4- f 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl~piperidine-1-carboxylate as an oil.
Part E
Ammonium hydroxide solution (20 mL) was added to a solution of the material from Part D in dichloromethane (20 mL). A solution of tosyl chloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was added over a period of 5 minutes. The resulting biphasic reaction mixture was allowed to stir overnight. The reaction mixture was diluted with chloroform and saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried over sodium sulfate, ftltered and then concentrated under reduced pressure to provide a brown glass. This material was purified by column chromatography (silica gel eluting ftrst with 50% ethyl acetate in hexanes and then with ethyl acetate) to provide 1.0 g of text-butyl 4- f 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate as pale yellow glassy foam.
Part F
Under a nitrogen atmosphere, tent-butyl 4- f 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate (1.00 g, 2.1 mmol) and ethanolic hydrochloric acid (10 ml, 20 mmol) were combined and the solution was stirred at ambient temperature for 14 hours. The solvent was removed ih vacuo and the resulting tan solid was dissolved in water. Saturated aqueous sodium carbonate was added until the pH reached 10. After extraction with dichloromethane (3X), the organic fractions were combined, washed with brine, dried (Na2S04), filtered, and the majority of the solvent was removed iia vacuo. Hexane was added to form a precipitate. Vacuum filtration yielded 0.5 g of 1- f 1-[(2-piperidin-4-ylethoxy)methyl]propyl~-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
IH-NMR (300MHz, DMSO-d6) : b 8.34 (bs, 1H), 8.19 (d, J = 8.49Hz, 1H), 7.61 (dd, J =
8.31, 1.13Hz, 1H), 7.45-7.39 (m, 1H), 7.25-7.19 (m, 1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H), 3.5-3.3 (m, 2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H), 2.09-1.99 (m, 2H), 1.8-1.63 (bs, 1H), 1.37-1.0 (m, SH), 0.95-0.7 (m, SH);
'3C-NMR (75MHz, DMSO-d6): 8 152.8, 145.8, 140.6, 133.0, 127.8, 127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1, 58.4, 46.1, 36.3, 33.1, 32.7, 24.5, 9.9;
MS (CI) m/e 368.2459 (368.2450 calcd for CZIH3oN50).
Part G
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme I above using the following general method.
The isocyanate or isothiocyanate (75 ~,mol.) was added to a test tube containing a solution of 1- f 1-[(2-piperidin-4-ylethoxy)methyl]propyl]-1H imidazo[4,5-c]quinolin-4-amine (25 mg, 68 pmol) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purred by semi-preparative HPLC using the method described above. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Stucture of Free Base Accurate Mass Number obs.
NHS
N \ N
\
N
22 \ '0 453.2983 '.O
~\!N
~CH3 N
NHZ
\ N
N
~\!N
~CH3 N
NHZ
\ N
N
23 °
c'H
467.3138 ,.o ~N
N
NHZ
N \ N
\
N
c'H
467.3138 ,.o ~N
N
NHZ
N \ N
\
N
24 0 487.2787 ~O
N
N \
NHZ
NI \ N
N
N
N \
NHZ
NI \ N
N
25 0 481.2930 CH3 '_ '-O
~N
Example Stucture of Free Base Accurate Mass Number obs.
NHz N~ ~ N
N
~N
Example Stucture of Free Base Accurate Mass Number obs.
NHz N~ ~ N
N
26 0 493.3270 O
N
N
NH ~z I /
O
N
N
NH ~z I /
O
27 °", 0 512.2757 N
N
\N
NHz N~ \ N
2$ CH3 O
0 517.2907 N
N
O~CH3 NHz 29 ~0 527.3112 N
N~~..
Example Stucture of Free Base Accurate Mass Number obs.
NHz N~ \ N
/ N
/ \ O
529.2911 N
N
NHZ
N~ \ N
31 cH, ° 533.2704 ~o 'N
N
S~CH3 NHZ
N \ N
N
32 ~° 547.3032 H
_O
~l~fN
N ~ ~
O
H3C~° CH3 NHZ
N \ N
/
33 0 565.2641 ~O
N
O
N~S
Example Stucture of Free Base Accurate Mass Number obs.
NHZ
N
N
(r 34 0 585.2056 ~O
~°~AN
N. SO
p ~ / CI
NHz NI \ N
N
35 .,~
~0 521.2297 ct~
~N /s ~ \
NI-h N
N
36 0 503.2589 cH~
s N
Examples 37 - 44 Part A
A solution of test-butyl 2-~2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65 mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 2 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 200 mL of CHZCIz and washed with saturated NaHC03, H20 and brine. The organic portion was dried over Na2S04 and concentrated to give a green oil. The green oil was dissolved in 200 mL of hot MeOH and treated with 10 g of activated charcoal. The hot solution was altered and concentrated to give 5.25 g of te~t-butyl 2-[2-(1H imidazo[4,5-c)quinolin-1-yl)ethoxy]ethylcarbarnate as a light yellow syrup.
Part B
A solution of tent-butyl 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7 mmol) in 200 mL of CHzCl2 was treated with MCPBA (77%, 3.63 g, 16.3 mmol). After stirring overnight, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over Na2S0ø and concentrated to give 4.60 g of test-butyl 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(5-oxido-1H imidazo[4,5-c)quinolin-1-yl)ethoxy]ethylcarbamate (4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH40H solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over a 10 min period. The reaction mixture was treated with an additional 2 mL of concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 3 h.
The reaction mixture was then cooled and treated with 100 mL of CHZC12. The reaction mixture was then washed with H20, 1 % Na2C03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 4.56 g of test-butyl 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Tert-butyl 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.56 g, 12.3 mmol) was dissolved in 100 mL of EtOH and treated with 30 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirnng. After 3 h, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (100 mL) and filtered to give the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of Ha0 and treating with 5 mL of concentrated NH4.OH. The aqueous suspension was extracted with CHZC12 (5 X 50 mL). The combined organic layers were dried over NaZS04 and concentrated to give 1.35 g of 1-[2-(2-aminoethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 272 (M + H)+;
1H NMR (300 MHz, CDCl3) 8 7.98 (d, J= 8.2 Hz, 1 H); 7.88 (s, 1 H); 7.84 (d, J=
8.4 Hz, 1 H); 7.54 (m, 1 H); 7.32 (rn, 1 H); 5.43 (s, 2 H); 4.74 (t, J = 5.2 Hz, 2 H);
3.97 (t, J = 5.2 Hz, 2 H); 3 .42 (t, J = 5.1 Hz, 2 H); 2.78 (t, J = 5.1 Hz, 2 H); 1.10 (br s, 2 H).
Part E
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme I above using the following general method.
1-[2-(2-Aminoethoxy)ethyl]-1H imidazo[4,5-a]quinolin-4-amine (20 mg, 74 ~mol) and 1-methyl-2-pyrrolidinone (5 mL) were combined in a test tube and then sonicated with heating to provide a solution. The isocyanate (81 ~mol.) was added, the test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC
using the method described above. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Accurate Mass Number Stucture of Free Base obs.
NHZ
N~ \ N
N
37 0 371.2204 N
O~,~ CH3 H3C \
NHZ
N~ \ N
N
38 °~ 391.1884 ~N
O
NHZ
N~ \ N
N
39 °~ 397.2373 ~N
°b NHZ
~ N
/\
N
40 ~ 416.1844 N
Example Accurate Mass Number Stucture of Free Base obs.
N~ \ N
N
41 421.1946 o'' H3C~0 NHZ
I \ N' f1\
N
42 ° 431.2206 ~N
O
i N~ \ N
N
43 ~ 451.2115 o / \
O~CH3 NHZ
NI ~
N
44 455.1513 ~N
i O
0 \\
O
CYTOKINE INDUCTION IN HUMAN CELLS
An in vitro human blood cell system is used to assess cytokine induction.
Activity is based on the measurement of interferon (a) 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 Hank'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 to the first well containing Rl'MI
complete and serial 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 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.
Separation 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) Anal shy 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) 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 concentration tested was 10 or 30 ~M.
Cytokine Induction in Hurnan Cells Example Lowest Effective Concentration (~,M) Number Interferon Tumor Necrosis Factor 3 0.01 0.37 7 0.0001 10 8 0.0001 10 9 0.0001 1 10 0.0001 10 11 0.0001 0.1 12 0.0001 1 13 0.0001 1 14 0.0001 10 0.0001 0.1 16 0.0001 10 17 * 10 19 0.1 10 0.01 10 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~.M) Number Interferon Tumor Necrosis Factor 22 0.1 1 24 0.1 1.
25 0.1 1 26 0.1 1-27 0.1 I
N
\N
NHz N~ \ N
2$ CH3 O
0 517.2907 N
N
O~CH3 NHz 29 ~0 527.3112 N
N~~..
Example Stucture of Free Base Accurate Mass Number obs.
NHz N~ \ N
/ N
/ \ O
529.2911 N
N
NHZ
N~ \ N
31 cH, ° 533.2704 ~o 'N
N
S~CH3 NHZ
N \ N
N
32 ~° 547.3032 H
_O
~l~fN
N ~ ~
O
H3C~° CH3 NHZ
N \ N
/
33 0 565.2641 ~O
N
O
N~S
Example Stucture of Free Base Accurate Mass Number obs.
NHZ
N
N
(r 34 0 585.2056 ~O
~°~AN
N. SO
p ~ / CI
NHz NI \ N
N
35 .,~
~0 521.2297 ct~
~N /s ~ \
NI-h N
N
36 0 503.2589 cH~
s N
Examples 37 - 44 Part A
A solution of test-butyl 2-~2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65 mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 2 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 200 mL of CHZCIz and washed with saturated NaHC03, H20 and brine. The organic portion was dried over Na2S04 and concentrated to give a green oil. The green oil was dissolved in 200 mL of hot MeOH and treated with 10 g of activated charcoal. The hot solution was altered and concentrated to give 5.25 g of te~t-butyl 2-[2-(1H imidazo[4,5-c)quinolin-1-yl)ethoxy]ethylcarbarnate as a light yellow syrup.
Part B
A solution of tent-butyl 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7 mmol) in 200 mL of CHzCl2 was treated with MCPBA (77%, 3.63 g, 16.3 mmol). After stirring overnight, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over Na2S0ø and concentrated to give 4.60 g of test-butyl 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(5-oxido-1H imidazo[4,5-c)quinolin-1-yl)ethoxy]ethylcarbamate (4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH40H solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over a 10 min period. The reaction mixture was treated with an additional 2 mL of concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 3 h.
The reaction mixture was then cooled and treated with 100 mL of CHZC12. The reaction mixture was then washed with H20, 1 % Na2C03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 4.56 g of test-butyl 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Tert-butyl 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.56 g, 12.3 mmol) was dissolved in 100 mL of EtOH and treated with 30 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirnng. After 3 h, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (100 mL) and filtered to give the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of Ha0 and treating with 5 mL of concentrated NH4.OH. The aqueous suspension was extracted with CHZC12 (5 X 50 mL). The combined organic layers were dried over NaZS04 and concentrated to give 1.35 g of 1-[2-(2-aminoethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 272 (M + H)+;
1H NMR (300 MHz, CDCl3) 8 7.98 (d, J= 8.2 Hz, 1 H); 7.88 (s, 1 H); 7.84 (d, J=
8.4 Hz, 1 H); 7.54 (m, 1 H); 7.32 (rn, 1 H); 5.43 (s, 2 H); 4.74 (t, J = 5.2 Hz, 2 H);
3.97 (t, J = 5.2 Hz, 2 H); 3 .42 (t, J = 5.1 Hz, 2 H); 2.78 (t, J = 5.1 Hz, 2 H); 1.10 (br s, 2 H).
Part E
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme I above using the following general method.
1-[2-(2-Aminoethoxy)ethyl]-1H imidazo[4,5-a]quinolin-4-amine (20 mg, 74 ~mol) and 1-methyl-2-pyrrolidinone (5 mL) were combined in a test tube and then sonicated with heating to provide a solution. The isocyanate (81 ~mol.) was added, the test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC
using the method described above. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Accurate Mass Number Stucture of Free Base obs.
NHZ
N~ \ N
N
37 0 371.2204 N
O~,~ CH3 H3C \
NHZ
N~ \ N
N
38 °~ 391.1884 ~N
O
NHZ
N~ \ N
N
39 °~ 397.2373 ~N
°b NHZ
~ N
/\
N
40 ~ 416.1844 N
Example Accurate Mass Number Stucture of Free Base obs.
N~ \ N
N
41 421.1946 o'' H3C~0 NHZ
I \ N' f1\
N
42 ° 431.2206 ~N
O
i N~ \ N
N
43 ~ 451.2115 o / \
O~CH3 NHZ
NI ~
N
44 455.1513 ~N
i O
0 \\
O
CYTOKINE INDUCTION IN HUMAN CELLS
An in vitro human blood cell system is used to assess cytokine induction.
Activity is based on the measurement of interferon (a) 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 Hank'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 to the first well containing Rl'MI
complete and serial 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 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.
Separation 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) Anal shy 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) 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 concentration tested was 10 or 30 ~M.
Cytokine Induction in Hurnan Cells Example Lowest Effective Concentration (~,M) Number Interferon Tumor Necrosis Factor 3 0.01 0.37 7 0.0001 10 8 0.0001 10 9 0.0001 1 10 0.0001 10 11 0.0001 0.1 12 0.0001 1 13 0.0001 1 14 0.0001 10 0.0001 0.1 16 0.0001 10 17 * 10 19 0.1 10 0.01 10 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~.M) Number Interferon Tumor Necrosis Factor 22 0.1 1 24 0.1 1.
25 0.1 1 26 0.1 1-27 0.1 I
28 0.1 1
29 0.1 1
30 1 i...
31 1 10
32 0.1 1
33 1 10
34 1 10 36 0.1 *
37 10 to -44 *
37 10 to -44 *
Claims (23)
1. A compound of the Formula (I):
wherein: X is ~CHR5-, -CHR5-alkyl-, or ~CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4~NR8~CR3~NR5~Z~R6~alkyl;
-R4~NR8~CR3~NR5~Z~R6~alkenyl;
-R4~NR8~CR3~NR5~Z~R6~aryl;
-R4~NR8~ CR3~NR5~Z~R6~heteroaryl;
-R4~NR8~ CR3~NR5~Z~R6~heterocyclyl;
-R4-NR8~CR3~NR5R7;
-R4~NR8~CR3~NR9~Z~R6~alkyl;
-R4~NR8~CR3~NR9~Z~R6~alkenyl;
-R4~NR8~CR3~NR9~Z~R6~aryl;
-R4~NR8~ CR3~NR9~Z~R6~heteroaryl; and -R4~NR8~ CR3~NR9~Z~R6~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 ox alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is H or C1-10 alkyl which may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, or arylalkyl; or R4 and R8 can join together to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
each Y is independently -O- or -S(O)0-2-;
Z is a bond, -CO-, or -SO2-;
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 ~CHR5-, -CHR5-alkyl-, or ~CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4~NR8~CR3~NR5~Z~R6~alkyl;
-R4~NR8~CR3~NR5~Z~R6~alkenyl;
-R4~NR8~CR3~NR5~Z~R6~aryl;
-R4~NR8~ CR3~NR5~Z~R6~heteroaryl;
-R4~NR8~ CR3~NR5~Z~R6~heterocyclyl;
-R4-NR8~CR3~NR5R7;
-R4~NR8~CR3~NR9~Z~R6~alkyl;
-R4~NR8~CR3~NR9~Z~R6~alkenyl;
-R4~NR8~CR3~NR9~Z~R6~aryl;
-R4~NR8~ CR3~NR9~Z~R6~heteroaryl; and -R4~NR8~ CR3~NR9~Z~R6~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 ox alkenyl substituted by one or more substituents selected from the group consisting of:
-OH;
-halogen;
-N(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is H or C1-10 alkyl which may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, or arylalkyl; or R4 and R8 can join together to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
each Y is independently -O- or -S(O)0-2-;
Z is a bond, -CO-, or -SO2-;
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 X is -CH(alkyl)(alkyl)- , wherein the alkyl groups can be the same or different.
3. A compound or salt of claim 1 wherein X is -CH2-CH2-.
4. A compound or salt of claim 1 wherein X is -CH(C2H5)(CH2)-.
5. A compound or salt of claim 1 wherein R2 is H.
6. A compound or salt of claim 1 wherein R2 is alkyl.
7. A compound or salt of claim 1 wherein R2 is -alkyl-O-alkyl.
A compound selected from the group consisting of:
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N'-phenylurea;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N'-phenylurea;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmorpholine-4-carboxamide;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N'-phenylurea;and N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N'-phenylurea;
or a pharmaceutically acceptable salt thereof.
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N'-phenylurea;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N'-phenylurea;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)morpholine-4-carboxamide;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmorpholine-4-carboxamide;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N'-phenylurea;and N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N'-phenylurea;
or a pharmaceutically acceptable salt thereof.
9. A compound of the formula (II) wherein: X is ~CHR5-, -CHR5-alkyl-, or ~CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4~NR8~CR3~NR5~Z~R6~alkyl;
-R4~NR8~CR3~NR5~Z~R6~alkenyl;
-R4~NR8~CR3~NR5~Z~R6~aryl;
-R4~NR8~CR3~NR5~Z~R6~heteroaryl;
-R4~NR8~CR3~NR5~Z~R6~heterocyclyl;
-R4~NR8~CR3~NR5R7;
-R4~NR8~CR3~NR9~Z~R6~alkyl;
-R4~NR8~CR3~NR9~Z~R6~alkenyl;
-R4~NR8~CR3~NR9~Z~R6~aryl;
-R4~NR8~CR3~NR9~Z~R6~heteroaryl; and -R4~NR8~CR3~NR9~Z~R6~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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more ~O~ groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more ~O~ groups;
R7 is H or C1-10 alkyl which may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, or arylalkyl; or R4 and R8 can join together to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
each Y is independently ~O~ or ~S(O)0-2;
Z is a bond, ~CO~, or ~SO2~;
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:
-R4~NR8~CR3~NR5~Z~R6~alkyl;
-R4~NR8~CR3~NR5~Z~R6~alkenyl;
-R4~NR8~CR3~NR5~Z~R6~aryl;
-R4~NR8~CR3~NR5~Z~R6~heteroaryl;
-R4~NR8~CR3~NR5~Z~R6~heterocyclyl;
-R4~NR8~CR3~NR5R7;
-R4~NR8~CR3~NR9~Z~R6~alkyl;
-R4~NR8~CR3~NR9~Z~R6~alkenyl;
-R4~NR8~CR3~NR9~Z~R6~aryl;
-R4~NR8~CR3~NR9~Z~R6~heteroaryl; and -R4~NR8~CR3~NR9~Z~R6~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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more ~O~ groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more ~O~ groups;
R7 is H or C1-10 alkyl which may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, or arylalkyl; or R4 and R8 can join together to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
each Y is independently ~O~ or ~S(O)0-2;
Z is a bond, ~CO~, or ~SO2~;
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.
10. A compound or salt of claim 9 wherein R2 is H or alkyl.
11. A compound or salt of claim 9 wherein R2 is ~alkyl~O~alkyl.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
13. 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.
14. The method of claim 13 wherein the cytokine is IFN-.alpha..
15. 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.
16. 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.
17. A compound of the formula (III):
wherein: X is ~CHR6-, -CHR5-alkyl-, or ~CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4~NR8~CR3~NR5~Z~R6~alkyl;
-R4~NR8~CR3~NR5~Z~R6~alkenyl;
-R4~NR8~CR3~NR5~Z~R6~aryl;
-R4~NR8~CR3~NR5~Z~R6~heteroaryl;
-R4-NR8- CR3-NR5-Z-R6-heterocyclyl;
-R4-NR8-CR3-NR5R7;
-R4-NR8-CR3-NR9-Z-R6-alkyl;
-R4-NR8-CR3-NR9-Z-R6-alkenyl;
-R4-NR8-CR3-NR9-Z-R6-aryl;
-R4-NR8-CR3-NR9-Z-R6 heteroaryl; and -R4-NR8-CR3-NR9-Z-R6-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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is H or C1-10 alkylwhich may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, arylalkyl; or R4 and R8 can join to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
each Y is independently-O- or-S(O)0-2-;
Z is a bond, -CO-, or-SO2-;
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 ~CHR6-, -CHR5-alkyl-, or ~CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4~NR8~CR3~NR5~Z~R6~alkyl;
-R4~NR8~CR3~NR5~Z~R6~alkenyl;
-R4~NR8~CR3~NR5~Z~R6~aryl;
-R4~NR8~CR3~NR5~Z~R6~heteroaryl;
-R4-NR8- CR3-NR5-Z-R6-heterocyclyl;
-R4-NR8-CR3-NR5R7;
-R4-NR8-CR3-NR9-Z-R6-alkyl;
-R4-NR8-CR3-NR9-Z-R6-alkenyl;
-R4-NR8-CR3-NR9-Z-R6-aryl;
-R4-NR8-CR3-NR9-Z-R6 heteroaryl; and -R4-NR8-CR3-NR9-Z-R6-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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3 is =O or =S;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is H or C1-10 alkylwhich may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, arylalkyl; or R4 and R8 can join to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
each Y is independently-O- or-S(O)0-2-;
Z is a bond, -CO-, or-SO2-;
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.
18. A compound of the formula (IV):
wherein: X is -CHR5-, -CHR5-alkylene-, or -CHR5-alkenylene-;
R1 is selected from the group consisting of:
-R4-NR8-CR3-NR5-Z-R6-alkyl;
-R4-NR8-CR3-NR5-Z-R6-alkyl;
-R4-NR8-CR3-NR5-Z-R6-aryl;
-R4-NR8-CR3-NR5-Z-R6-heteroaryl;
-R4-NR8-C R3-NR5-Z-R6-heterocyclyl;
-R4-NR8-CR3-NR5R7;
-R4-NR8-CR3-NR9-Z-R6-alkyl;
-R4-NR8-CR3-NR9-Z-R6-alkenyl;
-R4-NR8-CR3-NR9-Z-R6-aryl;
-R4-NR8-CR3-NR9-Z-R6-heteroaryl; and -R4-NR8-CR3-NR9-Z-R6-heterocyclyl;
each Y is independently -O- or -S(O)0-2-;
Z is a bond, -CO-, or -SO2-;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is H or C1-10 alkyl which may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, or arylalkyl; or R4 and R8 can join to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is -CHR5-, -CHR5-alkylene-, or -CHR5-alkenylene-;
R1 is selected from the group consisting of:
-R4-NR8-CR3-NR5-Z-R6-alkyl;
-R4-NR8-CR3-NR5-Z-R6-alkyl;
-R4-NR8-CR3-NR5-Z-R6-aryl;
-R4-NR8-CR3-NR5-Z-R6-heteroaryl;
-R4-NR8-C R3-NR5-Z-R6-heterocyclyl;
-R4-NR8-CR3-NR5R7;
-R4-NR8-CR3-NR9-Z-R6-alkyl;
-R4-NR8-CR3-NR9-Z-R6-alkenyl;
-R4-NR8-CR3-NR9-Z-R6-aryl;
-R4-NR8-CR3-NR9-Z-R6-heteroaryl; and -R4-NR8-CR3-NR9-Z-R6-heterocyclyl;
each Y is independently -O- or -S(O)0-2-;
Z is a bond, -CO-, or -SO2-;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R5 is independently H or C1-10 alkyl;
R6 is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is H or C1-10 alkyl which may be interrupted by a hetero atom, or R7 can join with R5 to form a ring;
R8 is H, C1-10 alkyl, or arylalkyl; or R4 and R8 can join to form a ring;
R9 is C1-10 alkyl which can join together with R8 to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 9 and a pharmaceutically acceptable carrier.
20. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 9 to the animal.
21. The method of claim 20 wherein the cytokine is IFN-.alpha..
22. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 9 to the animal.
23. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 9 to the animal.
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/US2001/046696 WO2002046191A2 (en) | 2000-12-08 | 2001-12-06 | Urea substituted imidazoquinoline ethers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2436984A1 true CA2436984A1 (en) | 2002-06-13 |
Family
ID=22963391
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2436980A Expired - Fee Related CA2436980C (en) | 2000-12-08 | 2001-12-06 | Amido ether substituted imidazoquinolines |
| CA2436846A Expired - Fee Related CA2436846C (en) | 2000-12-08 | 2001-12-06 | Thioether substituted imidazoquinolines |
| CA002436983A Abandoned CA2436983A1 (en) | 2000-12-08 | 2001-12-06 | Sulfonamido ether substituted imidazoquinolines |
| CA002436984A Abandoned CA2436984A1 (en) | 2000-12-08 | 2001-12-06 | Urea substituted imidazoquinoline ethers |
| CA002431151A Withdrawn CA2431151A1 (en) | 2000-12-08 | 2001-12-06 | Heterocyclic ether substituted imidazoquinolines |
| CA002430844A Withdrawn CA2430844A1 (en) | 2000-12-08 | 2001-12-06 | Aryl ether substituted imidazoquinolines |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2436980A Expired - Fee Related CA2436980C (en) | 2000-12-08 | 2001-12-06 | Amido ether substituted imidazoquinolines |
| CA2436846A Expired - Fee Related CA2436846C (en) | 2000-12-08 | 2001-12-06 | Thioether substituted imidazoquinolines |
| CA002436983A Abandoned CA2436983A1 (en) | 2000-12-08 | 2001-12-06 | Sulfonamido ether substituted imidazoquinolines |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002431151A Withdrawn CA2431151A1 (en) | 2000-12-08 | 2001-12-06 | Heterocyclic ether substituted imidazoquinolines |
| CA002430844A Withdrawn CA2430844A1 (en) | 2000-12-08 | 2001-12-06 | Aryl ether substituted imidazoquinolines |
Country Status (32)
| Country | Link |
|---|---|
| US (8) | US6683088B2 (en) |
| EP (6) | EP1341789A2 (en) |
| JP (7) | JP4437189B2 (en) |
| KR (6) | KR20030070050A (en) |
| CN (6) | CN1253452C (en) |
| AR (6) | AR035665A1 (en) |
| AT (3) | ATE353895T1 (en) |
| AU (12) | AU2002239530B2 (en) |
| BR (6) | BR0116464A (en) |
| CA (6) | CA2436980C (en) |
| CY (2) | CY1105586T1 (en) |
| CZ (6) | CZ295848B6 (en) |
| DE (3) | DE60111076T2 (en) |
| DK (3) | DK1341791T3 (en) |
| EE (6) | EE200300274A (en) |
| ES (3) | ES2242782T3 (en) |
| HK (3) | HK1064383A1 (en) |
| HR (6) | HRP20030464A2 (en) |
| HU (6) | HUP0400704A2 (en) |
| IL (6) | IL156044A0 (en) |
| MX (6) | MXPA03004973A (en) |
| NO (6) | NO20032452L (en) |
| NZ (6) | NZ526106A (en) |
| PL (7) | PL207340B1 (en) |
| PT (2) | PT1341790E (en) |
| RU (6) | RU2315049C2 (en) |
| SI (1) | SI1341790T1 (en) |
| SK (6) | SK7112003A3 (en) |
| TW (3) | TWI222972B (en) |
| UA (2) | UA75622C2 (en) |
| WO (6) | WO2002046191A2 (en) |
| ZA (6) | ZA200305271B (en) |
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