CA2518740A1 - Pyridyloxymethyl and benzisoxazole azabicyclic derivatives - Google Patents
Pyridyloxymethyl and benzisoxazole azabicyclic derivatives Download PDFInfo
- Publication number
- CA2518740A1 CA2518740A1 CA002518740A CA2518740A CA2518740A1 CA 2518740 A1 CA2518740 A1 CA 2518740A1 CA 002518740 A CA002518740 A CA 002518740A CA 2518740 A CA2518740 A CA 2518740A CA 2518740 A1 CA2518740 A1 CA 2518740A1
- Authority
- CA
- Canada
- Prior art keywords
- isoxazol
- octahydro
- pyrido
- benzo
- pyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
An aminomethylpyridyloxymethyl/benzisoxazole substituted azabicyclic compound according to formula (I) a pharmaceutical composition comprising same, and a method of treating one or more CNS or other disorders, including concurrent treatment of disorders such as chizophrenia and depression. Or the (R) or (S) enantiomer thereof, or the cis or trans isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or of any of the foregoing, wherein m is 0 or 1, Z is wherein R7 is hydrogen or (C1-C3)alkoxy; R8 is hydrogen, hydroxy, or (C1-C3)alkoxy; and R9 is (C1-C3)alkoxy; X is oxygen or NR, wherein R is hydrogen or (C1-C6)alkyl; Y is methylene, wherein n is 0, 1 or 2; or oxygen, nitrogen or sulfur, wherein n is 2, 3 or 4; R1 and R2 are each independently hydrogen, halogen, or a (C1-C6)alkyl, (C1-C6)alkoxy or a (C1-C6)alkoxy(C1-C6)alkyl group, any one of which groups may be unsbustituted or substituted with one or more halogens.
Claims (15)
1. A compound having the formula or the (R) or (S) enantiomer thereof, or the cis or trans isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or of any of the foregoing, wherein m is 0 or 1; Z
is wherein R7 is hydrogen or (C1-C3)alkoxy; R8 is hydrogen, hydroxy, or (C1-C3)alkoxy; and R9 is (C1-C3)alkoxy;
X is oxygen or NR, wherein R is hydrogen or (C1-C6)alkyl;
Y is methylene, wherein n is 0, 1 or 2; or oxygen, nitrogen or sulfur, wherein n is 2, 3 or 4;
R1 and R2 are each independently hydrogen, halogen, or a (C1-C6)alkyl, (C1-C6)alkoxy or a (C1-C6)alkoxy(C1-C6)alkyl group, any one of which groups may be unsubstituted or substituted with one or more halogens;
R3 and R4 are each independently hydrogen, a (C1-C6)alkyl, a (C3-C7)cycloalkyl, or a to 6 membered heterocyclic group, any one of which groups may be unsubstituted or substituted with one or more of any of the following: (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, (C6-C10)aryl, a 5 to 6 member heterocyclic, amino, halogen or hydroxy groups; or R3 and R4 together with the nitrogen atom to which they are attached form:
(i) a 3 to 7 membered optionally unsaturated monocyclic ring; or (ii) a 4 to 10 membered optionally unsaturated polycyclic ring, wherein said monocyclic or polycyclic ring optionally has one or two additional heteroatoms selected from nitrogen, oxygen and sulfur, wherein any of said rings (i) or (ii) may be unsubstituted or substituted with one or more (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C3-C7)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C7 to C13)aralkyl, a 5 to 10 membered heteroaryl, hydroxy, amino, cyano, or halogen groups.
is wherein R7 is hydrogen or (C1-C3)alkoxy; R8 is hydrogen, hydroxy, or (C1-C3)alkoxy; and R9 is (C1-C3)alkoxy;
X is oxygen or NR, wherein R is hydrogen or (C1-C6)alkyl;
Y is methylene, wherein n is 0, 1 or 2; or oxygen, nitrogen or sulfur, wherein n is 2, 3 or 4;
R1 and R2 are each independently hydrogen, halogen, or a (C1-C6)alkyl, (C1-C6)alkoxy or a (C1-C6)alkoxy(C1-C6)alkyl group, any one of which groups may be unsubstituted or substituted with one or more halogens;
R3 and R4 are each independently hydrogen, a (C1-C6)alkyl, a (C3-C7)cycloalkyl, or a to 6 membered heterocyclic group, any one of which groups may be unsubstituted or substituted with one or more of any of the following: (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, (C6-C10)aryl, a 5 to 6 member heterocyclic, amino, halogen or hydroxy groups; or R3 and R4 together with the nitrogen atom to which they are attached form:
(i) a 3 to 7 membered optionally unsaturated monocyclic ring; or (ii) a 4 to 10 membered optionally unsaturated polycyclic ring, wherein said monocyclic or polycyclic ring optionally has one or two additional heteroatoms selected from nitrogen, oxygen and sulfur, wherein any of said rings (i) or (ii) may be unsubstituted or substituted with one or more (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C3-C7)alkyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C7 to C13)aralkyl, a 5 to 10 membered heteroaryl, hydroxy, amino, cyano, or halogen groups.
2. The compound of Claim 1 having the structure:
wherein Z is X is oxygen; n is 0; R1 is hydrogen; R2 is hydrogen or halogen; and R3 is hydrogen or a (C1-C3)alkyl.
wherein Z is X is oxygen; n is 0; R1 is hydrogen; R2 is hydrogen or halogen; and R3 is hydrogen or a (C1-C3)alkyl.
3. The compound of Claim 1 wherein Z is wherein Y is methylene; X is oxygen; n is 0; R1 is hydrogen; R2 is hydrogen;
and R3 and R4 together with the nitrogen atom to which they are attached form I) a saturated non-aromatic 3 to 7 membered monocyclic ring, said ring t) being unsubstituted or substituted with one or more (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, or hydroxy groups.
and R3 and R4 together with the nitrogen atom to which they are attached form I) a saturated non-aromatic 3 to 7 membered monocyclic ring, said ring t) being unsubstituted or substituted with one or more (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, or hydroxy groups.
4. The compound of Claim 1 wherein Z is wherein Y is methylene; wherein X is oxygen; n is 0; R1 is hydrogen; R2 is hydrogen; and R3 and R4 together with the nitrogen atom to which they are attached form iii) an unsubstituted 5 to 6 membered heterocyclic ring, which heterocyclic ring, in addition to the nitrogen atom to which R3 and R4 are attached, has one additional nitrogen atom, or one sulfur or one oxygen atom.
5. The compound of Claim 1 wherein R2 is halogen; and R3 and R4 together with the nitrogen atom to which they are attached form i) a saturated 3 to 7 membered monocyclic ring, which monocylcic ring may be unsubstituted or substituted with one or more phenyl, (C1-C3)alkyl, or (C1-4)alkoxy(C1-4)alkyl groups; or ii) a 5 to 6 membered ring, which ring may be unsubstituted or substituted with one or more (C1-C3) alkyl groups, and which ring has one additional nitrogen or one oxygen atom.
6. The compound of Claim 1 wherein said compound is selected from the goup consisting of:
(7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-(6-morpholin-4-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-(5-piperidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine 7R, 9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(5-pyrrolidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-diethyl-amine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-dimethyl-amine (7R, 9aS)-traps-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-ethyl-methyl-amine (7R, 9aS)-traps-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy-1-methyl-ethyl)-amine (7R, 9aS)-traps- [6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy-ethyl)-methyl-amine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclopentyl-methyl-amine (7R, 9aS)-trans-7-(5-Azetidin-1-ylmethyl-pyridin-2-yloxymethyl)-2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-[5-(2-methyl-aziridin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-[5-(2-methoxymethyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-tert-butyl-amine (7S, 9aS)-cis-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-ethyl-methyl-amine (7S, 9aS)-cis-7-(5-Azetidin-1-ylmethyl-pyridin-2-yloxymethyl)-2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-dimethyl-amine (7R, 9aS)-trans-Cyclohexyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-2-(Ethyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amino)-ethanol (7R, 9aS)-trans- 7-[6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yloxymethyl]-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-(1,2-Dimethyl-propyl)-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(2-methoxy-ethyl)-methyl-amine (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(S)-pyrrolidin-3-ol (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(R)-pyrrolidin-3-ol (7R, 9aS)-trans- 2-Benzo[d]isoxazol-3-yl-7-[5-(2-methyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-piperidin-4-ol (7R, 9aS)-trans-Cyclopropyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-Cyclopropylmethyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(6-piperidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-{6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-
(7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-(6-morpholin-4-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-(5-piperidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine 7R, 9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(5-pyrrolidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-diethyl-amine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-dimethyl-amine (7R, 9aS)-traps-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-ethyl-methyl-amine (7R, 9aS)-traps-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy-1-methyl-ethyl)-amine (7R, 9aS)-traps- [6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(2-methoxy-ethyl)-methyl-amine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclopentyl-methyl-amine (7R, 9aS)-trans-7-(5-Azetidin-1-ylmethyl-pyridin-2-yloxymethyl)-2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-[5-(2-methyl-aziridin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-[5-(2-methoxymethyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-tert-butyl-amine (7S, 9aS)-cis-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-ethyl-methyl-amine (7S, 9aS)-cis-7-(5-Azetidin-1-ylmethyl-pyridin-2-yloxymethyl)-2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-dimethyl-amine (7R, 9aS)-trans-Cyclohexyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-2-(Ethyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amino)-ethanol (7R, 9aS)-trans- 7-[6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yloxymethyl]-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-(1,2-Dimethyl-propyl)-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(2-methoxy-ethyl)-methyl-amine (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(S)-pyrrolidin-3-ol (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-(R)-pyrrolidin-3-ol (7R, 9aS)-trans- 2-Benzo[d]isoxazol-3-yl-7-[5-(2-methyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-piperidin-4-ol (7R, 9aS)-trans-Cyclopropyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-Cyclopropylmethyl-{6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-amine (7R, 9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(6-piperidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-{6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-
7-ylmethoxy]-pyridin-2-ylmethyl}-dimethyl-amine (7R, 9aS)-trans-{6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-(tetrahydro-furan-2-ylmethyl)-amine (7R, 9aS)-trans-7-[6-(2,5-Dimethyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxymethyl]-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-{6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl}-[3-(4-methyl-piperazin-1-yl)-propyl]-amine (7R, 9aS)-trans-{6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridi(7R, 9aS)-trans-7-(6-Azepan-1-ylmethyl-pyridin-2-yloxymethyl)-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazinen-2-ylmethyl}-pyrrolidin-1-yl-amine 7S, 9aS)-cis-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-ylmethyl]-cyclohexyl-methyl-amine (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(S)-pyrrolidin-3-ol (7R, 9aS)-trans-1-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-(R)-pyrrolidin-3-ol (7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-(6-pyrrolidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine (7R, 9aS)-trans-[6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl]-benzyl-amine 7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-(5-pyrrolidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine; and (7S, 9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(5-pyrrolidin-1-ylmethyl-pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazine.
7. A compound of the formula:
or an (R) or (S) enantiomer thereof, or the cis or trans isomer thereof, wherein X is oxygen or NR, wherein R is hydrogen or (C1-C6)alkyl;
R1 and R2 are each independently hydrogen, halogen, or a (C1-C6 )alkyl, (C1-C6)alkoxy or a (C1-C6)alkoxy (C1-C6)alkyl group, any one of which groups may be unsubstituted or substituted with one or more halogens; and wherein R7 is hydrogen or (C1-C3)alkoxy; R8 is hydrogen, hydroxy, or (C1-C3)alkoxy; and R9 is (C1-C3)alkoxy.
7. A compound of the formula:
or an (R) or (S) enantiomer thereof, or the cis or trans isomer thereof, wherein X is oxygen or NR, wherein R is hydrogen or (C1-C6)alkyl;
R1 and R2 are each independently hydrogen, halogen, or a (C1-C6 )alkyl, (C1-C6)alkoxy or a (C1-C6)alkoxy (C1-C6)alkyl group, any one of which groups may be unsubstituted or substituted with one or more halogens; and wherein R7 is hydrogen or (C1-C3)alkoxy; R8 is hydrogen, hydroxy, or (C1-C3)alkoxy; and R9 is (C1-C3)alkoxy.
8. The compound of Claim 7 wherein said compound is selected from the group consisting of:
(7R, 9aS)-trans-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-nicotinic acid methyl ester;
(7R, 9aS)-trans-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-yl]-methanol.
(7R, 9aS)-trans-Methanesulfonic acid 6-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyoxy)-pyridin-2-ylmethyl ester;
(7R, 9aS)-trans-Methanesulfonic acid 6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl ester;
(7R, 9aS)-trans-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[7 ,2-a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester;
(7R, 9aS)-traps-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]-methanol;
(7R, 9aS)-trans-{6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-yl}-methanol;
(7R, 9aS)-trans-6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridine-2-carboxylic acid ester;
(~R, 9aS)-cis-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester;
(7R, 9aS)-cis-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]-methanol;
(7R, 9aS)-cis-Methanesulfonic acid 6-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyoxy)-pyridin-2-ylmethyl ester;
(7R, 9aS)-trans-5-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester;
(7R, 9aS)-trans-[5-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]-methanol; and (7R, 9aS)-trans-Methanesulfonic acid 5-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl ester.
(7R, 9aS)-trans-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-nicotinic acid methyl ester;
(7R, 9aS)-trans-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-3-yl]-methanol.
(7R, 9aS)-trans-Methanesulfonic acid 6-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyoxy)-pyridin-2-ylmethyl ester;
(7R, 9aS)-trans-Methanesulfonic acid 6-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-ylmethyl ester;
(7R, 9aS)-trans-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[7 ,2-a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester;
(7R, 9aS)-traps-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]-methanol;
(7R, 9aS)-trans-{6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridin-2-yl}-methanol;
(7R, 9aS)-trans-6-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-pyridine-2-carboxylic acid ester;
(~R, 9aS)-cis-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester;
(7R, 9aS)-cis-6-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]-methanol;
(7R, 9aS)-cis-Methanesulfonic acid 6-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyoxy)-pyridin-2-ylmethyl ester;
(7R, 9aS)-trans-5-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester;
(7R, 9aS)-trans-[5-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-yl]-methanol; and (7R, 9aS)-trans-Methanesulfonic acid 5-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridin-2-ylmethyl ester.
9. A pharmaceutical composition comprising the compound of Claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
10. A compound having binding activity for D2 and 5HT1B receptors wherein the ratio of D2:5HT1B inhibitory activity is about 20 or less.
11. A compound having effective binding activity to each of human D2, human 5HT1B and human 5HT2A receptors, wherein said effective binding activity comprises an in vivo effective Ki of no more than 20 nM at each of said D2 and 5HT2A receptors and no more than 5nM at the 5HT1B receptor.
12. A method for treating one or more central nervous system disorders comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of Claim 1 or of Claim 11.
13. A method of treating one or more central nervous system disorders comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound which has at least 80% antagonism, or inverse agonist to each of D2, 5HT1B and 5HT2A receptors.
14. A method of treating one or more central nervous system disorders comprising administering to a mammal in need of such treatment a therapeutically effective amount of a D2, 5HT1B inhibitor having effective inhibitory activity with an in vivo effective Ki of no more than 15 nM at each of said receptors.
15. A method of treating a disorder selected from schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder;
substance-induced psychotic disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, panic disorder, phobias, obsessive-compulsive disorder, stress disorders, generalized anxiety disorder, movement disorders involving Huntington's disease, dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, chemical dependencies, disorders comprising as a symptom thereof a deficiency in cognition, demential, mood disorders and episodes in a mammal; anxiety or psychotic disorders including schizophrenia, of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, panic disorder;
agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder;
acute stress disorder; chemical dependencies: for alcohol, amphetamine, cocaine, opiate, nicotine addiction; disorders comprising, as a symptom thereof, a deficiency in cognition, a subnormal functioning in one or more cognitive aspects; deficiency in memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population; reduction in any particular individual's functioning in one or more cognitive aspects, age-related cognitive decline; dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; Alzheimer's related dementia;
delirium;
amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression;
attention-deficit/hyperactivity disorder; and age-related cognitive decline;
mood disorders or mood episodes; major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder;
post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder; delusional disorder or schizophrenia; a bipolar disorder, bipolar I disorder, bipolar II disorder, and cyclothymic disorder, disorders subject to treatment by inhibition of any or all of the D2, 5HT1B, and 5HT2A receptors:
hypertension, depression; depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression, generalized anxiety disorder, phobias; agoraphobia, social phobia and simple phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders;
anorexia nervosa and bulimia nervosa, obesity, chemical dependencies, addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders;
dementia, amnestic disorders, and age-related cognitive decline (ARCD), Parkinson's diseases;
dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias, endocrine disorders; hyperprolactinaemia, vasospasm, vasospasm in the cerebral vasculature, cerebellar ataxia, gastrointestinal tract disorders involving changes in motility and secretion, negative symptoms of schizophrenia, schizoaffective disorder, obsessive compulsive disorder, mania, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer;
small cell lung carcinoma, chronic paroxysmal hemicrania and headache associated with vascular disorders. comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of Claim 1 or Claim 11.
substance-induced psychotic disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, panic disorder, phobias, obsessive-compulsive disorder, stress disorders, generalized anxiety disorder, movement disorders involving Huntington's disease, dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, chemical dependencies, disorders comprising as a symptom thereof a deficiency in cognition, demential, mood disorders and episodes in a mammal; anxiety or psychotic disorders including schizophrenia, of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, panic disorder;
agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder;
acute stress disorder; chemical dependencies: for alcohol, amphetamine, cocaine, opiate, nicotine addiction; disorders comprising, as a symptom thereof, a deficiency in cognition, a subnormal functioning in one or more cognitive aspects; deficiency in memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population; reduction in any particular individual's functioning in one or more cognitive aspects, age-related cognitive decline; dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; Alzheimer's related dementia;
delirium;
amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression;
attention-deficit/hyperactivity disorder; and age-related cognitive decline;
mood disorders or mood episodes; major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder;
post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder; delusional disorder or schizophrenia; a bipolar disorder, bipolar I disorder, bipolar II disorder, and cyclothymic disorder, disorders subject to treatment by inhibition of any or all of the D2, 5HT1B, and 5HT2A receptors:
hypertension, depression; depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression, generalized anxiety disorder, phobias; agoraphobia, social phobia and simple phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders;
anorexia nervosa and bulimia nervosa, obesity, chemical dependencies, addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders;
dementia, amnestic disorders, and age-related cognitive decline (ARCD), Parkinson's diseases;
dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias, endocrine disorders; hyperprolactinaemia, vasospasm, vasospasm in the cerebral vasculature, cerebellar ataxia, gastrointestinal tract disorders involving changes in motility and secretion, negative symptoms of schizophrenia, schizoaffective disorder, obsessive compulsive disorder, mania, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer;
small cell lung carcinoma, chronic paroxysmal hemicrania and headache associated with vascular disorders. comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of Claim 1 or Claim 11.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45392503P | 2003-03-12 | 2003-03-12 | |
| US60/453,925 | 2003-03-12 | ||
| PCT/IB2004/000499 WO2004081007A1 (en) | 2003-03-12 | 2004-02-23 | Pyridyloxymethyl and benzisoxazole azabicyclic derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2518740A1 true CA2518740A1 (en) | 2004-09-23 |
| CA2518740C CA2518740C (en) | 2011-01-11 |
Family
ID=32990837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2518740A Expired - Fee Related CA2518740C (en) | 2003-03-12 | 2004-02-23 | Pyridyloxymethyl and benzisoxazole azabicyclic derivatives |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US7345038B2 (en) |
| EP (1) | EP1608648B1 (en) |
| JP (2) | JP3910627B2 (en) |
| KR (2) | KR100767854B1 (en) |
| CN (1) | CN100389115C (en) |
| AP (1) | AP2005003390A0 (en) |
| AR (1) | AR043537A1 (en) |
| AU (2) | AU2004220327B2 (en) |
| BR (1) | BRPI0408248A (en) |
| CA (1) | CA2518740C (en) |
| EA (1) | EA009527B1 (en) |
| EC (1) | ECSP056011A (en) |
| GT (1) | GT200400041A (en) |
| HK (1) | HK1085725A1 (en) |
| HR (1) | HRP20050798A2 (en) |
| IL (1) | IL170290A (en) |
| MA (1) | MA27747A1 (en) |
| MX (1) | MXPA05009660A (en) |
| NL (1) | NL1025710C2 (en) |
| NO (1) | NO20054095L (en) |
| OA (1) | OA13038A (en) |
| PA (1) | PA8597501A1 (en) |
| PE (1) | PE20041057A1 (en) |
| PL (1) | PL378749A1 (en) |
| RS (1) | RS20050692A (en) |
| TN (1) | TNSN05224A1 (en) |
| TW (1) | TW200502234A (en) |
| UA (1) | UA78437C2 (en) |
| UY (1) | UY28225A1 (en) |
| WO (1) | WO2004081007A1 (en) |
| ZA (1) | ZA200506373B (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6994726B2 (en) * | 2004-05-25 | 2006-02-07 | Calcitec, Inc. | Dual function prosthetic bone implant and method for preparing the same |
| AU2004282219C1 (en) * | 2003-10-15 | 2009-12-17 | Osi Pharmaceuticals, Inc. | Imidazo [1, 5 - a] pyrazine tyrosine kinase inhibitors |
| BRPI0507250A (en) * | 2004-01-29 | 2007-06-26 | Pfizer Prod Inc | combinations to treat snc disorders |
| EA012873B1 (en) * | 2004-04-02 | 2009-12-30 | Оси Фармасьютикалз, Инк. | 6,6-bicyclic ring substituted heterocyclic protein kinase inhibitors |
| AR053090A1 (en) | 2004-07-20 | 2007-04-25 | Osi Pharm Inc | IMIDAZOTRIAZINS AS PROTEIN KINASE INHIBITORS AND THEIR USE FOR THE PREPARATION OF MEDICINES |
| JP2008512441A (en) * | 2004-09-10 | 2008-04-24 | ファイザー・プロダクツ・インク | Method for treating cognitive impairment using pyridyloxymethyl and benzisoxazole azabicyclo derivatives |
| US8575164B2 (en) * | 2005-12-19 | 2013-11-05 | OSI Pharmaceuticals, LLC | Combination cancer therapy |
| US20110046144A1 (en) * | 2008-01-18 | 2011-02-24 | Mulvihill Mark J | Imidazopyrazinol derivatives for the treatment of cancers |
| WO2009143051A1 (en) * | 2008-05-19 | 2009-11-26 | Osi Pharmaceuticals, Inc. | Substituted imidazopyr-and imidazotri-azines |
| JP2012524119A (en) | 2009-04-20 | 2012-10-11 | オーエスアイ・ファーマシューティカルズ，エルエルシー | Preparation of C-pyrazine-methylamine |
| EP2427192A1 (en) * | 2009-05-07 | 2012-03-14 | OSI Pharmaceuticals, LLC | Use of osi-906 for treating adrenocortical carcinoma |
| EP2630136A1 (en) * | 2010-10-21 | 2013-08-28 | Universität des Saarlandes | Selective cyp11b1 inhibitors for the treatment of cortisol dependent diseases |
| WO2014078568A1 (en) | 2012-11-14 | 2014-05-22 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
| US9980945B2 (en) | 2015-01-13 | 2018-05-29 | Vanderbilt University | Benzoisoxazole-substituted compounds as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction |
| US9585867B2 (en) | 2015-08-06 | 2017-03-07 | Charles Everett Ankner | Cannabinod formulation for the sedation of a human or animal |
| WO2020183011A1 (en) | 2019-03-14 | 2020-09-17 | Institut Curie | Htr1d inhibitors and uses thereof in the treatment of cancer |
| WO2023083445A1 (en) | 2021-11-10 | 2023-05-19 | Symrise Ag | Compositions comprising trpm8 agonistic cooling agents |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990008148A1 (en) | 1989-01-23 | 1990-07-26 | Pfizer Inc. | Bis-aza-bicyclic anxiolytic agents |
| US5167034A (en) * | 1990-06-18 | 1992-11-24 | International Business Machines Corporation | Data integrity for compaction devices |
| US5157034A (en) | 1991-02-27 | 1992-10-20 | Pfizer Inc. | Neuroleptic perhydro-1H-pyrido[1,2-a]pyrazines |
| DE69215886T2 (en) | 1991-09-25 | 1997-04-03 | Pfizer | NEUROLEPTIC 2-SUBSTITUTED PERHYDRO-1H-PYRIDO [1,2-a] PYRAZINE |
| DK0646116T3 (en) | 1992-06-16 | 1999-12-27 | Pfizer | Process and intermediates for the preparation of bis-aza-bicyclic anxiolytic agents |
| US5731307A (en) | 1994-09-30 | 1998-03-24 | Pfizer, Inc. | Neuroleptic 2,7-disubtituted perhydro-1h-pyrido 1, 2-A!pyrazines |
| NZ500642A (en) | 1997-05-30 | 2001-11-30 | Neurosearch As | 8-azabicyclo[3,2,1]oct-2-ene and octane derivatives as cholinergic ligands at nicotinic ACH receptors |
| PA8469101A1 (en) * | 1998-04-09 | 2000-09-29 | Pfizer Prod Inc | AZABICICLIC LEAGUES OF RECEIVERS 5HT1 |
| EP1114028B1 (en) | 1998-08-26 | 2006-11-29 | Aventis Pharma Limited | Aza-bicycles which modulate the inhibition of cell adhesion |
| CN1335849A (en) | 1998-09-18 | 2002-02-13 | 巴斯福股份公司 | Pyrrolopyrimidines as protein kinase inhibitors |
| CZ2001959A3 (en) | 1998-09-18 | 2001-12-12 | Basf Aktiengesellschaft | 4-Aminopyrrolopyrimidines functioning as kinase inhibitors |
| UA62015C2 (en) * | 1998-12-28 | 2003-12-15 | Pfizer Prod Inc | Benzoizoxazol derivatives, a pharmaceutical composition (variants) based thereon (variants) and a method for treatment (variants) |
| JP4820488B2 (en) | 1999-03-12 | 2011-11-24 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | Compounds useful as anti-inflammatory drugs |
| EP1177792A3 (en) * | 2000-07-27 | 2002-10-23 | Pfizer Products Inc. | Dopamine D4 Ligands for the treatment of novelty-seeking disorders |
-
2004
- 2004-02-23 EP EP04713592A patent/EP1608648B1/en not_active Expired - Lifetime
- 2004-02-23 KR KR1020057016859A patent/KR100767854B1/en not_active IP Right Cessation
- 2004-02-23 JP JP2006506261A patent/JP3910627B2/en not_active Expired - Fee Related
- 2004-02-23 WO PCT/IB2004/000499 patent/WO2004081007A1/en active Application Filing
- 2004-02-23 CA CA2518740A patent/CA2518740C/en not_active Expired - Fee Related
- 2004-02-23 BR BRPI0408248-6A patent/BRPI0408248A/en not_active IP Right Cessation
- 2004-02-23 UA UAA200508639A patent/UA78437C2/en unknown
- 2004-02-23 AU AU2004220327A patent/AU2004220327B2/en not_active Ceased
- 2004-02-23 EA EA200501148A patent/EA009527B1/en not_active IP Right Cessation
- 2004-02-23 OA OA1200500259A patent/OA13038A/en unknown
- 2004-02-23 PL PL378749A patent/PL378749A1/en not_active Application Discontinuation
- 2004-02-23 CN CNB2004800066516A patent/CN100389115C/en not_active Expired - Fee Related
- 2004-02-23 KR KR1020077013527A patent/KR20070074667A/en not_active Application Discontinuation
- 2004-02-23 RS YUP-2005/0692A patent/RS20050692A/en unknown
- 2004-02-23 AP AP2005003390A patent/AP2005003390A0/en unknown
- 2004-02-23 MX MXPA05009660A patent/MXPA05009660A/en active IP Right Grant
- 2004-03-08 PA PA20048597501A patent/PA8597501A1/en unknown
- 2004-03-09 PE PE2004000256A patent/PE20041057A1/en not_active Application Discontinuation
- 2004-03-10 AR ARP040100770A patent/AR043537A1/en not_active Application Discontinuation
- 2004-03-11 TW TW093106481A patent/TW200502234A/en unknown
- 2004-03-11 GT GT200400041A patent/GT200400041A/en unknown
- 2004-03-11 UY UY28225A patent/UY28225A1/en not_active Application Discontinuation
- 2004-03-12 US US10/800,328 patent/US7345038B2/en not_active Expired - Fee Related
- 2004-03-12 NL NL1025710A patent/NL1025710C2/en not_active IP Right Cessation
-
2005
- 2005-08-10 ZA ZA200506373A patent/ZA200506373B/en unknown
- 2005-08-15 IL IL170290A patent/IL170290A/en not_active IP Right Cessation
- 2005-09-02 NO NO20054095A patent/NO20054095L/en unknown
- 2005-09-12 MA MA28495A patent/MA27747A1/en unknown
- 2005-09-12 TN TNP2005000224A patent/TNSN05224A1/en unknown
- 2005-09-12 HR HR20050798A patent/HRP20050798A2/en not_active Application Discontinuation
- 2005-09-12 EC EC2005006011A patent/ECSP056011A/en unknown
-
2006
- 2006-05-16 HK HK06105638.1A patent/HK1085725A1/en not_active IP Right Cessation
- 2006-10-26 JP JP2006291545A patent/JP2007051155A/en active Pending
-
2010
- 2010-07-23 AU AU2010203303A patent/AU2010203303A1/en not_active Abandoned
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2518740A1 (en) | Pyridyloxymethyl and benzisoxazole azabicyclic derivatives | |
| RU2744988C2 (en) | Compounds and compositions for suppressing shp2 activity | |
| JP6736559B2 (en) | Triazolopyrimidine compounds and uses thereof | |
| EP3489238B1 (en) | Pharmaceutical compositions of 6h-pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-one and [1,2,4]triazolo[1,5-c]pteridin-5(6h)-one derivatives as pde1 inhibitors for treating e.g. neurological disorders | |
| JP2007051155A5 (en) | ||
| CN107108614A (en) | It is used as the substituted pyrrolopyridine of Bu Luomo domain inhibitor | |
| WO2017221100A1 (en) | Imidazopyrimidine compounds useful for the treatment of cancer | |
| US10786492B2 (en) | Formylated N-heterocyclic derivatives as FGFR4 inhibitors | |
| US10689378B2 (en) | Triazolopyridine compounds and uses thereof | |
| CN105209460A (en) | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH | |
| CN107108613A (en) | Bu Luomo domain inhibitor and application thereof | |
| MX2012011912A (en) | Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an mtor inhibitor for treating cancer. | |
| CN107207493A (en) | It is used as the pyrrolopyridine being substituted of Bu Luomo domain inhibitor | |
| EA031201B1 (en) | Imidazopyridazine compounds | |
| JP2017525721A (en) | Products for the treatment and prevention of neurological disorders that progress with cognitive deficits or cognitive impairments and neurodegenerative diseases | |
| CA3127373A1 (en) | P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd | |
| CN105566321A (en) | Heterarylation compound and application thereof to drugs | |
| JP2016027059A (en) | Pyridonaphthyridine pi3k/mtor dual inhibitors and preparation and use thereof | |
| CN107074823A (en) | Therapeutic compound and application thereof | |
| CN107406429A (en) | Pyridazinone derivative and its purposes in treating cancer | |
| KR20220070229A (en) | Aza-quinoline compounds and uses thereof | |
| IL271154B2 (en) | Compounds and compositions for inducing chondrogenesis | |
| CN107406418A (en) | 4,5 glyoxalidine derivatives and its purposes as histone demethylase (KDM2B) inhibitor | |
| CN105801563A (en) | Pyrazole derivatives and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20140225 |