Claims
- 1. A method of treatment of a disease or condition which is caused by a disorder of the serotonin system which comprises administering to a mammal in need of such treatment a compound of the formula
- 2. A method of claim 1 wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl; Ar1 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; A is O, S, or CH2; n is 0 or 1; and wherein Ar and Ar1 are independently and optionally substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, nitro, cyano, —NRR, -(CC6)alkoxy, —COOR, —CONR1R2, and -(C1-C6)alkyl.
- 3. A method of claim 2 wherein Ar is optionally substituted phenyl; Ar1 is optionally substituted and is selected from phenyl, pyridinyl, and pyrimidinyl; A is O; and n is 1.
- 4. A method of claim 3 wherein Ar1 is 5-fluoro-pyrimidin-2-yl or pyrimidin-2-yl.
- 5. A method of claim 1 wherein the compound of formula I is selected from:
(7S,9aS)-7-((3-Methyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl )-2,3,4,6, 7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-carbomethoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-nitro-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1 ,2-a]pyrazine; (7S,9aS)-7-(3-cyano-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1 ,2-a]pyrazine; (7S,9aS)-7-(3-methoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-acetamido-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-(1, 1 -dimethyl)ethyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; and pharmaceutically acceptable salts thereof.
- 6. A method of treatment of a disease or condition which is caused by a disorder of the serotonin system or a disorder of the dopamine system which comprises administering to a mammal in need of such treatment a compound of the formula
- 7. A method of claim 6 wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl; Ar1 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; A is O, S, or CH2; n is 0 or 1; and wherein Ar and Ar1 are independently and optionally substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, nitro, cyano, —NR1R2, -(C1C6)alkoxy, —COOR, —CONR1R2, and -(C1-C6)alkyl.
- 8. A method of claim 7 wherein Ar is optionally substituted phenyl; Ar1 is optionally substituted and is selected from phenyl, pyridinyl, and pyrimidinyl; A is O; and n is 1.
- 9. A method of claim 8 wherein Ar1 is 5-fluoro-pyrimidin-2-yl or pyrimidin-2-yl.
- 10. A method of claim 6 wherein the compound of formula I is selected from:
(7S,9aS)-7-((3-Methyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-carbomethoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-n itro-phenoxy)methyl-2-(5-fluoropyrim idin-2-yl )-2 ,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-cyano-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-methoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-acetamido-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-(1, 1 -dimethyl)ethyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; and pharmaceutically acceptable salts thereof.
- 11. A method of treating a disorder or condition selected from the group consisting of migraine, headache, cluster headache, anxiety, depression, dysthymia, major depressive disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, avoidant personality disorder, borderline personality disorder, phobia, a disorder of cognition, a memory disorder, a learning disorder (including age related memory disorder), a neurodegenerative disease (including Alzheimer's disease), anxiety and/or depression associated with senile dementia or Alzheimer's disease, cancer (including prostate cancer), cerebral infarct (including that caused by stroke, ischemia or traumatic head injury), a sexual disorder, dizziness, an eating disorder, pain, chemical dependency or addiction, peptic ulcer, and attention deficit hyperactivity disorder in a mammal, comprising administering to said mammal an amount of a compound of the formula
- 12. A method of claim 11 wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl; Ar1 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; A is O, S, or CH2; n is 0 or 1; and wherein Ar and Ar1 are independently and optionally substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, nitro, cyano, -NRLR. -(C, C8)alkoxy, —COOR, —CONR1R2, and -(C1-C6)alkyl.
- 13. A method of claim 12 wherein Ar is optionally substituted phenyl; Ar1 is optionally substituted and is selected from phenyl, pyridinyl, and pyrimidinyl; A is O; and n is 1.
- 14. A method of claim 13 wherein Ar1 is 5-fluoro-pyrimidin-2-yl or pyrimidin-2-yl.
- 15. A method of claim 11 wherein the compound of formula I is selected from:
(7S,9aS)-7-((3-Methyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-carbomethoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-nitro-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-cyano-phenoxy)methyl-2-(5-fl uoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; (7S,9aS)-7-(3-methoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1 ,2-a]pyrazine; (7S,9aS)-7-(3-acetamido-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1 ,2-a]pyrazine; (7S,9aS)-7-(3-(1,1-dimethyl)ethyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1 ,2-a]pyrazine; and pharmaceutically acceptable salts thereof.
- 16. A method according to claim 11 wherein the disorder or condition being treated is migraine, headache, or cluster headache.
- 17. A method according to claim 11 wherein the disorder or condition being treated is anxiety, depression, dysthymia, major depressive disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, avoidant personality disorder, borderline personality disorder, or phobia.
- 18. A method according to claim 11 wherein the disorder or condition being treated is a disorder of cognition, a memory disorder, a learning disorder (including age related memory disorder), or a neurodgenerative disease (including Alzheimer's disease).
- 19. A method according to claim 11 wherein the disorder or condition being treated is anxiety and/or depression associated with senile dementia or Alzheimer's disease.
- 20. A method according to claim 11 wherein the disorder or condition being treated is cancer (including prostate cancer).
- 21. A method according to claim 11 wherein the disorder or condition being treated is cerebral infarct (including that caused by stroke, ischemia or traumatic head injury).
- 22. A method according to claim 21, wherein the compound of formula I is administered in combination with a 5HT2 antagonist.
- 23. A method according to claim 11 wherein the disorder or condition being treated is a sexual disorder.
- 24. A method according to claim 11 wherein the disorder or condition being treated is dizziness.
- 25. A method according to claim 11 wherein the disorder or condition being treated is an eating disorder.
- 26. A method according to claim 11 wherein the disorder or condition being treated is pain.
- 27. A method according to claim 11 wherein the disorder or condition being treated is chemical dependency or addiction.
- 28. A method according to claim 11 wherein the disorder or condition being treated is attention deficit hyperactivity disorder.
- 29. A method according to claim 11 wherein the disorder or condition being treated is peptic ulcer.
- 30. A method according to claim 1, wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.
- 31. A method according to claim 6, wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.
- 32. A method according to claim 11, wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.
- 33. A method according to claim 17, wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.
- 34. A method according to claim 27, wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.
- 35. A method of imaging an organ in a mammal, comprising administering to said mammal a radioactive form of a compound of the formula
- 36. A method of imaging an organ in a mammal, comprising administering to said mammal a compound of the formula
Parent Case Info
[0001] This is a continuation-in-part of U.S. application Ser. No. 09/135,946, filed Aug. 18, 1998, which is a continuation-in-part of 08/809,145, filed Mar. 26, 1997, the national stage of International Application PCT/IB95/00689, filed Aug. 24, 1995, now U.S. Pat. No. 5,852,031, issued Dec. 22, 1998. PCT/IB95/00689 is a continuation of U.S. application Ser. No. 08/315,470, filed Sep. 30, 1994, now abandoned.
Continuations (2)
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Number |
Date |
Country |
Parent |
09368984 |
Aug 1999 |
US |
Child |
09784567 |
Feb 2001 |
US |
Parent |
08315470 |
Sep 1994 |
US |
Child |
PCT/IB95/00689 |
Aug 1995 |
US |
Continuation in Parts (3)
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Number |
Date |
Country |
Parent |
09135946 |
Aug 1998 |
US |
Child |
09368984 |
Aug 1999 |
US |
Parent |
08809145 |
Mar 1997 |
US |
Child |
09135946 |
Aug 1998 |
US |
Parent |
PCT/IB95/00689 |
Aug 1995 |
US |
Child |
09135946 |
Aug 1998 |
US |