Pyrrolo[1,2-a]pyrazine derivatives as 5HT1A ligands

• US 6,284,757 B1
• Filed: 08/11/1999
• Issued: 09/04/2001
• Est. Priority Date: 08/17/1998
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc.
• Inventors: Sanner, Mark Allen
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US09/372,438
• Time in Patent Office: 755 Days
• Field of Search: 514/249
• US Class Current: 514/249
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 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
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

This invention relates to the use of compounds of formula I

wherein R₁, R₂, R₃, X, m and n are defined as in the specification, and their pharmaceutically acceptable salts, for the treatment of disorders of the serotonin system.

Claims

1. A method of treating a disorder or condition that can be treated by altering serotonin mediated neurotransmission in a mammal, comprising administering to such mammal an amount of a compound of formula I

wherein R₁ is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;

R₂ is H or (C₁-C₆)alkyl;

R₃ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl;

R₄ is H or (C₁-C₆)alkyl;

R₅ is H or (C₁-C₆)alkyl;

wherein each group of R₁ and R₃ may be independently and optionally substituted with one to four substituents independently selected from the groups consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —

SR₄, —

SOR₄, —

SO₂R₄, —

NHSO₂R₄, —

(C₁-C₆)alkoxy, —

NR₄R₅, —

NR₄COR₅, —

CONR₄R₅, phenyl, —

COR₄, —

COOR₄, —

(C₁-C₆)alkyl, —

(C₁-C₆)alkyl substituted one to six halogens, —

(C₃-C₆)cycloalkyl, and trifluoromethoxy;

X is O, S, SO, SO₂, NR₄, C═

O, CH(OH), CHR₄,

m is 0, 1 or 2;

n is 0, 1 or 2;

or

a pharmaceutically acceptable salt thereof;

that is effective in treating such disorder or condition.

2. A method according to claim 1, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein R₁ is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl;

and wherein R₁ and R₃ may be independently substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, —

NR₄R₅, —

(C₁-C₆)alkoxy, —

COOR₄, —

CONR₄R₅, —

(C₁-C₆)alkyl, —

(C₁-C₆)alkyl substituted with one to six halogens, —

(C₃-C₆)cycloalkyl, and trifluoromethoxy;

R₂ is H or CH₃;

X is O, C═

O, CHOH, —

C(═

O)O—

, or CH₂;

m is 0 or 1; and

n is 0 or 1.

3. A method according to claim 2, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein

R₁ is phenyl or substituted phenyl;

R₃ is substituted or unsubstituted phenyl, pyridinyl, or pyrimidinyl; and

X is O, —

C(═

O)O—

, or CH₂.

4. A method according to claim 3, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein

R₂ is H;

X is O;

m is 0; and

n is 1.

5. A method according to claim 4, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein

R₁ is fluorophenyl, cyanophenyl or (trifluoromethyl)phenyl;

and

R₃ is chloropyridinyl.

6. A method according to claim 4, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein

R₁ is fluorophenyl, cyanophenyl or (trifluoromethyl)phenyl;

and

R₃ is fluroropyrimidinyl.

7. A method according to claim 5, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein

R₃ is 5-chloro-2-pyridinyl.

8. A method according to claim 6, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein

R₃ is 5-fluoro-2-pyrimidinyl.

9. A method according to claim 1, wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one of the following compounds or a pharmaceutically acceptable salt thereof:

(7S,8aS)-7-(4-fluorophenoxy)methyl-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;

(7S,8aS)-7-(3-cyanophenoxy)methyl-2-(5-chloropyidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;

(7S,8aS)-7-(4-fluorophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;

(7S,8aS)-7-(3-(trifluoromethyl)phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;

(7S,8aS)-7-(3-cyanophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;

or

(7S,8aS)-7-(4-cyanophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine.

10. A method of treating a disorder or condition that can be treated by altering serotonin mediated neurotransmission in a human, comprising administering to said human an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.

11. A method of treating migraine, headache or cluster headache in a mammal comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

12. A method of treating a disorder selected from anxiety, depression, dysthymia, major depressive disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, avoidant personality disorder, borderline personality disorder and phobias in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

13. A method of treating a disorder of cognition, memory or learning, or Alzheimer'"'"'s disease in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

14. A method of treating anxiety or depression associated with senile dementia or Alzheimer'"'"'s disease in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

15. A method of treating prostate cancer in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

16. A method of treating cerebral infarct caused by stroke, ischemia or traumatic head injury in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

17. A method according to claim 16, wherein the compound of formula I, or pharmaceutically acceptable salt thereof, is administered in combination with a 5HT₂ antagonist, or a pharmaceutically acceptable salt thereof.

18. A method of treating a sexual disorder in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

19. A method of treating dizziness in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

20. A method of treating an eating disorder in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

21. A method of treating pain in a mammal, comprising administering to said mammal an amount of a compound of the formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

22. A method according to claim 12, wherein the compound of formula I or pharmaceutically acceptable salt thereof is adminstered in combination with a serotonin reuptake inhibitor.

23. A method according to claim 14, wherein the compound of formula I or pharmaceutically acceptable salt thereof is adminstered in combination with a serotonin reuptake inhibitor.

24. A method of treating attention deficit hyperactivity disorder in a mammal, comprising administering to said mammal an amount of a compound according to claim 1 that is effective in treating such disorder.

25. A method of imaging an organ in a mammal, comprising administering to said mammal a radioactive form of a compound according to claim 1, and detecting the emissions of the radioactive compound.

26. A method of imaging an organ in a mammal comprising administering to said mammal a compound according to claim 1 in combination with a radioactive agent, and detecting the emissions of the radioactive agent.