Cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives

• US 20020107242A1
• Filed: 11/02/2001
• Published: 08/08/2002
• Est. Priority Date: 11/03/2000
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Welmaker, Gregory S., Nelson, James A., Sabalski, Joan E., Sabb, Annmarie L., Rosenzweig-Lipson, Sharon J., Vogel, Robert L.
• Granted Patent: US 6,777,407 B2
• Time in Patent Office: Days
• US Class Current: 514/219
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• 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 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07D 209/94 containing carbocyclic rings other than six-membered
• CPC Class Codes: C07D 487/06 Peri-condensed systems

Abstract

This invention provides compounds of the formulae:

wherein:

R₁ is hydrogen, —C(O)CH₃ or alkyl of 1-6 carbon atoms;

R₂ and R₃ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl, alkoxy of 1-6 carbon atoms, —CH₂OH, fluoroalkyl, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, aryl, or aroyl;

R₄ and R₅ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluoroalkyl, —CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, fluoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;

R₆ and R₇ are each independently hydrogen, C₁-C₆ alkyl or cycloalkyl;

or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions containing these compounds and methods for their use, including treatment of obsessive-compulsive disorder, panic disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, migraine, sleep disorders, eating disorders, obesity, epilepsy, and spinal cord injury.

Claims

1. A compound of the formula:

2. A compound of claim 1 having the formulae:

3. A compound of claim 1 wherein R₁ and R₇ are hydrogen and R₁, R₄, R₅, and R₆ are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 having the formulae:

5. A compound of claim 1 which is 1,2,3,4,9,10-Hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 which is 1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 which is 3-Acetyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 which is (7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 which is 6-Methyl-1,2,3,4,9,10-hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 which is (2S)-(rel-7bR, 10aR)-2-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7, 1-hi]indole or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 which is (2S)-(rel-7bS,10aS)-2-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7, 1-hi]Indole or a pharmaceutically acceptable salt thereof.

12. A compound of claim 1 which is (2R)-(rel-7bR, 10aR)-2-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH-Cyclopenta[b][1,4]Diazepino[6,7,1-hi]indole or a pharmaceutically acceptable salt thereof.

13. A compound of claim 1 which is (2R)-(rel-7bS,10aS)-2-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7, 1-hi]Indole or a pharmaceutically acceptable salt thereof.

14. A compound of claim 1 which is (2R,7bS,10aS)-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7,1-hi]Indol-2-ylmethanol or a pharmaceutically acceptable salt thereof.

15. A compound of claim 1 which is rel-(4S,7bS,10aS)-4-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7, 1-hi]Indole or a pharmaceutically acceptable salt thereof.

16. A compound of claim 1 which is rel-(4R,7bS,10aS)-4-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7, 1-hi]Indole or a pharmaceutically acceptable salt thereof.

17. A compound of claim 1 which is 9-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7,1-hi]Indole or a pharmaceutically acceptable salt thereof.

18. A compound of claim 1 which is (7bR,9R,10aR)-9-Methyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7,1-hi]Indole or a pharmaceutically acceptable salt thereof.

19. A compound of claim 1 which is 9,9-Dimethyl-1,2,3,4,8,9,10,10a-Octaydro-7bH—

Cyclopenta[1,4]Diazepino[6,7,1-hi]Indole or a pharmaceutically acceptable salt thereof.

20. A compound of claim 1 which is (7b,10aR)-9,9-Dimethyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7,1-hi]Indole or a pharmaceutically acceptable salt thereof.

21. A compound of claim 1 which is (7bS,10aS)-9,9-Dimethyl-1,2,3,4,8,9,10,10a-Octahydro-7bH—

Cyclopenta[b][1,4]Diazepino[6,7,1-hi]Indole or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. A method of treatment of schizophrenia in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

24. A method of treatment in a mammal of obsessive-compulsive disorder, depression, anxiety, panic disorder, anxiety, generalized anxiety disorder, obesity or epilepsy, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.