Therapeutic combinations for the treatment or prevention of psychotic disorders

• US 20070238725A1
• Filed: 03/23/2007
• Published: 10/11/2007
• Est. Priority Date: 03/24/2006
• Status: Abandoned Application

• Current Assignee: Wyeth LLC (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Rosenzweig-Lipson, Sharon
• Application Number:
  US11/726,927
• Publication Number:
  US 20070238725A1
• Time in Patent Office: Days
• US Class Current: 514/220
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Therapeutic combinations useful in the treatment or prevention of psychotic disorders, to pharmaceutical compositions containing said combinations, and to their use in the treatment or prophylaxis of psychotic disorders are provided. Such compounds are of formula I:
or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, n, and m are as defined and described herein.

Claims

1. A composition comprising:

(a) either a typical or atypical anti-psychotic drug;

(b) a compound of formula I;

or a pharmaceutically acceptable salt thereof, wherein;

designates a single or double bond;

n is 1 or2;

m is 0 or 1;

R¹ and R² are each independently halogen, —

CN, —

R, —

OR, —

C_1-6 perfluoroalkyl, or —

OC_{1- 6} perfluoroalkyl;

each R is independently hydrogen or a C_1-6 alkyl group;

R³ and R⁴ are taken together, with the carbon atoms to which they are bound, to form a saturated or unsaturated 4-8 membered ring, wherein said ring is optionally substituted with 1-3 groups independently selected from halogen, —

R, or OR; and

R⁵ and R⁶ are each independently —

R; and

(c) optionally a pharmaceutically acceptable carrier, adjuvant, or vehicle.

2. The composition according to claim 1, wherein designates a single bond.

3. The composition according to claim 1, wherein:

R¹ is R, OR, halogen, cyano, or —

C_1-3 perfluoroalkyl; and

R² is R, OR, halogen, cyano, or —

C_1-3 perfluoroalkyl.

4. The composition according to claim 3, wherein at least one of R¹ and R² is —

OH.

5. The composition according to claim 3, wherein R³ and R⁴ are taken together, with the carbon atoms to which they are bound, to form a saturated or unsaturated 5-8 membered ring, wherein said ring is optionally substituted with 1-3 groups independently selected from halogen, —

R, or OR.

6. The composition according to claim 1, wherein said compound is of formula I-a or I-b:

7. The composition according to claim 1, wherein said compound is of formula I-c or I-d:

8. The composition according to claim 7, wherein said compound is of formula II or III:

9. The composition according to claim 1, wherein said compound is of formula I-e or I-f:

10. The composition according to claim 9, wherein said compound is of formula IV or V:

11. The composition according to claim 1, wherein said compound is selected from:

2-bromo-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino [6,7,1-ij]quinoline;

2-bromo-4,5,6,7,9,9a,10,11,12,13,14,14a-dodecahydrocyclohepta[c][1,4 ]diazepino[6,7,1-ij]quinoline;

2-chloro-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino [6,7,1-ij]quinoline;

2-chloro-4,5,6,7,9,9a,10,11,12,13,14,14a-dodecahydrocyclohepta[c][1,4] diazepino[6,7,1-ij]quinoline;

2-phenyl-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino [6,7,1-ij]quinoline;

2-methoxy-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino [6,7,1-ij]quinoline;

1-fluoro-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4] diazepino [6,7,1-ij] quinoline;

1-fluoro-4,5,6,7,9,9a,10,11,12,13,14,14a-dodecahydrocyclohepta[c][1,4] diazepino[6,7,1-ij]quinoline;

1-(trifluoromethyl)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4] diazepino [6,7,1-ij]quinoline;

1-fluoro-2-methoxy-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4] diazepino[6,7,1-ij]quinoline;

1-fluoro-2-methoxy-4,5,6,7,9,9a,10,11,12,13,14,14a-dodecahydrocyclo-hepta[c][1,4]diazepino[6,7,1-ij]quinoline;

4,5,6,7,9,9a 10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino[6,7,1-ij] quinoline;

4,5,6,7,9,9a,10,11,12,13,14,14a-dodecahydrocyclohepta[c][1,4]diazepino [6,7,1-ij]quinoline;

(−

)-4,5,6,7,9,9a 10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino [6,7,1-ij] quinoline;

(9aR, 14aS)-4,5,6,7,9,9a,10,11,12,13,14,14a-dodecahydrocyclohepta[c][1,4] diazepino[6,7,1-ij]quinoline;

(9aS, 14aR)-4,5,6,7,9,9a,10,11,12,13,14,14a-dodecahydrocyclohepta[c][1,4] diazepino[6,7,1-ij]quinoline;

4,5,6,7,9a,10,11,12,13,13a-decahydro-9H-[1,4]diazepino[6,7,1-de]phenanthridine;

1,2,3,4,9,10-hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,-hi]indole;

1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

(7bS,10aS)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole;

(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole;

6-methyl-1,2,3,4,9,10-hexahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

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;

(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;

(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;

(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;

(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;

(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;

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

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;

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;

9-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole;

(7bR,9R,10aR)-9-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]d iazepino[6,7,1-hi]indole;

9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[1,4]diazepino[6,7,1-hi]indole;

(7bR,10aR)-9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4] diazepino[6,7,1-hi]indole; and

(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.

12. The composition of claim 11, wherein said compound is the hydrochloride salt.

13. A method of treating a patient suffering from a psychotic disorder comprising administering to said patient the composition according to claim 1.

14. The method according to claim 13, wherein the anti-psychotic agent is an atypical anti-psychotic.

15. The method according to claim 13, wherein the anti-psychotic agent is a typical anti-psychotic.

16. The method according to claim 13, wherein the anti-psychotic agent is selected from chlorpromazine, mesoridazine, thioridazine, fluphenazine, trifluoperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, thiothixene, risperidone, seroquel, or olanzapine.

17. The method according to claim 13, wherein administration of the composition is oral.

18. The method according to claim 13, wherein the patient is suffering from schizophrenia.

19. The method according to claim 13, wherein the patient is suffering from schizoaffective disorder.

20. The method according to claim 13, wherein the patient is suffering from bipolar disorder.