Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders

• US 20050192268A1
• Filed: 12/21/2004
• Published: 09/01/2005
• Est. Priority Date: 12/22/2003
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Ek, Fredrik, Ohlsson, Jorgen
• Granted Patent: US 7,550,454 B2
• Time in Patent Office: Days
• US Class Current: 514/211.13
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 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: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.

Claims

1. A compound of Formula I, II, or XV:

2. The compound of claim 1, wherein said compound has a structure set forth in Formulas III or IV.

3. The compound of claim 1, wherein said compound is selected from the group consisting of:

4. The compound of claim 3, wherein said compound is selected from the group consisting of:

5. The compound of claim 1, wherein none of a, b, c, or d is absent.

6. The compound of claim 1, wherein none of e, f, g, or h is absent.

7. The compound of claim 1, wherein a, b, c, and d are carbon.

8. The compound of claim 1, wherein e, f, g, and h are carbon.

9. The compound of claim 1, wherein R₂ is selected from the group consisting of hydrogen, halogen, optionally substituted C_1-6 alkyl, and optionally substituted C_1-6 alkyloxy.

10. The compound of claim 9, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

11. The compound of claim 9, wherein said alkyloxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy.

12. The compound of claim 9, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

13. The compound of claim 1, wherein R₂ is selected from the group consisting of hydrogen, methyl, methoxy, and chloro.

14. The compound of claim 1, wherein R₃ is selected from the group consisting of hydrogen, halogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 alkyloxy, and NO₂

15. The compound of claim 14, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

16. The compound of claim 14, wherein said alkyloxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy.

17. The compound of claim 14, wherein said halogen is selected from the group consisting of chloro, bromo, and iodo.

18. The compound of claim 1, wherein R₃ is selected from the group consisting of hydrogen, methyl, methoxy, chloro, bromo, iodo, and NO₂.

19. The compound of claim 1, wherein R₄ is selected from the group consisting of hydrogen, halogen, optionally substituted C_1-6 alkyl, perhaloalkyl, SO₂R₁₀, and NO₂.

20. The compound of claim 19, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

21. The compound of claim 19, wherein said perhaloalkyl is perfluoroalkyl.

22. The compound of claim 21. wherein said perfluoroalkyl is trifluoromethyl.

23. The compound of claim 19, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

24. The compound of claim 19, wherein R₁₀ is hydrogen or optionally substituted C_1-6 alkyl.

25. The compound of claim 24, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

26. The compound of claim 1, wherein R₄ is selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, trifluoromethyl, SO₂CH₃, and NO₂.

27. The compound of claim 1, wherein R₅ is selected from the group consisting of hydrogen, halogen, and optionally substituted C_1-6 alkyl.

28. The compound of claim 27, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

29. The compound of claim 27, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

30. The compound of claim 1, wherein R₅ is hydrogen or chloro.

31. The compound of claim 1, wherein R₆ is hydrogen or optionally substituted C_1-6 alkyl.

32. The compound of claim 1, wherein R₆ is hydrogen.

33. The compound of claim 1, wherein R₇ is selected from the group consisting of hydrogen, halogen, optionally substituted C_1-6 alkyl, perhaloalkyl, CN, SO₂R₁₀, and NO₂.

34. The compound of claim 33, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

35. The compound of claim 33, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

36. The compound of claim 33, wherein said perhaloalkyl is perfluoroalkyl.

37. The compound of claim 36. wherein said perfluoroalkyl is trifluoromethyl.

38. The compound of claim 33, wherein R₁₀ is hydrogen or optionally substituted C_1-6 alkyl.

39. The compound of claim 38, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

40. The compound of claim 1, wherein R₇ is selected from the group consisting of hydrogen, methyl, chloro, trifluoromethyl, SO₂CH₃, CN, and NO₂.

41. The compound of claim 1, wherein R₈ is selected from the group consisting of hydrogen, halogen, optionally substituted C_1-6 alkyl.

42. The compound of claim 41, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

43. The compound of claim 41, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

44. The compound of claim 1, wherein R₈ is selected from the group consisting of hydrogen, chloro, and bromo.

45. The compound of claim 1, wherein R₉ is selected from the group consisting of hydrogen, halogen, optionally substituted C_1-6 alkyl, and perhaloalkyl.

46. The compound of claim 45, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

47. The compound of claim 45, wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo.

48. The compound of claim 45, wherein said perhaloalkyl is perfluoroalkyl.

49. The compound of claim 48, wherein said perfluoroalkyl is trifluoromethyl.

50. The compound of claim 1, wherein R₉ is selected from the group consisting of hydrogen, chloro, methyl, and trifluoromethyl.

51. The compound of claim 1, wherein R₁ is selected from the group consisting of hydrogen, optionally substituted C_1-6 alkyl, and optionally substituted aryl.

52. The compound of claim 51, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

53. The compound of claim 1, wherein R₁ is hydrogen.

54. The compound of claim 1, wherein X is nitrogen.

55. The compound of claim 1, wherein Y is NH.

56. The compound of claim 1, wherein L is absent or is selected from the group consisting of —

NHCH₂—

, —

NH—

, and —

CH₂—

.

57. The compound of claim 1, wherein A is selected from the group consisting of:

58. The compound of claim 1 selected from the group consiting of:

2,7-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Bromo-2-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine,

6-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine,

7-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Bromo-1-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Bromo-2-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

4,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-2-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-2-fluoro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

3,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2-Bromo-8-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

3,7-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Bromo-3-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

3-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

3-Chloro-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine,

7-Chloro-2-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2-Methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2-Methyl-11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-4-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

1,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Bromo-5-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

7,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

11-(piperazin-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine,

11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Fluoro-1-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine-8-carbonitrile,

8-Bromo-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

3-Fluoro-6-piperazin-1-yl-11H-dibenzo[b,e]azepine,

2-(Trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2-(Trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]oxazepine,

8-Chloro-2-(trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-(Trifluoromethanesulfonyloxy)-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

11-(piperazin-1-yl)-dibenzo[b,f][1,4]thiazepin,

11-(piperazin-1-yl)-2,3-dihydro-1,4-benzodioxino[6,7-b][1,4]benzothiazepin,

8-Chloro-11-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepine,

N′

-(8-Chloro-5H-dibenzo[b,e][1,4]diazepine-11-yl)-N,N-dimethyl-ethane-1,2-diamine,

N′

-(8-Chloro-5H-dibenzo[b,e][1,4]diazepine-11-yl)-N,N-diethyl-ethane-1,2-diamine,

8-Chloro-11-(4-methyl-[1,4]diazepam-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-2-methoxy-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

N′

-(5H-dibenzo[b,e][1,4]diazepine-11-yl)-N,N-dimethyl-ethane-1,2-diamine,

11-[1,4]Diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepine,

N′

-(8-Fluoro-5H-dibenzo[b,e][1,4]diazepine-11-yl)-N,N-dimethyl-ethane-1,2-diamine,

8-Fluoro-11-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepine,

N′

-(8-Chloro-5H-dibenzo[b,e][1,4]diazepine-11-yl)-N-methyl-ethane-1,2-diamine,

8-Chloro-11-(trans-2,5-dimethyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(3,5-dimethyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(3-methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(3-phenyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-5-methyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-5-benzyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Iodo-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

2-Iodo-8-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Phenyl-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(piperidin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(morpholin-4-yl)-5H-dibenzo[b,e][1,4]diazepine,

5-Allyl-8-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

6-Chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-5-piperazin-1-yl-11H-benzo[b]pyrido[2,3-e][1,4]diazepine,

2-Chloro-10-piperazin-1-yl-5H-dibenzo[b,f]azepin,

8-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]thiazepine,

8-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Chloro-11-(4-methyl-piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

3-Chloro-6-piperazin-1-yl-11H-dibenzo[b,e]azepine,

8-Bromo-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

7-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Chloro-3-methoxy-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Bromo-3-methoxy-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

3-Methoxy-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

7-Chloro-3-methoxy-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Bromo-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

4-Methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

2-Bromo-8-chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

2,8-Dibromo-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

2-Bromo-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

2-Bromo-7-chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,f][1,4]oxazepine,

4-Methyl-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,f][1,4]oxazepine,

8-Fluoro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Fluoro-3-methoxy-1-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Fluoro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

2-Bromo-8-fluoro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

3-Methoxy-8-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

4,8-Dimethyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

3-Methoxy-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,f][1,4]oxazepine,

2-Bromo-11-(piperazin-1-yl)-8-trifluoromethyl-dibenzo[b,f][1,4]oxazepine,

6-Chloro-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

2-Bromo-8-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

7-Chloro-4-methyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Phenyl-11-(piperazin-1-yl)-dibenzo[b,f][1,4]oxazepine,

8-Chloro-11-(piperidin-4-yl)-5H-dibenzo[b,e][1,4]diazepine

5-Benzyl-8-chloro-11-(piperidin-4-yl)-5H-dibenzo[b,e][1,4]diazepine,

8-Bromo-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one,

5,10-Dihydro-dibenzo[b,e][1,4]diazepine-11-one,

8-Fluoro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one,

8,5-Dichloro-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine

(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(S)-1-pyrrolidin-2-yl-methyl-amine,

1-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-piperidine-4-yl-amine,

1-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-pyrrolidin-3-yl-amine,

(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(R)-1-pyrrolidin-2-yl-methyl-amine,

(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-pyrrolidin-3-yl-amine,

8-Chloro-11-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-5H-dibenzo[b,e][1,4]diazepine,

Acetidin-3-yl-(8-chloro-5H-dibenzo[b,e][1,4]diazepine-11-yl)amine,

7-Bromo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine,

7-Bromo-2-methyl-(piperazin-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine

7-Bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine,

7-Bromo-10-(piperazin-1-yl)-1,2,3,3a,4,10a-hexahydro-benzo[b]cyclopenta[e][1,4]diazepine,

8-Chloro-11-(4-fluorobenzyl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(4-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(4-nonylphenyl)-5H-dibenzo[b,e][1,4]diazepine,

8-Chloro-11-(pyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepine, and

8-Chloro-11-(1H-pyrazol-4-yl)-5H-dibenzo[b,e][1,4]diazepine.

62. A pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient, or a combination thereof;

and a compound of claim 1.

63. A method of treating a neuropsychiatric disorder comprising administering to said patient a therapeutically effective amount of a compound of claim 1.

64. A method of treating a neuropsychiatric disorder comprising contacting a therapeutically effective amount of a compound of claim 1 with said patient.

65. A pharmaceutical composition comprising a compound of claim 1 and an neuropsychiatric agent.

66. The composition of claim 65, wherein said neuropsychiatric agent is selected from the group consisting of a selective serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine agonist, muscarinic receptor antagonist, antipsychotic agent, serotonin 2A antagonist, and inverse serotonin 2A agonist.

67. The composition of claim 66, wherein said antipsychotic agent is selected from the group consisting of a phenothiazine, phenylbutylpiperadine, debenzapine, benzisoxidil, and salt of lithium.

68. The composition of claim 67, wherein said phenothiazine is selected from the group consisting of chlorpromazine (Thorazine(V), mesoridazine (Serentil®

), prochlorperazine (Compazine®

), and thioridazine (Mellaril®

).

69. The composition of claim 67, wherein said phenylbutylpiperadines is selected from the group consisting of haloperidol (Haldol®

), and pimozide (Orap®

).

70. The composition of claim 67, wherein said debenzapine is selected from the group consisting of clozapine (Clozaril®

), loxapine (Loxitane®

), olanzapine (Zyprexa®

) and quetiapine (Seroquel®

).

71. The composition of claim 67, wherein said benzisoxidil is selected from the group consisting of resperidone (Resperidal®

) and ziprasidone (Geodon®

).

72. The composition of claim 67, wherein said salt of lithium is lithium carbonate.

73. The composition of claim 66, wherein said antipsychotic agent is selected from the group consisting of Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Orap, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon, and Zyprexa.

74. The composition of claim 66, wherein said selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.

75. The composition of claim 66, wherein said norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.

76. The composition of claim 66, wherein said dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.

77. The composition of claim 66, wherein said inverse serotonin 2A agonist is the compound of Formula XIII, or a related analog thereof.

78. The composition of claim 66, where in said serotonin 2A antagonist is the compound of Formula XIV, or a related analog thereof:

79. A method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a composition of claim 65.

80. A method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 and a therapeutically effective amount of a neuropsychiatric agent.

81. The method of claim 80, wherein said administering step comprises administering said compound of claim 1 and said neuropsychiatric agent nearly simultaneously.

82. The method of claim 80, wherein said administering step comprises administering one of said compound of claim 1 and said neuropsychiatric agent first and then administering the other one of said compound of claim 1 and said neuropsychiatric agent.

83. The method of claim 80, wherein said neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette'"'"'s Syndrome, drug-induced psychoses, psychoses secondary to neurodegenerative disorders such Alzheimer'"'"'s or Huntington'"'"'s Disease.

59. A method of synthesizing a compound of Formula V or VI,

60. A combinatorial library of at least 220 dibenzo[b,e][1,4]diazepine[a,d]cycloheptene compounds that can be formed by reacting a compound of Formula VII,

61. A combinatorial library of at least 220 dibenzo[b,e][1,4]diazepine[a,d]cycloheptene compounds that can be formed by reacting a compound of Formula VII,