AMINO SUBSTITUTED DIARYL[a,d]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS

• US 20070197502A1
• Filed: 04/10/2007
• Published: 08/23/2007
• Est. Priority Date: 12/22/2003
• Status: Active Grant

• Current Assignee: Fredrik Ek, Jorgen Ohlsson, Roger Olsson
• Original Assignee: Fredrik Ek, Jorgen Ohlsson, Roger Olsson
• Inventors: Olsson, Roger, Ek, Fredrik, Ohlsson, Jorgen
• Granted Patent: US 7,622,461 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 neuropsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.

Claims

1. A method of treating cognitive impairment, comprising administering to a subject exhibiting one or more symptoms of cognitive impairment a therapeutically effective amount of a compound of Formula I, II, or XV:

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

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

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

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

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

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

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

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

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

11. The method 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

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

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

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

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

16. The method of claim 1, wherein R₅ is hydrogen or chloro.

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

18. The method 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.

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

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

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

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

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

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

25. The method of claim 1, wherein X is nitrogen.

26. The method of claim 1, wherein Y is NH.

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

NHCH₂—

, —

NH—

, and —

CH₂—

.

28. The method of claim 1, wherein A is selected from the group consisting of:

29. The method of claim 1, wherein the compound has the structure set forth in Formula I or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:

A has the structure

 

wherein each bond represented by a dashed and solid line in A represents a carbon-carbon single bond;

a, b, c, and d are each carbon;

e, f, g, and h are each carbon;

X is nitrogen;

X′

is C;

L is absent;

each n is 1;

Y is nitrogen;

W is nitrogen;

R₁ is hydrogen;

R₂, R₃, and R₄, are each hydrogen;

R₆, R₈, and R₉, are each hydrogen;

R₅ is selected from the group consisting of halogen, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, perhaloalkyl, and CN;

R₇ is selected from the group consisting of halogen, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, perhaloalkyl, and CN;

Z is selected from the group consisting of NR₁₁, oxygen, sulfur, and CH₂;

R₁₁ is selected from the group consisting of hydrogen, optionally substituted C_1-6 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, and optionally substituted arylalkyl; and

each bond represented by a dashed and solid line in Formula I represents a carbon-carbon double bond.

30. The method of claim 29, wherein R₅ is selected from the group consisting of halogen and optionally substituted C_1-6 alkyl.

31. The method of claim 30, wherein R₅ is chloro.

32. The method of claim 29, wherein R₇ is selected from the group consisting of halogen, optionally substituted C_1-6 alkyl, perhaloalkyl, and CN.

33. The method of claim 29, wherein the compound is selected from the group consisting of:

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

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

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)-8-trifluoromethyl-dibenzo[b,f][1,4]oxazepine,

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

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

34. The method of claim 1, wherein the compound is selected from the group consisting 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,

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

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

3-Chloro-1-(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,

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-11-(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-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,

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,

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,

8-Fluoro-3-methoxy-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,

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.

35. The method of claim 1, wherein the compound is selected from the group consisting of:

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

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

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

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

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

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

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

36. The method of claim 1, wherein the compound is selected from the group consisting of:

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

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

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

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