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

• US 7,622,461 B2
• Filed: 04/10/2007
• Issued: 11/24/2009
• Est. Priority Date: 12/22/2003
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Ohlsson, Jörgen, Olsson, Roger, Ek, Fredrik
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US11/733,476
• Publication Number:
  US 20070197502A1
• Time in Patent Office: 959 Days
• Field of Search: 514/211.13, 540/551
• 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 associated with Alzheimer'"'"'s disease, schizophrenia or related idiopathic psychoses, Huntington'"'"'s disease, Tourette'"'"'s syndrome, anxiety, affective disorders, drug-induced psychoses, psychoses secondary to neurodegenerative disorders, major depression, bipolar disorder, depression with psychotic features, or sleep disorders, comprising administering to a subject exhibiting one or more symptoms of cognitive impairment a therapeutically effective amount of a compound of Formula I:

2. 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.

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

4. 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.

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

6. 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.

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

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

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

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

11. 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.

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

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

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

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

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

17. The method of claim 1, wherein:

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; and

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.

18. The method of claim 17, wherein R₅ is selected from the group consisting of halogen and optionally substituted C_1-6 alkyl.

19. The method of claim 18, wherein R₅ is chloro.

20. The method of claim 17, wherein R₇ is selected from the group consisting of halogen, optionally substituted C_1-6 alkyl, perhaloalkyl, and CN.

21. The method of claim 17, 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-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.

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

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

8-Chloro-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,

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, and

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

23. 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,

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.

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

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.

25. The method of claim 1, wherein:

R₂, R₃, and R₄, are each hydrogen;

R₆, R₇, 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; and

R₈ 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.

26. The method of claim 1, wherein R₅ is selected from the group consisting of halogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 alkyloxy, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted C_1-6-alkoxyalkyl, optionally substituted C_1-6 alkylthio, perhaloalkyl, CN, COR₁₀, CONHR₁₀, NHCONHR₁₀, SO₂NHR₁₀, SO₂R₁₀, OSO₂R₁₀, NO₂, and NHCOR₁₀.