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

• US 7,491,715 B2
• Filed: 05/03/2006
• Issued: 02/17/2009
• Est. Priority Date: 12/22/2003
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Ohlsson, Jörgen, Ek, Fredrik
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US11/417,441
• Publication Number:
  US 20060194784A1
• Time in Patent Office: 1,021 Days
• Field of Search: 514/217, 540/587
• US Class Current: 514/217
• 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 compound having the structure set forth in Formula I:

2. The compound of claim 1, wherein R₇ is selected from the group consisting of fluoro, chloro, and bromo.

3. The compound of claim 1, wherein R₂, R₃, R₄, R₆, R₈, and R₉ are each hydrogen.

4. The compound of claim 3, wherein R₇ 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.

5. The compound of claim 4, wherein R₅ is selected from the group consisting of halogen and optionally substituted C_1-6 alkyl.

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

7. The compound of claim 1, wherein R₂, R₃, R₄, R₆, R₇, and R₉ are each hydrogen.

8. The compound of claim 7, wherein R₈ 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.

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

10. The compound of claim 1, wherein R₈ is selected from the group consisting of halogen, optionally substituted C_1-6 alkyl, perhaloalkyl, and CN.

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

and a compound of claim 1.

12. A method of treating a neuropsychiatric disorder selected from Alzheimer'"'"'s disease, schizophrenia and related idiopathic psychoses, Huntington'"'"'s disease, Tourette'"'"'s syndrome, anxiety, appetite disorders, affective disorders, drug-induced psychoses, psychoses secondary to neurodegenerative disorders, major depression, bipolar disorder, depression with psychotic features, and sleep disorders, comprising administering to a patient a therapeutically effective amount of a compound of claim 1.

13. A method of treating a neuropsychiatric disorder selected from Alzheimer'"'"'s disease, schizophrenia and related idiopathic psychoses, Huntington'"'"'s disease, Tourette'"'"'s syndrome, anxiety, appetite disorders, affective disorders, drug-induced psychoses, psychoses secondary to neurodegenerative disorders, major depression, bipolar disorder, depression with psychotic features, sleep disorders, and psychosis, comprising contacting a therapeutically effective amount of a compound of claim 1 with a patient.

14. The method of claim 12, wherein said neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders, Tourette'"'"'s Syndrome, drug-induced psychoses, and psychoses secondary to neurodegenerative disorders.

15. The method of claim 14, wherein the affective disorders are selected from major depression, bipolar disorder, and depression with psychotic features.

16. The method of claim 14, wherein the neurodegenerative disorders are selected from Alzheimer'"'"'s and Huntington'"'"'s Disease.

17. The method of claim 13, wherein said neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders, Tourette'"'"'s Syndrome, drug-induced psychoses, and psychoses secondary to neurodegenerative disorders.

18. The method of claim 17, wherein the affective disorders are selected from major depression, bipolar disorder, and depression with psychotic features.

19. The method of claim 17, wherein the neurodegenerative disorders are selected from Alzheimer'"'"'s and Huntington'"'"'s Disease.