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

• US 20060194784A1
• Filed: 05/03/2006
• Published: 08/31/2006
• 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 7,491,715 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 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.

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

and a compound of claim 1.

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

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

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

9. The composition of claim 8, 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.

10. The composition of claim 9, wherein said antipsychotic agent is selected from the group consisting of a phenothiazine, phenylbutylpiperadine, debenzapine, benzisoxidil, and salt of lithium.

11. The composition of claim 10, wherein said phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®

), mesoridazine (Serentil®

), prochlorperazine (Compazine®

), and thioridazine (Mellaril®

).

12. The composition of claim 10, wherein said phenylbutylpiperadines is selected from the group consisting of haloperidol (Haldol®

), and pimozide (Orap®

).

13. The composition of claim 10, wherein said debenzapine is selected from the group consisting of clozapine (Clozaril®

), loxapine (Loxitane®

), olanzapine (Zyprexa®

) and quetiapine (Seroquel®

).

14. The composition of claim 10, wherein said benzisoxidil is selected from the group consisting of resperidone (Resperidal®

) and ziprasidone (Geodon®

).

15. The composition of claim 10, wherein said salt of lithium is lithium carbonate.

16. The composition of claim 9, 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.

17. The composition of claim 9, 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.

18. The composition of claim 9, wherein said norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.

19. The composition of claim 9, 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.

20. The composition of claim 9, wherein said inverse serotonin 2A agonist is the compound of Formula XIII, or a related analog thereof.

21. The composition of claim 9, where in said serotonin 2A antagonist is the compound of Formula XIV, or a related analog thereof:

22. A method of treating a neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a composition of claim 18.

23. A method of treating a 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.

24. The method of claim 23, wherein said administering step comprises administering said compound of claim 1 and said neuropsychiatric agent nearly simultaneously.

25. The method of claim 23, 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.

26. The method of claim 23, 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.

29. A composition comprising a compound of claim 1 and a neuropsychiatric agent for use in treating a neuropsychiatric disorder.

30. The composition of claim 29, 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.

3. A method of synthesizing a compound of Formula V,

4. 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,