Selective serotonin receptor inverse agonists as therapeutics for disease

• US 20090155389A1
• Filed: 02/11/2009
• Published: 06/18/2009
• Est. Priority Date: 05/21/2004
• Status: Active Grant

• Current Assignee: David M. Weiner, Mark R. Brann, Robert B. Davis
• Original Assignee: David M. Weiner, Mark R. Brann, Robert B. Davis
• Inventors: Davis, Robert E., Brann, Mark R., Weiner, David M.
• Granted Patent: US 7,875,632 B2
• Time in Patent Office: Days
• US Class Current: 424/715
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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 25/36 Opioid-abuse
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed herein are pharmaceutical compositions comprising an inverse serotonin receptor agonist or a serotonin receptor antagonist and an anti-psychotic agent. Disclosed herein are also methods of treating psychotic disorders using the disclosed pharmaceutical compositions.

Claims

1. A pharmaceutical composition comprising:

a first compound selected from the group consisting of an inverse agonist of a serotonin receptor, an antagonist of a serotonin receptor, and pharmaceutically acceptable salts thereof; and

a second compound selected from the group consisting of a SSRI, a SNRI, a MAO-I, a TCA, an antipsychotic agent, a norepinephrine reuptake inhibitor, a dopamine agonist, an anti-insomnia drug, an anti-manic drug, an anti-phobia drug, the compound of Formula (II)

2. The pharmaceutical composition of claim 1 wherein the serotonin receptor is a 5HT2A receptor.

3. The pharmaceutical composition of claim 2 wherein the first compound is a compound of Formula (I):

4. The pharmaceutical composition of claim 2 wherein the first compound is a compound of Formula (II):

5. The pharmaceutical composition of claim 1 wherein the SSRI is selected from the group consisting of bupropion (Wellbutrin, Zyban), citalopram (Celexa), duloxetine, escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), nefazodone (Serzone), paroxetine (Paxil), sertaline (Zoloft), sibutramine, trazodone (Dividose), and venlafaxine.

6. The pharmaceutical composition of claim 1 wherein the SNRI is selected from the group consisting of citalopram (Celexa), dulexetine, escitalopram (Lexapro), fluvoxamine (Luvox), and venfalaxine (effexor).

7. The pharmaceutical composition of claim 1 wherein the MAO-I is selected from the group consisting of tranylcypromine (Pamate), phenelzine (Nardil), maprotiline, and isocarboxazid (Marplan).

8. The pharmaceutical composition of claim 1 wherein the TCA is selected from the group consisting of amitryptiline (Norpramine), amoxapineclomipramine (Anafranil), desipramine, doxepin (Sinequan), imipramine (Tofranil), maprotiline, (Elavil), protryptiline, and trimipramine.

9. The pharmaceutical composition of claim 1 wherein the antipsychotic agent is selected from the group consisting of a phenothiazine, a phenylbutylpiperadine, a debenzapine, a benzisoxidil, and a salt of lithium.

10. The pharmaceutical composition of claim 9 wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®

), mesoridazine (Serentil®

), prochlorperazine (Compazine®

), and thioridazine (Mellaril®

).

11. The pharmaceutical composition of claim 9 wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®

) and pimozide (Orap®

).

12. The pharmaceutical composition of claim 9 wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®

), loxapine (Loxitane®

), olanzapine (Zyprexa®

), and quetiapine (Seroquel®

).

13. The pharmaceutical composition of claim 9 wherein the benzisoxidil is selected from the group consisting of resperidone (Resperidal®

) and ziprasidone (Geodon®

).

14. The pharmaceutical composition of claim 9 wherein the salt of lithium is lithium carbonate.

15. The pharmaceutical composition of claim 1 wherein the antipsychotic agent is selected from the group consisting of Aripiprazole (Abilify), Etrafon Haldol, Inapsine, Mellaril, Moban, Navane, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Stelazine, Taractan, Triavil, and Trilafon.

16. The pharmaceutical composition of claim 1 wherein the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.

17. The pharmaceutical composition of claim 1 wherein the dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.

18. The pharmaceutical composition of claim 1 wherein the anti-insomnia drug is selected from the group consisting of alprazolam (Xanax), chlordiazepoxide (Librium, Limbitrol), clorazepate (Tranxene), estazolam (ProSom), flurazepam (Dalmane), hydroxyzine (Atarax), lorazepam (Ativan), pentobarbital (Nembutal), quazepam (Doral), secobarbital (Seconal), temazepam (Restoril), triazolam (Halcion), valium, zaleplon (Sonata), zolpidem (Ambien), and the benzodiazepine family of drugs.

19. The pharmaceutical composition of claim 1 wherein the anti-manic drug is selected from the group consisting of divalproex (Depakote), lithium carbonate (Eskalith), and lithium citrate.

20. The pharmaceutical composition of claim 1 wherein the anti-phobia drug is D-cycloserine.

21. The pharmaceutical composition of claim 1, further comprising physiologically acceptable carrier, diluent, or excipient, or a combination thereof.

22. The pharmaceutical composition of claim 1 wherein the first compound is the compound of Formula (I):

31. The pharmaceutical composition of claim 1 wherein the SNRI is selected from the group consisting of citalopram (Celexa), dulexetine, escitalopram (Lexapro), fluvoxamine (Luvox), and venfalaxine (effexor).

23. A method of treating a disorder in a patient, the disorder selected from the group consisting of depression, mania, social phobia, psychosis, and a neuropsychiatric disorder, the method comprising:

identifying a patient in need of said treatment, and

administering to said patient a therapeutically effective amount of a combination of a first compound and a second compound, the first compound selected from the group consisting of an inverse agonist of a serotonin receptor, an antagonist of a serotonin receptor, and pharmaceutically acceptable salts thereof, the second compound selected from the group consisting of a SSRI, a SNRI, a MAO-I, a TCA, an antipsychotic agent, a norepinephrine reuptake inhibitor, a dopamine agonist, an anti-insomnia drug, an anti-manic drug, an anti-phobia drug, the compound of Formula (II)

24. The method of claim 23 wherein the 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.

25. The method of claim 24 wherein said affective disorders is selected from the group consisting of major depression, bipolar disorder, and depression with psychotic features.

26. The method of claim 24 wherein said neurodegenerative disorders are selected from the group consisting of Alzheimer'"'"'s and Huntington'"'"'s Disease

27. The method of claim 23 wherein the serotonin receptor is a 5HT2A receptor.

28. The method of claim 27 wherein the first compound is a compound of Formula (I):

29. The method of claim 27 wherein the first compound is a compound of Formula (II):

30. The method of claim 23 wherein the SSRI is selected from the group consisting of bupropion (Wellbutrin, Zyban), citalopram (Celexa), duloxetine, escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), nefazodone (Serzone), paroxetine (Paxil), sertaline (Zoloft), sibutramine, trazodone (Dividose), and venlafaxine.

32. The method of claim 23 wherein the MAO-I is selected from the group consisting of tranylcypromine (Parnate), phenelzine (Nardil), maprotiline, and isocarboxazid (Marplan).

33. The method of claim 23 wherein the TCA is selected from the group consisting of amitryptiline (Norpramine), amoxapineclomipramine (Anafranil), desipramine, doxepin (Sinequan), imipramine (Tofranil), maprotiline, (Elavil), protryptiline, and trimipramine.

34. The method of claim 23 wherein the antipsychotic agent is selected from the group consisting of a phenothiazine, a phenylbutylpiperadine, a debenzapine, a benzisoxidil, and a salt of lithium.

35. The method of claim 34 wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®

), mesoridazine (Serentil®

), prochlorperazine (Compazine®

), and thioridazine (Mellaril®

).

36. The method of claim 34 wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®

) and pimozide (Orap®

).

37. The method of claim 34 wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®

), loxapine (Loxitane®

), olanzapine (Zyprexa®

), and quetiapine (Seroquel®

).

38. The method of claim 34 wherein the benzisoxidil is selected from the group consisting of resperidone (Resperidal®

) and ziprasidone (Geodon®

).

39. The method of claim 34 wherein the salt of lithium is lithium carbonate.

40. The method of claim 23 wherein the antipsychotic agent is selected from the group consisting of Aripiprazole (Abilify), Etrafon Haldol, Inapsine, Mellaril, Mob an, Navane, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Stelazine, Taractan, Triavil, and Trilafon.

41. The method of claim 23 wherein the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.

42. The method of claim 23 wherein the dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.

43. The method of claim 23 wherein the anti-insomnia drug is selected from the group consisting of alprazolam (Xanax), chlordiazepoxide (Librium, Limbitrol), clorazepate (Tranxene), estazolam (ProSom), flurazepam (Dalmane), hydroxyzine (Atarax), lorazepam (Ativan), pentobarbital (Nembutal), quazepam (Doral), secobarbital (Seconal), temazepam (Restoril), triazolam (Halcion), valium, zaleplon (Sonata), zolpidem (Ambien), and the benzodiazepine family of drugs.

44. The method of claim 23 wherein the anti-manic drug is selected from the group consisting of divalproex (Depakote), lithium carbonate (Eskalith), and lithium citrate.

45. The method of claim 23 wherein the anti-phobia drug is D-cycloserine.

46. The method of claim 23 wherein the disorder is depression, the first compound is the compound of Formula (I):