Claims for Patent: 9,956,227

Summary for Patent: 9,956,227

Title:	Method for the treatment of residual symptoms of schizophrenia
Abstract:	The disclosure provides the use of particular substituted heterocycle fused gamma-carboline compounds as pharmaceuticals for the treatment of residual symptoms of psychosis or schizophrenia. The disclosure also provides novel long acting injectable formulations of particular substituted heterocycle fused gamma-carboline compounds and use of such long acting injectable formulations for the treatment of residual symptoms of psychosis or schizophrenia.
Inventor(s):	Vanover; Kimberly (New York, NY), Li; Peng (New Milford, NJ), Mates; Sharon (New York, NY), Davis; Robert (San Diego, CA), Wennogle; Lawrence P. (Hillsborough, NJ)
Assignee:	INTRA-CELLULAR THERAPIES, INC. (New York, NY)
Application Number:	15/101,874
Patent Claims:	1. A method for the treatment of residual symptoms of schizophrenia as defined in the Positive and Negative Syndrome Scale (PANSS) for Schizophrenia, comprising administering to a patient in need thereof, after treatment of acute symptoms of schizophrenia with an antipsychotic agent, an effective amount of a compound of Formula I: ##STR00015## wherein: X is --O--, --NH-- or --N(CH.sub.3)--; Y is --O--, --C(R.sub.2)(OH)--, --C(R.sub.3)(OR.sub.1) or --C(O)--; and R.sub.1 is --C.sub.1-6alkyl or --C(O)--C.sub.1-21alkyl, optionally saturated or unsaturated and optionally substituted with one or more hydroxyl or C.sub.1-22alkoxy groups wherein such compound hydrolyzes to form the residue of a natural or unnatural, saturated or unsaturated fatty acid; R.sub.2 is H or --C.sub.1-6alkyl; and R.sub.3 is H or --C.sub.1-6alkyl; in free or pharmaceutically acceptable salt form; wherein the patient significantly improves on the Prosocial PANSS Factor change from baseline. 2. The method according to claim 1, wherein the compound of Formula I is a compound wherein: X is --O--, --NH-- or --N(CH.sub.3)--; Y is --O--, --C(H)(OH)--, --C(H)(OR.sub.1) or --C(O)--; and R.sub.1 is --C(O)--C.sub.1-21alkyl, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C.sub.1-22alkoxy groups, wherein such compound hydrolyzes to form the residue of a natural or unnatural, saturated or unsaturated fatty acid, in free or pharmaceutically acceptable salt form. 3. The method according to claim 1, wherein the compound of Formula I is selected from a group consisting of compounds of formula I wherein: X is --O-- and Y is --C(H)(OH)--, X is --NH-- and Y is --C(H)(OH)--, X is --N(CH.sub.3)-- and Y is --C(H)(OH)--, X is --O-- and Y is --C(O)--, X is --O-- and Y is --O--, X is --N(CH.sub.3)-- and Y is --C(O)--, X is --N(CH.sub.3)-- and Y is --O--, X is --NH-- and Y is --C(O)--, X is --NH-- and Y is --O--, X is --N(CH.sub.3)-- and Y is --C(H)(OR.sub.1), X is --NH-- and Y is --C(H)(OR.sub.1), or X is --O-- and Y is --C(H)(OR.sub.1); X is --O-- and Y is --C(CH.sub.3)(OH)--, X is --NH-- and Y is C(CH.sub.3)(OH)--, X is --N(CH.sub.3)-- and Y is C(CH.sub.3)(OH)--. 4. The method of claim 1 wherein X is --N(CH.sub.3)-- and Y is --C(O)-- or --C(H)(OH). 5. The method of claim 1 wherein said residual symptoms are selected from blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation and stereotyped thinking; somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation and active social avoidance; cognitive impairment and sleep disorders. 6. The method of claim 1, further comprising the administration of one or more other therapeutic agents selected from additional antipsychotic agents and/or anti-depressive agents and/or hypnotic agents. 7. The method of claim 6, wherein the one or more other therapeutic agents are selected from compounds that modulate GABA activity, a GABA-B agonist, a 5-HT modulator, a melatonin agonist, an ion channel modulator, a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptor antagonist, an H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug; and antipsychotic agents, in free or pharmaceutically acceptable salt form. 8. The method of claim 6, wherein the one or more other therapeutic agents are selected from a group consisting of modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis, France), repinotan, sarizotan, eptapirone, buspirone, MN-305 (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM.RTM., Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine, lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a benzamide derivative, Org 50081 (Organon-Netherlands), ritanserin, nefazodone, serzone, trazodone, Casopitant (GlaxoSmithKline), amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, velafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, amisulpride, zotepine, and sertindole, in free or pharmaceutically acceptable salt form. 9. The method of claim 6, wherein the administration of the compound of Formula I is adjunct to the administration of the one or more other therapeutic agents. 10. The method of claim 6, wherein the one or more other therapeutic agents are antipsychotic agents selected from chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, amisulpride, zotepine, and sertindole, in free or pharmaceutically acceptable salt form. 11. The method of claim 6, wherein the administration of one or more other therapeutic agents is adjunct to the administration of the compound of Formula I. 12. The method of claim 6, wherein the one or more other therapeutic agents are anti-depressive agents selected from one or more of amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine. 13. The method of claim 6 wherein the one or more other therapeutic agents are anti-depressive agent selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants. 14. The method of claim 13, wherein the anti-depressive agent is a SSRI. 15. The method according to claim 1 wherein the compound of Formula I is administered orally as a composition comprising a pharmaceutically acceptable diluent or carrier as an oral unit dose form that is a tablet, or capsule. 16. The method according to claim 1 wherein the effective amount of the compound of Formula I is a daily dose of about 1 mg to about 140 mg. 17. The method according to claim 1 wherein the effective amount of the compound of Formula I is a daily dose of about 10 mg to about 120 mg. 18. The method according to claim 1 wherein the effective amount of the compound of Formula I is a daily dose of about 20 mg to about 60 mg. 19. The method according to claim 1 wherein the effective amount of the compound of Formula I is a daily dose of about 20 mg, about 40 mg or about 60 mg. 20. The method of claim 1 wherein the patient has not responded adequately to treatment with another antipsychotic agent or combination of antipsychotic agents. 21. The method of claim 20, wherein the patient has not responded to treatment with one or more antipsychotic agents selected from chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, amisulpride, zotepine, and sertindole. 22. The method of claim 21 wherein the patient has not responded to treatment with risperidone. 23. The method according to claim 1 wherein the compound of Formula I is formulated in a sustained or delayed release formulation. 24. The method according to claim 23, wherein the sustained or delayed release formulation is a long-acting injectable microsphere formulation. 25. A method for the treatment of residual symptoms of schizophrenia as defined in the Positive and Negative Syndrome Scale (PANSS) for Schizophrenia, comprising administering, after treatment of acute symptoms of schizophrenia with an antopsychotic agent, to a patient in need thereof a long acting injectable composition comprising a PLGA matrix of 75:25 PLA/PLG with either carboxylic acid or carboxylic acid end groups, and an effective amount of a compound of Formula I: ##STR00016## wherein: X is --O--, --NH-- or --N(CH.sub.3)--; Y is --O--, --C(R.sub.2)(OH)--, --C(R.sub.3)(OR.sub.1) or --C(O)--; and R.sub.1 is --C.sub.1-6alkyl or --C(O)--C.sub.1-21alkyl, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C.sub.1-22alkoxy groups, wherein such compound hydrolyzes to form the residue of a natural or unnatural, saturated or unsaturated fatty acid; R.sub.2 is H or --C.sub.1-6 alkyl; and R.sub.3 is H or --C.sub.1-6 alkyl; in free or pharmaceutically acceptable salt form; wherein the patient significantly improves on the Prosocial PANSS Factor change from baseline.