Novel methods

Abstract

To provide methods for the treatment of residual symptoms such as active social avoidance, passive social withdrawal, emotional withdrawal, anxiety, tension, stereotyped thinking, and somatic concerns.SOLUTION: The present invention provides a method for the treatment of residual symptoms, comprising administering to a patient in need thereof an effective amount of the following compound, for example.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Application No. 61 / 911,416, filed December 3, 2013; U.S. Provisional Application No. 61 / 925,607, filed January 9, 2014; U.S. Provisional Application No. 61 / 975,702, filed April 4, 2014; and U.S. Provisional Application No. 62 / 032,326, filed August 1, 2014 (each of which is incorporated herein by reference in its entirety).

[0002] The present invention relates to the use of certain substituted heterocyclic fused γ-carbolines as described herein in free or pharma- ceutical acceptable salt form as medicaments and compositions as primary or adjunctive treatment in the treatment of acute and residual phases of schizophrenia, specifically including the treatment of residual symptoms such as active social avoidance, passive withdrawal, emotional withdrawal, anxiety, tension, stereotypic thinking, and somatic concerns. The compounds described herein may be used to treat both acute and residual symptoms that emerge during acute exacerbations but define the residual phase of the illness (e.g., schizophrenia) once the acute symptoms subside. Thus, the compounds described herein may be used alone or in combination with other antipsychotics and other active agents treating co-morbid disorders such as depression and / or sleep disorders. The compounds described herein may be used to improve social integration and social functioning, as the response profile beyond symptoms associated with schizophrenia may be particularly beneficial for improving social functioning. Such a response profile may be beneficial for the prodromal, exacerbation, and residual phases. [Background technology]

[0003] Mental disorders, particularly schizophrenia, affect 1.1% of the world's population. The disease includes three stages: prodromal, active, and residual. The prodromal stage is the early stage where asymptomatic signs and symptoms are present. These symptoms can include loss of interest in everyday pursuits, withdrawal from friends and family, confusion, impaired concentration, and feelings of low energy and emotional blunting. The active stage is characterized by an exacerbation of positive symptoms such as delusions, hallucinations, and suspiciousness. The residual stage is characterized by negative symptoms such as emotional withdrawal, passive withdrawal, and stereotypic thinking, as well as symptoms of generalized psychopathology that include active social avoidance, anxiety, tension, and somatic concerns. Residual symptoms are often accompanied by depression, cognitive impairment, and insomnia. Collectively, these residual symptoms are not adequately treated by many of the antipsychotic drugs currently on the market, and are usually observed after the active symptoms have subsided following treatment. This stage of the disease is when patients want to return to a richer and more fulfilling life, but this goal is hindered because residual negative symptoms and cognitive impairment are not properly treated. Still, there is an urgent need for antipsychotic drugs that can treat not only the active or acute symptoms of psychosis (e.g., schizophrenia) but also the residual symptoms.

[0004] Substituted heterocycle-fused γ-carbolines have been shown to activate the 5-HT2 receptor, particularly the 5-HT 2A Receptors and 5-HT 2C These compounds are known to be agonists or antagonists of the 5-HT receptor. These compounds are disclosed in U.S. Patent No. 5,393,636, ... 2AIt has been disclosed as a medical use for the treatment of disorders related to receptor modulation. Patent Documents 9 and 10 also disclose a method for preparing substituted heterocycle-fused γ-carbolines and the use of these γ-carbolines as serotonin agonists and antagonists useful for controlling and preventing central nervous system disorders such as addictive behaviors and sleep disorders.

[0005] In addition, U.S. Patent No. 5,393,636, U.S. Patent No. 5,433,363, U.S. Patent No. 5,433,665 ... and U.S. Patent No. 5,433,665 disclose further substituted heterocyclic fused γ-carboline compounds and / or 5-HT 2A The present invention teaches the use of the compounds for the treatment of one or more disorders in which the serotonin transporter (SERT) and / or dopamine D1 / D2 pathways are implicated.

[0006] Although the above-mentioned documents relating to substituted heterocycle-fused γ-carboline compounds teach the treatment of certain disorders related to psychosis and / or depression, these documents make no disclosure regarding the treatment of residual symptoms of psychosis, particularly residual symptoms of schizophrenia. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 6,548,493 [Patent Document 2] U.S. Patent No. 7,238,690 [Patent Document 3] U.S. Patent No. 6,552,017 [Patent Document 4] U.S. Patent No. 6,713,471 [Patent Document 5] U.S. Reissue Patent No. 39680 [Patent Document 6] U.S. Reissue Patent No. 39679 [Patent Document 7] U.S. Patent No. 7,183,282 [Patent Document 8] U.S. Patent No. 7,071,186 [Patent Document 9] International Patent Application No. PCT / US08 / 03340 [Patent Document 10] U.S. Patent Application No. 10 / 786935 [Patent Document 11] International Publication No. 2009 / 145900 [Patent Document 12] International Publication No. 2011 / 133224 [Patent Document 13] International Publication No. 2013 / 155505 [Patent Document 14] International Publication No. 2013 / 155504 [Patent Document 15] International Publication No. 2013 / 155506 Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention We have now discovered that certain substituted heterocycle-fused γ-carboline compounds (compounds shown below) have a mechanism of action that we believe may provide a first-in-class antipsychotic therapy. Compounds of formula I are potent serotonin 5-HT 2AIt is a single drug candidate for the treatment of acute and residual schizophrenia, combining receptor antagonism, dopamine receptor phosphoprotein modulation, or DPPM, glutamatergic modulation and serotonin reuptake inhibition. At the dopamine D2 receptor, the compound of formula I has dual properties, acting as both a postsynaptic antagonist and a presynaptic partial agonist. The compound of formula I also stimulates phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors in a mesolimbic-specific manner. It is believed that this regional selectivity in brain regions thought to mediate the efficacy of antipsychotic drugs, together with serotonergic, glutamatergic and dopaminergic interactions, may result in antipsychotic effects for the positive, negative, affective and cognitive symptoms associated with schizophrenia. Serotonin reuptake inhibition may enable antidepressant activity for the treatment of schizoaffective disorder and comorbid depression, and / or as a standalone treatment for major depressive disorder. It is believed that the compounds of formula I may also be useful in the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disorders associated with dementia, autism, and other CNS diseases. These characteristics of the compounds of formula I may allow for an improvement in the quality of life of patients with schizophrenia, improving social functioning and allowing patients to be more fully integrated into their families and workplaces. In addition, the compounds of formula I may be indicated for treating disorders at low doses (e.g., sleep, aggression, and agitation) or at high doses (e.g., acute exacerbation and residual schizophrenia, bipolar disorder, and mood disorders).

[0009] Since the compounds described below are effective in treating not only acute symptoms of psychosis but also residual symptoms, the present invention in one aspect provides a method for using certain substituted heterocycle-fused γ-carboline compounds (the compounds described below) alone or as adjunctive therapy for the treatment of residual symptoms of psychosis (particularly schizophrenia), which is a novel and unexpected utility.

[0010] Thus, the present invention provides a method for treating residual symptoms, comprising administering to a patient in need of treatment for said symptoms a compound of formula I, in free form or in pharma- ceutical acceptable salt form: [ka] [In the formula, X is -O-, -NH- or -N(CH3)-; Y is -O-, -C(R2)(OH)-, -C(R3)(OR1) or -C(O)-; R1 is C 1-6 alkyl (e.g., methyl) or, for example, -C(O)-C 1-21 Alkyl (e.g., -C(O)-C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 For example, R1 is selected from -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15 alkyl, for example, the compound is hydrolyzed to provide a natural or unnatural saturated or unsaturated fatty acid of formula R1-OH and a compound of formula 1, where Y is -C(R2)(OH)-, for example, the compound is hydrolyzed to form, on the one hand, a hydroxy compound of formula I, where Y is -C(R2)(OH)-, and on the other hand, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid; R2 is H or -C 1-6 alkyl (e.g., methyl); R3 is H or -C 1-6 alkyl (e.g., methyl); For example, herein, "alkyl" may be saturated or unsaturated and may contain one or more hydroxy or C 1-22 A straight-chain hydrocarbon group which may be substituted with an alkoxy (e.g., ethoxy) group. The present invention is directed to a method (Method A) comprising administering an effective amount of a compound represented by the formula:

[0011] In a further embodiment, the compound of formula I of method A is X is -O-, -NH- or -N(CH3)-; Y is -O-, -C(H)(OH)-, -C(H)(OR1) or -C(O)-; R1 is a physiologically hydrolyzable and tolerated acyl, e.g., -C(O)-C 1-21 Alkyl (e.g., -C(O)-C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 For example, R1 is selected from -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15 alkyl, for example, which hydrolyzes to provide natural or unnatural saturated or unsaturated fatty acids represented by R1-OH and compounds of formula I, where Y is -C(R2)(OH)-, for example, which hydrolyzes to form, on the one hand, hydroxy compounds of formula I, where Y is -C(R2)(OH)-, and on the other hand, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid; For example, herein, "alkyl" may be saturated or unsaturated and may contain one or more hydroxy or C 1-22 refers to a straight-chain hydrocarbon group which may be substituted with an alkoxy (e.g., ethoxy) group; The compound is in free form or in a pharma- ceutically acceptable salt form.

[0012] In another embodiment, the patient of method A suffers from residual psychosis, such as schizophrenia (e.g., residual subtype), delusional disorder (e.g., somatic type), major depression with psychosis, bipolar disorder with psychotic symptoms, brief psychosis, schizophreniform disorder, schizoaffective disorder, or residual psychosis caused by medical condition or substance use.Preferably, the patient suffers from residual schizophrenia.

[0013] In another further embodiment, residual symptoms include negative symptoms, such as blunted affect, emotional withdrawal, poor rapport, passive or apathetic social withdrawal, abstract thinking difficulties, loss of spontaneity and conversation flow, and stereotyped thinking; general psychopathology symptoms, such as physical concerns, anxiety, guilt, tension, mannerisms and unnatural posturing, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, poor attention, poor judgment and insight, impaired willpower, poor impulse control, preoccupation and active social avoidance; cognitive impairment and sleep disorder (e.g., insomnia).In certain embodiments, Method A treats residual symptoms (negative symptoms, effective symptoms and cognitive symptoms) associated with schizophrenia.

[0014] In another further embodiment, the effective amount of the compound represented by formula I is about 1 mg to about 140 mg / administration / day, in another embodiment, about 2.5 mg to about 120 mg / administration / day, in another embodiment, about 10 mg to about 120 mg / administration / day, in another embodiment, about 60 mg to about 120 mg / administration / day, in yet another embodiment, about 10 mg to about 60 mg / administration / day, in another embodiment, about 20 mg to about 60 mg / administration / day, in yet another embodiment, about 20 mg, about 40 mg or about 60 mg / administration / day. The compounds of the present invention are effective in treating positive symptoms occurring during the active or acute phase of psychosis (e.g., effective in treating positive symptoms such as delusions and hallucinations), and are also effective in treating negative symptoms and other residual symptoms commonly seen in the residual phase. Preferably, the effective amount for treating acute and residual symptoms of schizophrenia is about 60 mg / day. In certain embodiments, the dosages described herein for oral administration are based on the amount of the compound of Formula I in acid addition salt form, particularly the toluenesulfonic acid addition salt form.

[0015] Accordingly, the present invention provides a method as follows: 1.1 Method A comprising a compound of formula I, wherein X is -N(CH3); 1.2 Method A, comprising a compound of formula I, where X is -NH; 1.3 Method A comprising a compound of formula I where X is O; 1.4 Any of method A or 1.1-1.3 comprising a compound of formula I where Y is -C(O)-; 1.5 Any of Method A or 1.1-1.3 comprising a compound of Formula I where Y is -O-; 1.6 Any of Method A or 1.1-1.3 comprising a compound of Formula I where Y is -C(R2)(OH)-, e.g., -C(H)(OH)-; 1.7 Any of Method A or 1.1-1.3 comprising a compound of Formula I where Y is -C(R3)(OR1), e.g., -C(H)(OR1); 1.8 R1 is -C(O)-C 1-21 Alkyl (e.g., -C(O)-C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 alkyl), preferably the alkyl is linear, may be saturated or unsaturated, and contains one or more hydroxy or C 1-22 It may be substituted with an alkoxy (e.g., ethoxy) group, for example, R1 may be -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15 alkyl, Method A or Formula 1.7 (wherein the compound is hydrolyzed to form the residue of a natural or unnatural saturated or unsaturated fatty acid, e.g., the compound is hydrolyzed to form a hydroxy compound on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other); 1.9 R1 is -C(O)-C 6-15alkyl, e.g., -C(O)-C9 alkyl, method A or formula 1.7; 1.10 R1 is -C(O)-C 1-5 alkyl, e.g., -C(O)-C3 alkyl, method A or formula 1.7;

[0016] 1.11 R1 is -C 1-6 alkyl (e.g., methyl), Method A or Formula 1.7; 1.12 R2 is H or -C 1-6 alkyl (e.g., methyl), Method A or Formulas 1.1-1.11; 1.13 Method A or formulas 1.1-1.11, where R2 is H; 1.14 R2 is -C 1-6 alkyl (e.g., methyl), Method A or Formulas 1.1-1.11; 1.15 R3 is H or -C 1-6 alkyl (e.g., methyl), Method A or Formulas 1.1-1.11; 1.16 Method A or formulas 1.1-1.11, where R3 is H; 1.17 R3 is -C 1-6 alkyl (e.g., methyl), Method A or Formulas 1.1-1.11; 1.18 Compounds of formula I X is -O- and Y is -C(H)(OH)-; or X is -NH- and Y is -C(H)(OH)-; or X is -N(CH3)- and Y is -C(H)(OH)-; or X is -O- and Y is -C(O)-, or X is -O- and Y is -O-; or X is -N(CH3)- and Y is -C(O)-; or X is -N(CH3)- and Y is -O-; or X is -NH- and Y is -C(O)-; or X is -NH- and Y is -O-; or X is -N(CH3)- and Y is -C(H)(OR1); X is -NH- and Y is -C(H)(OR1); X is -O- and Y is -C(H)(OR1), or X is -O- and Y is -C(CH3)(OH)-; or X is -NH- and Y is C(CH3)(OH)-, or X is -N(CH3)- and Y is C(CH3)(OH)- Any of the above methods, wherein the compound is selected from the group consisting of a compound of formula I: 1.19 Any of the above processes, wherein in the compound of formula I, X is -O- and Y is -C(O)-; 1.20 Any of the above processes, wherein in the compound of formula I, X is -NH- and Y is -C(H)(OH)-;

[0017] 1.21 Any of the above processes, wherein in the compound of formula I, X is -N(CH3)- and Y is -C(H)(OH)-; 1.22 Any of the above processes, wherein in the compound of formula I, X is -O- and Y is -C(O)-; 1.23 Any of the above processes, wherein in the compound of formula I, X is -O- and Y is -O-; 1.24 Any of the above processes, wherein in the compound of formula I, X is -N(CH3)- and Y is -C(O)-; 1.25 Any of the above processes, wherein in the compound of formula I, X is -O- and Y is -C(H)(OH)-; 1.26 Any of the above processes, wherein in the compound of formula I, X is -NH- and Y is -C(H)(OH)-; 1.27 Any of the above processes, wherein in the compound of formula I, X is -N(CH3)- and Y is -C(H)(OH)-; 1.28 In the compound of formula I, X is -N(CH3)-, Y is -C(H)(OR1) and R1 is -C(O)-C 1-21 Any of the above methods wherein is alkyl; 1.29 In the compound of formula I, X is -N(H)-, Y is -C(H)(OR1), and R1 is -C(O)-C 1-21 Any of the above methods wherein is alkyl; 1.30 In the compound of formula I, X is -O-, Y is -C(H)(OR1), and R1 is -C(O)-C 1-21 Any of the above methods wherein is alkyl;

[0018] 1.31 The compound of formula I has the formula IA: [ka] Any of the above methods, wherein the compound is 1.32 The compound of formula I has the formula IB: [ka] Any of the above methods, wherein the compound is 1.33 The compound of formula I has the formula IC: [ka] Any of the above methods, wherein the compound is 1.34 The compound of formula I has the formula ID: [ka] Any of the above methods, wherein the compound is a compound represented by the formula: 1.35 The compound of formula I has the formula IE: [ka] Any of the above methods, wherein the compound is a compound represented by the formula: 1.36 The compound of formula I is represented by the formula IF: [ka] Any of the above methods, wherein the compound is 1.37 The compound of formula I has the formula IG: [ka] Any of the above methods, wherein the compound is 1.38 Any of the above methods, wherein the compound of formula I is administered orally, e.g., in tablet or capsule form, e.g., once daily in a single daily dose or twice daily in divided doses. 1.39 An effective amount of a compound of formula I is an oral daily dose of 10 to 120 mg / day, e.g., a compound of formula IE: [ka] any of the above methods, wherein the compound is a p-toluenesulfonic acid addition salt of about 60 mg; 1.40 Compounds of formula I are administered as sustained release injectable dosage forms, e.g., as injectable depot dosage forms, e.g., once or twice a month, e.g., in the form of bioerodible microparticles, e.g., compounds of formula IE: [ka] Any of the above methods, wherein the compound is

[0019] 1.41 Any of the above methods comprising administering a sustained release injectable formulation of a compound of formula I, e.g., composition 2, e.g., any of composition 2.1, et seq.; 1.42 Any of the above methods further comprising administering one or more other therapeutic agents, such as an additional antipsychotic and / or antidepressant and / or hypnotic; 1.43 The one or more other therapeutic agents may be an antidepressant, a GABA-B receptor agonist, a 5-HT modulator (e.g., a 5-HT 1A Receptor agonist, 5-HT 2A Receptor antagonist, 5-HT 2Amethod 1.38, wherein the therapeutic agent is selected from: an antipsychotic, such as an atypical antipsychotic; a serotonin receptor inverse agonist, a melatonin receptor agonist, an ion channel modulator (e.g., a blocker), a serotonin-2 receptor antagonist / reuptake inhibitor (SARI), an orexin receptor antagonist, an H3 receptor agonist, a noradrenergic receptor antagonist, a galanin receptor agonist, a CRH receptor antagonist, a human growth hormone, a growth hormone receptor agonist, an estrogen, an estrogen receptor agonist, a neurokinin 1 drug; and an antipsychotic, such as an atypical antipsychotic; 1.44 Method 1.42 or 1.43, wherein the one or more other therapeutic agents are an antipsychotic, e.g., chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetirapine, risperidone, ziprasidone, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, amisulpride, zotepine, sertindole, and the one or more other therapeutic agents are administered as an adjunct to a compound of Formula I or a compound of Formula I is an adjunct to the one or more other therapeutic agents; 1.45 Any of the above methods, wherein the effective amount is 1 mg to 120 mg / day, or 10 mg to 120 mg / day, or 10 mg to 60 mg / day, or 10 mg to 40 mg / day, or 1 mg to 10 mg / day, or 10 mg / day, 20 mg / day, 40 mg / day or 60 mg / day; in certain embodiments, the effective amount of the compound of formula I described in this formulation is based on the amount of the compound of formula I in an acid addition salt, non-prodrug form, e.g., a toluenesulfonic acid addition salt, non-prodrug form; 1.46 Method A or any of 1.38-1.45, wherein the one or more other therapeutic agents is an antidepressant, e.g., one or more antidepressants selected from selective serotonin reuptake inhibitors (SSRIs) (e.g., selected from citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, dapoxetine), serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., selected from venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, sibutramine), and tricyclic antidepressants; triple reuptake inhibitors, anxiolytics, buspirone, and trazodone; 1.47 Method 1.45, wherein a compound of Formula I is administered as an adjunct to one or more other therapeutic agents, such as an SSRI antidepressant, or the SSRI antidepressant is administered as an adjunct to a compound of Formula I; 1.48 The method of 1.47, wherein said one or more antidepressants are selected from SSRIs such as citalopram (Celexa, Cipramil, Emocal, Sepram, Seropram), escitalopram oxalate (Lexapro, Cipralex, Esertia), fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR)), fluvoxamine maleate (Luvox, Faberline), paroxetine (Paxil, Seroxat, Alopax, Deloxat, Paroxat), sertraline (Zoloft, Rustral, Serlain), dapoxetine, in free form or a pharma- ceutically acceptable salt form; 1.49 Any of the above methods, wherein the compound of formula I is administered as part of a sustained release injectable microsphere composition; 1.50 The method of 1.49, wherein the sustained release injectable microsphere composition is a composition according to any one of 2.1 to 2.22 below.

[0020] In certain embodiments of Method A below, the patient is a patient who has not responded or has not responded adequately to treatment with another antipsychotic drug, such as chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetirapine, risperidone, ziprasidone, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, amisulpride, zotepine, sertindole.Thus, the compound of formula I can be administered as a primary therapy or an adjunct therapy, for example, as an adjunct to another antipsychotic drug.

[0021] In another embodiment, the present invention provides a method for treating any of the following disorders (Method B), comprising administering to a patient in need of treatment an effective amount of a compound of formula I in free form or in pharma- ceutically acceptable salt form: schizoaffective disorder, comorbid depression, major depressive disorder, bipolar disorder (e.g., bipolar I and / or bipolar II), autism spectrum disorder (e.g., autistic disorder, Asperger's disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), Rett's disorder (Rett's syndrome), childhood disintegrative disorder). In a particular embodiment, the disorder of Method B is bipolar disorder (e.g., bipolar I and / or bipolar II). In another particular embodiment, the disorder of Method B is autism spectrum disorder. In yet another particular embodiment, the disorder of Method B is major depressive disorder.

[0022] Thus, depending on the combination of disorders to be treated, the compounds of formula I can be used strategically. For example, at low doses (e.g., 1-10 mg of the compound of formula I in toluenesulfonic acid addition salt form, e.g., 1 mg, 5 mg and 10 mg oral daily doses), the compounds of formula I are useful for treating sleep disorders, aggression and agitation, Alzheimer's disease and other dementias, autism spectrum disorders, Parkinson's disease and intermittent explosive disorder (IED). At high doses (e.g., 60 mg of the compound of formula I in toluenesulfonic acid addition salt form, oral daily doses), the compounds of formula I are useful for treating acute exacerbation and residual schizophrenia, bipolar depression, major depressive disorder, generalized anxiety disorder. At very high doses (e.g., 120 mg of the compound of formula I in toluenesulfonic acid addition salt form, oral daily doses), morning administration can produce somnolence / sedation. Thus, at such high daily doses, nighttime administration is preferred.

[0023] The compounds of formula I may exist in free form or in salt form, for example as an acid addition salt. In this specification, unless otherwise specified, terms such as "compounds of formula I", "antipsychotics", "antidepressants", "other therapeutic agents" and similar terms should be understood to include the compounds in any form, for example, in free form or in acid addition salt form, or in base addition salt form if the compound contains an acidic substituent. The compounds of formula I are used as medicines, and therefore pharma- ceutically acceptable salts are preferred. Salts that are not suitable for pharmaceutical use may be useful, for example, for the isolation or purification of the free compounds of formula I or their pharma- ceutically acceptable salts, and therefore are also included. Pharmaceutically acceptable salts include, for example, hydrochloride, mesylate and tosylate. Preferably, the compounds of formula I, particularly those compounds of formula I where X is -N(CH3)- and Y is -C(O)-, are in the form of tosylate (toluenesulfonic acid addition salt). When the dosage of salt is indicated by weight, for example mg / day or mg / unit dose, the dosage of said salt can be based on the weight of corresponding free base, or as otherwise indicated.In certain embodiments, the dosage of the compound of formula I for oral administration in acid addition salt form is based on the weight of toluenesulfonic acid addition salt form, not the free base form.For example, in certain embodiments, the dosage of 10mg, 60mg and 120mg of the compound of formula I for oral administration is based on 10mg, 60mg and 120mg of the compound of formula I for oral administration in toluenesulfonic acid addition salt form, respectively, not the amount of free base.For example, the dosage of 60mg of the compound of formula I for oral administration in toluenesulfonic acid addition salt form (for example, X is -N(CH3)- and Y is -C(O)-) refers to the compound of tosylate, which is equivalent to about 41.7mg of the compound of free base form.

[0024] The invention also provides methods, e.g., Method A, e.g., any of 1.1 to 1.50, and Method B, as described above, wherein a compound of formula I, in free form or in pharma- ceutically acceptable salt form, is administered in a composition, wherein the compound of formula I, in free form or in pharma- ceutically acceptable salt form, is in admixture or association with a pharma- ceutically acceptable diluent or carrier.

[0025] In certain embodiments, the present invention also provides the above methods, e.g., Method A, e.g., any of 1.1-1.50, and Method B, wherein the compound of Formula I, in free form or in a pharma- ceutically acceptable salt form, is administered in an immediate release formulation or an extended or delayed release formulation, e.g., a depot formulation.

[0026] In one embodiment, the sustained or delayed release formulation comprises a compound of formula I as described herein (e.g., a compound of formula I or any of formulas 1.1-1.50) in a polymer matrix. In another embodiment, the compound of formula I is dispersed or dissolved in the polymer matrix. In a further embodiment, the polymer matrix comprises a polymer selected from standard polymers used in depot formulations, such as polyesters of hydroxy fatty acids and their derivatives, or polymers of α-alkyl cyanoacrylates, polyalkylene oxalates, poly(ortho)esters, polycarbonates, polyorthocarbonates, polyamino acids, hyaluronic acid esters, and mixtures thereof. In a further embodiment, the polymer is selected from the group consisting of polylactide, poly d,l-lactide, polyglycolide, PLGA50:50, PLGA75:25, PLGA85:15, and PLGA90:10 polymers. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers thereof, poly(aliphatic carboxylic acid), copolyoxalate, polycaprolactone, polydioxonone, poly(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoester, poly(glycolic acid-caprolactone), polyanhydride, and natural polymers including albumin, casein and wax, such as glycerol monostearate and glycerol distearate, and the like.In a particular embodiment, the polymer matrix comprises poly(d,l-lactide-co-glycolide).The compound of formula I in the polymer matrix may be mixed or blended with a pharmaceutically acceptable diluent or carrier.

[0027] Such sustained or delayed release formulations are particularly useful for sustained or delayed release, where the compound of formula I is released after the degradation of the polymer matrix. These formulations can release the compound of formula I for up to 180 days, for example, from about 14 days to about 30 days to about 180 days. For example, the polymer matrix can degrade and release the compound of formula I for about 30 days, about 60 days, or about 90 days. In another example, the polymer matrix can degrade and release the compound of formula I for about 120 days or about 180 days.

[0028] In yet another embodiment, a sustained or delayed release formulation is formulated for administration by injection.

[0029] For example, the present invention provides a sustained release injectable (LAI) formulation of the compound of formula I. Such LAI formulations can be optimized with respect to carrier composition, particle size, carrier molecular weight, active ingredient loading, and dosage, for example as described in the Examples. In addition to ensuring convenient administration and patient compliance, the LAI formulation of the compound of formula I unexpectedly provides benefits with respect to pharmacokinetics and side effects. When the compound of formula I is administered using an LAI formulation, in contrast to oral dosage forms, first-pass metabolism in the liver is avoided, which means that a lower proportion of the compound of formula I is metabolized before reaching the brain. The sustained release or delayed release formulations described herein generally have fewer extrapyramidal side effects, are better tolerated, and require a lower total dose than the corresponding immediate release formulations. The sustained release or delayed release formulations, particularly the sustained release injectable formulations, are capable of achieving and maintaining a therapeutically effective amount of the drug in the CNS of the patient, despite administering a total dose that is much lower than the total dose required to achieve the same body level of the drug using an immediate release oral formulation. For long-acting injectable formulations, in particular, this advantage is due in part to the avoidance of first-pass metabolism that occurs with oral administration, including sustained or delayed release oral administration.

[0030] Therefore, it is understood that the effective amount of the compound of formula I when administered as a sustained release injectable formulation is much less than the effective amount when administered orally, for example, about 100 mg / month to about 600 mg / month, preferably 150 mg / month to 300 mg / month.

[0031] Thus, in certain embodiments, the present invention provides a sustained release injectable formulation comprising polymeric microspheres, the microspheres comprising: a poly(D,L-lactide-co-glycolide) polymer (PLGA) polymer matrix, and an effective amount of a compound of formula I, as described herein above, in free form or in pharma- ceutical acceptable salt form, wherein the compound of formula I is dispersed, dissolved or encapsulated in a polymer matrix; The present invention provides a sustained-release injectable formulation (Composition 2) comprising:

[0032] For example, the present invention provides: 2.1 Composition 2, in which the PLGA polymer is about 75:25 PLA / PLG with either carboxylic acid or carboxylic ester end groups. 2.2 Composition 2 or 2.1, wherein the PLGA polymer is about 75:25 PLA / PLG with carboxylic acid ester end groups. 2.3 Compositions 2, 2.1 or 2.2, wherein the compound of formula I is in free base form. 2.4 Any of the above compositions wherein the compound of formula I is selected from compounds of formula IA, IB, IC, ID and IE. 2.5 When the compound of formula I is a compound of formula IE, for example in free base form: [ka] Any of the above compositions, wherein the compound is 2.6 The compound of formula I may have the formula ID: [ka] Any of the above compositions, wherein the compound is 2.7 Any of the above compositions, wherein the average molecular weight range of the PLGA polymer is, for example, 20 kD to 200 kD, such as 24,000 to 38,000 Daltons, or about 113,000 Daltons or about 159,000 Daltons. 2.8 Any of the above compositions, wherein the time frame for complete degradation of the microspheres and release of the encapsulated pharmaceutical compound is, for example, less than 6 months, less than 4 months, less than 3 months, less than 2 months, or less than 1 month. 2.9 Particle size of the microspheres, e.g., mean particle size (or D 50 ), 10th percentile particle size (D 10 ), 25th percentile particle size (D 25 ), 75th percentile particle size (D 75 ), or the 90th percentile particle size (D 90) is about 10 μm to about 200 μm, for example, about 20 μm to about 160 μm, or about 20 μm to about 120 μm, or about 20 μm to about 100 μm, or about 20 μm to about 80 μm, or about 20 μm to about 70 μm, or about 20 μm to about 60 μm, or about 20 μm to about 50 μm, or about 20 μm to about 40 μm, or about 20 μm to about 30 μm, or about 25 μm to about 70 μm. m, or about 25 μm to about 60 μm, or about 25 μm to about 50 μm, or about 25 μm to about 40 μm, or about 30 μm to about 60 μm, or about 30 to 50 μm, or about 30 μm to about 40 μm, or about 30 μm to about 120 μm, or about 40 μm to about 120 μm, or about 40 μm to about 100 μm, or about 40 μm to about 80 μm, or about 40 μm to about 70 μm, or about 40 μm to about 60 μm, or about 40 μm to about 50 μm, or about 50 μm to about 100 μm, or about 50 μm to about 80 μm, or about 50 μm to about 70 μm, or about 50 μm to about 60 μm, or about 60 μm to about 100 μm, or about 60 μm to about 90 μm, or about 60 μm to about 80 μm, or about 60 μm to about 70 μm, or about 70 μm to about 100 μm, or about 70 μm to about 90 μm, or about 70 μm to about 80 μm, or about 75 μm to about 110 μm, or about 40 μm to about 160 μm, or about 50 μm to about 160 μm, or about 50 μm to about 120 μm, or about 20 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, or about 100 μm. 2.10 Particle size of microspheres, e.g., mean particle size (or D 50 ), 10th percentile particle size (D 10 ), 25th percentile particle size (D 25 ), 75th percentile particle size (D 75 ), or the 90th percentile particle size (D 90 ) is 10 μm to 160 μm, for example, 20 μm to 70 μm, 25 μm to 70 μm, 40 to 120 μm, or 20 μm to 60 μm, or 20 μm to 50 μm, 30 μm to 60 μm, 30 to 50 μm, 40 μm to 50 μm, or about 30 μm, or about 40 μm, or about 50 μm.

[0033] 2.11 Any of the above compositions, wherein the amount of the compound of formula I dispersed in, dissolved in, or encapsulated in each microsphere is, on average, about 5% to about 50% by weight, e.g., about 10% to about 50% by weight, or about 20% to about 40% by weight, or about 30% to about 40% by weight, or, e.g., about 8.5% by weight, or about 16% by weight, or about 30% by weight, or about 35% by weight, or about 40% by weight. 2.12 Any of the above compositions, wherein the intrinsic viscosity is about 0.1 to about 1, for example, about 0.3 to about 0.4, about 0.7, about 0.8, or about 0.9 dL / g. 2.13 Any of the compositions above for use in Method A above, e.g., any of Methods 1.1 et seq., or Method B. 2.14 Any of the above compositions for use in a patient who, intentionally or unintentionally, has difficulty complying with a normal treatment regimen. 2.15 Any of the above compositions for administration to a patient once weekly, twice weekly or once monthly, or once every 2, 3, 4, 5 or 6 months. 2.16 Any of the above compositions for intramuscular, intraperitoneal, intrathecal, epidural, or subcutaneous injection, e.g., subcutaneous or intramuscular injection, e.g., intramuscular injection. 2.17 Any of the above compositions for intramuscular injection. 2.18 Any of the above compositions further comprising an antioxidant, eg, in an amount effective to inhibit or reduce the oxidation of the compound of Formula I. 2.19 Any of the above compositions further comprising an antioxidant, wherein the antioxidant is a water soluble antioxidant (e.g., ascorbic acid, lipoic acid), or a fat soluble antioxidant (e.g., lipoic acid, vitamin E, tocopherol, carotene, or phenolic antioxidant), or a neutral or weakly basic antioxidant, or a catalytic antioxidant (e.g., ebselen), or a metal-containing antioxidant. 2.20 Any of the above compositions further comprising a lipid or neutral or weakly basic antioxidant, e.g., the polymer comprises a carboxy end group.

[0034] 2.21 Any of the above compositions further comprising an antioxidant, wherein the antioxidant is a phenolic antioxidant (e.g., butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT)). 2.22 Any of the above compositions further comprising an antioxidant, wherein the antioxidant is BHT.

[0035] In yet another embodiment, the present invention provides the above method A or B, wherein the compound of Formula I is formulated in an osmotic controlled release oral delivery system (OROS) for delivery of the compound of Formula I, e.g., a delivery system similar to those described in WO 2000 / 35419 and EP 1539115 (U.S. Patent Application Publication No. 2009 / 0202631), the contents of each of which are incorporated herein by reference in their entirety. Thus, in one embodiment, the present invention provides the above method A or B, wherein the compound of formula I is formulated in a device comprising: (a) a gelatin capsule containing the compound of formula I in free form or in a pharma- ceutically acceptable salt form; (b) a multi-layered wall superimposed on the gelatin capsule, the multi-layered wall comprising, in order from the gelatin capsule outward, (i) a barrier layer, (ii) an expandable layer, and (iii) a semi-permeable layer; and (c) an orifice formed or capable of being formed through the multi-layered wall. (Composition P.1)

[0036] In yet another embodiment, the present invention provides Method A or B above, wherein the compound of formula I is formulated in a composition comprising a gelatin capsule containing the compound of formula I in a liquid, free form or pharma- ceutically acceptable salt form, the gelatin capsule being surrounded by a composite wall, the composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer surrounding the expandable layer, and an exit orifice formed or capable of being formed in the wall (Composition P.2).

[0037] In yet another embodiment, the present invention provides Method A or B above, wherein the compound of formula I is formulated in a composition comprising a gelatin capsule containing the compound of formula I in a liquid, free form or pharma- ceutically acceptable salt form, the gelatin capsule being surrounded by a composite wall, the composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer surrounding the expandable layer, and an exit orifice formed or capable of being formed in the wall, the barrier layer forming a seal between the expandable layer and the periphery of the exit orifice. (Composition P.3)

[0038] In yet another embodiment, the present invention provides a composition comprising a gelatin capsule containing a liquid, a compound of formula I in free form or in pharma- ceutically acceptable salt form, the gelatin capsule being surrounded by a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with a portion of the barrier layer, a semipermeable layer surrounding at least the expandable layer, and an exit orifice extending from the outer surface of the gelatin capsule to the environment of use and formed or capable of being formed in the dosage form. (Composition P.4). The expandable layer may be formed of one or more discontinuous compartments, for example, two compartments located on both sides or both ends of the gelatin capsule.

[0039] In certain embodiments, the compound of formula I in the above osmotic controlled release oral delivery system (i.e., compositions P.1-P.4) is a liquid formulation, which can be a liquid active agent concentrate, or a liquid active agent in a solution, suspension, emulsion, self-emulsifying composition, or the like.

[0040] Further information on osmotically controlled release oral delivery system compositions, including the characteristics of the gelatin capsule, barrier layer, expandable layer, semipermeable layer, and orifice, can be obtained from WO 2000 / 35419, the disclosure of which is incorporated herein by reference in its entirety. Other osmotically controlled release oral delivery systems can be obtained from EP 1539115 (US 2009 / 0202631), the disclosure of which is incorporated herein by reference in its entirety.

[0041] In yet another embodiment, the invention provides Method A or B as described above, wherein the compound of Formula I is formulated in a device comprising: (a) two or more layers, including a first layer and a second layer, wherein the first layer comprises the compound of Formula I in free form or in a pharma- ceutical acceptable salt form as described above, and the second layer comprises a polymer; (b) an outer wall surrounding the two or more layers; and (c) an orifice in the outer wall (Composition P.5).

[0042] Composition P.5 preferably utilizes a semipermeable membrane surrounding the trilayer core described herein. In these embodiments, the first layer, referred to as the first drug layer, contains a small amount of drug (e.g., a compound of Formula I) and an osmotic agent such as a salt; the middle layer, referred to as the second drug layer, contains a larger amount of drug, excipients, and no salt; the third layer, referred to as the push layer, contains an osmotic agent and no drug. At least one orifice is drilled in the membrane on the first drug layer end of the capsule-shaped tablet (composition P.6).

[0043] Composition P.5 or P.6 may comprise a membrane defining a compartment, the membrane surrounding an inner protective subcoat, at least one exit orifice being or can be formed in the membrane, at least a portion of the membrane being semipermeable; an expandable layer in the compartment remote from the exit orifice and in fluid communication with the semipermeable portion of the membrane; a first drug layer adjacent the exit orifice; and a second drug layer in the compartment between the first drug layer and the expandable layer, the drug layers comprising a compound of Formula I, free or a pharma- ceutical acceptable salt. Depending on the relative viscosities of the first and second drug layers, different release profiles are obtained. It is essential to identify the optimal viscosity of each layer. In the present invention, the viscosity is adjusted by the addition of salts, e.g., sodium chloride. The delivery profile from the core depends on the weight, formulation and thickness of each drug layer (Composition P.7).

[0044] In certain embodiments, composition P.7 comprises a first drug layer that comprises a salt and a second drug layer that does not contain a salt. Compositions P.5-P.7 may also comprise a flux enhancing layer between the membrane and the drug layer. Compositions P.1-P.7 are generally referred to as osmotically controlled release oral delivery system compositions.

[0045] The invention further provides a pharmaceutical composition as described above comprising a compound of formula I, in free form or in a pharma- ceutically acceptable salt form, in admixture with a pharma- ceutically acceptable diluent or carrier, e.g. as described in Method A or any of 1.1-1.50 or Method B, in immediate release or sustained or delayed release formulation, e.g. including sustained release injectable formulation, for use in the treatment of residual symptoms as described in Method A or any of 1.1-1.50 or for use in the treatment of a disorder as described in Method B.

[0046] In another aspect, the invention provides the use of a pharmaceutical composition as described above comprising a compound of formula I or a compound of formula I in free form or in pharma- ceutical acceptable salt form as described in Method A or any of 1.1-1.50, formulated in an immediate release or extended or delayed release formulation, including a sustained release injectable formulation as described above, for the treatment of residual symptoms as described in Method A or any of 1.1-1.50, or for the treatment of a disorder as described in Method B (in the manufacture of a medicament).

[0047] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I or any of the above described pharmaceutical compositions (e.g., Compositions P.1-P.7 or Composition 2) comprising a compound of Formula I in free form or in pharma- ceutically acceptable salt form as described in Method A or 1.1-1.50, wherein the compound is mixed or combined with an antioxidant. Without being bound by theory, it is believed that the presence of an antioxidant in the composition stabilizes the compound of Formula I. In a preferred embodiment, the sustained release injectable microspheres contain an antioxidant, wherein the antioxidant is believed to stabilize the compound of Formula I during release from the microspheres. [Brief description of the drawings]

[0048] [Figure 1] Graph showing the PANSS Negative Symptoms subscale for the subgroup of patients with prominent negative symptoms at baseline. [Diagram 2] Graph showing total PANSS in the subgroup of patients with depression at baseline. [Diagram 3] Graph showing the PANSS Negative Symptoms subscale in the subgroup of patients with depression at baseline. [Figure 4] Graph showing prosocial PANSS factor change from baseline compared to placebo. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] Detailed Description of the Invention The present invention provides an unmet need in the treatment of residual symptoms of psychosis (especially schizophrenia) as well as acute symptoms. Schizophrenia patients are currently treated with either typical or atypical antipsychotics. These drugs, which may be effective in treating the positive symptoms of psychosis, are generally inappropriate for treating residual symptoms. Thus, there is a need for alternative or additional treatments to improve prognosis. In one embodiment, the method of the present invention uses the compound of formula I above alone or in combination with one or more different antipsychotics for treating residual and acute symptoms of psychosis.

[0050] As used herein, "residual symptoms" includes negative symptoms and generalized psychopathological symptoms as described in the Positive and Negative Symptom Scale for Schizophrenia (PANSS) described in Kay et al., Schizophr. Bull. (1987) 13(2):261-276, the contents of which are incorporated herein by reference in their entirety. Negative symptoms include blunted affect, emotional withdrawal, poor interpersonal relationships, passive / amotivated social withdrawal, difficulty with abstract thinking, loss of spontaneity and flow of speech, and stereotyped thinking. Generalized psychopathological symptoms include physical concerns, anxiety, guilt, tension, habits and unnatural postures, depression, delayed motor development, uncooperativeness, abnormal thought content, disorientation, decreased attention, poor judgment and insight, impaired willpower, poor impulse control, preoccupation, and active social avoidance. Residual symptoms may also include depression, cognitive impairment, and sleep disorders (e.g., insomnia). Compounds of formula I are useful for treating these residual symptoms, particularly passive withdrawal, stereotypic thinking, somatic concerns, anxiety, tension, active social avoidance, and depression. Most schizophrenia patients exhibit social dysfunction that hinders successful social reintegration. Social dysfunction can be measured using the prosocial factor from the PANSS. The prosocial factor is composed of items from the positive, negative, and general psychopathology subscales, such as active social avoidance, emotional withdrawal, passive withdrawal, stereotypic thinking, hallucinatory behavior, and suspiciousness. This factor has been shown to be sensitive to changes in the clinical trial environment. Compounds of formula I, particularly compound A as defined in Example 1, reduce negative symptoms and also treat several other symptom domains, so it is believed that compounds of formula I may be useful for treating social dysfunction. Thus, the compounds of the present invention are particularly useful for improving social integration and social function in schizophrenia patients. Social functioning is the ability to perceive, understand, process, and use external factors to solve problems, maintain job performance, and conduct interpersonal relationships.

[0051] The treatment of these residual symptoms is also particularly effective in schizophrenia patients who also suffer from depression. 60 mg of the compound of formula I, particularly the compound A in the form of toluenesulfonic acid addition salt as defined in Example 1, administered once daily in the morning improves symptoms related to schizophrenia as measured by a statistically significant and clinically meaningful reduction in PANSS total score after 28 days of treatment. This compound A also does not cause hyperprolactinemia, EPS / akathisia, weight gain or cardiovascular safety issues. At the same dose, this compound A also statistically significantly improves the positive symptoms subscale and general psychopathology subscale of the PANSS. 60 mg of the compound of formula I, particularly the compound A in the form of toluenesulfonic acid addition salt as defined in Example 1, also improves negative symptoms in a subgroup of patients who have significant negative symptoms at baseline. Certain items of the negative symptoms and general psychopathology subscales also improve significantly, which is consistent with improved social functioning.

[0052] The term "acute symptoms" of psychosis or schizophrenia refers to positive symptoms on the PANSS such as delusions, disorganization, hallucinatory behavior, and suspiciousness.

[0053] The term "psychosis" refers to illnesses such as schizophrenia, delusional disorder, major depression with psychosis, bipolar disorder with psychotic symptoms, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, or psychosis caused by a medical condition or substance use. Preferably, the patient suffering from residual symptoms of psychosis is a patient suffering from residual symptoms of schizophrenia.

[0054] The term "bipolar disorder" refers to a disorder characterized by extreme mood changes. Bipolar disorder patients may experience intense feelings of hyperexcitability, irritability, and impulsivity with grandiose beliefs and racing thoughts, referred to as manic episodes. Depressive symptoms may include fatigue, hopelessness, and sadness, with poor concentration and thoughts of suicide. Some people experience both types of symptoms in the same "mixed" episode. Severe symptoms of bipolar disorder may be accompanied by hallucinations or delusions, otherwise referred to as psychosis.

[0055] The terms "treatment" and "treating" should therefore be understood to include prevention and treatment or amelioration of symptoms of disease, and / or treatment of the cause of said disease.

[0056] The term "patient" can include human or non-human patients.

[0057] Unless otherwise specified or clear from the context, the following terms used herein have the following meanings: (i) "Alkyl," as used herein, unless otherwise specified, is a saturated or unsaturated hydrocarbon group, e.g., 1 to 21 carbon atoms in length, which may be straight-chained or branched (e.g., n-butyl or tert-butyl), and is preferably straight-chained. For example, "C 1-21 "Alkyl" refers to an alkyl having 1 to 21 carbon atoms. In one embodiment, the alkyl is selected from the group consisting of one or more hydroxyl or C 1-22 It may be substituted with an alkoxy (e.g., ethoxy) group. In another embodiment, the alkyl contains 1-2 carbon atoms, is preferably straight-chained, and may be saturated or unsaturated, e.g., R1 is an alkyl chain containing 1-21, preferably 6-15, 16-21 carbon atoms, such that when cleaved from the compound of formula I, together with the -C(O)- to which it is attached, it forms the residue of a natural or unnatural saturated or unsaturated fatty acid.

[0058] Methods for preparing compounds of formula I The compounds of formula I and their pharma- ceutically acceptable salts can be prepared using the methods described and exemplified in any of the following patents or applications: U.S. Patent Nos. 6,548,493, 7,238,690, 6,552,017 and 6,713,471; U.S. Patent Reissue No. 39680; U.S. Patent Reissue No. 39679; International Patent Application PCT / US08 / 03340; U.S. Patent Application No. 10 / 786,935; WO 2011 / 133224A1, WO 2009 / 114181 and WO 2013 / 155505. If not commercially available, the starting materials for these methods can be prepared by procedures selected from chemical techniques using techniques similar or analogous to the synthesis of known compounds. All references cited herein are incorporated herein by reference in their entirety.

[0059] The compound of formula I is any of the compounds of formula I or the compounds described in methods 1.1 to 1.50, in free form or in the form of a pharma- ceutically acceptable salt. [ka] Compounds of formula I also include certain other compounds where Y is -C(H)(OH)- or -C(H)(OR1), R1 is as defined above, and X is -O-, -N(H)-, or -N(CH3)-. These compounds include, for example, compounds in free form or in pharma- ceutically acceptable salt form. [ka] Specific compounds of formula I also include compound A, which is a compound of formula I where X is -N(CH3)- and Y is -C(O)-. The terms "compound of formula I" and "compound of formula I" can be used interchangeably and can be used as a single therapeutic agent or they can be used in combination or co-administration with other active agents. In the method of the present invention, the term "compound of formula I" can also include two or more compounds of formula I.

[0060] The compounds of formula I may, in some cases, exist in a prodrug form. A prodrug form is a compound that is converted to the active compound of formula I in the body. The term "prodrug" is an art-recognized term and refers to a drug precursor prior to administration that generates or releases an active metabolite by some chemical or physiological process in vivo after administration. For example, when a compound of formula I contains hydroxy or carboxy substituents, these substituents may form a physiologically hydrolyzable and acceptable ester. As used herein, "physiologically hydrolyzable and acceptable ester" refers to an ester of a compound of formula I that is hydrolyzable under physiological conditions to produce an acid (in the case of a compound of formula I having a hydroxy substituent) or an alcohol (in the case of a compound of formula I having a carboxy substituent) that is itself physiologically tolerable at the dose to be administered. For example, when Y of a compound of formula I is -C(H)(OR1) and R1 is a physiologically hydrolyzable and acceptable acyl, e.g., -C(O)-C 1-21 When Y is an alkyl, e.g., -C(O)-C3 alkyl or -C(O)-C9 alkyl, these compounds are hydrolyzable under physiological conditions and when Y is, on the one hand, -C(H)(OH) and, on the other hand, -C(H)(OH), 1-21 Compounds of formula I can be produced which are alkyl-C(O)OH, e.g., C alkyl-C(O)OH or C alkyl-C(O)OH. In particular, Y is -O-, -C(R2)(OH)-, -C(R3)(OR1) or -C(O)-, R1 is C1-6 alkyl (e.g., methyl), and R2 and R3 are H or C 1-6 Compounds of formula I in which R is alkyl (e.g., methyl) are the active ingredient. In contrast, 1-21 Compounds of formula I that are alkyl are physiologically labile moieties with weak or no activity, but are hydrolyzed under physiological conditions to produce compounds of formula I in which R1 is cleaved to release -C(R2)(OH) or -C(R3)(OH), and the other hydrolysis products are not toxic at relevant concentrations, e.g., concentrations resulting from in vivo hydrolysis of a dose of the prodrug compound. Under some physiological conditions, compounds where R1 is C 1-6 Compounds of formula I where R1 is alkyl (e.g., methyl) may also be converted in vivo to more active compounds where R1 is H; therefore, these compounds are considered to be both active ingredients and prodrugs.

[0061] As will be understood, the term prodrug thus encompasses conventional pharmaceutical prodrug forms. Prodrugs (e.g., where R is -C(O)-C 1-21 When an active compound of formula (I) is used, the dosage is the same as that of an active compound of formula I, e.g., Y is -O-, -C(R2)(OH)-, -C(R3)(OR1) or -C(O)-, and R1 is C 1-6 alkyl (e.g., methyl), and R2 and R3 are H or C 1-6 It is calculated based on the amount of active compound of formula I which is alkyl (e.g. methyl), particularly the amount of compound of formula (I) where Y is C(=O) or Y is C(H)(OH), in free base form or in salt form, such as the toluenesulfonic acid addition salt form.

[0062] The compounds of formula I may contain one or more chiral carbon atoms. Thus, the compounds may exist in individual isomers, e.g., enantiomers or diastereoisomers, or as mixtures of individual forms, e.g., as racemic / diastereomeric mixtures. Isomers in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration may exist. The present invention should be understood to include both individual optically active isomers and mixtures thereof (e.g., racemic / diastereomeric mixtures). Thus, the compounds of formula I may be racemic mixtures, or they may be predominantly, e.g., in pure or substantially pure isomeric form, e.g., greater than 70% enantiomeric / diastereomeric excess ("ee"), preferably greater than 80% ee, more preferably greater than 90% ee, and most preferably greater than 95% ee. The purification of said isomers and separation of isomeric mixtures can be carried out by standard techniques known in the art, such as column chromatography, preparative TLC, preparative HPLC, simulated moving bed, and the like.

[0063] Geometric isomers by the nature of substituents on double bonds or rings may exist in cis (Z) or trans (R) configuration and both isomeric forms are encompassed within the scope of the present invention.

[0064] The compound of formula I may be included in a sustained or delayed release formulation, e.g., a depot formulation, e.g., by dispersing, dissolving or encapsulating the compound of formula I in a polymer matrix, e.g., as described above in P.1-P.7, such that the compound is released intermittently as the polymer degrades over time. Release of the compound of formula I from the polymer matrix results in a controlled and / or delayed and / or sustained release of the compound, e.g., from the pharmaceutical depot formulation, to a subject administered the pharmaceutical depot formulation, e.g., a warm-blooded animal such as a human. Thus, the pharmaceutical depot formulation delivers the compound of formula I to the subject over an extended period of time, e.g., 14 to 180 days, preferably about 30 days, about 60 days or about 90 days, at a concentration effective to treat a particular disease or medical condition.

[0065] Polymers useful for the polymer matrix in the compositions of the invention (e.g., depot compositions of the invention) include polyesters of hydroxy-fatty acids and their derivatives, or other agents, such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymers, lactic acid-glycolic acid copolymers, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers, or polyglycolic acid-polyethylene glycol copolymers), polymers of α-cyanoalkyl acrylates (e.g., poly Poly(butyl 2-cyanoacrylate)), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyorthocarbonates, polyamino acids (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), hyaluronic acid esters, and the like, one or more of which polymers can be used.

[0066] When the polymers are copolymers, they can be either random, block and / or graft copolymers. When the above-mentioned α-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any one of D-isomers, L-isomers and / or DL-isomers can be used. In particular, α-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), their esters, poly-α-cyanoacrylic acid esters, etc. can be used, with lactic acid-glycolic acid copolymers (also called poly(lactide-α-glycolide) or poly(butyric acid-co-glycolic acid), hereinafter referred to as PLGA) being preferred. Thus, in one embodiment, the polymer useful for the polymer matrix is ​​PLGA. As used herein, the term PLGA includes polymers of lactic acid (also called polylactide, poly(lactic acid) or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer.

[0067] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not induce significant inflammation in body tissues. The matrix material is biodegradable such that the polymeric material is broken down by bodily processes into products that are easily disposable by the body and do not accumulate in the body. The products of biodegradation are also biocompatible with the body in that the polymer matrix is ​​biocompatible with the body. Particularly useful examples of polymer matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers thereof, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxonones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as glycerol monostearate and glycerol distearate, and the like. A preferred polymer for use in the practice of the invention is dl-(polylactide-co-glycolide). The molar ratio of lactide to glycolide in such polymers is preferably in the range of about 75:25 to 50:50.

[0068] Useful PLGA polymers can have a weight average molecular weight of about 5,000 to 500,000 daltons, such as about 150,000 daltons, or 20,000 to 200,000 daltons, such as 24,000 to 38,000 daltons, or about 113,000 daltons or about 159,000 daltons. For example, the PLGA polymer has a weight average molecular weight of 24,000 to 38,000 daltons. Depending on the rate of degradation to be achieved, polymers of different molecular weights can be used. For a diffusion mechanism of drug release, the polymer remains intact until all of the drug is released from the polymer matrix and degrades. The drug is also released from the polymer matrix when the polymeric excipient is bioeroded.

[0069] The PLGA can be prepared by conventional methods or can be commercially available. For example, PLGA can be prepared from cyclic lactide, glycolide, etc. by ring-opening polymerization with a suitable catalyst (see EP 0058481; Effect of variable polymerization on PLGA properties: molecular weight, composition and chain structure).

[0070] It is believed that PLGA is biodegradable by degradation of the entire solid polymer composition due to the destruction of hydrolytic and enzymatically cleavable ester bonds under biological conditions (e.g., in the presence of water and biological enzymes in the tissues of warm-blooded animals such as humans), forming lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, and can be further biodegraded to form carbon dioxide and water. In other words, it is believed that PLGA degrades in the body of a warm-blooded animal, such as a human, by hydrolysis of its esters in the presence of water to produce lactic acid and glycolic acid, creating an acidic microclimate. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal, such as a human, under normal physiological conditions, and are therefore well tolerated and cause minimal systemic toxicity.

[0071] In another embodiment, the polymer matrix useful in the present invention may include star polymers, in which the structure of the polyester is star-shaped. These polyesters have a single polyol residue as a central moiety surrounded by chains of acid residues. The polyol moiety may be, for example, glucose, or, for example, mannitol. These esters are known and are described in British Patent No. 2,145,422 and U.S. Patent No. 5,538,739, the contents of which are incorporated herein by reference in their entirety.

[0072] The star polymers can be produced using polyhydroxy compounds, such as polyols, such as glucose or mannitol, as initiators. The polyols contain at least three hydroxy groups, have a molecular weight of up to about 20,000 Daltons, and at least one, preferably at least two, for example an average of three, of the hydroxy groups of the polyol are in the form of ester groups, and contain polylactide or co-polylactide chains. Branched polyesters, such as poly(d,l-lactide-co-glycolide), have a central glucose moiety with multiple linear polylactide chains.

[0073] The sustained or delayed release formulations may include polymers in which the compound of formula I is dispersed or encapsulated, in the form of microparticles (e.g., microspheres) or nanoparticles or in liquid form. By "microparticles" is meant solid particles containing the compound of formula I in liquid or solid form, the compound being dispersed or dissolved within a polymer that acts as the matrix of the particle. By appropriate selection of polymeric materials, microparticle formation can be produced in which the resulting microparticles exhibit both diffusional and biodegradable release properties.

[0074] When the polymer is in the form of microparticles, the microparticles can be prepared using a suitable method, such as solvent evaporation or solvent extraction.For example, in the solvent evaporation method, the compound of formula I and the polymer can be dissolved in a volatile organic solvent (e.g., ketones such as acetone, halogenated hydrocarbons such as chloroform or methylene chloride, halogenated aromatic hydrocarbons, cyclic ethers such as dioxane, esters such as ethyl acetate, nitriles such as acetonitrile, or alcohols such as ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabilizer (e.g., polyvinyl alcohol, PVA).The organic solvent is then evaporated to obtain microparticles encapsulating the compound of formula I.In the solvent extraction method, the compound of formula I and the polymer can be dissolved in a polar solvent (e.g., acetonitrile, dichloromethane, methanol, ethyl acetate or methyl formate) and then dispersed in an aqueous phase (e.g., water / PVA solution).An emulsion is formed to obtain microparticles encapsulating the compound of formula I.Spray drying is an alternative manufacturing method for producing microparticles.

[0075] Alternative methods for producing the microparticles of the present invention are also described in US Pat. Nos. 4,389,330 and 4,530,840, the contents of which are incorporated herein by reference in their entireties.

[0076] The microparticles of the present invention can be manufactured by any method that can produce microparticles in the size range acceptable for use in injectable compositions.One preferred manufacturing method is that described in U.S. Pat. No. 4,389,330.In this method, the active agent is dissolved or dispersed in a suitable solvent.A polymer matrix material is added to the drug-containing medium in an amount relative to the active ingredient that provides a product with the desired loading of active agent.If desired, all components of the microparticle product can be blended together in a solvent medium.

[0077] Solvents for the compound of formula I and polymer matrix material that can be used in the practice of the present invention include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, methylene chloride and the like; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate; and the like.In one embodiment, the solvent for use in the practice of the present invention can be a mixture of benzyl alcohol and ethyl acetate.More information on the preparation of microparticles useful in the present invention can be found in U.S. Patent Application Publication No. 2008 / 0069885, the contents of which are incorporated herein by reference in their entirety.

[0078] The amount of the compound represented by formula I incorporated in the microparticles is usually in the range of about 1% by weight to about 90% by weight, preferably 30% by weight to 50% by weight, and more preferably 35% by weight to 40% by weight. The weight % means the amount of the compound represented by formula I per total weight of the microparticle.

[0079] The sustained or delayed release formulation may include a pharma- ceutically acceptable diluent or carrier, such as a water-miscible diluent or carrier.

[0080] In one embodiment, the sustained release or delayed release formulation is a sustained release injectable formulation.In a further embodiment, the sustained release injectable formulation is formulated using polymeric microspheres, such as microspheres comprising a PLGA matrix in which the compound of formula I in free form or in pharma-ceutically acceptable salt form is dispersed, dissolved or encapsulated.In a preferred embodiment, the PLGA polymer is about 75:25 PLA / PLG (lactide:glycolide) with carboxylic acid or carboxylic acid ester end groups.In a preferred embodiment, the compound of formula I is present in the microsphere as a free base.The microspheres can be prepared using methods known in the art, such as by emulsion-solvent evaporation without microsieving, or by emulsion-solvent evaporation with dry microsieving, or by emulsion-solvent evaporation with wet microsieving.

[0081] The rate at which PLGA microspheres degrade is highly dependent on the selected molecular weight range of the polymer molecules and the size of the microspheres. In one embodiment, the average molecular weight range of the PLGA polymer is 24,000-38,000 Daltons. In another embodiment, the PLGA polymer has an average molecular weight of about 113,000 Daltons. In yet another embodiment, the PLGA polymer has an average molecular weight of about 159,000 Daltons. In some embodiments, the time frame for complete degradation of the microspheres and release of the encapsulated drug compound is, for example, less than 6 months, less than 4 months, less than 3 months, less than 2 months, or less than 1 month.

[0082] The particle size of the microspheres, for example, the average particle size (or D50), the 10th percentile particle size (D10), the 25th percentile particle size (D25), the 75th percentile particle size (D75), or the 90th percentile particle size (D90), is about 1 μm to about 100 μm, or about 2 μm to about 80 μm, or about 2 μm to about 60 μm, or about 2 μm to about 50 μm, or about 2 μm to about 40 μm, or about 2 μm to about 30 μm, or about 5 μm to about 35 μm, or about 5 μm to about 25 μm, or about 5 μm to about 2 0 μm, or about 10 μm to about 20 μm, or about 10 μm to about 200 μm, or about 20 μm to about 160 μm, or about 20 μm to about 120 μm, or about 20 μm to about 100 μm, or about 20 μm to about 80 μm, or about 20 μm to about 70 μm, or about 20 μm to about 60 μm, or about 20 μm to about 50 μm, or about 20 μm to about 40 μm, or about 20 μm to about 30 μm, or about 25 μm to about 70 μm, or about 25 μm to about 60 μm, or about 25 μm to about 50 μm, or about 25 μm to about 4 0 μm, or about 30 μm to about 60 μm, or about 30 to 50 μm, or about 30 μm to about 40 μm, or about 30 μm to about 120 μm, or about 40 μm to about 120 μm, or about 40 μm to about 100 μm, or about 40 μm to about 80 μm, or about 40 μm to about 70 μm, or about 40 μm to about 60 μm, or about 40 μm to about 50 μm, or about 50 μm to about 100 μm, or about 50 μm to about 80 μm, or about 50 μm to about 70 μm, or about 50 μm to about 60 μm, or about 60 μm to about 1 00μm, or about 60μm to about 90μm, or about 60μm to about 80μm, or about 60μm to about 70μm, or about 70μm to about 100μm, or about 70μm to about 90μm, or about 70μm to about 80μm, or about 75μm to about 110μm, or about 40μm to about 160μm, or about 50μm to about 160μm, or about 50μm to about 120μm, or about 20μm, about 30μm, about 40μm, about 50μm, about 60μm, about 70μm, about 80μm, about 90μm, or about 100μm. Such particle size measurements can be performed, for example, using optical microscopy, scanning electron microscopy, laser diffraction, light scattering, and other techniques known to those skilled in the art.

[0083] The amount of drug encapsulated in each microsphere can be, on average, about 5% to about 50% by weight, e.g., 10% to about 50% by weight, or about 20% to about 40% by weight, or about 30% to about 35% by weight, or about 8.5% by weight, or about 16% by weight, or about 30% by weight, or about 35% by weight, or about 40% by weight. In a preferred embodiment, the amount of drug encapsulated in each microsphere is about 8.5% by weight or about 16% by weight.

[0084] Details of osmotic controlled release oral delivery system compositions can be found in European Patent No. 1539115 (U.S. Patent Application Publication No. 2009 / 0202631) and International Publication No. WO 2000 / 35419, the contents of which are incorporated herein by reference in their entirety.

[0085] A "therapeutically effective amount" is an amount of a compound of Formula I that, when administered to a subject suffering from a disease or disorder, is effective to bring about the relief, remission, or regression of the disease or disorder over the period of time contemplated for treatment.

[0086] Depression is estimated to occur in 50% of schizophrenia patients. Schizophrenia patients with comorbid depression generally have poorer overall mental and physical health, lower quality of life, greater impairment in social relationships, and lower sleep satisfaction, ability to perform daily activities, work capacity, transportation, social support, and self-esteem than patients with schizophrenia alone. Thus, depressive symptoms exacerbate psychosocial functioning deficits and increase the risk of psychotic relapse. Unlike dopamine receptor antagonists, the compounds of formula I, and in particular the compounds of formula A as defined in Example 1, normalize brain dopamine activity, especially in the prefrontal cortex. The compounds of formula I, and in particular the compounds of formula A as defined in Example 1, inhibit 5-HT 2A and dopamine D2 receptors. In addition, the compounds of formula I also bind to glutamatergic phosphoproteins (D1 / GluN 2B) and dopamine phosphorylation protein (DPPM). The compound of formula I also exhibits nanomolar binding affinity to the serotonin transporter compared to known antidepressants. Thus, the compound of formula I is useful for treating depression and / or sleep disorder in addition to treating acute symptoms (e.g., hallucinations and delusions) and residual symptoms. For schizophrenia patients who also suffer from depression, the compound of formula I is particularly useful for improving total PANSS and negative symptoms. Although risperidone, an atypical antipsychotic, is useful for treating some negative symptoms, this compound is less effective than the subgroup of patients with baseline depression treated with the compound of formula I (see Figures 2 and 3 and Example 1). Thus, in some embodiments, the method of the present invention is particularly useful for treating depression and / or sleep disorder in patients suffering from acute and / or residual symptoms of psychosis, and for treating acute and / or residual symptoms of psychosis in patients suffering from depression and / or sleep disorder.

[0087] In further embodiments, the present invention provides a method for treating residual symptoms by administering the compound of formula I in combination with one or more other therapeutic agents, such as antipsychotics and / or antidepressants and / or hypnotics. In such methods, the antipsychotics and / or antidepressants and / or hypnotics may be adjuncts to the compound of formula I, or the compound of formula I may be adjuncts to antipsychotics and / or antidepressants and / or hypnotics. As used herein, the term "adjunct" or "adjunct" refers to a treatment that is used in combination with another to increase the chance of cure or to increase the effect of the first treatment. In other words, adjunct treatment serves as an adjunct to the primary treatment. In another embodiment, the compound of formula I is used as a monotherapy to treat acute symptoms and / or residual symptoms of schizophrenia and depression and / or sleep disorders (e.g., insomnia) in patients suffering from schizophrenia.

[0088] Other therapeutic agents that may be administered to a patient in need thereof include compounds that modulate GABA activity (e.g., enhance activity and facilitate GABA transmission), GABA-B receptor agonists, 5-HT modulators (e.g., 5-HT 1A Receptor agonist, 5-HT 2A Receptor antagonist, 5-HT 2A receptor inverse agonists, melatonin receptor agonists, ion channel modulators (e.g., blockers), serotonin-2 receptor antagonists / reuptake inhibitors (SARIs), orexin receptor antagonists, H3 receptor agonists, noradrenaline receptor antagonists, galanin receptor agonists, CRH receptor antagonists, human growth hormone, growth hormone receptor agonists, estrogen, estrogen receptor agonists, neurokinin 1 agents, and antipsychotics, e.g., atypical antipsychotics.

[0089] The term "GABA" refers to gamma-aminobutyric acid. GABA compounds are compounds that bind to GABA receptors, including, but not limited to, one or more of 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), and estazolam.

[0090] Any other therapeutic agent may be 5HT 2AReceptor antagonists, such as ketanserin, risperidone, eplivanserin, vorinanserin (Sanofi-Aventis, France), pulvanserin, pimavanserin (ACP-103), MDL 100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena Pharmacenticals, San Diego, CA) or AVE8488 (Sanofi-Aventis, France).

[0091] Further optional therapeutic agents include pizotifen.

[0092] Any other therapeutic agent may be 5HT 1A Receptor agonists, such as repinotan, sarizotan, eptapirone, buspirone or MN-305 (MediciNova, San Diego, Calif.).

[0093] Other optional compounds are melatonin receptor agonists, such as melatonin, ramelteon (ROZEREM®, Takeda Pharmaceutical Co., Ltd., Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II Discovery) or agomelatine.

[0094] Another optional therapeutic agent is an ion channel blocker, such as lamotrigine, gabapentin, or pregabalin.

[0095] Another optional therapeutic agent is an orexin receptor antagonist, such as orexin, 1,3-biaryl urea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline) or a benzamide derivative.

[0096] Another optional therapeutic agent is a serotonin-2 receptor antagonist / reuptake inhibitor (SARI), such as Org 50081 (Organon-Netherlands), ritanserin, nefazodone, serzone or trazodone.

[0097] Another optional therapeutic agent is a neurokinin 1 drug, such as casopitant (GlaxoSmithKline).

[0098] Specific examples of additional therapeutic agents include, in free form or in pharma- ceutical acceptable salt form, modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin, risperidone, eplivanserin, vorinanserin (Sanofi-Aventis, France), pulvanserin, MDL 100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego, CA), AVE8488 (Sanofi-Aventis, France), repinotan, sarizotan, eptapyrone, buspirone, MN-305 (MediciNova, San Diego, CA), melatonin, ramelteon (ROZEREM®, Takeda Pharmaceutical Co., Ltd., Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II Discovery), agomelatine, lamotrigine, gabapentin, pregabalin, orexin, 1,3-biarylurea, SB-334867-a (GlaxoSmithKline,UK), GW649868 (GlaxoSmithKline), benzamide derivatives, 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, These include tranylcypromine, trazodone, trimipramine, bellafaxine, 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.

[0099] The combination compositions of the present invention can include mixtures of combination drugs, as well as two or more separate pharmaceutical compositions, which individual compositions can, for example, be co-administered to a patient together at the same time or at different times.

[0100] In another aspect, the present invention provides the use of a compound of formula I or any of the above pharmaceutical compositions (compositions P.1 to P.7, and compositions 2 and 2.1 to 2.17) comprising a compound of formula I in free form or in pharma- ceutically acceptable salt form as described in Method A or 1.1 to 1.50, wherein the compound is mixed with an antioxidant. In a preferred embodiment, the sustained release injectable microsphere formulation of the present invention contains an antioxidant. In some embodiments, the antioxidant is a water-soluble antioxidant (e.g., ascorbic acid, lipoic acid), while in other embodiments, the antioxidant is a fat-soluble antioxidant (e.g., lipoic acid, vitamin E, tocopherol, carotene, and phenolic antioxidants). In some embodiments, the antioxidant is a neutral or weakly basic antioxidant. Other possible antioxidants include catalytic antioxidants (e.g., ebselen) and metal-containing antioxidants. In a preferred embodiment, the antioxidant is a phenolic antioxidant, such as butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA). In a more preferred embodiment, the antioxidant is BHT.

[0101] The dosage used in the practice of the present invention will of course vary, for example, depending on the specific disease or condition to be treated, the specific compound of formula I used, the mode of administration, and the desired therapeutic method.Unless otherwise stated, the amount of the compound of formula I for administration (whether administered as free base, as prodrug, or as salt form) refers to or is based on the amount of the compound of formula I in free base form (i.e., the amount is calculated based on the amount of free base).However, in certain embodiments, the dosage of the compound of formula I is administered based on the amount of salt form, for example, toluenesulfonic acid addition salt form.The compound of formula I can be administered by any suitable route, including oral, parenteral, or transdermal, but is preferably administered orally. As a monotherapy, the compound of formula I may be administered at about 1 mg to 120 mg per day, or 10 mg to 120 mg per day, or 10 mg to 60 mg per day, or 10 mg to 40 mg per day, or 1 mg to 10 mg per day, or 10 mg per day, 20 mg per day, 40 mg per day, or 60 mg per day, preferably about 60 mg of the compound in toluenesulfonic acid addition salt form per day. When 120 mg is administered, it is preferably administered at night.

[0102] As a sustained release injectable microsphere formulation, the dosage of the compound of formula I will depend on both the average loading of drug in the microspheres (expressed in % w / w) and the amount of microspheres administered (mg / kg). As a monotherapy, the compound of formula I may be administered as microspheres to provide a dosage of 1-50 mg / kg, e.g., 5-25 mg / kg, preferably 5-10 mg / kg, e.g., about 5 mg / kg, of the compound of formula I. A dosage of about 5 mg / kg of the compound of formula I may be provided by using a dosage of 60 mg / kg of microspheres, each containing an average loading of about 8.5% w / w of the compound of formula I.

[0103] The dosage of the compound of formula I and / or other antipsychotics and / or antidepressants in Method A may be the same as or lower than the approved dosage of the drug, the dosage in clinical trials or literature studies, or the dosage used for the drug as monotherapy. For example, the dosage of the compound of formula I administered in combination with another antipsychotic and / or antidepressant is about 1 mg to about 140 mg of the compound in free base or toluenesulfonic acid addition salt form, in another embodiment about 1 mg to about 120 mg, in another embodiment about 10 mg to about 120 mg, in another embodiment about 10 mg to about 60 mg, in another embodiment about 10 mg to about 40 mg, in another embodiment about 20 mg to about 40 mg, in another embodiment about 1 mg to about 10 mg, and in yet another embodiment about 60 mg. The amount of the antipsychotic administered in combination with the compound of formula I is about 0.01 mg to about 1000 mg, in another embodiment about 0.1 mg to about 600 mg, for example about 1 mg to about 200 mg, for example about 1 mg to about 50 mg, for example about 1 mg to about 15 mg, for example about 4 mg. The amount of the antidepressant administered in combination with the compound of formula I is about 0.01 mg to about 2000 mg, in another embodiment about 0.1 mg to about 200 mg, in another embodiment about 10 mg to about 200 mg. In a particular embodiment, the second therapeutic agent is the antipsychotic risperidone at a daily dose of about 2 mg to about 4 mg, and the antidepressant is sertraline, and the daily dose of sertraline is about 20 mg to 100 mg.

[0104] In certain embodiments, the compound of formula I and / or the second (or third) therapeutic agent of method A are less than when used as monotherapy.Thus, in certain embodiments, the daily dose of the compound of formula I is less than 100mg, or less than 60mg, or less than 40mg, or less than 30mg, or less than 20mg, or less than 10mg once a day.In another preferred embodiment, the dose of both the compound of formula I and the antipsychotic and / or antidepressant of method A is less than the dose used for each drug as monotherapy. Thus, in certain embodiments, for example, Method A comprises administering (1) a compound of Formula I, in free form or in a pharma- ceutically acceptable salt form, once daily in a dose of less than 100 mg, e.g., less than 60 mg or less than 40 mg; and / or (2) an antidepressant, e.g., an SSRI, e.g., sertraline, in a daily dose of less than 50 mg, more preferably less than 20 mg, even more preferably less than 10 mg, and most preferably less than 6 mg; and / or (3) an antipsychotic, e.g., risperidone, in a daily dose of less than 100 mg.

[0105] For the treatment of disorders described herein, where sustained or delayed release formulations are used to achieve longer duration of action, the dosage is higher than compositions with shorter duration of action, for example, higher than 1-100 mg, for example, 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or higher than 1000 mg. In certain embodiments, the administration schedule of sustained or delayed release formulations includes an initial oral immediate release administration and a depot release to provide a steady state blood concentration of the drug. The duration of action of the compound of formula I can be controlled by manipulating the polymer composition, i.e., the polymer:drug ratio and the microparticle size. When the formulation of the present invention is a depot formulation, administration by injection is preferred. In a preferred embodiment, the formulation is a sustained release injectable microsphere formulation as described above.

[0106] The compound to be administered in the method of the present invention may be in the form of free acid or free base, or as a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt" refers to the derivative of the above compound, which is modified by making its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. Preferably, the compound of formula I is in the toluenesulfonic acid addition salt form.

[0107] The pharma- ceutically acceptable salts of the compounds to be used in the method of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods.Generally, such salts can be prepared by reacting the free base form of these compounds with stoichiometric amounts of suitable acids in water or organic solvent or their mixtures; generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.More detailed descriptions of the preparation methods of these salts, such as toluenesulfonic acid salts in amorphous or crystalline form, can be found in International Patent Application PCT / US08 / 03340 (WO2008 / 112280) and / or WO2009 / 114181 and WO2011 / 133224.

[0108] Pharmaceutical compositions containing the compounds of formula I can be prepared using conventional diluents or excipients and techniques known in the galenic art. For example, the compounds can be administered in a variety of different dosage forms, i.e., they can be combined with various pharma- ceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, injection solutions, elixirs, and the like.

[0109] For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., pregelatinized corn, polyvinylpyrrolidone or pyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents or humectants (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be provided as a dry preparation for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharma- ceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated vegetable fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid).

[0110] For immediate release formulations, the compounds of formula I, either in free form or in a pharma- ceutically acceptable salt form, may be formulated with a pharma- ceutically acceptable diluent or carrier. For sustained or delayed release formulations, the compounds of formula I, either in free form or in a pharma- ceutically acceptable salt form, may be formulated as described in any of compositions P.1-P.7.

[0111] In certain embodiments, the compound of formula I is formulated into a capsule as follows: [Table 1]

[0112] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0113] The compound of formula I can be formulated for parenteral administration by injection, including the use of conventional catheter techniques or infusion.The preparation for injection can be provided in unit dosage form, for example, in ampoules, or in multi-dose containers with added preservatives.The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents.Alternatively, the active ingredient can be in powder form for reconstitution with suitable vehicle, for example, sterile pyrogen-free water, before use.

[0114] The compounds of formula I may also be formulated into enteral compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0115] For intranasal or inhalation administration, the compound of formula I is conveniently delivered in the form of a solution or suspension from a pump-action spray container that is squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by equipping a valve to deliver a metered amount. The pressurized container or nebulizer can dispense a solution or suspension of the active compound. Capsules and cartridges (e.g., made of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mix of the active compound and a suitable powder base (e.g., lactose or starch). When aqueous suspensions and / or elixirs are desired for oral administration, the essential active ingredient therein can be combined with a diluent such as water, ethanol, propylene glycol, glycerin, and the like and combinations thereof, along with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0116] All documents cited herein are hereby incorporated by reference in their entirety.

[0117] The following examples are illustrative of the present invention and are not intended to be limiting thereof. EXAMPLES

[0118] Example 1: Treatment of Acute and Residual Symptoms of Schizophrenia For the purposes of this example, Compound A refers to the compound of formula I where X is -N(CH3)- and Y is -C(O)-; tosylate salt unless otherwise specified. A randomized, double-blind, placebo-controlled, inpatient study is conducted. There are four treatment arms, a four-week treatment period, and QAM dosing as follows: Compound A 60 mg; Compound A 120 mg; positive control (risperidone 4 mg); and placebo. The primary outcome is measured by change from baseline in Positive and Negative Symptom Scale (PANSS) total score at day 28. The secondary criteria explore key discriminatory features.

[0119] The Compound A 60 mg treatment arm will receive 60 mg of Compound A once daily for 28 days. The Compound A 120 mg treatment arm will receive 60 mg of Compound A on study day 1, then 120 mg of Compound A once daily for 27 days. The Risperidone treatment arm will receive 2 mg of Risperidone on study day 1, then 4 mg of Risperidone once daily for 27 days. The Placebo treatment arm will receive placebo once daily for 28 days. All administration will be in the morning with breakfast.

[0120] Key inclusion criteria: Clinical diagnosis of schizophrenia according to DSM-IV-TR confirmed by modified SCID-CT. Screening Brief Psychiatric Reading Scale (BPRS) score of 40 or more (18 items each scored 1-7). Minimum score of 4 or more for at least two of the following positive items: suspiciousness, disorganized concepts, hallucination-like behavior, abnormal thought content. Current worsening episode lasting 4 weeks or less. Adequate medical history and / or neutral reporter must establish that the current state is a worsening state for the individual. Previous response to antipsychotic treatment within the last 5 years, defined as a clinically significant, documented reduction in delusions and / or hallucinations during a documented worsening episode (and at least 3 months of previous exposure to antipsychotic treatment).

[0121] The clinical trial has a high subject completion rate (74%) compared to an average completion rate of 62% in another 4-week antipsychotic clinical trial. 19% discontinue during the study treatment period (between days 1 and 28). 7% complete the 28 days of study treatment but are lost to follow-up. At 60 mg, the clinical trial shows that Compound A demonstrates antipsychotic activity on the primary endpoint PANSS total change from baseline at day 28:

[0122] [Table 2]

[0123] For patients with significant negative symptoms at baseline (e.g., patients with a score of 4 or greater on at least three negative symptom items at baseline), Compound A 60 mg qualitatively improves negative symptoms (see Figure 1).

[0124] In the subgroup of patients with symptoms of depression secondary to schizophrenia as measured by the cut-off score for depression at baseline (Calgary Depression Scale for Schizophrenia, CDSS, score >6) (representing approximately 16% of patients in the study), Compound A 60 mg significantly reduces depression as measured by CDSS (p=0.044). Compound A 60 mg also reliably improves total PANSS (see Figure 2) and negative symptoms (see Figure 3).

[0125] At 60 mg, Compound A is also shown to significantly improve prosocial PANSS factor change from baseline compared to placebo (see Figure 4).

[0126] Examples 2-10: Preparation of long-acting injectable microsphere formulations

[0127] Example 2: Preparation of PLGA (PLA / PLG=75 / 25, 0.32-0.44 dl / g) microspheres of Compound A free base (Lot A) For purposes of Examples 2-10, Compound A refers to the free base form of a compound of Formula I, where X is -N(CH3)- and Y is -C(O)-. 2 g of poly(vinyl alcohol) (PVA, 87-89% hydrolysis, typical molecular weight 13,000-23,000) in 400 mL of deionized water is sonicated in an ultrasonicator for 5-10 minutes, then filtered to obtain a 0.5% aqueous PVA solution. The filtrate is transferred to a 500 mL flat-bottom flask. 0.80 g of compound A and 1.2 g of PLGA polymer (PLA / PLG=75 / 25, 0.32-0.44 dl / g, acid end groups) are dissolved in 15 mL of dichloromethane. With vigorous stirring, this solution is added dropwise into the 0.5% aqueous PVA solution. A mechanical overhead stirrer is used, and the stirring speed is about 700 ppm throughout the addition. After the addition is complete, the mixture is stirred at this speed for 1 hour, then at about 550 ppm for 4 hours. An argon flow is added throughout the process to promote the evaporation of dichloromethane from the aqueous solution. A 75 μm size microsieve is layered on top of a 20 μm microsieve. The suspension is poured onto the layered microsieve and then washed with water at least five times. The microspheres collected on the 20 μm microsieve are transferred into a 50 mL Falcon tube with deionized water and then freeze-dried to obtain 1.43 g Compound A PLGA microspheres with a particle size distribution of 20-60 μm. The drug content in the resulting microspheres is 37.5% as measured by HPLC. The initial loading of this formulation is 40% (calculated based on 0.8 g Compound A free base in 1.2 g PLGA polymer). The drug encapsulation efficiency is 93.8%.

[0128] Example 3: Preparation of PLGA (PLA / PLG=75 / 25, 0.32-0.44 dl / g) microspheres of Compound A free base (Lot B) This lot of Compound A PLGA microspheres is prepared using a procedure similar to that described in Example 2, except that sterile water is used instead of deionized water throughout the process and all labware that comes into contact with the microspheres is sterilized. 1.49 g of Compound A PLGA microspheres with a particle size distribution of 20-50 μm are obtained. The drug content in the resulting microspheres is 38% as measured by HPLC. The initial drug loading of this lot is 40%, and the drug encapsulation efficiency is 85.8%.

[0129] Example 4: Preparation of PLGA (PLA / PLG=75 / 25, 0.89 dl / g) microspheres of Compound A free base (Lot C) 2 g of poly(vinyl alcohol) (PVA, 87-89% hydrolysis, typical molecular weight 13000-23000) in 400 mL of sterile water is sonicated in an ultrasonicator for 5-10 minutes, then filtered to obtain a 0.5% aqueous PVA solution. The filtrate is transferred to a 500 mL flat-bottom flask. 0.80 g of compound A and 1.2 g of PLGA polymer (PLA / PLG=75 / 25; 0.89 dl / g; MW: 159,000 d; ester end groups) are dissolved in 16 mL of dichloromethane with sonication. This solution is added dropwise into the 0.5% aqueous PVA solution. A mechanical overhead stirrer is used, and the stirring speed is about 700 ppm throughout the addition. After the addition is complete, the mixture is stirred at this speed for 1 hour, then at about 550 ppm for 4 hours. An argon flow is added throughout the process to promote the evaporation of dichloromethane from the aqueous solution. A 75 μm size microsieve is layered on top of a 20 μm microsieve. The suspension is poured onto the layered microsieve and then washed with water at least five times. The microspheres collected on the 20 μm microsieve are transferred into a 50 mL Falcon tube with deionized water and then freeze-dried to obtain Compound A 0.78 g PLGA microspheres with a particle size distribution of 20-70 μm. The drug content in the resulting microspheres is 36% as measured by HPLC. The initial loading of this formulation is 40% (calculated based on 0.8 g of Compound A free base in 1.2 g of PLGA polymer). The drug encapsulation efficiency is 90%.

[0130] Example 5: Preparation of PLGA (PLA / PLG=75 / 25, 0.68 dl / g) microspheres of Compound A free base (Lot D) This lot of Compound A PLGA microspheres is prepared using a procedure similar to that described in Example 4, except that a new type of PLGA polymer (PLA / PLG=75 / 25; 0.68 dl / g; MW: 113,000 d; acid end groups) is used in the microsphere preparation. 1.11 g of Compound A PLGA microspheres with a particle size distribution of 25-75 μm are obtained. The drug content in the resulting microspheres is 36% as measured by HPLC. The initial drug loading of this lot is 40%, and the drug encapsulation efficiency is 90%.

[0131] Example 6: Preparation of PLGA (PLA / PLG=75 / 25, 0.68 dl / g) microspheres of Compound A free base (Lot E) This lot of PLGA microspheres is prepared using a procedure similar to that described in Example 4, except that a different type of PLGA polymer (PLA / PLG=75 / 25; 0.68 dl / g; MW: 113,000 d; acid end groups) and a microsieve with a pore size of 75 μm are used in the microsphere preparation. 0.25 g of compound A PLGA microspheres with a particle size distribution of 75-110 μm are obtained. The drug content in the obtained microspheres is 37% as measured by HPLC. The initial drug loading of this lot is 40%, and the drug encapsulation efficiency is 93%.

[0132] Example 7: Preparation of PLGA (PLA / PLG=75 / 25, 0.68 dl / g) microspheres of Compound A free base (Lot F) This lot of Compound A PLGA microspheres is prepared using a procedure similar to that described in Example 4, except that a new type of PLGA polymer (PLA / PLG=75 / 25; 0.68 dl / g; MW: 113,000 d; acid end groups) and microsieves with pore sizes of 53 μm and 106 μm, respectively, are used in the microsphere preparation. 1.22 g of PLGA microspheres with a particle size distribution of 52-101 μm are obtained. The drug content in the obtained microspheres is 37% as measured by HPLC. The initial drug loading of this lot is 40%, and the drug encapsulation efficiency is 93%.

[0133] Example 7-A: Preparation of PLGA (PLA / PLG=75 / 25, 0.32-0.44 dl / g) microspheres of Compound A free base (Lot F) 2 g of poly(vinyl alcohol) (PVA, 87-89% hydrolysis, typical molecular weight 13000-23000) in 400 mL of sterile water is sonicated in an ultrasonicator for 5-10 minutes, then filtered to obtain a 0.5% PVA aqueous solution. The filtrate is transferred to a 500 mL flat-bottom flask. 0.40 g of compound A and 2.1 g of PLGA polymer (PLA / PLG=75 / 25; 0.32-0.44 dl / g; acid end groups) are dissolved in 21 mL of dichloromethane with sonication. This solution is added dropwise into the 0.5% PVA aqueous solution. A mechanical overhead stirrer is used, and the stirring speed is about 500 ppm throughout the addition. After the addition is complete, the mixture is stirred at about 500 ppm for 5 hours. An argon flow is added throughout the process to promote the evaporation of dichloromethane from the aqueous solution. A 75 μm size microsieve is layered on top of the 30 μm microsieve. The suspension is poured onto the stack of microsieves and then washed with water at least five times. The microspheres collected on the 30 μm microsieve are transferred into a 1 / 4 ounce glass vial and then dried under vacuum to obtain 1.43 g of Compound A free base PLGA microspheres with a particle size distribution of 25-70 μm. The drug content in the resulting microspheres is 8.5% as measured by HPLC. The initial loading of this formulation is 16% (calculated based on 0.4 g of Compound A free base in 2.1 g of PLGA polymer). The drug encapsulation efficiency is 53%.

[0134] Example 8: Preparation of PLGA (PLA / PLG=75 / 25, 0.68 dl / g) microspheres of Compound B free base (Lot G) For the purposes of this example, compound B refers to the compound of formula I where X is -N(CH3)- and Y is -CH(OH)-. 2 g of poly(vinyl alcohol) (PVA, 87-89% hydrolysis, typical molecular weight 13000-23000) in 400 mL of deionized water is sonicated in an ultrasonicator for 5-10 minutes, then filtered to obtain a 0.5% aqueous PVA solution. The filtrate is transferred to a 500 mL flat-bottom flask. 0.80 g of compound B (free base) and 1.2 g of PLGA polymer (PLA / PLG=75 / 25, 0.32-0.44 dl / g, acid end groups) are dissolved in 15 mL of dichloromethane. This solution is added dropwise into the 0.5% aqueous PVA solution. A mechanical overhead stirrer is used, and the stirring speed is about 700 ppm throughout the addition. After the addition is complete, the mixture is stirred at this rate for 1 hour, then at about 550 ppm for 4 hours. An argon flow is applied throughout the process to promote the evaporation of dichloromethane from the aqueous solution. A 75 μm size microsieve is layered on top of the 20 μm microsieve. The suspension is poured onto the layered microsieve, then washed with water at least 5 times. The microspheres collected on the 20 μm microsieve are transferred into a 50 mL Falcon tube with deionized water, then lyophilized to obtain 1.36 g of compound B PLGA microspheres with a particle size distribution of 13-60 μm. The drug content in the resulting microspheres is 29% as measured by HPLC. The initial loading of this formulation is 40% (calculated based on 0.8 g of compound B free base in 1.2 g of PLGA polymer). The drug encapsulation efficiency is 72.5%.

[0135] Example 9: Loading Determination of Long-Acting Injectable Microspheres Approximately 5 mg of microspheres are dissolved in 10 mL of a 1:2 v / v mixture of dichloromethane / acetonitrile. 1 mL of the solution is transferred into a 1.5 mL microtube and the solvent is removed using a Savant Speed ​​Vac; the residue is then reconstituted with 95% acetonitrile / 5% water. The solution is filtered (Waters 0.2 μm nylon syringe filter) and run in triplicate on a Waters Acquity UPLC equipped with a PDA UV absorbance detector set at 314 nm. The mobile phase is an acetonitrile-water gradient with 0.1% v / v formic acid. A Waters Acquity UPLC HSS T3 (2.1×50 mm) column is used with a flow rate of 0.3 ml / min. A standard curve is generated to include expected concentrations of compound A of approximately 0.1-0.7 mg / mL.

[0136] Drug loading is determined as follows: Percent drug loading = 100 x (10 x filtered solution concentration) / weight of microspheres used. Results are reported as mean ± SD.

[0137] Example 10: Drug release measurement of long-acting injectable microspheres Microsphere drug release experiments are carried out in 0.1 M phosphate buffer (pH 7.4) containing 10 mM ascorbic acid. A microsphere suspension containing a known amount of drug (approximately 30 mg) is placed in a regenerated cellulose membrane dialysis device (Float-a-Lyzer). The Float-a-Lyzer is placed in a 45 mL Falcon tube containing 40 mL of buffer, and the release medium is maintained at 37°C in an oven with horizontal shaking at 100 rpm. The buffer is replaced with fresh solution at regular time intervals. The drug content of the release medium is measured by UPLC using UV-vis absorbance at 314 nm together with a standard curve constructed using known concentrations of ITI07 (3-30 μg / mL).

[0138] Example 11: Pharmacokinetics of long-acting injectable microspheres For in vivo characterization, in vivo drug release (pharmacokinetic studies) is measured. The pharmacokinetics of the formulations are studied in adult male Sprague-Dawley rats. Rats (N=12 per experiment) are injected subcutaneously in the scapular region with a suspension (2 ml / kg) of Compound A free base formulated in biodegradable PLGA microspheres (approximately 60 mg per rat) suspended in a solution of 0.5% low viscosity carboxymethylcellulose in sterile saline containing 0.1% Tween 20. At specific times post-injection (i.e., 24 hours to 28 days), rats (N=2 or 3 per time point) are monitored for changes in 5-HT due to circulating Compound A levels. 2A 5-HT as a functional indicator of antagonist activity 2A Test for agonist-induced head twitch behavior. For these measurements, 2,5-dimethoxy-4-iodoamphetamine (DOI) (2.5 mg / kg) is injected intraperitoneally into rats in a volume of 2 ml / kg. After 5 min, rats are observed for stereotypic head twitch behavior, which is counted and recorded manually. At specific time points (i.e., 24 h to 28 days after formulation injection), rats are sacrificed by decapitation and trunk blood and brain tissue are collected for analysis of levels of Compound A and its known metabolite (Compound B) using HPLC-MS / MS methods.

[0139] Using the above or similar procedures, several sustained release injectable microsphere formulations are analyzed for the in vivo release profile of the compound of formula I, where X is -N(CH3)- and Y is -C(O)- (Compound A free base). The results are summarized in the table below. Table 2 shows the physical characteristics of LAI microsphere formulations 2-7 and 7A. Particle size distribution is measured using microscopy.

[0140] [Table 3]

[0141] The actual drug loading reports the % weight / weight of Compound A in the microspheres. The microspheres are administered to the animals at either 60 mg / kg or 30 mg / kg. The Compound A dose in Table 2 represents the amount of drug administered to the animals (actual drug loading x microsphere dose). Plasma and brain levels of both Compound A and the major metabolite of Compound A (Compound B) are measured on days 1, 3, 7, 10, 14 and 21 after subcutaneous injection in rats. The results are shown in Table 3.

[0142] [Table 4]

[0143] Unexpectedly, it is observed that a superior release profile (extended release) is obtained using lower microsphere loading. The microsphere formulation with 8.5 wt% loading (Example 7-A) produces a release profile with peak drug brain levels on day 7 and measurable levels of drug up to day 21 of the study (day 21 brain level 11 ng / mL). In contrast, microspheres with high drug loading have an earlier peak drug level and do not maintain measurable or low levels beyond day 10 of the study.

Claims

1. A method for treating residual symptoms comprising administering to a patient in need of such treatment a compound of formula I: 【Chemistry 1】 [In the formula, X is -O-, -NH- or -N(CH 3 )--and Y is -O-, -C(R 2 )(OH)-, -C(R 3 )(OR 1 )- or -C(O)-; R 1 is -C 1-6 Alkyl (e.g., methyl) or -C(O)-C 1-21 Alkyl (e.g., —C(O)—C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 alkyl), preferably the alkyl is linear, may be saturated or unsaturated, and has one or more hydroxy or C 1-22 It may be substituted with an alkoxy (e.g., ethoxy) group, e.g., R 1 is -C(O)-C 6 Alkyl, -C(O)-C 7 Alkyl, -C(O)-C 9 Alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15 alkyl, where the compound is hydrolyzed to form the residue of a natural or unnatural saturated or unsaturated fatty acid, e.g., the compound is hydrolyzed to form a hydroxy compound on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand; R 2 is H or -C 1-6 alkyl (e.g., methyl); R 3 is H or -C 1-6 alkyl (e.g., methyl). The method comprises administering an effective amount of a compound represented by the formula:

2. The compound of formula I is X is -O-, -NH- or -N(CH 3 )--and Y is -O-, -C(H)(OH)-, -C(H)(OR 1 )- or -C(O)-; R 1 GA-C(O)-C 1-21 Alkyl (e.g., —C(O)—C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 alkyl), preferably the alkyl is linear, may be saturated or unsaturated, and has one or more hydroxy or C 1-22 It may be substituted with an alkoxy (e.g., ethoxy) group, e.g., R 1 GA-C(O)-C 6 Alkyl, -C(O)-C 7 Alkyl, -C(O)-C 9 Alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15 alkyl, which hydrolyze to form the residue of a natural or unnatural saturated or unsaturated fatty acid, e.g., which hydrolyzes to form a hydroxy compound on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand.

10. The method of claim 1, wherein the compound is in free form or in a pharma- ceutically acceptable salt form.

3. The compound of formula I is X is -O- and Y is -C(H)(OH)-; X is -NH- and Y is -C(H)(OH)-; X is -N(CH 3 )-- and Y is -C(H)(OH)--; X is -O- and Y is -C(O)-; X is -O- and Y is -O-; or X is -N(CH 3 )-- and Y is -C(O)--, or X is -N(CH 3 )— and Y is —O—; X is -NH- and Y is -C(O)-; X is -NH- and Y is -O-; X is -N(CH 3 )- and Y is -C(H)(OR 1 ) - or X is -NH- and Y is -C(H)(OR 1 ) - or X is -O- and Y is -C(H)(OR 1 ) - or X is -O- and Y is -C(CH 3 )(OH)- or X is -NH- and Y is -C(CH 3 )(OH)- or X is -N(CH 3 )- and Y is -C(CH 3 )(OH)- 2. The method of claim 1, wherein the compound is selected from the group consisting of compounds of formula I:

4. X is -N(CH 3 2. The method of claim 1, wherein Y is -C(O)- or -C(H)(OH)-.

5. 5. The method according to any one of claims 1 to 4, wherein the patient is suffering from psychosis, such as schizophrenia, delusional disorder, major depression with psychosis, bipolar disorder with psychotic symptoms, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder or psychosis caused by a medical condition or substance use, preferably the patient is suffering from residual symptoms of schizophrenia.

6. 6. The method according to any one of claims 1 to 5, wherein the residual symptoms are selected from negative symptoms, such as blunted affect, emotional withdrawal, poor interpersonal relationships, passive or amotivated social withdrawal, difficulties with abstract thinking, loss of spontaneity and flow of speech, and stereotyped thinking; generalized psychopathological symptoms, such as somatic concerns, anxiety, guilt, tension, habits and unnatural postures, depression, delayed motor development, uncooperativeness, abnormal thought content, disorientation, impaired attention, poor judgment and insight, impaired volition, poor impulse control, preoccupations and active social avoidance; cognitive disorders and sleep disorders (e.g. insomnia).

7. The method of any one of claims 1 to 6, further comprising administering one or more other therapeutic agents, such as a further antipsychotic and / or antidepressant and / or hypnotic.

8. 8. The method of claim 7, wherein the one or more other therapeutic agents are selected from antidepressants, e.g., compounds that modulate GABA activity (e.g., enhance the activity and enhance GABA transmission), GABA-B agonists, 5-HT modulators (e.g., 5-HT1a agonists, 5-HT2a antagonists, 5-HT2a inverse agonists, etc.), melatonin agonists, ion channel modulators (e.g., blockers), serotonin-2 antagonists / reuptake inhibitors (SARIs), orexin receptor antagonists, H3 agonists, noradrenaline antagonists, galanin agonists, CRH antagonists, human growth hormone, growth hormone agonists, estrogen, estrogen agonists, neurokinin 1 drugs; and antipsychotics, e.g., atypical antipsychotics, in free form or in pharma- ceutically acceptable salt form.

9. The one or more other therapeutic agents may be selected from the 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, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin, risperidone, eplivanserin, vorinancerin (Sanofi-Aventis, France), pulvanserin, MDL 100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego, CA), AVE8488 (Sanofi-Aventis, France), repinotan, sarizotan, eptapyrone, buspirone, MN-305 (MediciNova, San Diego, CA), melatonin, ramelteon (ROZEREM®, Takeda Pharmaceutical Co., Ltd., Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II Discovery), agomelatine, lamotrigine, gabapentin, pregabalin, orexin, 1,3-biarylurea, SB-334867-a (GlaxoSmithKline,UK), GW649868 (GlaxoSmithKline), benzamide derivatives, 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, 9. The method of claim 7 or 8, wherein the active ingredient is selected from the group consisting of 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.

10. 10. The method according to any one of claims 7 to 9, wherein the administration of a compound of formula I is adjunctive to the administration of one or more other therapeutic agents, such as an antipsychotic and / or an antidepressant and / or a hypnotic.

11. 11. The method of any one of claims 7 to 10, wherein the one or more other therapeutic agents is an antipsychotic selected from chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetirapine, risperidone, ziprasidone, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, amisulpride, zotepine, sertindole, in free form or in a pharma- ceutically acceptable salt form.

12. 12. A method according to any one of claims 7 to 11, wherein the administration of said one or more other therapeutic agents, such as antipsychotics and / or antidepressants and / or hypnotics, is adjunctive to the administration of a compound of formula I.

13. 13. The method of any one of claims 7 to 12, wherein the one or more other therapeutic agents is an antidepressant selected from one or more of 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, and velafaxine.

14. 14. The method of any one of claims 7 to 13, wherein the one or more other therapeutic agents is an antidepressant selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), and a tricyclic antidepressant.

15. 15. The method of claim 14, wherein the antidepressant is an SSRI.

16. The method according to any one of claims 1 to 15, wherein the compound of formula I is orally administered as a composition comprising a pharma- ceutically acceptable diluent or carrier in an oral unit dosage form which is a tablet or capsule.

17. The method of any one of claims 1 to 16, wherein the effective amount of the compound of formula I is a daily dose of about 1 mg to about 140 mg.

18. The method of any one of claims 1 to 17, wherein the effective amount of the compound of formula I is a daily dose of about 10 mg to about 120 mg.

19. The method of any one of claims 1 to 18, wherein the effective amount of the compound of formula I is a daily dose of about 20 mg to about 60 mg.

20. The method of any one of claims 1 to 19, 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.

21. 21. The method of any one of claims 1 to 20, wherein the patient does not respond adequately to treatment with other antipsychotics or combinations of antipsychotics.

22. 22. The method of claim 21, wherein the patient is unresponsive to treatment with one or more antipsychotic drugs selected from chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetirapine, risperidone, ziprasidone, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, amisulpride, zotepine, and sertindole.

23. 23. The method of claim 22, wherein the patient is non-responsive to treatment with risperidone.

24. The method of any one of claims 1 to 23, wherein the compound of formula I is formulated in a sustained or delayed release formulation.

25. 25. The method of claim 24, wherein the sustained or delayed release formulation is a sustained release injectable microsphere formulation.

26. A method for treating residual symptoms comprising administering to a patient in need of said treatment a PLGA matrix of 75:25 PLA / PLG having carboxylic acid or carboxylic acid end groups and a compound represented by formula I: 【Chemistry 2】 [In the formula, X is -O-, -NH- or -N(CH 3 )--and Y is -O-, -C(R 2 )(OH)-, -C(R 3 )(OR 1 ) or -C(O)-; R 1 is -C 1-6 Alkyl (e.g., methyl) or -C(O)-C 1-21 Alkyl (e.g., —C(O)—C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 alkyl), preferably the alkyl is linear, may be saturated or unsaturated, and has one or more hydroxy or C 1-22 It may be substituted with an alkoxy (e.g., ethoxy) group, e.g., R 1 is -C(O)-C 6 Alkyl, -C(O)-C 7 Alkyl, -C(O)-C 9 Alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15 alkyl, where the compound is hydrolyzed to form the residue of a natural or unnatural saturated or unsaturated fatty acid, e.g., the compound is hydrolyzed to form a hydroxy compound on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand; R 2 is H or -C 1-6 alkyl (e.g., methyl); R 3 is H or -C 1-6 alkyl (e.g., methyl). The method comprises administering a sustained release injectable composition comprising an effective amount of a compound represented by the formula:

27. 26. A pharmaceutical composition for the treatment of residual symptoms according to any one of claims 1 to 25, comprising a compound of formula I, in free form or in a pharma- ceutical acceptable salt form, as defined in any one of claims 1 to 4, in admixture or formulation with a pharma- ceutical acceptable diluent or carrier.

28. Use of a compound of formula I as defined in any one of claims 1 to 4 in the manufacture of a medicament for the treatment of residual symptoms as defined in any one of claims 1 to 25.

29. A sustained release injectable composition comprising a PLGA matrix of 75:25 PLA / PLG having either carboxylic acid or carboxylic acid end groups, and an effective amount of a compound of formula I in free form or in a pharma- ceutically acceptable salt form, such as composition 1 above or composition 2.1 below.

30. 30. The sustained release injectable composition of claim 29, wherein the amount of the compound of formula I dispersed, dissolved or encapsulated in each microsphere is, on average, about 5% to about 50% by weight, such as about 10% to about 50% by weight, or about 20% to about 40% by weight, or about 30% to about 40% by weight, or such as about 8.5% by weight, or about 16% by weight, or about 30% by weight, or about 35% by weight, or about 40% by weight.

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