New Method

Abstract

Medicaments for the treatment of psychosis (such as schizophrenia), or depression (such as bipolar depression) and / or anxiety are provided. [Solution] 5-HT 2A or 5-HT 2A A pharmaceutical composition for treating schizophrenia and / or depression, comprising a 5-HT / D2 receptor ligand, 2A or 5-HT 2A The pharmaceutical composition of claim 1, wherein the D2 receptor ligand is a compound of formula I in free form or a pharmaceutically acceptable salt form, and the pharmaceutical composition is for use in combination with a nitric oxide donor, wherein the nitric oxide donor is selected from sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate), amyl nitrate, diethylene glycol dinitrate, isosorbide mononitrate, isosorbide dinitrate, itramin tosylate, pentaerythritol tetranitrate, propatyl nitrate, dinitrodyl, tenitramine, trolnitrate, molsidomine, linsidomine, and naproxcinod. JPEG0007821366000023.jpg3573

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This is an international application claiming priority to and benefit of U.S. Provisional Patent Application No. 62 / 906,042, filed September 25, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical Field The present disclosure provides a method for the treatment of psychosis (such as schizophrenia), or depression (such as bipolar depression) and / or anxiety, comprising: (i) 5-HT 2A or 5-HT 2A The present invention relates to the use of (i) a substituted heterocycle-fused gamma-carboline described herein, in free form, a pharmaceutically acceptable salt form, or a prodrug form, and (ii) a nitric oxide donor, either separately (sequentially or simultaneously) or in combination (e.g., as a fixed-dose combination). [Background technology]

[0003] Background of the Invention Recent psychiatric genomic studies have suggested that major psychiatric disorders, such as schizophrenia, bipolar disorder, and major depressive disorder (MDD), which are now classified as separate disorder categories, exhibit both clinical overlap and familial co-aggregation, and share genetic risk factors. Potential mechanisms underlying this clinical overlap are also emerging, implicating genes involved in neurodevelopment, synaptic plasticity, and cognitive function.

[0004] Preclinical and clinical data accumulated over the past several decades have collectively depicted the key roles of prefrontal dopamine and D1 receptors, as well as serotonin and glutamatergic NMDA receptor-mediated transmission, in the above-mentioned cognitive modalities. Evidence is emerging regarding the partially overlapping dysfunction of these transmitters and receptors in schizophrenia and MDD. Therefore, the combination of atypical antipsychotics (APDs), which primarily exhibit potent 5-HT2A receptor-blocking properties and modest D2 receptor-blocking properties, with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) is frequently used in these psychiatric disorders, although APD doses are reduced in treatment-resistant depression (TRD). Previous studies have shown that this drug combination activates both dopamine release and D1 receptor-mediated glutamatergic NMDA receptor-mediated transmission in the prefrontal cortex (PFC), even with relatively low D2 receptor occupancy.

[0005] Add-on treatment of low-to-moderate doses of atypical APDs to SSRIs in TRD potently enhances antidepressant efficacy with a rapid onset of action. However, the rapid and potent antidepressant effects of ketamine are highly dependent on glutamatergic AMPA receptor activation in the PFC, which promotes activation of the mTOR pathway and the associated increase in synapse number and function, reversing synaptic deficits in TRD.

[0006] Recent data indicate that combinations of the above drugs exert the same effects as ketamine in this regard, exemplified by the combination of olanzapine and fluoxetine or the combination of brexpiprazole and escitalopram, and also reverse changes in BDNF-TrkB signaling and dendritic spine density in the PFC in an inflammatory model of secondary depression.

[0007] Accumulating evidence suggests that inflammation plays a role in the pathophysiology of mood disorders, including bipolar and unipolar depressive disorders. Elevated levels of proinflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and especially interleukin-6 (IL-6), are also found in the serum / plasma and CSF of depressed patients in the absence of comorbid medical conditions. Furthermore, stimulation of the immune system by lipopolysaccharide (LPS) can induce depressive symptoms even in individuals without previous depression. Several findings indicate a pathophysiological role for IL-6 in depression, particularly in patients unresponsive to SSRIs.

[0008] Preclinically, peripheral administration of LPS can induce depressive-like behavior in rodents, which is associated with the induction of inflammation and thus provides an animal model of inflammation-related dysphoria. Furthermore, LPS-induced depressive-like behavior can be blocked by pretreatment with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs). Another, but complementary, experimental approach is to use Flinders Sensitive Line (FSL) rats, which provide a genetically defined animal model of depression with many behavioral and neurochemical similarities to human depression. FSL rats also appear to exhibit increased neuroinflammation, as characterized by increased brain levels of leptin, IL-1α, and BDNF.

[0009] Substituted heterocycle-fused gamma-carbolines, such as lumateperone, are useful in the treatment of central nervous system disorders, including 5-HT 2A or 5-HT 2A These compounds are known to be serotonin 2A (5-HT 2A) receptors and / or modulate dopamine receptor signaling at the level of key intracellular phosphoproteins. Such compounds are primarily known to be useful in treating the positive and negative symptoms of schizophrenia. At the dopamine D2 receptor, these compounds have dual properties, acting as both postsynaptic antagonists and presynaptic partial agonists. They also stimulate phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors in a mesolimbic-specific manner. This regional selectivity in brain regions thought to mediate the effects of antipsychotic drugs, along with serotonergic, glutamatergic, and dopaminergic interactions, is thought to result in antipsychotic effects against the positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compounds also exhibit serotonin reuptake inhibition, providing antidepressant activity in the treatment of schizoaffective disorder, comorbid depression, and / or as a stand-alone treatment for major depressive disorder. The 5-HT 2A or 5-HT 2A 5-HT / D2 receptor ligands are also 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 can improve the quality of life of schizophrenic patients, enhancing their social functioning and enabling them to integrate more fully into their families and workplaces. At low doses, these compounds inhibit the activity of 5-HT 2A They selectively target D2 receptors and exhibit differential dose-dependent effects, interacting gradually with D2 receptors at higher doses. As a result, they are useful in treating sleep, aggression, and agitation at low doses. At higher doses, they can treat acute and residual schizophrenia, bipolar disorder, and mood disorders.

[0010] formula: [ka] Lumateperone, which has a potent (Ki=0.5 nM) 5-HT2A Lumateperone is a novel therapeutic agent with receptor antagonism, in vivo activity consistent with presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki = 32 nM), high D1 receptor affinity (Ki = 52 nM), and inhibition of the serotonin transporter (SERT) (Ki = 26-62 nM, using different assays for SERT activity). Lumateperone is approved by the U.S. Food and Drug Administration for the treatment of schizophrenia and is in Phase III clinical development for the treatment of bipolar depression and agitation in dementia, including Alzheimer's disease.

[0011] In patients with schizophrenia, lumateperone has been shown to significantly improve social functioning, positive and negative symptoms, and cognitive impairment, with low striatal D2 receptor occupancy similar to that of clozapine. Furthermore, in patients with comorbid depression, lumateperone improves depressive symptoms without metabolic or extrapyramidal side effects, while maintaining a placebo-level safety profile.

[0012] Lumateperone also exhibits antidepressant-like effects in a social defeat model, reversing impaired socialization and social withdrawal after chronic stress. Recent data show that lumateperone alone independently activates both NMDA- and AMPA-receptor-induced currents in pyramidal cells of rat mPFC slices and increases the phosphorylation of key proteins in the mTOR pathway, including the protein kinase Akt and p70S6 kinase, supporting a ketamine-like mechanism of action for lumateperone in both MDD and TRD.

[0013] Lumateperone and related compounds are disclosed in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,071,186; 7,183,282; U.S. Patent No. Re. 39,680; and U.S. Patent No. Re. 39,679 for the treatment of 5-HT agonists, such as anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache-related conditions, and social phobia. 2AThey are disclosed as novel compounds useful for the treatment of disorders associated with receptor modulation. U.S. Patent Nos. 7,071,186 and 7,183,282 also disclose methods for preparing substituted heterocycle-fused gamma-carbolines and the use of these gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders, such as addictive behaviors and sleep disorders. Nos. 8,598,119, 9,168,28, 9,616,061, 10,117,867, and U.S. Patent Application Publication No. 2015 / 0080404 (each incorporated herein by reference) disclose the use of certain substituted heterocycle-fused gamma-carbolines for the treatment of combined psychotic and depressive disorders, and sleep disorders, depressive disorders, and / or mood disorders in psychotic or Parkinson's disease patients, as well as for the treatment or prevention of dementia-related disorders, particularly behavioral or mood disorders, such as agitation, irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts, and dementia-related psychotic and sleep disorders. U.S. Patent Nos. 9,956,117 and 10,322,134 specifically disclose methods for treating negative or residual symptoms of schizophrenia using certain such substituted heterocycle-fused gamma-carbolines. International Publication No. WO 2019 / 178484 discloses the use of such compounds for the acute treatment of depression and anxiety. U.S. Pat. Nos. 8,648,077, 9,119,995, and 9,586,960 (each of which is incorporated herein by reference) disclose methods for preparing crystalline toluenesulfonic acid addition salts of certain substituted heterocyclic-fused γ-carbolines, such as the toluenesulfonic acid addition salt of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

[0014] U.S. Patent No. 8,993,572 and U.S. Patent No. 9,371,324 (each incorporated herein by reference) disclose prodrugs / metabolites of substituted heterocyclic ring-fused γ-carbolines for improved formulations, e.g., sustained / controlled release formulations. The applications disclose that heterocyclic ring-fused γ-carbolines N-substituted with a 4-fluorophenyl(4-hydroxy)butyl moiety have been shown to have high selectivity for the serotonin transporter (SERT) compared to heterocyclic ring-fused γ-carbolines containing 4-fluorophenylbutanone.

[0015] US Patent No. 8,598,119 teaches that selected substituted heterocyclic-fused gamma-carboline compounds have nanomolar affinity for the serotonin reuptake transporter (SERT) and are therefore selective serotonin reuptake inhibitors.

[0016] As disclosed in U.S. Pat. No. 10,077,267, U.S. Patent Application Publication No. 2017 / 0183350, and U.S. Patent Application Publication No. 2019 / 0231780 (each incorporated herein by reference), deuterated forms of lumateperone and related compounds have been shown to have improved metabolic stability.

[0017] Thus, unique among APDs, fused heterocyclic gamma-carbolines such as lumateperone exhibit both dopamine receptor modulation and SSRI activity in a single compound. Like ketamine, they potentiate both NMDA- and AMPA-induced currents in rat mPFC pyramidal neurons via D1 receptor activation and increase phosphorylation of key proteins in the mTOR pathway, which is thought to be downstream of AMPA receptor activation. Therefore, these compounds may be potential new, fast-acting antidepressants for mood disorders. More recent studies have shown that lumateperone exhibits anti-inflammatory properties, but unlike other drugs (e.g., ketamine), it does not directly affect microglial cells.

[0018] In recent years, the glutamate-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway has been of increasing interest as a target for novel antipsychotic drugs (APDs) due to its involvement in the pathogenesis of schizophrenia. It has been found that brain NO levels in the cerebrospinal fluid (CSF) are reduced in patients with schizophrenia compared with healthy controls. Postmortem studies have shown that patients with schizophrenia have significantly fewer striatal interneurons containing NO synthase (NOS).

[0019] NO is synthesized after activation of N-methyl-D-aspartate receptors (NMDARs), diffuses, and activates soluble guanylyl cyclase, which then produces cGMP. Brain NMDAR dysfunction has been well documented in schizophrenia, which may contribute to reduced brain NO levels in patients. Furthermore, polymorphisms in the NOS1 gene have been shown to be associated with schizophrenia, and reduced NOS1 expression may predispose patients to schizophrenia by contributing to a hypoglutamatergic state in the hippocampus.

[0020] Studies have shown that a single injection of the hypotensive NO donor sodium nitroprusside (SNP) can induce rapid (within 4 hours) and sustained (for weeks) antipsychotic effects in young, treatment-resistant schizophrenic patients stably receiving antipsychotic medications. A further case study demonstrated similar effects in clozapine-resistant schizophrenic patients. Because clozapine is the only FDA-approved antipsychotic for treatment-resistant schizophrenia, these findings highlight the clinical potential of SNP. Another double-blind study in healthy volunteers showed that SNP reduced ketamine-induced psychotomimetic symptoms.

[0021] Previous preclinical behavioral studies have also suggested that SNP may have antipsychotic potential. Thus, administration of SNP to rats completely abolished phencyclidine (PCP)-induced hyperactivity. Furthermore, a single dose of SNP was found to prevent ketamine-induced hyperactivity up to 1 week after SNP injection and also reversed ketamine-induced memory impairment in a novel object recognition test.

[0022] Using whole-cell patch-clamp recordings, we have shown that a single intraperitoneal (ip) injection of SNP (3 mg / kg) induces both rapid and sustained changes in brain synaptic plasticity, including enhancement of excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in rat medial prefrontal cortex (mPFC) brain slices.

[0023] Recently, we used behavioral and biochemical techniques to study the antipsychotic-like effects of SNP in rats, both when administered alone and in combination with subeffective doses of risperidone. Low doses of SNP rapidly and potently potentiated the antipsychotic-like effects of subeffective doses of risperidone in the conditioned avoidance response (CAR) test. Correlative biochemical studies of local dopamine release in freely moving rats showed that SNP significantly enhanced risperidone-induced dopamine release in the mPFC but not in the nucleus accumbens (NAc). Furthermore, preliminary data from in vivo voltammetry experiments showed increased NO responses in the NAc and PFC after SNP administration in rats, suggesting that increased NO signaling and increased intracellular levels of cGMP may mediate the antipsychotic activity of SNP in rats. Interestingly, a proinflammatory immune state (increased markers of cell-mediated immunity), including increased levels of cytokines such as IL-6, is regularly observed in schizophrenia.

[0024] There remains a need for improved treatments for schizophrenia, depression, anxiety and other central nervous system disorders, particularly in treatment-resistant patients. Summary of the Invention

[0025] Brief Summary of the Invention We have surprisingly found that the substituted heterocycle-fused gamma-carbolines described herein, particularly lumateperone, exhibit unexpected synergistic improvements in efficacy when combined with nitric oxide donors such as SNP.

[0026] Accordingly, the present disclosure provides a method for treating psychosis (e.g., schizophrenia), depression (e.g., bipolar depression) and / or anxiety, or other CNS disorders for which lumateperone has been shown to be effective, comprising: (i) administering an effective amount of 5-HT 2A or 5-HT 2A The present invention also provides methods for treating rheumatoid arthritis, including administering, separately (sequentially or simultaneously) or in combination (e.g., as a fixed-dose combination), a 5-HT 2+ / D2 receptor ligand, e.g., a substituted heterocyclic-fused gamma-carboline described herein, in free form, a pharmaceutically acceptable salt, or a prodrug form, and (ii) an effective amount of a nitric oxide donor, e.g., SNP. The present invention also provides, for example, methods for treating rheumatoid arthritis, including administering, separately (sequentially or simultaneously), or in combination (e.g., as a fixed-dose combination), (i) a 5-HT 2+ / D2 receptor ligand, e.g., a substituted heterocyclic-fused gamma-carboline described herein, in free form, a pharmaceutically acceptable salt, or a prodrug form, and (ii) an effective amount of a nitric oxide donor, e.g., SNP. 2A or 5-HT 2A and (ii) a nitric oxide donor.

[0027] In some embodiments, the present disclosure provides the above methods, further comprising the concurrent administration of a PDE1 inhibitor, such as the compound of Formula II disclosed herein. Such compounds have been disclosed, for example, in U.S. Patent No. 9,545,406, the contents of which are incorporated herein by reference in their entirety, to have utility in treating diseases, disorders, and injuries of the central nervous system, and to be neuroprotective and / or neuroregenerative agents. [Brief explanation of the drawings]

[0028] [Figure 1]Conditioned avoidance responding (CAR) in male Wistar rats 20 minutes after treatment with vehicle, lumateperone (1 mg / kg, 3 mg / kg, or 10 mg / kg), or risperidone (0.4 mg / kg). **p<0.01 compared to vehicle + saline; ***p<0.001 compared to vehicle + saline; n=11.

[0029] [Figure 2] CAR in male Wistar rats 90 min after treatment with vehicle, lumateperone (1 mg / kg, 3 mg / kg, or 10 mg / kg), or risperidone (0.4 mg / kg). *p<0.05 compared to vehicle+saline; n=11.

[0030] [Figure 3] CAR in male Wistar rats 20 min after treatment with vehicle / saline, lumateperone (3 mg / kg or 7 mg / kg) / saline, vehicle / SNP (1.5 mg / kg), or lumateperone (3 mg / kg or 7 mg / kg) / SNP (1.5 mg / kg). **p<0.01 compared with vehicle+saline; [ka] ## p<0.01; n=11 as indicated.

[0031] [Figure 4] CAR in male Wistar rats 90 min after treatment with vehicle / saline, lumateperone (3 mg / kg or 7 mg / kg) / saline, vehicle / SNP (1.5 mg / kg), or lumateperone (3 mg / kg or 7 mg / kg) / SNP (1.5 mg / kg). [ka] # p<0.05; n=11 as indicated. DETAILED DESCRIPTION OF THE INVENTION

[0032] Detailed Description 5-HT 2A or 5-HT 2A / D2 receptor ligands are serotonin 2A (5-HT 2A These compounds antagonize dopamine receptor signaling at the dopamine D2 receptor and / or modulate dopamine receptor signaling at the level of key intracellular phosphoproteins, and are therefore useful for treating not only acute symptoms but also residual symptoms of psychosis, particularly schizophrenia. At the dopamine D2 receptor, these compounds have dual properties, acting as both postsynaptic antagonists and presynaptic partial agonists. They also stimulate phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors in a mesolimbic-specific manner. This regional selectivity in brain regions thought to mediate the effects of antipsychotic drugs, along with serotonergic, glutamatergic, and dopaminergic interactions, is thought to result in antipsychotic effects on the positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compounds also exhibit serotonin reuptake inhibition, providing antidepressant activity in the treatment of schizoaffective disorder, comorbid depression, and / or as a stand-alone treatment for major depressive disorder. 5-HT listed 2A or 5-HT 2A / D2 receptor ligands are also useful in the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disorders associated with dementia, autism and other CNS diseases.

[0033] Lumateperone is a 5-HT 2A Lumateperone is a novel therapeutic agent with strong (Ki=0.5nM) binding to 5-HT receptors and moderate binding to D1 and D2 receptors and SERT transporters. Functionally, such binding can generally result in either agonist activity, partial agonist activity, or antagonist activity. Lumateperone inhibits 5-HT 2ALumateperone has been shown to exhibit potent antagonist activity at D1 and D2 receptors and mixed agonist / antagonist activity at D1 and D2 receptors (cell type dependent). In particular, lumateperone exhibits in vivo partial agonism at presynaptic D2 receptors and antagonism at postsynaptic D2 receptors (Ki = 32 nM), high D1 receptor affinity (Ki = 52 nM), and activity as a mesolimbic / mesocortical selective dopamine receptor protein phosphorylation modulator consistent with inhibition of serotonin transporter (SERT) activity (Ki = 26-62 nM, using different assays for SERT activity). Lumateperone is in Phase III clinical development for the treatment of agitation in schizophrenia, bipolar depression, and dementia, including Alzheimer's disease.

[0034] In certain embodiments, the present disclosure provides a method for treating psychosis (e.g., schizophrenia), depression (e.g., bipolar depression) and / or anxiety, or other CNS disorders for which lumateperone has been shown to be effective, comprising: (i) administering an effective amount of 5-HT 2A or 5-HT 2A The present invention provides a method (Method 1) comprising administering (i) a D2 receptor ligand, e.g., a substituted heterocyclic-fused gamma-carboline described herein, in free form, a pharmaceutically acceptable salt form, or a prodrug form, and (ii) an effective amount of a nitric oxide donor, e.g., SNP, separately (sequentially or simultaneously) or in combination (e.g., as a fixed-dose combination). For example, Method 1 can be as follows:

[0035] 1.1. 5-HT 2A or 5-HT 2A / D2 receptor ligands may be in deuterated form, in free form, in the form of a pharmaceutically acceptable salt or in the form of a prodrug, of formula I: [ka] [In the formula, X is -N(H)-, -N(CH3)-, or -O-; Y is -C(=O)-, -C(H)(OH)-, or -C(H)(OR)-; R1 is -C(O)-C 1-21 Alkyl or -C(O)OC 1-21 alkyl] Method 1, wherein the compound is a substituted heterocycle-fused γ-carboline compound represented by the formula:

[0036] 1.2. Method 1 or 1.1, wherein X in the compound of formula I is -N(H);

[0037] 1.3. Method 1 or 1.1, wherein X in the compound of formula I is -N(CH3)-;

[0038] 1.4. Method 1 or 1.1, wherein X in the compound of formula I is -O-;

[0039] 1.5. Method 1 or any of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(=O)-;

[0040] 1.6. Method 1 or any of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(H)(OH)-;

[0041] 1.7. Method 1 or any of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(H)(OR1)-;

[0042] 1.8. Compounds of formula I in which 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 wherein the alkyl may be saturated or unsaturated and contains one or more hydroxy or C 1-22 It is a straight chain optionally substituted with an alkoxy (e.g., ethoxy) group, for example, R1 is -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 15alkyl, wherein the compound hydrolyzes to form the residue of a natural or unnatural saturated or unsaturated fatty acid, for example, the compound 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; for example, R in the compound of formula I is -C(O)-C 6-15 alkyl, for example, —C(O)—C alkyl; or R in the compound of formula I is —C(O)—C 1-5 Alkyl, e.g., —C(O)—C3 alkyl, Method 1.7;

[0043] 1.9. Compounds of Formula I in which R1 is -C(O)OC 1-21 Alkyl (e.g., -C(O)OC 1-5 Alkyl, -C(O)OC 6-15 Alkyl or -C(O)OC 16-21 alkyl), preferably wherein the alkyl may be saturated or unsaturated and contains one or more hydroxy or C 1-22 It is a straight chain optionally substituted with an alkoxy (e.g., ethoxy) group, for example, R1 is -C(O)O-C6 alkyl, -C(O)O-C7 alkyl, -C(O)O-C9 alkyl, -C(O)OC 11 Alkyl, -C(O)OC 13 Alkyl or -C(O)OC 15 alkyl, wherein the compound hydrolyzes to form the residue of a natural or unnatural saturated or unsaturated fatty acid, for example, the compound 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; for example, R in the compound of formula I is -C(O)OC 6-15 alkyl, for example, —C(O)O—C alkyl; or R in the compound of formula I is —C(O)OC 1-5 Alkyl, e.g., —C(O)O—C3 alkyl, Method 1.7;

[0044] 1.10. Compounds of formula I [ka] Method 1 or any of 1.1 to 1.4 or 1.6;

[0045] 1.11. Compounds of formula I [ka] Method 1 or any of 1.1 to 1.4 or 1.6;

[0046] 1.12. Compounds of formula I [ka] any of the preceding methods 1, 1.3 or 1.5;

[0047] 1.13. Method 1 or any of methods 1.1 to 1.12, wherein the compound of formula I is in the form of a toluenesulfonic acid addition salt (monotosylate or ditosylate), optionally in the form of a crystalline salt;

[0048] 1.14. Method 1 or any of methods 1.1-1.12, wherein the compound of formula I is in the form of the free base;

[0049] 1.15. Method 1, or any of 1.1-1.14, wherein the compound of formula I is in a deuterated form, e.g., the deuterium:protium ratio for a particular carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, e.g., at least 2-fold, e.g., at least 10-fold higher;

[0050] 1.16. The compound of formula I is in free form or in the form of a pharmaceutically acceptable salt, for example in the form of a toluenesulfonic acid addition salt, [ka] wherein D represents hydrogen positions that substantially exceed the natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Selected from, Method 1.15;

[0051] 1.17. 5-HT 2A or 5-HT 2A any of the foregoing methods, wherein the D2 receptor ligand is a compound of Formula I, wherein X is —N(CH3)— and Y is —C(═O)—, in the form of a toluenesulfonic acid addition salt (e.g., monotosylate, ditosylate, or a combination thereof);

[0052] 1.18. Method 1.17, wherein the compound of formula I is administered in a daily dose equivalent to about 1-100 mg of the monotosylate salt, e.g., 1-75 mg, or 1-60 mg, or 1-40 mg, or 1-30, or 1-20 mg, or 1-10 mg, or 1-5 mg of the monotosylate salt;

[0053] 1.19. Method 1.17, wherein the method comprises once-daily administration of an oral unit dosage form, e.g., a tablet or capsule, comprising a compound of Formula I in an amount equivalent to 1-100 mg of the monotosylate salt, e.g., 1-75 mg, or 1-60 mg, or 1-40 mg, or 1-30 mg, or 1-20 mg, or 1-10 mg, or 1-5 mg of the monotosylate salt, and a pharmaceutically acceptable diluent or carrier;

[0054] 1.20. Method 1.17, wherein the method comprises once-daily administration of a unit dosage form for subcutaneous or transmucosal administration, e.g., a sublingual or buccal orally disintegrating tablet or film, comprising a compound of Formula I in an amount equivalent to 1 to 100 mg of the monotosylate salt, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg, or 1 to 5 mg of the monotosylate salt, and a pharmaceutically acceptable diluent or carrier;

[0055] 1.21. Method 1 or any of 1.1-1.20, wherein the nitric oxide donor is a nitrate compound (--O-NO2) or a nitrite compound (-O-NO);

[0056] 1.22. Method 1, or any of 1.1 through 1.20, wherein the nitric oxide donor is an N-nitroso compound (-N-NO), an S-nitroso compound (-S-NO), a diazeniumdiolate compound (-N-(NO)=(NO) or -NN(O)-N=O), or a furoxan compound;

[0057] 1.23. Any of Methods 1 or 1.1-1.22, wherein the nitric oxide donor is a compound that generates nitric oxide by in vivo enzymatic action (e.g., biotransformation), e.g., by denitration and / or reduction;

[0058] 1.24. Any of Methods 1 or 1.1-1.22, wherein the nitric oxide donor is a compound that generates nitric oxide in vivo without enzymatic action (e.g., biotransformation), e.g., by hydrolysis and / or spontaneous decomposition, e.g., an N-nitroso compound or a precursor thereof;

[0059] 1.25. Method 1, or any of 1.1-1.24, wherein the nitric oxide donor is a nitrate prodrug (e.g., a compound that releases a nitrate compound by in vivo hydrolysis or enzymatic action);

[0060] 1.26. If the nitric oxide donor is sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate or GTN), amyl nitrate, diethylene glycol dinitrate, isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), itramin tosylate, pentaerythritol tetranitrate (PETN), propatyl nitrate, dinitrodyl, tenitramine, trolnitrate, molsidomine, linsidomine, naproxcinod, amyl nitrite, diethylamine diazeniumdiolate (DEA / NO), diethyltriamine diazeniumdiolate (DETA / NO), spermine diazeniumdiolate ( SPER / NO), proline diazeniumdiolate (PROLI / NO), dipropyltriamine diazeniumdiolate (DPTA / NO), methylamine hexamethylenemethylamine diazeniumdiolate (MAHMA / NO), propylamine propylamine diazeniumdiolate (PAPA / NO or NOC-15), isopropylamine propylamine diazeniumdiolate (IPAPA / NO or NOC-5), isopropylamine diazeniumdiolate (IPA / NO), heparin diazeniumdiolate, pyrrolidine diazeniumdiolate (PYRRO / NO), O 2 -vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO / NO), O 2 -Vinyl-1-isopropyl-diazen-1-ium-1,2-diolate (V-IPA / NO), O 2 -vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI / NO), O 2 -(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), O 2 -vinyl-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate, O 2-acetoxymethyl-isopropyldiazen-1-ium-1,2-diolate (AcOM-IPA / NO), S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-valerylpenicillamine (SNVP), S-nitroso-N-acetylcysteine ​​(SNAC), S-nitrosoalbumin, and NO hybrid drugs (e.g., 2-(acetyloxy)-benzoic acid 3-[(nitrooxy)methyl]phenyl ester) (NCX4016), 5-nitrooxypentyl 2-acetyloxybenzoate (NCX4215), nicorandil (2-nicotinamidoethyl nitrate), nipradilol (K-351), NO-pravastatin, NO-fluvastatin, NO-losartan, NO-indomethacin, NO-ibuprofen, NO-sulindac, NO-naproxen, S-nitroso-diclofenac, S-nitroso-captopril), Methods 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 3.6, 3.7, 3.8, 4.9, 4.1, 4.2, 4.3, 4.4, 4.5, 5.6, 5.7, 5.8, 5.9, 6.1, 6.2, 6.3, 6.4, 6.5, 7.2, 7.3, 7.4, 7.5, 8.1, 8.2, 8.3, 8.4, 8.5, 9.2, 9.3, 9.4, 10.4, 11.5, 12.5, 13.6, 14.6, 15.6, 16.6, 17.6, 18.6, 19.6, 19.7, 18.7, 19.8, 19.9, 20.9, 21.9, 22.9, 23.9, 24.9, 25.9, 26.9, 27.9, 28.9, 29.9, 30.9,

[0061] 1.27. Any of the preceding methods further comprising administration of an agent that stimulates the nitric oxide signaling pathway, e.g., by stimulating the production or inhibiting the degradation of cyclic guanosine monophosphate (cGMP);

[0062] 1.28. Method 1.27, wherein the agent is a phosphodiesterase (PDE) inhibitor, e.g., a PDE1 and / or PDE5 inhibitor, preferably a PDE inhibitor that crosses the blood-brain barrier (e.g., ITI-214);

[0063] 1.29. Any of the foregoing methods wherein the condition being treated is psychosis, e.g., schizophrenia (e.g., prodromal, acute, and / or residual symptoms of psychosis; or negative and / or positive symptoms of psychosis), delusional disorder (e.g., somatic type), 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;

[0064] 1.30. Method 1.29, wherein the condition being treated is a symptom (e.g., residual symptoms) of a psychosis (e.g., schizophrenia) selected from (1) negative symptoms, e.g., blunted affect, emotional withdrawal, poor rapport, passive or apathetic withdrawal, difficulty with abstract thinking, lack of speech spontaneity and fluency, and stereotypic thinking; and (2) general psychopathological symptoms, e.g., somatic concerns, anxiety, self-blame, tension, mannerisms and awkward posturing, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, inattention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance; cognitive dysfunction, and sleep disorders (e.g., insomnia);

[0065] 1.31. Method 1.29, in which the condition being treated is a symptom (e.g., prodromal) of a psychosis (e.g., schizophrenia) selected from loss of interest in usual pursuits, withdrawal from friends and family, confusion, trouble with concentration, fatigue, and apathy;

[0066] 1.32. Method 1.29, wherein the condition being treated is a symptom (e.g., an active or acute symptom) of a psychosis (e.g., schizophrenia) selected from positive symptoms, e.g., delusions, hallucinations, and suspiciousness;

[0067] 1.33. Methods 1.29 to 1.32, in which the psychosis (e.g., schizophrenia) is treatment-resistant psychosis (e.g., treatment-resistant schizophrenia), e.g., psychosis (or schizophrenia) that has not responded to treatment with one or more antipsychotic medications;

[0068] 1.34. Method 1.33, in which the one or more antipsychotics are selected from typical antipsychotics (first generation), atypical antipsychotics (second generation);

[0069] 1.35. One or more antipsychotic drugs, including acepromazine, amisulpride, aripiprazole, asenapine, benperidol, blonanserin, brexiprazole, bromperidol, cariprazine, carpipramine, chlorpromazine, chlorprothixene, clocapramine, clopenthixol, chlorothepin, clothiapine, clozapine, cyamemazine, dixyrazine, droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, iloperidone, levomepromazine, loxapine, lurasidone, melperone, mesoridazine, molindone, peroxidase, thiazol-2, thiazol-3, thiazol-4, thiazol-5, thiazol-6, thiazol-7, thiazol-8, thiazol-9, thiazol-10, thiazol-11, thiazol-12, thiazol-13, thiazol-14, thiazol-15, thiazol-16, thiazol-17, thiazol-18, thiazol-19, thiazol-20, thiazol-21, thiazol-22, thiazol-23, thiazol-24, thiazol-19 ... Method 1.33 or 1.34, selected from phenazine, moperone, mosapramine, nemonapride, olanzapine, paliperidone, penfluridol, perazine, pericyazine, perospirone, pimavanserin, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, prothipendyl, quetiapine, remoxipride, risperidone, sertindole, sulpiride, sultopride, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, triflupromazine, veralipride, ziprasidone, zotepine, and zuclopenthixol;

[0070] 1.36. Any of the foregoing methods wherein the condition being treated is anxiety, e.g., acute anxiety (e.g., generalized anxiety disorder, panic disorder, specific anxiety disorder, or short-term anxiety episodes associated with social anxiety disorder or social avoidance);

[0071] 1.37. Any of the foregoing methods wherein the condition being treated is depression, e.g., acute depression (e.g., acute major depressive episode, acute brief depressive episode, acute recurrent brief depressive episode);

[0072] 1.38. Any of the preceding methods wherein the condition being treated is treatment-resistant depression, e.g., depression that has not responded to treatment with one or more antidepressants;

[0073] 1.39. Method 1.38, wherein the one or more antidepressants are selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or a combination thereof;

[0074] 1.40. One or more antidepressants are citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, vilazodone, vortioxetine, nefazodone, trazodone, atomoxetine, reboxetine, teniloxazine, viloxazine, bupropion, tofenacin, amitriptyline, amytriptyline, ami ... Method 1.38, selected from mitriptyline N-oxide, clomipramine, desipramine, dibenzepine, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, opipramol, pipofezin, protriptyline, trimipramine, amoxapine, maprotiline, mirtazapine, mianserin, and setiptiline;

[0075] 1.41. Any of the preceding methods wherein the condition being treated is selected from bipolar depression and major depressive disorder;

[0076] 1.42. 5-HT 2A or 5-HT 2A / Any of the preceding methods, wherein the D2 receptor ligand and the nitric oxide donor are provided in a fixed combination unit dosage form;

[0077] 1.43. 5-HT 2A or 5-HT 2A / Any of Methods 1, or 1.1 to 1.41, wherein the D2 receptor ligand and the nitric oxide donor are provided in separate pharmaceutical compositions that are administered simultaneously or sequentially (e.g., within 24 hours);

[0078] 1.44. Any of the foregoing methods wherein the patient has not responded to, or has not responded adequately to, or is suffering from undesirable side effects from, treatment with another antipsychotic or antidepressant, as defined herein.

[0079] 1.45. 5-HT 2A or 5-HT 2A / D2 receptor ligand is 5-HT 2A IC<250 nM for activity at the receptor (agonism and / or antagonism) 50 or an EC of less than 250 nM 50 , for example, an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 Any of the preceding methods, comprising:

[0080] 1.46. 5-HT 2A or 5-HT 2A / D2 receptor ligands have an IC of less than 250 nM for activity (agonism and / or antagonism) at the D2 receptor 50 or an EC of less than 250 nM 50 , for example, an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 Any of the preceding methods, comprising:

[0081] 1.47. 5-HT 2Aor 5-HT 2A / D2 receptor ligands have an IC of less than 250 nM for activity (agonism and / or antagonism) at D1 receptors 50 or an EC of less than 250 nM 50 , e.g., an IC for activity at the receptor (agonism or antagonism) of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM 50 or EC 50 Any of the preceding methods, comprising:

[0082] 1.48. 5-HT 2A or 5-HT 2A / D2 receptor ligands with an IC of less than 250 nM for activity (agonism and / or antagonism) at the serotonin transporter (SERT) 50 or an EC of less than 250 nM 50 , e.g., an IC for activity (agonism or antagonism) at the transporter of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 Any of the preceding methods, comprising:

[0083] 1.49. 5-HT 2A or 5-HT 2A / Any of the preceding methods wherein the D2 receptor ligand and / or nitric oxide donor is administered in the form of a long-acting injectable (LAI) composition, e.g., for intramuscular or subcutaneous injection;

[0084] 1.50. 5-HT 2A or 5-HT 2A / D2 receptor ligand is a compound of Formula I, and the LAI composition comprises the compound in an amount sufficient to provide an amount equivalent to a daily dose of 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, released over a period ranging from about 1 week to about 3 months, e.g., from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks;

[0085] 1.51. Method 1.50, wherein the LAI composition comprises a compound of Formula I dissolved, dispersed, suspended, or encapsulated in a polymer matrix;

[0086] 1.52. Method 1.51, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxycarboxylic acids), poly(amino acids), cellulose polymers, modified cellulose polymers, polyamides, and polyesters;

[0087] 1.53. Method 1.52, wherein the one or more polymers comprise poly(lactic acid), poly(glycolic acid), poly(citric acid), poly(malic acid), poly(β-hydroxybutyric acid), poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, poly(alkyl α-cyanoacrylate) such as poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyortho-carbonate, polyamino acids, (e.g., poly-γ-L-alanine, poly-γ-benzyl-L-glutamic acid, or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester;

[0088] 1.54. Method 1.53, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, poly(citric acid), poly(malic acid), or poly(lactic-co-glycolic acid);

[0089] 1.55. Method 1.53, wherein the one or more polymers include a poly(lactic acid-glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide;

[0090] 1.56. 5-HT 2A or 5-HT 2A Any of the foregoing methods, wherein the D2 receptor ligand and nitric oxide donor are not administered concurrently or in conjunction with an antidepressant, antipsychotic, or anti-anxiety drug.

[0091] In another aspect, the present disclosure provides a method for treating psychosis, depression, and / or anxiety, comprising administering to a subject a 5-HT agonist in combination with a nitric oxide donor, e.g., SNP, for use in the treatment of psychosis, depression, and / or anxiety, e.g., for use in any of Methods 1 onward. 2A or 5-HT 2A / D2 receptor ligands, such as compounds of formula I, e.g., lumateperone, as described herein above, in free or salt form, optionally in deuterated form.

[0092] In another aspect, the disclosure provides a method for treating psychosis, depression, and / or anxiety, comprising administering 5-HT 2000 in combination with a nitric oxide donor, e.g., SNP, for use in the manufacture of a medicament for the treatment of psychosis, depression, and / or anxiety, e.g., for any of Methods 1 et seq. 2A or 5-HT 2A The present invention provides the use of a D2 receptor ligand, such as a compound of formula I, e.g., lumateperone, as described herein above, in free or salt form, which may be in deuterated form.

[0093] In another aspect, the present invention provides a method for treating, e.g., psychosis, depression, and / or anxiety, e.g., for any of Methods 1 et seq., (i) 5-HT 2A or 5-HT 2AA pharmaceutical composition (Composition 1) is provided, which comprises an effective amount of a D2 receptor ligand, e.g., a substituted heterocyclic-fused gamma-carboline described herein, in free form, a pharmaceutically acceptable salt form, or a prodrug form, and (ii) an effective amount of a nitric oxide donor, e.g., SNP. For example, Composition 1 can be as follows:

[0094] 1.1. 5-HT 2A or 5-HT 2A / D2 receptor ligands may be in deuterated form, in free form, in the form of a pharmaceutically acceptable salt or in the form of a prodrug, of formula I: [ka] [In the formula, X is -N(H)-, -N(CH3)-, or -O-; Y is -C(=O)-, -C(H)(OH)-, or -C(H)(OR)-; R1 is -C(O)-C 1-21 Alkyl or -C(O)OC 1-21 alkyl] Composition 1 is a substituted heterocyclic fused gamma carboline compound represented by the formula:

[0095] 1.2. Composition 1 or 1.1, wherein X in the compound of formula I is —N(H);

[0096] 1.3. Composition 1 or 1.1, wherein X in the compound of formula I is -N(CH3)-;

[0097] 1.4. Composition 1 or 1.1, wherein X in the compound of formula I is -O-;

[0098] 1.5. Composition 1 or any of formulae 1.1-1.4, wherein Y in the compound of formula I is -C(=O)-;

[0099] 1.6. Composition 1 or any of formulae 1.1-1.4, wherein Y in the compound of formula I is —C(H)(OH)—;

[0100] 1.7. Composition 1 or any of formulae 1.1-1.4, wherein Y in the compound of formula I is -C(H)(OR1)-;

[0101] 1.8. Compounds of Formula I in which 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 wherein the alkyl may be saturated or unsaturated and contains one or more hydroxy or C 1-22 It is a straight chain optionally substituted with an alkoxy (e.g., ethoxy) group, for example, R1 is -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, wherein the compound hydrolyzes to form the residue of a natural or unnatural saturated or unsaturated fatty acid, for example, the compound 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; for example, R in the compound of formula I is -C(O)-C 6-15 alkyl, for example, —C(O)—C alkyl; or R in the compound of formula I is —C(O)—C 1-5 Composition 1.7, which is alkyl, e.g., —C(O)—C3 alkyl;

[0102] 1.9. Compounds of Formula I in which R1 is -C(O)OC 1-21 Alkyl (e.g., -C(O)OC 1-5 Alkyl, -C(O)OC 6-15 Alkyl or -C(O)OC 16-21 alkyl), preferably wherein the alkyl may be saturated or unsaturated and contains one or more hydroxy or C 1-22It is a straight chain optionally substituted with an alkoxy (e.g., ethoxy) group, for example, R1 is -C(O)O-C6 alkyl, -C(O)O-C7 alkyl, -C(O)O-C9 alkyl, -C(O)OC 11 Alkyl, -C(O)OC 13 Alkyl or -C(O)OC 15 alkyl, wherein the compound hydrolyzes to form the residue of a natural or unnatural saturated or unsaturated fatty acid, for example, the compound 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; for example, R in the compound of formula I is -C(O)OC 6-15 alkyl, for example, —C(O)O—C alkyl; or R in the compound of formula I is —C(O)OC 1-5 Composition 1.7, which is alkyl, e.g., —C(O)O—C3 alkyl;

[0103] 1.10. The compound of formula I is [ka] Composition 1 or any of 1.1 to 1.4 or 1.6;

[0104] 1.11. The compound of formula I [ka] Composition 1 or any of 1.1 to 1.4 or 1.6;

[0105] 1.12. The compound of formula I is [ka] Composition 1, 1.3 or 1.5;

[0106] 1.13. Composition 1, or any of 1.1-1.12, wherein the compound of Formula I is in the form of a toluenesulfonic acid addition salt (e.g., monotosylate or ditosylate), optionally in crystalline salt form;

[0107] 1.14. Composition 1 or any of 1.1-1.12, wherein the compound of Formula I is in the form of the free base;

[0108] 1.15. Composition 1, or any of 1.1-1.14, wherein the compound of formula I is in a deuterated form, e.g., the deuterium:protium ratio for a particular carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, e.g., at least 2-fold, e.g., at least 10-fold higher;

[0109] 1.16. The compound of formula I is in free form or in the form of a pharmaceutically acceptable salt, for example in the form of a toluenesulfonic acid addition salt, [ka] wherein D represents hydrogen positions that substantially exceed the natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Composition 1.15 selected from:

[0110] 1.17. 5-HT 2A or 5-HT 2A any of the preceding compositions wherein the D2 receptor ligand is a compound of formula I, wherein X is -N(CH3)- and Y is -C(=O)-, in the form of a toluenesulfonic acid addition salt (e.g., monotosylate, ditosylate, or a combination thereof);

[0111] 1.18. Composition 1.17, wherein the composition comprises a daily dose of a compound of formula I equivalent to about 1-100 mg of the monotosylate salt, e.g., 1-75 mg, or 1-60 mg, or 1-40 mg, or 1-30, or 1-20 mg, or 1-10 mg, or 1-5 mg of the monotosylate salt;

[0112] 1.19. Composition 1.17, wherein the composition is an oral unit dosage form, e.g., a tablet or capsule, comprising a compound of Formula I in an amount corresponding to 1-100 mg of the monotosylate salt, e.g., 1-75 mg, or 1-60 mg, or 1-40 mg, or 1-30 mg, or 1-20 mg, or 1-10 mg, or 1-5 mg of the monotosylate salt, and a pharmaceutically acceptable diluent or carrier;

[0113] 1.20. Composition 1.17, wherein the unit dosage form is formulated for subcutaneous or transmucosal administration, e.g., a sublingual or buccal orally disintegrating tablet or film, comprising a compound of Formula I in an amount equivalent to 1-100 mg of the monotosylate salt, e.g., 1-75 mg, or 1-60 mg, or 1-40 mg, or 1-30 mg, or 1-20 mg, or 1-10 mg, or 1-5 mg of the monotosylate salt, and a pharmaceutically acceptable diluent or carrier;

[0114] 1.21. Composition 1 or any of 1.1-1.20, wherein the nitric oxide donor is a nitrate compound (--O-NO2) or a nitrite compound (-O-NO);

[0115] 1.22. Composition 1 or any of 1.1-1.20, wherein the nitric oxide donor is an N-nitroso compound (-N-NO), an S-nitroso compound (-S-NO), a diazeniumdiolate compound (-N-(NO)=(NO) or -NN(O)-N=O), or a furoxan compound;

[0116] 1.23. Composition 1 or any of 1.1-1.22, wherein the nitric oxide donor is a compound that generates nitric oxide by in vivo enzymatic action (e.g., biotransformation), e.g., by denitration and / or reduction;

[0117] 1.24. Composition 1 or any of 1.1-1.22, wherein the nitric oxide donor is a compound that generates nitric oxide in vivo without enzymatic action (e.g., biotransformation), e.g., by hydrolysis and / or spontaneous decomposition, e.g., an N-nitroso compound or a precursor thereof;

[0118] 1.25. Composition 1 or any of 1.1-1.24, wherein the nitric oxide donor is a prodrug of an alkyl nitrate (e.g., a compound that releases an alkyl nitrate upon in vivo hydrolysis or enzymatic action);

[0119] 1.26. If the nitric oxide donor is sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate or GTN), amyl nitrate, diethylene glycol dinitrate, isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), itramin tosylate, pentaerythritol tetranitrate (PETN), propatyl nitrate, dinitrodyl, tenitramine, trolnitrate, molsidomine, linsidomine, naproxcinod, amyl nitrite, diethylamine diazeniumdiolate (DEA / NO), diethyltriamine diazeniumdiolate (DETA / NO), spermine diazeniumdiolate ( SPER / NO), proline diazeniumdiolate (PROLI / NO), dipropyltriamine diazeniumdiolate (DPTA / NO), methylamine hexamethylenemethylamine diazeniumdiolate (MAHMA / NO), propylamine propylamine diazeniumdiolate (PAPA / NO or NOC-15), isopropylamine propylamine diazeniumdiolate (IPAPA / NO or NOC-5), isopropylamine diazeniumdiolate (IPA / NO), heparin diazeniumdiolate, pyrrolidine diazeniumdiolate (PYRRO / NO), O 2 -vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO / NO), O 2 -Vinyl-1-isopropyl-diazen-1-ium-1,2-diolate (V-IPA / NO), O 2 -vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI / NO), O 2 -(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), O 2-vinyl-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate, O 2 -acetoxymethyl-isopropyldiazen-1-ium-1,2-diolate (AcOM-IPA / NO), S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-valerylpenicillamine (SNVP), S-nitroso-N-acetylcysteine ​​(SNAC), S-nitrosoalbumin, and NO hybrid drugs (e.g., 2-(acetyloxy)-benzoic acid 3-[(nitrooxy)methyl]phenyl ester) (NCX4016), 5-nitrooxypentyl 2-acetyloxybenzoate (NCX4215), nicorandil (2-nicotinamidoethyl nitrate), nipradilol (K-351), NO-pravastatin, NO-fluvastatin, NO-losartan, NO-indomethacin, NO-ibuprofen, NO-sulindac, NO-naproxen, S-nitroso-diclofenac, S-nitroso-captopril).

[0120] 1.27. Any of the preceding compositions wherein the composition is formulated for the treatment of psychosis, depression and / or anxiety, or other CNS disorders for which lumateperone has been shown to be effective;

[0121] 1.28. Composition 1.27, wherein the condition to be treated is a psychosis, e.g., schizophrenia (e.g., prodromal, acute, and / or residual symptoms of psychosis; or negative and / or positive symptoms of psychosis), delusional disorder (e.g., somatic type), 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;

[0122] 1.29. Composition 1.27, wherein the condition being treated is a symptom (e.g., residual symptoms) of a psychosis (e.g., schizophrenia) selected from (1) negative symptoms, e.g., blunted affect, emotional withdrawal, poor rapport, passive or apathetic withdrawal, difficulty with abstract thinking, lack of speech spontaneity and fluency, and stereotypic thinking; and (2) general psychopathological symptoms, e.g., somatic concerns, anxiety, self-blame, tension, mannerisms and awkward posturing, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, inattention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance; cognitive dysfunction, and sleep disorders (e.g., insomnia).

[0123] 1.30. Composition 1.27 wherein the condition being treated is a symptom (e.g., prodromal symptom) of a psychosis (e.g., schizophrenia) selected from loss of interest in usual pursuits, withdrawal from friends and family, confusion, trouble with concentration, fatigue, and apathy.

[0124] 1.31. Composition 1.27, wherein the condition being treated is a symptom (e.g., active or acute phase symptom) of a psychosis (e.g., schizophrenia) selected from positive symptoms, e.g., delusions, hallucinations, and suspiciousness;

[0125] 1.32. Compositions 1.27-1.31, wherein the psychosis (e.g., schizophrenia) is treatment-resistant psychosis (e.g., treatment-resistant schizophrenia), e.g., psychosis (or schizophrenia) that has not responded to treatment with one or more antipsychotic medications;

[0126] 1.33. Composition 1.32, wherein the one or more antipsychotics are selected from typical antipsychotics (first generation), atypical antipsychotics (second generation);

[0127] 1.34. One or more antipsychotics, including acepromazine, amisulpride, aripiprazole, asenapine, benperidol, blonanserin, brexiprazole, bromperidol, cariprazine, carpipramine, chlorpromazine, chlorprothixene, clocapramine, clopenthixol, chlorothepin, clothiapine, clozapine, cyamemazine, dixyrazine, droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, iloperidone, levomepromazine, loxapine, lurasidone, melperone, mesoridazine, molindone, peroxidase, thiazol-2, thiazol-3, thiazol-4, thiazol-5, thiazol-6, thiazol-7, thiazol-8, thiazol-9, thiazol-10, thiazol-11, thiazol-12, thiazol-13, thiazol-14, thiazol-15, thiazol-16, thiazol-17, thiazol-18, thiazol-19, thiazol-20, thiazol-21, thiazol-22, thiazol-23, thiazol-24, thiazol-19 ... Composition 1.32 or 1.33 selected from phenazine, moperone, mosapramine, nemonapride, olanzapine, paliperidone, penfluridol, perazine, pericyazine, perospirone, pimavanserin, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, prothipendyl, quetiapine, remoxipride, risperidone, sertindole, sulpiride, sultopride, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, triflupromazine, veralipride, ziprasidone, zotepine, and zuclopenthixol;

[0128] 1.35. Compositions 1.27-1.34, wherein the condition to be treated is anxiety, e.g., acute anxiety (e.g., generalized anxiety disorder, panic disorder, specific anxiety disorder, or short-term anxiety episodes associated with social anxiety disorder or social avoidance);

[0129] 1.36. Compositions 1.27-1.35 wherein the condition being treated is depression, e.g., acute depression (e.g., acute major depressive episode, acute brief depressive episode, acute recurrent brief depressive episode);

[0130] 1.37. Compositions 1.27-1.36, wherein the condition being treated is treatment-resistant depression, e.g., depression that has not responded to treatment with one or more antidepressants;

[0131] 1.38. Composition 1.37, wherein the one or more antidepressants are selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or a combination thereof;

[0132] 1.39. One or more antidepressants are citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, vilazodone, vortioxetine, nefazodone, trazodone, atomoxetine, reboxetine, teniloxazine, viloxazine, bupropion, tofenacin, amitriptyline, amytriptyline, ami ... Composition 1.37 selected from mitriptyline N-oxide, clomipramine, desipramine, dibenzepine, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, opipramol, pipofezin, protriptyline, trimipramine, amoxapine, maprotiline, mirtazapine, mianserin, and setiptiline;

[0133] 1.40. Compositions 1.27-1.39 wherein the condition being treated is selected from bipolar depression and major depressive disorder;

[0134] 1.41. 5-HT 2A or 5-HT 2A / Any of the preceding compositions, wherein the D2 receptor ligand and the nitric oxide donor are provided in a fixed combination unit dosage form;

[0135] 1.42. 5-HT 2A or 5-HT 2A / D2 receptor ligand is 5-HT 2A IC<250 nM for activity at the receptor (agonism and / or antagonism) 50 or an EC of less than 250 nM 50 , for example, an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 Any of the preceding compositions having:

[0136] 1.43. 5-HT 2A or 5-HT 2A / D2 receptor ligands have an IC of less than 250 nM for activity (agonism and / or antagonism) at the D2 receptor 50 or an EC of less than 250 nM 50 , for example, an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 Any of the preceding compositions having:

[0137] 1.44. 5-HT 2A or 5-HT 2A / D2 receptor ligands have an IC of less than 250 nM for activity (agonism and / or antagonism) at D1 receptors 50 or an EC of less than 250 nM 50, for example, an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 Any of the preceding compositions having:

[0138] 1.45. 5-HT 2A or 5-HT 2A / D2 receptor ligands with an IC of less than 250 nM for activity (agonism and / or antagonism) at the serotonin transporter (SERT) 50 or an EC of less than 250 nM 50 , e.g., an IC for activity (agonism or antagonism) at the transporter of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 Any of the preceding compositions having:

[0139] 1.46. Any of the preceding compositions in the form of a long-acting injectable (LAI) composition, e.g., for intramuscular or subcutaneous injection;

[0140] 1.47. 5-HT 2A or 5-HT 2A / Composition 1.46, wherein the D2 receptor ligand is a compound of Formula I, and the LAI composition comprises the compound in an amount sufficient to provide an amount equivalent to a daily dose of 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, released over a period ranging from about 1 week to about 3 months, e.g., from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks;

[0141] 1.48. Composition 1.47, wherein the LAI composition comprises a compound of Formula I dissolved, dispersed, suspended, or encapsulated in a polymer matrix;

[0142] 1.49. Composition 1.48, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxycarboxylic acids), poly(amino acids), cellulose polymers, modified cellulose polymers, polyamides, and polyesters;

[0143] 1.50. Composition 1.49, wherein the one or more polymers comprise polylactic acid, poly(glycolic acid), poly(citric acid), poly(malic acid), poly(β-hydroxybutyric acid), poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, poly(alkyl α-cyanoacrylate) such as poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyortho-carbonate, polyamino acid, (e.g., poly-γ-L-alanine, poly-γ-benzyl-L-glutamic acid, or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester;

[0144] 1.51. Composition 1.49, wherein the one or more polymers comprise poly(lactic acid), poly(glycolic acid), poly(citric acid), poly(malic acid), or poly(lactic-co-glycolic acid);

[0145] 1.52. Composition 1.49, wherein the one or more polymers comprise a poly(lactic acid-glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide.

[0146] The term "5-HT 2A "Receptor ligand" means at least serotonin 5-HT 2ACompounds that exhibit pharmacological activity at the receptor, e.g., an IC of less than 250 nM for activity (agonism and / or antagonism) at said receptor. 50 or an EC of less than 250 nM 50 In some embodiments, the term refers to a compound having an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM. 50 or EC 50 A compound having the formula:

[0147] The term "5-HT 2A / D2 receptor ligand" means that at least serotonin 5-HT 2A Compounds that exhibit pharmacological activity at both the D1 receptor and the D2 receptor, e.g., an IC of less than 250 nM for activity (agonism and / or antagonism) at each of the receptors. 50 or an EC of less than 250 nM 50 In some embodiments, the term refers to compounds that have an IC of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for activity (agonism or antagonism) at one or both of these receptors. 50 or EC 50 A compound having the formula:

[0148] The terms "treatment" and "treating" should be understood accordingly to encompass prevention and treatment or amelioration of disease, and / or treatment of the cause of disease. In certain embodiments, the terms "treatment" and "treating" refer to the prevention or amelioration of symptoms of the disease.

[0149] The term "patient" can include a human patient or a non-human patient.

[0150] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ("DSM-5") includes a class of disorders called psychotic disorders, which include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to another condition, substance- or medication-induced psychotic disorder, and schizophrenia spectrum and other psychotic disorders not otherwise specified.

[0151] The DSM-5 defines schizophrenia as characterized by delusions, hallucinations, disorganized speech (frequent digressions or disconnections), disorganized or catatonic behavior, and negative symptoms (e.g., reduced emotional expressivity). For a clinician to diagnose schizophrenia, at least two of a set of specific symptoms must be present for a total of at least six months and actively present for at least one month (active symptoms). Furthermore, there must be impairment in at least one major area of ​​social or occupational functioning, such as work or schoolwork, interpersonal relationships, or self-care, for a significant period following the onset of the disorder. Patients who meet the basic criteria except for the active symptoms are said to be experiencing a prodromal or residual phase. During these two phases, manifestations of the disorder are often limited to negative symptoms.

[0152] DSM-5 defines "major depressive disorder" (MDD) as the presence of five or more symptoms within the same two-week period, which represent a change from the patient's premorbid functioning. The five symptoms are selected from the following: depressed mood, markedly reduced interest or pleasure in almost all activities, significant weight change, insomnia or hyposomnia, psychomotor agitation or slowness, fatigue, feelings of worthlessness or excessive guilt, impaired thinking or indecisiveness, and recurrent thoughts of death or suicidal ideation, each of which is present nearly every day. A diagnosis of MDD requires at least depressed mood or loss of interest and pleasure as one of the five symptoms. MDD can consist of one or more "major depressive episodes," which may be separated by weeks or months (separate episodes must occur at least two weeks apart). DSM-5 also notes that there is always a risk of suicidal behavior during a major depressive episode.

[0153] MDD is, by its very nature, an acute disorder, insofar as the DSM-5 distinguishes it from "persistent depressive disorder," in which patients have many of the same symptoms as MDD but persist for at least two years. In addition to MDD, the DSM-5 also defines a "brief depressive episode" as a period of at least four days but fewer than 14 days in which depressed mood and at least four of the other symptoms that define MDD are present. The DSM further defines "recurrent brief depression" as a period of depressed mood and at least four other symptoms of depression present concurrently at least once a month for two to 13 days, persisting for at least 12 consecutive months. Thus, recurrent brief depression similarly consists of regularly recurring brief episodes of depression.

[0154] The DSM-5 also includes a major depressive episode as one of the diagnostic criteria for patients with bipolar disorder. Thus, patients who present with a major depressive episode may have either major depressive disorder or bipolar disorder.

[0155] The DSM-5 defines various anxiety disorders, including generalized anxiety disorder, panic disorder, social anxiety disorder, and specific anxiety disorder. Similar to the depressive disorders mentioned above, anxiety disorders can be characterized by brief, recurrent episodes, such as panic attacks, that may persist over the course of a chronic disorder. For example, generalized anxiety disorder is defined by the DSM-5 as excessive anxiety and worry about many events or activities, occurring more frequently than not for at least six months. Panic attacks are defined as sudden surges of intense fear or intense discomfort that peak within minutes and may occur repeatedly in response to either expected or unexpected stimuli. Therefore, similar to the depressive disorders mentioned above, there is a need for fast-acting anxiolytic medications that can treat symptoms of anxiety or panic. However, some of the most common treatments for anxiety disorders are SSRIs and other antidepressants, which take 2 to 4 weeks to provide relief.

[0156] Social avoidance can be a significant debilitating symptom in patients with anxiety disorders, especially social anxiety disorder, and in patients with post-traumatic anxiety disorder. Social avoidance is often one of the key determinants of whether or not a person with severe anxiety disorder can maintain family or employment relationships. Unexpectedly, 5-HT inhibitors such as lumateperone have been shown to be effective in treating these conditions. 2ACertain substituted fused gamma-carbolines with dopamine receptor activity have been found to be effective in treating emotionally experienced symptoms of psychotic disorders (e.g., negative emotional symptoms in patients with schizophrenia). Negative symptoms of schizophrenia can be divided into two categories: emotional experience (e.g., emotional withdrawal, passive withdrawal, active social avoidance) and emotional expression (e.g., blunted effect, poor rapport, lack of spontaneity, and delayed motor development). In two clinical trials of patients with acutely exacerbated schizophrenia, lumateperone (60 mg PO) administered once daily for up to 28 days significantly and unexpectedly improved symptoms of emotional experience compared with placebo. These are the symptoms most highly correlated with interpersonal functioning. As such, the compounds, including those of formula I, may be highly effective in treating the emotionally experiential symptoms of other psychiatric disorders such as social anxiety disorder or other psychiatric illnesses in which social withdrawal and social avoidance are symptoms.

[0157] Unless otherwise specified or clear from context, the following terms used herein have the following meanings:

[0158] "Alkyl," as used herein, unless otherwise specified, is a saturated or unsaturated hydrocarbon moiety, e.g., 1 to 21 carbon atoms in length, which may be straight or branched (e.g., n-butyl or tert-butyl), preferably straight chain. For example, "C 1-21 "Alkyl" means an alkyl having 1 to 21 carbon atoms. In one embodiment, the alkyl is selected from the group consisting of one or more hydroxy or C 1-22It may be substituted with an alkoxy (e.g., ethoxy) group. In another embodiment, the alkyl contains 1 to 21 carbon atoms, is preferably straight-chained, and may be saturated or unsaturated, e.g., R1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms, 16 to 21 carbon atoms, e.g., together with the -C(O)- to which it is attached, e.g., when cleaved from a compound of formula I, it may form the residue of a natural or unnatural saturated or unsaturated fatty acid.

[0159] 5-HT 2A or 5-HT 2A / D2 receptor ligands, such as the substituted heterocyclic fused gamma carbolines described herein, can be in free form, pharmaceutically acceptable salt form or prodrug form. Pharmaceutically acceptable salts include, for example, tosylate salts in the case of compounds of Formula I. When the dosage or amount of a salt is indicated by weight, for example, milligrams per day or milligrams per unit dose, the dosage of the salt is indicated as the weight of the corresponding free base, unless otherwise specified.

[0160] In any and all embodiments described herein, 5-HT 2A or 5-HT 2A The / D2 receptor ligand may also be a SERT ligand, i.e., the compound is capable of inhibiting 5-HT 2A / SERT or 5-HT 2A / D2 / SERT receptor ligands.

[0161] In any and all embodiments described herein, 5-HT 2A or 5-HT 2A / D2 receptor ligands have no or substantially no opioid receptor activity (e.g., IC greater than 50 nM, or greater than 100 nM, or greater than 150 nM). 50 and having no or substantially no μ-opioid receptor activity).

[0162] 5-HT 2Aor 5-HT 2A In some cases, D2 receptor ligands may also exist in prodrug form. A prodrug form is a compound that is converted into an active compound in the body. For example, a compound containing a hydroxy or carboxy substituent may form a physiologically hydrolyzable and acceptable ester. As used herein, "physiologically hydrolyzable and acceptable ester" refers to an ester that is hydrolyzed under physiological conditions to produce an acid (in the case of a compound having a hydroxy substituent) or an alcohol (in the case of a compound having a carboxy substituent), and that is itself physiologically acceptable at the dose to be administered. For example, in the compound of Formula I, Y is -C(H)(OR1) and R1 is -C(O)-C 1-21 When Y is alkyl, e.g., —C(O)—C3 alkyl or —C(O)—C9 alkyl, these compounds hydrolyze under physiological conditions to give —C(H)(OH) on the one hand and —C(H)(OH) on the other hand. 1-21 Compounds of formula I can be produced that are alkyl-C(O)OH, e.g., C3 alkyl-C(O)OH or C9 alkyl-C(O)OH. Thus, as will be understood, this term encompasses conventional pharmaceutical prodrug forms. Prodrugs (e.g., compounds where R1 is -C(O)-C 1-21 When a compound of formula (I) where Y is -C(=O)- or -CH(OH)- is used, the dosage is calculated based on the amount of the compound of formula (I) where Y is -C(=O)- or -CH(OH)- in free base form.

[0163] Nitric oxide donors include compounds with alkyl nitrate groups, compounds with alkyl nitrite groups, S-nitroso compounds, N-nitroso compounds, diazeniumdiolates, and furoxan compounds. In some embodiments, nitric oxide donors are compounds that generate nitric oxide spontaneously in vivo, i.e., through non-enzymatic hydrolysis, decomposition, or other mechanisms. In other embodiments, nitric oxide donors are compounds that require enzymatic action to release nitric oxide, such as bioactivation. For example, C-nitroso compounds, such as typical alkyl nitrate esters (RO-NO), are thought to require enzymatic action, such as reduction, denitration, and / or other steps, to generate NO in vivo. Enzymes such as mitochondrial aldehyde dehydrogenase, glutathione S-transferase, cytochrome P450 oxidase, and xanthine oxidoreductase have been implicated, although recent evidence supports the role of mitochondrial aldehyde dehydrogenase. S-nitroso compounds are also thought to require enzymatic action to generate NO in vivo. In contrast, diazeniumdiolate compounds release NO at reproducible first-order rates when dissolved in aqueous media. These compounds do not require enzymatic or redox chemistry.

[0164] Diazeniumdiolates are compounds that possess the tautomeric -N-(NO)=(NO) or -NN(O)-N=O functional groups, hence their alias NONOates. These compounds undergo simple hydrolysis to generate, ideally, two equivalents of nitric oxide. [ka]

[0165] These compounds can be derived from most primary or secondary amines, and their rate of hydrolysis to release NO depends on the structure of the organic side group (R in the above scheme). Generally, these compounds are derived from small primary and secondary alkylamines and cyclic secondary amines. Typical (unprotected) diazeniumdiolates are anionic and therefore are usually provided as salts with appropriate cations (e.g., ammonium or alkali metal cations, or mono- or dialkylammonium cations corresponding to the amino groups of the diazeniumdiolates).

[0166] Due to the need for a hydrolysis or enzymatic deprotection step to provide the reactive diazeniumdiolate compound, the terminal oxygen (O) provides a slower and more prolonged release of NO. 2 ) Protected diazeniumdiolates are also known. Vinyl and aryl O 2 Protected diazeniumdiolates have been developed. These compounds can also be activated in vivo by reaction with the sulfhydryl groups of glutathione. The acetoxymethyl-protected diazeniumdiolates are particularly useful because they can be activated by common esterase enzymes.

[0167] Unique among nitric oxide donors is sodium nitroprusside, Na2[Fe(CN)5NO], a complex coordination compound containing an iron(III) center coordinated to five cyanide ligands and one nitric oxide ligand. Upon binding to oxyhemoglobin in red blood cells, the complex dissociates, releasing cyanide and nitric oxide.

[0168] Molsidomine is another unique nitric oxide donor drug and a prodrug of the active species linsidomine. Molsidomine and linsidomine contain a mesoionic N-morpholino-5-aminoacyl 1,2,3-oxadioazole ring. In vivo, linsidomine is formed when the carbamate group of molsidomine is enzymatically cleaved. This compound is unstable and decomposes to release NO. [ka]

[0169] NO hybrid drugs are existing drugs, including analgesics, nonsteroidal anti-inflammatory drugs, anticholesterol statins, and antivirals, that possess free hydroxy, amino, thiol, or other groups that can be covalently attached to a nitric oxide donor moiety (generally an alkyl nitrate). For example, aspirin (2-acetylsalicylic acid) can be converted to two distinct NO-aspirin derivatives. Each of these compounds undergoes the release of NO in vivo to regenerate the underlying drug (aspirin), which retains its normal in vivo pharmacological activity. [ka]

[0170] Examples of suitable nitric oxide donors include, but are not limited to, sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate or GTN), amyl nitrate, diethylene glycol dinitrate, isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), itramine tosylate, pentaerythritol tetranitrate (PETN), propatyl nitrate, dinitrodyl, tenitramine, trolnitrate, molsidomine, linsidomine, naproxcinod, amyl nitrite, diethylamine diazeniumdiolate (DEA / NO), diethylamine triamine diazeniumdiolate (DETA / NO), spermine Diazeniumdiolate (SPER / NO), proline diazeniumdiolate (PROLI / NO), dipropyltriamine diazeniumdiolate (DPTA / NO), methylamine hexamethylenemethylamine diazeniumdiolate (MAHMA / NO), propylamine propylamine diazeniumdiolate (PAPA / NO or NOC-15), isopropylamine propylamine diazeniumdiolate (IPAPA / NO or NOC-5), isopropylamine diazeniumdiolate (IPA / NO), heparin diazeniumdiolate, pyrrolidine diazeniumdiolate (PYRRO / NO), O 2-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO / NO), O 2 -Vinyl-1-isopropyl-diazen-1-ium-1,2-diolate (V-IPA / NO), O 2 -vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI / NO), O 2 -(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), O 2 -vinyl-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate, O 2 -acetoxymethyl-isopropyldiazen-1-ium-1,2-diolate (AcOM-IPA / NO), S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-valerylpenicillamine (SNVP), S-nitroso-N-acetylcysteine ​​(SNAC), S-nitrosoalbumin, and NO hybrid drugs (e.g., 2-(acetyloxy)-benzoic acid 3-[(nitrooxy)methyl]methyl]-2-methyl ... [ethyl]phenyl ester (NCX4016), 5-nitrooxypentyl 2-acetyloxybenzoate (NCX4215), nicorandil (2-nicotinamidoethyl nitrate), nipradilol (K-351), NO-pravastatin, NO-fluvastatin, NO-losartan, NO-indomethacin, NO-ibuprofen, NO-sulindac, NO-naproxen, S-nitroso-diclofenac, and S-nitroso-captopril.

[0171] In some embodiments, the nitric oxide donor is selected from sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate), amyl nitrate, diethylene glycol dinitrate, isosorbide mononitrate, isosorbide dinitrate, itramine tosylate, pentaerythritol tetranitrate, propatyl nitrate, dinitrodyl, tenitramine, trolnitrate, molsidomine, linsidomine, and naproxcinod.

[0172] The term "concurrently," when referring to therapeutic applications, means the administration of two or more active ingredients to a patient as part of a regimen for treating a disease or disorder, regardless of whether the two or more active agents are administered at the same time or at different times, or by the same or different routes of administration. Concurrent administration of two or more active ingredients may be at different times on the same day, on different days, or with different frequencies.

[0173] The term "simultaneously" when referring to therapeutic use means that two or more active ingredients are administered at or about the same time by the same route of administration.

[0174] The term "separately" when referring to therapeutic use means that two or more active ingredients are administered at or about the same time by different routes of administration.

[0175] Dosages used in practicing the present disclosure will, of course, vary depending, for example, on the particular disease or condition to be treated, the particular active compound used, the mode of administration, and the desired therapy. Unless otherwise specified, the amount of active compound for administration (whether administered as a free base or as a salt form) refers to or is based on the amount of the compound in free form (i.e., the amount calculation is based on the amount of the active moiety in free form, and in the case of salts, the weight of the counterion is not taken into account). Prodrugs (e.g., those in which R is -C(O)-C 1-21 When a compound of formula (I) where Y is C(=O) is used, the dosage is calculated based on the amount of the compound of formula (I) in free base form where Y is C(=O). 2A or 5-HT 2A The 5-HT / D2 receptor ligand can be administered by any suitable route, including orally, intramuscularly, subcutaneously, parenterally, or transdermally, but is preferably administered orally. 2A or 5-HT 2AThe / D2 receptor ligand may be administered by any suitable route, including orally, parenterally, transdermally, or transmucosally, for example in the form of a tablet, capsule, subcutaneous injection, or a rapidly disintegrating tablet or film for sublingual or buccal administration.

[0176] For the avoidance of doubt, disclosures of numerical ranges, e.g., amounts "up to X," are intended to include the upper numerical limit X. Thus, a disclosure of "up to 60 mg" is intended to include 60 mg.

[0177] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms can include tablets, capsules, solutions, suspensions, etc.

[0178] The compounds of the present disclosure can be contained in a depot formulation, for example, by dispersing, dissolving, suspending, or encapsulating the compounds of the present disclosure in a polymer matrix as described herein, so that the compound is continuously released over time as the polymer degrades. The release of the compounds of the present disclosure from the polymer matrix provides, for example, controlled and / or delayed and / or sustained release of the compounds from the pharmaceutical depot composition to a subject, for example, a warm-blooded animal such as a human, to whom the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers the compounds of the present disclosure to the subject at concentrations effective for treating a particular disease or medical condition for a sustained period, for example, from one week to three months.

[0179] 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., Examples of suitable polymers include 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-γ-L-alanine, poly-γ-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), hyaluronic acid esters, and one or more of these polymers can be used.

[0180] When the polymer is a copolymer, it can be either a tandem, block, and / or graft copolymer. 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-cyanoacrylates, etc. can be used, and lactic acid-glycolic acid copolymers (also referred to as poly(lactide-α-glycolide) or poly(lactide-co-glycolic acid), hereinafter referred to as PLGA) are preferred. Therefore, in one embodiment, the polymer useful for the polymer matrix is ​​OLGA. As used herein, the term PLGA includes polymers of lactic acid (also referred to as polylactide, poly(lactic acid), or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer, such as PLGA50:50, PLAG85:15, and PLGA90:10.

[0181] 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 must be biodegradable; the polymeric material should be broken down by internal processes into products that can be easily disposed of within the body and should not accumulate within the body. The products of biodegradation should also be biocompatible with the body in that the polymeric 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 of the following: poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers such as albumin, casein, and waxes, such as glycerol monostearate and glycerol distearate. A preferred polymer for use in the practice of the present invention is dl(polylactide-co-glycolide). The molar ratio of lactide to glycolide in such copolymers preferably ranges from about 75:25 to 50:50.

[0182] Useful PLGA polymers can have a weight-average molecular weight of approximately 5,000 to 500,000 daltons, preferably approximately 150,000 daltons. Depending on the degradation rate to be achieved, polymers of different molecular weights can be used. For a diffusion mechanism of drug release, the polymer should remain intact until all the drug is released from the polymer matrix and then degraded. Drugs can also be released from the polymer matrix as the polymeric excipient bioerodes.

[0183] PLGA can be prepared by conventional methods or can be commercially available. For example, PLGA can be produced from cyclic lactide, glycolide, etc. by ring-opening polymerization using a suitable catalyst (see EP 0058481 (B2); Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0184] PLGA is believed to be biodegradable through degradation of the entire solid polymer composition due to the breakdown of hydrolyzable and enzymatically cleavable ester bonds to form lactic acid and glycolic acid under biological conditions (e.g., in the presence of water and biological enzymes found in the tissues of warm-blooded animals such as humans). Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism and can further biodegrade to form carbon dioxide and water. In other words, PLGA is believed to degrade in warm-blooded animals, such as humans, through hydrolysis of its ester groups in the presence of water to produce lactic acid and glycolic acid, creating an acidic microclimate. Because lactic acid and glycolic acid are by-products of various metabolic pathways in warm-blooded animals, such as humans, under normal physiological conditions, they are well tolerated and cause minimal systemic toxicity. [Example]

[0185] Example 1: Lumateperone, when combined with sodium nitroprusside, produces synergistic improvements in conditioned avoidance responding (CAR) The compound of formula I where X is N(CH3) and Y is C=O is lumateperone (ITI-007): [ka] and is sold in its tosylate salt form as CAPLYTA®. Lumateperone provides selective and simultaneous modulation of serotonin, dopamine, and glutamate neurotransmission and is of particular interest in the context of psychiatric disorders.

[0186] Male Wistar rats, weighing approximately 18 g upon arrival, are housed in groups of four under standard laboratory conditions at room temperature. Cages are reinforced with wooden housing and paper for nesting. Food and water are provided ad libitum. Animals are maintained on a 12:12-hour reversed light:dark cycle (lights off at 6:00 AM). Animals are allowed to acclimate for at least two weeks before beginning any experiments or training.

[0187] Rats are trained and tested in a conventional shuttle box apparatus, separated into two equal-sized compartments by a plastic divider with a central opening. Rats are allowed 5 minutes to habituate to the shuttle box before testing. An 80 dB white noise conditioned stimulus (CS) is presented to the rats, and they have 10 seconds to move from one compartment of the shuttle box to the other. This is called an "escape." If the rat remains in the same compartment for more than 10 seconds, an unconditioned stimulus (UCS), an intermittent electric shock (approximately 0.4 mA), is presented on the grid floor until an escape occurs. Once the rat moves to the other compartment, both the noise and the shock cease. The shock is administered for 0.5 seconds and repeated at 2.5-second intervals. If the animal does not respond within 50 seconds of the shock period, the test ends (escape failure). After three consecutive escape failures, the session is terminated. Animals are trained daily for 5 days, with each session consisting of approximately 20 randomized trials over a 15-minute period. Rats had to reach an 85% avoidance rate to participate in the study. Experimental sessions lasted 10 min and were conducted before drug administration (pretest) and 20, 90, and 240 min after drug injection. Experimental days were separated by at least two non-experimental days.

[0188] Data from CARs are analyzed by Friedman analysis of variance (ANOVA), and if significant differences emerge, a Wilcoxon matched-pairs signed-rank test is performed as a follow-up test. All data are presented as median + interquartile range.

[0189] Lumateperon tosylate was dissolved in a vehicle of 5% dimethyl sulfoxide, 5% Tween 20, 15% PEG-400, and distilled water. SNP was dissolved in saline (0.9% NaCl) and kept in the dark until injection (it is photosensitive). All drugs were administered intraperitoneally at a volume of 1 ml / kg. Depending on the experiment, rats were administered 1 mg / kg, 3 mg / kg, 7 mg / kg, or 10 mg / kg of lumateperon tosylate. As a control, rats were administered 0.4 mg / kg of risperidone.

[0190] As shown in Figure 1, when treated with lumateperone or risperidone alone, a significant effect of treatment was found in the CAR test 20 minutes after drug administration (p<0.0001). Follow-up tests showed that lumateperone at 3 mg / kg and 10 mg / kg, as well as risperidone, significantly suppressed CAR compared to vehicle. At 90 minutes, as shown in Figure 2, there was a significant treatment effect for lumateperone at 10 mg / kg, but not for other doses or risperidone.

[0191] As shown in Figure 3, treatment with the combination of lumateperone and SNP demonstrated a significant therapeutic effect 20 minutes after drug administration. Follow-up tests demonstrated that 3 mg / kg and 7 mg / kg lumateperone combined with 1.5 mg / kg SNP significantly increased CAR inhibition compared to vehicle / SNP. Furthermore, 7 mg / kg lumateperone significantly inhibited CAR compared to vehicle / saline. 3 mg / kg lumateperone plus SNP was significantly different from lumateperone / saline and lumateperone (7 mg / kg) / SNP.

[0192] Ninety minutes after drug administration, a significant treatment effect was observed, as shown in Figure 4. Lumateperone at 7 mg / kg was significantly different from lumateperone (3 mg / kg) / saline, and lumateperone (7 mg / kg) / SNP was significantly different from vehicle / saline.

[0193] Taken together, the data support an unexpected synergistic antipsychotic effect for the combination of lumateperone and SNP. The present application also includes the following aspects. [Aspect 1] 1. A method for treating psychosis (e.g., schizophrenia), depression (e.g., bipolar depression), and / or anxiety, or other CNS disorders for which lumateperone has been shown to be effective, comprising: (i) administering an effective amount of 5-HT 2A or 5-HT 2A A method comprising administering (i) a D2 receptor ligand, e.g., a substituted heterocyclic-fused gamma-carboline described herein, in free form, a pharmaceutically acceptable salt form, or a prodrug form, and (ii) an effective amount of a nitric oxide donor, e.g., SNP, separately (sequentially or simultaneously) or in combination (e.g., as a fixed-dose combination). [Aspect 2] 5-HT 2A or 5-HT 2A / D2 receptor ligands may be in deuterated form, in free form, in the form of a pharmaceutically acceptable salt or in the form of a prodrug, of formula I: [ka] [In the formula, X is -N(H)-, -N(CH 3 )- or -O-; Y is -C(=O)-, -C(H)(OH)- or -C(H)(OR 1 )-and; R 1 is -C(O)-C 1-21 Alkyl or -C(O)OC 1-21 alkyl] The method of embodiment 1, wherein the compound is [Aspect 3] In compounds of formula I, X is -N(H)- or -N(CH 3 3. The method of embodiment 2, wherein [Aspect 4] In the compound of formula I, X is —N(CH 3 4. The method of embodiment 3, wherein [Aspect 5] The method of embodiment 2, wherein Y in the compound of formula I is —C(═O)—. [Aspect 6] The compound of formula I [ka] 3. The method of embodiment 2, wherein [Aspect 7] The method of embodiment 6, wherein the compound of formula I is in the form of a tosylate salt (e.g., a monotosylate or ditosylate salt), which may be in crystalline form. [Aspect 8] 5-HT 2A or 5-HT 2A / D2 receptor ligand, X is -N(CH 3 2. The method of embodiment 1, wherein the compound of formula I is —C(═O)—, and Y is —C(═O)—. [Aspect 9] The method of any one of aspects 1-8, wherein the nitric oxide donor is selected from sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate), amyl nitrate, diethylene glycol dinitrate, isosorbide mononitrate, isosorbide dinitrate, itramine tosylate, pentaerythritol tetranitrate, propatyl nitrate, dinitrodyl, tenitramine, trolnitrate, molsidomine, linsidomine, and naproxcinod. [Aspect 10] 10. The method of any one of aspects 1-9, wherein the method comprises once-daily administration of an oral administration unit dosage form, e.g., a tablet or capsule, comprising a compound of Formula I in an amount equivalent to 1-100 mg of the monotosylate salt, e.g., 1-75 mg, or 1-60 mg, or 1-40 mg, or 1-30 mg, or 1-20 mg, or 1-10 mg, or 1-5 mg of the monotosylate salt, and a pharmaceutically acceptable diluent or carrier. [Aspect 11] 11. The method of any one of aspects 1-10, wherein the condition being treated is psychosis, such as schizophrenia (e.g., prodromal, acute, and / or residual symptoms of psychosis; or negative and / or positive symptoms of psychosis), delusional disorder (e.g., somatic type), 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. [Aspect 12] The method of embodiment 11, wherein the condition being treated is a symptom (e.g., residual symptoms) of a psychosis (e.g., schizophrenia) selected from (1) negative symptoms, e.g., blunted affect, emotional withdrawal, poor rapport, passive or apathetic withdrawal, difficulty with abstract thinking, lack of conversational spontaneity and fluency, and stereotypic thinking; and (2) general psychopathological symptoms, e.g., somatic concerns, anxiety, self-blame, tension, mannerisms and awkward posturing, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, inattention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance; cognitive dysfunction, and sleep disorders (e.g., insomnia). [Aspect 13] The method of embodiment 11, wherein the psychosis (e.g., schizophrenia) is treatment-resistant psychosis (e.g., treatment-resistant schizophrenia), e.g., psychosis (or schizophrenia) that has not responded to treatment with one or more antipsychotic drugs. [Aspect 14] 14. The method of any one of aspects 1-13, wherein the patient has not responded to or has not responded adequately to treatment with another antipsychotic or antidepressant, or is suffering from undesirable side effects. [Aspect 15] (i) an effective amount of 5-HT 2A or 5-HT 2A A pharmaceutical composition comprising: (i) a D2 receptor ligand, e.g., a substituted heterocyclic-fused gamma-carboline described herein, in free form, a pharmaceutically acceptable salt form, or a prodrug form; and (ii) an effective amount of a nitric oxide donor, e.g., SNP. [Aspect 16] 5-HT 2A or 5-HT 2A / D2 receptor ligands may be in deuterated form, in free form, in the form of a pharmaceutically acceptable salt or in the form of a prodrug, of formula I:

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Claims

1. 5-HT 2A or 5-HT 2A A pharmaceutical for treating schizophrenia and / or depression, comprising a D2 receptor ligand, The 5-HT 2A or 5-HT 2A / D2 receptor ligand is a compound of formula I, in free form or in pharmaceutically acceptable salt form: 【Chemistry 1】 and The medicament is for use in combination with a nitric oxide donor, wherein the nitric oxide donor is selected from sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate), amyl nitrate, diethylene glycol dinitrate, isosorbide mononitrate, isosorbide dinitrate, itramine tosylate, pentaerythritol tetranitrate, propatyl nitrate, dinitrodyl, tenitramine, trolnitrate, molsidomine, linsidomine, and naproxcinod. The medicine.

2. 5-HT 2A or 5-HT 2A 2. The method of claim 1, wherein the D2 receptor ligand and the nitric oxide donor are administered separately, sequentially, simultaneously, or as a fixed-dose combination.

3. 5-HT 2A or 5-HT 2A 3. The pharmaceutical composition according to claim 1, wherein the D2 receptor ligand and the nitric oxide donor are present in separate pharmaceutical compositions.

4. The method according to any one of claims 1 to 3, wherein the compound of formula I is in the form of a tosylate salt.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the nitric oxide donor is selected from sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate), isosorbide mononitrate, isosorbide dinitrate, and molsidomine.

6. 6. The medicament of any one of claims 1 to 5, wherein the medicament is in a unit dosage form for oral administration comprising the compound of formula I in an amount equivalent to 1 to 100 mg of the monotosylate salt, and a pharmaceutically acceptable diluent or carrier.

7. 6. The method of claim 1, wherein the medicament is in a unit dosage form for oral administration containing the compound of formula I in an amount corresponding to 1 to 60 mg of the monotosylate salt.

8. 6. The method of claim 1, wherein the medicament is in a unit dosage form for oral administration containing the compound of formula I in an amount corresponding to 1 to 20 mg of the monotosylate salt.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the condition to be treated is schizophrenia.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the condition to be treated is depression.

11. 10. The method of claim 9, wherein the condition to be treated is a symptom of schizophrenia selected from negative symptoms, general psychopathological symptoms, cognitive dysfunction, and sleep disorders.

12. 12. The pharmaceutical composition of claim 11, wherein the negative symptoms are selected from blunted affect, emotional withdrawal, poor rapport, passive or apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and fluency in speech, and stereotypic thinking; and the general psychopathological symptoms are selected from somatic concerns, anxiety, self-blame, tension, mannerisms and awkward posturing, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, inattention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance.

13. 12. The method of claim 11, wherein the negative symptoms are selected from emotional withdrawal and passive or apathetic withdrawal; and the common psychopathological symptom is active social avoidance.

14. The pharmaceutical composition according to claim 9, wherein the schizophrenia is treatment-resistant schizophrenia.

15. The pharmaceutical composition according to claim 14, wherein the treatment-resistant schizophrenia is schizophrenia that has not responded to treatment with one or more antipsychotic drugs.

16. 16. A medicament according to any one of claims 1 to 15, wherein the medicament is administered to a patient who has not responded, or has not responded adequately, to treatment with another antipsychotic or antidepressant, or who is suffering from undesirable side effects.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the nitric oxide donor is sodium nitroprusside (SNP).

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