New method

Abstract

To provide medicines for the treatment of mental illness (such as schizophrenia), or depression (such as bipolar depression), and / or anxiety. [Solution] 5-HT 2A or 5-HT 2A A pharmaceutical product for the treatment of schizophrenia and / or depression comprising a 5-HT2 receptor ligand, wherein the 5-HT2 receptor ligand is present. 2A or 5-HT 2A / D2 receptor ligand is a compound of formula I, in free form or pharmaceutically acceptable salt form, and the pharmaceutically is a pharmaceutically 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 disnitrate, isosorbide mononitrate, isosorbide disnitrate, itramine tosylate, pentaerythritol tetranitrate, propatil nitrate, cynitrodil, tenitramine, trolnitrate, morcidomin, lincidomin, and naproxinod. JPEG2026047365000022.jpg3573

Description

[Technical Field]

[0001] Cross-reference of related applications This application is an international application claiming priority and benefits of U.S. Provisional Patent Application No. 62 / 906,042, filed on 25 September 2019 (the contents of which, as such, are included in this specification by attribution).

[0002] Technical field This disclosure relates to (i) 5-HT for the treatment of psychosis (such as schizophrenia) or depression (such as bipolar depression) and / or anxiety. 2A or 5-HT 2A The present invention relates to the use of (ii) a D2 receptor ligand, for example, in free form, pharmaceutically acceptable salt form or prodrug form, of a substituted heterocyclic condensed γ-carbolin as described herein, and (ii) a nitric oxide donor, separately (sequentially or simultaneously) or in combination (for example, as a fixed-dose combination). [Background technology]

[0003] Background of the Invention Recent psychiatric genomic research suggests that major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder (MDD), currently classified as separate disorder categories, exhibit both clinical overlap and familial co-sets, and share genetic risk factors. Furthermore, potential mechanisms underlying this clinical overlap are emerging, involving genes involved in neurodevelopment, synaptic plasticity, and cognitive function.

[0004] Preclinical and clinical data accumulated over the past several decades collectively depict the major roles of prefrontal cortex dopamine and D1 receptors, as well as serotonin and glutamatergic NMDA receptor-mediated transmission in the cognitive modalities described above, and evidence is emerging for partially overlapping dysfunction of these neurotransmitters and receptors in schizophrenia and MDD. Therefore, combinations of atypical antipsychotics (APDs), which primarily exhibit potent 5-HT2A receptor blocking properties and moderate D2 receptor blocking properties, with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are frequently used in treatment-resistant depression (TRD), albeit with reduced APD dosages. 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 occupancy.

[0005] Add-on therapy with low-to-medium doses of SSRIs for atypical APD in TRD potently enhances antidepressant effects with rapid onset. However, the rapid and potent antidepressant effect of ketamine is highly dependent on glutamatergic AMPA receptor activation in the PFC, which promotes activation of the mTOR pathway and associated increases in synapse number and function, reversing the synaptic deficiency in TRD.

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

[0007] Accumulated evidence suggests that inflammation plays a role in the pathophysiology of mood disorders, including bipolar and unipolar depressive disorders. Elevated levels of inflammatory 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 who have never previously experienced depression. Several findings indicate a pathophysiological role of IL-6 in depression, particularly in patients who do not respond to SSRIs.

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

[0009] Substituted heterocyclic condensed gamma-carbolins such as lumateperone are useful in treating central nervous system disorders. 2A or 5-HT 2A These compounds are known to be serotonin 2A(5-HT) receptor ligands. 2AThey antagonize the receptor and / or modulate dopamine receptor signaling at the level of important intracellular phosphoproteins. Such compounds are known to be useful primarily in the treatment of positive and negative symptoms of schizophrenia. At the dopamine D2 receptor, these compounds have dual properties, acting as both postsynaptic antagonists and presynaptic agonists. They also stimulate phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors specifically in the mesolimbic system. Along with serotonergic, glutamatergic, and dopaminergic interactions, this local selectivity in brain regions thought to mediate the effects of antipsychotic drugs is thought to contribute to antipsychotic effects against positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compounds also exhibit serotonin reuptake inhibition and provide antidepressant activity in the treatment of schizoaffective disorder, comorbid depression, and / or as a stand-alone treatment for major depressive disorder. 2A or 5-HT 2A D2 receptor ligands are also useful in treating bipolar disorder as well as other mental and neurodegenerative disorders, particularly dementia, autism, and behavioral disorders associated with other CNS disorders. These properties can improve the quality of life for schizophrenic patients, enhance social functioning, and allow them to integrate more fully into their families and workplaces. These compounds are effective at low doses, including 5-HT 2A They selectively target receptors and exhibit a differential dose-dependent effect, gradually interacting with D2 receptors at high doses. Consequently, at low doses, they are useful in treating sleep disorders, aggression, and agitation. At high doses, they can treat acute exacerbations and residual schizophrenia, bipolar disorder, and mood disorders.

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

[0011] In patients with schizophrenia, lumateperone has been found to significantly improve social function, positive and negative symptoms, and cognitive impairment at a similarly low striatal D2 receptor occupancy as clozapine. Furthermore, in schizophrenia with comorbid depression, lumateperone improves depressive symptoms without metabolic changes or extrapyramidal side effects, while having a placebo-level safety profile.

[0012] Lumateperone also shows antidepressant-like effects in the social defeat model, restoring socialization deficits and withdrawal after chronic stress. Recent data demonstrate that lumateperone alone uniquely activates both NMDA receptor - evoked and AMPA receptor - evoked currents in pyramidal cells of rat mPFC slices, increasing phosphorylation of key proteins in the mTOR pathway including protein kinase Akt and p70S6 kinase, supporting a ketamine - like mechanism of action of lumateperone in both MDD and TRD.

[0013] Lumateperone and related compounds are described in US Patents No. 6,548,493; No. 7,238,690; No. 6,552,017; No. 6,713,471; No. 7,071,186; No. 7,183,282; US Reissue Patent Invention No. 39,680 and US Reissue Patent Invention No. 39,679 for conditions related to anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache, and social phobia, etc. related to 5 - HT 2AThese are disclosed as novel compounds useful for treating disorders related to receptor modulation. U.S. Patents 7,071,186 and 7,183,282 also disclose methods for producing substituted heterocyclic condensed gamma-carbolines, as well as the use of these gamma-carbolines as serotonin agonists and antagonists useful for controlling and preventing central nervous system disorders such as addictive behaviors and sleep disorders. U.S. Patents 8,598,119, 9,168,28, 9,616,061, 10,117,867, and U.S. Patent Application Publication 2015 / 0080404 (each of which is part of this Specified Patent Publication as indicated) disclose the use of certain substituted heterocyclic condensed gamma-carbolines for the treatment of combinations of psychotic and depressive disorders, and for the treatment of sleep disorders, depressive disorders and / or mood disorders in patients with psychosis or Parkinson's disease, as well as for the treatment or prevention of disorders associated with dementia, particularly behavioral or mood disorders, such as agitation, irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts, and psychosis and sleep disorders associated with dementia. U.S. Patents 9,956,117 and 10,322,134 specifically disclose methods for treating negative or residual symptoms of schizophrenia using certain substituted heterocyclic condensed gamma-carbolines. International Publication 2019 / 178484 discloses the use of such compounds for the acute treatment of depression and anxiety. U.S. Patents 8,648,077, 9,119,995, and 9,586,960 (each included herein by appropriate attribution) disclose methods for producing toluenesulfonate addition salt crystals of specific substituted heterocyclic condensed γ-carbolines, such as 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

[0014] U.S. Patents 8,993,572 and 9,371,324 (each, as explicitly stated herein) disclose prodrugs / metabolites of substituted heterocyclic condensed gamma-carbolines for improved formulations, e.g., sustained-release / controlled-release formulations. These applications disclose that heterocyclic condensed gamma-carbolines with N-substituted 4-fluorophenyl(4-hydroxy)butyl moieties exhibit higher selectivity for serotonin transporters (SERTs) compared to heterocyclic condensed gamma-carbolines containing 4-fluorophenylbutanone.

[0015] U.S. Patent No. 8,598,119 teaches that selected substituted heterocyclic condensed γ-carboline compounds have nanomolar affinity for serotonin reuptake transporters (SERTs) and are therefore selective serotonin reuptake inhibitors.

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

[0017] Thus, condensed heterocyclic γ-carbolins such as lumateperone, unique among APDs, exhibit both dopamine receptor modulation and SSRI activity in a single compound. Like ketamine, they enhance both NMDA-induced and AMPA-induced currents in rat mPFC pyramidal neurons via D1 receptor activation and increase phosphorylation of major proteins in the mTOR pathway, which appears to be downstream of AMPA receptor activation. Therefore, these compounds could be new rapid-acting antidepressants for mood disorders. More recent studies have shown that lumateperone exhibits anti-inflammatory effects, but unlike other drugs (such as ketamine), it does not directly act on microglial cells.

[0018] In recent years, the glutamate-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway has attracted increasing attention as a target for novel antipsychotic drugs (APDs) due to its involvement in the development of schizophrenia. It has been observed that schizophrenia patients have lower levels of NO in the cerebrospinal fluid compared to healthy individuals. Post-mortem studies have shown that schizophrenia patients have significantly fewer striatal interneurons containing NO synthase (NOS).

[0019] NO is synthesized after activation of N-methyl-D-aspartate receptors (NMDARs), diffuses, activates soluble guanylyl cyclase, and subsequently produces cGMP. Since brain NMDAR dysfunction is clearly demonstrated in schizophrenia, this can obviously contribute to decreased brain NO levels in patients. Furthermore, since polymorphisms in the NOS1 gene have been shown to be associated with schizophrenia, decreased NOS1 expression may contribute to a hypoglutamatogenic state in the hippocampus, making individuals more susceptible to developing schizophrenia.

[0020] The study shows that a single injection of sodium nitroprusside (SNP), an antihypertensive NO donor, can induce rapid (within 4 hours) and sustained (several weeks) antipsychotic effects in young, treatment-resistant schizophrenia patients who are stably taking antipsychotic medications. Further case studies have shown similar effects in clozapine-resistant schizophrenia patients. These findings highlight the clinical potential of SNP, as clozapine is the only antipsychotic approved by the FDA for treatment-resistant schizophrenia. Another double-blind study in healthy controls showed that SNP reduced ketamine-induced psychotropic symptoms.

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

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

[0023] Recently, we studied the antipsychotic-like effects of SNPs in rats using behavioral and biochemical methods, both when administered alone and in combination with sub-effective doses of risperidone. Low doses of SNPs rapidly and potently enhanced the antipsychotic-like effects of sub-effective doses of risperidone in conditioned avoidance response (CAR) tests. Correlated biochemical studies of local dopamine release in freely moving rats showed that SNPs 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 elevated intracellular levels of cGMP may be involved in mediating the antipsychotic activity of SNPs in rats. Interestingly, pro-inflammatory immune states (increased markers of cellular immunity), such as elevated levels of cytokines like IL-6, are regularly observed in schizophrenia.

[0024] Improvements in the treatment of schizophrenia, depression, anxiety, and other central nervous system disorders remain particularly needed in treatment-resistant patients. [Overview of the Initiative]

[0025] Brief summary of the invention We have found, surprisingly, that the substituted heterocyclic condensed γ-carbolins described herein, particularly lumateperone, exhibit unexpected synergistic improvements in efficacy when combined with nitric oxide donors such as SNPs.

[0026] Therefore, this disclosure relates to a method for treating psychosis (such as schizophrenia), depression (such as bipolar depression), and / or anxiety, or other CNS disorders for which lumateperone has been shown to be effective, comprising (i) an effective amount of 5-HT 2A or 5-HT 2A The present invention provides a method comprising administering (i) a D2 receptor ligand, e.g., in free form, pharmaceutically acceptable salt form or prodrug form, of a substituted heterocyclic condensed γ-carbolin as described herein, and (ii) an effective amount of a nitric oxide donor, e.g., a SNP, separately (sequentially or simultaneously) or in combination (e.g., as a fixed-dose combination). The present invention also provides, for example, (i) 5-HT for use in such a method. 2A or 5-HT 2A The present invention provides a pharmaceutical composition comprising (ii) a D2 receptor ligand and (ii) a nitric oxide donor.

[0027] In some embodiments, the Disclosure further provides the above methods, including concurrent administration of PDE1 inhibitors, such as compounds of Formula II disclosed herein. Such compounds are disclosed, for example, in U.S. Patent No. 9,545,406 (which, with due attribution, constitutes part of this Specified Publication) as being useful in the treatment of diseases, disorders, and injuries of the central nervous system, and as neuroprotective and / or nerve regenerative agents. [Brief explanation of the drawing]

[0028] [Figure 1]Conditioned avoidance response (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] Caribogenic carcinoma (CAR) in male Wistar rats 90 minutes after treatment with vehicle, lumateperone (1 mg / kg, 3 mg / kg, or 10 mg / kg), or risperidone (0.4 mg / kg). * Compared to vehicle + saline, p<0.05; n=11.

[0030] [Figure 3] Caribou cardiometabolism (CAR) in male Wistar rats 20 minutes 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 to vehicle + saline; [ka] ## As shown, p<0.01; n=11.

[0031] [Figure 4] CAR in male Wistar rats 90 minutes 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] # As shown, p<0.05; n=11. [Modes for carrying out the invention]

[0032] Detailed explanation 5-HT 2A or 5-HT 2A / D2 receptor ligand is serotonin 2A (5-HT 2A These compounds antagonize dopamine receptors and / or modulate dopamine receptor signaling at the level of important intracellular phosphoproteins, and are therefore useful in 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 agonists. They also stimulate phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors specifically in the mesolimbic system. This local selectivity in brain regions thought to mediate the effects of antipsychotics, along with serotonergic, glutamatergic, and dopaminergic interactions, is thought to contribute to antipsychotic effects against positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compounds also exhibit serotonin reuptake inhibition and provide antidepressant activity in the treatment of schizoaffective disorder, comorbid depression, and / or as a stand-alone treatment for major depressive disorder. The 5-HT listed 2A or 5-HT 2A / D2 receptor ligands are also useful in treating bipolar disorder as well as other mental and neurodegenerative disorders, particularly behavioral disorders associated with dementia, autism, and other CNS disorders.

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

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

[0035] 1.1. 5-HT 2A or 5-HT 2A The / D2 receptor ligand may be in a free form, a pharmaceutically acceptable salt form, or a prodrug form, or a deuterated form, Formula I: [ka] [In the formula, X is -N(H)-, -N(CH3)-, or -O-; Y is -C(=O)-, -C(H)(OH)-, or -C(H)(OR1)-; R1 is -C(O)-C 1-21 Alkyl or -C(O)OC 1-21 It is alkyl. Method 1: A substituted heterocyclic condensed γ-carboline compound represented by [formula];

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

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

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

[0039] 1.5. In the compound of formula I, Y is -C(=O)-, either by method 1 or formulas 1.1 to 1.4;

[0040] 1.6. Method 1 or one of the formulas 1.1 to 1.4, wherein Y in the compound of formula I is -C(H)(OH)-;

[0041] 1.7. In the compound of formula I, Y is -C(H)(OR1)-, either by method 1 or formulas 1.1 to 1.4;

[0042] 1.8. In the compound of formula I, R1 is -C(O)-C 1-21 Alkyl (for example, -C(O)-C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 It is an alkyl group, preferably the alkyl group may be saturated or unsaturated, and it contains one or more hydroxyl or C atoms. 1-22 A linear chain which may be substituted with an alkoxy (e.g., ethoxy) group, for example, R1 may be -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15It is an alkyl compound, where the compound hydrolyzes to form natural or unnatural saturated or unsaturated fatty acid residues, 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, R1 in the compound of formula I is -C(O)-C 6-15 Alkyl, for example, -C(O)-C9 alkyl; or R1 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. In the compound of formula I, 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 It is an alkyl group, preferably the alkyl group may be saturated or unsaturated, and it contains one or more hydroxyl or C atoms. 1-22 It is a linear chain that may be substituted with an alkoxy (e.g., ethoxy) group, for example, R1 may be -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 It is an alkyl compound, where the compound hydrolyzes to form natural or unnatural saturated or unsaturated fatty acid residues, 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, R1 in the compound of formula I is -C(O)OC 6-15 Alkyl, for example, -C(O)O-C9 alkyl; or R1 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. The compound of formula I [ka] Method 1 or any of 1.1-1.4 or 1.6;

[0045] 1.11. The compound of formula I [ka] Method 1 or any of 1.1-1.4 or 1.6;

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

[0047] 1.13. The compound of formula I is in the form of a toluenesulfonic acid addition salt (monotosylate or nitrotosylate), and may also be in the form of a crystalline salt, according to either Method 1 or 1.1 to 1.12;

[0048] 1.14. The compound of formula I is in the form of a free base, by method 1, or any of 1.1-1.12;

[0049] 1.15. The compound of formula I is in a deuterated form, for example, the deuterium:protium ratio for a particular carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, for example, at least twice, for example, at least ten times higher, by any of Method 1 or 1.1-1.14;

[0050] 1.16. The compound of formula I, in free form or in pharmaceutically acceptable salt form, for example, in the form of a toluenesulfonic acid addition salt, [ka] [In the formula, D represents a hydrogen position that substantially exceeds natural deuterium uptake (i.e., substantially exceeds 0.0156%), for example, exceeding 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%.] Method 1.15, selected from;

[0051] 1.17. 5-HT 2A or 5-HT 2A The D2 receptor ligand is a compound of formula I in the form of a toluenesulfonate addition salt (e.g., monotosylate, ditosylate, or a combination thereof), where X is -N(CH3)- and Y is -C(=O)-, in any of the above methods;

[0052] 1.18. Method 1.17, in which the compound of formula I is administered in a daily dose equivalent to approximately 1 to 100 mg of monotosylate, for example, 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 monotosylate;

[0053] 1.19. Method 1.17, comprising administering once daily an oral unit dosage form, such as a tablet or capsule, comprising 1 to 100 mg of a monotosylate, for example, 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 a compound of formula I, and a pharmaceutically acceptable diluent or carrier;

[0054] 1.20. Method 1.17, comprising administering once daily a unit dosage form for subcutaneous or transmucosal administration, such as a sublingual or buccal orally disintegrating tablet or film, comprising an amount of a compound of formula I equivalent to 1 to 100 mg of monotosylate, for example, 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 monotosylate, and a pharmaceutically acceptable diluent or carrier;

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

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

[0057] 1.23. The nitric oxide donor is a compound that produces nitric oxide by in vivo enzymatic action (e.g., biotransformation), for example, by denitrification and / or reduction, according to Method 1 or any of 1.1 to 1.22;

[0058] 1.24. The nitric oxide donor is a compound that produces nitric oxide in vivo without enzymatic action (e.g., in vivo changes), for example by hydrolysis and / or spontaneous decomposition, such as an N-nitroso compound or its precursor, according to Method 1 or any of 1.1 to 1.22;

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

[0060] 1.26. Nitric oxide donors include sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate or GTN), amyl nitrate, diethylene glycol disnitrate, isosorbide mononitrate (ISMN), isosorbide disnitrate (ISDN), itramine tosylate, pentaerythritol tetranitrate (PETN), propatil nitrate, cynitrodyl, tenitramine, trolnitrate, morcidomin, lincidomin, naproxinod, amyl nitrite, diethylamine diazenium diolate (DEA / NO), diethyltriamine diazenium diolate (DETA / NO), spermine diazenium diolate ( SPER / NO), proline diazenium diolate (PROLI / NO), dipropyltriamine diazenium diolate (DPTA / NO), methylamine hexamethylene methylamine diazenium diolate (MAHMA / NO), propylamine propylamine diazenium diolate (PAPA / NO or NOC-15), isopropylamine propylamine diazenium diolate (IPAPA / NO or NOC-5), isopropylamine diazenium diolate (IPA / NO), heparin diazenium diolate, pyrrolidine diazenium diolate (PYRRO / NO), O 2 -Vinyl-1-(pyrroridine-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO / NO), O 2 -Vinyl-1-isopropyl-diazene-1-ium-1,2-diolate (V-IPA / NO), O 2 -Vinyl-[2-(carboxylato)pyrrolidine-1-yl]diazen-1-ium-1,2-diolate (V-PROLI / NO), O 2 -(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazine-1-yl]diazen-1-ium-1,2-diolate (JS-K), O 2 -Vinyl-1-[(4-ethoxycarbonyl)piperazine-1-yl]diazen-1-ium-1,2-diolate, O 2-Acetoxymethyl-isopropyldiazene-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-nitrosalbumin, and NO hybrid drugs (e.g., 2-(acetyloxy)-benzoate 3-[(nitrooxy)methyl]phenylesterates) Method 1, or one of 1.1-1.24, selected from (NCX4016), 2-acetyloxybenzoate 5-nitrooxypentyl (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);

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

[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 methods described above, wherein the condition being treated is a psychosis, e.g., schizophrenia (e.g., prodromal symptoms, acute symptoms and / or residual symptoms of psychosis; or negative symptoms and / or positive symptoms of psychosis), delusional disorder (e.g., somatic type), major depressive disorder with psychosis, bipolar disorder with psychotic symptoms, brief psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, or a psychosis caused by a medical condition or substance use;

[0064] 1.30. The condition to be treated is (1) negative symptoms, e.g., emotional blunting, emotional withdrawal, poor rapport, passive or apathetic withdrawal, difficulty with abstract thinking, lack of spontaneity and fluency in conversation, and stereotyped thinking; and (2) general psychopathological symptoms, e.g., body anxiety, guilt, tension, mannerisms and unnatural posture, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, inattention, lack of judgment and insight, disturbance of volition, impulse control, preoccupation and active social avoidance; symptoms of psychosis (e.g., schizophrenia) selected from cognitive impairment and sleep disorders (e.g., insomnia) (e.g., residual symptoms), Method 1.29;

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

[0066] 1.32. The condition being treated is a symptom of a psychosis (e.g., schizophrenia) selected from positive symptoms, e.g., delusions, hallucinations, and paranoia (e.g., active or acute symptoms), method 1.29;

[0067] 1.33. A psychosis (e.g., schizophrenia) is a treatment-resistant psychosis (e.g., treatment-resistant schizophrenia), such as a psychosis (or schizophrenia) that has not responded to treatment with one or more antipsychotic drugs, Methods 1.29-1.32;

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

[0069] 1.35. One or more antipsychotic drugs: acepromazine, amisulpride, aripiprazole, asenapine, bemperidol, blonanserin, brexiprazole, bromperidol, caliprazine, caliprazine, carpipramine, chlorpromazine, chlorprothixen, clocapramine, clopentixol, chlorotepine, clotiapine, clozapine, siamemazine, dixilazine, droperidol, flupentixol, fluphenazine, fluspirylene, haloperidol, iloperidone, levomepromazine, roxapine, lurasidone, merperone, mesolidazine, morindone, per Method 1.33 or 1.34, selected from phenazine, moperone, mosapramine, nemonapride, olanzapine, paliperidone, penfluridol, perazine, periciazine, perospirone, pimavanserin, pimozide, pipemperone, pipothiazine, prochlorperazine, promazine, protipendyl, quetiapine, remoxiprid, risperidone, certindol, sulpiride, sultopride, thioproperazine, thioridazine, thiothixen, thimiperone, trifluoperazine, triflupromazine, veraliprid, ziprasidone, zotepine, and zuclopentixol;

[0070] 1.36. Any of the aforementioned methods, wherein the condition being treated is anxiety, for example, 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 methods described above, wherein the condition being treated is depression, for example, acute depression (e.g., an acute major depressive episode, an acute short-term depressive episode, or an acute recurrent short-term depressive episode);

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

[0073] 1.39. Method 1.38, in which one or more antidepressants are selected from selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants, monoamine oxidase inhibitors, norepinephrine reuptake inhibitors (NRIs), dopamine reuptake inhibitors (DRIs), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitors), serotonin receptor antagonists, or combinations thereof;

[0074] 1.40. One or more antidepressants include citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, venlafaxine, desvenlafaxine, duloxetine, levomilunacipran, milnacipran, bilazodone, vortioxetine, nefazodone, trazodone, atomoxetine, leboxetine, teniroxazine, biloxazine, bupropion, tofenacin, amitriptyline, and Method 1.38, selected from mitriptyline N-oxide, clomipramine, desipramine, dibenzepine, dimethacrine, dosurepin, doxepin, imipramine, lofepramine, melitracene, nitroxazepine, nortriptyline, noxyptyline, opipramole, pipofezin, protriptyline, trimipramine, amoxapine, maprotiline, mirtazapine, mianserin, and setiptyline;

[0075] 1.41. Any of the above 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 above 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 2AMethod 1, or any of 1.1 to 1.41, wherein the D2 receptor ligand and the nitric oxide donor are provided in separate pharmaceutical compositions administered simultaneously or sequentially (e.g., within 24 hours);

[0078] 1.44. Any of the aforementioned methods in which the patient has not responded to, or has not responded adequately to, treatment with another antipsychotic or antidepressant as defined herein, or has suffered from undesirable side effects.

[0079] 1.45. 5-HT 2A or 5-HT 2A / D2 receptor ligand, 5HT 2A IC250 nM for receptor activity (agonism and / or antagonist) 50 or EC less than 250nM 50 For example, ICs with activity (agonism or antagonistism) at the receptor 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 methods having;

[0080] 1.46. 5-HT 2A or 5-HT 2A / D2 receptor ligands have an IC250 nM of activity (agonism and / or antagonistism) at the D2 receptor. 50 or EC less than 250nM 50 For example, ICs with activity (agonism or antagonistism) at the receptor 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 methods having;

[0081] 1.47. 5-HT 2Aor 5-HT 2A / D2 receptor ligands have an IC250 nM of activity (agonism and / or antagonistism) at the D1 receptor. 50 or EC less than 250nM 50 For example, ICs with receptor activity (agonism or antagonist) 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 methods having;

[0082] 1.48. 5-HT 2A or 5-HT 2A / D2 receptor ligands exhibit less than 250 nM IC for activity (agonism and / or antagonistism) at the serotonin transporter (SERT). 50 or EC less than 250nM 50 For example, ICs with activity (agonism or antagonistism) in the transporter 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 methods having;

[0083] 1.49. 5-HT 2A or 5-HT 2A The method wherein the D2 receptor ligand and / or nitric oxide donor are administered in the form of a long-acting injectable (LAI) composition, for example, for intramuscular or subcutaneous injection;

[0084] 1.50. 5-HT 2A or 5-HT 2AMethod 1.49, wherein the / D2 receptor ligand is a compound of formula I, and the LAI composition contains a sufficient amount of the compound to provide 1 to 100 mg of free base, for example, 1 to 75 mg, or 1 to 6 mg, or 1 to 4 mg, or 1 to 3 weeks, or 1 to 2 weeks, which is released over a period of about 1 week to about 3 months, for example, about 1 week to about 8 weeks, or about 1 week to about 6 weeks, or about 1 week to about 4 weeks, or about 1 week to about 3 weeks, or about 1 week to about 2 weeks, equivalent to a daily dose of 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 free base;

[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 acid), poly(amino acid), cellulose polymer, modified cellulose polymer, polyamide, and polyester;

[0087] 1.53. Method 1.52, wherein the one or more polymers include poly(lactic acid), poly(glycolic acid), poly(citric acid), poly(malic acid), poly(β-hydroxybutyrate), poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyrate-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, poly(butylcyanoacrylate) or poly(2-octylcyanoacrylate), 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 esters;

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

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

[0090] 1.56. 5-HT 2A or 5-HT 2A In any of the foregoing methods, the 5-HT or 5-HT / D2 receptor ligand and the nitric oxide donor are not administered concurrently or in conjunction with an antidepressant, antipsychotic or anxiolytic agent.

[0091] In another aspect, the disclosure provides a 5-HT or 5-HT / D2 receptor ligand, such as a compound of formula I as described herein, for example lumateperone, in free or salt form, which may be in deuterated form, in combination with a nitric oxide donor, such as SNP, for use in the treatment of psychosis, depression and / or anxiety, for example for use in any of methods 1 onwards. 2A or 5-HT 2A / D2 receptor ligand, for example, a compound of formula I as described herein, which may be in deuterated form, in free or salt form, such as lumateperone, for use in the manufacture of a medicament for the treatment of psychosis, depression and / or anxiety, for example for any of methods 1 onwards.

[0092] In another aspect, the disclosure provides the use of a 5-HT or 5-HT / D2 receptor ligand, such as a compound of formula I as described herein, which may be in deuterated form, in free or salt form, such as lumateperone, in combination with a nitric oxide donor, such as SNP, for use in the manufacture of a medicament for the treatment of psychosis, depression and / or anxiety, for example for any of methods 1 onwards. 2A or 5-HT 2A In another aspect, the invention provides (i) a 5-HT or 5-HT for use in the treatment of psychosis, depression and / or anxiety, for example for any of methods 1 onwards.

[0093] In another aspect, the invention provides, for example, for use in the treatment of psychosis, depression and / or anxiety, for example for any of methods 1 onwards, (i) a 5-HT 2A or 5-HT 2AA pharmaceutical composition (Composition 1) is provided that contains (i) an effective amount of a D2 receptor ligand, such as a free form, pharmaceutically acceptable salt form or prodrug form of a substituted heterocyclic-fused γ-carboline described herein, and (ii) an effective amount of a nitric oxide donor, such as SNP. For example, Composition 1 can be as follows:

[0094] 1.1. 5-HT 2A or 5-HT 2A The D2 receptor ligand may be a deuterated form, in free form, pharmaceutically acceptable salt form or prodrug form, of Formula I:

Chemical 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 Formulas 1.1 to 1.4, wherein Y in the compound of Formula I is -C(=O)-;

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

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

[0101] 1.8. In the compound of formula I, R1 is -C(O)-C 1-21 Alkyl (for example, -C(O)-C 1-5 Alkyl, -C(O)-C 6-15 Alkyl or -C(O)-C 16-21 It is an alkyl group, preferably the alkyl group may be saturated or unsaturated, and it contains one or more hydroxyl or C atoms. 1-22 A linear chain which may be substituted with an alkoxy (e.g., ethoxy) group, for example, R1 may be -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 Alkyl, -C(O)-C 13 Alkyl or -C(O)-C 15 It is an alkyl compound, where the compound hydrolyzes to form natural or unnatural saturated or unsaturated fatty acid residues, 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, R1 in the compound of formula I is -C(O)-C 6-15 Alkyl, for example, -C(O)-C9 alkyl; or R1 in the compound of formula I is -C(O)-C 1-5 Alkyl, for example, -C(O)-C3 alkyl, composition 1.7;

[0102] 1.9. In the compound of formula I, 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 It is an alkyl group, preferably the alkyl group may be saturated or unsaturated, and it contains one or more hydroxyl or C atoms. 1-22It is a linear chain that may be substituted with an alkoxy (e.g., ethoxy) group, for example, R1 may be -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 It is an alkyl compound, where the compound hydrolyzes to form natural or unnatural saturated or unsaturated fatty acid residues, 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, R1 in the compound of formula I is -C(O)OC 6-15 It is an alkyl group, for example, a -C(O)O-C9 alkyl group; or R1 in the compound of formula I is -C(O)OC 1-5 Alkyl, for example, -C(O)O-C3 alkyl, composition 1.7;

[0103] 1.10. The compound of formula I, [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, [ka] Composition 1, 1.3, or 1.5;

[0106] 1.13. Composition 1, or any of 1.1 to 1.12, wherein the compound of formula I is in the form of a toluenesulfonate addition salt (e.g., monotosylate or ditosylate), and may also be in the form of a crystalline salt;

[0107] 1.14. Composition 1, or any of 1.1 to 1.12, wherein the compound of formula I is in the form of a 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, for example, the deuterium:protium ratio for a particular carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, for example, at least twice, for example, at least ten times higher;

[0109] 1.16. The compound of formula I, in free form or in pharmaceutically acceptable salt form, for example, in the form of a toluenesulfonic acid addition salt, [ka] [In the formula, D represents a hydrogen position that substantially exceeds natural deuterium uptake (i.e., substantially exceeds 0.0156%), for example, exceeding 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%.] Composition 1.15 selected from;

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

[0111] 1.18. Composition 1.17, which contains a daily dose of a compound of formula I equivalent to about 1 to 100 mg of monotosylate, for example, 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 monotosylate;

[0112] 1.19. Composition 1.17, which is an oral dosage form, such as a tablet or capsule, comprising 1 to 100 mg of a monotosylate, for example, 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 a compound of formula I, and a pharmaceutically acceptable diluent or carrier;

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

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

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

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

[0117] 1.24. Composition 1, or any of 1.1 to 1.22, wherein the nitric oxide donor is a compound that produces nitric oxide in vivo without enzymatic action (e.g., in vivo changes), for example by hydrolysis and / or spontaneous decomposition, such as an N-nitroso compound or its precursor;

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

[0119] 1.26. Nitric oxide donors include sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate or GTN), amyl nitrate, diethylene glycol disnitrate, isosorbide mononitrate (ISMN), isosorbide disnitrate (ISDN), itramine tosylate, pentaerythritol tetranitrate (PETN), propatil nitrate, cynitrodyl, tenitramine, trolnitrate, morcidomin, lincidomin, naproxinod, amyl nitrite, diethylamine diazenium diolate (DEA / NO), diethyltriamine diazenium diolate (DETA / NO), spermine diazenium diolate ( SPER / NO), proline diazenium diolate (PROLI / NO), dipropyltriamine diazenium diolate (DPTA / NO), methylamine hexamethylene methylamine diazenium diolate (MAHMA / NO), propylamine propylamine diazenium diolate (PAPA / NO or NOC-15), isopropylamine propylamine diazenium diolate (IPAPA / NO or NOC-5), isopropylamine diazenium diolate (IPA / NO), heparin diazenium diolate, pyrrolidine diazenium diolate (PYRRO / NO), O 2 -Vinyl-1-(pyrroridine-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO / NO), O 2 -Vinyl-1-isopropyl-diazene-1-ium-1,2-diolate (V-IPA / NO), O 2 -Vinyl-[2-(carboxylato)pyrrolidine-1-yl]diazen-1-ium-1,2-diolate (V-PROLI / NO), O 2 -(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazine-1-yl]diazen-1-ium-1,2-diolate (JS-K), O 2-Vinyl-1-[(4-ethoxycarbonyl)piperazine-1-yl]diazen-1-ium-1,2-diolate, O 2 -Acetoxymethyl-isopropyldiazene-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-nitrosalbumin, and NO hybrid drugs (e.g., 2-(acetyloxy)-benzoate 3-[(nitrooxy)methyl]phenyl ester). Composition 1, or any of 1.1 to 1.24, selected from (NCX4016), 2-acetyloxybenzoate 5-nitrooxypentyl (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 compositions which are 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 in which the condition being treated is psychosis, e.g., schizophrenia (e.g., prodromal symptoms, acute symptoms and / or residual symptoms of psychosis; or negative symptoms and / or positive symptoms of psychosis), delusional disorder (e.g., somatic type), major depressive disorder with psychosis, bipolar disorder with psychotic symptoms, brief psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, or psychosis caused by a medical condition or substance use;

[0122] 1.29. Composition 1.27, in which the condition to be treated is (1) negative symptoms, e.g., emotional blunting, emotional withdrawal, poor rapport, passive or apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and fluency in conversation, and stereotyped thinking; and (2) general psychopathological symptoms, e.g., body anxiety, anxiety, guilt, tension, mannerisms and unnatural posture, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, inattention, lack of judgment and insight, disturbance of volition, impulse control, preoccupation and active social avoidance; and symptoms of psychosis (e.g., schizophrenia) selected from cognitive impairment and sleep disorders (e.g., insomnia) (e.g., residual symptoms).

[0123] 1.30. Composition 1.27, in which the condition to be 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, in which 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 paranoia;

[0125] 1.32. Compositions 1.27-1.31 in which the psychosis (e.g., schizophrenia) is a treatment-resistant psychosis (e.g., treatment-resistant schizophrenia), such as a psychosis (or schizophrenia) that has not responded to treatment with one or more antipsychotic drugs;

[0126] 1.33. Composition comprising one or more antipsychotic drugs selected from typical antipsychotics (first generation) and atypical antipsychotics (second generation); 1.32;

[0127] 1.34. One or more antipsychotic drugs: acepromazine, amisulpride, aripiprazole, asenapine, bemperidol, blonanserin, brexiprazole, bromperidol, caliprazine, caliprazine, carpipramine, chlorpromazine, chlorprothixen, clocapramine, clopentixol, chlorotepine, clotiapine, clozapine, siamemazine, dixilazine, droperidol, flupentixol, fluphenazine, fluspirylene, haloperidol, iloperidone, levomepromazine, roxapine, lurasidone, merperone, mesolidazine, morindone, per Composition 1.32 or 1.33, selected from phenazine, moperone, mosapramine, nemonapride, olanzapine, paliperidone, penfluridol, perazine, periciazine, perospirone, pimavanserin, pimozide, pipemperone, pipothiazine, prochlorperazine, promazine, protipendyl, quetiapine, remoxiprid, risperidone, certindol, sulpiride, sultopride, thioproperazine, thioridazine, thiothixen, thymiperone, trifluoperazine, triflupromazine, veraliprid, ziprasidone, zotepine, and zuclopentixol;

[0128] 1.35. Compositions 1.27-1.34 in which 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);

[0129] 1.36. Compositions 1.27-1.35 in which the condition being treated is depression, for example, acute depression (e.g., acute major depressive episode, acute short-term depressive episode, acute recurrent short-term depressive episode);

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

[0131] 1.38. Compositions in which one or more antidepressants are selected from selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants, monoamine oxidase inhibitors, norepinephrine reuptake inhibitors (NRIs), dopamine reuptake inhibitors (DRIs), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitors), serotonin receptor antagonists, or combinations thereof. 1.37;

[0132] 1.39. One or more antidepressants include citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, venlafaxine, desvenlafaxine, duloxetine, levomilunacipran, milnacipran, bilazodone, vortioxetine, nefazodone, trazodone, atomoxetine, leboxetine, teniroxazine, biloxazine, bupropion, tofenacin, amitriptyline, and Composition 1.37, selected from mitriptyline N-oxide, clomipramine, desipramine, dibenzepine, dimethacrine, dosurepin, doxepin, imipramine, lofepramine, melitracene, nitroxazepine, nortriptyline, noxyptyline, opipramole, pipofezin, protriptyline, trimipramine, amoxapine, maprotiline, mirtazapine, mianserin, and setiptyline;

[0133] 1.40. Compositions 1.27-1.39 in which the condition to be treated is selected from bipolar depression and major depressive disorder;

[0134] 1.41. 5-HT 2A or 5-HT 2AAny of the 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, 5HT 2A IC250 nM for receptor activity (agonism and / or antagonist) 50 or EC less than 250nM 50 For example, ICs with activity (agonism or antagonistism) at the receptor 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 above compositions having;

[0136] 1.43. 5-HT 2A or 5-HT 2A / D2 receptor ligands have an IC250 nM of activity (agonism and / or antagonistism) at the D2 receptor. 50 or EC less than 250nM 50 For example, ICs with activity (agonism or antagonistism) at the receptor 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 above compositions having;

[0137] 1.44. 5-HT 2A or 5-HT 2A / D2 receptor ligands have an IC250 nM of activity (agonism and / or antagonistism) at the D1 receptor. 50 or EC less than 250nM 50For example, ICs with activity (agonism or antagonistism) at the receptor 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 above compositions having;

[0138] 1.45. 5-HT 2A or 5-HT 2A / D2 receptor ligands exhibit less than 250 nM IC for activity (agonism and / or antagonistism) at the serotonin transporter (SERT). 50 or EC less than 250nM 50 For example, ICs with activity (agonism or antagonistism) in the transporter 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 above compositions having;

[0139] 1.46. Any of the compositions, for example, in the form of a long-acting injectable (LAI) composition 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 contains an amount of the compound sufficient to provide 1 to 100 mg of free base, for example, 1 to 75 mg, or 1 to 6 mg, or 1 to 4 mg, or 1 to 3 weeks, or 1 to 2 weeks, which is released over a period of about 1 to 3 months, for example, about 1 to 8 weeks, or about 1 to 6 weeks, or about 1 to 4 weeks, or about 1 to 3 weeks, or about 1 to 2 weeks, equivalent to a daily dose of 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 free base;

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

[0142] 1.49. Composition 1.48 in which the polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxycarboxylic acid), poly(amino acid), cellulose polymer, modified cellulose polymer, polyamide, and polyester;

[0143] 1.50. Composition 1.49 in which one or more polymers include 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(butylcyanoacrylate) or poly(2-octylcyanoacrylate) and other poly(alkylα-cyanoacrylates), poly(orthoesters), polycarbonates, polyortho-carbonates, 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 esters;

[0144] 1.51. Composition 1.49 in which one or more polymers include poly(lactic acid), poly(glycolic acid), poly(citric acid), poly(malic acid), or poly(lactic acid-glycolic acid) copolymer;

[0145] 1.52. Composition 1.49 in which one or more polymers include a poly(lactic acid-glycolic acid) copolymer, for example, poly-d,l-lactide-co-glycolide.

[0146] The term "5-HT" 2A A "receptor ligand" refers to at least serotonin 5-HT 2ACompounds exhibiting pharmacological activity at a receptor, for example, IC250 nM with activity (agonism and / or antagonistism) at the receptor. 50 or EC less than 250nM 50 This term refers to a compound having the following characteristics: In some embodiments, this term refers to 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 in terms of activity (agonism or antagonistism) at the receptor. 50 or EC 50 This refers to compounds that possess [a certain characteristic].

[0147] The term "5-HT" 2A "D2 receptor ligand" refers to at least serotonin 5-HT 2A Compounds that exhibit pharmacological activity at both the receptor and the D2 receptor, for example, IC250 nM for activity at each receptor (agonism and / or antagonist). 50 or EC less than 250nM 50 This term refers to compounds having the following characteristics: In some embodiments, this term refers to compounds with 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 antagonistism) in one or both of these receptors. 50 or EC 50 This refers to compounds that possess [a certain characteristic].

[0148] The terms “treatment” and “to treat” should be understood accordingly to encompass the prevention and treatment or remission of a disease, as well as / or treatment of the cause of the disease. In certain embodiments, the terms “treatment” and “to treat” mean the prevention or remission of the symptoms of the disease.

[0149] The term "patient" may include human patients or non-human patients.

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

[0151] The DSM-5 defines schizophrenia as characterized by delusions, hallucinations, disorganized speech (frequent digressions or incoherence), disorganized or catatonic behavior, and negative symptoms (e.g., reduced affectiveness). 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 active 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 school, interpersonal relationships, or self-management, for a considerable period following the onset of the disorder. Patients who meet the basic criteria except for active symptoms are said to be experiencing a prodromal or residual phase. During these two phases, signs of disorder are often limited to negative symptoms only.

[0152] The DSM-5 defines "major depressive disorder" (MDD) as the presence of five or more of a set of symptoms within the same two-week period, and these symptoms represent a change from the patient's premorbid functioning. The five symptoms are selected from depressed mood, marked loss of interest or pleasure in almost all activities, marked 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, with each of these symptoms present on or near daily. A diagnosis of MDD requires at least one of these five symptoms to be depressed mood or loss of interest and pleasure. MDD can consist of one or more "major depressive episodes" that may occur at intervals of several weeks or months (at least two weeks apart to be recognized as separate episodes). The DSM-5 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 the patient has many of the same symptoms as MDD but the symptoms persist for at least two years. In addition to MDD, the DSM-5 also defines a “short-term depressive episode” as a depressed mood and at least four of the other symptoms that define MDD lasting for at least four days but less than fourteen days. The DSM further defines “recurrent short-term depression” as a depressed mood and at least four other symptoms of depression occurring at least once a month for two to thirteen days in parallel and lasting for at least twelve consecutive months. Thus, recurrent short-term depression also consists of short episodes of depression that recur regularly.

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

[0155] The DSM-5 defines a range of 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 recurrent episodes of short durations, such as panic attacks, which can persist over the course of a chronic disorder. For example, generalized anxiety disorder is defined by the DSM-5 as requiring excessive anxiety and worry about many events or activities for at least six months compared to other days. A panic attack is defined as a sudden surge of intense fear or extreme discomfort that peaks within minutes, and can recur in response to either anticipated or unexpected stimuli. Therefore, as with the depressive disorders mentioned above, there is a need for fast-acting anxiolytics that can treat anxiety or panic symptoms, although some of the most common medications for anxiety disorders are SSRIs and other antidepressants, which take 2-4 weeks to provide relief.

[0156] Social avoidance can be a significant debilitating symptom in patients with anxiety disorders, particularly social anxiety disorder, and traumatic anxiety disorder. Social avoidance is often a key determinant of whether individuals with severe anxiety disorders can maintain family or employment relationships. Unexpectedly, 5-HT drugs such as lumateperone are also a contributing factor. 2ACertain substituted condensed gamma-carbolins with dopamine receptor activity have been found to be effective in treating emotional experience symptoms of mental disorders (e.g., negative emotional experience symptoms in schizophrenia patients). 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 motor developmental delay). In two clinical trials of patients with acute exacerbation of schizophrenia, administration of lumateperone once daily (60 mg PO) for up to 28 days resulted in significant and unexpected improvement in emotional experience symptoms compared to placebo. These are the symptoms that are most highly correlated with interpersonal functioning. Thus, compounds containing the compound of formula I may be very effective in treating other mental disorders such as social anxiety disorder, or the emotional experiential symptoms of other mental illnesses characterized by social withdrawal and social avoidance.

[0157] Unless otherwise specified or unless evident from the context, the following terms in this specification have the following meanings:

[0158] Where used herein, "alkyl" means, unless otherwise specified, a linear or branched (e.g., n-butyl or tert-butyl) saturated or unsaturated hydrocarbon moiety, preferably linear, for example, having a length of 1 to 21 carbon atoms. For example, "C 1-21 "Alkyl" means an alkyl group having 1 to 21 carbon atoms. In one embodiment, alkyl is one or more hydroxyl 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 linear, and may be saturated or unsaturated, for example, R1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms, or 16 to 21 carbon atoms, such that when cleaved together with the bonded -C(O)-, for example, from the compound of formula I, it can form natural or unnatural saturated or unsaturated fatty acid residues.

[0159] 5-HT 2A or 5-HT 2A / D2 receptor ligands, such as the substituted heterocyclic condensed γ-carbolins described herein, may be in free form, pharmaceutically acceptable salt form, or prodrug form. Examples of pharmaceutically acceptable salts include tosylates in the case of compounds of formula I. Where the dose or amount of a salt is given by weight, for example, milligrams per day or milligrams per unit dose, the dose of the salt is given by weight of the corresponding free base unless otherwise specified.

[0160] In all embodiments described herein, 5-HT 2A or 5-HT 2A The / D2 receptor ligand can also be a SERT ligand, meaning the compound is 5-HT 2A / SERT or 5-HT 2A It may be a / D2 / SERT receptor ligand.

[0161] In all embodiments described herein, 5-HT 2A or 5-HT 2A / D2 receptor ligands are those that do not have opioid receptor activity or substantially do not have opioid receptor activity (e.g., IC2 above 50 nM, 100 nM, or 150 nM). 50 It may be a substance that has μ-opioid receptor activity, or has substantially no μ-opioid receptor activity.

[0162] 5-HT 2Aor 5-HT 2A / D2 receptor ligands may, in some cases, also exist in prodrug form. A prodrug form is a compound that is converted in the body to an active compound. For example, compounds containing a hydroxy substituent or a carboxy substituent may form physiologically hydrolyzable and acceptable esters. As used herein, “physiologically hydrolyzable and acceptable ester” means an ester that, under physiological conditions, is hydrolyzed to produce an acid (in the case of a compound with a hydroxy substituent) or an alcohol (in the case of a compound with a carboxy substituent), and is physiologically acceptable in itself at the dose to be administered. For example, in a compound of formula I, Y is -C(H)(OR1) and R1 is -C(O)-C 1-21 If the alkyl group is, for example, -C(O)-C3 alkyl or -C(O)-C9 alkyl, these compounds hydrolyze under physiological conditions, resulting in Y being -C(H)(OH) on one side and C on the other. 1-21 Compounds of formula I can be produced, where R1 is alkyl-C(O)OH, for example, C3 alkyl-C(O)OH or C9 alkyl-C(O)OH. Therefore, as can be understood, this term encompasses the conventional pharmaceutical prodrug form. Prodrugs (e.g., R1 is -C(O)-C 1-21 When using a compound of formula (I) that is alkyl, the dose is calculated based on the amount of the compound of formula (I) in its free base form, where Y is -C(=O)- or -CH(OH)-.

[0163] Examples of nitric oxide donors include compounds having alkyl nitrates, alkyl nitrites, S-nitroso compounds, N-nitroso compounds, diazenium diolates, and floxane compounds. In some embodiments, the nitric oxide donor is a compound that produces nitric oxide spontaneously in vivo, i.e., via non-enzymatic hydrolysis, degradation, or other mechanisms. In other embodiments, the nitric oxide donor is a compound that requires enzymatic action to release nitric oxide, such as bioactivation. For example, C-nitroso compounds such as typical alkyl nitrates (RO-NO2) are thought to require enzymatic action, such as reduction, denitration, and / or other steps, to produce NO in vivo. Enzymes such as mitochondrial-localized aldehyde dehydrogenases, glutathione S-transferases, cytochrome P450 oxidases, and xanthine oxidoreductases are involved, but recent evidence supports the role of mitochondrial-localized aldehyde dehydrogenases. S-nitroso compounds are also thought to require enzymatic action to produce NO in vivo. In contrast, diazenium diolate compounds release NO at a reproducible primary rate when dissolved in an aqueous medium. These compounds do not require enzymatic or redox chemistry.

[0164] Diazenium diolates are compounds having tautomer -N-(NO)=(NO) or -NN(O)-N=O functional groups, and are therefore also known as NONOates. These compounds undergo simple hydrolysis, ideally producing two equivalents of nitric oxide. [ka]

[0165] These compounds can be derived from most primary or secondary amines, and their hydrolysis rates for releasing NO depend on the structure of the organic side group (R in the scheme above). Generally, these compounds are derived from small primary and secondary alkylamines as well as cyclic secondary amines. Ordinary (unprotected) diazenium diolates are anionic and are therefore usually provided as salts with a suitable cation (e.g., an ammonium or alkali metal cation, or a mono or dialkylammonium cation corresponding to the amino group of the diazenium diolate).

[0166] Due to the need for hydrolysis or enzymatic deprotection steps to provide reactive diazenium diolate compounds, terminal oxygen (O) is provided, which offers slower and longer-lasting release of NO. 2 Protected diazenium diolates are also known. Vinyl and aryl O 2 Protected diazenium diolates have been developed. These compounds can also be activated in vivo by reaction with the SH group of glutathione. Acetoxymethyl-protected diazenium diolates are particularly useful because they can be activated by common esterase enzymes.

[0167] A unique nitric oxide donor is sodium nitroprusside, Na2[Fe(CN)5NO], a complex coordination compound containing five cyanide ligands and an iron(III) center coordinated to one nitric oxide ligand. When it binds to oxyhemoglobin in red blood cells, the complex dissociates and releases cyanide and nitric oxide.

[0168] Morcidomin is another unique nitric oxide donor drug and a prodrug of the active species lincidomin. Both morcidomin and lincidomin possess a mesoionic N-morphyrino-5-aminoacyl 1,2,3-oxadiazole ring. In vivo, when the carbamate group of morcidomin is enzymatically cleaved, lincidomin is formed. This compound is unstable and decomposes to release NO. [ka]

[0169] NO hybrid drugs are existing drugs, including analgesics, nonsteroidal anti-inflammatory drugs, anti-cholesterol statins, and antivirals, that have a free hydroxyl, amino, thiol, or other group that can be covalently bonded to a nitric oxide donor (generally alkyl nitrate). For example, aspirin (2-acetylsalicylic acid) can be converted into two different NO-aspirin derivatives. Each of these compounds receives NO release in vivo, regenerating the underlying drug (aspirin) which continues to have 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), propatil nitrate, cynitrodyl, tenitramine, trolnitrate, morcidomin, lincidomin, naprixinod, amyl nitrite, diethylamine diazenium diolate (DEA / NO), diethylamine triamine diazenium diolate (DETA / NO), and spermine. Diazenium diolate (SPER / NO), proline diazenium diolate (PROLI / NO), dipropyltriamine diazenium diolate (DPTA / NO), methylamine hexamethylene methylamine diazenium diolate (MAHMA / NO), propylamine propylamine diazenium diolate (PAPA / NO or NOC-15), isopropylamine propylamine diazenium diolate (IPAPA / NO or NOC-5), isopropylamine diazenium diolate (IPA / NO), heparin diazenium diolate, pyrrolidine diazenium diolate (PYRRO / NO), O 2-Vinyl-1-(pyrroridine-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO / NO), O 2 -Vinyl-1-isopropyl-diazene-1-ium-1,2-diolate (V-IPA / NO), O 2 -Vinyl-[2-(carboxylato)pyrrolidine-1-yl]diazen-1-ium-1,2-diolate (V-PROLI / NO), O 2 -(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazine-1-yl]diazen-1-ium-1,2-diolate (JS-K), O 2 -Vinyl-1-[(4-ethoxycarbonyl)piperazine-1-yl]diazen-1-ium-1,2-diolate, O 2 -Acetoxymethyl-isopropyldiazene-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-nitrosalbumin, and NO hybrid drugs (e.g., 2-(acetyloxy)-benzoic acid 3-[(nitrooxy) Examples include [Tyl]phenyl ester (NCX4016), 2-acetyloxybenzoate 5-nitrooxypentyl (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 disnitrate, isosorbide mononitrate, isosorbide disnitrate, itramine tosylate, pentaerythritol tetranitrate, propatil nitrate, cynitrodyl, tenitramine, trolnitrate, morcidomin, lincidomin, and naproxinod.

[0172] When referring to therapeutic use, the term "concurrently" means the administration of two or more active ingredients to a patient as part of a regimen for the treatment of a disease or disorder, regardless of whether the two or more active agents are administered at the same time or at different times, or via the same or different routes of administration. Concurrent administration of two or more active ingredients may occur at different times on the same day, on different dates, or at different frequencies.

[0173] When referring to therapeutic use, the term "simultaneously" means administering two or more active ingredients at the same time or approximately at the same time via the same route of administration.

[0174] When referring to therapeutic use, the term "separately" means administering two or more active ingredients at the same time or approximately at the same time via different routes of administration.

[0175] The dosage used in implementing this disclosure will, of course, vary depending on, for example, the specific disease or condition to be treated, the specific active compound used, the mode of administration, and the desired therapy. Unless otherwise specified, the amount of the active compound for administration (whether administered as a free base or as a salt) refers to or is based on the amount of the compound in its free form (i.e., the calculation of the amount is based on the amount of the active portion in its free form, and in the case of a salt, the weight of the counterion is not considered). Prodrugs (e.g., R1 is -C(O)-C) 1-21 When an alkyl compound of formula (I) is used, the dose is calculated based on the amount of the compound of formula (I) in its free base form, where Y is C (=O). 5-HT 2A or 5-HT 2A The / D2 receptor ligand can be administered via an appropriate route, including orally, intramuscularly, subcutaneously, parenterally, or transdermally, but is preferably administered orally. 5-HT 2A or 5-HT 2A / D2 receptor ligands can be administered by preferred routes, including orally, parenterally, transdermally, or transmucosally, in dosage forms such as tablets, capsules, subcutaneous injections, or rapidly disintegrating orally orally for sublingual or buccal administration, or in film formulations.

[0176] To avoid misunderstanding, when a numerical range is disclosed, for example, "up to X," it is intended to include the upper limit X. Therefore, when a disclosure is "up to 60 mg," it is intended to include 60 mg.

[0177] Pharmaceutical compositions containing the compounds of this disclosure can be prepared using conventional diluents or excipients and techniques known in the Galenic art. Therefore, oral dosage forms may include tablets, capsules, liquids, suspensions, and the like.

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

[0179] Polymers useful for the polymer matrix in the composition of the present invention (for example, the depot composition of the present invention) include hydroxy fatty acid polyesters and their derivatives or other agents, for example, polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer or polyglycolic acid-polyethylene glycol copolymer), and α-cyanoacrylate alkyl polymers (for example, Examples of suitable polymers include poly(2-butyl cyanoacrylate), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyortho-carbonates, 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] If the polymer is a copolymer, it may be a tandem, block, and / or graft copolymer. If the above α-hydroxycarboxylic acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have optical activity in their molecules, one of the D isomers, L isomers, and / or DL ​​isomers can be used. In particular, α-hydroxycarboxylic acid polymers (preferably lactate-glycolic acid polymers), their esters, poly-α-cyanoacrylate esters, etc., can be used, and lactate-glycolic acid copolymers (also referred to as poly(lactide-α-glycolide) or poly(lactide-co-glycolic acid), hereinafter referred to as PLGA) are preferred. Thus, in one embodiment, a polymer useful for the polymer matrix is ​​OLGA. As used herein, the term PLGA includes polymers of lactate (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 preferred embodiments, the polymer matrix of the present invention is a biocompatible and biodegradable polymer material. The term "biocompatible" is defined as a polymer material that is non-toxic, non-carcinogenic, and does not significantly induce inflammation in body tissues. The matrix material must be biodegradable, and the polymer material must be broken down by bodily processes into easily disposable products within the body and should not accumulate in the body. The biodegradable products should also be biocompatible with the body in the sense that the polymer matrix is ​​biocompatible with the body. Particularly useful examples of polymer matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the following: poly(aliphatic carboxylic acid), copolyoxalate, polycaprolactone, polydioxanone, poly(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoester, poly(glycolic acid-caprolactone), polyanhydride, and natural polymers such as albumin, casein, and waxes such as glycerol monostearate and glycerol distearate. A preferred polymer for use in the implementation of the present invention is dl(polylactide-co-glycolide). The molar ratio of lactide to glycolide in such copolymers is preferably in the range of about 75:25 to 50:50.

[0182] Useful PLGA polymers may have a weight-average molecular weight of approximately 5,000 to 500,000 daltons, preferably about 150,000 daltons. Polymers with different molecular weights can be used depending on the degradation rate to be achieved. Regarding the drug release diffusion mechanism, the polymer should remain intact until it degrades after all the drug has been released from the polymer matrix. The drug may also be released from the polymer matrix as the polymer excipient bio-erodes.

[0183] PLGAs can be prepared by conventional methods or may be commercially available. For example, PLGAs can be produced from cyclic lactides, glycosides, etc., by ring-opening polymerization using a suitable catalyst (see European Patent No. 0058481(B2); Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0184] PLGA is thought to exhibit biodegradability through the breakdown of the entire solid polymer composition, due to the decomposition of hydrolyzable and enzymatically cleavable ester bonds under biological conditions (e.g., in the presence of water and biological enzymes found in the tissues of warm-blooded animals such as humans), which form lactic acid and glycolic acid. 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 thought to decompose in the body of a warm-blooded animal such as a human, for example, by hydrolysis of its ester groups in the presence of water, producing lactic acid and glycolic acid and forming an acidic microclimate. Because lactic acid and glycolic acid are byproducts of various metabolic pathways in the body of a warm-blooded animal such as a human under normal physiological conditions, they are well-tolerated and produce only minimal systemic toxicity. [Examples]

[0185] Example 1: Lumateperone, when used in combination with sodium nitroprusside, provides synergistic improvement in conditioned avoidance reactions (CARs). The compound of formula I, where X is N(CH3) and Y is C=O, is lumateperone (ITI-007): [ka] It is sold in the form of its tosylate salt as CAPLYTA®. Lumateperone provides selective and simultaneous modulation of serotonin, dopamine, and glutamate neurotransmission, and is of particular interest in relation to mental disorders.

[0186] Male Wistar rats, weighing approximately 18g upon arrival, are housed in groups of four at room temperature under standard laboratory conditions. The cages are reinforced with wooden houses and paper for nesting. Food and water are freely provided. The animals are maintained on a 12-hour:12-hour inverted light-dark cycle (lights off at 6am). The animals are allowed to acclimate for at least two weeks before starting any experiments or training.

[0187] Rats are trained and tested in a conventional shuttlebox apparatus, which consists of two identically sized compartments separated by a plastic partition with a central opening. Rats are allowed to acclimate to the shuttlebox for 5 minutes prior to the test. When a conditioned stimulus (CS) of 80 dB white noise is applied to the rats, it takes 10 seconds for them to move from one compartment of the shuttlebox to the other. If they do this, it is called "avoidance." If a rat remains in the same compartment for more than 10 seconds, an unconditioned stimulus (UCS), consisting of intermittent electric shocks (approximately 0.4 mA), is applied to the grid floor until escape occurs. Once the rat moves to the other compartment, both the noise and shocks stop. The shocks are applied for 0.5 seconds, repeated at 2.5-second intervals. If the animal does not respond within 50 seconds of the shock period, the test is terminated (failed escape). If escape fails three times in a row, the session is terminated. Animals are trained daily for 5 days, with each session consisting of approximately 20 random trials over 15 minutes. Rats had to achieve an 85% avoidance rate to participate in the study. Experimental sessions lasted 10 minutes and were conducted before drug administration (pre-test), as well as 20, 90, and 240 minutes after drug injection. Experimental days were separated by at least two non-experimental days.

[0188] Data from CAR are analyzed using Friedman's analysis of variance (ANOVA), and if significant differences are found, Wilcoxon's matched pair signed-rank test is performed as a follow-up test. All data are presented as median + interquartile range.

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

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

[0191] As shown in Figure 3, a significant therapeutic effect was observed 20 minutes after drug administration with the combination of lumateperone and SNP. Follow-up tests showed that lumateperone at 3 mg / kg and 7 mg / kg combined with 1.5 mg / kg SNP significantly increased CAR suppression compared to vehicle / SNP. Furthermore, 7 mg / kg lumateperone significantly suppressed CAR compared to vehicle / saline. Lumateperone at 3 mg / kg and SNP differed significantly from lumateperone / saline and lumateperone (7 mg / kg) / SNP.

[0192] 90 minutes after drug administration, a significant therapeutic 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] Overall, the data support an unexpected synergistic antipsychotic effect from the combination of lumateperone and SNPs.

Claims

1. A method for treating psychosis (such as schizophrenia), depression (such as bipolar depression), and / or anxiety, or other CNS disorders for which lumateperone has been shown to be effective, wherein (i) an effective amount of 5-HT 2A or 5-HT 2A A method comprising administering (ii) an effective amount of a D2 receptor ligand, e.g., in free form, pharmaceutically acceptable salt form or prodrug form, of a substituted heterocyclic condensed γ-carbolin as described herein, and (ii) an effective amount of a nitric oxide donor, e.g., an SNP, separately (sequentially or simultaneously) or in combination (e.g., as a fixed-dose combination).

2. 5-HT 2A or 5-HT 2A The D2 receptor ligand may be in a free form, a pharmaceutically acceptable salt form, or a prodrug form, or a deuterated form, formula I: 【Chemistry 1】 [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)O-C 1-21 alkyl]] The method according to claim 1, wherein the compound is represented by [formula].

3. In the compound of formula I, X is -N(H)- or -N(CH 3 The method according to claim 2, wherein the method is as follows:

4. In the compound of formula I, X is -N(CH 3 The method according to claim 3, wherein the method is as follows:

5. The method according to claim 2, wherein Y in the compound of formula I is -C(=O)-.

6. The compound of formula I 【Chemistry 2】 The method according to claim 2.

7. The method according to claim 6, wherein the compound of formula I is in the form of a tosylate (e.g., monotosylate or ditosylate), which may be in crystalline form.

8. 5-HT 2A or 5-HT 2A / The D2 receptor ligand is in the form of a toluenesulfonate addition salt (e.g., monotosylate, ditosylate, or a combination thereof), where X is -N(CH 3 The method according to claim 1, wherein the compound is of formula I, and Y is -C(=O)-.

9. The method according to any one of claims 1 to 8, wherein the nitric oxide donor is selected from sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate), amyl nitrate, diethylene glycol disnitrate, isosorbide mononitrate, isosorbide disnitrate, itramine tosylate, pentaerythritol tetranitrate, propatil nitrate, cynitrodil, tenitramine, trolnitrate, morcidomin, lincidomin, and naproxinod.

10. The method according to any one of claims 1 to 9, comprising administering once daily an oral unit dosage form, such as a tablet or capsule, comprising 1 to 100 mg of a monotosylate, for example, 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 a compound of formula I, and a pharmaceutically acceptable diluent or carrier.

11. The method according to any one of claims 1 to 10, wherein the condition being treated is a psychosis, for example, schizophrenia (e.g., prodromal symptoms, acute symptoms and / or residual symptoms of psychosis; or negative symptoms and / or positive symptoms of psychosis), delusional disorder (e.g., somatic type), major depressive disorder with psychosis, bipolar disorder with psychotic symptoms, brief psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, or a psychosis caused by a medical condition or substance use.

12. The method according to claim 11, wherein the condition to be treated is (1) negative symptoms, e.g., emotional blunting, emotional withdrawal, poor rapport, passive or apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and fluency in conversation, and stereotyped thinking; and (2) general psychopathological symptoms, e.g., body anxiety, anxiety, guilt, tension, mannerisms and posturing, depression, motor developmental delay, uncooperativeness, abnormal thought content, disorientation, inattention, lack of judgment and insight, disturbance of volition, impulse control, preoccupation and active social avoidance; symptoms of psychosis (e.g., schizophrenia) selected from cognitive impairment and sleep disorders (e.g., insomnia) (e.g., residual symptoms).

13. The method according to claim 11, wherein the psychosis (e.g., schizophrenia) is a treatment-resistant psychosis (e.g., treatment-resistant schizophrenia), for example, a psychosis (or schizophrenia) that has not responded to treatment with one or more antipsychotic drugs.

14. The method according to any one of claims 1 to 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.

15. (i) an effective amount of 5-HT 2A or 5-HT 2A A pharmaceutical composition comprising (ii) an effective amount of a D2 receptor ligand, for example, a substituted heterocyclic condensed γ-carbolin as described herein, in free form, a pharmaceutically acceptable salt form, or a prodrug form; and (ii) an effective amount of a nitric oxide donor, for example, an SNP.

16. 5-HT 2A or 5-HT 2A The D2 receptor ligand may be in a free form, a pharmaceutically acceptable salt form, or a prodrug form, or a deuterated form, formula I: 【Transformation 3】 [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)O-C 1-21 It is alkyl. The composition according to claim 15, wherein the compound is represented by [the compound shown].

17. In the compound of formula I, X is -N(H)- or -N(CH 3 The composition according to claim 16, wherein the composition is as follows:

18. In the compound of formula I, X is -N(CH 3 The composition according to claim 17, wherein the composition is as follows:

19. The composition according to claim 16, wherein Y in the compound of formula I is -C(=O)-.

20. The compound of formula I 【Chemistry 4】 The composition according to claim 16.

21. The composition according to claim 20, wherein the compound of formula I is in the form of a tosylate (e.g., monotosylate or ditosylate), which may be in crystalline form.

22. 5-HT 2A or 5-HT 2A / The D2 receptor ligand is in the form of a toluenesulfonate addition salt (e.g., monotosylate, ditosylate, or a combination thereof), where X is -N(CH 3 The composition according to claim 16, wherein Y is a compound of formula I, and Y is -C(=O)-.

23. The composition according to claim 16, wherein the nitric oxide donor is selected from sodium nitroprusside (SNP), nitroglycerin (glyceryl trinitrate), amyl nitrate, diethylene glycol disnitrate, isosorbide mononitrate, isosorbide disnitrate, itramine tosylate, pentaerythritol tetranitrate, propatil nitrate, cynitrodyl, tenitramine, trolnitrate, morcidomin, lincidomin, and naproxinod.

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