Psychotropic drugs and their uses

Abstract

This specification describes the use of amisulpride derivatives and pharmaceutical compositions thereof, alone or in combination with other CNS active agents, to inhibit dopamine receptors, serotonin receptors (e.g., 5-HT 2a The present specification discloses a novel use of the amisulpride derivative or pharmaceutical composition thereof for antagonizing dopamine receptors, serotonin receptors (e.g., 5-HT7) and / or α2 receptors in a subject, either alone or in combination with other CNS active agents. 2a The amisulpride derivatives or pharmaceutical compositions thereof disclosed herein can be used, alone or in combination with other CNS active agents, to treat one or more disorders associated with abnormalities in dopamine and / or serotonin levels in the brain.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 189,905, filed May 18, 2021, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION This invention is generally in the field of pharmaceutical compositions and methods for the treatment of neuropsychiatric and / or psychological diseases or disorders. [Background technology]

[0003] Schizophrenia is a chronic, debilitating mental illness that affects approximately 1% of the population. The illness manifests as delusional behavior, disorganized thinking, restlessness, social withdrawal and depression. Patients with schizophrenia have a significantly reduced quality of life and are 10 times more likely to commit suicide than the general population.

[0004] Dopamine (especially D2 and D3) antagonists are well recognized as medicines that improve the symptoms of schizophrenia and have been in clinical use for decades. In the last two decades, it has become recognized that the treatment of schizophrenia, like many psychiatric disorders, can benefit from engaging multiple receptors, including serotonin and adrenergic receptors. Despite the approval of dozens of drugs for the treatment of schizophrenia, many patients remain inadequately treated. Side effects of current drugs include dyskinesia, akathisia, weight gain, mood disorders, sexual dysfunction, hypersedation, orthostatic hypotension, hypersalivation, and (in some cases) agranulocytosis.

[0005] Amisulpride (4-amino-N-(((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide) is an antipsychotic drug that was patented in 1981. It binds to the human dopamine D2 receptor (K i 2.8 nM) and D3 receptors (K i3.2 nM) and shows no affinity for D1, D4, or D5 receptors. Unlike classical and atypical neuroleptics, amisulpride has low affinity for serotonin receptors, α-adrenergic receptors, histamine receptors, muscarinic receptors, and sigma sites, whereas it binds 5-HT 2B Receptors and 5-HT 7a The receptor has a K of two orders of magnitude smaller, in the nanomolar range (nM). i Amisulpride's ability to bind to 5-HT receptors may translate to its ability to treat symptoms of depression (sometimes seen in schizophrenia patients) and improve cognition, which may explain its ability to treat the negative symptoms of schizophrenia. Interestingly, compared to other antipsychotics, amisulpride has a greater ability to bind to 5-HT 2a The lack of activity towards the receptor is noted.

[0006] Despite the unique properties of amisulpride, the drug has a poor ability to cross the blood-brain barrier (BBB) ​​and interact with receptors in the brain. A 2014 study showed that passive diffusion (P e The amelioration of mood swings (measured as anxiety, anxiety disorder, anxiety dysphoria ... Summary of the Invention

[0007] The present specification provides the use of amisulpride derivatives and pharmaceutical compositions thereof. In certain embodiments, the amisulpride derivatives disclosed herein are dopamine and / or serotonin antagonists. In certain embodiments, the amisulpride derivatives disclosed herein have improved membrane (e.g. BBB) permeability compared to amisulpride. In certain embodiments, the amisulpride derivatives act as central nervous system (CNS) dopamine and / or serotonin antagonists. These amisulpride derivatives have a structure of formula IA, IB or IC as disclosed herein, including pharma- ceutically acceptable salts thereof, stereoisomers thereof (e.g., formula IA-S, formula IA-R, formula IB-S, formula IB-R, formula IC-S and formula IC-R), or deuterated analogs of the structure of formula IA, formula IB, formula IC, formula IA-S, formula IA-R, formula IB-S, formula IB-R, formula IC-S or formula IC-R.

[0008] The present specification provides a unit dose of the amisulpride derivative disclosed herein, the unit dose comprising a pharmaceutical composition containing a therapeutically effective amount of the amisulpride derivative, the therapeutically effective amount being about 10 mg to about 250 mg, about 10 mg to about 225 mg, about 10 mg to about 200 mg, about 10 mg to about 175 mg, about 10 mg to about 150 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 25 mg, about 25 mg to about 250 mg, about 25 mg to about 225 mg, about 25 mg to about 200mg, about 25mg to about 175mg, about 25mg to about 150mg, about 25mg to about 125mg, about 25mg to about 100mg, about 25mg to about 75mg, about 25mg to about 50mg, about 50mg to about 250mg, about 50mg to about 225mg, about 50mg to about 200mg, About 50mg to about 175mg, about 50mg to about 150mg, about 50mg to about 125mg, about 50mg to about 100mg, about 50mg to about 75mg, about 75mg to about 250mg, about 75mg to about 225mg, about 75mg to about 200mg, about 75mg to about 175mg, about 75mg ~150mg, 75mg~125mg, 75mg~100mg, 100mg~250mg, 100mg~225mg, 100mg~200mg, 100mg~175mg, 100mg~150mg, 100mg~125mg, 12 5mg to about 250mg, about 125mg to about 225mg, about 125mg to about 200mg, about 125mg to about 175mg, about 125mg to about 150mg, about 150mg to about 250mg, about 150mg to about 225mg, about 150mg to about 200mg, about 150mg to about 175m g, about 175 mg to about 250 mg, about 175 mg to about 225 mg, about 175 mg to about 200 mg, about 200 mg to about 250 mg, about 200 mg to about 225 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg.

[0009] The present specification relates to a method for treating dopamine receptors, serotonin receptors (e.g., 5-HT 2 receptors), and / or serotonin receptors, comprising administering to the subject a therapeutically effective amount of an amisulpride derivative or a pharmaceutical composition thereof disclosed in the present specification. 2a Also provided is a method for delivering a dopamine receptor, serotonin receptor and / or alpha-2 adrenergic (alpha2) receptor antagonist to the brain of a subject, where the levels of the dopamine receptor, serotonin receptor and / or alpha2 receptor antagonist in the brain are higher than when the subject is administered an equivalent amount of amisulpride. In certain embodiments, the method comprises administering 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein to the subject. In certain embodiments, the method comprises administering 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein to the subject once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days or once a week. In certain embodiments, the unit dose is 50 mg, 75 mg or 100 mg. In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to achieve a striatal dopamine RO (receptor occupancy) % or a mean dopamine (e.g., D2 / D3) RO % in the caudate and putamen of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90% measured in the treated subject.

[0010] The present specification provides a method for the treatment of dopamine receptors, serotonin receptors (e.g., 5-HT agonists) in a subject, comprising administering to the subject a therapeutically effective amount of an amisulpride derivative or a pharmaceutical composition thereof disclosed herein, alone or in combination with another CNS active agent. 2a, 5-HT7) and / or alpha2 receptors. In certain embodiments, the method comprises administering 1, 2, 3, or 4 unit doses of an amisulpride derivative disclosed herein to a subject. In certain embodiments, the method comprises administering 1, 2, 3, or 4 unit doses of an amisulpride derivative disclosed herein to a subject once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once a week. In certain embodiments, the unit dose is 50 mg, 75 mg, or 100 mg. In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to achieve a striatal dopamine RO% or a mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90% as measured in the treated subject.

[0011] The present specification provides a method for the treatment of dopamine receptors, serotonin receptors (e.g., 5-HT agonists) in a subject, comprising administering to the subject a therapeutically effective amount of an amisulpride derivative or a pharmaceutical composition thereof disclosed herein, alone or in combination with another CNS active agent. 2a Also provided is a method for treating one or more conditions responsive to modulation of α2 receptors (5-HT7, 5-HT8, 5-HT9, 5-HT10, 5-HT11, 5-HT12, 5-HT13, 5-HT14, 5-HT15, 5-HT16, 5-HT17, 5-HT18, 5-HT19, 5-HT20, 5-HT21, 5-HT22, 5-HT23, 5-HT24, 5-HT25, 5-HT26, 5-HT27, 5-HT28, 5-HT29, 5-HT30, 5-HT31, 5-HT32, 5-HT33, 5-HT34, 5-HT35, 5-HT36, 5-HT37, 5-HT38, 5-HT39, 5-HT40, 5-HT41, 5-HT42, 5-HT43, 5-HT44, 5-HT45, 5-HT46, 5-HT47, 5-HT48, 5-HT49, 5-HT410, 5-HT411, 5-HT412, 5-HT413, 5-HT424, 5-HT435, 5-HT445, 5-HT451, 5-HT461, 5-HT472, 5-HT481, 5-HT492, 5-HT414, 5-HT415, 5-HT425, 5-HT435, 5-HT441, 5-HT451, 5-HT461, 5-HT472, 5-HT481, 5-HT492, 5-HT415, 5-HT415, In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to achieve a striatal dopamine RO% or a mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90% measured in the treated subject.

[0012] Also provided herein is a method for treating one or more disorders associated with abnormalities in dopamine and / or serotonin levels in the brain, comprising administering to a subject a therapeutically effective amount of an amisulpride derivative disclosed herein or a pharmaceutical composition thereof, alone or in combination with other CNS active agents.In certain embodiments, the method comprises administering to a subject 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein.In certain embodiments, the method comprises administering to a subject 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days or once a week.In certain embodiments, the unit dose is 50 mg, 75 mg or 100 mg. In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to achieve a striatal dopamine RO% or a mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90% measured in the treated subject.

[0013] Dopamine receptors, serotonin receptors (e.g. 5-HT 2a Examples of conditions responsive to modulation of α2 receptors (5-HT7) and / or α2 receptors and / or disorders associated with abnormalities in dopamine and / or serotonin levels in the brain include, but are not limited to, psychiatric disorders, including, but not limited to, schizophrenia, symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, depression, obsessive-compulsive disorder, psychiatric symptoms of Parkinson's disease, psychiatric symptoms of Alzheimer's disease, oppositional defiant disorder, aggressive behavior, suicidality, hostility, personality disorders, chronic fatigue syndrome, predominantly negative symptoms of schizophrenia, Charles Bonnet syndrome, autism, and Tourette's syndrome. [Brief description of the drawings]

[0014] [Figure 1A] Dopamine receptor (e.g. D2 / D3) occupancy following oral administration of 50 mg of LB-102 to humans (n=4). [Figure 1B]Dopamine receptor (e.g. D2 / D3) occupancy following oral administration of 100 mg of LB-102 to humans (n=3). [Diagram 2] Plasma concentrations of LB-102 (diamonds), amisulpride (squares), and total benzamides (triangles) following oral administration of 50 mg of LB-102 to humans (n=4). [Diagram 3] Plasma concentrations as a function of time following single oral administration of 10 mg (large x), 50 mg (triangles), 100 mg (squares), 150 mg (small x), and 200 mg (diamonds) of LB-102 to humans. [Figure 4] FIG. 4A is the previously published PK profile of amisulpride after a 50 mg dose, and FIG. 4B is the PK profile of a single oral dose of LB-102 (50 mg) in humans. [Figure 5A] Mean dopamine (eg, D2 / D3) RO% in the caudate and putamen in subjects treated with LB-102, and PK analysis following a single oral dose of 50 mg LB-102 in said subjects. [Figure 5B] Mean dopamine (eg, D2 / D3) RO% in the caudate and putamen in subjects treated with LB-102, and PK analysis following a single oral dose of 75 mg LB-102 in said subjects. [Figure 5C] Mean dopamine (eg, D2 / D3) RO% in the caudate and putamen in subjects treated with LB-102, and PK analysis following a single oral dose of 100 mg LB-102 in said subjects. [Figure 6A] Mean dopamine (e.g. D2 / D3) RO% in the caudate and putamen in subjects treated with LB-102, and PK analysis following LB-102 administration on day 4 of oral dosing of 50 mg / day LB-102 in said subjects. [Figure 6B] Mean dopamine (e.g. D2 / D3) RO% in the caudate and putamen in subjects treated with LB-102, and PK analysis following LB-102 administration on day 4 of oral dosing of 100 mg / day LB-102 in said subjects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description of the Invention Dopamine receptor occupancy (RO) is a well-established marker of antipsychotic efficacy: an RO of 60-75% correlates with a significant improvement in PANSS scores in schizophrenic patients [Pani, L., Pira, L., Marchese, G., 2007. "Antipsychotic efficacy: Relationship to optimal D2-receptor occupancy", European Psychiatry, 22, 267-275.]. The amisulpride derivatives disclosed herein (also referred to as 4-amino-substituted derivatives of amisulpride, 4-amino amisulpride derivatives, and 4-amino-substituted amisulpride derivatives) achieved desired dopamine (e.g., D2 / D3) RO in the caudate nucleus and putamen of the human brain at doses significantly lower than the doses of amisulpride required to achieve the desired dopamine (e.g., D2 / D3) RO, as disclosed herein. For example, referring to Example 1, single oral doses of 50 mg and 100 mg of LB102 demonstrated approximately 50% (FIG. 1A) and 75% (FIG. 1B) dopamine D2 / D3RO in the human caudate / putamen, respectively, whereas doses of over 400 mg of amisulpride were required to achieve a dopamine (e.g., D2 / D3)RO of 75% [Meisenzahl, E. M., Schmitt, G., Gruender, G., Dresel, S., Frodl, T., la Fougere, C., Scheuerecker, J. Schwarz, M., Strauss, J. Hahn, K., and Moeller, H.-J., 2008, "Striatal D2 / D3Receptor Occupancy, Clinical Response and Side Effects with Amisulpride: An Iodine-123-Iodobenzamide SPET Study", Pharmacopsychiatry, 41, 169-175.].

[0016] The exposure of LB-102 to human plasma was significantly higher than expected, compared to published data on animal models and amisulpride. In preclinical animal models, LB-102 was significantly demethylated and metabolized to amisulpride, up to 50%. However, as shown in Example 2, the metabolism of LB-102 to amisulpride was minimal (less than 3%) in humans (Figure 2). Furthermore, for example, referring to Example 2, oral administration of 50 mg of LB102 to humans resulted in an AUC (1,595 ngh / mL) (Figure 4B) approximately 2.5 times that of 50 mg of amisulpride (603 ngh / mL) (Figure 4A) [MP Curran and CM Perry "Amisulpride: a review of its use in the management of schizophrenia", Drugs, 2001, 61, 2132-2150.].

[0017] Unexpectedly, mean dopamine (e.g., D2 / D3) RO% in the caudate, putamen, and thalamus of subjects treated with LB-102 (50 mg SS and 100 mg SS) stabilized significantly from at least 4 days after treatment initiation (Example 3, Tables 3-E and 3-F summarizing data after dosing on day 4; and Tables 3-B and 3-D summarizing data after first dose on day 1), while the plasma concentration profiles of LB102 and amisulpride were similar after dosing on days 1 (Figures 5A and 5C) and 4 (Figures 5D and 5E). It was surprising to observe that higher plasma concentrations of LB102 and amisulpride did not result in higher dopamine RO%.

[0018] The present specification provides the use of amisulpride derivatives and pharmaceutical compositions thereof. In certain embodiments, the amisulpride derivatives disclosed herein are dopamine and / or serotonin antagonists. In certain embodiments, the amisulpride derivatives disclosed herein have improved membrane (e.g., BBB) permeability compared to amisulpride. In certain embodiments, the amisulpride derivatives act as central nervous system (CNS) dopamine and / or serotonin antagonists. In certain embodiments, the amisulpride derivatives disclosed herein selectively bind to dopamine D2 and / or D3 receptors over dopamine D1, D4 and / or D5 receptors. In certain embodiments, the amisulpride derivatives disclosed herein can interact with dopamine receptors, serotonin receptors and / or α2 receptors in the CNS.

[0019] These amisulpride derivatives have a structure of formula IA, IB or IC as disclosed herein, including pharma- ceutically acceptable salts thereof, stereoisomers thereof (e.g., formula IA-S, formula IA-R, formula IB-S, formula IB-R, formula IC-S and formula IC-R), or deuterated analogs of the structure of formula IA, formula IB, formula IC, formula IA-S, formula IA-R, formula IB-S, formula IB-R, formula IC-S or formula IC-R.

[0020] In certain embodiments, a deuterated analog of a compound has one or more hydrogen atoms of the compound replaced with deuterium, hi certain embodiments, the one or more deuterium atoms in the deuterated analog are present at at least 100 times their natural abundance.

[0021] Provided herein is a pharmaceutical composition comprising one or more of the amisulpride derivatives disclosed herein and a pharma- ceutically acceptable carrier.In certain embodiments, one or more of the amisulpride derivatives contained in the pharmaceutical composition are enantiomerically substantially pure, and such pharmaceutical composition is also referred to as an enantiomerically substantially pure pharmaceutical composition.In certain embodiments, the term "enantiomerically substantially pure" means that the enantiomeric purity is about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 98% or more.

[0022] The present specification provides a unit dose of the amisulpride derivative disclosed herein, the unit dose comprising a pharmaceutical composition containing a therapeutically effective amount of the amisulpride derivative, the therapeutically effective amount being about 10 mg to about 250 mg, about 10 mg to about 225 mg, about 10 mg to about 200 mg, about 10 mg to about 175 mg, about 10 mg to about 150 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 25 mg, about 25 mg to about 250 mg, about 25 mg to about 225 mg, about 25 mg to about 200mg, about 25mg to about 175mg, about 25mg to about 150mg, about 25mg to about 125mg, about 25mg to about 100mg, about 25mg to about 75mg, about 25mg to about 50mg, about 50mg to about 250mg, about 50mg to about 225mg, about 50mg to about 200mg, About 50mg to about 175mg, about 50mg to about 150mg, about 50mg to about 125mg, about 50mg to about 100mg, about 50mg to about 75mg, about 75mg to about 250mg, about 75mg to about 225mg, about 75mg to about 200mg, about 75mg to about 175mg, about 75mg ~150mg, 75mg~125mg, 75mg~100mg, 100mg~250mg, 100mg~225mg, 100mg~200mg, 100mg~175mg, 100mg~150mg, 100mg~125mg, 12 5mg to about 250mg, about 125mg to about 225mg, about 125mg to about 200mg, about 125mg to about 175mg, about 125mg to about 150mg, about 150mg to about 250mg, about 150mg to about 225mg, about 150mg to about 200mg, about 150mg to about 175m g, about 175 mg to about 250 mg, about 175 mg to about 225 mg, about 175 mg to about 200 mg, about 200 mg to about 250 mg, about 200 mg to about 225 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg.

[0023] The present specification relates to a method for treating dopamine receptors, serotonin receptors (e.g., 5-HT 2 receptors), and / or serotonin receptors, comprising administering to the subject a therapeutically effective amount of an amisulpride derivative or a pharmaceutical composition thereof disclosed in the present specification. 2a Also provided is a method for delivering a dopamine receptor, serotonin receptor and / or alpha-2 adrenergic (alpha2) receptor antagonist to the brain of a subject, where the levels of the dopamine receptor, serotonin receptor and / or alpha2 receptor antagonist in the brain are higher than when the subject is administered an equivalent amount of amisulpride. In certain embodiments, the method comprises administering 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein to the subject. In certain embodiments, the method comprises administering 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein to the subject once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days or once a week. In certain embodiments, the unit dose is 50 mg, 75 mg or 100 mg. In certain embodiments, the striatal dopamine RO% or the mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen measured in the treated subject is about 60% to about 80%, about 50% to about 85%, or about 40% to about 90%. In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to obtain a striatal dopamine RO% or the mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen measured in the treated subject of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90%.

[0024] The present specification provides a method for the treatment of dopamine receptors, serotonin receptors (e.g., 5-HT agonists) in a subject, comprising administering to the subject a therapeutically effective amount of an amisulpride derivative or a pharmaceutical composition thereof disclosed herein, alone or in combination with another CNS active agent. 2a, 5-HT7) and / or alpha2 receptors. In certain embodiments, the method comprises administering 1, 2, 3, or 4 unit doses of an amisulpride derivative disclosed herein to a subject. In certain embodiments, the method comprises administering 1, 2, 3, or 4 unit doses of an amisulpride derivative disclosed herein to a subject once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once a week. In certain embodiments, the unit dose is 50 mg, 75 mg, or 100 mg. In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to achieve a striatal dopamine RO% or a mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90% as measured in the treated subject.

[0025] The present specification provides a method for the treatment of dopamine receptors, serotonin receptors (e.g., 5-HT agonists) in a subject, comprising administering to the subject a therapeutically effective amount of an amisulpride derivative or a pharmaceutical composition thereof disclosed herein, alone or in combination with another CNS active agent. 2a Also provided is a method for treating one or more conditions responsive to modulation of α2 receptors (5-HT7, 5-HT8, 5-HT9, 5-HT10, 5-HT11, 5-HT12, 5-HT13, 5-HT14, 5-HT15, 5-HT16, 5-HT17, 5-HT18, 5-HT19, 5-HT20, 5-HT21, 5-HT22, 5-HT23, 5-HT24, 5-HT25, 5-HT26, 5-HT27, 5-HT28, 5-HT29, 5-HT30, 5-HT31, 5-HT32, 5-HT33, 5-HT34, 5-HT35, 5-HT36, 5-HT37, 5-HT38, 5-HT39, 5-HT40, 5-HT41, 5-HT42, 5-HT43, 5-HT44, 5-HT45, 5-HT46, 5-HT47, 5-HT48, 5-HT49, 5-HT410, 5-HT411, 5-HT412, 5-HT413, 5-HT424, 5-HT435, 5-HT445, 5-HT451, 5-HT461, 5-HT472, 5-HT481, 5-HT492, 5-HT414, 5-HT415, 5-HT425, 5-HT435, 5-HT441, 5-HT451, 5-HT461, 5-HT472, 5-HT481, 5-HT492, 5-HT415, 5-HT415, In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to achieve a striatal dopamine RO% or a mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90% measured in the treated subject.

[0026] Also provided herein is a method for treating one or more disorders associated with abnormalities in dopamine and / or serotonin levels in the brain, comprising administering to a subject a therapeutically effective amount of an amisulpride derivative disclosed herein or a pharmaceutical composition thereof, alone or in combination with other CNS active agents.In certain embodiments, the method comprises administering to a subject 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein.In certain embodiments, the method comprises administering to a subject 1, 2, 3 or 4 unit doses of an amisulpride derivative disclosed herein once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days or once a week.In certain embodiments, the unit dose is 50 mg, 75 mg or 100 mg. In certain embodiments, the method further comprises adjusting the dose of the amisulpride derivative to achieve a striatal dopamine RO% or a mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90% measured in the treated subject.

[0027] In certain aspects of the methods disclosed herein, the methods include: a) administering a first unit dose of said amisulpride derivative to said subject once every day, once every two days, once every three days, once every four days, once every five days, once every six days or once a week; b) obtaining a first mean dopamine RO% in the caudate and putamen of said subject; c) administering to the subject a second unit dose of the amisulpride derivative once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week, if the subject's first striatal dopamine RO% or first average dopamine (e.g., D2 / D3) RO% in the caudate nucleus and putamen is not within a predetermined range of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90%; d) obtaining a second striatal dopamine RO% or a second mean dopamine (e.g., D2 / D3) RO% in the caudate and putamen of the subject; and e) repeating steps c) and d) until the subject's striatal dopamine RO% or average dopamine (e.g., D2 / D3) RO% of the caudate and putamen is within the predetermined range (e.g., about 60% to about 80%, about 50% to about 85%, or about 40% to about 90%); Further includes:

[0028] Dopamine receptors, serotonin receptors (e.g. 5-HT 2a Examples of conditions responsive to modulation of α2 receptors (5-HT7) and / or α2 receptors and / or disorders associated with abnormalities in dopamine and / or serotonin levels in the brain include, but are not limited to, psychiatric disorders, including, but not limited to, schizophrenia, symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, depression, obsessive-compulsive disorder, psychiatric symptoms of Parkinson's disease, psychiatric symptoms of Alzheimer's disease, oppositional defiant disorder, aggressive behavior, suicidality, hostility, personality disorders, chronic fatigue syndrome, predominantly negative symptoms of schizophrenia, Charles Bonnet syndrome, autism, and Tourette's syndrome.

[0029] [ka]

[0030] In certain embodiments, the amisulpride derivative has formula IA: [ka]

[0031] and 4-amino substituted derivatives of amisulpride having the structure: X and Z are the same or different and are selected from the group consisting of hydrogen, alkyl (branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl and s-butyl), alkenyl (branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl and s-butyl), alkynyl (branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl and s-butyl), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), cycloalkylalkyl (e.g., ... and each of the heterocyclic groups is independently selected from the group consisting of aryl, cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl), heterocyclyl, heterocyclylalkyl, aryl (e.g., phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl), arylalkyl (e.g., -CH2C6H5 and -C2H5C6H5), heteroarylalkyl (e.g., -CH2C6H4N and C2H5C6H4N), and heteroaryl having one, two, or more hetero ring atoms (e.g., pyridine, pyrrole, furan, thiophene, or pyrimidine); Optionally, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl groups are further substituted with one or more substituents selected from the group consisting of halogens such as chlorine, bromine and fluorine, amines, hydroxyl, carboxyl, nitro, carbonyl and other alkyl and aryl groups as defined herein; with the proviso that at least one of X and Z is not hydrogen.

[0032] In certain embodiments, the 4-amino substituted derivative of amisulpride has the formula IA-R: [ka]

[0033] and pharma- ceutically acceptable salts thereof, wherein X and Z are as described in formula IA.

[0034] In certain embodiments, the 4-amino substituted derivative of amisulpride has the formula IA-S: [ka]

[0035] and pharma- ceutically acceptable salts thereof, wherein X and Z are as described in formula IA.

[0036] In certain embodiments, the amisulpride derivative has formula IB: [ka]

[0037] and 4-amino substituted derivatives of amisulpride having the structure:

[0038] In certain embodiments, the 4-amino substituted derivative of amisulpride has the formula IB-R: [ka]

[0039] and pharma- ceutically acceptable salts thereof, wherein Z is as described in formula IA, except that Z is not H.

[0040] In certain embodiments, the 4-amino substituted derivative of amisulpride has the formula IB-S: [ka]

[0041] and pharma- ceutically acceptable salts thereof, wherein Z is as described in formula IA, except that Z is not H.

[0042] In certain embodiments, the amisulpride derivative has the formula IC: [ka]

[0043] and Z is as described in formula IA, except that Z is not H, including pharma- ceutically acceptable salts and stereoisomers thereof.

[0044] In certain embodiments, the amisulpride derivative has the formula IC-R: [ka]

[0045] and pharma- ceutically acceptable salts thereof, wherein Z is as described in formula IA, except that Z is not H.

[0046] In certain embodiments, the amisulpride derivative has the formula IC-S: [ka]

[0047] and pharma- ceutically acceptable salts thereof, wherein Z is as described in formula IA, except that Z is not H.

[0048] As used herein, the singular forms "a," "an," and "the" include the plural, unless the context clearly indicates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Similarly, the use of a "compound" in the context of treatment with a medicament or manufacture of a medicament as described herein contemplates the use of one or more compounds of the invention for such treatment or manufacture, unless the context clearly indicates otherwise.

[0049] As used herein, the terms "comprise, contain, have" are intended to mean that the compositions and methods include the recited elements, but do not exclude others. Thus, a composition consisting essentially of the elements defined in this specification does not exclude trace contaminants from the isolation and purification methods, as well as pharma- ceutically acceptable carriers such as phosphate buffered saline, preservatives, etc. "Consisting of" means excluding more than trace elements of other components and more than substantial methods of administering the compositions of the invention. The embodiments defined by each transition term are within the scope of this invention.

[0050] The term "alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms and containing no unsaturated bonds. Unless otherwise defined, the term "alkyl" refers to groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (e.g., 1-6 carbon atoms or 1-4 carbon atoms) attached to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl, and s-pentyl.

[0051] The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and may be straight-chained or branched. Unless otherwise defined, the term "alkenyl" refers to groups having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0052] The term "alkynyl" refers to a straight or branched chain hydrocarbyl group having at least one carbon-carbon triple bond. Unless otherwise defined, the term "alkynyl" refers to groups having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 2-10, 2-10 carbon atoms), such as ethynyl, propynyl, butynyl.

[0053] The term "cycloalkyl" refers to a non-aromatic mono- or polycyclic ring system of 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0054] The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above directly bonded to an alkyl group as defined above.

[0055] The term "aryl" refers to monocyclic or polycyclic aromatic groups having 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0056] The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, for example, -CH2C6H5 and -C2H5C6H5.

[0057] The term "heterocyclyl" refers to a non-aromatic 3- to 15-membered ring group consisting of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, phosphorus, oxygen, and sulfur. The heterocycle may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may contain fused, bridged, or spiro rings, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocycle may be oxidized to various oxidation states. Additionally, the nitrogen atom may be optionally quaternized.

[0058] The term "heterocyclylalkyl" refers to a heterocyclyl group as defined above directly bonded to an alkyl group as defined above.

[0059] The term "heteroaryl" refers to an optionally substituted 5- to 14-membered aromatic ring having one or more hetero ring atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring atoms. Heteroaryl may be a monocyclic, bicyclic, or tricyclic ring system. Examples of such heteroaryl rings include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, and isoquinolyl.

[0060] The term "heteroarylalkyl" refers to a heteroaryl group as defined above directly bonded to an alkyl group as defined above, for example, -CH2C6H4N and -C2H5C6H4N.

[0061] The term "subject" refers to a mammal, such as a household pet (e.g., dog, cat) or a human. In certain embodiments, the subject is a human.

[0062] The phrase "effective amount" refers to the amount that, when administered to a subject or patient for treating a disease, is sufficient to effect treatment.

[0063] "Treatment" or "treating" includes (1) preventing a disease (e.g., halting further progression of the disease and / or symptoms) in a subject or patient suffering from or experiencing a disease symptom, (2) ameliorating a disease (e.g., reversing pathology and / or symptomology) in a subject or patient suffering from or experiencing a disease symptom, and (3) causing a measurable reduction in a disease in a subject or patient suffering from or experiencing a disease symptom.

[0064] The term "pharmaceutical acceptable carrier" refers to a carrier that is compatible with other ingredients in the formulation and does not cause allergic reactions or other adverse effects in patients to whom it is administered. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers that are appropriately selected for each formulation and consistent with conventional pharmaceutical practice. For example, solid carriers / diluents include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, glucose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.

[0065] In this specification, the term "salt" refers to a salt formed with an amisulpride derivative, and is not particularly limited as long as it is pharma- ceutically acceptable, and preferred examples thereof include hydrohalide salts (e.g., hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salts (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carboxylate salts (e.g., acetate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonate salts (e.g., methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (e.g., aspartate, glutamate, etc.), and quaternary ammonium salts. In addition, hydrochloride, sulfate, methanesulfonate, acetate, etc. are preferred as "pharmacologically acceptable salts" of the amisulpride derivatives disclosed in this specification.

[0066] Isomers (e.g., geometric isomers, optical isomers, rotamers, tautomers, etc.) of the amisulpride derivatives disclosed in this specification can be purified by common separation means including, for example, recrystallization, optical resolution such as the diastereomeric salt method, enzymatic fractionation, and various types of chromatography (thin layer chromatography, column chromatography, glass chromatography, etc.).

[0067] Pharmaceutical formulations and routes of administration The amisulpride derivatives disclosed herein can be administered by a variety of routes, including orally and by injection (e.g., subcutaneously, intravenously, and intraperitoneally). The amisulpride derivatives disclosed herein can be formulated into pharmaceutical compositions for use in the disclosed methods. Such compositions are prepared according to acceptable pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference.

[0068] The amisulpride derivatives disclosed herein can be orally administered as solid or liquid formulations. In either case, the amisulpride derivatives disclosed herein can be coated with a material that protects them from the action of acids and other conditions that may inactivate the compound. The amisulpride derivatives disclosed herein can be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups and wafers. Oral formulations may contain additives known in the art, such as binders, disintegrants, flavorings, antioxidants and preservatives. Liquid formulations may contain diluents, such as saline or aqueous buffer solutions.

[0069] The amisulpride derivatives disclosed in this specification may be administered by injection. Formulations suitable for injection may include sterile aqueous solutions (if water soluble) or dispersions and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical composition may be sterile and may be fluid to such an extent that it is easily syringable. It may be stable under the conditions of manufacture and storage and may be preserved against the contaminating action of microorganisms such as bacteria and fungi. The pharmaceutically acceptable carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyol (such as glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, the use of surfactants, and by maintaining the required particle size in the case of dispersions. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, and ascorbic acid). In many cases, it is preferable to incorporate isotonic agents, such as sugars, sodium chloride, or polyalcohols (e.g., mannitol and sorbitol) into the composition. Prolonged absorption of the injectable compositions can be achieved by incorporating in the composition an agent which delays absorption, such as aluminum monostearate or gelatin.

[0070] Sterile injectable solutions can be prepared by combining the required amount of therapeutic compound and a suitable solvent with one or a combination of ingredients previously described as required, followed by filtration and sterilization. Generally, dispersions are prepared by combining the therapeutic compound with a sterile carrier having a basic dispersion medium and the required ingredients previously described. Methods for preparing sterile powders for preparing sterile injectable solutions include vacuum drying and freeze-drying, which yield a powder of the active ingredient (i.e., therapeutic compound) and any additional desired ingredients from a previously sterile-filtered solution.

[0071] The actual dosage of the compound administered to a subject will depend on physical and physiological factors such as age, sex, weight, symptoms, type of disease being treated, previous or concurrent treatments, specific symptoms of the subject, and route of administration. These factors can be determined by those skilled in the art. The physician responsible for administration will usually determine the concentration of active ingredient in the composition and the appropriate dose for the subject.

[0072] In one embodiment, the daily dose for a human is from about 0.01 mg / kg to about 100 mg / kg.

[0073] Amisulpride derivative is intended to be administered in a single dose or multiple doses.The desired interval of multiple doses can be determined by those skilled in the art through routine experimentation.As an example, it may be administered twice a day, about 12 hours apart.In some embodiments, Amisulpride derivative is administered once a day.

[0074] The amisulpride derivative or pharmaceutical composition thereof disclosed herein can be administered on a regular schedule. In this specification, a regular schedule refers to a predetermined period of time. The regular schedule may include periods of the same length or periods of different lengths, as long as the schedule is predetermined. For example, the regular schedule may include administration twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, every week, every month, or for any number of days or weeks. Alternatively, the predetermined regular schedule may be administration twice a day for the first period, followed by administration once a day for several months. In another aspect, the present invention provides that the amisulpride derivative or pharmaceutical composition thereof disclosed herein can be taken orally, the timing of which may or may not depend on food intake. Thus, for example, the drug can be taken every morning and / or every evening, regardless of the subject's mealtime.

[0075] Combination therapy In addition to being used as a monotherapy, the amisulpride derivatives disclosed herein or their pharmaceutical compositions can also be used in combination therapy. Effective combination therapy can be achieved by a single pharmaceutical composition or pharmacological preparation that contains both drugs, or by the simultaneous administration of two different pharmaceutical compositions or pharmacological preparations, one composition that contains the compound of the present invention and the other composition that contains the second drug. Alternatively, combination therapy can be performed before or after treatment with the other drug, with an interval ranging from minutes to months.

[0076] The other agent can be selected from agents useful for treating psychiatric disorders, such as agents useful for treating imbalances of dopamine, serotonin, histamine, or glutamate. In some embodiments, the additional agent is one useful for improving mental function, such as an antipsychotic agent, such as quetiapine, diodon, zyprexa, latuda, olanzapine, risperidone, iloperidone, ziprasidone, clozapine, haloperidol, chlorpromazine, citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, desvenlafaxine, duloxetine, milnacipran, venlafaxine, vilazodone, and combinations thereof.

[0077] Although the present invention has been described with reference to embodiments and representative examples, those skilled in the art will appreciate modifications to the invention described and illustrated that do not depart from the spirit and scope of the invention disclosed herein. The examples are provided to aid in the understanding of the invention, but are not intended to, and should not be construed as, limiting its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those skilled in the art and are described in numerous publications. Furthermore, all references cited in this specification are incorporated herein by reference in their entirety as if fully set forth in this specification. EXAMPLES

[0078] Example 1 Analysis of D2 / D3RO when LB-102 was administered to healthy subjects Healthy volunteers were orally administered 50 mg (n=4) or 100 mg (n=3) of LB-102, and the results were as follows: baseline, 2.5, 7.5, and 23.5 hours after LB-102 administration. 11 Dynamic PET scans of C-raclopride were performed to obtain the D2 / D3RO (Tables 1-A and 1-B). See also Figure 1A (50 mg) and Figure 1B (100 mg), which show the D2 / D3RO in the caudate nucleus (diamond) and putamen (square).

[0079] [Table 1]

[0080] Example 2 PK analysis of LB-102 administered to healthy subjects I) Plasma concentrations of LB-102 (diamonds), amisulpride (squares), and total benzamides (triangles) following oral administration of 50 mg of LB-102 to humans are shown in FIG. 2 (n=4).

[0081] II) Clinical Trial Plan and Subjects This study was conducted at a single site in accordance with all Institutional Review Board regulations. All local regulations and good clinical practice were adhered to.

[0082] BMI ≥ 18 and 30 kg / m 2 Healthy men and women aged 18-55 years were enrolled in the study. Exclusion criteria included a history or presence of psychiatric disorders, drug or alcohol abuse, a history of QT prolongation or arrhythmia, fasting plasma glucose level ≥126 mg / dL, or allergy to the drug or its metabolites. The study was designed in two parts. Part A consisted of five single-dose study arms, each with eight subjects. Part B consisted of three repeat-dose studies, each with eight subjects, administered twice daily for 7 days (total of 13 doses). All subjects were randomly assigned to drug:placebo in a 3:1 ratio. The primary endpoint of the study was safety, and the secondary objective was pharmacokinetics.

[0083] demographics A total of 64 healthy volunteers were enrolled in this trial. Demographic data are summarized in Table 2-A. There were numerical differences between the treatment and placebo groups in mean age, male / female ratio, and African American / Black ratio. There was good match for BMI.

[0084] [Table 2-A]

[0085] [Table 2-B]

[0086] [Table 2-C]

[0087] Plasma concentrations of LB-102 as a function of time following single oral doses of 10 mg (large x), 50 mg (triangles), 100 mg (squares), 150 mg (small x), and 200 mg (diamonds) of LB-102 in humans are shown in Figure 3.

[0088] The PK profile of a single oral dose of LB-102 (50 mg) in humans (Figure 4B) showed that the AUC (1,595 ngh / mL) was approximately 2.5-fold higher than the AUC (603 ngh / mL) obtained from the previously published PK profile of amisulpride (50 mg) (Figure 4A).

[0089] Orally administered LB-102 was rapidly absorbed, with exposure increasing slightly more than proportional to dose. In the MAD trial, LB-102 trough concentrations plateaued before the morning dose on day 4, with mild to moderate accumulation at each dose.

[0090] Plasma exposure of LB-102 was significantly higher than expected compared to animal models and published data for amisulpride.

[0091] Example 3 Analysis of dopamine (e.g. D2 / D3) RO and PK following administration of LB-102 to healthy subjects at various dosing regimens Healthy subjects were orally administered LB102 at 50 mg QD (n=4), 75 mg QD (n=4), 100 mg QD (n=4), 50 mg SS (steady state) (n=2), or 100 mg SS (n=2). The mean age of subjects was 33 years. QD subjects received a single dose on day 1 and had PET scan images obtained thereafter. SS, or steady state, subjects were dosed once daily for 4 days and had PET scan images obtained after dosing on day 4.

[0092] 11 Dynamic PET scans of C-raclopride were obtained at 0, 2.5, 7.5, and 23.5 hours after LB-102 administration for the 50 mg and 100 mg QD treatment groups, after LB-102 administration on day 4 for the 50 mg and 100 mg SS treatment groups, and at 0, 3.5, 23.5, and 47.5 hours after LB-102 administration for the 75 mg QD treatment group. Dopamine %RO was calculated using the STRM method (https: / / pubmed.ncbi.nlm.nih.gov / 9345505 / , incorporated herein by reference). Total RO% (average of caudate and putamen RO%) is shown as boxes in Figure 5A (50 mg QD), Figure 5B (75 mg QD), Figure 5C (100 mg QD), Figure 6A (50 mg SS day 4) and Figure 6B (100 mg SS day 4) and summarized in Table 3-A below.

[0093] Total plasma concentrations of LB-102 and amisulpride were obtained and the results are shown as diamonds in Figures 5A (50 mg QD), 5B (75 mg QD), 5C (100 mg QD), 6A (50 mg SS day 4) and 6B (100 mg SS day 4) and the data are summarized in Table 3-A below.

[0094] Typically, dopamine RO resulting from treatment with dopamine antagonists closely tracks the corresponding plasma concentrations (e.g., brexpiprazole [DF Wong, A. Raufinia, P. Bricmont, JR Brasic, RD McQuade, RA Forbes, T. Kikuchi, and H. Kuwabara, "An open-label, positron emission tomography study of the striatal D2 / D3 receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants," European Journal of Clinical Pharmacology, 2021, 77, 717-725.], lumateperone [RE Davis, KE Vanover, Y. Zhou, JR Brasic, M. Buevara, B. Bisuna, W. Ye, V. Raymont, W. Willis, A. Kumar, L. Gapasin, RR Goldwater, S. Mates, and DF Wong, "ITI-007 demonstrates brain occupancy at serotonin 5-HT 2Aand dopamine D2receptors and serotonin transporters using positron emission tomography in healthy volunteers", Psychopharmacology, 2015, 232, 2863-2872.], ziprasidone [RE Davis, KE Vanover, Y. Zhou, JR Brasic, M. Buevara, B. Bisuna, W. Ye, V. Raymont, W. Willis, A. Kumar, L. Gapasin, RR Goldwater, S. Mates, and DF Wong, "ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2receptors and serotonin transporters using positron emission tomography in healthy volunteers", Psychopharmacology, 2015, 232, 2863-2872.]]).

[0095] Unexpectedly, the dopamine RO of LB-102 was prominently maintained even after the combined plasma concentration of LB-102 and amisulpride had fallen below 10 ng / mL.

[0096] [Table 3-A]

[0097] To calculate Dopamine RO% 11 Dynamic PET scan results of C-raclopride were measured in the subjects' caudate nucleus, putamen, thalamus, and temporal lobe, and are summarized in Tables 3-B to 3-F below.

[0098] [Table 3-B]

[0099] [Table 3-C]

[0100] [Table 3-D]

[0101] [Table 3-E]

[0102] [Table 3-F]

[0103] References The references set forth below, and all references cited throughout this specification, are hereby incorporated by reference in their entirety as if fully set forth herein. 1) HY Meltzer and SS Stahl, "The Dopamine Hypothesis of Schizophrenia- A Review," Schizophr. Bull., 1976, 2, 19-76. 2) JJ Joyce and JH Meador-Woodruff, "Linking the Family of D2 Receptors to Neuronal Circuits in Human Brain: Insights into Schizophrenia," Neuropsychopharmacology, 1997, 16, 1444-1449. 3) S. Wulff, L. Hageman Pinborg, C. Svarer, L. Thorbjorn Jensen, M. Odegaard Nielsen, P. Allerup, N. Bak, H. Rasmussen, E. Frandsen, E. Rostrup, and B. Yding Glenthoj, "Striatal D2 / 3 Binding Potential Values in Drug-Naive First-Episode Schizophrenia Patients Correlate with Treatment Outcome," Schizophrenia Bulletin, 2015, 41, 1143-1152. 4) B. L. Roth, D. J. Sheffler, and W. K. Kroeze, "Magic Shotguns Versus Magic Bullets: Selectively Non-Selective Drugs for Mood Disorders and Schizophrenia," Nature Reviews Drug Discovery, 2004, 3, 353-359. 5) M. Thominet, J. Acher, and J.-C. Monier, "Derivatives of 4-Amino-5-Alkyl Sulphonyl Orthoamides," US Patent 4,401,822, Filed Oct. 9, 1981 (Issued Aug. 30, 1983). 6) H. Shoemaker, Y. Claustre, D. Fage, L. Rouquier, K. Chergui, O. Curet, A. Oblin, F. Gonon, J. Benavides, and B. Scatton, "Neurochemical Characteristics of Amisulpride, An Atypical Dopamine D2 / D3 Receptor Antagonist with Both Presynaptic and Limbic Selectivity," J. Pharmacol. Exp. Ther., 1997, 280, 83-97. 7) A. A. Abbas, P. B. Hedlund, X-P. Huang, T. B. Tran, H. Y. Meltzer, and B. L. Roth, "Amisulpride Is a Potent 5-HT7Antagonist: Relevance for Antidepressant Actions In Vivo," Psychopharmacology, 2009, 119-128. 8) S. Jafari, F. Fernandez-Enright, and X.-F. Huang, "Structural Contributions of Antipsychotic Drugs to Their Therapeutic Profiles and Metabolic Side Effects," J. Neurochemistry, 2012, 120, 371-384. 9) J. N. Dos Santos Pereira, S. Tadjerpisheh, M. Abu Abed, A. R. Saadatmand, B. Weksler, I. A. Romero, P.-O. Couraud, J. Brockmoeller, and M. V. Tzvetkov, "The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family," The AAPS Journal, 2014, 16, 1247-1258. 10) J. C. Neill, S. Barnes, S. Cook, B. Grayson, N. F. Idris, S. L. McLean, S. Snigdha, L. Rajagopal, and M. K. Harte, "Animal Models of Cognitive Dysfunction and Negative Symptoms of Schizophrenia: Focus on NMDA Receptor Antagonism," Pharmacology & Therapeutics, 2010, 128, 419-432. 11) J. C. Neill, M. K. Harte, P. M. Haddad, E. S. Lydall, and D. M. Dwyer, "Acute and Chronic Effects of Nmda Receptor Antagonists in Rodents, Relevance to Negative Symptoms of Schizophrenia: A Translational Link to Humans," European Neuropsychopharmacology, 2014, 24, 822-835. 12) J. C. Neill, B. Grayson, B. Kiss, I. Gyertyan, P. Ferguson, and N. Adham, "Effects of Cariprazine, A Novel Antipsychotic, On Cognitive Deficit and Negative Symptoms in a Rodent Model of Schizophrenia Symptomatology," European Neuropsychopharmacology, 2016, 26, 3-14.

Claims

1. Dopamine receptors, serotonin receptors (e.g., 5-HT ２ａ , 5-HT ７ ) and / or alpha-2 adrenergic (alpha2) receptor antagonists to the brain of a subject.

2. Dopamine receptors, serotonin receptors (e.g., 5-HT) in the subject ２ａ , 5-HT ７ ) and / or the use of a therapeutically effective amount of an amisulpride derivative, alone or in combination with other CNS active agents, for the manufacture of a medicament and / or pharmaceutical composition that antagonizes alpha-2 receptors.

3. Dopamine receptors, serotonin receptors (e.g., 5-HT) in the subject ２ａ , 5-HT ７ ) and / or the use of a therapeutically effective amount of an amisulpride derivative, alone or in combination with other CNS active agents, for the manufacture of a medicament and / or pharmaceutical composition for the treatment of one or more conditions responsive to modulation of alpha-2 receptors.

4. The use according to any one of claims 1 to 3, characterized in that the amisulpride derivative is LB-102.

5. The use described in any one of claims 1 to 3, characterized in that the medicament and / or pharmaceutical composition includes instructions for providing a dose of the amisulpride derivative selected from 1, 2, 3 or 4 unit doses of the amisulpride derivative.

6. The use according to any one of claims 1 to 3, characterized in that the medicament and / or pharmaceutical composition comprises instructions to provide the amisulpride derivative once a day, once every two days, once every three days, once every four days, once every five days, once every six days or once a week.

7. 6. The use according to claim 5, characterized in that the unit dose is 50 mg, 75 mg or 100 mg.

8. The striatal dopamine RO% or mean dopamine in the caudate and putamen (e.g., D ２ / D ３ 4. The use according to any one of claims 1 to 3, wherein the medicament and / or pharmaceutical composition comprises an instruction to adjust the dose of the amisulpride derivative so that the RO% is about 60% to about 80%, about 50% to about 85%, or about 40% to about 90%.

9. The pharmaceutical and / or pharmaceutical composition, a) providing a first unit dose of the amisulpride derivative to the subject once daily, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week; b) obtaining a first mean dopamine RO% in the caudate nucleus and putamen of said subject; c) measuring a first striatal dopamine RO% or a first mean dopamine (e.g., D ２ / D ３ ) if RO% is not within the predetermined range of about 60% to about 80%, about 50% to about 85%, or about 40% to about 90%, providing the subject with a second dose of the amisulpride derivative once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week; d) measuring a second striatal dopamine RO% or a second mean dopamine (e.g., D) in the caudate and putamen of said subject; ２ / D ３ ) obtaining RO%; and e) the subject's striatal dopamine RO% or mean dopamine in the caudate and putamen (e.g., D ２ / D ３ ) repeating steps c) and d) until the RO% is within the predetermined range (e.g., about 60% to about 80%, about 50% to about 85%, or about 40% to about 90%); The use according to any one of claims 1 to 3, characterized in that it comprises instructions:

10. The amisulpride derivative, 【Chemical 1】 Use according to any one of claims 1 to 3, characterized in that it is selected from:

11. A pharmaceutical composition comprising an amisulpride derivative and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, further comprising another CNS active agent.

13. A pharmaceutical composition as described in claim 11 or 12, characterized in that it delivers a dopamine receptor, serotonin receptor (e.g., 5-HT2a, 5-HT7) and / or alpha-2 adrenergic (alpha2) receptor antagonist to the brain of a subject, antagonizes dopamine receptor, serotonin receptor (e.g., 5-HT2a, 5-HT7) and / or alpha2 receptor in a subject, and / or treats one or more conditions responsive to modulation of dopamine receptor, serotonin receptor (e.g., 5-HT2a, 5-HT7) and / or alpha2 receptor in a subject.

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