Psychotropic agents and uses thereof

Abstract

The amisulpride derivatives and the R enantiomer of amisulpride, or pharmaceutical compositions thereof, disclosed herein can be used alone or in combination with other CNS active agents to antagonize serotonin (e.g., 5-HT2a, 5-HT7) receptors in a subject. The amisulpride derivatives and the R enantiomer of amisulpride, or pharmaceutical compositions thereof, disclosed herein can be used alone or in combination with other CNS active agents to treat one or more conditions responsive to modulation of serotonin (e.g., 5-HT2a, 5-HT7) receptors in a subject. The amisulpride derivatives and the R enantiomer of amisulpride, 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 abnormal levels of serotonin in the brain.

Description

[0001] CLAIM OF PRIORITY

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 508,263, filed May 18, 2017, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0003] The present invention relates generally to pharmaceutical compositions and methods for treating neuropsychiatric and / or psychological diseases or disorders. BACKGROUND

[0004] Schizophrenia is a chronic debilitating mental illness affecting about 1% of the population. The disease is manifested by delusional behavior, disorganized thinking, agitated physical movement, social withdrawal, and depression. Schizophrenia patients suffer from a greatly reduced quality of life and the likelihood of suicide is ten times that of the general population.

[0005] Dopamine (particularly D2 and D3) antagonists are recognized to ameliorate symptoms of schizophrenia and have been used clinically for decades. In the past two decades, it has been recognized that treatment of schizophrenia, like many psychiatric diseases, benefits from the involvement of multiple receptors including serotonin receptors and adrenergic receptors. Even so, in practice, dozens of drugs approved for the treatment of schizophrenia still have poor therapeutic efficacy in many patients. Side effects of existing agents include: movement disorders, akathisia, weight gain, mood disturbances, sexual dysfunction, sedation, orthostatic hypotension, hypersalivation, and (in some cases) agranulocytosis.

[0006] Amperozide (4-amino-N-(((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide) is an antipsychotic drug patented in 1981. Amperozide selectively binds to human dopamine D2 (K i 2.8 nM) and D3 (K i 3.2 nM) receptor subtypes, while showing no affinity for D1, D4, and D5 receptor subtypes. Unlike typical and atypical neuroleptics, amperozide exhibits low affinity for serotonin, alpha-adrenergic, histamine receptor subtypes, muscarinic receptors, and sigma sites, although it has also been shown to bind to 5-HT i and HT 2B receptors with low double-digit nM K 7a This ability of amperozide to bind to 5-HT receptors is thought to give amperozide the ability to treat symptoms of depression (sometimes manifested in schizophrenic patients). Interestingly, amperozide has not been found to have any activity on 5-HT 2a receptors compared to other antipsychotic drugs.

[0007] Despite its unique activity, amperozide has a low ability to cross the blood brain barrier (BBB) to interact with receptors in the brain. In a 2014 study, amperozide had the lowest passive diffusion across PAMPA membranes (P e ) of the 30 psychotropic drugs tested. As a result, amperozide is dosed at a high amount, typically 400 to 800 mg / d (notwithstanding, up to 1,200 mg / day is not uncommon). Such a high dose can have adverse effects on the subject receiving treatment. SUMMARY

[0008] Provided herein are novel amperozide derivatives and pharmaceutical compositions thereof. In some examples, the amperozide derivatives disclosed herein are dopamine and / or serotonin antagonists. In some examples, the amperozide derivatives disclosed herein have improved membrane (e.g., BBB) permeability compared to amperozide. In some examples, the amperozide derivatives can act as central nervous system (CNS) dopamine and / or serotonin antagonists. These amperozide derivatives have the structure of Formula I, Formula IA, Formula IB, or Formula IC, including pharmaceutically acceptable salts thereof, and stereoisomers thereof (e.g., Formula I-S, Formula I-R, Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, and Formula IC-R) disclosed herein. Also provided herein are deuterated analogs of the amperozide derivatives disclosed herein.

[0009] Also provided herein are methods of delivering a serotonin (e.g., 5-HT2a, 5-HT7) receptor antagonist to the brain of a subject, comprising administering to the subject an amperozide derivative disclosed herein or a pharmaceutical composition thereof; and a higher level of serotonin receptor antagonist in the brain than would be achieved by administering amperozide (racemic mixture) to the subject at a comparable dose.

[0010] Also provided herein are methods for antagonizing a serotonin (e.g., 5-HT2a, 5-HT7) receptor in a subject, comprising administering to the subject an amperozide derivative disclosed herein and / or the R isomer of amperozide or a pharmaceutical composition thereof, alone or in combination with other CNS active agents.

[0011] Further provided herein are methods of treating one or more conditions responsive to modulation of a serotonin (e.g., 5-HT2a, 5-HT7) receptor in a subject, comprising administering to the subject an amperozide derivative disclosed herein and / or the R isomer of amperozide or a pharmaceutical composition thereof, alone or in combination with other CNS active agents.

[0012] It is further provided herein methods for treating one or more disorders associated with abnormalities in serotonin levels in the brain, comprising administering to a subject an amperozide derivative and / or the R isomer of amperozide, or a pharmaceutical composition thereof, disclosed herein, alone or in combination with other CNS active agents.

[0013] Examples of conditions responsive to serotonin (e.g., 5-HT2a, 5-HT7) receptors and / or disorders associated with abnormalities in serotonin levels in the brain include, but are not limited to, for example, psychiatric disorders. Examples of psychiatric disorders include, but are not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, depression, obsessive-compulsive disorder, Parkinson's psychosis, Alzheimer's psychosis, oppositional defiant disorder, aggression, suicidality, hostility, personality disorder, chronic fatigue syndrome, major negative symptoms of schizophrenia, Charles Bonnet syndrome, autism, and Tourette's syndrome.

[0014] BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1A : Novel object exploration data from subchronic PCP NOR study in rats (± SEM, n = 10 / group). Difference in discrimination index ((time exploring novel objects - time exploring familiar objects) / total exploration time) is depicted.

[0016] Figure 1B : Discrimination index data from subchronic PCP NOR study in rats (n = 10 / group). Difference in discrimination index ((time exploring novel objects - time exploring familiar objects) / total exploration time) is depicted.

[0017] Figure 2 : Total distance traveled (over 1 hour) + SEM (n = 10 / group). p < 0.05 for all treatment groups compared to amphetamine.

[0018] Figure 3 : Binding of compounds 102, 103, 104, and amperozide (101) to 5-HT7 receptors.

[0019] Figure 4 : Binding of amperozide (Ami(rac)), the R enantiomer of amperozide (Ami(r)), and the S enantiomer of amperozide (Ami(d)) to 5-HT7 receptors. DETAILED DESCRIPTION

[0021] As disclosed herein, 4-amino substituted derivatives of amperozide (also referred to as 4-amino amperozide derivatives and 4-amino substituted amperozide derivatives) show improved membrane (e.g., BBB) permeability and can be used at lower doses than amperozide to target relevant receptors in the brain with fewer side effects to the subject receiving treatment as compared to amperozide. For example, 4-amino substituted amperozide derivative compound 102 (also referred to as LB-102, N-methyl amperozide and 4-methylamino substituted amperozide derivative) was prepared (Examples 1 and 2) and showed unexpectedly high membrane permeability as compared to amperozide (Example 4, 216.7 fold improvement at pH 7.4, 87.5 fold improvement at pH 5). Stereoisomers of compound 102 (compound 103 and compound 104) were also prepared (Example 3), as were other 4-amino amperozide derivative compounds 105-110. In addition, 4-amino substituted amperozide derivatives show potent binding to dopamine D2 receptors and various CNS receptors (Examples 5-7). Unexpectedly, 4-amino substituted amperozide derivatives show alpha2 (e.g., alpha2A, alpha2B, and alpha2C) receptor antagonism (Table 4, Example 7), while amperozide exhibits low affinity for alpha2 receptors. 4-amino substituted amperozide derivatives show 5-HT 2a receptor antagonism (Table 4, Example 7), while amperozide was not found to have any activity at 5-HT 2a receptors. In addition, compound 102 and compound 103 showed restoration of known object exploration behavior in rats in the novel object recognition (NOR) test (Example 8), with impaired discrimination between novel and familiar objects. In the amphetamine-induced locomotor activity (LMA) test, the normalized amphetamine overactivity of compounds 102 and 103 was statistically superior to or indistinguishable from amperozide (Example 9). Further, the stereoisomers of compound 102 (compound 103 and compound 104) showed unexpectedly different K i differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K i differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K i differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K i differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K Figure 4 differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K

[0022] differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K 4-amino substituted sulpiride derivatives differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K

[0023] differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K

[0024] differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K differences in binding to 5-HT7 receptors (Example 10). Unexpectedly, the R enantiomer of amperozide showed unexpectedly lower K

[0025] including pharmaceutically acceptable salts and stereoisomers thereof, wherein:

[0026] R1is and

[0027] X and Z are the same or different and independently selected from the group consisting of hydrogen, alkyl (branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and sec-butyl), alkenyl (branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and sec-butyl), alkynyl (branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and t-butyl), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl), heterocyclyl, heterocyclylalkyl, aryl (e.g., phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl), aralkyl (e.g., -CH2C6H5and -C2H5C6H5), heteroarylalkyl (e.g., -CH2C6H4N and -C2H5C6H4N), and heteroaryl having one or two or three or more heterocyclic atoms (such as pyridine, pyrrole, furan, thiophene, or pyrimidine), optionally alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroarylalkyl, and heteroaryl are further substituted with one or more substituents selected from the group consisting of halogen such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, and other alkyl and aryl groups defined herein; provided that at least one of X and Z is not hydrogen.

[0028] In some examples, the amperozine derivative is a stereoisomer having the structure of Formula I-S:

[0029]

[0030] including pharmaceutically acceptable salts and stereoisomers thereof, wherein Z, X, and R1are the same as defined above in Formula I.

[0031] In some examples, the amperozine derivative is a stereoisomer having the structure of Formula I-R:

[0032]

[0033] including pharmaceutically acceptable salts and stereoisomers thereof, wherein Z, X, and R1are the same as defined above in Formula I.

[0034] In some examples, the amperozine derivative is a 4-amino substituted derivative of amperozine having the structure of Formula IA:

[0035]

[0036] including pharmaceutically acceptable salts and stereoisomers thereof, and X and Z are as defined above in Formula I.

[0037] In some examples, the 4-amino substituted derivative of amperoglide is a stereoisomer having the structure of Formula IA-S:

[0038]

[0039] including pharmaceutically acceptable salts thereof, and X and Z are as defined above in Formula I.

[0040] In some examples, the 4-amino substituted derivative of amperoglide is a stereoisomer having the structure of Formula IA-R:

[0041]

[0042] including pharmaceutically acceptable salts thereof, and X and Z are as defined above in Formula I.

[0043] In some examples, the amperoglide derivative is a 4-amino substituted derivative of amperoglide having the structure of Formula IB:

[0044]

[0045] including pharmaceutically acceptable salts and stereoisomers thereof, and Z is as defined above in Formula I, with the proviso that Z is not H.

[0046] In some examples, the 4-amino substituted derivative of amperoglide is a stereoisomer having the structure of Formula IB-S:

[0047]

[0048] including pharmaceutically acceptable salts thereof, and Z is as defined above in Formula I, with the proviso that Z is not H.

[0049] In some examples, the 4-amino substituted derivative of amperoglide is a stereoisomer having the structure of Formula IB-R:

[0050]

[0051] including pharmaceutically acceptable salts thereof, and Z is as defined above in Formula I, with the proviso that Z is not H.

[0052] In some examples, the amperoglide derivative has the structure of Formula IC:

[0053]

[0054] including pharmaceutically acceptable salts and stereoisomers thereof, and Z is as defined above in Formula I, with the proviso that Z is not H.

[0055] In some examples, the amperozine derivative is a stereoisomer having the structure of Formula IC-S:

[0056]

[0057] including pharmaceutically acceptable salts thereof, and Z is as defined above in Formula I, with the proviso that Z is not H.

[0058] In some examples, the amperozine derivative is a stereoisomer having the structure of Formula IC-S:

[0059]

[0060] including pharmaceutically acceptable salts thereof, and Z is as defined above in Formula I, with the proviso that Z is not H.

[0061] In some examples, the amperozine derivative disclosed herein has greater membrane (e.g., BBB) permeability than amperozine. In some examples, the amperozine derivative disclosed herein is a dopamine and / or serotonin and / or alpha2 antagonist. For example, the amperozine derivative disclosed herein binds to dopamine D2 and / or D3 receptors. In some examples, the amperozine derivative disclosed herein binds more selectively to dopamine D2 and / or D3 receptors than dopamine D1, D4, and / or D5 receptors. In some examples, the amperozine derivative disclosed herein is capable of interacting with dopamine and / or serotonin and / or alpha2 receptors in the CNS.

[0062] Also provided herein are deuterated analogs of the amperozine derivative disclosed herein, wherein one or more hydrogens of the amperozine derivative are replaced with deuterium. In some examples, the one or more deuteriums in the deuterated analog are present at a level that is at least 100 times the natural abundance level.

[0063] Also provided herein are pharmaceutical compositions comprising one or more amperozine derivatives disclosed herein and deuterated analogs thereof and a pharmaceutically acceptable carrier. In some examples, the pharmaceutical composition comprises one or more amperozine derivatives that are substantially enantiomerically pure, and such a pharmaceutical composition is also referred to as a substantially enantiomerically pure pharmaceutical composition. In some examples, the term "substantially enantiomerically pure" means enantiomeric purity of about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater, about 90% or greater, about 95% or greater, or about 98% or greater.

[0064] Also provided herein are methods of treating a CNS disorder comprising administering to a subject in need thereof a therapeutically effective amount of a dopamine and / or serotonin (e.g., 5-HT 2aMethods of delivering dopamine and / or serotonin (e.g., 5-HT7) and / or α2 receptor antagonists to a subject's brain, comprising administering to the subject one or more of the amisulpride derivatives disclosed herein and their deuterated analogs, or pharmaceutical compositions thereof; and dopamine and / or serotonin (e.g., 5-HT7) in the brain 2a The levels of 5-HT7 and / or α2 receptor antagonists were higher than those of amisulpride (racemic mixture) administered to subjects at comparable doses. In some examples, the amisulpride derivatives, deuterated analogs, and / or pharmaceutical compositions were substantially enantiomeric pure.

[0065] This also provides antagonistic dopamine and / or serotonin (e.g., 5-HT) in subjects. 2a Methods involving α5-HT7 and / or α2 receptors include administering, alone or in combination with a CNS active agent, one or more of the amisulpride derivatives disclosed herein and their deuterated analogs, the R enantiomers of amisulpride, or pharmaceutical compositions thereof to a subject. In some examples, the amisulpride derivatives, deuterated analogs, and / or pharmaceutical compositions are substantially enantiomerically pure.

[0066] This also provides for the treatment of dopamine and / or serotonin (e.g., 5-HT) in subjects. 2a Methods for regulating one or more conditions of α5-HT7 and / or α2 receptors, including administering to a subject, alone or in combination with other CNS active agents, a therapeutically effective amount of one or more of the amisulpride derivatives and their deuterated analogs, the R enantiomers of amisulpride, or pharmaceutical compositions thereof disclosed herein. In some examples, the amisulpride derivatives, deuterated analogs, and / or pharmaceutical compositions are substantially enantiomerically pure.

[0067] This document provides a method for treating one or more disorders associated with abnormal levels of dopamine and / or serotonin in the brain of a subject, comprising administering to the subject a therapeutically effective amount of one or more of the amisulpride derivatives and their deuterated analogs, the R enantiomers of amisulpride, or pharmaceutical compositions thereof disclosed herein. In some examples, the amisulpride derivatives, deuterated analogs, and / or pharmaceutical compositions are substantially enantiomerically pure.

[0068] In some examples, the therapeutically effective amount of the disclosed amisulpride derivative, the R enantiomer of amisulpride, or a pharmaceutical composition thereof is lower than the therapeutically effective amount of amisulpride. Therefore, the methods disclosed herein may produce fewer adverse events in treated subjects.

[0069] In response to dopamine and / or serotonin (e.g., 5-HT) 2aExamples of conditions associated with modulation of 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT6, 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. Examples of psychiatric disorders include, but are not limited to, schizophrenia, symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, depression, obsessive-compulsive disorder, Parkinson's psychosis, Alzheimer's psychosis, oppositional defiant disorder, aggression, suicidality, hostility, personality disorder, autism, chronic fatigue syndrome, major negative symptoms of schizophrenia, Charles Bonnet syndrome, and Tourette's syndrome.

[0070] As used herein, the singular "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. By way of example, the term "a cell" includes plural cells, comprising mixtures thereof. Similarly, the term "compound" as used herein in the description of the pharmaceutical formulations or treatments described herein includes the use of one or more compounds of the invention to perform such treatment or preparation.

[0071] As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but not excluding others. Therefore, "consisting essentially of will not exclude trace amounts of contaminants from isolation and purification processes and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of is to be interpreted as excluding additional elements of substantial significance to the basic and novel characteristics of the composition. Examples of each of these transitional terms are within the scope of the application.

[0072] The term "alkyl" refers to straight or branched chain hydrocarbon radicals consisting only of carbon and hydrogen atoms, having no unsaturation. Unless otherwise specified, the term "alkyl" refers to groups having one, two, three, four, five, six, seven, or eight carbon atoms (e.g., one to six carbon atoms, or one to four carbon atoms), and is attached to the rest 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.

[0073] The term "alkenyl" refers to aliphatic hydrocarbon groups containing carbon-carbon double bonds, which can be straight-chain or branched. Unless otherwise specified, 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.

[0074] The term "alkynyl" refers to straight-chain or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond. Unless otherwise indicated, the term "alkynyl" refers to groups having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 2 to 10, 2 to 10 carbon atoms), such as ethynyl, propynyl, and butynyl.

[0075] The term "cycloalkyl" denotes a non-aromatic monocyclic 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.

[0076] The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above directly bonded to an alkyl group as defined above.

[0077] The term "aryl" refers to a monocyclic or polycyclic aromatic radical having 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0078] The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, such as -CH2C6H5, and -C2H5C6H5.

[0079] The term "heterocyclyl" refers to a non-aromatic 3- to 15-membered ring radical composed of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen, and sulfur. The heterocyclic radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, bridged, or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic radical can be optionally oxidized to the various oxidation states. Additionally, the nitrogen atoms can be optionally quaternized.

[0080] The term "heterocyclylalkyl" refers to a heterocyclyl group as defined above directly bonded to an alkyl group as defined above.

[0081] The term "heteroaryl" refers to an optionally substituted 5-14 membered aromatic ring having one or more hetero ring atoms selected from N, O, and S as ring atoms. The heteroaryl can be a monocyclic, bicyclic, or tricyclic ring system. Examples of such heteroaromatic ring radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolinyl, and isoquinolinyl.

[0082] The term "heteroarylalkyl" refers to a heteroaryl group as defined above directly bonded to an alkyl group as defined above, such as -CH2C6H4N, and -C2H5C6H4N.

[0083] The term "subject" refers to a mammal, such as a domesticated pet (e.g., a dog or cat) or a human. In some examples, the subject is a human.

[0084] The phrase "effective amount" means the amount that, when administered to a subject or patient for treating a disease, is sufficient to make such treatment effective for the disease.

[0085] "Treatment" or "treating" includes (1) inhibiting the disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of a disease (e.g., arresting further development of the pathology and / or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of a disease (e.g., reversing the pathology and / or symptomatology), and / or (3) causing any measurable decrease in a pathology or symptomatology of a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of a disease.

[0086] The term "pharmaceutically acceptable carrier" means a carrier that does not cause an allergic or other untoward reaction when administered to a patient to whom it is administered and is compatible with other ingredients in the formulation. Pharmaceutically acceptable carriers include, for example, a pharmaceutical diluent, excipient or carrier suitably selected with respect to the intended form of administration, 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, dextrose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. Pharmaceutically acceptable carriers can further comprise 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.

[0087] The term "salt" used herein is not limited as long as the salt is formed from a compound of the amoxapine derivative and is pharmaceutically acceptable; preferred examples of the salt include a hydrohalide salt (e.g., hydrochloride, hydrobromide, hydroiodide, etc.), an inorganic acid salt (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), an organic carboxylic acid salt (e.g., acetate, maleate, tartrate, fumarate, citrate, etc.), an organic sulfonic acid salt (e.g., methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), an amino acid salt (e.g., aspartate, glutamate, etc.), a quaternary ammonium salt, etc. In addition, hydrochloride, sulfate, methanesulfonate, acetate, etc. are preferred as "pharmacologically acceptable salts" of the amoxapine derivative disclosed herein.

[0088] Isomers (e.g., geometric isomers, optical isomers, rotational isomers, tautomers, etc.) of the amoxapine derivative disclosed herein can be purified into single isomers using conventional separation methods, including, for example, recrystallization, optical resolution such as diastereomeric salt methods, enzyme resolution methods, various chromatographic methods (e.g., thin layer chromatography, column chromatography, glass chromatography, etc.).

[0089] Pharmaceutical formulations and routes of administration

[0090] The amisulpride derivatives and / or deuterated analogs thereof disclosed herein can be administered by a variety of routes, including orally and by injection (e.g., subcutaneous, intravenous, and intraperitoneal). The amisulpride derivatives disclosed herein can be prepared 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 Ed., Alfonso R. Gennaro, Ed., Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference.

[0091] The amisulpride derivatives and / or deuterated analogs thereof disclosed herein can be administered orally in the form of solid or liquid dosages. In both, the amisulpride derivative compounds disclosed herein can be encased in a material that protects it from acids and other natural conditions that can inactivate the compound. The amisulpride derivatives disclosed herein can be formulated into aqueous solutions, liquid dispersions, (ingestible) tablets, lozenges, troches, capsules, elixirs, suspensions, syrups, and wafers. Oral dosage forms can include excipients known in the art, such as binders, disintegrants, flavoring agents, antioxidants, and preservatives. Liquid dosage forms can include diluents, such as saline or aqueous buffers.

[0092] The amisulpride derivatives and / or deuterated analogs thereof disclosed herein can also be administered by injection. Formulations suitable for injection can include sterile aqueous solutions (water-miscible) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical compositions can be sterile and can be fluid to the extent that can be easily injected. It can be stable under the conditions of manufacture and storage and can be protected against the contaminating action of microorganisms such as bacteria and fungi. The pharmaceutically acceptable carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of coating agents such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and ascorbic acid. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate or gelatin.

[0093] A sterile injectable solution can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze drying which yields a powder of the active ingredient (i.e., a therapeutic compound) plus any additional desired ingredient from the previously sterile-filtered solution.

[0094] The actual dose of the compound administered to a subject can be determined by physical and physiological factors such as age, sex, body weight, severity of the condition, type of disease being treated, previous or concurrent therapeutic interventions, idiosyncratic response of the subject, and route of administration. These factors can be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient in the composition and appropriate dose for an individual subject.

[0095] In one example, a human subject is administered a daily dose of about 0.01 mg / kg to about 100 mg / kg.

[0096] Single or multiple doses of the compound are contemplated. The required interval between administration of multiple doses can be determined using only routine experimentation by a person of ordinary skill in the art. For example, a subject can be administered two doses per day at about 12 hour intervals. In some examples, the compound is administered once per day.

[0097] The amisulpride derivative or pharmaceutical composition thereof disclosed herein can be administered by a routine regimen. As used herein, a routine regimen refers to a predetermined specified period of time. A routine regimen can include periods of time of the same length or different lengths so long as the regimen is predetermined. For example, a routine regimen can involve administration twice per day, administration per day, administration every two days, administration every three days, administration every four days, administration every five days, administration every six days, administration per week, administration per month, or any set number of days or weeks therebetween. Alternatively, a predetermined routine regimen can involve administration twice per day for the first week, followed by administration per day for several months. In other examples, the amisulpride derivative or pharmaceutical composition thereof disclosed herein provided by the present invention can be taken orally and the timing thereof is dependent or independent of food intake. Thus, for example, the dosage can be taken every morning and / or every evening, regardless of when the subject eats or will eat.

[0098] Combination therapy

[0099] In addition to use as a monotherapy, the amisulpride derivatives disclosed herein or pharmaceutical compositions thereof can also be used in combination therapy. Effective combination therapy can be achieved with a single pharmaceutical composition or pharmacological formulation comprising two agents or two different pharmaceutical compositions or pharmacological formulations administered simultaneously, where one composition comprises a compound of the present application and the other comprises a second agent. Alternatively, therapy can precede or follow the other agent therapy by intervals ranging from minutes to months.

[0100] The additional agent or agents can be selected from any agent or agents useful in the treatment of a psychiatric disorder, for example, any agent or agents useful in the treatment of dopamine, serotonin, histamine or glutamate imbalance and / or alpha2. In one example, the additional agent or agents can be useful in improving mental function, for example, antipsychotic drugs, for example, quetiapine, ziprasidone, risperidone, lurasidone, olanzapine, risperidone, iloperidone, ziprasidone, clozapine, haloperidol, chloφromazine, citalopram, escitalopram, paroxetine, fluvoxamine, fluoxetine, fluvoxamine, sertraline, duloxetine, venlafaxine, vilazodone, and combinations thereof.

[0101] Synthesis of sulpiride derivatives

[0102] The amisulpride derivatives disclosed herein of the present application can be prepared from amisulpride (4-amino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide), which is readily available. The synthesis of amisulpride is described, for example, in U.S. Patent No. 4,401,822.

[0103] The following synthesis for preparing compounds of Formula IB can be adapted to prepare other compounds of the present application, for example, compounds of Formulas I, IA, and IC. Compounds of Formula IB can be prepared by the following steps: (a) treating amisulpride with a mixture of a carboxylic acid and its corresponding acid anhydride to obtain the corresponding amide, (b) reducing the amide to an amine with a suitable reducing agent, for example, borane:dimethyl sulfide, to form a compound of Formula IB:

[0104]

[0105] wherein Z is as defined above and Z = -C-R.

[0106] This reaction scheme is shown below:

[0107]

[0108] Scheme 1. Preparation of Amisulpride Derivatives

[0109] Similarly, compounds of Formula IA can be prepared by further substituting N-H in the corresponding compound of Formula IB with the corresponding X group; compounds of Formula IC can be prepared by acylation of the aniline in the corresponding compound of Formula IB and subsequent reduction.

[0110] Alternatively, 4-methylamino substituted amperozine derivatives can be prepared by reacting amperozine with N,N-dimethylformamide dimethyl acetal to provide the corresponding amide, followed by reduction with a reducing agent (e.g., NaBH4, DMS:BH3, Red-Al, and LiAlH4) to provide the corresponding 4-methylamino substituted amperozine derivative.

[0111]

[0112] Scheme 2. Preparation of 4-methylamino substituted amperozine derivatives

[0113] The stereoisomers of the amperozine derivatives disclosed herein can be similarly prepared by using the corresponding stereoisomer of amperozine as the starting material. For example, the synthesis of ((S)-4-amino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide can be carried out according to the description in U.S. Patent No. 6,169,094, which is incorporated herein by reference. The S isomer of the amperozine derivative can be prepared using the S isomer of amperozine (Schemes 3 and 4). The R isomer of the amperozine derivative can be similarly prepared using the R isomer of amperozine.

[0114]

[0115] Scheme 3. Preparation of amperozine derivatives (using the S-isomer as an example)

[0116]

[0117] Scheme 4. Preparation of 4-methylamino substituted amperozine derivatives (S-isomer)

[0118] When neither Z nor X of the amperozine derivative of Formula I is hydrogen, the amperozine derivative (disubstituted 4-amino amperozine derivative) can be prepared by a two-step substitution of the 4-amino group. First, the 4-amino group is substituted with the Z or X first substituent as shown above to give a monosubstituted 4-amino amperozine derivative; then a second substitution is made at the 4-amino group of the monosubstituted 4-amino amperozine derivative to give the desired disubstituted 4-amino amperozine derivative. See, for example, Examples 3C and 3D.

[0119] The application has been described with reference to the examples and illustrative examples, and modifications to the application described and illustrated herein can be understood by those skilled in the art without departing from the spirit and scope of the application disclosed in the specification. The examples are set forth to aid in understanding the application but are not intended to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. In addition, all references cited above and below are incorporated herein by reference in their entirety as if fully set forth herein.

[0120] Examples

[0121] Example 1: 4-Formamido-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzene Synthesis of formamides (Compound 1)

[0122]

[0123] Compound 1

[0124] To a solution of 4-amino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide (2 g, 5.5 mmol) in 20 mL formic acid was added acetic anhydride (0.68 g, 6.6 mmol) in portions at 5-10 °C. The reaction mixture was stirred at room temperature overnight and was carefully poured into an aqueous K2CO3 solution at 5-10 °C. Solid NaCl was added and the mixture was extracted with CHCl3. The combined organic extracts were dried over Na2SO4 overnight and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5-10% MeOH in CHCl3 to give 1.82 g (83%) of a yellow gum. 1 HNMR (400 MHz, CDC13): δ 1.1 (t, 3H, CH3), 1.3 (t, 3H, CH3) 1.6 (br s, 2H), 1.7 (br s, 2H), 1.9 (br s, 1H), 2.3 (br s, 2H), 2.7 (br s, 1H), 2.9 (br s, 1H), 3.2 (q, 2H), 3.3 (br s, 1H), 3.4 (br s, 1H), 3.7 (m, 1H), 4.1 (s, 3H, OCH3), 8.4 (br s, 1H, NH), 8.5 (s, 1H, H ar ), 8.6 (s, 1H, H ar ), 8.7 (s, 1H, CHO), 10.1 (s, 1H, NH). Expected molar mass [C 18 H 27 N3O s S]: 397.2, observed molar mass 398.1 [M+H]+ ]。

[0125] Example 2: 4-Formamido-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzene Synthesis of formamides (Compound 1)

[0126]

[0127] Compound 102

[0128] To a solution of 4-formamide-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide (Compound 1, 1.82 g, 4.6 mmol) in 80 mL THF was added BH3.Me2S (1.09 mL, 11.5 mmol) in portions at 5-10 °C. The reaction mixture was stirred at 60 °C for 3 h and carefully quenched with MeOH (40 mL). The reaction mixture was acidified with 10% HC1 (15 mL) and the mixture was stirred at 60 °C overnight. The solvent was evaporated under reduced pressure, the residue was diluted with H2O and basified with aqueous NaOH to pH 10. The mixture was extracted with CHC13, the combined organic extracts were dried over Na2S04and evaporated. The residue was purified by column chromatography on silica gel eluting with 5-10% MeOH in CHC13, then by RP-HPLC eluting with a gradient of MeCN-H2O + 0.1% TFA. Fractions containing the desired material were partially evaporated under reduced pressure, basified with aqueous NaOH to pH 10 and extracted with CH2C12. The combined extracts were dried over Na2S04and evaporated under reduced pressure to give the product as a white solid which solidified upon storage (0.93 g, 53%). 1 H NMR (400 MHz, CDC13): δ 1.1 (t, 3H, CH3), 1.3 (t, 3H, CH3), 1.6 (m, 3H), 1.9 (m, 1H), 2.2 (m, 2H), 2.5 (m, 1H), 2.7 (m, 1H), 2.9 (app d, 3H, NHCH3), 3.1 (q, 2H, CH2), 3.2 (m, 1H), 3.3 (m, 1H), 3.6 (m, 1H), 4.0 (s, 3H, OCH3), 6.1 (s, 1H, H ar ), 6.8 (br s, 1H, H ar ), 8.1 (br s, NH), 8.5 (s, 1H, NH). 13 C NMR (75 MHz, CDC13): δ 8.2, 14.9, 21.2, 29.0, 29.9, 40.5, 47.8, 49.5, 53.7, 56.9, 61.0, 92.1, 110.2, 111.9, 136.1, 150.0, 162.2, 164.0. Expected molar mass [C18 H 29 [N3O4S]: 383.2, observed molar weight 384.5 [M+H] + ].

[0129] Example 3: Synthesis of stereoisomers of Compound 102 (Compounds 103 and 104), and 4- amino sulpiride derivatives (Compounds 105 to 110). Example 4: Membrane permeability of Compound 102

[0130] A): Synthesis of ((S)-4-methylaminoN-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (compound 103)

[0131] ((S)-4-amino-N-((1-ethyl-2-pyrrolyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (11.1 g) was suspended in N,N-dimethylformamide dimethyl acetal (33 mL) and stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature and NaBH4 (4 g) was added in portions. The mixture was stirred at room temperature for 1 h. Saturated NaCHO3 (50 mL) was added to quench the reaction, and the resulting suspension was extracted with dichloromethane (2 x 50 mL). The organic phase was washed with brine, dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography, eluting with CH2Cl2 / MeOH / NH3 to give a white solid product, which was further purified by recrystallization from acetone (5.3 g).

[0132] 1 H NMR (400MHz, DMSO-d6): δ1.1 (2t, 2X3H, CH3), 1.5 (2, 1H) 1.6 (m, 2H), 1.8 (m, 1H), 2.1 (m, 1H), 2.3 (m, 2H), 2.5 (t, 1H ), 2.6(m, 1H), 2.7(m, 1H), 2.9(t, 3H), 3.1(3, 2H), 3.2(m, 2H), 3.3(m, 3H), 3.5(m, 1H), 4.0(s, 3H, OCH3), 6.3(s, 1H ar ), 6.6 (m, 1H) ar ), 8.1 (m, 1H, NH), 8.3 (s, 1H, NH). 13 C10 NMR (100MHz, DMSO-d6): δ 7.56, 14.51, 23.05, 28.54, 30.39, 41.64, 47.90, 48.77, 53.62, 56.79, 62.36, 94.45, 109.94, 111.63, 135.68, 151.48, 163.14, 163.82. Expected molar weight [C10] 18 H 27N3O4S] 383.2, observed molar mass 384.2 [M+H] + ].

[0133] B) Synthesis of ((R)-4-methylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide (Compound 104)

[0134] ((S)-4-amino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide (11.2 g) was suspended in N,N-dimethylformamide dimethyl acetal (33 mL) and stirred at 90 °C for 2 hours. The temperature was lowered to 70 °C and NaBH4(4 g) was added in 1 g portions at 20 minute intervals. After the addition was complete, the reaction mixture was stirred at 90 °C for an additional hour. The reaction mixture was cooled in an ice bath and the reaction was quenched by the addition of 150 mL of saturated NaHCO3. The resulting solution was extracted with CH2Cl2(5 X 50 mL) and the combined organic extracts were dried over Na2SO4. Purification was carried out by column chromatography eluting with 10% MeOH / CH2Cl2to give 7.9 g of a white solid.

[0135] 1 H NMR (300 MHz, CDC13): δ 1.2 (t, 3H, CH3), 1.3 (t, 3H, CH3), 1.7 (m, IH) 1.8 (m, 2H), 1.9 (m, IH), 2.3 (m, 2H), 2.7 (m, IH), 2.9 (m, IH), 2.9 (d, IH), 3.1 (q, 2H), 3.3 (m, 2H), 3.7 (m, IH), 4.0 (s, 3H, OCH3), 6.1 (s, IH ar ), 6.8 (m, IH ar ), 8.1 (m, IH, NH), 8.6 (s, IH, NH). Expected molar mass [C 18 H 27 N3O4S] 383.2, observed molar mass 384.2 [M+H] + ].

[0136] C) Synthesis of ((R)-4-methylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide (Compound 104)

[0137] Stir 4-methylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide (500 mg) in 10 mL formic acid at 30 °C for 21 h while adding NaBH4(8 eq) in two portions and washing with aqueous NaOH to give 408 mg of compound 105.

[0138] 1 H NMR (400 MHz, CDC13): δ 1.2 (t, 3H, CH3s), 1.7 (m, 1H), 1.8 (m, 2H), 1.9 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.2 (m, 1H), 3.3 (m, 1H), 3.4 (q, 2H), 4.0 (s, 3H, OCH3), 6.8 (s, 1H ar ), 8.0 (s, 1H, NH) 8.8 (s, 1H). 13 C NMR (100 MHz, CDC13): δ 7.38, 14.21, 22.96, 28.40, 41.24, 46.14, 48.39, 53.66, 56.11, 62.19, 104.94, 118.52, 126.17, 136.07, 157.93, 161.56, 163.79. Expected molar mass [C 19 H 31 N3O4S] 397.2, observed molar mass 398.2 [M+H + ].

[0139] D) Synthesis of (4-ethylmethylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide (compound 106)

[0140] Stir 4-methylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide (500 mg) in 10 mL formic acid at 30 °C for 21 h while adding NaBH4(8 eq) in two portions and washing with aqueous NaOH to give 408 mg of compound 105.

[0141] 1 H NMR (400 MHz, CDC13): δ 1.2 (t, 3H, CH3s), 1.7 (m, 1H), 1.8 (m, 2H), 1.9 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.2 (m, 1H), 3.3 (m, 1H), 3.4 (q, 2H), 4.0 (s, 3H, OCH3), 6.8 (s, 1H 3s), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 2H), 2.6 (m, 1H), 2.9 (m, 1H), 3.1 (q, 1H), 3.3 (m, 2H), 3.5 (q, 1H), 3.8 (m, 1H) 4.0 (s, 3H, OCH3), 6.8 (s, 1H ar ), 8.0 (s, 1H, NH) 8.8 (s, 1H). 13 C NMR (100 MHz, CDC13): δ 7.36, 12.84, 23.00, 28.42, 41.27, 42.99, 48.12, 52.30, 53.70, 56.16. 106.05, 126.41, 130.05, 142.41, 157.554, 157.54, 161.48, 163.90. Expected molar mass [C 20 H 33 N3O4S] 411.3, observed molar mass 412.3 [M+H + .

[0142] E) Synthesis of (4-ethylamino N-((l-ethyl 2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzamide (Compound 107)

[0143] (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 6 mL of 1,2-dichloroethane and 0.4 mL of acetic acid. The mixture was cooled on an ice bath and 1.15 g of sodium triacetoxyborohydride was added. The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of aqueous NaOH, the product was extracted into dichloromethane, and purified by column chromatography, recrystallized from acetone / MTBE to give 309 mg of Compound 107.

[0144] 1 H NMR (400 MHz, CDC13): δ 1.1 (br t, 3H, CH3), 1.3 (t, 3H, CH3), 1.4 (t, 3H, CH3), 1.5-1.8 (m, 5H), 1.8 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9 (m, 1H), 3.1 (q, 2H), 3.3 (m 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH3), 6.1 (s, 1H ar ), 6.7 (s, 1H ar ), 8.1 (s, 1H, NH) 8.6 (s, 1H). 13C NMR (100 MHz, CDC13): δ 7.34, 14.17, 22.96, 28.47, 37.99, 41.35, 48.00, 49.82, 53.70, 55.80, 62.38, 93.35, 110.89, 111.91, 136.76, 150.76, 162.90, 164.29. Expected molar mass [C 19 H 31 N3O4S] 397.2, observed molar mass 398.2 [M + H + ].

[0145] F) Synthesis of (4-isopropylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide (Compound 108)

[0146] (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 6 mL of DMF and 0.12 mL of acetone. The mixture was cooled on an ice bath and 0.3 mL of TFA was added, followed by 441 mg of sodium triacetoxyborohydride. The mixture was stirred overnight at 40 °C. The reaction mixture was poured into aqueous NaOH and the product was extracted into dichloromethane and purified by column chromatography to give 550 mg of Compound 108.

[0147] 1 H NMR (400 MHz, CDC13): δ 1.1 (br t, 3H, CH3), 1.2 (t, 3H, CH3), 1.3 (t, 6H, CH3), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 1H), 2.6 (m, 1H), 2.9 (m, 1H), 2.1 (q, 2H), 3.2 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH3), 6.1 (s, 1H ar ), 6.7 (s, 1H ar ), 8.0 (s, 1H, NH) 8.6 (s, 1H). 13 C NMR (100 MHz, CDC13): δ 7.36, 22.45, 23.02, 28.48, 41.35, 44.15, 49.95, 53.74, 55.80, 93.65, 111.83, 136.69, 150.03, 162.87, 164.33. Expected molar mass [C 20 H 33 N3O4S] 411.2, observed molar mass 412.2 [M + H + ].

[0148] G) Synthesis of (4-n-propylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide (Compound 109)

[0149] (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 6 mL of 1,2-dichloroethane and 0.3 mL of propionaldehyde. Sodium triacetoxyborohydride (1.2 g) was added in two portions at 10 minute intervals and the mixture was stirred overnight. The reaction mixture was poured into aqueous NaOH and the product was extracted into ethyl acetate and purified by column chromatography to give 518 mg of Compound 109.

[0150] 1 H NMR (400 MHz, CDC13): δ 1.1 (br t, 3H, CH3), 1.2 (t, 3H, CH3), 1.3 (t, 6H, CH3), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 1H), 2.6 (m, 1H), 2.9 (m, 1H), 2.1 (q, 2H), 3.2 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH3), 6.1 (s, 1H ar ), 6.7 (s, 1H ar ), 8.0 (s, 1H, NH) 8.6 (s, 1H). 13 C NMR (100 MHz, CDC13): δ 7.36, 22.45, 23.02, 28.48, 41.35, 44.15, 49.95, 53.74, 55.80, 93.65, 111.83, 136.69, 150.03, 162.87, 164.33. Expected molar mass [C 20 H 33 N3O4S] 411.2, observed molar mass 412.2 [M+H + ].

[0151] H) Synthesis of (4-n-propylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide (Compound 109)

[0152] (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 7 mL of DMF and 1.25 mL of benzaldehyde and 1 mL of TFA. Sodium triacetoxyborohydride (3.5 g) was added in two portions and the mixture was stirred overnight at 40 °C. The reaction mixture was poured into aqueous NaOH and the product was extracted into dichloromethane and purified by column chromatography to give 366 mg of compound 110.

[0153] 1 H NMR (400 MHz, CDC13): δ 1.2 (t, 3H, CH3), 1.2-1.3 (3, 3H, ), 1.5-1.8 (m, 3H), 1.8-2.0 (m, 1H), 2.3 (m, 2H), 2.6 (br s, 1H), 2.9 (m, 1H), 3.1-3.3 (m, 1H), 3.7 (m, 1H), 3.8 (s, 3H), 4.5 (br s, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH3), 6.1 (s, 1H ar ), 7.4 (m, 5H), 8.0 (s, 1H, NH) 8.6 (s, 1H). 13 C NMR (100 MHz, CDC13): δ 7.36, 14.20, 22.91, 28.5, 41.32, 47.52, 50.03, 53.65, 55.77, 62.32, 94.62, 111.36, 112.24, 126.95, 128.97, 136.59, 137.43, 150.53, 162.69, 1664.15. Expected molar mass [C 24 H 33 N3O4S] 459.2, observed molar mass 460.2 [M+H + ].

[0154] Example 5: Binding of Compound 102 to dopamine D2 receptors (cell-based assay)

[0155] The membrane permeability of 4-methylamino-N-((l-ethyl-2-pyrrolidinyl)methyl)-5- (ethylsulfonyl))-2-methoxybenzamide) (compound 102) was determined using the PAMPA assay at pH 5 and 7.4. Specifically, 10 mM solutions of ranitidine control (3.5 mg in 1 mL DMSO), propanolol (2.9 mg in 1 mL DMSO), N-methyl sulpiride (3.3 mg in 0.8 mL DMSO), and sulpiride (3.4 mg in 0.9 mL DMSO) were prepared. Diffusion across Pion PAMPA membranes was determined at pH 5 and pH 7.4, as shown in Table 1, respectively.

[0156] Table 1: Permeability of Compound 102, amperozine, propranolol, and ranitidine across PAMPA membranes at pH 5 and 7.4.

[0157]

[0158] Example 6: Binding of Compound 102 to dopamine D2 receptors (membrane preparation)

[0159] The ability of Compound 102 to bind to the dopamine D2 receptor was determined in a cell-based assay. Dopamine D2 receptor cells were seeded in half black, clear bottom 96 well plates. A volume of 25 μL was reached at a density of 15,000 cells / well and incubated overnight. A solution of the calcium 5 dye in HEPES-buffered HBSS (Hanks' Balanced Salt Solution) was prepared and 10 μL was added to each well and the mixture was allowed to stand at 37°C for 1 hour. After equilibration, 5 μL of test compound and controls were added to the wells and incubated at room temperature for 10 minutes. Fluorescence was measured every 1.52 seconds. After 20 seconds, 10 μL of dopamine (at EC 80 concentration) was added and fluorescence was monitored for 2 minutes with an excitation wavelength of 452 nm and an emission wavelength of 525 nm. The cell-based IC 50 values for Compound 102, along with the known dopamine D2 inhibitors risperidone, amperozine, and clozapine, are listed in Table 2.

[0160] Table 2: IC values (cell-based assay) for Compound 102, risperidone, amperozine, and clozapine relative to the dopamine D2 receptor. 50

[0161]

[0162] Example 7: Compound 102 and Compound 103 binding to various CNS receptors (dopamine D2, dopamine D3, alpha2 adrenergic, serotonin 5HT2A, serotonin 5HT2C, serotonin 5HT6, serotonin 5HT7, histamine H3, muscarinic Ml, muscarinic M2, muscarinic M3, and nicotinic receptors)

[0163] The ability of Compound 102 to bind to the dopamine D2 receptor was determined in a cell-based assay. Dopamine D2 receptor cells were seeded in half black, clear bottom 96 well plates. A volume of 25 μL was reached at a density of 15,000 cells / well and incubated overnight. A solution of the calcium 5 dye in HEPES-buffered HBSS (Hanks' Balanced Salt Solution) was prepared and 10 μL was added to each well and the mixture was allowed to stand at 37°C for 1 hour. After equilibration, 5 μL of test compound and controls were added to the wells and incubated at room temperature for 10 minutes. Fluorescence was measured every 1.52 seconds. After 20 seconds, 10 μL of dopamine (at EC

[0164] The membrane preparation was incubated with 3 ​Hspiperone was incubated with test compound or reference ligand for <120 minutes. Prior to filtration, the 96 well harvest filter plates were coated with 0.33% polyethyleneimine for 30 minutes and then washed with assay buffer. The binding reaction was transferred to the filter plate and washed three times with wash buffer, dried, scintillation cocktail was added, and the radioactivity was counted on the Topcount NXT. 3 Hspiperone and 10 μL of test compound or reference ligand were mixed and incubated for <120 minutes. Prior to filtration, the 96 well harvest filter plates were coated with 0.33% polyethyleneimine for 30 minutes and then washed with assay buffer. The binding reaction was transferred to the filter plate and washed three times with wash buffer, dried, scintillation cocktail was added, and the radioactivity was counted on the Topcount NXT.

[0165] Test compound 102, risperidone, sulpiride, and clozapine were tested in triplicate against Hspiperone. IC50values for the membrane-based assay are shown in Table 3. 3 Hspiperone was incubated with test compound 102, risperidone, sulpiride, and clozapine. IC50values for the membrane-based assay are shown in Table 3. 50 Values (membrane-based assay).

[0166] Table 3: IC50values for compound 102, risperidone, sulpiride, and clozapine against dopamine D2receptors (membrane-based assay). 50 Values (membrane-based assay).

[0167]

[0168] Example 8: Novel object recognition (NOR) assay demonstrates efficacy of Compounds 102 and 103 and 5-HT 2a binding (Table 4)

[0169] The ability of compounds 102 and 103 to bind α2(non-selective), α 2A , α 2B , α 2C , 5-HT 2A (agons), 5-HT 2A (antagonists), D 2L , D 2s , and D3was determined at a concentration range of 10 X 10 -5 to 10 X 10 -9 M and the reference ligand displacing the binding of each individual receptor was determined (prazosin for α2(non-selective), yohimbine for α 2A , α 2B , and α 2C , DOI ([2,5-dimethoxy-4-iodophenyl]-2-aminopropane) for 5-HT 2A (agons), ketanserin for 5-HT 2A (antagonists), butaclamol for D 2L , and 7-OH-DPAT for D2S and (+) butaclamol for D3). Inhibition data are reported in Table 4.

[0170] Table 4: IC50and Ki values for compound 102 (LB102) and compound 103 (LB103) versus various CNS receptors in cell-based assays.

[0171]

[0172] Figure 1A

[0173] The utility of compounds 102 and 103 was evaluated in the novel object recognition (NOR) assay in rats, a well-established model that recapitulates the cognitive and negative aspects of the PANSS scale in schizophrenia. In this assay, animals are treated with a low dose of phencyclidine (PCP) for several weeks to impair the ability of rats to discriminate between novel and familiar objects. Typically, like humans, rats will spend more time exploring a novel object relative to a familiar object. The ability of test treatments to reverse the PCP- impaired performance demonstrates utility in this study.

[0174] In this NOR study, the utility of compounds 102 and 103 was compared to the known antipsychotic drugs amisulpride and risperidone to evaluate the restoration of normal differentiation between novel and familiar object exploration in PCP-treated rats. Rats (n=10 / group) were dosed intraperitoneally twice daily (i.p., b.i.d.) with 2 mg / kg for 7 days, followed by 7 days of no drug administration. Cognitive assays were performed 3 hours after dosing with compounds 102, 103, and amisulpride, and 30 minutes after dosing with risperidone at various PO doses of test agents. Novel object exploration time was measured in test subjects in a subchronic PCP NOR study (n=10 / group) performed in rats. The difference in exploration time between novel (Tnovel-) and familiar (Tfamiliar) objects is shown as Figure 1B (*: p<0.05; and **: p<0.01). Figure 1A The discrimination index for the NOR study was shown to be obtained by the following Equation 1:

[0175] Discrimination Index = (Time spent exploring novel objects - Time spent exploring familiar objects) / Total exploration time) (Equation 1)

[0176] Figure 1A and 1B All doses of compounds 102 (Cpd 102) and 103 (Cpd 103), except one, increased the difference between novel and familiar object exploration time in a manner consistent with the currently used antipsychotic drugs amisulpride and risperidone.

[0177] In Example 9: Amphetamine-induced locomotor activity (LMA) assay demonstrates efficacy of Compounds 102 and 103 and 1B the NOR study, compounds 102 and 103 were able to restore known object exploration behavior in rats treated with PCP to levels similar to untreated rats and on par with values obtained using the known antipsychotic drugs amperozide and risperidone.

[0178] Figure 2

[0179] In the amphetamine-induced locomotor activity (LMA) test, the utility of compounds 102 and 103 was investigated in rats, which is a measure of the positive aspects of the PANSS scale. In the LMA assay, rats were given amphetamine (Amp, 1 mg / kg, s.c.) which causes hyperlocomotion, and the distance each rat moved was monitored in a cage with sensors. Rats given amphetamine alone tend to show hyperactivity, while rats given antipsychotic drugs show more normal, calmer activity.

[0180] In this LMA study, compounds 102 (Cpd 102, 30 mg / kg) and 103 (Cpd 103, 30 mg / kg), amperozide (30 mg / kg) and risperidone (1 mg / kg) were administered orally in groups of 10 rats. Amperozide-risperidone was given 6 hours after administration of compounds 102 and 103 and 1 hour prior to the assay, and the distance moved in one hour was measured. The endpoint of the study was total ambulation distance (distance traveled in the cage by each animal). The total ambulation distance data from this amphetamine-induced LMA study is summarized in Figure 2 (*: p<0.01; **: p<0.05).

[0181] In the LMA study in rats, as shown in Figure 3 the normalized amphetamine hyperactivity of compound 102 (Cpd 102) was statistically superior to amperozide (p<0.05) and the normalized amphetamine hyperactivity of compound 103 (Cpd 103) was statistically indistinguishable from amperozide (p<0.01).

[0182] Example 10: Binding of compounds 102, 103, and 104 to 5-HT7receptors

[0183] The ability of compounds 102, 103, and 104 to bind 5-HT7was measured at a concentration range of 1 x 10 -7 to 3 x 10 -10 M, and displacement of a calcium-sensitive fluorescent indicator in cells expressing 5-HT7was measured. Through this assay, compound 102 (LB-102, solid circles, dotted line B,Figure 3 K i The value is 31 nM, while amisulpride (LB101, solid circle, dotted line A, Figure 3 The concentration was 106 nM. Compound 103 (the S enantiomer of compound 102) was unexpectedly a stronger binder to the dopamine receptor than compound 104 (the R enantiomer of compound 102), whose binding provided 16 nM of K. i (LB104, solid circle, dotted line D) Figure 3 ), while compound 103 (the S enantiomer of compound 102) (LB103, solid triangle, dotted line C, Figure 4 K i The value is >1,000 nM. Surprisingly, the R enantiomer of amisulpride (Ami(r), solid circle, dotted line A, ...) Figure 4 The image shows the S enantiomer of amisulpride (Ami(s), solid circles, dotted line C,). Figure 4 Lower K i Amic(rac) racemic mixture, solid circle, dotted line B. REFERENCES K i It is lower than the R enantiomer of amisulpride, but higher than the S enantiomer of amisulpride.

[0184] CLAIM OF PRIORITY BRIEF DESCRIPTION OF DRAWINGS Figure 1A Figure 1B Figure 2 Figure 3 Figure 4 DETAILED DESCRIPTION Figure 4 4-amino substituted sulpiride derivatives Pharmaceutical formulations and routes of administration Combination therapy Synthesis of sulpiride derivatives Examples Example 1: 4-Formamido-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzene Synthesis of formamides (Compound 1) Example 2: 4-Formamido-N-((l-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2- methoxybenzene Synthesis of formamides (Compound 1) Example 3: Synthesis of stereoisomers of Compound 102 (Compounds 103 and 104), and 4- amino sulpiride derivatives (Compounds 105 to 110). Example 4: Membrane permeability of Compound 102 Example 5: Binding of Compound 102 to dopamine D2 receptors (cell-based assay) Example 6: Binding of Compound 102 to dopamine D2 receptors (membrane preparation) Example 7: Compound 102 and Compound 103 binding to various CNS receptors (dopamine D2, dopamine D3, alpha2 adrenergic, serotonin 5HT2A, serotonin 5HT2C, serotonin 5HT6, serotonin 5HT7, histamine H3, muscarinic Ml, muscarinic M2, muscarinic M3, and nicotinic receptors) Example 8: Novel object recognition (NOR) assay demonstrates efficacy of Compounds 102 and 103 Figure 1A Figure 1B Figure 1A Figure 1A Example 9: Amphetamine-induced locomotor activity (LMA) assay demonstrates efficacy of Compounds 102 and 103 Figure 2 Figure 2 Figure 3 Figure 3 Figure 3 Figure 3 Figure 4 Figure 4 Figure 4 REFERENCES CLAIM OF PRIORITY BRIEF DESCRIPTION OF DRAWINGS Figure 1

[0185] The references listed below and all references cited in the specification are incorporated herein by reference in their entirety as if they were fully described herein.

[0186] 1) H.H. Meltzer and S.S. Stahl, “The Dopamine Hypothesis of Schizophrenia – A Review,” Schizophrenia Bulletin, 1976, 2, 19-76.

[0187] 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.

[0188] 3)S.Wulff, L.Hageman Pinborg, C.Svarer, L. Jensen, M. Nielsen, P. Allerup, N. Bak, H. Rasmussen, E. Frandsen, E. Rostrup, and B. Yding "Striatal D2 / 3 Binding Potential Values ​​in Drug-Initiated Treatment-Related Schizophrenia Patients Are Correlated with Treatment Outcomes" First-Episode Schizophrenia Patients Correlate with Treatment Outcome,” Schizophrenia Bulletin, 2015, 41, 1143-1152.

[0189] 4) BL Roth, DJ Sheffler, and WK Kroeze, “Magic Shotguns Versus Magic Bullets: Selectively Non-Selective Drugs for Mood Disorders and Schizophrenia,” Nature Reviews Drug Discovery, 2004, 3, 353-359.

[0190] 5) M. Thominet, J. Acher, and J.-C. Monier, “Derivatives of 4-Amino-5-Alkyl Sulphonyl Orthoamides,” U.S. Patent No. 4,401,822, filed October 9, 1981 (granted August 30, 1983).

[0191] 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.

[0192] 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-Ht7 Antagonist: Relevance for Antidepressant Actions In Vivo," Psychopharmacology, 2009, 119-128.

[0193] 8) S. Jafari, F. Fernandez-Enright, and X.-F. Huang, "Structural Contributions of Antipsychtoic Drugs to Their Therapeutic Profiles and Metabolic Side Effects," J. Neurochemistry, 2012, 120, 371-384.

[0194] 9) J. N. Dos Santos Pereira, S. Tadjerpisheh, M. Abu Abed, A. R. Saadatmand, B. Weksler, I. A. Romero, P.-O. Couraud, J. and M. V. Tzvetkov, "The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpride Are Substrates of the Organic Cation Transporters from the SLC22 Family," The AAPS Journal, 2014, 16, 1247-1258.

[0195] 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.

[0196] 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.

[0197] 12) J. C. Neill, B. Grayson, B. Kiss, I. Gyertyán, 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. Use of a substantially enantiomerically pure R isomer of a compound having a structure of Formula IA, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of schizophrenia in a subject, wherein, A therapeutically effective amount of a substantially enantiomerically pure R isomer of a compound having a structure according to Formula IA, or a pharmaceutically acceptable salt thereof, is administered to a subject, alone or in combination with other CNS active agents: and wherein: X = H and Z = CH3. wherein, the substantially enantiomerically pure means that the enantiomeric purity is 50% or more.

2. Use according to claim 1, wherein, The subject is further administered a therapeutically effective amount of another agent.

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