CN110944630A - Psychotropic agents and uses thereof - Google Patents

Abstract

Amisulpride derivatives and the R enantiomer of amisulpride or pharmaceutical compositions thereof disclosed herein may be used alone or in combination with other CNS active agents to antagonize serotonin (e.g., 5-HT2a, 5-HT) in a subject₇) A receptor. Amisulpride derivatives and the R enantiomer of amisulpride or pharmaceutical compositions thereof disclosed herein may be used alone or in combination with other CNS active agents for the treatment of one or more serotonin (e.g., 5-HT2a, 5-HT) responses in a subject₇) Disorders of modulation of receptors. The amisulpride derivatives and the R enantiomer of amisulpride or pharmaceutical compositions thereof disclosed herein may be used alone or in combination with other CNS active agents for the treatment of one or more disorders associated with abnormal levels of serotonin in the brain.

Description

Psychotropic agents and uses thereof

Priority requirement

This application claims the benefit of U.S. provisional application No. 62/508,263 filed on 2017, month 5, and day 18, which is incorporated herein by reference in its entirety.

Technical Field

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

Background

Schizophrenia is a chronic debilitating psychotic disorder affecting about 1% of the population. The disease is manifested by delusional behavior, dysfunctional thinking, agitated body movements, social withdrawal, and depression. Schizophrenic patients suffer from an extremely reduced quality of life, with a suicide potential ten times that of the general population.

Dopamine (especially D)₂And D₃) Antagonists are well known to ameliorate the symptoms of schizophrenia and have been used clinically for decades. In the past two decades, it has been recognized that the treatment of schizophrenia, like many psychiatric disorders, benefits from the involvement of a variety of receptors, including serotonin and adrenergic receptors. Even so, in fact, tens of approved drugs for the treatment of schizophrenia still have poor therapeutic efficacy in many patients. Side effects of existing agents include: movement disorders, loss of quiescence, weight gain, mood disorders, sexual dysfunction, sedation, orthostatic hypotension, excessive salivation, and (in some cases) agranulocytosis.

Amisulpride (4-amino-N- (((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide) was patented as an antipsychotic agent in 1981. Amisulpride selectively reacts with human dopamine D₂(K_i2.8nM) and D₃(K_i3.2nM) receptor subtype binding to D₁，D₄And D₅Receptor subtypes do not have any affinity. With the spirit of typical and atypicalUnlike the inhibitory drugs, amisulpride exhibits low affinity for serotonin, α -epinephrine, histamine receptor subtype, muscarinic receptors, and sigma sites, although it has also been shown to bind low dibit numbers nM K_i5-HT of_2BAnd HT_7aReceptor binding. This ability of amisulpride to bind to the 5-HT receptor is believed to confer amisulpride the ability to treat the symptoms of depression (sometimes manifested in schizophrenic patients). Interestingly, amisulpride was not found to be on 5-HT as compared to other antipsychotics_2aThe receptor has any activity.

Despite its unique activity, amisulpride has a low ability to cross the Blood Brain Barrier (BBB) to interact with receptors in the brain. In one study in 2014, amisulpride crossed a PAMPA membrane (P)_e) The passive diffusion of (a) was the lowest among the 30 psychiatric drugs tested. Thus, the dose of amisulpride is very high, typically 400 to 800mg/d (although, up to 1,200 mg/day is not uncommon). Such high doses may adversely affect the subject being treated.

Summary of The Invention

Provided herein are novel amisulpride derivatives and pharmaceutical compositions thereof. In some examples, the amisulpride derivatives disclosed herein are dopamine and/or 5 serotonin antagonists. In some examples, the amisulpride derivatives disclosed herein have improved membrane (e.g., BBB) permeability as compared to amisulpride. In some examples, the amisulpride derivative may act as a Central Nervous System (CNS) dopamine and/or serotonin antagonist. These amisulpride derivatives have the structure of formula I, formula IA, formula IB or formula IC disclosed herein, 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). Also provided herein are deuterated analogs of the amisulpride derivatives disclosed herein.

Also provided herein are serotonin (e.g., 5-HT2a, 5-HT)₇) A method of delivering a receptor antagonist to the brain of a subject, comprising administering to the subject an amisulpride derivative disclosed herein or a pharmaceutical composition thereof; and serum in brainThe level of the hormone receptor antagonist is higher than amisulpride (racemic mixture) administered to the subject at comparable doses.

Also provided herein are methods for antagonizing serotonin (e.g., 5-HT2a, 5-HT) in a subject₇) A method of receptor comprising administering to a subject amisulpride derivatives and/or R isomers of amisulpride or pharmaceutical compositions thereof as disclosed herein, alone or in combination with other CNS active agents.

Further provided herein are methods of treating a subject responsive to serotonin (e.g., 5-HT2a, 5-HT)₇) A method of one or more conditions of modulation of a receptor comprising administering to a subject amisulpride derivatives and/or R isomers of amisulpride or pharmaceutical compositions thereof disclosed herein, alone or in combination with other CNS active agents.

Still further provided herein are methods for treating one or more disorders associated with abnormal serotonin levels in the brain comprising administering to a subject amisulpride derivatives and/or the R isomer of amisulpride or pharmaceutical compositions thereof disclosed herein, alone or in combination with other CNS active agents.

In response to serotonin (e.g., 5-HT2a, 5-HT)₇) Examples of disorders of the receptor and/or disorders associated with abnormal 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, schizophrenic symptoms, schizoaffective disorders, bipolar disorder, depression, obsessive compulsive disorder, parkinson's disease, alzheimer's disease, oppositional defiant disorder, aggression, suicide, hostility, personality disorders, chronic fatigue syndrome, the major negative symptoms of schizophrenia, charbant syndrome, autism, and tourette's syndrome.

Brief description of the drawings

FIG. 1A: new object exploration data from sub-chronic PCP NOR studies in rats (± SEM, n ═ 10/group). The difference in discriminatory index ((time to explore new object-time to explore familiar object)/total exploration time) is described.

FIG. 1B: differential index data from a subchronic PCRNOR study in rats (n-10/group). The difference in discriminatory index ((time to explore new object-time to explore familiar object)/total exploration time) is described.

FIG. 2: total walking distance (over 1 hour) + SEM (n ═ 10/group). Compared with amphetamine, p is < 0.05 for all treatment groups.

FIG. 3: compounds 102, 103, 104, and amisulpride (101) with 5-HT₇Binding of the receptor.

FIG. 4: amisulpride (ami) (rac)), the R enantiomer of amisulpride (ami (R)), and the S enantiomer of amisulpride (Amid (S)) and 5-HT₇Binding of the receptor.

Detailed Description

As disclosed herein, 4-amino substituted derivatives of amisulpride (also referred to as 4-amino amisulpride derivatives and 4-amino substituted amisulpride derivatives) exhibit improved membrane (e.g., BBB) permeability and can be used to target related receptors in the brain at lower doses than amisulpride, with fewer side effects on the subject being treated than amisulpride. For example, 4-amino substituted amisulpride derivative compound 102 (also known as LB-102, N-methyl amisulpride and 4-methylamino substituted amisulpride derivatives) was prepared (examples 1 and 2) and showed unexpectedly high membrane permeability compared to amisulpride (example 4, 216.7 fold improvement at pH7.4, 87.5 fold improvement at pH 5). Stereoisomers of compound 102 (compound 103 and compound 104) (example 3), as well as other 4-aminoamisulpride derivative compounds 105 to 110, were also prepared. Furthermore, 4-amino substituted amisulpride derivatives were shown to react with dopamine D₂Effective binding of receptors to various CNS receptors (examples 5-7). unexpectedly, 4-amino substituted amisulpride derivatives showed α 2 (e.g., α 2A, α 2B, and α 2C) receptor antagonism (Table 4, example 7), whereas amisulpride showed low affinity for α 2 receptors.4-amino substituted amisulpride derivatives showed 5-HT_2aAntagonism of the receptor (Table 4, example 7), while amisulpride was not found in 5-HT_2aThe receptor has any activity. Furthermore, compound 102 and compound 103 showed recovery of known object exploration in rats in a New Object Recognition (NOR) assay (example 8)The ability to distinguish between new and familiar objects is impaired. Normalized amphetamine overactivity in the amphetamine-induced locomotor activity (LMA) assay, compounds 102 and 103 were statistically superior to or indistinguishable from amisulpride (example 9). Further, stereoisomers of compound 102 (compound 103 and compound 104) are disclosed in combination with 5-HT₇Unexpectedly different Ks were shown in receptor binding_iWherein K of R enantiomer (Compound 104)_iAt 16nM, in contrast to the K of the S enantiomer (Compound 103)_i(> 1,000nM (example 10). Unexpectedly, the R enantiomer of amisulpride showed an unexpectedly lower K than the S enantiomer of amisulpride_i(FIG. 4).

4-amino-substituted amisulpride derivatives

Provided herein are amisulpride derivatives having the structure shown in formula I:

including pharmaceutically acceptable salts and stereoisomers thereof, wherein:

R₁is that

And is

X and Z are the same or different and are independently selected from the group consisting of hydrogen, alkyl (branched or unbranched such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl), alkenyl (branched or unbranched such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl), alkynyl (branched or unbranched such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-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., -CH, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl), and the like₂C₆H₅and-C₂H₅C₆H₅) Hetero aromatic hydrocarbonArylalkyl (e.g., -CH)₂C₆H₄N and-C₂H₅C₆H₄N), and heteroaryl having one or two or three or more heterocyclic atoms (e.g., 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; with the proviso that at least one of X and Z is not hydrogen.

In some examples, the amisulpride derivative is a stereoisomer having the structure of formula I-S:

including pharmaceutically acceptable salts thereof, wherein Z, X, and R₁As defined above in formula I.

In some examples, the amisulpride derivative is a stereoisomer having the structure of formula I-R:

including pharmaceutically acceptable salts thereof, wherein Z, X, and R₁As defined above in formula I.

In some examples, the amisulpride derivative is a 4-amino substituted derivative of amisulpride having the structure of formula IA:

including pharmaceutically acceptable salts and stereoisomers thereof, and X and Z are as defined above in formula I.

In some examples, the 4-amino substituted derivative of amisulpride is a stereoisomer having the structure of formula IA-S:

including pharmaceutically acceptable salts thereof, and X and Z are as defined above in formula I.

In some examples, the 4-amino substituted derivative of amisulpride is an isomer having the structure of formula IA-R:

including pharmaceutically acceptable salts thereof, and X and Z are as defined above in formula I.

In some examples, the amisulpride derivative is a 4-amino substituted derivative of amisulpride having the structure of formula IB:

including pharmaceutically acceptable salts and stereoisomers thereof, and Z is as defined above for formula I, with the proviso that Z is not H.

In some examples, the 4-amino substituted derivative of amisulpride is a stereoisomer having formula IB-S:

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

In some examples, the 4-amino substituted derivative of amisulpride is a stereoisomer having the structure of formula IB-R:

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

In some examples, the amisulpride derivative has the structure of formula IC:

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

In some examples, the amisulpride derivative is a stereoisomer having the structure of formula IC-S:

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

In some examples, the amisulpride derivative is a stereoisomer having the structure of formula IC-R:

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

In some examples, the amisulpride derivatives disclosed herein have greater membrane (e.g., BBB) permeability than amisulpride in some examples, the amisulpride derivatives disclosed herein are dopamine and/or serotonin and/or α 2 antagonists₂And/or D₃Receptor binding. In some examples, dopamine D is compared₁，D₄And/or D₅The receptor, amisulpride derivatives disclosed herein, binds more selectively to dopamine D₂And/or D₃In some examples, the amisulpride derivatives disclosed herein are capable of interacting with dopamine and/or serotonin and/or α 2 receptors in the CNS.

Also provided herein are deuterated analogs of the amisulpride derivatives disclosed herein, wherein one or more hydrogens of the amisulpride derivative are replaced with deuterium. In some examples, one or more of the deuterated analogs are present at a level at least 100 times greater than the natural abundance level.

Provided herein are pharmaceutical compositions comprising one or more of the amisulpride derivatives and deuterated analogs thereof disclosed herein and a pharmaceutically acceptable carrier. In some examples, the pharmaceutical composition comprises one or more amisulpride derivatives that are substantially enantiomerically pure, and such pharmaceutical compositions are also referred to as substantially enantiomerically pure pharmaceutical compositions. In some examples, the term "substantially enantiomerically pure" refers to an 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.

Also provided herein are methods of administering dopamine and/or serotonin (e.g., 5-HT)_2a，5-HT₇) And/or α 2 receptor antagonist, comprising administering to the subject one or more of the amisulpride derivatives and deuterated analogs thereof disclosed herein, or a pharmaceutical composition thereof, and dopamine and/or serotonin (e.g., 5-HT) in the brain_2a，5-HT₇) And/or α 2 receptor antagonist levels are higher than amisulpride (racemic mixture) administered to a subject at comparable doses.

Also provided herein are methods of antagonizing dopamine and/or serotonin (e.g., 5-HT) in a subject_2a，5-HT₇) And/or α 2 receptor, comprising administering to a subject one or more of the amisulpride derivatives disclosed herein and deuterated analogs thereof, the R enantiomer of amisulpride, or pharmaceutical compositions thereof, alone or in combination with a CNS active agent.

Also provided herein are methods for treating a subject responsive to dopamine and/or serotonin (e.g., 5-HT)_2a，5-HT₇) And/or α 2 receptors, comprising administering to a subject a therapeutically effective amount of one or more of the amisulpride derivatives and deuterated analogs thereof disclosed herein, the R enantiomer of amisulpride, or a pharmaceutical composition thereof, alone or in combination with other CNS active agents.

Provided herein are methods 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 deuterated analogs thereof disclosed herein, the R enantiomer of amisulpride, or a pharmaceutical composition thereof. In some examples, the amisulpride derivative, deuterated analog, and/or pharmaceutical composition is substantially enantiomerically pure.

In some examples, the therapeutically effective amount of the amisulpride derivative, the R enantiomer of amisulpride, or the pharmaceutical composition thereof disclosed herein is less than the therapeutically effective amount of amisulpride. Thus, the methods disclosed herein may result in fewer adverse events to the subject being treated.

Responsive to dopamine and/or serotonin (e.g., 5-HT)_2a，5-HT₇) Examples of psychiatric disorders include, but are not limited to, schizophrenia, symptoms of schizophrenia, schizoaffective disorders, depression, obsessive compulsive disorders, Parkinson's disease, Alzheimer's disease, oppositional defiant disorder, aggressiveness, suicidality, hostility, personality disorders, autism, chronic fatigue syndrome, the primary negative symptoms of schizophrenia, Charles Banner syndrome, and Torreya.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "cell" includes a plurality of cells, including mixtures thereof. Similarly, unless the context clearly indicates otherwise, the use of "a compound" in the preparation or treatment of a pharmaceutical formulation described herein includes the use of one or more compounds of the invention to effect such treatment or preparation.

As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but not exclude other elements. Thus, a composition consisting essentially of the elements defined herein does not exclude trace contaminants from isolation and purification processes and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like. Constitute "shall mean excluding trace elements in excess of other ingredients and the essential method steps for administering the compositions of the present invention. Examples defined by each transition term are within the scope of the present invention.

The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, with no unsaturation. Unless otherwise specified, the term "alkyl" refers to a group 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 remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, and sec-pentyl.

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched. Unless otherwise indicated, 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.

The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond. Unless otherwise specified, 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 carbon atoms), such as ethynyl, propynyl, and butynyl.

The term "cycloalkyl" denotes non-aromatic mono-or polycyclic ring systems of 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

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

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅and-C₂H₅C₆H₅。

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

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

The term "heteroaryl" refers to an optionally substituted 5-14 membered aromatic ring having as ring atoms one or more heteroatoms selected from N, O, and S. Heteroaryl groups may be monocyclic, bicyclic or tricyclic ring systems. Examples of such heteroaryl ring radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolinyl, and isoquinolinyl.

The term "heteroarylalkyl" refers to a heteroaryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₄N, and-C₂H₅C₆H₄N。

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

The phrase "effective amount" refers to an amount sufficient to effect such treatment on a disease when administered to a subject or patient to treat the disease.

"treating" or "treating" includes (1) inhibiting the disease (e.g., arresting further development of the condition and/or symptom) in a subject or patient experiencing or presenting with the condition or symptom of the disease, (2) ameliorating the disease (e.g., reversing the condition and/or symptom) in a subject or patient experiencing or presenting with the condition or symptom of the disease, and/or (3) causing any measurable reduction in the disease in a subject or patient experiencing or presenting with the condition or symptom of the disease.

The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause an allergic or other untoward reaction in the patient receiving the administration and is compatible with the other ingredients in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers appropriately selected for the intended form of administration and are in accordance 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., polymethacrylates), calcium carbonate, magnesium oxide, talc, or mixtures thereof. The pharmaceutically acceptable carrier may further comprise minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffering agents, which enhance the shelf-life or effectiveness of the therapeutic agent.

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

The isomers (e.g., geometric isomers, optical isomers, rotamers, tautomers, etc.) of the amisulpride derivatives disclosed herein can be purified as single isomers using conventional separation methods, including, for example, recrystallization, optical resolution such as the diastereomeric salt method, enzymatic fractionation methods, various chromatographic methods (e.g., thin layer chromatography, column chromatography, glass chromatography, etc.).

Pharmaceutical formulations and routes of administration

The amisulpride derivatives and/or deuterated analogs thereof disclosed herein can be administered by a variety of routes including oral administration and injection (e.g., subcutaneous, intravenous, and intraperitoneal). 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, 17 th edition, Alfonso R.Gennaro, Mac Publishing Company (Mack Publishing Company), Pennsylvania, 1985, which is incorporated herein by reference.

The amisulpride derivatives and/or deuterated analogs thereof disclosed herein can be administered orally in the form of solid or liquid dosage forms. In both cases, the amisulpride derivative compounds disclosed herein may be encapsulated in a material to protect them from the action of acids and other natural conditions that may inactivate the compounds. The amisulpride derivatives disclosed herein may be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and tablets (wafers). Oral dosage forms may include excipients known in the art such as binders, disintegrants, flavoring agents, antioxidants, and preservatives. The liquid dosage form may include a diluent, such as saline or an aqueous buffer.

Amisulpride derivatives and/or deuterated analogs thereof disclosed herein can also be administered by injection. Formulations suitable for injection may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical composition may be sterile and may be a liquid to the extent that it is easily injectable. It may be stable under the conditions of manufacture and storage and may prevent 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 (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. For example, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The action of microorganisms can be prevented 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 including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions 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. Typically, dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle that contains a base dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.

The actual dose of the compound administered to the subject may be determined by physical and physiological factors such as age, sex, weight, severity of the condition, type of disease to be treated, previous or concurrent therapeutic intervention, the subject's idiopathy and the route of administration. These factors can be determined by the skilled person. The practitioner responsible for administration will typically determine the concentration of the active ingredient in the composition and the appropriate dosage for the individual subject.

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

Single or multiple doses of the compound are contemplated. The time interval required to deliver multiple doses can be determined by one of ordinary skill in the art using no more than routine experimentation. For example, two doses per day may be administered to a subject at about 12 hour intervals. In some examples, the compound is administered once daily.

The amisulpride derivatives or pharmaceutical compositions thereof disclosed herein may be administered by conventional regimens. As used herein, a conventional protocol refers to a predetermined specified period of time. The conventional schemes may include time periods of the same duration or time periods of different durations, so long as the schemes are predetermined. For example, a conventional regimen may involve dosing twice daily, every second day, every third day, every fourth day, every fifth day, every sixth day, weekly, monthly or any set number of days or weeks in between. Alternatively, the predetermined routine may involve dosing twice daily for the first week, followed by daily dosing for months. In other examples, the amisulpride derivatives disclosed herein or pharmaceutical compositions thereof provided by the invention may be administered orally, with or without timing dependent on food intake. Thus, for example, the medicament may be taken every morning and/or every evening, whenever the subject is or will be eating.

Combination therapy

In addition to being used as monotherapy, the amisulpride derivatives or pharmaceutical compositions thereof disclosed herein may also be used in combination therapy. Effective combination therapy can be achieved with a single pharmaceutical composition or pharmacological formulation comprising two agents administered simultaneously or two different pharmaceutical compositions or pharmacological formulations, wherein one composition comprises a compound of the invention and the other comprises a second agent. Alternatively, treatment may be preceded or followed by other agents and separated by a period of minutes to months.

The additional agent or agents may be selected from any agent or agents useful for treating a psychological disorder, such as any agent or agents useful for treating dopamine, serotonin, histamine, or glutamate imbalance and/or α 2 in one example, additional agents or agents may be useful for improving psychological function, such as antipsychotics, such as quetiapine, clonidine, replanole, lurasidone, olanzapine, risperidone, iloperidone, ziprasidone, clozapine, haloperidol, chlorpromazine, citalopram (citrlopram), escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, venlafaxine, duloxetine, milnacipran, venlafaxine, vilazone, and combinations thereof.

Synthesis of amisulpride derivatives

The amisulpride derivatives disclosed herein of the present invention can be prepared from amisulpride (4-amino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide), which is readily available. The synthesis of amisulpride is described, for example, in us patent No. 4,401,822.

The following syntheses for preparing compounds of formula IB may be adapted to prepare other compounds of the invention, for example, compounds of formulae I, IA, and IC. The compounds of formula IB can be prepared by the following steps: (a) treating amisulpride with a mixture of a carboxylic acid and its corresponding anhydride to obtain the corresponding amide, (b) treating amisulpride with, for example, borane: a suitable reducing agent for dimethyl sulfide reduces the amide to an amine to form a compound of formula IB:

wherein Z is as defined above, and Z ═ C-R.

The reaction scheme is shown below:

scheme 1. preparation of amisulpride derivatives

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

Alternatively, amisulpride is reacted with N, N-dimethylformamide dimethyl acetal to provide the corresponding amide, followed by a reducing agent (e.g., NaBH)₄，DMS：BH₃Red-Al, and LiAlH₄) Reduction to provide the corresponding 4-methylamino-substituted amisulpride derivative, whereby the 4-methylamino-substituted amisulpride derivative can be prepared.

Scheme 2.4 preparation of methylamino-substituted amisulpride derivatives

The stereoisomers of the amisulpride derivatives disclosed herein may be prepared analogously by using the corresponding stereoisomers of amisulpride as starting materials. For example, the synthesis of ((S) -4-amino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide can be performed as described in U.S. patent No. 6,169,094, which is incorporated herein by reference. The S isomer of amisulpride derivatives can be prepared using the S isomer of amisulpride (schemes 3 and 4). The R isomer of amisulpride derivatives can be similarly prepared using the R isomer of amisulpride.

Scheme 3. preparation of amisulpride derivatives (exemplified by the S-isomer)

Scheme 4.4 preparation of methylamino-substituted amisulpride derivatives (S-isomers)

When neither Z nor X of the amisulpride derivative of formula I is hydrogen, amisulpride derivatives (di-substituted 4-aminoamisulpride derivatives) can be prepared by two-step substitution of the 4-amino group. Firstly, as shown above, substituting a first substituent of Z or X for 4-amino to obtain a monosubstituted 4-amino amisulpride derivative; then carrying out secondary substitution on the 4-amino group of the mono-substituted 4-amino amisulpride derivative to obtain the required di-substituted 4-amino amisulpride derivative. See, for example, examples 3C and 3D.

Having described the invention with reference to examples and illustrative examples, those skilled in the art will appreciate that modifications may be made to the invention as described and illustrated without departing from the spirit and scope of the invention as disclosed in the specification. Examples are set forth to aid in understanding the invention, but are not intended to, and should not be construed to, limit its scope in any way. These examples do not include detailed descriptions of conventional methods. These 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 in the following examples are hereby incorporated by reference in their entirety as if fully set forth herein.

Examples of the present invention

Example 1: 4-carboxamide-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzene Synthesis of formamide (Compound 1)

Compound 1

To a solution of 4-amino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (2g, 5.5mmol) in 20mL of formic acid at 5-10 deg.C was added acetic anhydride (0.68g, 6.6mmol) in portions. The reaction mixture was stirred at room temperature overnight and K was poured carefully into the flask at 5-10 deg.C₂CO₃In aqueous solution. Adding solid NaCl, and adding CHCl₃The mixture is extracted. With Na₂SO₄The combined organic extracts were dried overnight and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CHCl₃5-10% of MeOH to give 1.82g (83%) of a yellow gum.¹HNMR(400MHz，CDCl₃)：δ1.1(t，3H，CH₃)，1.3(t，3H，CH₃)1.6(br s，2H)，1.7(br s，2H)，1.9(brs，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)₁₈H₂₇N₃O_sS]: 397.2, observed molar weight 398.1[ M + H ]⁺]。

Example 2: 4-methylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzene Synthesis of formamide (Compound 102)

Compound 102

To a solution of 4-carboxamide-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (compound 1, 1.82g, 4.6mmol) in 80mL THF at 5-10 deg.C was added BH portionwise₃·Me₂S (1.09mL, 11.5 mmol). The reaction mixture was stirred at 60 ℃ for 3h and carefully quenched by MeOH (40 mL). The reaction mixture was acidified with 10% HCl (15mL) and the mixture was stirred at 60 ℃ overnight. The solvent is evaporated under reduced pressure and the aqueous residue is taken up with H₂Diluted with O and basified with aqueous NaOH to pH 10. With CHCl₃Extracting the mixture with Na₂SO₄The combined organic extracts were dried and evaporated. The residue was purified by column chromatography on silica gel using CHCl₃Eluted with 5-10% MeOH, then purified by RP-HPLC using MeCN-H₂Elution with an O + 0.1% TFA gradient. The fractions containing the target substance were partially evaporated under reduced pressure, basified to pH10 with aqueous NaOH solution and diluted with CH₂C1₂And (4) extracting. The combined extracts were extracted with Na₂SO₄Dried and evaporated under reduced pressure to give the product as a white solid,after storage and standing, the mixture was solidified (0.93g, 53%).¹H NMR(400MHz，CDCl₃)：δ1.1(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).¹³C NMR(75MHz，CDCl₃): 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 weight [ C₁₈H₂₉N₃O₄S]: 383.2, observed molar weight 384.5[ M + H⁺]。

Example 3: stereoisomers of compound 102 (compounds 103 and 104), and 4-Aminosulpride derivatives Compounds 105 to 110).

A) The method comprises the following steps Synthesis of ((S) -4-methylamino N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 103)

((S) -4-amino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (11.1g) was suspended in N, N-dimethylformamide dimethyl acetal (33mL) and stirred at 90 ℃ for 2 h. The reaction mixture was cooled to room temperature and NaBH was added portionwise₄(4g) In that respect The mixture was stirred at room temperature for 1 h. Addition of saturated NaCHO₃(50mL) to quench the reaction and extract the resulting suspension with dichloromethane (2X50 mL). The organic phase was washed with brine, dried, filtered and the solvent removed under reduced pressure. Purifying the residue by column chromatography with CH₂C1₂/MeOH/NH₃The elution gave the product as a white solid which was further purified by recrystallization from acetone (5.3 g).

¹H 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).¹³C 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 [ C₁₈H₂₇N₃O₄S]383.2, observed molar weight 384.4[ M + H⁺]。

B) The method comprises the following steps Synthesis of ((R) -4-methylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 104)

((S) -4-amino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (11.2g) was suspended in N, N-dimethylformamide dimethyl acetal (33mL) and stirred at 90 ℃ for 2 hours. The temperature was lowered to 70 ℃ and NaBH was added in an amount of 1g per batch at 20 minute intervals₄(4g) In that respect After the addition was complete, the reaction mixture was further stirred at 90 ℃ for 1 hour. The reaction mixture was cooled in an ice bath and purified by addition of 150mL of saturated NaHCO₃To quench the reaction. By CH₂Cl₂(5X50mL) the resulting solution was extracted and the combined organic extracts were washed with Na₂SO₄And drying. Purification was by column chromatography with 10% MeOH/CH₂Cl₂Elution afforded 7.9g of a white solid.

¹H NMR(300MHz，CDCl₃)：δ1.2(t，3H，CH₃)，1.3(t，3H，CH₃)，1.7(m，1H)1.8(m，2H)，1.9(m，1H)，2.3(m，2H)，2.7(m，1H)，2.9(m，1H)，2.9(d，1H)，3.1(q，2H)，3.3(m，2H)，3.7(m，1H)，4.0(s，3H，OCH₃)，6.1(s，1H_ar)，6.8(m，1H_ar) 8.1(m, 1H, NH), 8.6(s, 1H, NH)₁₈H₂₇N₃O₄S]383.2, observed molar weight 384.2[ M + H [)⁺]。

C) The method comprises the following steps Synthesis of (4-dimethylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 105)

4-methylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (500mg) was stirred in 10mL of formic acid at 30 ℃ for 21h while NaBH₄(8 eq) was added in two portions and washed with aqueous NaOH to give 408mg of compound 105.

¹H NMR(400MHz，CDCl₃)：δ1.2(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).¹³C NMR(100MHz，CDCl₃): 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 weight [ C₁₉H₃₁N₃O₄S]397.2, observed molar weight 398.2[ M + H ]⁺]。

D) The method comprises the following steps Synthesis of (4-ethylmethylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 106)

4-methylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (500mg) was stirred in 6mL of 1, 2-dichloromethane, sodium triacetoxyborohydride (1g) and acetaldehyde (219uL) were added and stirred at room temperature for 17 hours. The reaction was quenched by addition of aqueous NaOH, and the product was extracted into dichloromethane and purified by column chromatography to afford 98mg of compound 106.

¹H NMR(400MHz，CDCl₃)：δ1.2(m，6H，2CH_3s)，1.6(m，1H)，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).¹³C NMR(100MHz，CDCl₃)：δ7.36，12.84，23.00，28.42，41.27，42.99，48.12，52.30，53.70，56.16.106.05，126.41，130.05，142.41，157.554，157.54，161.48, 163.90 expected molar weight [ C ]₂₀H₃₃N₃O₄S]411.3, observed molar weight 412.3[ M + H [)⁺].

E) The method comprises the following steps Synthesis of (4-ethylamino N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 107)

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

¹H NMR(400MHz，CDCl₃)：δ1.1(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(100MHz，CDCl₃): 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 weight [ C₁₉H₃₁N₃O₄S]397.2, observed molar weight 398.2[ M + H ]⁺]。

F) The method comprises the following steps Synthesis of (4-isopropylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 108)

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

¹H NMR(400MHz，CDCl₃)：δ1.1(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).¹³C NMR(100MHz，CDCl₃): 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 weights [ C₂₀H₃₃N₃O₄S]411.2, observed molar weight 412.2[ M + H [)⁺]。

G) The method comprises the following steps Synthesis of (4-N-propylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 109)

(Ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (500mg) was stirred in 6mL of 1, 2-dichloroethane and 0.3mL of propionaldehyde. Sodium triacetoxyborohydride (1.2g) 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 518mg of compound 109.

¹H NMR(400MHz，CDCl₃)：δ1.1(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).¹³C NMR(100MHz，CDCl₃): 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 weights [ C₂₀H₃₃N₃O₄S]411.2, observed molar weight 412.2[ M + H [)⁺]。

H) The method comprises the following steps Synthesis of (4-benzylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide (Compound 110)

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

¹H NMR(400MHz，CDCl₃)：δ1.2(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).¹³C NMR(100MHz，CDCl₃): 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 the expected molar weight [ C₂₄H₃₃N₃O₄S]459.2, observed molar weight 460.2[ M + H [)⁺]。

Example 4: membrane permeability of Compound 102

The membrane permeability of 4-methylamino-N- ((1-ethyl-2-pyrrolidinyl) methyl) -5- (ethylsulfonyl)) -2-methoxybenzamide) (compound 102) was determined by using the PAMPA assay at pH5 and 7.4. Specifically, 10mM control ranitidine solutions (3.5 mg in 1mL DMSO), propanol (2.9 mg in 1mL DMSO), N-methyl amisulpride (3.3 mg in 0.8mL DMSO), and amisulpride (3.4 mg in 0.9mL DMSO) were prepared. Diffusion across the Pion PAMPA membrane was measured at pH5 and pH7.4, as shown in table 1, respectively.

Table 1: the permeability of compound 102, amisulpride, propranolol, and ranitidine across PAMPA membranes at pH5 and 7.4.

Example 5: binding of Compound 102 to the dopamine D2 receptor (cell-based assay)

Determination of Compound 102 binding to dopamine D in cell-based assays₂The ability of the receptor. Mixing dopamine D₂Recipient cells were seeded in a 96-well plate with a semi-black clear bottom. At a density of 15,000 cells/well to a volume of 25 μ L, it was incubated overnight. A solution of calcium 5 dye in HEPES-buffered HBSS (Hanks' balanced salt solution) was prepared and 10. mu.L was added to each well and the mixture was allowed to stand at 37 ℃ for 1 hour. After equilibration, 5 μ L of test compound and control were added to the wells and incubated at room temperature for 10 minutes. Fluorescence was measured every 1.52 seconds. After 20 seconds 10. mu.L of dopamine (in EC) was added₈₀At concentration), fluorescence was monitored for 2 minutes with an excitation wavelength of 452nm and an emission wavelength of 525 nm. Cell-based IC of Compound 102₅₀Value and known dopamine D₂The inhibitors risperidone, amisulpride and clozapine are collectively listed in table 2.

Table 2: compound 102, risperidone, amisulpride, and clozapine relative to dopamine D₂IC of receptor₅₀Values (cell-based assays).

₂Example 6: binding of Compound 102 to dopamine D receptor (membrane preparation)

Examination of Compound 102 binding to dopamine D in Membrane preparation₂The ability of the receptor. From dopamine D₂Recipient cells were removed from the medium and washed with PBS. Lysis buffer (250mM sucrose, 1nM EDTA, 10mM Tris HCl buffer pH7.2 plus protease inhibitor) was added and the cells were scraped off using a plate scraper. Cells were homogenized in a glass homogenizer by 20 manual up-and-down strokes. Removing intact cells, nuclei, and cell debris by centrifuging the homogenate at 500Xg for 10 minutes at 4 deg.C, removing the supernatant, andthe particles were resuspended in assay buffer.

Preparing a film with³H-spiperone is incubated together until equilibrium. The bound product was separated from free radioligand using a Packard Filtermate Harvester and glass filter plates. Radioactivity was measured using a Packard Topcount. 20 μ L of D ₂20 μ L in binding buffer in membrane and non-binding 96-well plates³H spiroperone was mixed with 10. mu.L of test compound or reference ligand and incubated < 120 min. 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 a filter plate and washed three times with wash buffer, dried, added with scintillator, and counted for radioactivity on Topcount NXT.

0.1nM at concentrations of 1000, 100, 10, 1, 0.1, and 0.01nM are used³ Compound 102, risperidone, amisulpride and clozapine were tested in triplicate for H spiroperone. IC of the film-based assay₅₀The values are shown in table 3.

Table 3: compound 102, risperidone, amisulpride, and clozapine relative to dopamine D₂IC of receptor₅₀Values (membrane based test).

_{2 3}Example 7 compounds 102 and 103 are useful as antagonists of various CNS receptors (dopamine D, α 2 epinephrine, _2aand 5-HT receptor) (Table 4)

Compounds 102 and 103 bind α₂(non-Selective), α_2A，α_2B，α_2C，5-HT_2A(agonists), 5-HT_2A(antagonists) D_2L，D_2sAnd D₃The ability of (2) is at 10X 10^-5To 10X 10^-9M concentration range, and the replacement of the reference ligand binding to each individual receptor (prazosin for α)₂(non-Selective), yohimbine for α_2A，α_2BAnd α_2CDOI ([2, 5-dimethoxy)Radical-4-iodophenyl]-2-aminopropane) for 5-HT_2A(agonists), ketanserin for 5-HT_2A(antagonists) of butalamol for D_2L7-OH-DPAT for D_2SAnd (+) butalamol for D₃). The inhibition data are reported in table 4.

Table 4: IC50 and Ki values for compound 102(LB102) and compound 103(LB103) relative to various CNS receptors in cell-based assays.

Example 8: new object identification (NOR) assays demonstrate the utility of Compounds 102 and 103

The utility of compounds 102 and 103 was evaluated in rats in a New Object Recognition (NOR) assay, a well-known model that recapitulates the cognitive and negative aspects of the PANSS scale of schizophrenia. In this experiment, animals were treated for several weeks with low doses of phencyclidine (PCP) to impair the ability of rats to discriminate between new and familiar objects. Generally, like humans, rats spend more time exploring a new object than familiar objects. The utility in this study is demonstrated by the ability of the test treatment to restore normal brain function, shown by reversal of PCP damage.

In this NOR study, the utility of compounds 102 and 103 was compared to the known antipsychotic drugs amisulpride and risperidone to evaluate the normal differentiation between new and familiar object exploration in rats that restored PCP treatment. Rats (n-10/group) were dosed intraperitoneally twice daily with 2mg/kg (i.p., b.i.d.) for 7 days, followed by 7 days without drug. Cognitive assays were performed at 3 hours after administration of compounds 102, 103, and amisulpride, and at 30 minutes after administration of risperidone, under various PO dosing test agents. The time to explore new objects was determined for test subjects in a subchronic PCP NOR study (n-10/group) performed on rats. The difference in exploration time between the new (Tnovel-) and familiar (Tfoamiar) objects is shown in FIG. 1A (: p < 0.05; and: p < 0.01). Fig. 1B shows the discrimination index of the NOR study obtained by equation 1 below:

identification index ═ (time spent exploring new object-time spent exploring familiar object)/total exploration time) (equation 1)

Figures 1A and 1B show that all doses of compounds 102(Cpd 102) and 103(Cpd 103), except one, add to the difference between new and familiar object exploration times in a manner consistent with the currently used antipsychotic drugs amisulpride and risperidone.

In the NOR study shown in figures 1A and 1B, compounds 102 and 103 were able to restore the known object-finding behavior in rats treated with PCP to a level similar to that of untreated rats and to an equivalent level to the values obtained with the known antipsychotic drugs amisulpride and risperidone.

Example 9: amphetamine-induced locomotor activity (LMA) assay shows the utility of compounds 102 and 103

The utility of compounds 102 and 103 was studied in rats in the amphetamine-induced locomotor activity (LMA) assay, which is a measure of the positive aspect of the PANSS scale. In the LMA assay, rats were given amphetamine (Amp, 1mg/kg, s.c.) causing excessive movement, and the distance each rat traveled was monitored in a cage with a sensor. Rats given amphetamine alone tend to show hyperactivity, whereas rats given antipsychotic drugs show more normal, calmer activity.

In this LMA study, compounds 102(Cpd 102, 30mg/kg) and 103(Cpd 103, 30mg/kg), amisulpride (30mg/kg) and risperidone (1mg/kg) were administered orally in groups of 10 rats. Amisulpride-risperidone was administered 6 hours after administration of compounds 102 and 103 and 1 hour before the assay, and the distance traveled within one hour was determined. The endpoint of the study was the total walking distance (the distance each animal traveled in the cage). The total walking distance data from this amphetamine-induced LMA study is summarized in figure 2 (: p < 0.01;: p < 0.05).

In the LMA study in rats, as shown in figure 2, the normalized amphetamine overactivity of compound 102(Cpd 102) was statistically superior to amisulpride (p < 0.05), and the normalized amphetamine overactivity of compound 103(Cpd 103) was statistically indistinguishable from amisulpride (p < 0.01).

Example 10: compounds 102, 103, and 104 with 5-HT₇Binding of receptors

At 1X 10^-7To 3X 10^-10Measuring binding of Compounds 102, 103, and 104 to 5-HT at concentration ranges of M₇And measuring the ability of the calcium-sensitive fluorescent indicator to express 5-HT₇Replacement in the cell of (1). From this experiment, K was found for compound 102(LB-102, filled circle, dotted line B, FIG. 3)_iAt 31nM, and amisulpride (LB101, filled circle, dotted line A, FIG. 3) at 106 nM. Compound 103 (the S enantiomer of compound 102) was unexpectedly a stronger conjugate (binder) to the dopamine receptor than compound 104 (the R enantiomer of compound 102), the binding of compound 104 (the R enantiomer of compound 102) providing a K of 16nM_i(LB104, filled circle, dotted line D, FIG. 3), and K for compound 103 (S enantiomer of compound 102) (LB103, filled triangle, dotted line C, FIG. 3)_iIs > 1,000 nM. Unexpectedly, the R enantiomer of amisulpride (ami) (R), filled circle, dotted line a, fig. 4) shows a lower K than the S enantiomer of amisulpride (ami (S), filled circle, dotted line C, fig. 4)_i. K of racemic mixture of amisulpride (amic (rac), filled circle, dotted line B, FIG. 4)_iLess than the R enantiomer of amisulpride but greater than the S enantiomer of amisulpride.

Reference to the literature

The references listed below and all references cited in the specification are hereby incorporated by reference in their entirety as if fully set forth herein.

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Claims (27)

1. A method of antagonizing one or more serotonin receptors in a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure shown in formula I and/or the R isomer of amisulpride, alone or in combination with other CNS active agents:

including pharmaceutically acceptable salts and stereoisomers thereof, wherein:

R₁is that

And

x and Z are the same or different and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl, optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl are further substituted with one or more substituents selected from halogen such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, and other alkyl and aryl groups defined herein; with the proviso that at least one of X and Z is not hydrogen.

2. A method of treating one or more conditions responsive to modulation of one or more serotonin receptors in a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure shown in formula I and/or the R isomer of amisulpride, either alone or in combination with other CNS active agents:

including pharmaceutically acceptable salts and stereoisomers thereof, wherein R₁Is that

And X and Z are the same or different and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl, optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl are further substituted with one or more substituents selected from halogen such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, and other alkyl and aryl groups defined herein; with the proviso that at least one of X and Z is not hydrogen.

3. A method of treating one or more disorders associated with abnormal serotonin levels in the brain of a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure shown in formula I and/or the R isomer of amisulpride, alone or in combination with other CNS active agents:

including pharmaceutically acceptable salts and stereoisomers thereof, wherein:

R₁is that

And

x and Z are the same or different and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl, optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl are further substituted with one or more substituents selected from halogen such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, and other alkyl and aryl groups defined herein; with the proviso that at least one of X and Z is not hydrogen.

4. The method of any one of claims 1-3, wherein the compound is a stereoisomer having a structure represented by formula I-S:

including pharmaceutically acceptable salts thereof.

5. The method of any one of claims 1-3, wherein the compound is a stereoisomer having a structure represented by formula I-R:

including pharmaceutically acceptable salts thereof.

6. The method of any one of the preceding claims, wherein R₁Is that

7. The method of any one of the preceding claims, wherein R₁Is that

8. The method of any one of the preceding claims, wherein X and Z are the same or different and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, and heteroaryl, optionally further substituted with one or more substituents selected from halogen such as chloro, bromo, and fluoro, amine, hydroxy, carboxylic acid, nitro, carbonyl, and other alkyl and aryl groups defined herein; with the proviso that at least one of X and Z is not hydrogen.

9. A compound according to any preceding claim, wherein X is H.

10. A compound as claimed in any one of the preceding claims, wherein X ═ H and Z ═ CH₃。

11. The method of any of the preceding claims, wherein the disorder or condition is a psychiatric disease.

12. The method of claim 11, wherein the psychiatric disorder is schizophrenia.

13. The method of any one of the preceding claims, wherein the method further comprises administering to the subject a therapeutically effective amount of another agent.

14. The method of any of the preceding claims, wherein the disorder or condition is depression.

15. The method of any of the preceding claims, wherein the disorder or condition is bipolar disorder.

16. The method of any of the preceding claims, wherein the disorder or condition is tourette's syndrome.

17. The method of any of the preceding claims, wherein the disorder or condition is a schizoaffective disorder.

18. The method of any one of the preceding claims, wherein the disorder or condition is Parkinson's disease.

19. The method of any one of the preceding claims, wherein the disorder or condition is alzheimer's disease.

20. The method of any one of the preceding claims, wherein the disorder or condition is an oppositional defiant disorder.

21. The method of any of the preceding claims, wherein the disorder or condition is personality disorder.

22. The method of any of the preceding claims, wherein the disorder or condition is childhood schizophrenia.

23. The method of any of the preceding claims, wherein the disorder or condition is dysthymia.

24. The method of any of the preceding claims, wherein the disorder or condition is refractory schizophrenia.

25. The method of any one of the preceding claims, wherein the serotonin receptor is 5-HT_2aOr 5-HT₇A receptor.

26. The method of any of the preceding claims, wherein the disorder or condition is chronic fatigue syndrome.

27. The method of any of the preceding claims, wherein the disorder or condition is predominantly a negative symptom of schizophrenia.

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