TW202023540A - Psychotropic agents and uses thereof - Google Patents

Abstract

The R enantiomer of amisulpride and amisulpride derivative disclosed herein or a pharmaceutical composition thereof may be used for antagonizing serotonin (e.g., 5-HT2a, 5-HT7) receptor in a subject, either individually or in combination with one or more other CNS active agents. The R enantiomer of amisulpride and amisulpride derivative disclosed herein or a pharmaceutical composition thereof may be used for treating one or more conditions responsive to modulation of serotonin (e.g., 5-HT2a, 5HT7) receptor in a subject, either individually or in combination with one or more other CNS active agents. The R enantiomer of amisulpride and amisulpride derivative disclosed herein or a pharmaceutical composition thereof may be used for treating one or more disorders associated with an abnormality in levels of serotonin in the brain, either individually or in combination with one or more other CNS active agents.

Description

Psychotropics and their uses

This patent application requests the benefit of U.S. Provisional Application No. 62/734,974 filed on September 21, 2018, which is incorporated herein by reference in its entirety.

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

Schizophrenia is a chronic debilitating mental illness that affects approximately 1% of the population. This disease manifests as delusional behavior, dysfunctional thinking, agitated body movements, social withdrawal, and depression. Patients with schizophrenia suffer from extremely reduced quality of life and are ten times more likely to commit suicide than the general population.

Dopamine (especially D ₂ and D ₃ ) antagonists are recognized to improve 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 mental illnesses, benefits from the participation of multiple receptors including serotonin receptors and adrenaline receptors. Even so, in fact, dozens of drugs approved for the treatment of schizophrenia still have poor therapeutic effects in many patients. Side effects of existing drugs include: movement disorders, loss of calm, 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) It is an antipsychotic drug patented in 1981. Amisulpride selectively binds to human dopamine D ₂ (K _i 2.8 nM) and D ₃ (K _i 3.2 nM) receptor subtypes, but does not have any effect on D ₁ , D ₄ , and D ₅ receptor subtypes. Affinity. Unlike typical and atypical neuroleptics, amisulpride shows low affinity for serotonin, α-adrenergic, histamine receptor subtypes, muscarinic receptors, and sigma sites, although it is also Proven to bind to 5-HT _2B and HT _7a receptors with low double-digit nM K _i . The ability of amisulpride to bind to 5-HT receptors is thought to enable amisulpride to treat the symptoms of depression (sometimes manifested in patients with schizophrenia). Interestingly, compared with other antipsychotic drugs, amisulpride has not been found to have any activity on 5-HT _2a receptors.

Although amisulpride has a unique activity, amisulpride has a low ability to cross the blood-brain barrier (BBB) to interact with receptors in the brain. In a 2014 study, the passive diffusion of amisulpride across the PAMPA membrane (P _e ) was the lowest among the 30 psychiatric drugs tested. Therefore, the dose of amisulpride is very high, usually 400 to 800 mg/d (although, up to 1,200 mg/day is not uncommon). Such a high dose may adversely affect the subjects receiving treatment.

Provided herein are amisulpride derivatives and pharmaceutical compositions thereof. In some examples, the amisulpride derivatives disclosed herein are dopamine and/or serotonin 5 antagonists. In some examples, the amisulpride derivatives disclosed herein have improved membrane (eg, BBB) permeability compared to amisulpride. In some examples, amisulpride derivatives can act as central nervous system (CNS) dopamine and/or serotonin antagonists. These amisulpride derivatives have the structures of formula I, formula IA, formula IB or formula IC disclosed herein, including their pharmaceutically acceptable salts, and their stereoisomers (for example, formula IS, formula IR, 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 amisulpride and the deuterated analogs of amisulpride derivatives disclosed herein.

Also provided herein is a method for delivering a serotonin (eg, 5-HT _2a , 5-HT ₇ ) receptor antagonist to the brain of a subject, including administering to the subject the amisulpride derivative disclosed herein or its Pharmaceutical composition; and the level of serotonin receptor antagonist in the brain is higher than that of amisulpride (racemic mixture) administered to the subject at a comparable dose.

Also provided herein are methods for antagonizing serotonin (eg, 5-HT _2a , 5-HT ₇ ) receptors in a subject, including methods for antagonizing receptors alone or in combination with one or more other CNS active agents The subject administers one or more R enantiomers selected from the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein (for example, 4-amino The R enantiomer of a substituted amisulpride derivative), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of amisulpride derivative disclosed herein , Or a pharmaceutical composition comprising the one or more R enantiomers. In some examples, the one or more R enantiomers are substantially enantiomerically pure.

Also provided herein are methods for modulating 5-HT ₇ receptors in a subject, comprising administering to the subject one or more R enantiomers alone or in combination with one or more other CNS active agents The R enantiomer is selected from the R enantiomer of amisulpride, the R enantiomer of the amisulpride derivative disclosed herein (for example, the R pair of a 4-amino-substituted amisulpride derivative Enantiomers), the R enantiomer of the deuterated analog of amisulpride, and the R enantiomer of the deuterated analog of amisulpride derivatives disclosed herein, or comprise the one or more R pairs Enantiomer pharmaceutical composition. In some examples, the one or more R enantiomers are substantially enantiomerically pure.

Provided herein are methods for modulating both D _2/3 and 5-HT ₇ receptors in a subject, including administering to the subject alone or in combination with one or more other CNS active agents Or a plurality of R enantiomers, the R enantiomer selected from the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein (e.g., 4-amino substituted sulfonamide R enantiomer of amisulpride derivatives), R enantiomer of deuterated analogues of amisulpride, and R enantiomer of deuterated analogues of amisulpride derivatives disclosed herein, or containing all Said pharmaceutical composition of one or more R enantiomers. In some examples, the one or more R enantiomers are substantially enantiomerically pure.

Provided herein are further methods for treating one or more disorders that are responsive to the modulation of dopamine and/or serotonin (eg, 5-HT _2a , 5-HT ₇ ) and/or α2 receptors in a subject, including the Or in combination with one or more other CNS active agents, a therapeutically effective amount of one or more R enantiomers is administered to the subject, wherein the R enantiomer is selected from the R enantiomer of amisulpride, herein The R enantiomer of the disclosed amisulpride derivative (for example, the R enantiomer of a 4-amino-substituted amisulpride derivative), the R enantiomer of a deuterated analogue of amisulpride, and The R enantiomer of the deuterated analog of amisulpride derivatives disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers. In some examples, the one or more R enantiomers are substantially enantiomerically pure. In some examples, the one or more conditions are responsive to modulation of the 5-HT ₇ receptor (eg, without limitation, anxiety, depression, migraine, and obsessive-compulsive disorder). ^15-21

Provided herein is a method for treating one or more disorders associated with abnormal levels of dopamine and/or serotonin in the brain of a subject, including treating a subject alone or in combination with one or more other CNS agents Administering a therapeutically effective amount of one or more R enantiomers selected from the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein (for example, R enantiomer of 4-amino-substituted amisulpride derivatives), R enantiomer of deuterated analogs of amisulpride, and R of deuterated analogs of amisulpride derivatives disclosed herein Enantiomers, or pharmaceutical compositions comprising the one or more R enantiomers. In some examples, the one or more R enantiomers and/or pharmaceutical compositions comprising one or more R enantiomers are substantially enantiomerically pure. In some examples, the one or more disorders are selected from anxiety, depression, migraine, and obsessive-compulsive disorder.

As disclosed herein, 4-amino-substituted derivatives of amisulpride (also known as 4-amino-aminosulpride derivatives and 4-amino-substituted amisulpride derivatives) show improved membranes (eg, BBB ) Permeability and can be used at lower doses than amisulpride to target related receptors in the brain, and compared with amisulpride, it has fewer side effects on subjects receiving treatment. For example, the 4-amino-substituted amisulpride derivative compound 102 (also known as LB-102, N-methyl amisulpride, the N-methylated analog of amisulpride, and 4- Methylamino-substituted amisulpride derivatives) (examples 1 and 2) and compared with amisulpride (example 4, 216.7 times improvement at pH 7.4 and 87.5 times improvement at pH 5) showed unexpected High membrane permeability. The stereoisomer of compound 102 (the S enantiomer of compound 102 (compound 103) and the R enantiomer of compound 102 (compound 104)) (Example 3) and other 4-aminosulpride derivatives were also prepared. Compounds 105 to 110. In addition, 4-amino-substituted amisulpride derivatives showed effective binding to dopamine D ₂ receptors and various CNS receptors (Examples 5-7). Unexpectedly, 4-amino-substituted amisulpride derivatives showed α2 (for example, α2A, α2B, and α2C) receptor antagonism (Table 4, Example 7), while amisulpride had an effect on α2 receptors. Shows low affinity. The 4-amino-substituted amisulpride derivative showed 5-HT _2a receptor antagonism (Table 4, Example 7), but amisulpride was not found to have any activity on the 5-HT _2a receptor. In addition, compound 102 and compound 103 in the new object recognition (NOR) test (Example 8) showed recovery of known object exploration behavior in rats, and the ability to distinguish between new and familiar objects was impaired. In the amphetamine-induced motor activity (LMA) test, the standardized amphetamine overactivity of compounds 102 and 103 was statistically superior to or indistinguishable from amisulpride (Example 9). Furthermore, the stereoisomers of compound 102 (compound 103 and compound 104) showed unexpectedly different K _i in binding to the 5-HT ₇ receptor, in which the R enantiomer of compound 102 (compound 104) the K _i of 16 nM, in contrast, the compound of the enantiomer S 102 (compound 103) K _i> 1,000 nM (example 10). Surprisingly, amisulpride the R enantiomer shows unexpected amisulpride ratio S of the lower K _i (FIG. 4) enantiomer. Stereoisomers of the compounds (Compound 103 and Compound 104) 102 displays different K _i in conjunction with D ₂ receptor, wherein the compound of R 102 K _i enantiomer (Compound 104) was 14.1 ± 2.2 nM In contrast, the K _i of the S enantiomer of compound 102 (compound 103) is 0.4 ± 0.04 nM (Example 11, Figure 5B). Compound 102 (LB-102) binds to D ₂ receptor with a K _i of 0.82 ± 0.02 nM (Example 11, Figure 5B), and amisulpride (LB-101) binds to D ₂ receptor with a K _i of 1.1 ± 0.12 nM (Example 11, Figure 5A). 4- amino substituted amisulpride derivative

式I 包括其藥學上可接受的鹽和立體異構體，其中： R₁ 是

或

；且 X和Z相同或不同，並且獨立地選自氫，烷基（分支或未分支，如甲基，乙基，正丙基，異丙基，正丁基，和仲丁基），烯基（分支或未分支，如甲基，乙基，正丙基，異丙基，正丁基，和仲丁基），炔基（分支或未分支，如甲基，乙基，正丙基，異丙基，正丁基，和叔丁基），環烷基（例如環丙基，環丁基，環戊基，和環己基），環烷基烷基（例如環丙基甲基，環丁基乙基，和環戊基乙基），雜環基，雜環基烷基，芳基（例如苯基，萘基，四氫萘基，茚滿基，和聯苯基），芳烷基（例如-CH₂ C₆ H₅ 和-C₂ H₅ C₆ H₅ ），雜芳基烷基（例如-CH₂ C₆ H₄ N和-C₂ H₅ C₆ H₄ N），以及具有一個或兩個或三個或更多個雜環原子的雜芳基（如吡啶，吡咯，呋喃，噻吩，或嘧啶），任選地烷基，烯基，炔基，環烷基，環烷基烷基，雜環基，雜環基烷基，芳基，芳烷基，雜芳基烷基，和雜芳基進一步被一或多個取代基取代，所述取代基選自諸如氯，溴，和氟的鹵素，胺，羥基，羧酸，硝基，羰基，和其它本文定義的烷基和芳基；前提條件是X和Z中至少有一個不是氫，並且當R₁ 為

時，R₁ 可由如下所示的「*」標記的任意位置進行鍵合：

。Amisulpride derivative having the structure shown in formula I is provided here:

Formula I includes its pharmaceutically acceptable salts and stereoisomers, wherein: R ₁ is

or

And X and Z are the same or different, and are independently selected from hydrogen, alkyl (branched or unbranched, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl), alkene Group (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 (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), cycloalkylalkyl (such as cyclopropylmethyl, Cyclobutylethyl, and cyclopentylethyl), heterocyclyl, heterocyclylalkyl, aryl (such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl), aromatic Alkyl (eg -CH ₂ C ₆ H ₅ and -C ₂ H ₅ C ₆ H ₅ ), heteroarylalkyl (eg -CH ₂ C ₆ H ₄ N and -C ₂ H ₅ C ₆ H ₄ N) , And heteroaryl groups with 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 by one or more substituents selected from Halogens such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, and other alkyl and aryl groups as defined herein; provided that at least one of X and Z is not hydrogen, and when R ₁ for

When, R ₁ can be bonded at any position marked with "*" as shown below:

.

式I-S 包括其藥學上可接受的鹽，其中Z，X，和R₁ 與式I中的上述限定相同。In some examples, amisulpride derivatives are stereoisomers with the structure of formula IS:

Formula IS includes its pharmaceutically acceptable salts, wherein Z, X, and R ₁ are the same as defined above in Formula I.

式I-R 包括其藥學上可接受的鹽，其中Z，X，和R₁ 與式I中的上述限定相同。In some examples, the amisulpride derivative is a stereoisomer with a structure of formula IR:

Formula IR includes its pharmaceutically acceptable salts, wherein Z, X, and R ₁ are the same as defined above in Formula I.

式IA 包括其藥學上可接受的鹽和立體異構體，且X和Z與式I中的上述限定相同。In some examples, the amisulpride derivative is a 4-amino substituted derivative of amisulpride and has the structure of formula IA:

Formula IA includes its pharmaceutically acceptable salts and stereoisomers, and X and Z are the same as defined above in Formula I.

式IA-S 包括其藥學上可接受的鹽，且X和Z的限定與式I中的上述限定相同。In some examples, the 4-amino substituted derivative of amisulpride is a stereoisomer with the structure of formula IA-S:

Formula IA-S includes its pharmaceutically acceptable salts, and the definitions of X and Z are the same as the above definitions in formula I.

式IA-R 包括其藥學上可接受的鹽，且X和Z與式I中的上述限定相同。In some examples, the 4-amino substituted derivative of amisulpride is an isomer with the structure of formula IA-R:

Formula IA-R includes its pharmaceutically acceptable salts, and X and Z are the same as defined above in Formula I.

式IB 包括其藥學上可接受的鹽和立體異構體，且Z與式I的上述限定相同，前提條件是Z不為H。In some examples, the amisulpride derivative is a 4-amino substituted derivative of amisulpride and has the structure of formula IB:

Formula IB includes its pharmaceutically acceptable salts and stereoisomers, and Z is the same as the above definition of Formula I, provided that Z is not H.

式IB-S 包括其藥學上可接受的鹽，且Z與式I中的上述限定相同，前提條件是Z不為H。In some examples, the 4-amino substituted derivative of amisulpride is a stereoisomer of formula IB-S:

Formula IB-S includes its pharmaceutically acceptable salts, and Z is the same as the above definition in Formula I, provided that Z is not H.

式IB-R 包括其藥學上可接受的鹽，且Z與式I中的上述限定相同，前提條件是Z不為H。In some examples, the 4-amino substituted derivative of amisulpride is a stereoisomer with the structure of formula IB-R:

Formula IB-R includes its pharmaceutically acceptable salts, and Z is the same as the above definition in Formula I, provided that Z is not H.

式IC 包括其藥學上可接受的鹽和立體異構體，且Z與式I中的上述限定相同，前提條件是Z不為H。In some examples, amisulpride derivatives have the structure of formula IC:

Formula IC includes its pharmaceutically acceptable salts and stereoisomers, and Z is the same as the above definition in Formula I, provided that Z is not H.

式IC-S 包括其藥學上可接受的鹽，且Z與式I中的上述限定相同，前提條件是Z不為H。In some examples, amisulpride derivatives are stereoisomers with the structure of formula IC-S:

Formula IC-S includes its pharmaceutically acceptable salts, and Z is the same as the above definition in Formula I, provided that Z is not H.

式IC-R 包括其藥學上可接受的鹽，且Z與式I中的上述限定相同，前提條件是Z不為H。In some examples, amisulpride derivatives are stereoisomers with the structure of formula IC-R:

Formula IC-R includes its pharmaceutically acceptable salts, and Z is the same as the above definition in Formula I, provided that Z is not H.

In some examples, the membrane (eg, BBB) permeability of the amisulpride derivative disclosed herein is greater than that of amisulpride. In some examples, the amisulpride derivatives disclosed herein are dopamine and/or serotonin and/or α2 antagonists. For example, the amisulpride derivatives disclosed herein bind to dopamine D ₂ and/or D ₃ receptors. In some examples, the amisulpride derivatives disclosed herein more selectively bind to dopamine D ₂ and/or D ₃ receptors than dopamine D ₁ , D ₄ , and/or D ₅ receptors. In some examples, the amisulpride derivatives disclosed herein can interact with dopamine and/or serotonin and/or α2 receptors in the CNS.

In some examples, the R enantiomer of amisulpride or the R isomer of amisulpride derivatives disclosed herein is a 5-HT ₇ antagonist superior to the corresponding S enantiomer. In some examples, amisulpride S-enantiomers or disclosed herein amisulpride derivative S enantiomer is better than the corresponding R D ₂ antagonist enantiomer. In some examples, S amisulpride amisulpride derivative S-enantiomer or than the herein disclosed enantiomer and corresponding R enantiomer of the K _{i (K i (S: R)} ) when the ratio for 5-HT ₇ receptors _{(K i (S: R)} 5-HT7) higher than the corresponding ratio of the R enantiomer to the S enantiomer of the K _{i (K i (R: S)} ) for D ₂ receptor ratio (K _i (R:S) _D2 ). In some examples, the K _i (R:S) _D2 of amisulpride or amisulpride derivatives disclosed herein is about 10 to about 100, about 20 to about 80, about 30 to about 60, about 30 to About 50, about 30 to about 40, or about 36; and the corresponding K _i (S:R) _5-HT7 is at least 50, at least 62.5, at least 100, at least 500, or at least 1000.

For example, the K _i (R:S) _D2 of compound 102 is about 36, while the K _i (S:R) _{5-HT7 of} compound 102 is above 62.5.

Also provided herein are deuterated analogs of amisulpride, the deuterated analogs of amisulpride derivatives disclosed herein, wherein one or more hydrogens of amisulpride or amisulpride derivatives are replaced by deuterium . In some examples, the presence of one or more deuterium in the deuterated analog is at least 100 times the natural abundance level.

Provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more therapeutic compounds selected from amisulpride, amisulpride derivatives disclosed herein, and deuterated analogs disclosed herein Things. In some examples, the pharmaceutical composition disclosed herein comprises a pharmaceutically acceptable carrier and one or more R enantiomers selected from the R enantiomer of amisulpride, the amphetamine disclosed herein The R enantiomer of the amisulpride derivative (for example, the R enantiomer of a 4-amino-substituted amisulpride derivative), the R enantiomer of a deuterated analogue of amisulpride, and the ammonia disclosed herein The R enantiomer of the deuterated analog of sulpiride derivatives. In some examples, the one or more R enantiomers contained in the pharmaceutical composition 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" means that the enantiomeric purity is about 50% or higher, about 60% or higher, about 70% or higher, about 80% or higher, About 90% or higher, about 95% or higher, or about 98% or higher.

Also provided herein is a method of delivering dopamine and/or serotonin (eg, 5-HT _2a , 5-HT ₇ ) and/or α2 receptor antagonist to the brain of a subject, including administering to the subject disclosed herein One or more amisulpride derivatives and deuterated analogues thereof, or pharmaceutical compositions thereof; and dopamine and/or serotonin (such as 5-HT _2a , 5-HT ₇ ) and/or α2 in the brain The level of body antagonist is higher than that of amisulpride (racemic mixture) given to subjects in comparable doses. In some examples, amisulpride derivatives, and/or deuterated analogs are substantially enantiomerically pure, for example, the enantiomerically pure R isomer. In some examples, the pharmaceutical composition is substantially enantiomerically pure and includes one or more substantially enantiomerically pure R enantiomer selected from the amisulpride disclosed herein The R enantiomer of a derivative (for example, the R enantiomer of a 4-amino-substituted amisulpride derivative), the R enantiomer of a deuterated analog of amisulpride, and the amisulpride disclosed herein The R enantiomer of the deuterated analogue of the derivative. .

Also provided herein are methods for antagonizing dopamine and/or serotonin (for example, 5-HT _2a , 5-HT ₇ ) and/or α2 receptors in a subject, including methods for antagonizing dopamine and/or serotonin (eg 5-HT _2a , 5-HT ₇ ) and/or α2 receptors alone or in combination with one or more other CNS activities One or more R enantiomers are administered to the subject in a combination of agents, the R enantiomer selected from the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein (For example, the R enantiomer of a 4-amino-substituted amisulpride derivative), the R enantiomer of a deuterated analogue of amisulpride, and the deuterated analogue of amisulpride derivative disclosed herein R enantiomer of a compound, or a pharmaceutical composition comprising the one or more R enantiomers. In some examples, one or more R enantiomers are substantially enantiomerically pure.

Also provided herein are methods for modulating 5-HT ₇ receptors in a subject, including administering to the subject a therapeutically effective amount of one or more of them, alone or in combination with one or more other CNS active agents R enantiomer, the R enantiomer is selected from the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein (for example, 4-amino-substituted amisulpride derivatives The R enantiomer of amisulpride), the R enantiomer of the deuterated analog of amisulpride, and the R enantiomer of the deuterated analog of amisulpride derivatives disclosed herein, or the one or Pharmaceutical compositions of multiple R enantiomers. In some examples, the one or more R enantiomers are substantially enantiomerically pure.

Provided herein are methods for modulating both D _2/3 and 5-HT ₇ receptors in a subject, including administering treatment to the subject alone or in combination with one or more other CNS active agents An effective amount of one or more R enantiomers, the R enantiomer selected from the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein (for example, 4-amino The R enantiomer of a substituted amisulpride derivative), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of amisulpride derivative disclosed herein , Or a pharmaceutical composition comprising the one or more R enantiomers. In some examples, the one or more R enantiomers are substantially enantiomerically pure.

Also provided herein are methods for treating one or more disorders that respond to modulation of dopamine and/or serotonin (eg 5-HT _2a , 5-HT ₇ ) and/or α2 receptors in a subject, including A therapeutically effective amount of one or more R enantiomers selected from the R enantiomer of amisulpride is administered to the subject alone or in combination with one or more other CNS active agents, The R enantiomer of amisulpride derivatives disclosed herein (for example, the R enantiomer of a 4-amino-substituted amisulpride derivative), the R enantiomer of a deuterated analogue of amisulpride, And the R enantiomer of the deuterated analog of amisulpride derivatives disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers. In some examples, the one or more R enantiomers are substantially enantiomerically pure. In some examples, the one or more conditions are responsive to modulation of the 5-HT ₇ receptor (eg, without limitation, anxiety, depression, migraine, and obsessive-compulsive disorder).

Provided herein is a method for treating one or more disorders associated with abnormal levels of dopamine and/or serotonin in the brain of a subject, including treating a subject alone or in combination with one or more other CNS agents Administering a therapeutically effective amount of one or more R enantiomers selected from the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein (for example, R enantiomer of 4-amino-substituted amisulpride derivatives), R enantiomer of deuterated analogs of amisulpride, and R of deuterated analogs of amisulpride derivatives disclosed herein Enantiomers, or pharmaceutical compositions comprising the one or more R enantiomers. . In some examples, one or more R enantiomers and/or pharmaceutical compositions comprising the one or more R enantiomers are substantially enantiomerically pure. In some examples, the one or more disorders are selected from anxiety, depression, migraine, and obsessive-compulsive disorder.

In some examples, the R enantiomer of amisulpride or the R isomer of amisulpride derivatives disclosed herein is a 5-HT ₇ antagonist superior to the corresponding S enantiomer. In some examples, amisulpride S-enantiomers or disclosed herein amisulpride derivative S enantiomer is better than the corresponding R D ₂ antagonist enantiomer. In some examples, S amisulpride amisulpride derivative S-enantiomer or than the herein disclosed enantiomer and corresponding R enantiomer of the K _{i (K i (S: R)} ) when the ratio for 5-HT ₇ receptors _{(K i (S: R)} 5-HT7) higher than the corresponding ratio of the R enantiomer to the S enantiomer of the K _{i (K i (R: S)} ) for D2 receptor ratio (K _i (R:S) _D2 ). In some examples, the K _i (R:S) _D2 of amisulpride or amisulpride derivatives disclosed herein is about 10 to about 100, about 20 to about 80, about 30 to about 60, about 30 to About 50, about 30 to about 40, or about 36; and the corresponding K _i (S:R) _5-HT7 is at least 50, at least 62.5, at least 100, at least 500, or at least 1000.

In some examples of the methods disclosed herein, the amisulpride derivative disclosed herein is an N-methylated analog of amisulpride, ie, compound 102. In some examples of the methods disclosed herein, the R enantiomer of the amisulpride derivative disclosed herein is the R enantiomer of the N-methylated analog of amisulpride, ie, compound 104.

In some examples of the methods disclosed herein, the R enantiomer of the amisulpride derivative disclosed herein (for example, the R enantiomer of a 4-amino-substituted amisulpride derivative) and the amisulpride derivative disclosed herein The therapeutically effective amount of the R enantiomer of the deuterated analogue of the Li derivative, or the pharmaceutical composition thereof, is lower than the therapeutically effective amount of amisulpride. Therefore, the methods disclosed herein can cause fewer adverse events to the subjects receiving treatment. In some examples of the methods disclosed herein, at least one of the one or more R enantiomers has a degree of dopamine binding significantly lower than the corresponding S enantiomer (K _i (R:S) _D2 > 1) , And at least one of the one or more R enantiomers has a significantly higher serotonin binding degree than the corresponding S enantiomer (K _i (S:R) _5HT7 ), so the method disclosed herein is less likely to cause Side effects driven by dopamine receptors (for example, without limitation, extrapyramidal side effects or elevated prolactin). In some examples, K _i (R:S) _D2 > K _i (S:R) _5HT7 .

Responding to disorders of dopamine and/or serotonin (eg, 5-HT _2a , 5-HT ₇ ) and/or α2 receptor modulation and/or disorders related to abnormal dopamine and/or serotonin levels in the brain Examples include, but are not limited to, mental illness. Examples of mental illness include, but are not limited to, schizophrenia, symptoms of schizophrenia, schizoaffective disorder, manic disorder, anxiety, depression, migraine, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's psychosis, opposition Major negative symptoms of defiant disorder, aggressiveness, suicide, hostility, personality disorder, autism, chronic fatigue syndrome, schizophrenia, Charles Bonnet syndrome, and Tourette syndrome.

As used herein, the singular of "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, the term "cell" includes multiple cells, including mixtures thereof. Similarly, unless the context clearly dictates otherwise, the use of a "compound" in the preparation or treatment of the pharmaceutical formulations described herein includes the use of one or more compounds of the invention for such treatment or preparation.

As used herein, the term "comprising" is intended to mean that the compositions and methods include the listed elements, but do not exclude other elements. Therefore, a composition consisting essentially of the elements defined herein does not exclude trace contaminants from separation and purification methods and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like. "Consisting of" shall refer to the elimination of trace elements more than other ingredients and the essential method steps for administering the composition 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 atom groups without unsaturation. Unless otherwise specified, the term "alkyl" refers to 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 are connected to the rest of the molecule through a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-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 specified, the term "alkenyl" refers to a group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, such as vinyl, 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 with at least one carbon-carbon triple bond. Unless otherwise stated, the term "alkynyl" means 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 ) Groups such as ethynyl, propynyl, and butynyl.

The term "cycloalkyl" means 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.

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 a monocyclic or polycyclic aromatic radical 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 that is directly bonded to an alkyl group as defined above, for example -CH ₂ C ₆ H ₅ , and -C ₂ H ₅ C ₆ H ₅ .

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 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 oxidize to various oxidation states. In addition, the nitrogen atom may optionally be quaternized.

The term "heterocyclylalkyl" refers to a heterocyclic 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 which has one or more heterocyclic atoms selected from N, O, and S as ring atoms. Heteroaryl groups can be monocyclic, bicyclic or tricyclic ring systems. Examples of such heteroaromatic radicals include but are not limited to oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzene And thiazolyl, benzoxazolyl, azazolyl, quinolinyl, and isoquinolinyl.

The term "heteroarylalkyl" refers to an alkyl group as defined above directly bonded to a heteroaryl group as defined above, for example, -CH ₂ C ₆ H ₄ N, and _{-C 2 H 5 C 6 H 4} N.

The term "subject" refers to mammals, such as domestic pets (eg, dogs or cats) or humans. In some examples, the subject is a human.

The phrase "effective amount" refers to an amount that, when administered to a subject or patient to treat a disease, is sufficient to make such treatment effective for the disease.

"Treatment" or "treating" includes (1) inhibiting the disease of a subject or patient experiencing or presenting the symptoms or symptoms of the disease (for example, preventing the further development of the symptoms and/or symptoms), (2) Improving the disease of the subject or patient experiencing or presenting the symptoms or symptoms of the disease (for example, reversing the symptoms and/or symptoms), and/or (3) enabling the experience or presenting the symptoms or symptoms of the disease Any measurable reduction in the subject or patient’s disease occurs.

The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause allergic reactions or other adverse reactions in patients receiving administration and is compatible with other ingredients in the formulation. The pharmaceutically acceptable carrier includes, for example, a pharmaceutical diluent, excipient or carrier appropriately selected for the intended administration form, and is consistent with general pharmaceutical practice. For example, solid carriers/diluents include but are not limited to gums, starches (such as corn starch, pregelatinized starch), sugars (such as lactose, mannitol, sucrose, dextrose), cellulosic materials (such as microcrystalline cellulose) ), acrylate (for example, polymethacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. The pharmaceutically acceptable carrier may further contain 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" used herein is not limited, as long as the salt is formed by a compound of amisulpride derivative and is pharmaceutically acceptable; preferred examples of the salt include hydrohalide salts (e.g., hydrochloride, hydrobromide Acid salt, hydroiodide, etc.), inorganic acid salt (for example, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carboxylate (for example, acetate, horse Lysoate, tartrate, fumarate, citrate, etc.), organic sulfonate (for example, methanesulfonate, ethanesulfonate, benzenesulfonate, tosylate, camphorsulfonate, etc.) ), amino acid salt (for example, aspartate, glutamate, etc.), quaternary ammonium salt, etc. In addition, hydrochloride, sulfate, methanesulfonate, acetate, etc. are preferable as the "pharmacologically acceptable salt" of the amisulpride derivative disclosed herein.

The isomers of amisulpride or the isomers of amisulpride derivatives disclosed herein (for example, geometric isomers, optical isomers, rotamers, tautomers, etc.) can be separated using general separation Methods for purification into single isomers include, for example, recrystallization, optical resolution such as diastereomeric salt methods, enzymatic fractionation methods, various chromatography methods (for example, thin layer chromatography, column chromatography, glass chromatography, etc.). Pharmaceutical formulation and route of administration

One or more therapeutic compounds disclosed herein (eg, the R enantiomer of amisulpride, the R enantiomer of amisulpride derivatives disclosed herein, and/or the R pair of deuterated analogs disclosed herein Enantiomers) can be administered by a variety of routes, including oral and injection (eg, subcutaneous, intravenous, and intraperitoneal). The therapeutic compounds disclosed herein can be prepared into pharmaceutical compositions for use in the disclosed methods. Such compositions are prepared according to acceptable pharmaceutical methods, such as those described in Remington's Pharmaceutical Sciences, 17th edition, edited by Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pennsylvania (1985) Method, which is incorporated herein by reference.

One or more of the therapeutic compounds disclosed herein can be administered orally in solid or liquid dosage forms. Of the two, one or more of the therapeutic compounds disclosed herein can be encapsulated in a material to protect it from acids and other natural conditions that may inactivate the compound. One or more of the therapeutic compounds disclosed herein can be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, and tablets ( wafer). Oral dosage forms may include excipients known in the art, such as binders, disintegrants, flavoring agents, antioxidants, and preservatives. Liquid dosage forms may include diluents such as saline or aqueous buffer.

One or more of the therapeutic compounds disclosed herein can also be administered by injection. Formulations suitable for injection may include sterile aqueous solutions (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 liquid to the extent that it can be easily injected. It can be stable under manufacturing and storage conditions, and can prevent the contaminating action of microorganisms such as bacteria and fungi. The pharmaceutically acceptable carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. For example, it is possible to maintain proper fluidity by using a coating such as lecithin, by maintaining the required fineness in the case of dispersion, and by using a surfactant. 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 is preferable to include isotonic agents in the composition, such as sugars, sodium chloride, or polyols such as mannitol and sorbitol. Prolonged absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate or gelatin.

One or more therapeutic compounds are incorporated in a suitable solvent in the required amount, and one or a combination of the above-listed ingredients is used as required, and then filtered and sterilized, thereby preparing a sterile injectable solution. Generally, a dispersion is prepared by incorporating one or more therapeutic compounds into a sterile carrier that contains a basic dispersion medium and other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods include vacuum drying and freeze drying, which produce a powder of the active ingredient (ie the therapeutic compound) and any other required ingredients from the previous sterile filtered solution .

The actual dosage of one or more therapeutic compounds administered to the subject can be determined by physical and physiological factors, such as age, sex, weight, severity of the disease, type of disease to be treated, previous or simultaneous therapeutic intervention, and subject The idiopathic nature and route of administration. These factors can be determined by the skilled person. The practitioner responsible for administration will generally determine the concentration of the active ingredient in the composition and the appropriate dosage for the individual subject.

In one example, a human subject is administered a daily dose of one or more therapeutic compounds disclosed herein from about 0.01 mg/kg to about 100 mg/kg.

A single dose or multiple doses of one or more of the therapeutic compounds disclosed herein are contemplated. Those of ordinary skill in the art can determine the required time interval for delivering multiple doses using only general experiments. For example, the subject may be given two doses per day at about 12 hour intervals. In some examples, the compound is administered once a day.

One or more of the therapeutic compounds disclosed herein can be administered by a general schedule. As used herein, the general plan refers to a predetermined designated period of time. A general plan may include time periods of the same duration or time periods of different durations, as long as the plan is predetermined. For example, a general regimen may involve administration twice a day, administration every day, administration every two days, administration every three days, administration every four days, administration every five days, administration every six days, administration every week, Dosing monthly or any set number of days or weeks in between. Alternatively, a predetermined general regimen may involve dosing twice a day for the first week and then daily for several months thereafter. In other examples, one or more of the therapeutic compounds disclosed herein provided by the present invention can be taken orally, and its timing depends or does not depend on food intake. Thus, for example, one or more of the therapeutic compounds disclosed herein can be taken every morning and/or every evening, regardless of when the subject consumes or will consume it. Combination therapy

In addition to being used as a monotherapy, one or more of the therapeutic compounds disclosed herein can also be used in combination therapy. Effective combination therapy can be achieved with a single pharmaceutical composition or pharmacological preparation, the pharmaceutical composition or pharmacological preparation includes two drugs or two different pharmaceutical compositions or pharmacological preparations administered simultaneously, one of which is a composition One or more of the therapeutic compounds disclosed herein are included, and the other includes a second agent. Alternatively, the treatment may precede or follow other medications, with an interval of several minutes to several months.

The additional one or more agents may be selected from any agent or agents that can be used to treat psychological disorders, for example, any agent or agents used to treat imbalance of dopamine, serotonin, histamine or glutamate and/or α2. In one example, additional agents or agents can be used to improve mental function, such as antipsychotic drugs, such as quetiapine, zolonidine, zaprolide, lurasidone, olanzapine, risperidone, ipandril Ketones, ziprasidone, clozapine, flupiridol, chlorpromazine, citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, devenlafaxine , Duloxetine, milnacipran, venlafaxine, verazodone, and combinations thereof. Synthesis of Amisulpride Derivatives

The amisulpride derivative disclosed herein can be made of amisulpride (4-amino- N -((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl) )-2-Methoxybenzamide) preparation, amisulpride is easily available. The synthesis of amisulpride is described, for example, in U.S. Patent No. 4,401,822.

式IB 其中Z與上文同樣限定，且Z = -C-R。 該反應方案如下所示：

方案1.  氨磺必利衍生物的製備The following synthesis used to prepare compounds of formula IB can be adjusted to prepare other compounds of the invention, such as compounds of formula I, IA, and IC. The compound of formula IB can be prepared by the following steps: (a) treating amisulpride with a mixture of carboxylic acid and its corresponding anhydride to obtain the corresponding amide, (b) using a suitable one such as borane: dimethyl sulfide The reducing agent reduces the amide to an amine to form a compound of formula IB:

Formula IB where Z is defined as above, and Z = -CR. The reaction scheme is as follows:

Scheme 1. Preparation of Amisulpride Derivatives

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

方案2.  4-甲氨基取代的氨磺必利衍生物的製備In addition, amisulpride is reacted with N,N -dimethylformamide dimethyl acetal to provide the corresponding amide, and then passed through a reducing agent (for example, NaBH ₄ , DMS: BH ₃ , Red-Al, And LiAlH ₄ ) reduction to provide the corresponding 4-methylamino-substituted amisulpride derivative, whereby a 4-methylamino-substituted amisulpride derivative can be prepared.

Scheme 2. Preparation of 4-methylamino-substituted amisulpride derivatives

方案3.  氨磺必利衍生物的製備 (以S-異構體為例)

方案4.  4-甲氨基取代的氨磺必利衍生物(S-異構體)的製備The stereoisomers of the amisulpride derivatives disclosed herein can be similarly prepared by using the corresponding stereoisomers of amisulpride as starting materials. For example, ((S)-4-amino- N -((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide The synthesis of can be carried out according to the description in US Patent No. 6,169,094, which is incorporated herein by reference. S isomer amisulpride derivative may be used amisulpride preparation of S isomer (Scheme 3 and 4). R isomer amisulpride derivatives can be similarly prepared using the R isomer of amisulpride.

Scheme 3. Preparation of amisulpride derivatives (taking S-isomer as an example)

Scheme 4. Preparation of 4-methylamino-substituted amisulpride derivative (S-isomer)

When neither Z nor X of the amisulpride derivative of formula I is hydrogen, the amisulpride derivative (disubstituted 4-amino amisulpride derivative) can be substituted by two steps of 4-amino group preparation. First, as shown above, the first substituent of Z or X is substituted for the 4-amino group to obtain the monosubstituted 4-aminosulpride derivative; then the 4-aminosulpride derivative of the monosubstituted 4-aminosulpride is The amino group is further substituted for the second time to obtain the desired disubstituted 4-aminosulpride derivative. See, for example, examples 3C and 3D.

化合物1The present invention has been described with reference to examples and illustrative examples, and those skilled in the art can understand that the described and illustrated invention can be modified without departing from the spirit and scope of the invention disclosed in the specification. Examples are listed to help understand the present invention, but are not intended and should not be construed as limiting its scope in any way. These examples do not include detailed descriptions of traditional methods. These methods are well known to those of ordinary skill in the art and are described in many publications. In addition, all references cited above and in the following examples are incorporated herein by reference in their entirety as if fully set forth herein. Example Example 1: 4 -Methoxybenzamide- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzamide ( Compound 1) Synthesis

Compound 1

化合物102To 4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide at 5-10°C To a solution of the amine (2 g, 5.5 mmol) in 20 mL of formic acid was added acetic anhydride (0.68 g, 6.6 mmol) in portions. The reaction mixture was stirred overnight at room temperature and carefully poured into the K ₂ CO ₃ aqueous solution at 5-10°C. Solid NaCl, the mixture _was extracted with CHCl. The combined organic extracts were dried overnight with Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 5-10% MeOH in CHCl ₃ to obtain 1.82 g (83%) of a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.1 (t, 3H, CH ₃ ), 1.3 (t, 3H, CH ₃ ) 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, OCH ₃ ), 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 weight [C ₁₈ H ₂₇ N ₃ O ₅ S]: 397.2, observed molar weight 398.1 [M + H ⁺ ]. Example 2: 4 - Methylamino - N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzamide ( compound 102 ) synthesis

Compound 102

To 4-formamide-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzene at 5-10°C a Amides (compound 1,1.82 g, 4.6 mmol) in solution in 80 mL THF portionwise added ^{_{BH 3. Me 2 S (1.09}} mL, 11.5 mmol). The reaction mixture was stirred at 60 °C for 3 h, and carefully quenched by MeOH (40 mL). The reaction mixture was acidified with 10% HCl (15 mL), and the mixture was stirred at 60° C. overnight. The solvent was evaporated under reduced pressure, the aqueous residue was diluted with H ₂ O and basified to pH 10 with aqueous NaOH. The mixture was extracted with CHCl ₃ , and the combined organic extracts were dried with Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography on silica gel, eluted with 5-10% MeOH in CHCl ₃ , and then purified by RP-HPLC with a gradient of MeCN-H ₂ O + 0.1% TFA. The fraction containing the target substance was partially evaporated under reduced pressure, basified to pH 10 with an aqueous NaOH solution, and extracted with CH ₂ Cl ₂ . The combined extract was dried with Na ₂ SO ₄ and evaporated under reduced pressure to obtain a white solid product, which solidified after storage (0.93 g, 53%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.1 (t, 3H, CH ₃ ), 1.3 (t, 3H, CH ₃ ), 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, NHC H ₃ ), 3.1 (q, 2H, CH ₂ ), 3.2 (m, 1H), 3.3 (m, 1H), 3.6 (m, 1H), 4.0 (s, 3H, OCH ₃ ), 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, CDCl ₃ ): 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 [C ₁₈ H ₂₉ N ₃ O ₄ S]: 383.2, observed molar weight 384.5 [M + H ⁺ ]. Example 3: Synthesis of stereoisomers of compound 102 ( compounds 103 and 104) and 4- aminosulpride derivatives ( compounds 105 to 110) . A): ((S)-4 -methylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzyl Synthesis of Amide ( Compound 103)

(( S )-4-amino- N -((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (11.1 g) in N, N - suspended and stirred for 2 hours at 90 ^o C dimethylformamide dimethyl acetal (33 mL). The reaction mixture was cooled to room temperature and NaBH ₄ (4 g) was added in portions. The mixture was stirred at room temperature for 1 h. Saturated NaCHO ₃ (50 mL) was added to quench the reaction, and the resulting suspension was extracted with dichloromethane (2×50 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, eluted with CH ₂ Cl ₂ /MeOH/NH ₃ to obtain a white solid product, which was further purified by recrystallization from acetone (5.3 g).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 1.1 (2t, 2X3H, CH ₃ ), 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, OCH ₃ ), 6.3 (s, 1H _ar ), 6.6 (m, 1H _ar ), 8.1 (m, 1H, NH), 8.3 (s, 1H, NH). ¹³ C NMR (100 MHz, DMSO- d ₆ ): 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 [C ₁₈ H ₂₇ N ₃ O ₄ S] 383.2, observed molar weight 384.4 [M + H ⁺ ]. B): ((R)-4 -methylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzyl Synthesis of Amide ( Compound 104)

(( R )-4-amino- N -((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (11.2 g) in N, N - suspended and stirred for 2 hours at 90 ^o C dimethylformamide dimethyl acetal (33 mL). The temperature was lowered to 70 ^o C and NaBH ₄ (4 g) was added at 20 minute intervals in 1 g batches. After complete addition, the reaction mixture was further stirred for 1 hour at 90 ^o C. The reaction mixture was cooled in an ice bath, and the reaction was quenched by adding 150 mL of saturated NaHCO ₃ . The resulting solution was extracted with CH ₂ Cl ₂ (5×50 mL), and the combined organic extracts were dried over Na ₂ SO ₄ . It was purified by column chromatography, eluted with 10% MeOH/CH ₂ Cl ₂ to obtain 7.9 g of white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.2 (t, 3H, CH ₃ ), 1.3 (t, 3H, CH ₃ ), 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, OCH ₃ ), 6.1 (s, 1H _ar ), 6.8 (m, 1H _ar ), 8.1 (m, 1H, NH), 8.6 (s, 1H, NH). Expected molar weight [C ₁₈ H ₂₇ N ₃ O ₄ S] 383.2, the observed molar weight 384.2 [M + H ⁺ ]. C): (4 -Dimethylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzamide ( Compound 105) Synthesis

Combine 4-methylamino- N -((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxy in 10 mL formic acid at 30 ^o C Benziamide (500 mg) was stirred for 21 h, while NaBH ₄ (8 equivalents) was added in two batches, and washed with NaOH aqueous solution to obtain 408 mg of compound 105.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.2 (t, 3H, CH ₃ s), 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, OCH ₃ ), 6.8 (s, 1H _ar ), 8.0 (s , 1H, NH) 8.8 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): 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. The expected molar weight [C ₁₉ H ₃₁ N ₃ O ₄ S] 397.2, the observed molar weight 398.2 [M + H ⁺ ]. D): (4- Ethylmethylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzamide ( Compound 106) Synthesis

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

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.2 (m, 6H, 2 CH ₃ s), 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, OCH ₃ ), 6.8 (s, 1H _ar ), 8.0 (s, 1H, NH) 8.8 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): 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 weight [C ₂₀ H ₃₃ N ₃ O ₄ S] 411.3, observed molar weight 412.3 [M + H ⁺ ]. E): (4- Ethylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzyl Synthesis of Amine ( Compound 107)

Stir (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzene in 6 mL of 1,2-dichloroethane and 0.4 mL of acetic acid Formamide (500 mg). 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 adding an aqueous NaOH solution, the product was extracted into dichloromethane, and purified by column chromatography, and recrystallized from acetone/MTBE to obtain 309 mg of compound 107.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.1 (br t, 3H, CH ₃ ), 1.3 (t, 3H, CH ₃ ), 1.4 (t, 3H, CH ₃ ), 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, OCH ₃ ), 6.1 (s, 1H _ar ), 6.7 (s, 1H _ar ), 8.1 (s, 1H, NH) 8.6 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): 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 [C ₁₉ H ₃₁ N ₃ O ₄ S] 397.2, the observed molar weight 398.2 [M + H ⁺ ]. F): (4- isopropylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzamide ( Compound 108) Synthesis

Stir (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) 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. Stir the mixture overnight at 40 ^o C. The reaction mixture was poured into NaOH aqueous solution, and the product was extracted into dichloromethane, and purified by column chromatography to obtain 550 mg of compound 108.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.1 (br t, 3H, CH ₃ ), 1.2 (t, 3H, CH ₃ ), 1.3 (t, 6H, CH ₃ ), 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, OCH ₃ ), 6.1 (s, 1H _ar ), 6.7 (s, 1H _ar ), 8.0 (s, 1H, NH) 8.6 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): 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 weight [C ₂₀ H ₃₃ N ₃ O ₄ S] 411.2, the observed molar weight 412.2 [M + H ⁺ ]. G): (4- n-propylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzamide ( Compound 109) Synthesis

Stir (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxy in 6 mL of 1,2-dichloroethane and 0.3 mL of propionaldehyde Benzamide (500 mg). Sodium triacetoxyborohydride (1.2 g) was added in two batches at 10 minute intervals, and the mixture was stirred overnight. The reaction mixture was poured into aqueous NaOH solution and the product was extracted into ethyl acetate, and purified by column chromatography to obtain 518 mg of compound 109.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.1 (br t, 3H, CH ₃ ), 1.2 (t, 3H, CH ₃ ), 1.3 (t, 6H, CH ₃ ), 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, OCH ₃ ), 6.1 (s, 1H _ar ), 6.7 (s, 1H _ar ), 8.0 (s, 1H, NH) 8.6 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): 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 weight [C ₂₀ H ₃₃ N ₃ O ₄ S] 411.2, the observed molar weight 412.2 [M + H ⁺ ]. H): (4- Benzylamino- N-((1- ethyl -2- pyrrolidinyl ) methyl )-5-( ethylsulfonyl ))-2 -methoxybenzamide ( compound 110) Synthesis

Stir (ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzyl in 7 mL of DMF and 1.25 mL of benzaldehyde and 1 mL of TFA Amide (500 mg). Three acetyl group with sodium borohydride (3.5 g) was added in two portions, at 40 ^o C and the mixture was stirred overnight. The reaction mixture was poured into NaOH aqueous solution and the product was extracted into dichloromethane, and purified by column chromatography to obtain 366 mg of compound 110.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.2 (t, 3H, CH ₃ ), 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, OCH ₃ ), 6.1 (s, 1H _ar ), 7.4 (m, 5H), 8.0 (s, 1H, NH) 8.6 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): 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 weight [C ₂₄ H ₃₃ N ₃ O ₄ S] 459.2 and observed molar weight 460.2 [M + H ⁺ ]. Example 4: Membrane permeability of compound 102

4-methylamino- N -((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide) (Compound 102) The membrane permeability was determined by using the PAMPA test at pH 5 and 7.4. Specifically, a 10 mM control ranitidine solution (3.5 mg in 1 mL DMSO), propanol (2.9 mg in 1 mL DMSO), and N -methylamisulpride (3.3 mg in 0.8 mL DMSO) were prepared. ), and amisulpride (3.4 mg in 0.9 mL DMSO). The diffusion through the Pion PAMPA membrane was measured at pH 5 and pH 7.4, as shown in Table 1, respectively.

Table 1: Permeability of compound 102, amisulpride, Propanolol, and ranitidine across the PAMPA membrane at pH 5 and 7.4. Test compound Permeability (cm/s) pH 5 Permeability (cm/s) pH 7.4 Amisulpride 2.4 X 10 ^-10 2.4 X 10 ^-11 N-Methyl Susulpride (Compound 102) 2.1 X 10 ^-8 5.2 X 10 ^-9 Propanolol 3.1 X 10 ^-8 7.8 X 10 ^-6 Ranitidine 1.1 X 10 ^-10 1.5 X 10 ^-10 Example 5: Binding of compound 102 to the dopamine D2 receptor ( cell-based test )

The ability of Compound 102 to bind to dopamine D ₂ receptors was determined in a cell-based assay. The dopamine D ₂ receptor cells were seeded in a translucent 96-well plate with a transparent bottom. To reach a volume of 25 μL at a density of 15,000 cells/well, it was incubated overnight. A solution of calcium 5 dye in HEPES buffered HBSS (Hanks' Balanced Salt Solution) was prepared, 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 control were added to the wells and incubated at room temperature for 10 minutes. Fluorescence is measured every 1.52 seconds. After 20 seconds, add 10 μL of dopamine (at EC ₈₀ concentration), and monitor the fluorescence for 2 minutes with an excitation wavelength of 452 nm and an emission wavelength of 525 nm. The cell-based IC ₅₀ values of compound 102 are listed in Table 2 together with the known dopamine D ₂ inhibitors risperidone, amisulpride and clozapine.

例子 6: 化合物 102 與多巴胺 D₂ 受體的結合 ( 膜準備 (membrane preparation)) Table 2: IC50 values of compound 102, risperidone, amisulpride, and clozapine relative to the dopamine D2 receptor (cell-based test).

Examples 6: Compound 102 binding to dopamine D ₂ receptors (membrane preparation (membrane preparation))

The ability of compound 102 to bind to dopamine D ₂ receptors in membrane preparation was examined. The medium was removed from the dopamine D ₂ receptor cells and washed with PBS. Add lysis buffer (250 mM sucrose, 1 nM EDTA, 10 mM Tris HCl buffer pH 7.2 plus protease inhibitor), and scrape the cells using a plate scraper. The cells are homogenized in a glass homogenizer through 20 manual up and down strokes. The homogenate was homogenized by centrifugation at 500Xg at 4°C for 10 minutes to remove intact cells, nuclei, and cell debris, remove the supernatant, and resuspend the pellet in the assay buffer.

The membrane preparation was incubated with ³ H spironolone until equilibrium. Use Packard Filtermate Harvester and glass filter plates to separate the bound product from the free radioligand. The radioactivity was measured using Packard Topcount. Mix 20 μL of D ₂ membrane with 20 μL of ³ H spironolone and 10 μL of test compound or reference ligand in binding buffer in a non-binding 96-well plate, and incubate for >120 minutes. Before filtration, the 96-well harvest filter plate was coated with 0.33% polyethyleneimine for 30 minutes, and then washed with test buffer. The binding reaction was transferred to the filter plate and washed three times with washing buffer, dried, scintillant was added, and the radioactivity was counted on Topcount NXT.

Compound 102, risperidone, amisulpride, and clozapine were tested in triplicate using 0.1 nM ³ H spiroperone at concentrations of 1000, 100, 10, 1, 0.1, and 0.01 nM. The IC ₅₀ values of this film-based test are shown in Table 3.

例子 7: 化合物 102 和化合物 103 與多種 CNS 受體 ( 多巴胺 D₂ ，多巴胺 D₃ , α2 腎上腺素，和 5-HT_2a 受體 ) 的結合 ( 表 4) Table 3: Compound 102, risperidone, amisulpride, clozapine, and IC ₅₀ values with respect to dopamine D ₂ receptors (membrane-based assay).

Example 7: Binding of compound 102 and compound 103 to various CNS receptors ( dopamine D ₂ , dopamine D ₃ , α2 adrenaline, and 5-HT _2a receptor ) ( Table 4)

Compounds 102 and 103 bind α ₂ (non-selective), α _2A , α _2B , α _2C , 5-HT _2A (agonist), 5-HT _2A (antagonist), D _2L , D _2S , and D ₃ Ability is measured in the concentration range of 10 X 10 ^-5 to 10 X 10 ^-9 M, and the reference ligand bound to each individual receptor is determined (Pazosin for α ₂ (non-selective), Yohimbine For α _2A , α _2B , and α _2C , DOI ([2,5-dimethoxy-4-iodophenyl]-2-aminopropane) for 5-HT _2A (agonist), ketanserin Used for 5-HT _2A (antagonist), butaramol for D _2L , 7-OH-DPAT for D _2S , and (+) butaramol for D ₃ ) replacement. The suppression data package is reported in Table 4.

例子 8: 新物體辨識 (NOR) 試驗表明了化合物 102 和 103 的效用 Table 4: Cell-based test, compound 102 (LB102) and Compound 103 (LB103) relative IC50 and K _i values for various CNS receptors.

Example 8: New Object Identification (NOR) test shows the effectiveness of compounds 102 and 103

In the New Object Recognition (NOR) assay, the utility of compounds 102 and 103 was evaluated in rats, a well-known model that summarizes the cognitive and negative aspects of the PANSS scale for schizophrenia. In this test, the animals were treated with low-dose phencyclohexidine (PCP) for several weeks to impair the rat's ability to distinguish between new and familiar objects. Generally, like humans, rats will spend more time exploring a new object than familiar objects. The ability of the test treatment to restore normal brain function demonstrated by reversing PCP injury demonstrates the utility of this study.

In this NOR study, the effectiveness of compounds 102 and 103 was compared with the known antipsychotic drugs amisulpride and risperidone to evaluate the restoration of normality between new and familiar object exploration in PCP-treated rats Differentiation. Rats (n = 10/group) were administered 2 mg/kg (i.p., b.i.d.) intraperitoneally twice a day for 7 days, and then no drug was administered for 7 days. Under various PO dose test agents, the cognitive test was performed at 3 hours after the administration of Compound 102, 103, and amisulpride, and at 30 minutes after the administration of risperidone. The new object exploration time of test subjects in a subchronic PCP NOR study (n = 10/group) conducted on rats was measured. The difference in exploration time between new (Tnovel-) and familiar (Tfamliar) objects is shown in Figure 1A (*: p> 0.05; and **: p> 0.01). Figure 1B shows the discrimination index of the NOR study obtained by the following equation 1: Discrimination Index = (Time spent exploring new objects-Time spent exploring familiar objects)/Total exploration time) (Equation 1)

Figures 1A and 1B show all doses of compound 102 (Cpd 102) and 103 (Cpd 103), except for one, adding new and familiar objects in a manner consistent with the currently used antipsychotic drugs amisulpride and risperidone Explore the difference between time.

In the NOR study shown in Figures 1A and 1B, compounds 102 and 103 were able to restore the exploration behavior of known objects in PCP-treated rats to a level similar to that of untreated rats, and compared with the use of known antipsychotics. The values obtained for amisulpride and risperidone are equivalent. Example 9: amphetamine - induced locomotor activity (LMA) test showed the effectiveness of Compound 102 and 103

The efficacy of compounds 102 and 103 was studied in rats in the amphetamine-induced motor activity (LMA) test, which is a measure of the positive aspects of the PANSS scale. In the LMA determination, rats were given amphetamine (Amp, 1 mg/kg, s.c.), which caused excessive exercise, and the distance moved by each rat was monitored in a cage with a sensor. Rats given amphetamine alone tended to show hyperactivity, while rats given antipsychotics showed more normal, calmer activity.

In this LMA study, compounds 102 (Cpd 102, 30 mg/kg) and 103 (Cpd 103, 30 mg/kg), amisulpride (30 mg/kg) and risperidone (1 mg/kg) 10 rats were orally administered as a group. Amisulpride-risperidone was administered 6 hours after the administration of compounds 102 and 103 and 1 hour before the measurement, and the movement distance within one hour was measured. The end point of the study is the total walking distance (the distance traveled by each animal 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 standardized amphetamine overactivity of compound 102 (Cpd 102) was statistically superior to amisulpride (p>0.05), and compound 103 (Cpd 103) ) Standardized amphetamine overactivity is statistically indistinguishable from amisulpride (p>0.01). Example 10: Binding of Compounds 102, 103, and 104 to 5-HT ₇ Receptor

Measure the ability of compounds 102, 103, and 104 to bind 5-HT ₇ in the concentration range of 1×10 ^-7 to 3×10 ^-10 M, and measure the calcium-sensitive fluorescent indicator in cells expressing 5-HT7的 permutation. Through this experiment, it was found that the K _i of compound 102 (LB-102, solid circle, dotted line B, Figure 3) was 31±1.0 nM, while amisulpride (LB101, solid circle, dotted line A, Figure 3) was 44 nM. Compound 103 (the S enantiomer of compound 102) is unexpectedly a stronger binder for dopamine receptors than compound 104 (the R enantiomer of compound 102), compound 104 (compound 102) R 102 for binding enantiomer) provides 15.6 ± 0.9 nM of K _i (LB104, solid circles, dotted line D, FIG. 3), and compound 103 (compound 102 S-enantiomer) (LB103 , Solid triangle, dotted line C, Fig. 3) K _i is> 1,000 nM. Unexpectedly, the R enantiomer of amisulpride (Ami(r), filled circle, dotted line A, Figure 4) shows that the S enantiomer (Ami( s), solid circles, dotted line C, Figure 4) a lower _{K i (21.8 ± 1.5 nM)} . The K _i (44 nM) of the racemic mixture of amisulpride (Amic (rac), filled circle, dotted line B, Figure 4) is higher than the R enantiomer of amisulpride, but lower than that of amisulpride The S enantiomer of Pride. Example 11: Binding of compounds 102, 103, and 104 to D ₂ receptors

The ability of compounds 101, 102, 103, and 104 to bind to D ₂ receptors was performed on the GPCR screening platform. In short, the test is based on ligand replacement. In the presence of increasing concentrations of benzamide antagonists, the apparent affinity of the natural ligand dopamine for D ₂ receptors was tested. The apparent affinity constant (EC ₅₀ ) of the ligand is determined by the 4-parameter response formula (the following formula 2): (maximum-minimum)/(1+(EC ₅₀ /[ligand])^n)+minimum (formula 2) Among them: "maximum" is the signal at the saturated ligand (dopamine or serotonin); "minimum" is the signal when no ligand (or saturated antagonist) is present; EC ₅₀ is the ligand that produces 1/2 of the maximum signal Body concentration; and n is the Hill coefficient.

Using the Cheng-Prusoff contention ligand relationship (the following formula 3), the antagonist dissociation constant K (DA) and the ligand dissociation constant K (DL) are determined by the global fits of the EC ₅₀ v antagonist concentration : EC ₅₀ = K(DL)*(1 + [A]/K(DA)) (Equation 3)

When checking the enantiomeric system (enantiomerically pure R enantiomer, enantiomerically pure S enantiomer, and racemate), the overall fit is as follows (formula 4-6): EC ₅₀ = K (DL)*(1 + [A(s)]/K(DA(s))) (Formula 4 for the enantiomerically pure S enantiomer) EC ₅₀ = K(DL)*(1 + [A (R)]/K(DA(s))) (Formula 5 for the enantiomerically pure R enantiomer) EC ₅₀ = K(DL)*(1 + 0.5*[A(rac)]/K( DA(s)+ 0.5*[A(rac)]/K(DA(r))) (Equation 6 for racemates)

5A and 5B, for binding ₂ D, LB-103 binding _{D K i (0.4 ± 0.04nM)} 2 is less than LB-102 or LB-104; LB-104 to K _i (14.4 ± 2.2 nM) above LB-102 (0.82 ± 0.02 nm ); LB-101 and the K _i (1.1 ± 0.12 nm) than LB-102 and LB-103, but lower than LB-104. reference document

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Figure 1A: New object exploration data from a subchronic PCP NOR study in rats (+SEM, n=10/group). Describes the difference in discrimination index ((time to explore new objects-time to explore familiar objects)/total exploration time).

Figure 1B: Discrimination index data from a subchronic PCR NOR study in rats (n = 10/group). Describes the difference in discrimination index ((time to explore new objects-time to explore familiar objects)/total exploration time).

Figure 2: Total walking distance (over 1 hour) + SEM (n=10/group). Compared with amphetamine, p>0.05 in all treatment groups.

Figure 3: Binding of compounds 102, 103, 104, and amisulpride (101) to 5-HT ₇ receptors.

Figure 4: Amisulpride (Ami(rac)), the R enantiomer of amisulpride (Ami(r)), and the S enantiomer (Ami(s)) and 5-HT of amisulpride ₇ Receptor binding.

Figure 5A: Binding of amisulpride (LB-101) to the D ₂ receptor.

Figure 5B: Binding of compounds 102 (LB-102), 103 (LB-103), and 104 (LB-104) to the D ₂ receptor.

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Claims (14)

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

Formula I includes its pharmaceutically acceptable salts and stereoisomers, wherein: R ₁ is

or

; And X and Z are the same or different, and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aralkyl , Heteroaralkyl, and heteroaryl group, optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, Aralkyl, heteroaralkyl, and heteroaryl groups are further substituted with one or more substituents selected from halogens such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, and carbonyl , And other alkyl and aryl groups as defined herein; provided that at least one of X and Z is not hydrogen, and when R ₁ is

When, R ₁ can be bonded at any position marked with "*" as shown below:

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

Formula I includes its pharmaceutically acceptable salts and stereoisomers, wherein: R ₁ is

or

; And X and Z are the same or different, and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aralkyl , Heteroaralkyl, and heteroaryl group, optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aryl Alkyl, heteroaralkyl, and heteroaryl groups are further substituted with one or more substituents selected from halogens such as chlorine, bromine, and fluorine, amines, hydroxyl groups, carboxylic acids, nitro groups, carbonyl groups, And other alkyl and aryl groups as defined herein; provided that at least one of X and Z is not hydrogen, and when R ₁ is

When, R ₁ can be bonded at any position marked with "*" as shown below:

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

Formula I includes its pharmaceutically acceptable salts and stereoisomers, wherein: R ₁ is

or

; And X and Z are the same or different, and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aralkyl , Heteroaralkyl, and heteroaryl group, optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, aryl Alkyl, heteroaralkyl, and heteroaryl groups are further substituted with one or more substituents selected from halogens such as chlorine, bromine, and fluorine, amines, hydroxyl groups, carboxylic acids, nitro groups, carbonyl groups, And other alkyl and aryl groups as defined herein; provided that at least one of X and Z is not hydrogen, and when R ₁ is

When, R ₁ can be bonded at any position marked with "*" as shown below:

. Such as the method of claim 1, where R ₁ is

. Such as the method of claim 1, where R ₁ is

. The method of claim 1, 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 the alkyl, alkene Groups, alkynyl groups, aryl groups, and heteroaryl groups are further substituted with one or more substituents selected from halogens such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, And other alkyl and aryl groups as defined herein; provided that at least one of X and Z is not hydrogen. Such as the method of claim 2, where R ₁ is

. The method of claim 2, 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 the alkyl, alkenyl Groups, alkynyl groups, aryl groups, and heteroaryl groups are further substituted with one or more substituents selected from halogens such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, And other alkyl and aryl groups as defined herein; provided that at least one of X and Z is not hydrogen. The method of claim 2, wherein the disorder is a mental illness. The method of claim 9, wherein the mental illness is selected from anxiety, depression, migraine, and obsessive-compulsive disorder. Such as the method of claim 3, where R ₁ is

. The method of claim 3, 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 the alkyl, alkene Groups, alkynyl groups, aryl groups, and heteroaryl groups are further substituted with one or more substituents selected from halogens such as chlorine, bromine, and fluorine, amine, hydroxyl, carboxylic acid, nitro, carbonyl, And other alkyl and aryl groups as defined herein; provided that at least one of X and Z is not hydrogen. The method of claim 3, wherein the disorder is a mental illness. The method of claim 13, wherein the mental illness is selected from the group consisting of anxiety, depression, migraine, and obsessive-compulsive disorder.

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