D 3 / d 2 receptor partial agonist and preparation method therefor

Abstract

Provided are a compound as a D3 / D2 receptor partial agonist which has a structure as represented by formula (I), or an isomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, a synthesis method therefor, and the use thereof. Compared with marketed drug cariprazine with the same target, the compound exhibits a stronger D3 receptor activity and a higher concentration of active metabolite didesmethyl cariprazine (DDCAR) in the brain of animals, and is expected to provide a superior therapeutic efficacy for the treatment of psychiatric disorders.

Description

D3 / D2 receptor partial agonists and their preparation methods

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese Patent Application No. 202510081037X, filed on January 20, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention belongs to the field of biomedical technology, specifically relating to a D3 / D2 receptor partial agonist or its isomer, hydrate, solvate and pharmaceutically acceptable salt thereof having the structure shown in formula (I), its synthesis method and uses. Background Technology

[0004] Caliprazine acts as a dopamine D3, preferred D3 / D2 receptor, and serotonin 5-HT receptor. 1A The receptor partial agonist, with the structure shown in formula (II), is mainly used to treat schizophrenia, manic or mixed episodes associated with bipolar I disorder, depressive episodes associated with bipolar I disorder, and as an adjunct treatment for major depressive disorder.

[0005] Cariprazine hydrochloride capsules (brand name Vraylar) require daily dosing to maintain their blood concentration, but this frequent dosing leads to poor patient adherence. Poor medication adherence is a common problem in various chronic diseases, but it is particularly prominent in patients with schizophrenia. The main reasons may be the side effects of psychiatric medications, such as the distress induced by extrapyramidal symptoms, which may interfere with the patient's perception of the drug's efficacy by impairing their ability to understand its benefits, disrupting the combined effects of treatment, and exacerbating drug-related stigma. Alternatively, in patients with cognitive impairment, insufficient insight coupled with memory loss may lead to forgetting to take medication, thus failing to correctly assess its effectiveness, resulting in decreased adherence. Previous literature reports medication non-adherence rates among schizophrenia patients ranging from 30% to 60%. Furthermore, studies have shown that poor medication adherence may increase the risk of violent behavior towards others and / or oneself, posing significant harm to patients, families, and society.

[0006] Long-acting injectable medications used to treat mental illnesses such as schizophrenia can be administered subcutaneously or intramuscularly. They create a drug reservoir at the injection site, providing a sustained release of the drug and extending the dosing cycle from once daily to once a month, or even once every three or six months. This maintains stable blood drug concentrations, effectively controlling symptoms and reducing disease fluctuations. This treatment approach not only improves patient adherence but also significantly reduces the risk of relapse and readmission, helping patients better reintegrate into society and resume normal lives.

[0007] Patent document CN108261394A discloses an injectable product of caliprazine hydrochloride, comprising an aqueous suspension and a lyophilized agent, providing sustained release for at least one week or longer. Patent document WO2020056929A discloses a novel crystal form of caliprazine hydrochloride, mentioning that caliprazine hydrochloride rapidly degrades into a free base in a pH 6.5 buffer solution, thus posing a dissociation risk in the suspension, altering drug solubility and absorption, and affecting drug efficacy and patient safety. Patent document CN114099512A discloses a caliprazine pharmaceutical composition comprising an aqueous suspension of caliprazine dihydroxynaphthyl salt, providing sustained release for at least one week in SD rats; however, due to the inevitable dissociation risk associated with salt formation, drug release is still affected. Existing technologies primarily address slow release by reducing solubility through caliprazine salt formation; there are no reports of modifying caliprazine to reduce water solubility.

[0008] Furthermore, while caliprazine offers certain advantages as a novel schizophrenia medication, it still has some drawbacks: In two late-stage clinical trials, the most common side effects in the schizophrenia treatment group using caliprazine included tremors, slurred speech, and involuntary muscle tremors, while the treatment group for bipolar disorder mostly experienced drug-related adverse events such as hyperactivity, indigestion, vomiting, drowsiness, and restlessness. Like other FDA-approved schizophrenia and bipolar disorder medications, caliprazine carries a black-box warning, alerting healthcare professionals to the potential increased risk of death in patients with dementia-related psychosis.

[0009] Given the aforementioned shortcomings, developing new antipsychotic drugs with better efficacy, safety, and patient compliance, and addressing the deficiencies of existing drugs, remains an urgent medical need. Summary of the Invention

[0010] In one aspect, the present invention provides a compound as a partial agonist of the D3 / D2 receptor, having the structure shown in formula (I):

[0011] Or its isomers, hydrates, solvates, or pharmaceutically acceptable salts.

[0012] in:

[0013] R1 is a hydrogen, amino, cyano, hydroxyl, halogen, or a straight-chain or branched C-type group, whether unsubstituted or substituted. 1-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-12 Alkenyl, unsubstituted or substituted straight or branched C 2-12 Alkyne group, unsubstituted or substituted straight or branched C 1-12Alkoxy, unsubstituted or substituted cycloalkyl or heterocyclic, or unsubstituted or substituted aryl or heteroaryl;

[0014] R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 4-12 Alkenyl, unsubstituted or substituted straight or branched C 4-12 Alkyne group, or unsubstituted or substituted straight or branched C 4-12 Alkyl group.

[0015] In other embodiments, R1 is hydrogen, amino, cyano, hydroxyl, halogen, or an unsubstituted or substituted straight-chain or branched C. 1-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-12 Alkenyl, unsubstituted or substituted straight or branched C 2-12 Alkyne group, unsubstituted or substituted straight or branched C 1-12 Alkoxy, unsubstituted or substituted aryl or heteroaryl;

[0016] R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 alkyl.

[0017] In other embodiments, R1 is hydrogen, unsubstituted or substituted straight-chain or branched C. 1-6 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-6 Alkenyl, unsubstituted or substituted straight or branched C 2-6 Alkyne group, unsubstituted or substituted straight or branched C 1-6 Alkoxy, unsubstituted or substituted phenyl, benzoyl or naphthyl;

[0018] R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 alkyl.

[0019] In another embodiment, R1 is hydrogen, unsubstituted or substituted straight-chain or branched C. 1-6 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-6 Alkenyl, unsubstituted or substituted straight or branched C 2-6 Alkyne group, unsubstituted or substituted straight or branched C 1-6 Alkoxy, unsubstituted or substituted phenyl, benzoyl or naphthyl;

[0020] R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 alkyl.

[0021] In other embodiments of the invention, R1 is hydrogen, unsubstituted or substituted straight-chain or branched C. 1-6 Alkyl group; R2 is an unsubstituted or substituted straight-chain or branched C2. 4-12 alkyl.

[0022] Preferably, R1 is methyl, ethyl, n-propyl or isopropyl, n-butyl, isobutyl or tert-butyl; R2 is an unsubstituted or substituted straight-chain C 4-12 Alkyl group.

[0023] R2 is a linear C that is either unsubstituted or substituted. 4-12 Alkyl groups, preferably C4, C8, or C6. 12 Alkyl, more preferably C4 or C8 alkyl.

[0024] On the other hand, the compound, or its isomer, hydrate, solvate, or pharmaceutically acceptable salt, provided by the present invention as a partial agonist of the D3 / D2 receptor, has the following structure:

[0025] The present invention provides compounds, isomers, hydrates, solvates, or pharmaceutically acceptable salts of D3 / D2 receptor partial agonists that are capable of binding to D2 / D3 receptors and 5-HT. 2B Receptors with EC50 values ​​below 10 nM in D3 receptor binding assays 50 In 5-HT 2B In receptor binding assays, the IC50 corresponds to values ​​below 20 nM. 50 .

[0026] On the other hand, the present invention also relates to a method for preparing the above-mentioned compound or its isomers, hydrates, solvates or pharmaceutically acceptable salts, comprising the following steps:

[0027] (1) Compound E is activated by p-methanesulfonyl chloride to generate active ester F;

[0028] (2) Compound H is prepared by a substitution reaction between active ester F and compound G;

[0029] (3) Compound H was further deprotected from BOC by hydrochloric acid to obtain compound I;

[0030] (4) Compound I reacts with the corresponding amine under the action of N,N'-carbonyldiimidazole to produce the final product shown in formula (I);

[0031] The specific reaction formula is as follows:

[0032] R1 and R2 are defined as above.

[0033] The present invention provides the use of the above-described compounds or their isomers, hydrates, solvates or pharmaceutically acceptable salts in the preparation of medicaments for the treatment and / or prevention of dopamine receptor-related diseases.

[0034] The dopamine receptor-related diseases include, but are not limited to, schizophrenia, schizoaffective disorder, cognitive impairment, dementia, dementia with comorbid psychotic disorders, bipolar disorder, depression, mania, bipolar disorder, anxiety disorder, and autism spectrum disorder. The dopamine receptor-related diseases include both negative and positive symptoms of schizophrenia, preferably negative symptoms of schizophrenia.

[0035] The present invention also provides a pharmaceutical composition comprising the above-described compound or its isomer, hydrate, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0036] The present invention also provides a pharmaceutical composition comprising the above-described compound or its isomers, hydrates, solvates or pharmaceutically acceptable salts, and another therapeutic molecule having therapeutic activity against mental illness.

[0037] Technical effect

[0038] The compound of formula (I) provided by this invention has stronger D3 receptor activity than cariprazine, and the concentration of active metabolite desdimethylcariprazine (DDCAR) in the animal brain is higher, which is expected to produce better efficacy in treating neuropsychiatric diseases; and the compound of formula (I) has lower water solubility than cariprazine, which can be further used in the development of long-acting formulations.

[0039] The inventors of this application, through research, surprisingly discovered that C4-C 12 Modifying cariprazine with long-chain alkyl groups as substituents can significantly reduce its water solubility (as described in Example 3). Developing the modified cariprazine derivatives into injectable suspensions can achieve sustained release for at least one month or longer (as described in Example 6), which will greatly improve patient compliance.

[0040] Further research by the inventors of this application has revealed that substituent-modified cariprazine exhibits stronger D3 receptor activity than cariprazine (Example 4), potentially leading to better therapeutic activity for treating neuropsychiatric disorders. When administered via injection, substituent-modified cariprazine can also significantly increase the concentration of the active metabolite desdimethylcariprazine (DDCAR) in the animal brain (Example 5). The literature [Preclinical pharmacodynamics and pharmacokinetic characteristics of major metabolites of cariprazine. Drug Design, Development and Therapy 2019:13,3229–3248.] shows that cariprazine (CAR) can be metabolized in the human body into the active metabolites desmethylcariprazine (DCAR) and desdimethylcariprazine (DDCAR), and the three have similar D3 / D2 target activities. Since the half-lives of CAR, DCAR and DDCAR in the human body are 1-3 days, 1-2 days and 2-3 weeks, respectively, after multiple administrations (more than 3 weeks) to reach steady-state blood drug concentrations, DDCAR is 2-3 times the CAR exposure. Since the activities of CAR, DCAR and DDCAR are comparable, it can be considered that DDCAR plays a more important role in maintaining drug efficacy. This demonstrates that the substituent-modified cariprazine provided by this invention, compared to cariprazine, produces a higher DDCAR concentration in the animal brain as a central nervous system drug, and can cross the blood-brain barrier, thereby increasing the drug concentration in the brain. It is evident that the pharmacokinetic properties of the compound of this invention are superior. It can be further reasonably understood that the clinical dosage of the compound of this invention will be lower, thereby reducing drug side effects. Attached Figure Description

[0041] Figure 1 shows caliprazine hydrochloride. 1 H-NMR spectrum.

[0042] Figure 2 shows the compound L 1 H-NMR spectrum.

[0043] Figure 3 shows the compound M. 1 H-NMR spectrum.

[0044] Figure 4 shows the pharmacokinetic results of intramuscular injection of compound L suspension in rats.

[0045] Figure 5 shows the results of the total distance of an open field test of compound L in rats administered via intramuscular injection in Example 7.

[0046] Figures 6, 7, and 8 show the results of the central distance, central time, and central average velocity of the open field test of compound L in rats administered via intramuscular injection in Example 7. Detailed Implementation

[0047] The following description of the invention is intended only to illustrate various embodiments of the invention. The specific embodiments described should not be construed as limiting the scope of the invention. Various equivalent substitutions, changes, or modifications can be made by those skilled in the art without departing from the spirit and essence of the invention, and it should be understood that these equivalent embodiments are also included herein. All documents cited herein, including publications, patents, and patent applications, are incorporated herein by reference in their entirety.

[0048] I. Terminology

[0049] In this invention, unless the context otherwise requires, the words, phrases, and symbols used below have the following meanings. The meanings of the following abbreviations and terms are consistent throughout the text:

[0050] The term "alkyl" refers to a hydrocarbon group selected from saturated straight-chain and branched hydrocarbon groups, comprising 1-12, 1-8, or 1-6 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), and 1,1-dimethylethyl or tert-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0051] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, which includes at least one C=C double bond and 2-12 or 2-6 carbon atoms. Examples of alkenyl groups may be selected from vinyl, propenyl, propenyl, 2-propenyl, 2-methylpropenyl, butenyl, butenyl, butenyl, 3-alkenyl, butenyl-1,3-dienyl, 2-methylbutenyl-1,3-dienyl, hexenyl, hexenyl-2-alkenyl, hexenyl-3-alkenyl, hexenyl-4-alkenyl, and hexenyl-1,3-dienyl groups.

[0052] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, which includes at least one C≡C triple bond and 2-12 or 2-6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0053] The term "alkoxy" refers to an alkyl group with a specified number of carbon atoms connected by an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. In specific embodiments of the present invention, the alkoxy group typically has 1 to 12 carbon atoms connected to the oxygen bridge, preferably 1 to 6 carbon atoms connected to the oxygen bridge.

[0054] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cycloalkyl groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group can have 3-12, 3-8, or 3-6 carbon atoms. Additionally, a cycloalkyl group can be a monocyclic group having 3-12, 3-8, or 3-6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include bicyclic rings consisting of 7-12 ring atoms arranged in a ring system selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or bridged bicyclic rings selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. The rings may be saturated or have at least one double bond (i.e., partially unsaturated), but are not fully conjugated and are not aromatic (as defined herein).

[0055] The term "heterocyclic group" refers to a cycloalkyl group that includes at least one heteroatom, such as containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, or saturated and partially unsaturated rings selected from 4-12 member monocyclic, bicyclic and tricyclic rings, which contain at least one carbon atom in addition to 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0056] The term "aryl" refers to a group selected from: 5- and 6-membered carbocyclic aromatic rings, such as phenyl; bicyclic systems such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic ring and an aromatic ring, selected from, for example, naphthalene, 1,2-dihydroindene, and 1,2,3,4-tetrahydroquinoline; and tricyclic systems such as 10- to 15-membered tricyclic systems, wherein at least one ring is a carbocyclic ring and an aromatic ring, such as fluorene.

[0057] The term "heteroaryl" refers to a group selected from the following:

[0058] 5-7 aryl aromatic monocyclic rings, which contain 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon;

[0059] An 8-12 membered bicyclic ring comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, and at least one ring being aromatic, and at least one heteroatom present in the aromatic ring; and

[0060] 11-14 membered tricyclic rings, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon, and at least one of the rings being aromatic, and at least one heteroatom being present in the aromatic ring.

[0061] The term "halogen" or "halogen" refers to F, Cl, Br, or I.

[0062] The term "pharmaceutically acceptable salt" refers to a salt that retains the bioavailability and properties of a compound, including, for example, metal salts, salts formed with organic bases, salts formed with inorganic acids, and salts formed with basic or acidic amino acids. For example, non-limiting examples of metal salts include, but are not limited to, salts of alkali metals, such as sodium and potassium salts; and salts of alkaline earth metals, such as calcium, magnesium, barium, and aluminum salts. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0063] The term "dopamine receptor" refers to a collection of extracellular proteins that can receive signals and activate internal signal transduction pathways, triggering cellular responses. Dopamine receptors are found on cells within the central nervous system of organisms. Known dopamine receptors include dopamine D1, dopamine D2, and dopamine D3 receptors. Multiple studies have shown that drugs can improve cognitive impairment, psychotic disorders, neurotransmitter-mediated disorders, and / or neuronal diseases by binding to, blocking, or affecting dopamine receptor activity.

[0064] The term “treatment” refers to administering at least one compound and / or at least one stereoisomer of the compound and / or at least one pharmaceutically acceptable salt thereof to a subject deemed to be in need of treatment, such as schizophrenia.

[0065] The term "effective amount" refers to an amount of at least one compound and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective in treating a subject's disease or condition, such amount eliciting a biological or medical response in the studied tissue, system, animal, or human, and sufficient to prevent, treat, or halt the development of one or more symptoms of the disease. Therapeutic effective amounts vary depending on the compound, the disease and its severity, the age and weight of the mammal to be treated, etc.

[0066] Compounds of Formula I include, but are not limited to, optical isomers, racemates, and other mixtures of compounds of Formula I. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or resolution of the racemate. Resolution of the racemate can be achieved by conventional methods such as crystallization in the presence of a resolving agent, or by chromatography using a chiral high-performance liquid chromatography (HPLC) column. When compounds of Formula I exist in a variety of tautomeric forms, the chemical entities of the present invention include all tautomeric forms of the compound. The compound may contain one asymmetric center and thus may exist as an enantiomer. When the compound has two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall into the broader category of stereoisomers. All these possible stereoisomers include substantially pure resolved enantiomers, mixtures of their racemates, and mixtures of diastereomers. A mixture of diastereomers can be separated into individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. This includes all stereoisomers of the compound and / or pharmaceutically acceptable salts thereof. Unless otherwise stated, the reference to one isomer applies to any possible isomer. When an isomer component is not specifically specified, all possible isomers are included. In a specific embodiment of the invention, the structure involved is its trans configuration.

[0067] II. Compounds

[0068] This invention provides compounds represented by Formula I.

[0069] R1 is a hydrogen, amino, cyano, hydroxyl, halogen, or a straight-chain or branched C-type group, whether unsubstituted or substituted. 1-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-12 Alkenyl, unsubstituted or substituted straight or branched C 2-12 Alkyne group, unsubstituted or substituted straight or branched C 1-12 Alkoxy, unsubstituted or substituted cycloalkyl or heterocyclic, or unsubstituted or substituted aryl or heteroaryl;

[0070] R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 4-12 Alkenyl, unsubstituted or substituted straight or branched C 4-12 Alkyne group, or unsubstituted or substituted straight or branched C 4-12 Alkyl group.

[0071] In some specific embodiments of the present invention, R2 is an unsubstituted or substituted linear or branched C 4-12 alkyl.

[0072] In some specific embodiments of the present invention, R1 is hydrogen, unsubstituted or substituted straight-chain or branched C. 1-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-12 Alkenyl, unsubstituted or substituted straight or branched C 2-12 Alkyne group, unsubstituted or substituted straight or branched C 1-12 Alkyl, unsubstituted or substituted phenyl, benzoyl, or naphthyl. In some specific embodiments of the invention, R1 is hydrogen, unsubstituted or substituted straight-chain or branched C. 1-6 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-6 Alkenyl, unsubstituted or substituted straight or branched C 2-6 Alkyne group, unsubstituted or substituted straight or branched C 1-6 Alkoxy, unsubstituted or substituted phenyl, benzoyl or naphthyl.

[0073] In some specific embodiments of the present invention, R1 is hydrogen, unsubstituted or substituted straight-chain or branched C. 1-6 Alkyl group; R2 is an unsubstituted or substituted straight-chain or branched C2. 4-12 Alkyl group. Preferably, in some embodiments of the present invention, R1 is hydrogen, methyl, ethyl, n-propyl or isopropyl, n-butyl, isobutyl or tert-butyl. For example, in some embodiments of the present invention, R2 is an unsubstituted or substituted straight-chain or branched C2. 4-12 Alkyl group, where R1 is hydrogen. In another preferred embodiment of the invention, R2 is an unsubstituted or substituted straight-chain or branched C2. 4-12 Alkyl group, R1 is methyl. In other embodiments of the invention, R2 is an unsubstituted or substituted straight-chain or branched C2. 4-12 Alkyl group, R1 is ethyl group.

[0074] In some specific embodiments of the present invention, R1 is a methyl group.

[0075] In some specific embodiments of the present invention, R2 is C4, C8, C 12 alkyl.

[0076] This invention includes all combinations of the specific or preferred embodiments listed.

[0077] On the other hand, the compound of formula I provided by the present invention, wherein R1 is methyl and R2 is C4, C8, or C6. 12Alkyl group. In a preferred embodiment of the present invention, R2 is a C4 or C8 alkyl group.

[0078] In a specific embodiment, the present invention provides a compound as a partial agonist of the D3 / D2 receptor, having the following structure:

[0079] This invention provides compounds of formula (I), isomers, hydrates, solvates, or pharmaceutically acceptable salts of compounds of formulas (L, M, N). For example, pharmaceutically acceptable salts include metal salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids. Examples include sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, aluminum salts, hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, formates, acetates, trifluoroates, fumarates, oxalates, malic acid, maleate, tartrates, citrates, succinates, methanesulfonates, benzenesulfonates, and p-toluenesulfonates. Salts described herein include monobasic, dibasic, ternary, and other possible polybasic salts.

[0080] The compound shown in formula (I) can bind to the D3 / D2 receptor and 5-HT. 2B Receptors, used as partial agonists of D3 / D2 receptors. In embodiments of the invention, the inventors unexpectedly discovered that the compound of formula (I) exhibits superior binding activity to the D3 receptor compared to cariprazine, EC 100%. 50 The values ​​differ by 7 to 13 times, while 5-HT 2B The receptor activity is substantially equivalent to that of cariprazine. In some embodiments of the invention, the compound of formula (I) has an EC50 corresponding to less than 10 nM in the D3 receptor binding assay. 50 In 5-HT 2B In receptor binding assays, the IC50 corresponds to values ​​below 20 nM. 50 In other embodiments of the present invention (Example 7), in pharmacological studies of the compound represented by Formula I, relative to cariprazine hydrochloride, compound L significantly increased the central distance, central time, and central average velocity of animals in open field experiments, and can serve as a new potential drug molecule for improving negative symptoms of schizophrenia.

[0081] III. Treatment Methods and Pharmaceutical Uses

[0082] This invention relates to the use of compounds of formula (I) or isomers thereof, hydrates, solvates or pharmaceutically acceptable salts in the preparation of medicaments for the treatment and / or prevention of dopamine receptor-related diseases.

[0083] On the other hand, the present invention also relates to methods for treating and / or preventing dopamine receptor-related diseases, comprising administering to a patient suffering from a dopamine receptor-related disease an effective amount of the compound or isomer, hydrate, solvate or pharmaceutically acceptable salt of formula (I) above.

[0084] The dopamine receptor-related diseases involved in this invention include schizophrenia, schizoaffective disorder, dementia, dementia with accompanying psychotic and behavioral disorders, bipolar disorder, depression, mania, bipolar disorder, anxiety disorder, and autism spectrum disorder. Schizophrenia, as discussed here, includes both positive and negative symptoms of schizophrenia; bipolar disorder includes recurrent, intermittent manic or hypomanic and depressive symptoms, or a combination thereof; and depression includes mild, moderate, and severe depression. In a preferred embodiment of this invention, the invention relates to the use of compounds of formula (I) or isomers thereof, hydrates, solvates, or pharmaceutically acceptable salts in the preparation of medicaments for treating and / or preventing negative and positive symptoms of schizophrenia, preferably negative symptoms of schizophrenia.

[0085] In a specific embodiment of the present invention, the compound involved in the present invention (e.g., compound L) is administered to rats, and the results of the open field test in the rats after administration are evaluated. The compound involved in the present invention can significantly and effectively reduce the total distance traveled and average speed of experimental animals, and in particular, can significantly increase the central distance traveled and central time traveled, superior to cariprazine hydrochloride, and therefore serves as a potential drug for improving negative symptoms of schizophrenia. The open field test, also known as the open-box test, is a method for evaluating the autonomous behavior, exploratory behavior, and anxiety-like behavior of experimental animals in unfamiliar environments. The frequency and duration of normal activity, fear of open environments, and exploration of new environments in the experimental animal within the open box are used to reflect the autonomous and exploratory behavior of the experimental animal in an unfamiliar environment. Analysis of the open field test results can be used to assess depressive and anxiety-like behaviors in animals, for example, by evaluating schizophrenia symptoms and the levels of negative and positive symptoms based on total distance traveled and central area activity (time, distance). Generally, a decrease in central area activity corresponds to negative symptoms of schizophrenia and / or anxiety and avoidance behaviors, while an increase corresponds to the relief of behavioral inhibition or improvement of negative symptoms, or is associated with positive symptoms or impulse control disorders.

[0086] In the described uses or treatments, the compound or isomer, hydrate, solvate or pharmaceutically acceptable salt or pharmaceutical composition thereof represented by formula (I) of the present invention can be administered in a known manner, such as oral, rectal, parenteral (e.g., subcutaneous, intradermal, intravenous, intramuscular or infusion), inhalation spray, etc.

[0087] The dosage will vary depending on the route of administration, the patient's age, weight, and the type and severity of the disease being treated. Typically, the daily dose of the active ingredient can be variable, for example, 0.001-30 mg / kg body weight (oral) or 0.001-30 mg / kg body weight (injection), administered once or multiple times to effectively achieve the desired effect.

[0088] The compound or isomer, hydrate, solvate or pharmaceutically acceptable salt or pharmaceutical composition thereof of formula (I) of the present invention may be administered alone as the sole active ingredient to treat or prevent dopamine receptor-related mental disorders.

[0089] In some embodiments of the present invention, the compound or isomer of formula (I), hydrate, solvate or pharmaceutically acceptable salt or pharmaceutical composition thereof, or in combination with another therapeutic molecule that has therapeutic activity against mental illness, such as in combination with drugs like trazodone, clozapine, quetiapine, lurasidone, mianserin, lithium salt, lamotrigine, etc., are used to treat mental illness. However, when drugs are used in combination, the dosage is adjusted according to the patient's disease type, severity, and in conjunction with the physician's professional judgment.

[0090] IV. Pharmaceutical Compositions

[0091] The present invention also provides pharmaceutical compositions of the compound or isomer, hydrate, solvate or pharmaceutically acceptable salt of formula (I), comprising the above-described compound or isomer, hydrate, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0092] In some embodiments of the present invention, the pharmaceutical composition is a solid dosage form, such as capsules, tablets, sugar-coated tablets, granules, and powders, typically including diluents, excipients, binders, fillers, disintegrants, etc. In other embodiments, the pharmaceutical composition is a liquid oral dosage form, such as syrups, emulsions, dispersants, suspensions, etc. The pharmaceutical compositions involved in the present invention can also be sterile liquid dosage forms, such as dispersants, suspensions, or solutions. Liquid formulations typically include solubilizers, suspending agents, buffers, pH adjusters, etc. Additionally, the pharmaceutical compositions involved in the present invention can be aerosol sprays, powder compositions for inhalation or nasal administration, or ophthalmic solutions, suspensions, etc., for ocular administration.

[0093] In some embodiments of the present invention, the pharmaceutical composition of the present invention comprises the compound or isomer shown in (I), a hydrate, a solvate or a pharmaceutically acceptable salt, and another therapeutic molecule; this other therapeutic molecule has therapeutic activity for mental illness, or therapeutic / preventive activity for other diseases, such as complications of mental illness, such as cardiovascular diseases like hypertension and coronary heart disease, neurological diseases like epilepsy and Parkinson's disease, endocrine diseases like thyroid disease and diabetes, and digestive diseases like gastritis and ulcers.

[0094] V. Preparation Method

[0095] The present invention also provides a method for preparing the above-mentioned compound or its isomers, hydrates, solvates or pharmaceutically acceptable salts, characterized by comprising the following steps:

[0096] (1) Compound E is activated by p-methanesulfonyl chloride to generate active ester F;

[0097] (2) Compound H is prepared by a substitution reaction between active ester F and compound G;

[0098] (3) Compound H was further deprotected from BOC by hydrochloric acid to obtain compound I;

[0099] (4) Compound I reacts with the corresponding amine under the action of N,N'-carbonyldiimidazole to produce the final product shown in formula (I);

[0100] The specific reaction formula is as follows:

[0101] R1 and R2 are as described in this article.

[0102] The compounds of the present invention or their isomers, hydrates, solvates or pharmaceutically acceptable salts may be prepared from: (a) commercially available starting materials; (b) known starting materials prepared as described in the literature; and (c) intermediates described in the examples and experimental procedures herein.

[0103] Example

[0104] Example 1: Synthesis of caliprazine hydrochloride

[0105] Step 1:

[0106] In a dry 500 mL double-necked flask, 100 mL of anhydrous tetrahydrofuran was added. After cooling to 0 °C, NaH (60%, 9.844 g, 246 mmol, 5.35 equiv.) was added dropwise. Under nitrogen atmosphere, triethyl phosphonoacetate B (10 mL, 50.6 mmol, 1.1 equiv.) was slowly added dropwise. After the addition was complete, a solution of 4-N-Boc-aminocyclohexanone A (9.810 g, 46 mmol, 1.0 equiv.) in 100 mL of anhydrous tetrahydrofuran was added dropwise. After the addition was complete, the mixture was brought to room temperature. After the reaction was complete, the mixture was cooled to 0 °C, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, the organic phase was separated, dried over sodium sulfate, filtered, and concentrated to give compound C (12.4 g).

[0107] Step Two:

[0108] Compound C (12.4 g), methanol (80 mL), and 10% palladium on carbon (0.62 g) were added to a 200 mL reaction flask. Hydrogen gas was displaced three times under ice bath conditions, and the reaction was carried out at room temperature. After the reaction was complete, the palladium on carbon was removed by filtration with diatomaceous earth. The filtrate was concentrated to obtain the crude product. Recrystallization with n-hexane yielded a white solid D (11.6 g).

[0109] Step 3:

[0110] Lithium aluminum hydride (1.441 g, 37.9 mmol, 3.0 equiv.) and anhydrous THF (22 mL) were added to a 100 mL reaction flask. After cooling to 0 °C, compound D (3.6 g, 12.6 mmol, 1.0 equiv.) was added. After the reaction was complete, the mixture was quenched by slowly adding 15% KOH solution under ice bath conditions. The mixture was filtered through diatomaceous earth and concentrated to obtain compound E (2.3 g).

[0111] Step Four:

[0112] Add E (2.3 g, 9.57 mmol, 1.0 equiv) and dichloromethane (32 mL) to a 100 mL reaction flask. After cooling to 0 °C, slowly add triethylamine (2.66 mL, 19.14 mmol, 2.0 equiv.) and p-toluenesulfonyl chloride (2.7 g, 14.4 mmol, 1.5 equiv.). Raise to room temperature. After the reaction is complete, add water and dichloromethane, stir, allow to stand and separate into layers, separate the organic phase, dry with sodium sulfate, filter, and concentrate. Column chromatography yields compound F (3.36 g).

[0113] Step 5:

[0114] Compound F (3.36 g, 8.46 mmol, 1.0 equiv.), acetonitrile (38 mL), compound G (2.605 g, 9.74 mmol, 1.15 equiv.), and potassium carbonate (2.576 g, 18.63 mmol, 2.2 equiv.) were added to 100 mL reaction flasks. The mixture was heated under reflux for 8 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, water (40 mL) was added, and the mixture was stirred. The mixture was then filtered and dried to obtain compound H (4.13 g).

[0115] Step Six:

[0116] Dichloromethane (40 mL) and compound H (4.13 g, 1.0 equiv.) were added to a 100 mL reaction flask. After cooling to 0 °C, trifluoroacetic acid (8.5 mL, 84.6 mmol, 10 equiv.) was slowly added dropwise. The mixture was then allowed to react at room temperature for 1 hour. After the reaction was complete, the pH was adjusted to 10 with 4N NaOH. The organic phase was separated, dried, filtered, and concentrated to obtain compound I (2.15 g).

[0117] Step Seven:

[0118] Add I (2.15 g, 1.0 equiv.) and tetrahydrofuran (30 mL) to a 100 mL reaction flask. After cooling to 0 °C, slowly add triethylamine (1.69 mL, 12.14 mmol, 2.0 equiv.) and N,N-dimethylformyl chloride (0.9 mL, 9.7 mmol, 1.6 equiv.), respectively. After the addition is complete, move the mixture to room temperature. After the reaction is complete, add water and dichloromethane, stir, and allow to stand for phase separation. Separate the organic phase, dry it with sodium sulfate, filter, and concentrate. Silica gel column chromatography yields carrillazine free base J (2.4 g).

[0119] Step 8:

[0120] The free base J of cariprazine was dissolved in ethyl acetate, and concentrated HCl was slowly added dropwise at 0°C, with pH ≤ 2. The solution was concentrated under reduced pressure to obtain compound K. The NMR spectrum of compound K is shown in Figure 1.

[0121] Example 2: Synthesis of compounds L1, L, M and N

[0122] 2.1 Synthesis of compound L1:

[0123] Compound I (2.15 g, 6.06 mmol) and anhydrous tetrahydrofuran (30 mL) were added to a 100 mL reaction flask. After cooling to 0 °C, triethylamine (1.24 g, 12.14 mmol) and N-methyl-N-n-propylcarbamoyl chloride (0.82 g, 6.06 mmol) were slowly added, respectively. After the addition was complete, the mixture was moved to room temperature. After the reaction was complete, water and dichloromethane were added, the mixture was stirred, and allowed to stand to separate the layers. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated. Silica gel column chromatography was used to obtain compound L1 (2.56 g), the structure of which was confirmed by mass spectrometry (MS = 455.24 (M+H)). + .

[0124] 2.2 Synthesis of compound L:

[0125] Compound I (20.0 g, 56.34 mmol), DMF (300 mL), N,N'-carbonyldiimidazole (9.12 g, 56.34 mmol), and N,N-diisopropylethylamine (7.27 g, 56.34 mmol) were added to a 500 mL reaction flask. The mixture was reacted at 25 °C for 1 hour. Then, N-methylbutanamine (4.90 g, 56.34 mmol) was added, and the mixture was reacted at 25 °C for 2 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, the organic phase was separated, dried, filtered, and concentrated. Silica gel column chromatography yielded 22.24 g of compound L. The structure was confirmed by mass spectrometry and nuclear magnetic resonance (MS = 469.24 (M+H)). + .

[0126] 1 H NMR (400MHz, CDCl3) δ=7.19–7.11(m,2H),6.96(dd,J=6.6,3.0Hz,1H),4.09(d,J=7.6H z,1H),3.69–3.52(m,1H),3.28–3.18(m,2H),3.10(s,4H),2.86(d,J=11.2Hz,3H),2.6 The NMR spectrum of compound L is shown in Figure 2. (Note: The original text contains inconsistencies and inconsistencies in the NMR spectrum, which are not translated as they are not part of the main NMR spectrum.)

[0127] 2.3 Synthesis of compound M:

[0128] Compound I (2.15 g, 6.06 mmol) and tetrahydrofuran (30 mL) were added to a 100 mL reaction flask. Triethylamine (1.24 g, 12.14 mmol) and N-methyl-N-octylcarbamoyl chloride (1.24 g, 6.06 mmol) were slowly added separately under ice bath conditions. After the addition was complete, the mixture was moved to room temperature. After the reaction was complete, water and dichloromethane were added, the mixture was stirred, and allowed to stand for phase separation. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated. Silica gel column chromatography was used to obtain compound M. The structure was confirmed by NMR, and the NMR spectrum of compound M (2.89 g) is shown in Figure 3.

[0129] 2.4 Synthesis of Compound N

[0130] Compound I (2.15 g, 6.06 mmol) and anhydrous tetrahydrofuran (30 mL) were added to a 100 mL reaction flask. After cooling to 0 °C, triethylamine (1.24 g, 12.14 mmol) and N-methyl-N-dodecylcarbamoyl chloride (1.58 g, 6.06 mmol) were slowly added, respectively. After the addition was complete, the mixture was allowed to react at room temperature. After the reaction was complete, water and dichloromethane were added, the mixture was stirred, and allowed to stand to separate the layers. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated. Silica gel column chromatography was used to give compound N (3.38 g). The structure was confirmed by mass spectrometry, MS = 581.37 (M+H). + .

[0131] Example 3: Solubility determination of compounds L1, L, M, and N

[0132] The solubility of compounds L1, L, M, and N in saturated aqueous solutions (pH 6.0–7.0) was determined, and the results are shown in Table 1. The results indicate that the solubility of compound L1 is comparable to that of cariprazine, while compounds L, M, and N have significantly lower water solubility (more than 10 times lower) compared to cariprazine.

[0133] Table 1 Solubility of Compounds

[0134] Example 4: The compound's D3 receptor and 5-HT 2B Receptor affinity assay

[0135] This embodiment analyzes the effects of the compounds of the present invention on the D3 receptor and 5-HT. 2B Receptor affinity. Cariporazine possesses partial affinity for D2 receptors and D3 receptors, preferentially acting on D3 receptors, and its potency against D3 receptors is 10 times that against D2 receptors. It also has affinity for 5-HT. 2BThe receptors also exhibit high affinity, characteristics that distinguish this drug from other second-generation antipsychotics. Therefore, the inventors of this patent focused on measuring the affinity of compounds L1, L, M, and N for D3 receptors and 5-HT. 2B In vitro activity of the receptor.

[0136] The assay method is LANCE or HTRF, which measures the effect of compounds on D by detecting changes in intracellular cAMP or IP1 levels. 2S D 2L D3,5-HT 1A 5-HT 2A and 5-HT 2B The role of the receptor. Eight concentrations of compounds from all targets were detected in two replicates, including D. 2S D 2L In the D3 agonist assay, the detection concentration was 2 μM, with 5-fold serial dilutions; 5-HT 1A In the agonist assay, the detection concentration was 10 μM, with 5-fold serial dilutions; 5-HT 2A and 5-HT 2B In the partial agonist assay, the detection concentration was 50 μM, with 5-fold serial dilutions. The results showed that different compounds exhibited varying degrees of agonist or partial agonist activity at different target sites (D...). 2S D 2L D3, 5-HT 1A 5-HT was detected using the LANCE method. 2A and 5-HT 2B Detection was performed using the HTRF method. Target point D was tested. 2S D 2L The positive drug for group D3 was dopamine; the target was 5HT. 1A The positive drug in this group was 5HT; the target was 5HT. 2A The positive drug in this group was ketanserin; target 5HT. 2B The positive drug in the group was 5-HT 2B The receptor partial agonist RS127445.

[0137] The results are shown in Table 2. The results indicate that the in vitro activity of compound L1 is comparable to that of cariprazine, while compounds L, M, and N exhibit significantly better activity against the D3 receptor than cariprazine (ECG). 50 The values ​​differed by 7 to 13 times, and the highest inhibition rate was significantly increased at high concentrations, for 5-HT 2B The receptor activity is comparable to that of cariprazine, suggesting that compounds L, M, and N may produce better therapeutic effects in patients.

[0138] Table 2. In vitro target activity of the compounds

[0139] Example 5: Pharmacokinetic study of compound administered intravenously to rats

[0140] The literature [Preclinical Pharmacodynamics and Pharmacokinetic Characteristics of Major Metabolites of Cariprazine. Drug Design, Development and Therapy. 2019:13,3229–3248.] shows that cariprazine (CAR) can be metabolized in the human body into the active metabolites desmethylcariprazine (DCAR) and desdimethylcariprazine (DDCAR), and all three have similar D3 / D2 target activities. Since the half-lives of CAR, DCAR, and DDCAR in the human body are 1-3 days, 1-2 days, and 2-3 weeks, respectively, after multiple administrations (more than 3 weeks) to reach steady-state plasma concentrations, DDCAR is 2-3 times the CAR exposure. Given the comparable activity of CAR, DCAR, and DDCAR, it can be considered that DDCAR plays a more important role in maintaining efficacy. Therefore, the inventors of this patent used SD rats and administered the drug intravenously (2.5 mg / kg) to determine the plasma and brain tissue concentrations of the active metabolite DDCAR after intravenous administration.

[0141] Measurement method:

[0142] 1. Pharmacokinetic study of intravenous administration of caliprazine hydrochloride, compounds L, and M to SD rats

[0143] Six male SD rats were included in each test group and administered the drug intravenously at a dose of 2.5 mg / kg. Blood samples were collected before administration and at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, and 144 h after administration.

[0144] Collection method: At the corresponding time point, collect about 150 μL of whole blood per animal per collection from the jugular vein and place it in an anticoagulant blood collection tube containing EDTA-K2. Gently invert the tube several times to ensure that the sample and anticoagulant are thoroughly mixed. After blood collection, place the blood in an ice box / wet ice for temporary storage and centrifuge at about 5000 rpm for 10 min at 4°C within 0.5 h after blood collection. After centrifugation, collect the plasma and transfer it to an ultra-low temperature freezer (-60°C to -86°C) for storage.

[0145] Sample pretreatment and analysis: Add 200 μL of internal standard solution (30 ng / mL glipizide) to 30 μL of plasma sample, vortex for 5 minutes, centrifuge at 4500 rpm for 8 minutes at 4℃, transfer 100 μL of supernatant to a new plate, add 50 μL of water, vortex, and take 5 μL for LC-MS / MS to detect the parent drug, DCAR, and DDCAR in the plasma (limit of quantitation is 0.5 ng / mL). Calculate the Tg using PhoenixWinNonlin. 1 / 2 T max C max MRT, CL, Vd, AUC 0-t AUC 0-∞ Pharmacokinetic parameters, etc.

[0146] 2. Drug distribution in the brain tissue of SD rats after intravenous administration of caliprazine hydrochloride, compounds L, and M

[0147] Eighteen male SD rats were included in each test group. The rats were administered the drug intravenously at a dose of 2.5 mg / kg. Animals numbered 01–03, 04–06, 07–09, 10–12, 13–15, and 16–18 were assigned to the group at 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. Approximately 300 μL of whole blood was collected from the jugular vein per rat at each time point. The blood was placed in an anticoagulant blood collection tube containing EDTA-K2 and gently inverted several times to ensure thorough mixing with the anticoagulant. The collected blood was immediately placed on ice / wet ice for temporary storage and centrifuged at approximately 5000 rpm for 10 min at 4°C within 0.5 h of collection. After centrifugation, the plasma was collected and stored in an ultra-low temperature freezer (-60°C to -86°C).

[0148] After blood collection, an overdose of veterinary anesthetic (Shutai 50) was immediately administered, followed by thoracotomy. After perfusion of the heart with physiological saline, the complete brain tissue (including the cerebellum and olfactory bulb) was extracted. After sampling, the brain tissue was evenly divided into left and right halves along the midline. The right hemisphere was homogenized for testing, while the left hemisphere was stored in an ultra-low temperature freezer (-60℃ to -86℃). The homogenate of the right hemisphere was homogenized and then stored in an ultra-low temperature freezer (-60℃ to -86℃).

[0149] Sample pretreatment and analysis: Add 200 μL of internal standard solution (30 ng / mL glipizide) to 30 μL of plasma sample, vortex for 5 minutes, centrifuge at 4500 rpm for 8 minutes at 4℃, transfer 100 μL of supernatant to a new plate, add 50 μL of water, vortex, and take 5 μL for LC-MS / MS to detect the parent drug, DCAR, and DDCAR in plasma / brain tissue (limit of quantitation: 0.5 ng / mL). Calculate T using Phoenix WinNonlin. 1 / 2 Tmax C max Pharmacokinetic parameters such as MRT, CL, Vd, AUC0-t, and AUC(0-∞) were measured.

[0150] The results are shown in Tables 3 and 4. The results indicate that compounds L and M provided by this invention, especially compound L, have higher concentrations and exposure levels of DDCAR in rat plasma and brain than cariprazine.

[0151] Table 3. Pharmacokinetic parameters of DDCAR in plasma after intravenous administration to rats.

[0152] Table 4. Distribution of DDCAR in rat brain tissue after intravenous administration (ng / g)

[0153] Example 6: Pharmacokinetic study of intramuscular injection of compound L suspension in rats

[0154] A suspension of compound L was prepared by grinding and administered to rats via a single intramuscular dose to evaluate the pharmacokinetics of cariprazine and compound L.

[0155] Sixteen male SD rats were divided into two groups. Before administration, the rats were fasted for more than 12 hours and allowed free access to water. The rats in the two groups were injected intramuscularly with the same dose of compound L suspension and cariprazine hydrochloride solution (both calculated as free cariprazine base; sealed and stored at 2-8℃). The rats were fed 2 hours after administration.

[0156] Design of plasma sample collection time points for rats in the compound L suspension group: before drug administration, 0.25h, 1h, 2h, 5h, 7h, 24h, 48h (2 days), 72h (3 days), 96h (4 days), 120h (5 days), 144h (6 days), 168h (7 days), 216h (9 days), 288h (12h), 336h (14 days), 408h (17 days), 504h (21 days), 672h (28 days), and 840h (35 days);

[0157] The time points for collecting plasma samples from rats in the cariprazine hydrochloride solution group were designed as follows: before administration, 0.083h, 0.025h, 0.5h, 1h, 5h, 7h, 24h and 48h after administration.

[0158] Plasma sample collection: 150 μL of blood was collected from the jugular vein (whole blood was centrifuged to separate plasma within 30 minutes) and placed in a test tube containing the anticoagulant EDTA-K2. Within 0.5 h after blood collection, the plasma was centrifuged at 4°C and approximately 5000 rpm for 10 min. After centrifugation, the plasma was collected and stored in an ultra-low temperature freezer (-60°C to -86°C) for testing.

[0159] Plasma sample pretreatment and analysis: Add 200 μL of internal standard solution (30 ng / mL glipizide) to 30 μL of plasma sample, vortex mix for 5 minutes, centrifuge at 4500 rpm for 8 minutes at 4℃, transfer 100 μL of supernatant to a new plate, add 50 μL of water, vortex mix, and take 5 μL for LC-MS / MS analysis of active substances / metabolites in plasma sample: parent drug, desmethylcariprazine and desdimethylcariprazine (DCAR, DDCAR), and calculate the sum of the concentrations of the three (as the blood drug concentration).

[0160] The pharmacokinetic results in rats are shown in Figure 4. The results indicate that cariprasazine hydrochloride injection solution (solution group) rapidly reaches peak concentration in vivo and then is quickly eliminated. In contrast, compound L suspension (suspension group) shows sustained and stable drug release after intramuscular injection, demonstrating the ability to achieve long-acting drug delivery.

[0161] Example 7: Pharmacodynamic study of intramuscular injection of compound L suspension in rats

[0162] In this embodiment, open field tests were conducted on experimental animals at different time points after administration of compound L to study the changes in activity of rats after a single intramuscular injection of compound L suspension.

[0163] Experimental methods

[0164] Thirty-six male Wistar rats (SPF grade) were randomly divided into three groups according to their body weight, with six rats in each group at each time point. Cariporazine hydrochloride and compound L were administered via a single intramuscular injection at a volume of 1.0 mL / kg. The date of the first administration was recorded as day 1 (D1).

[0165] At 8 h, 72 h, and 168 h after drug administration, rats in each group were subcutaneously injected with apomorphine (0.5 mg / kg). Five minutes after injection, the rats were placed in an open field box and allowed to explore freely for 30 minutes. A camera above the open field box recorded the entire activity process. The total distance traveled, central distance traveled, central time traveled, and central average speed of the rats during the exploration period were calculated by an automatic data acquisition and processing system. The activity trajectory was analyzed to assess the rats' motor function and spontaneous activity.

[0166] Experimental results

[0167] Based on the open field test results of the cariprazine hydrochloride group and the compound L group at 8 hours, 72 hours, and 168 hours after animal administration, respectively, after injection of apomorphine (0.5 mg / kg), the movement results are shown in Figure 5-8 for the total distance, central distance, central time, and central average speed at 8 hours, 72 hours, and 168 hours. Compared with cariprazine hydrochloride, compound L increased the central distance, central time, and central average speed of the animals.

Claims

1. A compound that acts as a partial agonist of the D3 / D2 receptor, having the structure shown in formula (I): Or its isomers, hydrates, solvates, or pharmaceutically acceptable salts. in: R1 is a hydrogen, amino, cyano, hydroxyl, halogen, or a straight-chain or branched C-type group, whether unsubstituted or substituted. 1-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-12 Alkenyl, unsubstituted or substituted straight or branched C 2-12 Alkyne group, unsubstituted or substituted straight or branched C 1-12 Alkoxy, unsubstituted or substituted cycloalkyl or heterocyclic, or unsubstituted or substituted aryl or heteroaryl; R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 4-12 Alkenyl, unsubstituted or substituted straight or branched C 4-12 Alkyne group, or unsubstituted or substituted straight or branched C 4-12 Alkyl group.

2. The compound according to claim 1, wherein, R1 is a hydrogen, amino, cyano, hydroxyl, halogen, or a straight-chain or branched C-type group, whether unsubstituted or substituted. 1-12 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-12 Alkenyl, unsubstituted or substituted straight or branched C 2-12 Alkyne group, unsubstituted or substituted straight or branched C 1-12 Alkoxy, unsubstituted or substituted aryl or heteroaryl; R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 alkyl.

3. The compound according to any one of claims 1-2, wherein, R1 is hydrogen, an unsubstituted or substituted straight-chain or branched C12. 1-6 Alkyl groups, unsubstituted or substituted straight-chain or branched C4 groups 2-6 Alkenyl, unsubstituted or substituted straight or branched C 2-6 Alkyne group, unsubstituted or substituted straight or branched C 1-6 Alkoxy, unsubstituted or substituted phenyl, benzoyl or naphthyl; R2 is the C of an unsubstituted or substituted straight or branched chain. 4-12 alkyl.

4. The compound according to any one of claims 1-3, wherein, R1 is hydrogen, an unsubstituted or substituted straight-chain or branched C12. 1-6 Alkyl group; R2 is an unsubstituted or substituted straight-chain or branched C2. 4-12 alkyl.

5. The compound according to any one of claims 1-4, wherein, R1 is methyl, ethyl, n-propyl or isopropyl, n-butyl, isobutyl or tert-butyl; R2 is an unsubstituted or substituted straight-chain C. 4-12 alkyl.

6. The compound according to any one of claims 1-5, wherein R1 is methyl, ethyl, preferably methyl; R2 is a linear C that is either unsubstituted or substituted. 4-12 Alkyl groups, preferably C4, C8, or C6. 12 Alkyl, more preferably C4 or C8 alkyl.

7. A compound, or its isomer, hydrate, solvate, or pharmaceutically acceptable salt, that is a partial agonist of the D3 / D2 receptor and has the following structure:

8. The compound of any one of claims 1-7, an isomer of the D3 / D2 receptor partial agonist, or an isomer thereof, hydrate, solvate, or pharmaceutically acceptable salt thereof, capable of binding to the D2 / D3 receptor and 5-HT. 2B Receptors with EC50 values ​​below 10 nM in D3 receptor binding assays 50 In 5-HT 2B In receptor binding assays, the IC50 corresponds to values ​​below 20 nM. 50 .

9. A method for preparing the compound or its isomers, hydrates, solvates or pharmaceutically acceptable salts as described in claims 1-8, comprising the following steps: (1) Compound E is activated by p-methanesulfonyl chloride to generate active ester F; (2) Compound H is prepared by a substitution reaction between active ester F and compound G; (3) Compound H was further deprotected from BOC by hydrochloric acid to obtain compound I; (4) Compound I reacts with the corresponding amine under the action of N,N'-carbonyldiimidazole to produce the final product shown in formula (I); The specific reaction formula is as follows: in, R1 and R2 are as defined in claims 1-8.

10. Use of the compound or its isomers, hydrates, solvates or pharmaceutically acceptable salts according to any one of claims 1-8 in the preparation of medicaments for the treatment and / or prevention of dopamine receptor-related diseases.

11. The use according to claim 10, characterized in that... The dopamine receptor-related diseases mentioned include, but are not limited to, schizophrenia, schizoaffective disorder, cognitive impairment, dementia, dementia with comorbid psychotic disorders, bipolar disorder, depression, mania, bipolar disorder, anxiety disorder, autism spectrum disorder, etc.

12. The use according to any one of claims 10-11, characterized in that, The dopamine receptor-related diseases include negative and positive symptoms of schizophrenia, preferably negative symptoms of schizophrenia.

13. A pharmaceutical composition comprising the compound or isomer thereof of any one of claims 1-8, a hydrate, a solvate or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

14. A pharmaceutical combination comprising the compound or isomer thereof, hydrate, solvate or pharmaceutically acceptable salt of any one of claims 1-8, and another therapeutic molecule having therapeutic activity against a mental illness.

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