WO2021022890A1 - 环己烷胺类d 3/d 2受体部分激动剂 - Google Patents

环己烷胺类d 3/d 2受体部分激动剂 Download PDF

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WO2021022890A1
WO2021022890A1 PCT/CN2020/094376 CN2020094376W WO2021022890A1 WO 2021022890 A1 WO2021022890 A1 WO 2021022890A1 CN 2020094376 W CN2020094376 W CN 2020094376W WO 2021022890 A1 WO2021022890 A1 WO 2021022890A1
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present
pharmaceutically acceptable
partial agonist
cyclohexaneamine
acceptable salt
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French (fr)
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郑永勇
魏农农
金华
周峰
黄美花
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上海勋和医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the invention belongs to the technical field of biomedicine, and specifically relates to a type of cyclohexaneamine D 3 /D 2 receptor partial agonists.
  • Schizophrenia is a type of mental illness characterized by the division of thinking, emotion, and behavior, and the incoordination between mental activities and the environment.
  • the prevalence of schizophrenia worldwide is nearly 1%.
  • Male patients are about 1.4 times that of female patients. It is more common in young adults, and it is more common in men between 20 to 28 years old and women in 26 to 32 years old.
  • the clinical symptoms of schizophrenia can be divided into three types: positive symptoms, negative symptoms and cognitive symptoms.
  • schizophrenic drugs There are two main categories of schizophrenic drugs: typical anti-schizophrenics and atypical anti-schizophrenics.
  • Typical anti-schizophrenia drugs (such as chlorpromazine and haloperidol) block dopamine receptors and have a good effect on the positive symptoms of schizophrenia.
  • adverse reactions such as extrapyramidal reaction (EPS), tardive dyskinesia and increased prolactin have been caused, and it is ineffective for negative symptoms of schizophrenia.
  • EPS extrapyramidal reaction
  • Atypical anti-schizophrenics represented by clozapine and risperidone, not only have a strong effect on D 2 receptors, but also have a strong effect on 5-HT 2A receptors.
  • these drugs have great advantages: they have a good effect on the positive symptoms of schizophrenia; side effects such as extrapyramidal reactions and tardive dyskinesias are significantly reduced; some atypical anti-schizophrenics are effective Negative symptoms and cognitive impairment have a certain improvement effect.
  • the atypical anti-schizophrenics currently in clinical use all have adverse effects such as QT interval prolongation and high prolactin. Therefore, it is very important to find new drugs that can effectively cure schizophrenia with less side effects.
  • D 3 receptors belong to the D 2 receptor family, which are mainly distributed in the midbrain limbic system. Antagonizing D 3 receptors can regulate the release of acetylcholine in the prefrontal cortex (PFC), thereby improving cognitive symptoms.
  • Multi-target anti-schizophrenia drugs containing D 3 are a new direction of anti-schizophrenia drug research in recent years.
  • RGH-188 is a selective D 3 receptor antagonist/D 2 receptor partial agonist developed by Gedeon Richter. It was approved by the FDA in 2015 for use in patients with schizophrenia and bipolar I disorder related mania or mixed Patients with seizures.
  • RGH-188 has high affinity and selectivity for D 3 receptor in vitro (compared to D 2 receptor, D 3 /D 2 selectivity is about 5 times).
  • Other features that distinguish RGH-188 from antipsychotics currently used include its relatively low affinity for 5-HT 2C and adrenergic alpha 1 receptors, and hERG channels, which are believed to be related to antipsychotic metabolism or cardiovascular side effects.
  • RGH-188 has certain advantages as a new schizophrenia drug, it still has certain shortcomings: In 2 late-stage clinical trials, the most common side effects in the schizophrenia treatment group were tremor, slurred speech, and involuntary muscles. Tremor, and patients with manic depression experience at most adverse events such as hyperactivity, indigestion, vomiting, lethargy, and restlessness. RGH-188, like other FDA-approved drugs for schizophrenia and manic depression, has a black box warning, prompting medical staff and elderly patients with dementia to increase the risk of death when using RGH-188, so RGH-188 has not been approved Treat such patients. It is precisely based on the above shortcomings that the development of such schizophrenia drugs to make up for the defects of existing schizophrenia drugs is still an urgent medical need.
  • the purpose of the present invention is to provide a type of cyclohexaneamine D 3 /D 2 receptor partial agonists.
  • the present invention adopts the following technical solution: a cyclohexaneamine D 3 /D 2 receptor partial agonist and pharmaceutically acceptable salts thereof as shown in structural formula I:
  • X is NH, NR or not present, when X is not present, W is directly connected to the carbonyl group;
  • W is N or CH
  • R is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or C 1-6 carbonyl;
  • Y and Z are each independently selected from H, Br, Cl, F or I; Y and Z can be substituted on the same C atom, or on two different C atoms in the ring;
  • n 0, 1 or 2;
  • n 0, 1, or 2.
  • X is NH, NR or not present, when X is not present, W is directly connected to the carbonyl group;
  • W is N or CH
  • R is hydrogen or C 1-6 alkyl
  • Y and Z are each independently selected from H, Br, Cl, F or I; Y and Z can be substituted on the same C atom, or on two different C atoms in the ring;
  • n 0 or 1
  • n 0 or 1.
  • X is NH, NR or not present, when X is not present, W is directly connected to the carbonyl group;
  • W is N or CH
  • R is hydrogen or C 1-4 alkyl
  • Y and Z are each independently selected from H, Br, Cl or F; Y and Z can be substituted on the same C atom or on two different C atoms in the ring;
  • n 0 or 1
  • n 0 or 1.
  • the L is selected from the following groups:
  • the R is hydrogen, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, or a C 1-6 carbonyl group.
  • the L is selected from the following groups:
  • the R is hydrogen or C 1-4 alkyl.
  • Typical compounds of the present invention include, but are not limited to the following compounds in Table 1:
  • the second objective of the present invention is to provide a synthetic method of the above compound:
  • Compound 1 is activated by methanesulfonyl chloride to produce active ester 2;
  • the third object of the present invention is to provide the use of the above-mentioned compound as a novel D 3 /D 2 receptor partial agonist in the treatment of diseases related to the D 3 /D 2 target, and the above is related to the D 3 /D 2 target
  • the disease mainly refers to the treatment of the following diseases: schizophrenia, depression, anxiety, drug abuse, Alzheimer’s, mania, eating disorders, attention deficit disorders, childhood hyperactivity, neuropathic pain, delusions or Parkinson’s disease.
  • the derivatives of the present invention can be formed into a composition by oral, injection, etc., to treat related cancers and other diseases.
  • oral administration it can be prepared into conventional solid preparations such as tablets, powders or capsules; when used for injection, it can be prepared into injections.
  • the fourth object of the present invention is to provide a composition that includes a therapeutically effective amount of the above cyclohexaneamine D 3 /D 2 receptor partial agonist, its stereoisomers, and its pharmaceutically acceptable And a pharmaceutically acceptable carrier.
  • metal salts for example, metal salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc.
  • metal salts include, but are not limited to, alkali metal salts, such as sodium salt, potassium salt, etc.; alkaline earth metal salts, such as calcium salt, magnesium salt, barium salt, aluminum salt, and the like.
  • salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene Sulfonic acid, p-toluene sulfonic acid and other salts.
  • the carrier mentioned refers to the conventional carriers in the pharmaceutical field, such as diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch, etc.; disintegrating agents such as carbonic acid Calcium, sodium bicarbonate; in addition, other auxiliary agents such as flavoring and sweetening agents can also be added to the composition.
  • diluents such as water, etc.
  • binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.
  • fillers such as starch, etc.
  • disintegrating agents such as carbonic acid Calcium, sodium bicarbonate
  • other auxiliary agents such as flavoring and sweetening agents can also be added to the composition.
  • composition of the present invention can be prepared by conventional methods in the medical field, and the content of the active ingredient is 0.1%-99.5% (weight ratio).
  • the dosage of the present invention can be changed according to the route of administration, the age, weight of the patient, the type and severity of the disease to be treated, etc.
  • the daily dosage is 0.001-30 mg/kg body weight (oral) or 0.001-30 mg/kg body weight ( injection).
  • the N-fluorocyclic carbamoyl group connected to cyclopentylamine in the molecular structure provided by the present invention has stronger metabolic stability than the original N,N-dimethylcarbamoyl group, and prolongs the drug Action time in the body.
  • the introduction of fluorocyclic amino groups changed the physical and chemical properties of the original molecules, thereby changing the pharmacokinetic properties, enhancing the distribution of drugs in target tissues, and improving the bioavailability of drugs.
  • the inventor also surprisingly discovered that the introduction of fluorocyclic amino groups affects the local conformation of the compound, enhances the ability of the ligand to bind to the target protein, and improves the selectivity of the target.
  • step 1 the crude intermediate 2 (10 mmol) was concentrated and added to acetonitrile (20 mL), potassium carbonate (2.76 g, 20 mmol), compound 3 (2.54 g, 11 mmol) were added, and the temperature was raised to reflux and the reaction was stirred for 8 h. After the reaction is completed, the temperature is reduced to room temperature, and the solvent is concentrated to dryness under pressure. The concentrated residue was extracted with dichloromethane (30mL) and water (20mL). The organic layer was washed with saturated brine (10mL). The organic layer was concentrated to dryness. The residue was purified by silica gel column chromatography (mobile phase is dichloromethane). Methane/methanol: 30/1) to obtain pale yellow solid intermediate 4 (2.9 g, two-step yield 64%). MS Calcd.:456.4,MS Found:457.2[M+H] + .
  • Test Example 1 The compound D 2 , D 3 , 5-HT 1A receptor binding experiment
  • D 2 Infect HEK-293 cells with a plasmid vector containing the D 2 receptor protein gene. After 48-72 hours, the receptor protein will be expressed on the membrane in large quantities. The cells are centrifuged at 1000 rpm for 5 minutes and the culture medium is discarded, the cells are collected and stored Keep in the refrigerator at -20°C for later use, and resuspend in Tris-HCl reaction buffer (pH 7.5) during the experiment.
  • Tris-HCl reaction buffer pH 7.5
  • D 2 receptor competition binding experiment the reaction of mixing different concentrations of each compound, Tris-HCl reaction buffer and Spipeone with the radioligand [ 3 H]Spiperone and adding them to HEK-293 cells expressing D 2 receptor
  • the tube to be tested the combined tube and the non-specific tube are obtained.
  • each tube was incubated in a water bath at 30°C for 50 minutes, it was moved to an ice bath to terminate the reaction.
  • Inhibition rate (I%) (total binding tube cpm—compound cpm)/(total binding tube cpm-non-specific binding tube cpm) ⁇ 100%, using software Fitting the concentration-response curve yields the Ki value of the compound binding to the D 2 receptor.
  • I% (total binding tube cpm—compound cpm)/(total binding tube cpm-non-specific binding tube cpm) ⁇ 100%
  • test method is similar to D 2 , using [ 3 H]Methyl-Spiperone as the D 3 receptor isotope ligand.
  • Transfect CHO cells with a plasmid vector containing 5-HT 1A receptor protein gene use calcium phosphate transfection method, and culture the transfected cells with G418-containing medium, and select cell monoclonal and radioactive cultures. Based on the binding experiment, a stable cell line capable of stably expressing 5-HT 1A receptor protein was finally obtained.
  • the cells were centrifuged at 1000 rpm for 5 minutes, the culture solution was discarded, and the cell bodies were collected and stored in a refrigerator at -20°C for later use. Resuspend in Tris-HCl reaction buffer (pH 7.7) during the experiment.
  • the compound of the present invention has the same affinity for D2 and 5-HT1A receptors as RGH-188; because the compound of the present invention replaces N,N-dimethylcarbamoyl in the structure of RGH-188 with N-fluorocyclic carbamoyl group,
  • the compound of the present invention has a significantly stronger affinity for D3 receptor than RGH-188, and the compound of the present invention has good selectivity for D2/D3 receptor, which is better than RGH-188.
  • the compound of the present invention has a stronger affinity for the D3 receptor, which may bring additional clinical benefits and reduce the side effects of traditional schizophrenia drugs.
  • Test Example 2 Tissue distribution evaluation of the compound of the present invention
  • the LC/MS/MS method was used to determine the rat after intragastric administration of RGH-188 and the compound of the preferred embodiment of the present invention, and then the drug concentration in plasma and brain tissue at different times was measured to study the present invention The pharmacokinetic characteristics of the compound in rats.
  • the plasma and tissue sample collection process is as follows:
  • Plasma Use a 1.5mL EDTA-K2 anticoagulant tube to collect blood (60 ⁇ L), immediately centrifuge at 7000rpm and 4°C for 10 minutes to obtain plasma (30 ⁇ L), and store the plasma sample at -80°C for drug concentration determination.
  • Tissue Use a 5mL cryotube to collect the brain, immediately freeze it in liquid nitrogen, and store it at -80°C after sampling for drug concentration determination to compare distribution.
  • the compound of the example of the present invention shows good pharmacokinetic properties. Compared with RGH-188, the compound of the example of the present invention has better blood drug concentration. The brain and blood drug concentrations are both reference More than 10 times of RGH-188. In addition, the compounds of the present invention have better performance in penetrating the blood-brain barrier, indicating that the compounds of the examples of the present invention have high brain penetration rates and conform to the pharmacokinetic characteristics of central nervous system drugs.
  • Test Example 3 Acute toxicity test of the compound of the present invention
  • Dosing preparation Weigh the required test products and prepare them with 5% Tween 80 solution to the concentration of 10, 40, 80 and 120 mg/mL (equivalent to 300, 1200, 2400, 3600 mg/kg respectively) Suspension.
  • Administration route The administration route of the test product and the vehicle control group (0.5% Tween-80) is oral administration.
  • Dosing frequency single administration, fasting overnight before administration.
  • Observations include but are not limited to: general conditions, behavioral activities, gait posture, eyes, mouth, nose, gastrointestinal tract, skin coat, urogenital tract.
  • the weight data is expressed as the mean ⁇ standard deviation, and the Levene ⁇ s test and one-way analysis of variance are used for comparison between groups. If there are differences, Dunnet's t test is used.
  • the animal's tolerance to the drug is examined, and the maximum tolerable dose is when the administered dose reaches the animal's frequent death.
  • Test substance MTD (mg/kg) RGH-188 300 I-1 3600 I-3 2400 I-5 3600 I-9 2400 I-10 3600
  • Test Example 4 In vivo anti-schizophrenic activity test of the compound of the present invention (apomorphine-induced climbing model)
  • KM mice were randomly divided into negative control group, model group, positive control (RGH-188) each dose group and each compound dose group, each with 10 mice.
  • the negative control group and the model group were given the corresponding double distilled water by gavage, and the positive drug group and the corresponding drug of each dose group of the compound of the present invention were gavage.
  • One hour after intragastric administration subcutaneous injection of apomorphine (1mg/kg), immediately after the injection of apomorphine, put it in a climbing cage, adapt to 5 minutes, observe the 10-11, 20-21 after the injection of apomorphine , 30-31 minutes of behavior and score, scoring criteria: four feet on the floor score 0; two forefoot on the net cage score 1; four feet on the net cage score 2.
  • the measurement index is expressed as mean ⁇ standard error (Mean ⁇ SEM), the nonparametric two-tailed Mann-Whitney U-test is used for comparative analysis, and the probability unit regression method is used for ED 50 calculation.
  • test results show that: compared with the positive control drug RGH-188, the compounds of the present invention can significantly improve the stereotyped behavior of mice, and the apomorphine-induced schizophrenia model is a classic model of schizophrenia, so the series of compounds of the present invention Has a good anti-schizophrenia effect.
  • Compounds I-1, I-3, I-5, I-9 and I-10 are better than the positive control drug RGH-188 in improving stereotyped behavior (ED 50 ) in mice.

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Abstract

本发明属于生物医药技术领域，具体涉及一种环己烷胺类D 3/D 2受体部分激动剂及其药学上可接受的盐、其合成方法及用途。与现有技术相比，本发明提供的分子结构中环戊胺所连接的N-氟代环氨基甲酰基比原有N,N-二甲基氨基甲酰基具有更强的代谢稳定性，延长药物体内作用时间。氟代环氨基的引入改变了原有分子的物理化学特性，从而改变了药代动力学特性，增强药物在靶组织的分布，提高药物的生物利用度。发明人还惊奇的发现通过氟代环氨基的引入，影响了化合物的局部构象，增强配体与靶标蛋白的相互结合能力，并提高了靶点的选择性。

Description

环己烷胺类D 3/D 2受体部分激动剂 技术领域
本发明属于生物医药技术领域，具体涉及一类环己烷胺类D 3/D 2受体部分激动剂。
背景技术
精神分裂症是以思维、情感、行为的分裂，精神活动与环境的不协调为主要特征的一类精神性疾病。世界范围内精神分裂症的患病率近1％。男性患者约为女性患者的1.4倍。多于青壮年开始发病，男性多见于20～28岁、女性多见于26～32岁。精神分裂症的临床症状可以分为三种类型：阳性症状、阴性症状和认知症状。
虽然精神分裂症具体发病机制目前尚不明确，但药理学研究表明，精神分裂症患者表现出多种递质神经元的功能异常。现在认为，皮层下结构多巴胺D 2受体功能亢进及前额叶皮层D 1/NMDA受体功能减低是精神分裂症的中心病理学特征，同时伴随着5-羟色胺(5-HT)和γ-氨基丁酸(GABA)能神经元的功能异常。
现有精神分裂药物主要有两大类：典型抗精神分裂药物和非典型抗精神分裂药物。典型抗精神分裂药物(如氯丙嗪和氟哌啶醇)阻断多巴胺受体，对精神分裂症阳性症状具有良好疗效。但由于强烈阻断多巴胺受体，导致了锥体外系反应(EPS)、迟发性运动障碍以及泌乳素增加等不良反应，而且对精神分裂症阴性症状无效。
非典型抗精神分裂药物，是以氯氮平和利培酮为代表，不仅对D 2受体有较强作用，同时对5-HT 2A受体也有较强作用。与典型抗精神分裂药物相比这类药物有很大的优势：对精神分裂症阳性症状有良好疗效；锥体外系反应和迟发性运动障碍等副作用显著降低；部分非典型抗精神分裂药物对阴性症状和认知障碍有一定改善作用。然而，目前临床应用的非典型抗精神分裂药物都有不同程度的QT间期延长和高泌乳素等不良反应。因此，寻找新的既能有效地治愈精神分裂症而且副作用小的药物是非常重要。
D 3受体属于D 2类受体家族，主要分布于中脑边缘系统，拮抗D 3受体可调节前额叶皮质(PFC)中乙酰胆碱的释放，进而改善认知症状。含D 3的多靶点抗精神分裂症药物为近年抗精神分裂症药物研究的新方向。RGH-188为Gedeon Richter公司开发的选择性D 3受体拮抗剂/D 2受体部分激动剂，2015年FDA批准上市，用于精神分裂症患者和双相Ⅰ型障碍相关的躁狂或混合发作患者。
Figure PCTCN2020094376-appb-000001
RGH-188与其他非典型抗精神病药的区别在于，对D 3受体在体外亲和力和选择性高(相比于D 2受体，D 3/D 2选择性约为5倍)。RGH-188区别于目前所用抗精神病药的其他特征包括它对被认为与抗精神病药代谢或心血管副作用有关的5-HT 2C和肾上腺素α 1受体以及hERG通道的亲和力相对较低。
虽然RGH-188作为新型精神分裂症药物具有了一定优势，但其仍然存在一定的缺陷：在2个晚期临床试验中，精神分裂症治疗组最常见副作用有震颤、言语不清、不自主的肌肉颤动，而狂躁型抑郁症患者最多经历多动、消化不良、呕吐、嗜睡、和不安等的不良事件。RGH-188和其它FDA批准的精神分裂症和狂躁型抑郁症药物一样都带有黑框警告，提示医务人员和痴呆相关的老年患者使用RGH-188时死亡风险增加，所以RGH-188没有获批治疗这类患者。正是基于上述不足，研发该类精神分裂药物，弥补现有精神分裂症药物缺陷仍是亟需的医疗需求。
发明内容
为了克服现有技术中所存在的问题，本发明的目的在于提供一类环己烷胺类D 3/D 2受体部分激动剂。
为了实现上述目的，本发明采用如下技术方案：如结构式Ⅰ所示的环己烷胺类D 3/D 2受体部分激 动剂及其药学上可接受的盐：
Figure PCTCN2020094376-appb-000002
其中L的结构如式Ⅱ所示：
Figure PCTCN2020094376-appb-000003
X为NH、NR或不存在，当X不存在时，W直接与羰基相连；
W为N或CH；
R为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、C 1～6烷氧基、或C 1～6羰基；
Y和Z各自独立的选自H、Br、Cl、F或I；Y和Z可以取代在同一个C原子上，也可以取代在环上不同的两个C原子上；
m为0、1或2；
n为0、1或2。
优选的，其中：
X为NH、NR或不存在，当X不存在时，W直接与羰基相连；
W为N或CH；
R为氢或C 1～6烷基；
Y和Z各自独立的选自H、Br、Cl、F或I；Y和Z可以取代在同一个C原子上，也可以取代在环上不同的两个C原子上；
m为0或1；
n为0或1。
优选的，其中：
X为NH、NR或不存在，当X不存在时，W直接与羰基相连；
W为N或CH；
R为氢或C 1～4烷基；
Y和Z各自独立的选自H、Br、Cl或F；Y和Z可以取代在同一个C原子上，也可以取代在环上不同的两个C原子上；
m为0或1；
n为0或1。
更加优选的，所述L选自如下基团：
Figure PCTCN2020094376-appb-000004
Figure PCTCN2020094376-appb-000005
所述R为氢、C 1～6 烷基、C 2～6烯基、C 2～6炔基、C 1～6烷氧基、或C 1～6羰基。
进一步优选的，所述L选自如下基团：
Figure PCTCN2020094376-appb-000006
Figure PCTCN2020094376-appb-000007
所述R为氢或C 1～4烷基。
本发明的典型化合物包括，但不限于以下表1化合物：
表1
Figure PCTCN2020094376-appb-000008
Figure PCTCN2020094376-appb-000009
本发明的第二目的在于提供了上述化合物的合成方法：
(1)化合物1经甲烷磺酰氯活化生产活性酯2；
(2)活性酯2与中间体3经缩合反应制得化合物4；
(3)化合物4再经盐酸脱保护得化合物5；
(4)化合物5与相应胺化物在三光气(BTC)作用下生成终产物I；
具体反应式如下：
Figure PCTCN2020094376-appb-000010
本发明的第三目的在于提供上述化合物作为新型D 3/D 2受体部分激动剂在治疗与D 3/D 2靶点相关疾病的药物中的用途，上述与D 3/D 2靶点相关的疾病主要是指治疗下列疾病：精神分裂症、抑郁症、焦虑症、药物滥用、老年痴呆、躁狂症、进食障碍、注意力缺陷疾病、儿童多动症、神经性疼痛、妄想症或帕金森氏病。
本发明的衍生物在实施疾病治疗过程中，可以组合物的形成通过口服、注射等方式，用于治疗相关癌症及其他疾病。用于口服时，可将其制备成常规的固体制剂如片剂、粉剂或胶囊等；用于注射时，可将其制备成注射液。
本发明的第四目的在于提供一种组合物，所述组合物包括治疗有效量的上述环己烷胺类D 3/D 2受体部分激动剂、其立体异构体、其药学上可接受的盐和药学上可接受的载体。
药学上可接受的盐，例如，可以提及金属盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。金属盐的非限制性实例包括但不限于碱金属的盐，例如钠盐、钾盐等；碱土金属的盐，例如钙盐、镁盐、钡盐、铝盐等。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。
所述及的载体是指药学领域常规的载体，如：稀释剂、赋形剂如水等；粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮等；填充剂如淀粉等；崩裂剂如碳酸钙、碳酸氢钠；另外，还可以在组合物中加入其他辅助剂如香味剂和甜味剂。
本发明的组合物的各种剂型可以采用医学领域常规的方法进行制备，其中活性成分的含量为0.1％～99.5％(重量比)。
本发明的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等进行变化，其日剂量为0.001-30mg/kg体重(口服)或0.001-30mg/kg体重(注射)。
与现有技术相比，本发明提供的分子结构中环戊胺所连接的N-氟代环氨基甲酰基比原有N,N-二甲基氨基甲酰基具有更强的代谢稳定性，延长药物体内作用时间。氟代环氨基的引入改变了原有分子的物理化学特性，从而改变了药代动力学特性，增强药物在靶组织的分布，提高药物的生物利用度。发明人还惊奇的发现通过氟代环氨基的引入，影响了化合物的局部构象，增强配体与靶标蛋白的相互结合能力，并提高了靶点的选择性。进一步的，动物体内实验数据显示，在等剂量下，本发明化合物血浆AUC显著升高，其Brain/Plasma比也明显提高。作为中枢神经系统(CNS)药物，透过血-脑屏障尤为重要，由此可见，本发明化合物的PK性质更优，可进一步合理推测，本发明化合物应用于临床剂量将更低，从而降低药物副作用，药物更为经济实用。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
参考例1：通用中间体5的合成路线。
Figure PCTCN2020094376-appb-000011
操作步骤：
步骤1：中间体2的合成。
化合物1(2.43g,10mmol)、三乙胺(2g,20mmol)加入二氯甲烷(30mL)中，降温至内温0～5℃，搅拌下滴加甲烷磺酰氯(1.1g,10mmol)的二氯甲烷(10mL)溶液，滴加完毕后，升至室温反应3h；反应完毕后浓缩溶剂至干，得中间体2粗品。
步骤2：中间体4的合成
步骤1中浓缩中间体2粗品(10mmol)加入乙腈(20mL)中，再加入碳酸钾(2.76g,20mmol)、化合物3(2.54g,11mmol)，升温至回流搅拌反应8h。反应完毕后降温至室温，加压浓缩溶剂至干。浓缩剩余物中加二氯甲烷(30mL)、水(20mL)萃取，有机层再经饱和食盐水(10mL)洗涤，浓缩有机层至干，剩余物经硅胶柱层析纯化(流动相为二氯甲烷/甲醇：30/1)，得淡黄色固体中间体4(2.9g,两步收率64％)。MS Calcd.:456.4,MS Found:457.2[M+H] +。
步骤3：中间体5的合成。
向化合物4(2g,4.4mmol)的乙酸乙酯(20mL)溶液中，滴加浓盐酸(3.6mL,44mmol)，滴加完毕后搅拌反应12h，TLC监控反应完全。反应混合物降至内温0-5℃搅拌30min，过滤，滤饼经真空干燥(50℃) 制得白色固体中间体5(1.5g,收率87％)。MS Calcd.:356.3,MS Found:357.0[M+H] +。 1H NMR(400MHz,CD 3OD+D 2O):δ＝7.25(m,2H),6.78(m,1H),3.67(m,8H),2.57-2.44(m,3H),1.78(m,2H),1.55-1.38(m,9H)。
实施例1:I-1的合成
合成路线：
Figure PCTCN2020094376-appb-000012
操作步骤：
化合物5(500mg,1.27mmol)、IA-1(142mg,1.27mmol)、三乙胺(643mg,6.36mmol)加入二氯甲烷(5mL)中，体系降温至内温0-5℃，加入三光气(453mg,1.53mmol)。加完后，升至室温搅拌反应4h,TLC监控反应完全。反应液中加二氯甲烷(10mL)、水(10mL)萃取，有机层再经饱和食盐水(10mL)洗涤，浓缩有机层至干，剩余物经硅胶柱层析纯化(流动相为二氯甲烷/甲醇：30/1)，得淡白色固体产物I-1(250mg,收率43％)。MS Calcd.:457.4,MS Found:458.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.23(m,2H),6.81(m,1H),4.13-3.89(m,5H),3.67(m,1H),3.47(m,8H),2.49(t,J＝5.6Hz,2H),1.76(m,2H),1.53-1.37(m,9H)。
实施例2:I-2的合成
合成路线：
Figure PCTCN2020094376-appb-000013
操作步骤：
操作步骤及纯化方法参见实施例1，收率50％。MS Calcd.:475.4,MS Found:476.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.25(m,2H),6.83(m,1H),4.16(t,J＝15.6Hz,4H),3.65(m,1H),3.47(m,8H),2.48(t,J＝5.6Hz,2H),1.77(m,2H),1.55-1.37(m,9H)。
实施例3:I-3的合成
合成路线：
Figure PCTCN2020094376-appb-000014
操作步骤：
操作步骤及纯化方法参见实施例1，收率55％。MS Calcd.:471.4,MS Found:472.0[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.27(m,2H),6.83(m,1H),4.13(m,1H),3.75(m,1H),3.54(m,1H),3.45(m,8H),2.49-2.27(m,6H),1.77(m,2H),1.55-1.39(m,9H)。
实施例4:I-4的合成
合成路线：
Figure PCTCN2020094376-appb-000015
操作步骤：
操作步骤及纯化方法参见实施例1，收率50％。MS Calcd.:489.4,MS Found:490.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.30(m,2H),6.80(m,1H),4.09(m,1H),3.55(m,1H),3.47(m,8H),2.63-2.48(m,6H),1.75(m,2H),1.56-1.39(m,9H)。
实施例5:I-5的合成
合成路线：
Figure PCTCN2020094376-appb-000016
操作步骤：
操作步骤及纯化方法参见实施例1，收率49％。MS Calcd.:485.5,MS Found:486.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.24(m,2H),6.83(m,1H),4.07(m,1H),3.75(m,1H),3.56(m,1H),3.45(m,8H),3.25(s,3H),2.55-2.41(m,6H),1.77(m,2H),1.59-1.40(m,9H)。
实施例6:I-6的合成
合成路线：
Figure PCTCN2020094376-appb-000017
操作步骤：
操作步骤及纯化方法参见实施例1，收率54％。MS Calcd.:503.5,MS Found:504.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.25(m,2H),6.84(m,1H),4.08(m,1H),3.54(m,1H),3.44(m,8H),3.27(s,3H),2.57-2.38(m,6H),1.76(m,2H),1.61-1.41(m,9H)。
实施例7:I-7的合成
合成路线：
Figure PCTCN2020094376-appb-000018
操作步骤：
操作步骤及纯化方法参见实施例1，收率57％。MS Calcd.:485.5,MS Found:486.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.23(m,2H),6.82(m,1H),3.55(m,1H),3.47(m,8H),3.39-3.29(m,5H),2.45(t,J＝5.6Hz,2H),1.79(m,4H),1.55-1.39(m,11H)。
实施例8:I-8的合成
合成路线：
Figure PCTCN2020094376-appb-000019
操作步骤：
操作步骤及纯化方法参见实施例1，收率52％。MS Calcd.:503.5,MS Found:504.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.24(m,2H),6.83(m,1H),3.77(m,4H),3.57(m,1H),3.45(m,8H),2.44(t,J＝5.6Hz,2H),1.82-1.74(m,6H),1.47-1.35(m,9H)。
实施例9:I-9的合成
合成路线：
Figure PCTCN2020094376-appb-000020
操作步骤：
操作步骤及纯化方法参见实施例1，收率47％。MS Calcd.:499.5,MS Found:500.1[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.23(m,2H),6.86(m,1H),3.54(m,2H),3.45(m,8H),3.27(m,1H),2.49(t,J＝5.2Hz,2H),1.74(m,4H),1.49-1.31(m,15H)。
实施例10:I-10的合成
合成路线：
Figure PCTCN2020094376-appb-000021
操作步骤：
操作步骤及纯化方法参见实施例1，收率49％。MS Calcd.:517.5,MS Found:518.2[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.21(m,2H),6.80(m,1H),3.55(m,1H),3.43(m,8H),2.47(t,J＝5.2Hz,2H),1.77(m,4H),1.47-1.32(m,15H)。
实施例11:I-11的合成
合成路线：
Figure PCTCN2020094376-appb-000022
操作步骤：
操作步骤及纯化方法参见实施例1，收率44％。MS Calcd.:513.5,MS Found:514.2[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.21(m,2H),6.80(m,1H),3.56(m,2H),3.43(m,8H),3.27(m,4H),2.45(t,J＝5.2Hz,2H),1.76(m,4H),1.45-1.32(m,15H)。
实施例12:I-12的合成
合成路线：
Figure PCTCN2020094376-appb-000023
操作步骤：
操作步骤及纯化方法参见实施例1，收率46％。MS Calcd.:531.5,MS Found:532.2[M+H] +。 1H NMR(400MHz,CD 3OD):δ＝7.25(m,2H),6.82(m,1H),3.54(m,2H),3.44(m,8H),3.27(s,3H),2.46(t,J＝5.2Hz,2H),1.75(m,4H),1.49-1.28(m,15H)。
活性测试
测试例1、所述化合物D 2、D 3、5-HT 1A受体结合实验
实验方法：
D 2：用含有D 2受体蛋白基因的质粒载体感染HEK-293细胞，48～72小时后受体蛋白在膜上大量表达，将细胞以1000rpm离心5min后弃去培养液，收胞体，保存于-20℃冰箱内备用，实验时用Tris-HCl反应缓冲液(pH 7.5)重悬。
D 2受体竞争结合实验:将不同浓度的各化合物、Tris-HCl反应缓冲液和Spiperone分别与放射性配基[ 3H]Spiperone混合，加入到表达了D 2受体的HEK-293细胞的反应试管中，得到待测管、总结合管和非特异管。各管经30℃水浴孵育50min后，移至冰浴终止其反应。在Millipore细胞样品收集器上，经过GF/B玻璃纤维滤纸快速抽滤，以洗脱液(50mM Tris-HCl,pH＝7.5)3ml洗3次，微波炉5～6min烘干。将滤纸移入0.5ml离心管中，加入500ul脂溶性闪烁液，避光静置30min以上，计数测定放射性强度。
按以下公式计算各化合物对同位素配基结合的抑制百分率：抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm-非特异结合管cpm)×100％，用软件拟合浓度-效应曲线得出化合物与D 2受体结合的Ki值。D 3：
测试方法类似D 2，使用[ 3H]Methyl-Spiperone为D 3受体同位素配体。
5-HT 1A：
用含有5-HT 1A受体蛋白基因的质粒载体转染CHO细胞，使用磷酸钙转染法，并从转染后的细胞中，通过含G418的培养液培养，以及挑选细胞单克隆和放射性培基结合实验，最终获得能稳定表达5-HT 1A受体蛋白的稳定细胞株。进行细胞培养，将细胞1000rpm离心5min后弃培液，收胞体，保存于-20℃冰箱内备用。实验时用Tris-HCl反应缓冲液(pH 7.7)重悬。
将不同浓度的各化合物、Tris-HCl反应缓冲液和5-HT分别与放射性配基[ 3H]8-OH-DPAT混合，加入到表达了5-HT 1A受体的HEK-293细胞的反应试管中，得到待测管、总结合管和非特异管。按D 2受体亲和力试验方法测定化合物与5-HT 1A受体结合的Ki值。
表2、化合物体外受体结合实验结果
化合物 D 2Ki(nM) D 3Ki(nM) 5-HT 1A Ki(nM) D 2/D 3 5-HT 1A/D 3
RGH-188 0.51 0.088 2.47 5.8 28
I-1 0.47 0.032 2.49 14.7 78
I-2 0.50 0.043 2.52 11.6 58.6
I-3 0.43 0.029 1.48 14.8 51
I-4 0.61 0.053 2.38 11.5 45
I-5 0.47 0.025 1.98 18.8 79
I-6 0.58 0.051 2.54 11.4 57.7
I-7 0.56 0.044 2.25 12.7 51
I-8 0.70 0.057 2.59 12.3 45.4
I-9 0.50 0.025 2.01 20 80.4
I-10 0.54 0.033 1.97 16.4 59.7
I-11 0.49 0.040 2.12 12.3 53
I-12 0.51 0.038 2.03 13.4 53.4
注：以上对照均品、本发明化合物均为同一实验条件实测值。
结论：本发明化合物对D2、5-HT1A受体亲和力与RGH-188相当；由于本发明化合物中N-氟代环氨基甲酰基取代RGH-188结构中N,N-二甲基氨基甲酰基，本发明化合物对D3受体亲和力明显强于RGH-188，本发明化合物对D2/D3受体具有良好选择性，选择性优于RGH-188。本发明化合物对D3受体的亲和力更强，从而可能带来额外的临床获益，降低传统精神分裂症药物副作用。
测试例2、本发明化合物药物组织分布评价
以SD大鼠为受试动物，采用LC/MS/MS法测定大鼠灌胃给予RGH-188和本发明优选实施例化合物后，测定其不同时刻血浆、脑组织中的药物浓度，研究本发明化合物在大鼠体内药代动力学特征。
给药剂量及浓度：2mg/kg；1mg/mL
制剂处方：0.5％methylcellulose
取样点：5min，15min，30min，1h，2h，4h，8h，24h.
血浆和组织样品收集过程如下：
血浆：使用1.5mL的EDTA-K2抗凝管收集血液(60μL)，立即在7000rpm、4℃条件下离心10分钟得到血浆(30μL)，将血浆样品保存在-80℃下用于药物浓度测定。
组织：使用5mL的冻存管收集大脑，立即丢人液氮中进行速冻，在取样结束后保存在-80℃下用于药物浓度测定以比较分布。
本发明优选化合物药代动力学参数如表3所示。
表3：优选化合物药代动力学参数
Figure PCTCN2020094376-appb-000024
结论：在同等剂量下，本发明实施例化合物表现出良好的药代动力学性质，与RGH-188相比，本发明实施例化合物具有更优的血药浓度，脑、血药浓度均为参照RGH-188的10倍以上。且本发明化合物穿透血脑屏障性能更优，说明本发明实施例化合物透脑率高，符合中枢神经系统类药物药代特征。
测试例3、本发明化合物急性毒性试验
选取5种本发明所述的化合物(I-1、I-3、I-5、I-9和I-10)，以及RGH-188进行急性毒性实验。
(1)实验方案
①、观察其口服给予ICR小鼠RGH-188、本发明所述I-1等化合物后动物出现的毒性征状和死亡情况，比较其急性毒性。
②、溶媒配制：称取适量吐温-80，用去离子水稀释至浓度为5％(g/v)吐温-80。
③、给药制剂：分别称取所需的供试品，用5％吐温80溶液配制成浓度为10、40、80和120mg/mL(分别相当于300、1200、2400、3600mg/kg)混悬液。
④、给药途径：供试品及溶媒对照组(0.5％吐温-80)的给药途径均为经口服给予。
⑤、给药频率：单次给药，给药前均隔夜禁食。
⑥、给药容量：30mL/kg。
一般征状观察：给药当天于第一次给药后约0.5、1、2、4、6小时分别观察1次；观察期第2～6天，每天观察2次，上、下午各1次。观察内容包括但不限制于：一般状况、行为活动、步态姿势、眼、口、鼻、胃肠道、皮肤被毛、泌尿生殖道。
(2)统计分析
体重数据以均数±标准差表示，并采用组间比较采用Levene`s检验和单因素方差分析，如果显示有差异，再采用Dunnet t检验。
(3)实验结果
选取5种本发明所述的化合物，以及RGH-188如上述进行急性毒性实验。实验结果见表4。
MTD试验中，考察动物对药物的耐受情况，给药剂量达到动物频临死亡时，即是最大耐受量。
表4：I-1等化合物及RGH-188单次口服给药急性毒性实验结果
受试物 MTD(mg/kg)
RGH-188 300
I-1 3600
I-3 2400
I-5 3600
I-9 2400
I-10 3600
注：MTD：最大耐受量。
结果表明：上述受试物中本发明化合物I-1、I-3、I-5、I-9和I-10的MTD值均大于或等于2400mg/kg，安全性远高于RGH-188。
测试例4、本发明化合物体内抗精神分裂活性试验(阿扑吗啡诱导攀爬模型)
KM小鼠，随机分为阴性对照组、模型组、阳性对照(RGH-188)各剂量组以及化合物各剂量组，每组10只。阴性对照组和模型组灌胃给予相应双蒸水，灌胃给予阳性药物组和本发明化合物各剂量组相应药物。灌胃给药1小时后皮下注射阿扑吗啡(1mg/kg)，注射阿扑吗啡后，立即放入攀爬笼中，适应5分钟，观察注射阿扑吗啡后第10-11,20-21,30-31分钟的行为并进行评分，评分标准：四足在地板上得分为0；两前足在网笼上得分为1；四只足在网笼上得分为2。
计量指标用均数±标准误差(Mean±S.E.M)表示，比较分析用the nonparametric two-tailed Mann-Whitney U-test,ED 50计算用概率单位回归法。
具体的实验结果见表5。
表5：单次口服给予I-1等化合物对阿扑吗啡诱导的攀爬结果(ED 50)
化合物 ED 50(mg/kg)
RGH-188 0.48
I-1 0.31
I-3 0.27
I-5 0.22
I-9 0.33
I-10 0.19
本试验结果表明：相比阳性对照药RGH-188，本发明所述化合物均能显著改善小鼠刻板行为，而阿扑吗啡诱导精神分裂症模型为精神分裂症的经典模型，因而本发明系列化合物具良好抗精神分裂症作用。化合物I-1、I-3、I-5、I-9和I-10对小鼠刻板行为的改善作用(ED 50)优于阳性对照药RGH-188。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种如式I所示的环己烷胺类D 3/D 2受体部分激动剂及其药学上可接受的盐：
    Figure PCTCN2020094376-appb-100001
    其中L的结构如式Ⅱ所示：
    Figure PCTCN2020094376-appb-100002
    其中：
    X为NH、NR或不存在，当X不存在时，W直接与羰基相连；
    W为N或CH；
    R为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、C 1～6烷氧基、或C 1～6羰基；
    Y和Z各自独立的选自H、Br、Cl、F或I；Y和Z可以取代在同一个C原子上，也可以取代在环上不同的两个C原子上；
    m为0、1或2；
    n为0、1或2。
  2. 如权利要求1所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐，其特征在于，其中：
    X为NH、NR或不存在，当X不存在时，W直接与羰基相连；
    W为N或CH；
    R为氢或C 1～6烷基；
    Y和Z各自独立的选自H、Br、Cl或F；Y和Z可以取代在同一个C原子上，也可以取代在环上不同的两个C原子上；
    m为0或1；
    n为0或1。
  3. 如权利要求1所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐，其特征在于，其中：
    X为NH、NR或不存在，当X不存在时，W直接与羰基相连；
    W为N或CH；
    R为氢或C 1～4烷基；
    Y和Z各自独立的选自H或F；Y和Z可以取代在同一个C原子上，也可以取代在环上不同的两个C原子上；
    m为0或1；
    n为0或1。
  4. 如权利要求1所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐，其特征在于，所述L选自如下基团：
    Figure PCTCN2020094376-appb-100003
    Figure PCTCN2020094376-appb-100004
    所述R为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、C 1～6烷氧基、或C 1～6羰基。
  5. 如权利要求4所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐，其特征在于，所述L选自如下基团：
    Figure PCTCN2020094376-appb-100005
    Figure PCTCN2020094376-appb-100006
    所述R为氢或C 1～4烷基。
  6. 如权利要求1所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐，其特征在于，选自如下化合物：
    Figure PCTCN2020094376-appb-100007
    Figure PCTCN2020094376-appb-100008
  7. 一种制备如权利要求1～6任一项所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐的方法，其特征在于包括如下步骤：
    (1)化合物1经甲烷磺酰氯活化生产活性酯2；
    (2)活性酯2与中间体3经缩合反应制得化合物4；
    (3)化合物4再经盐酸脱保护得化合物5；
    (4)化合物5与相应胺化物在三光气作用下生成终产物I；
    具体反应式如下：
    Figure PCTCN2020094376-appb-100009
  8. 如权利要求1～6任一项所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐在制备与D 3/D 2靶点相关疾病的药物中的用途。
  9. 如权利要求8所述的用途，其特征在于所述与D 3/D 2靶点相关的疾病包括：精神分裂症、抑郁症、焦虑症、药物滥用、老年痴呆、躁狂症、进食障碍、注意力缺陷疾病、儿童多动症、神经性疼痛、妄想症或帕金森氏病。
  10. 一种组合物，所述组合物包括治疗有效量的如权利要求1～6任一项所述的环己烷胺类D 3/D 2受体部分激动剂或其药学上可接受的盐和药学上可接受的载体。
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