WO2017045599A1 - 环己烷衍生物或其立体异构体或盐及其制备与应用 - Google Patents

环己烷衍生物或其立体异构体或盐及其制备与应用 Download PDF

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WO2017045599A1
WO2017045599A1 PCT/CN2016/098953 CN2016098953W WO2017045599A1 WO 2017045599 A1 WO2017045599 A1 WO 2017045599A1 CN 2016098953 W CN2016098953 W CN 2016098953W WO 2017045599 A1 WO2017045599 A1 WO 2017045599A1
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compound
group
ethyl
acid
trans
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PCT/CN2016/098953
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English (en)
French (fr)
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黄悦
郑飞
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浙江京新药业股份有限公司
上海京新生物医药有限公司
上虞京新药业有限公司
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Priority claimed from CN201610643389.0A external-priority patent/CN106518841B/zh
Application filed by 浙江京新药业股份有限公司, 上海京新生物医药有限公司, 上虞京新药业有限公司 filed Critical 浙江京新药业股份有限公司
Priority to ES16845713T priority Critical patent/ES2820842T3/es
Priority to CA2998758A priority patent/CA2998758A1/en
Priority to US15/759,119 priority patent/US10301277B2/en
Priority to JP2018532500A priority patent/JP6772272B2/ja
Priority to EP16845713.3A priority patent/EP3351540B1/en
Publication of WO2017045599A1 publication Critical patent/WO2017045599A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to medicinal chemistry, in particular to cyclohexane compounds or stereoisomers or salts thereof, and in particular to cyclohexane derivatives of formula IB and formula I or stereoisomers or salts thereof, and their preparation and application.
  • Patent WO 9967206 A1 describes the use of cyclohexane derivatives in the treatment of pain disorders, but does not publicly report their use in psychotic diseases, especially on the dopamine D 2 /D 3 receptor.
  • Patent CN 1829703A describes the use of a cyclohexane derivative having a (thio)carbamoyl side chain in the regulation of a dopamine receptor disorder, wherein the D 2 /D 3 antagonist and 5 jointly developed by Forest Laboratories and Gedeon Richter -
  • the HT 1A partial agonist, Cariprazine (RGH-188) has been completed in clinical trials for the treatment of schizophrenia and mania and depression.
  • the chemical structure of the cariprazine is shown in the following formula.
  • the affinity (Ki value) of the drug for the D 2 /D 3 receptor and 5-HT 1A is 0.72 nmol, 0.08 nmol and 3.42 nmol, respectively, for D 2 /D.
  • the 3 receptor has certain selectivity, it is still not ideal, so it may cause the drug to have a low probability of clinically (approximately 5% probability at 3 mg dose) of sedation and the cause of extracorporeal reaction. Because these side effects are associated with excessive blockade of the D 2 receptor.
  • the patent CN 103130737A has further structural modification of the cariprazine to achieve higher D 3 receptor selectivity.
  • the technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, and to study and design to improve the structure of a cyclohexane derivative, and to provide a cyclohexane derivative or a stereoisomer thereof or a salt thereof as shown in Formula IB and Formula I, It has D 2 /D 3 antagonist action and serotonin absorption inhibition, as well as anti-schizophrenia, increases the broad spectrum of treatment for psychotic diseases, and reduces side effects.
  • the cyclohexane derivative or a stereoisomer or salt thereof provided by the present invention has the structure shown in the following formula IB:
  • the R group may be optionally substituted by one or more substituents selected from halogen, substituted or unsubstituted C 1 -C 6 alkyl;
  • the halogen is selected from F, Cl, One or more of Br or I;
  • the substituted or unsubstituted C 1 -C 6 alkyl group is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, such as methyl, ethyl, propyl or Butyl
  • the substituent is a halogen, such as one or more of F, Cl, Br or I
  • the substituted C 1 -C 4 alkyl group is preferably a trifluoromethyl group.
  • the cyclohexane derivative provided by the present invention or a stereoisomer or salt thereof, has the structure shown in the following formula I:
  • the R group may be optionally substituted by one or more substituents selected from halogen, substituted or unsubstituted C 1 -C 6 alkyl;
  • the halogen is selected from F, Cl, One or more of Br or I;
  • the substituted or unsubstituted C 1 -C 6 alkyl group is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, such as methyl, ethyl, propyl or Butyl
  • the substituent is a halogen, such as one or more of F, Cl, Br or I
  • the substituted C 1 -C 4 alkyl group is preferably a trifluoromethyl group.
  • the stereoisomer of the cyclohexane derivative of the present invention is a cis stereoisomer or a trans stereoisomer, preferably a trans stereoisomer.
  • the salt of the cyclohexane derivative of the present invention is formed from a cyclohexane derivative which is an organic acid or an inorganic acid, and the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; From formic acid, acetic acid, oxalic acid malonic acid, maleic acid, fumaric acid, succinic acid or benzoic acid; and other physiologically acceptable salts.
  • the cyclohexane derivative of the present invention or a stereoisomer or salt thereof is selected from the following compounds or salts thereof:
  • Another object of the present invention is to provide a process for the preparation of the cyclohexane derivative, or a stereoisomer or salt thereof, which comprises the steps of:
  • the molar ratio of the compound II to the compound III is 1-1.5:1, the reaction temperature is 0 ° C - 50 ° C, the acid binding agent is an organic basic substance or an inorganic basic substance; the organic basic substance is selected from the group consisting of three One or more of an amine, diisopropylethylamine or pyridine selected from one or more of sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, the binding
  • the molar ratio of acid agent (basic compound) to compound II is 1-1.5:1.
  • the invention also provides a preparation method of the compound II, the method comprising the following steps:
  • R and X are as defined above, and Pg is an amino protecting group selected from the group consisting of benzyl Bn, benzyl formate CBz or t-butoxycarbonyl Boc.
  • Pg is an amino protecting group selected from the group consisting of benzyl Bn, benzyl formate CBz or t-butoxycarbonyl Boc.
  • the compound of formula II may itself be cis or trans, or the compound of formula IB may be finally chromatographed or crystallized to obtain its cis stereoisomer.
  • the coupling reaction is carried out under the palladium catalysis, in the presence of a strong base potassium t-butoxide, sodium t-butoxide, potassium carbonate or cesium carbonate, the reaction temperature is 50-150 ° C, the molar ratio of piperazine to bromine 1-5:1; or,
  • the reducing agent is a boron compound such as sodium triacetoxyborohydride or sodium borohydride; the molar ratio of the intermediate IV to the 4-amino protected cyclohexaneacetaldehyde is 1-1.2:1; the boron compound and the intermediate The body IV molar ratio is 1-2:1;
  • Pg is t-butoxycarbonyl Boc
  • an acid deamination protecting group is added; the acid is an organic solution of hydrogen chloride or trifluoroacetic acid; or, when Pg is benzyl Bn or benzyl formate CBz, A palladium carbon hydrodeamination protecting group is used, and the hydrogenation pressure is from 0.1 to 1 MPa.
  • a further object of the present invention is to provide use of the cyclohexane derivative or a stereoisomer or salt thereof for the preparation of a medicament for anti-neuropsychiatric diseases.
  • the cyclohexane derivative or the stereoisomer or salt thereof according to the present invention is a drug-effect structure having potential action on dopamine D 3 receptor and has potential serotonin absorption according to the design principle of the compound pharmacodynamic structure fusion drug. Inhibition of the pharmacodynamic structure of the fusion, through the structural modification of the compound, preparation, in vitro activity test, in vivo anti-schizophrenia activity test, structure-activity relationship study and re-optimization of new compounds.
  • the results of pharmacological studies indicate that the cyclohexane derivative of the present invention or a stereoisomer or salt thereof has a strong affinity for the D 3 receptor and serotonin, and has a weak affinity for the D 2 receptor, showing a pair D.
  • the high selectivity of the 3 /D 2 receptor achieves unexpected results.
  • the in vitro receptor binding assay showed that most of the compounds involved in the cyclohexane derivative or its stereoisomer or salt of the present invention have a strong affinity for the dopamine D 3 receptor and the 5-HT 1A receptor (Ki ⁇ 10 nmol).
  • the in vivo anti-schizophrenia activity test showed that the cyclohexane derivative of the present invention or a stereoisomer or salt thereof has a strong anti-schizophrenia symptom.
  • benzoheterocyclic fragment such as benzothiophene, benzisothiazole or benzisoxazole fragment in the structure of the cyclohexane derivative series compound is closely related (the corresponding fragment of the existing carilazide is 2, 3 chlorobenzene).
  • the cyclohexane derivative of the present invention or a stereoisomer or salt thereof can be used for the preparation of a neuropsychiatric drug.
  • the medicament according to the present invention means a pharmaceutical composition comprising the cyclohexane derivative or a stereoisomer or salt thereof as an active ingredient and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition of the present invention can be selected for any convenient mode of administration.
  • oral, gastrointestinal, buccal, sublingual, nasal, rectal or transdermal administration It can be developed into different dosage forms such as solid dosage forms and liquid dosage forms such as suspensions, tablets, capsules.
  • the composition in the form of a solid tablet may contain a filler, a lubricant, a binder, a disintegrator conventionally used in the formulation.
  • the liquid preparation is a liquid carrier such as a water-soluble solvent such as water, ethanol or glycerin, or a water-insoluble solvent such as polyethylene glycol or a suspension or solution in an oil.
  • the pharmaceutical composition of the present invention is a solid tablet comprising a cyclohexane derivative of the formula IB or the formula I or a stereoisomer or salt thereof as an active ingredient and a pharmaceutically acceptable adjuvant.
  • the solid tablet consists of the following weight ratio components:
  • the diluent is selected from the group consisting of starch, lactose or microcrystalline cellulose; the binder is selected from the group consisting of hydroxybenzylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone; the disintegrant is selected from hydroxyB Based on sodium starch or crospovidone, the lubricant is magnesium stearate.
  • the present invention provides N'-[trans-4-[2-[4-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexyl]-N,N-dimethyl
  • a base urea compound is used as a solid tablet composed of an active ingredient and a pharmaceutically acceptable adjuvant.
  • the solid tablet consists of the following weight ratio components:
  • the diluent is selected from the group consisting of starch, lactose or microcrystalline cellulose
  • the binder is selected from the group consisting of hydroxybenzylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone
  • the disintegrant is selected from sodium hydroxyethyl starch or Dividone
  • the lubricant is magnesium stearate.
  • the pharmaceutical composition of the present invention is a suspension comprising a cyclohexane derivative of the formula IB or the formula I or a stereoisomer or salt thereof as an active ingredient and a pharmaceutically acceptable adjuvant.
  • the suspension consists of the following weight ratio components:
  • the suspending agent is selected from the group consisting of xanthan gum or microcrystalline cellulose; the preservative is selected from sodium benzoate, methyl p-hydroxybenzoate or ethyl p-hydroxybenzoate, the diluent being selected from water or sorbitol;
  • the buffering agent is a citrate;
  • the cosolvent is selected from the group consisting of cyclodextrin, ethanol, propylene glycol or polyethylene glycol;
  • the flavoring agent may be a sweetener (such as sugar, saccharin, etc.) well known to those skilled in the art;
  • the agent may be a fat-soluble colorant or a water-soluble colorant such as carotene, Cocoa pigment, caramel color, etc.
  • the present invention provides N'-[trans-4-[2-[4-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexyl]-N,N-dimethyl
  • a base urea compound is used as a suspension of the active ingredient and a pharmaceutical excipient.
  • the suspension consists of the following weight ratio components:
  • the suspending agent is selected from the group consisting of xanthan gum or microcrystalline cellulose
  • the preservative is selected from the group consisting of sodium benzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate
  • the diluent is selected from the group consisting of water, sorbitol
  • the buffer is lemon.
  • the acid salt, the co-solvent is selected from the group consisting of cyclodextrin, ethanol, propylene glycol or polyethylene glycol
  • the flavoring agent may be a sweetener (such as sugar, saccharin, etc.) well known to those skilled in the art
  • the coloring agent is a fat-soluble coloring agent or water-soluble.
  • Sexual coloring agents such as carotene, cocoa pigment or caramel coloring.
  • cyclohexane derivative of the present invention or a stereoisomer or salt thereof is a novel therapeutic drug for anti-neuropsychiatric diseases, has a good clinical application prospect, and brings good news to patients. Social benefits.
  • the preparation method of the compound of the invention is simple and easy, and is suitable for industrial production, and has great application value.
  • the solid was added to 50 ml of a dichloromethane solution, and 50 ml of a saturated sodium hydrogencarbonate solution was stirred for half an hour, and then the mixture was separated and extracted, and the organic phase was concentrated (0.01 MPa, 40 ° C) to give the object product 3.30 g.
  • Composition Dosage (g) Compound 1 (active ingredient) obtained in Example 4 20.0 lactose 126.0 Microcrystalline cellulose 42.0 Hydroxypropylmethylcellulose 4.0 Sodium hydroxyethyl starch 6.0 Magnesium stearate 2.0
  • Preparation method the active ingredient, lactose, microcrystalline cellulose and sodium hydroxyethyl starch are mixed, added to a high shear wet granulator, and stirred uniformly at a certain rotation speed; then an aqueous solution of hydroxypropylmethylcellulose is added to the mixture. 50.0 g, suitable pellets were prepared under high shear conditions; then the wet granules were dried by a fluidized bed; the obtained dry granules were uniformly mixed with magnesium stearate and tableted.
  • Composition Dosage (g) Compound 1 (active ingredient) obtained in Example 4 50.0 water 3500.0 Polyethylene glycol 50.0 Sorbitol 500.0 Microcrystalline cellulose 25.0 Xanthan gum 5.0 Methylparaben 1.25 Ethyl p-hydroxybenzoate 1.25 Citrate Adjust pH 4 ⁇ 8
  • Preparation method methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate are dissolved in hot water, cooled to room temperature (25 ° C ⁇ 2 ° C), and then added sorbitol, polyethylene glycol, xanthan gum, citric acid The salt, the compound 1 having an average particle size of 30 ⁇ m, and the microcrystalline cellulose were uniformly stirred to obtain an oral suspension.
  • D 2 receptor cell transfection HEK293 cells were transfected with a plasmid vector containing the D 2 receptor protein gene, and subjected to calcium phosphate transfection, and cultured from the transfected cells through a medium containing G418. As well as the selection of cell monoclonal and radioligand binding experiments, a stable cell line stably expressing the D 2 receptor protein was finally obtained.
  • Receptor binding experimental materials isotopic ligand [ 3 H]Spiperone (113.0 Ci/mmol); purchased from Sigma; (+) spiperone, purchased from RBI; GF/B glass fiber filter paper, purchased from Whatman; Tris imported sub-package; PPO, POPOP purchased from Shanghai Reagent No. 1; fat-soluble scintillation liquid. Beckman LS-6500 multi-function liquid scintillation counter.
  • Inhibition rate (I%) total binding tube cpm - compound cpm / total binding tube cpm - non-specific binding tube cpm x 100%.
  • 5-HT 1A receptor isotope [ 3 H].8-OH-DPAT (purchased from PE), (+) 5-hydroxytrptamine (purchased from Sigma), GF/B glass fiber filter (purchased from Whatman) ), fat-soluble scintillation fluid: PPO, POPOP (purchased from Shanghai Reagent No. 1), toluene (purchased from Sinopharm Chemical Reagent Co., Ltd.), and Tris imported and packaged.
  • HEK-293 cells stably expressing 5-HT 1A receptor by gene recombination were cultured in 3-5 cells cultured with DMEM + 10% serum, and cells were harvested with PBS, and the cells were centrifuged at -4 to 3000 rpm. After a minute, discard the supernatant, collect the cells, and store in a -80 degree refrigerator. Resuspend with D 1 Binding Buffer (pH 7.4) during the experiment.
  • the competitive inhibition rate of [ 3 H]8-OH-DPAT binding to 5-HT 1A receptor was determined by coarse screening for each compound at a concentration of 10 umol/L.
  • Table 1 Compounds for D 2 and D 3 receptor binding assays and nucleophilicity of the 5-HT 1A receptor (Ki: nmol)
  • Mode of administration the cyclohexane derivative group of the present invention and the positive control drug cariprazine group are orally administered, MK-801
  • the model control group was administered intraperitoneally.
  • mice After the mice were administered MK-801, they were immediately placed in a soundproof box, and the total distance of the mouse's voluntary activities in 2.5 hours was observed.
  • Table 2 Effect of a single oral administration of a cyclohexane derivative of the invention on the total distance of the open field movement induced by MK-801 in a mouse model of schizophrenia
  • the positive control drug kalidazine group significantly inhibited MK-801-induced high spontaneous activity in rats at a dose of 0.3 kg/kg (P ⁇ 0.0001);
  • the cyclohexane derivative compounds 1, 2, 3 and 5 of the present invention significantly inhibited MK-801-induced high spontaneous activity in rats at a dose of 0.3 kg/kg (P ⁇ 0.0001), the cyclohexane derivative of the present invention.
  • Compounds 6, 7 and 14 also significantly inhibited MK-801-induced high spontaneous activity in rats at a dose of 0.3 kg/kg (P ⁇ 0.05), which was comparable to the positive control drug kalidazine group. Since the MK-801-induced open field exercise model is closely related to the symptoms of schizophrenia, it is indicated that the cyclohexane derivative series of the present invention has a strong anti-schizophrenia symptom.
  • the ICR mice were evaluated for oral administration of the compounds of the present invention, and the signs of toxicity and mortality of the animals after oral administration were observed, and the acute toxicity was compared by the Bliss method.
  • Observations include, but are not limited to, general conditions, behavioral activities, gait posture, eyes, mouth, nose, gastrointestinal tract, skin coat, genitourinary tract.

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Abstract

提供一种式IB所示的环己烷衍生物或其立体异构体或其盐，及其制备与应用。所述环己烷衍生物对D3受体、5-羟色胺具有较强亲和力，对D2受体亲和力较弱，表现出对D3/D2受体的高选择性，用作抗神经精神性疾病的治疗药物，其制备方法简单易行。

Description

环己烷衍生物或其立体异构体或盐及其制备与应用 技术领域
本发明涉及药物化学，具体涉及环己烷类化合物或其立体异构体或盐，尤其涉及如式IB和式I所示的环己烷衍生物或其立体异构体或盐及其制备与应用。
背景技术
伴随着社会的飞速发展，人们生活节奏和压力日益增加，精神类疾病已经成为一种严重影响人类健康的疾病，为患者及其家庭带来了严重的后果。由于自杀、缺乏医疗照顾、较高的并发症风险(如营养不良、缺乏锻炼、肥胖和吸烟)等，导致患者平均寿命缩短。大量研究表明，精神疾病与中枢多种神经递质及受体功能异常相关，如脑内单胺递质，尤其是多巴胺(DA)系统和5-羟色胺(5-HT)系统与人体正常精神活动密切相关。当DA和5-HT系统功能紊乱时，易导致多种神经精神类疾病的发生，如精神分裂症、抑郁症、神经性疼痛、躁狂症、焦虑症、帕金森氏疾病等。
专利WO 9967206A1描述了环己烷类衍生物在疼痛疾病治疗中的应用，但是并未公开报道其在精神类疾病中的应用，尤其是对多巴胺D2/D3受体的作用。
专利CN 1829703A描述了具有(硫代)氨基甲酰基侧链的环己烷衍生物在调节多巴胺受体病症中的应用，其中由Forest Laboratories和Gedeon Richter共同开发的D2/D3拮抗剂和5-HT1A部分激动剂卡利拉嗪(Cariprazine，RGH-188)目前已经完成临床实验处于注册审批阶段，用于精神分裂症和躁狂症及抑郁症的治疗。卡利拉嗪的化学结构如下式所示，该药物对D2/D3受体和5-HT1A的亲和力(Ki值)分别为0.72nmol、0.08nmol和3.42nmol，其对D2/D3受体虽然有一定的选择性，但仍不够理想，因此可能使该药物在临床上仍具有低概率(3mg剂量下有近5％的概率)的静坐不能、椎体外系反应的原因，因为这些副作用都跟D2受体的过度阻断有关。
Figure PCTCN2016098953-appb-000001
基于以上问题，专利CN 103130737A对卡利拉嗪进行了进一步的结构修饰，以实现更高的D3受体选择性。
但是，由于精神类疾病产生的原理有多种，虽然上述化合物目前对抗精神分裂具有较好的药效，但是还不能满足精神类疾病治疗的需要，宜进一步研究开发。
发明内容
本发明所要解决的技术问题在于克服上述不足之处，研究设计改进环己烷衍生物结构，提供如式IB和式I所示的环己烷衍生物或其立体立体异构体或其盐，使其具有D2/D3拮抗剂作用和5-羟色胺吸收抑制作用，以及抗精神分裂作用，增加对精神类疾病治疗的广谱性，减少副作用。
本发明提供的环己烷衍生物或其立体异构体或盐，其结构如下式IB所示：
Figure PCTCN2016098953-appb-000002
其中X为N或C；
R为
Figure PCTCN2016098953-appb-000003
并且，所述R基团可任选的被一个或多个取代基取代，所述取代基选自卤素、取代或未取代的C1-C6烷基；所述卤素选自F、Cl、Br或I中的一种或多种；所述取代或未取代的C1-C6烷基选自取代或未取代的C1-C4烷基，例如甲基、乙基、丙基或丁基，所述取代基为卤素，例如F、Cl、Br或I中的一种或多种，所述取代的C1-C4烷基优选为三氟甲基。
优选地，本发明提供的环己烷衍生物、或其立体异构体或盐，其结构如下式I所示：
Figure PCTCN2016098953-appb-000004
其中R为
Figure PCTCN2016098953-appb-000005
并且，所述R基团可任选的被一个或多个取代基取代，所述取代基选自卤素、取代或未取代的C1-C6烷基；所述卤素选自F、Cl、Br或I中的一种或多种；所述取代或未取代的C1-C6烷基选自取代或未取代的C1-C4烷基，例如甲基、乙基、丙基或丁基，所述取代基为卤素，例如F、Cl、Br或I中的一种或多种，所述取代的C1-C4烷基优选为三氟甲基。
本发明所述环己烷衍生物的立体异构体为顺式立体异构体或反式立体异构体，优选为反式立体异构体。
本发明所述环己烷衍生物的盐由环己烷衍生物与酸形成，所述酸为有机酸或无机酸，所述无机酸选自盐酸、硫酸、硝酸或磷酸；所述有机酸选自甲酸、乙酸、草酸丙二酸、马来酸、富马酸、琥珀酸或苯甲酸；以及其他生理学上可以接受的盐。
优选的，本发明所述环己烷衍生物或其立体异构体或盐选自以下化合物或其盐：
N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物1)
Figure PCTCN2016098953-appb-000006
N'-[反式-4-[2-[7-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物2)
Figure PCTCN2016098953-appb-000007
N'-[反式-4-[2-[4-(苯并[c]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物3)
Figure PCTCN2016098953-appb-000008
N'-[反式-4-[2-[4-(苯并[d]异噻唑)-3-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物4)
Figure PCTCN2016098953-appb-000009
N'-[反式-4-[2-[4-(6-氟-苯并[d]异恶唑)-3-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物5)
Figure PCTCN2016098953-appb-000010
N'-[反式-4-[2-[4-(3-氯-苯并[d]异恶唑)-6-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物6)
Figure PCTCN2016098953-appb-000011
N'-[反式-4-[2-[4-(6-氟-苯并[d]异恶唑)3-哌啶基]乙基]环己基]-N,N-二甲基脲(化合物7)
Figure PCTCN2016098953-appb-000012
N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌啶基]乙基]环己基]-N,N-二甲基脲(化合物8)
Figure PCTCN2016098953-appb-000013
N'-[反式-4-[2-[7-(苯并[b]噻吩)-7-哌啶基]乙基]环己基]-N,N-二甲基脲(化合物9)
Figure PCTCN2016098953-appb-000014
N'-[反式-4-[2-[4-(苯并[c]噻吩)-7-哌啶基]乙基]环己基]-N,N-二甲基脲(化合物10)
Figure PCTCN2016098953-appb-000015
N'-[反式-4-[2-[4-(苯并[d]异噻唑)-3-哌啶基]乙基]环己基]-N,N-二甲基脲(化合物11)
Figure PCTCN2016098953-appb-000016
N'-[反式-4-[2-[4-(3-氯-苯并[d]异恶唑)-6-哌啶基]乙基]环己基]-N,N-二甲基脲(化合物12)
Figure PCTCN2016098953-appb-000017
N'-[反式-4-[2-[4-(3-甲基-苯并[d]异恶唑)-6-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物13)
Figure PCTCN2016098953-appb-000018
N'-[反式-4-[2-[4-(6-甲基-苯并[d]异恶唑)-4-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物14)
Figure PCTCN2016098953-appb-000019
本发明的另一目的是提供所述环己烷衍生物、或其立体异构体或盐的制备方法，该方法包括下列步骤：
4-乙基环己胺衍生物II与N,N-二甲酰基甲酰氯III在缚酸剂存在下反应，得到IB化合物IB：
Figure PCTCN2016098953-appb-000020
其中R、X同上述定义。
所述化合物II与化合物III的摩尔比为1-1.5:1，反应温度为0℃-50℃，缚酸剂为有机碱性物或无机碱性物；所述有机碱性物选自三乙胺、二异丙基乙胺或吡啶中的一种或者几种，所述无机碱性物选自碳酸钠、碳酸钾、碳酸氢钠或碳酸氢钾中的一种或几种，所述缚酸剂(碱性物)与化合物II的摩尔比为1-1.5:1。
本发明还提供了化合物II的制备方法，该方法包括下列步骤：
Figure PCTCN2016098953-appb-000021
或者
Figure PCTCN2016098953-appb-000022
其中R、X同上述定义，Pg为氨基保护基，选自苄基Bn、甲酸苄酯CBz或叔丁氧羰基Boc。式II化合物自身可以是顺式或者反式，亦可以最后使式IB化合物通过色谱分离或者结晶以获得其顺反立体异构体。
(1)当X为氮时，采用哌嗪与溴代物进行偶联反应，得中间体IV；
所述偶联反应是在钯催化下，强碱性物叔丁醇钾、叔丁醇钠、碳酸钾或碳酸铯的存在下进行，反应温度为50-150℃，哌嗪与溴代物摩尔比为1-5:1；或者，
当X为C时，中间体IV可商业购得(上海竺钥化工)。
(2)中间体IV与4-氨基保护的环己烷乙醛进行缩合亚胺还原反应，得中间体V；
所述还原剂为硼化合物，如三乙酰氧基硼氢化钠或硼氢化合钠；中间体IV与4-氨基保护的环己烷乙醛投料摩尔比为1-1.2:1；硼化合物与中间体IV摩尔比为1-2:1；
(3)脱氨基保护基；
更为具体的是当Pg为叔丁氧羰基Boc时，加入酸脱氨基保护基；所述酸为氯化氢有机溶液或三氟乙酸等；或者，当Pg为苄基Bn或甲酸苄酯CBz时，使用钯碳加氢脱氨基保护基，加氢压力为0.1-1Mpa。
本发明的又一目的是提供所述环己烷衍生物或其立体异构体或盐在制备抗神经精神性疾病药物中的应用。
本发明所述的环己烷衍生物或其立体异构体或盐是根据化合物药效结构融合药物 设计原理，将具有潜在对多巴胺D3受体作用的药效结构和具有潜在5-羟色胺吸收抑制作用的药效结构进行融合，经过对化合物的结构改造、制备、体外活性试验、体内抗精神分裂活性试验、构效关系研究以及再优化而得到的新化合物。药理研究结果表明：本发明的环己烷衍生物或其立体异构体或盐对D3受体、5-羟色胺具有较强亲和力，而对D2受体亲和力则较弱，表现出对D3/D2受体的高选择性，达到了意想不到的效果。体外受体结合试验表明：本发明的环己烷衍生物或其立体异构体或盐所涉及的大部分化合物特别对多巴胺D3受体、5-HT1A受体具有强亲和力(Ki<10nmol)，对多巴胺D2受体则弱亲和力(Ki>50nmol)，体现出良好的D3/D2受体选择性，以及对5-HT1A受体的强亲和力。体内抗精神分裂活性试验表明，本发明的环己烷衍生物或其立体异构体或盐有较强的抗精神分裂症症状作用。构效关系研究表明，对多巴胺D3受体、5-HT1A受体的强亲和力和对D3/D2受体的高选择性，以及具有抗精神分裂症症状作用，与本发明的所述环己烷衍生物系列化合物结构中的苯并杂环片段例如苯并噻吩、苯并异噻唑或苯并异恶唑片段有密切关系(现有卡利拉嗪的相应片段是2,3二氯苯)。
因此，本发明的环己烷衍生物或其立体异构体或盐可用于制备神经精神类疾病药物。
本发明所述的药物是指由所述环己烷衍生物或其立体异构体或盐作为活性成分与药用辅料组成的药物组合物。
本发明所述的药物组合物可以选择任何便利的给药方式。例如口服、胃肠道、口腔、舌下、鼻腔、直肠或者透皮给药。可以开发成不同剂型如固体剂型和液体剂型，例如悬浮剂、片剂、胶囊。
固体片剂形式的组合物可以包含制剂中常规使用的填充剂、润滑剂、粘合剂、崩解剂。液体制剂采用适当的液体载体例如水溶性溶剂如水、乙醇或者甘油，或者非水溶性溶剂如聚乙二醇或者油中的混悬剂或者溶液。
更为具体的，本发明所述药物组合物是由式IB或式I所示的环己烷衍生物或其立体异构体或盐作为活性成分与药用辅料组成的固体片剂。
所述固体片剂由下列重量配比的成分组成：
Figure PCTCN2016098953-appb-000023
Figure PCTCN2016098953-appb-000024
所述稀释剂选自淀粉、乳糖或微晶纤维素；所述粘合剂选自羟基苯甲基纤维素、羟丙基甲基纤维素或聚乙烯吡咯烷酮；所述崩解剂选自羟基乙基淀粉钠或交联聚维酮，所述润滑剂为硬脂酸镁。
优选的，本发明提供由N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲化合物作为活性成分与药用辅料组成的固体片剂。
所述固体片剂由下列重量配比的成分组成：
Figure PCTCN2016098953-appb-000025
其中稀释剂选自淀粉、乳糖或微晶纤维素，粘合剂选自羟基苯甲基纤维素、羟丙基甲基纤维素或聚乙烯吡咯烷酮，崩解剂选自羟基乙基淀粉钠或交联聚维酮，润滑剂为硬脂酸镁。
或者，本发明所述药物组合物是由式IB或式I所示的环己烷衍生物或其立体异构体或盐作为活性成分与药用辅料组成的混悬剂。
所述混悬剂由下列重量配比的成分组成：
Figure PCTCN2016098953-appb-000026
所述助悬剂选自黄原胶或微晶纤维素；所述防腐剂选自苯甲酸钠、对羟基苯甲酸甲酯或对羟基苯甲酸乙酯，所述稀释剂选自水或山梨醇；所述缓冲剂为柠檬酸盐；所述共溶剂选自环糊精、乙醇、丙二醇或聚乙二醇；调味剂可以是本领域技术人员众所周知的甜味剂(如糖、糖精等)；着色剂可以是脂溶性着色剂或水溶性着色剂，如胡萝卜素、 可可色素、焦糖色素等。
优选的，本发明提供由N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲化合物作为活性成分与药用辅料组成的混悬剂。
所述混悬剂由下列重量配比的成分组成：
Figure PCTCN2016098953-appb-000027
所述助悬剂选自黄原胶或微晶纤维素，防腐剂选自苯甲酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯，稀释剂选自水、山梨醇，缓冲剂为柠檬酸盐，共溶剂选自环糊精、乙醇、丙二醇或聚乙二醇，调味剂可以是本领域技术人员众所周知的甜味剂(如糖、糖精等)；着色剂为脂溶性着色剂或水溶性着色剂，如胡萝卜素、可可色素或焦糖色素等。
本发明的又一目的是提供所述环己烷衍生物或其立体异构体或盐在制备抗神经精神性疾病药物中的应用，所述应用是指制备对神经精神类疾病具有改善/治疗作用的药物，可用于制备改善/治疗精神分裂、精神紊乱、精神障碍、精神错乱、情绪紊乱、双相类精神障碍、抑郁症、恐惧症、强制性障碍、焦虑症或认知障碍疾病的药物。
急性毒性实验表明，本发明所述的环己烷衍生物或其立体异构体或盐仅有极低的毒性(LD50＞1000mg/Kg)，极优于卡利拉嗪(Cariprazine)(LD50＝75.3mg/Kg)。说明本发明药物毒性小，安全性好。
药理试验表明，本发明的环己烷衍生物或其立体异构体或盐是一类新型的抗神经精神性疾病的治疗药物，有较好的临床应用前景，为患者带来福音，有良好的社会效益。并且本发明化合物制备方法简单易行，宜于工业化生产，有较大的应用价值。
具体实施方式
以下实施例所用原料和试剂除特别说明外，均可市售得到。
实施例1
1-苯并[b]噻吩-4-哌嗪盐酸盐的制备
Figure PCTCN2016098953-appb-000028
将7.20g 4-溴苯并[b]噻吩、19.9g哌嗪酐、4.70g叔丁氧基钠、0.32g(R)-(+)-2,2′-双(二苯膦基)-1,1′-二萘(BINAP)、0.63g二钯三(二亚苄基丙酮)和150ml甲苯的混合物在氮气氛围中回流1小时。在反应溶液中倒入150ml水，然后用100ml×3乙酸乙酯萃取，经水洗后，无水硫酸镁干燥，使溶剂在减压下蒸发(0.01MPa，45℃)。剩余物通过硅胶柱层析(二氯甲烷:甲醇:25％氨水＝100:10:1)提纯，获得4.60g黄色油形式的1-苯并[b]噻吩-4-基-哌嗪。将2ml浓盐酸加入含有4.6g 1-苯并[b]噻吩-4-基-哌嗪的甲醇溶液(25ml)中，并将溶剂在减压条件下蒸发(0.01MPa，45℃)。在剩余物中加入乙酸乙酯(50ml)，沉淀结晶经过滤，在15ml甲醇中回流溶解后冷却至室温(25℃)重结晶，获得无色针状结晶的1-苯并[b]噻吩-4-基-哌嗪盐酸盐。
实施例2
反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基-氨基甲酸叔丁酯的制备
Figure PCTCN2016098953-appb-000029
将2.54g(10mmol)1-苯并[b]噻吩-4-哌嗪盐酸盐(实施例1制得)和2.40g(10mmol)反式-2-{1-[4-(N-叔丁氧碳基)氨基]环己基}-乙醛溶于120ml二氯甲烷中，在室温(25℃±2℃)下加入1.40ml(10mmol)三乙胺缓慢搅拌10分钟，然后逐步加入3.16g(14.8mmol)三乙酰氧基硼氢化钠，室温下继续搅拌反应24小时，反应结束后加入10％碳酸氢钠溶液120ml。反应体系直接萃取分液，有机相用无水硫酸钠干燥，最后过滤旋蒸至干，固体用15ml乙酸乙酯回流溶解冷却至室温(25℃±2℃)结晶得到3.70g目标产物。
1H-NMR(CDCl3)δppm：7.81(1H,brs)，7.78(1H,d,J＝5.5Hz)，7.73(1H,d,J＝8.1Hz)， 7.41(1H,m)，7.30(1H,d,7.6Hz)，6.94(1H,d,J＝7.6Hz)，3.54(1H,m)，3.35-3.23(8H,m)，2.46(2H,m)，1.86-1.65(8H,m)，1.51-1.49(1H,m)，1.42(9H,s)，1.37-1.35(2H,m)。
实施例3
反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己胺的制备
Figure PCTCN2016098953-appb-000030
冰水浴下，将4.43g反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基-氨基甲酸叔丁酯(实施例2制得)置于反应瓶中，加入80ml饱和氯化氢的乙酸乙酯溶液，搅拌反应8小时进行脱保护反应，最后生成白色沉淀，得到标题化合物的盐酸盐3.42g。将上述固体加入50ml二氯甲烷溶液中，50ml饱和碳酸氢钠溶液搅拌半小时后，分液萃取，有机相浓缩(0.01MPa，40℃)得到目标产物3.30g。
1H-NMR(CDCl3)δppm：7.78(1H,d,J＝5.5Hz)，7.76(1H,d,J＝8.1Hz)，7.37(1H,m)，7.29(1H,d,7.6Hz)，6.96(1H,d,J＝7.6Hz)，3.48-3.38(8H,m)，2.53(1H,m)，2.46(2H,m)，1.78-1.63(8H,m)，1.51-1.49(1H,m)，1.42(2H,brs)，1.37-1.35(2H,m)。
实施例4
N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物1)的制备
Figure PCTCN2016098953-appb-000031
将1.73g反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己氨(实施例3制得)溶于50ml二氯甲烷中，加入三乙胺1.40ml，接着加入5.50mmol的N,N-二甲酰基甲酰氯。室温(25℃±2℃)搅拌48小时。反应结束加入50ml水萃取分液，有机相浓缩(0.01MPa， 45℃)，用甲醇:二氯甲烷＝1:10柱层析(400目硅胶型号)收集目标组份，浓缩得到1.89g无定形的目标产物。
1H-NMR(CDCl3)δppm：7.79(1H,d,J＝5.5Hz)，7.76(1H,d,J＝8.1Hz)，7.33(1H,m)，7.28(1H,d,7.6Hz)，6.96(1H,d,J＝7.6Hz)，6.48(1H,brs)，3.44-3.36(8H,m)，3.58(1H,m)，3.01(6H,s)，2.46(2H,m)，1.68-1.42(8H,m)，1.52-1.48(1H,m)，1.38-1.36(2H,m)。
实施例5
N'-[反式-4-[2-[7-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物2)的制备
7-溴苯并[b]噻吩为起始原料制备，参照实施例1-4方法制备化合物2。
1H-NMR(CDCl3)δppm：7.78(1H,d,J＝5.6Hz)，7.76(1H,d,J＝8.0Hz)，7.31(1H,m)，7.27(1H,d,7.6Hz)，6.98(1H,d,J＝7.2Hz)，6.44(1H,brs)，3.48-3.42(8H,m)，3.54(1H,m)，3.00(6H,s)，2.46(2H,m)，1.68-1.42(8H,m)，1.52-1.48(1H,m)，1.38-1.36(2H,m)。
实施例6
N'-[反式-4-[2-[4-(苯并[C]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物3)的制备
以4-溴苯并[c]噻吩为起始原料，参照实施例1-4方法制备化合物3。
1H-NMR(CDCl3)δppm：7.33(2H,s)，7.27-7.25(1H,m)，7.27(1H,d,7.6Hz)，6.77(1H,d,J＝7.2Hz)，6.73(1H,d,J＝7.2Hz)，6.44(1H,brs)，3.48-3.42(8H,m)，3.54(1H,m)，2.99(6H,s)，2.46(2H,m)，1.68-1.42(8H,m)，1.52-1.48(1H,m)，1.46-1.42(2H,m)。
实施例7
N'-[反式-4-[2-[4-(6-氟-苯并[d]异恶唑)-4-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物5)的制备
以6-氟-3-溴-1,2苯并[d]异恶唑为起始原料，参照实施例1-4方法制备化合物5。
1H-NMR(CDCl3)δppm：7.41(1H,d)，7.12(1H,d)，6.98(1H,s)，6.52(1H,brs)，3.55(1H,m)，3.46-3.42(8H,m)，2.99(6H,s)，2.45(2H,m)，1.68-1.40(8H,m)，1.50-1.48(1H,m)，1.37-1.35(2H,m)。
实施例8
N'-[反式-4-[2-[4-(3-氯-苯并[d]异恶唑)-6-哌嗪基]乙基]环己基]-N,N-二甲基脲(化合物6)的制备
以3-氯-6-溴-苯并[d]异恶唑为起始原料制备，参照实施例1-4方法制备化合物6。
1H-NMR(CDCl3)δppm：7.25(1H,d)，6.78(1H,s)，6.72(1H,d)，6.51(1H,brs)，3.54(1H,m)，3.46-3.42(8H,m)，2.99(6H,s)，2.45(2H,m)，1.67-1.40(8H,m)，1.50-1.48(1H,m)，1.42-1.35(2H,m)。
实施例9
N'-[反式-4-[2-[4-(6-氟-苯并[d]异恶唑)-4-哌啶基]乙基]环己基]-N,N-二甲基脲(化合物7)的制备
Figure PCTCN2016098953-appb-000032
以6-氟-3-哌啶-4-基-1,2苯并[d]异恶唑为起始原料(购于上海竺钥化工)，参照实施例2-4方法制备化合物7。
1H-NMR(CDCl3)δppm：7.41(1H,d)，7.12(1H,d)，6.97(1H,s)，6.51(1H,brs)，3.55-3.53(1H,m)，2.99(6H,s)，2.78-2.76(1H，m)，2.66-2.37(4H,m)，2.46-2.40(2H,m)，1.78-1.68(12H,m)，1.50-1.48(1H,m),1.37-1.34(2H,m)。
实施例10
N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲化合物1的固体片剂
按照下表中的配方制备1000片，每片重200mg。
组成成分 用量(g)
实施例4制得的化合物1(活性成分) 20.0
乳糖 126.0
微晶纤维素 42.0
羟丙基甲基纤维素 4.0
羟基乙基淀粉钠 6.0
硬脂酸镁 2.0
制备方法：将活性成分、乳糖、微晶纤维素和羟基乙基淀粉钠混合，加入高剪切湿法制粒机中，在一定转速下搅拌均匀；然后向混合物中加入羟丙甲基纤维素水溶液50.0g，在高速剪切条件下制得合适的颗粒；然后采用流化床干燥湿颗粒；将所得干颗粒与硬脂酸镁混合均匀，压片。
实施例11
N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲化合物1的口服混悬液
按照下表中的口服混悬液的配方(按照规格10mg/ml)制备1000瓶，每瓶5ml。
组成成分 用量(g)
实施例4制得的化合物1(活性成分) 50.0
水 3500.0
聚乙二醇 50.0
山梨醇 500.0
微晶纤维素 25.0
黄原胶 5.0
对羟基苯甲酸甲酯 1.25
对羟基苯甲酸乙酯 1.25
柠檬酸盐 调pH 4～8
制备方法：将对羟基苯甲酸甲酯和对羟基苯甲酸乙酯在热水中溶解后冷却至室温(25℃±2℃)，依次加入山梨醇、聚乙二醇、黄原胶、柠檬酸盐、平均粒度为30μm的化合物1和微晶纤维素，搅拌均匀，获得口服混悬液。
实施例12药理实验
一、本发明环己烷衍生物的体外生物活性研究
按照江苏恒谊药业有限公司专利CN 103130737A描述的多巴胺D2/D3受体结合试验以及5-HT1A受体结合试验的方法进行药理实验。使用非线性分析程序由浓度-依赖反应计算出IC50值。使用Cheng-Prussoff公式由IC50值计算出Ki值。即：Ki＝IC50/(1+[L]/KD)，Ki为药物与受体的亲和力，L为待测化合物浓度，KD为放射性配基与受体的亲和力。
(一)多巴胺D2受体结合试验
1、实验材料：
①、D2受体细胞转染：用含有D2受体蛋白基因的质粒载体转染HEK293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配基结合实验，最终获得能稳定表达D2受体蛋白的稳定细胞株。
②、受体结合实验材料：同位素配基[3H]Spiperone(113.0Ci/mmol)；购自Sigma公司；(+)spiperone，购自RBI公司；GF/B玻璃纤维滤纸，购自Whatman公司；Tris进口分装；PPO、POPOP购自上海试剂一厂；脂溶性闪烁液。Beckman LS-6500型多功能液体闪烁计数仪。
2、实验方法：
①、细胞：用含以上各种基因的重组病毒分别感染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＝7.5)重悬。
②、受体竞争结合实验：
将待测化合物与放射性配基各20μL及160μL受体蛋白加入反应试管中，使受试化合物及阳性药物终浓度均为10μmol/L，30℃水浴孵育50min后，即刻移至冰浴终止其反应；在Millipore细胞样品收集器上，经过GF/C玻璃纤维滤纸快速抽滤，并用洗脱液(50mMTris-HCl，pH 7.5)3mL×3次，用微波5～6min烘干，将滤纸移入0.5mL离心管中，加入500μL脂溶性闪烁液。避光静置30min以上，计数测定放射性强度。化合物浓度为10umol/L，按以下公式计算各化合物对同位素配基结合的抑制率百分率：
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％。
(二)多巴胺D3受体结合试验
化合物10umol/L浓度，实验方法参照Journal of Pharmacology and Experimental Therapeutics2010，333(1):328进行。
(三)5-HT1A受体结合试验
1、实验材料：
5-HT1A受体同位素配基[3H].8-OH-DPAT(购自PE公司)，(+)5-hydroxytrptamine(购自Sigma公司)，GF/B玻璃纤维滤纸(购自Whatman公司)，脂溶性闪烁液：PPO，POPOP(购自上海试剂一厂)，甲苯(购自国药集团化学试剂有限公司)，Tris进口分装。
细胞：用基因重组稳定表达5-HT1A受体的HEK-293细胞，用DMEM+10％血清的细胞培养液培养3-5后，用PBS收细胞，将细胞用-4度3000转离心10分钟后弃上清液，收胞体，存于-80度冰箱保存。实验时用D1Binding Buffer(pH 7.4)重悬。
2、实验方法：
粗筛测定每个化合物10umol/L浓度对[3H]8-OH-DPAT与5-HT1A受体结合的竞争抑制率。
具体实验数据如表1所示。
表1：化合物对D2和D3受体结合试验及5-HT1A受体的亲核力(Ki：nmol)
Figure PCTCN2016098953-appb-000033
Figure PCTCN2016098953-appb-000034
结论：从表1实验结果可以看出，本发明系列化合物对D3的亲核力很强，对D2亲核力非常弱，两者相差近万倍，说明本发明系列化合物对D2/D3受体选择性很强，避免了对D2受体选择产生的副作用；同时对5-HT1A受体也表现出较强的亲核力，增加了抗神经精神类疾病的广谱性。
实施例13本发明环己烷衍生物的体内抗精神分裂活性试验
1、MK-801模型
(1)、MK-801诱导小鼠精神分裂症实验模型建立
Sprague-Dawley大鼠100只(上海莱克实验动物有限公司提供)，均为雄性，按体重均衡随机分为10组：空白对照组，MK-801模型对照组，本发明环己烷衍生物C1-C8组(分别对应本发明化合物1至化合物7，化合物14)(0.3mg/kg)、阳性对照药卡利拉嗪(按照专利CN 103130737 A方法制备)组(0.3mg/kg)。每只动物于实验前一天放入隔音箱适应30min，第二天给予受试物后30分钟，用浓度为0.3mg/kg的MK-801溶液，按照5.0mL/kg小鼠体重进行腹腔注射诱导建立小鼠精神分裂症实验模型。
给药方式：本发明环己烷衍生物组、阳性对照药卡利拉嗪组为口服灌胃，MK-801 模型对照组为腹腔注射给药。
(2)、旷场跑动行为学观察
小鼠给药MK-801后，立即放入隔音箱，观察记录2.5小时内小鼠自主活动的总路程。
改善率＝(模型对照组活动总路程-给药组活动总路程)/(模型对照组活动总路程)×100％。
(3)、统计方法
全部数据以
Figure PCTCN2016098953-appb-000035
表示，用SPSS 17.0软件统计包处理，进行两个样本均数比较的t检验及单因素方差分析，以P<0.05为显著性差异。
(4)、实验结果
具体结果参看下表2。
表2：单次口服给予本发明环己烷衍生物对MK-801诱导小鼠精神分裂症模型旷场运动总路程的影响
Figure PCTCN2016098953-appb-000036
Figure PCTCN2016098953-appb-000037
表2结果显示，与MK-801模型对照组相比较，阳性对照药卡利拉嗪组和本发明的环己烷衍生物化合物1至化合物7均降低了大鼠150分钟内的总活动路程。其中*P<0.05，****P<0.0001。
本试验结果表明：
①与空白对照组相比较，MK-801模型对照组旷场运动距离明显增加，说明MK-801能造成小鼠精神分裂症。
②与MK-801模型阳性对照药卡利拉嗪组相比较，阳性对照药卡利拉嗪组在剂量0.3kg/kg下明显抑制MK-801诱导的大鼠高自发活动(P<0.0001)；本发明的环己烷衍生物化合物1、2、3和5在剂量0.3kg/kg下均能显著抑制MK-801诱导的大鼠高自发活动(P<0.0001)，本发明的环己烷衍生物化合物6、7和14在剂量0.3kg/kg下也能明显抑制MK-801诱导的大鼠高自发活动(P<0.05)，与阳性对照药卡利拉嗪组相当。由于MK-801诱导的旷场运动模型与精神分裂症症状密切相关，因此说明本发明的环己烷衍生物系列有较强的抗精神分裂症状作用。
实施例14本发明环己烷衍生物急性毒性研究
评价ICR小鼠口服给予本发明化合物，观察其口服给予后动物出现的毒性征状和死亡情况，用Bliss法统计，比较其急性毒性。
实验方案
(1)、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。
(2)、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0.94、1.88、3.75、7.5、15、30、60mg/mL(分别相当于18.75、37.5、75、150、300、600、1200mg/kg)混悬液。
(3)、给药途径：供试品及溶媒对照组(0.5％吐温-80)的给药途径均为口服。
一般症状观察：给药当天于第一次给药后约10分钟、0.5、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。
实验结果见表4。
表4：化合物单次口服给药急性毒性实验结果
Figure PCTCN2016098953-appb-000038
结论：表明本发明的环己烷衍生物急性毒性远远低于阳性对照药卡利拉嗪(RGH-188，75.3mg/kg)，安全性良好。

Claims (13)

  1. 环己烷衍生物或其立体异构体或盐，其特征在于，所述环己烷衍生物的结构如下式IB所示：
    Figure PCTCN2016098953-appb-100001
    其中X为N或C；
    R为
    Figure PCTCN2016098953-appb-100002
    并且，所述R基团可任选的被一个或多个取代基取代，所述取代基选自卤素、取代或未取代的C1-C6烷基；所述卤素选自F、Cl、Br或I中的一种或多种；所述取代或未取代的C1-C6烷基选自取代或未取代的C1-C4烷基，例如甲基、乙基、丙基或丁基，所述取代基为卤素，例如F、Cl、Br或I中的一种或多种，所述取代的C1-C4烷基优选为三氟甲基。
  2. 环己烷衍生物或其立体异构体或盐，其特征在于，所述环己烷衍生物的结构如下式I所示：
    Figure PCTCN2016098953-appb-100003
    其中R为
    Figure PCTCN2016098953-appb-100004
    并且，所述R基团可任选的被一个或多个取代基取代，所述取代基选自卤素、取代或未取代的C1-C6烷基；所述卤素选自F、Cl、Br或I中的一种或多种；所述取代或未取代的C1-C6烷基选自取代或未取代的C1-C4烷基，例如甲基、乙基、丙基或丁基， 所述取代基为卤素：F、Cl、Br或I中的一种或多种，所述取代的C1-C4烷基优选为三氟甲基。
  3. 根据权利要求1或2所述的环己烷衍生物或其立体异构体或盐，其特征在于，所述立体异构体为顺式立体异构体或反式立体异构体，优选为反式立体异构体。
  4. 根据权利要求1或2所述的环己烷衍生物或其立体异构体或盐，其特征在于，所述环己烷衍生物的盐由环己烷衍生物与酸形成，所述酸为有机酸或无机酸，所述无机酸选自盐酸、硫酸、硝酸或磷酸；所述有机酸选自甲酸、乙酸、草酸丙二酸、马来酸、富马酸、琥珀酸或苯甲酸；以及其他生理学上可以接受的盐。
  5. 根据权利要求1或2所述的环己烷衍生物或其立体异构体或盐，其特征在于，所述环己烷衍生物或其立体异构体或盐选自以下化合物或其盐：
    N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲，化合物1；
    N'-[反式-4-[2-[7-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲，化合物2；
    N'-[反式-4-[2-[4-(苯并[c]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲，化合物3；
    N'-[反式-4-[2-[4-(6-氟-苯并[d]异恶唑)-3-哌嗪基]乙基]环己基]-N,N-二甲基脲，化合物5；
    N'-[反式-4-[2-[4-(3-氯-苯并[d]异恶唑)-6-哌嗪基]乙基]环己基]-N,N-二甲基脲，化合物6；
    N'-[反式-4-[2-[4-(6-氟-苯并[d]异恶唑)3-哌啶基]乙基]环己基]-N,N-二甲基脲，化合物7；
    N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌啶基]乙基]环己基]-N,N-二甲基脲，化合物8；
    N'-[反式-4-[2-[7-(苯并[b]噻吩)-7-哌啶基]乙基]环己基]-N,N-二甲基脲，化合物9；
    N'-[反式-4-[2-[4-(苯并[C]噻吩)-7-哌啶基]乙基]环己基]-N,N-二甲基脲，化合物10；
    N'-[反式-4-[2-[4-(苯并[d]异噻唑)-3-哌啶基]乙基]环己基]-N,N-二甲基脲，化合物11；
    N'-[反式-4-[2-[4-(3-氯-苯并[d]异恶唑)-6-哌啶基]乙基]环己基]-N,N-二甲基脲，化合物12；
    N'-[反式-4-[2-[4-(3-甲基-苯并[d]异恶唑)-6-哌嗪基]乙基]环己基]-N,N-二甲基脲，化合物13；
    N'-[反式-4-[2-[4-(6-甲基-苯并[d]异恶唑)-4-哌嗪基]乙基]环己基]-N,N-二甲基脲，化合物14。
  6. 如权利要求1或2所述环己烷衍生物或其立体异构体或盐的制备方法，其特征在于，所述方法包括下列步骤：
    4-乙基环己胺衍生物II与N,N-二甲酰基甲酰氯III在缚酸剂存在下反应，得到化合物IB：
    Figure PCTCN2016098953-appb-100005
    其中R、X同权利要求1或2所述定义；
    化合物II与化合物III的摩尔比为1-1.5:1，反应温度为0℃-50℃，缚酸剂为有机碱性物或无机碱性物；所述有机碱性物选自三乙胺、二异丙基乙胺或吡啶中的一种或者几种，所述无机碱性物选自碳酸钠、碳酸钾、碳酸氢钠或碳酸氢钾中的一种或几种，所述缚酸剂与化合物II的摩尔比为1-1.5:1；
    所述化合物II的制备方法，包括下列步骤：
    Figure PCTCN2016098953-appb-100006
    其中R、X如权利要求1或2所述定义，Pg为氨基保护基；
    (1)当X为氮时，采用哌嗪与溴代物进行偶联反应，得中间体IV；
    其中所述偶联反应是在钯催化下，强碱性物叔丁醇钾、叔丁醇钠、碳酸钾或碳酸铯的存在下进行，反应温度为50-150℃，哌嗪与溴代物的摩尔比为1-5:1；或
    当X为C时，中间体IV商业购得；
    (2)中间体IV与4-氨基保护的环己烷乙醛进行缩合亚胺还原反应，得到中间体V；
    其中所述还原剂为硼化合物，选自三乙酰氧基硼氢化钠或硼氢化合钠；中间体IV与4-氨基保护的环己烷乙醛的摩尔比为1-1.2:1；硼氢化合物与中间体IV的摩尔比为 1-2:1；
    (3)脱氨基保护基；
    当氨基保护基为叔丁氧羰基Boc时，加入酸脱氨基保护基；所述酸为氯化氢有机溶液或三氟乙酸；或
    当氨基保护基为苄基Bn或甲酸苄酯CBz时，使用钯碳加氢脱氨基保护基，加氢压力为0.1-1Mpa，即得到式II化合物。
  7. 如权利要求1或2所述的环己烷衍生物或其立体异构体或盐在制备抗神经精神性疾病药物中的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述应用是指环己烷衍生物或其立体异构体或盐在制备改善/治疗精神分裂、精神紊乱、精神障碍、精神错乱、情绪紊乱、双相类精神障碍、抑郁症、恐惧症、强制性障碍、焦虑症或认知障碍疾病的药物中的应用。
  9. 根据权利要求7或8所述的应用，其特征在于，所述药物为由式IB或式I所示的环己烷衍生物或其立体异构体或盐作为活性成分与药用辅料组成的药物组合物，所述药物组合物为口服、胃肠道、口腔、舌下、鼻腔、直肠或透皮给药的固体制剂或液体制剂。
  10. 根据权利要求9所述的应用，其特征在于，所述药物组合物是由式IB或式I所示的环己烷衍生物或其立体异构体或盐作为活性成分与药用辅料组成的固体片剂；所述固体片剂由下列重量配比的成分组成：
    Figure PCTCN2016098953-appb-100007
    所述稀释剂选自淀粉、乳糖或微晶纤维素；所述粘合剂选自羟基苯甲基纤维素、羟丙基甲基纤维素或聚乙烯吡咯烷酮；所述崩解剂选自羟基乙基淀粉钠或交联聚维酮，所述润滑剂为硬脂酸镁。
  11. 根据权利要求10所述的应用，其特征在于，所述药物组合物是由N'-[反式-4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲化合物作为活性成分与药用辅料组成的固体片剂；所述固体片剂由下列重量配比的成分组成：
    Figure PCTCN2016098953-appb-100008
    所述稀释剂选自淀粉、乳糖或微晶纤维素，粘合剂选自羟基苯甲基纤维素、羟丙基甲基纤维素或聚乙烯吡咯烷酮，崩解剂选自羟基乙基淀粉钠或交联聚维酮，润滑剂为硬脂酸镁。
  12. 根据权利要求9所述的应用，其特征在于，所述物组合物是由式IB或式I所示的环己烷衍生物或其立体异构体或盐作为活性成分与药用辅料组成的混悬剂；所述混悬剂由下列重量配比的成分组成：
    Figure PCTCN2016098953-appb-100009
    所述助悬剂选自黄原胶或微晶纤维素；所述防腐剂选自苯甲酸钠、对羟基苯甲酸甲酯或对羟基苯甲酸乙酯，所述稀释剂选自水或山梨醇；所述缓冲剂为柠檬酸盐；所述共溶剂选自环糊精、乙醇、丙二醇或聚乙二醇；调味剂为甜味剂，选自糖或糖精；着色剂为脂溶性着色剂或水溶性着色剂，选自胡萝卜素、可可色素或焦糖色素。
  13. 根据权利要求12所述的应用，其特征在于，所述药物组合物由N'-[反式 -4-[2-[4-(苯并[b]噻吩)-7-哌嗪基]乙基]环己基]-N,N-二甲基脲化合物作为活性成分与药用辅料组成的混悬剂；所述混悬剂由下列重量配比的成分组成：
    Figure PCTCN2016098953-appb-100010
    所述助悬剂选自黄原胶或微晶纤维素，防腐剂选自苯甲酸钠、对羟基苯甲酸甲酯或对羟基苯甲酸乙酯，稀释剂选自水、山梨醇，缓冲剂为柠檬酸盐，共溶剂选自环糊精、乙醇、丙二醇或聚乙二醇，调味剂为甜味剂，选自糖或糖精；着色剂为脂溶性着色剂或水溶性着色剂，选自胡萝卜素、可可色素或焦糖色素。
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