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WO2017045599A1 - Dérivé de cyclohexane ou stéréoisomère ou sel de ce dernier, préparation et utilisation de ce dernier - Google Patents

Dérivé de cyclohexane ou stéréoisomère ou sel de ce dernier, préparation et utilisation de ce dernier Download PDF

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Publication number
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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Prior art keywords
compound
group
ethyl
acid
trans
Prior art date
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Ceased
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PCT/CN2016/098953
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English (en)
Chinese (zh)
Inventor
黄悦
郑飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Jingxin Biomedical Co ltd
Shangyu Jingxin Pharmaceutical Co ltd
Zhejiang Jingxin Pharmaceutical Co Ltd
Original Assignee
Shanghai Jingxin Biomedical Co ltd
Shangyu Jingxin Pharmaceutical Co ltd
Zhejiang Jingxin Pharmaceutical Co Ltd
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Filing date
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Priority claimed from CN201610643389.0A external-priority patent/CN106518841B/zh
Application filed by Shanghai Jingxin Biomedical Co ltd, Shangyu Jingxin Pharmaceutical Co ltd, Zhejiang Jingxin Pharmaceutical Co Ltd filed Critical Shanghai Jingxin Biomedical Co ltd
Priority to US15/759,119 priority Critical patent/US10301277B2/en
Priority to EP16845713.3A priority patent/EP3351540B1/fr
Priority to ES16845713T priority patent/ES2820842T3/es
Priority to JP2018532500A priority patent/JP6772272B2/ja
Priority to CA2998758A priority patent/CA2998758A1/fr
Publication of WO2017045599A1 publication Critical patent/WO2017045599A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

L'invention concerne un dérivé de cyclohexane tel que représenté par la formule IB ou un stéréoisomère ou un sel de ce dernier, ainsi que la préparation et l'utilisation de ce dernier. Le dérivé de cyclohexane présente une affinité élevée pour les récepteurs D3 et la 5-hydroxytryptamine, présente une affinité réduite pour les récepteurs D2, présente une sélectivité élevée pour les récepteurs D3/D2, et peut être utilisé en tant que médicament thérapeutique contre des maladies neuropsychiatriques; et le procédé de préparation de ce dernier est simple et facile.
PCT/CN2016/098953 2015-09-15 2016-09-14 Dérivé de cyclohexane ou stéréoisomère ou sel de ce dernier, préparation et utilisation de ce dernier Ceased WO2017045599A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US15/759,119 US10301277B2 (en) 2015-09-15 2016-09-14 Substituted ureas and methods of treating mental illness using the same
EP16845713.3A EP3351540B1 (fr) 2015-09-15 2016-09-14 Dérivé de cyclohexane ou stéréoisomère ou sel de ce dernier, préparation et utilisation de ce dernier
ES16845713T ES2820842T3 (es) 2015-09-15 2016-09-14 Derivado de ciclohexano o estereoisómero o sal del mismo, y preparación y uso del mismo
JP2018532500A JP6772272B2 (ja) 2015-09-15 2016-09-14 シクロヘキサン誘導体、又はその立体異性体、又はその塩及びその調製と応用
CA2998758A CA2998758A1 (fr) 2015-09-15 2016-09-14 Derive de cyclohexane ou stereoisomere ou sel de ce dernier, preparation et utilisation de ce dernier

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510582267.0 2015-09-15
CN201510582267 2015-09-15
CN201610643389.0 2016-08-08
CN201610643389.0A CN106518841B (zh) 2015-09-15 2016-08-08 环己烷衍生物或其立体异构体或盐及其制备与应用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020034946A1 (fr) * 2018-08-14 2020-02-20 浙江京新药业股份有限公司 Procédé de préparation d'un dérivé de cyclohexane
WO2020034945A1 (fr) * 2018-08-14 2020-02-20 浙江京新药业股份有限公司 Procédé de préparation d'un dérivé de cyclohexane
WO2020042903A1 (fr) * 2018-08-30 2020-03-05 浙江京新药业股份有限公司 Sel de dérivé de cyclohexane
WO2021088920A1 (fr) * 2019-11-05 2021-05-14 上海翰森生物医药科技有限公司 Régulateur de dérivé de benzothiophène, son procédé de préparation et son utilisation
CN114634479A (zh) * 2020-12-16 2022-06-17 北京盈科瑞创新药物研究有限公司 一种派嗪衍生物、其制备方法及应用

Citations (9)

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