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Cyclohexane derivative or stereoisomer or salt and preparation and application thereof

一种立体异构体、衍生物的技术，应用在药物化学领域，能够解决不能满足精神类疾病治疗等问题

Active Publication Date: 2017-03-22
ZHEJIANG JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, since there are many reasons for the occurrence of mental diseases, although the above-mentioned compounds have good efficacy against schizophrenia, they still cannot meet the needs of the treatment of mental diseases, and should be further researched and developed.

Method used

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  • Cyclohexane derivative or stereoisomer or salt and preparation and application thereof
  • Cyclohexane derivative or stereoisomer or salt and preparation and application thereof
  • Cyclohexane derivative or stereoisomer or salt and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Preparation of 1-benzo[b]thiophene-4-piperazine hydrochloride

[0094]

[0095]7.20g 4-bromobenzo[b]thiophene, 19.9g piperazine anhydride, 4.70g sodium tert-butoxide, 0.32g (R)-(+)-2,2′-bis(diphenylphosphino)- A mixture of 1,1'-binaphthalene (BINAP), 0.63 g of dipalladium tris(dibenzylideneacetone) and 150 ml of toluene was refluxed for 1 hour under a nitrogen atmosphere. Pour 150ml of water into the reaction solution, then extract with 100ml×3 ethyl acetate, wash with water, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure (0.01MPa, 45°C). The residue was purified by silica gel column chromatography (dichloromethane:methanol:25% aqueous ammonia=100:10:1) to obtain 4.60 g of 1-benzo[b]thiophen-4-yl-piperazine as a yellow oil. 2ml of concentrated hydrochloric acid was added to a methanol solution (25ml) containing 4.6g of 1-benzo[b]thiophen-4-yl-piperazine, and the solvent was evaporated under reduced pressure (0.01MPa, 45°C). E...

Embodiment 2

[0097] Preparation of trans-4-[2-[4-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexyl-carbamic acid tert-butyl ester

[0098]

[0099] 2.54g (10mmol) 1-benzo[b]thiophene-4-piperazine hydrochloride (prepared in Example 1) and 2.40g (10mmol) trans-2-{1-[4-(N-tert Butoxycarbonyl)amino]cyclohexyl}-acetaldehyde was dissolved in 120ml of dichloromethane, and at room temperature (25°C±2°C), 1.40ml (10mmol) of triethylamine was added and stirred slowly for 10 minutes, then gradually added 3.16g (14.8mmol) sodium triacetoxyborohydride, stirring reaction was continued at room temperature for 24 hours, after the reaction was completed, 120ml of 10% sodium bicarbonate solution was added. The reaction system was directly extracted and separated, the organic phase was dried with anhydrous sodium sulfate, and finally filtered and rotary evaporated to dryness, the solid was refluxed with 15ml of ethyl acetate and cooled to room temperature (25°C±2°C) for crystallization to obtain 3.70g of...

Embodiment 3

[0102] Preparation of trans-4-[2-[4-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexylamine

[0103]

[0104] Under ice-water bath, 4.43g trans-4-[2-[4-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexyl-carbamic acid tert-butyl ester (prepared in Example 2 ) was placed in a reaction flask, 80ml of saturated hydrogen chloride in ethyl acetate was added, stirred and reacted for 8 hours to carry out the deprotection reaction, and finally a white precipitate was formed to obtain 3.42g of the hydrochloride of the title compound. The above solid was added to 50ml of dichloromethane solution, and 50ml of saturated sodium bicarbonate solution was stirred for half an hour, then separated and extracted, and the organic phase was concentrated (0.01MPa, 40°C) to obtain 3.30g of the target product.

[0105] 1 H-NMR (CDCl 3 )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....

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Abstract

The invention provides a cyclohexane derivative or stereoisomer or salt and preparation and application thereof. The structure of the cyclohexane derivative is as shown in the formula IB. it shows through pharmacological testing results that the cyclohexane derivative has strong affinity to D3 receptor and 5-hydroxytryptamine but has weak affinity to D2 receptor, shows high selectivity to D3 / D2 receptors and achieves unexpected effects. The cyclohexane derivative is a novel therapeutic for treating neuropsychiatric diseases and has good clinical application prospect and social benefit. The preparation method is simple and feasible, is suitable for industrial production and has great application value.

Description

technical field [0001] The present invention relates to medicinal chemistry, in particular to cyclohexane compounds or their stereoisomers or salts, especially cyclohexane derivatives as shown in formula IB and formula I or their stereoisomers or salts and their preparation and application. Background technique [0002] With the rapid development of society and the increasing pace and pressure of people's life, mental illness has become a disease that seriously affects human health and has brought serious consequences for patients and their families. The average life expectancy of patients is shortened due to suicide, lack of medical attention, higher risk of complications such as malnutrition, lack of exercise, obesity and smoking. A large number of studies have shown that mental illness is related to the dysfunction of various neurotransmitters and receptors in the central nervous system. closely related. When the DA and 5-HT systems are dysfunctional, it is easy to lea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/54C07D275/04C07D261/20C07D413/04C07D409/04C07D417/04A61K31/496A61K31/454A61K31/4535A61P25/18A61P25/24A61P25/22A61P25/28
CPCC07D261/20C07D275/04C07D333/54C07D409/04C07D413/04C07D417/04A61K31/454A61K31/496A61P25/18C07D333/72A61K9/2013A61K9/2018A61K9/2054A61K9/2059
Inventor 黄悦郑飞
Owner ZHEJIANG JINGXIN PHARMA
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