Piperazine (piperidine) cyclohexyl derivative and applications of piperazine (piperidine) cyclohexyl derivative in treatment of neuropsychiatric diseases

A kind of derivative, cyclohexyl technology, applied in the field of piperazine cyclohexyl derivatives, can solve the problems of cognitive impairment and poor curative effect

Active Publication Date: 2016-03-02
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] One of the technical problems to be solved in the present invention is to disclose a piperazine (pyridine) cyclohexyl derivative to overcome the side effects of existing drugs such as obesity

Method used

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  • Piperazine (piperidine) cyclohexyl derivative and applications of piperazine (piperidine) cyclohexyl derivative in treatment of neuropsychiatric diseases
  • Piperazine (piperidine) cyclohexyl derivative and applications of piperazine (piperidine) cyclohexyl derivative in treatment of neuropsychiatric diseases
  • Piperazine (piperidine) cyclohexyl derivative and applications of piperazine (piperidine) cyclohexyl derivative in treatment of neuropsychiatric diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Trans-N-(4-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)oxazol-2-amine (I-1 ) and its salt preparation

[0179] Trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amine (prepared according to General Method 7) ( 3.45g, 10mmol), 2-chlorooxazole (1.04g, 10mmol) were added to acetonitrile (50mL), (DIPEA, 50mmol) was added dropwise, and the reaction was refluxed for 12h. The reaction solution was cooled to room temperature, and a white solid was precipitated, which was filtered to obtain The crude product was recrystallized from 95% ethanol to obtain 2.42 g of white solid with a yield of 58.7%.

[0180] 1 HNMR (DMSO-d6 ,δ:ppm):0.95-1.04(m,2H,A-H),1.18-1.27(m,3H,A-H),1.38-1.40(m,2H,A-H),1.75-1.77(m,2H,A-H), 1.87-1.91(m,2H,A-H),2.40(t,2H,J=7.8Hz,N-CH 2 ),2.61-2.66(m,4H,piperazine-CH 2 ),3.43-3.48(m,4H,piperazine-CH 2 ),3.60-3.67(m,1H,A-H),6.82(d,1H,J=2.4Hz,Ar-H),7.02(d,1H,J=8.0Hz,NH-H)7.43(t,1H, J=7.6Hz, Ar-H), 7.55(t, 1H, J=7.6...

Embodiment 2

[0189] 3-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)oxazolidin-2-one (I- 14) Preparation of its salt

[0190] Trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amine (prepared according to General Method 7) ( 3.45g, 10mmol) and bromoethanol (1.25g, 10mmol) were added to dichloromethane (50mL), refluxed for 48h, the reaction solution was cooled to room temperature, and washed once with saturated sodium carbonate solution, water, and saturated brine successively. The organic phase was concentrated to dryness under reduced pressure to obtain 2-(trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclo Hexyl)amino)ethanol crude product. Dissolve triphosgene (0.74g, 2.5mmol) in dichloromethane (20mL), and add 2-(trans-N-(4-(2-(4-(benzo[d] Isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amino)ethanol (1.94g, 5mmol), triethylamine (12.5mmol) in dichloromethane (10mL) solution, stirring reaction at room temperature Af...

Embodiment 3

[0200] 3-(trans-4-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)quinazoline-2,4(1H ,3H)-diketone (I-15) and its salt preparation

[0201] Trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amine (prepared according to General Method 7) ( 3.45g, 10mmol) and isatoic anhydride (1.48g, 9.1mmol) were added to dichloromethane (50mL), reacted at an external temperature of 50°C for 12h, added triphosgene (9.1mmol), potassium carbonate (45.5mmol), and reacted for 12h , to stop the reaction, the reaction solution was cooled to room temperature, washed once with saturated ammonium chloride solution, water, and saturated brine successively, and the organic phase was concentrated to dryness under reduced pressure to obtain a white solid, which was separated by a Flash column to obtain 3.1 g of a white solid. The rate is 69.4%.

[0202] 1 HNMR (DMSO-d 6 ,δ:ppm):1.03-1.09(m,2H,A-H),1.23-1.44(m,4H,A-H),1.58-1.61(m,2H,A-H),1.84-1.87(m,2H,A-H), 2.39-2....

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Abstract

The present invention discloses a piperazine (piperidine) cyclohexyl derivative and applications of the piperazine (piperidine) cyclohexyl derivative in treatment of neuropsychiatric diseases. According to the present invention, the pharmacological experiment results show that the piperazine (piperidine) cyclohexyl derivative provides high affinity with a dopamine D2 receptor, a dopamine D3 receptor, a serotonin 5-HT1A receptor and a serotonin 5-HT2A receptor, provides good D3/D2 receptor selectivity and good 5-HT1A/5-HT2A receptor selectivity, and provides low affinity with alpha receptor; the in vivo test results show that the preferred compound has characteristics of good anti-schizophrenia effect, good pharmacokinetic property, low side effect, low acute toxicity and high safety, and has the development value of being adopted as the novel efficient and low-toxic anti-neuropsychiatric disease; and the piperazine (piperidine) cyclohexyl derivative is a compound represented by the structural general formula (I), or a geometric isomer, an optical isomer, a salt, a hydrate or a solvate thereof. The formula (I) is defined in the specification.

Description

technical field [0001] The present invention relates to a piperazine (pyridine) cyclohexyl derivative with anti-schizophrenia activity and its application in treating mental and nervous diseases. Background technique [0002] Schizophrenia is a chronic and persistent disease. It is the most serious and harmful mental disease, affecting the normal life of about 1% of the world's population. The number of patients in my country exceeds 10,000,000, and it is the seventh largest disease of social burden. The symptoms of schizophrenia are complex and often manifest differently with the course of the disease. Clinically, schizophrenia mainly includes positive symptoms, such as delusions and hallucinations; negative symptoms, such as social withdrawal and apathy; and cognitive dysfunction, such as loss of working memory. [0003] The etiology of schizophrenia is complex and has not yet been clarified. There are several hypotheses in the academic circles, including the neurodevelo...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D275/04C07D417/14C07D413/14C07D263/20A61K31/496A61K31/506A61K31/517A61K31/454A61P25/18A61P25/24A61P25/22A61P25/30A61P25/28A61P25/04A61P25/16
Inventor 李建其陈晓文张飞龙王慧慧张志国
Owner SHANGHAI INST OF PHARMA IND
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