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Cyclohexane amine compounds and their application as anti-schizophrenia drugs

A kind of technology of cyclohexaneamine and compound, applied in the field of cyclohexaneamine compound

Inactive Publication Date: 2015-12-02
JIANGSU HENGYI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] One of the technical problems to be solved in the present invention is to disclose a cyclohexane amine compound to reduce the toxic and side effects of existing drugs such as akathisia and high probability of extrapyramidal system reactions, improve safety, and solve clinical problems and meet clinical drug requirements. need;

Method used

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  • Cyclohexane amine compounds and their application as anti-schizophrenia drugs
  • Cyclohexane amine compounds and their application as anti-schizophrenia drugs
  • Cyclohexane amine compounds and their application as anti-schizophrenia drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0144] The preparation of trans-N-(4-(2-(4-(benzo [d] isothiazol-3-yl) piperazin-1-yl) ethyl) cyclohexyl) acetamide (I-1) ( 1), the preparation of trans-N-tert-butoxycarbonyl-4-aminocyclohexyl ethanol (2)

[0145] Add trans-N-tert-butoxycarbonyl-4-aminocyclohexylacetic acid (25.7g, 0.1mol) and 200mL dichloromethane into a 1000mL four-neck flask, cool to 0°C in an ice bath, drop triethylamine ( 0.25mol), slowly add isopropyl chloroformate (0.15mol) dropwise, and control the temperature not to exceed 10 degrees Celsius. Wash (200mL×1), evaporate to dryness, N 2 Under protection, add 200 mL of anhydrous tetrahydrofuran to the residue, cool down to 0 °C, and slowly add KBH in batches 4 (0.1mol), the temperature control does not exceed 5°C, after the addition is complete, stir at room temperature for 2h, cool to below 5°C, slowly add saturated ammonium chloride solution dropwise until no bubbles overflow, the system is concentrated under reduced pressure to dryness, and water (20...

Embodiment 2

[0175] Preparation of trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)n-pentanamide (I-2)

[0176] Using intermediate 5 (10 mmol) and n-valeryl chloride (12 mmol) as raw materials, according to the preparation method of compound I-1, the target compound I-23.72g was obtained with a yield of 87%.

[0177] 1 HNMR (CDCl 3 ,δ:ppm):0.93(t,3H,J=7.2Hz,CH 3 ),1.07-1.11(m,4H,A-H),1.28-1.33(m,3H,A-H),1.39-1.43(m,2H,A-H),1.50-1.55(m,2H,A-H),1.88-1.93( m,2H,A-H),2.10-2.21(m,4H,A-H),2.44(t,2H,J=7.6Hz,N-CH 2 ),2.69-2.73(m,4H,piperazine-CH 2 ),3.52-3.56(m,4H,piperazine-CH 2 ),4.07-4.09(m,1H,A-H),7.38(d×t,1H,J=8.4Hz,0.8Hz,Ar-H),7.49(d×t,1H,J=8.4Hz,0.8Hz, Ar-H),7.85(d,1H,J=8.4Hz,Ar-H),7.89(d,1H,J=8.0Hz,Ar-H).

[0178] ESI-MS:429[M+H + ]

[0179] Preparation of compound 1-2 hydrochloride

[0180] Using compound I-2 (5 mmol) and 5% (5 mmol) hydrochloric acid as starting materials, the synthesis method of compound I-1 hydrochloride was used to obtain 2.0 g of w...

Embodiment 3

[0192] trans-N-(4-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-2,2,2-trifluoroethane Preparation of Amide (I-3)

[0193] Using intermediate 5 (10 mmol) and trifluoroacetic acid (12 mmol) anhydride as raw materials, according to the preparation method of compound I-1, the target compound I-33.82g was obtained with a yield of 86.7%.

[0194] 1 HNMR (CDCl 3 ,δ:ppm):1.06-1.19(m,3H,A-H),1.22-1.30(m,2H,A-H),1.42-1.58(m,2H,A-H),1.85-1.89(m,2H,A-H), 2.15-2.18(m,2H,A-H),2.43(t,2H,J=7.6Hz,N-CH 2 ),2.63-2.65(m,4H,piperazine-CH 2 ),3.34-3.49(m,1H,A-H),3.54-3.58(m,4H,piperazine-CH 2 ),4.08(m,1H,A-H),7.30-7.35(m,1H,Ar-H),7.42-7.46(m,1H,Ar-H),7.79(d,1H,J=8.0Hz),7.88 (d,1H,J=8.0Hz).

[0195] ESI-MS:441[M+H + ]

[0196] Preparation of compound 1-3 hydrochloride

[0197] Using compound I-3 (5 mmol) and 5% hydrochloric acid (5 mmol) as starting materials, the synthesis method of compound I-1 hydrochloride was used to obtain 1.96 g of white solid with a yield of 82%. ...

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Abstract

The invention discloses a cyclohexane amine compound and application of the cyclohexane amine compound as anti-schizophrenia medicine. The cyclohexane amine compound has high affinity to a dopamine D3 receptor and a 5-HT1A, and representative compounds have a high selectivity of D3 / D2 receptors. According to in vivo tests, the representative compounds such as I-1 compound can remarkably improve relative symptoms of apomorphine model mice and MK-801 model mice. The cyclohexane amine compound has the advantages of being good in anti-schizophrenia effect, low in acute toxicity and good in safety, and having development value of serving as novel high-efficiency and low-toxicity medicine for anti-neurological disorder diseases. The cyclohexane amine compound is a compound with a structural general formula (I) or stereomer, free alkali, aquo-complex or salt.

Description

technical field [0001] The invention relates to a cyclohexaneamine compound with antipsychotic activity and its application as an antipsychotic drug. Background technique [0002] Schizophrenia is a disease that seriously affects human health. It currently affects the normal life of about 1% of the world's population and has brought serious consequences to patients and their families. It is the seventh largest disease in social burden. Due to suicide, lack of medical attention, and higher risk of complications (such as malnutrition, lack of exercise, obesity, and smoking), the average life expectancy of patients is shortened by 12 to 15 years. [0003] 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. Monoamine transmitters in the brain, especially the dopamine (DA) system and 5-hydroxytryptamine (5-HT) system are related to the normal mental state of the human body...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D275/04C07D417/12A61K31/496A61K31/5377A61P25/18A61P25/24A61P25/04A61P25/22A61P25/16
Inventor 李建其辜顺林蔡王平陈晓文
Owner JIANGSU HENGYI PHARMA
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