Cyclohexane amine compound and application of cyclohexane amine compound as anti-schizophrenia medicine

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

Inactive Publication Date: 2013-06-05
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

Method used

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  • Cyclohexane amine compound and application of cyclohexane amine compound as anti-schizophrenia medicine
  • Cyclohexane amine compound and application of cyclohexane amine compound as anti-schizophrenia medicine
  • Cyclohexane amine compound and application of cyclohexane amine compound as anti-schizophrenia medicine

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0143] Example 1

[0144] 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-aminocyclohexylethanol (2)

[0145] Trans-N-tert-butoxycarbonyl-4-aminocyclohexylacetic acid (25.7g, 0.1mol) and 200mL of dichloromethane were added to a 1000mL four-necked flask, cooled to 0°C in an ice bath, and triethylamine ( 0.25mol), slowly add isopropyl chloroformate (0.15mol) dropwise, control the temperature not to exceed 10 degrees Celsius, after the addition, stir at room temperature for 2 h, cool to 5 °C, add 200 mL of cold water, stir, and separate the organic layer with saturated brine Washed (200mL×1), evaporated to dryness, N 2 Under the protection, 200 mL of anhydrous tetrahydrofuran was added to the residue, the temperature was lowered to 0 °C, and KBH was slowly added in batches. 4 (0.1mol), the temperature should not exceed 5 °C, the addition was completed, stirred at roo...

Example Embodiment

[0174] Example 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-23.72 g was obtained with a yield of 87%.

[0177] 1 H NMR (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 I-2 hydrochloride

[0180] Using compound I-2 (5 mmol) and 5% (5 mmol) hydrochloric acid as starting materials, and adopting the synthesis method of compound I-1 hydroch...

Example Embodiment

[0191] Example 3

[0192] trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-2,2,2-trifluoroethyl Preparation of amide (I-3)

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

[0194] 1 H NMR (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 I-3 hydrochloride

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

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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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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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