Indole-heteroaromatic piperazine (piperidine) derivatives and application thereof in resisting depression

A technology of aromatic heterocycles and indole, which is applied in the fields of new drug design, synthesis and discovery, can solve the problems of inability to improve cognitive impairment, large side effects, and low curative effect, and achieve ideal pharmacokinetic characteristics, small side effects, and wide indications Effect

Active Publication Date: 2019-03-15
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The invention discloses a class of 5-HT reuptake, 5-HT 1A and 5-HT 7 Indole-aromatic heterocyclic piperazine (pyridine) derivatives (or called compounds) or pharmaceutically acceptable salts thereof and their application in the preparation of antidepressant drugs with three target activity, the new derivatives can To overcome the defects of slow onset of action, low curative effect, large side effects and inability to improve cognitive impairment in existing antidepressant drugs, and meet the needs of depression treatment

Method used

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  • Indole-heteroaromatic piperazine (piperidine) derivatives and application thereof in resisting depression
  • Indole-heteroaromatic piperazine (piperidine) derivatives and application thereof in resisting depression
  • Indole-heteroaromatic piperazine (piperidine) derivatives and application thereof in resisting depression

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Preparation of 3-(4-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperazin-1-yl)benzo[d]isothiazole (VI-1) hydrochloride

[0072] 5-Fluoro-1H-indole (I) (0.1 mol) and AlCl 3 (0.1mol) was dissolved in dichloromethane (200mL), the temperature was lowered to 0°C, and a dichloromethane solution (50mL) of chloroacetyl chloride (II) (0.1mol) was slowly added dropwise with stirring. According to General Method 1, 14.81 g of Intermediate III (colorless liquid) was obtained with a yield of 70%. MS (m / z): 212.03[M+1] + .

[0073] The above intermediate (III) (0.05mol) was dissolved in trifluoroacetic acid (50mL), cooled to 0°C, and HSiEt was slowly added dropwise under stirring 3 (0.15 mol). According to the operation of General Method 2, 6.92 g of intermediate IV (colorless liquid) was obtained, and the yield was 70%. MS(m / z): 198.16[M+1] + .

[0074] Above-mentioned intermediate IV (0.01mol) and the hydrochloride (0.01mol) of piperazine compound (V) are dissolved in DMF (100mL), add...

Embodiment 2

[0076] Preparation of 3-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)benzo[d]isothiazole (VI-2) hydrochloride

[0077] 5-Fluoro-1H-indole (I) (0.1 mol) and AlCl 3 (0.1mol) was dissolved in dichloromethane (200mL), the temperature was lowered to 0°C, and a dichloromethane solution (50mL) of 3-chloropropionyl chloride (II) (0.1mol) was slowly added dropwise under stirring. According to General Method 1, 13.54 g of Intermediate III (colorless liquid) was obtained with a yield of 60%. MS(m / z): 226.05[M+1] + .

[0078] The above intermediate (III) (0.05mol) was dissolved in trifluoroacetic acid (50mL), cooled to 0°C, and HSiEt was slowly added dropwise under stirring 3 (0.15 mol). According to the operation of General Method 2, 6.35 g of intermediate IV (colorless liquid) was obtained, and the yield was 60%. MS (m / z): 212.04[M+1]+ .

[0079] Above-mentioned intermediate IV (0.01mol) and the hydrochloride (0.01mol) of piperazine compound (V) are dissolved in DMF (100mL)...

Embodiment 3

[0081] Preparation of 3-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)benzo[d]isothiazole (VI-3) hydrochloride

[0082] 5-Fluoro-1H-indole (I) (0.1 mol) and AlCl 3 (0.1mol) was dissolved in dichloromethane (200mL), cooled to 0°C, and a dichloromethane solution (50mL) of 4-chlorobutyryl chloride (II) (0.1mol) was slowly added dropwise under stirring. According to General Method 1, 20.37 g of Intermediate III (colorless liquid) was obtained, with a yield of 85%. MS(m / z): 240.15[M+1] + .

[0083] The above intermediate (III) (0.05mol) was dissolved in trifluoroacetic acid (50mL), cooled to 0°C, and HSiEt was slowly added dropwise under stirring 3 (0.15 mol). According to the operation of General Method 2, 9.03 g of intermediate IV (colorless liquid) was obtained, and the yield was 80%. MS (m / z): 226.14[M+1] + .

[0084] Above-mentioned intermediate IV (0.01mol) and the hydrochloride (0.01mol) of piperazine compound (V) are dissolved in DMF (100mL), add K 2 CO 3 (0.0...

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Abstract

The invention discloses indole-heteroaromatic piperazine (piperidine) derivatives or officinal salt thereof. The indole-heteroaromatic piperazine (piperidine) derivatives or officinal salt has the following structure as shown in a formula. The compounds and compositions contained therein have activity to 5-HT reuptake, a 5-HT1A acceptor and a 5-HT7 acceptor, and can be applied to preparing novel anti-depression drugs.

Description

technical field [0001] The invention belongs to the field of new drug design, synthesis and discovery, and specifically relates to an indole-aromatic heterocyclic piperazine (pyridine) derivative and its application as a novel multi-target antidepressant. Background technique [0002] Depression is a common mental illness that is chronic and prone to relapse. According to the World Health Organization, about 350 million people around the world suffer from depression. It is estimated that by 2020, depression will become the second disease affecting the quality of human life. [0003] To date, the mechanism of action of antidepressant drugs has not been fully elucidated. Drugs with clear curative effects basically act on the synaptic site of nerve endings, and exert therapeutic effects by regulating the level of neurotransmitters in the synaptic cleft. Biochemical studies of its etiology have shown that depression is mainly related to the central five-hydroxytryptamine (5-H...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D417/14C07D413/14A61K31/496A61K31/4439A61P25/24
CPCC07D413/14C07D417/12C07D417/14
Inventor 李建其谷正松周爱南肖莹
Owner SHANGHAI INST OF PHARMA IND
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