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Benzylamine acetyl piperidine acylamide derivative as well as application of benzylamine acetyl piperidine acylamide derivative as cranial nerve protective agent

A technology of acetylbenzylamine piperidine amide and derivatives, applied in the application field of brain neuroprotective agents, which can solve the problems of high cardiotoxicity and weak activity

Active Publication Date: 2018-10-16
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Therefore, the technical problem to be solved in the prior art is to disclose a class of acetylbenzylamine piperidine amide derivatives and their application as brain neuroprotective agents, so as to overcome the weak activity and cardiotoxicity of existing neuroprotective agents. major defect

Method used

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  • Benzylamine acetyl piperidine acylamide derivative as well as application of benzylamine acetyl piperidine acylamide derivative as cranial nerve protective agent
  • Benzylamine acetyl piperidine acylamide derivative as well as application of benzylamine acetyl piperidine acylamide derivative as cranial nerve protective agent
  • Benzylamine acetyl piperidine acylamide derivative as well as application of benzylamine acetyl piperidine acylamide derivative as cranial nerve protective agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: (E)-N-(1-(2-(benzylamine)-2-ethoxy)piperidine)-3-(4-methoxyphenyl)acrylamide (T- 1) Preparation of its salt

[0067] Using 4-methoxycinnamic acid as raw material, according to the general synthetic method, 1.45 g of the target product was obtained with a yield of 85%.

[0068] ESI-MS[M+H] + m / z=408.2; 1 H NMR (400MHz, DMSO-d6) δppm: 10.17(s, 1H), 9.30(t, J=8.0Hz, 1H), 8.38(d, J=8.0Hz, 1H), 7.50(d, J=12.0Hz ,2H),7.41(s,1H),7.37~7.25(m,5H),6.98(d,J=8.0Hz,2H),6.53(d,J=16.0Hz,1H),4.36(d,J= 4.0Hz, 2H), 4.15~4.00(m, 3H), 3.79(s, 3H), 3.51(d, J=12.0Hz, 2H), 3.25~3.18(m, 2H), 2.08~1.98(m, 2H ),1.88~1.79(m,2H).

[0069] Preparation of compound T-1 hydrochloride

[0070] Compound T-1 (0.3g) and 5% hydrochloric acid aqueous solution (0.8mmol) were added to ethanol (10mL), refluxed and dissolved, and a white solid was precipitated by cooling, which was filtered to obtain 0.3g of white T-1 hydrochloride solid.

[0071] Preparation of compound T-1 mesylate

[007...

Embodiment 2

[0077] Example 2: (E)-N-(1-(2-(benzylamine)-2-ethoxy)piperidine)-3-(3,4,5-trimethoxyphenyl)propene Preparation of amides (T-2) and their salts

[0078] Using 3,4,5-trimethoxycinnamic acid as a raw material, and operating according to the general synthetic method, 1.45 g of the target product was obtained with a yield of 85%.

[0079] ESI-MS[M+H] + m / z=468.1; 1 H NMR (400MHz, DMSO-d6) δppm: 10.08(s, 1H), 9.25(t, J=8.0Hz, 1H), 8.35(d, J=8.0Hz, 1H), 7.40(s, 1H), 7.37 ~7.26(m, 5H), 6.90(d, J=4.0Hz, 2H), 6.61(d, J=16.0Hz, 1H), 4.36(d, J=4.0Hz, 2H), 4.06~3.99(m, 3H), 3.81(s, 6H), 3.68(s, 3H), 3.52~3.47(m, 2H), 3.25~3.11(m, 2H), 1.99(s, 2H), 1.86~1.78(m, 2H) .

[0080] Preparation of compound T-2 hydrobromic acid salt

[0081] Using compound T-2 (2.0 mmol) and 5% hydrobromic acid aqueous solution (2.1 mmol) as raw materials, the preparation method of compound T-1 hydrobromide was used to obtain 0.9 g of white T-2 hydrobromide solid.

Embodiment 3

[0082] Example 3: (E)-N-(1-(2-(benzylamine)-2-ethoxy)piperidine)-3-(3,4-dimethoxyphenyl)acryloyl Preparation of amine (T-3) and its salt

[0083] Using 3,4-dimethoxycinnamic acid as raw material, according to the general method, the target product was obtained 1.45g, and the yield was 85%.

[0084] ESI-MS[M+H] + m / z=438.2; 1H NMR (400MHz, DMSO-d6) δppm: 10.06(s, 1H), 9.23(d, J=8.0Hz, 1H), 8.29(d, J=8.0Hz, 1H), 7.38( d, J=8.0Hz, 2H), 7.35~7.25(m, 5H), 7.13(t, J=8.0Hz, 2H), 6.99(d, J=8.0Hz, 1H), 6.53(d, J=12.0 Hz, 1H), 4.36(d, J=4.0Hz, 2H), 4.12~3.88(m, 3H), 3.78(d, J=4.0Hz, 6H), 3.50(d, J=12.0Hz, 2H), 3.20(q, J=12.0Hz, 2H), 2.06~1.98(m, 2H), 1.85~1.77(m, 2H).

[0085] Preparation of Compound T-3 Fumarate

[0086] Using compound T-3 (2.3 mmol) and fumaric acid (2.4 mmol) as raw materials, the preparation method of compound T-1 hydrobromide was adopted to obtain 1.0 g of white solid.

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Abstract

The invention discloses a benzylamine acetyl piperidine acylamide derivative having a cranial nerve protection effect as well as application of the benzylamine acetyl piperidine acylamide derivative.A pharmacological test proves that the compound of the derivative disclosed by the invention has a better neuronal cell protection effect and obvious anti-hypoxia activity in a body, and a herg test proves that the compound of the derivative disclosed by the invention has the advantages of low potential cardiac toxicity and high security. The benzylamine acetyl piperidine acylamide derivative is free alkali or salt of the compound shown in the following chemical structural formulas. The formula (1) is shown in the description.

Description

technical field [0001] The invention relates to a kind of acetylbenzylamine piperidine amide derivative or a pharmaceutically acceptable salt thereof, and its application as a brain neuroprotective agent. Background technique [0002] Cerebral stroke, also known as "stroke" or "cerebral vascular accident" (cerebral vascular accident, CVA), is a group of diseases that cause brain tissue damage due to sudden rupture of blood vessels in the brain or blockage of blood vessels that prevent blood from flowing into the brain, including Hemorrhagic and ischemic stroke. Stroke has the characteristics of high morbidity, disability, recurrence and mortality, and is a worldwide health problem. The currently used anti-stroke drugs are mainly thrombolytic and anticoagulant agents, vasodilators, free radical scavengers, neuroprotective agents, and some traditional Chinese medicine prescriptions for promoting blood circulation and removing blood stasis. Studies have shown that neuroprotec...

Claims

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Application Information

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IPC IPC(8): C07D211/58A61K31/4468A61P25/00A61P9/10
CPCC07D211/58
Inventor 李建其张庆伟姜玲张子学
Owner SHANGHAI INST OF PHARMA IND
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