Acetylbenzylamine piperazine (piperidine) derivatives and application of derivatives as cerebral nerve protective agent

A technology of acetylbenzylamine piperazine and its derivatives, which is applied in the field of acetylbenzylamine piperazine derivatives, can solve the problems of imperfect clinical experiment schemes, toxic and side effects, narrow treatment time window, etc., and achieve high neuroprotective activity , small cardiac side effects, novel structure effect

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

Analysis of its possible reasons has the following aspects: (1) the drug concentration entering the brain has not reached the therapeutic concentration; (2) the treatment time window is narrow; (3) the clinical trial program is not perfect; (4) serious toxicity occurs. Side effects, such as psychosis-like side effects, movement disorders, cognitive impairments, etc.; (5) There are species differences between humans and animals in terms of activity and toxicity

Method used

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  • Acetylbenzylamine piperazine (piperidine) derivatives and application of derivatives as cerebral nerve protective agent
  • Acetylbenzylamine piperazine (piperidine) derivatives and application of derivatives as cerebral nerve protective agent
  • Acetylbenzylamine piperazine (piperidine) derivatives and application of derivatives as cerebral nerve protective agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 Preparation of N-benzyl-2-(4-(3-phenylureido)piperidine)acetamide (T-1) and its salts

[0052] Using aniline as raw material, according to method 1, 0.51 g of the target product was obtained with a yield of 59.3%. ESI-MS[M+H] + : m / z=367.2, 1 H NMR (400MHz, DMSO-d6) δppm: 9.94 (s, 1H, CONH), 9.24-9.18 (m, 1H), 7.58 (s, 3H), 7.37-7.26 (m, 5H), 6.79 (d, J =4.0Hz,1H),6.88(t,J=8.0Hz,1H),4.37(d,J=8.0Hz,2H),4.05-3.98(m,2H),3.74-3.67(m,1H),3.49 (d,J=8.0Hz,2H),3.17(q,J=8.0Hz,1H),2.09-1.99(m,2H),1.91(s,1H),1.83-1.70(m,2H).

[0053] Preparation of compound T-1 hydrochloride

[0054] 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.

[0055] Preparation of compound T-1 mesylate

[0056] Compound T-1 (0.3g) and methanesulfonic acid aqueous solution (0.8mmol) were added to ethan...

Embodiment 2

[0061] Example 2 N-benzyl-2-(4-(3-(4-(trifluoromethyl)phenylureido)piperidine)acetamide (T-2) and its salt preparation

[0062] Using p-trifluoromethylaniline as raw material, according to method 1, 0.43 g of the target product was obtained with a yield of 55.4%. ESI-MS[M+H] + :m / z=435.2; 1 H NMR (400MHz, DMSO-d6) δppm: 9.83(s, 1H), 9.24-9.19(m, 1H), 8.92(s, 1H), 7.40-7.25(m, 7H), 7.05(t, J=8.0 Hz, 2H), 4.36(d, J=4.0Hz, 2H), 4.06-3.98(m, 2H), 3.72-3.65(m, 1H), 3.48(d, J=12.0Hz, 2H), 3.22-3.14 (m,1H),2.09-1.99(m,2H),1.91(s,1H),1.79-1.68(m,2H).

[0063] Preparation of compound T-2 hydrobromic acid salt

[0064] 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

[0065] Example 3 Preparation of N-benzyl-2-(4-(3-(4-fluorophenyl)urea)piperidine)acetamide (T-3) and its salts

[0066] Using p-fluoroaniline as raw material, according to General Method 1, 0.87 g of the target product was obtained with a yield of 67%. ESI-MS[M+H] + :m / z=385.2; 1 H NMR (400MHz, DMSO-d6) δppm: 9.96(s, 1H), 9.12(t, J=8.0Hz, 2H), 9.24-9.18(m, 1H), 8.80(s, 1H), 7.38-7.25( m,7H),7.21(t,J=8.0Hz,2H),6.88(t,J=8.0Hz,1H),4.36(d,J=4.0Hz,2H),4.05-4.02(m,1H), 3.98(d, J=4.0Hz, 2H), 3.49(d, J=12.0Hz, 2H), 3.39(s, 1H), 3.18(q, J=12.0Hz, 1H), 2.04-1.99(m, 2H ),1.79-1.69(m,2H).

[0067] Preparation of Compound T-3 Fumarate

[0068] 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 acetylbenzylamine piperazine (piperidine) derivatives. As a cerebral nerve protective agent, the derivatives disclosed by the invention are expected to overcome the disadvantages of low activity or high cardiotoxicity of a current nerve protective agent medicine, wherein the acetylbenzylamine piperazine (piperidine) derivatives are compounds or salts of the compounds represented by a general formula I shown in the description.

Description

technical field [0001] The invention relates to a class of acetylbenzylamine piperazine (pyridine) derivatives and the use of the compound as a protective agent for brain nerves. 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 neuroprotective agents can reduce the...

Claims

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Application Information

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IPC IPC(8): C07D295/32C07D285/135C07D213/75C07D263/48C07D231/40C07D261/14C07D277/46A61K31/4468A61K31/454A61K31/4545A61K31/495A61P9/10A61P25/00
CPCC07D213/75C07D231/40C07D261/14C07D263/48C07D277/46C07D285/135C07D295/32
Inventor 李建其张庆伟姜玲张子学
Owner SHANGHAI INST OF PHARMA IND
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