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Acetylbenzylamine piperazine and/or piperidine derivatives and their application as brain neuroprotective agents

A technology of acetobenzamide piperazine and piperidine, which is applied in the field of brain neuroprotective agents, can solve the problems of cognitive impairment, narrow treatment time window, imperfect clinical experiment scheme, etc., and achieves the effect of good curative effect.

Active Publication Date: 2022-02-15
SHANGHAI INST OF PHARMA IND CO LTD +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 and/or piperidine derivatives and their application as brain neuroprotective agents
  • Acetylbenzylamine piperazine and/or piperidine derivatives and their application as brain neuroprotective agents
  • Acetylbenzylamine piperazine and/or piperidine derivatives and their application as brain neuroprotective agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1N- Benzyl -2-(4-(3- Phenylureido ) piperidine ) Acetamide ( T-1 ) and its salt preparation

[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 ...

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 a class of acetylbenzylamine piperazine and / or piperidine derivatives, which are expected to overcome the shortcomings of low activity or high cardiotoxicity in existing neuroprotective agents as brain neuroprotective agents. Wherein said acetylbenzylamine piperazine and / or piperidine derivatives are compounds represented by general formula I or salts thereof:

Description

technical field [0001] The invention relates to a class of acetylbenzylamine piperazine and / or piperidine 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 red...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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 CO LTD
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