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Application of acetyl amantadine piperazine (piperidine) compound as cerebral neuroprotective agent

A kind of technology of acetylamantadine piperazine and compound, which is applied in the field of brain nerve protective agent, and achieves the effect of ideal pharmacokinetic characteristics, strong protective activity and high bioavailability

Active Publication Date: 2019-11-26
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compounds involved in the present invention and their neuroprotective effects have not been reported so far

Method used

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  • Application of acetyl amantadine piperazine (piperidine) compound as cerebral neuroprotective agent
  • Application of acetyl amantadine piperazine (piperidine) compound as cerebral neuroprotective agent
  • Application of acetyl amantadine piperazine (piperidine) compound as cerebral neuroprotective agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Preparation of Example 1N-(1-(2-(adamantyl-1-amino)-2-acetyl)piperidine-4-substituted)cinnamide (I-1) and salts thereof

[0072] Prepare according to general synthesis method V-1, and the specific operation is as follows:

[0073] Preparation of intermediate chloroacetylamantadine:

[0074] Dissolve 1-adamantanamine (4.87g, 32.2mmol) in 50mL of DCM, under nitrogen protection, slowly add triethylamine (4.94mL, 35.5mmol) dropwise at 0°C, stir for 15min, then slowly add chloroacetyl chloride ( 2.82mL, 37.4mmol), maintain this temperature, continue to stir for 2h. After the reaction was completed, water was added to the reaction liquid to separate the layers, and the organic layer was washed with dilute hydrochloric acid and saturated sodium bicarbonate in sequence, and the concentrated product of the organic layer was collected and recrystallized with petroleum ether / ethyl acetate to obtain acetylamantadine chloride, 6.28 g, The rate is 85.6%. ESI-MS(m / z):228.2[M+H]+. ...

Embodiment 2

[0089]Example 2 (E)-N-(1-(2-(adamantyl-1-amino)-2-acetyl)piperidine-4-substituted)-3-(2-methoxyphenyl)propene Preparation of amides (I-2) and their salts

[0090] According to the general synthesis method V-1 operation, the target product I-20.43g was obtained with a yield of 55.4%. ESI-MS[M+H] + : m / z=452.1, 1 H NMR (400MHz, DMSO-d6) δppm: 7.99 (d, 1H, J = 7.6Hz), 7.24 (d, 1H, J = 15.6Hz), 7.07 (s, 1H), 6.88 (s, 2H), 6.47 (d,1H,J=15.6Hz),3.81(m,4H),2.80(m,4H),2.01(s,4H),1.93(d,6H,J=2.4Hz),1.78(d,4H, J=10.4Hz), 1.63(s, 6H), 1.43(m, 4H).

[0091] The preparation of compound 1-2 hydrobromide

[0092] Using compound I-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 I-2 hydrobromide solid.

[0093] Preparation of compound I-1 oxalate

[0094] Compound I-2 (2.0mmol) and oxalic acid dihydrate (2.4mmol) were added to ethanol (10mL), refluxed to dissolve, and...

Embodiment 3

[0095] Example 3 (E)-N-(1-(2-(adamantyl-1-amino)-2-acetyl)piperidine-4-substituted)-3-(4-hydroxyl-3-methoxy Preparation of phenyl)acrylamide (I-3) and its salt

[0096] According to the general synthesis method V-1 operation, the target product I-30.73g was obtained with a yield of 65.4%. ESI-MS[M+H] + : m / z=468.2, 1 H NMR (400MHz, DMSO-d6) δppm: 8.11 (d, 1H, J = 7.6Hz), 7.24 (d, 1H, J = 15.6Hz), 6.88 (s, 2H), 6.43 (d, 1H, J = 15.6Hz), 3.81(m, 4H), 2.81(m, 4H), 2.21(s, 4H), 1.93(d, 6H, J=2.4Hz), 1.78(d, 4H, J=10.4Hz), 1.63 (s,6H), 1.43(m,4H).

[0097] Preparation of compound 1-3 acetate

[0098] Add compound I-3 (0.3g) and acetic acid (0.8mmol) to ethanol (10mL), reflux to dissolve, cool and reduce pressure to concentrate the acid to obtain a solid, beat with acetone and cool to precipitate a white solid, filter to obtain 0.22g of white I-3 Acetate solid.

[0099] Preparation of compound 1-3 sulfate

[0100] Add compound I-3 (0.3 g) and sulfuric acid (0.8 mmol) into wa...

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Abstract

The present invention discloses an application of acetamantadine piperazine (piperidine) compound as cerebral neuroprotective agent. The structure of the acetamantadine piperazine (piperidine) compound is novel, and the application of the acetamantadine piperazine (piperidine) compound as cerebral neuroprotective agent achieves unexpected technical effect. The compound and the medicinal preparation thereof have good curative effect on treating cerebral stroke and related diseases, have low acute toxicity and no potential cardiotoxicity risk, have ideal pharmacokinetic characteristics, and showoutstanding technical effect and substantial scientific progress compared with the existing drugs. The acetamantadine piperazine (piperidine) compound is a compound represented by the formula (I) anda pharmaceutically acceptable salt thereof.

Description

technical field [0001] The invention relates to a class of acetylamantadine piperazine (pyridine) compounds and the use of the compounds as brain neuroprotective agents. 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 size of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58C07D295/182C07D241/04A61K31/445A61K31/495A61P9/10A61P25/00
CPCC07D211/58C07D295/182C07D241/04A61K31/445A61K31/495A61P9/10A61P25/00Y02A50/30
Inventor 李建其张庆伟周爱南张闯郭政苏晓静
Owner SHANGHAI INST OF PHARMA IND
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