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n, n-disubstituted benzazine heterocyclo-2-amine compounds and uses thereof

A technology of amine compounds and benzonitrogen, which is applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of low brain penetration ability, extremely poor membrane permeability, easy degradation in vivo, and limited therapeutic use, etc., and achieve strong inhibition active effect

Inactive Publication Date: 2016-04-20
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its low brain penetration ability, recently scientists are studying how to make it into liposomes to treat cerebral vasospasm caused by subarachnoid hemorrhage, hoping to increase local drug concentration through targeted administration, reduce adverse reactions, and improve treatment. Effect
[0008] Due to the unsatisfactory aspects of the existing RhoA kinase (ROCK) inhibitors, looking for its upstream protein RhoA inhibitors has become another direction. At present, the only RhoA inhibitors are a class called exoenzyme C3transferase (exoenzymeC3transferase, C3) macromolecule or its derivatives, due to its extremely poor membrane permeability and easy to degrade in vivo defects, which limits its therapeutic use, the C3 fusion protein BA-210 developed by Tremblay et al. Neuroprotective drugs are undergoing phase II clinical research. Lee et al. have developed a recombinant protein TAT-C3 with good membrane permeability for nerve regeneration therapy

Method used

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  • n, n-disubstituted benzazine heterocyclo-2-amine compounds and uses thereof
  • n, n-disubstituted benzazine heterocyclo-2-amine compounds and uses thereof
  • n, n-disubstituted benzazine heterocyclo-2-amine compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Preparation of 2-Chloroquinoxaline (Intermediate II-1).

[0081]

[0082] Dissolve 2.000g of 2-hydroxyquinoxaline in 20mL of phenylphosphonyl dichloride, and react under reflux at 110°C for 12h under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled to room temperature, slowly poured into ice water and kept stirring. After the product was precipitated, it was suction filtered, washed with water, and dried to obtain 1.830 g of 2-chloroquinoxaline (intermediate II-1), with a yield of 81%.

[0083] 1 H-NMR (400MHz, CDCl 3 ):δ8.54(s,1H),7.92–7.81(m,1H),7.80–7.72(m,1H),7.63–7.50(m,2H).

Embodiment 2

[0085] Preparation of 2-Chloroquinoline (Intermediate II-2).

[0086]

[0087] Except for replacing 2-hydroxyquinoxaline with 2-hydroxyquinoline, the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain 1.911g of intermediate 2-chloroquinoline (intermediate II-2). The rate is 85%.

[0088] 1 H-NMR (400MHz, CDCl 3 ):δ8.14(d,J=8.6Hz,1H),8.08(d,J=8.5Hz,1H),7.83(d,J=8.2Hz,1H),7.80–7.73(m,1H),7.58 (m,1H),7.41(d,J=8.6Hz,1H).

Embodiment 3

[0090] Preparation of ethyl m-nitrocinnamate (Intermediate III).

[0091]

[0092] Dissolve 2.000g of m-nitrocinnamic acid in 40mL of ethanol, slowly add 1mL of concentrated sulfuric acid dropwise, and reflux for 12h under nitrogen protection. The reaction was monitored by TLC. After the reaction, the reaction system was cooled to room temperature, the solvent was evaporated under reduced pressure, the reaction system was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic layer was taken, dried, suction filtered, and evaporated under reduced pressure. solvent to obtain a crude product. After separation and purification by column chromatography, 2.000 g of intermediate ethyl m-nitrocinnamate (intermediate III) was obtained, with a yield of 88%.

[0093] 1 H-NMR (400MHz, CDCl 3 ):δ7.62(d,J=15.8Hz,1H),7.20(t,J=7.6Hz,1H),6.98(d,J=7.8Hz,1H),6.88(s,1H),6.76(d ,J=8.1Hz,1H),6.40(d,J=16.2Hz,1H),4.28(q,J=7.2Hz,2H),1.36(t,J=...

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PUM

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Abstract

The invention mainly relates to an N,N-double substituted benzoazacyclo-2-amide compound and an application thereof. The N,N-double substituted benzoazacyclo-2-amide compound is a compound shown as formula I or a salt formed by a medical acid or alkali. The compound provided by the invention has strong inhibition activity on RhoA protease which is tightly related with cardiovascular and cerebrovascular diseases. The compound provided by the invention is hopeful to be developed into a RhoA protease small-molecule inhibitor type cardiovascular and cerebrovascular disease treatment medicine.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, and more specifically relates to N,N-disubstituted benzazine-2-amine compounds and their preparation methods and applications. Background technique [0002] Cardiovascular and cerebrovascular disease is a common disease that seriously threatens the health of human beings, especially middle-aged and elderly people over 50 years old. It is particularly prominent in our country. The total morbidity and mortality of cardiovascular and cerebrovascular diseases in my country have approached or surpassed many developed countries, and are still on the rise. Statistics show that the mortality rate of cardiovascular and cerebrovascular diseases in my country's urban population is 200 / 100,000, and that in rural areas is 142 / 100,000, accounting for 37% and 28% of deaths respectively, ranking first among the causes of death. Therefore, cardiovascular and cerebrovascular di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/44C07D215/38C07D401/12C07D403/12C07F7/18C07F9/6509C07F9/60A61P9/10A61P9/00
CPCC07D215/38C07D241/44C07D401/12C07D403/12C07F7/1804C07F9/60C07F9/650994
Inventor 李剑缪丽燕李秀江马晟闫兆威
Owner EAST CHINA UNIV OF SCI & TECH
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