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Aromatic acid pro-drug with nitrogen monoxide donor, and preparation method and application thereof

A nitric oxide, prodrug technology, applied in the field of medicinal chemistry research, can solve the problems of strong molecular hydrophilicity and influence on drug efficacy and so on

Inactive Publication Date: 2013-10-30
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although aromatic acid compounds have a variety of pharmacological activities, because of their strong hydrophilicity, it is difficult to penetrate the lipid bilayer of biological membranes and affect their pharmacological effects (Wang Rutao, Zhou Yuan, Zhang Feng, etc. Protective effect of ethyl ferulate on human vascular endothelial cells injured by hydrogen peroxide [J]. Chinese Clinical Pharmacology and Therapeutics, 2004, 9(7): 763-765.)

Method used

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  • Aromatic acid pro-drug with nitrogen monoxide donor, and preparation method and application thereof
  • Aromatic acid pro-drug with nitrogen monoxide donor, and preparation method and application thereof
  • Aromatic acid pro-drug with nitrogen monoxide donor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 1. Preparation of (E)-3-(4-hydroxyl-3-methoxyphenyl)acrylic acid-3-bromopropyl ester (I1a)

[0057] Dissolve 5.0g (25.8mmol) of ferulic acid and 1,3-dibromopropane (100mmol) in 150mL of acetone, add 10mL of triethylamine, heat and stir at 60°C for 4h, take the reaction solution, filter, concentrate, and coat the concentrate with silica gel Column chromatography, eluting with ethyl acetate:petroleum ether=1:4, gave the monobrominated product I1a as a dark red oil with a yield of 55.8%.

[0058] 1 H NMR (CDCl 3 )δ: 2.26 (m, 2H, CH 2 ), 3.52(t, J=3.7Hz, 2H, CH 2 Br), 3.94(s, 3H, OCH 3 ), 4.34(t, J=3.7Hz, 2H, COOCH 2 ), 5.83(s, 1H, OH), 6.30(d, J=9.5Hz, 1H, C=CH), 6.92(d, 1H, Ar-H), 7.06-7.15(m, 2H, Ar-H) , 7.65 (d, J=9.5Hz, 1H, CH=C).ESI-MS: 353 [M+K] + .

[0059] 2. Preparation of (E)-3-(4-hydroxyl-3-methoxyphenyl)acrylic acid-3-nitroxylpropyl ester (Ⅰ1)

[0060] Dissolve I1a (0.7mmol) prepared in 1 in 20mL acetonitrile, add AgNO 3 0.6g (2.5mmol), stirred at 50°...

Embodiment 2

[0063] 1. Preparation of (E)-3-(4-hydroxyl-3-methoxyphenyl)acrylic acid-4-bromobutyl ester (I2a)

[0064] Referring to the preparation method of I1a in Example 1, a white solid was prepared by reacting ferulic acid with 1,4-dibromobutane, the yield was 43.0%, and Mp: 81.9-82.3°C. 1 H NMR (CDCl 3 )δ: 1.87-2.07 (m, 4H, CH 2 ), 3.47(t, J=6.4Hz, 2H, CH 2 Br), 3.93(s, 3H, OCH 3 ), 4.24(t, J=6.4Hz, 2H, COOCH 2), 5.85 (s, 1H, OH), 6.28 (d, J=15.9Hz, 1H, C=CH), 6.92 (d, 1H, Ar-H), 7.62 (d, J=15.9Hz, 1H, CH =C).ESI-MS: 351 [M+Na] + .

[0065] 2. Preparation of (E)-3-(4-hydroxyl-3-methoxyphenyl)acrylic acid-4-nitroxylbutyl ester (I2)

[0066] With reference to the preparation method of I1 in Example 1, by I2a and AgNO 3 The white powder was obtained by reaction with a yield of 91.7%, Mp: 58.1-62.7°C. 1 HNMR (CDCl 3 )δ: 1.81-1.90 (m, 4H, CH 2 ), 3.93 (s, 3H, OCH 3 ), 4.24(t, J=5.9Hz, 2H, COOCH 2 ), 4.52(t, J=6.2Hz, 2H, CH 2 ONO 2 ), 5.90 (s, 1H, OH), 6.28 (d, J=15.9Hz, 1H,...

Embodiment 3

[0068] 1. Preparation of (E)-3-(4-hydroxyl-3-methoxyphenyl)acrylate-5-bromopentyl ester (I3a)

[0069] Referring to the preparation method of I1a in Example 1, it is prepared by reacting ferulic acid with 1,5-dibromopentane. White solid, yield 65.8%, Mp: 66.3-66.6°C. 1 H NMR (CDCl 3 )δ: 1.58 (m, 2H, CH 2 ), 1.70 (m, 2H, CH 2 ), 1.90 (m, 2H, CH 2 ), 3.44 (m, 2H, CH 2 Br), 3.92(s, 3H, OCH 3 ), 4.20 (m, 2H, COOCH 2 ), 5.91 (s, 1H, OH), 6.28 (d, J=15.9Hz, 1H, C=CH), 6.91 (d, 1H, Ar-H), 7.61 (d, J=15.9Hz, 1H, CH =C).ESI-MS: 365[M+Na] + .

[0070] 2. Preparation of (E)-3-(4-hydroxyl-3-methoxyphenyl)acrylate-5-nitroxylpentyl ester (I3)

[0071] Referring to the preparation method of I1 in Example 1, by I3a and AgNO 3 The reaction is made. Blue-yellow crystals, yield 83.0%, Mp: 51.3-53.7°C. 1 H NMR (CDCl 3 )δ: 1.49-1.63 (m, 2H, CH 2 ), 1.71-1.84 (m, 4H, CH 2 ), 3.93 (s, 3H, OCH 3 ), 4.21(t, J=6.4Hz, 2H, COOCH 2 ), 4.47(t, J=6.5Hz, 2H, CH 2 ONO 2 ), 5.91 (s, 1H, OH)...

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Abstract

The invention relates to the field of research into pharmaceutical chemistry, and particularly discloses a novel aromatic acid pro-drug with nitrogen monoxide donor, and a preparation method and application thereof in preventing and treating thrombotic diseases. In the invention, natural aromatic acid compounds with strong antithrombotic actions are structurally modified, and the carboxylic acid groups are incorporated with nitrogen monoxide donor to obtain the nitrogen monoxide donor type aromatic acid pro-drug with favorable liposolubility. The aromatic acid pro-drug with nitrogen monoxide donor has favorable solubility, can effectively permeate into the biomembrane lipid bimolecular layer, and can enhance the bioavailability after the human body takes the pro-drug. The pro-drug can be resolved into aromatic acid compounds and release nitrogen monoxide, and the aromatic acid compounds and nitrogen monoxide can cooperate to perform the pharmacological activities of resisting thrombi, resisting platelet aggregation and the like. The aromatic acid pro-drug with nitrogen monoxide donor can be used for preventing and treating thrombotic diseases and cerebral ischemia diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry research, in particular to a novel aromatic acid prodrug with nitric oxide donor, its preparation method and its application in anti-thrombotic or anti-cerebral ischemic diseases. Background technique [0002] With the intensification of population aging, accelerated pace of life, and changes in living environment and eating habits, the incidence and mortality of cardiovascular and cerebrovascular diseases are increasing year by year, which is increasingly endangering human life and health. The formation of thrombus plays an important role in the pathogenesis and development of cardiovascular and cerebrovascular diseases, atherosclerosis, hypertension and diabetic complications (Viles-Gonzalez JF, Fuster V, Badimon JJ. Links between inflammation and thrombogenicity inatherosclerosis [J].Curr.Mol.Med.2006,6:489-499.), and platelet aggregation and coagulation abnormalities are the main causes of t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C203/04C07C201/02C07D307/60C07D271/08A61K31/216A61K31/341A61K31/4245A61P7/02A61P9/10
Inventor 李念光唐于平段金廒
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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