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Picotamide analogues as well as preparation method and application thereof

A technology of picotamide and its analogues, applied in the field of medicinal chemistry, can solve the problems of unreported drug efficacy and activity of compounds, and achieve the effect of treating thromboembolic diseases and inhibiting platelet aggregation

Active Publication Date: 2014-03-26
ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tong Zeen and others replaced aniline, benzylamine, bisbenzylamine, cyclohexylamine, piperidine, morpholine, tetrahydropyrrole, methylpiperazine, 4,5-dimethoxy with methylaniline, 4-nitroaniline, etc. 15 picotamide analogues were synthesized by substituting tetrahydroisoquinoline (3-pyridylmethylamine), but the pharmacodynamic activity of related compounds was not reported [see Tong Zeen, Chen Wenhao, Peng Sixun. Antiplatelet aggregation drug Picotamide and its Synthesis of analogues. Journal of China Pharmaceutical University, 1992,23(1):1-4]

Method used

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  • Picotamide analogues as well as preparation method and application thereof
  • Picotamide analogues as well as preparation method and application thereof
  • Picotamide analogues as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 4-methoxy-N 1 , N 3 -Synthesis of bis(3,5,6-trimethylpyrazin-2-yl)methyl)isophthalamide (PKL1)

[0032] 1.1 Synthesis of 2-bromomethyl-3,5,6-trimethylpyrazine

[0033]

[0034] In a 250ml three-necked bottle, add raw materials anhydrous ligustrazine (20g, 0.147mol), NBS (26.75g, 0.15mol), benzoyl peroxide (0.05g, 0.0002mol), solvent CCl 4 (75mL), the solution was orange-yellow turbid, irradiated by an incandescent lamp, the oil bath was heated to 75°C, and refluxed for 10 hours. TLC [V (petroleum ether): V (ethyl acetate) = 2:1 as developing agent] showed The reaction is complete (raw material Rf=0.4, product Rf=0.6), the reaction solution is purple, and the generated succinimide is removed by filtration to obtain a purple filtrate, and CCl is recovered under reduced pressure 4 The final purple-red viscous liquid was distilled under reduced pressure, and the product was collected at 99-101°C / 2mmHg fraction to obtain 20 g of 2-bromomethyl-3,5,6-trimethylpyrazine co...

Embodiment 2

[0046] 4-methoxy-N 1 , N 3 -Synthesis of bis(5-methylpyrazin-2-yl)methyl)isophthalamide (PKL2)

[0047] 2.1 Synthesis of 2-chloromethyl-5-methylpyrazine

[0048]

[0049] Add 2,5-dimethylpyrazine (6g, 55.6mmol) and carbon tetrachloride (50mL) successively in a three-necked flask, stir and dissolve and add N-chlorosuccinimide (NCS) (7.4g, 55.6mmol) and benzoyl peroxide (0.05g, 0.21mmol), the reaction mixture was stirred under incandescent light, and refluxed for about 18h, TLC [V (ethyl acetate): V (petroleum ether) = 1:2 As a developing agent] After detecting that the reaction is basically complete, the reaction solution is cooled to 0°C, and after standing for 1 hour, it is filtered, the filter cake is washed with cold carbon tetrachloride, the filtrate and washing liquid are combined, and the carbon tetrachloride is evaporated under reduced pressure. A light brown oil was obtained, which was dissolved in dichloromethane and decolorized by activated carbon to obtain a l...

Embodiment 3

[0060] 4-methoxy-N 1 , N 3 -Synthesis of bis(pyrazin-2-yl)methyl)isophthalamide (PKL3)

[0061]

[0062] (Pyrazin-2-yl) methylamine is operated according to embodiment 2.1, 2.2, 2.3, 4-methoxy-N 1 , N 3 -The synthesis of two (pyrazine-2-yl) methyl) isophthalamides is operated according to Example 2.4 to obtain PKL 3 White crystals, yield 28.6%, m.p.176.4-178.2°C. 1 H NMR (CDCl 3 ,400MHz)δ:8.83(brs,1H,NH),8.69(s,1H,pyrazine ring-H),8.67(s,1H,pyrazine ring-H),8.65(s,1H,pyrazine ring-H) H),8.55(s,1H,pyrazine ring-H),8.53(s,1H,pyrazine ring-H),8.52(s,1H,pyrazine ring-H),8.51(s,1H,ArH) ,8.18(d,J=8.8Hz,1H,ArH),7.45(brs,1H,NH),7.12(d,J=8.8Hz,1H,ArH),4.86(d,J=5.2Hz,2H,- NHCH 2 -),4.83(d,J=5.2Hz,2H,-NHCH 2 -),4.08(s,3H,CH 3 O-); 13 C NMR (CDCl 3 ,100MHz) δ:166.17,164.74,160.12,152.86,152.51,144.14,144.07,143.90,143.87,143.52,143.45,133.67,130.18,126.84,120.47,111.89,52K18,Br(IR -1 )υ: 3360, 3080, 2929, 1673, 1599, 1661, 1490, 1408, 1276, 843, 760, 617; ESI-MS for C 19 ...

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Abstract

The invention relates to the field of medicinal chemistry and particularly relates to picotamide analogues (I), a preparation method and a pharmaceutical composition containing the picotamide analogues, wherein R represents hydrogen, 3, 5, 6- trimethyl, 5-methyl or 6-methyl. The picotamide analogues provided by the invention can be used for treating or preventing thromboembolic diseases.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, and in particular relates to a picobutamide analog, a preparation method, and a pharmaceutical composition containing them. The picotamide analog of the present invention can be used for treating or preventing thromboembolic diseases. Background technique [0002] Cardiovascular and cerebrovascular diseases are one of the most serious diseases that threaten human health in the world today. Most cardiovascular and cerebrovascular diseases are closely related to thrombosis. Platelet aggregation is a key link in the normal coagulation mechanism, and the adhesion, aggregation and release of platelets can lead to thrombus formation. Anti-platelet aggregation drugs can inhibit the adhesion and aggregation of platelets, play an important role in the treatment of thrombosis, and have always been a research hotspot [see Yuan Ming, Zhao Yonghai, Li Jiaming, etc. Synthesis of syringic acid derivat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/12A61K31/497A61P7/02A61P9/00
CPCC07D241/12
Inventor 李家明何广卫胡敏华黄伟军朱小雨王杰叶文峰张恩立
Owner ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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