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5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof

A technology of substituents and alkyl groups, used in 5,5-disubstituted-2-iminopyrrolidine derivatives, their preparation and their application in medicine, can solve the problem of increased bleeding, influence, weakening, etc. question

Inactive Publication Date: 2014-04-02
SHANGHAI HENGRUI PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, neither has a direct inhibitory effect on the thrombin-platelet activation pathway via the PAR1 receptor (Davi G, et al; N Engl J Med., 2007, 357:2482-2494)
At the same time, because the two can weaken or interfere with the collagen-induced platelet aggregation process, which may affect the normal hemostasis process, the probability of bleeding during treatment increases

Method used

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  • 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof
  • 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof
  • 5,5-disubstituted-2-imino-pyrrolidine derivatives, preparation methods and pharmaceutical uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0229] 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(3′-imino-5′,6′-dimethoxy-spiro[cyclopropane-1,1′-iso Indoline]-2'-yl)ethanone hydrobromide

[0230]

[0231] first step

[0232] 4,5-Dimethoxyphthalonitrile

[0233] Dissolve 1,2-dibromo-4,5-dimethoxybenzene 1a (20.01g, 68mmol) in 100mL N,N-dimethylformamide, add cuprous cyanide (24.00g, 272mmol), The reaction was stirred at 150°C for 1 hour, and continued at 170°C for 5 hours. The reaction solution was poured into 100 mL of ammonia water, 400 mL of ethyl acetate was added, filtered, and the filter cake was washed with ethyl acetate (100 mL×6). The filtrate was extracted with ethyl acetate (200mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by recrystallization (methanol:ethyl acetate=10mL:20mL) to obtain the title product 4 , 5-dimethoxyphthalonitrile 1b (4.50 g, white solid), yield: 35.0%.

[...

Embodiment 2

[0251] 1-(3-tert-butyl-4-methoxy-5-morpholine phenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, 1'-isoindoline]-2'-yl)ethanone hydrobromide

[0252]

[0253] first step

[0254] 1-(3-tert-butyl-4-hydroxyphenyl)ethanone

[0255] Under a dry ice-acetone bath, dissolve aluminum chloride (71.0 g, 0.53 mol) in 250 mL of dichloromethane, add 2-tert-butyl-phenol 2a (81.6 mL, 0.53 mol), stir for 2 hours, add ethyl Acid chloride 2b (37.9 mL, 0.53 mol), continued stirring for 1 hour. 300 mL of ice water was added to the reaction liquid, filtered, and the solid was dried in vacuo to obtain the title product 1-(3-tert-butyl-4-hydroxyphenyl)ethanone 2c (32 g, white solid), yield: 31.3%.

[0256] MS m / z(ESI): 191[M-1]

[0257] second step

[0258] 1-(3-tert-butyl-4-hydroxy-5-iodo-phenyl)ethanone

[0259] Dissolve 1-(3-tert-butyl-4-hydroxyphenyl)ethanone 2c (16.2 g, 84.3 mmol) in 200 mL of acetonitrile, add N-iodosuccinimide (20.9 g, 92.8 mmol), The reaction was stirred for...

Embodiment 3

[0285] 1-(3-tert-butyl-4-methoxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoind Indoline]-2'-yl)ethanone hydrobromide

[0286]

[0287] first step

[0288] 1-(3-tert-butyl-4-methoxyphenyl)ethanone

[0289] Dissolve 1-(3-tert-butyl-4-hydroxyphenyl)ethanone 2c (6.3 g, 32.8 mmol) in 50 mL of acetone, add potassium carbonate (13.6 g, 98.4 mmol) and iodomethane (11.65 g, 82 mmol ), stirred and reacted at 50°C for 2 hours. Filtrate, concentrate the filtrate under reduced pressure, add 50mL water and 50mL dichloromethane, separate the layers, wash the organic phase with saturated sodium chloride solution (20mL×3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 1-(3-tert-butyl-4-methoxyphenyl)ethanone 3a (6.0 g, white solid), yield: 88.6%.

[0290] 1 H NMR (400MHz, CDCl 3 , ppm): δ7.99 (d, J=2.0Hz, 1H), 7.87 (dd, J 1 =8.4Hz,J 2 =2.0Hz, 1H), 6.94(d, J=8.4Hz, 1H), 3.97(s, 3H), 2.60(...

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PUM

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Abstract

Disclosed are 5,5-disubstituted-2-imino-pyrrolidine derivatives of formula (I) and their pharmaceutically acceptable salts, preparation methods and uses thereof in medicine as thrombin receptor antagonists, wherein each substituents of formula (I) is defined as the description.

Description

technical field [0001] The present invention relates to a new 5,5-disubstituted-2-iminopyrrolidine derivative, its preparation method and pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a thrombin receptor antagonist the use of. Background technique [0002] Currently, thrombotic disease is the main cause of high morbidity and mortality of cardiovascular diseases worldwide. Arterial thrombosis can cause a variety of acute symptoms including acute coronary syndrome, ischemic stroke / transient ischemia, and peripheral arterial disease. These symptoms are all caused by the damage of atherosclerotic plaque or the damage of vascular endothelial cells, which induces the formation of arterial thrombosis and occlusion, which leads to insufficient blood supply. Platelets play a very important role in the formation of arterial thrombus. In this pathological process, damage to atherosclerotic plaques or damage to vascular endothe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/96C07D413/06A61K31/4035A61P9/00A61P11/00A61P35/00
CPCC07D209/96A61K31/4035C07D413/06A61P7/02A61P9/00A61P9/12A61P11/00A61P11/06A61P13/12A61P19/10A61P25/00A61P29/00A61P35/00
Inventor 吕贺军邓炳初陈一千王胜蓝王华张蕾李军
Owner SHANGHAI HENGRUI PHARM CO LTD
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