5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof

An alkyl and aryl technology, applied in the field of 5,5-disubstituted-2-iminopyrrolidine derivatives, its preparation and its application in medicine, can solve the problem of increased bleeding, weakened and disturbed platelets Aggregation process etc.

Inactive Publication Date: 2011-11-16
JIANGSU HENGRUI MEDICINE CO LTD +1
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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-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof
  • 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof
  • 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(3′-imino-5′,6′-dimethoxy-spiro[cyclopropane-1,1′-iso indole

[0185] Phenyl]-2'-yl)ethanone hydrobromide

[0186]

[0187] first step

[0188] 4,5-Dimethoxyphthalonitrile

[0189] 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 t...

Embodiment 2

[0208] 1-(3-tert-butyl-4-methoxy-5-morpholine phenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, 1′-isoindole

[0209] Indoline]-2'-yl)ethanone hydrobromide

[0210]

[0211]

[0212] first step

[0213] 1-(3-tert-butyl-4-hydroxyphenyl)ethanone

[0214] 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 the reaction for 2 hours, add ethyl alcohol dropwise 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%.

[0215] MS m / z(ESI): 191[M-1]

[0216] second step

[0217] 1-(3-tert-butyl-4-hydroxy-5-iodo-phenyl)ethanone

[021...

Embodiment 3

[0244] 1-(3-tert-butyl-4-methoxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoind indole

[0245] Phenyl]-2'-yl)ethanone hydrobromide

[0246]

[0247] first step

[0248] 1-(3-tert-butyl-4-methoxyphenyl)ethanone

[0249] 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%.

[0250] 1 H NMR (400MHz, CDCl 3 , ppm): δ7.99 (d, J=2....

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Abstract

The invention relates to a type of 5,5-disubstituted-2-iminopyrrolidine derivatives, a preparation method thereof, and medical applications thereof. Specifically, the invention relates to novel 5,5-disubstituted-2-iminopyrrolidine derivatives represented by a general formula (I), and medicinal salts of the derivatives. The invention also relates to applications of the derivatives and the salts as therapeutic agents, especially thrombin receptor antagonists. Each substituent in the general formula (I) is defined as that in the specification.

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 Applications(China)
IPC IPC(8): C07D209/96C07D413/06C07D471/04C07D209/44C07D498/08C07D491/107C07F7/10A61K31/403A61K31/5377A61K31/538A61K31/454A61K31/496A61K31/4035A61K31/437A61K31/5386A61K31/695A61K31/4545A61P7/02A61P9/00A61P11/00A61P9/12A61P29/00A61P11/06A61P13/12A61P19/10A61P35/00A61P25/00
CPCC07D413/06A61K31/4035C07D209/96A61P7/02A61P9/00A61P9/12A61P11/00A61P11/06A61P13/12A61P19/10A61P25/00A61P29/00A61P35/00
Inventor 吕贺军邓炳初陈一千王胜蓝王华张蕾李军
Owner JIANGSU HENGRUI MEDICINE CO LTD
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