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Thiazole derivatives and their preparation and use

A technology of thiazoles and drugs, applied in the field of preparing drugs or pharmaceutical compositions for the prevention and/or treatment of thromboembolic diseases, capable of solving the problems of oral ineffectiveness, narrow therapeutic index, non-selective inhibition, etc.

Active Publication Date: 2019-01-18
南京帕隆材料科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thrombin inhibitors represented by heparin and low molecular weight heparin have disadvantages such as oral ineffectiveness, non-selective inhibition and high bleeding risk
Although vitamin K antagonists represented by warfarin can be taken orally, they have a narrow therapeutic index, large interactions with food and drugs, and large individual dose differences.

Method used

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  • Thiazole derivatives and their preparation and use
  • Thiazole derivatives and their preparation and use
  • Thiazole derivatives and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Compound I-1: N-(4-chlorophenyl)-2-((4-(5-oxo-2-thioimidazolidin-1-yl)phenyl)amino)thiazole-4-carboxamide ;

[0040]

[0041] Add 5.00g p-iodoaniline (compound VIII-1), 25ml tetrahydrofuran, 4.60g triethylamine, 0.1g DMAP (4-dimethylaminopyridine) in the reaction flask, stir and drop 3.86g chloroacetyl chloride, add 25 Stir at -35 for 2 hours, raise the temperature to 50°C, keep the reaction for 2 hours, evaporate the solvent under reduced pressure, add 30ml of water, stir, filter, and dry to obtain 5.6g of gray solid, which is compound VII-1.

[0042] Put 5.0 g of compound VII-1, 1.7 g of sodium thiocyanate, and 0.5 g of tetra-n-butylammonium iodide into 50 ml of acetonitrile, stir and raise the temperature to reflux, keep stirring while maintaining the temperature, touch the plate to control the completion of the reaction, and evaporate the solvent under reduced pressure. Add 250ml of water, stir and filter, wash the filter cake with water (20ml×2), and dry to obt...

Embodiment 2

[0048] Compound I-2: N-(4-bromophenyl)-2-((4-(5-oxo-2-thioimidazolidin-1-yl)phenyl)amino)thiazole-4-carboxamide ;

[0049]

[0050] This example adopts the same synthetic method as Example 1, the difference is that compound II-2 is different, specifically as follows,

[0051]

[0052] 1 H-NMR (DMSO-d 6 ), δ (ppm): 4.015 (s, 2H), 6.510 (d, 2H), 6.682 (s, 1H), 7.126 (d, 2H), 7.558 (d, 2H), 7.748 (d, 2H), 8.688 (s,1H),10.743(s,1H),11.482(s,1H).

Embodiment 3

[0054] Compound I-3: N-(4-bromophenyl)-2-((2-fluoro-4-(5-oxo-2-thioimidazolidin-1-yl)phenyl)amino)thiazole- 4-formamide;

[0055]

[0056] This example adopts the same synthetic method as Example 1, the difference is that compounds VIII-3 and II-3 are different, specifically as follows,

[0057]

[0058] 1 H-NMR (DMSO-d 6 ), δ(ppm): 4.108(s,2H), 6.686(s,1H), 7.005(d,1H), 7.146(d,1H), 7.346-7.568(m,5H), 8.480(s,1H) ,10.446(s,1H),11.382(s,1H).

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PUM

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Abstract

The invention relates to a novel thiazole derivative having a general formula (I) structure and a pharmaceutically acceptable salt thereof. The definitions of all groups are described in the specifications. The invention further relates to a preparing method of the compound, drug compositions containing the novel thiazole derivative and the pharmaceutically acceptable salt thereof and an application of the novel thiazole derivative and the pharmaceutically acceptable salt thereof to the preparation of drugs for preventing and / or treating thromboembolism diseases as bioactive substances.

Description

technical field [0001] The present invention relates to the field of anticoagulation, and in particular, the present invention relates to novel thiazole derivatives, their preparation methods and their use in the preparation of drugs or pharmaceutical compositions for preventing and / or treating thromboembolic diseases. Background technique [0002] In the human cardiovascular system, the process of coagulation of blood or the formation of certain solid masses in the blood is called thrombus formation, and the formed solid masses are thrombus. Blood coagulation is originally a protective mechanism of the organism. However, in the case of abnormal blood flow, abnormal blood vessel wall or abnormal coagulation factors, the abnormal coagulation process is triggered, and the blood can form thrombus or embolism, resulting in such as myocardial infarction , stroke, deep vein thrombosis or pulmonary embolism and other thromboembolic diseases. Thromboembolic disease is the most seri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12A61K31/427A61P7/02
CPCC07D417/12
Inventor 王文喜
Owner 南京帕隆材料科技有限公司