Prasugrel derivatives, preparation method thereof and application of medicinal composition

A technology of derivatives and thunderbolts, applied in the field of prasugrel derivatives and their non-toxic pharmaceutically acceptable salts, can solve the problems of increased risk of bleeding, high incidence of bleeding, and psychological rejection of patients, so as to increase compliance Sexuality, good water solubility, reduce or eliminate the effect of injection pain

Inactive Publication Date: 2017-10-20
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although prasugrel can inhibit platelet aggregation faster and more effectively, the stronger its antiplatelet effect is, the more likely it is to cause bleeding
In the phase III clinical TRITON-TIMI38 trial of 13,608 intermediate-risk to high-risk patients who planned to undergo coronary intervention, the incidence of major bleeding in the prasugrel group was 2.4 higher than that in the clopidogrel treatment group. % vs. 1.8%; and life-threatening bleeding was also higher in the prasugrel group, 1.4% vs. 0.9% (P=0.01), which included nonfatal bleeding (1.1% vs. 0.9%, P=0.23) and fatal bleeding (0.4% vs. 0.1%, P=0.002), therefore, in the elective interventional treatment of acute coronary syndrome, prasugrel can significantly reduce the incidence of ischemic events, including stent thrombosis, compared with clopidogrel, but its Increased risk of bleeding (N Eng J Med.2007357(20): 2001-2015)
Other adverse reactions of prasugrel are adverse reactions such as thrombocytopenia and neutropenia, which can easily cause rejection in patients and are not conducive to medication

Method used

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  • Prasugrel derivatives, preparation method thereof and application of medicinal composition
  • Prasugrel derivatives, preparation method thereof and application of medicinal composition
  • Prasugrel derivatives, preparation method thereof and application of medicinal composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Synthesis of compound 1

[0025]

[0026] Cool the chloroform solution of 45g of chloroacetic acid with an ice bath to lower the temperature of the solution to below 5°C, then add 11.5g of compound (II) in batches, control the internal temperature not to exceed 10°C, and let the bath temperature naturally rise to room temperature after the addition , and stirred the reaction for 4h, then filtered off the insoluble matter, washed with a small amount of chloroform and combined the chloroform solution, then washed twice with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was separated by HPLC to give compound 1.

Embodiment 2

[0028] Synthesis of Compound 2

[0029]

[0030] Cool the chloroform solution of 64g of ethyl chloroacetate with an ice bath to lower the temperature of the solution to below 5°C, then add 11.5g of compound (II) in batches, control the internal temperature not to exceed 10°C, and let the bath temperature rise naturally after the addition to room temperature, and stirred for 4 h, then filtered off the insoluble matter, washed with a small amount of chloroform and combined with chloroform, then washed twice with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was separated by HPLC to give compound 2.

Embodiment 3

[0032] Synthesis of compound 3

[0033]

[0034] Cool the chloroform solution of 72g of ethyl chloroacetate with an ice bath to lower the temperature of the solution to below 5°C, then add 11.5g of compound (II) in batches, control the internal temperature not to exceed 10°C, and let the bath temperature rise naturally after the addition to room temperature, and stirred for 4 h, then filtered off the insoluble matter, washed with a small amount of chloroform and combined with chloroform, then washed twice with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was separated by HPLC to give compound 3.

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PUM

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Abstract

The invention discloses prasugrel derivatives, a preparation method thereof and an application of medicinal composition, and particularly relates to a compound as shown in a general formula (I) in the description, or a stereoisomer, hydrate, solvate, eutectic, pharmaceutically acceptable salt or prodrug thereof, the preparation method thereof, the medicinal composition containing the same, and the medical application of the compound or the medicinal composition. The invention particularly discloses the application of the medicinal composition in preventing or treating atherosclerosis, myocardial infarction, stroke, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or thrombosis after coronary intervention. The definition of each substituent in the general formula (I) is the same as the definition in the description.

Description

technical field [0001] The present invention relates to prasugrel derivatives and their non-toxic pharmaceutically acceptable salts, their preparation methods, pharmaceutical compositions containing them and their use as medicines, especially for preventing or treating atherosclerotic diseases, myocardial Infarction, stroke, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome, or thrombosis after coronary intervention. Background technique [0002] Myocardial infarction is one of the diseases with the highest fatality rate in the world today, and it is mainly caused by coronary artery thrombosis. After atherosclerotic plaque rupture causes endothelial injury, platelets will adhere to the subendothelial matrix and aggregate with each other to form a thrombotic obstructive surface, which will further cause vascular obstruction (Nature Reviews, 2010, 9, 154-169). In view of the key role played by platelets in the process of thrombus formation, th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/04A61K31/435A61P9/10A61P7/02
CPCC07D221/04
Inventor 陆华龙
Owner HC SYNTHETIC PHARMA CO LTD
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