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Phosphoryl carboxylic acid derivatives, preparation method thereof and application of pharmaceutical composition

A technology of phosphoryl carboxylic acid and derivatives, applied in the field of prasugrel derivatives and their non-toxic pharmaceutically acceptable salts, can solve the problems of increased bleeding risk, patient rejection psychology, and high incidence of bleeding, and achieve increased Compliance, reduce or remove injection pain, good water solubility

Inactive Publication Date: 2017-10-20
HC SYNTHETIC PHARMA CO LTD +1
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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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  • Phosphoryl carboxylic acid derivatives, preparation method thereof and application of pharmaceutical composition
  • Phosphoryl carboxylic acid derivatives, preparation method thereof and application of pharmaceutical composition
  • Phosphoryl carboxylic acid derivatives, preparation method thereof and application of pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthesis of compound 1

[0036]

[0037] Cool the chloroform solution of 33.88g of chloroacetyl chloride with an ice bath to lower the temperature of the solution to below 5°C, then add 13.48g of compound (a) in batches, one teaspoon each time, control the internal temperature not to exceed 10°C, and complete the addition After that, the bath temperature was naturally raised to room temperature, and stirred for 4 hours, then the insoluble matter was filtered off, washed with a small amount of chloroform, combined with the chloroform solution, 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

[0039] Synthesis of compound 2

[0040]

[0041]In a three-neck flask, add sodium thiophosphate (72.03g), compound 1 (56.05g) and 160ml of distilled water at one time, stir, and under ice water cooling, the temperature in the flask naturally drops to about 15°C, while adding dimethyl Sulfoxide (DMSO) 120ml The reaction temperature rises gradually and does not exceed 20°C. After the addition is complete, continue stirring until the reaction is complete to obtain a product solution; concentrate to dryness. The residue was separated by HPLC to give compound 2.

Embodiment 3

[0043] Synthesis of Compound 3

[0044]

[0045] In a three-neck flask, add sodium phosphate (76.02g), compound 1 (56.05g) and 160ml of distilled water at one time, stir, and under ice water cooling, the temperature in the flask naturally drops to about 15°C, while adding dimethyl sulfoxide dropwise (DMSO) 120ml The reaction temperature rises gradually and does not exceed 20°C. After the addition is complete, continue stirring until the reaction is complete to obtain a product solution; concentrate 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 phosphoryl carboxylic acid Prasugrel derivatives, a preparation method thereof and an application of pharmaceutical 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 pharmaceutical composition containing the same, and the medical application of the compound or the pharmaceutical composition. The invention particularly discloses the application of the pharmaceutical 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): C07F9/6561A61K31/675A61P9/10A61P7/02
CPCC07F9/6561
Inventor 陆华龙
Owner HC SYNTHETIC PHARMA CO LTD