Ester compound and preparation method and application thereof

A compound, C1-C4 technology, applied in the field of medicine, can solve the problems of patients with excessive bleeding and high bleeding risk, and achieve platelet aggregation inhibition and obvious effect of platelet aggregation

Inactive Publication Date: 2011-02-16
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The results of its clinical controlled trial with clopidogrel also show that it can effectively reduce the death caused by non-fatal heart disease and stroke, but it leads to more bleeding in patients
Because this product still has some adverse reactions closely related to its clinical efficacy, especially due to the higher risk of bleeding, although the FDA approved prasugrel for marketing, it requires it to add a black box warning on the new drug label To warn of the risk of bleeding and advise against use in patients with active pathological bleeding, history of transient ischemic attack or stroke, or recent need for surgery including coronary artery bypass surgery

Method used

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  • Ester compound and preparation method and application thereof
  • Ester compound and preparation method and application thereof
  • Ester compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0059] Intermediate IV-1

[0060]

[0061] Add 13.9 g of intermediate III-1 to a reaction flask equipped with stirring, a condenser, and a thermometer, dissolve it with 40 mL of dichloromethane, and add 17.8 g of NBS while stirring. React under light at room temperature for 6 hours (the plate layer shows that the reaction is complete). with 3 x 30mL 35% Na 2 S 2 o 3 The reaction liquid was washed with aqueous solution, and the dichloromethane layer was fully dried with anhydrous sodium sulfate, filtered, and the dichloromethane was evaporated under reduced pressure to obtain a light yellow oily product (HPLC: 97.2%). Rf = 0.35 [single site, developing solvent: v (dichloromethane): v (methanol) = 6: 1]. 1 H NMR (DMSO-d 6 , 400MHz) δ: 2.324 (s, 1H, -OH), 7.572-7.961 (m, 4H, phenyl-H). Referring to the method of Reference Example 2, intermediates IV-2 to IV-7 can be synthesized.

[0062]

Embodiment 3

[0064] Intermediate V-1

[0065]

[0066] Add 2.2g of intermediate IV-1 into a reaction flask equipped with stirring, a condenser, and a thermometer, dissolve it with 10mL of anhydrous methanol, and add 2.76g of anhydrous potassium carbonate while stirring. 1.6 g of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-(4H)-one was added to the reaction system in batches. After the addition was completed, the reaction was continued for 3.5h under reflux (the plate showed that the reaction was complete). Filter out the solid matter, evaporate anhydrous methanol to dryness, wash the reaction solution with 3×10 mL water, extract with dichloromethane, dry thoroughly with anhydrous sodium sulfate, filter, and evaporate dichloromethane under reduced pressure to obtain a black oil. Column separation [mobile phase: v (dichloromethane): v (methanol) = 9: 1], Rf = 0.45, gave a light yellow solid (HPLC: 99.3%). 1 H NMR (DMSO-d 6 , 400MHz) δ: 2.336 (s, 1H, -OH), 2.732~2.781 (s, 2H, -CH 2 -), 2...

Embodiment 1

[0070] 5-((2-Chlorophenyl)(oximino)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl-acetate (Compound 1)

[0071]

[0072] Add 2.9 g of intermediate V-1 to a reaction flask equipped with a stirring, condenser, and thermometer, dissolve it with 10 mL of dichloromethane, and add 2.18 g of triethylamine while stirring. 1.2 g of acetic anhydride was added to the reaction system. After the addition was completed, the reaction was continued for 3.5 hours under reflux (the plate layer showed that the reaction was complete). Cool the reaction solution, wash the reaction solution with 3×10mL water, separate the dichloromethane layer, fully dry it with anhydrous sodium sulfate, filter, and evaporate the dichloromethane under reduced pressure to obtain a yellow oil, which is separated by column [mobile phase: v (Petroleum ether): v (ethyl acetate) = 4: 1], Rf = 0.46 to give a white solid (HPLC: 99.7%).

[0073] Example 2 :

[0074] 5-((4-fluorophenyl)(O-methyl-oximino)methyl)-...

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PUM

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Abstract

The invention discloses an ester derivative with a structure of a formula I and pharmaceutically acceptable salt thereof. In the formula I, R1 is halogen; R2, R3 and R4 are hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitryl, nitrile and phenyl simultaneously or respectively; R5 is hydrogen, C1-C4 straight-chain or branched-chain alkyl, or phenyl substituted by hydrogen, nitryl, nitrile, C1-C4 alkyl, C1-C4 alkoxy, amino or C1-C4 alkyl acylamino; and R6 is C1-C4 straight-chain or branched-chain alkyl. The invention also discloses a preparation method for the compound, a medicinal composition using the compound or the pharmaceutically acceptable salt thereof as an active effective ingredient, and application thereof in preparing a platelet aggregation resistant medicament, in particular preparing medicaments for preventing or treating heart cerebrovascular diseases such as coronary artery syndrome, myocardial infarction, myocardial ischemia and the like caused by platelet aggregation.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and more specifically, relates to a class of compounds with anti-platelet aggregation and their preparation methods, pharmaceutical compositions containing them and their use as anti-platelet drugs. Background technique [0002] The incidence of thromboembolic diseases, mainly coronary thrombosis and cerebral thrombosis, is on the rise, seriously endangering human health. Platelet aggregation is a key link in the normal blood coagulation mechanism, so drugs that inhibit platelet aggregation have become a hot spot in the research of drugs for the treatment of such diseases in recent years. [0003] Ticlopidine, developed and marketed by Sanofi in France, is the first ADP receptor antagonist antiplatelet drug, which inhibits the activation of ADP receptors by binding to P2Y-type special sulfhydryl receptors, and acts as an antiplatelet agent. Aggregation. Because ticlopidine not only inh...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P9/00A61K31/4365A61P7/02
Inventor 刘登科刘颖刘冰妮刘默黄长江支爽龙丽王景阳
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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