Tetrahydrothienopyridine deuterated derivative as well as preparation method and pharmaceutical application thereof

A technology of tetrahydrothienopyridine and derivatives, applied in the field of deuterated tetrahydrothienopyridine derivatives and their preparation, prevention or treatment of thrombosis and embolism-related diseases, can solve the problem of insufficient duration of antiplatelet drug effect, individual Large differences, disruption of the bleeding-coagulation balance, etc., to avoid excessive hydrolysis of the gastrointestinal tract, balance the risks of bleeding and coagulation, and optimize safety and efficacy

Active Publication Date: 2022-07-12
ZHONGRONG KAITE BEIJING BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in practical application, clopidogrel still faces two problems: first, the conversion rate of the active metabolite is low, and about 85% of the original drug will be metabolized into clopidogrel acid and its metabolism by esterase due to the 7-ester group. Second, the individual differences are large, and the differences in the expression of CYP450 enzymes in different patients will cause large individual differences in the clinical therapeutic effect of clopidogrel, which relies on the metabolism of CYP450 enzymes, and also cause the so-called " A major factor in the phenomenon of "clopidogrel resistance" (Circulation, 2004, 109:166)
Excessively high peak concentration exceeds the tolerance of the body to anticoagulation, leading to the destruction of the hemorrhage-coagulation balance in the body, and the excessive anticoagulant effect is reflected as a side effect, which is the potential cause of the high risk of prasugrel bleeding
Simply reducing the dosage will lead to too low concentration of active metabolites and insufficient duration of antiplatelet effect; to solve the risk of fatal severe bleeding should start with reducing the peak concentration of active metabolites and delaying the peak time

Method used

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  • Tetrahydrothienopyridine deuterated derivative as well as preparation method and pharmaceutical application thereof
  • Tetrahydrothienopyridine deuterated derivative as well as preparation method and pharmaceutical application thereof
  • Tetrahydrothienopyridine deuterated derivative as well as preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] (R) Deuterated methyl o-acid chloride mandelic acid

[0112]

[0113] Dissolve 47 g of (R)-o-acyl chloride mandelic acid in 150 mL of deuterated methanol, add 1.5 mL of 4M hydrogen chloride / dioxane solution, heat under reflux for 5 hours, evaporate the solvent under reduced pressure after cooling, and dissolve the residue in dichloromethane , washed with 5% aqueous sodium carbonate solution and water once, dried the dichloromethane solution with anhydrous sodium sulfate, filtered to remove the desiccant and evaporated to dryness to obtain (R)-deuterated methyl o-acyl chloride mandelic acid 47.8g as a colorless and transparent oil. , the yield is 93.1%. 1 H-NMR (300MHz, CDCl 3 ): δ3.69 (d, 1H), 5.6 (d, 1H), 7.27-7.32 (m, 2H), 7.39-7.44 (m, 2H). ESI-MS m / z226.1[M+Na] + .

Embodiment 2

[0115] (R)-2-(2-Chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid deuterated methyl ester (II-1)

[0116]

[0117] (R) 51 g of deuterated methyl o-acyl chloride mandelic acid was dissolved in 200 mL of anhydrous dichloromethane, 42 mL of triethylamine and catalytic amount of DMAP were added, stirred, cooled to 0°C, and 70 g of p-nitrobenzene was added dropwise at the same temperature. A solution of sulfonyl chloride in 200 mL of anhydrous dichloromethane was then incubated for 4 hours. Add 200 mL of water to the reaction solution, stir, let stand, and separate the liquid. The water tank is then extracted with 150 mL of dichloromethane three times. After combining the organic phases, dry with anhydrous sodium sulfate, filter to remove the desiccant, and evaporate the dichloromethane to dryness under reduced pressure. 102 g of dark red oily crude product was recrystallized from methanol to obtain 78 g of pale yellow solid powder (II-1) with a yield of 80.3%. Melting po...

Embodiment 3

[0119] (2S)-2-(2-Chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl) -Deuterated methyl acetate (V-1)

[0120]

[0121] (R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid deuterated methyl ester (II-1) 77.8g (0.2mol), 5,6, 7,7a-Tetrahydrothieno[3,2-c]pyridine 2(4H)-one (IV) 28.8g (0.21mol) and 60g (0.71mol) sodium bicarbonate were added to 500mL acetonitrile, the reaction system was purged with nitrogen protection and stirred at room temperature for 26 hours. After the reaction solution was allowed to stand, the insolubles were filtered to obtain a dark red mother liquor. The solvent was evaporated to dryness under reduced pressure and recrystallized with ethanol to obtain 57 g of light yellow solid powder with a yield of 83.5%. Melting point 143.9-145 ℃. 1H-NMR (300MHz, CDCl 3 ): δ1.89(dq, 1H), 2.35-2.39(m, 1H), 2.62(dt, 1H), 3.04(d, 1H), 4.93(s, 1H), 6.05(s, 1H), 7.30- 7.34 (m, 2H), 7.43-7.46 (m, 1H), 7.54-7.56 (m, 1H). 13 C-NMR (1...

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Abstract

The invention discloses a tetrahydrothienopyridine deuterated derivative as well as a preparation method and pharmaceutical application thereof. The derivative can be used for preparing medicines for preventing or treating thrombus-related diseases. The thienopyridine derivative can balance and optimize the safety and effectiveness of a medicine, the thienopyridine derivative is prevented from being hydrolyzed too fast in the gastrointestinal tract, and a better treatment effect is achieved on the premise that the bleeding risk of a patient is not increased.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to optically active deuterated tetrahydrothienopyridine derivatives, a preparation method thereof and use in pharmacy, in particular to (S)-5-(1-(2-chlorophenyl) -2-(methoxy-d3)-2-carbonylethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl derivatives in the prevention or treatment of thrombosis and Use in medicines for embolism-related diseases. Background technique [0002] Thienopyridines are typical P2Y 12 receptor antagonists. The original drug itself has no activity. It is first oxidized by CYP450 enzyme to the intermediate product 2-oxygen metabolite in the body, and then the 2-oxygen metabolite is metabolized by CYP450 enzyme to the active metabolite with pharmacological activity. The active metabolite and P2Y 12 The receptors are covalently bound by disulfide bonds to exert their efficacy. Affected by the genetic polymorphism of each subtype of CYP450 enzymes involved ...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D519/00A61P7/02A61P9/10A61K31/4365A61K31/4545A61K31/551A61K31/496
CPCC07D495/04C07D519/00A61P7/02A61P9/10C07B2200/07C07B2200/05Y02P20/55
Inventor 顾景凯孙冬刘英泽许志萍张瑀峣李海鹏
Owner ZHONGRONG KAITE BEIJING BIOTECH CO LTD
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