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Tetrahydrothienopyridine deuterated derivatives, preparation method and pharmaceutical use thereof

A technology for tetrahydrothienopyridine and its derivatives, which is applied in the field of N--tetrahydrothienopyridine derivatives, drugs for the prevention or treatment of thrombosis and embolism-related diseases, and can solve the problem of inactive carboxylic acid derivatives that have not been metabolized , small dose, increased risk of bleeding, etc.

Active Publication Date: 2016-01-27
吉林敖东创新医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The "2-hydroxytetrahydrothienopyridine derivatives" proposed by the invention patent CN102120744A tried to solve the phenomenon of "clopidogrel resistance", but did not solve the problem of metabolism into inactive carboxylic acid derivatives
Compared with clopidogrel, prasugrel has a small dose and high bioavailability, and can inhibit platelet aggregation faster and more effectively, but it has a greater risk of bleeding
In elective coronary intervention for acute coronary syndrome, although prasugrel can significantly reduce the incidence of ischemic events (including stent thrombosis) compared with clopidogrel, the risk of bleeding increases ( NEng1JMed, 2007, 357:2001)

Method used

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  • Tetrahydrothienopyridine deuterated derivatives, preparation method and pharmaceutical use thereof
  • Tetrahydrothienopyridine deuterated derivatives, preparation method and pharmaceutical use thereof
  • Tetrahydrothienopyridine deuterated derivatives, preparation method and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] (R)-Deuteromethyl o-chloromandelate

[0085]

[0086] Dissolve 9.4 g of (R)-o-chloromandelic acid in 36 mL of deuterated methanol, add 1 mL of 4M hydrogen chloride / dioxane solution, heat to reflux for 5 hours, evaporate the solvent under reduced pressure after cooling, and dissolve the residue in dichloromethane , washed with 5% potassium carbonate aqueous solution and water successively, dried the dichloromethane solution with anhydrous sodium sulfate, filtered to remove the desiccant and evaporated to dryness to obtain 9.2 g of colorless transparent oil (R)-deuterated methyl o-chloromandelate , yield 89.7%.

Embodiment 2

[0088] (R)-2-(2-Chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-deuteromethyl acetate (Ⅱ-1)

[0089]

[0090] Dissolve 10.2 g of (R)-deuteromethyl o-chloromandelate in 50 mL of anhydrous dichloromethane, add 65.6 g of triethylamine and a catalytic amount of DMAP, stir, cool down to 0°C, and add 12.2 g dropwise at the same temperature 50mL of anhydrous dichloromethane solution of p-nitrobenzenesulfonyl chloride, and then incubated for 4 hours. Add 100mL of water to the reaction solution, stir, let it stand, and separate the liquids. The water phase is then extracted three times with 150mL of dichloromethane. After combining the organic phases, dry them with anhydrous sodium sulfate. After filtering to remove the desiccant, evaporate the dichloromethane to dryness under reduced pressure. 20.9 g of a dark red oily crude product was obtained, and 15.8 g of a solid product (II-1) was obtained by methanol recrystallization, with a yield of 81.3%.

Embodiment 3

[0092] (2S)-2-(2-Chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl) - deuteromethyl acetate (V-1)

[0093]

[0094] (R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid deuterated methyl ester (II-1) 58.1g (0.15mol), 5,6, 7,7a-Tetrahydrothieno[3.2-c]pyridin-2(4H)-one hydrochloride (Ⅳ-1) 32.3g (0.17mol) and 37.8g (0.38mol) potassium bicarbonate were added in 500ml of acetonitrile , the reaction system was protected with nitrogen, and stirred at room temperature for 26 hours. After the reaction solution was allowed to stand, the insoluble matter was filtered to obtain a dark red mother liquor. The solvent was evaporated to dryness under reduced pressure, and 35.4 g of an oily product was obtained by flash column chromatography (petroleum ether: ethyl acetate = 4:1), with a yield of 70%.

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Abstract

The invention relates to tetrahydrothieno-[2,3-c]pyridine deuterated derivatives and a preparation method and medicament applications thereof, belonging to the field of medicinal chemistry. The derivatives contain salt of a compound in the formula I, and enantiomer and racemate of the compound in the formula I. The in-vitro whole-blood hydrolysis experiment results show that the stability of the compound in the formula I on esterase is good, and the hydrolysis rate of methyl carboxylate is obviously slower than that of non-deuterated methyl ester. The compound in the formula I can be effectively converted into pharmacological active metabolite in a human body to achieve the effect of inhibiting the platelet aggregation, and the concentration of the active metabolite is obviously higher than that of a non-deuterated compound of clopidogrel or a corresponding structure. The pharmacodynamic experiment results show that the compound in the formula I has the effect of obviously inhibiting the platelet aggregation, and the effect of inhibiting the platelet aggregation is obviously better than that of the non-deuterated compound of clopidogrel and the corresponding structure. Therefore, the compound in the formula I can be used for preparing medicaments for preventing or treating related thrombus and embolism diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to optically active N-(deuteromethyl phenylacetate-2-yl)-tetrahydrothienopyridine derivatives and their preparation methods and applications in pharmacy, in particular to N- Use of (deuteromethyl phenylacetate-2-yl)-tetrahydrothienopyridine derivatives in drugs for preventing or treating thrombosis and embolism-related diseases. Background technique [0002] Clopidogrel is the most widely used antiplatelet aggregation drug in the world. It is clinically used to treat atherosclerosis, acute coronary syndrome and thrombotic complications. Years of clinical trials have confirmed the efficacy and safety of clopidogrel on thrombotic cardiovascular and cerebrovascular diseases (Lancet, 1996, 348:1329). Clopidogrel is a prodrug, which undergoes two-step oxidation of the liver P450 enzyme system in the body, and metabolizes to produce active metabolites, which interact with P2Y on the s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61K31/4365A61P9/10A61P7/02A61P9/00
CPCC07D495/04
Inventor 顾运博
Owner 吉林敖东创新医药科技有限公司
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