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Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof

A technology of hydroxytetrahydrothiazide and phenopyridine, which is applied in the field of medicine, can solve the problems of loss of enzyme activity, reduction of oral bioavailability of clopidogrel, and high genetic mutation rate, and achieves the improvement of oral bioavailability and inhibition of platelet aggregation. Effect

Active Publication Date: 2014-03-26
BEIJING PRELUDE PHARM SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the study found that 85% of the prototype drug of clopidogrel was esterified into inactive clopidogrel carboxylic acid derivatives by human liver carboxylase 1 in the liver, which greatly reduced the oral bioavailability of clopidogrel
In addition, due to differences in the expression of CYP450 enzymes in the liver of different individuals, the clinical effect of clopidogrel, which relies on the metabolism of CYP450 enzymes, has large individual differences in clinical treatment effects, and the phenomenon of "clopidogrel resistance" appears
Moreover, the CYP2C19 genetic mutation rate is high in the Asian population (in the Chinese population, the mutation rate is 18.7% in the Han nationality, 25% in the Hui nationality, and 10.9% in the Mongolian nationality), resulting in loss of enzyme activity

Method used

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  • Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof
  • Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof
  • Optically active 2-hydroxyltetrahydrothienopyridine derivative as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Preparation of compound of formula V

[0059] Synthesis scheme

[0060]

[0061] Step 1: Synthesis of (R)-(2-chloro-phenyl)-hydroxy-acetic acid methyl ester (2)

[0062]

[0063] To a stirred solution of compound 1 (18.6 g, 0.1 mol) in methanol (100 mL) was added concentrated sulfuric acid (2 mL). The mixture was then heated at reflux 3, and the excess methanol was removed under vacuum. The oily residue was put into 200 mL of dichloromethane, and then washed with a 10% potassium carbonate aqueous solution (240 mL), the organic solvent was extracted, dried, and then concentrated under vacuum to obtain compound 2 (19 g, 95%) as colorless Of oil.

[0064] 1 H NMR: (Y0859-04567-023,CDCl 3 ,400MHz)δ7.52-7.50(m,1H),7.45-7.43(m,1H),7.39-7.32(m,2H),6.36-6.34(d,J=6.4Hz,1H),5.43-5.42( d,J=6.4Hz,1H),3.62(s,3H).

[0065] Step 2: Synthesis of (R)-(2-chloro-phenyl)-(4-nitro-benzenesulfonyloxy)-acetic acid methyl ester (4)

[0066]

[0067] At 0°C and N 2 Next, to a stirred solut...

Embodiment 2

[0083] Example 2: Preparation of compound of formula VI

[0084] Preparation scheme:

[0085]

[0086] Step 1: (S)-(2-Chloro-phenyl)-[2-(di-tert-butoxy-phosphoryloxymethoxy)-6,7-dihydro-4H-thiophene [3, Synthesis of 2-c]pyridin-5-yl]-methyl acetate (10)

[0087]

[0088] At -78°C and N 2 To the stirring solution of compound 6 (480mg, 1.41mmol) and NaI (430mg, 2.82mmol) prepared in step 3 of Example 1 in anhydrous THF (3mL) was added dropwise LHMDS (4.23mL, 1.0M in THF) , 2.85 mmol), and then the mixture was stirred at room temperature for 30 minutes, after which compound 9 (540 mg, 2.11 mmol) was added, and the mixture was stirred for another 10 hours. Use NH 4 The reaction was quenched with Cl solution and extracted with EA. Use NaHCO 3 The organic layer was washed with solution and brine, and then subjected to anhydrous Na 2 SO 4 Dry and concentrate to dryness. The residue was purified with a silica gel column (PE:EA=50:1-3:1) to obtain compound 10 (52 mg, 7%) as a white solid...

Embodiment 3

[0096] Example 3: In vivo pharmacokinetic test

[0097] The in vivo pharmacokinetics of the compound of formula V, compound of formula VI, clopidogrel (formula VII) and the first metabolite of clopidogrel (formula VIII) of the present invention were tested. Specifically, the compound of formula V, the compound of formula VI, and clopidogrel and its first metabolite were administered orally or intravenously to rats to evaluate the pharmacokinetic characteristics of the compound of the present invention and clopidogrel in rats, and investigate The conversion of the compound of the present invention into the first metabolite in vivo, and the bioavailability of the compound of the present invention and clopidogrel was compared by measuring the plasma concentration of the first metabolite (formula VIII) in the rat at a certain time degree.

[0098] The experimental animals were male SD rats, 6 to 8 weeks old, weighing 190-215 grams, and were purchased from Beijing Weilitonghua Experim...

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Abstract

The invention provides an optically active 2-hydroxyltetrahydrothienopyridine derivative shown by formula I, or a pharmaceutically acceptable salt, solvate, polycrystal, enantiomer or racemization mixture thereof, wherein in the formula I, R1 is F, Cl, Br or I; m is 0 or 1; n is an integer from 1 to 6; R2 or R3 is independently hydrogen, C1-C6 alkyl or optionally substituted C1-6 alkyl; R4 or R5 is independently hydrogen, C1-C10 alkyl, C1-C10 alkenyl, C1-10 alkoxy, C1-10 aryl, halogen, acylamino, sulfmidyl, acyloxy or C(O)R', and R' is hydrogen, C1-C10 alkyl, C1-C10 alkenyl, C1-10 alkoxy, C1-10 aryl, halogen, acylamino, sulfmidyl or acyloxy. The compound has obvious platelet agglomeration resistance action, and the bioavailability of the compound is obviously higher than that of clopidogrel. The invention further provides a preparation method of the compound, a pharmaceutical composition containing the compound, and a pharmaceutical use of the compound and the pharmaceutical composition.

Description

Technical field [0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to a derivative having 2-hydroxytetrahydrothienopyridine, a method for preparing the derivative, a pharmaceutical composition containing the derivative, and the derivative and medicine Use of the composition in the preparation of prevention or treatment of thrombosis and embolism related diseases. Background technique [0002] Clopidogrel (Clopidogrel, see formula VII below) is currently the most widely used anti-platelet aggregation drug in the world. It is clinically used to treat atherosclerotic diseases, acute coronary syndromes and thrombotic complications. [0003] [0004] Clopidogrel is a prodrug that undergoes a two-step oxidation reaction in the liver CYP450 enzyme system to produce active metabolites. The main enzyme activities are CYP2C19 and CYP3A4. [0005] [0006] The active metabolites produced by the above two steps of oxidative metabolism and ...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P7/02A61P9/10A61P9/00
CPCY02P20/55
Inventor 王志岩
Owner BEIJING PRELUDE PHARM SCI & TECH
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