Optically active 2-hydroxytetrahydrothienopyridine derivatives and preparation methods and uses 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, high genetic mutation rate, etc., and achieve the goal of increasing oral bioavailability and inhibiting platelet aggregation Effect

Active Publication Date: 2016-03-16
BEIJING PRELUDE PHARM SCI & TECH
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  • Abstract
  • Description
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  • 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-hydroxytetrahydrothienopyridine derivatives and preparation methods and uses thereof
  • Optically active 2-hydroxytetrahydrothienopyridine derivatives and preparation methods and uses thereof
  • Optically active 2-hydroxytetrahydrothienopyridine derivatives and preparation methods and uses thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: the preparation of formula V compound

[0059] Synthetic 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 for 3 h and excess methanol was removed under vacuum. The oily residue was taken up in 200 mL of dichloromethane, then washed with 10% potassium carbonate in water (240 mL), the organic solvent was extracted, dried, and then concentrated in vacuo to give compound 2 (19 g, 95%) as a colorless of oil.

[0064] 1 HNMR: (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...

Embodiment 2

[0083] Embodiment 2: the preparation of formula VI compound

[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]-acetic acid methyl ester (10)

[0087]

[0088] at -78°C and N 2 Add LHMDS (4.23 mL, 1.0 M , 2.85mmol), then the mixture was stirred at room temperature for 30 minutes, then compound 9 (540mg, 2.11mmol) was added, and stirred for another 10 hours. use NH 4 The reaction was quenched with Cl solution and extracted with EA. with NaHCO 3 solution and brine, washed the organic layer with anhydrous Na 2 SO 4 Dry and concentrate to dryness. The residue was purified with silica gel column (PE:EA=50:1-3:1) to give compound 10 (52 mg, 7%) as a white solid.

[0089] 1 HNMR: (CDCl 3 ,400MHz)δ7.69-7.66(m,1H),7.41-7.39(m,1H),7.30-7.24(m,2H),6.11(s,1H),5.44(s,1H),5.41(s, 1H),4.89(s,1H),3.72(s,3H),3.62-3.58(m,1H),3.49-3.46(m,1H),2.87-2.85(...

Embodiment 3

[0096] Embodiment 3: Pharmacokinetic test in vivo

[0097] The in vivo pharmacokinetics of the compound of formula V, the compound of formula VI, clopidogrel (formula VII) and the first metabolite of clopidogrel (formula VIII) of the present invention were detected. Specifically, the compounds of formula V, compounds of formula VI and clopidogrel and their first metabolites were given orally or intravenously to rats, and the pharmacokinetic characteristics of the compounds of the present invention and clopidogrel in rats were evaluated, and the The conversion of the compound of the present invention into the first metabolite in vivo, and by measuring the blood concentration of the first metabolite (formula VIII) in rats at a certain time, compare the bioavailability of the compound of the present invention and clopidogrel Spend.

[0098] The experimental animals were male SD rats, aged 6 to 8 weeks, weighing 190-215 grams, purchased from Beijing Weili Tonghua Experimental A...

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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 invention belongs to the field of medicine, in particular, the invention relates to a 2-hydroxytetrahydrothienopyridine derivative, a preparation method of the derivative, a pharmaceutical composition containing the derivative, and the derivative and medicine Use of the composition for preventing or treating 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, and is clinically used to treat atherosclerosis, acute coronary syndrome and thrombotic complications. [0003] [0004] Clopidogrel is a prodrug, which undergoes a two-step oxidation reaction by the liver CYP450 enzyme system in the body to produce active metabolites, the main enzyme activities of which are CYP2C19 and CYP3A4. [0005] [0006] The active metabolites produced by the above two steps of oxidative metabolism and P2Y on the sur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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