CN112851570A - Preparation method and medical application of unsaturated cyclic amine cysteine disulfide derivative - Google Patents

Preparation method and medical application of unsaturated cyclic amine cysteine disulfide derivative Download PDF

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CN112851570A
CN112851570A CN202110040049.XA CN202110040049A CN112851570A CN 112851570 A CN112851570 A CN 112851570A CN 202110040049 A CN202110040049 A CN 202110040049A CN 112851570 A CN112851570 A CN 112851570A
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methoxy
amino
oxoethyl
tetrahydropyridin
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艾海马
张卫锋
冯美香
王磊
贾晓栋
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Beijing Voban Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention relates to the field of medicinal chemistry, in particular to a series of unsaturated cyclic amine cysteine disulfide derivatives, and also discloses a preparation method and medical application of the compounds. Especially for the treatment of atherosclerotic disease, myocardial infarction, stroke, peripheral artery disease, acute coronary syndrome and thrombosis during anti-angiogenic surgery.

Description

Preparation method and medical application of unsaturated cyclic amine cysteine disulfide derivative
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a series of unsaturated cyclic amine cysteine disulfide derivatives, and also discloses a preparation method and medical application of the compounds.
Background
The cardiovascular and cerebrovascular thrombotic diseases are common diseases, and the incidence rate of the thromboembolic diseases mainly including coronary artery thrombosis and cerebral thrombosis is on the rise in recent years, which seriously harms human health, so the research on the prevention and treatment of the diseases is very important. Platelet aggregation is a key link in the normal coagulation mechanism, but platelet adhesion and aggregation are also the initiation links of thrombus formation. Therefore, drugs that inhibit platelet aggregation play an important role in the treatment of thrombotic diseases (Stroke,1999, 30: 878). Anti-platelet aggregation drugs have been the focus of research.
Clopidogrel (Clopidogrel) developed by Senofura pharmaceutical company, France, is currently the most widely used anti-platelet aggregation drug worldwide. Clopidogrel is a prodrug. Early in vivo metabolism studies showed that clopidogrel undergoes two-step oxidation by the liver P450 enzyme system in vivo, with ring-opening metabolism to produce an active metabolite of an unsaturated cyclic amine structure (shown below). Active metabolites and platelet surface P2Y12 receptors form covalent binding, and inhibit platelet aggregation by antagonizing P2Y12 receptors (Thromb Haemost,2000, 84: 89D. Nippon Sancosmopharmacy company and American Gift pharmaceutical company develop a new generation of antiplatelet Drug Prasugrel (Prasugrel) on the basis of clopidogrel structure, Prasugrel is also a prodrug. early in vivo metabolism research discovers that Prasugrel forms an active metabolite with a saturated cyclic amine structure through esterase hydrolysis and oxidative ring opening of a P450 enzyme system in vivo, and antagonizes antiplatelet P2Y12 receptors (Drug Metab Dispos, 2007, 35: 1096).
In 2012, french researchers found that clopidogrel is metabolized not only into an active metabolite of a saturated cyclic amine structure but also into a metabolite of an unsaturated cyclic amine structure which is transferred with a small amount of double bonds through other esterases in vivo (Chem Res Toxicol,2012, 25: 348). The anti-platelet activity of the metabolites with unsaturated cyclic amine structures in vivo and in vitro is not reported in the literature so far. Clopidogrel, DT-678, 2M3 and the unsaturated cyclic amine cysteine disulfide derivative are metabolized into a H4 derivative in vivo and have anti-platelet activity in vitro and in vivo. The discovery of the Chengqing of the university of Michigan in 2015 shows that the drug effect of disulfide DT-678 formed by combining an active body of clopidogrel and 3-nitropyridine is 10 times that of clopidogrel, but 3-nitropyridine has reproductive toxicity, and the 3-nitropyridine is replaced by serial derivatives such as cysteine, homocysteine, glutathione and the like, so that the drug effect is improved by 15 times, and the reproductive toxicity is avoided.
Figure BDA0002895061610000021
Comparison of in vivo metabolic pathways of clopidogrel and unsaturated cyclic amine cysteine disulfide derivatives
Based on the structure of saturated cyclic amine metabolites, three companies in Japan have filed a number of patents, such as W098088H, W09943648, and W09943648. These patents protect a series of derivatives with saturated cyclic amine structure and report the situation of anti-platelet activity in vivo and in vitro, but no literature report is available for the research on derivatives with unsaturated cyclic amine structure and anti-platelet activity thereof.
Disclosure of Invention
During the synthesis of saturated cyclic amine derivatives, we have occasionally obtained a series of cysteine disulfide derivatives of unsaturated cyclic amine structures. After testing these compounds for antiplatelet activity, we have surprisingly found that these unsaturated cyclic amine derivatives exhibit more potent antiplatelet activity in animals than prasugrel. Therefore, the unsaturated cyclic amine derivatives are worthy of further research and development.
Based on the structures of clopidogrel and prasugrel metabolites reported in the previous documents, the invention discloses for the first time novel unsaturated cyclic amine cysteine disulfide derivatives, their preparation methods and uses, in particular for the treatment of atherosclerotic diseases, myocardial infarction, stroke, peripheral arterial disease, acute coronary syndrome and thrombosis during anti-angiogenic surgery. S-clopidogrel oxydans is synthesized according to the method provided by US8,536,337B2; the preparation of the final disulfide compound of the formula I, VI was described in the literature (Tetrahedron Lett., 2005,46, 3583-85; Tetrahedron, 2011,67, 8895-.
The invention aims to provide a compound, a pharmaceutically acceptable salt or a solvate of formula I.
Figure BDA0002895061610000031
Wherein R is1Represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons.
R2Represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group. X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.
R3Represents C1-C10 unsubstituted or X substituted straight or branched chain alkyl, alkenyl, alkynyl, phenyl or X substituted phenyl, benzyl or X substituted benzyl, naphthyl or X substituted naphthyl, C1-C10 unsubstituted or X substituted straight or branched chain alkoxy, C3-C7 unsubstituted or X substituted cycloalkoxy, C1-C10 unsubstituted or X substituted straight or branched chain alkanoyl, unsubstituted or X substituted benzoyl, C3-C7 unsubstituted or X substituted cycloalkanoyl. X represents fluorine, chlorine, bromine, iodine, nitrile groupNitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxy, methoxyacyl, ethoxyacyl, aryloxy, phenyl or Y-substituted phenyl; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.
Preferably, the compound shown in the formula I, the pharmaceutically acceptable salt or the solvate is adopted.
R1Represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons.
R2Represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group.
X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.
R3Represents C1-C10 unsubstituted or X-substituted straight-chain or branched alkyl, alkenyl, alkynyl, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, C1-C10 unsubstituted or X-substituted straight-chain or branched alkoxyA group, an unsubstituted or X-substituted cycloalkoxy group of 3 to 7 carbons, an unsubstituted or X-substituted straight or branched alkanoyl group of 1 to 10 carbons, an unsubstituted or X-substituted benzoyl group, an unsubstituted or X-substituted cycloalkanoyl group of 3 to 7 carbons. X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.
Further preferably, the compound of the present invention is selected from:
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-pivaloylmethyl-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-pivalic acid methyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-pivaloylmethyl-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) butanoic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-pivalic acid methyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-pivaloylmethyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione
All of the above compounds are racemic in the 7-position.
The present invention provides compounds of formula I having an optical purity of 70%, 100%, preferably 90%, 100%, more preferably 95%, 100%, most preferably 98%, 100%.
The compound shown in the formula I, the pharmaceutically acceptable salt or the solvate is selected from salts formed by the compound shown in the formula I and sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.
It is another object of the present invention to provide a process for the preparation of the compounds of formula I.
Method (1): preparation of active intermediate by hydrolysis of clopidogrel oxydans
Figure BDA0002895061610000071
Synthesis of unsaturated cyclic amine cysteine disulfide derivatives
Reacting a compound shown as a formula II or a salt thereof with cysteine in the presence of alkali to obtain a compound shown as a formula I, wherein X represents fluorine, chlorine, bromine, iodine, C1-C10 unsubstituted or X substituted straight chain or branched chain alkyl sulfonyl, phenyl or X substituted benzenesulfonyl.
Wherein, the solvent used in the reaction process is selected from: benzene, toluene, chloroform, N-hexane, cyclohexane, dichloromethane, 1, 2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile, N-dimethylformamide or dimethylsulfoxide, preferably methanol or ethanol;
the base is selected from: sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1, 8-diazacyclo [5, 4, 0] undecene-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, preferably sodium methoxide, sodium bicarbonate, potassium carbonate, triethylamine;
the reaction temperature is 0 ℃ to 100 ℃, and the preferred temperature is 20 ℃ to 50 ℃;
in the above reaction, R1、R2And X is as defined above for compounds of formula I.
Specifically, the preparation method comprises the following steps:
Figure BDA0002895061610000081
preparation of unsaturated cyclic amine cysteine disulfide derivatives from clopidogrel oxydans
(1) A compound of formula IV or a salt thereof with R2And (3) reacting OH in the presence of a base to obtain the compound shown in the formula II.
Wherein, the preparation of the compound of formula IV can refer to patent CN102120744, the synthesis method for obtaining the compound of formula 11 by synthesizing the compound of formula IV is disclosed in the literature, and can refer to Chem Res Toxicol,2012, 25: 348.
(2) reacting a compound of formula II or a salt thereof with cysteine in the presence of a base to give a compound of formula I, wherein the substituted cysteine 3-Z represents fluorine, chlorine, bromine, iodine, a C1-C10 unsubstituted or X substituted straight or branched alkylsulfonyl group, a phenyl group or an X substituted benzenesulfonyl group. The solvent is selected from one or more mixed solvents of benzene, toluene, chloroform, N-hexane, cyclohexane, dichloromethane, 1, 2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile, N-dimethylformamide or dimethyl sulfoxide, preferably methanol and ethanol; the base is selected from sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1, 8-diazacyclo [5, 4, 0] undecene-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, wherein sodium methoxide, sodium bicarbonate, potassium carbonate and triethylamine are preferred; the reaction temperature is from 0 ℃ to 100 ℃, preferably from 20 ℃ to 50 ℃.
In the above reaction, R1、R2And X is as defined above for compounds of formula I.
Method (2): preparation of reactive intermediates from piperidones
Figure BDA0002895061610000091
Preparation of unsaturated cyclic amine cysteine disulfide derivatives from piperidones
The method specifically comprises the following steps:
(1) referring to patent CN1192019, the compound of formula V undergoes multi-step reaction to obtain the compound of formula VI, and the specific synthesis method is shown in the examples.
(2) Compounds of formula VI with R3SK reaction to obtain the compound of formula I.
The reaction conditions for this step are disclosed in patent CN1192019, but in the present invention we found that unsaturated cyclic amine disulfide with double bond transfer can be obtained by using the conditions disclosed in the patent.
In the above reaction, R1、R2And R3As defined above for compounds of formula I.
The compound involved in the production method of the present invention is a known compound, and can be either commercially available or produced by a conventional method.
The invention also aims to provide the application of the compound shown in the formula I in pharmacy.
Pharmacodynamic studies show that the compound of the formula I provided by the invention has a remarkable platelet aggregation inhibiting effect, and the platelet aggregation inhibiting effect is better than that of prasugrel.
The compound of formula I, the pharmaceutically acceptable salt or the solvate provided by the invention can be used for preparing medicines for preventing or treating diseases related to thrombus and embolism. In particular to a medicine for preventing or treating atherosclerosis diseases, myocardial infarction, apoplexy, ischemic cerebral thrombosis, peripheral artery diseases, acute coronary syndrome or thrombosis after coronary intervention operation.
The invention also aims to provide a pharmaceutical composition which takes the compound shown in the formula I, the pharmaceutically acceptable salt or the solvate as an active ingredient.
The pharmaceutical composition of the invention comprises 0.1-99.9% of the compound shown in formula I, pharmaceutically acceptable salt or solvate, and the balance of pharmaceutically acceptable carriers.
The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage forms, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches. The formulations of the present invention, preferably oral dosage forms, are: capsule, tablet, oral liquid, granule, pill, powder, pellet, and unguent. Most preferred are capsules.
The pharmaceutical composition of the present invention, its preparation for oral administration, may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.
Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
The solid oral compositions can be prepared by conventional methods of mixing, filling, tabletting and the like. Repeated mixing can distribute the active throughout those compositions that use large amounts of filler.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethyl alcohol; preservatives, for example p-hydroxybenzyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
For injections, liquid unit dosage forms are prepared containing the active substances of the invention and a sterile carrier. Depending on the carrier and concentration, the compound may be suspended or dissolved. Solutions are generally prepared by dissolving the active substance in a carrier, filter sterilising before filling it into a suitable vial or ampoule and then sealing. Adjuvants such as a local anaesthetic, preservatives and buffering agents may also be dissolved in the vehicle. To improve its stability, the composition can be frozen after filling into vials and the water removed under vacuum.
The traditional Chinese medicine preparation of the invention can be selectively added with a proper pharmaceutically acceptable carrier when being prepared into a medicament, and the pharmaceutically acceptable carrier is selected from: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, EDTA disodium, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.
Compared with the existing products of clopidogrel and prasugrel, the clopidogrel compound has the following advantages that:
(1) the platelet aggregation inhibition rate is high;
(2) the pharmacokinetics speed is high;
(3) for Asian people lacking P450 enzyme, the medicine is easier to absorb and has better efficacy.
Clopidogrel metabolites and inhibition of platelet receptor activity: because the active ingredients of the clopidogrel metabolite are few, the (7S,4R, 2R) dimer or (7S,4 ethylenic bond) unsaturated cyclic amine dithiocysteine derivative with high activity is invented.
Figure BDA0002895061610000111
Configuration of clopidogrel metabolites
Table 1: detection condition of 4 isomers of clopidogrel in human microsome incubation product and in-vitro inhibition33Activity of P-2MeS-ADP binding to platelet receptors
Figure BDA0002895061610000112
Figure BDA0002895061610000121
Derivatization of clopidogrel activity and unsaturated cyclic amine cysteine derivative metabolites and structure of each isomer
Detailed Description
The present invention is further illustrated by the following specific examples, which are set forth to better illustrate the invention and are not intended to limit the scope of the invention.
Example 1
Synthesis of 1-trityl-4-piperidone
Figure BDA0002895061610000131
After 72.5g (0.260mol) of chlorotriphenylmethane was added little by little to a solution of 40g (0.260mol) of 4-piperidone-hydrate hydrochloride and 550mL (0.78mol) of triethylamine in 550mL of dimethylformamide at 60 ℃ under stirring, the mixture was stirred at that temperature for 5 hours, and after cooling, the precipitated triethylamine hydrochloride was filtered. The filtrate was poured into 2500mL of water, stirred while standing, and then filtered under suction to obtain 77.7g of a white solid with a yield of 70.2%.
Example 2
Synthesis of E-2- (4-carbonyl-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester
Figure BDA0002895061610000132
60g (0.1757mol) of 1-trityl-4-piperidone and 15.8mL (0.1933mol) of pyrrolidine in 600mL of toluene were azeotroped with a water separator under reflux for 3 hours, and after cooling, 20.2mL (0.1933mol) of ethyl glyoxylate was added, followed by azeotropic dehydration under reflux for 2 hours. After cooling, 400mL of water was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 49.35g of a pale yellow oil with a yield of 60.2%.1HNMR(500MHz,CDC13)：d 7.51-7.17(m，15H)，6.59(s，1H)，4.10(q，2H，J＝7.1Hz)，3.71(s，2H)，2.79(t，2H，J＝6.OHz)，2.65(s，2H)，1.17(t，2H，J＝7.1Hz).
ESI-MS m/z 448.1[M+Na]+
Example 3
Synthesis of E-2- (4-hydroxy-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester
Figure BDA0002895061610000133
22g (0.0517mol) of E-2- (4-carbonyl-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester was dissolved in 50mL of dichloromethane, 200mL of methanol was added thereto, and 2.34g (0.0619mol) of sodium borohydride was added dropwise under ice-cooling, followed by stirring at room temperature for lh. After the reaction mixture was concentrated under reduced pressure, 150mL of water was added, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give M3-7 as a pale yellow oil, 12.8g, yield 57.9%,1HNMR(300MHz,CDC13):d 7.45(d，6H，J＝7.3Hz)，7.25-7.11(m，9H)，6.05(s，1H)，4.48(s，1H)，4.14-3.96(m，3H)，2.99(s，1H)，2.30-2.22(m，1H)，2.10-2.03(m，1H)，1.93-1.85(m，3H)，1.12(t，3H，J＝7.1Hz)。ESI-MS m/z426.2[M-H]-。
example 4
Synthesis of E-2- (4-hydroxypiperidin-3-enyl) -acetic acid ethyl ester p-toluenesulfonate
Figure BDA0002895061610000141
After 8.77g (20.51mmol) of E-2- (4-hydroxy-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester was dissolved in 100mL of tetrahydrofuran, 5.13g (26.97mmol) of p-toluenesulfonic acid monohydrate was added, the mixture was stirred at 50 ℃ for lh, the solvent was evaporated under reduced pressure, the resulting residue was washed with toluene, and after standing, the upper layer was poured out and the lower layer was used in the next reaction.
Example 5
Synthesis of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-hydroxypiperidin-1-yl) -acetate
Figure BDA0002895061610000142
Adding E-2- (4-hydroxypiperidine-3-alkenyl) -acetic acid ethyl ester into methylThe benzenesulfonate salt was dissolved in 100mL of acetonitrile, and 6.86g (17.77mmol) of methyl (R) -2- (2-chlorophenyl) -2- (4-nitrobenzenesulfonyloxy) -acetate and 4.44g (44.42mmol) of potassium hydrogencarbonate were added and reacted overnight under nitrogen. The filtrate was concentrated under reduced pressure by suction filtration, and the obtained residue was purified by silica gel column chromatography to obtain 3.47g of a pale yellow oil with a yield of 46.0% in two steps. Specific rotation degree: [ alpha ] to]D 205.7 ° (c 5, dissolved in ethanol).1HNMR(500MHz,CDC13)：d 7.59-7.53(m，1H)，7.38-7.35(m，1H)，7.27-7.21(m，2H)，5.98-5.97(m，1H)，4.85-4.81(m，1H)，4.59-4.48(m，1H)，4.10-4.05(m，3H)，3.70-3.68(m，3H)，3.24-3.14(m，1H)，2.91-2.87(m，1H)，2.66-2.50(m，1H)，2.31(s，1H)，2.03-1.97(m，1H)，1.81-1.74(m，2H)，1.23-1.95(m，3H)，ESI-MS m/z 368.1[M+H]+。
Example 6
Synthesis of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-bromopiperidin-1-yl) -acetate
Figure BDA0002895061610000151
To 35mL of anhydrous dichloromethane were added 2.08g (5.65mmol) of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-hydroxypiperidin-1-yl) -acetate, 2.25g (6.78mol) of carbon tetrabromide, and 1.78g (6.78mmol) of triphenylphosphine, and the mixture was stirred at room temperature for lh, followed by concentrating the reaction mixture and purifying the resulting residue by silica gel column chromatography to obtain 1.9g of a pale yellow oily substance, and the yield was 79.2%. Specific rotation degree: [ alpha ] to]D 2010.5 ° (c 5 in ethanol).1HNMR(500MHz,CDC13)：d 7.62-7.58(m，1H)，7.40-7.37(m，1H)，7.29-7.23(m，2H)，5.93(d，1H，J＝4.OHz)，4.89-4.88(m，1H)，4.83(s，1H)，4.65-4.50(m，1H)，4.13-4.05(m，2H)，3.72(d，3H，J＝7.3Hz),3.65-3.55(m，1H)，3.04-2.87(m，1H)，2.80-2.77(m，1H)，2.31(s，1H)，2.09-2.03(m,1H)，1.24(qd,3H,J＝14.1,6.9Hz)，ESI-MS m/z 430.1，[M+H]+。
Example 7
Synthesis of(s) -methyl 2- (2-chlorophenyl) -2- (3- (2-ethoxy-2-carbonylethyl) -4-acetylmercapto-dihydropiperidin-1- (2H) -yl) -acetate
Figure BDA0002895061610000152
2.7g (6.2mmol) of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-bromopiperidin-1-yl) -acetate and 2.8g (24.5mmol) of potassium thioacetate were dissolved in 80mL of N, N-dimethylformamide or 80mL of dimethyl sulfoxide and all the starting materials disappeared after stirring with heating at 40 ℃ for 48 h. To the reaction solution was added a large amount of water, and the aqueous phase was extracted with ethyl acetate and dried over anhydrous sodium sulfate overnight. Evaporating the organic phase to dryness and then separating the organic phase by a column to obtain a pure product 2.lg, wherein the yield is as follows: 78.9%, specific rotation: [ alpha ] to]D 2015.8 ° (c ═ 5, dissolved in ethanol).1HNMR(500MHz,CDC13):d 7.66(d，1H,J＝7.OHz)，7.40-7.24(m，3H)，4.86(s，1H)，4.09(q，2H，J＝7.1Hz)，3.71(s,3H)，3.33(ABq,2H,J＝16.5Hz)，3.18(ABq,2H,J＝16.1Hz)，2.79(s，2H)，2.45(s，2H)，2.33(s，3H)，1.22(t，3H，J＝7.1Hz)；13CNMR(125MHz,
CDC13)：d 197.6，193.7，170.9，169.7，137.9，134.6，129.9，129.7，129.4，127.1，124.0，67.2，60.8，54.5，52.1，47.6，38.8，32.5，30.3，29.6，14.0.ESI-MS m/z 426.1[M+H]+；HRMS calcd for C20H24N05SClNa[M+H]+m/z 448.0916，found 448.0964。
Example 8
Synthesis of methyl(s) -2- (2-chlorophenyl) -2- (3- (2-methoxy-2-carbonylethyl) -4-mercapto-5, 6-dihydropyridin-1 (2H) -yl) -acetate
Figure BDA0002895061610000161
169mg (0.5mmoI) (2S) -2- (2-oxo-7, 7 a-dihydrothieno [3, 2-c)]Pyridin-5 (2H, 4H, 6H) -yl) -2- (2-chlorophenyl) -acetic acid methyl ester was dissolved in 15mL of methanol and 724mg (5mmol) of methanol was addedPotassium carbonate hydrate. The reaction liquid is protected by nitrogen gas, the raw materials are completely disappeared after stirring for 12 hours at room temperature, the reaction liquid is filtered to remove insoluble solids, the pH value is adjusted to be neutral by 2N hydrochloric acid, a large amount of water is added, extraction is carried out by ethyl acetate, the organic phase is washed by saturated salt water, and anhydrous sodium sulfate is dried. Evaporating the organic phase to dryness, and separating by column to obtain oily substance. Specific rotation degree: [ alpha ] to]D 2035.8 ° (c ═ 5, dissolved in ethanol).1HNMR(300MHz,CDC13)：d 7.65-7.62(m，1H)，7.40-7.38(m，1H)，7.28-7.24(m，2H)，4.79(s，1H)，3.69(s，3H)，3.66(s，3H)，3.24-3.17(m，2H)，3.10(d，2H，J＝15.6Hz)，2.69(t，2H，J＝5.7Hz),2.57(s，1H)，2.38(s，2H)；1HNMR(300MHz,CDC13+D20)d 7.65-7.62(m，1H)，7.40-7.37(m，1H)，7.28-7.24(m，2H)，4.79(s，1H)，3.69(s，3H)，3.66(s，3H)，3.16-3.10(m，2H)，3.12-3.05(m，2H)，2.69(t，2H，J＝5.7Hz),2.38(s，2H)。13C NMR(75MHz,CDC13)：d 171.0，170.6，134.6，133.4，129.8，129.7，129.4，127.0，125.1，124.0，67.4，54.4，52.1，47.6，38.3，35.2。ESI-MS m/z 392.l[M+Na]+。HRMS calcd for C17H20N04NaSCl[M+Na]+m/z 392.0699，found 392.0703。
Example 9
Synthesis of methyl(s) -2- (2-chlorophenyl) -2- (3- (2-methoxy-2-carbonylethyl) -4-mercaptomethyl-5, 6-dihydropyridin-1 (2H) -yl) -acetate
Figure BDA0002895061610000162
338mg (1mmol) of (2S) -2- (2-oxo-7, 7 a-dihydrothieno [3, 2-c)]Pyridin-5 (2H, 4H, 6H) -yl) -2- (2-chlorophenyl) -acetic acid methyl ester was dissolved in 10mL of methanol, 1.38g (10mmol) of anhydrous potassium carbonate was added, and after stirring for 12 hours under nitrogen, all the starting materials disappeared. After insoluble matter was filtered, the reaction mixture was neutralized or weakly acidic with dilute hydrochloric acid, and 0.18mL (3mmol) of methyl iodide was added thereto and stirred for 0.5 hour. Water was added to the reaction solution, and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate overnight. Evaporating the organic phase to dryness to obtain a crude product,column chromatography gave 282mg of oil, yield: 73.4 percent. Specific rotation degree: [ alpha ] to]D 2037.4 ° (c ═ 5, in ethanol).1HNMR(500MHz,CDC13)：d 7.65(d，1H,J＝7.2Hz)，7.39-7.38(m,1H)，7.29-7.23(m，3H)，4.80(s，1H)，3.70(s，4H)，3.66(d，3H，J＝9.3Hz),3.37(d，1H，J＝15.7Hz)，3.25-3.20(m，2H)，3.11(d，lH，J＝15.8Hz)，2.72(s，2H)，2.42(s，2H)，2.18(s，3H)。13CNMR(125MHz,CDC13):d 171.1，171.0，134.6，133.5，129.8，129.7，129.3，129.1，127.7，127.0，67.5，54.7，52.0，51.8，47.6，38.0，29.8，14.3。ESI-MS m/z 406.1[M+Na]+。
HRMS calcd for C18H22N04NaSCl[M+Na]+:m/z 406.0856，found 406.0860。
Example 10
Synthesis of methyl(s) -2- (1- (1- (2-chlorophenyl) -2-carboxyethyl) -4-mercaptomethyl-1, 2,5, 6-tetrahydropyridin-3-yl) -acetate
Figure BDA0002895061610000171
233mg (0.61mmol) of(s) -2- (2-chlorophenyl) -2- (3- (2-methoxy-2-carbonylethyl) -4-mercaptomethyl-5, 6-dihydropyridin-1 (2H) -yl) -acetic acid methyl ester were dissolved in 2mL of methanol, 0.07mL of 30% aqueous sodium hydroxide solution (0.73mmol) were added, and after stirring for 4 days under nitrogen, the starting material disappeared completely. The reaction solution was adjusted to neutral or weakly acidic with dilute hydrochloric acid, water was added thereto and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate overnight. Evaporating the organic phase to dryness to obtain a crude product, and performing column chromatography to obtain an oily substance of 102mg, wherein the yield is as follows: 45.4 percent. Specific rotation degree: [ alpha ] to]D 2033.6 ° (c ═ 5, in ethanol).1HNMR (500MHz, CDC 13): d 7.65-7.63(m,1H), 7.40-7.38(m, 1H), 7.29-7.25(m, 2H), 4.84(s, 1H), 3.70(s, 3H), 3.38(d, 1H, J ═ 16, OHz), 3.28-3.25 (m, 2H), 3.13(d, 1H, J ═ 15.8Hz), 2.28-2.75(m, 1H), 2.72-2.69(m, 1H), 2.43(s, 2H), 2.19(s, 3H).13CNMR(75MHz,CDC13)：d 175.67，171.0，134.7，133.1，129.9，129.7，129.6，129.4，127.3，127.1,67.2，54.6，52.1,47.5，37.9，29.6，14.3。ESI-MS m/z 370.1，[M+H]+。HRMS calcd forC17H21N04SCl，[M+H]m/z 370.0880，found 370.0881。
Example 11
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
Figure BDA0002895061610000181
In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine are added, the temperature is maintained at 0-5 ℃, 2mmol of thiophenol (II) and 2.2mmol of cysteine are added and stirred for 1h, and the mixture is heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, column chromatography gave 670mg of oil, which was recrystallized from ethanol to give 493mg of bright yellow solid, yield: 65.8 percent. Specific rotation degree: [ alpha ] to]D 207.9 ° (c ═ 5, dissolved in ethanol).1HNMR (500MHz, d 6-DMSO): d11.0(br,2H), 7.15-7.13(m,1H), 7.00-7.02(m, 3H), 4.74(s, 1H), 3.77(dd, 1H, J ═ 12.6Hz), 3.67(s, 3H), 3.17(d, 1H, J ═ 8.8Hz), 2.92(d, 1H, J ═ 8.8Hz), 2.90(s, 2H), 2.83(s, 2H), 2.45(dd, 2H, J ═ 16, OHz), 2.07-2.05 (m, 2H), 2.02-1.96(m, 2H).13CNMR(500MHz,d6-DMSO)：d 174.9，171.7，171.6，136.0，135.4，135.1，131.2，129.3，129.0，127.3，65.8，55.4，51.9，51.1,44.2，42.7，35.2，34.0。ESI-MS m/z474.07，[M+H]+。HRMS calcd forC32H34Cl2N208S2，[M+H]m/z474.98，found 475.00。
Example 12
(R) -2-amino-3- (2- (2-methoxy-3-oxoethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
Figure BDA0002895061610000191
In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine are added, the temperature is maintained at 0-5 ℃, 2mmol of thiophenol (II) and 2.2mmol of cysteine are added and stirred for 1h, and the mixture is heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, column chromatography gave 670mg of oil, which was recrystallized from ethanol to give a bright yellow solid.
Example 13
(R) -2-amino-3- (2- (2-ethoxy-2-oxoethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
Figure BDA0002895061610000192
In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine are added, the temperature is maintained at 0-5 ℃, 2mmol of thiophenol (IV) and 2.2mmol of cysteine are added and stirred for 1h, and the mixture is heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, 694mg of oil isolated on a column, and recrystallized from ethanol to give a bright yellow solid.
Example 14
(R) -2-amino-3- (2- (2-propoxy-2-oxoethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
Figure BDA0002895061610000201
In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine are added, the temperature is maintained at 0-5 ℃, 2mmol of thiophenol (V) and 2.2mmol of cysteine are added and stirred for 1h, and the mixture is heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, column chromatography gave 720mg of oil, which was recrystallized from ethanol to give a bright yellow solid.
Example 15
(R) -2-amino-3- (2- (2-isopropoxy-2-oxoethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
Figure BDA0002895061610000202
In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine are added, the temperature is maintained at 0-5 ℃, 2mmol of thiophenol (VI) and 2.2mmol of cysteine are added and stirred for 1h, and the mixture is heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, column chromatography gave 718mg of oil, which was recrystallized from ethanol to give a bright yellow solid.
Example 16
(R) -2-amino-3- (2- (2-carboxyethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
Figure BDA0002895061610000211
In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine is added, the temperature is maintained at 0-5 ℃, 2mmol of thiophenol (VII) and 2.2mmol of cysteine are added and stirred for 1h, and the mixture is heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, column chromatography to give 615mg of oil, and recrystallization from ethanol to give a bright yellow solid.
Example 17
Anti-platelet aggregation activity assay
Medicine and preparation: the positive drug was prasugrel and the test compound was example 11. The positive drug and the test compound are mixed into a suspension with 0.5% CMC-Na for animal administration.
Animals: male SD rats, weighing around 250 g.
The instrument comprises the following steps: centrifuge, platelet aggregation apparatus, and the like.
The method comprises the following steps: the compounds of the present invention were tested for their pharmacological activity against platelet aggregation by reference to BORN turbidimetry (Nature,1962, 194: 927). Platelet-rich plasma (PRP) is mixed with the addition of the procoagulant Adenosine Diphosphate (ADP) to aggregate the platelets. The aggregation of platelets causes a change in optical density, which can be detected by a spectrophotometer. This assay allows the assessment of platelet aggregation induced by in vivo or in vitro administration of the test compound.
Male SD rats were orally gavaged with prasugrel and test drug (0.5% CMC-Na homogeneous suspension, drug concentration 1mg/ml) at a dose of 3mg/kg, and blank controls were orally gavaged with the same volume of 0.5% CMC-Na. After 2h, blood is taken from the orbit, 3.8 percent of sodium citrate is anticoagulated, and the ratio of the whole blood to the anticoagulant is 9: platelet-rich Plasma (PRI)) was prepared by centrifugation at 1,1000 rpm for 7 min. PRI modulation with Platelet Poor Plasma (PPP) to maintain platelet counts at 2x 106One per ml. PRI) was added to a test cup, incubated at 37 ℃ for 10min, adjusted to zero by PRI), adjusted to 100% by PPP, and then measured for the percentage of platelet aggregation by a platelet aggregation meter by turbidimetry using ADP (final concentration of 5uM) as an inducer, and statistically compared by t-test to obtain the platelet aggregation inhibition (%) [1- (dose tube aggregation percentage/control tube aggregation percentage)]×100％。
As a result: the platelet aggregation rate of the rats after oral administration of the test compound was measured by turbidimetry, and the experimental results are shown in table one. The results indicate that the compound of example 11 shows stronger anti-platelet aggregation activity than prasugrel.
TABLE 2 platelet aggregation inhibition of rats orally administered prasugrel with compounds prepared according to the examples of the present invention
Figure BDA0002895061610000221
The above tables only show the biological activity data of some compounds of the present invention, and other compounds of the present invention have similar structures and the same or similar activity effects as the above compounds, which are not listed herein due to space limitation.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims (10)

1. A compound shown as a formula I, pharmaceutically acceptable salt or solvate,
Figure FDA0002895061600000011
wherein R is1Represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons,
R2represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group,
x represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group;
y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 position of benzene ring,
R3represents C1-C10 unsubstituted or X-substituted straight-chain or branched alkyl, alkenyl, alkynyl, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, C1-C10 unsubstituted or X-substituted straight-chain or branched alkoxy, C3-C unsubstituted or X-substituted cycloalkoxy, C1-C10 unsubstituted or X-substituted straight-chain or branched alkanoyl, unsubstituted or X-substituted benzoyl3-7 carbon unsubstituted or X-substituted cycloalkanoyl, X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.
2. The compound, pharmaceutically acceptable salt or solvate of formula I according to claim 1,
R1represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons,
R2represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group,
x represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 position of benzene ring,
R3represents a C1-C10 unsubstituted or X-substituted straight or branched chain alkyl, alkenyl, alkynyl, or alkynyl group,Alkynyl, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkanoyl of 1 to 10 carbons, unsubstituted or X-substituted benzoyl, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons, X represents fluorine, chlorine, bromine, iodine, nitrile, nitro, amino, amido, sulfonamide, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxyacyl, ethoxyacyl, aryloxy, phenyl or Y-substituted phenyl; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.
3. The compound, pharmaceutically acceptable salt or solvate of formula I according to claim 1,
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-pivaloylmethyl-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-pivalic acid methyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propanoic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) propionic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-pivaloylmethyl-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) propionic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-bromophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) butanoic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-pivalic acid methyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) butanoic acid
(R) -2-amino-3- (2- (3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione
(R) -2-amino-3- (2- (2-methoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-ethoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-propoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-isopropoxy-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione
(R) -2-amino-3- (2- (2-tert-butyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) glutathione
(R) -2-amino-3- (2- (2-pivaloylmethyl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione
(R) -2-amino-3- (2- (2-pyrrfuryl-3-carboxymethyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) glutathione.
4. The compound, pharmaceutically acceptable salt or solvate of formula I according to claim 1,
the salt is selected from salts formed by the compound shown in the formula I and sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.
5. A process for the preparation of a compound, pharmaceutically acceptable salt or solvate of formula I according to claim 1,
method (1): preparation of active intermediate by hydrolysis of clopidogrel oxydans
Figure FDA0002895061600000061
Reacting a compound shown as a formula II or a salt thereof with cysteine in the presence of alkali to obtain a compound shown as a formula I, wherein X represents fluorine, chlorine, bromine, iodine, C1-C10 unsubstituted or X substituted straight chain or branched chain alkyl sulfonyl, phenyl or X substituted benzenesulfonyl;
wherein, the solvent used in the reaction process is selected from: benzene, toluene, chloroform, N-hexane, cyclohexane, dichloromethane, 1, 2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile, N-dimethylformamide or dimethylsulfoxide, preferably methanol or ethanol;
the base is selected from: sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1, 8-diazacyclo [5, 4, 0] undecene-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, preferably sodium methoxide, sodium bicarbonate, potassium carbonate, triethylamine;
the reaction temperature is 0 ℃ to 100 ℃, and the preferred temperature is 20 ℃ to 50 ℃;
in the above reaction, R1、R2And X is as defined above for compounds of formula I.
6. The compound, pharmaceutically acceptable salt or solvate of formula I according to claim 1,
method (2): preparation of reactive intermediates from piperidones
Figure FDA0002895061600000071
The method specifically comprises the following steps:
(1) referring to patent CN1192019, the compound of formula V is subjected to multi-step reaction to obtain the compound of formula VI,
(2) compounds of formula VI with R3SK reaction to obtain the compound of formula I,
in the above reaction, R1、R2And R3As defined above for compounds of formula I.
7. The use of a compound of formula I, a pharmaceutically acceptable salt or solvate according to claim 1 for the manufacture of a medicament for the prevention or treatment of diseases associated with thrombosis and embolism.
8. The use of a compound of formula I, a pharmaceutically acceptable salt or solvate according to claim 1, in the manufacture of a medicament for the prevention or treatment of atherosclerotic disease, myocardial infarction, stroke, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or thrombosis following coronary intervention.
9. A pharmaceutical composition comprises a compound represented by formula I, a pharmaceutically acceptable salt or a solvate as an active ingredient.
10. The pharmaceutical composition of claim 9, wherein the compound, pharmaceutically acceptable salt or solvate of formula I is 0.1-99.9% by weight, with the balance being pharmaceutically acceptable carriers.
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* Cited by examiner, † Cited by third party
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CN112812098A (en) * 2021-01-13 2021-05-18 北京沃邦医药科技有限公司 Preparation method and medical application of unsaturated cyclic amine pyridine disulfide derivative
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CN115327005A (en) * 2022-08-12 2022-11-11 成都施贝康生物医药科技有限公司 Method for detecting related substances of clopidogrel oxide
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1298389A (en) * 1998-02-27 2001-06-06 三共株式会社 Cyclic amino compounds
CN105051025A (en) * 2013-01-09 2015-11-11 密执安大学评议会 Mixed disulfide conjugates of thienopyridine compounds and uses thereof
CN111362864A (en) * 2018-12-25 2020-07-03 北京翼方生物科技有限责任公司 Unsaturated cyclic amine disulfide derivative, preparation method and medical application thereof
CN111484446A (en) * 2020-04-02 2020-08-04 北京翼方生物科技有限责任公司 Clopidogrel metabolic active body disulfide derivative, preparation method and medical application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1298389A (en) * 1998-02-27 2001-06-06 三共株式会社 Cyclic amino compounds
CN105051025A (en) * 2013-01-09 2015-11-11 密执安大学评议会 Mixed disulfide conjugates of thienopyridine compounds and uses thereof
CN111362864A (en) * 2018-12-25 2020-07-03 北京翼方生物科技有限责任公司 Unsaturated cyclic amine disulfide derivative, preparation method and medical application thereof
CN111484446A (en) * 2020-04-02 2020-08-04 北京翼方生物科技有限责任公司 Clopidogrel metabolic active body disulfide derivative, preparation method and medical application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FARID, NAGY A.等: "The disposition of prasugrel, a novel thienopyridine, in humans", 《DRUG METABOLISM AND DISPOSITION》 *
K. HAGIHARA等: "Absorption, distribution and excretion of the new thienopyridine agent prasugrel in rats", 《XENOBIOTICA》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112812098A (en) * 2021-01-13 2021-05-18 北京沃邦医药科技有限公司 Preparation method and medical application of unsaturated cyclic amine pyridine disulfide derivative
CN115327005A (en) * 2022-08-12 2022-11-11 成都施贝康生物医药科技有限公司 Method for detecting related substances of clopidogrel oxide
CN115327005B (en) * 2022-08-12 2024-01-26 成都施贝康生物医药科技有限公司 Method for detecting clopidogrel oxide related substances
CN115260086A (en) * 2022-09-28 2022-11-01 吉林大学 Fluoro internal standard substance and application and preparation method thereof
CN116444407A (en) * 2023-04-28 2023-07-18 南通大学 Compound containing clustered disulfide bond unit and synthesis method and application thereof

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