Metabolin marker of 2-hydroxyl radical tetrahydro-thiophene pyridine derivative with optical activity as well as preparation and application thereof

A technology for metabolites and uses, applied in the field of preparation of novel metabolite markers, can solve problems such as drug efficacy and safety uncertainty

Active Publication Date: 2014-05-07
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although optically active 2-hydroxytetrahydrothienopyridine derivatives can overcome clopidogrel resistance (JOURNAL OF MEDICINAL CHEMISTRY2012, 55, 3342), however, how to minimize the bleeding of this type of drug while ensuring the efficacy of the drug Risk remains a key unresolved puzzle
In addition, due to the different metabolic pathways of this class of drugs and clopidogrel, the identity and / or exposure of metabolites of optically active 2-hydroxytetrahydrothienopyridine derivatives may be different from that of clopidogrel. large differences, resulting in great uncertainty about the efficacy and safety of the drug
[0008] In conclusion, there are still many unresolved key technical problems in the development or preparation of optically active 2-hydroxytetrahydrothienopyridine derivatives as novel antiplatelet aggregation drugs

Method used

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  • Metabolin marker of 2-hydroxyl radical tetrahydro-thiophene pyridine derivative with optical activity as well as preparation and application thereof
  • Metabolin marker of 2-hydroxyl radical tetrahydro-thiophene pyridine derivative with optical activity as well as preparation and application thereof
  • Metabolin marker of 2-hydroxyl radical tetrahydro-thiophene pyridine derivative with optical activity as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Pharmacokinetic study of vicagrel in cynomolgus monkeys, beagle dogs and SD rats

[0049] 1. Purpose of the test: To identify the metabolites in the plasma of cynomolgus monkeys, beagle dogs and SD rats after intragastric administration of vicagrelor, and to compare the differences in drug metabolism in vivo.

[0050] 2. Sample collection: 2 healthy cynomolgus monkeys, 1 male and 1 male, each weighing 3-4 kg, were given vicagrelor by intragastric administration at 5 mg / kg. Two healthy Beagle dogs, male, weighing 8-10 kg, were given Vicarrel by gavage at 5 mg / kg. Two healthy SD rats, male, weighing 180-220 g, were given vicagrelor by intragastric administration at 10 mg / kg. Fasting for 12 hours before the test, drinking water freely, taking medicine on an empty stomach in the morning, and eating uniformly 2 hours after taking the medicine. Take 0.5ml of venous blood before administration and 0.5, 1, 4 and 8h after administration, and add 25μl of derivatization reagent ...

Embodiment 2

[0063] Research on the metabolic behavior of vicagrelor in human body

[0064] 1. Purpose of the test: To use UPLC / Q-TOF MS to qualitatively and quantitatively identify the metabolites in the plasma of voluntary subjects after oral administration of vicagrel tablets.

[0065] 2. Materials and methods

[0066] Reagent:

[0067] 3'-Methoxybromoacetophenone

American Sigma Corporation

Acetonitrile (chromatographically pure)

American Sigma Corporation

Ammonium acetate (chromatographically pure)

American Tedia Corporation

formic acid

American Fluka Corporation

[0068] Sample collection: 3 healthy male voluntary subjects, fasted for 12 hours before the test, took 25 mg of vicagrelor with 200ml of warm water on the day of the test, and could drink water 2 hours after taking the medicine, and eat after 4 hours. Before taking the medicine (0h) and 1, 2 and 6h after taking the medicine, 2 mL of blood was collected. Immediately after...

Embodiment 3

[0081] Pharmacokinetic study of compound of formula I-3 in SD rats

[0082] 1. Purpose of the test: To identify the metabolites in the plasma of SD rats given the compound of formula I-3 by intragastric administration, and to study the drug metabolism behavior in vivo.

[0083] 2. Sample collection: 2 healthy SD rats, male, weighing 180-220 g, were intragastrically administered the compound of formula I-3 at 10 mg / kg. Fasting for 12 hours before the test, drinking water freely, taking medicine on an empty stomach in the morning, and eating uniformly 2 hours after taking the medicine. Take 0.5 ml of venous blood before administration and 1, 4 and 8 hours after administration, and immediately add 25 μl of derivatization reagent (3'-methoxybromoacetophenone (BMP) acetonitrile solution) in EDTA In the anticoagulant tube, gently invert the test tube 5-6 times as soon as possible, place at room temperature for 10 minutes, centrifuge at 3500rpm for 10 minutes, separate the plasma, p...

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Abstract

The invention relates to the field of medicines, in particular to a novel metabolin marker and application of the metabolin marker to develop or prepare a medicine containing the 2-hydroxyl radical tetrahydro-thiophene pyridine derivative with the optical activity. The medicines can be used for preventing or treating diseases caused by thrombus. The invention further provides a preparation method of the novel metabolin marker.

Description

technical field [0001] The invention relates to the field of medicine, in particular to novel metabolite markers and their use in the development or preparation of drugs containing optically active 2-hydroxytetrahydrothienopyridine derivatives, which can be used to prevent or treat thrombosis disease. The invention also provides a preparation method of the novel metabolite marker. [0002] This patent claims the priority of the Chinese patent application (application number 201210395415.4, application date: October 17, 2012, invention and creation name: metabolite marker of vicagrelor, its preparation method and use). Background technique [0003] Clopidogrel as irreversible P2Y 12 Receptor antagonists are currently the most widely used anti-platelet aggregation drugs. It is clinically used to treat atherosclerotic diseases, acute coronary syndrome and thrombotic complications. Clinical studies have found that the oral bioavailability of clopidogrel is very low, and its ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/72A61K49/00A61P7/00A61P9/10G01N33/15
CPCC07D211/76C07D211/72C07D495/04A61B5/145A61P7/00A61P7/02A61P9/00A61P9/10G01N33/5088
Inventor 孙宏斌张秀玲吕伏生祁小伟
Owner JIANGSU VCARE PHARMATECH
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