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The Synthesis and Determination of Apparent Oil/water Partition Coefficient and Activity of a Series of New Produrgs of Indomethacin Morpholine Ester

Author: LingWei
Tutor: XuZhi
School: Central South University
Course: Drug analysis
Keywords: Indomethacin morpholino ester derivative synthetic COX-1 / COX-2 activity of inhibiting Apparent oil-water partition coefficient
CLC: R96
Type: Master's thesis
Year: 2011
Downloads: 34
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Abstract

Objective cyclooxygenase two fellow workers isomerase (COX-1 and COX-2) design and synthesis of structural differences appropriate enhanced COX-2 selective inhibition, while inhibition of 5 - lipoxygenase (5 -LOX) series indomethacin morpholino ester derivative mainly for the carboxyl group in indomethacin structure is modified in order to be able to seek to while reducing the adverse reactions of gastrointestinal and cardiovascular drugs; by COX 2 selective inhibitors representative drugs stuffed celecoxib as a reference object, study its inhibition of COX-1 and COX-2 activity, screening isomerase activity of two co-workers suppression better indomethacin morpholinyl ester derivative; simulate the in vivo environment under ideal conditions, indomethacin, a series of indole, morpholine ester derivative in a different pH buffer solution under the apparent water partition coefficient was measured, and to predict its stability and carried out for the proposed future correlation The pharmacokinetic study provides meaningful experimental data. Second, the method of oxalyl chloride to the acid chloride reagent, dichloromethane as a solvent after drying, the indomethacin carboxy is transformed into the acid chloride group of the activity-enhanced, polar aprotic reagent tetrahydrofuran as the reaction solvent, the indole octanoyl chloride different substituents morpholine alcohol esterification reaction, indomethacin 2 - aryl mofetil series of compounds; celecoxib as reference, the determination of a series of indole indomethacin morpholine ester derivatives preferred compounds of mouse peritoneal macrophages inhibition rate, study the inhibition of COX-1 and COX-2 activity; Under ideal conditions, the gastrointestinal simulation of the human body environment, using the shake flask method , using high performance liquid chromatography with UV spectrophotometer preferred indomethacin morpholino ester derivative apparent Pow phosphate buffer solution at different pH values. Results discussed preparing a synthesis method of the nine kinds of indomethacin 2 - aryl morpholino ethyl series derivatives and salts thereof, and its structure was determined by proton NMR spectrum. 2 Determination of indole indomethacin morpholino ester derivatives are preferably the compounds of COX-1 and COX-2 activity inhibition, and were compared with the activity of celecoxib, found indometacin 2 - [2 - (4 - IC50COX-butoxyphenyl) morpholinyl] ethyl ester hydrochloride and indole indomethacin 2 - [2 - (2,4 - dichloro-5 - fluorophenyl) morpholin-yl] ethyl ester hydrochloride 1/COX-2 ratio closest celecoxib for IC50 COX-1/COX-2 of the ratio. 3 lipid-water distribution coefficient measured experimental discovery series indomethacin morpholine the ester derivatives hydrochloride at pH 4, apparent lipid-water distribution coefficient is the maximum, when the spatial configuration increases with the molecular weight of the group introduced increased large, indomethacin morpholino ester derivative apparent Pow also with the increase. IV Conclusions 1 through indol indomethacin 2 - aryl morpholino ethyl series of synthetic experiments, and provides a new method for the other indomethacin Xinyan Sheng was Its hydrochloride. Inhibit COX-1 and COX-2 activity experiments investigated found close celecoxib indole indomethacin 2 - aryl mofetil derivatives the IC50 COX-1/COX-2 ratio, for the follow-up screening for both co-workers isomerase activity inhibition better indomethacin morpholine ester derivatives provide a reference. 3 Indomethacin 2 - aryl morpholino ethyl ester derivatives in the Determination of octanol phosphate buffer apparent Pow their log p, depends not only on the molecular structure of the drug itself, but also with the drug in different The pH conditions, the type of molecule in which the ratio, and the molecular weight of the introduction of the spatial configuration of the group and the introduction of a group.

The Synthesis and Determination of Apparent Oil/water Partition Coefficient and Activity of a Series of New Produrgs of Indomethacin Morpholine Ester

Abstract

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