Synthesis and biological identification of the acyl glucuronide of the antiinflammatory drug ML-3000

被引:14
作者
Kirschning, A
Ries, M
Domann, S
Martin, W
Albrecht, W
Arnold, P
Laufer, S
机构
[1] PHARMAKIN GMBH,D-89079 ULM,GERMANY
[2] MERCKLE GMBH,D-89135 BLAUBEUREN,GERMANY
关键词
D O I
10.1016/S0960-894X(97)00123-6
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis and identification in biological samples of the 1-O-acyl glucuronide 6 of the antiinflammatory drug ML-3000 is described. Starting with D-glucuronic acid gamma-lactone, 2,3,4-tris(tert.-butyldimethysilyl) glucuronic acid trichloroethylester 4 was prepared (in seven steps) and subsequently coupled with 1 under Mitsunobu conditions. Deprotection, i. e. removal of the trichloroethoxy group with zinc dust and desilylation with hydrofluoric acid in acetonitrile afforded a mixture of alpha- and beta-6 which could be separated by preparative HPLC. The abundance of 6 in bile and plasma samples obtained from animal studies with the cynomolgus monkey and the rabbit following repeated administration of 1 could be demonstrated by LC-electrospray MS analysis. (C) 1997 Elsevier Science Ltd.
引用
收藏
页码:903 / 906
页数:4
相关论文
共 11 条
[1]  
ALGATE DR, 1995, ARZNEIMITTEL-FORSCH, V45-1, P159
[2]   THE SYNTHESIS OF ARYL-D-GLUCOPYRANOSIDURONIC ACIDS [J].
BOLLENBACK, GN ;
LONG, JW ;
BENJAMIN, DG ;
LINDQUIST, JA .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1955, 77 (12) :3310-3315
[4]  
GYGAX D, 1991, TETRAHEDRON, V47, P5122
[5]  
LAUFER S, 1994, ARZNEIMITTEL-FORSCH, V44-1, P629
[6]   (6,7-DIARYLDIHYDROPYRROLIZIN-5-YL)ACETIC ACIDS, A NOVEL CLASS OF POTENT DUAL INHIBITORS OF BOTH CYCLOOXYGENASE AND 5-LIPOXYGENASE [J].
LAUFER, SA ;
AUGUSTIN, J ;
DANNHARDT, G ;
KIEFER, W .
JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (12) :1894-1897
[7]  
SALMON M, 1975, LIFE SCI, V15, P2069
[8]  
SPAHNLANGGUTH H, 1992, DRUG METAB REV, V24, P5
[9]  
STOGNIEW M, 1982, DRUG METAB DISPOS, V10, P609
[10]   SYNTHESIS OF GLUCURONIDES OF ALPHA,BETA-UNSATURATED CARBOXYLIC-ACIDS [J].
TANAKA, M ;
OKITA, M ;
YAMATSU, I .
CARBOHYDRATE RESEARCH, 1993, 241 :81-88