Syntheses of potential metabolites of a potent κ-opioid receptor agonist, TRK-820

被引：11

作者：

Kawamura, K ^{[1
]}

Horikiri, H ^{[1
]}

Hayakawa, J ^{[1
]}

Seki, C ^{[1
]}

Yoshizawa, K ^{[1
]}

Umeuchi, H ^{[1
]}

Nagase, H ^{[1
]}

机构：

[1] Toray Industries Ltd, Pharmaceut Res Labs, Kamakura, Kanagawa 2488555, Japan

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2004年 / 52卷 / 06期

关键词：

kappa-opioid receptor agonist; TRK-820; metabolite; glucuronide;

D O I：

10.1248/cpb.52.670

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Chemical syntheses of three kinds of potential metabolites of TRK-820, a potent kappa-opioid receptor agonist, were described. One of the potential metabolites 2, 17-N-dealkylated TRK-820, was synthesized starting from noroxycodone through 8 steps in 21% total yield. Glucuronidation of intermediate 10 and compound 1, the free base of TRK-820, was carried out stereoselectively to give 3-O-beta-D-glucuronides 15 and 16 in good yields, respectively. Syntheses of potential conjugated metabolites 3 and 4 were accomplished through 10 steps and 2 steps in 11% and 43% total yields, respectively. Among the potential metabolites of TRK-820, compounds 2 and 4 were identified as metabolites in human hepatocytes. The results of pharmacological studies of compounds 2, 3, and 4 are described.

引用

页码：670 / 674

页数：5

共 14 条

[1]

Berrang B, 1997, SYNTHESIS-STUTTGART, P1165

[2] SYNTHESIS OF A MORPHINE-6-GLUCURONIDE HAPTEN, N-(4-AMINOBUTYL)NORMORPHINE-6-GLUCURONID AND RELATED HAPTENS [J].

BROWN, RT ;

CARTER, NE ;

LUMBARD, KW ;

SCHEINMANN, F .

TETRAHEDRON LETTERS, 1995, 36 (47) :8661-8664

[3]

CASY AF, 1986, OPIOID ANALSICS, P87

[4] A NOVEL METHOD FOR STEREOSELECTIVE GLUCURONIDATION [J].

FISCHER, B ;

NUDELMAN, A ;

RUSE, M ;

HERZIG, J ;

GOTTLIEB, HE ;

KEINAN, E .

JOURNAL OF ORGANIC CHEMISTRY, 1984, 49 (25) :4988-4993

[5] ON THE DIRECT EPOXIDATION OF GLYCALS - APPLICATION OF A REITERATIVE STRATEGY FOR THE SYNTHESIS OF BETA-LINKED OLIGOSACCHARIDES [J].

HALCOMB, RL ;

DANISHEFSKY, SJ .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1989, 111 (17) :6661-6666

[6] AN EXTREMELY MILD AND STEREOCONTROLLED CONSTRUCTION OF 1,2-TRANS-BETA-GLYCOSIDIC LINKAGES CAPITALIZING ON BENZYL-PROTECTED GLYCOPYRANOSYL DIETHYL PHOSPHITES AS GLYCOSYL DONORS [J].

HASHIMOTO, S ;

UMEO, K ;

SANO, A ;

WATANABE, N ;

NAKAJIMA, M ;

IKEGAMI, S .

TETRAHEDRON LETTERS, 1995, 36 (13) :2251-2254

[7] On some derivatives of dextrose and galactose. [J].

Koenigs, W ;

Knorr, E .

BERICHTE DER DEUTSCHEN CHEMISCHEN GESELLSCHAFT, 1901, 34 :957-981

[8] A SYNTHESIS OF MORPHINE-6-GLUCURONIDE [J].

LACY, C ;

SAINSBURY, M .

TETRAHEDRON LETTERS, 1995, 36 (22) :3949-3950

[9]

Nagase H, 1998, CHEM PHARM BULL, V46, P366

[10] STEREOSPECIFIC SYNTHESIS OF THE 6-ALPHA-AMINO AND 6-BETA-AMINO DERIVATIVES OF NALTREXONE AND OXYMORPHONE [J].

SAYRE, LM ;

PORTOGHESE, PS .

JOURNAL OF ORGANIC CHEMISTRY, 1980, 45 (16) :3366-3368

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