- Highly selective aldose reductase inhibitors. II. Optimization of the aryl part of 3-(arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic acids
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Accumulation of intracellular sorbitol, the product of glucose reduction catalyzed by aldose reductase (AR) [EC 1.1.1.21], is thought to be the main culprit in the development of diabetic complications. A series of 3- arylalkyl-2,4,5-trioxoimidazolidine-1-acetic acids was prepared and tested for inhibitory activities towards AR and aldehyde reductase (ALR) [EC 1.1.1.2]. These derivatives showed strong inhibitory activity against AR without markedly inhibiting ALR. In particular, the compounds with 3- nitrophenyl, 4-chloro-3-nitrophenyl, and chloro-substituted benzothiazolyl groups as the aryl part showed powerful AR-inhibitory activity. The chloro- substituted benzothiazolyl compound showed an AR selectivity of more than 5000 fold.
- Kotani, Takayuki,Ishii, Akira,Nagaki, Yasuhiro,Toyomaki, Yoshio,Yago, Hisashi,Suehiro, Seishi,Okukado, Nobuhisa,Okamoto, Kaoru
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p. 297 - 304
(2007/10/03)
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- Process for preparing halomethyl thiazoles
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A process for the preparation of a compound of the formula wherein R1 is hydrogen or (C1-C4)alkyl, X is chloro or bromo and A represents a 6 membered carbocylic aromatic or a 5 or 6 membered heterocyclic ring which is optionally substituted by one of iodo or trifluoro-methylthio, or one or two of fluoro, chloro, bromo, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, or trifluoromethyl, comprising reacting haloacetonitrile with a compound of the formula wherein A is as defined above or a hydrohalide salt thereof. The compounds of the formula (I) are useful intermediates in the preparation of heterocyclic oxophthalazinyl acetic acids having aldose reductase inhibitory activity. Some of the compounds of the formula (I) are novel, and these also form a part of the invention.
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