92740-47-1

Reaction of alkyl/arylsulfonyl halides with glycine afforded a series of derivatives which were first N-benzylated by treatment with benzyl chloride, and then converted to the corresponding hydroxamic acids with hydroxylamine in the presence of carbodiimide derivatives. Other derivatives were obtained by reaction of N-benzyl-glycine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by conversion of their COOH group into the CONHOH moiety, as mentioned above. The 90 new compounds reported here were assayed as inhibitors of the Clostridium histolyticum collagenase (EC 3.4.24.3), a zinc enzyme which degrades triple helical regions of native collagen. The prepared hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of synthesized hydroxamates, substitution patterns leading to the best inhibitors were those involving perfluoroalkylsulfonyl- and substituted- arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4- carboxyphenylsulfonyl-, 3-trifluoromethyl-phenylsulfonyl or 1- and 2-naphthyl among others. Thus, it seems that similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, Clostridium histolyticum collagenase inhibitors should incorporate hydrophobic moieties at the P1, and P2, sites, whereas the α-carbon substituent may be a small and compact moiety (such as H. for the Gly derivatives reported here). Such compounds might lead to the design of collagenase inhibitor-based drugs useful as anti-cancer, anti-arthritis or anti-bacterial agents for the treatment of corneal keratitis. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Accumulation of intracellular sorbitol, formed from glucose by aldose reductase, is believed to play an important role in the development of certain chronic complications of diabetes mellitus.Several 1-(naphthalenylsulfonyl)hydantoins inhibit aldose reductase isolated from bovine lens in vitro, and decrease galactitol formation in sciatic nerves of galactosemic rats in vivo.The 5-bromo analogue (entry 12, table I) was found to be the most orally active aldose reductase inhibitor of this series with an ED50 value of 8.1 mg/kg po.The 1-(naphthalenylsulfonyl)-2-thiohydantoin analogues with the exception of entry 11 (table I) which showed good in vivo activity, were either inactive or had only marginal activity.

Disclosed herein are naphthalenylsulfonylimidazolidinediones and their thioxo analogs and methods for their preparation. The compounds are new aldose reductase inhibitors useful for the treatment or prevention of diabetic complications.

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