Sulfamylurea hypoglycemic agents. 6. High-potency derivatives

Synthetic methods for a series of novel sulfamylurea derivatives have been developed. The hypoglycemic activity of simple 1-piperidinosulfonylureas is greatly enhanced by attaching an acylaminoethyl function in the 4 position of the piperidine ring. Optimum activity is achieved when the acyl radical is 5-chloro-2-methoxybenzoyl, 2-methoxynicotinyl, 5-chloro-2-methoxynicotinyl, 1,2-dihydro-1-methyl-2-ketonicotinyl, 2,3-ethylenedioxybenzoyl, quinoline-8-carbonyl, or 6-chloroquinoline-8-carbonyl. Optimal substituents on the terminal urea nitrogen are cyclohexyl, bicycloheptenylmethyl, and in certain cases propyl, 7-oxabicycloheptanylmethyl, and adamantyl. One of these compounds (81, gliamilide) was found to be well tolerated in man and it displayed a very short plasma half-life.