79466-08-3

In order to minimize the deleterious effects of histamine release resulting from the administration to rats and humans of some potent gonadotropin-releasing hormone (GnRH) antagonists, various arginine residues were replaced with the less basic Nω-cyano-Nω'-alkyl- or -arylhomoarginine, -arginine, or -p-aminophenylalanine and Nω-triazolyllysine, -ornithine or -p-aminophenylalanine residues in active analogues.These novel analogues were synthesized on a solid-phase support via a two-step modification of the Nω-NH2 of lysine, ornithine, or p-aminophenylalanineresidues in otherwise protected resin bound peptides.Most analogues were tested in the rat antiovulatory assay (AOA) and three in vitro assays: a pituitary cell culture assay, a binding assay to pituitary cell membranes, and a histamine release assay.Introduction of the cyanoguanidino and Nω-triazolyl moieties into GnRH analogues yielded several water-soluble antagonists which showed a desirable therapeutic ratio (low histamine release activity to high in vivo potency).Among them, "Azaline" (10, 1,DCpa2,DPal3,Lys5(atz),DLys6(atz),ILys8,DAla10>GnRH), inhibited ovulation in the rat by 90percent at 2 μg/rat with an ED50 in the in vitro histamine release assay comparable to that of GnRH itself.

Glycyrrhizinic acid hydrolase produced by Aspergillus niger selectively hydrolyzed the 3-O-β-D-glucuronide linkage of glycyrrhizinic acid.The substrate specificity of this enzyme was investigated for synthetic glucuronides of aliphatic alcohols as well as natural glucuronide saponins.It was revealed that the glucuronide linkage with low molecular weight alcohols was not cleaved by this enzyme, while the 3-O-β-D-glucuronide linkage saponins of oleanolic acid was selectively hydrolyzed.It was also disclosed that both the 4-hydroxyl and carboxyl groups of the glucuronide moiety must be unsubstituted for hydrolysis by this enzyme.

A simple high yield synthesis of diphenyl cyanocarbonimidate is reported.This synthon may be used to prepare functionalized benzimidazoles, benzoxazoles and triazoles in good yield under mild conditions.