Synthesis of a novel class of heteroaromatic amino acids and their use in the preparation of analogs of luteinizing hormone-releasing hormone

Abstract

A novel class of heterocyclic aromatic amino acids based on the 3-(2-benzimidazolyl)alanine system was generated by chiral synthesis from D-or L-Asp. The use of variously substituted o-phenylenediamines for condensation with the .beta.-carboxyl function of .alpha.-benzyl N-(benzyloxycarbonyl)-D-aspartate led to a series of amino acids of graded hydrophobicity with a steric bulk similar to that of Trp. 3-(2-Benzothiazolyl)-D-alanine was similarly prepared from o-aminothiophenol and 3-(2-benzoxazolyl)-D-alanine from o-aminophenol. Incorporation of these amino acids into the 6-position of LHRH led to a series of very potent agonist analogs (up to 160 times LHRH potency), active in doses ranging from 0.1-0.5 .mu.g by twice daily injection in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds.