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 has been generated by chiral synthesis from D- or L-aspartic acid. The use of variously substituted o-phenylenediamines for condensation with the beta-carboxyl function of alpha-benzyl N-(benzyloxycarbonyl)-D-aspartate has led to a series of amino acids of graded hydrophobicity with a steric bulk similar to that of tryptophan. In a similar fashion, we have prepared 3-(2-benzothiazolyl)-D-alanine from o-aminothiophenol and 3-(2-benzoxazolyl)-D-alanine from o-aminophenol. Incorporation of these amino acids into the 6-position of luteinizing hormone-releasing hormone (LH-RH) led to a series of very potent agonist analogues (up to 160 times LH-RH potency), active in doses ranging from 0.1 to 0.5 microgram by twice daily injection in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds.

Synthesis, Biological Evaluation, and Structure–Activity Relationships of Potent Noncovalent and Nonpeptidic Cruzain Inhibitors as Anti-Trypanosoma cruzi Agents

“…This transformation comprised the reduction of the nitro group with metallic iron in boiling acetic acid 31 and the concomitant cyclization of intermediate amines to the target compounds. 32 Following this one-pot strategy, C-substituted benzimidazoles 19M−19O were isolated in good yield and excellent purity. However, it should be noted that the hydrogen atom of the NH-group may move between both nitrogen atoms within the benzimidazole moiety.…”

“…32 Next, the effect of the N-substitution of the benzimidazole moiety on inhibitory activity was probed. Thus, the NH group of the benzimidazole system of a set of three selected compounds (8c, 8g, and 8l) was modified through N-alkylation or N-acylation, giving rise to compounds of type 22 (Scheme 5).…”

Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

“…Final Nterminal Boc deprotection with TFA and purification by preparative HPLC, gave compounds (1)(2)(3)(4)(5)(6). The intermediates (benzo [d]oxazol-2-yl)methanamine (H 2 N-CH 2 -Boa) and (benzo [d] thiazol-2-yl)methanamine (H 2 N-CH 2 -Bta) were prepared according to the procedure of Nestor et al 13 Mixed carbonic anhydride coupling of Z-Gly-OH with o-aminophenol gave the crude intermediate amide, which was converted without purification to the desired benzoxazole (Z-NH-CH 2 -Boa) by cyclization and dehydration in refluxing propionic acid (~140°C). Nterminal Z deprotection was accomplished by catalytic hydrogenation (H 2 ; Pd/C).…”

Hydrophobic, aza‐glycine analogues of luteinizing hormone‐releasing hormone

“…Side chain protection was as follows: Arg(Tos) (25), Tyr(2,6-Cl ,Bzl) (26), Ser(Bzl), Bia(Boc) (19), Dmb(Boc) (19). used on all amino acids except < Glu which was unprotected.…”

“…Side chain protection was as follows: Arg(Tos) (25), Tyr(2,6-Cl ,Bzl) (26), Ser(Bzl), Bia(Boc) (19), Dmb(Boc) (19). The unnatural Damino acids were prepared in optically pure form by chiral synthesis (Bia, Dmb) (19) or were resolved enzymatically (1 8) as described previously. All three crude nonapeptide acids were converted to the aza-Gly analogues and then purified by preparative reversed-phase high performance liquid chromatography (prepHPLC) (18,28), as described in Experimental Procedures.…”