Nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists, their preparation and compositions containing them

Abstract

Abstract Nonapeptide and decapeptide analogs of LHRH which have the formula and the pharmaceutically acceptable salts thereof, wherein: A is an amino acyl residue selected from the group consisting of L-pyroglutamyl, D-pyroglutamyl, N-acyl-D,L-tryptophanyl, N-acyl-glycyl, N-Ac-D,L-Δ 3,4 -prolyl, N-Ac-D,L-prolyl, N-Ac-L-alkylprolyl, N-Ac-D,L-phenylalanyl, N-Ac-D,L-p-chlorophenylalanyl, N-Ac-D,L-seryl, N-Ac-D,L-threonyl, N-Ac-D,L-alanyl, 3-(1-naphthyl)-D,L-alanyl, 3-(2-naphthyl)-D,L-alanyl, 3-(2,4,6-trimethylphenyl)-D,L-alanyl, 3-(4-trifluoromethylphenyl)-D,L-alanyl, 3-(9-anthryl)-D,L-alanyl, 3-(2-fluorenyl)-D,L-alanyl, and 3-(Het)-D,L-alanyl wherein Het is a heterocyclic aryl containing radical selected from wherein A" and A' are independently selected from the group consisting of hydrogen, lower alkyl, chlorine and bromine, and G is selected from the group consisting of oxygen, nitrogen and sulfur; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-Cl-phenylalanyl, D-p-F-phenylalanyl, D-p-nitrophenylalanyl, 3-(3,4,5-trimethoxyphenyl)-D-alanyl, 2,2-diphenylglycine, D-a-methyl-p-Cl-phenylalanine and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from the group consisting of L-tryptophanyl, D-tryptophanyl, D-phenylalanyl, D-Me s phenylalanyl, 3-(2-pyridyl)-D-alanyl, 3-(3-pyridyl)D-alanyl, 3-(1-naphthyl)-D-alanyl, 3-(2-naphthyl)-D-alanyl and 3-(4-pyridyl)-D-alanyl. D is an amino acyl residue selected from the group consisting of L-seryl, and D-alanyl; E is an amino acyl residue selected from the group consisting of L-phenylalanyl and L-tyrosyl; F is an amino acyl selected from the group consisting of the radicals represented by the following structural formulas: wherein n is 1 to 5 ; R, is alkyl of 1 to 12 carbon atoms, -NRR 3 wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R 3 is alkyl of 1 to 12 carbon atoms, cycloalkyl, phenyl, benzyl, -(CH 2 ) n -morpholino or -(CH 2 ) n N(R 4 ) 2 wherein n is 1 to 5 and R 4 is lower alkyl; R 2 is hydrogen or R 3 ; or R, and R 2 comprise a ring represented by the following structural formulas: wherein n is 1 to 7; A is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl; and X is halo or A or b) H 2 N-CH-CO 2 H wherein R 5 is alkyl of 1 to 6 carbon atoms, benzyl, phenylethyl, cyclohexyl, cyclopentyl; and R 6 , R 7 and R 8 are hydrogen or alkyl of 1 to 4 carbon atoms; and n is the integer 2-5; or C) a substituent of the formula wherein R 9 is hydrogen, alkyl of 1 to 12 carbon atoms, phenyl or phenylloweralkyl; G is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl and L-norvatyl; H is D-alaninamide, D-leucinamide, glycinamide or -NHR 5 wherein R 5 is lower alkyl, cycloalkyl, fluoro lower alkyl, or NHCONH-R 10 wherein R, o is hydrogen or lower alkyl; and the pharmaceutically acceptables salts thereof.

Inventors

• 👤 John J. Nestor
• 👤 Brian H. Vickery

Bibliographic Details