Nona and decapeptide analogs of LHRH useful as LHRH antagonists

Claim 2

A compound of the formula ##STR7## or a pharmaceutically acceptable salt thereof, wherein: A is an amino acyl residue selected from the group consisting of 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-Cl-phenylalanyl, N-Ac-D,L-seryl, N-Ac-D,L-threonyl, N-Ac-D,L-alanyl, N-Ac-3-(1-naphthyl)-D,L-alanyl, N-Ac-3-(2-naphthyl)-D,L-alanyl, N-Ac-3-(2,4,6-trimethylphenyl)-D,L-alanyl, and N-Ac-3-(4-trifluoromethylphenyl)-D,L-alanyl; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-Cl-phenylalanyl, D-p-Br-phenylalanyl, D-p-F-phenylalanyl, D-p-nitrophenylalanyl, 3-(3,4,5-trimethoxyphenyl)-D-alanyl, 2,2-diphenylglycine, D-α-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from the group consisting of D-tryptophanyl, D-phenylalanyl, D-pentamethyl-phenylalanyl, 3-(3-pyridyl)-D-alanyl, 3-(1-naphthyl)-D-alanyl, and 3-(2-naphthyl)-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 residue selected from the group consisting of the radicals represented by the following structural formula: ##STR8## wherein n is 1 to 5; R 1 is lower alkyl substituted with one to three halo atoms; R 2 is hydrogen; R 3 is R 1 , methyl, ethyl or --CH 2 CH 2 OH; G is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; and H is D-alaninamide, D-leucinamide, glycinamide or --NHR 5 wherein R 5 is lower alkyl or NHCONH 2 .

Claim 3

The compound of claim 1 wherein n is 3 or 4.

Claim 4

The compound of claim 2 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-FDeh-Leu-Arg-Pro-D-AlaNH 2 or a pharmaceutically acceptable salt thereof.

Claim 5

The compound of claim 2 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-FDeh-Trp-Arg-Pro-D-AlaNH 2 or a pharmaceutically acceptable salt thereof.

Claim 6

The compound of claim 2 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-FDeh-Nal(2)-Arg-Pro-D-AlaNH 2 or a pharmaceutically acceptable salt thereof.

Claim 7

The compound of claim 2 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-mfph-Nal(2)-Arg-Pro-D-AlaNH 2 or a pharmaceutically acceptable salt thereof.

Claim 8

A compound of the formula ##STR9## or a pharmaceutically acceptable salt thereof, wherein: A is an amino acyl residue selected from the group consisting of 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-Cl-phenylalanyl, N-Ac-D,L-seryl, N-Ac-D,L-threonyl, N-Ac-D,L-alanyl, N-Ac-3-(1-naphthyl)-D,L-alanyl, N-Ac-3-(2-naphthyl)-D,L-alanyl, N-Ac-3-(2,4,6-trimethylphenyl)-D,L-alanyl, and N-Ac-3-(4-trifluoromethylphenyl)-D,L-alanyl; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-Cl-phenylalanyl, D-p-Br-phenylalanyl, D-p-F-phenylalanyl, D-p-nitrophenylalanyl, 3-(3,4,5-trimethoxyphenyl)-D-alanyl, 2,2-diphenylglycine, D-α-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from the group consisting of D-tryptophanyl, D-phenylalanyl, D-pentamethyl-phenylalanyl, 3-(3-pyridyl)-D-alanyl, 3-(1-naphthyl)-D-alanyl, and 3-(2-naphthyl)-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 residue selected from the group consisting of the radicals represented by the following structural formula: ##STR10## wherein n is 1 to 5; R 1 is lower alkyl substituted with one to three fluoro atoms; R 2 is hydrogen; R 3 is R 1 , methyl, ethyl or --CH 2 CH 2 OH; G is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; and H is D-alaninamide, D-leucinamide, glycinamide or --NHR 5 wherein R 5 is lower alkyl or NHCONH 2 .

Claim 9

A compound of the formula ##STR9## or a pharmaceutically acceptable salt thereof, wherein: A is an amino acyl residue selected from the group consisting of 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-Cl-phenylalanyl, N-Ac-D,L-seryl, N-Ac-D,L-threonyl, N-Ac-D,L-alanyl, N-Ac-3-(1-naphthyl)-D,L-alanyl, N-Ac-3-(2-naphthyl)-D,L-alanyl, N-Ac-3-(2,4,6-trimethylphenyl)-D,L-alanyl, and N-Ac-3-(4-trifluoromethylphenyl)-D,L-alanyl; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-Cl-phenylalanyl, D-p-Br-phenylalanyl, D-p-F-phenylalanyl, D-p-nitrophenylalanyl, 3-(3,4,5-trimethoxyphenyl)-D-alanyl, 2,2-diphenylglycine, D-α-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from the group consisting of D-tryptophanyl, D-phenylalanyl, D-pentamethyl-phenylalanyl, 3-(3-pyridyl)-D-alanyl, 3-(1-naphthyl)-D-alanyl, and 3-(2-naphthyl)-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 residue selected from the group consisting of the radicals represented by the following structural formula: ##STR10## wherein n is 1 to 5; R 1 is lower alkyl substituted with one to three fluoro atoms; R 2 is hydrogen; R 3 is R 1 , methyl, ethyl or --CH 2 CH 2 OH; G is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; and H is D-alaninamide, D-leucinamide, glycinamide or --NHR 5 wherein R 5 is lower alkyl or NHCONH 2 .

Claim 10

A compound of claim 7 wherein the one to three fluoro atoms substituted on the lower alkyl group of R 1 are on the ω-carbon of said lower alkyl group.

Claim 11

A compound of the formula ##STR11## or a pharmaceutically acceptable salt thereof, wherein: A is an amino acyl residue selected from the group consisting of 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-Cl-phenylalanyl, N-Ac-D,L-seryl, N-Ac-D,L-threonyl, N-Ac-D,L-alanyl, N-Ac-3-(1-naphthyl)-D,L-alanyl, N-Ac-3-(2-naphthyl)-D,L-alanyl, N-Ac-3-(2,4,6-trimethylphenyl)-D,L-alanyl, and N-Ac-3-(4-trifluoromethylphenyl)-D,L-alanyl; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-Cl-phenylalanyl, D-p-Br-phenylalanyl, D-p-F-phenylalanyl, D-p-nitrophenylalanyl, 3-(3,4,5-trimethoxyphenyl)-D-alanyl, 2,2-diphenylglycine, D-α-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from the group consisting of D-tryptophanyl, D-phenylalanyl, D-pentamethyl-phenylalanyl, 3-(3-pyridyl)-D-alanyl, 3-(1-naphthyl)-D-alanyl, and 3-(2-naphthyl)-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 residue selected from the group consisting of the radicals represented by the following structural formula: ##STR12## wherein n is 1 to 5; R 1 is trifluoroethyl; R 2 is hydrogen; R 3 is trifluoroethyl; G is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; and H is D-alaninamide, D-leucinamide, glycinamide or --NHR 5 wherein R 5 is lower alkyl or NHCONH 2 .

Claim 12

A compound of the formula ##STR11## or a pharmaceutically acceptable salt thereof, wherein: A is an amino acyl residue selected from the group consisting of 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-Cl-phenylalanyl, N-Ac-D,L-seryl, N-Ac-D,L-threonyl, N-Ac-D,L-alanyl, N-Ac-3-(1-naphthyl)-D,L-alanyl, N-Ac-3-(2-naphthyl)-D,L-alanyl, N-Ac-3-(2,4,6-trimethylphenyl)-D,L-alanyl, and N-Ac-3-(4-trifluoromethylphenyl)-D,L-alanyl; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-Cl-phenylalanyl, D-p-Br-phenylalanyl, D-p-F-phenylalanyl, D-p-nitrophenylalanyl, 3-(3,4,5-trimethoxyphenyl)-D-alanyl, 2,2-diphenylglycine, D-α-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from the group consisting of D-tryptophanyl, D-phenylalanyl, D-pentamethyl-phenylalanyl, 3-(3-pyridyl)-D-alanyl, 3-(1-naphthyl)-D-alanyl, and 3-(2-naphthyl)-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 residue selected from the group consisting of the radicals represented by the following structural formula: ##STR12## wherein n is 1 to 5; R 1 is trifluoroethyl; R 2 is hydrogen; R 3 is trifluoroethyl; G is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; and H is D-alaninamide, D-leucinamide, glycinamide or --NHR 5 wherein R 5 is lower alkyl or NHCONH 2 .

Claim 13

A compound of claim 9 wherein the three fluoro atoms substituted on the ethyl group of R 1 are on the ω-carbon of said ethyl group.

Claim 14

A pharmaceutical composition for use as a LHRH antagonist comprising a therapeutically effective amount of a compound of claim 1 in admixture with at least one pharmaceutically acceptable excipient.

Claim 15

A method for treating endometriosis in a female subject, said method comprising administering to said subject, a therapeutically effective amount of a compound of claim 1.

Claim 16

A method for treating endometriosis in a female subject, said method comprising administering to said subject, a therapeutically effective amount of a compound of claim 3.