EP0182262A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Nona and decapeptide analogs of LHRH useful as LHRH antagonists
Assignee: Syntex USA LLC
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Filing: 1985-11-12
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Granted: —
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Expires: 2005-11-12
Abstract
Abstract Synthetic nonapeptide and decapeptide LHRH antagonist analogs having a halo lower alkyl guanadino-substituted amino acyl residue at position six are disclosed herein.
Inventors
- 👤 John Joseph Nestor
- 👤 Brian Henry Vickery
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-01 20:56
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/23; A; A61; A61P; A61P13/00; A61P13/02; A61P15/00; A61P43/00; A61K; A61K38/00; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/13
Claims Analysis
Total Claims: 18
Claim 1
Independent Claim
176 words
A compound of the formula and the pharmaceutically acceptable salts thereof, wherein: A is an amino acyl residue selected from 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 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-a-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from 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 L-seryl, and D-alanyl; E is an amino acyl residue selected from L-phenylalanyl and L-tyrosyl; F is an amino acyl selected from the radicals represented by the following structural formulas: wherein n is 1 to 5; R 1 is halo lower alkyl; R 2 is hydrogen, methyl or ethyl; R 3 is R 1 , methyl, ethyl or -CH 2 CH 2 0H; G is an amino acyl residue selected from L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; H is D-alaninamide, D-leucinamide, glycinamide or -NHR 5 wherein R 5 is lower alkyl or NHCONH 2 ; or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
176 words
A compound of the formula and the pharmaceutically acceptable salts thereof, wherein: A is an amino acyl residue selected from 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 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-a-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from 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 L-seryl, and D-alanyl; E is an amino acyl residue selected from L-phenylalanyl and L-tyrosyl; F is an amino acyl selected from the radicals represented by the following structural formulas: wherein n is 1 to 5; R 1 is halo lower alkyl; R 2 is hydrogen, methyl or ethyl; R 3 is R 1 , methyl, ethyl or -CH 2 CH 2 0H; G is an amino acyl residue selected from L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; H is D-alaninamide, D-leucinamide, glycinamide or -NHR 5 wherein R 5 is lower alkyl or NHCONH 2 ; or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
176 words
A compound of the formula and the pharmaceutically acceptable salts thereof, wherein: A is an amino acyl residue selected from 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, 3-(1-naphthyl)-D,L-alanyl, 3-(2-naphthyl)-D,L-alanyl, 3-(2,4,6-trimethylphenyl)-D,L-alanyl, and 3-(4-trifluoromethylphenyl)-D,L-alanyl; B is an amino acyl residue selected from 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-a-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from D-tryptophanyl, D-phenylalanyl, D-pentamethyl-phenylalanyl, 3-(3-pyridyl)-D-alanyl, 3-(l-naphthyl)-D-alanyl, and 3-(2-naphthyl)-D-alanyl; D is an amino acyl residue selected from L-seryl, and D-alanyl; E is an amino acyl residue selected from L-phenylalanyl and L-tyrosyl; F is an amino acyl selected from the radicals represented by the following structural formulas: wherein n is 1 to 5; R 1 is halo lower alkyl; R 2 is hydrogen, methyl or ethyl; R 3 is R 1 , methyl, ethyl or -CH 2 CH 2 OH; G is an amino acyl residue selected from L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; H is D-alaninamide, D-leucinamide, glycinamide or - NHR5 wherein R 5 is lower alkyl or NHCONH 2 ; or a pharmaceutically acceptable salt thereof.
Claim 4
Dependent Claim
176 words
A compound of the formula and the pharmaceutically acceptable salts thereof, wherein: A is an amino acyl residue selected from 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, 3-(1-naphthyl)-D,L-alanyl, 3-(2-naphthyl)-D,L-alanyl, 3-(2,4,6-trimethylphenyl)-D,L-alanyl, and 3-(4-trifluoromethylphenyl)-D,L-alanyl; B is an amino acyl residue selected from 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-a-methyl-p-Cl-phenylalanyl and 3-(2,4,6-trimethylphenyl)-D-alanyl; C is an amino acyl residue selected from D-tryptophanyl, D-phenylalanyl, D-pentamethyl-phenylalanyl, 3-(3-pyridyl)-D-alanyl, 3-(l-naphthyl)-D-alanyl, and 3-(2-naphthyl)-D-alanyl; D is an amino acyl residue selected from L-seryl, and D-alanyl; E is an amino acyl residue selected from L-phenylalanyl and L-tyrosyl; F is an amino acyl selected from the radicals represented by the following structural formulas: wherein n is 1 to 5; R 1 is halo lower alkyl; R 2 is hydrogen, methyl or ethyl; R 3 is R 1 , methyl, ethyl or -CH 2 CH 2 OH; G is an amino acyl residue selected from L-leucyl, L-norleucyl, L-tryptophanyl, L-Nal(2) and L-norvalyl; H is D-alaninamide, D-leucinamide, glycinamide or - NHR5 wherein R 5 is lower alkyl or NHCONH 2 ; or a pharmaceutically acceptable salt thereof.
Claim 5
Dependent Claim
13 words
The compound of claim 1 or 2 wherein n is 3 or 4.
Claim 6
Dependent Claim
15 words
The compound of claim 3 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 7
Dependent Claim
15 words
The compound of claim 3 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 8
Dependent Claim
15 words
The compound of claim 3 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 9
Dependent Claim
15 words
The compound of claim 3 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-mPfh-Nal(2)-Arg-Pro-D-AlaNH 2 or a pharmaceutically acceptable salt thereof.
Claim 10
Dependent Claim
16 words
The compound of Claim 3 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-mPfh-Leu-Arg-Pro-D -AlaNH 2 or a pharmaceutically acceptable salt thereof.
Claim 11
Dependent Claim
15 words
The compound of Claim 3 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Pal(3)-Ser-Tyr-D-FDeh-L-Leu-Arg-Pro-D-AlaNH 2 or a pharmaceutically acceptable salt thereof.
Claim 12
Dependent Claim
15 words
The compound of Claim 3 which is N-Ac-D-Nal(2)-D-p-Cl-Phe-D-Pal(3)-Ser-Tyr-D-FDeh-L-Trp-Arg-Pro-D-AlaNH 2 or a pharmaceutically acceptable salt thereof.
Claim 13
Dependent Claim
24 words
A pharmaceutical composition comprising a compound of any one of the Claims 1 to 10 in admixture with at least one pharmaceutically acceptable excipient.
Claim 14
Dependent Claim
14 words
A compound according to Claims 1 to 10 for use as a LHRH antagonist.
Claim 15
Dependent Claim
19 words
The use of a compound according to Claims 1 to 10 for preparing a medicament having LHRH antagonist activity.
Claim 16
Dependent Claim
101 words
A process for'preparing a compound according to Claim 1 or 2 which process comprises removing protecting groups and, optionally, covalently bound solid support from a protected polypeptide to afford a compound of Formula (I) or a salt thereof; or coupling together in the required sequence two fragments of the desired compound of formula (I); or (a) converting a compound of Formula (I) to a pharmaceutically acceptable salt, or (b) converting a salt of a compound of Formula (I) to a pharmaceutically acceptable salt, or (c) converting a salt of a compound of Formula (I) to a free polypeptide of Formula (I).
Claim 17
Dependent Claim
39 words
A compound of formula (II): wherein n is 1 or 5; R 1 is halo lower alkyl; R 2 is hydrogen, methyl or ethyl; and R 3 is R 1 , methyl, ethyl or -CH 2 CH 2 0H.
Claim 18
Dependent Claim
39 words
A compound of formula (II): wherein n is 1 or 5; R 1 is halo lower alkyl; R 2 is hydrogen, methyl or ethyl; and R 3 is R 1 , methyl, ethyl or -CH 2 CH 2 0H.
References Cited (Backward Citations)
No citation records indexed.
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