LH-RH ANALOGUES

摘要

1535602 LHRH peptides ADMINISTRATORS OF THE TULANE UNIVERSITY EDUCATIONAL FUND 11 June 1976 [12 June 1975 (2) 27 Jan 1976] 24273/76 Heading C3H Peptides of Formula (I) wherein (i) X is Ser, Y is D-Trp, Z is Gly-NH 2 ; or (ii) X is Ser, Y is D-Phe, Z is Gly-NH 2 ; or (iii) X is D-Ser, Y is D-Leu, Z is NHR1 wherein R1 is C 1 -C 3 alkyl; and the non-toxic, pharmaceutically-acceptable salts thereof. The salt may be an acid addition salt, preferably of acetic acid, lactic acid, succinic acid, benzoic acid, salicylic acid, methanesulphonic acid, p - toluenesulphonic acid, hydrochloric acid, phosphoric acid, tannic acid or carboxymethylcellulose. Peptides of Formula (II) wherein (i) X1 is Ser(R6), Y is D-Trp, Z1 is Gly-R2; or (ii) X1 is Ser(R6), Y is D-Phe, Z1 is Gly-R2; or (iii) X1 is D-Ser(R6), Y is D-Leu, Z1 is OR3 wherein R2 is amino or O(C 1 -C 3 alkyl), R3 is C 1 -C 3 alkyl, R4, R5, R6, R7 are protective groups which may be eliminated without affecting the compounds of Formula (I), R8 is hydrogen or one of said protective groups. Peptides of Formula (III) R8-Pyroglu-His-Trp-D-Ser(R6)-Tyr(R5)-D-Leu- Leu-Arg(R4)-Pro-NHR1 wherein R1 is C 1 -C 3 alkyl. Peptides of Formula (IV) R8-Pyroglu-His(R7)-Trp-X1-Tyr(R5)-Y-Leu- Arg(R4)-Pro-Z2 wherein (i) X1 is Ser(R6), Y is D-Trp, Z2 is Gly-A; or (ii) X1 is Ser(R6), Y is D-Phe, Z2 is Gly-A; or (iii) X1 is D-Ser(R6), Y is D-Leu, Z2 is A1 wherein A is A1 is (Formula II as shown above) wherein # is phenyl and #1 is phenylene, R4 is preferably tosyl, nitro, benzyloxycarbonyl or adamantyloxycarbonyl wherein, if R4 is nitro or tosyl, protection is on one of the N#,N#1nitrogen atoms and, if R4 is benzyloxycarbonyl or adamantyloxycarbonyl, protection is on the N nitrogen atom and one of the N#,N#1- nitrogen atoms; R5 is preferably benzyl, 2. bromobenzyloxycarbonyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4- dichlorobenzyl or benzyloxycarbonyl; R7 is preferably tosyl or 2,4-dinitrophenyl; R8 is preferably t-butyloxycarbonyl, benzyloxycarbonyl, t-amyloxycarbonyl, cyclopentyloxycarbonyl or isobornyloxycarbonyl; R6 is preferably benzyl, 2-bromobenzyloxycarbonyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, 2,4-dichlorobenzyl, trityl or benzyloxycarbonyl. The peptides may be prepared by solid phase synthesis, preferably using chloromethylated, hydroxymethyl or benzhydrylamine resin. In the examples peptides prepared are: H - Pyroglu - His - Trp - Ser - Tyr - D - Trp- Leu - Arg - Pro - Gly - NH 2 ; H - Pyroglu - His- Trp - Ser - Tyr - D - Phe - Leu - Arg - Pro - Gly- NH 2 ; H - Pyroglu - His - Trp - D - Ser - DLeu - Leu - Arg - Pro - NHC 2 H 5 ; H - Pyroglu- His(Tos) - Ser(Bzl) - Tyr(2BrCbz) - D - Trp- Leu - Arg(Tos) - Pro - Gly - benzhydrylamine resin; H - Pyroglu - His(Tos) - Ser(Bzl) - Tyr- (2BrCbz) - D - Phe - Leu - Arg(Tos) - Pro - Glybenzhydrylamine resin; H - Pyroglu - His- (Dnp) - Trp - D - Ser(Bzl) - Tyr(2BrCbz) - DLeu - Leu - Arg(Tos) - Pro - OCH2 - resin support; H - Pyroglu - His - Trp - D - Ser(Bzl)- Tyr(2BrCbz) - D - Leu - Leu - Arg(Tos) - Pro- NHC 2 H 5 . Pharmaceutical compositions, which may be used to inhibit fertility in female mammals, preferably in unit doage form, comprise peptides (I), or a pharmaceutically-acceptable, non-toxic salt thereof, in admixture with a pharmaceutically-acceptable carrier.