[D-Trp6 ]-LH-RH and intermediates therefor

Claim 2

A compound of the formula R 6 -(Pyra)-Glu-His(N lm -R 5 )-Trp-Ser(R 4 )-Tyr(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-R 1 in which R 1 is amino or 0-(lower alkyl), R 2 is a protective group for the N.sup.δ , N.sup.ω , and N.sup.ω ' nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromobenzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichlorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; R 5 is a protective group for the imidazole nitrogen atoms of histidine selected from the group of dinitrophenyl, tosyl, 2,2,2-trifluoro-1-benzoyloxycarbonylaminoethyl and 2,2,2-trifluoro-t-butyloxycarbonylaminoethyl; and R 6 is hydrogen or an α-amino protective group selected from the group consisting of t-butyloxycarbonyl, benzyloxycarbonyl, cyclopentyloxycarbonyl, t-amyloxy-carbonyl and d-isobornyloxycarbonyl.

Claim 3

The compound of claim 1 in which R 1 is amino.

Claim 4

The compound of claim 1 wherein R 1 is amino, R 2 is tosyl, R 3 is 2-bromo-benzyloxycarbonyl, R 4 is benzyl, R 5 is tosyl and R 6 is hydrogen.

Claim 5

The compound which is L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycinamide, or a non-toxic, pharmaceutically acceptable addition salt thereof.

Claim 6

The compound which is L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycinamide, or a non-toxic, pharmaceutically acceptable addition salt thereof.

Claim 7

A compound selected from the group consisting of R 6 -(pyro)-Glu-His-(N lm -R 5 )-Trp-Ser(R 4 )-Tyr(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -His(N lm -R 5 )-Trp-Ser(R 4 )-Tyr-(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -Trp-Ser(R 4 )-tyr-(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -Ser(R 4 )-Tyr-(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -Tyr(R 3 )-D-Trp-Leu-Arg-(N G -R 2 )-Pro-Gly-A, and R 7 -D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, in which [R 2 , R 3 , R 4 and R 5 are protective groups capable of being removed by one or more chemical treatments which do not effect (pyro)-Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH 2 ,] R 2 is a protective group for the N.sup.σ , N.sup.ω , and N.sup.ω nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromo-benzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichlorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; R 5 is a protective group for the imidazole nitrogen atoms of histidine selected from the group of dinitrophenyl, tosyl, 2,2,2-trifluoro-1-benzoyloxycarbonylaminoethyl and 2,2,2-trifluoro-t-butyloxycarbonylaminoethyl; and R 6 is hydrogen or an α-amino protective group and R 7 is an α-amino protective group, and A is selected from the class consisting of: ##STR3##

Claim 8

A compound selected from the group consisting of R 6 -(pyro)-Glu-His-(N lm -R 5 )-Trp-Ser(R 4 )-Tyr(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -His(N lm -R 5 )-Trp-Ser(R 4 )-Tyr-(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -Trp-Ser(R 4 )-tyr-(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -Ser(R 4 )-Tyr-(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, R 7 -Tyr(R 3 )-D-Trp-Leu-Arg-(N G -R 2 )-Pro-Gly-A, and R 7 -D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A, in which [R 2 , R 3 , R 4 and R 5 are protective groups capable of being removed by one or more chemical treatments which do not effect (pyro)-Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH 2 ,] R 2 is a protective group for the N.sup.σ , N.sup.ω , and N.sup.ω nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromo-benzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichlorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; R 5 is a protective group for the imidazole nitrogen atoms of histidine selected from the group of dinitrophenyl, tosyl, 2,2,2-trifluoro-1-benzoyloxycarbonylaminoethyl and 2,2,2-trifluoro-t-butyloxycarbonylaminoethyl; and R 6 is hydrogen or an α-amino protective group and R 7 is an α-amino protective group, and A is selected from the class consisting of: ##STR3##

Claim 9

The compound according to claim 5 in which A is a benzhydrylamine resin.

Claim 10

The compound of claim 5 having the formula R 6 -(pyro)-Glu-His-(N lm -R 5 )-Trp-Ser(R 4 )-Tyr(R 3 )-D-Trp-Leu-Arg(N G -R 2 )-Pro-Gly-A in which R 2 is tosyl, R 3 is 2-bromo-benzyloxycarbonyl, R 4 is benzyl, R 5 is tosyl, R 6 is hydrogen and A is benzhydrylamine resin.