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Generated: September 20, 2017

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Title: Nonapeptide and decapeptide derivatives of luteinizing hormone releasing hormone
Abstract:Nonapeptide and decapeptide analogs of LH-RH of the formula and the pharmaceutically acceptable salts thereof wherein: V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl; W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl; X is a D-amino acid residue ##STR1## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl; Z is glycinamide or --NH--R.sup.1, wherein R.sup.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR2## wherein R.sup.2 is hydrogen or lower alkyl, are disclosed. These compounds exhibit potent LH-RH agonist properties.
Inventor(s): Nestor; John J. (San Jose, CA), Jones; Gordon H. (Cupertino, CA), Vickery; Brian H. (Cupertino, CA)
Assignee: Syntex (U.S.A.) Inc. (Palo Alto, CA)
Application Number:06/047,661
Patent Claims: 1. A compound of the formula

and the pharmaceutically acceptable salts thereof wherein:

V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl;

W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl;

X is a D-amino acid residue ##STR9## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or

(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl;

Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl;

Z is glycinamide or --NH--R.sup.1, wherein R.sup.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR10## wherein R.sup.2 is hydrogen or lower alkyl.

2. The compound of claim 1 wherein V is tryptophyl or phenylalanyl; W is tyrosyl; X is 3-(2-naphthyl)-D-alanyl or 3-(2,4,6-trimethylphenyl)-D-alanyl; Y is leucyl or N-methyl-leucyl; and Z is glycin-amide or --NHEt.

3. The compound of claim 2 wherein X is 3-(2-naphthyl)-D-alanyl.

4. The compound of claim 2 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH.sub.2 and the pharmaceutically acceptable acid salts thereof.

5. The compound of claim 3 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-N-methyl-Leu-Arg-Pro-Gly -NH.sub.2 and the pharmaceutically acceptable salts thereof.

6. The compound of claim 3 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-Leu-Arg-Pro-NHEt and the pharmaceutically acceptable salts thereof.

7. The compound of claim 3 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-N-methyl-Leu-Arg-Pro-NHE t and the pharmaceutically acceptable salts thereof.

8. The compound of claim 3 which is (pyro)Glu-His-Phe-Ser-Syr-3-(2-naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH.sub.2 and the pharmaceutically acceptable salts thereof.

9. The compound of claim 2 wherein X is 3-(2,4,6-trimethylphenyl)-D-alanyl.

10. The compound of claim 9 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2,4,6-trimethylphenyl)-D-alanyl-Leu-Arg-Pro-G ly-NH.sub.2 and the pharmaceutically acceptable salts thereof.

11. A method of inhibiting ovulation in a female mammalian subject which method comprises administering to said subject an effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof wherein:

V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl;

W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl;

X is a D-amino acid residue ##STR11## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or

(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl;

Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl;

Z is glycinamide or --NH--R.sup.1, wherein

R.sup.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR12## wherein R.sup.2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.

12. A pharmaceutical composition for inhibition of ovulation and treating endometriosis in a female mammalian subject and treating benign prostatic hypertrophy and inhibiting spermatogenesis in a male mammalian subject comprising an effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof wherein:

V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl;

W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl;

X is a D-amino acid residue ##STR13## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or

(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl;

Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl;

Z is glycinamide or --NH--R.sup.1, wherein

R.sup.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR14## wherein R.sup.2 is hydrogen or lower alkyl, in admixture with a pharmaceutically acceptable non-toxic carrier.

13. A method of treating endometriosis in a female mammalian subject which method comprises administering to said subject an effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof wherein:

V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl;

W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl;

X is a D-amino acid residue ##STR15## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluoroenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or

(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl;

Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl;

Z is glycinamide or --NH--R.sup.1, wherein

R.sup.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR16## wherein R.sup.2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.

14. A method of treating benign prostatic hypertrophy in a male mammalian subject which method comprises administering to said subject an effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof wherein:

V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl;

W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl;

X is a D-amino acid residue ##STR17## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or

(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl;

Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl;

Z is glycinamide or --NH--R.sup.1, wherein

R.sup.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR18## wherein R.sup.2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.

15. A method of inhibiting spermatogenesis in a male mammalian subject which method comprises administering to said subject an effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof wherein:

V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl;

W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl;

X is a D-amino acid residue ##STR19## wherein R is (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or

(b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl;

Y is leucyl, isoleucyl, nor-leucyl or N-methyl-leucyl;

Z is glycinamide or --NH--R.sup.1, wherein

R.sup.1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR20## wherein R.sup.2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
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