US4234571A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Nonapeptide and decapeptide derivatives of luteinizing hormone releasing hormone
Assignee: GD Searle LLC
•
Filing: 1979-06-11
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Granted: 1980-11-18
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Expires: 1999-06-11
Abstract
Abstract Nonapeptide and decapeptide analogs of LH-RH of the formula (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 <IMAGE> 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-R1, wherein R1 is lower alkyl, cycloalkyl, fluoro lower alkyl or <IMAGE> wherein R2 is hydrogen or lower alkyl, are disclosed. These compounds exhibit potent LH-RH agonist properties.
Inventors
- 👤 John J. Nestor
- 👤 Gordon H. Jones
- 👤 Brian H. Vickery
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 18:21
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/06; C07K7/23; A; A61; A61P; A61P5/00; A61K; A61K38/00; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/12; Y10S930/13
Claims Analysis
Total Claims: 21
Claim 1
Independent Claim
127 words
A compound of the formula (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR10## wherein R 2 is hydrogen or lower alkyl.
Claim 2
Dependent Claim
127 words
A compound of the formula (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR10## wherein R 2 is hydrogen or lower alkyl.
Claim 3
Dependent Claim
30 words
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.
Claim 4
Dependent Claim
9 words
The compound of claim 2 wherein X is 3-(2-naphthyl)-D-alanyl.
Claim 5
Dependent Claim
16 words
The compound of claim 2 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH 2 and the pharmaceutically acceptable acid salts thereof.
Claim 6
Dependent Claim
15 words
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 2 and the pharmaceutically acceptable salts thereof.
Claim 7
Dependent Claim
14 words
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.
Claim 8
Dependent Claim
14 words
The compound of claim 3 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-alanyl-N-methyl-Leu-Arg-Pro-NHEt and the pharmaceutically acceptable salts thereof.
Claim 9
Dependent Claim
15 words
The compound of claim 3 which is (pyro)Glu-His-Phe-Ser-Syr-3-(2-naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH 2 and the pharmaceutically acceptable salts thereof.
Claim 10
Dependent Claim
9 words
The compound of claim 2 wherein X is 3-(2,4,6-trimethylphenyl)-D-alanyl.
Claim 11
Dependent Claim
15 words
The compound of claim 9 which is (pyro)Glu-His-Trp-Ser-Tyr-3-(2,4,6-trimethylphenyl)-D-alanyl-Leu-Arg-Pro-Gly-NH 2 and the pharmaceutically acceptable salts thereof.
Claim 12
Independent Claim
154 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR12## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
Claim 13
Independent Claim
154 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR12## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
Claim 14
Dependent Claim
168 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR14## wherein R 2 is hydrogen or lower alkyl, in admixture with a pharmaceutically acceptable non-toxic carrier.
Claim 15
Dependent Claim
168 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR14## wherein R 2 is hydrogen or lower alkyl, in admixture with a pharmaceutically acceptable non-toxic carrier.
Claim 16
Independent Claim
154 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR16## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
Claim 17
Independent Claim
154 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR16## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
Claim 18
Independent Claim
156 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR18## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
Claim 19
Independent Claim
156 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR18## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
Claim 20
Independent Claim
154 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR20## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
Claim 21
Independent Claim
154 words
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 (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z (I) 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 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR20## wherein R 2 is hydrogen or lower alkyl, or a pharmaceutical composition containing same.
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| 3.5 Years (Year 4) | 1983-11-18 | 1984-05-19 | 1984-11-18 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1987-11-18 | 1988-05-19 | 1988-11-18 | $3760.00 | Window Closed / Lapsed |
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