US4419347A
Expired / Lapsed
US
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Nonapeptide and decapeptide analogs of LHRH, useful as LHRH antagonists
Assignee: Syntex USA LLC
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Filing: 1982-04-08
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Granted: 1983-12-06
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Expires: 2002-04-08
Abstract
Abstract Nonapeptide and decapeptide analogs of LHRH which have the formula <IMAGE> (I) and the pharmaceutically acceptable salts thereof, wherein: X is a D-alanyl residue wherein one hydrogen on C-3 is replaced by: (a) a carbocyclic aryl-containing radical selected from the group consisting of phenyl substituted with three or more straight chain lower alkyl groups, naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl and benzhydryl; 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; or (c) a heterocyclic aryl containing radical selected from the group consisting of radicals represented by the following structural formulas: <IMAGE> <IMAGE> <IMAGE> wherein A'' and A' are independently selected from the group consisting of hydrogen, lower alkyl, chlorine, and bromine, and G is selected from the group consisting of oxygen, nitrogen, and sulfur; A is an aminoacyl residue selected from the group consisting of L-pyroglutamyl, D-pyroglutamyl, N-acyl-L-prolyl, N-acyl-D-prolyl, N-acyl-D-tryptophanyl, N-acyl-D-phenylalanyl, N-acyl-D-p-halophenylalanyl, and N-acyl-X wherein X is as defined previously; B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-halophenylalanyl, 2,2-diphenylglycyl, and X wherein X is as defined previously; C is an amino acyl residue selected from the group consisting of L-tryptophanyl, D-tryptophanyl, D-phenylalanyl and X wherein X is as defined above; E 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 are LHRH antagonists.
Inventors
- 👤 John J. Nestor
- 👤 Gordon H. Jones
- 👤 Brian H. Vickery
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-03 23:06
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/23; A; A61; A61K; A61K38/00; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/13
Claims Analysis
Total Claims: 29
Claim 1
Independent Claim
219 words
A compound of the formula A--B--C--Ser--Tyr--X--Leu--Arg--Pro--E ( I) and the pharmaceutically acceptable salts thereof, wherein: X is a D-alanyl residue wherein one hydrogen on C-3 is replaced by: (a) a carbocyclic aryl-containing radical selected from the group consisting of phenyl substituted with three or more straight chain lower alkyl groups, naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl and benzhydryl; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl sustituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2, 2-diphenylmethyl, and adamantyl; or (c) a heterocyclic aryl containing radical selected from the group consisting of radicals represented by the following structural formulas: ##STR15## wherein A" and A' are independently selected from the group consisting of hydrogen, lower alkyl, chlorine, and bromine, and G is selected from the group consisting of oxygen, nitrogen, and sulfur; A is an aminoacyl residue selected from the group consisting of L-pyroglutamyl, D-pyroglutamyl, N-acyl-L-prolyl, N-acyl-D-prolyl, N-acyl-D-tryptophanyl, N-acyl-D-phenylalanyl, N-acyl-D-p-halophenylalanyl, and N-acyl-X, wherein X is as defined previously; B is a D-p-halophenylalanyl residue; C is an amino acyl residue selected from the group consisting of L-tryptophanyl, D-tryptophanyl, D-phenylalanyl and X wherein X is as defined above; E 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.
Claim 2
Dependent Claim
219 words
A compound of the formula A--B--C--Ser--Tyr--X--Leu--Arg--Pro--E ( I) and the pharmaceutically acceptable salts thereof, wherein: X is a D-alanyl residue wherein one hydrogen on C-3 is replaced by: (a) a carbocyclic aryl-containing radical selected from the group consisting of phenyl substituted with three or more straight chain lower alkyl groups, naphthyl, anthryl, fluorenyl, phenanthryl, biphenylyl and benzhydryl; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl sustituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2, 2-diphenylmethyl, and adamantyl; or (c) a heterocyclic aryl containing radical selected from the group consisting of radicals represented by the following structural formulas: ##STR15## wherein A" and A' are independently selected from the group consisting of hydrogen, lower alkyl, chlorine, and bromine, and G is selected from the group consisting of oxygen, nitrogen, and sulfur; A is an aminoacyl residue selected from the group consisting of L-pyroglutamyl, D-pyroglutamyl, N-acyl-L-prolyl, N-acyl-D-prolyl, N-acyl-D-tryptophanyl, N-acyl-D-phenylalanyl, N-acyl-D-p-halophenylalanyl, and N-acyl-X, wherein X is as defined previously; B is a D-p-halophenylalanyl residue; C is an amino acyl residue selected from the group consisting of L-tryptophanyl, D-tryptophanyl, D-phenylalanyl and X wherein X is as defined above; E 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.
Claim 3
Dependent Claim
98 words
The compound of claim 1, and the pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of L-( pyro)Glu, D-( pyro)Glu, NAc-D-Phe, NAc-D-Nal(1), NAc-D-Nal(2), NAc-D-p-halo-Phe, NAc-D-Me5Phe, NAc-D-TMP, NAc-D-BIA, NAc-D-TBA, and NAc-L-Pro; B is D-p-F-Phe; C is selected from the group consisting of L-Trp, D-Trp, D-Phe, D-Nal(1), D-Nal(2), D-p-halo-Phe, D-Me5Phe, D-TMP, D-BIA and D-TBA; X is selected from the group consisting of D-Nal(1), D-Nal(2), D-p-halo-Phe, D-Me5Phe, D-TMP, D-BIA and D-TBA; and E is glycinamide or --NH-R, wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR17## wherein R 2 is hydrogen or lower alkyl.
Claim 4
Dependent Claim
17 words
The compound of claim 2 and the pharmaceutically acceptable acid addition salts thereof, wherein: X is D-Nal(2).
Claim 5
Dependent Claim
30 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-Pro, C is D-Nal(2), and E is Gly-NH 2 , i.e. NAc-Pro-D-p-F-Phe-D-Nal(2)-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-GlyNH 2 .
Claim 6
Dependent Claim
26 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-Pro, C is D-Nal(2), and E is ProNHEt, i.e. NAc-Pro-D-p-F-Phe-D-Nal(2)-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-ProNHEt.
Claim 7
Dependent Claim
30 words
The compount of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-Pro, C is D-Nal(2) and E is AzaGlyNH 2 , i.e. NAc-Pro-D-p-F-Phe-D-Nal(2)-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-AzaGlyNH 2 .
Claim 8
Dependent Claim
30 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-D-Nal(2), C is D-Nal(2) and E is GlyNH 2 , i.e. NAc-D-Nal(2)-D-p-F-Phe-D-Nal(2)-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-GlyNH 2 .
Claim 9
Dependent Claim
26 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-D-Nal(2), C is D-Nal(2) and E is ProNHEt, i.e. NAc-D-Nal(2)-D-p-F-Phe-D-Nal(2)-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-ProNHEt.
Claim 10
Dependent Claim
28 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-D-Nal(2), C is D-Nal(2) and E is AzaGlyNH 2 , i.e., NAc-D-Nal(2)-D-p-F-Phe-D-Nal(2)-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-AzaGlyNH.sub.
Claim 11
Dependent Claim
30 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-Pro, C is L-Trp and E is GlyNH 2 , i.e., NAc-Pro-D-p-F-Phe-L-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-GlyNH 2 .
Claim 12
Dependent Claim
31 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc- Pro, C is L-Trp and E is AzaGlyNH 2 , i.e., NAc-Pro-D-p-F-Phe-L-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-AzaGlyNH 2 .
Claim 13
Dependent Claim
30 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-D-Nal(2), C is L-Trp and E is GlyNH 2 , i.e., NAc-D-Nal(2)-D-p-F-Phe-L-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-GlyNH 2 .
Claim 14
Dependent Claim
28 words
The compound of claim 3 and the pharmaceutically acceptable acid addition salts thereof, wherein: A is NAc-D-Nal(2), C is L-Trp and E is AzaGlyNH 2 , i.e., NAc-D-Nal(2)-D-p-F-Phe-L-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-AzaGlyNH.
Claim 15
Dependent Claim
31 words
The compound of claim 1 and the pharmaceutically acceptable salts thereof, wherein A is NAc-L-Pro, B is D-p-Cl-Phe, C is D-Trp, and E is AzaGlyNH 2 , i.e., NAc-L-Pro-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-AzaGlyNH 2 .
Claim 16
Dependent Claim
31 words
The compound of claim 1 and the pharmaceuticaly acceptable salts thereof, wherein A is NAc-L-Pro, B is D-p-Cl-Phe, C is D-Trp, and E is GlyNH 2 , i.e., NAc-L-Pro-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-GlyNH 2 .
Claim 17
Dependent Claim
28 words
The compound of claim 1 and the pharmaceutically acceptable addition salts thereof wherein A is NAc-L-Pro, B is D-p-Cl-Phe, C is D-Trp and E is PronNHEt, i.e., NAc-L-Pro-D-p-Cl-Phe-Pro-D-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-ProNHEt.
Claim 18
Dependent Claim
31 words
The compound of claim 1 and the pharmaceutically acceptable salts thereof, wherein A is NAc-L-Pro, B is D-p-Cl-Phe, C is D-Trp, and E is AzaGlyNH 2 , i.e., NAc-L-Pro-D-p-Cl-Phe-D-Trp-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-AzaGlyNH 2 .
Claim 19
Dependent Claim
34 words
The compound of claim 2 and the pharmaceutically acceptable salts thereof wherein A is NAc-Pro, B is D-p-F-Phe, C is D-Phe, X is Nal(2) and E is GlyNH 2 , i.e. NAc-Pro-D-p-F-Phe-D-Phe-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-GlyNH 2 .
Claim 20
Dependent Claim
34 words
The compound of claim 2 and the pharmaceutically acceptable salts thereof wherein A is NAc-Pro, B is D-p-F-Phe, C is D-Phe, X is Nal(2) and E is AzaGlyNH 2 , i.e. NAc-Pro-D-p-F-Phe-D-Phe-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-AzaGlyNH 2 .
Claim 21
Dependent Claim
30 words
The compound of claim 2 and the pharmaceutically acceptable salts thereof wherein A is NAc-Pro, B is D-p-F-Phe, C is D-Phe, X is Nal(2) and E is ProNHEt, i.e., NAc-Pro-D-p-F-Phe-D-Phe-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-ProNHEt.
Claim 22
Dependent Claim
34 words
The compound of claim 1 and the pharmaceutically acceptable salts thereof wherein A is NAc-Pro, B is D-p-Cl-Phe, C is D-Phe, X is Nal(2) and E is GlyNH 2 , i.e. NAc-Pro-D-p-Cl-Phe-D-Phe-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-GlyNH 2 .
Claim 23
Dependent Claim
34 words
The compound of claim 1 and the pharmaceutically acceptable salts thereof wherein A is NAc-Pro, B is D-p-Cl-Phe, C is D-Phe, X is Nal(2) and E is AzaGlyNH 2 , i.e. NAc-Pro-D-p-Cl-Phe-D-Phe-Ser-Tyr-D-Nal(2)-Leu-ArgPro-AzaGlyNH 2 .
Claim 24
Dependent Claim
30 words
The compound of claim 1 and the pharmaceutically acceptable salts thereof wherein A is NAc-Pro, B is D-p-Cl-Phe, C is D-Phe, X is Nal(2) and E is ProNHEt, i.e., NAc-Pro-D-p-Cl-Phe-D-Phe-Ser-Tyr-D-Nal(2)-Leu-Arg-Pro-ProNHEt.
Claim 25
Dependent Claim
32 words
A method of inhibiting ovulation in a female mammalian subject, which method comprises administering to said subject an effective amount of the compound of claim 2 or a pharmaceutical composition containing same.
Claim 26
Dependent Claim
32 words
A method of treating endometriosis in a female mammalian subject, which method comprises administering to said subject an effective amount of the compound of claim 1 or a pharmaceutical composition containing same.
Claim 27
Dependent Claim
33 words
A method of treating prostatic hypertrophy in a male mammalian subject, which method comprises administering to said subject an effective amount of the compound of claim 1 or a pharmaceutical composition containing same.
Claim 28
Dependent Claim
32 words
A method of inhibiting spermatogenesis in a male mammalian subject, which method comprises administering to said subject an effective amount of the compound of claim 1 or a pharmaceutical composition containing same.
Claim 29
Dependent Claim
48 words
A pharmaceutical composition for inhibiting of ovulation or for treating endometriosis in a female mammalian subject and for treating prostatic hypertrophy or inhibiting spermatogenesis in a male mammalian subject comprising an effective amount of the compound of claim 1 in admixture with at least one pharmaceutically acceptable excipient.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1986-12-05 | 1987-06-06 | 1987-12-06 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-12-05 | 1991-06-06 | 1991-12-06 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-12-05 | 1995-06-06 | 1995-12-06 | $7700.00 | Window Closed / Lapsed |