US4661472A
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GnRH antagonists IX
Assignee: Salk Institute for Biological Studies
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Filing: 1985-05-09
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Granted: 1987-04-28
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Expires: 2005-05-09
Abstract
Abstract Peptides which inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. These peptides may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are cyclic analogs of the decapeptide GnRH wherein there is a covalent bond between the residue in the 4-position and the residue in the 10-position. Examples of such bonds include the disulfide linkage between Cys residues, an amide linkage between a side chain amino group and a side chain carboxyl group, a dicarba linkage between side-chain alkyl groups, and a carba linkage between a side-chain alkyl group and a side-chain sulfhydryl group.
Inventors
- 👤 Jean E. F. Rivier
- 👤 Janos I. Varga
- 👤 Arnold T. Hagler
- 👤 R. Scott Struthers
- 👤 Marilyn H. Perrin
- 👤 Catherine L. Rivier
- 👤 Wylie W. Vale, Jr.
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 22:50
CPC Classifications
C; C07; C07K; C07K14/00; C07K7/00; C07K7/04; C07K7/23; A; A61; A61K; A61K38/00; A61K38/16; A61K38/17; A61K38/22; A61K38/27; A61P; A61P5/00; C07K7/06; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/13
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
259 words
A peptide or a nontoxic salt thereof, said peptide having the formula: X-R 1 -(A)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -(G)Pro-R 10 -NH 2 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is dehydro-Pro, D-pGlu, (A)D-Phe, (B)D-Trp, Pro, or β-D-NAL; A is H,Cl, F, NO 2 , CH 3 , OCH 3 , C a Me/4Cl, Cl 2 or Br; B is H, NO 2 , NH 2 , OCH 3 , F, Cl, Br, CH 3 , N in For or N in Ac; R 3 is D-PAL, β-D-NAL or (B)D-Tro; R 4 is Cys, Asp, Glu, Orn, daB, daP or aBu; R 5 is Tyr, (C)Arg, (A)Phe, (3I)Tyr or His; R 6 is β-D-NAL, (B)D-Trp, (A')D-Phe, (D)D-Lys, (D)D-Orn, D-Har, D-Tyr, (E)D-His, D-PAL or (C)D-Arg; A' is A, NH 2 , NHCH 3 or gua; C is (lower alkyl) n where n is 0, 1 or 2; D is X or an aryl group; E is H, imBzl or dinitrophenyl; R 7 is Nle, Leu, NML, Phe, Met, Nva, Tyr, Trp or PAL; R 8 is Arg, Ser, Tyr, Thr or PAL; G is H, OH or dehydro and R 10 is cys, asp, glu, orn, dab, dap or abu; provided however that when R 4 is Cys or aBu, R 10 is cys or abu; when R 4 is Asp or Glu, R 10 is orn, dab or dap; and When r4 is Orn, daB or daP, R 10 is asp or glu.
Claim 2
Dependent Claim
259 words
A peptide or a nontoxic salt thereof, said peptide having the formula: X-R 1 -(A)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -(G)Pro-R 10 -NH 2 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is dehydro-Pro, D-pGlu, (A)D-Phe, (B)D-Trp, Pro, or β-D-NAL; A is H,Cl, F, NO 2 , CH 3 , OCH 3 , C a Me/4Cl, Cl 2 or Br; B is H, NO 2 , NH 2 , OCH 3 , F, Cl, Br, CH 3 , N in For or N in Ac; R 3 is D-PAL, β-D-NAL or (B)D-Tro; R 4 is Cys, Asp, Glu, Orn, daB, daP or aBu; R 5 is Tyr, (C)Arg, (A)Phe, (3I)Tyr or His; R 6 is β-D-NAL, (B)D-Trp, (A')D-Phe, (D)D-Lys, (D)D-Orn, D-Har, D-Tyr, (E)D-His, D-PAL or (C)D-Arg; A' is A, NH 2 , NHCH 3 or gua; C is (lower alkyl) n where n is 0, 1 or 2; D is X or an aryl group; E is H, imBzl or dinitrophenyl; R 7 is Nle, Leu, NML, Phe, Met, Nva, Tyr, Trp or PAL; R 8 is Arg, Ser, Tyr, Thr or PAL; G is H, OH or dehydro and R 10 is cys, asp, glu, orn, dab, dap or abu; provided however that when R 4 is Cys or aBu, R 10 is cys or abu; when R 4 is Asp or Glu, R 10 is orn, dab or dap; and When r4 is Orn, daB or daP, R 10 is asp or glu.
Claim 3
Dependent Claim
13 words
A peptide in accordance with claim 1 wherein A is 4Cl or 4F.
Claim 4
Dependent Claim
22 words
A peptide in accordance with claim 1 wherein R 4 is Asp or Glu and R 10 is orn, dab or dap.
Claim 5
Dependent Claim
22 words
A peptide in accordance with claim 1 wherein R 4 is Orn, daB or daP and R 10 is asp or glu.
Claim 6
Dependent Claim
19 words
A peptide in accordance with claim 1 wherein R 4 is Cys and R 10 is cys or abu.
Claim 7
Dependent Claim
21 words
A peptide in accordance with claim 1 wherein R 3 is (B)D-Trp and B is 6NO 2 or N in For.
Claim 8
Dependent Claim
21 words
A peptide in accordance with claim 1 wherein R 1 is β-D-2NAL, R 3 is D-PAL and R 5 is Arg.
Claim 9
Dependent Claim
19 words
A peptide in accordance with claim 7 wherein R 6 is D-Trp, D-PAL, β-D-NAL, (imBzl)D-His or (6NO 2 )D-Trp.
Claim 10
Dependent Claim
21 words
A peptide in accordance with claim 7 wherein R 6 is (imBzl)D-His or (6NO 2 )D-Trp and R 7 is Leu.
Claim 11
Dependent Claim
19 words
A peptide in accordance with claim 6 wherein R 4 is Cys or aBu and R 10 is cys.
Claim 12
Dependent Claim
17 words
A peptide in accordance with claim 1 wherein R 4 is aBu and R 10 is abu.
Claim 13
Dependent Claim
16 words
A peptide in accordance with claim 1 wherein R 8 is Arg and G is H.
Claim 14
Dependent Claim
18 words
A peptide in accordance with claim 12 wherein D and E are both H and n is O.
Claim 15
Dependent Claim
20 words
A peptide in accordance with claim 1 wherein X is Ac, A is 4Cl or 4F and G is H.
Claim 16
Dependent Claim
21 words
A peptide in accordance with claim 1 wherein R 4 is Asp, R 8 is Arg and R 10 is D-Orn.
Claim 17
Dependent Claim
25 words
A peptide in accordance with claim 1 wherein R 3 is (B)D-Trp, B is 6NO 2 or N in For and R 8 is Arg.
Claim 18
Dependent Claim
25 words
A peptide in accordance with claim 1 wherein R 1 is dehydroPro, R 3 is D-PAL, R 5 is Arg and R 8 is Arg.
Claim 19
Dependent Claim
21 words
A peptide in accordance with claim 1 wherein R 4 is Orn, R 8 is Arg and R 10 is D-Asp.
Claim 20
Dependent Claim
29 words
A peptide in accordance with claim 14 wherein R 6 is (imBzl)D-His or (6NO 2 )D-Trp, R 7 is Leu, Nle, NML or PAL and R 8 is Arg.
Claim 21
Dependent Claim
17 words
A peptide in accordance with claim 1 wherein R 4 is daP and R 10 is Asp.
Claim 22
Dependent Claim
21 words
A peptide in accordance with claim 20 wherein R 3 is D-3Pal, R 5 is Arg and R 6 is D-3Pal.
Claim 23
Dependent Claim
16 words
A peptide in accordance with claim 21 wherein X is Ac and R 1 is D-2-Nal.
Claim 24
Dependent Claim
25 words
A peptide in accordance with claim 22 wherein A is 4Cl or 4F, R 7 is Leu, R 8 is Arg and G is H.
Claim 25
Dependent Claim
26 words
A method for regulating the secretion of gonadotropins comprising administering an effective amount of a peptide or a nontoxic salt thereof as defined in claim 1.
References Cited (Backward Citations)
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