US5296468A
Expired / Lapsed
US
⏱️ 0.0 years remaining
GnRH analogs
Assignee: Salk Institute for Biological Studies
•
Filing: 1993-01-21
•
Granted: 1994-03-22
•
Expires: 2013-01-21
Abstract
Abstract Peptides which include unnatural amino acids and which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such peptides that are GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The antagonists may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions. Such unnatural amino acids are useful in the synthesis of peptides and have the formula U * : ##STR1## where W is (CH 2 ) n or ##STR2## n is an integer from 1 to 6; and j=1, 2 or 3. Preferably, either Y is N--CN, X is NH and R 2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pridyl or ##STR3## where R 11 is H or acyl.
Inventors
- 👤 Carl A. Hoeger
- 👤 Jean E. F. Rivier
- 👤 Paula G. Theobald
- 👤 John S. Porter
- 👤 Catherine L. Rivier
- 👤 Wylie W. Vale, Jr.
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 13:19
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/02; C07C; C07C279/00; C07C279/20; C07C279/24; C07C279/28; C07C313/00; C07C313/08; C07C313/18; C07C313/26; C07C313/30; C07D; C07D249/00; C07D249/02; C07D249/08; C07D249/10; C07D249/14; C07K7/04; C07K7/23; A; A61; A61K; A61K38/00; C07C2601/00; C07C2601/12; C07C2601/14; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/11
Claims Analysis
Total Claims: 32
Claim 1
Independent Claim
37 words
A GnRH antagonist peptide or a nontoxic salt thereof having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-A 5 (3-amino 1,2,4 triazole)-A 6 (3-amino 1,2,4 triazole)-Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 , wherein A 5 is Lys or Aph and A 6 is D-Lys or D-Aph.
Claim 2
Dependent Claim
37 words
A GnRH antagonist peptide or a nontoxic salt thereof having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-A 5 (3-amino 1,2,4 triazole)-A 6 (3-amino 1,2,4 triazole)-Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 , wherein A 5 is Lys or Aph and A 6 is D-Lys or D-Aph.
Claim 3
Dependent Claim
23 words
A GnRH antagonist peptide or a nontoxic salt thereof according to claim 1 having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(3-amino 1,2,4 triazole)-D-Aph(3-amino 1,2,4 triazole)-Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 .
Claim 4
Dependent Claim
23 words
A GnRH antagonist peptide or a nontoxic salt thereof according to claim 1 having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Lys(3-amino 1,2,4 triazole)-D-Lys(3-amino 1,2,4 triazole)-Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 .
Claim 5
Dependent Claim
33 words
A method for inhibiting the secretion of gonadotropins in mammals comprising administering to a mammal an effective amount of a GnRH antagonist peptide or a nontoxic salt thereof as defined in claim 1.
Claim 6
Dependent Claim
41 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-U * -Ser-Tyr-D-3PAL-Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 , wherein U * is a D-isomer having the formula either ##STR38## where R 2 is lower alkyl (C 1 -C 6 ).
Claim 7
Dependent Claim
41 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-U * -Ser-Tyr-D-3PAL-Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 , wherein U * is a D-isomer having the formula either ##STR38## where R 2 is lower alkyl (C 1 -C 6 ).
Claim 8
Dependent Claim
15 words
A GnRH antagonist peptide in accordance with claim 5 wherein U * has formula (a).
Claim 9
Dependent Claim
15 words
A GnRH antagonist peptide in accordance with claim 5 wherein U * has formula (b).
Claim 10
Dependent Claim
14 words
A GnRH antagonist peptide in accordance with claim 5 wherein R 2 is isopropyl.
Claim 11
Dependent Claim
74 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-U * -U * -AA 7 -Lys(isopropyl)-Pro-AA 10 wherein AA 7 is Leu or N.sup.αCH 3 Leu; AA 10 is D-Ala-NH 2 , Gly-NH 2 , or NHCH 2 CH 3 ; and U * is either ##STR39## where R 2 is lower alkyl, pyridyl or methyl pyridyl; provided, however, that U * in the 6-position is always a D-isomer.
Claim 12
Dependent Claim
74 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-U * -U * -AA 7 -Lys(isopropyl)-Pro-AA 10 wherein AA 7 is Leu or N.sup.αCH 3 Leu; AA 10 is D-Ala-NH 2 , Gly-NH 2 , or NHCH 2 CH 3 ; and U * is either ##STR39## where R 2 is lower alkyl, pyridyl or methyl pyridyl; provided, however, that U * in the 6-position is always a D-isomer.
Claim 13
Dependent Claim
29 words
A GnRH antagonist peptide in accordance with claim 9 wherein U * in the 5-position is Aph(3-amino 1,2,4 triazole) and U * in the 6-position is D-Aph(3-amino 1,2,4 triazole).
Claim 14
Dependent Claim
12 words
A peptide in accordance with claim 9 wherein U * is (b).
Claim 15
Dependent Claim
14 words
A GnRH antagonist peptide in accordance with claim 11 wherein R 2 is butyl.
Claim 16
Dependent Claim
14 words
A GnRH antagonist in accordance with claim 11 wherein R 2 is methyl pyridyl.
Claim 17
Dependent Claim
18 words
A GnRH antagonist peptide according to claim 9 having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(3-amino 1,2,4 triazole)-D-Aph(3-amino 1,2,4 triazole)-Leu-Lys(isopropyl)-Pro-AA 10 .
Claim 18
Dependent Claim
93 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-U * -U * -AA 7 -Lys(isopropyl)-Pro-AA 10 wherein AA 7 is Leu or N.sup.α CH 3 -Leu; AA 10 is D-Ala-NH 2 , Gly-NH 2 or NHCH 2 CH 3 ; and U * is ##STR40## where W is (CH 2 ) n or ##STR41## n is an integer from 1 to 6; and R 11 is H or an acyl radical having 1 to 6 carbon atoms; provided, however, U * in the 6-position is a D-isomer.
Claim 19
Dependent Claim
93 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-U * -U * -AA 7 -Lys(isopropyl)-Pro-AA 10 wherein AA 7 is Leu or N.sup.α CH 3 -Leu; AA 10 is D-Ala-NH 2 , Gly-NH 2 or NHCH 2 CH 3 ; and U * is ##STR40## where W is (CH 2 ) n or ##STR41## n is an integer from 1 to 6; and R 11 is H or an acyl radical having 1 to 6 carbon atoms; provided, however, U * in the 6-position is a D-isomer.
Claim 20
Dependent Claim
19 words
A GnRH antagonist peptide according to claim 15 wherein W is (CH 2 ) n and n is 4.
Claim 21
Dependent Claim
14 words
A GnRH antagonist peptide in accordance with claim 16 wherein R 11 is H.
Claim 22
Dependent Claim
14 words
A GnRH antagonist peptide in accordance with claim 16 wherein R 11 is acetyl.
Claim 23
Dependent Claim
74 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-AA 5 -AA 6 -Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 wherein AA 5 is U * or Lys(carboxypyridine); AA 6 is U * or D-Lys(carboxypyridine); and U * is ##STR42## where W is (CH 2 ) n and n is 4; provided, however, that either AA 5 is U * or AA 6 is U * , with AA 6 always being a D-isomer.
Claim 24
Dependent Claim
74 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-AA 5 -AA 6 -Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 wherein AA 5 is U * or Lys(carboxypyridine); AA 6 is U * or D-Lys(carboxypyridine); and U * is ##STR42## where W is (CH 2 ) n and n is 4; provided, however, that either AA 5 is U * or AA 6 is U * , with AA 6 always being a D-isomer.
Claim 25
Dependent Claim
17 words
A GnRH antagonist peptide according to claim 19 having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-Phe-D-3PAL-Ser-Lys(3-amino 1,2,4 triazole) D-Lys-Leu-Lys(isopropyl)-Pro-D-Ala-NH 2 .
Claim 26
Dependent Claim
51 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-AA 5 -AA 6 -Leu-U * -Pro-D-Ala-NH 2 wherein AA 5 is Lys(carboxypyridine) or Tyr: AA 6 is D-Lys(carboxypyridine) or D-Arg; and U * is ##STR43## where W is (CH 2 ) n and n is 4.
Claim 27
Dependent Claim
51 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-AA 5 -AA 6 -Leu-U * -Pro-D-Ala-NH 2 wherein AA 5 is Lys(carboxypyridine) or Tyr: AA 6 is D-Lys(carboxypyridine) or D-Arg; and U * is ##STR43## where W is (CH 2 ) n and n is 4.
Claim 28
Dependent Claim
73 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-U * -Ser-AA 5 -AA 6 -Leu-AA 8 -Pro-D-Ala-NH 2 wherein AA 5 is Arg or Tyr; AA 6 is U * , β-D-2NAL, D-3PAL or D-Arg; AA 8 is Lys(isopropyl) or Arg; and U * is a D-isomer having the formula: ##STR44## where W is (CH 2 ) n and n is an integer from 1 to 6.
Claim 29
Dependent Claim
73 words
A GnRH antagonist peptide or a nontoxic salt thereof, said peptide having the formula: Ac-β-D-2NAL-(4Cl)D-Phe-U * -Ser-AA 5 -AA 6 -Leu-AA 8 -Pro-D-Ala-NH 2 wherein AA 5 is Arg or Tyr; AA 6 is U * , β-D-2NAL, D-3PAL or D-Arg; AA 8 is Lys(isopropyl) or Arg; and U * is a D-isomer having the formula: ##STR44## where W is (CH 2 ) n and n is an integer from 1 to 6.
Claim 30
Dependent Claim
12 words
A GnRH antagonist peptide according to claim 22 wherein n is 4.
Claim 31
Dependent Claim
14 words
A GnRH antagonist peptide in accordance with claim 22 wherein AA 8 is Lys(isopropyl).
Claim 32
Dependent Claim
14 words
A GnRH antagonist peptide in accordance with claim 22 wherein AA 5 is Tyr.
References Cited (Backward Citations)
US4935491A
Cited
US5110904A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1997-03-21 | 1997-09-20 | 1998-03-22 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2001-03-21 | 2001-09-20 | 2002-03-22 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2005-03-21 | 2005-09-20 | 2006-03-22 | $7700.00 | Window Closed / Lapsed |