US4569927A
Expired / Lapsed
US
⏱️ 0.0 years remaining
GnRH Antagonists IV
Assignee: Salk Institute for Biological Studies
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Filing: 1984-05-21
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Granted: 1986-02-11
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Expires: 2004-05-21
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 prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The peptides have the structure: X-R.sub.1 -(W)D-Phe-R.sub.3 -R.sub.4 -R.sub.5 -R.sub.6 -R.sub.7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is dehydro-Pro, D-pGlu, D-Phe, D-Trp of β-D-NAL; W is F, Cl, Cl 2 Br, NO 2 or C.sup.α Me-Cl; R 3 is (N in For)D-Trp or D-Trp which is substituted in the 5- or 6-position with NO 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is (4NH 2 )D-Phe, D-Lys, D-Orn, D-Har, D-His, (4gua)D-Phe, D-Tyr, a D-isomer of a lipophilic amino or D-Arg; R 7 is Leu, NML, Nle or Nva; and R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR1## where Q is H or lower alkyl, provided however that when R 5 is Arg, R 6 is D-Tyr.
Inventors
- 👤 Jean E. F. Rivier
- 👤 Wylie W. Vale, Jr.
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-04 16:30
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: 24
Claim 1
Independent Claim
197 words
A peptide or a nontoxic salt thereof, said peptide having the formula: X-R 1 -(W)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is dehydro-Pro, D-pGlu, D-Phe, D-Trp or β-D-NAL; W is 4F, 4Cl, 2,4Cl 2 , 3,4Cl 2 , 4Br, 4NO 2 or C.sup.α Me-4Cl; R 3 is (N in For) D-Trp or D-Trp which is substituted in the 5- or 6-position with NO 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is (4NH 2 )D-Phe, D-Lys, D-Orn, D-Har, D-His, (4gua)D-Phe, D-Tyr, D-Trp, D-Phe, D-Leu, D-Ile, D-Nle, D-Val, D-Ala, D-Ser(OtBu), β-D-2NAL, (imBzl)D-His, or D-Arg; R 7 is Leu, NML, Nle or Nva; and R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or NHCONHQ, where Q is H or lower alkyl, provided however that when R 5 is Arg, R 6 is D-Tyr.
Claim 2
Dependent Claim
197 words
A peptide or a nontoxic salt thereof, said peptide having the formula: X-R 1 -(W)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is dehydro-Pro, D-pGlu, D-Phe, D-Trp or β-D-NAL; W is 4F, 4Cl, 2,4Cl 2 , 3,4Cl 2 , 4Br, 4NO 2 or C.sup.α Me-4Cl; R 3 is (N in For) D-Trp or D-Trp which is substituted in the 5- or 6-position with NO 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is (4NH 2 )D-Phe, D-Lys, D-Orn, D-Har, D-His, (4gua)D-Phe, D-Tyr, D-Trp, D-Phe, D-Leu, D-Ile, D-Nle, D-Val, D-Ala, D-Ser(OtBu), β-D-2NAL, (imBzl)D-His, or D-Arg; R 7 is Leu, NML, Nle or Nva; and R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or NHCONHQ, where Q is H or lower alkyl, provided however that when R 5 is Arg, R 6 is D-Tyr.
Claim 3
Dependent Claim
14 words
A peptide in accordance with claim 1 wherein R 3 is (6NO 2 )D-Trp.
Claim 4
Dependent Claim
12 words
A peptide in accordance with claim 2 wherein R 1 is β-D-2NAL.
Claim 5
Dependent Claim
12 words
A peptide in accordance with claim 3 wherein R 6 is D-Arg.
Claim 6
Dependent Claim
11 words
A peptide in accordance with claim 4 wherein X is acyl.
Claim 7
Dependent Claim
14 words
A peptide in accordance with claim 5 wherein R 10 is D-Ala-NH 2 .
Claim 8
Dependent Claim
14 words
A peptide in accordance with claim 5 wherein R 10 is Gly-NH 2 .
Claim 9
Dependent Claim
14 words
A peptide in accordance with claim 1 wherein R 3 is (N in For)D-Trp.
Claim 10
Dependent Claim
16 words
A peptide in accordance with claim 2 wherein X is acyl and R 1 is dehydro-Pro.
Claim 11
Dependent Claim
12 words
A peptide in accordance with claim 9 wherein R 6 is β-D-2NAL.
Claim 12
Dependent Claim
16 words
A peptide in accordance with claim 1 wherein R 1 is β-D-2NAL and X is acyl.
Claim 13
Dependent Claim
14 words
A peptide in accordance with claim 11 wherein R 5 is (2CH 3 )Phe.
Claim 14
Dependent Claim
14 words
A peptide in accordance with claim 1 wherein R 3 is (50CH 3 )D-Trp.
Claim 15
Dependent Claim
14 words
A peptide in accordance with claim 1 wherein R 3 is (N in For)D-Trp.
Claim 16
Dependent Claim
14 words
A peptide in accordance with claim 1 wherein R 3 is (6NH 2 )D-Trp.
Claim 17
Dependent Claim
14 words
A peptide in accordance with claim 1 wherein R 3 is (5CH 3 )D-Trp.
Claim 18
Dependent Claim
12 words
A peptide in accordance with claim 1 wherein R 3 is (5Cl)D-Trp.
Claim 19
Dependent Claim
12 words
A peptide in accordance with claim 1 wherein R 3 is (5F)D-Trp.
Claim 20
Dependent Claim
12 words
A peptide in accordance with claim 1 wherein R 3 is (5Br)D-Trp.
Claim 21
Dependent Claim
211 words
A pharmaceutical composition for regulating the secretion of gonadotropins comprising as an active ingredient an effective amount of a peptide having the formula: X-R 1 -(W)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is dehydro-Pro, D-pGlu, D-Phe, D-Trp or β-D-NAL; W is 4F, 4Cl, 2,4Cl 2 , 3,4Cl 2 , 4Br, 4NO 2 or C.sup.α Me-4Cl; R 3 is (N in For)D-Trp or D-Trp which is substituted in the 5- or 6-position with NO 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is (4NH 2 )D-Phe, D-Lys, D-Orn, D-Har, D-His, (4gua)D-Phe, D-Tyr, D-Trp, D-Phe, D-Leu, D-Ile, D-Nle, D-Val, D-Ala, D-Ser(OtBu), β-D-2NAL, (imBzl)D-His, or D-Arg; R 7 is Leu, NML, Nle or Nva; and R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or NHCONHQ, where Q is H or lower alkyl, provided however that when R 5 is Arg, R 6 is D-Tyr; in a pharmaceuticaly-acceptable carrier.
Claim 22
Dependent Claim
211 words
A pharmaceutical composition for regulating the secretion of gonadotropins comprising as an active ingredient an effective amount of a peptide having the formula: X-R 1 -(W)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is dehydro-Pro, D-pGlu, D-Phe, D-Trp or β-D-NAL; W is 4F, 4Cl, 2,4Cl 2 , 3,4Cl 2 , 4Br, 4NO 2 or C.sup.α Me-4Cl; R 3 is (N in For)D-Trp or D-Trp which is substituted in the 5- or 6-position with NO 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is (4NH 2 )D-Phe, D-Lys, D-Orn, D-Har, D-His, (4gua)D-Phe, D-Tyr, D-Trp, D-Phe, D-Leu, D-Ile, D-Nle, D-Val, D-Ala, D-Ser(OtBu), β-D-2NAL, (imBzl)D-His, or D-Arg; R 7 is Leu, NML, Nle or Nva; and R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or NHCONHQ, where Q is H or lower alkyl, provided however that when R 5 is Arg, R 6 is D-Tyr; in a pharmaceuticaly-acceptable carrier.
Claim 23
Dependent Claim
178 words
A peptide or a nontoxic salt thereof, said peptide having the formula: X-β-D-NAL-(W)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; W is 4F, 4Cl, 2,4Cl 2 , 3,4Cl 2 , 4Br, 4NO 2 or C.sup.α Me-4Cl; R 3 is A(N in For)D-Trp, (N in AC)D-Trp or D-Trp which is substituted in the 5- or 6-position with NO 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is (4NH 2 )D-Phe, D-Lys, D-Orn, D-Har, D-His, (4gua)D-Phe, D-Tyr, or D-Arg; R 7 is Leu, NML, Nle or Nva; and R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or NHCONHQ, where Q is H or lower alkyl, provided however that when R 5 is Arg, R 6 is D-Tyr.
Claim 24
Dependent Claim
178 words
A peptide or a nontoxic salt thereof, said peptide having the formula: X-β-D-NAL-(W)D-Phe-R 3 -R 4 -R 5 -R 6 -R 7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; W is 4F, 4Cl, 2,4Cl 2 , 3,4Cl 2 , 4Br, 4NO 2 or C.sup.α Me-4Cl; R 3 is A(N in For)D-Trp, (N in AC)D-Trp or D-Trp which is substituted in the 5- or 6-position with NO 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is (4NH 2 )D-Phe, D-Lys, D-Orn, D-Har, D-His, (4gua)D-Phe, D-Tyr, or D-Arg; R 7 is Leu, NML, Nle or Nva; and R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or NHCONHQ, where Q is H or lower alkyl, provided however that when R 5 is Arg, R 6 is D-Tyr.
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) | 1989-02-10 | 1989-08-12 | 1990-02-11 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1993-02-10 | 1993-08-12 | 1994-02-11 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1997-02-10 | 1997-08-12 | 1998-02-11 | $7700.00 | Window Closed / Lapsed |