US4024121A
Expired / Lapsed
US
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(Pyro)-Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHR and intermediates
Assignee: Individual
•
Filing: 1976-01-27
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Granted: 1977-05-17
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Expires: 1996-01-27
Abstract
Abstract [D-Ser 4 ,D-Leu 6 ,desGly-NH 2 10 ]-LH-RH (lower alkyl)amides, salts thereof, and intermediates used for the synthesis thereof are disclosed. The compounds have potent LH- and FSH-releasing hormone properties.
Inventors
- 👤 Andrew V. Schally
- 👤 David H. Coy
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-26 18:59
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/23; C08; C08L; C08L23/00; C08L23/02; C08L23/04; C08L23/08; C08L23/0807; C08L23/0815; A; A61; A61K; A61K38/00; C08L23/18; C08L23/20; C08L23/22; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/13
Claims Analysis
Total Claims: 12
Claim 1
Independent Claim
20 words
A compound of formula 1 (pyro)-Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHR (1) in which R is lower alkyl, or a non-toxic pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
20 words
A compound of formula 1 (pyro)-Glu-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHR (1) in which R is lower alkyl, or a non-toxic pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
17 words
The compound of claim 1 which is L-pyroglutamyl-L-histidyl-L-tryptophyl-D-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-L-prolyl ethylamide, or a non-toxic, pharmaceutically acceptable addition salt thereof.
Claim 4
Dependent Claim
115 words
A compound of the formula R.sup.6 -(pryo)-Glu-His-Trp-D-Ser(R.sup.4)-Tyr(R.sup.3)-D-Leu-Leu-Arg-(N.sup.G -R.sup.2)-Pro-NHR in which R is lower alkyl; R 2 is a protective group for the N.sup.δ, N.sup.ω, N.sup.ω ' nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromobenzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichlorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; and R 6 is hydrogen or an α-amino protective group selected from the group consisting of t-butyloxycarbonyl, benzyloxycarbonyl, cyclopentyloxycarbonyl, t-amyloxycarbonyl and d-isobornyloxycarbonyl.
Claim 5
Dependent Claim
115 words
A compound of the formula R.sup.6 -(pryo)-Glu-His-Trp-D-Ser(R.sup.4)-Tyr(R.sup.3)-D-Leu-Leu-Arg-(N.sup.G -R.sup.2)-Pro-NHR in which R is lower alkyl; R 2 is a protective group for the N.sup.δ, N.sup.ω, N.sup.ω ' nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromobenzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichlorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; and R 6 is hydrogen or an α-amino protective group selected from the group consisting of t-butyloxycarbonyl, benzyloxycarbonyl, cyclopentyloxycarbonyl, t-amyloxycarbonyl and d-isobornyloxycarbonyl.
Claim 6
Dependent Claim
10 words
The compound of claim 3 in which R is ethyl.
Claim 7
Dependent Claim
27 words
The compound of claim 3 in which R is ethyl, R 2 is tosyl, R 3 is 2-bromobenzyloxycarbonyl, R 4 is benzyl and R 6 is hydrogen.
Claim 8
Dependent Claim
138 words
A compound of the formula R.sup.6 -(pyro)-Glu-His(N.sup.1m -R.sup.5)-Trp-D-Ser(R.sup.4)-Tyr(R.sup.3)-D-Leu-Leu-Arg(N.sup.G -R.sup.2)-Pro-OR.sup.1 in which R 1 is lower alkyl; R 2 is a protective group for the N.sup.δ, N.sup.ω, N.sup.ω ' nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromobenzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichiorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; R 5 is a protective group for the imidazole nitrogen atoms of histidine selected from the group of dinitropenyl and tosyl; and R 6 is hydrogen or an α-amino protective group selected from the group consisting of t-butyloxycarbonyl, benzyloxycarbonyl, cyclopentyloxycarbonyl, t-amyloxycarbonyl and d-isobornyloxycarbonyl.
Claim 9
Dependent Claim
138 words
A compound of the formula R.sup.6 -(pyro)-Glu-His(N.sup.1m -R.sup.5)-Trp-D-Ser(R.sup.4)-Tyr(R.sup.3)-D-Leu-Leu-Arg(N.sup.G -R.sup.2)-Pro-OR.sup.1 in which R 1 is lower alkyl; R 2 is a protective group for the N.sup.δ, N.sup.ω, N.sup.ω ' nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromobenzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichiorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; R 5 is a protective group for the imidazole nitrogen atoms of histidine selected from the group of dinitropenyl and tosyl; and R 6 is hydrogen or an α-amino protective group selected from the group consisting of t-butyloxycarbonyl, benzyloxycarbonyl, cyclopentyloxycarbonyl, t-amyloxycarbonyl and d-isobornyloxycarbonyl.
Claim 10
Dependent Claim
184 words
A compound selected from the group consisting of R 6 -(pyro)-Glu-His(N 1m -R 5 )-Trp-D-Ser(R 4 )-Tyr(R 3 )-D-Leu-Leu-Arg(N G -R 2 )Pro-A,R 7 -His(N 1m -R 5 )-Trp-D-Ser(R 4 )-Tyr-(R 3 )-D-Leu-Leu-Arg(N G -R 2 )-Pro-A,R 7 -Trp-D-Ser(R 4 )-Tyr-(R 3 )-D-Leu-Leu-Arg(N G -R 2 )-Pro-A and R 7 -D-Ser(R 4 )-Tyr(R 3 )-D-Leu-Leu-Arg(N G -R 2 )-Pro-A, in which R 2 is protective group for the N.sup.δ, Nω, Nω' nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromobenzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichlorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; R 5 is a protective group for the imidazole nitrogen atoms of histidine selected from the group of dinitrophenyl and tosyl; wherein R is lower alkyl, R 6 is hydrogen or an α-amino protective group, R 7 is an α-amino protective group, and A is ##STR5##
Claim 11
Dependent Claim
184 words
A compound selected from the group consisting of R 6 -(pyro)-Glu-His(N 1m -R 5 )-Trp-D-Ser(R 4 )-Tyr(R 3 )-D-Leu-Leu-Arg(N G -R 2 )Pro-A,R 7 -His(N 1m -R 5 )-Trp-D-Ser(R 4 )-Tyr-(R 3 )-D-Leu-Leu-Arg(N G -R 2 )-Pro-A,R 7 -Trp-D-Ser(R 4 )-Tyr-(R 3 )-D-Leu-Leu-Arg(N G -R 2 )-Pro-A and R 7 -D-Ser(R 4 )-Tyr(R 3 )-D-Leu-Leu-Arg(N G -R 2 )-Pro-A, in which R 2 is protective group for the N.sup.δ, Nω, Nω' nitrogen atoms of arginine selected from the group consisting of tosyl, nitro, benzyloxycarbonyl and adamantyloxycarbonyl; R 3 is a protective group for the hydroxyl of tyrosine selected from the group consisting of 2-bromobenzyloxycarbonyl, benzyl, acetyl, tosyl, benzoyl, t-butyl, tetrahydropyran-2-yl, trityl, 2,4-dichlorobenzyl and benzyloxycarbonyl; R 4 is a protective group for the hydroxyl group of serine and is selected from the group defined hereinbefore for R 3 ; R 5 is a protective group for the imidazole nitrogen atoms of histidine selected from the group of dinitrophenyl and tosyl; wherein R is lower alkyl, R 6 is hydrogen or an α-amino protective group, R 7 is an α-amino protective group, and A is ##STR5##
Claim 12
Dependent Claim
50 words
The compound of claim 7 having the formula R 6 -(pyro)-Glu-His(N 1m -R 5 )-Trp-D-Ser(R 4 )-Tyr(R 3 )-D-Leu-Leu-Arg(N G -R 2 )-Pro-A in which R 2 is tosyl, R 3 is 2-bromobenzyloxycarbonyl, R 4 is benzyl, R 5 is 2,4-dinitrophenyl, R 6 is hydrogen and A is a ##STR6##
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) | 1980-05-16 | 1980-11-15 | 1981-05-17 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1984-05-16 | 1984-11-15 | 1985-05-17 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1988-05-16 | 1988-11-15 | 1989-05-17 | $7700.00 | Window Closed / Lapsed |