US4098777A
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Process for the preparation of pyroglutamyl-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn
Assignee: Merck and Co Inc
•
Filing: 1977-03-14
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Granted: 1978-07-04
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Expires: 1997-03-14
Abstract
Abstract This invention is directed to the chemical process for the preparation of the polypeptide, pyroglutamyl-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn and to intermediates in said process. The polypeptide prepared by the present process is useful in the treatment of autoimmune diseases such as Lupus like pathology and specifically for the treatment of Lupus Erythematosus in man. This polypeptide is also useful for selectively stimulating T-cell activity in aging subjects.
Inventors
- 👤 Daniel F. Veber
- 👤 Robert G. Strachan
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 17:46
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/06; C07K7/062; A; A61; A61K; A61K38/00; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/28
Claims Analysis
Total Claims: 15
Claim 1
Independent Claim
139 words
The process for the preparation of the peptide having the structure, < Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn, which comprises converting the blocked heptapeptide hydrazide having the structure, < Glu-Ala-(ε-R)Lys-(O-R.sub.1 ')Ser-Gln-Gly-Gly-NH-NH.sub.2 to the corresponding azide and condensing said azide with the hydroxy blocked or unblocked dipeptide, (O-R.sub.2)Ser-Asn to obtain the blocked nonapeptide having the structure, < Glu-Ala-(ε-R)Lys-(O-R.sub.1 ')Ser-Gln-Gly-Gly-(O-R.sub.2)Ser-Asn wherein R is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl and isonicotinyloxycarbonyl, R 2 is hydrogen or a protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl, R 1 ' is hydrogen or a protecting group for the hydroxy group of the seryl moiety selected from the group consisting of t-butyl and benzyl, and removing said protecting groups.
Claim 2
Dependent Claim
139 words
The process for the preparation of the peptide having the structure, < Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn, which comprises converting the blocked heptapeptide hydrazide having the structure, < Glu-Ala-(ε-R)Lys-(O-R.sub.1 ')Ser-Gln-Gly-Gly-NH-NH.sub.2 to the corresponding azide and condensing said azide with the hydroxy blocked or unblocked dipeptide, (O-R.sub.2)Ser-Asn to obtain the blocked nonapeptide having the structure, < Glu-Ala-(ε-R)Lys-(O-R.sub.1 ')Ser-Gln-Gly-Gly-(O-R.sub.2)Ser-Asn wherein R is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl and isonicotinyloxycarbonyl, R 2 is hydrogen or a protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl, R 1 ' is hydrogen or a protecting group for the hydroxy group of the seryl moiety selected from the group consisting of t-butyl and benzyl, and removing said protecting groups.
Claim 3
Dependent Claim
141 words
The process for the preparation of the peptide having the structure, < Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn, which comprises condensing the blocked heptapeptide active ester having the structure, < Glu-Ala-(ε-R.sub.3)Lys-(O-R.sub.4 ')Ser-Gln-Gly-Gly-R.sub.6 with the hydroxy blocked or unblocked dipeptide, (O-R.sub.5)Ser-Asn wherein R 3 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of INOC, trifluoroacetyl, phthaloyl, tosyl, p-nitrobenzyloxycarbonyl, TROC and FMOC; R 4 ' is hydrogen, p-nitrobenzyl or benzoyl, R 5 is hydrogen or a protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzyl, substituted benzyl wherein the substituent is o-chloro or p-nitro; t-butyl and benzoyl, R 6 is an active ester selected from the group consisting of 1-hydroxybenzotriazole ester, N-hydroxysuccinimide ester and p-nitrophenyl ester, to obtain the blocked nonapeptide having the structure, < Glu-Ala-(ε-R.sub.3)Lys-(O-R.sub.4 ')Ser-Gln-Gly-Gly-(O-R.sub.5)Ser-Asn, and removing said blocking groups.
Claim 4
Dependent Claim
141 words
The process for the preparation of the peptide having the structure, < Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn, which comprises condensing the blocked heptapeptide active ester having the structure, < Glu-Ala-(ε-R.sub.3)Lys-(O-R.sub.4 ')Ser-Gln-Gly-Gly-R.sub.6 with the hydroxy blocked or unblocked dipeptide, (O-R.sub.5)Ser-Asn wherein R 3 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of INOC, trifluoroacetyl, phthaloyl, tosyl, p-nitrobenzyloxycarbonyl, TROC and FMOC; R 4 ' is hydrogen, p-nitrobenzyl or benzoyl, R 5 is hydrogen or a protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzyl, substituted benzyl wherein the substituent is o-chloro or p-nitro; t-butyl and benzoyl, R 6 is an active ester selected from the group consisting of 1-hydroxybenzotriazole ester, N-hydroxysuccinimide ester and p-nitrophenyl ester, to obtain the blocked nonapeptide having the structure, < Glu-Ala-(ε-R.sub.3)Lys-(O-R.sub.4 ')Ser-Gln-Gly-Gly-(O-R.sub.5)Ser-Asn, and removing said blocking groups.
Claim 5
Dependent Claim
78 words
The process according to claim 1 for the preparation of the peptide having the structure, < Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn, which comprises converting the blocked heptapeptide hydrazide having the structure, < Glu-Ala-(ε-INOC)Lys-(O-Bzl)Ser-Gln-Gly-Gly-NH-NH.sub.2 to the corresponding azide by the action of isoamyl nitrite and condensing said azide with the blocked dipeptide, (O-Bzl)Ser-Asn.HCl to obtain the blocked nonapeptide having the structure, < Glu-Ala-(ε-INOC)Lys-(O-Bzl)Ser-Gln-Gly-Gly-(O-Bzl)Ser-Asn and removing the benzyl group with hydrogen fluoride and anisole and removing the INOC group with hydrogen and Pd/C catalyst.
Claim 6
Dependent Claim
92 words
The compounds having the structure, Glu-Ala-(ε-R 8 )Lys-(O-R 9 )Ser-Gln-Gly-Gly-(O-R 10 )Ser-Asn wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 and R 10 are independently hydrogen or R 9 and R 10 are protecting groups for the hydroxy group of the seryl moieties, independently selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.
Claim 7
Dependent Claim
92 words
The compounds having the structure, Glu-Ala-(ε-R 8 )Lys-(O-R 9 )Ser-Gln-Gly-Gly-(O-R 10 )Ser-Asn wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 and R 10 are independently hydrogen or R 9 and R 10 are protecting groups for the hydroxy group of the seryl moieties, independently selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.
Claim 8
Dependent Claim
91 words
The compounds having the structure, < Glu-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-Gly-R.sub.7 wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro, R 7 is --NH--NH 2 , OH, 1-oxybenzotriazole, N-oxysuccinimide, p-nitrophenoxy or OCH 3 .
Claim 9
Dependent Claim
91 words
The compounds having the structure, < Glu-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-Gly-R.sub.7 wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro, R 7 is --NH--NH 2 , OH, 1-oxybenzotriazole, N-oxysuccinimide, p-nitrophenoxy or OCH 3 .
Claim 10
Dependent Claim
79 words
The compounds having the structure, < Glu(or BOC-Gln)-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-Gly-O-CH.sub.2 -φ-resin wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.
Claim 11
Dependent Claim
79 words
The compounds having the structure, < Glu(or BOC-Gln)-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-Gly-O-CH.sub.2 -φ-resin wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.
Claim 12
Dependent Claim
91 words
The compounds having the structure, < Glu-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-R.sub.7 wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro, R 7 is --NH--NH 2 , OH, 1-oxybenzotriazole, N-oxysuccinimide, p-nitrophenoxy or OCH 3 .
Claim 13
Dependent Claim
91 words
The compounds having the structure, < Glu-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-R.sub.7 wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro, R 7 is --NH--NH 2 , OH, 1-oxybenzotriazole, N-oxysuccinimide, p-nitrophenoxy or OCH 3 .
Claim 14
Dependent Claim
79 words
The compounds having the structure, < Glu(or BOC-Gln)-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-O-CH.sub.2 -φ-resin wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.
Claim 15
Dependent Claim
79 words
The compounds having the structure, < Glu(or BOC-Gln)-Ala-(ε-R.sub.8)Lys-(O-R.sub.9)Ser-Gln-Gly-O-CH.sub.2 -φ-resin wherein R 8 is the protecting group for the ε-amino of the lysyl moiety selected from the group consisting of formyl, toluene sulfonyl, benzyloxycarbonyl; 2,6-dichlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isonicotinyloxycarbonyl, trifluoroacetyl, phthaloyl, TROC and FMOC, R 9 is hydrogen or the protecting group for the hydroxy group of the seryl moiety, selected from the group consisting of benzoyl, t-butyl, benzyl and substituted benzyl wherein the substituent is o-chloro or p-nitro.
References Cited (Backward Citations)
No citation records indexed.
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1981-07-03 | 1982-01-02 | 1982-07-04 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1985-07-03 | 1986-01-02 | 1986-07-04 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1989-07-03 | 1990-01-02 | 1990-07-04 | $7700.00 | Window Closed / Lapsed |