US4105652A
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Synthesis of human β-endorphin
Assignee: DSM Nutritional Products LLC
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Filing: 1977-08-05
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Granted: 1978-08-08
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Expires: 1997-08-05
Abstract
Abstract Human β-endorphin (β h -endorphin) is prepared by solution phase peptide synthesis. Synthesis proceeded via the protected β-endorphin fragments 1-9, 10-18, 19-21 and 22-31.
Inventors
- 👤 Johannes A. Meienhofer
- 👤 Su-Sun Wang
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-24 15:27
CPC Classifications
C; C07; C07K; C07K14/00; C07K14/435; C07K14/665; C07K14/675
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
110 words
A compound of the formula R.sup.1 -Try(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu((OR.sup.4)-OR.sup.7 where R 1 is a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group, R 6 is hydrogen or a conventional protecting group for the carboxamide group, R 7 is hydrogen or a conventional carboxyl protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 2
Dependent Claim
110 words
A compound of the formula R.sup.1 -Try(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu((OR.sup.4)-OR.sup.7 where R 1 is a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group, R 6 is hydrogen or a conventional protecting group for the carboxamide group, R 7 is hydrogen or a conventional carboxyl protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 3
Dependent Claim
39 words
The compound of claim 1 wherein R 1 is benzyloxycarbonyl, R 2 is hydrogen, R 3 is benzyl, R 4 is benzyl, R 5 is benzyloxycarbonyl, R 6 is hydrogen, R 7 is benzyl and R 8 is benzyl.
Claim 4
Dependent Claim
79 words
A compound of the formula R.sup.1 -Tyr(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-OH where R 1 is a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 5
Dependent Claim
79 words
A compound of the formula R.sup.1 -Tyr(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-OH where R 1 is a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 6
Dependent Claim
31 words
The compound of claim 3 wherein R 1 is benzyloxycarbonyl, R 2 is hydrogen, R 3 is benzyl, R 4 is benzyl, R 5 is benzyloxycarbonyl and R 8 is benzyl.
Claim 7
Dependent Claim
110 words
A compound of the formula A-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where A is hydrogen or a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group, R 6 is hydrogen or a conventional protecting group for the carboxamide group, R 7 is hydrogen or a conventional carboxyl protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 8
Dependent Claim
110 words
A compound of the formula A-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where A is hydrogen or a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group, R 6 is hydrogen or a conventional protecting group for the carboxamide group, R 7 is hydrogen or a conventional carboxyl protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 9
Dependent Claim
38 words
The compound of claim 5 wherein A is hydrogen, R 2 is hydrogen, R 3 is benzyl, R 4 is benzyl, R 5 is benzyloxycarbonyl, R 6 is hydrogen, R 7 is benzyl and R 8 is benzyl.
Claim 10
Dependent Claim
38 words
The compound of claim 5 wherein A is benzyloxycarbonyl, R 2 is hydrogen, R 3 is benzyl, R 4 is benzyl, R 5 is benzyloxycarbonyl, R 6 is hydrogen, R 7 is benzyl and R 8 is benzyl.
Claim 11
Dependent Claim
76 words
A compound of the formula B-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where B is hydrogen or a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group, R 6 is hydrogen or a conventional protecting group for the carboxamide group and R 7 is hydrogen or a conventional carboxyl protecting group.
Claim 12
Dependent Claim
76 words
A compound of the formula B-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where B is hydrogen or a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group, R 6 is hydrogen or a conventional protecting group for the carboxamide group and R 7 is hydrogen or a conventional carboxyl protecting group.
Claim 13
Dependent Claim
30 words
The compound of claim 8 wherein B is hydrogen, R 2 is hydrogen, R 4 is benzyl, R 5 is benzyloxycarbonyl, R 6 is hydrogen and R 7 is benzyl.
Claim 14
Dependent Claim
30 words
The compound of claim 8 wherein B is benzyloxycarbonyl, R 2 is hydrogen, R 4 is benzyl, R 5 is benzyloxycarbonyl, R 6 is hydrogen and R 7 is benzyl.
Claim 15
Dependent Claim
64 words
A compound of the formula A-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-OH where A is hydrogen or a conventional α-amino protecting group, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 6 is hydrogen or a conventional protecting group for the carboxamide group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 16
Dependent Claim
64 words
A compound of the formula A-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-OH where A is hydrogen or a conventional α-amino protecting group, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 6 is hydrogen or a conventional protecting group for the carboxamide group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue.
Claim 17
Dependent Claim
22 words
The compound of claim 11 wherein A is hydrogen, R 3 is benzyl, R 6 is hydrogen and R 8 is benzyl.
Claim 18
Dependent Claim
22 words
The compound of claim 11 wherein A is benzyloxycarbonyl, R 3 is benzyl, R 6 is hydrogen and R 8 is benzyl.
Claim 19
Dependent Claim
228 words
A process for the preparation of human β-endorphin which process comprises in combination: (A) reacting a protected nonapeptide of the formula R.sup.1 -Try(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-OH, where R 1 is a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue with a 22 amino acid partially protected peptide amine of the formula H.sub.2 N-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are as above and R 6 is hydrogen or a conventional protecting group for the carboxamide group and R 7 is hydrogen or a conventional carboxyl protecting group under peptide bond forming conditions consisting of treatment with dicyclohexylcarbodiimide/1-hydroxybenzotriazole so as to produce a compound of the formula R.sup.1 -Tyr(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as above; and (B) removing the protective groups with strong acid so as to yield the desired human β-endorphin.
Claim 20
Dependent Claim
228 words
A process for the preparation of human β-endorphin which process comprises in combination: (A) reacting a protected nonapeptide of the formula R.sup.1 -Try(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-OH, where R 1 is a conventional α-amino protecting group, R 2 is hydrogen or a conventional protecting group for the phenolic hydroxyl group of the tyrosine residue, R 3 is hydrogen or a conventional protecting group for the hydroxyl group of the threonine residue, R 4 is hydrogen or a conventional carboxyl protecting group, R 5 is a conventional ω-amino protecting group and R 8 is hydrogen or a conventional protecting group for the hydroxyl group of the serine residue with a 22 amino acid partially protected peptide amine of the formula H.sub.2 N-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are as above and R 6 is hydrogen or a conventional protecting group for the carboxamide group and R 7 is hydrogen or a conventional carboxyl protecting group under peptide bond forming conditions consisting of treatment with dicyclohexylcarbodiimide/1-hydroxybenzotriazole so as to produce a compound of the formula R.sup.1 -Tyr(R.sup.2)-Gly-Gly-Phe-Met-Thr(R.sup.3)-Ser(R.sup.8)-Glu(OR.sup.4)-Lys(R.sup.5)-Ser(R.sup.8)-Gln(R.sup.6)-Thr(R.sup.3)-Pro-Leu-Val-Thr(R.sup.3)-Leu-Phe-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Ile-Ile-Lys(R.sup.5)-Asn(R.sup.6)-Ala-Tyr(R.sup.2)-Lys(R.sup.5)-Lys(R.sup.5)-Gly-Glu(OR.sup.4)-OR.sup.7 where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as above; and (B) removing the protective groups with strong acid so as to yield the desired human β-endorphin.
References Cited (Backward Citations)
US4038222A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1981-08-07 | 1982-02-06 | 1982-08-08 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1985-08-07 | 1986-02-06 | 1986-08-08 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1989-08-07 | 1990-02-06 | 1990-08-08 | $7700.00 | Window Closed / Lapsed |