US4386026A
Expired / Lapsed
US
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Cell-specific glycopeptide ligands
Assignee: Merck and Co Inc
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Filing: 1981-04-20
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Granted: 1983-05-31
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Expires: 2001-04-20
Abstract
Abstract Cell-specific ligands comprising conjugates of saccharides and amino acids or peptides are synthesized from amino acids such as ornithine, lysine, peptides such as dilysine, diornithine or oligolysine and selected saccharides having reactive functional groups protected by appropriate blocking groups. Such glycopeptides are useful as tissue specific substances, which when coupled with bioactive materials through metabolizable or hydrolyzable linkages, deliver such bioactive materials to the selected site. In this manner, antiinflammatory drugs such as dexamethasone are linked through a metabolizable or hydrolyzable linkage and on administration to an animal suffering from inflammatory disease carries the drug to the site of inflammation for intracellular release. Other examples include the macrophage ligand N 2 -N 2 , N 6 -Bis-[3-(α-D-mannopyranosylthio)propionyl]-6-lysyl-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysine, 5, which when coupled to β-glucocerebrosidase, can deliver the enzyme selectively to kupffer cells. This is useful in the enzyme replacement therapy of Gaucher's disease.
Inventors
- 👤 Mitree M. Ponpipom
- 👤 Robert L. Bugianesi
- 👤 James C. Robbins
- 👤 Tsung-Ying Shen
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 20:15
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/02; C07H15/14; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/549; C07H15/04; C07J; C07J31/00; C07J31/006; C07J41/00; C07J41/0033; C07J41/005
Claims Analysis
Total Claims: 9
Claim 1
Independent Claim
46 words
A glycopeptide selected from compounds of the formula: ##STR14## wherein R is a saccharide compound selected from the group consisting of ##STR15## and R 1 is selected from the group consisting of hydroxyl and NHR 2 wherein R 2 is 6-aminohexyl and acid addition salts thereof.
Claim 2
Dependent Claim
46 words
A glycopeptide selected from compounds of the formula: ##STR14## wherein R is a saccharide compound selected from the group consisting of ##STR15## and R 1 is selected from the group consisting of hydroxyl and NHR 2 wherein R 2 is 6-aminohexyl and acid addition salts thereof.
Claim 3
Dependent Claim
121 words
A compound according to claim 1 selected from the group consisting of compounds N 2 -{N 2 ,N 6 -Bis-[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysine, N 2 -{N 2 ,N 6 -Bis[1-imino-2-(α-D-mannopyranosylthio)ethyl]-L-lysyl}N 6 -[1-imino-2-(α-D-mannopyranosylthio)ethyl]-L-lysine, N-6-Aminohexyl-N 2 -{N 2 ,N 6 -bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3(α-D-mannopyranosylthio)propionyl]-L-lysinamide trifluoroacetate salt, N 2 ,N 6 -Bis[3-(α-D-mannopyranosylthio)proionyl]-L-lysine, N 2 ,N 6 -Bis[3-(α-D-mannopyranosylthio)propionyl]-D-lysine, N 2 -{N 2 -{N 2 ,N 6 -Bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysine, N 2 -{N 2 ,N 6 -Bis[3-(β-D-galactopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(β-D-galactopyranosylthio)propionyl]-L-lysine, N-6-Aminohexyl-N 2 -{N 2 ,N 6 -bis[3-(β-D-galactopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(β-D-galactopyranosylthio)propionyl]-L-lysinamide trifluoroacetate salt, N 2 -{N 2 ,N 6 -Bis[3-(β-L-fucopyranosylthio)propionyl]-L-lysyl}-N 6 [3-(β-L-fucopyranosylthio)propionyl]-L-lysine, N 2 -{N 2 ,N 6 -Bis[(α-D-mannopyranosylthio)acetyl]-L-lysyl}-N 6 -[(α-D-mannopyranosylthio)acetyl]-L-lysine, N-6-Aminohexyl-N 2 ,N 6 -bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysinamide trifluoroacetate salt, N 2 ,N 5 -Bis[3-(α-D-mannopyranosylthio)propionyl]-L-ornithine, and Man 9 -Lys 8 .
Claim 4
Dependent Claim
36 words
A composition comprising a glvcopeptide as defined in claim 1 conjugated with a bioactive substance, selected from the group consisting of a drug, an enzyme a hormone, a genetic fragment, an antibiotic, or a radioactive isotope.
Claim 5
Dependent Claim
70 words
A composition according to claim 3 selected from the group consisting of compounds N-6-[3-(p-Hydroxyphenyl)propionamido]hexyl-N 2 -{N 2 ,N 6 -bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysinamide, N-6-(6"-Deoxyraffinosyl)aminohexyl-N 2 -{N 2 ,N 6 -bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysinamide, N-α-N.sup.α,N.sup.ε -Bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N-[6-(carboxyamino)hexyl]-N.sup.ε -[3-(α-D-mannopyranosylthio)propionyl]-L-lysinamide, 21-ester with dexamethasone, N 2 -{N 2 ,N 6 -Bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysine, 21-ester with dexamethasone, N-6-(5-Cholesten-3β-yloxy)hexyl-N 2 -{N 2 ,N 6 -bis[3-(α-D-mannopyranosylthio)propionyl-L-lysyl}N 6 -[3-(α-D-mannopyranosylthio)propionyl-L-lysinamide, N-6-[3-(p-Hydroxyphenyl)propionamido]hexyl-N 2 ,N 6 -bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysinamide, and Man 3 Lys 2 -Glucocerebrosidase Conjugate.
Claim 6
Dependent Claim
21 words
A compound according to claim 3 which is N 2 N 2 ,N 6 -Bis[3-(α-D-mannopyranosylthio)propionyl]-L-lysyl-N 6 -[3-(α-D-mannopyranosylthio)propionyl]-L-lysine, 21-ester with dexamethasone (10A).
Claim 7
Dependent Claim
14 words
A compound according to claim 3 which is Man 3 Lys 2 -glucocerebrosidase conjugate.
Claim 8
Dependent Claim
27 words
A per-o-acetylated glycopeptide according to claim 1 selected from compounds of the formula: ##STR16## wherein R is a saccharide compound selected from the group consisting of: ##STR17##
Claim 9
Dependent Claim
108 words
An intermediate compound according to claim 7 selected from the group consisting of compounds N 2 -{N 2 ,N 6 -Bis[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysine, N-6-t-Butyloxycarbonylaminohexyl-N 2 -{N 2 ,N 6 -bis[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(2,3,4,6tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysinamide, N 2 N 6 -Bis[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysine, N 2 ,N 6 -Bis[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-D-lysine, N 2 -{N 2 -{N 2 ,N 6 -Bis[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysine, N 2 -{N 2 ,N 6 -Bis[3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)propionyl]-L-lysine, N-6-t-Butyloxycarbonylaminohexyl-N 2 -{N 2 ,N 6 -bis[3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylthio)propionyl]-L-lysyl}-N 6 -[3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylthio)propionyl]-L-lysinamide, N 2 -{N 2 ,N 6 -Bis[3-(2,3,4-tri-O-acetyl-β-L-fucopyranosylthio)propionyl]-L-lysyl}-N 6 [3-(2,3,4-tri-O-acetyl-β-L-fucopyranosylthio)propionyl]-L-lysine, N 2 -{N 2 ,N 6 -Bis[(2,3,4,6-tetra-O-acetyl-α-mannopyranosylthio)acetyl]-L-lysyl}-N 6 -[(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)acetyl]-L-lysine, N-6-t-Butyloxycarbonylaminohexyl-N 2 ,N 6 -bis[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-lysinamide, N 2 ,N 5 -Bis[3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosylthio)propionyl]-L-ornithine, and Per O-acetyl-Man 9 Lys 8 .
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1986-05-30 | 1986-11-29 | 1987-05-31 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-05-30 | 1990-11-29 | 1991-05-31 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-05-30 | 1994-11-29 | 1995-05-31 | $7700.00 | Window Closed / Lapsed |