Patent US3868356A successfully refreshed from Google Patents.
US3868356A
Expired / Lapsed
US
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N-Acylated, O-substituted insulin derivatives
Assignee: National Research Development Corp UK
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Filing: 1972-01-26
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Granted: 1975-02-25
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Expires: 1992-01-26
Abstract
Abstract Insulin derivatives which are water soluble, readily isolated, immunologically acceptable and which retain hypolgycaemic activity are those in which at least one of the A1, B1 and B29 aminoacid amino groups is converted into a blocked amino group having a substituent capable of forming an anion e.g. by substitution with dicarboxylic acid radicals. An additional refinement comprises blocking tyrosine hydroxyl groups with substituents which are releasable in vivo thereby achieving latent activity which is revealed progressively in order to provide prolonged action.
Inventors
- 👤 Derek George Smyth
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-01 17:03
CPC Classifications
C; C07; C07K; C07K14/00; C07K14/435; C07K14/575; C07K14/62; C07K14/625; A; A61; A61K; A61K38/00
Claims Analysis
Total Claims: 29
Claim 1
Independent Claim
87 words
A SUBSTITUTED INSULIN IN WHICH THE SUBSTITUENTS ARE LOCATED ON ONE OR MORE OF THE AMINO GROUPS OF THE A1(GLYCINE), B1(PHENYLALANINE), AND B29(LYSINE) AMINO ACID UNITS AND ON ONE OR MORE OF THE TYROSINE HYDROXYL GROUPS, AT LEAST ONE OF SAID AMINO GROUPS IS MONOACYLATED WITH THE MONOBASIC ACYL RESIDUE OF A DICARBOXYLIC ACID CONTAINING NO MORE THAN EIGHT CARBON ATOMS, AND AT LEAST ONE OF THE TYROSINE HYDROXYL GROUPS IS BLOCKED BY AN O-SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF ACETYL, GLUTARYL, CYCLOPROPANECARBONYL, CYCLOBUTANECARBONYL AND CARBAMYL.
Claim 2
Dependent Claim
87 words
A SUBSTITUTED INSULIN IN WHICH THE SUBSTITUENTS ARE LOCATED ON ONE OR MORE OF THE AMINO GROUPS OF THE A1(GLYCINE), B1(PHENYLALANINE), AND B29(LYSINE) AMINO ACID UNITS AND ON ONE OR MORE OF THE TYROSINE HYDROXYL GROUPS, AT LEAST ONE OF SAID AMINO GROUPS IS MONOACYLATED WITH THE MONOBASIC ACYL RESIDUE OF A DICARBOXYLIC ACID CONTAINING NO MORE THAN EIGHT CARBON ATOMS, AND AT LEAST ONE OF THE TYROSINE HYDROXYL GROUPS IS BLOCKED BY AN O-SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF ACETYL, GLUTARYL, CYCLOPROPANECARBONYL, CYCLOBUTANECARBONYL AND CARBAMYL.
Claim 3
Dependent Claim
20 words
An insulin according to claim 1 in which at least one of the tyrosine hydroxyl groups is blocked by carbamyl.
Claim 4
Dependent Claim
13 words
An insulin according to claim 1 in which the acid is succinic acid.
Claim 5
Dependent Claim
15 words
An insulin according to claim 1 in which two of the amino groups are substituted.
Claim 6
Dependent Claim
16 words
An insulin according to claim 4 in which the A1 and B1 amino groups are substituted.
Claim 7
Dependent Claim
16 words
An insulin according to claim 4 in which the A1 and B29 amino groups are substitued.
Claim 8
Dependent Claim
9 words
An insulin according to claim 4 which is tri-N-substituted.
Claim 9
Dependent Claim
24 words
An insulin according to claim 1 in which one or two of the amino groups which are not acylated are carbamylated or N-alkyl carbamylated.
Claim 10
Dependent Claim
17 words
An insulin according to claim 1 in which two or more of the hydroxyl groups are substituted.
Claim 11
Dependent Claim
14 words
An insulin according to claim 1 in which the hydroxyl blocking sutstituent is carbamyl.
Claim 12
Dependent Claim
12 words
An insulin according to claim 1 wherein the acid is glutaric acid.
Claim 13
Dependent Claim
23 words
An insulin according to claim 1 wherein the acid is selected from the group consisting of maleic acid, monomethylmaleic acid and dimethylmaleic acid.
Claim 14
Dependent Claim
22 words
An insulin according to claim 1 in which at least one of the tyrosine hydroxyl groups is blocked by acetyl or glutaryl.
Claim 15
Dependent Claim
10 words
An A1(glycine)-N-succinyl-B1(phenylalanine), B29(lysine)-N'', N''''-dicarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 16
Dependent Claim
10 words
An A1(glycine)-N-succinyl-B1(phenylalanine), B29(lysine)-N'', N''''-dicarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 17
Dependent Claim
10 words
A B1(phenylalanine)-N-succinyl-A1(glycine), B29(lysine)-N'', N''''-dicarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 18
Dependent Claim
10 words
A B1(phenylalanine)-N-succinyl-A1(glycine), B29(lysine)-N'', N''''-dicarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 19
Dependent Claim
10 words
A B29(lysine)-N-succinyl-A1(glycine), B1(phenyalanine)-N'', N''''-dicarbamyl mono-, di-, tri-, or tetra-O-carbamyl insulin.
Claim 20
Dependent Claim
10 words
A B29(lysine)-N-succinyl-A1(glycine), B1(phenyalanine)-N'', N''''-dicarbamyl mono-, di-, tri-, or tetra-O-carbamyl insulin.
Claim 21
Dependent Claim
10 words
An A1(glycine), B1(phenylalanine), B29(lysine)-N,N'',N''''-tri-succinyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 22
Dependent Claim
10 words
An A1(glycine), B1(phenylalanine), B29(lysine)-N,N'',N''''-tri-succinyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 23
Dependent Claim
10 words
An A1(glycine), B1(phenylalanine), B29(lysine)-N,N'',N''''-tri-glutaryl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 24
Dependent Claim
10 words
An A1(glycine), B1(phenylalanine), B29(lysine)-N,N'',N''''-tri-glutaryl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 25
Dependent Claim
9 words
An A1(glycine), B1(phenylalanine)-N,N''-disuccinyl-B29(lysine)-N-carbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 26
Dependent Claim
9 words
An A1(glycine), B1(phenylalanine)-N,N''-disuccinyl-B29(lysine)-N-carbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.
Claim 27
Dependent Claim
107 words
A process for the preparation of an insulin according to claim 1 which comprises acylating one or more of the A1, B1 and B29 amino groups with an excess of 2 to 3 moles for each of said amino groups of a dicarboxylic acid halide or anhydride containing no more than eight carbon atoms, per mole of insulin for the mono- and di-substituted insulins and an excess of about 10 moles for each of said amino groups per mole of insulin for tri-substituted insulins and thereafter blocking at least one of the tyrosine hydroxyl groups with 10 to 50 moles of said O-substituent per mole of insulin.
Claim 28
Dependent Claim
39 words
Process according to claim 20 in which an excess of the dicarboxylic acid halide or anhydride of from two to three moles for each of said three amino groups is used thereby effecting predominantly disubstitution of said amino groups.
Claim 29
Dependent Claim
39 words
Process according to claim 20 in which an excess of the dicarboxylic acid halide or anhydride of the order of ten moles for each of said three amino groups is used thereby effectint predominantly trisubstitution of said amino groups.
References Cited (Backward Citations)
US3308028A
Cited
US3471464A
Cited
US3481917A
Cited
US3591574A
Cited
US3684791A
Cited
US3528960A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1978-02-24 | 1978-08-26 | 1979-02-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1982-02-24 | 1982-08-26 | 1983-02-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1986-02-24 | 1986-08-26 | 1987-02-25 | $7700.00 | Window Closed / Lapsed |