N-Acylated, O-substituted insulin derivatives

• US 3,868,356 A
• Filed: 01/26/1972
• Issued: 02/25/1975
• Est. Priority Date: 01/28/1971
• Status: Expired due to Term

• Current Assignee: Derek George Smyth
• Original Assignee: Derek George Smyth
• Inventors: Smyth, Derek George
• Primary Examiner(s): Gotts, Lewis
• Assistant Examiner(s): Suyat, Reginald J.
• Application Number:
  US05/221,059
• Time in Patent Office: 1,126 Days
• Field of Search: 260/112.7,112.5 424/178
• US Class Current: 530/303
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 14/625 Extraction from natural sources

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.

Claims

1. 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.

2. An insulin according to claim 1 in which at least one of the tyrosine hydroxyl groups is blocked by carbamyl.

3. An insulin according to claim 1 in which the acid is succinic acid.

4. An insulin according to claim 1 in which two of the amino groups are substituted.

5. An insulin according to claim 4 in which the A1 and B1 amino groups are substituted.

6. An insulin according to claim 4 in which the A1 and B29 amino groups are substitued.

7. An insulin according to claim 4 which is tri-N-substituted.

8. 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.

9. An insulin according to claim 1 in which two or more of the hydroxyl groups are substituted.

10. An insulin according to claim 1 in which the hydroxyl blocking sutstituent is carbamyl.

11. An insulin according to claim 1 wherein the acid is glutaric acid.

12. An insulin according to claim 1 wherein the acid is selected from the group consisting of maleic acid, monomethylmaleic acid and dimethylmaleic acid.

13. An insulin according to claim 1 in which at least one of the tyrosine hydroxyl groups is blocked by acetyl or glutaryl.

14. An A1(glycine)-N-succinyl-B1(phenylalanine), B29(lysine)-N'"'"''"'"', N'"'"''"'"''"'"''"'"'-dicarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.

15. A B1(phenylalanine)-N-succinyl-A1(glycine), B29(lysine)-N'"'"''"'"', N'"'"''"'"''"'"''"'"'-dicarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.

16. A B29(lysine)-N-succinyl-A1(glycine), B1(phenyalanine)-N'"'"''"'"', N'"'"''"'"''"'"''"'"'-dicarbamyl mono-, di-, tri-, or tetra-O-carbamyl insulin.

17. An A1(glycine), B1(phenylalanine), B29(lysine)-N,N'"'"''"'"',N'"'"''"'"''"'"''"'"'-tri-succinyl mono-, di-, tri- or tetra-O-carbamyl insulin.

18. An A1(glycine), B1(phenylalanine), B29(lysine)-N,N'"'"''"'"',N'"'"''"'"''"'"''"'"'-tri-glutaryl mono-, di-, tri- or tetra-O-carbamyl insulin.

19. An A1(glycine), B1(phenylalanine)-N,N'"'"''"'"'-disuccinyl-B29(lysine)-N-carbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.

20. 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.

21. 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.

22. 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.