Alkanedioic acid derivatives of insulin
First Claim
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1. A MONO-, DI- OR TRISIBSTITUTED 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, AT LEAST ONE OF SAID GROUPS BEING MONOACYLATED WITH THE MONOBASIC ACYL RESIDUE OF A DICARBOXYLIC ACID SELECTED FROM THE GROUP CONSISTING OF SUCCINEC ACID AND GLUTARIC ACID.
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Abstract
Insulin derivatives which are water soluble, readily isolated, immunologically acceptable and which retain hypoglycaemic 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.
18 Citations
18 Claims
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1. A MONO-, DI- OR TRISIBSTITUTED 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, AT LEAST ONE OF SAID GROUPS BEING MONOACYLATED WITH THE MONOBASIC ACYL RESIDUE OF A DICARBOXYLIC ACID SELECTED FROM THE GROUP CONSISTING OF SUCCINEC ACID AND GLUTARIC ACID.
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2. An insulin according to claim 1, in which the acid is succinic acid.
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3. An insulin according to claim 1 in which at least two of the recited amino groups are acylated.
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4. An insulin according to claim 3 which is tri-N substituted.
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5. An insulin according to claim 1 in which one or two of the recited amino groups which are not acylated are carbamylated or N-methyl carbamylated.
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6. An insulin according to claim 1 in which the acid is glutaric acid.
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7. A1(glycine)-N-succinyl insulin.
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8. B1(phenylalanine)-N-succinyl insulin.
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9. B29(lysine)-N-succinyl insulin.
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10. A1(glycine),B1(phenylalanine)-N,N'"'"''"'"' -disuccinyl insulin.
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11. A1(glycine), B1(phenylalanine), B29(lysine)-N,N'"'"''"'"',N'"'"''"'"''"'"''"'"'-trisuccinyl insulin.
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12. A1(glycine),B1(phenylalanine), B29(lysine)-N,N'"'"''"'"',N'"'"''"'"''"'"''"'"'-triglutaryl insulin.
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13. A1(glycine),B1(phenylalanine)N,N'"'"''"'"'-disuccinyl-B29(lysine)-N'"'"''"'"''"'"''"'"'-carbamyl insulin.
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14. A1(glycine),B29(lysine)-N,N'"'"''"'"''"'"''"'"'-disuccinyl insulin.
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15. 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 of insulin with a member selected from the group consisting of succinic anhydride and glutaric anhydride in an excess of from 2 to 10 moles for each of said amino groups per mole of insulin.
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16. A process according to claim 15 in which the product is separated from the reaction mixture by precipitation at acid pH.
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17. A process according to claim 15, in which an excess of the anhydride of from two to three moles for each amino group per mole of insulin is used thereby effecting predominantly disubstitution.
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18. A process according to claim 15, in which an excess of the anhydride of ten moles for each amino group per mole of insulin is used thereby effecting predominantly trisubstitution.
Specification