(N.sup.Al, N.sup.Bl, N.sup.B29, carbamoyl)-(O.sup.A14, O.sup.B16, O.sup.B26 aryl) insulin derivatives

• US 3,864,325 A
• Filed: 11/13/1972
• Issued: 02/04/1975
• Est. Priority Date: 11/18/1971
• 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:
  US05/306,369
• Time in Patent Office: 813 Days
• Field of Search: 260/112.7,112.5
• 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

Abstract

Insulin derivatives which have an improved profile of hypoglycaemic activity, or which are intermediates for the production of such derivatives, are those in which at least one of the A1(glycine, B1(phenylalanine) and B29 (lysine) amino acid units is blocked by a carbamyl group or a substituted carbamyl group R1R2NCO- wherein R1 and R2 can be hydrogen, alkyl, aryl or other radicals. Masking of the initial activity is achieved by blocking tryosine hydroxyl groups with substituents which are releasable in vivo. N, N'"'"''"'"', N'"'"''"'"''"'"''"'"'- tricarbamyl and -triethylcarbamyl insulin, and Osubstituted derivatives thereof are typical compounds of the invention.

Claims

1. AN INSULIN WHICH AT LEAST ONE OF THE AMINO GROUPS OF THE A1 (GLYCINE), B1 (PHENYLALANINE) AND B29 (LYSINE) AMINO ACID UNITS IS BLOCKED BY A CARBAMYL SUBSTITUENT OR A SUBSTITUTED CARBAMYL SUBSTITUENT OF THE FORMULA R1R2NCO- WHEREIN R1 AND R2 IS HYDROGEN, LOWER ALKYL, OR PHENYL AND AT LEAST ONE OF A14, A19, B16 AND B26 TYROSINE HYDROXYL GROUPS IS SUBSTITUTED BY ACETYL, CHLOROACETYL, ETHOXYCARBONYL, GLUTARYL, STEARYL, OCTADECYLSUCCINYL, NNAPHTHOYL, CARBAMYL OR SUBSTITUTED CARBAMYL OF THE FORMULA R1R2NCO-, WHEREIN R1 AND R2 ARE AS ABOVE DEFINED.

2. A1 (Glycine), B1 (phenylalanine), B29 (lysine) N,N'"'"''"'"',N'"'"''"'"''"'"''"'"'-triethylcarbamyl insulin.

3. Substantially pure A1 (glycine)-N-carbamyl insulin.

4. An insulin according to claim 1 which is A1, B1, B29 -tricarbamyl mono-, di-, tri- or tetra-O-acetyl insulin. 5.. An insuliN according to claim 1 which is A1, B1, B29-triethylcarbamyl mono-, di-, tri- or tetra-O-acetyl insulin.

6. An insulin according to claim 1 which is A1, B1, B29-tricarbamyl mono-, di-, tri- or tetra-O-glutaryl insulin.

7. An insulin according to claim 1 which is A1, B1, B29-triethylcarbamyl mono-, di-, tri- or tetra-O-glutaryl insulin.

8. An insulin according to claim 1 which is A1, B1, B29 -tricarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.

9. An insulin according to claim 1 which is A1, B1, B29 -triethylcarbamyl mono-, di-, tri- or tetra-O-carbamyl insulin.

10. An insulin according to claim 1 in which the amino acid blocking substituent is carbamyl or ethylcarbamyl and the tyrosine hydroxyl group substituent is acetyl, glutaryl, carbamyl or ethylcarbamyl.