Process for the preparation of insulin derivatives, the B chain of which is lengthened c-terminally

• US 5,015,728 A
• Filed: 03/23/1988
• Issued: 05/14/1991
• Est. Priority Date: 09/17/1983
• Status: Expired due to Term

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Grau, Ulrich, Obermeier, Rainer, Geiger, Rolf
• Primary Examiner(s): Moezie, F. T.
• Application Number:
  US07/172,236
• Time in Patent Office: 1,147 Days
• Field of Search: 530/303, 530/305, 514/3
• 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: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a process for the preparation of an insulin derivative of the formula I ##STR1## in which R¹ denotes H or H-Phe, R³⁰ represents the radical of a naturally occurring L-aminoacid and R³¹ represents a physiologically acceptable organic group of neutral or basic character consisting of 1 to 3 α-aminoacids in which the terminal carboxyl function is present in the free form and which insulin derivative has an isoelectric point above 5.8, which comprises reacting an insulin of the formula I in which R³⁰ denotes the radical of a genetically codable L-aminoacid and R³¹ represents OH or a protective group of the carboxyl function, with a peptide or aminoacid derivatives of the formula R-R³⁰ -R³¹ consisting of 2 to 4 α-aminocacids, in which the terminal carboxyl function is in free form, in the presence of a trypsin-like endopeptidase at a pH value below the isoelectric point of the starting insulin.

Claims

1. A process for the preparation of an insulin derivative of formula I comprising an aqueous solvent reacting, in ndopeptidase and an insulin of formula II ##STR3## with a peptide of formula III

View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)

2. A process as claimed in claim 1, wherein said lysyl endopeptidase is in an enzyme solvent selected from the group consisting of (a) water and (b) water and an organic solvent, wherein said enzyme solvent is at a pH value below about the isoelectric point of the insulinderivative I,

3. A process as claimed in claim 1, wherein R¹ is H-Phe.

4. A process as claimed in claim 1, wherein R¹ is H.

5. A process as claimed in claim 1, wherein R³⁰ is selected from the group consisting of Ala, Thr and Ser.

6. A process as claimed in claim 1, wherein formula II represents human insulin.

7. A process as claimed in claim 1, wherein formula I represents human insulin-Arg^B 31--OH or human insulin-Arg^B 31--Arg^B 32--OH.

8. A process as claimed in claim 1, wherein said peptide of formula III comprises a peptide of formula IV

9. A process as claimed in claim 1, wherein said insulin of formula II is a porcine insulin.