Process for the manufacture of insulin, analogs and derivatives thereof

Abstract

A process for manufacture of insulin, analogs and derivatives thereof by treating an insulin compound wherein the A- and B-chains are linked by a bis-methionyl-carbonyl-bridge, with cyano bromide.

We claim: 
     
       1. A method for making an insulin compound of the formula ##STR7## and biologically-active analogs thereof in which one or more amino acids have been exchanged for other, preferably simpler, amino acids or in which the chains are modified, preferably shortened, and in which Y is hydrogen or acyl, which method comprises treating a compound of the formula ##STR8## or an analog thereof as hereinbefore defined, wherein R is ##STR9## Met is methionine, n is an integer from 1 to 4, and one --(CH 2 )-- may be replaced by oxygen, with cyano bromide in an acid medium. 
     
     
       2. An insulin compound of the formula ##STR10## wherein Y is hydrogen or acyl, R is ##STR11## Met is methionine, n is an integer from 1 to 4, and one --(CH 2 )-- group may be replaced by oxygen, and biologically-active analogs thereof in which one or more amino acids have been exchanged for other, preferably simpler, amino acids or in which the chains are modified, preferably shortened. .Iadd. 
     
     
       3.  A method for making an insulin compound of the formula ##STR12##.Iaddend. and biologically-active analogs thereof in which one or more amino acids have been exchanged for other, preferably simpler, amino acids or in which the chains are modified preferably shortened, and in which Y is hydrogen or acyl, which method comprises reacting an insulin A-chain fragment, an insulin B-chain fragment, and a bridging agent of the formula ##STR13## Met is methionine, n is an integer from 1 to 4, and one --(CH 2 )-- may be replaced by oxygen, and OV is an activated ester of methionine, to form a compound of the formula ##STR14## oxidizing the --SX groups to form a compound of the formula ##STR15## and then treating said last-mentioned compound with cyano bromide in an acid medium. .Iadd. 
     
     
       4.  A method for making an insulin compound which comprises reacting an A-chain fragment of insulin, a B-chain fragment of insulin, and an activated ester of a bridging agent of the formula ##STR16##.Iaddend. where met is methionine and n is an integer from 1 to 4, oxidizing the resulting compound to form disulfide crosslinks between the A-chain and B-chain, and then treating the product with cyano bromide in an acid medium.