Nova Patents
EP0140084A1

Process for the preparation of insulin derivatives with a C-terminally elongated B-chain, basically modified insulin derivatives, compositions containing them and their use.

Abstract

The invention relates to a method for producing insulin derivatives of the formula I,in which R1 H or H-Phe means R30 stands for the remainder of a naturally occurring L-amino acid and R31 stands for a physiologically harmless organic group of neutral or basic character and which has an isoelectric point above 5.8, which is characterized in that a) an insulin of the formula I, in which R30 represents the rest of a genetically encodable L-amino acid and R31 represents OH or a protective group of the carboxy function, or b) a proinsulin, proinsulin analog, preproinsulin or propeinsulin analog with a peptide or amino acid derivative of the formula HR30-R31 in the presence of an endopeptidase at a pH below the isoelectric point of the insulins, and any protective groups introduced are split off. The invention further relates to new, basic modified insulin derivatives, agents containing them and their use.

EP0140084A1, drawing sheet 1
Sheet 1 of 16

Term

Term ended

Projected expiry passed 11 September 2004, 22 years ago.

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51 claims: 3 independent, 48 dependent

  1. 1
    Process for the preparation of an insulin derivative of the formula I, in which R 1 H or H-Phe means a) R 30 stands for the rest of a neutral, naturally occurring L-amino acid and R 31 stands for a physiologically harmless organic group of basic character with up to 50 C atoms, in whose construction 0 to 3 a-amino acids are involved and any terminal carboxy function which may be present, freely, as an ester function, as a lactone or to CH 2 0H may be reduced, or b ) R 30 stands for the rest of a basic, naturally occurring L-amino acid and R 31 stands for a physiologically harmless organic group of neutral or basic character with up to 50 C atoms, in whose structure 0 to 3 a-amino acids are involved and their terminal carboxy function which may be present freely, as an ester function, as an amide function, as a lactone or to CH 20H may be reduced, and which has an isoelectric point above 5.8, characterized in that a) an insulin of formula I, in which R l H or H-Phe means R 30 means the rest of a genetically encodable L-amino acid and R 3 1 For O H or a protective group of the carboxy function, or b) a proinsulin, proinsulin analog, preproinaulin or preproinsulin analog of the formula II in which the C chain and X together represent a sequence of genetically encodable L-amino acids, Z R- or H- (D) m -Y- (Phe) n - M and n independently of one another are 0 or 1, D is a genetically encodable presequence of L-amino acids and Y is Arg or Lys, with a peptide or amino acid derivative of the formula III in which a) R 30 represents the rest of a neutral naturally occurring L-amino acid and R 3 1 stands for a physiologically harmless organic group of basic character with up to 50 C atoms, in whose structure 0 to 3 a-amino acids are involved and their. optionally present terminal carbox function freely, as an ester function, as an amide function, as a lactone or to CH 2 OH may be reduced, or b ) R 30 stands for the rest of a basic, naturally occurring L-amino acid and R 31 stands for a physiologically harmless organic group of neutral or basic character with up to 50 C atoms, the other structures of which involve 0 to 3 a-amino acids and their terminal carboxy function which may be present freely, as an ester function, as an amide function, as a lactone or to CH 2 OH may be reduced, in the presence of trypsin or a trypsin-like endopeptidase in water, if appropriate with the addition of a suitable organic solvent, at a pH below the isoelectric point of the insulins, and any protective groups introduced are split off.
  2. 9
    Insulin derivative of the formula I, in which R 30 stands for the rest of a basic, naturally occurring L-amino acid and R 3 1 stands for a physiologically harmless organic group of neutral or basic character with up to 50 C atoms, in whose structure 0 to 3 a-amino acids are involved and any terminal carboxy function which may be present freely, as an ester function, as an amide function, as a lactone or to CH 2 OH can be reduced, characterized by an isoelectric point greater than 5.8 and its physiologically acceptable salts.
  3. 27
    1. Process for the preparation of an insulin derivative of the formula I, in which R 1 H or H-Phe means a) R 30 stands for the rest of a neutral, naturally occurring L-amino acid and R 3 1 stands for a physiologically harmless organic group of basic character with up to 50 C atoms, in whose construction 0 to 3 a-amino acids are involved and any terminal carboxy function which may be present, freely, as an ester function, as a lactone or to CH 2 0H may be reduced, or b ) R 30 stands for the rest of a basic, naturally occurring L-amino acid and R 31 stands for a physiologically harmless organic group of neutral or basic character with up to 50 C atoms, in whose structure 0 to 3 a-amino acids are involved and their terminal carboxy function which may be present freely, as an ester function, as an amide function, as a lactone or to C. H20H may be reduced, and which has an isoelectric point above 5, 8, characterized in that a) an insulin of formula I, in which R 1 H or H-Phe means R 3 0 means the rest of a genetically encodable L-amino acid and R 31 represents OH or a protective group of the carboxy function, or b) a proinsulin, proinsulin analog, preproinsulin or preproinsulin analog of formula II in which the C chain and X together represent a sequence of genetically encodable L-amino acids, Z H- or H- (D) m -Y- (Phe) n - M and n are independently 0 or 1, D is a genetically encodable presequence of L-amino acids and Y Arg or Lys, with a peptide or amino acid derivative of the formula III in which a ) R 30 represents the rest of a neutral naturally occurring L-amino acid and R 31 stands for a physiologically harmless organic group of basic character with up to 50 C atoms, in whose structure 0 to 3 a-amino acids are involved and any terminal carboxy function which may be present is free, as an ester function, as an amide function, as a lactone or to CH 2 0H may be reduced, or b) R 30 stands for the rest of a basic, naturally occurring L-amino acid and R 31 stands for a physiologically harmless organic group of neutral or basic character with up to 50 C atoms, in whose structure 0 to 3 a-amino acids are involved and any terminal carboxy function which may be present freely, as an ester function, as an amide function, as a lactone or to CH 2 0H may be reduced, in the presence of trypsin or a trypsin-like endopeptidase in water, if appropriate with the addition of a suitable organic solvent, at a pH below the isoelectric point of the insulins, and any protective groups introduced are split off.
Independent claims3