Insulin derivatives, processes for their preparation and their use, and pharmaceutical agents for the treatment of diabetes mellitus
AssigneeHoechst Aktiengesellschaft
InventorUlrich Grau
Life of this patent
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Abstract
The invention relates to insulin derivatives of the formula I ##STR1## in which R.sup.1 denotes H or H--Phe, R.sup.30 represents the radical of a neutral L-aminoacid and R.sup.31 represents a physiologically acceptable organic group of basic character with up to 50 carbon atoms, these derivatives having an isoelectric point between 5.8 and 8.5, processes for their preparation and their use, and agents containing these derivatives for the treatment of diabetes mellitus.
Claims21
An insulin derivative of the formula I ##STR6## in which R.sup.1 denotes H or H-Phe
- R.sup.30 represents the radical of Ala, Thr or Ser and
- R.sup.31 represents a physiologically acceptable organic group of basic character of the formula X.sub.n -S which has up to 50 carbon atoms, in which
- n is 0, 1, 2 or 3,
- X represents identical or different radicals of naturally occurring neutral or basic .alpha.-amino acids and
- S denotes OH or a physiologically acceptable group which blocks the carboxyl group but S being, if n is 0, a positively charged or protonatable basic radical or, if n is greater than 0, S can carry such a radical, or in which, if n is 2 or 3, the C-terminus X-S can also represent the homoserine lactone radical,
- and which contains or does not contain a terminal carboxyl group or an ester or an amide thereof, and wherein, if R.sup.1 represents H-Phe, the C-terminus --R.sup.30 --R.sup.31 cannot denote --Thr(Arg).sub.m --OH, --Ala(Arg).sub.m --OH or --Ser--(Arg).sub.m --OH, where m is 1 or 2, which has an isoelectric point between 5.8 and 8.5, or a physiologically acceptable salt thereof.
A pharmaceutical composition comprising an effective amount of an insulin derivative, with an isoelectric point between 5.8 and 8.5, of the formula I, ##STR7## in which R.sup.1 denotes H or H--Phe
- R.sup.30 represents the radical of Ala, Thr or Ser and
- R.sup.31 represents a physiologically acceptable organic group of basic character of the formula X.sub.n --S which has up to 50 carbon atoms, in which
- n is 0, 1, 2 or 3,
- X represents identical or different radicals of naturally occurring neutral or basic .alpha.-amino acids and
- S denotes OH or a physiologically acceptable group which blocks the carboxyl group but S being, if n is 0, a positively charged or protonatable basic radical or, if n is greater than 0, S can carry such a radical, or in which, if n is 2 or 3, the C-terminus X-S can also represent the homoserine lactone radical,
- and which contains or does not contain a terminal carboxyl group or an ester or an amide thereof, or one of its physiologically acceptable salts.
A pharmaceutical composition comprising an effective amount of an insulin derivative, with an isoelectric point between 5.8 and 8.5, of the formula I. ##STR8## in which R.sup.1 denotes H or H--Phe
- R.sup.30 represents the radical of Ala, Thr or Ser and
- R.sup.31 represents --Arg--OH or --Arg--Arg--OH or an ester or an amide thereof, or one of its physiologically acceptable salts.
An insulin derivative of the formula I ##STR9## in which R.sup.1 denotes H or H-Phe,
- R.sup.30 represents the radical of Ala, Thr or Ser and
- R.sup.31 represents a physiologically acceptable organic group of basic character of the formula X.sub.n -S which has up to 50 carbon atoms, in which
- n is 0, 1, 2 or 3,
- X represents identical or different radicals of
- naturally occurring neutral or basic .alpha. amino acids and
- S denotes OH or a physiologically acceptable group which blocks the carboxyl group but S being, if n is 0, a positively charged or protonatable basic radical or, if n is greater than 0, S can carry such a radical, or in which, if n is 2 or 3, the C-terminus X-S can also represent the homoserine lactone radical,
- and the terminal group is a carboxyl group or an ester or an amide thereof, and wherein, if R.sup.1 represents H-Phe, the C-terminus -R.sup.30 -R.sup.31 cannot denote -Thr(Arg).sub.m OH, -Ala(Arg).sub.m OH or -Ser(Arg).sub.m OH, where m is 1 or 2, or ThrR.sup.31 in which R.sup.31 is (a) an amino acid, (b) a peptide or (c) an amide or ester of (a) or (b),
- which has an isoelectric point between 5.8 and 8.5, or a physiologically acceptable salt thereof.
Dependencies are inferred from the claim text.