Insulin derivatives, processes for their preparation and their use, and pharmaceutical agents for the treatment of diabetes mellitus

Claim 2

An insulin derivative of the formula I ##STR6## in which R 1 denotes H or H-Phe R 30 represents the radical of Ala, Thr or Ser and R 31 represents a physiologically acceptable organic group of basic character of the formula X 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 α-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 1 represents H-Phe, the C-terminus --R 30 --R 31 cannot denote --Thr(Arg) m --OH, --Ala(Arg) m --OH or --Ser--(Arg) 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.

Claim 3

An insulin derivative of the formula I as claimed in claim 1, in which (a) R 1 denotes H and R 31 (a 1) denotes a physiologically acceptable group S B which blocks the carboxyl group and carries a positively charged or protonatable basic radical, (a 2.1) represents X N --S B , in which X N denotes the radical of a naturally occurring neutral L-aminoacid, (a 2.2) represents X B --S, in which X B denotes the radical of a naturally occurring basic L-aminoacid and S denotes OH or a group which blocks the carboxyl group and may or may not carry a positively charged or protonatable basic radical, (a 3.1) represents --X n --S, in which n is 2 or 3, X denotes the radicals X N , X B or both and, if all the radicals X are X N , S can denote only S B , (a 3.2) represents --X n --Y, in which n is 1 or 2, (a 3.3) represents --X B --Z, --X B --X N --Z, --X N --X B --Z or X B --X B --Z, in which Z is Y or denotes the homoserine-lactone radical, or (b) R 1 denotes H-Phe and R 31 (b 1) is as defined under (a 1), (b 2.1) is as defined under (a 2.1), (b 2.2) denotes Lys--OH, Hyl--OH, Orn--OH, Cit--OH or His--OH, (b 2.3) represents X B --S', in which S' has the meaning of S, with the exception of OH, (b 3.1) represents X--X'--OH or --X'--X--OH, in which X' is as defined under (b 2.2), (b 3.2) represents X 2 --S', (b 3.3) is as defined under (a 3.1), in which n is 3, (b 3.4) is as defined under (a 3.2) or (a 3.3), or a physiologically acceptable salt thereof.

Claim 4

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 1 denotes H or H--Phe R 30 represents the radical of Ala, Thr or Ser and R 31 represents a physiologically acceptable organic group of basic character of the formula X 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 α-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.

Claim 5

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 1 denotes H or H--Phe R 30 represents the radical of Ala, Thr or Ser and R 31 represents a physiologically acceptable organic group of basic character of the formula X 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 α-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.

Claim 6

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 1 denotes H or H--Phe R 30 represents the radical of Ala, Thr or Ser and R 31 represents --Arg--OH or --Arg--Arg--OH or an ester or an amide thereof, or one of its physiologically acceptable salts.

Claim 7

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 1 denotes H or H--Phe R 30 represents the radical of Ala, Thr or Ser and R 31 represents --Arg--OH or --Arg--Arg--OH or an ester or an amide thereof, or one of its physiologically acceptable salts.

Claim 8

A method of treating a patient suffering from diabetes mellitus which comprises administering an effective amount of a composition according to claim 3 or a pharmaceutically acceptable salt thereof.

Claim 9

A pharmaceutical composition as claimed in claim 4, wherein R 31 represents --Arg--OH.

Claim 10

A composition as claimed in claim 4, wherein R 31 represents --Arg--Arg--OH.

Claim 11

An insulin derivative of claimed in claim 1, in which R 1 represents H--Phe.

Claim 12

An insulin derivative as claimed in claim 1, in which the A chain and the (B2-29) chain have the sequence of human insulin.

Claim 13

An insulin derivative as claimed in claim 2, in which the aminoacid radicals X, X N and X B and the radicals Y and Z are in the L-configuration.

Claim 14

An insulin derivative as claimed in claim 2, in which S or S' represents (C 1 to C 6 )-alkoxy, (C 3 to C 6 )-cycloalkoxy, NH 2 , (C 1 to C 6 )-alkylamino, di-(C 1 to C 6 )-alkylamino, amino-(C 2 to C 6 )-alkoxy, (C 1 to C 4 )-alkylamino-(C 2 to C 6 )-alkoxy, di-(C 1 to C 4 )-alkylamino-(C 2 to C 6 )-alkoxy, tri-(C 1 to C 4 )-ammonio-(C 2 to C 6 )-alkoxy, amino-(C 2 to C 6 )-alkylamino, [(C 1 to C 4 )-alkylamino]-(C 2 to C 6 )-alkylamino, [di-(C 1 to C 4 )-alkylamino]-(C 2 to C 6 )-alkylamino or [tri-(C 1 to C 4 )-alkylammonio]-(C 2 to C 6 )-alkylamino and S B has one of the last eight meanings mentioned.

Claim 15

A pharmaceutical composition comprising an effective amount of an insulin derivative or a mixture of compounds according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Claim 16

An agnet as claimed in claim 3, which has a pH value between 2.5 and 8.5 and contains a suitable isotonicity agent and a suitable preservative and in which the insulin derivative of the formula I is in dissolved form or in suspension or a combination thereof.

Claim 17

An agent as claimed in claim 3, which contains a suitable buffer and has a pH value between 4.0 and 8.5.

Claim 18

An agent as claimed in claim 3, which contains between 0 and 100 μg of zinc/100 I.U.

Claim 19

An agent as claimed in claim 3, in which the insulin derivative of the formula I is in the form of an alkali metal salt or the ammonium salt.

Claim 20

An agent as claimed in claim 3, in which any desired amount of one or more insulin derivatives of the formula I is mixed with other insulin derivatives of this type in dissolved, amorphous or crystalline form or in a combination thereof in each case, independently of one another.

Claim 21

An agent as claimed in claim 3, which contains a suitable amount of an auxiliary having a delaying action.

Claim 22

An agent as claimed in claim 18, in which this delayed action principle is used in combination with the entire content of active compound or with parts thereof or one or more insulin derivatives of the formula I, in a mixture.

Claim 23

An agent as claimed in claim 3, which contains various insulin derivatives of the formula I in combination with at least two different auxiliaries having a delaying action.

Claim 24

An insulin derivative of the formula I ##STR9## in which R 1 denotes H or H-Phe, R 30 represents the radical of Ala, Thr or Ser and R 31 represents a physiologically acceptable organic group of basic character of the formula X 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 α 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 1 represents H-Phe, the C-terminus -R 30 -R 31 cannot denote -Thr(Arg) m OH, -Ala(Arg) m OH or -Ser(Arg) m OH, where m is 1 or 2, or ThrR 31 in which R 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.

Claim 25

An insulin derivative of the formula I ##STR9## in which R 1 denotes H or H-Phe, R 30 represents the radical of Ala, Thr or Ser and R 31 represents a physiologically acceptable organic group of basic character of the formula X 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 α 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 1 represents H-Phe, the C-terminus -R 30 -R 31 cannot denote -Thr(Arg) m OH, -Ala(Arg) m OH or -Ser(Arg) m OH, where m is 1 or 2, or ThrR 31 in which R 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.