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

• US 4,701,440 A
• Filed: 06/06/1986
• Issued: 10/20/1987
• Est. Priority Date: 07/22/1983
• Status: Expired due to Term

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Grau, Ulrich
• Primary Examiner(s): Waddell, Frederick E.
• Application Number:
  US06/873,456
• Time in Patent Office: 501 Days
• Field of Search: 530/303, 514/3, 514/4
• US Class Current: 514/6.3
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 14/622 at least 1 amino acid in D-form
• CPC Class Codes: Y10S 930/26 Containing cys-cys disulfide bridge between nonadjacent cysteine residues

Abstract

The invention relates to insulin derivatives of the formula I ##STR1## in which R¹ denotes H or H--Phe, R³⁰ represents the radical of a neutral L-aminoacid and R³¹ 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.

Claims

1. An insulin derivative of the formula I ##STR6## in which R¹ denotes H or H-Phe

R³⁰ represents the radical of Ala, Thr or Ser and

R³¹ 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 R¹ represents H-Phe, the C-terminus --R³⁰ --R³¹ 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.

2. An insulin derivative of the formula I as claimed in claim 1, in which

(a)

R¹ denotes H and

R³¹

(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)

R¹ denotes H-Phe and

R³¹

(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 X₂ --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.

8. An insulin derivative of claimed in claim 1, in which R¹ represents H--Phe.

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

10. 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.

11. An insulin derivative as claimed in claim 2, in which S or S'"'"' represents (C₁ to C₆)-alkoxy, (C₃ to C₆)-cycloalkoxy, NH₂, (C₁ to C₆)-alkylamino, di-(C₁ to C₆)-alkylamino, amino-(C₂ to C₆)-alkoxy, (C₁ to C₄)-alkylamino-(C₂ to C₆)-alkoxy, di-(C₁ to C₄)-alkylamino-(C₂ to C₆)-alkoxy, tri-(C₁ to C₄)-ammonio-(C₂ to C₆)-alkoxy, amino-(C₂ to C₆)-alkylamino, [(C₁ to C₄)-alkylamino]-(C₂ to C₆)-alkylamino, [di-(C₁ to C₄)-alkylamino]-(C₂ to C₆)-alkylamino or [tri-(C₁ to C₄)-alkylammonio]-(C₂ to C₆)-alkylamino and S^B has one of the last eight meanings mentioned.

12. 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.

3. 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 R¹ denotes H or H--Phe

R³⁰ represents the radical of Ala, Thr or Ser and

R³¹ 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.

5. 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.

13. 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.

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

15. An agent as claimed in claim 3, which contains between 0 and 100 μ

g of zinc/100 I.U.

16. 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.

17. 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.

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

19. 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.

20. 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.

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. ##STR8## in which R¹ denotes H or H--Phe

R³⁰ represents the radical of Ala, Thr or Ser and

R³¹ represents --Arg--OH or --Arg--Arg--OH or an ester or an amide thereof, or one of its physiologically acceptable salts.

6. A pharmaceutical composition as claimed in claim 4, wherein R³¹ represents --Arg--OH.

7. A composition as claimed in claim 4, wherein R³¹ represents --Arg--Arg--OH.

21. An insulin derivative of the formula I ##STR9## in which R¹ denotes H or H-Phe,

R³⁰ represents the radical of Ala, Thr or Ser and

R³¹ 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 R¹ represents H-Phe, the C-terminus -R³⁰ -R³¹ cannot denote -Thr(Arg)_m OH, -Ala(Arg)_m OH or -Ser(Arg)_m OH, where m is 1 or 2, or ThrR³¹ in which R³¹ 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.