Details for Patent: 8,828,923

Title:	Insulin derivatives
Abstract:	The present invention relates to insulin derivatives which are naturally occurring insulins or analogues thereof which have a side chain attached either to the .alpha.-amino group of the N-terminal amino acid residue of the B chain or to the .epsilon.-amino group of a Lys residue present in the B chain of the parent insulin, the side chain being of the general formula: --W--X--Y--Z wherein W, X, Y and Z are as defined in the disclosure.
Inventor(s):	Jonassen; Ib (Valby, DK), Hoeg-Jensen; Thomas (Klampenborg, DK), Havelund; Svend (Bagsv.ae butted.rd, DK), Ribel-Madsen; Ulla (Virum, DK), Tagmose; Tina Moller (Ballerup, DK), Madsen; Peter (Bagsv.ae butted.rd, DK)
Assignee:	Novo Nordisk A/S (Bagsvaerd, DK)
Filing Date:	Sep 16, 2009
Application Number:	12/560,833
Claims:	1. An insulin derivative which is a naturally occurring insulin or an analogue thereof which has a side chain attached to the .alpha.-amino group of the N-terminal amino acid residue of the B chain or to the .epsilon.-amino group of a Lys residue present in the B chain of the parent insulin, the side chain being of the general formula: --W--X--Y--Z wherein W is two amino acid residues linked together via amide bonds, which chain--via an amide bond--is linked to the .alpha.-amino group of the N-terminal amino acid residue of the B chain or to the .epsilon.-amino group of a Lys residue present in the B chain of the parent insulin, the amino acid residues of W being selected from the group of amino acid residues having a neutral side chain and amino acid residues having a carboxylic acid group in the side chain so that W has at least one amino acid residue which has a carboxylic acid group in the side chain; X is --CO--; Y is --(CH.sub.2).sub.m-- where m is an integer in the range of 6 to 32; and Z is --COOH; and any Zn.sup.2+complexes thereof. 2. An insulin derivative according to claim 1, wherein side chain --W--X--Y--Z is attached to the .epsilon.-amino group of a Lys residue present in the B chain of the parent insulin. 3. An insulin derivative according to claim 1, wherein W is a chain composed of two .alpha.-amino acid residues of which one has from 4 to 10 carbon atoms and a free carboxylic acid group while the other has from 2 to 11 carbon atoms but no free carboxylic acid group. 4. An insulin derivative according to claim 3 wherein W is selected from the group consisting of .alpha.-Asp-Gly; Gly-.alpha.-Asp; .beta.-Asp-Gly; Gly-.beta.-Asp; .alpha.-Glu-Gly; Gly-.alpha.-Glu; .gamma.-Glu-Gly; Gly-.gamma.-Glu; .alpha.-hGlu-Gly; Gly-.alpha.-hGlu; .delta.-hGlu-Gly; and Gly-.delta.-hGlu. 5. An insulin derivative according to claim 1, wherein W is a chain composed of two .alpha.-amino acid residues, independently having from 4 to 10 carbon atoms, and both having a free carboxylic acid group. 6. An insulin derivative according to claim 5, wherein W is selected from the group consisting of .alpha.-Asp-.alpha.-Asp; .alpha.-Asp-.alpha.-Glu; .alpha.-Asp-.alpha.-hGlu; .alpha.-Asp-.beta.-Asp; .alpha.-Asp.gamma.-Glu; .alpha.-Asp-.delta.-hGlu;.beta.-Asp-.alpha.-Asp; .beta.-Asp-.alpha.-Glu; .beta.-Asp-.alpha.-hGlu; .beta.-Asp-.beta.-Asp; .beta.-Asp-.gamma.-Glu; .beta.-Asp-.delta.-hGlu; .alpha.-Glu-.alpha.-Asp; .alpha.-Glu-.alpha.-Glu; .alpha.-Glu-.alpha.-hGlu; .alpha.-Glu-.beta.-Asp; .alpha.-Glu-.gamma.-Glu; .alpha.-Glu-.delta.-hGlu; .gamma.-Glu-.alpha.-Asp; .gamma.-Glu-.alpha.-Glu; .gamma.-Glu-.alpha.-hGlu; .gamma.-Glu-.beta.-Asp; .gamma.-Glu-.gamma.-Glu; .gamma.-Glu-.delta.-hGlu; .alpha.-hGlu-.alpha.-Asp; .alpha.-hGlu-.alpha.-Glu; .alpha.-hGlu-.alpha.-hGlu; .alpha.-hGlu-.beta.-Asp; .alpha.-hGlu-.gamma.-Glu; .alpha.-hGlu-.delta.-hGlu; .delta.-hGlu-.alpha.-Asp; .delta.-hGlu-.alpha.-Glu; .delta.-hGlu-.alpha.-hGlu; .delta.-hGlu-.beta.-Asp; .delta.-hGlu-.gamma.-Glu; and .delta.-hGlu-.delta.-hGlu. 7. An insulin derivative according to claim 1, wherein Y is --(CH.sub.2).sub.m--where m is an integer in the range of from 12-16. 8. An insulin derivative according to claim 1, wherein the parent insulin is des(B30) human insulin. 9. An insulin derivative according to claim 1, wherein the insulin derivative is selected from the group consisting of N.sup..epsilon.B29--(N-HOOC(CH.sub.2).sub.16CO-.gamma.-Glu-N-(.gamma.-Glu- ) des(B30) human insulin; N.sup..epsilon.B29--(N-HOOC(CH.sub.2).sub.16CO-.alpha.-Glu)-N-(.beta.-Asp- ) des(B30) human insulin; and N.sup..epsilon.B29--(N-HOOC(CH.sub.2).sub.16CO-.alpha.-Glu)-N-(AspAsp) des(B30) human insulin. 10. A zinc complex of an insulin derivative according to claim 1, wherein each insulin hexamer in said complex binds two zinc ions. 11. A zinc complex of an insulin derivative according to claim 1, wherein each insulin hexamer in said complex binds three zinc ions. 12. A zinc complex of an insulin derivative according to claim 1, wherein each insulin hexamer in said complex binds four zinc ions. 13. A pharmaceutical composition for the treatment of diabetes in a patient in need of such treatment, said composition comprising a therapeutically effective amount of an insulin derivative according to claim 1 together with a pharmaceutically acceptable carrier. 14. A pharmaceutical composition for the treatment of diabetes in a patient in need of such treatment, said composition comprising a therapeutically effective amount of an insulin derivative according to claim 1 in mixture with an insulin or an insulin analogue which has a rapid onset of action, together with a pharmaceutically acceptable carrier. 15. A method of treating diabetes, said method comprising administering to a patient in need of such a treatment a therapeutically effective amount of an insulin derivative according to claim 1 together with a pharmaceutically acceptable carrier. 16. A method of treating diabetes, said method comprising administering to a patient in need of such a treatment a therapeutically effective amount of an insulin derivative according to claim 1 in mixture with an insulin or an insulin analogue which has a rapid onset of action, together with a pharmaceutically acceptable carrier.