Insulin derivatives

Abstract

The present invention relates to insulin derivatives having a side chain attached either to the α-amino group of the N-terminal amino acid residue of the B chain or to the ε-amino group of a Lys residue present in the B chain of the parent insulin via an amide bond which side chain comprises at least one aromatic group; at least one free carboxylic acid group or a group which is negatively charged at neutral pH, a fatty acid moiety with 4 to 22 carbon atoms in the carbon chain; and possible linkers which link the individual components in the side chain together via amide bonds.

The invention claimed is: 
     
       1. An insulin derivative having the formula 
       
         
           
           
               
               
           
         
         wherein Ins is the parent insulin moiety which via the α-amino group of the N-terminal amino acid residue of the B chain or an ε-amino group of a Lys residue present in the B chain of the insulin moiety is bound to the CO— group in the side chain via an amide bond; 
         X 1  is a bond; 
         W is an arylene; 
         m is 0 or 1; 
         X is a bond; 
         Y is —(CR 1 R 2 ) q —NR—CO—, where R 1  is H, R 2  is H, q is 1; and R —(CH 2 ) p —COOH where p is 1 or 2; 
         Q is —(CH 2 ) r — where r is 13, 14, 15 or 16; and 
         Z is —COOH; 
       
       and any Zn 2+  complex thereof. 
     
     
       2. An insulin derivative according to  claim 1 , wherein W is phenylene. 
     
     
       3. An insulin derivative according to  claim 1 , wherein the parent insulin moiety is a des(B30) human insulin or an analogue thereof. 
     
     
       4. An insulin derivative according to  claim 1 , wherein the parent insulin moiety is selected from the group consisting of human insulin; des(B1) human insulin; desB30 human insulin; GlyA21 human insulin; GlyA21 des(B30)human insulin; AspB28 human insulin; porcine insulin; LysB28ProB29 human insulin; GlyA21ArgB31ArgB32 human insulin; and LysB3GluB29 human insulin. 
     
     
       5. An insulin derivative according to  claim 1  selected from the group consisting of N εB29 —[N—(HOOC(CH 2 ) 14 CO)—N-(carboxymethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; N εB29 —[N—(HOOC(CH 2 ) 13 CO)—N-(carboxymethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; N εB29 —[N—(HOOC(CH 2 ) 15 CO)—N-(carboxymethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; N εB29 —[N—(HOOC(CH 2 ) 16 CO)—N-(carboxymethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; N εB29 —[N—(HOOC(CH 2 ) 14 CO)—N-(carboxyethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; N εB29 —[N—(HOOC(CH 2 ) 13 CO)—N-(carboxyethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; N εB29 —[N—(HOOC(CH 2 ) 15 CO)—N-(carboxyethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; N εB29 —[N—(HOOC(CH 2 ) 16 CO)—N-(carboxyethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin; and N εB29 —[N—(HOOC(CH 2 ) 14 CO)—N-(carboxymethyl)-CH 2 —C 6 H 4 CO] des(B30) human insulin. 
     
     
       6. A pharmaceutical composition for the treatment of diabetes in a patient in need of such treatment, comprising a therapeutically effective amount of an insulin derivative according to  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
       7. A pharmaceutical composition for the treatment of diabetes in a patient in need of such treatment, 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. 
     
     
       8. A method of treating diabetes in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of an insulin derivative according to  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
       9. A method of treating diabetes in a patient in need of such a treatment, comprising administering to the patient 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.