Peptide derivatives

Abstract

The present invention relates to derivatives of insulin and insulin analogues wherein the N-terminal amino group of the B-chain and/or the ε-amino group of Lys in position B28, B29 or B30 has a substituent of the formula —CO—W—COOH wherein W is a divalent long chain hydrocarbon group having from 12 to 22 carbon atoms and zinc complexes thereof are soluble at physiological pH values and exhibit a long disappearance half-life from the injection site after subcutaneous injection.

What we claim is:  
     
         1 . An insulin derivative having the sequence shown in Formula I:  
       
         
           
                 
                 
               
                     
                 
                   Formula I 
                     
                 
                 
                 
                 
               
                   A-Chain              S                     S 
                     
                     
                 
                                        |   7               | 
                 
                   Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser- 
                   (SEQ ID No. 1) 
                 
                    1   2   3   4   5   6   |   8   9   10  11  12 
                 
                                            S 
                 
                                            | 
                 
                     
                 
                   B-Chain                  S 
                 
                                            | 
                 
                   Xaa-Val-Xaa-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val- 
                   (SEQ ID No. 2) 
                 
                    1   2   3   4   5   6   7   8   9   10  11  12 
                 
                                                20 
                 
                     
                 
                   Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Xaa 
                 
                    13  14  15  16  17  18  19  |   21 
                 
                                                  S 
                 
                                            | 
                 
                                            S 
                 
                                            | 
                 
                   Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe- 
                 
                    13  14  15  16  17  18  19  20  21  22  23  24 
                 
                     
                 
                   Phe-Tyr-Thr-Xaa-Xaa-Xaa 
                 
                    25  26  27  28  29  30 
                 
                     
                 
             
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein 
 Xaa at positions A21 and B3 are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys;  
 Xaa at position B1 is (a) Phe, which is optionally substituted in the amino group with a substituent of the formula —CO—W—COOH wherein W is a divalent long chain hydrocarbon group having from 12 to 22 carbon atoms; or (b) deleted, in which case the amino group of Val at position B2 is either free or has a substituent of the formula —CO—W—COOH as defined above;  
 Xaa at position B28 is (a) Pro, in which case Xaa at position B29 is Lys which optionally, in its ε-amino group, has a substituent of the formula —CO—W—COOH as defined above; (b) Asp or Ser, in any of which cases Xaa at position B29 is Lys which optionally, in its ε-amino group, has a substituent of the formula —CO—W—COOH as defined above; or (c) Lys which optionally, in its ε-amino group, has a substituent of the formula —CO—W—COOH as defined above, in which case, whether the ε-amino group of the Lys has the optional substituent or not, Xaa at position B29 is Pro;  
 Xaa at position B30 is (a) Thr; (b) Ala; or (c) deleted; and any zinc complexes thereof, provided that the insulin derivative of formula I has at least one lipophilic substituent of the formula —CO—W—COOH.  
 
     
     
         2 . The insulin derivative according to  claim 1 , wherein Xaa at position A21 is an amino acid residue selected from the group comprising Ala, Gln, Gly, Ser and Asn.  
     
     
         3 . The insulin derivative according to  claim 2 , wherein Xaa at position A21 is Asn.  
     
     
         4 . The insulin derivative according to  claim 1 , wherein Xaa at position B3 is an amino acid residue selected from the group comprising Asp, Gln, Thr and Asn.  
     
     
         5 . The insulin derivative according to  claim 4 , wherein Xaa at position B3 is Asn.  
     
     
         6 . The insulin derivative according to  claim 1 , wherein Xaa at position B1 is Phe.  
     
     
         7 . The insulin derivative according to  claim 1 , wherein the amino acid at position B1 is deleted.  
     
     
         8 . The insulin derivative according to  claim 1 , wherein Xaa at position B28 is Pro and Xaa at position B29 is Lys.  
     
     
         9 . The insulin derivative according to  claim 1 , wherein Xaa at position B28 is Ser and Xaa at position B29 is Lys.  
     
     
         10 . The insulin derivative according to  claim 1 , wherein Xaa at position B28 is Lys and Xaa at position B29 is Pro.  
     
     
         11 . The insulin derivative according to  claim 1 , wherein Xaa at position B30 is Thr.  
     
     
         12 . The insulin derivative according to  claim 1 , wherein Xaa at position B30 is Ala.  
     
     
         13 . The insulin derivative according to  claim 1 , wherein Xaa at position B30 is deleted.  
     
     
         14 . The insulin derivative according to  claim 1 , wherein Xaa at position B1 is Phe and wherein solely the amino group of this Phe has a substituent of the general formula —CO—W—COOH.  
     
     
         15 . The insulin derivative according to  claim 1 , wherein Xaa at position B1 is deleted and wherein solely the amino group of Val in position B2 has a substituent of the general formula —CO—W—COOH.  
     
     
         16 . The insulin derivative according to  claim 1 , wherein solely the ε-amino group of Lys at position B28 has a substituent of the general formula —CO—W—COOH.  
     
     
         17 . The insulin derivative according to  claim 1 , wherein solely the ε-amino group of Lys at position B29 has a substituent of the general formula —CO—W—COOH.  
     
     
         18 . The insulin derivative according to  claim 1 , wherein Xaa at position B1 is Phe having a substituent of the general formula —CO—W—COOH in the amino group and Xaa at position B28 is Lys having a substituent of the general formula —CO—W—COOH in the ε-amino group.  
     
     
         19 . The insulin derivative according to  claim 1 , wherein Xaa at position B1 is Phe having a substituent of the general formula —CO—W—COOH in the amino group and Xaa at position B29 is Lys having a substituent of the general formula —CO—W—COOH in the ε-amino group.  
     
     
         20 . The insulin derivative according to  claim 1 , wherein the amino acid at position B1 is deleted and Val at position B2 has a substituent of the general formula —CO—W—COOH in the amino group and Xaa at position B28 is Lys having a substituent of the general formula —CO—W—COOH in the ε-amino group.  
     
     
         21 . The insulin derivative according to  claim 1 , wherein the amino acid at position B1 is deleted and Val at position B2 has a substituent of the general formula —CO—W—COOH in the amino group and Xaa at position B29 is Lys having a substituent of the general formula —CO—W—COOH in the ε-amino group.  
     
     
         22 . The insulin derivative according to  claim 1 , wherein W is selected from the group comprising —(CH 2 ) 12 —, —(CH 2 ) 14 —, —(CH 2 ) 16 —, —(CH 2 ) 18 —, —(CH 2 ) 20 — and —(CH 2 ) 22 —.  
     
     
         23 . 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.  
     
     
         24 . A pharmaceutical composition according to  claim 23 , further comprising an insulin or an insulin analogue which has a rapid onset of action.  
     
     
         25 . A method of treating diabetes in a patient in need of such a treatment, comprising administering to the patient a pharmaceutical composition according to  claim 23 .  
     
     
         26 . A method of treating diabetes in a patient in need of such a treatment, comprising administering to the patient a pharmaceutical composition according to  claim 24.