Peptides derivatized with a-b-c-d- and their therapeutical use

Abstract

The invention relates to protracted peptide derivatives such as Glucagon-Like Peptide-1 (GLP-1), exendin-4, and analogues thereof, as well as therapeutic uses thereof. The peptide derivative of the invention comprises a peptide wherein at least one amino acid residue is derivatized with A-B-C-, or A-B-C-D-. These compounds are useful in the treatment or prevention of diabetes type 2 and related diseases. The compounds are potent, have a low ratio of binding affinity to the GLP-1 receptor in the presence of high/low albumin concentrations, have long half-lives, and have a high affinity of binding to albumin, all of which is of potential relevance for the overall aim of achieving long-acting, stable and active GLP-1 derivatives with a potential for once weekly administration.

1 . A peptide derivative comprising a peptide wherein at least one amino acid residue is derivatized with A-B-C-D-
 wherein A- is   
       
         
           
           
               
               
           
         
         wherein R is lower linear or branched alkyl, p is selected from the group consisting of 10, 11, 12, 13 and 14, and d is selected from the group consisting of 0, 1, 2, 3, 4 and 5, and 
         -B- is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein x is selected from the group consisting of 0, 1, 2, 3 and 4, and y is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, 
         or A is 
       
       
         
           
           
               
               
           
         
         wherein n is selected from the group consisting of 14, 15, 16 17, 18 and 19, and B is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein x is selected from the group consisting of 0, 1, 2, 3 and 4, and 
         -C- is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein b and e are each independently selected from the group consisting of 0, 1 and 2, and c and f are each independently selected from the group consisting of 0, 1 and 2 with the proviso that b is 1 or 2 when c is 0, or b is 0 when c is 1 or 2, and e is 1 or 2 when f is 0, or e is 0 when f is 1 or 2, and 
         -D- is attached to said amino acid residue and is a linker, represents a bond, or is absent. 
       
     
     
         2 . The derivative according to  claim 1 , wherein at least one amino acid residue is derivatized with A-B-C-. 
     
     
         3 . The derivative according to  claim 1 , wherein said peptide is a GLP-1 peptide selected from GLP-1(7-37) and an analogue of GLP-1(7-37), wherein, in said peptide, at least one amino acid residue is derivatised with A-B-C-, or A-B-C-D-. 
     
     
         4 . The derivative according to  claim 3 , wherein the derivatised amino acid residue comprises an amino group. 
     
     
         5 . The derivative according to  claim 4 , wherein the derivatised amino acid residue is lysine. 
     
     
         6 . The derivative according to  claim 5 , wherein the linker comprises at least 5 non-hydrogen atoms, 30-50% of which are either N or O. 
     
     
         7 . The derivative according to  claim 6 , wherein D is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein k is selected from the group consisting of 0, 1, 2, 3, 4, 5, 11 and 27, and m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6, and D is attached to the amino acid residue in the end depicted with *. 
       
     
     
         8 . The derivative according to  claim 1 , wherein said GLP-1 analogue comprises an amino acid sequence according to formula (I): 
       
         
           
                 
               
                   Formula (I) 
                 
                 
               
                   (SE0 ID No: 2) 
                 
                 
               
                   Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -Ser- 
                 
                     
                 
                   Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Ala-Xaa 25 -Xaa 26 - 
                 
                     
                 
                   Xaa 27 -Phe-Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35 - 
                 
                     
                 
                   Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -Xaa 41 -Xaa 42 -Xaa 43 - 
                 
                     
                 
                   Xaa 44 -Xaa 45 -Xaa 46   
                 
             
                
               
            
             
                
               
            
             
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7  is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, Na-acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 2(3H-imidazol-4-yl)acetyl, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; 
         Xaa s  is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid; 
         Xaa 16  is Val, or Leu; 
         Xaa 18  is Ser, Lys, or Arg; 
         Xaa 19  is Tyr, or Gln; 
         Xaa 20  is Leu, Met, or Lys; 
         Xaa 22  is Gly, Glu, or Aib; 
         Xaa 23  is Gln, Glu, Lys, or Arg; 
         Xaa 25  is Ala, or Val; 
         Xaa 26  is Lys, Glu, or Arg; 
         Xaa 27  is Glu, or Leu; 
         Xaa 30  is Ala, Glu, Lys, or Arg; 
         Xaa 33  is Val, Thr(O-benzyl), or Lys; 
         Xaa 34  is Lys, Glu, Gln, Asn, or Arg; 
         Xaa 35  is Gly, Aib, or absent; 
         Xaa 36  is Arg, Gly, Lys, or absent; 
         Xaa 37  is Gly, Ala, Glu, Pro, Lys, epsilon-amino-Lys, amide or is absent; 
         Xaa 38  is Lys, Ser, amide, or is absent; 
         Xaa 39  is Ser, Lys, amide, or is absent; 
         Xaa 40  is Gly, amide, or is absent; 
         Xaa 41  is Ala, amide, or is absent; 
         Xaa 42  is Pro, amide, or is absent; 
         Xaa 43  is Pro, amide, or is absent; 
         Xaa 44  is Pro, amide, or is absent; 
         Xaa 45  is Ser, amide, or is absent; 
         Xaa 46  is amide, or is absent; 
         provided that if Xaa 38 , Xaa 39 , Xaa 40 , Xaa 41 , Xaa 42 , Xaa 43 , Xaa 44 , Xaa 45  or Xaa 46  is absent then each amino acid residue downstream is also absent. 
       
     
     
         9 . The derivative according to  claim 1 , wherein said GLP-1 analogue comprises an amino acid sequence according to formula (II): 
       
         
           
                 
               
                   Formula (II) 
                 
                 
               
                   (SE0 ID No: 3) 
                 
                 
               
                   Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser- 
                 
                     
                 
                   Xaa 18 -Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Ala-Ala-Xaa 26 -Glu- 
                 
                     
                 
                   Phe-Ile-Xaa 30 -Trp-Leu-Val-Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 - 
                 
                     
                 
                   Xaa 38   
                 
             
                
               
            
             
                
               
            
             
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7  is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 2(3H-imidazol-4-yl)acetyl, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; 
         Xaa 8  is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid; 
         Xaa 18  is Ser, Lys, or Arg; 
         Xaa 22  is Gly, Glu, or Aib; 
         Xaa 23  is Gln, Glu, Lys, or Arg; 
         Xaa 26  is Lys, Glu, or Arg; 
         Xaa 30  is Ala, Glu, Lys, or Arg; 
         Xaa 34  is Lys, Glu, Gln, or Arg; 
         Xaa 35  is Gly, Aib, or absent; 
         Xaa 36  is Arg, Lys, or absent; 
         Xaa 37  is Gly, Ala, Glu, Pro, Lys, or epsilon-amino-Lys; 
         Xaa 38  is Lys, amide, or is absent. 
       
     
     
         10 . The derivative according to  claim 1 , wherein said GLP-1 analogue comprises an amino acid sequence according to formula (III) which is derivatised in position 18, 23, 26, 30, 31, 34, 36, 37 or 38: 
       
         
           
                 
               
                   Formula (III) 
                 
                 
               
                   (SE0 ID No: 6) 
                 
                 
               
                   Xaa 7 -Xaa 8 -Xaa 9 -Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -Ser- 
                 
                     
                 
                   Xaa 18 -Tyr-Leu-Glu-Glu-Xaa 23 -Ala-Xaa 25 -Arg-Xaa 27 - 
                 
                     
                 
                   Phe-Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 - 
                 
                     
                 
                   Xaa 37 -Xaa 38 -Xaa 39   
                 
             
                
               
            
             
                
               
            
             
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7 -Xaa 8  is 2(3H-imidazol-4-yl)acetyl-alanine, L-histidine-Aib, desamino-histidine-alanine, or desamino-histidine-Aib; 
         Xaa 9  is Glu or a Glu derivative such as alpha,alpha dimethyl-Glu; 
         Xaa 16  is Val, or Leu; 
         Xaa 18  is Ser, Lys, or Arg; 
         Xaa 19  is Tyr, or Gln; 
         Xaa 23  is Gln, Glu, Lys, or Arg; 
         Xaa 25  is Ala, or Val; 
         Xaa 27  is Glu, or Leu; 
         Xaa 30  is Ala, Glu, Lys, Arg, or absent; 
         Xaa 33  is Val, Thr(O-benzyl), or Lys; 
         Xaa 34  is Lys, Glu, Gln, Asn, or Arg; 
         Xaa 35  is Gly, Aib, or absent; 
         Xaa 36  is Arg, Lys, or absent; 
         Xaa 37  is Gly, Aib, Pro, epsilon-amino-Lys, or absent 
         Xaa 38  is Lys, Glu, or absent 
         Xaa 39  is amide, or is absent; 
         provided that if Xaa 37  is absent then Xaa 38  is also absent. 
       
     
     
         11 . The derivative according to  claim 1 , wherein the GLP-1 peptide comprises an amino acid sequence according to formula (IV) which is derivatised with an albumin binding residue in position 18, 23, 26, 30, 31, 34, 36, 37, or 38: 
       
         
           
                 
               
                   Formula (IV) 
                 
                 
               
                   (SE0 ID No: 7) 
                 
                 
               
                   Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser- 
                 
                     
                 
                   Xaa 18 -Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Arg-Glu-Phe-Ile- 
                 
                     
                 
                   Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35-Xaa   36 -Xaa 37 -Xaa 38 - 
                 
                     
                 
                   Xaa 39   
                 
             
                
               
            
             
                
               
            
             
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7  is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 2(3H-imidazol-4-yl)acetyl, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; 
         Xaa 8  is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid; 
         Xaa 18  is Ser, Lys or Arg; 
         Xaa 30  is Ala, Glu, Lys or Arg; 
         Xaa 33  is Val or Lys; 
         Xaa 34  is Lys, Glu, Gln, or Arg; 
         Xaa 35  is Gly, Aib, or absent; 
         Xaa 36  is Arg, Lys, or absent; 
         Xaa 37  is Gly, Aib, Pro, epsilon-amino-Lys, or absent; 
         Xaa 38  is Lys, or absent; and 
         Xaa 39  is amide or is absent. 
       
     
     
         12 . The derivative according to  claim 11 , wherein Xaa 38  is absent. 
     
     
         13 . The derivative according to  claim 11 , wherein Xaa 37  and Xaa 38  are both absent. 
     
     
         14 . The derivative according to  claim 11 , wherein Xaa 7  is desamino-histidine. 
     
     
         15 . The derivative according to  claim 11 , wherein Xaa 8  is Aib. 
     
     
         16 . The derivative according to  claim 1 , which is selected from the following:
 N-ε 37 { 2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [desaminoHis 7 ,Glu 22 ,Arg 26 ,Arg 34 ,Lys 37 ]GLP-1(7-37)amide;   N-ε 20 -{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib 2 ,Leu 14 ,Lys 20 ,Gln 28 ,Ser(O-benzyl) 39 ]exendin-4 (1-39)amide;   N-ε 26 { 2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [desaminoHis 7 ,Arg 34 ]GLP-1-(7-37);   N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;   N-epsilon23-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-Carboxyheptadecanoylamino)piperidin-4-ylcarbonylamino]-3-(carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Arg26,Arg34]GLP-1-(7-37);   N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-Carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [DesaminoHis 7,Glu22,Arg26,Arg 34,Phe(m-CF3)28]GLP-1-(7-37)amide;   [DesaminoHis7,Glu22,Arg26,Arg34]GLP-1-(7-37)-Lys(2-{2-[2-(2-{2-[2-((S)-4-Carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl);   N-ε 20 ({2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(17-carboxyheptadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib 8 ,Lys 20 ,Arg 26 ,Glu 30 ,Thr(O-benzyl) 33 ]GLP-1-(7-37)amide;   N-epsilon30 {2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Lys30]GLP-1-(7-37);   N-epsilon31 {2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Lys 31]GLP-1-(7-37);   N-ε 20 ({2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(17-carboxyheptadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib 8 ,Lys 20 ,Arg 26 ,2-Naphtylalanine 28 , Glu 30 ]GLP-1(7-37)amide;   [Aib8,Glu22,Arg26, Arg34]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-((S)-4-[1-[19-Carboxynonadecanoyl]piperidine-4-carbonylamino]-4-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide;   N-ε 20 ({2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(17-carboxyheptadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib 8 ,Lys 20 ,Arg 26 ,2-Naphtylalanine 12 ,Glu 30 ]GLP-1-(7-37)amide;   [DesaminoHis7,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-((S)-4-[1-[19-Carboxynonadecanoyl]piperidine-4-carbonylamino]-4-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide   N-epsilon31-(2-{2-[2-(2-{2-[2-((S)-3-Carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib 8,Glu22,Arg26,Lys31,Arg34]GLP-1-(7-37);   N-epsilon26-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);   N-epsilon26-{4-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl} [Aib8,Arg34]GLP-1-(7-37);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-37);   N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-37)-amide;   N-epsilon18-{2-(2-(2-(2-[2-(2-[(S)-4-Carboxy-4-({4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoylamino]ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl} [Aib8,Lys18,Arg26,Arg34]GLP-1(7-37)   N-ε 20 -[2-(2-[2-(2-[2-(2-((S)-4-[trans-4-([19-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [desaminoHis 1 , Lys 20 ,Ser(O-benzyl) 33 ,Ser(O-benzyl) 39 ]exendin (1-39);   [Aib8,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-(S)-3-[4-([19-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide;   N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;   N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;   N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({4-[(trans-19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;   N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);   [DesaminoHis7,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-{2-[2-(2-{2-[4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]-amide;   [desaminoHis 7 ,Arg 26 ,Arg 34 ]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide;   N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl [Aib8,Lys 26]GLP-1 (7-37)amide;   N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Lys26]GLP-1(7-37)amide;   N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);   N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-37);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-37);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-37);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-34);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-34);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-34);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-35);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-35);   N-epsilon26[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-36)amide;   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-35);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Lys33,Arg34]GLP-1-(7-34);   N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-36)amide;   N-epsilon26[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Lys26,Arg34]GLP-1-(7-36)amide;   [Aib8,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}-butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl]amide;   N-epsilon20-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Lys20,Glu22,Arg26,Glu30,Pro37]GLP-1-(7-37)amide;   N-epsilon37-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;   N-epsilon37-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;   N-epsilon37-[[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;   [Aib8,Glu22,Arg26,Glu30,Pro37]GLP-1-(7-37)Lys[2-(2-{2-[4-Carboxy-4-(4-carboxy-4-{4-[4-(16-1H-tetrazol-5-yl-hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl];   [Aib8,Glu22,Arg26,Glu30,Pro37]GLP-1-((7-37)Lys (2-(2-(3-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-[4-(S)-carboxy-4-(4-(S)-carboxy-4-(4-{4-[16-(Tetrazol-5-yl)hexadecanoylsulfamoyl]butanoylamino}butanoylamino) butyrylamino)butyrylamino]; ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)propionylamino)ethoxy)ethoxy) peptide;   N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37);   N-alpha8-[2-(4-imidazolyl)acetyl]N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Glu22,Arg26,Arg34,Lys37]GLP-1-(8-37);   [DesaminoHis7,Glu22,Arg26,34]-GLP-1(7-37)-Lys-(2-{2-[2-((S)-4-carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetyl) peptide;   [DesaminoHis7,Glu22,Arg26,34]-GLP-1(7-37)-Lys-[2-(2-{2-[2-(2-{2-[4-Carboxy-4-({-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] peptide;   [DesaminoHis7,Glu22,Arg26,34]-GLP-1(7-37)-Lys((S)-4-carboxy-4-(2-{2-[2-((S)-4-carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)butyryl) peptide;   [DesaminoHis7,Glu22,Arg26,34]-GLP-1(7-37)-Lys-(2-(2-{2-[(S)-4-carboxy-4-(2-{2-[2-((S)-4-carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)butyrylamino]ethoxy}ethoxy)acetyl) peptide;   [DesaminoHis7,Arg26,34]-GLP-1(7-37)-Lys(2-{2-[2-(2-{2-[2-(S)-4-Carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) peptide;   N-epsilon37-(2-{2-[2-(2-{2-[2-((S)-4-Carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);   N-epsilon37-((S)-4-Carboxy-4-{[1-(19-carboxy-nonadecanoyl)-piperidine-4-carbonyl]-amino}-butyryl) [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);   [DesaminoHis7,Glu22,Arg26,34]-GLP-1(7-37)-Lys-((S)-4-Carboxy-4-{[1-(19-carboxy-nonadecanoyl)-piperidine-4-carbonyl]-amino}-butyryl) peptide;   N-epsilon26-[2-(2-{2-[(R)-4-Carboxy-4-((R)-4-carboxy-4-{12-[4-(16-1H-tetrazol-5-yl-hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl]-[Aib8,Arg34]GLP-1(7-37);   N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{-4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl} [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);   N-epsilon37-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);   N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);   [ImPr 7 ,Arg 26,34 ,Glu 22 ]GLP-1-(7-37)Lys[2-(2-[2-(4-((S)-4-(S)-4-(12-[4-(16-1H-tetrazol-5-ylhexadecanoylsulfamoyl)butyrylamino]dodecanoylamino)-4-carboxybutyrylamino)-4-carboxybutyrylamino)ethoxy]ethoxy)acetyl]-amid;   N-epsilon36-[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Glu22,Gln34]GLP-1-(7-37);   N-epsilon26-[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Glu22,Gln34]GLP-1-(7-37);   N-epsilon18-[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,22,35,Lys18,Arg26,34]GLP-1-(7-37); and   N-epsilon18-[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Lys18, Glu22,Gln34]GLP-1-(7-37).   
     
     
         17 . A pharmaceutical composition comprising a derivative according to  claim 1  or a pharmaceutically acceptable salt, amide, alkyl, or ester thereof, and a pharmaceutically acceptable excipient. 
     
     
         18 - 20 . (canceled) 
     
     
         21 . A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to  claim 17 .