Peptides

Abstract

The invention provides novel β-peptides comprising 2 or more different β-amino acid residues, preferably compounds of formula I wherein the the R residues, X and n are as defined. Compounds of the invention having as few as 5 or 6 β-amino acid residues exhibit stable structures in solution and the compounds generally exhibit good resistance to proteolytic degradation. The compounds of the invention provide a valuable new source of structural diversity for synthesis of biologically active compounds, e.g. for pharmaceutical uses.

1 . A β-peptide comprising 2 or more different β-amino acid residues.  
     
     
         2 . A β-peptide according to  claim 1 , comprising from 2 to 11 β-amino acid residues.  
     
     
         3 . A compound of formula I  
       
         
           
           
               
               
           
         
         wherein 
 each R is H, —R 5 , —OR 5 , —C(O)R 5 , —R 5 C(O)R 6 , —C(O)OR 5 , —R 5 C(O)OR 6 , —R 5 OC(O)R 6 , —R 5 OC(O)OR 6 , —R 5 NR 6 C(O)R 7 , —R 5 C(O)NR 6 R 7 , —C(O)NR 6 R 7 , —R 5 OC(O)NR 6 R 7 , —R 5 NR 6 C(O)NR 7 R 8 , —R 5 NR 6 C(O)OR 7 , —R 5 —O—R 6 , —R 5 —NR 6 R 7 , —R 5 —S—R 6 , —R 5 —SO m —R 6 , —R 5 OR—O—R 7 , —R 5 NR 6 R 7 —O—R 8 , —R 5 SO m R 6 —O—R 7 , —C(O)R 5 —O—R 6 , —C(O)OR 5 —O—R 6 , —R 5 C(O)R 6 —O—R 7 , —R 5 C(O)OR 6 —O—R 7 , —R 5 OC(O)R 6 —O—R 7 , —R 5 OC(O)OR 6 —O—R 7 , —R 5 NR 6 C(O)R 7 —O—R 8 , —C(O)NR 5 R 6 —O—R 7 , —R 5 C(O)NR 6 R 7 —O—R 8 , —R 5 OC(O)NR 6 R 7 —O—R 8 , —R 5 NR 6 C(O)NR 7 R 8 —O—R 9 , —R 5 NR 6 C(O)OR 7 —O—R 8 , —R 5 OR 6 —S—R 7 , —R 5 NR 6 R 7 —S—R 8 , —R 5 SO m R 6 —S—R 7 , —C(O)R 5 —S—R 6 , —C(O)OR 5 —S—R 6 , —R 5 C(O)R 6 —S—R 7 , —R 5 C(O)OR 6 —S—R 7 , —R 5 OC(O)R 6 —S—R 7 , —R 5 OC(O)OR 6 —S—R 7 , —R 5 NR 6 C(O)R 7 —S—R 8 , —C(O)NR 5 R 6 —S—R 7 , —R 5 C(O)NR 6 R 7 —S—R 8 , —R 5 OC(O)NR 6 R 7 —S—R 8 , —R 5 NR 6 C(O)NR 7 R 8 —S—R 9 , —R 5 NR 6 C(O)OR 7 —S—R 8 , —R 5 OR 6 —NR 7 R 8 , —R 5 NR 6 R 7 —NR 8 R 9 , —R 5 SO m R 6 —NR 7 R 8 , —C(O)R 5 —NR 6 R 8 , —C(O)OR 5 —NR 6 R 8 , —R 5 C(O)R 6 —NR 7 R 8 , —R 5 C(O)OR 6 —NR 7 R 8 , —R 5 OC(O)R 6   13  NR 7 R 8 , —R 5 OC(O)OR 6 —NR 7 R 8 , —R 5 NR 6 C(O)R 7 —NR 8 R 9 , —C(O)NR 5 R 6 —NR 7 R 8 , —R 5 C(O)NR 6 R 7 —NR 8 R 9 , —R 5 OC(O)NR 6 R 7 —NR 8 R 9 , —R 5 NR 6 C(O)NR 7 R 8 —NHR 9 , or —R 5 NR 6 C(O)OR 7 —NR 8 R 9′ ,  
 where R 5 , R 6 , R 7 , R 8  and R 9  are each independently C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 6-10 aryl, C 6-14 aralkyl, C 6-14 aralkenyl or C 6-14 aralkynyl and m is 1,2,3 or 4; and where R 5 , R 6 , R 7 , R 8  and R 9  are each unsubstituted or substituted with up to 6 substituents selected from halo, NO 2 , —OH, C 1-4 alkyl, —SH, —SO 3 , —NH 2 , C 1-4 acyl, C 1-4 acyloxy, C 1-4 alkylamino, C 1-4 dialkylamino, trihalomethyl, —CN, C 1-4 alkylthio, C 1-4 alkylsulfinyl, or C 1-4 alkylsulfonyl, provided that all the R substituents are not identical,  
 or R forms a cyclic structure, e.g. a carbocyclic or heterocyclic ring, with itself, with R 3  or with the carbonyl group attached to the immediately adjacent nitrogen atom;  
 
         R 1  and R 2 , which may be the same or different, are H, an N-protecting group or as defined above for R, or R 1  and R 2  are linked together in a 3 to 7 membered heterocyclic ring structure, or either R 1  or R 2  together with OX signify an amide bond;  
         each R 3 , which may be the same or different, is as defined above for R, or R 3  forms a cyclic structure, e.g. a carbocyclic or heterocyclic ring, with itself, with R or with the nitrogen atom of its β-amino acid residue, provided that R and R 3  are not both H;  
         X is H, an O-protecting group or as defined above for R, except that X is not —OR 5 , or OX together with R 1  or R 2  signify an amide bond;  
         n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.  
       
     
     
         4 . A compound according to  claim 3  in which n is 5 or 6.  
     
     
         5 . A compound according to  claim 3  of formula IV  
       
         
           
           
               
               
           
         
       
       wherein R, R 1 , R 2 , X and n are as defined in  claim 3 .  
     
     
         6 . A compound according to  claim 3  of formula V  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , X and n are as defined in  claim 3 .  
     
     
         7 . A compound according to  claim 1  or  3  which is a β-turn mimetic.  
     
     
         8 . A discrete compound collection (typically comprising from 2 to about 1000 compounds) or a library of compounds (typically comprising from 20 to 100 compounds up to many thousands of compounds, e.g. 100,000 compounds or more) comprising a plurality of compounds according to  claim 1  or  3 .  
     
     
         9 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  or  3  together with a pharmaceutically acceptable diluent or carrier.  
     
     
         10 . The use of a compound according to  claim 1  or  3  for the manufacture of a medicament for the treatment of any disease associated with any of the assays identified above.  
     
     
         11 . A process for the preparation of a compound according to  claim 1  or  3  comprising forming an amide bond between the β-amino group of a first β-amino acid residue or a precursor thereof and the α-carboxyl group of a second β-amino acid residue or a precursor thereof and repeating the amide bond forming step as required.  
     
     
         12  A process for the preparation of a compound according to  claim 3  comprising Arndt-Eisert homologation of an N-protected α-amino acid of formula VI  
       
         
           
           
               
               
           
         
       
       wherein Pg, is an amine protecting group and R and R 2  are as defined in  claim 3 , by reaction with diazomethane, e.g. in the presence of triethylamine/ethylchloroformate to yield a diazo ketone intermediate of formula VII  
       
         
           
           
               
               
           
         
       
     
     
         13 . A process for the preparation of a compound of formula I as defined in  claim 3  comprising coupling of a diazo ketone of formula VII  
       
         
           
           
               
               
           
         
       
       wherein Pg is an amine protecting group and R and R 2  are as defined in  claim 3 , with a β-amino acid of formula VIII  
       
         
           
           
               
               
           
         
       
       wherein R and R 3  are as defined in  claim 3  and Y is an O-protecting group, or with a β-amino acid or β-peptide residue of formula IX  
       
         
           
           
               
               
           
         
       
       wherein R, R 3 , are as defined in  claim 3 , P′g is an O-protecting group and p is 1, 2, 3, 4, 5, 6, 7, 8 or 9.