Beta-amino acids

Abstract

Disclosed are β-amino acid monomers containing cylcoalkyl, cycloalkenyl, and heterocylic substituents which encompass the α and β carbons of the peptide backbone and β-polypeptides made from such monomers. Method of generating combinatorial libraries of polypeptides containing the β-peptide residues and libraries formed thereby are disclosed.

1 . A β-amino acid selected from the group consisting of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubsituted C 4 -C 8  cycloalkyl, cycloalkenyl or heterocyclic ring having one or more nitrogen atoms as the sole heteroatom; 
 the substituents on carbon atoms of the rings being independently selected from the group consisting of linear or branched C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl, —(CH 2 ) n+1 —OR 4 , —(CH 2 ) n+1 —SR 4 , —(CH 2 ) n+1 —S(═O)—CH 2 —R 4 , —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 4 , —(CH 2 ) n+1 —NR 4 R 4 , —(CH 2 ) n+1 —NHC(═O)R 4 , —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 4 , —(CH 2 ) n+1 —O—(CH 2 ) m —R 5 , —(CH 2 ) n+1 —S—(CH 2 ) m —R 5 , —(CH 2 ) n+1 —S(═O)—(CH 2 ) m —R 5 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 5 , —(CH 2 ) n+1 —NH—(CH 2 ) m —R 5 , —(CH 2 ) n+1 —N—{(CH 2 ) m —R 5 } 2 , —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 5 , and —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 5 ; 
 wherein R 4  is independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; and  
 wherein R 5  is selected from the group consisting of hydroxy, C 1 -C 6 -alkyloxy, aryloxy, heteroaryloxy, thio, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C 1 -C 6 -alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C 1 -C 6 -alkylamino, carboxylic acid, carboxamide, mono- or di-C 1 -C 6 -alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C 1 -C 6 -alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C 1 -C 6 -alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and  
 m is an integer of from 2-6 and n is an integer of from 0-6;  
 the substituents on heteroatoms of the ring being independently selected from the group consisting of —S(═O) 2 —CH 2 —R 4  —C(═O)—R 4 —S(═O) 2 —(CH 2 ) m —R 5 , and —C(═O)—(CH 2 ) n+1 —R 5 ; wherein R 4  and R 5  are as defined hereinabove, and m is an integer of from 2-6 and n is an integer of from 0-6;  
 
 provided that when X & Y together with the carbons to which they are bonded define a five- or six-membered cycloalkyl or a five-membered heterocyclic ring having one nitrogen as the sole heteroatom, and the nitrogen is bonded to a carbon atom adjacent to the carboxy carbon of Formula I, the cycloalkyl or heterocyclic ring is substituted;  
 R 1  is selected from the group consisting hydrogen and an amino protecting group;  
 R 2  is selected from the group consisting of hydrogen and a carboxy protecting group;  
 racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof;  
 and salts thereof.  
 
     
     
         2 . The β-amino acid according to  claim 1 , wherein X and Y combined, together with the carbon atoms to which they are bonded, define a moiety selected from the group consisting of a substituted cycloalkyl, a substituted or unsubstituted C 4 -C 6  cycloalkenyl, and a substituted or unsubstituted heterocyclic ring having one nitrogen atom as the sole hetero atom.  
     
     
         3 . The β-amino acid according to  claim 1 , wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted cyclopentenyl, cyclohexenyl, pyrrolidinyl, or piperidinyl ring.  
     
     
         4 . The β-amino acid according to  claim 1 , wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, pyrrolidinyl, or piperidinyl ring, wherein the substituent is selected from the group consisting of amino, mono- or di-C 1 -C 6 -alkylamino, carboxamido, sulfonamido, urea, thio, and C 1 -C 6 -alkylthio.  
     
     
         5 . The β-amino acid according to  claim 1 , wherein X and Y combined, together with the carbon atoms to which they are bonded, define an amino-substituted cyclopentyl, cyclohexyl, cyclopentenyl, amino-substituted cyclohexenyl, amino-substituted pyrrolidinyl, or amino-substituted piperidinyl ring.  
     
     
         6 . A β-amino acid selected from the group consisting of:  
       
         
           
           
               
               
           
         
         R 1  is selected from the group consisting hydrogen and an amino protecting group;  
         R 2  is selected from the group consisting of hydrogen and a carboxy protecting group; and  
         when R 3  is bonded to a carbon atom, R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl, —(CH 2 ) n+1 , —OR 4 , —(CH 2 ) n+1 —SR 4 ,  
         —(CH 2 ) n+1 —S(═O)—CH 2 —R 4 , —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 4 , —(CH 2 ) n+1 —NR 4 R 4 , —(CH 2 ) n+1 —NHC(═O)R 4 , —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 4 , —(CH 2 ) n+1 —O—(CH 2 ) m —R 5 , —(CH 2 ) n+1 —S—(CH 2 ) m R 5 , —(CH 2 ) n+1 —S(═O)—(CH 2 ) m —R 5 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 5 , —(CH 2 ) n+1 —NH—(CH 2 ) m —R 5 , —(CH 2 ) n+1 —N—{(CH 2 ) m —R 5 } 2 , —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 5 , and —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 5 ; 
 wherein R 4  is independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to S heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; and  
 
         wherein R 5  is selected from the group consisting of hydroxy, C 1 -C 6 -alkyloxy, aryloxy, heteroaryloxy, thio, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C 1 -C 6 -alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C 1 -C 6 -alkylamino, carboxylic acid, carboxamide, mono- or di-C 1 -C 6 -alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C 1 -C 6 -alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C 1 -C 6 -alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and 
 m is an integer of from 2-6 and n is an integer of from 0-6; and  
 
         when R 3  is bonded to a nitrogen atom, R 3  is independently selected from the group consisting of those listed above for when R 3  is attached to a carbon atom, and further selected from the group consisting of —S(═O) 2 —CH 2 —R 4 , —C(═O)—R 4 —S(═O) 2 —(CH 2 ) m R 5 , and —C(═O)—(CH 2 ) n+1 —R 5 ; wherein R 4  and R 5  are as defined hereinabove, and m is an integer of from 2-6 and n is an integer of from 0-6;  
         provided that when the β-amino acid is of formula  
         
           
             
             
                 
                 
             
           
         
         R 3  is not hydrogen;  
         racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof;  
         and salts thereof.  
       
     
     
         7 . The β-amino acid according to  claim 6 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         8 . The β-amino acid according to  claim 6 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.  
     
     
         9 . The β-amino acid according to  claim 6 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 6 .  
     
     
         10 . The β-amino acid according to  claim 9 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         11 . The β-amino acid according to  claim 9 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.  
     
     
         12 . The β-amino acid according to  claim 6 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 6 .  
     
     
         13 . The β-amino acid according to  claim 12 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         14 . The β-amino acid according to  claim 12 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.  
     
     
         15 . The β-amino acid according to  claim 6 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 6 .  
     
     
         16 . The β-amino acid according to  claim 15 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         17 . The β-amino acid according to  claim 15 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.  
     
     
         18 . The β-amino acid according to  claim 6 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 6 .  
     
     
         19 . The β-amino acid according to  claim 18 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         20 . The β-amino acid according to  claim 18 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.  
     
     
         21 . The β-amino acid according to  claim 6 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 6 .  
     
     
         22 . The β-amino acid according to  claim 21 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         23 . The β-amino acid according to  claim 21 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.  
     
     
         24 . The β-amino acid according to  claim 6 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 6 .  
     
     
         25 . The β-amino acid according to  claim 24 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         26 . The β-amino acid according to  claim 24 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.  
     
     
         27 . The β-amino acid according to  claim 6 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are as defined in  claim 6 .  
       
     
     
         28 . The β-amino acid according to  claim 27 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, hydroxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxy-C 1 -C 6 -alkyl, amino, and mono- or di-C 1 -C 6 -alkylamino.  
     
     
         29 . The β-amino acid according to  claim 27 , wherein R 3  is selected from the group consisting of hydrogen, hydroxy, linear or branched C 1 -C 6 -alkyl, alkenyl, alkynyl, and hydroxy-C 1 -C 6 -alkyl.