Beta-amino acids

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Patent No.: US None
App. No.: 11/482,638

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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.

Claims (59)

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

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: