Peptide-oligourea chimeric compounds and methods of their use

Abstract

The present description provides compositions and methods for producing therapeutic oligomeric compounds. In another aspect the description provides methods for administering the oligomeric compounds for the treatment and prevention of disease in a mammal. In particular, the invention relates to medicaments comprising various novel oligomeric compounds and pharmaceutically acceptable salts thereof. The compounds of the invention may optionally be administered with at least one of a pharmaceutically acceptable excipient, additional pharmacologically active agent or a combination thereof.

1 . A peptide-oligourea chimeric compound comprising:
 a peptide portion including at least two consecutive α-amino acid residues, coupled to an oligourea portion including at least five consecutive peptidomimetic residues having N,N′-linked urea bridging unityes, wherein the peptidomimetic residues are selected from the group of substituted or unsubstituted N-2-aminoethylcarbamoyl residue, substituted and unsubstituted N-(2-aminoethyl)carbamothioyl residues, substituted and unsubstituted N-(2-aminoethyl)formamidinyl residues, substituted and unsubstituted 2-aminoethanoxycarbonyl and combinations thereof.   
     
     
         2 . The chimeric compound of  claim 1 , wherein the oligourea portion is coupled to the amino terminus or carboxy terminus of the peptide portion 
     
     
         3 . The chimeric compound of  claim 2 , wherein an oligourea sequence is coupled to both the amino and carboxy termini of the peptide portion. 
     
     
         4 . The chimeric compound of  claim 1 , wherein the compound has at least six peptidomimetic residues having N, N′-linked urea bridging units. 
     
     
         5 . The chimeric compound of  claim 1 , wherein the N-2-aminoethylcarbamoyl residue is a residue of formula (II) 
       
         
           
           
               
               
           
         
         wherein the Ra groups are independently selected the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic C1-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic aryl-C1-C6-alkyl, alkenyl or alkynyl; C1-C6-alkyloxy, aryloxy, heteroaryloxy, thio, C1-C6-alkylthio, amino, mono ordi-C1-C6-alkylamino, carboxylic acid, carboxamide mono- or di-C1-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, and guanidine. 
       
     
     
         6 . A therapeutic composition comprising an effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         7 . A method of treating a disease in a patient comprising administering to an individual in need thereof, and effective amount of the composition of  claim 6 , wherein the composition is effective in ameliorating the disease or condition. 
     
     
         8 . The chimeric compound of  claim 1 , wherein the oligourea segment comprises at least three adjacent N-2-aminoethylcarbamoyl residues. 
     
     
         9 . The chimeric compound of  claim 1 , wherein substituted and unsubstituted N-(2-amino-ethyl)carbamoyl residues is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein X is independently selected from the group consisting of O, S, NH. 
         wherein R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic C1-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic aryl-C1-C6-alkyl, alkenyl or alkynyl; C1-C6-alkyloxy, aryloxy, heteroaryloxy, thio, C1-C6-alkylthio, amino, mono ordi-C1-C6-alkylamino, carboxylic acid, carboxamide mono- or di-C1-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine. 
         wherein R 1  is independently selected from the group consisting of hydrogen, linear, branched or cyclic C1-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S 
         wherein R 2  is independently selected from the group consisting of hydrogen, linear, branched or cyclic C1-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S 
         wherein R 3  together with the carbon and nitrogen atoms to which it is attached independently defines a substituted or unsubstituted, monocyclic or bicyclic C3-C10 heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s); and substitutents on the cycloalkyl, cycloalkenyl or heterocycle moieties are independently selected from the group consisting of linear, branched or cyclic C1-C6 alkyl, aralkyl, O—C(O)—NR 1 R 2  or —N(R 1 )—C(O)—O—R 1 , C1-C6 alkylene-NR 1 R 2 , —(CH 2 ) n —NH—C(═NR 1 )NHR 2 , —NH—, —NHC(O)—, —O—, ═O, —(CH 2 ) m — (here, m and n are in context, 1, 2, 3, 4, 5 or 6), —S—, —S(O)—, SO 2 — or —NH—C(O)—NH—, —(CH 2 ) n OH, —(CH 2 ) n SH, —(CH 2 ) n COOH, —(CH 2 ) n O—(C1-C6 alkyl), —(CH 2 ) n C(O)—(C1-C6 alkyl), —(CH 2 ) n OC(O)—(C1-C6 alkyl), —(CH 2 ) n C(O)O—(C1-C6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(OCH 2 ) n OH, —(OCH 2 ) n 0-(C1-C6 alkyl), —(CH 2 O) n C(O)—(C1-C6 alkyl), —(OCH 2 ) n NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , —NO2, —CN, or -halogen.R1 and R2 are each, within context, H or a C1-C6 alkyl group 
         wherein R 4  together with the carbon atoms to which it is attached independently defines a substituted or unsubstituted, monocyclic or bicyclic C3-C10 cycloalkyl, cycloalkenyl or heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s); and substitutents on the cycloalkyl, cycloalkenyl or heterocycle moieties are independently selected from the group consisting of linear, branched or cyclic C1-C6 alkyl, aralkyl, —O—C(O)—NR 1 R 2  or —N(R 1 )—C(O)—O—R 1 , C1-C6 alkylene-NR 1 R 2 , —(CH 2 ) n —NH—C(═NR 1 )NHR 2 , —NH—, —NHC(O)—, —O—, ═O, —(CH 2 ) m — (here, m and n are in context, 1, 2, 3, 4, 5 or 6), —S—, —S(O)—, SO2- or —NH—C(O)—NH—, —(CH 2 ) n OH, —(CH 2 ) n SH, —(CH 2 ) n COOH, —(CH 2 ) n O—(C1-C6 alkyl), —(CH 2 ) n C(O)—(C1-C6 alkyl), —(CH 2 ) n OC(O)—(C1-C6 alkyl), —(CH 2 ) n C(O)O—(C1-C6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(OCH 2 ) n OH, —(OCH 2 ) n O—(C1-C6 alkyl), —(CH 2 O) n C(O)—(C1-C6 alkyl), —(OCH 2 ) n NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , —NO2, —CN, or -halogen.R1 and R2 are each, within context, H or a C1-C6 alkyl group 
         wherein V and W are combined, together with the carbon atoms to which they are bonded, and independently define a substituted or unsubstituted, monocyclic or bicyclic C3-C10 cycloalkyl, cycloalkenyl or heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s) 
       
     
     
         10 . The chimeric compound of  claim 1 , wherein N-2-aminoethylcarbamoyl residues are independently selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic C1-C6-alkyl, alkenyl or alkynyl; mono- or bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic aryl-C1-C6-alkyl, alkenyl or alkynyl; C1-C6-alkyloxy, aryloxy, heteroaryloxy, thio, C1-C6-alkylthio, amino, mono ordi-C1-C6-alkylamino, carboxylic acid, carboxamide mono- or di-C1-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine. 
         wherein R 1  is independently selected from the group consisting of hydrogen, linear, branched or cyclic C1-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S 
         wherein R 2  is independently selected from the group consisting of hydrogen, linear, branched or cyclic C1-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S 
         wherein R 3  together with the carbon and nitrogen atoms to which it is attached independently defines a substituted or unsubstituted, monocyclic or bicyclic C3-C10 heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s); and substitutents on the cycloalkyl, cycloalkenyl or heterocycle moieties are independently selected from the group consisting of linear, branched or cyclic C1-C6 alkyl, aralkyl, —O—C(O)—NR 1 R 2  or —N(R 1 )—C(O)—O—R 1 , C1-C6 alkylene-NR 1 R 2 , —(CH 2 ) n —NH—C(═NR 1 )NHR 2 , —NH—, —NHC(O)—, —O—, ═O, —(CH 2 ) m — (here, m and n are in context, 1, 2, 3, 4, 5 or 6), —S—, —S(O)—, SO 2 — or —NH—C(O)—NH—, —(CH 2 ) n OH, —(CH 2 ) n SH, —(CH 2 ) n COOH, —(CH 2 ) n O—(C1-C6 alkyl), —(CH 2 ) n C(O)—(C1-C6 alkyl), —(CH 2 ) n OC(O)—(C1-C6 alkyl), —(CH 2 ) n C(O)O—(C1-C6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(OCH 2 ) n OH, —(OCH 2 ) n O—(C1-C6 alkyl), —(CH 2 O) n C(O)—(C1-C6 alkyl), —(OCH 2 ) n NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , —NO2, —CN, or -halogen.R1 and R2 are each, within context, H or a C1-C6 alkyl group 
         wherein R 4  together with the carbon atoms to which it is attached independently defines a substituted or unsubstituted, monocyclic or bicyclic C3-C10 cycloalkyl, cycloalkenyl or heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s); and 
         substitutents on the cycloalkyl, cycloalkenyl or heterocycle moieties are independently selected from the group consisting of linear, branched or cyclic C1-C6 alkyl, aralkyl, —O—C(O)—NR 1 R 2  or —N(R 1 )—C(O)—O—R 1 , C1-C6 alkylene-NR 1 R 2 , —(CH 2 ) n —NH—C(═NR 1 )NHR 2 , —NH—, —NHC(O)—, —O—, ═O, —(CH 2 ) m — (here, m and n are in context, 1, 2, 3, 4, 5 or 6), —S—, —S(O)—, SO 2 — or —NH—C(O)—NH—, —(CH 2 ) n OH, —(CH 2 ) n SH, —(CH 2 ) n COOH, —(CH 2 ) n O—(C1-C6 alkyl), —(CH 2 ) n C(O)—(C1-C6 alkyl), —(CH 2 ) n OC(O)—(C1-C6 alkyl), —(CH 2 ) n C(O)O—(C1-C6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(OCH 2 ) n OH, —(OCH 2 ) n O—(C1-C6 alkyl), —(CH 2 O) n C(O)—(C1-C6 alkyl), —(OCH 2 ) n NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , —NO2, —CN, or -halogen.R1 and R2 are each, within context, H or a C1-C6 alkyl group 
         wherein V and W are combined, together with the carbon atoms to which they are bonded, and independently define a substituted or unsubstituted, monocyclic or bicyclic C3-C10 cycloalkyl, cycloalkenyl or heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s) 
       
     
     
         11 . The compound of  claim 1 , wherein the peptide segment comprises an amino acid sequence corresponding to a biologically active peptide or a fragment thereof. 
     
     
         12 . The compound of  claim 1 , wherein the compound mimics an α-helix chain. 
     
     
         13 . The compound of  claim 1 , wherein the compound is biologically active. 
     
     
         14 . The compound of  claim 1 , wherein the peptide or fragment thereof binds a GPCR receptor or a fragment thereof. 
     
     
         15 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: