Composition and method for the treatment of diseases affected by apoptosis

Abstract

The present invention includes methods of making and methods of using peptidomimetics compositions that mimic α-helical BH3 sequences in cells. The peptidomimetics can be used to mimic α-helical BH3 sequences and kill cancer cells.

1 . An oligo-benzamide compound comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2, R″3, and R″4 independently comprise a H, one or more optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, urea groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino, hydrazido, aminoxy, alkoxyamino, alkylamido, carboxylic ester groups, thioethers groups, carboxylic acids, phosphoryl groups, polycyclic aromatic substituted with a OH, NH 2 , SH, F, Cl, Br, I, NHR, NRR′, CN 3 H 4 , a N, a O, a S, a H, or combination thereof; 
         “X” independently comprise a C, a N, a O, a S, a H, —CH 2 —, —CH 2 CH 2 —, —CH═CH—, —C≡C—, —NH—, —NR—, —NH—NH—, —NH(CH 2 ) n NH, —NR(CH 2 ) n NR′—NR—NR′—, —NH—O—, —NR—O—, —NH(CH 2 ) n O—, —NR(CH 2 ) n O—, —NH(CH 2 ) n S—, —NR(CH 2 ) n S—, —O(CH 2 ) n O—, —O(CH 2 ) n S—, —S(CH 2 ) n S—, —CO—, —CO 2 —, —COS—, —CONH—, —CONR—, —OC(O)NH—, —NHCONH—, —CONHCO—, —CO(CH 2 ) n CO—, or combination thereof; 
         wherein “Y” comprises a N, a O, a C, a 5 or 2Hs; or a combination thereof; 
         “n” is 0, 1, 2, 3, 4, 5, 6, 7 or more; and 
         “A” and “B” independently comprises R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2, R″3, and R″4, an acetyl, a Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an amino acid analogue, an artificial amino acid, a peptide of 2-30 amino acids, a carbohydrate, a lipid, a nucleic acid, a sugar, a linker of 1-30 amino acids, a linker of an optionally substituted lower alkyl, a linker of an optionally substituted C1-C7 alkyl, a linker as seen below 
       
       
         
           
           
               
               
           
         
         wherein “Y” comprises a N, a O, a C, a S or 2Hs; or a combination thereof. 
       
     
     
         2 . The composition of  claim 1 , further comprising one or more of diluents excipients, active agents, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, aromatic substances, penetration enhancers, surfactants, fatty acids, bile salts, chelating agents, colloids and combinations thereof. 
     
     
         3 . The composition of  claim 1 , wherein the pharmaceutical composition is in the form of a solution, an emulsion, a liposome-containing formulation, a tablet, a capsule, a gel capsule, a liquid syrup, a soft gel, a suppository, an enema, a patch, an ointment, a lotion, a cream, a gel, a drop, a spray, a liquid or a powder. 
     
     
         4 . A composition comprising an oligo-benzamide compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 4 , further comprising one or more of diluents excipients, active agents, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, aromatic substances, penetration enhancers, surfactants, fatty acids, bile salts, chelating agents, colloids and combinations thereof. 
     
     
         6 . The composition of  claim 4 , wherein the pharmaceutical composition is in the form of a solution, an emulsion, a liposome-containing formulation, a tablet, a capsule, a gel capsule, a liquid syrup, a soft gel, a suppository, an enema, a patch, an ointment, a lotion, a cream, a gel, a drop, a spray, a liquid or a powder. 
     
     
         7 . A method of treating diseases affected by apoptosis comprising the steps of:
 identifying a subject in need of treatment for a diseases affected by apoptosis;   supplying an affective amount of an oligo-benzamide compound, wherein the oligo-benzamide compound comprises the formula:   
       
         
           
           
               
               
           
         
       
       wherein R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2, R″3, and R″4 independently comprise a H, one or more optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, urea groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino, hydrazido, aminoxy, alkoxyamino, alkylamido, carboxylic ester groups, thioethers groups, carboxylic acids, phosphoryl groups, polycyclic aromatic substituted with a OH, NH 2 , SH, F, Cl, Br, I, NHR, NRR′, CN 3 H 4 , a N, a O, a S, a H, or combination thereof; 
       “X” independently comprise a C, a N, a O, a S, a H, —CH 2 —, —CH 2 CH 2 —, —CH═CH—, —C≡C—, —NH—, —NR—, —NH—NH—, —NH(CH 2 ) n NH, —NR(CH 2 ) n NR′—NR—NR′—, —NH—O—, —NR—O—, —NH(CH 2 ) n O—, —NR(CH 2 ) n O—, —NH(CH 2 ) n S—, —NR(CH 2 ) n S—, —O(CH 2 ) n O—, —O(CH 2 ) n S—, —S(CH 2 ) n S—, —CO—, —CO 2 —, —COS—, —CONH—, —CONR—, —OC(O)NH—, —NHCONH—, —CONHCO—, —CO(CH 2 ) n CO—, or combination thereof; 
       wherein “Y” comprises a N, a O, a C, a S or 2Hs; or a combination thereof; 
       “n” is 0, 1, 2, 3, 4, 5, 6, 7 or more; and 
       “A” and “B” independently comprises R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2, R″3, and R″4, an acetyl, a Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an amino acid analogue, an artificial amino acid, a peptide of 2-30 amino acids, a carbohydrate, a lipid, a nucleic acid, a sugar, a linker of 1-30 amino acids, a linker of an optionally substituted lower alkyl, a linker of an optionally substituted C1-C7 alkyl, a linker as seen below 
       
         
           
           
               
               
           
         
       
       wherein “Y” comprises a N, a O, a C, a S or 2Hs; or a combination thereof. 
     
     
         8 . The method of  claim 7 , wherein the oligo-benzamide compound further comprises one or more of diluents excipients, active agents, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, aromatic substances, penetration enhancers, surfactants, fatty acids, bile salts, chelating agents, colloids and combinations thereof. 
     
     
         9 . The method of  claim 7 , wherein the oligo-benzamide compound is in the form of a solution, an emulsion, a liposome-containing formulation, a tablet, a capsule, a gel capsule, a liquid syrup, a soft gel, a suppository, an enema, a patch, an ointment, a lotion, a cream, a gel, a drop, a spray, a liquid or a powder. 
     
     
         10 . The method of  claim 7 , wherein the oligo-benzamide compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A method of making an oligo-benzamide compound comprising the steps of:
 reacting a first optionally substituted 4-aminobenzoic acid compound with a second optionally substituted alkyl 4-aminobenzoate compound to form a bis-benzamide;   reacting the bis-benzamide with a third optionally substituted alkyl 4-aminobenzoate compound to form a tris-benzamide compound, wherein the first optionally substituted 4-aminobenzoic acid compound, the second optionally substituted alkyl 4-aminobenzoate compound, and the third optionally substituted alkyl 4-aminobenzoate compound are individually substituted with a C, a N, a O, a S, a H, optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, urea groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino, hydrazido, aminoxy, alkoxyamino, alkylamido, carboxylic ester groups, thioethers groups, carboxylic acids, phosphoryl groups, polycyclic aromatic, substituted polycyclic aromatic, an acetyl, Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an amino acid analogue, an artificial amino acid, a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide a linker of 1-30 amino acids, a linker of an optionally substituted lower alkyl, a linker of an optionally substituted C1-C7 alkyl, a polycyclic aromatic substituted with a OH, a NH 2 , a SH, a F, a Cl, a Br, a I, a NHR, a NRR′, a CN 3 H 4 , a N, a O, a S, a H, a linker of 1-30 amino acids, an optionally substituted C1-C7 alkyl, an optionally substituted linker as seen below   
       
         
           
           
               
               
           
         
       
       wherein X comprises a N, a O, a C, a S, a H, —CH 2 —, —CH 2 CH 2 —, —CH═CH—, —C≡C—, —NH—, —NR—, —NH—NH—, —NH(CH 2 ) n NH, —NR(CH 2 ) n NR′—NR—NR′—, —NH—O—, —NR—O—, —NH(CH 2 ) n O—, —NR(CH 2 ) n O—, —NH(CH 2 ) n S—, —NR(CH 2 ) n S—, —O(CH 2 ) n O—, —S(CH 2 ) n S—, —CO—, —CO 2 —, —COS—, —CONH—, —CONR—, —OC(O)NH—, —NHCONH—, —CONHCO—, —CO(CH 2 ) n CO—, or combination thereof; or a combination thereof and Y comprises a N, a O, a C, a S, 2Hs or a combination thereof. 
     
     
         12 . The method of  claim 11 , further comprising the step of combining the oligo-benzamide compound with one or more of diluents excipients, active agents, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, aromatic substances, penetration enhancers, surfactants, fatty acids, bile salts, chelating agents, colloids or combinations thereof. 
     
     
         13 . The method of  claim 11 , further comprising the step of formulating the oligo-benzamide compound into the form of a solution, an emulsion, a liposome-containing formulation, a tablet, a capsule, a gel capsule, a liquid syrup, a soft gel, a suppository, an enema, a patch, an ointment, a lotion, a cream, a gel, a drop, a spray, a liquid or a powder.