p53 Inhibitors and therapeutic use of the same

Abstract

The therapeutic use of temporary p53 inhibitors in the treatment of p53-mediated diseases, conditions, and injuries is disclosed.

1 - 5 . (canceled)  
   
   
       6 . The method of  claim 22  wherein the temporary p53 inhibitor comprises a compound having the structural formula  
     
       
         
         
             
             
         
       
     
     and mixtures thereof, 
 wherein X is O, S, or NH,  
 m is 0 or 1,  
 n is 1 to 4,  
 R 1  and R 2 , independently, are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, haloalkyl, haloaryl, a heterocyclic, heteroaryl, heteroaralkyl, alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, halo, (alkylthio)alkyl, (arylthio)alkyl, and (aralkylthio)alkyl,  
 or R 1  and R 2  are taken together to form an aliphatic or aromatic, 5- to 8-membered ring, either carbocyclic or heterocyclic;  
 R 3  is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, haloaryl, heteroaralkyl, a heterocycle, alkoxy, aryloxy, halo, NR 4 R 5 , NHSO 2 NR 4 R 5 , NHSO 2 R 4 , and SO 2 NR 4 R 5 ; and  
 R 4  and R 5 , independently, are selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and a heterocycle,  
 or R 4  and R 5  are taken together to form an aliphatic or aromatic, 5- to 8-membered ring, either carbocyclic or heterocyclic;  
 or a pharmaceutically acceptable salt or hydrate thereof.  
 
   
   
       7 . The method of  claim 22  wherein the R 1  through R 5  groups, independently, are optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, OH, NR 4 R 5 , CN, C(═O)NR 4 R 5 , SR 4 , SO 2 R 4 , CO 2 R 6 , OC(═O)R 6 , OR 1 , CF 3 , halo, and NO 2  wherein R 6  is hydrogen or alkyl.  
   
   
       8 . The method of  claim 22  wherein X is S or NH; m and n each are 1; R 1  and R 2 , independently, are selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkaryl, haloalkyl, and haloaryl, or are taken together to form a 5- or 6-membered, carbocyclic or heterocyclic ring; and R 3  is selected from the group consisting of alkyl, haloalkyl, aryl, alkaryl, aralkyl, haloaryl, and a heterocycle.  
   
   
       9 . The method of  claim 22  wherein X is S; m and n each are 1; R 1  and R 2  are taken together to form a 5- or 6-membered aliphatic carbocyclic ring; and R 3  is selected from the group consisting of alkyl, haloaryl, aryl, alkaryl, aralkyl, and a heterocycle.  
   
   
       10 . (canceled)  
   
   
       11 . The method of  claim 22  wherein R 1  and R 2 , independently, are selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, haloaryl, aralkyl, and alkaryl, or R 1  and R 2  are taken together to form a 5- or 6-membered ring, carbocyclic or heterocyclic; and R 3  is selected from the group consisting of alkyl, haloalkyl, aryl, alkaryl, aralkyl, and a heterocycle.  
   
   
       12 . The method of  claim 11  wherein R 3  is aryl, optionally substituted with one to three substituents selected from the group consisting of halo, CF 3 , phenyl, alkyl, nitro, and  
     
       
         
         
             
             
         
       
     
   
   
       13 . (canceled)  
   
   
       14 . The method of  claim 22  wherein R 1  and R 2 , independently, are selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, haloaryl, aralkyl, and alkaryl, or R 1  and R 2  are taken together to form a 5- or 6-membered ring, carbocyclic or heterocyclic; and R 3  is selected from the group consisting of alkyl, haloalkyl, aryl, alkaryl, aralkyl, and a heterocycle.  
   
   
       15 . The method of  claim 14  wherein R 1  and R 2 , independently, are selected from the group consisting of hydrogen, alkyl, haloalkyl, haloaryl, and aryl, or R 1  and R 2  are taken together to form a 5- or 6-membered carbocyclic ring; and R 3  is selected from the group consisting of aryl, haloalkyl, and alkaryl.  
   
   
       16 . The method of  claim 15  wherein R 3  is aryl, optionally substituted with one to three substituents selected from the group consisting of halo, alkyl, CF 3 , phenyl, nitro,  
     
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 22  wherein R 3  is  
     
       
         
         
             
             
         
       
       wherein w is 0 through 5, and R 10  is selected from the group consisting of alkoxy, CF 3 , alkylthio, alkyl, aralkyl, and aryl.  
     
   
   
       18 . The method of  claim 22  wherein the p53 inhibitor has the structure  
     
       
         
         
             
             
         
       
     
     wherein R 9  is alkyl, aryl, or halo.  
   
   
       19 . The compound of  claim 18  wherein R 9  is methyl, phenyl, or iodo.  
   
   
       20 . The method of  claim 22  wherein the p53 inhibitor has the structure  
     
       
         
         
             
             
         
       
       wherein R 3  is selected from the group consisting of phenyl, 4-chlorophenyl, 4-nitrophenyl, 3-nitrophenyl, 4-methylphenyl, 4-phenylphenyl, and 4-bromophenyl; R 6  and R 7 , independently, are hydrogen or alkyl; and R 8  is CO 2 R 6  or hydrogen.  
     
   
   
       21 . The method of  claim 22  wherein the p53 inhibitor comprises 2-[2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-yl]-1-(4-methylphenyl)-1-ethanone; 2-(4-methylphenyl)-5,6,7,8-tetrahydrobenzo[d]imidazo[2,1-b]thiazole; 2-[2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-yl]-1-(4-iodophenyl)-1-ethanone; 2-[2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-yl]-1-(biphenyl)-1-ethanone; 2-phenyl-5,6,7,8-tetrahydrobenzo[d]imidazo[2,1-b]-thiazole; 3-methyl-6-phenylimidazo[2,1-b]thiazole; 2,3-dimethyl-6-phenylimidazo[2,1-b]thiazole; 2-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydrobenzo-[d]imidazo[2,1-b]thiazole; 2-(4-flourophenyl)-5,6,7,8-tetrahydrobenzo[d]imidazo[2,1-b]thiazole; 2-(4-nitrophenyl)-5,6,7,8-tetrahydrobenzo[d]imidazo-[2,1-b]thiazole; 2-(3-nitrophenyl)-5,6,7,8-tetrahydrobenzo[d]imidazo-[2,1-b]thiazole; or a mixture thereof, 
 or a pharmaceutically acceptable salt or a hydrate thereof.    
   
   
       22 . A method of reducing normal cell death attributable to a treatment of a cancer in a mammal suffering from the cancer and undergoing a chemotherapeutic drug treatment comprising administering a therapeutically effective amount of a temporary p53 inhibitor to the mammal to reversibly inhibit p53 activity in cells sensitive to the temporary p53 inhibitor.  
   
   
       23 - 24 . (canceled)  
   
   
       25 . A method of reducing normal cell death attributable to contraction of a cancer in a mammal suffering from the cancer and undergoing a chemotherapeutic treatment comprising administering a therapeutically effective amount of a temporary p53 inhibitor to the mammal to reversibly inhibit p53 activity in cells sensitive to the temporary p53 inhibitor.  
   
   
       26 . A method of reducing damage to normal tissue in a mammal suffering from a cancer, said damage attributable to a chemotherapeutic treatment for the cancer in the mammal that said mammal is undergoing comprising administering a therapeutically effective amount of a temporary p53 inhibitor to the mammal.  
   
   
       27 - 32 . (canceled)  
   
   
       33 . A method of reducing cell death in an individual suffering from a cancer, said cell death attributable to a stress-inducing chemotherapeutic cancer treatment that said individual is undergoing for the cancer that affects cells, and said method comprising treating the individual with a therapeutically effective amount of a temporary p53 inhibitor to reversibly inhibit p53 activity.  
   
   
       34 . (canceled)  
   
   
       35 . The method of  claim 33  wherein p53 activity is inhibited for a sufficient time for the cell to recover from the stress-inducing cancer treatment.  
   
   
       36 - 45 . (canceled)  
   
   
       46 . A method of reducing normal cell death in an individual suffering from a cancer, said cell death attributable to a radiation treatment of the cancer that said individual is undergoing, comprising administering a therapeutically effective amount of a temporary p53 inhibitor to the individual to reversibly inhibit p53 activity in cells sensitive to the temporary p53 inhibitor.  
   
   
       47 . The method of  claim 50  wherein the radiation dose and p53 inhibitor are administered simultaneously.  
   
   
       48 . The method of  claim 50  wherein the p53 inhibitor is administered prior to administration of the radiation dose.  
   
   
       49 . A method of reducing damage to normal tissue in an individual suffering from a cancer, said damage attributable to a radiation treatment of the cancer that said individual is undergoing, comprising administering a therapeutically effective amount of a temporary p53 inhibitor to the individual to reversibly inhibit p53 activity in tissue sensitive to the p53 inhibitor.  
   
   
       50 . A method of reducing cell death in an individual suffering from a cancer, said cell death attributable to a stress-inducing radiation treatment for the cancer that said individual is undergoing that affects cells, said method comprising treating the individual with a therapeutically effective amount of a temporary p53 inhibitor to reversibly inhibit p53 activity.