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.

What is claimed is:  
     
         1 . A method of treating a disease or condition wherein inhibition of p53 activity provides a benefit comprising administering a therapeutically effective amount of a temporary p53 inhibitor to an individual suffering from the disease or condition.  
     
     
         2 . The method of  claim 1  wherein the disease or condition comprises a p53-deficient cancerous tumor.  
     
     
         3 . The method of  claim 1  wherein the disease or condition comprises hyperthermia.  
     
     
         4 . The method of  claim 1  wherein the disease or condition comprises hypoxia, a burn, a trauma to the central nervous system, a seizure, or an acute inflammation.  
     
     
         5 . The method of  claim 1  wherein the disease or condition comprises senescence of fibroblasts.  
     
     
         6 . The method of  claim 1  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; and  
 pharmaceutically acceptable salts and hydrates thereof.  
 
     
     
         7 . The method of  claim 6  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 6 , CF 3 , halo, and NO 2  wherein R 6  is hydrogen or alkyl.  
     
     
         8 . The method of  claim 6  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 6  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 . The method of  claim 6  wherein the p53 inhibitor has the structure  
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10  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 . The method of  claim 6  wherein the p53 inhibitor has the structure  
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 13  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 13  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 6  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 6  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 1  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,  
       and pharmaceutically acceptable salts and hydrates thereof.  
     
     
         22 . A method of reducing or eliminating normal cell death attributable to a treatment of a disease or condition comprising administering a therapeutically effective amount of a temporary p53 inhibitor to a mammal to reversibly inhibit p53 activity.  
     
     
         23 . The method of  claim 22  wherein the disease or condition is a cancer, hyperthermia, hypoxia, stroke, ischemia, acute inflammation, a burn, or cell aging.  
     
     
         24 . The method of  claim 23  wherein the disease is a cancer comprising a tumor that lacks functional p53.  
     
     
         25 . A method of reducing or eliminating normal cell death attributable to contraction of a disease comprising administering a therapeutically effective amount of a temporary p53 inhibitor to a mammal to reversibly inhibit p53 activity.  
     
     
         26 . A method of reducing or eliminating damage to normal tissue attributable to a treatment for cancer comprising administering a therapeutically effective of a temporary p53 inhibitor to a mammal to reversibly inhibit p53 activity.  
     
     
         27 . The method of  claim 26  wherein the cancer treatment comprises chemotherapy.  
     
     
         28 . The method of  claim 26  wherein the cancer treatment comprises radiation therapy.  
     
     
         29 . A cancer treatment composition comprising: 
 (a) a chemotherapeutic drug; and    (b) a temporary p53 inhibitor.    
     
     
         30 . An improved method of treating cancer comprising administration of a therapeutically effective radiation dose to a mammal to treat a cancer, and administration of a therapeutically effective amount of a temporary p53 inhibitor to the mammal to reversibly inhibit p53 activity.  
     
     
         31 . The method of  claim 30  wherein the radiation dose and p53 inhibitor are administered simultaneously.  
     
     
         32 . The method of  claim 30  wherein the p53 inhibitor is administered prior to administration of the radiation dose.  
     
     
         33 . A method of preventing cell death attributable to a stress-inducing event affecting the cell, said method comprising treating the cell with therapeutically effective of a compound of a temporary p53 inhibitor to reversibly inhibit p53 activity.  
     
     
         34 . The method of  claim 33  wherein the stress-inducing event comprises a cancer treatment, a trauma, hyperthermia, hypoxia, ischemia, stroke, a burn, a seizure, a tissue or organ prior to transplanting, preparing a host for a bone marrow transplant, or DNA damage.  
     
     
         35 . The method of  claim 33  wherein p53 activity is inhibited for a sufficient time for the cell to recover from the stress-inducing event.  
     
     
         36 . A pharmaceutical composition for treating a disease comprising 
 (a) a drug capable of treating the disease, and    (b) a temporary p53 inhibitor.    
     
     
         37 . A pharmaceutical composition comprising 
 (a) a temporary p53 inhibitor, and    (b) a carrier.    
     
     
         38 . A method of modulating tissue aging comprising treating the tissue with a therapeutically effective amount of a temporary p53 inhibitor to reversibly inhibit p53 activity.  
     
     
         39 . A method of sensitizing p53-deficient cells to a cancer therapy comprising administering, in conjunction with the cancer therapy, a sufficient amount of a temporary p53 inhibitor to a mammal to destroy p53-deficient cells that survive in an absence of the p53 inhibitor.  
     
     
         40 . An improved method of treating cancer comprising administration of a therapeutically effective dose of a chemotherapeutic agent to a mammal to treat a cancer, and administration of a sufficient amount of a temporary p53 inhibitor to the mammal to reversibly inhibit p53 activity, wherein the dose of the chemotherapeutic agent is greater than a dose of the identical chemotherapeutic agent required to treat the cancer in the absence of administration of the p53 inhibitor.  
     
     
         41 . The method of  claim 40  wherein the mammal is free of a cancer induced by temporary p53 suppression.  
     
     
         42 . A method of reducing or eliminating p53-mediated side effects associated with a cancer therapy comprising administering a therapeutically effective dose of a temporary p53 inhibitor to a mammal in conjunction with the cancer therapy.  
     
     
         43 . The method of  claim 42  wherein the cancer therapy comprises radiation therapy.  
     
     
         44 . The method of  claim 42  wherein the cancer therapy comprises chemotherapy.  
     
     
         45 . The method of  claim 42  wherein the p53-mediated side effect comprises one or more of hair loss, testicular cell damage, intestinal epithelia cell damage, lymphoid system damage, or hemapoietic system damage.