Parp inhibitor compounds, compositions and methods of use

Abstract

The present invention relates to tetraaza phenalen-3-one compounds which inhibit poly (ADP-ribose) polymerase (PARP) and are useful in the chemosensitization of cancer therapeutics. The induction of peripheral neuropathy is a common side-effect of many of the conventional and newer chemotherapies. The present invention further provides means to reliably prevent or cure chemotherapy-induced neuropathy. The invention also relates to the use of the disclosed PARP inhibitor compounds in enhancing the efficacy of chemotherapeutic agents such as temozolomide. The invention also relates to the use of the disclosed PARP inhibitor compounds to radiosensitize tumor cells to ionizing radiation. The invention also relates to the use of the disclosed PARP inhibitor compounds for treatment of cancers with DNA repair defects.

1 - 49 . (canceled) 
     
     
         50 . A method of treating a mammal having a cancer characterized by having a defect in the homologous recombination (HR) pathway of double-stranded DNA repair, comprising administering to said mammal a compound selected from the compound 37: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, solvates or hydrates thereof. 
       
     
     
         51 . The method of  claim 50 , wherein the compound is a pharmaceutically acceptable salt, ester, solvate or hydrate of compound 37. 
     
     
         52 . The method of  claim 51 , wherein the pharmaceutically acceptable salt is the salt of an organic acid. 
     
     
         53 . The method of  claim 50 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         54 . The method of  claim 50 , further comprising administering a chemotherapeutic agent selected from the group consisting of temozolomide, adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, docetaxel, doxorubicin, interferon-alpha, interferon-beta, interferon-gamma, interleukin 2, irinotecan, paclitaxel, topotecan, a taxoid, dactinomycin, danorubicin, 4′-deoxydoxorubicin, bleomycin, pilcamycin, mitomycin, neomycin, gentamycin, etoposide, 4-OH cyclophosphamide, a platinum coordination complex, and mixtures thereof. 
     
     
         55 . The method of  claim 54 , wherein said chemotherapeutic agent is temozolomide, or a salt thereof. 
     
     
         56 . The method of  claim 50 , wherein said mammal is a human. 
     
     
         57 . The method of  claim 50 , wherein the cancer has a phenotype selected from the group consisting of i) a BRCA-I defect, ii) a BRC A-2 defect, iii) a BRCA-I and BRCA-2 defect, and iv) Fanconi anemia. 
     
     
         58 . The method of  claim 50 , wherein the cancer is selected from breast cancer or ovarian cancer.