Therapies for hematologic malignancies

Abstract

The invention provides methods that relate to a novel therapeutic strategy for the treatment of hematological malignancies and inflammatory diseases. In particular, the method comprises administering a compound of formula A, wherein R is H, halo, or C1-C6 alkyl; R′ is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable excipient; and administering at least one additional therapeutic agent.

1 . (canceled) 
     
     
         2 . A method for treating a solid tumor,
 comprising administering to a subject in need of such treatment an effective amount of a compound of formula A,   
       
         
           
           
               
               
           
         
         wherein R is H, halo, or C1-C6 alkyl; 
         R′ is C1-C6 alkyl; or 
         a pharmaceutically acceptable salt thereof; and 
         optionally a pharmaceutically acceptable excipient. 
       
     
     
         3 . The method according to  claim 2 , wherein the compound is predominantly the S-enantiomer. 
     
     
         4 . The method according to  claim 2 , wherein R is fluoro (F) and is attached to position 5 or 6 of the quinazolinyl ring. 
     
     
         5 . The method according to  claim 2 , wherein R is H or F; and R′ is methyl, ethyl or propyl. 
     
     
         6 . The method according to  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 2 , wherein the solid tumor is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma. 
     
     
         9 . The method according to  claim 2 , wherein the solid tumor is breast cancer. 
     
     
         10 . The method according to  claim 9 , wherein the breast cancer is metastatic breast cancer. 
     
     
         11 . The method according to  claim 2 , wherein the solid tumor is ovarian cancer. 
     
     
         12 . The method according to  claim 6 , wherein the solid tumor is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma. 
     
     
         13 . The method according to  claim 6 , wherein the solid tumor is breast cancer. 
     
     
         14 . The method according to  claim 13 , wherein the breast cancer is metastatic breast cancer. 
     
     
         15 . The method according to  claim 6 , wherein the solid tumor is ovarian cancer. 
     
     
         16 . The method according to  claim 2 , further comprising administering simultaneously or separately (i) a therapeutically effective amount of at least one additional therapeutic agent and/or (ii) a therapeutic procedure. 
     
     
         17 . The method according to  claim 16 , wherein the at least one additional therapeutic agent is a proteasome inhibitor. 
     
     
         18 . The method according to  claim 17 , wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, PR-047, disulfiram, lactacystin, PS-519, eponemycin, epoxomycin, acalacinomycin, CEP-1612, MG-132, CVT-63417, PS-341, a vinyl sulfone tripeptide inhibitor, ritonavir, PI-083, (+/−)-7-methylomuralide, and (−)-7-methylomuralide. 
     
     
         19 . The method according to  claim 16 , wherein the therapeutic procedure is selected from the group consisting of antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and high-dose chemotherapy. 
     
     
         20 . The method according to  claim 2 , wherein the subject is refractory to chemotherapy treatment or is in relapse after treatment with chemotherapy. 
     
     
         21 . The method according to  claim 2 , wherein the compound of formula A is present in a pharmaceutical composition comprising the compound of formula A and at least one pharmaceutically acceptable excipient.