Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof

Abstract

The present invention relates to novel “reverse amide” compounds comprising a zinc chelator group, and the use of such compounds in the inhibition of HDAC6 and in the treatment of various diseases, disorders or conditions related to HDAC6.

What is claimed: 
     
         1 . A pharmaceutical composition comprising a chemotherapeutic agent and a compound of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted by alkyl, aryl, aralkyl, haloalkyl, halo, OH, NH 2 , CN, or NO 2 ; 
 R 1  is aryl, arylalkyl, or heteroaryl, each of which may be optionally substituted by OH, halo, or alkyl; 
 and 
 R is H or alkyl. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein R 1  is substituted by OH or halo. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein B is phenyl, pyridinyl, or pyrimidinyl, each of which may be optionally substituted by alkyl or halo. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein R 1  is phenyl, pyridinyl, or pyrimidinyl, each of which may be optionally substituted by OH or halo. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the compound of formula (IV) is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the compound of formula (IV) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the compound of formula (IV) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the chemotherapeutic agent is selected from the group consisting of: trastuzamab, raloxifene, pamidronate disodium, anastrozole, exemestane, epirubicin, letrozole, toremifene, fulvestrant, fluoxymester-one, docetaxel, testolactone, aziridine, capecitabine, goselerin acetate, zoledronic acid, taxol, alkylating drugs, mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, antimetabolites, methotrexate, purine antagonists, pyrimidine antagonists, 6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine, spindle poisons, vinblastine, vincristine, vinorelbine, paclitaxel, podophyllotoxins, etoposide, irinotecan, topotecan, antibiotics, doxorubicin, bleomycin, mitomycin, nitrosoureas, carmustine, lomustine, inorganic ions, cisplatin, carboplatin, enzymes, asparaginase, hormones, tamoxifen, leuprolide, flutamide, and megestrol. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the chemotherapeutic agent is docetaxel or paclitaxel. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the chemotherapeutic agent and the compound of formula IV are in the form of a fixed combination. 
     
     
         11 . A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         12 . The method of  claim 11 , wherein the cancer is selected from the group consisting of: breast cancer, cervical cancer, colon cancer, rectal cancer, leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, lung cancer, small cell lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, liver cancer, brain cancer, kidney cancer, stomach cancer, skin cancer, melanoma, bone cancer, glioma, gliobastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, lymphomas, myelomas, solid tumors, multiple myeloma, retinoblastoma, bladder cancer, uterine cancer, testicular cancer, stomach cancer, and esophageal cancer. 
     
     
         13 . The method of  claim 12 , wherein the cancer is ovarian cancer. 
     
     
         14 . The method of  claim 12 , wherein the cancer is a solid tumor. 
     
     
         15 . The method of  claim 11 , wherein the chemotherapeutic agent and the compound of formula IV are administered in the form of a fixed combination. 
     
     
         16 . The method of  claim 11 , wherein the chemotherapeutic agent and the compound of formula IV are administered as a non-fixed combination. 
     
     
         17 . A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 6 . 
     
     
         18 . A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 7 .