Tartrate salts of quinazoline based egfr inhibitors containing a zinc binding moiety

Abstract

The present invention relates to tartrate salts of quinazoline containing zinc-binding moiety based derivatives of Formula II, below. These compounds are inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and may further act as HDAC inhibitors. The invention further relates to the use of these tartrate salts in the treatment of EGFR-TK related diseases and disorders such as cancer.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising (a) a tartaric acid salt or complex of a compound represented by formula (II): 
       
         
           
           
               
               
           
         
         wherein B is a C 3  to C 9  alkylene; 
         R 1  is selected from hydrogen, C 1  to C 4  alkoxy or substituted C 1  to C 4  alkoxy; 
         each R 2  is independently selected from halogen, C 1  to C 4  alkyl, C 2  to C 4  alkenyl, and 
         C 2  to C 4  alkynyl; and 
         n is 1, 2 or 3; and 
         (b) a cyclodextrin. 
       
     
     
         2 . The pharmaceutical composition of  claim 1  wherein B is a straight chain C 5  to C 7  alkylene. 
     
     
         3 . The pharmaceutical composition of  claim 2  wherein B is a straight chain C 6  alkylene. 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein n is 1. 
     
     
         5 . The pharmaceutical composition of  claim 4  wherein R 2  is ethynyl. 
     
     
         6 . The pharmaceutical composition of  claim 5  wherein R 1  is methoxy. 
     
     
         7 . The pharmaceutical composition of  claim 1  wherein the tartaric acid is the L-tartaric acid. 
     
     
         8 . The pharmaceutical composition of  claim 1  wherein the tartaric acid is the D-tartaric acid. 
     
     
         9 . The pharmaceutical composition of  claim 1  wherein the tartaric acid is D,L-tartaric acid. 
     
     
         10 . The pharmaceutical composition of  claim 1  wherein the tartaric acid is meso-tartaric acid. 
     
     
         11 . The pharmaceutical composition  claim 1  wherein the compound is represented by formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         12 . The pharmaceutical composition of  claim 11  wherein B is a straight chain C 5  to C 7  alkylene. 
     
     
         13 . The pharmaceutical composition of  claim 12  wherein R 1  is hydrogen and B is a straight chain C 6  alkylene. 
     
     
         14 . The pharmaceutical composition of  claim 1  wherein the compound is represented by formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         15 . The pharmaceutical composition of  claim 14  wherein B is a straight chain C 5  to C 7  alkylene. 
     
     
         16 . The pharmaceutical composition of  claim 15  wherein R 1  is methoxy and B is a straight chain C 6  alkylene. 
     
     
         17 . The pharmaceutical composition of  claim 1  wherein the compound is represented by formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         18 . The pharmaceutical composition of  claim 17  wherein B is a straight chain C 5  to C 7  alkylene. 
     
     
         19 . The pharmaceutical composition of  claim 17  wherein R 1  is hydrogen and B is a straight chain C 6  alkylene. 
     
     
         20 . The pharmaceutical composition of  claim 1  wherein the compound is represented by formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         21 . The pharmaceutical composition of  claim 20  wherein B is a straight chain C 5  to C 7  alkylene. 
     
     
         22 . The pharmaceutical composition of  claim 20  wherein R 1  is methoxy and B is a straight chain C 6  alkylene. 
     
     
         23 . The pharmaceutical composition of  claim 1  wherein the cyclodextrin is a α-cyclodextrin or a derivative thereof. 
     
     
         24 . The pharmaceutical composition of  claim 1  wherein the cyclodextrin is a β-cyclodextrin or a derivative thereof. 
     
     
         25 . The pharmaceutical composition of  claim 1  wherein the cyclodextrin is a γ-cyclodextrin or a derivative thereof. 
     
     
         26 . The pharmaceutical composition of  claim 24  wherein the β-cyclodextrin or a derivative thereof is selected from the group consisting of a 2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatized-β-cyclodextrin. 
     
     
         27 . The pharmaceutical composition of  claim 26  wherein the cyclodextrin is sulfobutylether (7)-β-cyclodextrin. 
     
     
         28 . The pharmaceutical composition of  claim 27  wherein the sulfobutylether (7)-β-cyclodextrin is present at a concentration between 0.5 and 40% (w/v). 
     
     
         29 . The pharmaceutical composition of  claim 28  wherein the sulfobutylether (7)-β-cyclodextrin is present at a concentration of about 30% (w/v). 
     
     
         30 . The pharmaceutical composition of  claim 1  further comprising dextran. 
     
     
         31 . The pharmaceutical composition of  claim 30  comprising 5% dextran. 
     
     
         32 . The pharmaceutical composition of  claim 1  formulated for intravenous administration. 
     
     
         33 . A method of treating an EFGR-tyrosine kinase related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         34 . A method of treating an HDAC-mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         35 . A method of treating a disease mediated by EGFR-tyrosine kinase and HDAC comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         36 . A method of treating a disease mediated by HER2 comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         37 . A method of treating a cell proliferative disorder comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         38 . The method of  claim 37 , wherein said cell proliferative disorder is selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, non-small cell lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease and Burkitt's disease.