Quinolone analogs and their salts, compositions, and method for their use

Abstract

The present invention includes a solid lyophilized form of 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (Compound I) and the process of producing the solid lyophilized form. Furthermore, the present invention provides compositions comprising Compound I, or a pharmaceutically acceptable salt and/or solvate thereof and therapeutic use of the composition.

1 .- 213 . (canceled) 
     
     
         214 . A pharmaceutical composition comprising Compound I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition comprises less than about 2% impurities when the composition is stored at room temperature for at least 7 days. 
       
     
     
         215 . The pharmaceutical composition of  claim 214 , wherein the composition comprises less than about 1% impurities. 
     
     
         216 . The pharmaceutical composition of  claim 214 , wherein the composition comprises less than 0.5% impurities. 
     
     
         217 . The pharmaceutical composition of  claim 214 , wherein the composition comprises less than 0.5% of 
       
         
           
           
               
               
           
         
       
       when the composition is stored for 3 months or less. 
     
     
         218 . A solid pharmaceutical composition comprising a lyophilized Compound I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition comprises less than about 2% impurities when the composition is stored at room temperature for at least 7 days. 
     
     
         219 . The solid pharmaceutical composition of  claim 218 , wherein the composition comprises less than 1.0% impurities. 
     
     
         220 . The solid pharmaceutical composition of  claim 218 , wherein the composition comprises less than 1.0% of 
       
         
           
           
               
               
           
         
       
     
     
         221 . The solid composition of  claim 220 , wherein the composition comprises less than 0.6% of 
       
         
           
           
               
               
           
         
       
     
     
         222 . The solid composition of  claim 220 , wherein the composition comprises less than 0.1% of 
       
         
           
           
               
               
           
         
       
     
     
         223 . The solid pharmaceutical composition of  claim 218 , wherein the composition the composition comprises less than about 1% impurities when the composition is stored at room temperature for 28 days. 
     
     
         224 . The solid pharmaceutical composition of  claim 218 , wherein the composition the composition comprises less than about 1.2% impurities after the composition is stored at a temperature in the range of about 2° C. to about 30° C. for 36 month. 
     
     
         225 . The solid pharmaceutical composition of  claim 218 , wherein the composition comprises a bulking agent. 
     
     
         226 . The solid pharmaceutical composition of  claim 225 , wherein the bulking agent is sucrose, mannitol, or trehalose. 
     
     
         227 . The solid pharmaceutical composition of  claim 218 , wherein a solution for lyophilization to provide the lyophilized Compound I or a pharmaceutically acceptable salt and/or solvate thereof comprises Compound I or a pharmaceutically acceptable salt and/or solvate thereof at a concentration greater than 15 mg/ml. 
     
     
         228 . The solid pharmaceutical composition of  claim 218 , wherein the solution for lyophilization comprises no more than 1 ppm of dissolved oxygen. 
     
     
         229 . A method for treating or ameliorating cancer in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 218 . 
     
     
         230 . The method of  claim 229 , wherein the cancer is heme cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, pancreatic cancer, cancer of the lymph nodes, colon cancer, prostate cancer, brain cancer, cancer of the head and neck, skin cancer, kidney cancer, osteosarcoma, cancer of the heart, uterine cancer, gastrointestinal malignancies, or carcinomas of the larynx and oral cavity. 
     
     
         231 . A pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt and/or solvate thereof; wherein the composition further comprises one or more compound selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         232 . The pharmaceutical composition of  claim 231 , wherein the composition further comprises one or more compounds selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         233 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         234 . A composition comprising a pharmaceutically acceptable excipient and a compound of  claim 233 . 
     
     
         235 . A composition comprising:
 (a) a pharmaceutically acceptable excipient; and   (b) substantially pure compound having the structure   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         236 . The composition of  claim 235 , wherein the compound is about 95% pure. 
     
     
         237 . A method for treating or ameliorating cancer in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 231 . 
     
     
         238 . A method for treating or ameliorating cancer in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 233 . 
     
     
         239 . A method for treating or ameliorating cancer in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of  claim 235 .