Deazaflavin compounds and methods of use thereof

Abstract

The present invention features 5-deazaflavin compounds, pharmaceutical compositions of 5-deazaflavin compounds and methods of treating a patient suffering from cancer, the method comprising administering to a patient one or more 5-deazaflavin compounds of the invention.

1 . A compound according to Formula I: 
     
       
         
         
             
             
         
       
       wherein: 
       Ar is a monosubstituted carbocyclic aryl group; 
       R 1  is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heteroalicyclic, or optionally substituted aminoalkyl; 
       R 2  and R 3  are independently selected from the group consisting of hydrogen, amino, hydroxy, cyano, nitro, carboxylate, carboxamide, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic aryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted mono- or di-alkyl amino, optionally substituted cycloalkyl, optionally substituted heteroalicyclic, or optionally substituted aminoalkyl; and 
       n is an integer from 0 to 3; and pharmaceutically acceptable salts thereof. 
     
   
   
       2 . A compound of Formula II 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heteroalicyclic, or optionally substituted aminoalkyl; 
       R 2  and R 3  are independently selected from the group consisting of hydrogen, amino, hydroxy, cyano, nitro, carboxylate, carboxamide, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic aryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted mono- or di-alkyl amino, optionally substituted cycloalkyl, optionally substituted heteroalicyclic, or optionally substituted aminoalkyl; 
       R 4  is selected from the group consisting of amino, halogen, hydroxy, cyano, nitro, carboxylate, carboxamide, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted mono- or di-alkyl amino, optionally substituted cycloalkyl, optionally substituted heteroalicyclic, or optionally substituted aminoalkyl; and 
       n is an integer from 0 to 3; and pharmaceutically acceptable salts thereof. 
     
   
   
       3 . The compound of  claim 2  wherein
 R 1  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 6-12 aryl, C 3-12 heteroaryl having between 1 and 4 ring heteroatoms, C 7-12 aralkyl, C 3-12 cycloalkyl, and C 3-12 cycloheteroalkyl;   R 2  and R 3  are independently selected from the group consisting of hydrogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 6-12 aryl, C 3-12 heteroaryl having between 1 and 4 ring heteroatoms, C 7-12 aralkyl, C 3-12 cycloalkyl, C 3-12 cycloheteroalkyl, mono or di (C 1-6 alkyl)amino, or carboxylate;   R 4  is selected from the group consisting of amino, halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or mono or di (C 1-6 alkyl)amino; and   n is an integer from 0 to 3; and pharmaceutically acceptable salts thereof.   
   
   
       4 . The compound of  claim 1  according to Formula III: 
     
       
         
         
             
             
         
       
       R 1  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 6-12 aryl, C 3-12 heteroaryl having between 1 and 4 ring heteroatoms, C 7-12 aralkyl, C 3-12 cycloalkyl, and C 3-12 cycloheteroalkyl; 
       R 2  is selected from the group consisting of hydrogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 6-12 aryl, C 3-12 heteroaryl having between 1 and 4 ring heteroatoms, C 7-12 aralkyl, C 3-12 cycloalkyl, C 3-12 cycloheteroalkyl, mono or di (C 1-6 alkyl)amino, or carboxylate; 
       R 4  is selected from the group consisting of amino, halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or mono or di (C 1-6 alkyl)amino; and 
       n is an integer from 0 to 3; and pharmaceutically acceptable salts thereof. 
     
   
   
       5 . The compound of  claim 1  wherein R 1 , R 2 , and each occurrence of R 3  are selected from the group consisting of hydrogen and C 1-6 alkyl; and
 R 4  is selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, hydroxy, and methoxy.   
   
   
       6 . The compound of  claim 1  according to Formula IV: 
     
       
         
         
             
             
         
       
       wherein R 4  is selected from the group consisting of amino, halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or mono or di (C 1-6 alkyl)amino; and pharmaceutically acceptable salts thereof. 
     
   
   
       7 . The compound of  claim 6  wherein R 4  is selected from the group consisting of a chloro, fluoro, or methyl group, and R 4  is attached to the 3 or 4 position of the phenyl ring. 
   
   
       8 . A compound selected from the group consisting of 10-(3-chloro-phenyl)-7-nitro-10H-pyrimido[4,5-b]quinoline-2,4-dione, 10-(4-chloro-phenyl)-7-nitro-10H-pyrimido[4,5-b]quinoline-2,4-dione, and 10-(4-methyl-phenyl)-7-nitro-10H-pyrimido[4,5-b]quinoline-2,4-dione; and pharmaceutically acceptable salts thereof. 
   
   
       9 . The compound of  claim 1  wherein the compound is capable of stabilizing p53 in transformed cells. 
   
   
       10 . The compound of  claim 1  wherein the compound is capable of inhibiting MDM2 activity. 
   
   
       11 . The compound of  claim 1  wherein the compound provides at least about 20 percent decreased self-ubiquitiylation of MDM2 relative to a control in a standard MDM2 activity in vitro assay. 
   
   
       12 . A pharmaceutical composition comprising one or more compounds according to  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       13 . A pharmaceutical composition comprising at least one of 10-(3-chloro-phenyl)-7-nitro-10H-pyrimido[4,5-b]quinoline-2,4-dione, 10-(4-chloro-phenyl)-7-nitro-10H-pyrimido[4,5-b]quinoline-2,4-dione, or 10-(4-methyl-phenyl)-7-nitro-10H-pyrimido[4,5-b]quinoline-2,4-dione, and a pharmaceutically acceptable carrier.