Method of Treating Tumors with Azaxanthones

Abstract

The use of azaxanthones for treating diseases associated with tumor cells which express one or more protein of S100 family, and in treating patients that have malignancies consisting of tumors of an epithelial or mesenchymal nature, where these compounds are effective in retarding the progression and/or metastasis of these tumors.

1 . A method for combating malignancies in patients where said malignancies consist of tumors of an epithelial or mesenchymal nature comprising (a) treating said tumors in said patient by reducing the size of or by removal of said tumor and, in conjunction with said treating, administering to said patient, to retard the progression or metastasis of said tumor, a compound in the formula: 
     
       
         
         
             
             
         
       
       wherein R 1  is hydrogen, lower alkyl, phenyl, carboxyl, hydroxy, amino, mono-lower alkyl amino, or di-lower alkyl amino; R 2  is lower alkyl, lower alkoxy, halogen, nitro, hydroxy or carboxyl; and n is the integer 0, 1, or 2; 
     
     or pharmacologically acceptable salts or esters thereof; with said compound being administered to said patient in an effective amount to retard the progression or metastasis of said tumors. 
   
   
       2 . The method of  claim 1  wherein said reduction or removal of said tumor is by chemotherapy, surgery or radiation. 
   
   
       3 . The method of  claim 1  wherein said compound is 2-amino-7-chloro-1-azaxanthone-3-carboxylic acid. 
   
   
       4 . The method of  claim 1  wherein said compound is 2-amino-7,9-dimethyl-1-azaxanthone-3-carboxylic acid. 
   
   
       5 . The method of  claim 1  wherein said compound is 2-amino-7-isopropyl-1-azaxanthone-3-carboxylic acid. 
   
   
       6 . The method of  claim 1  wherein said tumor is selected for the group consisting of tumors of the breast, skin, colon, lung, bladder, pancreas, esophagus, stomach or oral cavity. 
   
   
       7 . The method of  claim 1  wherein said compound is administered orally at daily dosages of from about 3 to 60 mg/kg of body weight. 
   
   
       8 . The method of  claim 7  wherein said compound is administered orally in a unit oral dosage form containing from about 20 mg to 600 mg of the compound. 
   
   
       9 . The method of  claim 6  wherein said tumor is a tumor of the breast. 
   
   
       10 . The method of  claim 6  wherein said tumor is a tumor of the colon. 
   
   
       11 . A method of treating patients who have had an epithelial or mesenchymal tumors treated by reducing its size or by removal, to retard the progression or metastasis of said tumor comprising administering to said patient, a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein R 1  is hydrogen, lower alkyl, phenyl, carboxyl, hydroxy, amino, mono-lower alkyl amino, or di-lower alkyl amino; R 2  is lower alkyl, lower alkoxy, halogen, nitro, hydroxy or carboxyl; and n is the integer 0, 1, or 2; 
       or pharmacologically acceptable salts or esters thereof; 
     
     said compound being administered in an effective amount retard the progression of metastasis of said tumor. 
   
   
       12 . The method of  claim 11  wherein said reduction or removal of said tumor is by chemotherapy, surgery or radiation. 
   
   
       13 . The method of  claim 11  wherein said compound is 2-amino-7-isopropyl-1-azaxanthone-3-carboxylic acid or pharmacologically acceptable salts or esters thereof. 
   
   
       14 . The method of  claim 11  wherein said tumor is selected for the group consisting of tumors of the breast, skin, colon, lung, bladder, pancreas, esophagus, stomach or oral cavity. 
   
   
       15 . The method of  claim 11  wherein said compound is administered orally at daily dosages of from about 3 to 60 mg/kg of body weight. 
   
   
       16 . The method of  claim 15  wherein said compound is administered in an oral unit dosage form containing from 20 to 600 mg of the compound. 
   
   
       17 . The method of  claim 14  where said tumor is a tumor of the breast. 
   
   
       18 . The method of  claim 14  wherein said tumor is a tumor of the colon. 
   
   
       19 . A salt of meglumine and a compound of the formula: 
     
       
         
         
             
             
         
       
       wherein R 1  is hydrogen, lower alkyl, phenyl, carboxyl, hydroxy, amino, mono-lower alkyl amino, or di-lower alkyl amino; R 2  is lower allyl, lower alkoxy, halogen, nitro, hydroxy or carboxyl; and n is the integer 0, 1, or 2. 
     
   
   
       20 . The salt of  claim 19  wherein said compound is 2-amino-7-isopropyl-1-azaxanthone-3-carboxylic acid. 
   
   
       21 . The salt of  claim 19  wherein said compound is 2-amino-7,9-dimethyl-1-azaxanthone-3-carboxylic acid. 
   
   
       22 . The salt of  claim 19  wherein said compound is 2-amino-7-chloro-1-azaxanthone-3-carboxylic acid. 
   
   
       23 . A pharmaceutical composition comprising a mixture of a pharmaceutically active ingredient of formula I with meglumine and a pharmaceutically acceptable carrier, said meglumine being present in the mixture in at least 0.5 parts by weight based upon the weight of said pharmaceutically active ingredient of the formula: 
     
       
         
         
             
             
         
       
       wherein R 1  is hydrogen, lower alkyl, phenyl, carboxyl, hydroxy, amino, mono-lower alkyl amino, or di-lower alkyl amino; R 2  is lower alkyl, lower alkoxy, halogen, nitro, hydroxy or carboxyl; and n is the integer 0, 1, or 2; 
     
     said active ingredient being present in the composition in an amount of from about 20 to 600 mg. 
   
   
       24 . The composition of  claim 23  wherein said meglumine is present in the composition in an amount of from about 0.5 to 1.0 parts by weight based upon the weight of the pharmaceutically active ingredient. 
   
   
       25 . The composition of  claim 24  wherein said active ingredient is present in the composition in an amount of from about 30 to 500 mg. 
   
   
       26 . The composition of  claim 23  wherein said active ingredient is 2-amino-7-isopropyl-1-azaxanthone-1-carboxylic acid. 
   
   
       27 . A liquid injectable composition comprising a meglumine salt of an active ingredient of the formula: 
     
       
         
         
             
             
         
       
       wherein R 1  is hydrogen, lower alkyl, phenyl, carboxyl, hydroxy, amino, mono-lower alkyl amino, or di-lower alkyl amino; R 2  is lower alkyl, lower alkoxy, halogen, nitro, hydroxy or carboxyl; and n is the integer 0, 1, or 2; 
     
     and a pharmaceutically acceptable injectable liquid carrier, said active ingredient being present in an amount from about 20 to 2,000 mg.