Anti-tumor composition

Abstract

The present invention provides composition having as active ingredients a stilbene derivative and a platinum coordination compound which is highly efficacious and highly safe for treating tumors, particularly for the treatment of solid or malignant tumors and thus methods of cancer and tumor treatment using the composition are also provided.

1 . A composition, comprising synergistic effective amounts of:
 (a) a stilbene compound of formula (1), or a pharmaceutically acceptable salt thereof, a compound of formula (2), or a pharmaceutically acceptable salt thereof:   
     
       
         
         
             
             
         
       
       wherein 
       R 1 , R 2  and R 3  are each independently a lower alkoxy group; 
       R 4 , R 5  and R 6  are each independently selected from the group consisting of: hydrogen, a halogen, a nitro group, a hydroxyl group, a lower alkoxy group, a phosphoric acid ester, a phosphoric acid amide, an amino lower alkoxy group, a lower alkyl amino lower alkoxy group, a di-lower alkyl amino lower alkoxy group, a mercapto group, a lower alkyl thio group, an amino group, a lower alkyl amino group, a di-lower alkyl amino group, a lower alkyl group, an amino lower alkyl group, a trifluoromethyl group, a lower alkanoyl group, a lower alkanoyl amino group, and an amino acid acylamino group; 
       X is a hydrogen atom or a nitrile group; and 
       Het is a heterocyclic ring; and 
       (b) a platinum coordination compound selected from the group consisting of cis-diaminedichloroplatinum (II), cis-diamminediaquoplatinum (II)-ion, chloro (diethylenetriamine)-platinum (II) chloride, dichloro(ethylenediamine) platinum (II), cis-diammine(1,1-cyclobutanedicarboxylato) platinum (II), Spiroplatin, Iproplatin, diammine (2-ethylmalonato)-platinum (II), ethylenediamminemalonatoplatinum (II), aqua(1,2-diaminocyclohexane)sulfatoplatinum (II), (1,2-diaminocyclohexane) malonatoplatinum (II), (4-caroxyphthalato)(1,2-diaminocyclohexane)-platinum (II), (1,2-diaminocyclohexane)(isocitrato)platinum (II), (1,2-diaminocyclohexane)cis (pyruvato)platinum (II), (1,2-diaminocyclohexane)oxalateplatinum (II), Ormaplatin, Tetraplatin, and Nedaplatin; 
       wherein: 
       a combination of cis-diaminedichloroplatinum (II) and a stilbene compound represented by formula (1) wherein R 1 , R 2 , R 3  and R 5  are a lower alkoxy group, R 4  or R 6  is a hydroxyl group or a hydrogen such that when R 4  is a hydroxyl group R 6  is a hydrogen and when R 4  is a hydrogen R 6  is a hydroxyl group and X is a hydrogen is excluded; and 
       a combination of cis-diaminedichloroplatinum (II) and a stilbene compound represented by formula (3): 
     
     
       
         
         
             
             
         
       
       is excluded. 
     
   
   
       2 . The composition of  claim 1 , wherein said stilbene compound is represented by formula (1): 
     
       
         
         
             
             
         
       
       or a salt thereof; 
       wherein 
       R 1 , R 2 , R 3  and R 5  are each a methoxy group; 
       R 4  is an amino group or an amino acid acylamino group; and 
       R 6  and X are hydrogen. 
     
   
   
       3 . The composition of  claim 1 , wherein said stilbene compound is: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       4 . The composition of  claim 1 , wherein said stilbene compound is: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       5 . The composition of  claim 1 , wherein the stilbene compound is 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof and said platinum coordination compound is diammine(1,1-cyclobutanedicarboxylato)platinum (II). 
     
   
   
       6 . The composition of  claim 1 , wherein the stilbene compound is 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof and said platinum coordination compound is diammine(1,1-cyclobutanedicarboxylato)platinum (II). 
     
   
   
       7 . The composition of  claim 1 , wherein the stilbene compound is 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof and said platinum coordination compound is (1,2-diaminocyclohexane)oxalateplatinum (II). 
     
   
   
       8 . The composition of  claim 1 , wherein the stilbene compound is 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof and said platinum coordination compound is (1,2-diaminocyclohexane)oxalateplatinum (II). 
     
   
   
       9 . The composition of  claim 1 , wherein the stilbene compound is 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof and said platinum coordination compound is (1,2-diaminocyclohexane)oxalateplatinum (II). 
     
   
   
       10 . The composition of  claim 1 , wherein Het is a tetrazole ring or a thiazole ring, said thiazole ring optionally substituted with a lower alkyl group, an amino group, a mono-lower alkyl amino group, a di-lower alkyl amino group, a hydrazino group, a halogen atom, or a lower alkoxy group. 
   
   
       11 . The composition of  claim 1 , wherein said (a) stilbene compound is present in a ratio of from 0.01 to 1,000 parts by weight per 1 part by weight of said (b) platinum coordination compound. 
   
   
       12 . The composition of  claim 1 , wherein said (a) stilbene compound is present in a ratio of from 0.1 to 100 parts by weight per 1 part by weight of said (b) platinum coordination compound. 
   
   
       13 . An anti-tumor agent, comprising the composition according to  claim 12 . 
   
   
       14 . A method for treating a neoplasm, cancer, a malignant tumor or a solid tumor in a patient, comprising administering an effective amount of the anti-tumor agent according to  claim 13  to a patient in need thereof. 
   
   
       15 . An anti-tumor agent, comprising the composition according to  claim 1 . 
   
   
       16 . A method for treating a neoplasm, cancer, a malignant tumor or a solid tumor in a patient, comprising administering an effective amount of the anti-tumor agent according to  claim 15  to a patient in need thereof.