Anti-cancer combinations

Abstract

The present invention relates to synergistic combinations of the compounds of formula I such as compounds of the xanthenone acetic acid class such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and NSAIDs, in particular diclofenac, which have anti-tumour activity. More particularly, the invention is concerned with the use of such combinations in the treatment of cancer and pharmaceutical compositions containing said combinations.

1 - 16 . (canceled) 
   
   
       17 . A pharmaceutical formulation comprising a combination of the compound of formula (I); 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or ester thereof and a non-steroidal anti-inflammatory drug (NSAID) compound wherein a unit dose of said pharmaceutical formulation comprises said NSAID compound in an amount which is less than that required to substantially alter the plasma pharmacokinetics of the compound of formula (I) in a subject to be treated, 
     wherein:
 (a) R 4  and R 5  together with the carbon atoms to which they are joined, form a 6-membered aromatic ring having a substituent —R 3  and a radical —(B)—COOH where B is a linear or branched substituted or unsubstituted C 1 -C 6  alkyl radical, which is saturated or ethylenically unsaturated, and wherein R 1 , R 2  and R 3  are each independently selected from the group consisting of H, C 1 -C 6 , CN, NO 2 , NH 2 , OH, OR, NHCOR, NHSO 2 R, SR, SO 2 R or NHR, wherein each R is independently C 1 -C 6  alkyl optionally substituted with one or more substituents selected from hydroxy, amino and methoxy; or 
 (b) one of R 4  and R 5  is H or a phenyl radical, and the other of R 4  and R 5  is H or a phenyl radical which may optionally be substituted, thenyl, furyl, naphthyl, a C 1 -C 6  alkyl, cycloalkyl, or aralkyl radical; R 1  is H or a C 1 -C 6  alkyl or C 1 -C 6  alkoxy radical; R 2  is the radical —(B)—COOH where B is a linear or branched substituted or unsubstituted C 1 -C 6  alkyl radical, which is saturated or ethylenically unsaturated. 
 
   
   
       18 . The pharmaceutical formulation of  claim 17  wherein the formulation is adapted for intravenous administration. 
   
   
       19 . The pharmaceutical formulation of  claim 17  wherein the NSAID compound is diclofenac. 
   
   
       20 . The pharmaceutical formulation of  claim 17  wherein the compound of formula (I) is 5,6-dimethylxanthenone-4-acetic acid (DMXAA). 
   
   
       21 . A process for the preparation of a pharmaceutical formulation which process comprises bringing into association a combination of a compound of formula (I); 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or ester thereof, wherein:
 (a) R 4  and R 5  together with the carbon atoms to which they are joined, form a 6-membered aromatic ring having a substituent —R 3  and a radical —(B)—COOH where B is a linear or branched substituted or unsubstituted C 1 -C 6  alkyl radical, which is saturated or ethylenically unsaturated, and wherein R 1 , R 2  and R 3  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, halogens, NHCOR, NHSO 2 R, SR, SO 2 R or NHR, wherein each R is independent C 1 -C 6  alkyl optionally substituted with one or more substituents selected from hydroxy, amino and methoxy; or 
 (b) one of R 4  and R 5  is H or a phenyl radical, and the other of R 4  and R 5  is H or a phenyl radical which may optionally be substituted, thenyl, furyl, naphthyl, a C 1 -C 6  alkyl cycloalkyl, or aralkyl radical; R 1  is H or a C 1 -C 6  alkyl or C 1 -C 6  alkoxy radical; R 2  is the radical —(B)—COOH where B is a linear or branched substituted or unsubstituted C 1 -C 6  alkyl radical, which is saturated or ethylenically unsaturated. 
 
     and a NSAID compound with one or more pharmaceutically acceptable carriers therefor in a unit dose in which said NSAID compound is in an amount which is less than that required to substantially alter the plasma pharmacokinetics of the compound of formula (I) in a subject to be treated. 
   
   
       22 . The process according to  claim 21  wherein the NSAID compound is diclofenac. 
   
   
       23 . The process according to  claim 21  or  claim 22  wherein the compound of formula (I) is DMXAA. 
   
   
       24 . A kit comprising in combination for simultaneous, separate or sequential use in modulating neoplastic growth, a compound of formula (I) as defined in  claim 17  or a pharmaceutically acceptable salt or ester thereof and a NSAID compound, wherein said NSAID is provided in a unit dose comprising an amount of NSAID which is less than that required to substantially alter the plasma pharmacokinetics of the compound of formula (I) in a subject to be treated. 
   
   
       25 . The kit according to  claim 24  wherein the NSAID compound is diclofenac. 
   
   
       26 . The kit according to  claim 25  wherein the compound of formula (I) is DMXAA. 
   
   
       27 . The pharmaceutical formulation of  claim 17  wherein the compound of Formula (I) is a compound of Formula (II): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 4 , R 5  and B are as defined for formula (I) in  claim 17  part (b). 
   
   
       28 . The pharmaceutical formulation of  claim 17  wherein the compound of Formula (I) is a compound of Formula (III): 
     
       
         
         
             
             
         
       
       wherein R 1 , R 2  and R 3  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, halogen, CF 3 , CN, NO 2 , NH 2 , OH, OR, NHCOR, NHSO 2 R, SR, SO 2 R or NHR, wherein each R is independently C 1 -C 6  alkyl optionally substituted with one or more substituents selected from hydroxy, amino and methoxy; 
     
     wherein B is as defined for formula (I) in  claim 17 ; 
     and wherein in each of the carbocyclic aromatic rings in formula (I), up to two of the methine (—CH═) groups may be replaced by an aza (—N═) group; 
     and wherein any two of R 1 , R 2  and R 3  may additionally together represent the group —CH═CH—CH═CH—, such that this group, together with the carbon or nitrogen atoms to which it is attached, forms a fused 6 membered aromatic ring. 
   
   
       29 . The pharmaceutical formulation of  claim 28  wherein the compound of Formula (III) is a compound of Formula (IV): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , and R 3  are as defined for formula (III) in  claim 28 . 
   
   
       30 . The pharmaceutical formulation of  claim 29  wherein the compound of Formula (IV) is a compound of Formula (V): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , and R 3  are as defined for formula (IV) in  claim 29 . 
   
   
       31 . The pharmaceutical formulation of  claim 17  wherein R 4  is H or a phenyl radical, R 5  is H or a phenyl radical which may optionally be substituted, thenyl, furyl, naphthyl, a C 1 -C 6  alkyl, cycloalkyl, or aralkyl radical; R 1  is H or a C 1 -C 6  alkyl or C 1 -C 6  alkoxy radical; R 2  is radical —(B)—COOH where B is a linear or branched substituted or unsubstituted C 1 -C 6  alkyl radical, which is saturated or ethylenically unsaturated. 
   
   
       32 . The pharmaceutical formulation of  claim 17  wherein the compound of formula (I) or pharmaceutically acceptable salt or ester thereof and the NSAID are present in a potentiating ratio. 
   
   
       33 . The pharmaceutical formulation of  claim 17  wherein the ratio of compound of formula (I):NSAID is in the range 10:1 to 1:1. 
   
   
       34 . The pharmaceutical formulation of  claim 17  wherein the ratio of compound of formula (I):NSAID is about 5:1.