Transition metal complexes for inhibiting resistance in the treatment of cancer and metastasis

Abstract

The present invention relates to organometallic compounds useful in the treatment of metastasis. The organometallic compounds comprise a ligand that is convalently bound to a bioactive compound, which is an inhibitor of a resistance pathway or a derivative thereof. Preferably, the organometallic compounds are half-sandwich (“piano-stool”) compounds. The compounds of the present invention offer a high variability with respect to the bioactive compound and to the nature of the ligand bound to a central transition metal.

1 - 13 . (canceled) 
     
     
         14 . A method for treating cancer or metastatic cancer comprising administering to an individual an effective amount of an organometallic compound of formula (XIV) 
       
         
           
           
               
               
           
         
         in which, 
         A is a monocyclic arene selected from the group of benzene, methylbenzene, cymene; R 18 , R 19 , R 20  are ligands of the central ruthenium atom which are, independently of each other, selected from the group of halogens consisting of F − , Cl − , Br −  and I − , from the group consisting of N-, P- and O-donor ligands or from a bioactive organic compound; 
         R 17  is an optional residue selected from alkyl, alkenyl, alkynyl, aryl, or from a bioactive organic compound;
 whereby at least one bioactive organic compound is at least one residue or ligand selected from R 17 , R 18 , R 19 , R 20  or is covalently linked to any of R 17 , R 18 , R 19 , R 20  via a covalent bond selected from the group consisting of a carbon-carbon alkyl bond, alkenyl bond and alkynyl bond, or selected from the group of carbon-heteronuclear bonds consisting of amide bond (—CONH—), ester bond (—CO 2 —), ether bond (—CH 2 O—), thioether (—CH 2 S—), amine bond (—CH 2 N—), imine bond (—CH═N—), and phosphorous bond (—CH 2 P—), with the proviso that the residue or ligand covalently linked to the bioactive organic molecule is not halogen; and 
 wherein
 the bioactive organic compound is selected from:
 an inhibitor of Glutathione S-transferase selected from ethacrynic acid, peptidomimetics of gluthatione, p-chlorophenoxyisobutyrate, Gossypol, indomethacin, non-steroidal anti-inflammatory compounds of ibuprofen and of ketoprofen, misonidazole, Piriprost, Sulfasalazine; 
 an inhibitor of γ-Glutamyl Cysteine Synthetase selected from sulfoxime-based compounds group consisting of buthinone sulfoxime and methinone sulfoxime, S-sulfocysteine, S-sulfohomocysteine, cystamine; 
 an inhibitor of the multidrug resistance protein selected from the group of quinidine, vinblastine, terfernadine, tamoxifen, verapamil, cyclosporin, amitriptyline, progesterone; or 
 an inhibitor of a cell signaling pathway selected from the group of pleurotin, azelaic acid, bischloroethylnitrosourea, palmarumycin; and 
 
 said N-donor ligand is an imidazole of formula (IV) or of formula (V), which is covalently linked to the bioactive compound 
 
 
       
       
         
           
           
               
               
           
         
         
           
             and wherein the “bioactive compound” moiety of formula (IV) and formula (V) represents a bioactive organic compound as described above and wherein the bioactive organic compound is linked to the —NH— of formula (IV) or the —O— of formula (V) via a carboxy group;
 n is 1-10, and M is the transition metal Ru of the organometallic compound of formula (XIV); 
 
             said P-donor ligand is selected from the group consisting of PTA, MePTA and DAPTA, wherein PTA is 1,3,5-triaza-7-phosphadamantane, MePTA is 3-methyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane and DAPTA is 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane; and 
             said O-donor ligand is selected from the group consisting of carbonate CO 3   − , carboxylate ligands R C CO 2   − , oxalate C 2 O 4   2− , nitrate NO 3   − , sulfate SO 4   2−  and sulphonate R S1 O 3   − , wherein R C  and R S1  is selected from alkyl, alkenyl, alkynyl, aryl. 
           
         
       
     
     
         15 . The method according to  claim 14 , wherein:
 R 20  and R 19  of formula (XIV) are independently selected from the group of halogens consisting of F, Cl − , Br −  and I − ; or from the group consisting of said P- and said O-donor ligands;   R 17  is present and A-R 17  of formula (XIV) is represented by formula (XI) or in formula (XII) below:   
       
         
           
           
               
               
           
         
         
           wherein
 m is 1-10, 
 the monocyclic arene A of the organometallic compound of formula (XIV) is the structure 
 
         
       
       
         
           
           
               
               
           
         
         
           
             and the “bioactive compound” of formula (XI) and formula (XII) represents the bioactive organic compound; 
           
           and wherein the bioactive organic compound is linked to the O— of formula (XI) or the —NH— of formula (XII) via a carboxy group; and 
         
         R 18  of formula (XIV) is selected from the group of halogens consisting of F − , Cl − , Br −  and I −  or from the group consisting of said P- and said O-donor ligands. 
       
     
     
         16 . The method according to  claim 14 , wherein A of formula (XIV) is benzene or cymene. 
     
     
         17 . The method according to  claim 14 , wherein, said bioactive organic compound is ethacrynic acid. 
     
     
         18 . The method according to  claim 14 , wherein halogen is Cl − ; said P-donor ligand is PTA; said O-donor ligand is selected from carboxylate ligands R C CO 2−  or oxalate C 2 O 4   2− , wherein R C  is selected from alkyl, alkenyl, alkynyl, aryl; and said bioactive organic compound is ethacrynic acid. 
     
     
         19 . The method according to  claim 14 , wherein R 20  and R 19  of formula (XIV) are independently selected from the group of halogens consisting of F − , Cl − , Br −  and I − ; R 18  is selected from the group consisting of said P-donor ligands. 
     
     
         20 . The method according to  claim 14 , wherein R 20  and R 19  a of formula (XIV) are independently selected from the group of halogens consisting of F − , Cl − , Br −  and I −  or from the group consisting of said P-donor ligands; R 18  of formula (XIV) is selected from said N-donor ligands of formula (IV) or of formula (V); and R 17  is absent. 
     
     
         21 . The method according to  claim 14 , wherein the organometallic compound of formula (XIV) is selected from the group consisting of (Ethacrynic-η 6 :phenylmethylamide)Ru(PTA)Cl 2 , (Ethacrynic-η 6 :phenylethanoate)Ru(PTA)Cl 2 , (η 6 -cymene)RuCl 2 (ethacrynic-propylamide-imidazole), and [(η 6 -cymene)RuCl(PTA)(ethacrynic-propylamide-imidazole)]BF4 − , wherein PTA is 1,3,5-triaza-7-phosphadamantane. 
     
     
         22 . The method according to  claim 14 , wherein:
 R 20  and R 19  of formula (XIV) are independently selected from the group of halogens consisting of F − , Cl − , Br −  and I − ; or from the group consisting of said P— and said O-donor ligands;   R 18  of formula (XIV) is selected from said N-donor ligands of formula (IV) or of formula (V) as defined in  claim 14  to which a bioactive organic molecule is covalently bound,   R 17  of formula (XIV) is present and selected from alkyl, alkenyl, alkynyl, aryl.   
     
     
         23 . The method according to  claim 14 , wherein:
 R 20  and R 19  of formula (XIV) are independently selected from the group of halogens consisting of F − , Cl − , Br −  and I − ; or from the group consisting of said P- and said O-donor ligands;   R 18  of formula (XIV) is selected from said N-donor ligand of formula (IV) or of formula (V); and R 17  of formula (XIV) is absent.   
     
     
         24 . The method according to  claim 14 , wherein R 20  and R 19  of formula (XIV) are independently selected from the group of halogens consisting of F − , Cl − , Br −  and I −  or from the group consisting of said P-donor ligands;
 R 18  of formula (XIV) is selected from said N-donor ligands of formula (IV) or of formula (V); and R 17  of formula (XIV) is present and is selected from alkyl, alkenyl, alkynyl, aryl. 
 
     
     
         25 . The method according to  claim 14 , wherein R 20  and R 19  of formula (XIV) are selected from the group of said O-donor ligands consisting of carboxylate ligands R C CO 2−  or oxalate C 2 O 4   2− , wherein R C  is selected from alkyl, alkenyl, alkynyl, aryl;
 R 18  of formula (XIV) is selected from said N-donor ligands of formula (IV) or of formula (V); 
 R 17  of formula (XIV) is selected from alkyl, alkenyl, alkynyl, aryl. 
 
     
     
         26 . The method according to  claim 14 , wherein R 19  of formula (XIV) is selected from the group of halogens consisting of F − , Cl − , Br −  and I −  and R 20  of formula (XIV) is selected or from the group consisting of said P-donor ligands;
 R 18  of formula (XIV) is selected from N-donor ligands of formula (IV) or of formula (V); and 
 R 17  of formula (XIV) is selected from alkyl, alkenyl, alkynyl, aryl. 
 
     
     
         27 . The method according to  claim 14 , wherein R 19  of formula (XIV) is selected from the group of halogens consisting of F − , Cl − , Br −  and I −  and R 20  of formula (XIV) is selected or from the group consisting of said P-donor ligands; R 18  of formula (XIV) is selected from said N-donor ligands of formula (IV) or of formula (V); and R 17  is absent. 
     
     
         28 . The method according to  claim 14 , wherein
 R 20  and R 19  of formula (XIV) are Cl − ; and R 18  of formula (XIV) is selected from the group consisting of said P-donor ligands.   
     
     
         29 . The method according to  claim 14 , wherein:
 A of formula (XIV) is cymene; R 20  and R 19  of formula (XIV) are independently selected from the group of halogens consisting of F − , Cl − , Br −  and I − ; or from the group consisting of said P- and O-donor ligands; R 18  of formula (XIV) is selected from said N-donor ligands of formula (IV) or of formula (V); and R 17  is absent.   
     
     
         30 . The method according to  claim 14 , wherein R 20  and R 19  of formula (XIV) are independently selected from the group of halogens consisting of F − , Cl − , Br −  and I − ; and R 18  is selected from the P-donor ligand PTA. 
     
     
         31 . The method according to  claim 14  comprising administering to the individual an effective amount of said organometallic compound of formula (XIV) and an effective amount of an anti-cancer drug. 
     
     
         32 . A method for reducing resistance of cancers or metastatic cancer comprising administering to an individual an effective amount of an organometallic compound of formula (XIV) 
       
         
           
           
               
               
           
         
         in which, 
         A is a monocyclic arene selected from the group of benzene, methylbenzene, cymene; 
         R 18 , R 19 , R 20  are ligands of the central ruthenium atom which are, independently of each other, selected from the group of halogens consisting of F − , Cl − , Br −  and I − , from the group consisting of N-, P- and O-donor ligands or from a bioactive organic compound; 
         R 17  is an optional residue selected from alkyl, alkenyl, alkynyl, aryl, or from a bioactive organic compound;
 whereby at least one bioactive organic compound is at least one residue or ligand selected from R 17 , R 18 , R 19 , R 20  or is covalently linked to any of R 17 , R 18 , R 19 , R 20  via a covalent bond selected from the group consisting of a carbon-carbon alkyl bond, alkenyl bond and alkynyl bond, or selected from the group of carbon-heteronuclear bonds consisting of amide bond (—CONH—), ester bond (—CO 2 —), ether bond (—CH 2 O—), thioether (—CH 2 S—), amine bond (—CH 2 N—), imine bond (—CH═N—), and phosphorous bond (—CH 2 P—), with the proviso that the residue or ligand covalently linked to the bioactive organic molecule is not halogen; and 
 wherein
 the bioactive organic compound is selected from:
 an inhibitor of Glutathione S-transferase selected from ethacrynic acid, peptidomimetics of gluthatione, p-chlorophenoxyisobutyrate, Gossypol, indomethacin, non-steroidal anti-inflammatory compounds of ibuprofen and of ketoprofen, misonidazole, Piriprost, Sulfasalazine; 
 an inhibitor of γ-Glutamyl Cysteine Synthetase selected from sulfoxime-based compounds group consisting of buthinone sulfoxime and methinone sulfoxime, S-sulfocysteine, S-sulfohomocysteine, cystamine; 
 an inhibitor of the multidrug resistance protein selected from the group of quinidine, vinblastine, terfernadine, tamoxifen, verapamil, cyclosporin, amitriptyline, progesterone; or 
 an inhibitor of a cell signaling pathway selected from the group of pleurotin, azelaic acid, bischloroethylnitrosourea, palmarumycin; and 
 
 said N-donor ligand is an imidazole of formula (IV) or of formula (V), which is covalently linked to the bioactive compound 
 
 
       
       
         
           
           
               
               
           
         
         
           
             and wherein the “bioactive compound” moiety of formula (IV) and formula (V) represents a bioactive organic compound as described above and wherein the bioactive organic compound is linked to the —NH— of formula (IV) or the —O— of formula (V) via a carboxy group;
 n is 1-10, and M is the transition metal Ru of the organometallic compound of formula (XIV); 
 
             said P-donor ligand is selected from the group consisting of PTA, MePTA and DAPTA, wherein PTA is 1,3,5-triaza-7-phosphadamantane, MePTA is 3-methyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane and DAPTA is 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane; and 
             said O-donor ligand is selected from the group consisting of carbonate CO 3   − , carboxylate ligands R C CO 2   − , oxalate C 2 O 4   2− , nitrate NO3 − , sulfate SO 4   2−  and sulphonate R S1 O 3   − , wherein R C  and R S1  is selected from alkyl, alkenyl, alkynyl, aryl.