Anti-cancer 2,3-dihydro-1H-pyrrole[3,2-f] quinoline compolexes of cobalt and chromium

Abstract

This invention relates to a class of heterocycles and their metal complexes, and is particularly concerned with the use of these compounds in the preparation of prodrugs or as prodrugs that may be activated under hypoxic conditions by enzymes or by therapeutic ionising radiation, in the treatment of cancer. The invention also relates to the use of these heterocycles and the corresponding metal complexes in the preparation of medicaments and to compositions including the heterocycles or their metal complexes and to methods for preparing these compounds.

1 . A metal complex represented by Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 B is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 D is selected from C or N;  
 E is selected from a direct bond, OH or NP 1   2 , where each R 1  independently represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, when D represents C; or  
 M is selected from Co III , Co II , Cr III ; or Cr II ;  
 Z is selected from O, NR 2 , where R 2  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups,  
 S 1  and S 2  together represent formula V  
                     
 wherein X is selected from a group including halogen, CH 2 -halogen, CH 2 OCO—(C 1 -C 6  alkyl optionally substituted with one or more amino or hydroxy groups), CH 2 -phosphate group or CH 2 OSO 2 R 3 , where R 3  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or CH 2 OSO 2 NHR 4  where R 4  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; and  
 R is selected from one of formulae VI or VII  
                     
 wherein each T 1 , T 2  and T 3  is independently selected from H, OPO(OH) 2 , OR 5 , NR 5   2  or NHCOR 5 , where each R 5  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; or O(CH 2 ) n NR 6   2 , where each n is independently 1, 2, 3 or 4 and each R 6  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups and  
 • represents the point of attachment of R to Formula V defined above, and S 3  is selected from H, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, halogen, CO 2 [(C 1-6  alkyl) wherein said alkyl is optionally substituted with amino, or hydroxy groups]; OR 7 , NR 7   2 , or CONHR 7 , where each R 7  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; or S 3  represents an optionally substituted 5 or 6 membered cyclic system optionally containing one or more heteroatoms fused to ring system A defined above, wherein said substituents are selected from OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, and halogen groups, and  
 wherein ligands L 1 -L 4  are each independently selected in combinations from anionic monodentate ligands, including CN − , SCN − , halide, NO 2   − ; bidentate ligands including MeCOCHJCOMe (Jacac; deprotonated in the complex), where J═H, Me, Cl, SMe, SO 2 Me, S(CH 2 ) n SO 3 H, S(CH 2 ) n CO 2 H, S(CH 2 ) n OP(O)(OH) 2 , CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H, CH 2 (CH 2 ) n OP(O)(OH) 2 , S(CH 2 ) n P(O)(OH) 2  or CH 2 (CH 2 ) n P(O)(OH) 2 , where n is from 1-4; or tridentate ligands VIIIa-VIIIc (=respectively TACH, TAME and TACN when R 1 -R 3 ═H).  
                     
 wherein each R 1 -R 4  are independently selected from H, Me, CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H or CH 2 (CH 2 ) n P(O)(OH) or CH 2 (CH 2 ) n NR 8   2 , where each n is independently 1, 2, 3 or 4 and each R 8  independently represents H, or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or  
 L 1 -L 4  can also be selected from any one of the tetradentate ligands IX-XVII, or any two of the bidentate ligands XVIII, or any combination of the bidentate ligands XVIII together with any of the monodentate ligands L 1 -L 4  defined above;  
                                       
 wherein in formulae IX-XVIII, R 1′  to R 8′  each independently represent H, Me, CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H or CH 2 (CH 2 ) n OP(O)(OH) 2  or CH 2 (CH 2 ) n NMe 2 , where each n is independently 1, 2, 3 or 4;  
 each Z 1 -Z 4  is independently selected from —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 OCH 2 — or —CH 2 N(R 9 )CH 2 —; where R 9  represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups and  
 each Y′ is independently selected from H, halogen, SO 2 Me, O(C 1 -C 6  alkyl), NR 10   2 , where each R 10  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or Q 1 (CH 2 ) n Q 2 , wherein Q 1  is selected from —O—, —CH 2 —, —NH—, —CONH—, —CO 2 — or —SO 2 —, and Q 2  is selected from —CO 2 H, —SO 3 H, —OP(O)(OH) 2  or —NR 11   2  where each R 11  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; and  
 wherein the overall charge on the complex is neutral, positive or negative and wherein in the case of a non-neutral complexF countercharge  is selected from a range of physiologically acceptable-counterions, including halide, NO 3   − , NH 4   +  or Na + ; and  
 wherein q is the required number to neutralise the overall charge on the complex; and including any enantiomeric or diastereomeric form, and any physiologically salt derivative thereof.  
 
     
     
         2 . The metal complex according to  claim 1  wherein the rings A and B of Formula I as defined in  claim 1  together represent an 8-substituted quinoline system.  
     
     
         3 . The metal complex according to  claim 1  wherein Z represents —O—.  
     
     
         4 . The metal complex according to  claim 1  wherein Z represents —NH—.  
     
     
         5 . The metal complex according to  claim 1  wherein R is selected from one of  
       
         
           
           
               
               
           
         
       
     
     
         6 . The metal complex according to  claim 1  wherein one of the ligands L 1 -L 4  is selected from the following  
       
         
           
           
               
               
           
         
       
     
     
         7 . The metal complex according to  claim 1  wherein X is CH 2 Cl.  
     
     
         8 . The metal complex according to  claim 1  selected from one of the following;  
       
         
           
           
               
               
           
         
       
     
     
         9 . A method of providing cancer treatment, which includes the steps of 
 (a) administering to a patient in need of such therapy an effective amount of a metal complex of Formula I as defined in  claim 1 , and    (a) activating the metal complex of Formula I under hypoxic conditions via reduction, either enzymatically or by a non-enzymatic endogenous reducing agents, or by ionizing radiation,    wherein said activation releases a sufficient amount of an effector from said metal complex of Formula I.    
     
     
         10 . The method according to  claim 9  including the alternative step of activation of the metal complex of Formula I as defined in  claim 1  by radiotherapy radiation.  
     
     
         11 . A composition comprising as an active agent a metal complex of Formula I as defined in  claim 1  and a pharmaceutically acceptable excipient, adjuvant or carrier.  
     
     
         12 . The use, in the manufacture of a medicament, of an effective amount of a metal complex of Formula I as defined in  claim 1  for use in treating a subject in need of cancer treatment.  
     
     
         13 . A metal complex represented by Formula Ia  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 B is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 D is selected from C or N;  
 E is selected from a 5 or 6 membered ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups  
 M is selected from Co III , Co II , Cr III  or Cr II ;  
 Z represents NH 2  or NHMe,  
 Q represents H, C 1-6  alkyl, or (CH 2 ) 2 NH 2 , when Q represents (CH 2 ) 2 NH 2 , Q will become a ligand for M and replace one of ligands L 1 -L 4  defined below,  
 S 1  and S 2  together represent formula V  
                     
 wherein X is selected from a group including halogen, CH 2 -halogen, CH 2 CN, CH 2 CO 2 -(C 1 -C 6  alkyl optionally substituted with one or more amino or hydroxy groups), CH 2 -phosphate group, CH 2 OSO 2 R 3  or OSO 2 R 3  where R 3  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or CH 2 OSO 2 NHR 4  where R 4  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; and  
 R is selected from one of formulae VI or VlI  
                     
 wherein each T 1 , T 2  and T 3  is independently selected from H, OPO(OH) 2 , OR 2 , NR 2   2  where each R 2  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or O(CH 2 ) n NR 3   2 , where each n is independently 1, 2, 3 or 4, and each R 3  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups and  
 • represents the point of attachment of R to Formula V defined above, and S 3  is selected from H, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, halogen, CO 2 (C 1-6  alkyl) wherein said alkyl is optionally substituted with amino, or halogen groups, OR 4 , NR 4   2 , CONHR 4 , where each R 4  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; or S 3  represents an optionally substituted 4-8 membered cyclic system optionally containing one or more hetoeroatoms fused to ring system A defined above, wherein said substituents are selected from OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, halogen groups, and  
 wherein ligands L 1 -L 4  are each independently selected in combinations from anionic monodentate ligands, including CN − , SCN − , halide, NO 3   − ; bidentate ligands including MeCOCHJCOMe (Jacac; deprotonated in the complex), where J═H, Me, Cl, SMe, SO 2 Me, S(CH 2 ) n SO 3 H, S(CH 2 ) n CO 2 H, S(CH 2 ) n OP(O)(OH) 2 , CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H, CH 2 (CH 2 ) n OP(O)(OH) 2 , S(CH 2 ) n P(O)(OH) 2  CH 2 (CH 2 ) n P(O)(OH) 2 , or where each n is independently 1, 2, 3 or 4; or tridentate ligands VIIIa-VIIIc (=respectively TACH, TAME and TACN when R 1 -R 3 ═H),  
                     
 wherein R 1 -R 4  are each independently selected from H, Me, CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H or CH 2 (CH 2 ) n OP(O)(OH) 2  CH 2 (CH 2 ) n P(O)(OH) 2  or CH 2 (CH 2 ) n NR 5   2 , where each n is independently 1, 2, 3 or 4 and each R 5  independently represents H, or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or  
 L 1 -L 4  can also be selected from any one of the tetradentate ligands IX-XVII, or any two of the bidentate ligands XVIII, or any combination of the bidentate ligands XVIII together with any of the monodentate ligands L 1 -L 4  defined above;  
                                       
 wherein in formulae IX-XVIII, R 1′  to R 8′  each independently represent H, Me, CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H or CH 2 (CH 2 ) n OP(O)(OH) 2  or CH 2 (CH 2 ) n NMe 2 , where each n is independently 1,2, 3 or 4;  
 each Z 1 -Z 4  is independently selected from —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 0CH 2 — or —CH 2 N(R 6 )CH 2 —; where R 6  represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups and  
 each Y′ is independently selected from H, halogen, SO 2 Me, O(C 1 -C 6  alkyl), NR 7   2 , where each R 7  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or Q 1 (CH 2 ) n Q 2 , wherein Q 1  is selected from —O—, —CH 2 —, —NH—, —CONH—, —CO 2 — or —SO 2 —, and Q 2  is selected from —CO 2 H, —SO 3 H, —OP(O)(OH) 2  or —NR 8   2  where each R 8  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; and  
 wherein the overall charge on the complex is neutral, positive or negative and wherein in the case of a non-neutral complex F countercharge  is selected from a range of physiologically acceptable-counterions; including halide, NO 3   − , NH 4   +  or Na + ; and  
 wherein q is the required number to neutralise the overall charge on the complex; and including any enantiomeric or diastereomeric form, and any physiologically salt derivative thereof.  
 
     
     
         14 . The metal complex according to  claim 13  wherein rings A and B together represent an 8-substituted quinoline system.  
     
     
         15 . The metal complex according to  claim 13  wherein Z represents —OH.  
     
     
         16 . The metal complex according to  claim 13  wherein Z represents —NH.  
     
     
         17 . The metal complex according to  claim 13  wherein R is selected from one of  
       
         
           
           
               
               
           
         
       
     
     
         18 . The metal complex according to  claim 13  wherein one of the ligands L 1 -L 4 ) is selected from the following  
       
         
           
           
               
               
           
         
       
     
     
         19 . The metal complex according to  claim 13  wherein X is CH 2 Cl.  
     
     
         20 . The metal complex according to  claim 13  which represents  
       
         
           
           
               
               
           
         
       
     
     
         21 . A method of providing cancer treatment, which includes the steps of 
 (a) administering to a patient in need of such therapy an effective amount of a metal complex of Formula Ia as defined in  claim 13 , and    (b) activating the compound of Formula la under hypoxic conditions via reduction, either enzymatically or by non-enzymatic endogenous reducing agents, or by ionising radiation,    wherein said activation releases a sufficient amount of an effector, from said effective amount of the compound of Formula Ia.    
     
     
         22 . The method according to  claim 21  including the alternative step of activation of the metal complex of Formula Ia as defined in  claim 13  by radiotherapy radiation.  
     
     
         23 . A composition comprising as an active agent a metal complex of Formula Ia as defined in  claim 13  and a pharmaceutically acceptable excipient, adjuvant or carrier.  
     
     
         24 . The use, in the manufacture of a medicament, of an effective amount of a compound of Formula Ia as defined in  claim 13  for use in treating a subject in need of cancer treatment.  
     
     
         25 . A heterocycic compound of Formula XIX.  
       
         
           
           
               
               
           
         
       
       wherein 
 A is selected from a 5 or 6 membered ring system optionally containing one or more additional heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups; B is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 Z is selected from OH or NR 1   2 , where each R 1  independently represents H or C 1 -C 6  alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;  
 S 1  and S 2  together represent formula V  
                     
 wherein X is selected from a leaving group including halogen, CH 2 -halogen, CH 2 CN, CH 2 CO 2 -(C 1 -C 6  alkyl optionally substituted with one or more amino or hydroxy groups), CH 2 -phosphate group, CH 2 OSO 2 R 3 where R 3  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or CH 2 OSO 2 NHR 4  where R 4  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; and  
 R is selected from one of formulae VI or VII  
                     
 wherein each T 1 , T 2  and T 3  is independently selected from H, OPO(OH) 2 , OR 5 , NR 5   2  where each R 5  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or O(CH 2 ) n NR 6   2 , where each n is independently 1, 2, 3 or 4 and each R 6  independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups;  
 • represents the point of attachment to Formula XIX defined above;  
 S 3  is selected from H, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, halogen, CO 2 [(C 1-6  alkyl) wherein said alkyl is optionally substituted with amino, or hydroxy groups], OR 7 , NR 7   2 , CONHR 7  where each R 7  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or ammo groups; or S 3  represents an optionally substituted 4-8 membered cyclic system optionally containing one or more hetoeroatoms fused to ring system A defined above, wherein said substituents are selected from OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, and halogen groups; and including any enantiomeric or diastereomeric form, and any physiologically salt derivative thereof, with the proviso that when Z, A, B, X, S 1 , S 2  and S 3  together represent  
                     
 R does not represent one of the following  
                     
 
     
     
         26 . The heterocyclic compound according to  claim 25  wherein the rings A and B together represent an 8-substituted quinoline system.  
     
     
         27 . The heterocyclic compound according to  claim 25  wherein Z represents —OH.  
     
     
         28 . The heterocyclic compound according to  claim 25  wherein Z represents —NH 2 .  
     
     
         29 . The heterocyolic compound according to  claim 25  wherein R is selected from one of  
       
         
           
           
               
               
           
         
       
     
     
         30 . The heterocyclic compound according to  claim 25  wherein X is —CH 2 C1.  
     
     
         31 . The heterocycic compound according to  claim 25  selected from one of the following 
 1-(chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-({5-[2-(dimethylamino)ethoxy]-indol-2-yl} carbonyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-((2E)-3-{4-[2-(dimethylamino)ethoxy]phenyl}-2-propenoyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(5-methoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(2E)-3-(4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(2E)-3-(3-hydroxy-4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline and,    5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline.    
     
     
         32 . A method of providing cancer treatment, which includes the step of administering to a patient in need of such therapy an effective amount of a heterocyclic compound of Formula XIX, as defined in  claim 25 .  
       
         
           
           
               
               
           
         
       
       wherein 
 A is selected from a 5 or 6 membered ring system optionally containing one or more additional heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups; B is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 Z is selected from OH or NR 1   2 , where each R 1  independently represents H or C 1 -C 6  alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;  
 S 1  and S 2  together represent formula V  
                     
 wherein X is selected from a leaving group including halogen, CH 2 -halogen, CH 2 CN, CH 2 -phosphate group, CH 2 CO 2 R 2 , where R 2  represents C 1 -C 6  alkyl optionally substituted with one or more amino or hydroxy groups; CH 2 OSO 2 R 3  where R 3  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or CH 2 OSO 2 NHR 4  where R 4  represents H or a C 1-6  alkyl optionally substituted with one or more hydrogen or amino groups; and R its selected from one of formulae VI or VII  
                     
 wherein each T 1 , T 2  and T 3  is independently selected from H, OPO(OH) 2 , OR 5 , NR 5   2  where each R 5  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or O(CH 2 ) n NR 6   2 , where each n is independently 1, 2, 3 or 4 and each R 6  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups;  
 • represents the point of attachment to Formula XIX defined above;  
 S 3  is selected from H, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, halogen, CO 2 [(C 1-6  alkyl) wherein said alkyl is optionally substituted with amino or hydroxy groups], OR 7 , NR 7   2 , CONHR 7  where each R 7  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; or S 3  represents an optionally substituted 4-8 membered cyclic system optionally containing one or more hetoeroatoms fused to ring system A defined above, wherein said substituents are selected from OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, and halogen group; and including any enantiomeric or diastereomeric form, and any physiologically salt derivative thereof.  
 
     
     
         33 . The method according to  claim 32  wherein the rings A and B of formula XIX together represent an 8-substituted quinoline system.  
     
     
         34 . The method according to  claim 32  wherein Z of Formula XIX represents —OH.  
     
     
         35 . The method according to  claim 32  wherein Z of Formula XIX represents —NH 2 .  
     
     
         36 . The method according to  claim 32  wherein R of Formula XIX is selected from one of  
       
         
           
           
               
               
           
         
       
     
     
         37 . The method according to  claim 32  wherein X of Formula XIX is —CH 2 Cl.  
     
     
         38 . The method according to  claim 32  wherein Formula XIX is selected from one of the following 
 1-(chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-({5-[2-(dimethylamino)ethoxy]-indol-2-yl} carbonyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-((2E)-3-{4-[2-(dimethylamino)ethoxy]phenyl}-2-propenoyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(5-methoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(2E)-3-(4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(2E)-3-(3-hydroxy-4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline and,    5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline.    
     
     
         39 . A composition comprising as an active agent a compound of Formula XIX  
       
         
           
           
               
               
           
         
       
       wherein 
 A is selected from a 5 or 6 membered ring system optionally containing one or more additional heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups; B is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 Z is selected from OH or NR 1   2 , where each R 1  independently represents H or C 1 -C 6  alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;  
 Z is selected from O or NR 1 , where R 1  represents H or C 1 -C 6 alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups; S 1  and S 2  together represent formula V  
                     
 wherein X is selected from a leaving group including halogen, CH 2 -halogen, CH 2 CN, CH 2 -phosphate group, CH 2 CO 2 R 2 , where R 2  represents C 1 -C 6  alkyl optionally substituted with one or more amino or hydroxy groups; CH 2 OSO 2 R 3  where R 3  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or CH 2 OSO 2 NHR 4  where R 4  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; and  
 R is selected from one of formulae VI or VII  
                     
 wherein each T 1 , T 2  and T 3  is independently selected from H, OPO(OH) 2 , OR 5 , NR 5   2  where each R 5  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or O(CH 2 ) n NR 6   2 , where each n is independently 1, 2, 3 or 4 and each R 6  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups;  
 • represents the point of attachment to Formula XIX defined above;  
 S 3  is selected from H, OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, halogen, CO 2 [(C 1-6  alkyl) wherein said alkyl is optionally substituted with amino, or hydroxy groups], OR 7 , NR 7 , CONHR 7  where each R 7  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; or S 3  represents an optionally substituted 4-8 membered cyclic system optionally containing one or more hetoeroatoms fused to ring system A defined above, wherein said substituents are selected from OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, and halogen groups; and including any enantiomeric or diastereomeric form, and any physiologically salt derivative thereof and a pharmaceutically acceptable excipient, adjuvant or carrier.  
 
     
     
         40 . The composition according to  claim 39  wherein the rings A and B of Formula XIX together represent an 8-substituted quinoline system.  
     
     
         41 . The composition according to  claim 39  wherein Z of Formula XIX represents —OH.  
     
     
         42 . The composition according to  claim 39  wherein Z of Formula XIX represents —NH 2 .  
     
     
         43 . The composition according to  claim 39  wherein R of Formula XIX is selected from one of  
       
         
           
           
               
               
           
         
       
     
     
         44 . The composition according to  claim 39  wherein X of Formula XIX is —CH 2 Cl.  
     
     
         45 . The composition according to  39  wherein Formula XIX represents one of the following 
 1-(chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-({5-[2-(dimethylamino)ethoxy]-indol-2-yl} carbonyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-((2E)-3-{4-[2-(dimethylamino)ethoxy]phenyl}-2-propenoyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(5-methoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(2E)-3-(4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(2E)-3-(3-hydroxy-4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline, and    5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline.    
     
     
         46 . The use, in the manufacture of a medicament, of an effective amount of a compound of Formula XIX  
       
         
           
           
               
               
           
         
       
       wherein 
 A is selected from a 5 or 6 membered ring system optionally containing one or more additional heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups; B is selected from a 5 or 6 membered aromatic ring system optionally containing one or more heteroatoms and optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;  
 Z is selected from OH or NR 1   2 , where each R 1  independently represents H or C 1 -C 6  alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;  
                     
 wherein X is selected from a leaving group including halogen, CH 2 -halogen, CH 2 CN, CH 2 -phosphate group, CH 2 CO 2 R 2 , where R 2  represents C 1 -C 6  alkyl optionally substituted with one or more amino or hydroxy groups; CH 2 OSO 2 R 3  where R 3  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or CH 2 OSO 2 NHR 5  where R 5  represents H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; and R is selected from one of formulae VI or VII  
                     
 wherein each T 1 , T 2  and T 3  is independently selected from H, OPO(OH) 2 , OR 5 , NR 5   2  where each R 5  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or O(CH 2 ) n NR 6   2 , where each n is independently 1, 2, 3 or 4, and each R 6  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups;  
 • represents the point of attachment to Formula XIX defined above;  
 S 3  is selected from H, OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, halogen, CO 2 [(C 1-6  alkyl) wherein said alkyl is optionally substituted with amino, or hydroxy groups], OR 7 , NR 7 , CONHR 7  where each R 7  independently represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups; or S 3  represents an optionally substituted 4-8 membered cyclic system optionally containing one or more hetoeroatoms fused to ring system A defined above, wherein said substituents are selected from OH, cyano, phosphate, amino, C 1-6  alkyl, C 1-6  alkoxy, and halogen groups, and including any enantiomerie or diastereomeric form, and any physiologically salt derivative thereof, for use in treating a subject in need of cancer treatment.  
 
     
     
         47 . The use according to  claim 46  wherein the rings A and B of Formula XIX together represent an 8-substituted quinoline system.  
     
     
         48 . The use according to  claim 46  wherein Z of Formula XIX represents —OH.  
     
     
         49 . The use according to  claim 46  wherein Z of Formula XIX represents —NH 2 .  
     
     
         50 . The composition according to wherein R of Formula XIX is selected from one of  
       
         
           
           
               
               
           
         
       
     
     
         51 . The composition according to  claim 46  wherein X of Formula XIX is —CH 2 Cl.  
     
     
         52 . The composition according to  claim 46  wherein Formula XIX represents one of the following 
 1-(chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-({5-[2-(dimethylamino)ethoxy]-indol-2-yl} carbonyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-((2E)-3-{4-[2-(dimethylamino)ethoxy]phenyl}-2-propenoyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(5-methoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-5-hydroxy-3-[(2E)-3-(4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline,    1-(chloromethyl)-3-[(2E)-3-(3-hydroxy-4-methoxyphenyl)-2-propenoyl]-2,3-dihydro-1 H-pyrrolo[3,2-f]quinolin-5-ol, and    5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline.    enantiomeric or diastereomeric forms, or any mixtures of such forms, and also any physiologically functional salt derivatives thereof.    
     
     
         53 . A method of preparing a metal complex according to  claim 1 , including the step of coupling a heterocyclic compound defined above with one or more of ligands L 1 -L 4 , wherein ligands L 1 -L 4  are each independently selected in combinations from anionic monodentate ligands, including CN − , SCN − , halide, NO 3   − ; bidentate ligands including MeCOCHJCOMe (Jacac; deprotonated in the complex), where J═H, Me, Cl, SMe, SO 2 Me, S(CH 2 ) n SO 3 H, S(CH 2 ) n CO 2 H, S(CH 2 ) n OP(O)(OH) 2 , CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H, S(CH 2 ) n P(O)(OH) 2  or CH 2 (CH 2 ) n P(O)(OH) 2 , where each n is independently 1, 2, 3 or 4; or tridentate ligands VIIIa-VIIIc (=respectively TACH, TAME and TACN when R 1 -R 3 ═H),  
       
         
           
           
               
               
           
         
         wherein R 1 -R 4  are each independently selected from H, Me, CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H or CH 2 (CH 2 ) n OP(O)(OH) 2  CH 2 (CH 2 ) n P(O)(OH) 2  or CH 2 (CH 2n NR 5   2 , where each n is independently 1, 2, 3 or 4 and each R 5  independently represents H, or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups or  
         L 1 -L 4  can also be selected from any one of the tetradentate ligands IX-XVII, or any two of the bidentate ligands XVIII, or any combination of the bidentate ligands XVIII together with any of the monodentate ligands L 1 -L 4  defined above;  
         
           
             
             
                 
                 
             
           
           
             
             
                 
                 
             
           
         
         wherein in formulae IX-XVIII, R 1′  to R 8′  each independently represent H, Me, CH 2 (CH 2 ) n SO 3 H, CH 2 (CH 2 ) n CO 2 H or CH 2 (CH 2 ) n OP(O)(OH) 2  or CH 2 (CH 2 ) n NMe 2 , where each n is independently 1, 2, 3 or 4; each Z 1 -Z 4  is independently selected from —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 OCH 2 — or —CH 2 N(R 6 )CH 2 —; where R 6  represents H, a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups and  
         each Y′ is independently selected from H, halogen, SO 2 Me, O(C 1 -C 6 alkyl), NR 7   2 , where each R 7  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, or Q 1 (CH 2 ) n Q 2 , wherein Q 1  is selected from —O—, —CH 2 —, —NH—, —CONH—, —CO 2 — or —SO 2 —, and Q 2  is selected from —CO 2 H, —SO 3 H, —OP(O)(OH) 2  or —NR 8   2  where each R 8  is independently selected from H or a C 1-6  alkyl optionally substituted with one or more hydroxy or amino groups, and wherein the ligands are complexed with a metal selected from Co III , Co II , Cr III  or Cr II .  
       
     
     
         54 . A method of preparing a heterocyclic compound as defined in  claim 25 , including the following reaction pathway  
       
         
           
           
               
               
           
         
       
     
     
         55 . The method according to  claim 54  including the further steps represented by the pathway