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

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 C1-6 alkyl, C1-6 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 C1-6 alkyl, C1-6 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 C1-6 alkyl, C1-6 alkoxy, halogen, hydroxy, phosphate, cyano or amino groups
• M is selected from CoIII, CoII, CrIII or CrII;
• Z represents NH2 or NHMe,
• Q represents H, C1-6 alkyl, or (CH2)2NH2, when Q represents (CH2)2NH2, Q will become a ligand for M and replace one of ligands L1-L4 defined below,
• S1 and S2 together represent formula V
• wherein X is selected from a group including halogen, CH2-halogen, CH2CN, CH2CO2-(C1-C6 alkyl optionally substituted with one or more amino or hydroxy groups), CH2-phosphate group, CH2OSO2R3 or OSO2R3 where R3 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups, or CH2OSO2NHR4 where R4 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• and
• R is selected from one of formulae VI or VlI
• wherein each T1, T2 and T3 is independently selected from H, OPO(OH)2, OR2, NR22 where each R2 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups or O(CH2)nNR32, where each n is independently 1, 2, 3 or 4, and each R3 is independently selected from H or a C1-6 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 S3 is selected from H, cyano, phosphate, amino, C1-6 alkyl, C1-6 alkoxy, halogen, CO2(C1-6 alkyl) wherein said alkyl is optionally substituted with amino, or halogen groups, OR4, NR42, CONHR4, where each R4 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• or S3 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, C1-6 alkyl, C1-6 alkoxy, halogen groups, and
• wherein ligands L1-L4 are each independently selected in combinations from anionic monodentate ligands, including CN−, SCN−, halide, NO3−;
• bidentate ligands including MeCOCHJCOMe (Jacac;
• deprotonated in the complex), where J═H, Me, Cl, SMe, SO2Me, S(CH2)nSO3H, S(CH2)nCO2H, S(CH2)nOP(O)(OH)2, CH2(CH2)nSO3H, CH2(CH2)nCO2H, CH2(CH2)nOP(O)(OH)2, S(CH2)nP(O)(OH)2 CH2(CH2)nP(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 R1-R3═H),
• wherein R1-R4 are each independently selected from H, Me, CH2(CH2)nSO3H, CH2(CH2)nCO2H or CH2(CH2)nOP(O)(OH)2 CH2(CH2)nP(O)(OH)2 or CH2(CH2)nNR52, where each n is independently 1, 2, 3 or 4 and each R5 independently represents H, or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups or
• L1-L4 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 L1-L4 defined above;
• wherein in formulae IX-XVIII, R1′ to R8′ each independently represent H, Me, CH2(CH2)nSO3H, CH2(CH2)nCO2H or CH2(CH2)nOP(O)(OH)2 or CH2(CH2)nNMe2, where each n is independently 1,2, 3 or 4;
• each Z1-Z4 is independently selected from —(CH2)2—, —(CH2)3—, —CH20CH2— or —CH2N(R6)CH2—;
• where R6 represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups and
• each Y′ is independently selected from H, halogen, SO2Me, O(C1-C6 alkyl), NR72, where each R7 is independently selected from H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups, or Q1(CH2)nQ2, wherein Q1 is selected from —O—, —CH2—, —NH—, —CONH—, —CO2— or —SO2—, and Q2 is selected from —CO2H, —SO3H, —OP(O)(OH)2 or —NR82 where each R8 is independently selected from H or a C1-6 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 Fcountercharge is selected from a range of physiologically acceptable-counterions;
• including halide, NO3−, NH4+ 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.

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 C1-6 alkyl, C1-6 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 C1-6 alkyl, C1-6 alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;
• Z is selected from OH or NR12, where each R1 independently represents H or C1-C6 alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;
• S1 and S2 together represent formula V
• wherein X is selected from a leaving group including halogen, CH2-halogen, CH2CN, CH2CO2-(C1-C6 alkyl optionally substituted with one or more amino or hydroxy groups), CH2-phosphate group, CH2OSO2R3where R3 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups, or CH2OSO2NHR4 where R4 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• and
• R is selected from one of formulae VI or VII
• wherein each T1, T2 and T3 is independently selected from H, OPO(OH)2, OR5, NR52 where each R5 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups or O(CH2)nNR62, where each n is independently 1, 2, 3 or 4 and each R6 independently selected from H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• • represents the point of attachment to Formula XIX defined above;
• S3 is selected from H, cyano, phosphate, amino, C1-6 alkyl, C1-6 alkoxy, halogen, CO2[(C1-6 alkyl) wherein said alkyl is optionally substituted with amino, or hydroxy groups], OR7, NR72, CONHR7 where each R7 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or ammo groups;
• or S3 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, C1-6 alkyl, C1-6 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, S1, S2 and S3 together represent
• R does not represent one of the following

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 C1-6 alkyl, C1-6 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 C1-6 alkyl, C1-6 alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;
• Z is selected from OH or NR12, where each R1 independently represents H or C1-C6 alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;
• Z is selected from O or NR1, where R1 represents H or C1-C6alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;
• S1 and S2 together represent formula V
• wherein X is selected from a leaving group including halogen, CH2-halogen, CH2CN, CH2-phosphate group, CH2CO2R2, where R2 represents C1-C6 alkyl optionally substituted with one or more amino or hydroxy groups;
• CH2OSO2R3 where R3 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups, or CH2OSO2NHR4 where R4 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• and
• R is selected from one of formulae VI or VII
• wherein each T1, T2 and T3 is independently selected from H, OPO(OH)2, OR5, NR52 where each R5 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups or O(CH2)nNR62, where each n is independently 1, 2, 3 or 4 and each R6 is independently selected from H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• • represents the point of attachment to Formula XIX defined above;
• S3 is selected from H, OH, cyano, phosphate, amino, C1-6 alkyl, C1-6 alkoxy, halogen, CO2[(C1-6 alkyl) wherein said alkyl is optionally substituted with amino, or hydroxy groups], OR7, NR7, CONHR7 where each R7 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• or S3 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, C1-6 alkyl, C1-6 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.

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.

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 C1-6 alkyl, C1-6 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 C1-6 alkyl, C1-6 alkoxy, halogen, hydroxy, phosphate, cyano or amino groups;
• Z is selected from OH or NR12, where each R1 independently represents H or C1-C6 alkyl optionally substituted with one or more amino, hydroxy, a halogen or cyano groups;
• wherein X is selected from a leaving group including halogen, CH2-halogen, CH2CN, CH2-phosphate group, CH2CO2R2, where R2 represents C1-C6 alkyl optionally substituted with one or more amino or hydroxy groups;
• CH2OSO2R3 where R3 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups, or CH2OSO2NHR5 where R5 represents H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• and R is selected from one of formulae VI or VII
• wherein each T1, T2 and T3 is independently selected from H, OPO(OH)2, OR5, NR52 where each R5 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups or O(CH2)nNR62, where each n is independently 1, 2, 3 or 4, and each R6 is independently selected from H or a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• • represents the point of attachment to Formula XIX defined above;
• S3 is selected from H, OH, cyano, phosphate, amino, C1-6 alkyl, C1-6 alkoxy, halogen, CO2[(C1-6 alkyl) wherein said alkyl is optionally substituted with amino, or hydroxy groups], OR7, NR7, CONHR7 where each R7 independently represents H, a C1-6 alkyl optionally substituted with one or more hydroxy or amino groups;
• or S3 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, C1-6 alkyl, C1-6 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.