Dna-targeted benzotriazine 1,4-dioxides and their use in cancer therapy

A compound of Formula I′,

• wherein
• Y1 represents at one or more of the available carbons 5-8 on the benzo ring the following groups:
• halo, H, R, OH, OR, NO2, NH2, NHR, NR2, SH, SR, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONH2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and morpholino;
• Y3 is selected from the following groups halo, H, R, OR, NH2, NHR, NR2, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONH2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and morpholino;
• wherein each R of groups Y1 and Y3 is independently selected from an optionally substituted C1-6 alicycic or an optionally substituted C3-6 cyclic alkyl group, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NO2, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1;
• R can also represent an optionally substituted aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1, and each heteroaryl group contains one or more heteroatoms in its ring system which are each independently selected from O, N or S;
• wherein each R1 is independently selected from an optionally substituted c1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional substituents are each independently selected from OH, OR, NH2, NHR2NR22 or N(OH)R2 wherein each R2 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH, and wherein X represents NH, NMe, CH2, SO, SO2, or O;
• wherein A represents an optionally substituted C1-2 alkyl group wherein the optional substituents are each independently selected from OH, OR, NH2, NHR3, NR32 or N(OH)R3 wherein each R3 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH;
• and wherein the optionally substituted C2-12 alkyl chain is optionally interrupted by one or more heteroatom containing linkage moieties selected from O, NH, NR4, CONH, CONR4, NHCO, NR4CO, wherein each R4 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional R4 substituents are each independently selected from OH, OR, NH2, NHR5, NR52 or N(OH)R5 wherein each R5 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH;
• and
• wherein the DNA-targeting unit is any moiety of a molecular weight below 700 Daltons that has an association constant (K) for binding to double-stranded random-sequence DNA of >103 M−1 at an ionic strength of 0.01 M at 20° C., or a pharmacologically acceptable salt thereof.

A method of making a compound of formula XVII

• wherein
• Y1 and Y2 at one or more of the available carbons 5-8 on the benzo ring:
• are each independently selected from the following groups:
• halo, H, R, OH, OR, NO2, NH2, NHR, NR2, SH, SR, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONH2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and morpholino;
• wherein each R is independently selected from an optionally substituted C16 alicydic or an optionally substituted C3-6 cyclic alkyl group, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NO2 NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1;
• R can also represent an optionally substituted aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1, and each heteroaryl group contains one or more heteroatoms in its ring system which are each independently selected from O, N or S;
• wherein each R1 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional substituents are each independently selected from OH, OR, NH2, NHR2NR22 or N(OH)R2 wherein each R2 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH, and
• A represents an optionally substituted C1-12 alkyl group wherein the optional substituents are each independently selected from OH, OR, NH2, NHR3NR32, or N(OH)R3 wherein each R3 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH;
• and wherein the optionally substituted C1-12 alkyl chain is optionally interrupted by one or more heteroatom containing linkage moieties selected from O, NH, NR4, CONH, CONR4, NHCO, NR4CO, where each R4 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional R4 substituents are each independently selected from OH, OR, NH2, NHR5, NR52 or N(OH)R5 wherein each R5 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH;
• or a pharmacologically acceptable salt thereof, including the step of coupling a compound (a) using a palladium reagent to form compound (b) which can then be converted into a compound of XVII as defined above;
• wherein in compound (a)
• V is halogen selected from Cl, Br or I and Y1, Y2 are as defined above in this claim;
• and wherein in compound (b) Y1, Y2 are as defined above in this claim, W is selected from an optionally substituted C1-2alkyl, optionally substituted C2-12 alkenyl, and optionally substituted C2-12alkynyl group, wherein the optional substituents is selected from halo, OH, OR6, NO2, NH2, NHR6NR6R6SH, SR6, imidazolyl, R6-piperazinyl, morpholino, SO2R6, CF3, CN, CO2H, CO2R6, CHO, COR6, CONH2, CONHR6, CONR6R6, wherein each R6 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional substituents are each independently selected from OH, OR, NH2, NHR7, NR72 or N(OH)R7 wherein each R7 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH.

A method of making a compound of formula XVII′

• wherein Y1 represents at one or more of the available carbons 5-8 on the benzo ring the following groups:
• halo, H, R, OH, OR, NO2, NH2, NHR, NR2, SH, SR, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONH2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and morpholino;
• Y3 is selected from the following groups H, R, OR, NH2, NHR, NR2, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONH2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and morpholino;
• wherein each R of groups Y1 and Y3 is independently selected from an optionally substituted C16 alicylic or an optionally substituted C3-6 cyclic alkyl group, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NO2, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1;
• R can also represent an optionally substituted aryl or an optionally substituted heteroazyl group having up to 12 carbon atoms, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1, and each heteroaryl group contains one or more heteroatoms in its ring system which are each independently selected from O, N or S;
• wherein each R1 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional substituents are each independently selected from OH, OR, NH2, NHR2NR22 or N(OH)R2 wherein each R2 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH, and
• wherein X represents NH, NMe, CH2, SO, SO2, or O;
• A represents an optionally substituted C1-12 alkyl group wherein the optional substituents are each independently selected from OH, OR, NH2, NHR3NR32, or N(OH)R3 wherein each R3 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2 NH2, CF3, CN, CO2H or SH;
• and wherein the optionally substituted C1-12 alkyl chain is optionally interrupted by one or more heteroatom containing linkage moieties selected from O, NH, NR4, CONH, CONR4, NHCO, NR4CO, wherein each R4 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional R4 substituents are each independently selected from OH, OR, NH2, NHR5, NR52 or N(OH)R5 wherein each R5 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2 NH2, CF3, CN, CO2H or SH;
• and or a pharmacologically acceptable salt thereof;
• including the steps of coupling a compound (a) using a palladium reagent to form compound (b) which is then converted into a compound of XVII′ as defined above in this claim;
• wherein in compound (a) V is halogen which is selected from Cl, Br or I;
• Y1, X and A is as defined above in this claim;
• and wherein in compound (b) Y1, X and A are as defined above in this claim, W is selected from an optionally substituted C1-12alkyl, optionally substituted C2-12alkenyl, and optionally substituted C2-12alkynyl group, wherein the optional substituents is selected from halo, OH, ORB, NO2, NH2, NHR6, NR6R6, SH, SR6, imidazolyl, R6-piperazinyl, morpholino, SO2R6, CF3, CN, CO2H, CO2R6, CHO, COR6, CONH2, CONHR6, CONR6R6, wherein each R6 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional substituents are each independently selected from OH, OR, NH2, NHR7, NR72 or N(OH)R7 wherein each R7 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH.

A compound of formula XVIII

• wherein
• Y1 and Y2 at one or more of the available carbons 5-8 on the benzo ring:
• are each independently selected from the following groups:
• halo, H, R, OH, OR, NO2, NH2, NHR, NR2, SH, SR, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONH2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and morpholino;
• wherein each R is independently selected from an optionally substituted C1-6 alicyclic or an optionally substituted C3-6 cyclic alkyl group, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NO2, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1;
• R can also represent an optionally substituted aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the optional substituents are each independently selected from halo, OH, OR1, NH2, NHR1, NR1R1, SH, SR1 imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1, and each heteroaryl group contains one or more heteroatoms in its ring system which are each independently selected from O, N or S;
• wherein each R1 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional substituents are each independently selected from OH, OR, NH2, NHR2, NR22 or N(OH)R2 wherein each R2 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH, and wherein X represents NH, NMe, CH2, SO, SO2, or O;
• A represents an optionally substituted C1-12 alkyl group wherein the optional substituents are each independently selected from OH, OR, NH2, NHR3, NR32, or N(OH)R3 wherein each R3 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH;
• and wherein the optionally substituted C1-12 alkyl chain is optionally interrupted by one or more heteroatom containing linkage moieties selected from O, NH, NR4, CONH, CONR4, NHCO, NR4CO, wherein each R4 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional R4 substituents are each independently selected from OH, OR, NH2, NHR5, NR52 or N(OH)R5 wherein each R5 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH;
• or a pharmacologically acceptable salt thereof, with the proviso that:
• 3-amino 6 or 7-decyl-1,2,4-benzotriazine 1,4 dioxide,
• 3-(3-N,N-diethylaiminopropylamino-1,2,4-benzotriazine 1,4 dioxide,
• 7-nitro-3-(2-N,N-diethylaminoethylamino)-1,2,4-benzotriazine 1,4 dioxide,
• 3-(2-methoxyethyl)-1,2,4-benzotriazine 1,4 dioxide,
• 3-amino 6 or 7-methoxy-1,2,4-benzotriazine 1,4 dioxide,
• N methy, 3-amino-1,2,4-benzotriazine 1,4 dioxide,
• 3-ethyl-1,2,4-benzotriazine 1,4 dioxide,
• 3-propyl-1,2,4-benzotriazine 1,4 dioxide and
• 3-methoxy, 1,2,4-benzotriazine 1,4 dioxide are excluded.

A compound of formula XVII′

• wherein
• Y1 represents at one or more of the available carbons 5-8 on the benzo ring the following groups:
• halo, H, R, OH, OR, NO2, NH2, NHR, NR2, SH, SR, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONH2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and marpholino;
• Y3 is selected from the following groups H, R, OR, NH2, NHR, NR2, SO2R, CF3, CN, CO2H, CO2R, CHO, COR, CONR2, CONHR or CONRR, cyclic alkylamino, imidazolyl, alkylpiperazinyl and morpholino
• wherein each R of groups Y1 and Y3 is independently selected from an optionally substituted C1-6 alicyclic or an optionally substituted C3-6 cyclic alkyl group, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NO2, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperazinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1;
• R can also represent an optionally substituted aryl or an optionally substituted heteroaryl group having up to 12 carbon atoms, and wherein the optional substituents are each independently selected from;
• halo, OH, OR1, NH2, NHR1, NR1R1, SH, SR1, imidazolyl, R1-piperizinyl, morpholino, SO2R1, CF3, CN, CO2H, CO2R1, CHO, COR1, CONH2, CONHR1, CONR1R1, and each heteroaryl group contains one or more heteroatoms in its ring system which are each independently selected from O, N or S;
• wherein each R1 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional substituents are each independently selected from OH, OR, NH2, NHR2, NR22 or N(OH)R2 wherein each R2 is independently selected from C1-4 alkyl C2-4 alkenyl, OH, NO2 NH2, CF3, CN, CO2H or SH, and
• wherein X represents NH, NMe, CH2, SO, SO2, or O;
• A represents an optionally substituted C1-12 alkyl group wherein the optional substituents are each independently selected from OH, OR, NH2, NHR3, NR32 or N(OH)R3 wherein each R3 is independently selected form C1-4 alkyl, C2-4 alkenyl, OH NO2 NH2, CF3, CN, CO2H or SH;
• and wherein the optionally substituted C1-12 alkyl chain is optionally interrupted by one or more heteroatom containing linkage moieties selected from O, NH, NR4, CONH, CONR4, NHCO, NR4CO, wherein each R4 is independently selected from an optionally substituted C1-4 alkyl or an optionally substituted C2-4 alkenyl group and wherein the optional R4 substituents are each independently selected from OH, OR, NH2, NHR5, NR5 or N(OH)R5 wherein each R5 is independently selected from C1-4 alkyl, C2-4 alkenyl, OH, NO2, NH2, CF3, CN, CO2H or SH;
• and
• wherein X represents NH, NMe, CH2, SO, SO2, or O;
• or a pharmacologically acceptable salt thereof, with the proviso that:
• 3-amino 6 or 7-decyl-1,2,4-benzotriazine 1,4 dioxide,
• 1,2 propanediol 3-[(1,4 dioxide-1,2,4-benzotriazine-7-yl)oxy] are excluded.