Patent EA-003361-B1 (EA)
Title: New compounds of 7-oxo-2,3,7,14-tetrehydro-1h-benzo[b]pyrano[3,2-h]acridine carboxylate and the pharmaceutical compounds containing them
Inventor: KOSH MICHEL
IPC: C07D491/052
Filed: 2000-06-15
Abstract: 1. Compounds of formula (I): wherein: X and Y, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group, and an amino group (optionally substituted by one or two identical or different linear or branched (C1-C6) alkyl groups which may themselves be substituted by a linear or branched (C1-C6) alkoxy group or by a group of formula -NR7R8 wherein R7 and R8, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched), or X and Y together form a methylenedioxy or ethylenedioxy group, it being understood that the substituents X and Y may be present on one or the other of the two adjacent benzene rings, R1 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, R1 represents: - a hydrogen atom, - a hydroxy group, - a linear or branched (C1-C6)alkyl group, - a linear or branched (C1-C6)alkoxy group optionally substituted by a group selected from: *a group of formula NR9R10 wherein R9 and R10, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)hydroxyalkyl group, and *a saturated or unsaturated monocyclic or bicyclic heterocycle having from 5 to 7 ring members containing one or two hetero atoms selected from oxygen and nitrogen, - a linear or branched (C1-C6)alkylcarbonyloxy group, or - an amino group optionally substituted by: *one or two, identical or different, linear or branched (C1-C6)alkyl groups, aryl groups or aryl-(C1-C6)alkyl groups in which the alkyl moiety is linear or branched, *a linear or branched (C1-C6)alkylcarbonyl group optionally substituted by a group *NR7R8 wherein R7 and R8 are as defined hereinbefore, *a group of formula -R11-NR9R10, wherein R11 represents a linear or branched (C1-C6)alkylene group, and R9 and R10, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)hydroxyalkyl group, *a linear or branched (C1-C6)alkylene group, substituted by a saturated or unsaturated, monocyclic or bicyclic heterocycle having from 5 to 7 ring members containing one or two hetero atoms selected from oxygen and nitrogen, or *by a group of formula -R11-CO-R12 wherein R11 is as defined hereinbefore, and R12 represents a hydroxy group or a linear or branched (C1-C6)alkoxy group, R3 and R4, which may be identical or different, each independently of the other represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, R5 and/or R6, represent(s) a group of formula -O-CO-U-V wherein: - U represents a linear or branched (C1-C6)alkylene chain, optionally substituted by one or more identical or different groups selected from aryl, hydroxy and linear or branched (C1-C6)alkoxy, - V represents a group selected from: * carboxy, *-CO2R13 wherein R13 represents a linear or branched (C1-C6)alkyl group (optionally substituted by one or more hydroxy groups), an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, * hydroxy, * linear or branched (C1-C6)alkoxy, * - NR7R8 wherein R7 and R8, which may be identical or different, are as defined hereinbefore, * -NR7-CO2R13 wherein R7 and R13 are as defined hereinbefore, * -NR7-COR13 wherein R7 and R13 are as defined hereinbefore, * -COR13 wherein R13 is as defined hereinbefore, and * -CO-NR7R8 wherein R7 and R8, which may be identical or different, are as defined hereinbefore, and when only one of the two groups R5 and R6 represents a group of formula -O-CO-U-V, then the other of the said R5 and R6 groups represents a group Z selected from: * hydroxy, * linear or branched (C1-C6)alkoxy, * linear or branched (C1-C6)alkylcarbonyloxy, * arylcarbonyloxy, * aryl-(C1-C6)alkylcarbonyloxy in which the alkyl moiety is linear or branched, and * amino optionally substituted by one or two identical or different linear or branched (C1-C6)alkyl groups, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to claim 1 characterized in that R3 and R4, which may be identical or different, represent a linear or branched (C1-C6) alkyl group, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to any one of claims 1 or 2, characterized in that R3 and R4, which are identical, each represents a methyl group, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1, characterized in that R2 represents a linear or branched (C1-C6) alkoxy group, or an optionally substituted amino group as defined for formula (I), their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1, characterized in that R5 represents a group of formula -O-CO-U-V wherein U and V are as defined for formula (I) and R6 represents a Z group as defined for formula (I), their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1, characterized in that R5 and R6, which are identical, each represents a group of formula -O-CO-U-V wherein U and V are as defined for formula (I), their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to any one of claims 1 or 5, characterized in that R5 represents a group of formula -O-CO-U-V wherein U represents a linear (C1-C6) alkylene chain and V represents a group selected from carboxy, -NR7R8, -NR7-CO2R13 and -NR7-COR13 wherein R7, R8 and R13, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of formula (I) according to claim 1, characterized in that R6 represents a linear or branched (C1-C6) alkylcarbonyloxy group, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. Compounds of formula (I) according to claim 1 which are: (+-)-cis-4-{[1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl]oxy}-4-oxobutanoic acid, (+-)-cis-4-({l-[(3-carboxypropanoyl)oxy]-6-memoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]]pyrano[3,2-h]acridm-2-yl} oxy)-4-oxobutanoic acid, (+-)-cis-5-1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl]oxy}-5-oxopentanoicacid, -cis-[1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]-pyrano[3,2-h]acridin-2-yl] (dimethylamino)acetate, and - cis-[1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]-pyrano[3,2-h]acridin-2-yl ] 4-(dimethylamino)butanoate, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. 10. Pharmaceutical compositions comprising as active ingredient at least one compound according to any one of claims 1 to 9, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. 11. Pharmaceutical compositions according to claim 11 comprising at least one active ingredient according to any one of claims 1 to 9 for use in the treatment of cancer.