Patent EA-003933-B1 (EA)
Title: Method for treating cancer, pharmaceutical compositions comprising 2-quinolones
Inventor: JOSEPH BENOIT
IPC: A61P35/00
Filed: 1999-07-13
Abstract: 1. A method for treating cancer, comprising administering an effective amount of antitumor agent selected from the citotoxic agents, and an effective amount of a compound selected from the formula: in which: X is selected from =O, =S and =N-NH-R7, R7 being a phenyl or pyridyl group, R1, R2, R3 and R4 are selected, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group -OCO-R8, R8 being a C1-C4 alkyl group, and a group derived from a saccharide, at least one of the substituents R1, R2, R3 and R4 being other than H, and R2 and R3 together possibly forming a methylenedioxy group, R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups selected from H, OH, a C1-C4 alkoxy group, a group -OCOR8, a phenyl (C1-C4 alkoxy) group, a group -O-SO2-R'8, R'8 being a C1-C4 alkyl group or a CF3 group, and a group derived from a saccharide, R6 is selected from H, a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R6a is selected from a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R9 being a C1-C4 alkyl group, A being a C1-C4 alkylene group, R10 being selected from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CCNR12R13, a group -NR14R15 and a group -COR16, R11, R12, R13, R14, R15 and R16 being selected independently from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group, R4 and R6 together also possibly forming a -CO-CH2-CH2-group. 2. The method according to claim 1, in which the compound is a compound of formula (I) in which: - R1 is a C1-C4 alkoxy group - R2 is a hydrogen atom - R3 is a C1-C4 alkoxy group - R4 is a hydrogen atom. 3. The method according to Claim 2, in which the compound is a compound of formula (I) in which: - R5 is a 4-(C1-C4 alkoxy)phenyl group. 4. The method according to Claim 3, in which: - R1 is a methoxy group, - R3 is a methoxy group, and - R5 is a 4-methoxyphenyl group. 5. The method according to Claim 4, in which the compound is 5,7-dimethoxy-3-(4-methoxyphenyl)-1,2-dihydro-2-quino-linone. 6. The method according to Claim 4, in which the compound is 3-[5,7-dimethoxy-3-(4-methoxyphenyl)-2-oxo-1,2-dihydro-1-quinolinyl]propanenitrile. 7. The method according to Claim 4, in which the compound is 1-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-5,7-dimethoxy-3-(4-methoxyphenyl)-1,2-dihydro-2-quinolinone. 8. The method according to Claim 4, in which the compound is N,N-diethyl-3-[5,7-dimethoxy-3-(4-methoxyphenyl)-2-oxo-1,2-dihydro-1-quinolinyl]propanamide. 9. Pharmaceutical composition having activity on the proliferation of clonogenic cells in tumors and which comprises an effective amount of a compound selected from the compounds of formula: in which: X is selected from =O, =S and =N-NH-R7, R7 being a phenyl or pyridyl group, R1, R2, R3 and R4 are selected, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group -OCO-R8, R8 being a C1-C4 alkyl group, and a group derived from a saccharide, at least one of the substituents R1, R2, R3 and R4 being other than H, and R2 and R3 together possibly forming a methylenedioxy group, R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups selected from H, OH, a C1-C4 alkoxy group, a group -OCOR8, a phenyl (C1-C4 alkoxy) group, a group -O-SO2-R'8, R'8 being a C1-C4 alkyl group or a CF3 group, and a group derived from a saccharide, R6 is selected from H, a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R6a is selected from a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R9 being a C1-C4 alkyl group, A being a C1-C4 alkylene group, R10 being selected from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CCNR12R13, a group -NR14R15 and a group -COR16, R11, R12, R13, R14, R15 and R16 being selected independently from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group, R4 and R6 together also possibly forming a -CO-CH2-CH2-group. 10. Composition according to Claim 9, in which the compound is a compound of formula (I) in which: - R1 is a C1-C4 alkoxy group - R2 is a hydrogen atom - R3 is a C1-C4 alkoxy group - R4 is a hydrogen atom. 11. Composition according to Claim 10, in which the compound is a compound of formula (I) in which: - R5 is a 4-(C1-C4 alkoxy)phenyl group. 12. Composition according to Claim 11, in which the compound is a compound of formula (I), R1 is a methoxy group, R3 is a methoxy group and R5 is a 4-methoxyphenyl group. 13. Composition according to Claim 12, in which the compound is 5,7-dimethoxy-3-(4-methoxyphenyl)-1,2-dihydro-2-quinolinone. 14. Composition according to Claim 12, in which the compound is 3-[5,7-dimethoxy-3-(4-methoxyphenyl)-2-oxo-1,2-dihydro-1-quinolinyl]propanenitrile. 15. Composition according to Claim 12, in which the compound is 1-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-5,7-dimethoxy-3-(4-methoxyphenyl)-1,2-dihydro-2-quinolinane. 16. Composition according to Claim 12, in which the compound is N,N-diethyl-3-[5,7-dimethoxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-1-quinolinyl]propanamide. 17. Compound of formula: in which: X is selected from =O, =S and =N-NH-R7, R7 being a phenyl or pyridyl group, R1, R2, R3 and R4 are selected, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group -OCO-R8, R8 being a C1-C4 alkyl group, and a group derived from a saccharide, at least one of the substituents R1, R2, R3 and R4 being other than H, and R2 and R3 together possibly forming a methylenedioxy group, R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups selected from H, OH, a C1-C4 alkoxy group, a group -OCOR8, a phenyl (C1-C4 alkoxy) group, a group -O-SO2-R'8, R'8 being a C1-C4 alkyl group or a CF3 group, and a group derived from a saccharide, R6 is selected from H, a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R6a is selected from a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R9 being a C1-C4 alkyl group, A being a C1-C4 alkylene group, R10 being selected from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CCNR12R13, a group -NR14R15 and a group -COR16, R11, R12, R13, R14, R15 and R16 being selected independently from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group, R4 and R6 together also possibly forming a -CO-CH2-CH2-group. in which: X is selected from =O, =S and =N-NH-R7, R7 being a phenyl or pyridyl group, R1, R2, R3 and R4 are selected, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group -OCO-R8, R8 being a C1-C4 alkyl group, and a group derived from a saccharide, at least one of the substituents R1, R2, R3 and R4 being other than H, and R2 and R3 together possibly forming a methylenedioxy group, R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups selected from H, OH, a C1-C4 alkoxy group, a group -OCOR8, a phenyl (C1-C4 alkoxy) group, a group -O-SO2-R'8, R'8 being a C1-C4 alkyl group or a CF3 group, and a group derived from a saccharide, R6 is selected from H, a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R6a is selected from a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R9 being a C1-C4 alkyl group, A being a C1-C4 alkylene group, R10 being selected from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CCNR12R13, a group -NR14R15 and a group -COR16, R11, R12, R13, R14, R15 and R16 being selected independently from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group, R4 and R6 together also possibly forming a -CO-CH2-CH2-group. 18. Compound according to Claim 17, which is 3-[5,7-dimethoxy-3-(4-methoxyphenyl)-2-oxo-1,2-dihydro-1-quinolinyl]propanenitrile. 19. Compound according to Claim 17, which is 1-[2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]-5,7-dimethoxy-3-(4-methoxyphenyl)-1,2-dihydro-2-quinolinone. 20. Compound according to Claim 17, which is N,N-diethyl-3-[5,7-dimethoxy-3-(4-methoxyphenyl)-2-oxo-1,2-dihydro-1-quinolinyl]propanamide. 21. Compounds of formula: in which: X is selected from =O, =S and =N-NH-R7, R7 being a phenyl or pyridyl group, R1, R2, R3 and R4 are selected, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group -OCO-R8, R8 being a C1-C4 alkyl group, and a group derived from a saccharide, at least one of the substituents R1, R2, R3 and R4 being other than H, and R2 and R3 together possibly forming a methylenedioxy group, R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups selected from H, OH, a C1-C4 alkoxy group, a group -OCOR8, a phenyl (C1-C4 alkoxy) group, a group -O-SO2-R'8, R'8 being a C1-C4 alkyl group or a CF3 group, and a group derived from a saccharide, R6 is selected from H, a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R6a is selected from a C1-C4 alkyl group, a group -CO-R9 and a group -A-R10, R9 being a C1-C4 alkyl group, A being a C1-C4 alkylene group, R10 being selected from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen, the CN group, a group -COOR11, -CCNR12R13, a group -NR14R15 and a group -COR16, R11, R12, R13, R14, R15 and R16 being selected independently from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group, 22. Compound of formula: in which: R1, R2, R3 and R4 are selected, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group -OCO-R8, R8 being a C1-C4 alkyl group, and a group derived from a saccharide, at least one of the substituents R1, R2, R3 and R4 being other than H, and R2 and R3 together possibly forming a methylenedioxy group, R5 is a phenyl group or a phenyl group sub