EP1202971A2 - Arzneimittel, welche 4-chinolonen enthalten zur behandlung von krebs - Google Patents
Arzneimittel, welche 4-chinolonen enthalten zur behandlung von krebsInfo
- Publication number
- EP1202971A2 EP1202971A2 EP00958676A EP00958676A EP1202971A2 EP 1202971 A2 EP1202971 A2 EP 1202971A2 EP 00958676 A EP00958676 A EP 00958676A EP 00958676 A EP00958676 A EP 00958676A EP 1202971 A2 EP1202971 A2 EP 1202971A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- chosen
- alkyl
- phenyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- HETSDWRDICBRSQ-UHFFFAOYSA-N 3h-quinolin-4-one Chemical class C1=CC=C2C(=O)CC=NC2=C1 HETSDWRDICBRSQ-UHFFFAOYSA-N 0.000 title description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 144
- 230000003021 clonogenic effect Effects 0.000 claims abstract description 14
- 230000035755 proliferation Effects 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 216
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 106
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 104
- 238000011282 treatment Methods 0.000 claims description 90
- -1 methylpiperazinyl group Chemical group 0.000 claims description 62
- 206010028980 Neoplasm Diseases 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 40
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 23
- 230000001472 cytotoxic effect Effects 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 239000011593 sulfur Substances 0.000 claims description 20
- 231100000433 cytotoxic Toxicity 0.000 claims description 18
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 11
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 10
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 229940127089 cytotoxic agent Drugs 0.000 claims description 9
- 239000002254 cytotoxic agent Substances 0.000 claims description 9
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- MHZBDCXGXVTPRL-UHFFFAOYSA-N 7-methoxy-3-(4-methoxyphenyl)-1h-quinolin-4-one Chemical compound C1=CC(OC)=CC=C1C1=CNC2=CC(OC)=CC=C2C1=O MHZBDCXGXVTPRL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- FDPXXRDTXYGIHX-UHFFFAOYSA-N 5,7-dimethoxy-3-(4-methoxyphenyl)-1-methylquinolin-4-one Chemical compound C1=CC(OC)=CC=C1C1=CN(C)C2=CC(OC)=CC(OC)=C2C1=O FDPXXRDTXYGIHX-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 201000011510 cancer Diseases 0.000 abstract description 23
- 231100000065 noncytotoxic Toxicity 0.000 abstract description 3
- 230000002020 noncytotoxic effect Effects 0.000 abstract description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 131
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 76
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 74
- 238000006243 chemical reaction Methods 0.000 description 73
- 239000012074 organic phase Substances 0.000 description 70
- 239000000377 silicon dioxide Substances 0.000 description 63
- 238000004587 chromatography analysis Methods 0.000 description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- 239000012299 nitrogen atmosphere Substances 0.000 description 56
- 238000001816 cooling Methods 0.000 description 55
- 239000003480 eluent Substances 0.000 description 50
- 239000002904 solvent Substances 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 42
- 239000012429 reaction media Substances 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 29
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 28
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 28
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 26
- 239000000725 suspension Substances 0.000 description 26
- 210000004369 blood Anatomy 0.000 description 24
- 239000008280 blood Substances 0.000 description 24
- 238000002512 chemotherapy Methods 0.000 description 24
- 238000001914 filtration Methods 0.000 description 24
- 239000003921 oil Substances 0.000 description 23
- 229910000027 potassium carbonate Inorganic materials 0.000 description 21
- 238000010992 reflux Methods 0.000 description 19
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 18
- 229940126639 Compound 33 Drugs 0.000 description 17
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- 238000000605 extraction Methods 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 14
- 235000010290 biphenyl Nutrition 0.000 description 14
- 239000004305 biphenyl Substances 0.000 description 14
- 229940127204 compound 29 Drugs 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 14
- 230000006698 induction Effects 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 13
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 11
- 229940125878 compound 36 Drugs 0.000 description 11
- 238000001802 infusion Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- KWEQCNBBWUSFBA-UHFFFAOYSA-N 8-methoxy-3-phenyl-1h-quinolin-4-one Chemical compound COC1=CC=CC(C2=O)=C1NC=C2C1=CC=CC=C1 KWEQCNBBWUSFBA-UHFFFAOYSA-N 0.000 description 8
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 229940009456 adriamycin Drugs 0.000 description 8
- 238000007596 consolidation process Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 229960005420 etoposide Drugs 0.000 description 8
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 8
- 229960002949 fluorouracil Drugs 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 206010027476 Metastases Diseases 0.000 description 7
- 229960000684 cytarabine Drugs 0.000 description 7
- 229960004679 doxorubicin Drugs 0.000 description 7
- 239000012467 final product Substances 0.000 description 7
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 7
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 6
- NYISTGNRDVIJLA-UHFFFAOYSA-N 7-methoxy-3-phenyl-1h-quinolin-4-one Chemical compound C=1C(OC)=CC=C(C2=O)C=1NC=C2C1=CC=CC=C1 NYISTGNRDVIJLA-UHFFFAOYSA-N 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 6
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 6
- 229960004630 chlorambucil Drugs 0.000 description 6
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 6
- 229960004397 cyclophosphamide Drugs 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000012423 maintenance Methods 0.000 description 6
- 231100000682 maximum tolerated dose Toxicity 0.000 description 6
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 6
- 229960001592 paclitaxel Drugs 0.000 description 6
- 239000012047 saturated solution Substances 0.000 description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 6
- SVGIDUUTBLBTPI-UHFFFAOYSA-N 5,8-dimethoxy-3-(4-methoxyphenyl)-1h-quinolin-4-one Chemical compound C1=CC(OC)=CC=C1C1=CNC2=C(OC)C=CC(OC)=C2C1=O SVGIDUUTBLBTPI-UHFFFAOYSA-N 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 208000017604 Hodgkin disease Diseases 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 5
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- 238000011156 evaluation Methods 0.000 description 5
- 229960001101 ifosfamide Drugs 0.000 description 5
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229960001924 melphalan Drugs 0.000 description 5
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 5
- 230000001394 metastastic effect Effects 0.000 description 5
- 206010061289 metastatic neoplasm Diseases 0.000 description 5
- 229960000485 methotrexate Drugs 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000003199 nucleic acid amplification method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 5
- 229960004528 vincristine Drugs 0.000 description 5
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
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- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- XGZAXRQNRRXUMY-MJCKVQKWSA-J tetrasodium;[4-[(e)-4-(4-phosphonatooxyphenyl)hex-3-en-3-yl]phenyl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].C=1C=C(OP([O-])([O-])=O)C=CC=1C(/CC)=C(\CC)C1=CC=C(OP([O-])([O-])=O)C=C1 XGZAXRQNRRXUMY-MJCKVQKWSA-J 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 208000029387 trophoblastic neoplasm Diseases 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- BXDTXNJFFKRYAP-BCJYHSTASA-N vad protocol Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1.C([C@H](C[C@]1(C(=O)OC)C=2C(=C3C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)=CC=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 BXDTXNJFFKRYAP-BCJYHSTASA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Definitions
- compositions comprising 4-quinolones
- the present invention relates to pharmaceutical compositions comprising 4-quinolones or derived compounds.
- Cancer is a disorder of the somatic genes in which genetic dysfunctions are amplified as the tumor process progresses from the precancerous lesion to that of malignant transformation, the cancerous tumor becoming metastatic and often resistant to drugs. cytotoxic.
- topoisomerase I inhibitors derived from camptothecin (topotecan and irinotecan), vinorelbine (new alkaloid from periwinkle), gemeitabine (new cytotoxic antimetabolic) , raltitrexed (thymidylate synthetase inhibitor) and miltefosine (first representative of the alkyl-lysophospholipid family).
- camptothecin topotecan and irinotecan
- vinorelbine new alkaloid from periwinkle
- gemeitabine new cytotoxic antimetabolic
- raltitrexed thymidylate synthetase inhibitor
- miltefosine first representative of the alkyl-lysophospholipid family.
- a first approach is that of the prevention or treatment of “multidrug-resistant” cancers (MDR) by the use of substances inhibiting or causing the reversibility of MDR resistance associated or not with the expression of the membrane transporter of glycoprotein- P.
- MDR multidrug-resistant cancers
- the inventors are interested in a different approach.
- the objective sought was to make the population of tumor cells more sensitive to reference anticancer treatments in order to achieve a double benefit:
- compositions capable of inducing a very significant increase in the cytotoxic activity of proven anticancer drugs.
- the inventors are interested in a particular group of original derivatives of the family of 3-aryl-4-quinolones. These compositions have the capacity either to stimulate the recruitment of clonogenic cells within the tumor making it more sensitive to conventional treatment with cytotoxic agents, or to inhibit the proliferation of clonogenic cells, thus contributing to the regression of the tumor. .
- a subject of the present invention is therefore the use, in the treatment of cancers with at least one antitumor chosen from cytotoxic agents, of a compound having an activity on the proliferation of clonogenic cells in tumors, but devoid of antitumor activity intrinsic (allowing therapeutic use) and chosen from the compounds of formulas:
- R is chosen from H, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, phenyl or a phenyl group 1 to 3 times substituted by groups chosen from H, OH, a group - OCOR 7 , R 7 being a C1-C4 alkyl group, a group -O-S0 2 -R ' 7 , R' 7 being a C1-C4 alkyl group or a group CF 3 , and a group -NR 16 R ⁇ 7 , Rie and R 17 being chosen independently of one another from hydrogen, (C1-C4) alkyl, C2-C4 alkenyl, phenyl (C1-C4) alkyl, a phenyl alkyl ( C1 -C4) 1 to 3 times substituted on the alkyl group by groups chosen from H, OH and alkoxy, in C1-C4, or a dimethylaminoalkyl group (C1-
- R 2 , R 3 and R 4 are chosen independently of one another from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, an -OCO-R 7 group , and a group derived from a ose, at least one of the substituents R 2 , R 3 or R 4 being other than H, and R 2 and R 3 can together form a methylenedioxy group,
- R 5 is a phenyl group or a phenyl group 1 to 3 times substituted by groups chosen from H, OH, a C1-C4 alkoxy group, a -OCOR 7 group, a phenyl (C1-C4 alkoxy) group, a group -O-SO 2 -R ' 7 , R' 7 being a C1-C40U alkyl group, a CF 3 group, a benzylamino group and a group derived from a ose,
- R 6 is chosen from H, a C1-C4 alkyl group, C2-C4 alkenyl, a group - CO-R 8 and a group -AR 9 ,
- R 6a is chosen from a C1-C4 alkyl group, C-2-C4 alkenyl, a group -
- A being a C1-C4 alkylene group
- R 9 being chosen from 5 or 6-membered heterocyclic groups having. 1 to 4 heteroatoms chosen from oxygen, sulfur and nitrogen, groups CN, hydroxy -COOR 10 , -CONRuR ⁇ , a group -NR 13 R 14 , a group -COR 15 , and OSO2RI6.
- R ⁇ and R 15 being independently chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group,
- R 16 being chosen from a phenyl group and an alkyl (C-
- Cytotoxic agents can be used at their usual dose and, in this case, their effectiveness is improved, or at lower doses given the increase in their antitumor efficacy, to reduce the severity of side effects (e.g. leukopenia, nausea, vomiting, ...) almost constantly encountered.
- the subject of the present invention is also a composition having an activity on the proliferation of clonogenic cells in tumors by interfering with the generation of clonogenic cells, either by stimulating proliferation and recruitment, or by inhibiting proliferation, and which comprises a effective amount of a compound of formulas:
- R T is chosen from H, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, phenyl or a phenyl group 1 to 3 times substituted by groups chosen from H, OH , a group -OCOR 7 , R 7 being a C1-C4 alkyl group, a group
- R' 7 being a C1-C4 alkyl group or a CF 3 group, and a group -
- NR 16 R 17 , R 16 and R 17 being chosen independently of one another from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, phenyl (C1-C4) alkyl, a phenyl group (C1-C4) alkyl 1 to 3 times substituted on the alkyl group by groups chosen from H,
- R 2 , R 3 and R 4 are chosen independently of one another from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, an -OCO-R 7 group , and a group derived from a dare, R 2 and R 3 can together form a methylenedioxy group,
- R 5 is a phenyl group or a phenyl group 1 to 3 times substituted by groups chosen from H, OH, a C1-C4 alkoxy group, a -OCOR 7 group, a phenyl (C1-C4 alkoxy) group, a group -O-SO 2 -R ' 7 , R' 7 being a C1-C40U alkyl group, a CF 3 group, a benzylamino group and a group derived from a ose,
- R 6 is chosen from H, a C1-C4 alkyl group, (C2-C4) alkenyl, a group -CO-R 8 and a group -AR 9
- R 6a is chosen from a C1-C4 alkyl group, C2-C4 alkenyl, a group -
- R 8 being a C1-C4 alkyl group
- A being a C1-C4 alkylene group
- R 9 being chosen from 5 or 6-membered heterocyclic groups having 1 to 4 heteroatoms chosen from oxygen, sulfur and nitrogen, groups CN, hydroxy, -COOR 10 , -CONRuR, a group -NR 13 R 14 , a group -COR 15 , and -OS ⁇ 2Rl6
- R 14 and R 15 are independently selected from a hydrogen atom, an alkyl group C1-C4 and phenyl (C1-C4),
- R16 being chosen from a phenyl group and an alkyl (C ⁇ -C-4) phenyl group
- R and R 6 can also form together a group -CO-CH 2 -CH 2 -.
- the present invention also relates to new compounds, namely compounds of formulas:
- R ⁇ is chosen from H, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, phenyl or a phenyl group 1 to 3 times substituted by groups chosen from H, OH , a group -OCOR 7 , R 7 being a C1-C4 alkyl group, a group -0-SO 2 -R ' 7 , R' 7 being a C1-C4 alkyl group or a group CF 3 , and a group - NR 16 R 17 , R 16 and R 17 being chosen independently of one another from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, phenyl (C1-C4) alkyl, a group phenyl alkyl (C1-C4) 1 to 3 times substituted on the alkyl group by groups chosen from H, OH and C- ⁇ -C-4 alkoxy, or a dimethylaminoalkyl group (C1
- R 2 , R 3 and R are chosen independently of one another from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, an -OCO-R 7 group , and a derivative group a dare, R 2 and R 3 which can together form a methylenedioxy group
- R 5 is a phenyl group or a phenyl group 1 to 3 times substituted by groups chosen from H, OH, a C ⁇ -C4 alkoxy group, a group -OCOR 7 , a phenyl group (C1-C4 alkoxy), a group -O-SO 2 -R ' 7l R' 7 being a C1-C40U alkyl group, a CF 3 group, a benzylamino group and a group derived from an ose
- R 6 is chosen from H, a C1 alkyl group -C4, (C2-C4) alkenyl, a group -CO
- R 6a is chosen from a C1-C4 alkyl group, (C2-C4) alkenyl, a group - CO-R 8 and a group -AR 9 ,
- R 8 being a C1-C4 alkyl group, A being a C1-C4 alkylene group,
- R 9 being chosen from 5 or 6-membered heterocyclic groups having 1 to 4 heteroatoms chosen from oxygen, sulfur and nitrogen, groups CN, hydroxy, -COOR 10 , -CONRnR 12 , a group -NR 13 R, a group -COR 15 , and -OSO2R16
- R10, R ⁇ > R ⁇ 2 , Ri3 > RM and R 15 being independently chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group,
- R 16 being chosen from a phenyl group and an alkyl (C ⁇ -C4) phenyl group, R 4 and R 6 can also form together a group -CO-CH 2 -CH 2 -. excluding compounds where:
- a particular group of compounds is that consisting of the compounds of formulas I or la according to which: R 1 is chosen from H, OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, phenyl or a phenyl group 1 to 3 times substituted with groups chosen from H, OH , a group -OCOR7, R7 being a C1-C4 alkyl group, a group -O-SO2- R'7, R'7 being a C1-C4 alkyl group or a group CF3, and a benzylamino group, R2.
- R3 and R4 are chosen independently of one another from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a -OCO-R7 group, and a group derived from an ose and R2 and R3 can together form a methylenedioxy group,
- R5 is a phenyl group or a phenyl group 1 to 3 times substituted by groups chosen from H, OH, a C1-C4 alkoxy group, a -OCOR7 group, a phenyl (C1-C4 alkoxy) group, a group - O-S ⁇ 2-R'7, R'7 being a C1-C4 alkyl group or a CF3 group, a benzylamino group and a group derived from a ose,
- R6 is chosen from H, a C1-C4 alkyl group, a -CO-Rs group and a -A-Rg group,
- R ⁇ a is chosen from a C1-C4 alkyl group, a -CO-Rs group and an -A-Rg group,
- R8 being a C1-C4 alkyl group, A being a C1-C4 alkylene group,
- Rg being chosen from 5 or 6-membered heterocyclic groups having 1 to 4 heteroatoms chosen from oxygen, sulfur and nitrogen, the group CN, a group - COOR10, -CONR1 1 R12, a group -NR13R-14 , and a group -COR15,
- R10. R11. R12- R 13- R14 and R15 being independently chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4 alkyl) group, R 4 and R 6 can also together form a group - CO-CH 2 -CH 2 -.
- Another particular group of compounds is that consisting of the compounds of formulas I or la in which:
- R 5 is a phenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl and 2,5-dimethoxyphenyl group,
- Another particular group of compounds is that consisting of the compounds of formulas I or la in which:
- R 1 is chosen from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, phenyl or a phenyl group 1 to 3 times substituted by groups chosen from H, OH, a group -OCOR 7 , R 7 being a group C1-C4 alkyl, a group -O-SO 2 -R ' 7 , R' 7 being a C1-C40U alkyl group a group CF 3 , and a group -NR 16 R ⁇ 7 , R ⁇ 6 and R 17 being chosen independently of one another among hydrogen, C1-C4 alkyl, C2-C4 alkenyl, phenyl (C1-C4) alkyl, a phenyl (C1-C4) alkyl group 1 to 3 times substituted on the alkyl group with groups chosen from H, OH and C ⁇ -C-4 alkoxy, or a dimethylaminoalkyl group (C1-C4), or forming together and, with the nitrogen
- Another particular group of compounds is that consisting of the compounds of formulas I or la in which:
- R2 > R3 and R4 are chosen from a hydrogen atom and a C ⁇ -C4 alkoxy group.
- a group derived from an ose denotes a group which forms, with the remainder of the molecule, a heteroside.
- these heterosides are capable of giving a compound of formula I or la with a hydroxy group and a ose.
- the dares can be in particular monosaccharide (glucose, rhamnose) or disaccharide (for example rutinose).
- the compounds of formulas (I) and (la) can be administered at the start of chemotherapeutic treatments either at once or over several days at the start of these treatments (for example for 5 to 7 days) and, depending on the chemotherapy protocol, at the start of each treatment cycle (for example for 2 to 5 days) during each course.
- the compounds of formulas (I) and (la) are advantageously administered by infusion (generally in 1 to 3 hours) at doses of 1 to 50 mg / kg / day or 40 to 2000 mg / n Vday.
- the compounds of formulas (I) and (la) must be administered in such a way that the tissue concentrations obtained are as high as possible. consider.
- the intravenous route is to be preferred using: - ready-to-use infusion solutions (bags, bottles, etc.) intended to be administered as such by intravenous infusion using an infusion line and at the recommended rate:
- lyocs for oral or perlingual absorption
- instant or delayed release tablets for oral solutions, suspensions, granules, capsules, etc.
- Cytotoxic agents can be chosen from: i) intercalating agents, in particular doxorubicin (Adriamycin), daunorubicin, epirubicin, idarubicin, zorubicin, aclarubicin, pirarubicin, acridin, mitoxanthrone, l actinomycin D, eptilinium acetate; ii) alkylating agents chosen from platinum derivatives (cisplatin, carboplatin, oxaliplatin); iii) a compound chosen from other groups of alkylating agents:
- BCNU carmustine
- CCNU lamelonine
- fotemustine fotemustine
- streptozotocin
- - ethyleneimines altretamine, triethylene-thiophosphoramide, iv) a compound chosen from other groups of anti-metabolic agents:
- - antipurics purinethol, thioguanine, pentostatin, cladribine
- vinca-alkaloids disorganizing the mitotic spindle: vincristine, vinblastine, vinguerine, navelbine
- paclitaxel agents blocking the depolymerization of the mitotic spindle: paclitaxel, docetaxel - agents inducing DNA breaks by inhibition of topoisomerase II: etoposide, teniposide
- - topoisomerase I inhibitors inducing DNA breaks topotecan, irinotecan, vi) a splitting agent, fragmenting DNA, such as bleomycin, vii) one of the following compounds; plicamycin, L-asparaginase, mitoguazone, dacarbazine, viii) an anti-cancer progestin steroid: medroxy-progesterone, megestrol, ix) an anti-cancer estrogenic steroid: diethylstilbestrol; tetrasodium fosfestrol, x) an anti-estrogen: tamoxifen, droloxifene, raloxifene, amino-gluthetimide, xi) a steroid antiandrogen (ex cyproterone) or a nonsteroidal antiandrogen (flutamide, nilutamide).
- a splitting agent fragmenting DNA, such as bleomycin
- the compounds of formula (I) and (la) can be associated with all the treatments with the major cytotoxic agents used in polychemotherapies of solid tumors such as:
- - anti-metabolites such as methotrexate, 5-FU, Ara-C, capecitabine
- vinca alkaloids vincristine, vinblastine, vindesine, navelbine
- taxoids paclitaxel, docetaxel
- epipodophyllotoxin derivatives etoposide, teniposide
- topoisomerase I inhibitors topotecan, irinotecan.
- the compounds of formula (I) and (la) can be combined with the treatments by the major cytotoxic agents used in oncohematology for the treatment of blood cancers:
- cyclophosphamide mechlorethamine, chlorambucil, melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin;
- - acute leukemias methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase
- - non-Hodgkin's malignant lymphomas mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunorubicin, carmustine, lomustine, cisplatin
- chronic lymphoid leukemia mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide.
- the alkoxy groups can be converted to hydroxy groups according to known methods.
- the hydroxy groups can be transformed into an ester or a sulfonate according to known methods, the sulfonates which can, in turn, be converted into alkenyl, phenyl or substituted phenyl groups and - NR 16 Ri7 according to known methods.
- the compound 10 (1.20 g, 3.66 mmol) is added quickly and this quickly to a solution of biphenyl (1.52 g) and diphenyl ether (11.60 g) heated to 250 ° vs. After 10 min, the heating is stopped. Upon cooling, the final product 11 precipitates from the reaction medium. The crude product is collected by filtration and then rinsed with petroleum ether. The latter is taken up in ethanol. The suspension is heated to reflux with stirring. After cooling and filtration, 753 mg (73%) of compound 11 are obtained in the form of white crystals.
- reaction mixture is diluted with toluene (10 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO 4 and then evaporated under reduced pressure. The residue is purified by chromatography on a silica column (eluent: CH 2 CI 2 ) to give 1.92 g (60%) of compound 13 in the form of an oil which crystallizes from methanol.
- the compound 20 (1.30 g, 3.97 mmol) is added in small portions and this quickly to a solution of biphenyl (1.36 g) and diphenyl ether (10.40 g) heated to 250 ° C. After 10 min, the heating is stopped. During the cooling of the reaction medium, the product precipitates. 972 mg (87%) of compound 21 are thus collected by filtration in the form of white crystals.
- EXAMPLE 15 7-Methoxy-3- (4-methoxyphenyl) -1,4-dihydro-4-quinolinone (compound 26) -CRL8358 and 5-Methoxy-3- (4-methoxyphenyl) -1, 4-dihydro-4 -quinolinone (compound 27) - CRL8491 a) (Z) -3- (3-Methoxyanilino) -2- (4-methoxyphenyl) -2-ethyl propenoate (25)
- the compound 28 (1.10 g, 3.08 mmol) is added in small portions and this quickly to a solution of biphenyl (3.00 g) and diphenyl ether (7.51 g) heated to 250 ° vs. After 10 min, the heating is stopped. During cooling, the quinolone 29 precipitates in the reaction medium. This product is collected by filtration and then rinsed with petroleum ether. After drying, 680 mg (71%) of compound 29 are obtained in the form of white crystals.
- the compound 30 (900 mg, 2.52 mmol) is added in small portions and this quickly to a solution of biphenyl (1.18 g) and diphenyl ether (8.05 g) heated to 250 ° vs. After 10 min, the heating is stopped. Upon cooling, the final product precipitates from the reaction medium. This product is collected by filtration and then rinsed thoroughly with petroleum ether. After drying,
- EXAMPLE 33 ⁇ / - [3- (Dimethylamino) ethyl] -5,7-dimethoxy-3- (4-methoxyphenyl) -1,4-dihydro-4-quinolinone (compound 54) - CRL 8350 and ⁇ - ⁇ 2 - [5,7-Dimethoxy-3- (4-methoxyphenyl) - 4-quinolyl] oxy ⁇ ethyl- ⁇ t, ⁇ / -dimethylamine (55) -CRL8505 a) ⁇ / - [3- (Dimethylamino) ethyl] -5 , 7-dimethoxy-3- (4-methoxyphenyl) -1,4-dihydro-4-quinolinone (compound 54) - CRL 8350
- EXAMPLE 36 2- [5,8-Dimethoxy-3- (4-methoxyphenyl) -4-oxo-1, 4-dihydro-1 -quinolinyl] ethyl acetate (compound 58) - CRL 8381 and 2 - ⁇ [ 5,8-Dimethoxy-3- (4-methoxyphenyl) -4-quinolinyl] oxy ⁇ ethyl acetate (compound 59) -CRL 8506 a) 2- [5,8-Dimethoxy-3- (4-methoxyphenyl) - 4-oxo-1, 4-dihydro-1 -quinolinyl] ethyl acetate (compound 58) - CRL 8381
- reaction solution is extracted with ethyl acetate (twice).
- organic phase obtained is dried over MgSO 4 , then evaporated under reduced pressure.
- residue obtained is purified by chromatography on a silica column (AcOEt / NH 3 95: 5 then 1% MeOH) to give 46 mg (12%) of compound 61 and 283 mg (74%) of derivative 60.
- this compound is dissolved in 2 ml of pyridine and 2 ml of anhydride acetic at 0 ° C. The reaction is stirred at room temperature for 48 h. The solvents are evaporated. The residue obtained is taken up in CH 2 CI 2 and washed twice with water. The organic phase obtained is dried over MgSO 4 , then evaporated under reduced pressure. The residue is purified by chromatography on a silica column (eluent: CH 2 CI 2 / AcOEt 7: 3) to give 235 mg (86%) of the derivative 76.
- EXAMPLE 53 4- [5,8-Dimethoxy-3- (4-methoxyphenyl) -4-oxo-1, 4-dihydro-1 -quinolinyl] butanenitrile (compound 80) - CRL8421 and ⁇ [5,8-Dimethoxy- 3- (4-methoxyphenyl) -4- quinolyl] oxy ⁇ butanenitrile (compound 81) -CRL8501
- EXAMPLE 57 3- [5,8-Dimethoxy-3- (4-methoxyphenyl) -4-oxo-1, 4-dihydro-1 - quinolinyljpentanenitrile (compound 86) - CRL8463 and ⁇ [5,8-Dimethoxy-3- (4-methoxyphenyl) -4-quinolyl] oxy ⁇ pentanenitrile (compound 87) -CRL8519
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9910492A FR2797444B1 (fr) | 1999-08-13 | 1999-08-13 | Compositions pharmaceutiques comprenant des 4-quinolones |
FR9910492 | 1999-08-13 | ||
PCT/FR2000/002310 WO2001012607A2 (fr) | 1999-08-13 | 2000-08-11 | Compositions pharmaceutiques comprenant des 4-quinolones pour le traitement des cancers |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1202971A2 true EP1202971A2 (de) | 2002-05-08 |
Family
ID=9549145
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00958676A Withdrawn EP1202971A2 (de) | 1999-08-13 | 2000-08-11 | Arzneimittel, welche 4-chinolonen enthalten zur behandlung von krebs |
Country Status (7)
Country | Link |
---|---|
US (1) | US6645983B1 (de) |
EP (1) | EP1202971A2 (de) |
AU (1) | AU7012200A (de) |
CA (1) | CA2381968A1 (de) |
FR (1) | FR2797444B1 (de) |
IL (1) | IL148106A0 (de) |
WO (1) | WO2001012607A2 (de) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7345018B2 (en) * | 2002-04-25 | 2008-03-18 | Reception Aps | Method of treating side effects induced by therapeutic agents |
MXPA05010143A (es) * | 2003-03-26 | 2006-03-17 | Reception Aps | Uso de compuestos para la prevencion de toxicidad celular inducida por farmaco. |
EP2522670A1 (de) | 2004-04-07 | 2012-11-14 | Takeda Pharmaceutical Company Limited | Heterozyklische CRF-Rezeptor-Antagonisten |
TWI366565B (en) | 2007-06-06 | 2012-06-21 | Otsuka Pharma Co Ltd | Quinolone compound and pharmaceutical composition |
TWI472525B (zh) * | 2008-12-05 | 2015-02-11 | Otsuka Pharma Co Ltd | 喹啉酮化合物及藥學組成物 |
WO2010064701A1 (ja) | 2008-12-05 | 2010-06-10 | 大塚製薬株式会社 | キノロン化合物を含む薬剤 |
US8598354B2 (en) | 2008-12-05 | 2013-12-03 | University Of South Florida | Compounds having antiparasitic or anti-infectious activity |
JP5769504B2 (ja) * | 2010-06-04 | 2015-08-26 | 大塚製薬株式会社 | 医薬 |
CN105017145B (zh) * | 2012-12-12 | 2017-12-05 | 王子厚 | 具有抗肿瘤活性的氯氧喹衍生物 |
Family Cites Families (3)
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WO1994002145A2 (en) * | 1992-07-22 | 1994-02-03 | Genelabs Technologies, Inc. | 2-aryl-4-quinolones as antitumor compounds |
US5726184A (en) * | 1995-05-19 | 1998-03-10 | Vertex Pharmaceuticals Incorporated | Tetralin compounds with improved MDR activity |
GB9621757D0 (en) * | 1996-10-18 | 1996-12-11 | Ciba Geigy Ag | Phenyl-substituted bicyclic heterocyclyl derivatives and their use |
-
1999
- 1999-08-13 FR FR9910492A patent/FR2797444B1/fr not_active Expired - Fee Related
-
2000
- 2000-08-11 CA CA002381968A patent/CA2381968A1/fr not_active Abandoned
- 2000-08-11 EP EP00958676A patent/EP1202971A2/de not_active Withdrawn
- 2000-08-11 WO PCT/FR2000/002310 patent/WO2001012607A2/fr not_active Application Discontinuation
- 2000-08-11 IL IL14810600A patent/IL148106A0/xx unknown
- 2000-08-11 US US10/049,512 patent/US6645983B1/en not_active Expired - Fee Related
- 2000-08-11 AU AU70122/00A patent/AU7012200A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO0112607A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO2001012607A2 (fr) | 2001-02-22 |
WO2001012607B1 (fr) | 2001-11-22 |
US6645983B1 (en) | 2003-11-11 |
FR2797444B1 (fr) | 2003-02-07 |
WO2001012607A3 (fr) | 2001-05-03 |
IL148106A0 (en) | 2002-09-12 |
FR2797444A1 (fr) | 2001-02-16 |
AU7012200A (en) | 2001-03-13 |
CA2381968A1 (fr) | 2001-02-22 |
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