CN112824416A - Propenone derivative for removing N-methyllevofloxacin, and preparation method and application thereof - Google Patents
Propenone derivative for removing N-methyllevofloxacin, and preparation method and application thereof Download PDFInfo
- Publication number
- CN112824416A CN112824416A CN201911139984.0A CN201911139984A CN112824416A CN 112824416 A CN112824416 A CN 112824416A CN 201911139984 A CN201911139984 A CN 201911139984A CN 112824416 A CN112824416 A CN 112824416A
- Authority
- CN
- China
- Prior art keywords
- methyllevofloxacin
- formula
- derivative
- preparation
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- POUXCZFBIBTXOL-UHFFFAOYSA-N C=CC(=O)C(=O)C(=O)C=C Chemical class C=CC(=O)C(=O)C(=O)C=C POUXCZFBIBTXOL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 16
- 229960003376 levofloxacin Drugs 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims description 15
- -1 imidazole amide compound Chemical class 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 10
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 5
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- NMIZONYLXCOHEF-UHFFFAOYSA-N 1h-imidazole-2-carboxamide Chemical compound NC(=O)C1=NC=CN1 NMIZONYLXCOHEF-UHFFFAOYSA-N 0.000 claims description 3
- 238000005882 aldol condensation reaction Methods 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 14
- 229940124307 fluoroquinolone Drugs 0.000 abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 206010059866 Drug resistance Diseases 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 239000013543 active substance Substances 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 26
- 239000013078 crystal Substances 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- 239000000376 reactant Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 10
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 10
- 229960001796 sunitinib Drugs 0.000 description 10
- 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 8
- 238000012360 testing method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 description 5
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 235000005513 chalcones Nutrition 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- RQCOKVKHMUILCX-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1Br)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1Br)=O)C2=O RQCOKVKHMUILCX-UHFFFAOYSA-N 0.000 description 2
- KGHLBUFYILWAAJ-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1F)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1F)=O)C2=O KGHLBUFYILWAAJ-UHFFFAOYSA-N 0.000 description 2
- HGLVCFNTTNBGAQ-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1O)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1O)=O)C2=O HGLVCFNTTNBGAQ-UHFFFAOYSA-N 0.000 description 2
- QEEIJZASBKTKEK-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1OC)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1OC)=O)C2=O QEEIJZASBKTKEK-UHFFFAOYSA-N 0.000 description 2
- QZCDYKOXLBAJJN-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1[N+]([O-])=O)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1)=CC=C1[N+]([O-])=O)=O)C2=O QZCDYKOXLBAJJN-UHFFFAOYSA-N 0.000 description 2
- XFKQKQAJLMCJEB-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1OC)=CC(OC)=C1OC)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=C1OC)=CC(OC)=C1OC)=O)C2=O XFKQKQAJLMCJEB-UHFFFAOYSA-N 0.000 description 2
- WWOGTQCQKXLGQQ-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=CC1=O)=CC1=O)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC(C=CC1=O)=CC1=O)=O)C2=O WWOGTQCQKXLGQQ-UHFFFAOYSA-N 0.000 description 2
- AAHMRGSIKVTWBN-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=C(C)C=C1)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=C(C)C=C1)=O)C2=O AAHMRGSIKVTWBN-UHFFFAOYSA-N 0.000 description 2
- KUGPAAJRUMFFRJ-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=CC=C1)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=CC=C1)=O)C2=O KUGPAAJRUMFFRJ-UHFFFAOYSA-N 0.000 description 2
- KQPRLMMLBYTZSZ-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=CN=C1)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=CN=C1)=O)C2=O KQPRLMMLBYTZSZ-UHFFFAOYSA-N 0.000 description 2
- MMSGKXHLUMEXTF-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=CO1)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(C=CC1=CC=CO1)=O)C2=O MMSGKXHLUMEXTF-UHFFFAOYSA-N 0.000 description 2
- 241000282552 Chlorocebus aethiops Species 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 150000001555 benzenes Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- HUBASKVNKVDZPU-UHFFFAOYSA-N CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(O)=O)C2=O Chemical compound CC(C)OC(C(N1CCNCC1)=C(C=C12)F)=C1NC=C(C(O)=O)C2=O HUBASKVNKVDZPU-UHFFFAOYSA-N 0.000 description 1
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 101710147108 Tyrosinase inhibitor Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001788 chalcone derivatives Chemical class 0.000 description 1
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- FMUNKBAIXLTEGC-UHFFFAOYSA-L magnesium;n,n-diethylethanamine;dichloride Chemical compound [Mg+2].[Cl-].[Cl-].CCN(CC)CC FMUNKBAIXLTEGC-UHFFFAOYSA-L 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- YLLIGHVCTUPGEH-UHFFFAOYSA-M potassium;ethanol;hydroxide Chemical compound [OH-].[K+].CCO YLLIGHVCTUPGEH-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention discloses an acrylketone derivative for removing N-methyl levofloxacin, a preparation method and application thereof, wherein the chemical structural general formula of the compound is as follows:
Description
Technical Field
The invention belongs to the technical field of innovative medicine synthesis, and particularly relates to an acrylketone derivative for removing N-methyllevofloxacin, a preparation method of the acrylketone derivative for removing N-methyllevofloxacin, and application of the acrylketone derivative in antitumor medicines.
Background
New drug innovation stems from the discovery of leads, and rational drug molecular design based on structure or mechanism is an effective method for discovering leads. In the drug effect groups with various structures, the acrylketone structure is not only the characteristic structure of a chalcone compound which is a natural effective component, but also the characteristic drug effect group of a targeted antitumor drug sunitinib. Therefore, compounds constructed with acrylketone as a structural fragment and having various pharmacological activities have been attracting attention. However, most of natural chalcone compounds are multi-hydroxyl benzene ring substituted propenone compounds, and the poor water solubility of the compounds causes low bioavailability and limits clinical application. In addition, the topoisomerase which is an action target point of the antibacterial fluoroquinolone medicine is also an important action target point of the antitumor medicine, the antibacterial activity of the antibacterial fluoroquinolone medicine can be converted into the antitumor activity, and the fluoroquinolone C-3 carboxyl is not a pharmacophore required by the antitumor activity and can be replaced by a biological electron isostere to improve the antitumor activity of the fluoroquinolone medicine. However, the research on the replacement of the C-3 carboxyl group of fluoroquinolone with aryl acrylketone has not been reported. Based on the above, in order to improve the water solubility of chalcone, hydrophilic piperazinyl is introduced to increase the water solubility and improve the bioavailability and the biological activity of the chalcone, the invention uses the skeleton of the advantageous pharmacophore of the fluoroquinolone medicament, namely '1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one', of N-methyllevofloxacin as a substituent of an aryl propenone structure, and further designs the fluoroquinolone 'chalcone-like' derivative with a novel structure.
Therefore, the invention aims to provide the propenone derivative for removing the N-methyllevofloxacin, which has the anti-tumor effect and efficacy, and the preparation method of the propenone derivative for removing the N-methyllevofloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the acrylketone derivative for removing N-methyllevofloxacin has a chemical structural formula shown as a general formula I:
in the formula I, Ar is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring, and the compound is a compound with the following specific structure:
the preparation method of the acrylketone derivative for removing N-methyl levofloxacin takes commercially obtained N-methyl levofloxacin shown in a formula II as a raw material to prepare the acrylic ketone derivative;
the preparation method comprises the following specific steps:
1) the method for preparing the de-N-methyllevofloxacin imidazole amide compound shown in the formula III by using commercially obtained de-N-methyllevofloxacin shown in the formula II as a raw material and reacting with Carbonyldiimidazole (CDI) comprises the following specific steps:
21.0g (60.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-carboxylic acid II was dissolved in 500mL of anhydrous acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole was added, and the reaction mixture was stirred in a water bath and refluxed until the starting material II disappeared. Standing at room temperature, filtering and collecting generated solid, and recrystallizing with acetone to obtain a light yellow crystal of de-N-methyllevofloxacin imidazole amide shown as a formula III, wherein the yield is 65.7%, and m.p.225-227 ℃.1H NMR(400MHz,CD3Cl)δ：1.63(3H,d,CH3) 3.05 to 3.76(8H, m, piperazine-H), 4.42 to 4.86(3H, m, O-CH)2CH-N), 7.48-7.74 (2H, m, imidazole-H), 8.16(1H, s, imidazole-H), 8.97(1H, d, 5-H), 9.15(1H, s, 2-H); MS (m/z): 398[ M + H]+Calculating (C)20H20FN5O3)：397.41。
As a further improvement, the molar ratio of the de-N-methyllevofloxacin shown in the formula II to the carbonyldiimidazole is 1: 1.0-2.0, and the solvent can be at least one of acetonitrile, tetrahydrofuran, dioxane and dimethylformamide or a mixed solvent of the acetonitrile, the tetrahydrofuran, the dioxane and the dimethylformamide.
2) The de-N-methyllevofloxacin imidazole amide shown in a formula III and monoethyl malonate potassium salt are subjected to condensation reaction under the catalysis of triethylamine-magnesium chloride to prepare a C-3 formyl ethyl acetate compound of the de-N-methyllevofloxacin shown in a formula IV, and the specific preparation method is as follows:
s- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (1H-imidazole-1-formyl) - [ quinolin-4 (1H) -one, 15.5g (39.0mmol) of formula III, 6.6g (69.1mmol) of magnesium chloride and 8.3g (49.0mmol) of potassium monoethyl malonate were taken, sequentially added to 600mL of anhydrous acetonitrile, 12.2g (12.0mmol) of triethylamine was added dropwise with stirring in an ice bath, and the reaction mixture was stirred in a water bath and refluxed until the starting material III disappeared. The solvent was evaporated under reduced pressure, 500mL of water was added, the mixture was extracted with methylene chloride (3X 150mL), the organic phases were combined, washed with water (3X 200mL), washed with saturated brine (2X 150mL), and dried over anhydrous sodium sulfate. And recovering dichloromethane at normal pressure, and recrystallizing the residue with absolute ethyl alcohol to obtain an off-white crystal shown as a formula IV, wherein the yield is 68.7%, and m.p.223-225 ℃.1H NMR(400MHz,CD3Cl)δ：1.26～1.65(6H，m，2×CH3) 3.12 to 3.76(8H, m, piperazine-H), 3.45 to 4.86(7H, m, COCH)2COOCH2And O-CH2CH-N)，8.97(1H，d，5-H)，9.15(1H，s,2-H)；MS(m/z)：418[M+H]+Calculating (C)21H24FN3O5)：417.44。
3) The C-3 ethyl formylacetate compound of the de-N-methyllevofloxacin shown in the formula IV is hydrolyzed and decarboxylated by using 6 percent of sodium hydroxide aqueous solution by mass fraction to conveniently prepare the C-3 ethanone compound of the de-N-methyllevofloxacin shown in the formula V, and the specific preparation method is as follows:
taking 10g (24.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-formylacetic acid ethyl ester shown in the formula IV and suspending the ethyl ester in 200mL of sodium hydroxide aqueous solution with the mass fraction of 6%, and stirring and refluxing the mixture in an oil bath until the raw material IV disappears. Standing at room temperature, filtering to collect the generated solid, washing with water to neutrality, drying, and recrystallizing with anhydrous ethanol to obtain light yellow crystal of formula V, with yield of 83.6%, m.p.226-228 deg.C.1H NMR(400MHz,CD3Cl)δ：1.63(3H,d,CH3),2.42(3H，s，COCH3) 3.16 to 3.78(8H, m, piperazine-H), 4.45 to 4.87(3H, m, O-CH)2CH-N)，8.96(1H，d，5-H)，9.15(1H，s,2-H)；MS(m/z)：346[M+H]+Calculating (C)18H20FN3O3)：345.38。
4) C-3 ethanone without N-methyllevofloxacin shown in a formula V and aromatic aldehyde are subjected to Claisen-Schmidt aldol condensation reaction in absolute ethyl alcohol under the catalysis of alkali, and after the reaction is completed, a target compound is obtained through treatment, wherein the target compound is shown in a formula I, and the specific process is as follows:
wherein Ar in the formula I is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring.
The general synthetic preparation procedure for the target compound of formula i is: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and an aromatic aldehyde (3.0mmol) and a base catalyst piperidine (0.1mL) were added. And (3) refluxing and reacting the mixed reactants for 15-24 h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal shown in the formula I.
As a further improvement, the mol ratio of the N-methyl-levofloxacin C-3 ethanone shown in the formula V to the aromatic aldehyde is 1: 1.0-1.5.
The base catalyst is at least one of piperidine, pyridine, triethylamine, morpholine, potassium acetate, sodium hydroxide ethanol solution or potassium hydroxide ethanol solution.
The application of the acrylketone derivative for removing the N-methyl levofloxacin in preparing the antitumor drugs is provided.
The anti-tumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
The acrylketone derivative for removing N-methyl levofloxacin disclosed by the invention is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the splicing principle of the pharmacophores, and the complementation and activity superposition of the pharmacophores with different structures are realized, so that the effects of synergism, toxicity reduction and drug resistance are achieved, and the acrylketone derivative can be developed as an anti-tumor drug with a brand new structure.
Detailed Description
Example 1
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical formula:
namely, Ar in the formula I is phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.40g (3.8mmol) of benzaldehyde and piperidine, a basic catalyst (0.1mL) were added. Refluxing the mixed reactants for 18h, standing at room temperature, filteringAnd (3) collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal shown as a formula I-1, wherein the yield is 72.4%, and m.p.235-237 ℃.1H NMR(400MHz,CD3Cl)δ：1.64(3H,d,CH3) 3.16 to 3.75(8H, m, piperazine-H), 4.46 to 4.88(3H, m, O-CH)2CH-N), 7.63-8.68 (7H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.17(1H, s, 2-H); MS (m/z): 434[ M + H]+Calculating (C)25H24FN3O3)：447.51。
Example 2
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical formula:
namely, Ar in the formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.57g (4.2mmol) of 4-methoxybenzaldehyde and piperidine, a basic catalyst (0.1mL) were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-2, wherein the yield is 76.2%, and the m.p.236-238 ℃.1H NMR(400MHz,CD3Cl)δ：1.66(3H,d,CH3) 3.18 to 3.76(8H, m, piperazine-H), 3.93(3H, s, OCH)3)，4.46～4.87(3H，m，O-CH2CH-N), 7.65-8.86 (6H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.17(1H, s, 2-H); MS (m/z): 464[ M + H ]]+Calculating (C)26H26FN3O4)：463.51。
Example 3
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (3, 4-dioxocinnamoyl) -quinolin-4 (1H) -one (I-3) having the chemical formula:
namely, Ar in the formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.53g (3.5mmol) of 3, 4-dioxytolualdehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-3, wherein the yield is 84.6%, and m.p.242-244 ℃.1H NMR(400MHz,CD3Cl)δ：1.66(3H,d,CH3) 3.17 to 3.82(8H, m, piperazine-H), 4.46 to 4.87(3H, m, O-CH)2CH-N)，6.23(2H，s，OCH2O), 7.65-8.84 (5H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.17(1H, s, 2-H); MS (m/z): 478[ M + H]+Calculating (C)26H24FN3O5)：477.50。
Example 4
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (3,4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (I-4) having the chemical formula:
namely, Ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.63g (3.2mmol) of 3,4, 5-trioxybenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-4, wherein the yield is 75.2%, and the m.p.231-233 ℃.1H NMR(400MHz,CD3Cl)δ：1.65(3H,d,CH3) 3.16 to 3.78(8H, m, piperazine-H), 3.87,3.96(9H, 2s,3 XOCH)3)，4.46～4.87(3H，m，O-CH2CH-N), 7.64-8.85 (4H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 524[ M + H]+Calculating (C)28H30FN3O6)：523.57。
Example 5
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the chemical formula:
namely, Ar in the formula I is p-methyl-phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.58g (4.8mmol) of 4-methylbenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-5, wherein the yield is 65.7%, and m.p.224-226 ℃.1H NMR(400MHz,CD3Cl)δ：1.64(3H,d,CH3),2.27(3H，s，Ph-CH3) 3.13 to 3.74(8H, m, piperazine-H), 4.42 to 4.80(3H, m, O-CH)2CH-N), 7.64-8.86 (6H, m, Ph-H, 3 '-H and 2' -H), 8.95(1H, d, 5-H),9.06(1H, s, 2-H); MS (m/z): 448[ M + H ]]+Calculating (C)26H26FN3O3)：447.51。
Example 6
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-fluorocinnamoyl) -quinolin-4 (1H) -one (I-6) having the chemical formula:
namely, Ar in the formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the following steps: taking S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V1.0 g (3.0mmol) was dissolved in 20mL of anhydrous ethanol, and 0.48g (3.8mmol) of 4-fluorobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 15h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-6, wherein the yield is 78.5%, and the m.p.235-237 ℃.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3) 3.17 to 3.83(8H, m, piperazine-H), 4.46 to 4.87(3H, m, O-CH)2CH-N), 7.66-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 9.05(1H, d, 5-H),9.18(1H, s, 2-H); MS (m/z): 452[ M + H]+Calculating (C)25H23F2N3O3)：451.48。
Example 7
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-chlorocinnamyl) -quinolin-4 (1H) -one (I-7) having the chemical formula:
namely, Ar in the formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.45g (3.2mmol) of 4-chlorobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-7, wherein the yield is 75.3%, and the m.p.230-232 ℃.1H NMR(400MHz,CD3Cl)δ：1.65(3H,d,CH3) 3.16 to 3.75(8H, m, piperazine-H), 4.46 to 4.86(3H, m, O-CH)2CH-N), 7.65-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 8.98(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 468[ M + H]+Calculating (C)25H23FClN3O3)：467.93。
Example 8
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical formula:
namely, Ar in the formula I is p-bromophenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.67g (3.6mmol) of 4-bromobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 24 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-8, wherein the yield is 72.6%, and the m.p.234-236 ℃.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3) 3.17 to 3.83(8H, m, piperazine-H), 4.47 to 4.85(3H, m, O-CH)2CH-N), 7.65-8.86 (6H, m, Ph-H, 3 '-H and 2' -H), 8.97(1H, d, 5-H),9.18(1H, s, 2-H); MS (m/z): 512 and 514[ M + H]+(79Br and81br), calculating (C)25H23FBrN3O3)：512.38。
Example 9
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical formula:
namely, Ar in the formula I is p-nitrophenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.54g (3.6mmol) of 4-nitrobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 24 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-9, wherein the yield is 76.6%, and the m.p.243-245 ℃.1H NMR(400MHz,CD3Cl)δ：1.68(3H,d,CH3) 3.25 to 3.86(8H, m, piperazine-H), 4.48 to 4.92(3H, m, O-CH)2CH-N), 7.67-8.95 (6H, m, Ph-H, 3 '-H and 2' -H),9.06(1H, d, 5-H),9.25(1H, s, 2-H); MS (m/z): 479[ M + H ]]+Calculating (C)25H23FN4O5)：478.48。
Example 10
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-hydroxy-cinnamoyl) -quinolin-4 (1H) -one (I-10) having the chemical formula:
namely, Ar in the formula I is 4-hydroxy-phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.49g (4.0mmol) of 4-hydroxy-benzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20 hours, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-10, wherein the yield is 67.4%, and the m.p.232-234 ℃.1H NMR(400MHz,CD3Cl)δ：1.65(3H,d,CH3) 3.07 to 3.83(8H, m, piperazine-H), 4.45 to 4.86(3H, m, O-CH)2CH-N), 7.63-8.86 (6H, m, Ph-H, 3 '-H and 2' -H), 8.97(1H, d, 5-H),9.13(1H, s,2-H), 10.65(1H, s, OH); MS (m/z): 450, calculate (C)25H24FN3O4)：449.49。
Example 11
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical formula:
namely, Ar in the formula I is 3-pyridyl.
The preparation method of the compound comprises the following steps: getS- (-) -1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V1.0 g (3.0mmol) was dissolved in 20mL of anhydrous ethanol, and 0.37g (3.6mmol) of 3-pyridylaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-11, wherein the yield is 78.6%, and the m.p.245-247 ℃.1H NMR(400MHz,CD3Cl)δ：1.70(3H,d,CH3) 3.32 to 3.87(8H, m, piperazine-H), 4.46 to 4.96(3H, m, O-CH)2CH-N), 7.68(1H, d, 2 '-H), 8.86-9.15 (6H, 5-H, 3' -H and pyridine-H), 9.21(1H, s, 2-H); MS (m/z): 435, calculating (C)24H23FN4O3)：434.47。
Example 12
S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical formula:
namely, Ar in the formula I is 2-furyl.
The preparation method of the compound comprises the following steps: the preparation method of the compound comprises the following steps: 1.0g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.38g (4.0mmol) of 2-furfural and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-12, wherein the yield is 73.6%, and the m.p.238-240 ℃.1H NMR(400MHz,CD3Cl)δ：1.67(3H,d,CH3) 3.16 to 3.85(8H, m, piperazine-H), 4.46 to 4.86(3H, m, O-CH)2CH-N), 7.35-8.20 (5H, m, 2 '-H, 3' -H and furan-H), 8.96(1H, d, 5-H),9.13(1H, s, 2-H); MS (m/z): 424[ M + H]+Calculating (C)23H22FN3O4S)：423.45。
Test examples
Examples 1-12 provide an in vitro assay for antitumor Activity of acrylketone derivatives without N-methyllevofloxacin
1. Test sample
15 of the propenone derivatives of de-N-methyllevofloxacin provided in examples 1-12, the classical antitumor TOPO inhibitor 10-Hydroxycamptothecin (HC), the chalcone tyrosinase inhibitor Sunitinib (SN), the broad spectrum anticancer drug Doxorubicin (DOX), and the parent compound levofloxacin (DMLOF) were used as test samples, wherein HC, SN, and DMLOF are used as control groups, and examples 1-12 are used as test groups;
thiazole blue (MTT), HC, SN and DMLOF are all products of Sigma company; the RPMI-1640 culture solution is a product of GIBCO company; other used reagents are all domestic analytical pure reagents.
The experimental cancer cell strains are respectively a human non-small cell lung cancer cell strain A549, a human kidney cancer cell strain 769-P, a human hepatoma cell strain Hep-3B, a human gastric cancer cell strain HGC27, a human pancreatic cancer cell strain Panc-1 and a human leukemia cell strain HL60, which are purchased from Shanghai cell banks of Chinese academy of sciences. The human renal clear cell carcinoma cell sunitinib-resistant strain 7SuR was purchased from shanghai zel biotechnology limited, and the normal cell was obtained from african green monkey kidney cell line VERO and purchased from shanghai tong biology limited.
2. Measurement method
The determination method comprises the following specific steps:
1) firstly, the 15 samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0X 10- 4mol·L-1Stock solution of concentration, then diluting the stock solution with 10% calf serum RPMI-1640 culture solution to have 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0 μmol. L)-1) The working fluid of (1);
2) taking non-small cell lung cancer cell strain A549, human kidney cancer cell strain 769-P, human liver cancer cell strain Hep-3B, human gastric cancer cell strain HGC27, human pancreatic cancer cell strain Panc-1, human leukemia cell strain HL60, human renal clear cell cancer cell sunitinib drug-resistant strain 7SuR and African green monkey kidney cell strain VERO in logarithmic growth phase, inoculating 6000 cells in each hole to 96-well plate, then adding the working solution with 5 concentration gradients of the above 15 samples, and after 48 hours, adding 5 g.L per well–1mu.L of MTT (thiazole blue) solution was added, and after further culturing for 4 hours, 100. mu.L of a 10% by mass Sodium Dodecyl Sulfate (SDS) solution was added. Culturing for 24 hours, and then measuring an absorbance (OD) value at a wavelength of 570nm by using a microplate reader;
3) the inhibition rate of the test samples with different concentrations on the cancer cells is calculated according to the following formula:
cancer cell inhibition rate ═ [ (1-experimental OD value)/control OD value ] × 100%;
then, performing linear regression on the cancer cell inhibition rate corresponding to each concentration by using the pair value of each concentration of the test sample to obtain a dose-effect equation, and calculating the half inhibition concentration (IC50) of the test sample to the experimental cancer cell from the obtained dose-effect equation; each data was measured in triplicate and averaged, the results are shown in Table 1.
TABLE 1 antitumor Activity (IC) of the test samples50)
As can be seen from Table 1, the inhibitory activity of the compounds provided in examples 1-12 on 7 cancer cells of experiment is significantly stronger than that of the parent compound des-N-methyllevofloxacin, especially the growth inhibitory activity of some compounds on human non-small cell lung cancer cell line A549 is stronger than that of the control Hydroxycamptothecin (HC), the tyrosine kinase inhibitors Sunitinib (SN) and adriamycin (DOX), and the IC of the compounds is IC50The value is reached or close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1 to 12 also show extremely strong sensitivity to sunitinib-resistant strain 7SuR, show strong drug-resistant activity, show low cytotoxicity to normal cells VERO, and have patent drugThe nature of sex. Therefore, according to the general approach of drug development, the conventional antitumor in vitro screening is carried out, and then the targeted research is carried out, so that the compound has strong antitumor activity, drug resistance activity and lower cytotoxicity, and can be used for preparing antitumor drugs by salifying with acid acceptable for human bodies or mixing with medicinal carriers.
Claims (5)
1. The propenone derivative for removing the N-methyllevofloxacin is specifically characterized by being a typical compound with the following structure:
2. the preparation method of the acrylketone derivative with the removal of N-methyllevofloxacin according to claim 1, which comprises the following steps:
1) taking de-N-methyllevofloxacin shown in a formula II as a raw material, reacting with Carbonyldiimidazole (CDI) to prepare a de-N-methyllevofloxacin imidazole amide compound shown in a formula III, and then carrying out condensation reaction with monoethyl malonate potassium salt to prepare a de-N-methyllevofloxacin C-3 formyl ethyl acetate compound shown in a formula IV; finally, the formula IV is subjected to hydrolysis decarboxylation reaction to obtain the de-N-methyl levofloxacin C-3 ethanone shown in the formula V:
2) the propenone derivative of N-methyllevofloxacin as shown in claim 1 can be prepared by carrying out Claisen-Schmidt condensation reaction on N-methyllevofloxacin-removed C-3 ethanone shown in a formula V and aromatic aldehyde under the catalysis of alkali to form an propenone structure and carrying out post-treatment.
3. The preparation method of the acrylketone derivative with the N-methyllevofloxacin removed as shown in the claim 2, is characterized in that the molar ratio of the N-methyllevofloxacin removed shown in the formula II to the CDI is 1: 1.0-2.0, the molar ratio of the N-methyllevofloxacin imidazole amide shown in the formula III to the monoethyl malonate potassium salt is 1: 1.0-1.5, and the molar ratio of the N-methyllevofloxacin removed-3 ethanone shown in the formula V to the aromatic aldehyde is 1: 1.0-2.0.
4. The use of the propenone derivative of des-N-methyllevofloxacin as claimed in claim 1 in the preparation of an anti-tumor medicament.
5. The use of the propenone derivative for removing N-methyllevofloxacin according to claim 4 in the preparation of an anti-tumor medicament, wherein the anti-tumor medicament is a medicament for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911139984.0A CN112824416A (en) | 2019-11-20 | 2019-11-20 | Propenone derivative for removing N-methyllevofloxacin, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911139984.0A CN112824416A (en) | 2019-11-20 | 2019-11-20 | Propenone derivative for removing N-methyllevofloxacin, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112824416A true CN112824416A (en) | 2021-05-21 |
Family
ID=75906806
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911139984.0A Pending CN112824416A (en) | 2019-11-20 | 2019-11-20 | Propenone derivative for removing N-methyllevofloxacin, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112824416A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113801140A (en) * | 2021-10-26 | 2021-12-17 | 黄河水利职业技术学院 | Isoleucinine analogs, and preparation method and application of isoleucinine analogs from levofloxacin to isoleucinine analogs |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045555A1 (en) * | 2001-07-19 | 2003-03-06 | Rivera Nelo R. | Process to chiral integrin antagonist beta-amino acid intermediate |
| CN106317074A (en) * | 2015-06-26 | 2017-01-11 | 河南大学 | Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof |
-
2019
- 2019-11-20 CN CN201911139984.0A patent/CN112824416A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045555A1 (en) * | 2001-07-19 | 2003-03-06 | Rivera Nelo R. | Process to chiral integrin antagonist beta-amino acid intermediate |
| CN106317074A (en) * | 2015-06-26 | 2017-01-11 | 河南大学 | Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113801140A (en) * | 2021-10-26 | 2021-12-17 | 黄河水利职业技术学院 | Isoleucinine analogs, and preparation method and application of isoleucinine analogs from levofloxacin to isoleucinine analogs |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106256823B (en) | A kind of α of gatifloxacin, alpha, beta-unsaturated ketone derivative and its preparation method and application | |
| CN111303026A (en) | Propenone derivative of enrofloxacin and preparation method and application thereof | |
| CN112824391B (en) | Gatifloxacin propenone derivative and preparation method and application thereof | |
| CN111303190A (en) | Propenone derivative for removing N-methylrufloxacin and preparation method and application thereof | |
| CN112824415A (en) | Ofloxacin acrylketone derivative and preparation method and application thereof | |
| CN111303189A (en) | Propenone derivative of rufloxacin, and preparation method and application thereof | |
| CN111303027A (en) | Fluroxacin acrylketone derivative and preparation method and application thereof | |
| CN106316946A (en) | Alpha, beta-unsaturated ketone derivative of ciprofloxacin, preparation method of derivative, and application of derivative | |
| CN111646974A (en) | N-methyl gatifloxacin propenone derivative and preparation method and application thereof | |
| CN106279019A (en) | A kind of α of enrofloxacin, alpha, beta-unsaturated ketone derivant and its preparation method and application | |
| CN111647004B (en) | Propenone derivative for removing N-methylofloxacin and preparation method and application thereof | |
| CN112824396B (en) | Acrylic ketone derivative of N-acetyl lomefloxacin and preparation method and application thereof | |
| CN112824397B (en) | Lomefloxacin propenone derivative and preparation method and application thereof | |
| CN111646975B (en) | N-methyl lomefloxacin allyl ketone derivative and preparation method and application thereof | |
| CN112824416A (en) | Propenone derivative for removing N-methyllevofloxacin, and preparation method and application thereof | |
| CN111646937B (en) | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof | |
| CN112824414A (en) | Propenone derivative of N-acetylofloxacin and preparation method and application thereof | |
| CN111320578A (en) | Propenone derivative for removing N-methylfleroxacin and preparation method and application thereof | |
| CN111393453A (en) | Acrylketone derivative of levofloxacin, and preparation method and application thereof | |
| CN112824401B (en) | Acrylic ketone derivative of N-acetyl gatifloxacin and preparation method and application thereof | |
| CN112824390B (en) | Acrylic ketone derivative of ciprofloxacin and preparation method and application thereof | |
| CN112824405B (en) | Acrylic ketone derivative of N-methyl enoxacin and preparation method and application thereof | |
| CN112824406B (en) | Enoxacin propenone derivative and preparation method and application thereof | |
| CN112830926B (en) | Acrylic ketone derivative of N-acetyl moxifloxacin and preparation method and application thereof | |
| CN112824388B (en) | Acrylic ketone derivative of norfloxacin and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210521 |
|
| WD01 | Invention patent application deemed withdrawn after publication |