CN106317074B - A kind of α of Ofloxacin, alpha, beta-unsaturated ketone derivative and its preparation method and application - Google Patents
A kind of α of Ofloxacin, alpha, beta-unsaturated ketone derivative and its preparation method and application Download PDFInfo
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- ofloxacin
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- unsaturated ketone
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- 229960001699 Ofloxacin Drugs 0.000 title claims abstract description 31
- 150000002576 ketones Chemical class 0.000 title claims abstract description 28
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N Levofloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 239000002585 base Substances 0.000 claims description 20
- FDPIMTJIUBPUKL-UHFFFAOYSA-N 3-Pentanone Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- -1 activated manganese dioxide Flucloxacillin aldehyde Chemical class 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- KWOLFJPFCHCOCG-UHFFFAOYSA-N methylphenylketone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 206010024324 Leukaemias Diseases 0.000 claims description 4
- 229940079593 drugs Drugs 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 3
- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical compound FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 210000000496 Pancreas Anatomy 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000000875 corresponding Effects 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 2
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 claims description 2
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 1-(4-methylphenyl)ethanone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 claims 1
- NTPLXRHDUXRPNE-UHFFFAOYSA-N Acetanisole Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 claims 1
- 229960004273 Floxacillin Drugs 0.000 claims 1
- TXFPEBPIARQUIG-UHFFFAOYSA-N Piceol Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 claims 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N benzohydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims 1
- 229960005394 flucloxacillin Drugs 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 claims 1
- 210000004027 cells Anatomy 0.000 abstract description 14
- 239000000126 substance Substances 0.000 abstract description 14
- 230000000259 anti-tumor Effects 0.000 abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 5
- 229930016212 chalcones Natural products 0.000 abstract description 3
- 235000005513 chalcones Nutrition 0.000 abstract description 3
- 150000002240 furans Chemical class 0.000 abstract description 3
- 210000002356 Skeleton Anatomy 0.000 abstract description 2
- DQFBYFPFKXHELB-UHFFFAOYSA-N 1,3-diphenylprop-2-en-1-one Chemical compound C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 abstract 1
- 231100000224 toxic side effect Toxicity 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000005977 Ethylene Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 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 4
- 230000000694 effects Effects 0.000 description 4
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 210000003501 Vero Cells Anatomy 0.000 description 2
- 230000000844 anti-bacterial Effects 0.000 description 2
- 230000000845 anti-microbial Effects 0.000 description 2
- 238000003556 assay method Methods 0.000 description 2
- 150000001555 benzenes Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001788 chalcone derivatives Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrugs Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- VWHKEYXRRNSJTN-UHFFFAOYSA-N 2-oxo-1H-quinoline-3-carbaldehyde Chemical class C1=CC=C2NC(=O)C(C=O)=CC2=C1 VWHKEYXRRNSJTN-UHFFFAOYSA-N 0.000 description 1
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-Hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 1
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 description 1
- RVMDVAAOUMDISP-VMPITWQZSA-N CC(COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3/C=C/C(c(cc4)ccc4F)=O)c1c2C3=O Chemical compound CC(COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3/C=C/C(c(cc4)ccc4F)=O)c1c2C3=O RVMDVAAOUMDISP-VMPITWQZSA-N 0.000 description 1
- XCBBZGJJTDGXTF-CMDGGOBGSA-N CC(COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3/C=C/C(c4ccc(C)cc4)=O)c1c2C3=O Chemical compound CC(COc1c(c(F)c2)N3CCN(C)CC3)N(C=C3/C=C/C(c4ccc(C)cc4)=O)c1c2C3=O XCBBZGJJTDGXTF-CMDGGOBGSA-N 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- TZJKHERXIDPDTK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C12.[F] Chemical compound N1=CC=CC2=CC=CC=C12.[F] TZJKHERXIDPDTK-UHFFFAOYSA-N 0.000 description 1
- 241000338310 Pseudofabraea citricarpa Species 0.000 description 1
- 239000007759 RPMI Media 1640 Substances 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001789 chalcones Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 125000006332 fluoro benzoyl group Chemical group 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-O hydron;2H-tetrazole Chemical compound C1=NN=[NH+]N1 KJUGUADJHNHALS-UHFFFAOYSA-O 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- VLCMRTMCMQJSKM-UHFFFAOYSA-N phenyl-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone Chemical class C=1C=CC=CC=1C(=O)C1=CN=C2C(C(F)(F)F)=CC=CC2=C1C1=CC=CC=C1 VLCMRTMCMQJSKM-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- PSBAZVJEUNOIDU-UHFFFAOYSA-L potassium;sodium;diacetate Chemical compound [Na+].[K+].CC([O-])=O.CC([O-])=O PSBAZVJEUNOIDU-UHFFFAOYSA-L 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2(1H)-one Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Abstract
The invention discloses a kind of α of Ofloxacin, beta unsaturated ketone derivatives and its preparation method and application, using such as I chemical structure of general formula of following formula：
Description
Technical field
The invention belongs to original new drug synthesis technical fields, and in particular to a kind of α of Ofloxacin, alpha, beta-unsaturated ketone derive
Object, also relates to a kind of α of Ofloxacin, the preparation method of alpha, beta-unsaturated ketone derivative and its in antitumor drug
Application.
Background technology
Discovery of the new drug innovation originating from primer, and structure-based rational drug MOLECULE DESIGN is to find primer
Effective ways.In the pharmacophore of various structures, there is α, the chalcone compounds of alpha, beta-unsaturated ketone structure feature are as weight
The natural constituent wanted is concerned due to a variety of pharmacological activity.However, natural chalcone compound is mostly polyhydroxy
The cyclosubstituted α of benzene, beta-unsaturated ketone compound, because its poor water solubility causes bioavilability relatively low, limitation is clinically
Application.In addition, in conjunction with antibacterial fluoroquinolone drug action target spot-topoisomerase be also antitumor drug important work
With target spot, its antibacterial activity can be converted to antitumor activity, and it is antitumor activity institute to find that fluoquinolone C-3 carboxyls are not
Required pharmacophore can be replaced with bioisostere to improve its antitumor activity.Based on this, to improve chalcones
Water solubility improves its bioavilability and activity, the advantage pharmacophore — oxazines of present invention flouroquinolone drugs Ofloxacin
And (1H) the -one skeleton of quinoline -4 is as α, the substituent group of alpha, beta-unsaturated ketone structure, and then devise new structural fluoquinolone
Class chalcone derivative.
For this purpose, the object of the present invention is to provide a kind of α of Ofloxacin, alpha, beta-unsaturated ketone derivative has antitumor
Effect and effect, while a kind of α of Ofloxacin, the preparation method of alpha, beta-unsaturated ketone derivative being provided.
In order to achieve the goal above, the technical solution adopted in the present invention is：A kind of α of Ofloxacin, alpha, beta-unsaturated ketone
Derivative, chemical structural formula is as shown in logical formula (I)：
Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring, such compound is the chemical combination of concrete structure below
Object：
A kind of α of Ofloxacin of the present invention, the preparation method of alpha, beta-unsaturated ketone derivative are husky with oxygen fluorine shown in formula II
Star is prepared as a raw material；
Specific preparation process is as follows：
1) base is reduced by sodium borohydride and then decarboxylated with Ofloxacin shown in formula II and reacts to obtain III compound represented of formula, then
IV compound represented of formula is made with Ethyl formate condensation reaction, last formula IV aoxidizes to obtain V oxygen fluorine sand of formula with activated manganese dioxide
Star aldehyde；
The Detailed operating procedures of step 1) are referred to document (Kondo H, Sakamoto F, et al.Studies on
prodrugs.7.Synthesis and antimicrobial activity of 3-formylquinolone
Derivatives, J.Med.Chem.1988,31,221~225.) prodrug research .7.3- formoxyl Carbostyril derivatives conjunction
At and antimicrobial acivity) method prepare, detailed process is as follows：
2) Ofloxacin aldehyde shown in formula V and aromatic radical ethyl ketone VI are subjected to aldol under the catalysis of alkali in absolute ethyl alcohol
Condensation reaction, after complete reaction, through handle target compound as shown in formula I, detailed process is as follows：
Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring in formula I.
The general operating procedure that is synthetically prepared of target compounds of formula I is：Take 1,8- (3,1- oxygen propyl group) -6- fluoro- 7- (4- first
Base-piperazine -1- bases)-quinoline -4 (1H) -one -3- formaldehyde formula V 1.1g (3.2mmol) be dissolved in 20mL absolute ethyl alcohols, be added
Aromatic radical ethyl ketone VI (3.2mmol) and base catalyst piperidines (0.1mL).Mixed reactant back flow reaction for 24 hours, places room temperature, filter
Collect the solid generated, absolute ethyl alcohol recrystallization obtains pale yellow crystals object formula I.
As a further improvement, the molar ratio of Ofloxacin aldehyde shown in formula V and aromatic radical ethyl ketone is 1:1.0~
1.2。
The basic catalyst is at least one of piperidines, pyridine, triethylamine, morpholine, potassium acetate and sodium acetate.
A kind of α of Ofloxacin, alpha, beta-unsaturated ketone derivative application in preparation of anti-tumor drugs.
The antitumor drug is treatment liver cancer, cancer of pancreas or leukemia medicament.
A kind of α of Ofloxacin of the present invention, principle of hybridization of the alpha, beta-unsaturated ketone derivative based on pharmacophore, by fluorine quinoline promise
Ketone skeleton and α, alpha, beta-unsaturated ketone pharmacophore are effectively combined, and design has synthesized the α of Ofloxacin, alpha, beta-unsaturated ketone derivative,
The complementation and active superposition for realizing different structure pharmacophore can be used as completely new knot to achieve synergistic and detoxifying effects
The antitumor drug of structure is developed.
Specific implementation mode
Embodiment 1
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- (2- benzoyls-ethylene -1- bases)-quinoline
Quinoline -4 (1H) -one (I-1), chemical structural formula are：
Ar i.e. in formula I is phenyl.
The preparation method of the compound is：Aromatic radical ethyl ketone VI is substituted with acetophenone (0.45g, 3.8mmol), according to above-mentioned
Object formula I general preparative methods, obtain pale yellow crystals object (I-1), yield 67.4%, m.p.135~137 DEG C.1H NMR(400MHz,CD3Cl)δ：1.44 (3H, d, CH3), 2.28 (3H, s, N-CH3), 3.15~3.46 (8H, m, piperazine-H),
4.57~4.68 (OCH2CHN), 7.53~8.05 (6H, m, Ph-H and 5-H), 8.23~8.76 (3H, m, 2-H, 1 '-H and 2 '-
H)；MS(m/z)：448[M+H]+；Calculate (C26H26FN3O3)：447.51.
Embodiment 2
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (4- methoxybenzoyls)-second
Alkene -1- bases]-quinoline -4 (1H) -one (I-2), chemical structural formula is：
Ar i.e. in formula I is p-methoxyphenyl.
The preparation method of the compound is：Aromatic radical ethyl ketone is substituted with 4- methoxy-acetophenones (0.48g, 3.2mmol)
VI obtains pale yellow crystals object (I-2) according to the general preparative methods of above-mentioned object formula I, yield 75.6%,
M.p.138~140 DEG C.1H NMR(400MHz,CD3Cl)δ：1.46 (3H, d, CH3), 2.31 (3H, s, N-CH3), 3.17~
3.48 (8H, m, piperazine-H), 3.88 (3H, s, OCH3), 4.57~4.72 (OCH2CHN), 7.56~7.83 (5H, m, Ph-H and 5-
H), 8.25~8.82 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：478[M+H]+；Calculate (C27H28FN3O4)：477.54.
Embodiment 3
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (3,4- dioxymethylenes-benzene first
Acyl)-ethylene -1- bases]-quinoline -4 (1H) -one (I-3), chemical structural formula is：
Ar i.e. in formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound is：Aryl second is substituted with 3,4- dioxymethylenes-acetophenone (0.52g, 3.2mmol)
Ketone VI obtains pale yellow crystals object object (I-3) according to the general preparative methods of above-mentioned object formula I, yield 78.5%,
M.p.167~169 DEG C.1H NMR(400MHz,CD3Cl)δ：1.48 (3H, d, CH3), 2.33 (3H, s, N-CH3), 3.18~
3.52 (8H, m, piperazine-H), 4.61~4.74 (OCH2CHN), 6.26 (3H, s, OCH2), 7.68~7.88 O (4H, m, Ph-H and
5-H), 8.26~8.85 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：491[M+H]+；Calculate (C27H26FN3O5)：
491.52。
Embodiment 4
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (3,4,5- trimethoxy methyl-benzene
Formyl)-ethylene -1- bases]-quinoline -4 (1H) -one (I-4), chemical structural formula is：
Ar i.e. in formula I is 3,4,5- 2,4,5-trimethoxyphenyls.
The preparation method of the compound is：With 3,4,5- trimethoxies-acetophenone (0.67g, 3.2mmol) substitutes aromatic radical
Ethyl ketone VI obtains pale yellow crystals object object (I-4), yield according to the general preparative methods of above-mentioned object formula I
70.5%, m.p.145~147 DEG C.1H NMR(400MHz,CD3Cl)δ：1.52 (3H, d, CH3), 2.35 (3H, s, N-CH3),
3.24~3.55 (8H, m, piperazine-H), 4.61~4.74 (OCH2CHN), 3.86,3.88 (9H, 2s, 3 × OCH3), 7.74~
8.13 (3H, m, Ph-H and 5-H), 8.31~8.87 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：538[M+H]+；It calculates
(C29H32FN3O6)：537.59.
Embodiment 5
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (4- methyl-benzoyls)-ethylene -
1- yls]-quinoline -4 (1H) -one (I-5), chemical structural formula is：
Ar i.e. in formula I is to methylphenyl.
The preparation method of the compound is：Aromatic radical ethyl ketone VI is substituted with 4- methyl-acetophenones (0.51g, 3.8mmol),
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-5) is obtained, yield 57.4%,
M.p.130~132 DEG C.1H NMR(400MHz,CD3Cl)δ：1.46 (3H, d, CH3), 2.25,2.32 (6H, 2s, Ph-CH3And N-
CH3), 2.63~3.43 (8H, m, piperazine-H), 4.54~4.64 (OCH2CHN), 7.53~7.75 (5H, m, Ph-H and 5-H),
8.18~8.85 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：462[M+H]+；Calculate (C27H28FN3O3)：461.54.
Embodiment 6
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (the fluoro- benzoyls of 4-)-ethylene -1-
Base]-quinoline -4 (1H) -one (I-6), chemical structural formula is：
Ar i.e. in formula I is to fluoro-phenyl.
The preparation method of the compound is：Aromatic radical ethyl ketone VI is substituted with the fluoro- acetophenones of 4- (0.44g, 3.2mmol), according to
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-6), yield 75.8%, m.p.156 are obtained
~158 DEG C.1H NMR(400MHz,CD3Cl)δ：1.54 (3H, d, CH3), 2.35 (3H, s, N-CH3), 3.23~3.57 (8H, m,
Piperazine-H), 4.63~4.75 (OCH2CHN), 7.72~7.92 (5H, m, Ph-H and 5-H), 8.16~8.87 (3H, m, 2-H,
1 '-H and 2 '-H)；MS(m/z)：466[M+H]+, calculate (C26H25F2N3O3)：465.50.
Embodiment 7
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (4- nitro-benzoyls)-ethylene -
1- yls]-quinoline -4 (1H) -one (I-7), chemical structural formula is：
Ar i.e. in formula I is p-nitrophenyl.
The preparation method of the compound is：Aromatic radical ethyl ketone VI is substituted with 4- nitro-acetophenones (0.53g, 3.2mmol),
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-7) is obtained, yield 74.5%,
M.p.168~170 DEG C.1H NMR(400MHz,CD3Cl)δ：1.56 (3H, d, CH3), 2.37 (3H, s, N-CH3), 3.25~
3.64 (8H, m, piperazine-H), 4.66~4.78 (OCH2CHN), 7.86~8.13 (5H, m, Ph-H and 5-H), 8.22~8.93
(3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：493[M+H]+, calculate (C26H25FN4O5)：492.51.
Embodiment 8
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (4- Hydroxy-benzoyIcarbamos)-ethylene -
1- yls]-quinoline -4 (1H) -one (I-8), chemical structural formula is：
Ar i.e. in formula I is 4- hydroxy-phenies.
The preparation method of the compound is：Aromatic radical ethyl ketone VI is substituted with 4- hydroxy-acetophenones (0.45g, 3.3mmol),
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-8) is obtained, yield 55.6%,
M.p.151~153 DEG C.1H NMR(400MHz,CD3Cl)δ：1.47 (3H, d, CH3), 2.33 (3H, s, N-CH3), 3.16~
3.52 (8H, m, piperazine-H), 4.58~4.71 (OCH2CHN), 7.66~8.06 (5H, m, Ph-H and 5-H), 8.23~8.85
(3H, m, 2-H, 1 '-H and 2 '-H), 10.56 (1H, brs, OH)；MS(m/z)：464[M+H]+, calculate (C26H26FN3O4)：
463.51。
Embodiment 9
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (4- pyridines-formoxyl)-ethylene -
1- yls]-quinoline -4 (1H) -one (I-9), chemical structural formula is：
Ar i.e. in formula I is 4- pyridyl groups.
The preparation method of the compound is：Aromatic radical ethyl ketone VI is substituted with 4- pyridines-ethyl ketone (0.39g, 3.2mmol), according to
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-9), yield 63.8%, m.p.177 are obtained
~179 DEG C.1H NMR(400MHz,CD3Cl)δ：1.54 (3H, d, CH3), 2.36 (3H, s, N-CH3), 3.27~3.58 (8H, m,
Piperazine-H), 4.62~4.74 (OCH2CHN), 7.83 (1H, d, 5-H), 8.27~8.87 (7H, m, 2-H, 1 '-H, 2 '-H and Py-
H)；MS(m/z)：449[M+H]+, calculate (C25H25FN4O3)：448.50.
Embodiment 10
1, the 8- fluoro- 7- of (3,1- oxygen propyl group) -6- (4- thyl-piperazin -1- bases) -3- [2- (4- furans-formyl)-ethylene -1-
Base]-quinoline -4 (1H) -one (I-10), chemical structural formula is：
Ar i.e. in formula I is 2- furyls.
The preparation method of the compound is：Aromatic radical ethyl ketone VI is substituted with 2- furans-ethyl ketone (0.42g, 3.8mmol), according to
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-10), yield 68.3%, m.p.162 are obtained
~164 DEG C.1H NMR(400MHz,CD3Cl)δ：1.51 (3H, d, CH3), 2.34 (3H, s, N-CH3), 3.22~3.58 (8H, m,
Piperazine-H), 4.60~4.73 (OCH2CHN), 6.83~7.86 (4H, m, 5-H and furans-H), 8.16~8.83 (3H, m, 2-H,
1 '-H and 2 '-H)；MS(m/z)：438[M+H]+, calculate (C24H24FN3O4)：437.47.
Test example
One, the anti tumor activity in vitro of the α for a kind of Ofloxacin that embodiment 1-10 is provided, alpha, beta-unsaturated ketone derivative are surveyed
It is fixed
1, test sample
With a kind of α of the embodiment 1-10 Ofloxacins provided, alpha, beta-unsaturated ketone derivative and classical antitumor TOPO suppressions
Preparation 10-hydroxycamptothecine (HC) and parent compound Ofloxacin (OF) are test sample, and totally 12 kinds, wherein HC and OF are pair
According to group, embodiment 1-10 samples are experimental group；
Experimental cancer cell line is respectively human liver cancer Hep-3B cells, human pancreas cancer Panc-1 cells and human leukemia HL60 thin
Born of the same parents' strain is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences.Normal cell uses VERO African green monkey kidney cells, purchase logical in Shanghai
Growth Science and Technology Ltd..
2, assay method
Assay method the specific steps are：
1) it uses dimethyl sulfoxide (DMSO) (DMSO) to dissolve respectively above-mentioned 12 kinds of test samples first, is configured to 1.0 × 10- 2mol·L-1The storing solution of concentration uses the RPMI-1640 culture solutions that mass percent concentration is 10% calf serum will later
Storing solution is diluted to 5 concentration gradients (0.1,1.0,5.0,10.0,50.0 μm of olL-1) working solution；
2) the human liver cancer Hep-3B cells, human pancreas cancer Panc-1 cells and human leukemia HL60 cells of logarithmic growth phase
And VERO cell strains are then separately added into the dense with 5 of above-mentioned 12 kinds of samples with 6000, every hole cell inoculation in 96 orifice plates
5gL is added in the working solution for spending gradient per hole after 48 hours–110 μ L of MTT (tetrazolium bromide) solution, continue to be further cultured for after 4 hours
Lauryl sodium sulfate (SDS) solution that 100 μ L mass percent concentrations are 10% is added.Culture 24 hours, then with enzyme mark
Instrument measures absorbance (OD) value at 570nm wavelength；
3) inhibiting rate of the test sample to cancer cell of various concentration is calculated by using the formula shown below,
Cancer inhibition rate=[(1- experimental group OD values)/control group OD values] × 100%；
Then linear regression is made to the corresponding cancer inhibition rate of each concentration with the logarithm of each concentration of test sample, obtained
To dose-effect equation, half-inhibition concentration of the test sample to experiment cancer cell is calculated from gained dose-effect equation
(IC50)；Each data parallel determination three times, is averaged, the results are shown in Table 1.
Antitumor activity (the IC of 1 each test sample of table50)
As it can be seen from table 1 the compound that embodiment 1-10 is provided is significantly stronger than the inhibitory activity for testing 3 kinds of cancer cells
The growth inhibitory activity of the activity of parent compound Ofloxacin, especially majority of compounds to human pancreas cancer Panc-1 cells
It is better than the activity of control hydroxycamptothecin, IC50Value has reached or is less than micro-molar concentration.What makes more sense is that embodiment 1-10
The compound of offer shows low toxicity VERO cells, the potentiality with druggability.Therefore, according to the one of drug development
As approach be first to carry out conventional antitumor in-vitro screening, then targetedly studied, thus the compound of the present invention have
There are strong antitumor activity and lower toxicity, it can be anti-by being mixed with acid human-acceptable at salt or with pharmaceutical carrier
Tumour medicine.
Claims (5)
1. a kind of α of Ofloxacin, the typical compound of alpha, beta-unsaturated ketone derivative, specific features structure are：
2. a kind of α of Ofloxacin according to claim 1, the preparation method of alpha, beta-unsaturated ketone derivative, feature exist
In specific preparation process includes：
1) it using Ofloxacin shown in formula II as raw material, is reduced by sodium borohydride and then decarboxylated base and reacts to obtain III compound represented of formula,
Then formula IV compound represented is made with Ethyl formate condensation reaction；Last formula IV aoxidizes to obtain V oxygen of formula with activated manganese dioxide
Flucloxacillin aldehyde：
2) Ofloxacin aldehyde shown in formula V and aromatic radical ethyl ketone are formed into α, alpha, beta-unsaturated ketone structure, after under the catalysis of alkali
A kind of α of Ofloxacin, alpha, beta-unsaturated ketone derivative shown in Li Ke get Shi I：
Wherein, aromatic radical ethyl ketone selects acetophenone corresponding with embodiment, acetanisole, 3,4- dioxymethylene benzene
Ethyl ketone, 3,4,5- trimethoxies acetophenone, melilotal, to fluoro acetophenone, parahydroxyacet-ophenone, p-nitroacetophenone,
4- pyridines ethyl ketone and 2- furans ethyl ketones, Ar is phenyl, p-methoxyphenyl, 3,4- (dioxymethylene) phenyl, 3,4,5- in formula I
Trimethoxyphenyl, p-methylphenyl, p-fluorophenyl, p-hydroxybenzene, p-nitrophenyl, 4- pyridyl groups or 2- furyls.
3. a kind of α of Ofloxacin according to claim 2, the preparation method of alpha, beta-unsaturated ketone derivative, feature exist
In the molar ratio of Ofloxacin aldehyde shown in the formula V and aromatic radical ethyl ketone is 1:1.0~1.2.
4. such as a kind of right such as α of Ofloxacin as described in requiring 1, alpha, beta-unsaturated ketone derivative is in the preparation of antitumor drugs
Using.
5. a kind of α of Ofloxacin according to claim 4, alpha, beta-unsaturated ketone derivative is in the preparation of antitumor drugs
Using, which is characterized in that the antitumor drug is the drug for treating liver cancer, cancer of pancreas or leukaemia.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510369204.7A CN106317074B (en) | 2015-06-26 | A kind of α of Ofloxacin, alpha, beta-unsaturated ketone derivative and its preparation method and application |
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| CN201510369204.7A CN106317074B (en) | 2015-06-26 | A kind of α of Ofloxacin, alpha, beta-unsaturated ketone derivative and its preparation method and application |
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