CN106317046B - A kind of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application - Google Patents

A kind of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application Download PDF

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CN106317046B
CN106317046B CN201510332217.7A CN201510332217A CN106317046B CN 106317046 B CN106317046 B CN 106317046B CN 201510332217 A CN201510332217 A CN 201510332217A CN 106317046 B CN106317046 B CN 106317046B
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pefloxacin
rhodanine
unsaturated ketone
amide derivatives
beta
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CN106317046A (en
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张春丽
胡国强
王蕊
闫强
吴书敏
倪礼礼
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Henan University
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The invention discloses a kind of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application, using such as following formula I general formula of the chemical structure:

Description

A kind of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives and preparation method thereof And application
Technical field
The invention belongs to original new drug synthesis technical fields, and in particular to a kind of pefloxacin (rhodanine beta-unsaturated ketone) acyl Amine derivant also relates to a kind of preparation method of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives, and Its application in anti-tumor drug.
Background technique
New drug innovation originates from the discovery of primer, and the split based on effective pharmacophore and dominance structure skeleton move more Rational drug design be construct primer molecule available strategy.In the pharmacophore of various structures, have extensive pharmacology living Five yuan of azoles heterocyclic ketones of property, have become pharmaceutical chemical advantage skeleton in particular about tannin ring and are widely used in new drug molecularization Learn the building of skeleton.It mainly includes that the condensation reaction of 5- active methylene groups and aldehyde forms C=C key and the α, β-insatiable hunger that construct And ketone derivatives, 3- bit amino and carboxylic acids split form the derivatives such as aminocarboxylic acids or amides at the same time.In addition, being The water solubility for improving Rhodanine derivant, is re-introduced into the modification side chain of multiamide base peptides on rhodanine skeleton substituent group, with It improves its bioavilability, promote it to patent medicine sexual development.In the recent period, effect target-topoisomerase based on antibacterial fluoroquinolone It is also therefore the main function target of anti-tumor drug can convert anti-tumor activity for its antibacterial activity.At the same time, with Fluoro- quinoline -4- the ketone of 6- is advantage skeleton, C-3 acylamino- is that connection chain carries the pharmacophore of another anti-tumor activity, it can be achieved that not With the activity superposition between pharmacophore, it is therefrom found to have the fluoquinolone candidate compound of anti-tumor activity.However, fluoquinolone The compound for the beta-unsaturated ketone amides that skeleton is constructed with rhodanine skeleton phase split has not been reported yet.
For this purpose, having the object of the present invention is to provide a kind of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives Antineoplastic action and effect, while a kind of preparation side of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives being provided Method.
In order to achieve the goal above, the technical scheme adopted by the invention is that: a kind of pefloxacin (rhodanine unsaturation Ketone) amide derivatives, 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 specific structure below Object:
The preparation method of a kind of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives of the invention, with formula (II) institute The pefloxacin shown is prepared as a raw material,
Specific preparation process is as follows:
1) with hydrazine hydrate hydrazinolysis is occurred into for pefloxacin shown in formula (II) and reacts pefloxacin acyl shown in obtained formula (III) Hydrazine；
Concrete operation step can refer to document, and (it is graceful that Chen Yinsheng etc., antitumor fluoquinolone C3 etc. arrange derivative-oxadiazoles Buddhist nun wish alkali derivant synthesis and anti-tumor activity, applied chemistry, 2012,29 (11): 1246-150.) method.
2) by C-3 hydrazide compound shown in formula (III) and double-(carboxymethyl) trithiocarbonate Yu Shuizhong back flow reaction 12 Hour, room temperature, ammonium hydroxide alkalization are placed, filtering is collected the solid of generation, recrystallized with DMF solvent, is made shown in formula (IV) and trains Flucloxacillin (rhodanine) amide intermediate.
Concrete operation step are as follows: pefloxacin hydrazides (10.0g, 29.0mmol) and double-(carboxymethyl) trithiocarbonate (7.5g, 35.0mmol) disappears in water (300mL) back flow reaction to raw material, and (TLC is detected, VChloroform: VMethanol=5:1).Cooling room temperature, It is alkalized with concentrated ammonia liquor to pH 8.0~9.0, placement is cooled to room temperature.The solid that filter collection generates, it is dry.Crude product dehydrated alcohol weight Crystallization, obtains yellow crystal formula (IV), yield 74.2%, 223~225 DEG C of mp.1H NMR (400MHz, CDCl3): 11.32 (1H, S, CONH), 8.76 (1H, s, 2-H), 7.86 (1H, d, 5-H), 7.26 (1H, d, 8-H), 4.68 (2H, s, SCH2), 4.47 (2H, Q, 1-NCH2), 3.36 (4H, t, piperazine-H), 2.63 (4H, t, piperazine-H), 2.32 (3H, s, N-CH3), 1.43 (3H, t, CH3)；MS (m/z): Calcd.for C20H22FN5O3S2: 463.56 [M]+；Found:464 [M+H]+。
4) by pefloxacin (rhodanine) amide compound shown in formula (IV) and aromatic aldehyde under the catalysis of alkali in glacial acetic acid Middle carry out condensation reaction, handled after complete reaction shown in target compound such as formula (I).
Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
General is synthetically prepared operating procedure are as follows: takes the fluoro- 7- of 1- ethyl -6- (4- thyl-piperazin -1- base)-quinoline -4 (1H) -one -3- (2- thioxo-thiazolidin -4- ketone -3- base]-amide (IV) 1.0g (2.0mmol) and anhydrous sodium acetate 0.20g (2.4mmol) is dissolved in 15mL glacial acetic acid, is added aromatic aldehyde (2.0mmol), mixed reactant back flow reaction 12h.Decompression is steamed Except solvent, residue is dissolved with water (20mL), and suitable active carbon is added in 60 DEG C of decoloration 0.5h, filtering.Filtrate concentrated ammonia liquor Alkalization merges organic phase with chloroform recovery (3 × 15mL) to pH 9.0, and anhydrous sodium sulfate is dry.Solvent is recovered under reduced pressure to dry, It is recrystallized with ethyl alcohol-DMF (V:V=5:1), obtains pale yellow crystals object (I).
As a further improvement, (rhodanine) amide of pefloxacin shown in formula IV and aromatic aldehyde mole is 1:1.0 ~1.2.
The alkali is at least one of pyridine, triethylamine, piperidines, morpholine, potassium acetate and sodium acetate.
A kind of described pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives answering in the preparation of antitumor drugs With.
The anti-tumor drug is treatment liver cancer, cancer of pancreas or leukemia medicament.
Split rationality of a kind of pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives based on pharmacophore of the invention Drug molecule design principle is effective between three kinds of alpha, beta-unsaturated ketone etc. different pharmacophores by fluoquinolone, amide and rhodanine α Combination, and then pefloxacin (rhodanine beta-unsaturated ketone) amide derivatives are devised, realize the mutual of different structure pharmacophore It mends and can be used as the anti-tumor drug exploitation of brand new to achieve synergistic and detoxifying effects with active superposition.
Specific embodiment
The technical scheme of the invention is described in detail through specific implementation examples.
Embodiment 1
The fluoro- 7- of 1- ethyl -6- (4- thyl-piperazin -1- base)-quinoline -4 (1H) -one -3- (thio -5- benzene methene base-of 2- Thiazolidin-4-one -3- base]-amide (I-1), chemical structural formula are as follows:
Ar i.e. in Formulas I is phenyl.
The compound the preparation method comprises the following steps: with benzaldehyde (0.25g, 2.4mmol) substitute aromatic aldehyde, according to above-mentioned target The general preparative methods of object (I) obtain target pale yellow crystals object (I-1), yield 73.2%, m.p.216~218 DEG C.1H NMR (400MHz,CDCl3) δ: 11.36 (1H, s, CONH), 8.78 (1H, s, 2-H), 8.13 (1H, s, Ph-CH=), 7.82 (1H, d, 5-H), 7.74~6.68 (5H, m, Ph-H), 4.46 (2H, t, 1-NCH2), 3.36 (4H, t, piperazine-H), 2.73 (4H, T, piperazine-H), 2.33 (3H, s, N-CH3), 1.45 (3H, t, CH3)；MS(m/z):Calcd.for C27H26FN5O3S2: 551.67[M]+；Found:552 [M+H]+。
Embodiment 2
(thio -5- of 2- is to methoxyl group by-quinoline -4 (1H) -one -3- by the fluoro- 7- of 1- ethyl -6- two (4- thyl-piperazin -1- base) Benzene methene base-thiazolidin-4-one -3- base]-amide (I-2), chemical structural formula are as follows:
Ar i.e. in Formulas I is p-methoxyphenyl.
The compound the preparation method comprises the following steps: with P-methoxybenzal-dehyde (0.28g, 2.2mmol) substitute aromatic aldehyde, according to upper The general preparative methods for the object (I) stated obtain target pale yellow crystals object (I-2), yield 75.6%, m.p.223~225 ℃。1H NMR(400MHz,CDCl3) δ: 11.38 (1H, s, CONH), 8.82 (1H, s, 2-H), 8.16 (1H, s, Ph-CH=), 7.85 (1H, d, 5-H), 7.75 (2H, d, Ph-H), 7.54 (2H, d, 2H, Ph-H), 7.36 (1H, d, 8-H), 4.47 (2H, t, 1- NCH2), 3.87 (3H, s, OCH3), 3.38 (4H, t, piperazine-H), 2.85 (4H, t, piperazine-H), 2.35 (3H, S, N-CH3), 1.45 (3H, t, CH3)；MS (m/z): Calcd.for C28H28FN5O4S2: 581.69 [M]+；Found:582 [M+ H]+。
Embodiment 3
The fluoro- 7- of 1- ethyl -6- (4- thyl-piperazin -1- base)-quinoline -4 (1H) -one -3- [2- thio -5- (3,4- dioxy Methylene) benzene methene base-thiazolidin-4-one -3- base]-amide (I-3), chemical structural formula are as follows:
Ar i.e. in Formulas I is 3,4- (dioxymethylene) base phenyl.
The compound the preparation method comprises the following steps: with 3,4-methylenedioxy benzaldehyde (0.3g, 2.0mmol) substitute aromatic aldehyde, According to the general preparative methods of above-mentioned object (I), target pale yellow crystals object (I-3), yield 82.0%, m.p.236 are obtained ~238 DEG C.
1H NMR(400MHz,CDCl3) δ: 11.36 (1H, s, CONH), 8.85 (1H, s, 2-H), 8.23 (1H, s, Ph-CH =), 7.88 (1H, d, 5-H), 7.77 (1H, s, Ph-H), 7.68~7.52 (3H, m, Ph-H and 8-H), 6.26 (s, 2H, OCH2O), 4.48 (2H, t, 1-NCH2), 3.41 (4H, t, piperazine-H), 3.05 (4H, t, piperazine-H), 2.33 (3H, s, N-CH3), 1.47 (3H, t, CH3)；MS (m/z): Calcd.for C28H26FN5O5S2: 595.68 [M]+；Found:596 [M+H]+。
Embodiment 4
The fluoro- 7- of 1- ethyl -6- (4- thyl-piperazin -1- base)-quinoline -4 (1H) -one -3- [thio -5- of 2- (3,4,5- tri- Methoxyl methyl) benzene methene base-thiazolidin-4-one -3- base]-amide (I-4), chemical structural formula are as follows:
Ar i.e. in Formulas I is 3,4,5- trimethoxy methylene phenyl.
The compound the preparation method comprises the following steps: with 3,4,5-Trimethoxybenzaldehyde (0.43g, 2.2mmol) substitute aromatic aldehyde, According to the general preparative methods of above-mentioned object (I), pale yellow crystals object (I-4), yield 71.6%, m.p.235 are obtained ~237 DEG C.1H NMR (400MHz, CDCl3) δ: 11.38 (1H, s, CONH), 8.86 (1H, s, 2-H), 8.25 (1H, s, Ph-CH =), 7.86 (1H, d, 5-H), 7.80 (2H, s, Ph-H), 7.56 (1H, d, 8-H), 4.47 (2H, t, 1-NCH2), 3.86,3.88 (9H, 2s, 3 × OCH3), 3.45 (4H, t, piperazine-H), 3.07 (4H, t, piperazine-H), 2.35 (3H, s, N- CH3), 1.48 (3H, t, CH3)；MS (m/z): Calcd.for C30H32FN5O6S2: 641.75 [M]+；Found:642 [M+H]+。
Embodiment 5
(thio -5- of 2- is to fluorobenzene methene by-quinoline -4 (1H) -one -3- by the fluoro- 7- of 1- ethyl -6- (4- thyl-piperazin -1- base) Base-thiazolidin-4-one -3- base)-amide (I-5), chemical structural formula are as follows:
Ar i.e. in Formulas I is p-fluorophenyl.
The compound the preparation method comprises the following steps: with 4-Fluorobenzaldehyde (0.30g, 2.4mmol) substitute aromatic aldehyde, according to above-mentioned The general preparative methods of object (I) obtain pale yellow crystals object (I-5), yield 81.3%, m.p.224~226 DEG C.1H NMR(400MHz,CDCl3) δ: 11.44 (1H, s, CONH), 8.92 (1H, s, 2-H), 8.18 (1H, s, Ph-CH=), 8.06 (2H, d, Ph-H), 7.88 (1H, d, 5-H), 7.66 (2H, d, Ph-H), 7.57 (1H, d, 8-H), 4.48 (2H, t, 1-NCH2), 3.46 (4H, t, piperazine-H), 3.13 (4H, t, piperazine-H), 2.37 (3H, s, N-CH3), 1.48 (3H, t, CH3)；MS (m/z): Calcd.for C27H25F2N5O3S2: 569.66 [M]+；Found:570 [M+H]+。
Embodiment 6
The fluoro- 7- of 1- ethyl -6- two (4- thyl-piperazin -1- base)-quinoline -4 (1H) -one -3- (thio -5- p-nitrophenyl of 2- Methene base-thiazolidin-4-one -3- base)-amide (I-6), chemical structural formula are as follows:
Ar i.e. in Formulas I is p-nitrophenyl.
The compound the preparation method comprises the following steps: with paranitrobenzaldehyde (0.30g, 2.0mmol) substitute aromatic aldehyde, according to above-mentioned Object (I) general preparative methods, obtain pale yellow crystals object (I-6), yield 67.5%, m.p.241~243 DEG C.
1H NMR(400MHz,CDCl3) δ: 11.47 (1H, s, CONH), 9.05 (1H, s, 2-H), 8.24 (1H, s, Ph-CH =), 8.14 (2H, d, Ph-H), 8.05 (1H, d, 5-H), 7.76 (2H, d, Ph-H), 7.68 (1H, d, 8-H), 4.51 (2H, t, 1-NCH2), 3.47 (4H, t, piperazine-H), 3.15 (4H, t, piperazine-H), 2.38 (3H, s, N-CH3), 1.51 (3H, t, CH3)；MS (m/z): Calcd.for C27H25FN6O5S2: 596.66 [M]+；Found:597 [M+H]+。
Embodiment 7
The fluoro- 7- of 1- ethyl -6- (4- thyl-piperazin -1- base)-quinoline -4 (1H) -one -3- (thio -5- pyridine -4- first of 2- Pitch base-thiazolidin-4-one -3- base)-amide (I-7), chemical structural formula are as follows:
Ar i.e. in Formulas I is 4- pyridyl group.
The compound the preparation method comprises the following steps: with Pyridine-4-Carboxaldehyde (0.24g, 2.2mmol) substitute aromatic aldehyde, according to above-mentioned Object (I) general preparative methods, obtain pale yellow crystals object (I-7), yield 76.3%, m.p.231~233 DEG C.1H NMR(400MHz,CDCl3) δ: 11.51 (1H, s, CONH), 9.12 (1H, s, 2-H), 8.87 (2H, d, Py-H), 8.74 (2H, D, Py-H), 8.26 (1H, s, Ph-CH=), 8.07 (1H, d, 5-H), 7.73 (1H, d, 8-H), 4.55 (2H, t, 1-NCH2), 3.51 (4H, t, piperazine-H), 3.17 (4H, t, piperazine-H), 2.42 (3H, s, N-CH3), 1.53 (3H, t, CH3)；MS (m/z): Calcd.for C26H25FN6O3S2: 552.65 [M]+；Found:553 [M+H]+。
Embodiment 8
1- ethyl-fluoro- 7- (4- thyl-piperazin -1- base)-quinoline -4 (1H) -one -3- (thio -5- furans -2- methene of 2- Base-thiazolidin-4-one -3- base)-amide (I-8), chemical structural formula are as follows:
Ar i.e. in Formulas I is 2- furyl.
The compound the preparation method comprises the following steps: with furans -2- formaldehyde (0.21g, 2.2mmol) substitute aromatic aldehyde, according to above-mentioned Object (I) general preparative methods, obtain pale yellow crystals object (I-8), yield 66.3%, m.p.225~227 DEG C.1H NMR(400MHz,CDCl3) δ:1H NMR (400MHz, CDCl3) δ: 11.48 (1H, s, CONH), 9.07 (1H, s, 2-H), 8.24 (1H, s, Ph-CH=), 8.02 (1H, d, 5-H), 7.76~6.87 (4H, m, 8-H and furan-H), 4.51 (2H, t, 1-NCH2), 3.47 (4H, t, piperazine-H), 3.06 (4H, t, piperazine-H), 2.38 (3H, s, N-CH3), 1.51 (3H, t, CH3)；MS (m/z): Calcd.for C25H24FN6O4S2: 541.63 [M]+；Found:542 [M+H]+。
Embodiment 9
(thio -5- of 2- is to carboxyl benzene by-quinoline -4 (1H) -one -3- by the fluoro- 7- of 1- ethyl -6- (4- thyl-piperazin -1- base) Base -2- methene base-thiazolidin-4-one -3- base)-amide (I-9), chemical structural formula are as follows:
Ar i.e. in Formulas I is 4- carboxyl phenyl.
The compound the preparation method comprises the following steps: with p -carboxybenzaldehyde (0.33g, 2.2mmol) substitute aromatic aldehyde, according to above-mentioned Object (I) general preparative methods, obtain pale yellow crystals object (I-9), yield 63.5%, m.p.226~228 DEG C.1H NMR(400MHz,CDCl3) δ: 15.56 (brs, 1H, COOH), 11.53 (1H, s, CONH), 9.18 (1H, s, 2-H), 8.96 (2H, d, Ph-H), 8.33 (1H, s, Ph-CH=), 8.15 (1H, d, 5-H), 7.78 (1H, d, 8-H), 7.68 (2H, d, Ph-H), 4.57 (2H, t, 1-NCH2), 3.55 (4H, t, piperazine-H), 3.21 (4H, t, piperazine-H), 2.44 (3H, s, N-CH3), 1.55 (3H, t, CH3)；MS (m/z): Calcd.for C28H26FN5O5S2: 595.68 [M]+；Found:596 [M+H]+。
Embodiment 10
(thio -5- of 2- is to sulfonamide for-quinoline -4 (1H) -one -3- carboxylic acid for 1- ethyl-fluoro- 7- (4- thyl-piperazin -1- base) Base phenyl -2- methene base-thiazolidin-4-one -3- base)-amide (I-10), chemical structural formula are as follows:
Ar i.e. in Formulas I is 4- sulfoamido phenyl.
The compound the preparation method comprises the following steps: with to aminosulfonyl benzaldehyde (0.37g, 2.0mmol) substitute aromatic aldehyde, according to According to the general preparative methods of above-mentioned object (I), obtain pale yellow crystals object (I-10), yield 78.6%, m.p.245~ 247℃。1H NMR(400MHz,CDCl3) δ: 15.54 (brs, 1H, COOH), 11.48 (1H, s, CONH), 9.15 (1H, s, 2- H), 8.92 (2H, d, Ph-H), 8.31 (1H, s, Ph-CH=), 8.13 (1H, d, 5-H), 7.76 (1H, d, 8-H), 7.62 (2H, D, Ph-H), 4.55 (2H, t, 1-NCH2), 3.51 (4H, t, piperazine-H), 3.12 (4H, t, piperazine-H), 2.42 (3H, s, N-CH3), 1.57 (3H, t, CH3)；MS (m/z): Calcd.for C27H27FN6O5S3: 630.74 [M]+； Found:631 [M+H]+。
Test example
One, a kind of pefloxacin (Rao Danning beta-unsaturated ketone) amide derivatives that embodiment 1-10 is provided is external anti-swollen Tumor activity measurement
1, test sample
It is anti-swollen with a kind of pefloxacin (Rao Danning beta-unsaturated ketone) amide derivatives that embodiment 1-10 is provided, and classics Tumor TOPO inhibitor 10-hydroxycamptothecine (HC) and pefloxacin (PF) are test sample, and totally 12 kinds, wherein HC and PF is control Group, embodiment 1-10 sample are experimental group；
Experimental cancer cell line is respectively human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell 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 cell, and purchase is logical in Shanghai Growth Science and Technology Ltd..
2, measuring method
The specific steps of measuring method are as follows:
(1) it uses dimethyl sulfoxide (DMSO) to dissolve respectively above-mentioned 12 kinds of test samples first, is configured to 1.0 × 10- 2mol·L-1The RPMI-1640 culture solution of the stock solution of concentration, the calf serum for being later 10% with mass percent concentration will Stock solution is diluted to 5 concentration gradients (0.1,1.0,5.0,10.0,50.0 μm of olL-1) working solution；
Human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and the human leukemia HL60 cell of logarithmic growth phase and VERO cell strain, with 6000, every hole cell inoculation in 96 orifice plates, be then separately added into above-mentioned 12 kinds of samples has 5 concentration The working solution of gradient.5gL is added in every hole after culture 48 hours–110 μ L of MTT (thiazolyl blue) solution adds after continuing culture 4 hours Enter lauryl sodium sulfate (SDS) solution that 100 μ L mass percent concentrations are 10% to be further cultured for 24 hours, then uses microplate reader Respective absorbance (OD) value is measured 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 value)/control group OD value] × 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, each test sample is calculated to the half-inhibitory concentration of experiment cancer cell from gained dose-effect equation (IC50)；Each data are measured in parallel three times, are averaged, the results are shown in Table 1.
Anti-tumor activity (the IC of each test sample of table 150)
As it can be seen from table 1 the compound that embodiment 1-10 is provided is significantly stronger than the inhibitory activity of 3 kinds of cancer cells of experiment The activity of parent compound pefloxacin, especially part of compounds are better than control hydroxyl to the activity of human pancreas cancer Panc-1 cell The activity of camptothecine, IC50Value has reached micro-molar concentration.What makes more sense is that the compound pair that embodiment 1-10 is provided VERO cell is shown low toxicity, the potentiality with druggability.It therefore, is first to carry out according to the general way of drug development Conventional antitumor in-vitro screening, is then targetedly studied, so the compound of the present invention has strong antitumor work Property and lower toxicity, can be by being mixed with anti-tumor drug at salt or with pharmaceutical carrier with acid human-acceptable.

Claims (6)

1. a kind of pefloxacin rhodanine beta-unsaturated ketone amide derivatives, are typically characterized by as with the typification of flowering structure Close object:
2. a kind of preparation method of pefloxacin rhodanine beta-unsaturated ketone amide derivatives according to claim 1, It is characterized in that, specific preparation step includes:
(1) it using pefloxacin shown in formula (II) as raw material, is reacted through hydrazinolysis and pefloxacin hydrazides shown in formula (III) is made.
(2) hydrazide compound shown in formula (III) and double-(carboxymethyl) trithiocarbonate are flowed back 24 hours in water, is sent out Raw condensation reaction, it is after reaction, post-treated that pefloxacin rhodanine amide derivatives shown in formula (IV) are made；So Afterwards
Formula (IV) and aromatic aldehyde form 5- virtue methene base rhodanine α, alpha, beta-unsaturated ketone structure, warp under the catalysis of weak base sodium acetate Post-processing can obtain a kind of pefloxacin rhodanine beta-unsaturated ketone amide derivatives shown in claim 1.
3. a kind of preparation of pefloxacin pefloxacin rhodanine beta-unsaturated ketone amide derivatives according to claim 2 Method, which is characterized in that pefloxacin hydrazides shown in the formula (III) and double-(carboxymethyl) trithiocarbonate compound Molar ratio be 1:1.0~1.2.
4. a kind of preparation of pefloxacin pefloxacin rhodanine beta-unsaturated ketone amide derivatives according to claim 2 Method, which is characterized in that the molar ratio of pefloxacin rhodanine amide shown in the formula (IV) and aromatic aldehyde be 1:1.0~ 1.2。
5. a kind of pefloxacin rhodanine beta-unsaturated ketone amide derivatives as claimed in claim 1 or 2 prepare it is antitumor Application in drug.
6. a kind of pefloxacin rhodanine beta-unsaturated ketone amide derivatives according to claim 5 are preparing antineoplastic Application in object, which is characterized in that the anti-tumor drug is the drug for treating liver cancer, cancer of pancreas or leukaemia.
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CN101400655A (en) * 2006-03-16 2009-04-01 安斯泰来制药有限公司 Quinolone derivative or pharmaceutically acceptable salt thereof
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CN101400655A (en) * 2006-03-16 2009-04-01 安斯泰来制药有限公司 Quinolone derivative or pharmaceutically acceptable salt thereof
CN101643471A (en) * 2009-08-24 2010-02-10 河南大学 C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof

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