CN106317051B - A kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application - Google Patents
A kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of N methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application, using such as following formula I chemical structure of general formula：
Description
Technical field
The invention belongs to original new drug synthesis technical fields, and in particular to a kind of N- methyl Enoxacin (rhodanine insatiable hunger
And ketone) amide derivatives, also relate to a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives
Preparation method and its application in antitumor drug.
Background technology
Discovery of the new drug innovation originating from primer, and the design of structure-based rational drug is the effective of discovery primer
Method, while the structure of drug molecule skeleton is crucial.In the pharmacophore of various structures, five yuan with extensive pharmacological activity
In azoles heterocyclic ketone, rhodanine (2- thioxo-thiazolidin -4- ketone) has become pharmaceutical chemical advantage skeleton and is widely used in new drug
The structure of molecular chemistry skeleton.Mainly condensation reaction including 5- active methylene groups and aldehyde forms C=C keys and the α that constructs for it,
Alpha, beta-unsaturated ketone derivative, at the same time 3- bit aminos and carboxylic acids split form the derivatives such as aminocarboxylic acids or amides.
In addition, to improve the water solubility of Rhodanine derivant, the modification of multiamide base peptides is re-introduced on rhodanine skeleton substituent group
Side chain, to improve its bioavilability, promote it to patent medicine sexual development.On the other hand, with the fluoro- quinoline of 1- substitutions -6- (naphthyridines) -
4- ketone -3- carboxylic acids are the antibacterial fluoroquinolone drug of advantage skeleton, because its action target spot-topoisomerase is also antineoplastic
The important function target of object can convert its antibacterial activity to antitumor activity.Structural modification research finds fluoquinolone C-3 carboxylics
Base is not pharmacophore necessary to antitumor activity, and the drug effect of another antitumor activity is carried using C-3 acylamino-s as connection chain
The superposition, it can be achieved that different pharmacophore activities is rolled into a ball, and is found that candidate compound with anti-tumor activity.However, fluorine quinoline promise
Ketone skeleton and the compound for the beta-unsaturated ketone amide class formation that rhodanine skeleton phase split is built are not yet reported.
For this purpose, the object of the present invention is to provide a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amides derivatives
Object has an antitumor effect and efficacy, while providing a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amides and spreading out
The preparation method of biology.
In order to achieve the goal above, the technical solution adopted in the present invention is：(rhodanine is or not a kind of N- methyl Enoxacin
Saturated 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 concrete structure below
Object：
The preparation method of a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives of the present invention, with formula
(II) N- methyl Enoxacin shown in is prepared as a raw material,
Specific preparation process is as follows：
1) (synthesis of Yang Yong's quinolones C-3 [1,3,4] triazole thioether and derivative and antitumor activity are ground reference literature
Study carefully.Master's thesis, He'nan University, 2011.) similar approach, reacted with formic acid and formaldehyde by Enoxacin and formula (III) be made
N- methyl Enoxacins；
Concrete operation step is：Enoxacin (50g, 156.0mmol) shown in formula (II) is dissolved in 85% formic acid
(300mL) and 37% formaldehyde (19.0g, 234.0mmol) in the mixed solvent, back flow reaction 6 hours.It removes solvent under reduced pressure, adds
Water (300mL) dissolved, with activated carbon (2.0g) reflux decoloration 1 hour.Filtering, filtrate are neutral with concentrated ammonia liquor tune.It places and is precipitated admittedly
Body, filtering, deionized water are washed 3 times.It is dry, obtain yellow crystal formula (III), yield 91.8%, 174~176 DEG C of mp.1H
NMR(400MHz,CDCl3)δ:15.56(1H,s,COOH),8.95(1H,s,2-H),8.14(1H,d,5-H),4.62(2H,q,
NCH 2CH3), 3.57~3.23 (7H, m, piperazine-H), 2.32 (3H, s, N-CH3),1.46(3H,t,CH3)；MS(m/
z):Calcd.for C16H19FN4O3:334.35[M]+；Found:335[M+H]+。
2) with hydrazine hydrate hydrazinolysis is occurred into for N- methyl Enoxacin shown in formula (III) and reacts N- first shown in obtained formula (IV)
Base Enoxacin hydrazides；
Concrete operation step is：N- methyl Enoxacin (20g, 60.0mmol) shown in formula (III) is dissolved in 85%
The in the mixed solvent of hydrazine hydrate (50mL) and absolute ethyl alcohol (200mL), back flow reaction 12 hours.Remove solvent under reduced pressure, add water without
Water-ethanol (100mL) and activated carbon (1.0g) reflux are decolourized 1 hour.Filtering, filtrate, which is placed, is precipitated solid, filtering, absolute ethyl alcohol
Washing 2 times.It is dry, obtain yellow crystal formula (IV), yield 72.3%, 164~166 DEG C of mp.1H NMR(400MHz,CDCl3)δ:
11.68(1H,s,CONH),8.93(1H,s,2-H),8.12(1H,d,5-H),5.46(2H,s,NH2),4.58(2H,q,
NCH 2CH3), 3.55~3.18 (7H, m, piperazine-H), 2.30 (3H, s, N-CH3),1.43(3H,t,CH3)；MS(m/
z):Calcd.forC16H21FN6O2:348.38[M]+；Found:349[M+H]+。
3) N- methyl Enoxacin hydrazides shown in formula (IV) and double-(carboxymethyl) trithiocarbonate are flowed back instead in water
It answers 12 hours, places room temperature, ammonium hydroxide alkalization, filtering is collected the solid of generation, recrystallized with absolute ethyl alcohol, is made shown in formula (V)
N- methyl Enoxacin (rhodanine) amide intermediate；
Concrete operation step is：N- methyl Enoxacin hydrazides (10.0g, 29.0mmol) and double-(carboxymethyl) three are thio
Carbonic ester (7.2g, 31.0mmol) disappears in water (300mL) back flow reaction to raw material, and (TLC is detected, VChloroform：VMethanol=5:1).It is cooling
Room temperature is alkalized with concentrated ammonia liquor to pH 8.0~9.0, and placement is cooled to room temperature.The solid that filter collection generates, it is dry.Crude product is with anhydrous
Ethyl alcohol recrystallization obtains yellow crystal formula (V), yield 82.7%, 162~164 DEG C of mp.1H NMR(400MHz,CDCl3):11.43
(1H,s,CONH),8.92(1H,s,2-H),8.16(1H,d,5-H),4.43(2H,q,NCH2),4.68(2H,s,SCH2),3.86
(4H,t,piperazine-H),3.16(4H,t,piperazine-H),2.41(3H,s,N-CH3),1.45(3H,t,CH3)；MS
(m/z):Calcd.for C19H21FN6O3S2:464.54[M]+；Found:465[M+H]+。
4) by N- methyl Enoxacin (rhodanine) amide compound shown in formula (V) and aromatic aldehyde under the catalysis of alkali in ice
Condensation reaction is carried out in acetic acid, after complete reaction through handle shown in target compound such as formula (I).
Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The general operating procedure that is synthetically prepared is：Take the fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)-naphthyridines -4
(1H) -one -3- (2- thioxo-thiazolidin -4- ketone -3- bases]-amide (V) 1.0g (2.2mmol) and anhydrous sodium acetate 0.20g
(2.4mmol) is dissolved in 15mL glacial acetic acids, and aromatic aldehyde (2.4mmol), mixed reactant back flow reaction 12h is added.Decompression is steamed
Except solvent, residue is dissolved with water (20mL), and suitable activated carbon is added and decolourize at 60 DEG C 0.5h, filters.Filtrate concentrated ammonia liquor
Alkalization merges organic phase, anhydrous sodium sulfate drying to pH 9.0 with chloroform recovery (3 × 15mL).Solvent is recovered under reduced pressure to dry,
With ethyl alcohol-DMF (V:V=5:1) it recrystallizes, obtains pale yellow crystals object (I).
As a further improvement, N- methyl Enoxacin (rhodanine) amide and aromatic aldehyde shown in Formula V mole is
1:1.0~1.2.
A kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives are preparing antitumor drug
In application.
The antitumor drug is treatment liver cancer, cancer of pancreas or leukemia medicament.
A kind of spelling of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives based on pharmacophore of the present invention
Principle is closed, by fluorine naphthyridones, amide and rhodanine α, the progress between the difference pharmacophore such as alpha, beta-unsaturated ketone is effectively combined, in turn
Construct N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives, realize different structure pharmacophore complementation and
Active superposition can be used as the antitumor drug exploitation of brand new to achieve synergistic and detoxifying effects.
Specific implementation mode
The technical scheme of the invention is described in detail through specific implementation examples.
Embodiment 1
The fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)-naphthyridines -4 (1H) -one -3- (thio -5- benzene methene bases-of 2-
Thiazolidin-4-one -3- bases]-amide (I-1), chemical structural formula is：
Ar i.e. in Formulas I is phenyl.
The preparation method of the compound is：Aromatic aldehyde is substituted with benzaldehyde (0.25g, 2.4mmol), according to above-mentioned target
The general preparative methods of object (I) obtain target pale yellow crystals object (I-1), yield 75.3%, m.p.174~176 DEG C.1H NMR
(400MHz,CDCl3)δ:11.45 (1H, s, CONH), 8.93 (1H, s, 2-H), 8.22 (s, 1H, CH=), 8.18 (1H, d, 5-
), H 7.68~7.32 (m, 5H, Ph-H), 4.46 (2H, q, NCH2),3.87(4H,t,piperazine-H),2.73(4H,t,
piperazine-H),2.42(3H,s,N-CH3),1.45(3H,t,CH3)；MS(m/z):Calcd.for C26H25FN6O3S2:
552.65[M]+；Found:553[M+H]+。
Embodiment 2
(thio -5- of 2- are to methoxybenzene by-naphthyridines -4 (1H) -one -3- by the fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)
Methene base-thiazolidin-4-one -3- bases]-amide (I-2), chemical structural formula is：
Ar i.e. in Formulas I is p-methoxyphenyl.
The preparation method of the compound is：Aromatic aldehyde is substituted with P-methoxybenzal-dehyde (0.28g, 2.2mmol), according to upper
The general preparative methods for the object (I) stated obtain target pale yellow crystals object (I-2), yield 76.4%, m.p.176~178
℃。1H NMR(400MHz,CDCl3)δ:11.46 (1H, s, CONH), 8.97 (1H, s, 2-H), 8.25 (s, 1H, CH=), 8.21
(1H,d,5-H),7.84(2H,d,Ph-H),7.53(2H,d,Ph-H),4.48(2H,q,NCH2),3.94(3H,s,OCH3),
3.87(4H,t,piperazine-H),2.76(4H,t,piperazine-H),2.43(3H,s,N-CH3),1.45(3H,t,
CH3)；MS(m/z):Calcd.for C27H27FN6O4S2:582.68[M]+；Found:583[M+H]+。
Embodiment 3
The fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)-naphthyridines -4 (1H) -one -3- [2- thio -5- (3,4- dioxies
Methylene) benzene methene base-thiazolidin-4-one -3- bases]-amide (I-3), chemical structural formula is：
Ar i.e. in Formulas I is 3,4- (dioxymethylene) base phenyl.
The preparation method of the compound is：Aromatic aldehyde is substituted with 3,4-methylenedioxy benzaldehyde (0.39g, 2.6mmol),
According to the general preparative methods of above-mentioned object (I), target pale yellow crystals object (I-3), yield 83.5%, m.p.181 are obtained
~183 DEG C.1H NMR(400MHz,CDCl3)δ:11.46 (1H, s, CONH), 8.96 (1H, s, 2-H), 8.23 (s, 1H, CH=),
8.18 (1H, d, 5-H), 7.88~6.87 (3H, m, Ph-H), 6.32 (2H, s, OCH2O),4.48(2H,q,NCH2),3.86(4H,
t,Jpiperazine-H),2.82(4H,t,piperazine-H),2.44(3H,s,N-CH3),1.45(3H,t,CH3)；MS(m/
z):Calcd.for C27H25FN6O5S2:596.66[M]+；Found:597[M+H]+。
Embodiment 4
The fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)-naphthyridines -4 (1H) -one -3- [thio -5- of 2- (3,4,5- tri-
Methoxyl methyl) benzene methene base-thiazolidin-4-one -3- bases]-amide (I-4), chemical structural formula is：
Ar i.e. in Formulas I is 3,4,5- trimethoxy methylene phenyl.
The preparation method of the compound is：Aromatic aldehyde is substituted with 3,4,5-Trimethoxybenzaldehyde (0.43g, 2.2mmol),
According to the general preparative methods of above-mentioned object (I), pale yellow crystals object (I-4), yield 76.0%, m.p.165 are obtained
~167 DEG C.1H NMR(400MHz,CDCl3)δ:11.48 (1H, s, CONH), 9.05 (1H, s, 2-H), 8.27 (s, 1H, CH=),
8.21(1H,d,5-H),7.86(2H,s,Ph-H),4.52(2H,q,NCH2), 3.92~3.87 (13H, m, 3 × OCH3and
piperazine-H),2.86(4H,t,piperazine-H),2.45(3H,s,N-CH3),1.46(3H,t,CH3)；MS(m/z):
Calcd.for C29H31FN6O6S2:642.73[M]+；Found:643[M+H]+。
Embodiment 5
(thio -5- of 2- are to fluorobenzene methene by-naphthyridines -4 (1H) -one -3- by the fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)
Base-thiazolidin-4-one -3- bases)-amide (I-5), chemical structural formula is：
Ar i.e. in Formulas I is p-fluorophenyl.
The preparation method of the compound is：Aromatic aldehyde is substituted with 4-Fluorobenzaldehyde (0.30g, 2.4mmol), according to above-mentioned
The general preparative methods of object (I) obtain pale yellow crystals object (I-5), yield 78.3%, m.p.172~174 DEG C.1H
NMR(400MHz,CDCl3)δ:11.48 (1H, s, CONH), 9.03 (1H, s, 2-H), 8.28 (s, 1H, CH=), 8.23 (1H, d,
5-H),7.86(2H,d,Ph-H),7.63(2H,d,Ph-H),4.51(2H,q,NCH2),3.88(4H,t,piperazine-H),
2.83(4H,t,Jpiperazine-H),2.44(3H,s,N-CH3),1.46(3H,t,CH3)；MS(m/z):Calcd.for
C26H24F2N6O3S2:570.64[M]+；Found:571[M+H]+。
Embodiment 6
The fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)-naphthyridines -4 (1H) -one -3- (thio -5- p-nitrophenyls first of 2-
Pitch base-thiazolidin-4-one -3- bases)-amide (I-6), chemical structural formula is：
Ar i.e. in Formulas I is p-nitrophenyl.
The preparation method of the compound is：Aromatic aldehyde is substituted with paranitrobenzaldehyde (0.36g, 2.4mmol), according to above-mentioned
Object (I) general preparative methods, obtain pale yellow crystals object (I-6), yield 58.2%, m.p.186~188 DEG C.1H NMR(400MHz,CDCl3)δ:11.53 (1H, s, CONH), 9.12 (1H, s, 2-H), 8.36 (s, 1H, CH=), 8.27 (1H,
d,5-H),8.13(2H,d,Ph-H),7.87(2H,d,Ph-H),4.53(2H,q,NCH2),3.93(4H,t,piperazine-
H),3.06(4H,t,piperazine-H),2.46(3H,s,N-CH3),1.48(3H,t,CH3)；MS(m/z):Calcd.for
C26H24FN7O5S2:597.65[M]+；Found:598[M+H]+。
Embodiment 7
The fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)-naphthyridines -4 (1H) -one -3- (thio -5- pyridines -4- first of 2-
Pitch base-thiazolidin-4-one -3- bases)-amide (I-7), chemical structural formula is：
Ar i.e. in Formulas I is 4- pyridyl groups.
The preparation method of the compound is：Aromatic aldehyde is substituted with Pyridine-4-Carboxaldehyde (0.24g, 2.2mmol), according to above-mentioned
Object (I) general preparative methods, obtain pale yellow crystals object (I-7), yield 64.3%, m.p.171~173 DEG C.1H NMR(400MHz,CDCl3)δ:11.57(1H,s,CONH),9.18(1H,s,2-H),8.87(2H,d,Py-H),8.76(2H,
D, Py-H), 8.38 (s, 1H, CH=), 8.30 (1H, d, 5-H), 4.56 (2H, q, NCH2),3.95(4H,t,piperazine-
H),3.13(4H,t,piperazine-H),2.48(3H,s,N-CH3),1.51(3H,t,CH3)；MS(m/z):Calcd.for
C25H24FN7O3S2:553.64[M]+；Found:554[M+H]+。
Embodiment 8
The fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)-naphthyridines -4 (1H) -one -3- (thio -5- furans -2- first of 2-
Pitch base-thiazolidin-4-one -3- bases)-amide (I-8), chemical structural formula is：
Ar i.e. in Formulas I is 2- furyls.
The preparation method of the compound is：Aromatic aldehyde is substituted with furans -2- formaldehyde (0.21g, 2.2mmol), according to above-mentioned
Object (I) general preparative methods, obtain pale yellow crystals object (I-8), yield 66.0%, m.p.176~178 DEG C.1H NMR(400MHz,CDCl3)δ:11.55 (1H, s, CONH), 9.16 (1H, s, 2-H), 8.35 (s, 1H, CH=), 8.26 (1H,
D, 5-H), 7.68~6.87 (3H, m, furan-H), 4.53 (2H, q, NCH2),3.91(4H,t,piperazine-H),3.03
(4H,t,piperazine-H),2.46(3H,s,N-CH3),1.48(3H,t,CH3)；MS(m/z):Calcd.for
C24H23FN6O4S2:542.62[M]+；Found:543[M+H]+。
Embodiment 9
(thio -5- of 2- are to carboxyl benzene by-naphthyridines -4 (1H) -one -3- by the fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)
Base -2- methenes base-thiazolidin-4-one -3- bases)-amide (I-9), chemical structural formula is：
Ar i.e. in Formulas I is 4- carboxyl phenyls.
The preparation method of the compound is：Aromatic aldehyde is substituted with p -carboxybenzaldehyde (0.33g, 2.2mmol), according to above-mentioned
Object (I) general preparative methods, obtain pale yellow crystals object (I-9), yield 65.4%, m.p.163~165 DEG C.1H NMR(400MHz,CDCl3)δ:15.63(brs,1H,COOH),11.62(1H,s,CONH),9.23(1H,s,2-H),8.44
~8.36 (3H, m, Ph-H and CH=), 8.25 (1H, d, 5-H), 7.86 (2H, d, Ph-H), 4.53 (2H, q, NCH2),
3.92(4H,t,piperazine-H),3.11(4H,t,piperazine-H),2.46(3H,s,N-CH3),1.52(3H,t,
CH3)；MS(m/z):Calcd.for C27H25FN6O5S2:596.66[M]+；Found:597[M+H]+。
Embodiment 10
(thio -5- of 2- are to sulfoamido by-naphthyridines -4 (1H) -one -3- by the fluoro- 7- of 1- ethyls -6- (4- thyl-piperazin -1- bases)
Phenyl -2- methenes base-thiazolidin-4-one -3- bases)-amide (I-10), chemical structural formula is：
Ar i.e. in Formulas I is 4- sulfoamido phenyl.
The preparation method of the compound is：Aromatic aldehyde is substituted with p -carboxybenzaldehyde (0.46g, 2.5mmol), according to above-mentioned
Object (I) general preparative methods, obtain pale yellow crystals object (I-10), yield 74.6%, m.p.191~193 DEG C
。1H NMR(400MHz,CDCl3)δ:11.62 (s, 1H, CONH), 9.25 (s, 1H, 2-H), 8.38~8.33 (3H, m, Ph-H
And CH=), 8.26 (d, 1H, 5-H), 7.89 (2H, d, Ph-H), 7.78 (s, 2H, NH2),4.56(2H,q,NCH2),3.97
(4H,t,piperazine-H),3.15(4H,t,piperazine-H),2.51(3H,s,N-CH3),1.55(3H,t,CH3)；MS
(m/z):Calcd.for C26H26FN7O5S2:631.73[M]+；Found:632[M+H]+。
Test example
A kind of body of N- methyl Enoxacin (rich tannin beta-unsaturated ketone) amide derivatives that one, embodiment 1-10 is provided
Outer antitumor cytolytic activity
1, test sample
A kind of N- methyl Enoxacin (the rich tannin beta-unsaturated ketone) amide derivatives provided with embodiment 1-10, and warp
The antitumor TOPO inhibitor 10-hydroxycamptothecine (HC) of allusion quotation and Enoxacin (EN) are test sample, totally 12 kinds, wherein HC and EN
For control 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；
Human liver cancer Hep-3B cells, human pancreas cancer Panc-1 cells and the human leukemia HL60 cells of logarithmic growth phase and
VERO cell strains, with 6000, every hole cell inoculation in 96 orifice plates, be then separately added into above-mentioned 12 kinds of samples has 5 concentration
5gL is added in the working solution of gradient per hole after 48 hours–110 μ L of MTT (tetrazolium bromide) solution are added 100 after continuing culture 4 hours
Lauryl sodium sulfate (SDS) solution that μ L mass percent concentrations are 10%, is further cultured for 24 hours, is then existed with 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 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 each 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 activity of parent compound Enoxacin, especially part of compounds are thin to human liver cancer Hep-3B cells and human pancreas cancer Panc-1
The activity of born of the same parents is better than the activity of control hydroxycamptothecin, IC50Value has reached or is less than micro-molar concentration.What makes more sense is that real
It applies the compound that a 1-10 is provided to show low toxicity VERO cells, the potentiality with druggability.Therefore, according to drug
The general way of exploitation is first to carry out conventional antitumor in-vitro screening, is then targetedly studied, so the present invention
Compound has strong antitumor activity and lower toxicity, can be by being mixed with acid human-acceptable at salt or with pharmaceutical carrier
Conjunction prepares antitumor drug.
Claims (7)
1. a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives, which is characterized in that have such as following formula (I)
General structure：
Wherein aromatic rings Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
2. a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives according to claim 1, tool
Body characteristics are the typical compound with lower structure：
3. a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives according to claim 1 or 2
Preparation method, which is characterized in that specifically preparation process includes：
(1) using Enoxacin shown in formula (II) as raw material, N- methyl Yi Nuosha shown in formula (III) is made through methylation reaction
Star, then formula (III) and hydrazine hydrate hydrazinolysis occurs react, N- methyl Enoxacin hydrazides shown in obtained formula (IV)；
(2) hydrazide compound shown in formula (IV) and double-(carboxymethyl) trithiocarbonate are flowed back 24 hours in water, is occurred
Condensation reaction, it is after reaction, post-treated to obtain N- methyl Enoxacin (rhodanine) amides derivative shown in formula (V)
Object；Then formula (V) and aromatic aldehyde form 5- virtue methene base rhodanine α under the catalysis of weak base sodium acetate, alpha, beta-unsaturated ketone structure,
It is post-treated to obtain a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives shown in formula (I)；
Aromatic rings Ar wherein in formula (I) is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
4. a kind of preparation of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives according to claim 3
Method, which is characterized in that N- methyl Enoxacin hydrazides shown in the formula (IV) and double-(carboxymethyl) trithiocarbonate
The molar ratio of compound is 1:1.0~1.2.
5. a kind of preparation of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives according to claim 3
Method, which is characterized in that the molar ratio of N- methyl Enoxacin (rhodanine) amide and aromatic aldehyde shown in the formula (V) is 1:
1.0~1.2.
6. prepared by a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives as claimed in claim 1 or 2
Application in antitumor drug.
7. a kind of N- methyl Enoxacin (rhodanine beta-unsaturated ketone) amide derivatives according to claim 6 are anti-in preparation
Application in tumour medicine, which is characterized in that the antitumor drug is the drug for treating liver cancer, cancer of pancreas or leukaemia.
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