CN106317083B - A kind of α of Rufloxacin, alpha, beta-unsaturated ketone derivative and its preparation method and application - Google Patents
A kind of α of Rufloxacin, alpha, beta-unsaturated ketone derivative and its preparation method and application Download PDFInfo
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- NJCJBUHJQLFDSW-UHFFFAOYSA-N CN(CC1)CCN1c(c(F)c1)c2SCCN(C=C3C(O)=O)c2c1C3=O Chemical compound CN(CC1)CCN1c(c(F)c1)c2SCCN(C=C3C(O)=O)c2c1C3=O NJCJBUHJQLFDSW-UHFFFAOYSA-N 0.000 description 1
- FXAMWSWMCSJBNQ-UHFFFAOYSA-N CN(CC1)CCN1c(c(F)c1)c2SCCN(CC3)c2c1C3=O Chemical compound CN(CC1)CCN1c(c(F)c1)c2SCCN(CC3)c2c1C3=O FXAMWSWMCSJBNQ-UHFFFAOYSA-N 0.000 description 1
- JPCYXLRBVWGMAM-UHFFFAOYSA-N CN(CC1)CCN1c(c(F)c1)c2SCCN(CC3C=O)c2c1C3=O Chemical compound CN(CC1)CCN1c(c(F)c1)c2SCCN(CC3C=O)c2c1C3=O JPCYXLRBVWGMAM-UHFFFAOYSA-N 0.000 description 1
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of α of Rufloxacin, 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 Rufloxacin, alpha, beta-unsaturated ketone derive
Object, also relates to a kind of α of Rufloxacin, 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 its bioisostere to improve its antitumor activity.Based on this, to improve chalcones
Water solubility, improve its bioavilability and activity, advantage pharmacophore-thiophene of present invention flouroquinolone drugs Rufloxacin
Piperazine and (1H) the -one skeleton of quinoline -4 devise new structural fluorine quinoline promise as α, the substituent group of alpha, beta-unsaturated ketone structure
Ketone " class chalcone " derivative.
For this purpose, the object of the present invention is to provide a kind of α of Rufloxacin, alpha, beta-unsaturated ketone derivative has antitumor
Effect and effect, while a kind of α of Rufloxacin, 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 Rufloxacin, alpha, beta-unsaturated ketone
Derivative, chemical structural formula is as shown in general formula I：
Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring in formula I, such compound is concrete structure below
Compound：
A kind of α of Rufloxacin of the present invention, the preparation method of alpha, beta-unsaturated ketone derivative are husky with reed 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 Rufloxacin 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 reed 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) Rufloxacin aldehyde shown in formula V and aromatic radical ethyl ketone VI are subjected to aldol under base catalysis 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 step 2) target compounds of formula I is：Take 1,8- (3,1- sulphur ethyl) -6- fluoro-
V 1.1g (3.2mmol) of 7- (4- thyl-piperazin -1- bases)-quinoline -4 (1H) -one -3- formaldehyde formula is dissolved in 20mL absolute ethyl alcohols
In, aromatic radical ethyl ketone Formula IV (3.2mmol) and base catalyst piperidines (0.1mL) is added.Mixed reactant back flow reaction for 24 hours, is put
Room temperature, the solid that filter collection generates are set, absolute ethyl alcohol recrystallization obtains pale yellow crystals target compound object formula I.
As a further improvement, Rufloxacin aldehyde shown in formula V and Formula IV aromatic radical ethyl ketone mole 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 Rufloxacin, 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 Rufloxacin 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 Rufloxacin, 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
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 Formula IV is substituted with acetophenone (0.45g, 3.8mmol), according to upper
The general preparative methods for the object formula I stated obtain pale yellow crystals object (I-1), yield 63.6%, m.p.153~155
℃。1H NMR(400MHz,CD3Cl)δ：2.32 (3H, s, N-CH3), 3.12~3.47 (10H, m, piperazine-H and thiazine-H),
4.72 (2H, t, thiazine-H), 7.55~7.87 (6H, m, Ph-H and 5-H), 8.20~8.91 (3H, m, 2-H, 1 '-H and 2 '-H)；
MS(m/z)：450[M+H]+, calculate (C25H24FN3O2S)：449.55.
Embodiment 2
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 formula 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 65.8%,
M.p.155~157 DEG C.1H NMR(400MHz,CD3Cl)δ：2.34 (3H, s, N-CH3), 3.15~3.48 (10H, m, piperazine-H
With thiazine-H), 3.87 (3H, s, OCH3), 4.74 (2H, t, thiazine-H), 7.62~7.88 (5H, m, Ph-H and 5-H), 8.23~
8.92 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：480[M+H]+, calculate (C26H26FN3O3S)：479.58.Embodiment 3
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 Formulas 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)
Keto-acid VI obtains pale yellow crystals object object (I-3), yield according to the general preparative methods of above-mentioned object formula I
72.6%, m.p.172~174 DEG C.1H NMR(400MHz,CD3Cl)δ：2.36 (3H, s, N-CH3), 3.17~3.52 (10H, m,
Piperazine-H and thiazine-H), 4.76 (2H, t, thiazine-H), 6.28 (3H, s, OCH2O), 7.67~7.93 (4H, m, Ph-H and 5-
H), 8.24~8.95 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：494[M+H]+, calculate (C26H24FN3O4S)：493.56.
Embodiment 4
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 Formula IV obtains pale yellow crystals object object (I-4), yield according to the general preparative methods of above-mentioned object formula I
67.2%, m.p.151~153 DEG C.1H NMR(400MHz,CD3Cl)δ：2.35 (3H, s, N-CH3), 3.18~3.55 (10H, m,
Piperazine-H and thiazine-H), 4.78 (2H, t, thiazine-H), 3.87,3.89 (9H, 2s, 3 × OCH3), 7.75~8.13 (3H, m,
Ph-H and 5-H), 8.28~8.93 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：540[M+H]+, calculate
(C28H30FN3O5S)：539.63.
Embodiment 5
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 formula is substituted with 4- methyl-acetophenones (0.51g, 3.8mmol)
VI obtains pale yellow crystals object object (I-5) according to the general preparative methods of above-mentioned object formula I, yield 53.8%,
M.p.136~138 DEG C.1H NMR(400MHz,CD3Cl)δ：2.25,2.32 (6H, 2s, 2s, Ph-CH3And N-CH3), 3.13~
3.46 (10H, m, piperazine-H and thiazine-H), 4.72 (2H, t, thiazine-H), 7.56~7.81 (5H, m, Ph-H and 5-H), 8.18
~8.91 (3H, m, 2-H, 1 '-H and 2 '-H)；MS(m/z)：464[M+H]+, calculate (C26H26FN3O2S)：463.58.
Embodiment 6
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 Formula IV is substituted with the fluoro- acetophenones of 4- (0.44g, 3.2mmol),
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-6) is obtained, yield 73.5%,
M.p.163~165 DEG C.1H NMR(400MHz,CD3Cl)δ：2.36 (3H, s, N-CH3), 3.17~3.52 (10H, m, piperazine-H
With thiazine-H), 4.76 (2H, t, thiazine-H), 7.73~7.94 (5H, m, Ph-H and 5-H), 8.25~8.94 (3H, m, 2-H,
1 '-H and 2 '-H)；MS(m/z)：468[M+H]+, calculate (C25H23F2N3O2S)：467.54.
Embodiment 7
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 formula is substituted with 4- nitro-acetophenones (0.53g, 3.2mmol)
VI obtains pale yellow crystals object object (I-7) according to the general preparative methods of above-mentioned object I, yield 74.5%,
M.p.168~170 DEG C.1H NMR(400MHz,CD3Cl)δ：2.42 (3H, s, N-CH3), 3.23~3.61 (8H, m, piperazine-H),
(4.78 2H, t, thiazine-H), 7.82~7.96 (5H, m, Ph-H and 5-H), 8.27~9.12 (3H, m, 2-H, 1 '-H and 2 '-H)；
MS(m/z)：495[M+H]+, calculate (C25H23FN4O4S)：494.55.
Embodiment 8
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 formula is substituted with 4- hydroxy-acetophenones (0.45g, 3.3mmol)
VI obtains pale yellow crystals object object (I-8) according to the general preparative methods of above-mentioned object formula I, yield 51.8%,
M.p.155~157 DEG C.1H NMR(400MHz,CD3Cl)δ：2.37 (3H, s, N-CH3), 3.21~3.58 (8H, m, piperazine-H),
4.77 (2H, t, thiazine-H), 7.76~7.87 (5H, m, Ph-H and 5-H), 8.21~9.06 (3H, m, 2-H, 1 '-H and 2 '-H),
10.57 (1H, brs, OH)；MS(m/z)：466[M+H]+, calculate (C25H24FN3O3S)：465.55.
Embodiment 9
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 Formula IV is substituted with 4- pyridines-ethyl ketone (0.39g, 3.2mmol),
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-9) is obtained, yield 58.2%,
M.p.183~185 DEG C.1H NMR(400MHz,CD3Cl)δ：2.38 (3H, s, N-CH3), 3.25~3.66 (8H, m, piperazine-H),
4.82 (2H, t, thiazine-H), 7.86 (1H, d, 5-H), 8.30~9.17 (7H, m, 2-H, 1 '-H, 2 '-H and Py-H)；MS(m/
z)：451[M+H]+, calculate (C24H23FN4O2S)：450.54.
Embodiment 10
1,8- (3,1- sulphur ethyl) fluoro- 7- of -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 Formula IV is substituted with 2- furans-ethyl ketone (0.42g, 3.8mmol),
According to the general preparative methods of above-mentioned object formula I, pale yellow crystals object object (I-10) is obtained, yield 63.4%,
M.p.167~169 DEG C.1H NMR(400MHz,CD3Cl)δ：2.38 (3H, s, N-CH3), 3.25~3.62 (8H, m, piperazine-H),
4.80 (2H, t, thiazine-H), 6.85~7.88 (4H, m, 5-H and furans-H), 8.17~8.93 (3H, m, 2-H, 1 '-H and 2 '-
H)；MS(m/z)：440[M+H]+, calculate (C23H22FN3O3S)：439.51.
Test example
One, the anti tumor activity in vitro of the α for a kind of Rufloxacin 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 Rufloxacins provided, alpha, beta-unsaturated ketone derivative and classical antitumor TOPO suppressions
Preparation 10-hydroxycamptothecine (HC) and parent compound Rufloxacin (LF) are test sample, and totally 12 kinds, wherein HC and LF 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 activity of parent compound Rufloxacin (LF), especially growth inhibition of the majority of compounds to human pancreas cancer Panc-1 cells
Activity 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
The compound that 1-10 is provided shows low toxicity VERO cells, the potentiality with druggability.Therefore, according to drug development
General way be first to carry out conventional antitumor in-vitro screening, then targetedly studied, thus the present invention chemical combination
Object has strong antitumor activity and lower toxicity, can be by mixing system with acid human-acceptable at salt or with pharmaceutical carrier
Standby antitumor drug.
Claims (5)
1. a kind of α of Rufloxacin, the compound of alpha, beta-unsaturated ketone derivative, specific features structure are：
2. a kind of α of Rufloxacin according to claim 1, the preparation method of alpha, beta-unsaturated ketone derivative, feature exist
In specific preparation process includes：
1) it using Rufloxacin shown in formula II as raw material, is reduced by sodium borohydride and then decarboxylated base reaction and chemical combination shown in formula III is made
Then IV compound represented of formula is made with Ethyl formate condensation reaction in object；Last formula IV is made with activated manganese dioxide oxidation
V Rufloxacin aldehyde of formula：
2) Rufloxacin 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 Rufloxacin, 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, p-nitroacetophenone, parahydroxyacet-ophenone,
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-nitrophenyl, p-hydroxybenzene, 4- pyridyl groups or 2- furyls.
3. a kind of α of Rufloxacin according to claim 2, the preparation method of alpha, beta-unsaturated ketone derivative, feature exist
In the molar ratio of Rufloxacin 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 Rufloxacin as described in requiring 1, alpha, beta-unsaturated ketone derivative is in the preparation of antitumor drugs
Using.
5. a kind of α of Rufloxacin 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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