CN106316945A - Alpha, beta-unsaturated ketone derivative of pefloxacin, preparation method of derivative, and application of derivative - Google Patents
Alpha, beta-unsaturated ketone derivative of pefloxacin, preparation method of derivative, and application of derivative Download PDFInfo
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The invention discloses an alpha, beta-unsaturated ketone derivative of pefloxacin, a preparation method of the derivative, and an application of the derivative. The chemical structure of the derivative is represented by formula I shown in the description; and in the formula I, aromatic nucleus Ar is a phenyl ring or a substituted phenyl ring or a furan ring or a pyridine ring. The alpha, beta-unsaturated ketone derivative of pefloxacin realizes effective merging of a fluoroquinolone skeleton and an alpha, beta-unsaturated ketone skeleton in order to construct a new fluoroquinolone "chalcone-like" compound, so the antitumor activity of the new compound is increased, the toxic and side effects on normal cells are reduced, and the compound can be used as an antitumor active substance to develop antitumor medicines with a brand new structure.
Description
Technical field
The invention belongs to original new drug synthesis technical field, be specifically related to the α of a kind of pefloxacin, alpha, beta-unsaturated ketone derivant, with
Time further relate to the α of a kind of pefloxacin, the preparation method of alpha, beta-unsaturated ketone derivant, and its application in antitumor drug.
Background technology
New drug innovation originates from the discovery of primer, and rational drug MOLECULE DESIGN based on structure be find primer have efficacious prescriptions
Method.In the pharmacophore of various structures, having α, the chalcone compounds of alpha, beta-unsaturated ketone architectural feature is as important natural
Effective ingredient, is concerned because having multiple pharmacologically active.But, natural chalcone compounds mostly is polyhydroxy phenyl ring and replaces
α, beta-unsaturated ketone compound, because its poor water solublity causes bioavailability relatively low, limit application clinically.Separately
Outward, also it is the important function target spot of antitumor drug in conjunction with the action target spot topoisomerase of antibacterial flouroquinolone drugs, can be by
Its antibacterial activity is converted into anti-tumor activity, and find fluoroquinolone C-3 carboxyl be not pharmacophore necessary to anti-tumor activity,
Available bioisostere is replaced to improve its anti-tumor activity.Based on this, for improving the water solublity of chalcones, improve it
Bioavailability and activity, the advantage pharmacophore 1-ethyl-6-fluoro-7-(methyl-piperazine of present invention flouroquinolone drugs pefloxacin
Piperazine-1-base)-quinoline-4 (1H)-one skeleton is as α, the substituent group of alpha, beta-unsaturated ketone structure, and then devise the fluorine quinoline promise of new structure
Ketone " class chalcone " derivant.
To this end, it is an object of the invention to provide the α of a kind of pefloxacin, alpha, beta-unsaturated ketone derivant, have antineoplastic action and
Effect, provides the α of a kind of pefloxacin, the preparation method of alpha, beta-unsaturated ketone derivant simultaneously.
In order to realize object above, the technical solution adopted in the present invention is: the α of a kind of pefloxacin, alpha, beta-unsaturated ketone derivant,
Its chemical structural formula is as shown in formula I:
In formula I, Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring, and this compounds is the compound of following concrete structure:
The α of a kind of pefloxacin of the present invention, the preparation method of alpha, beta-unsaturated ketone derivant, is former with the pefloxacin shown in formula II
Material is prepared from；
Concrete preparation process is as follows:
1) compound shown in formula III is reacted to obtain with the pefloxacin shown in formula II through sodium borohydride reduction decarboxylation, then with formic acid
Ethyl ester condensation reaction prepares the compound shown in formula IV, and it is husky that last formula IV and activated manganese dioxide oxidation prepare the training fluorine shown in formula V
Star aldehyde；
Step 1) Detailed operating procedures be 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.) the prodrug research synthesis of .7.3-formoxyl Carbostyril derivative and antimicrobial acivity) method prepare, detailed process
As follows:
2) pefloxacin aldehyde shown in formula V and aromatic radical ethyl ketone VI are carried out aldol condensation under the catalysis of alkali in dehydrated alcohol anti-
Should, after question response is complete, the treated target compound that obtains is as shown in formula I, and detailed process is as follows:
In formula I, Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The general synthetically prepared operating procedure of target compound formula I is: take the 1-fluoro-7-of ethyl-6-(4-thyl-piperazin-1-base)-quinoline
-4 (1H)-one-3-formaldehyde V 1.0g (3.2mmol) is dissolved in 20mL dehydrated alcohol, adds aromatic radical ethyl ketone formula VI (3.2
And base catalyst piperidines (0.1mL) mmol).Mixed reactant back flow reaction 24h, places room temperature, the solid that filter collection produces, nothing
Water-ethanol recrystallization, obtains pale yellow crystals thing formula I.
As further improving, the pefloxacin aldehyde shown in formula V and aromatic radical ethyl ketone formula VI mole are 1:1.0～1.2.
Described base catalyst is at least one in piperidines, pyridine, triethylamine, morpholine, potassium acetate and sodium acetate.
The α of described a kind of pefloxacin, the application in preparing antitumor drug of the alpha, beta-unsaturated ketone derivant.
Described antitumor drug is treatment hepatocarcinoma, cancer of pancreas or leukemia medicament.
The α of a kind of pefloxacin of the present invention, alpha, beta-unsaturated ketone derivant principle of hybridization based on pharmacophore, by fluoroquinolone skeleton
With α, alpha, beta-unsaturated ketone pharmacophore is effectively combined, and design has synthesized the α of pefloxacin, alpha, beta-unsaturated ketone derivant, it is achieved that
The complementation of different structure pharmacophore and the superposition of activity, thus reached the effect of potentiation toxicity reduction, can swell as the anti-of brand new
Tumor medicine is developed.
Detailed description of the invention
Embodiment 1
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-(2-benzoyl-ethylene-1-base)-quinoline-4 (1H)-one (I-1), its chemical constitution
Formula is:
I.e. Ar in formula I is phenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone formula VI with 1-Phenylethanone. (0.45g, 3.8mmol), according to above-mentioned
The general preparative methods of object formula I, obtains pale yellow crystals object (I-1), productivity 65.6%, m.p.132～134 DEG C.1H NMR
(400MHz,CD3Cl) δ: 1.46 (3H, t, CH3), 2.32 (3H, s, N-CH3), 2.53～3.42 (8H, m, piperazine-H),
4.35 (2H, q, N-CH2), 6.86～7.72 (6H, m, Ph-H and 8-H), 8.06 (1H, d, 5-H), 8.17～8.65 (3H,
M, 2-H, 1 '-H and 2 '-H)；MS (m/z): 420 [M+H]+, calculate (C25H26FN3O2): 419.50.
Embodiment 2
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(4-methoxybenzoyl)-ethylene-1-base]-quinoline-4 (1H)-one (I-2),
Its chemical structural formula is:
I.e. Ar in formula I is p-methoxyphenyl.
The preparation method of this compound is: substitutes aromatic radical ethyl ketone formula VI with 4-methoxy-acetophenone (0.48g, 3.2mmol), depends on
According to the general preparative methods of above-mentioned object formula I, obtain pale yellow crystals object (I-2), productivity 72.3%, m.p.
137～139 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.47 (3H, t, CH3), 2.33 (3H, s, N-CH3), 2.56～3.43
(8H, m, piperazine-H), 3.87 (3H, s, OCH3), 4.36 (2H, q, N-CH2), 7.52～7.82 (5H, m, Ph-H and
8-H), 8.08 (1H, d, 5-H), 8.21～8.68 (3H, m, 2-H, 1 '-H and 2 '-H)；MS (m/z): 450 [M+H]+,
Calculate (C26H28FN3O3): 449.53.
Embodiment 3
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(3,4-dioxymethylene-benzoyl)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-3), its chemical structural formula is:
I.e. Ar in formula I is 3,4-(dioxymethylene) phenyl.
The preparation method of this compound is: with 3, and 4-dioxymethylene-1-Phenylethanone. (0.52g, 3.2mmol) substitutes aryl methyl ketone formula
VI, according to the general preparative methods of above-mentioned object formula I, obtain pale yellow crystals object thing (I-3), productivity 75.6%, m.p.
155～157 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.46 (3H, t, CH3), 2.34 (3H, s, N-CH3), 2.67～3.45
(8H, m, piperazine-H), 4.36 (2H, q, N-CH2), 6.17 (2H, s, OCH2O), 7.63～7.86 (4H, m, Ph-H
And 8-H), 8.07 (1H, d, 5-H), 8.18～8.66 (3H, m, 2-H, 1 '-H and 2 '-H)；MS (m/z): 464 [M+H]+,
Calculate (C26H26FN3O4): 463.51.
Embodiment 4
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(3,4,5-trimethoxy methyl-benzoyl)-ethylene-1-base]-quinoline-4 (1H)-
Ketone (I-4), its chemical structural formula is:
I.e. Ar in formula I is 3,4,5-2,4,5-trimethoxyphenyls.
The preparation method of this compound is: with 3, and 4,5-trimethoxies-1-Phenylethanone. (0.67g, 3.2mmol) substitutes aromatic radical ethyl ketone
Formula VI, according to the general preparative methods of above-mentioned object formula I, obtains pale yellow crystals object thing (I-4), productivity 66.3%,
M.p.142～144 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.48 (3H, t, CH3), 2.35 (3H, s, N-CH3),
2.83～3.47 (8H, m, piperazine-H), 3.84,3.86 (9H, 2s, 3 × OCH3), 4.38 (2H, q, N-CH2), 7.66～7.86
(3H, m, Ph-H and 8-H), 8.07 (1H, d, 5-H), 8.16～8.67 (3H, m, 2-H, 1 '-H and 2 '-H)；MS (m/z):
510[M+H]+, calculate (C28H32FN3O5): 509.58.
Embodiment 5
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(4-methyl-benzoyl)-ethylene-1-base]-quinoline-4 (1H)-one (I-5), its
Chemical structural formula is:
I.e. Ar in formula I is to methylphenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone formula VI with 4-methyl-acetophenone (0.51g, 3.8mmol), according to
The general preparative methods of above-mentioned object formula I, obtains pale yellow crystals object thing (I-5), productivity 60.8%, m.p.
126～128 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.45 (3H, t, CH3), 2.24,2.30 (6H, 2s, Ph-CH3
And N-CH3), 2.57～3.43 (8H, m, piperazine-H), 4.36 (2H, q, N-CH2), 7.46～7.75 (5H, m, Ph-H and
8-H), 8.05 (1H, d, 5-H), 8.14～8.63 (3H, m, 2-H, 1 '-H and 2 '-H)；MS (m/z): 434 [M+H]+,
Calculate (C26H28FN3O2): 433.53.
Embodiment 6
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(the fluoro-benzoyl of 4-)-ethylene-1-base]-quinoline-4 (1H)-one (I-6), it is changed
Structural formula is:
I.e. Ar in formula I is to fluoro-phenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone formula VI with the fluoro-1-Phenylethanone. of 4-(0.44g, 3.2mmol), according to above-mentioned
The general preparative methods of object formula I, obtains pale yellow crystals object thing (I-6), productivity 72.6%, m.p.154～156 DEG C.1H
NMR(400MHz,CD3Cl) δ: 1.48 (3H, t, CH3), 2.38 (3H, s, N-CH3), 3.12～3.53 (8H, m, piperazines
Piperazine-H), 4.38 (2H, q, N-CH2), 7.68～7.86 (5H, m, Ph-H and 8-H), 8.12 (1H, d, 5-H), 8.23～8.72
(3H, m, 2-H, 1 '-H and 2 '-H)；MS (m/z): 438 [M+H]+, calculate (C25H25F2N3O2): 437.49.
Embodiment 7
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(4-nitro-benzoyl)-ethylene-1-base]-quinoline-4 (1H)-one (I-7), its
Chemical structural formula is:
I.e. Ar in formula I is p-nitrophenyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone formula VI with 4-nitro-acetophenone (0.53g, 3.2mmol), according to above-mentioned
The general preparative methods of object formula I, obtain pale yellow crystals object thing (I-7), productivity 68.4%, m.p.162～164 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.52 (3H, t, CH3), 2.43 (6H, 2s, Ph-CH3And N-CH3), 3.15～3.56
(8H, m, piperazine-H), 4.42 (2H, q, N-CH2), 7.82～8.18 (6H, m, Ph-H, 5-H and 8-H), 8.35～8.83
(3H, m, 2-H, 1 '-H and 2 '-H)；MS (m/z): 465 [M+H]+, calculate (C25H25FN4O4): 464.50.
Embodiment 8
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(4-Hydroxy-benzoyIcarbamo)-ethylene-1-base]-quinoline-4 (1H)-one (I-8), its
Chemical structural formula is:
I.e. Ar in formula I is 4-hydroxy-pheny.
The preparation method of this compound is: substitute aromatic radical ethyl ketone formula VI with 4-hydroxy-acetophenone (0.45g, 3.3mmol), according to above-mentioned
The general preparative methods of object formula I, obtain pale yellow crystals object thing (I-8), productivity 52.8%, m.p.146～148 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.47 (3H, t, CH3), 2.38 (3H, s, N-CH3), 2.76～3.47 (8H, m,
Piperazine-H), 4.38 (2H, q, N-CH2), 7.68～7.89 (6H, m, Ph-H, 5-H and 8-H), 8.26～8.77 (3H, m,
2-H, 1 '-H and 2 '-H), 10.54 (1H, brs, OH)；MS (m/z): 436 [M+H]+, calculate (C25H26FN3O3): 435.50.
Embodiment 9
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(4-pyridine-formoxyl)-ethylene-1-base]-quinoline-4 (1H)-one (I-9), its
Chemical structural formula is:
I.e. Ar in formula I is 4-pyridine radicals.
The preparation method of this compound is: substitute aromatic radical ethyl ketone formula VI with 4-pyridine-ethyl ketone (0.39g, 3.2mmol), according to above-mentioned
The general preparative methods of object formula I, obtains pale yellow crystals object thing (I-9), productivity 57.5%, m.p.168～170 DEG C.1H
NMR(400MHz,CD3Cl) δ: 1.52 (3H, t, CH3), 2.43 (3H, s, N-CH3), 3.13～3.56 (8H, m, piperazines
Piperazine-H), 4.42 (2H, q, N-CH2), 7.75 (1H, d, 8-H), 8.13 (1H, d, 5-H), 8.38～8.87 (7H, m, 1 '-H,
2 '-H, 2-H and Py-H)；MS (m/z): 421 [M+H]+, calculate (C24H25FN4O2): 420.49.
Embodiment 10
The fluoro-7-of 1-ethyl-6-(4-thyl-piperazin-1-base)-3-[2-(4-furan-formyl)-ethylene-1-base]-quinoline-4 (1H)-one (I-10), its
Chemical structural formula is:
I.e. Ar in Formulas I is 2-furyl.
The preparation method of this compound is: substitute aromatic radical ethyl ketone formula VI with 2-furan-ethyl ketone (0.42g, 3.8mmol), according to upper
The general preparative methods of the object (I) stated, obtains pale yellow crystals object thing (I-10), productivity 65.4%, m.p.155～157 DEG C.1H NMR(400MHz,CD3Cl) δ: 1.50 (3H, t, CH3), 2.41 (3H, s, N-CH3), 3.12～3.53 (8H, m,
Piperazine-H), 4.41 (2H, q, N-CH2), 6.74～7.73 (4H, m, furan-H and 8-H), 8.12 (1H, d, 5-H), 8.26～8.85
(3H, m, 5-H, 1 '-H, 2 '-H)；MS (m/z): 410 [M+H]+, calculate (C23H24FN3O3): 409.46.
Test example
One, the α of a kind of pefloxacin that embodiment 1-10 provides, the anti tumor activity in vitro of alpha, beta-unsaturated ketone derivant measures
1, test sample
With the α of a kind of pefloxacin that embodiment 1-10 provides, alpha, beta-unsaturated ketone derivant and classical antitumor TOPO inhibitor
10-hydroxycamptothecine (HC) and parent compound pefloxacin (PF) are test sample, and totally 12 kinds, wherein HC and PF is
Matched group, embodiment 1-10 sample is experimental group；
Experiment JEG-3 is people's hepatocarcinoma Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 cell respectively
Strain is all bought from Chinese Academy of Sciences's Shanghai cell bank.Normal cell uses VERO African green monkey kidney cell, buys and sends in upper Cacumen et folium clerodendri mandarinori (Clerodendron mandarinorum Diels)
Bio tech ltd.
2, assay method
Concretely comprising the following steps of assay method:
1) first above-mentioned 12 kinds of test samples are dissolved with dimethyl sulfoxide (DMSO) respectively, be configured to 1.0 × 10-2mol·L-1
The storing solution of concentration, dilutes storing solution with the RPMI-1640 culture fluid of the calf serum that mass percent concentration is 10% afterwards
Become there are 5 Concentraton gradient (0.1,1.0,5.0,10.0,50.0 μm ol L-1) working solution；
2) take the logarithm people's hepatocarcinoma Hep-3B cell of trophophase, human pancreas cancer Panc-1 cell and human leukemia HL60 cell and
VERO cell strain, is inoculated in 96 orifice plates with 6000, every hole cell, and be separately added into above-mentioned 12 kinds of samples subsequently has 5
The working solution of Concentraton gradient, after 48 hours, every hole adds 5g L–1MTT (tetrazolium bromide) solution 10 μ L, continues to be further cultured for 4 hours
Add sodium lauryl sulphate (SDS) solution that 100 μ L mass percent concentrations are 10% afterwards.Cultivate 24 hours, then
At 570nm wavelength, absorbance (OD) value is measured by microplate reader；
3) test sample of the variable concentrations suppression ratio to cancerous cell is calculated by following shown formula,
Inhibition of cancer cell rate=[(1-experimental group OD value)/matched group OD value] × 100%；
Then with the logarithm value of each concentration of test sample, the inhibition of cancer cell rate that each concentration is corresponding is made linear regression, obtain docs-effect
Equation, goes out the test sample half-inhibition concentration (IC to experiment cancerous cell from gained docs-effect Equation for Calculating50)；Each data
Parallel assay three times, seeks its meansigma methods, the results are shown in Table shown in 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 provides is significantly stronger than parent to the inhibitory activity of 3 kinds of cancerous cell of experiment
The activity of compound pefloxacin, especially part of compounds are better than comparison to the growth inhibitory activity of human pancreas cancer Panc-1 cell
The activity of hydroxycamptothecin, its IC50Value has reached micro-molar concentration.More meaningful, that embodiment 1-10 provides compound pair
VERO cell demonstrates relatively low toxicity, has the potentiality of druggability.Therefore, it is advanced according to the general way of drug development
The antitumor in-vitro screening that row is conventional, studies the most targetedly, so the compound of the present invention has strong antitumor and lives
Property and relatively low toxicity, salt can be become by acid acceptable with human body or be mixed with antitumor drug with pharmaceutical carrier.
Claims (6)
1. a α for pefloxacin, alpha, beta-unsaturated ketone derivant, it is characterised in that there is the general structure of following formula I:
Wherein, aromatic rings Ar is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The α of a kind of pefloxacin the most according to claim 1, alpha, beta-unsaturated ketone analog derivative, it is typically characterized by with following
The typical compound of structure:
The α of a kind of pefloxacin the most according to claim 1 and 2, the preparation method of alpha, beta-unsaturated ketone derivant, its feature exists
In, concrete preparation process includes:
1) with the pefloxacin shown in formula II as raw material, the compound shown in formula III is reacted to obtain through sodium borohydride reduction decarboxylation, so
The compound shown in formula IV is prepared afterwards with Ethyl formate condensation reaction；Last formula IV aoxidizes to obtain pefloxacin aldehyde with activated manganese dioxide
Formula V:
2) pefloxacin aldehyde shown in formula V and aromatic radical ethyl ketone are formed under the catalysis of alkali α, alpha, beta-unsaturated ketone structure, through after place
Reason can obtain the α of a kind of pefloxacin shown in formula I, alpha, beta-unsaturated ketone derivant:
Wherein, the aromatic radical Ar in formula I is phenyl ring or substituted benzene ring or furan nucleus or pyridine ring.
The α of a kind of pefloxacin the most according to claim 3, the preparation method of alpha, beta-unsaturated ketone derivant, it is characterised in that
Pefloxacin aldehyde shown in described formula V is 1:1.0～1.2 with the mol ratio of aromatic radical ethyl ketone.
5. as right is required the α of a kind of pefloxacin as described in 1 or 2, and alpha, beta-unsaturated ketone derivant is in preparing antitumor drug
Application.
The α of a kind of pefloxacin the most according to claim 5, the application in preparing antitumor drug of the alpha, beta-unsaturated ketone derivant,
It is characterized in that, described antitumor drug is treatment hepatocarcinoma, cancer of pancreas or leukemic medicine.
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| CN111646938B (en) * | 2019-11-20 | 2022-01-21 | 河南大学 | Propenone derivative of pefloxacin, and preparation method and application thereof |
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