CN111303189A - Propenone derivative of rufloxacin, and preparation method and application thereof - Google Patents
Propenone derivative of rufloxacin, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an acrylketone derivative of rufloxacin, a preparation method and application thereof, wherein the compound adopts a chemical structure general formula as shown in the following formula I:
Description
Technical Field
The invention belongs to the technical field of innovative drug synthesis, and particularly relates to an acrylketone derivative of rufloxacin, a preparation method of the acrylketone derivative of rufloxacin, and application of the acrylketone derivative of rufloxacin in antitumor drugs.
Background
New drug innovation stems from the discovery of leads, and rational drug molecular design based on structure or mechanism is an effective method for discovering leads. In the drug effect groups with various structures, the acrylketone structure is not only the characteristic structure of a chalcone compound which is a natural effective component, but also the characteristic drug effect group of a targeted antitumor drug sunitinib. Therefore, compounds constructed with acrylketone as a structural fragment and having various pharmacological activities have been attracting attention. However, most of natural chalcone compounds are multi-hydroxyl benzene ring substituted propenone compounds, and the poor water solubility of the compounds causes low bioavailability and limits clinical application. In addition, the topoisomerase which is an action target point of the antibacterial fluoroquinolone medicine is also an important action target point of the antitumor medicine, the antibacterial activity of the antibacterial fluoroquinolone medicine can be converted into the antitumor activity, and the fluoroquinolone C-3 carboxyl is not a pharmacophore required by the antitumor activity and can be replaced by a biological electron isostere to improve the antitumor activity of the fluoroquinolone medicine. However, the research on the replacement of the C-3 carboxyl group of fluoroquinolone with aryl acrylketone has not been reported. Based on the above, in order to improve the water solubility of chalcone, hydrophilic piperazinyl is introduced to increase the water solubility and improve the bioavailability and the bioactivity of the chalcone, the invention uses the skeleton of the advantageous pharmacophore of the fluoroquinolone drug rufloxacin, namely 1, 8-ethylthio-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one, as a substituent of an aryl propenone structure, and further designs the fluoroquinolone chalcone derivatives with novel structures.
Therefore, the invention aims to provide the acrylketone derivative of the rufloxacin, which has the anti-tumor effect and efficacy, and also provides a preparation method of the acrylketone derivative of the rufloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the acrylic derivative of the rufloxacin has a chemical structural formula shown as a general formula I:
in the formula I, Ar is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring, and the compound is a compound with the following specific structure:
the preparation method of the acrylketone derivative of the rufloxacin takes the commercially obtained rufloxacin shown in the formula II as a raw material to prepare the rufloxacin derivative;
the preparation method comprises the following specific steps:
1) the preparation method comprises the following steps of taking the rufloxacin shown in the formula II as a raw material, and reacting the rufloxacin with Carbonyldiimidazole (CDI) to obtain the rufloxacin imidazole amide compound shown in the formula III:
22.0g (60.0mmol) of 1, 8-ethylthio-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-carboxylic acid II is dissolved in 500mL of anhydrous acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole is added, and the mixture is stirred in a water bath and refluxed until the raw material II disappears. Standing at room temperature, filtering to collect the generated solid, and recrystallizing with acetone to obtain the rufloxacin imidazole amide light yellow crystal shown as the formula III with the yield of 76.4 percent and the m.p.239-241 ℃.1H NMR(400MHz,CD3Cl)δ：2.35(3H,s,N-CH3) 2.86 to 3.36(8H, m, piperazine-H), 3.68 to 4.66(4H, m, S-CH)2CH2-N), 7.46 to 7.63(2H, m, imidazole-H), 7.86(1H, d, 5-H), 8.17(1H, s, imidazole-H), 8.92(1H, s, 2-H); MS (m/z): 414[ M + H]+Calculating (C)20H20FN5O2S)：413.48。
As a further improvement, the molar ratio of the rufloxacin shown in the formula II to the carbonyldiimidazole is 1: 1.0-2.0, and the solvent can be at least one of acetonitrile, tetrahydrofuran, dioxane and dimethylformamide or a mixed solvent of the acetonitrile, the tetrahydrofuran, the dioxane and the dimethylformamide.
2) The preparation method comprises the following steps of carrying out condensation reaction on rufloxacin imidazole amide shown in a formula III and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride to obtain a C-3 formyl ethyl acetate compound of rufloxacin shown in a formula IV, wherein the specific preparation method comprises the following steps:
1, 8-ethylthio-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) - [ quinolin-4 (1H) -one, 16.0g (39.0mmol) of formula III, 6.6g (69.1mmol) of magnesium chloride and 8.3g (49.0mmol) of potassium monoethyl malonate were sequentially added to 600mL of anhydrous acetonitrile, 12.2g (12.0mmol) of triethylamine was added dropwise with stirring in an ice bath, and the mixture was reacted with reflux in a water bath until the disappearance of the raw material III. The solvent was evaporated under reduced pressure, 500mL of water was added, the mixture was extracted with methylene chloride (3X 150mL), the organic phases were combined, washed with water (3X 200mL), washed with saturated brine (2X 150mL), and dried over anhydrous sodium sulfate. And recovering dichloromethane at normal pressure, and recrystallizing the residue with absolute ethyl alcohol to obtain an off-white crystal shown as a formula IV, wherein the yield is 72.5%, and m.p.231-233 ℃.1H NMR(400MHz,CD3Cl)δ：1.25(3H，t，CH3)，2.34(3H,s,N-CH3) 2.87 to 3.37(8H, m, piperazine-H), 3.64(2H, m, S-CH)2)，4.16(2H，s，COCH2CO)，4.28(2H，q，CO2CH2)，4.67(2H，m，N-CH2)，7.84(1H，d，5-H)，8.95(1H，s,2-H)；MS(m/z)：434[M+H]+Calculating (C)21H24FN3O4S)：433.51。
3) The C-3 ethyl formylacetate compound of the rufloxacin shown in the formula IV is subjected to hydrolysis decarboxylation reaction by using a sodium hydroxide aqueous solution with the mass fraction of 6 percent, so that the C-3 ethanone compound of the rufloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:
taking 1, 8-ethylthio-6-fluoro-7- (4-methyl)Piperazine-1-yl) -quinoline-4 (1H) -ketone-3-formylacetic acid ethyl ester formula IV 10g (23.0mmol) is suspended in 200mL sodium hydroxide aqueous solution with the mass fraction of 6%, and the reaction is stirred and refluxed in oil bath until the raw material IV disappears. Standing at room temperature, collecting the generated solid by filtration, washing with water to be neutral, drying, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal of formula V, wherein the yield is 71.3%, and m.p.236-238 ℃.1H NMR(400MHz,CD3Cl)δ：2.34(3H,s,N-CH3)，2.44(3H，s，COCH3) 2.86 to 3.35(8H, m, piperazine-H), 3.64 to 4.67(4H, m, S-CH)2CH2-N)，7.86(1H，d，5-H)，8.94(1H，s,2-H)；MS(m/z)：362[M+H]+Calculating (C)18H20FN3O2S)：361.44。
4) C-3 ethanone of the rufloxacin shown in the formula V and aromatic aldehyde are subjected to Claisen-Schmidt aldol condensation reaction in absolute ethyl alcohol under the catalysis of alkali, and after the reaction is completed, a target compound is obtained by treatment, wherein the target compound is shown in the formula I, and the specific process is as follows:
wherein Ar in the formula I is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring.
The general synthetic preparation procedure for the target compound of formula i is: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) one-3-ethanone V was dissolved in 20mL of absolute ethanol, and an aromatic aldehyde (3.0mmol) and a base catalyst piperidine (0.1mL) were added. And (3) refluxing and reacting the mixed reactants for 15-24 h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal shown in the formula I.
As a further improvement, the molar ratio of the rufloxacin C-3 ethanone shown in the formula V to the aromatic aldehyde is 1: 1.0-1.5.
The base catalyst is at least one of piperidine, pyridine, triethylamine, morpholine, potassium acetate, sodium hydroxide ethanol solution or potassium hydroxide ethanol solution.
The application of the acrylketone derivative of the rufloxacin in preparing the antitumor drugs is provided.
The anti-tumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
The acrylketone derivative of the rufloxacin is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the split principle of the pharmacophores, realizes the complementation and activity superposition of the pharmacophores with different structures, achieves the effects of synergism, toxicity reduction and drug resistance, and can be developed as an anti-tumor drug with a brand new structure.
Detailed Description
Example 1
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical formula:
namely, Ar in the formula I is phenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.40g (3.8mmol) of benzaldehyde and piperidine as a base catalyst (0.1mL) were added. And (3) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-1, wherein the yield is 75.3%, and the m.p.236-238 ℃.1H NMR(400MHz,CD3Cl)δ：2.34(3H,s,N-CH3) 2.73 to 3.36(8H, m, piperazine-H), 3.64 to 4.67(4H, m, S-CH)2CH2-N), 7.53 to 7.88(7H, m, Ph-H, 5-H and 2 '-H), 8.56(1H, d, 3' -H),8.95(1H, s, 2-H); MS (m/z): 450[ M + H ]]+Calculating (C)25H24FN3O2S)：449.55。
Example 2
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical formula:
namely, Ar in the formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.57g (4.2mmol) of 4-methoxybenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-2, wherein the yield is 77.8%, and m.p.238-240 ℃.1H NMR(400MHz,CD3Cl)δ：2.36(3H,s,N-CH3) 2.75 to 3.38(8H, m, piperazine-H), 3.66 to 4.68(7H, m, S-CH)2CH2-N and OCH3) 7.57-7.92 (6H, m, Ph-H, 5-H and 2 '-H), 8.58(1H, d, 3' -H),8.97(1H, s, 2-H); MS (m/z): 480[ M + H ]]+Calculating (C)26H26FN3O3S)：479.58。
Example 3
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (3, 4-dioxamethylenecinnamoyl) -quinolin-4 (1H) -one (I-3), which has the chemical formula:
namely, Ar in the formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.53g (3.5mmol) of 3, 4-dioxytolualdehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-3, wherein the yield is 80.6%, and the m.p.242-244 ℃.1H NMR(400MHz,CD3Cl)δ：2.35(3H,s,N-CH3) 2.68 to 3.38(8H, m, piperazine-H), 3.67 to 4.65(4H,m，S-CH2CH2-N)，6.23(2H，s，OCH2o), 7.56-8.03 (5H, m, Ph-H, 5-H and 2 '-H), 8.60(1H, d, 3' -H),9.03(1H, s, 2-H); MS (m/z): 494[ M + H]+Calculating (C)26H24FN3O4S)：493.56。
Example 4
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (3,4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (I-4) having the chemical formula:
namely, Ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.63g (3.2mmol) of 3,4, 5-trioxybenzaldehyde and piperidine (0.1mL) as a basic catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-4, wherein the yield is 63.5%, and the m.p.231-233 ℃.1H NMR(400MHz,CD3Cl)δ：2.37(3H,s,N-CH3) 2.68 to 3.37(8H, m, piperazine-H), 3.67 to 4.66(13H, S-CH)2CH2-N and 3 XOCH3) 7.58-8.11 (4H, m, Ph-H, 5-H and 2 '-H), 8.63(1H, d, 3' -H),8.96(1H, s, 2-H); MS (m/z): 540[ M + H ]]+Calculating (C)28H30FN3O5S)：539.63。
Example 5
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the formula:
namely, Ar in the formula I is p-methyl-phenyl.
The preparation method of the compound comprises the following steps:1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.58g (4.8mmol) of 4-methylbenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-5, wherein the yield is 65.2%, and m.p.226-228 ℃.1H NMR(400MHz,CD3Cl)δ：2.28(3H，s，Ph-CH3)，2.35(3H,s,N-CH3) 2.66 to 3.36(8H, m, piperazine-H), 3.65 to 4.67(4H, m, S-CH)2CH2-N),7.55 to 7.93(6H, m, Ph-H, 5-H and 2 '-H), 8.57(1H, d, 3' -H),8.96(1H, s, 2-H); MS (m/z): 464[ M + H ]]+Calculating (C)26H26FN3O2S)：463.58。
Example 6
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-fluorocinnamoyl) -quinolin-4 (1H) -one (I-6) having the formula:
namely, Ar in the formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.48g (3.8mmol) of 4-fluorobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-6, wherein the yield is 78.6%, and the m.p.240-242 ℃.1H NMR(400MHz,CD3Cl)δ：2.41(3H,s,N-CH3) 2.78 to 3.38(8H, m, piperazine-H), 3.68 to 4.70(4H, m, S-CH)2CH2-N), 7.61-8.06 (6H, m, Ph-H, 5-H and 2 '-H), 8.64(1H, d, 3' -H),9.11(1H, s, 2-H); MS (m/z): 468[ M + H]+Calculating (C)25H23F2N3O2S)：467.54。
Example 7
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-chlorocinnamoyl) -quinolin-4 (1H) -one (I-7) having the chemical formula:
namely, Ar in the formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.45g (3.2mmol) of 4-chlorobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-7, wherein the yield is 76.3%, and the m.p.231-233 ℃.1H NMR(400MHz,CD3Cl)δ：2.40(3H,s,N-CH3) 2.73 to 3.37(8H, m, piperazine-H), 3.67 to 4.70(4H, m, S-CH)2CH2-N),7.58 to 8.04(6H, m, Ph-H, 5-H and 2 '-H), 8.62(1H, d, 3' -H),9.07(1H, s, 2-H); MS (m/z): 484[ M + H]+(35Cl), calculating (C)25H23FClN3O2S)：484.00。
Example 8
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical formula:
namely, Ar in the formula I is p-bromophenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.67g (3.6mmol) of 4-bromobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 24 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-8, wherein the yield is 75.0%, and the m.p.237-239 ℃.1H NMR(400MHz,CD3Cl)δ：2.37(3H,s,N-CH3) 2.71 to 3.38(8H, m, piperazine-H), 3.66 to 4.68(4H, m, S-CH)2CH2-N), 7.56-8.06 (6H, m, Ph-H, 5-H and 2 '-H), 8.60(1H, d, 3' -H),9.05(1H, s, 2-H); MS (m/z): 528 and 530[ M + H]+(79Br and81br), calculating (C)25H23FBrN3OS)：528.45。
Example 9
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical formula:
namely, Ar in the formula I is p-nitrophenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.54g (3.6mmol) of 4-nitrobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 24 hours, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely the formula I-9, wherein the yield is 78.3%, and the m.p.242-244 ℃.1H NMR(400MHz,CD3Cl)δ：2.42(3H,s,N-CH3) 3.03 to 3.41(8H, m, piperazine-H), 3.70 to 4.75(4H, m, S-CH)2CH2-N), 7.62-8.17 (6H, m, Ph-H, 5-H and 2 '-H), 8.66(1H, d, 3' -H),9.15(1H, s, 2-H); MS (m/z): 495, calculating (C)25H23FN4O4S)：494.55。
Example 10
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-hydroxy-cinnamoyl) -quinolin-4 (1H) -one (I-10) having the chemical formula:
namely, Ar in the formula I is 4-hydroxy-phenyl.
Preparation of the compoundThe preparation method comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.49g (4.0mmol) of 4-hydroxy-benzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-10, wherein the yield is 66.2%, and the m.p.234-236 ℃.1H NMR(400MHz,CD3Cl)δ：2.36(3H,s,N-CH3) 2.67 to 3.35(8H, m, piperazine-H), 3.67 to 4.68(4H, m, S-CH)2CH2-N), 7.58-8.02 (6H, m, Ph-H, 5-H and 2 '-H), 8.61(1H, d, 3' -H),9.03(1H, s,2-H), 10.56(1H, s, OH); MS (m/z): 466, calculating (C)25H24FN3O3S)：465.55。
Example 11
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical formula:
namely, Ar in the formula I is 3-pyridyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.37g (3.6mmol) of 3-pyridylaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal shown as a formula I-11, wherein the yield is 82.7%, and the m.p.243-245 ℃.1H NMR(400MHz,CD3Cl)δ：2.42(3H,s,N-CH3) 3.11 to 3.46(8H, m, piperazine-H), 3.70 to 4.73(4H, m, S-CH)2CH2-N),7.61(1H, d, 2 '-H), 8.64-9.13 (6H, 5-H, 3' -H and pyridine-H), 9.16(1H, s, 2-H); MS (m/z): 451, calculating (C)24H23FN4O2S)：450.54。
Example 12
1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical formula:
namely, Ar in the formula I is 2-furyl.
The preparation method of the compound comprises the following steps: the preparation method of the compound comprises the following steps: 1.1g (3.0mmol) of 1, 8-ethylsulfanyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.38g (4.0mmol) of 2-furfural and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-12, wherein the yield is 66.3%, and the m.p.238-240 ℃.1H NMR(400MHz,CD3Cl)δ：2.38(3H,s,N-CH3) 2.86 to 3.41(8H, m, piperazine-H), 3.68 to 4.71(4H, m, S-CH)2CH2-N),7.25 to 8.03(5H, m, 2 '-H, 5-H and furan-H), 8.64(1H, d, 3' -H),9.10(1H, s, 2-H); MS (m/z): 440[ M + H ]]+Calculating (C)23H22FN3O3S)：439.51。
Test examples
One, example 1-12 provides an in vitro anti-tumor activity assay of an acrylketone derivative of rufloxacin
1. Test sample
Taking 15 of the acrylketone derivative of rufloxacin provided in examples 1-12 and the classical antitumor TOPO inhibitor 10-Hydroxycamptothecin (HC), the chalcone tyrosinase inhibitor Sunitinib (SN), the broad-spectrum anticancer drug Doxorubicin (DOX) and the parent compound rufloxacin (LF) as test samples, wherein HC, SN and LF are control experimental groups, and the samples of examples 1-12 are test experimental groups;
thiazole blue (MTT), HC, SN and LF are all products of Sigma company; the RPMI-1640 culture solution is a product of GIBCO company; other used reagents are all domestic analytical pure reagents.
The experimental cancer cell strains are respectively a human non-small cell lung cancer cell strain A549, a human kidney cancer cell strain 769-P, a human hepatoma cell strain Hep-3B, a human gastric cancer cell strain HGC27, a human pancreatic cancer cell strain Panc-1 and a human leukemia cell strain HL60, which are purchased from Shanghai cell banks of Chinese academy of sciences. The human renal clear cell carcinoma cell sunitinib-resistant strain 7SuR was purchased from shanghai zel biotechnology limited, and the normal cell was obtained from african green monkey kidney cell line VERO and purchased from shanghai tong biology limited.
2. Measurement method
The determination method comprises the following specific steps:
1) firstly, the 15 samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0X 10- 4mol·L-1Stock solution of concentration, then diluting the stock solution with 10% calf serum RPMI-1640 culture solution to have 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0 μmol. L)-1) The working fluid of (1);
2) taking non-small cell lung cancer cell strain A549, human kidney cancer cell strain 769-P, human liver cancer cell strain Hep-3B, human gastric cancer cell strain HGC27, human pancreatic cancer cell strain Panc-1, human leukemia cell strain HL60, human renal clear cell cancer cell sunitinib drug-resistant strain 7SuR and African green monkey kidney cell strain VERO in logarithmic growth phase, inoculating 6000 cells in each hole to a 96-hole plate, then respectively adding working solution with 5 concentration gradients of the 15 samples, and adding 5 g.L.in each hole after 48 hours–1mu.L of MTT (thiazole blue) solution was added, and after further culturing for 4 hours, 100. mu.L of a 10% by mass Sodium Dodecyl Sulfate (SDS) solution was added. Culturing for 24 hours, and then measuring an absorbance (OD) value at a wavelength of 570nm by using a microplate reader;
3) the inhibition rate of the test samples with different concentrations on the cancer cells is calculated according to the following formula:
cancer cell inhibition rate ═ [ (1-experimental OD value)/control OD value ] × 100%;
then, performing linear regression on the cancer cell inhibition rate corresponding to each concentration by using the pair value of each concentration of the test sample to obtain a dose-effect equation, and calculating the half inhibition concentration (IC50) of the test sample to the experimental cancer cell from the obtained dose-effect equation; each data was measured in triplicate and averaged, the results are shown in Table 1.
TABLE 1 antitumor Activity (IC) of the test samples50)
As can be seen from Table 1, the inhibitory activity of the compounds provided in examples 1-12 on 7 cancer cells of experiment is significantly stronger than that of the parent compound of rufloxacin, especially the growth inhibitory activity of some compounds on human non-small cell lung cancer cell line A549 is stronger than that of the control Hydroxycamptothecin (HC), the tyrosine kinase inhibitors Sunitinib (SN) and adriamycin (DOX), and the IC of the compounds is IC50The value is reached or close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1 to 12 also show extremely strong sensitivity to sunitinib-resistant strain 7SuR, show strong drug-resistant activity, and simultaneously show low cytotoxicity to normal cells VERO, and have the property of becoming drug-resistant. Therefore, according to the general approach of drug development, the conventional antitumor in vitro screening is carried out, and then the targeted research is carried out, so that the compound has strong antitumor activity, drug resistance activity and lower cytotoxicity, and can be used for preparing antitumor drugs by salifying with acid acceptable for human bodies or mixing with medicinal carriers.
Claims (5)
1. The allyl ketone derivative of the rufloxacin is characterized by being a typical compound with the following structure:
2. the preparation method of the acrylketone derivative of rufloxacin according to claim 1, which comprises the following steps:
1) reacting rufloxacin shown in a formula II with Carbonyldiimidazole (CDI) to obtain an rufloxacin imidazole amide compound shown in a formula III, and then carrying out a condensation reaction with monoethyl malonate potassium salt to obtain a C-3 formyl ethyl acetate compound of rufloxacin shown in a formula IV; finally, the rufloxacin C-3 ethanone shown in the formula V is prepared by hydrolysis decarboxylation reaction of the formula IV:
2) the rufloxacin acrylketone derivative shown in the claim 1 can be prepared by carrying out Claisen-Schmidt condensation reaction on the C-3 ethanone shown in the formula V and aromatic aldehyde under the catalysis of alkali to form an acrylketone structure and carrying out post-treatment.
3. The preparation method of the acrylketone derivative of rufloxacin, as claimed in claim 2, wherein the molar ratio of rufloxacin represented by formula II to CDI is 1: 1.0-2.0, the molar ratio of rufloxacin imidazole amide represented by formula III to monoethyl malonate potassium salt is 1: 1.0-1.5, and the molar ratio of rufloxacin-3 ethanone represented by formula V to aromatic aldehyde is 1: 1.0-2.0.
4. The use of the acrylketone derivative of rufloxacin as claimed in claim 1 in the preparation of antitumor drugs.
5. The use of the acrylketone derivative of rufloxacin as described in claim 4, wherein the anti-tumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
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| US20030045555A1 (en) * | 2001-07-19 | 2003-03-06 | Rivera Nelo R. | Process to chiral integrin antagonist beta-amino acid intermediate |
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| CN111647004A (en) * | 2019-11-20 | 2020-09-11 | 河南大学 | Propenone derivative for removing N-methylofloxacin and preparation method and application thereof |
| CN111647004B (en) * | 2019-11-20 | 2021-08-17 | 河南大学 | Propenone derivative for removing N-methylofloxacin and preparation method and application thereof |
| CN114276369A (en) * | 2021-10-26 | 2022-04-05 | 河南大学 | Isoleucinine analogs, preparation method and application of isoleucinine analogs from rufloxacin to isoleucinine analogs |
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