CN111646937B - Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof - Google Patents

Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof Download PDF

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CN111646937B
CN111646937B CN202010757342.3A CN202010757342A CN111646937B CN 111646937 B CN111646937 B CN 111646937B CN 202010757342 A CN202010757342 A CN 202010757342A CN 111646937 B CN111646937 B CN 111646937B
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acetyl ciprofloxacin
ciprofloxacin
acetyl
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cyclopropyl
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CN111646937A (en
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黄帅
曹玉辉
崔红艳
胡国强
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Henan University
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Abstract

The invention belongs to the field of drug synthesis, relates to a derivative of N-acetyl ciprofloxacin, and particularly relates to an acrylketone derivative of N-acetyl ciprofloxacin and a preparation method and application thereof. Has the following structural general formula (I):
Figure 100004_DEST_PATH_IMAGE001
wherein Ar is any one selected from the group consisting of a benzene ring, a furan ring, a pyridine ring and a substituent thereof. A kind ofNThe acrylketone derivative of the acetyl ciprofloxacin realizes the effective combination of a fluoroquinolone framework and an acrylketone framework, so that a novel fluoroquinolone chalcone-like chalcone compound is constructed, the anti-tumor activity and the anti-drug resistance of the novel compound are increased, the toxic and side effects on normal cells are reduced, and the fluoroquinolone derivative can be used as an anti-tumor active substance to develop anti-tumor drugs with a brand new structure.

Description

Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, relates to a derivative of N-acetyl ciprofloxacin, and particularly relates to an acrylketone derivative of N-acetyl ciprofloxacin and a preparation method and application thereof.
Background
N-acetyl ciprofloxacin belongs to fluoroquinolones, has similar in vitro antibacterial action to that of norfloxacin and is slightly poorer than that of ciprofloxacin, but has in vivo antibacterial activity which is obviously better than that of norfloxacin on escherichia coli, pneumonia bacillus, pseudomonas aeruginosa and staphylococcus aureus. The action mechanism is the same as that of norfloxacin. At present, the medicine is mainly used for urogenital infection and intestinal infection. As a lead of new drugs, the research finds that the new drugs are effective methods for new drug innovation based on the structure or mechanism of N-methyl lomefloxacin.
The acrylketone structure is not only a characteristic structure of a chalcone compound which is a natural active ingredient, but also a characteristic pharmacophore 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 the clinical application; in addition, in the preparation and application of CN201811343703.9 bis-fluoroquinolone thiadiazole urea N-acetyl ciprofloxacin derivatives, 2 quinolone skeleton structural units are constructed into the bis-fluoroquinolone thiadiazole urea derivatives by taking thiadiazole urea as a connecting chain; preparing the targeted antitumor drug.
The applicant combines the action target of the antibacterial fluoroquinolone medicine, namely topoisomerase, to be an important action target of the antitumor medicine, can convert the antibacterial activity of the antibacterial fluoroquinolone medicine into the antitumor activity, and finds that 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 effect of substituting the C-3 carboxyl group of fluoroquinolone with a different group cannot be determined. To solve the technical problems and to explore new drugs with good therapeutic effect and no toxicity, a great deal of research and test are carried out in the subject group to improve the water solubility of chalcones and introduce hydrophilic piperazinyl to increase the water solubility, improve the bioavailability and bioactivity of chalcones.
Disclosure of Invention
The invention provides an acrylketone derivative of N-acetyl ciprofloxacin and a preparation method and application thereof, which are used for preparing a new medicament with excellent anti-tumor effect and improving the activity of a primer for inhibiting cancer cells.
The technical scheme of the invention is realized as follows:
an acrylketone derivative of N-acetyl ciprofloxacin has the following structural general formula (I):
Figure DEST_PATH_IMAGE001
wherein Ar is any one selected from the group consisting of a benzene ring, a furan ring, a pyridine ring and a substituent thereof.
Wherein Ar is selected from any one of phenyl, p-methoxyphenyl, 3,4- (dioxymethylene) phenyl, 3,4, 5-trimethoxyphenyl, p-methyl-phenyl, p-fluoro-phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 4-hydroxy-phenyl, 3-pyridyl or 2-furyl.
The preparation method of the propenone derivative of the N-acetyl ciprofloxacin comprises the following steps:
(1) carrying out water bath stirring reflux reaction on N-acetyl ciprofloxacin serving as a raw material and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing with acetone to obtain an N-acetyl ciprofloxacin imidazole amide compound; the technical route is as follows:
Figure DEST_PATH_IMAGE002
；
(2) carrying out condensation reaction on the N-acetyl ciprofloxacin imidazole amide compound in the step (1) and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride, and carrying out reduced pressure evaporation to remove a solvent, extraction, water washing, drying and recrystallization to obtain a C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin; the technical route is as follows:
Figure DEST_PATH_IMAGE003
；
(3) carrying out hydrolysis decarboxylation reaction on the C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin in the step (2) in a sodium hydroxide aqueous solution under the condition of oil bath stirring reflux, standing at room temperature, filtering to collect solid, washing with water, drying and recrystallizing to obtain C-3 ethanone of the N-acetyl ciprofloxacin; the technical route is as follows:
Figure DEST_PATH_IMAGE004
；
(4) carrying out Claisen-Schmidt condensation reaction on the C-3 ethanone of the N-acetyl ciprofloxacin in the step (3) and aromatic aldehyde in absolute ethyl alcohol under the catalysis of an alkali catalyst, and obtaining an acrylketone derivative of the N-acetyl ciprofloxacin after complete reaction; the technical route is as follows:
Figure DEST_PATH_IMAGE005
。
the solvent in the step (1) is at least one of anhydrous acetonitrile, tetrahydrofuran, dioxane or dimethylformamide; the molar ratio of the N-acetyl ciprofloxacin to the carbonyldiimidazole is 1 (1-2), and the reaction is stirred in a water bath and refluxed for 10 to 24 hours until the raw material N-acetyl ciprofloxacin disappears.
The molar ratio of the N-acetyl ciprofloxacin imidazole amide compound to the potassium monoethyl malonate in the step (2) is 1 (1-1.5.)
And (3) the mass fraction of the sodium hydroxide aqueous solution in the step (3) is 3%, and the reaction is carried out for 5 to 10 hours under stirring and reflux in an oil bath until the C-3 ethyl formylacetate compound of the reactant N-acetylciprofloxacin disappears.
The molar ratio of the C-3 ethanone of the N-acetyl ciprofloxacin to the aromatic aldehyde in the step (4) is 1 (1-2);
the aromatic aldehyde is any one of benzaldehyde, 4-methoxybenzene, 3, 4-dioxytoluylene aldehyde, 3,4, 5-trioxybenzaldehyde, 4-methylbenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-nitrobenzaldehyde, 4-hydroxy-benzaldehyde, 3-pyridine aldehyde or 2-furan aldehyde; 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 propenone derivative of the N-acetyl ciprofloxacin in preparing antitumor drugs.
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 invention has the following beneficial effects:
1. the acrylketone derivative of the N-acetyl ciprofloxacin is designed and synthesized by effectively combining a fluoroquinolone framework and an aryl acrylketone pharmacophore based on the splicing 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.
2. The invention uses the skeleton of the dominant pharmacophore of fluoroquinolone medicine N-acetyl ciprofloxacin, namely 1-cyclopropyl-6-fluoro-7- (4-acetyl piperazine-1-yl) -quinoline-4 (1H) -ketone, as the substituent of an aryl acrylketone structure, and further designs the fluoroquinolone 'chalcone-like' derivative with a novel structure. The method realizes the effective combination of the fluoroquinolone skeleton and the acrylketone skeleton, and further constructs a new fluoroquinolone chalcone-like chalcone compound, thereby increasing the anti-tumor activity and the anti-drug resistance of the new compound, reducing the toxic and side effects on normal cells, and being capable of being used as an anti-tumor active substance to develop an anti-tumor drug with a brand new structure.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical formula:
Figure DEST_PATH_IMAGE006
namely, Ar in the formula I is phenyl.
The preparation method of the compound comprises the following steps:
(1) the norfloxacin imidazole amide compound shown in the formula III is prepared by taking N-acetyl ciprofloxacin shown in the formula II as a raw material (purchased commercially) and reacting with Carbonyldiimidazole (CDI), and the specific preparation method is as follows:
Figure 443478DEST_PATH_IMAGE002
20 g (54.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-carboxylic acid II is dissolved in 500 mL of anhydrous acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole is added, and the mixture is stirred in a water bath and refluxed until the starting material II disappears. Standing at room temperature, filtering to collect the generated solid, and recrystallizing with acetone to obtain a light yellow crystal of formula III, wherein the yield is 87.4%, and m.p. is 237-239 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.26-1.35 (4H, m, cyclopropyl-H), 2.26 (3H, s, Ac), 2.71-3.53 (8H, m, piperazine-H), 4.36 (1H, m, cyclopropyl-H), 6.83-7.86 (3H, m, imidazole-H and 8-H), 8.05 (1H, d, 5-H), 8.40 (1H, s, imidazole-H), 8.92 (1H, s, 2-H); MS (m/z): 424 [ M + H]+Calculating (C)22H22FN5O3)：423.45。
(2) The preparation method comprises the following steps of carrying out condensation reaction on N-acetyl ciprofloxacin 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 N-acetyl ciprofloxacin shown in a formula IV, wherein the preparation method comprises the following steps:
Figure 829460DEST_PATH_IMAGE003
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) -quinolin-4 (1H) -one of formula III 15g (35.5 mmol), magnesium chloride 6.6g (69.1mmol) and potassium monoethyl malonate 8.3g (49.0 mmol) were added successively to 600 mL of anhydrous acetonitrile, triethylamine 12.5g (12.4 mmol) was added dropwise with stirring in an ice bath, and the mixture was stirred in a water bath under refluxReacting until the raw material III disappears. The solvent was distilled off under reduced pressure, 500 mL of water was added, the mixture was extracted with methylene chloride (3X 150 mL), the organic phases were combined, washed with water (3X 200 mL), washed with saturated brine (2X 150 mL), and dried over anhydrous sodium sulfate. And recovering dichloromethane at normal pressure, and recrystallizing the residue with absolute ethyl alcohol to obtain a white crystal shown as a formula IV, wherein the yield is 78.6%, and the m.p. is 234-236 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.20 to 1.35 (7H, m, cyclopropyl-H and CH)3) 2.28 (3H, s, Ac), 2.78-3.60 (8H, m, piperazine-H), 4.08 (2H, s, COCH)2CO), 4.37 (1H, m, cyclopropyl-H), 4.22 (2H, q, CO)2CH2)，7.83 (1H，d，8-H)，8.08 (1H，d，5-H)，8.86 (1H，s, 2-H)；MS (m/z)：444 [M+H]+Calculating (C)23H26FN3O5)：443.48。
(3) The C-3 ethyl formylacetate compound of the N-acetylciprofloxacin shown in the formula IV is subjected to hydrolysis decarboxylation reaction by using 3 percent of sodium hydroxide aqueous solution by mass fraction, so that the C-3 ethanone compound of the N-acetylciprofloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:
Figure 812459DEST_PATH_IMAGE004
taking 10g (22.6 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-formylacetic acid ethyl ester IV and suspending the ethyl ester in 200mL of sodium hydroxide aqueous solution with the mass fraction of 3%, stirring in an oil bath and refluxing to react until the raw material IV disappears. Standing at room temperature, filtering to collect the generated solid, washing with water to neutrality, drying, and recrystallizing with anhydrous ethanol to obtain light yellow crystal of formula V, with yield of 78.3%, m.p. 228-230 deg.C.1H NMR (400 MHz, CD3Cl) δ: 1.23-1.35 (4H, m, cyclopropyl-H), 2.28 (3H, s, N-Ac), 2.44 (3H, s, COCH)3) 2.76 to 3.55 (8H, m, piperazine-H), 4.34 (2H, m, cyclopropyl-H), 7.83 (1H, d, 8-H), 8.05 (1H, d, 5-H), 8.87 (1H, s, 2-H); MS (m/z): 372[ M + H ]]+Calculating (C)20H22FN3O3)：371.42。
(4) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.40 g (3.8 mmol) of benzaldehyde and piperidine, a basic catalyst (0.1 mL) 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 78.2%, and the m.p. is 230-232 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.23-1.35 (4H, m, cyclopropyl-H), 2.26 (3H, s, N-COH)3) 2.81 to 3.63 (8H, m, piperazine-H), 4.42 (1H, m, cyclopropyl-H), 7.45 to 7.86 (7H, m, 8-H, Ph-H and 2 ʹ -H), 8.25 (1H, d, 5-H), 8.57 (1H, d, 3 ʹ -H), 8.88 (1H, s, 2-H); MS (m/z): 460 [ M + H ]]+Calculating (C)27H26FN3O3)：459.52。
Example 2
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical formula:
Figure DEST_PATH_IMAGE007
namely, Ar in the formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps:
(1) preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with tetrahydrofuran, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.0;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.57 g (4.2 mmol) of 4-methoxybenzaldehyde and piperidine, a basic catalyst (0.1 mL) were added. And (3) refluxing and reacting the mixed reactants for 20 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-2, wherein the yield is 74.6%, and the m.p. is 232-234 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.24-1.36 (4H, m, cyclopropyl-H), 2.28 (3H, s, N-COH)3) 2.82 to 3.61 (8H, m, piperazine-H), 3.92 (3H, s, OCH)3) 4.42 (1H, m, cyclopropyl-H), 7.75-7.93 (6H, m, 8-H, Ph-H and 2 ʹ -H), 8.32 (1H, d, 5-H), 8.58 (1H, d, 3 ʹ -H), 8.92 (1H, s, 2-H); MS (m/z): 490 [ M + H [ ]]+Calculating (C)28H28FN3O4)：489.55。
Example 3
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (3, 4-dioxocinnamoyl) -quinolin-4 (1H) -one (I-3) having the chemical formula:
Figure DEST_PATH_IMAGE008
namely, Ar in the formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the following steps:
(1) preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with dioxane, and the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 2.0;
(2) 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3, 4-dimethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.53 g (3.5 mmol) of 3, 4-dioxytolualdehyde and piperidine (0.1 mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, 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-3, wherein the yield is 78.3%, and the m.p. is 236-238 ℃.1H NMR (400 MHz, CD3Cl) δ：1.37~1.63 (6H, m, 2´CH3)，2.38(3H，s，N-CH3) 3.07 to 3.68 (7H, m, piperazine-H), 4.72 (2H, q, N-CH)2)，6.23 (2H，s，OCH2O), 7.62-7.87 (5H, m, Ph-H, 5-H and 2 ʹ -H), 8.63 (1H, d, 3 ʹ -H), 8.97 (1H, s, 2-H); MS (m/z): 496 [ M + H]+Calculating (C)27H27FN3O4)：495.53。
Example 4
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (3,4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (I-4) having the chemical formula:
Figure DEST_PATH_IMAGE009
namely, Ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps:
(1) preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with a mixed solution of dioxane and dimethylformamide with V/V =1:1, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.63 g (3.2 mmol) of 3,4, 5-trioxybenzaldehyde and piperidine (0.1 mL) 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-4, wherein the yield is 68.7%, and the m.p. is 231-233 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.21 to 1.37 (4H, m, cyclopropyl-H), 2.26 (3H, s, N-COH)3) 2.80-3.63 (8H, m, piperazine-H), 3.86, 3.90 (9H, 2s, 3' OCH)3) 4.30 (1H, m, cyclopropyl-H), 7.85-7.92 (4H, m, 8-H, Ph-H and 2 ʹ -H), 8.32 (1H, d, 5-H), 8.57 (1H, d, 3 ʹ -H), 8.89 (1H, s, 2-H); MS (m/z): 550 [ M + H ]]+Calculating (C)30H32FN3O6)：549.60。
Example 5
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the chemical formula:
Figure DEST_PATH_IMAGE010
namely, Ar in the formula I is p-methyl-phenyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with a mixed solution of anhydrous acetonitrile and dimethylformamide with V/V =1:1, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.58 g (4.8 mmol) of 4-methylbenzaldehyde and piperidine, a basic catalyst (0.1 mL) 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 63.6%, and the m.p. is 223-225 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.22 to 1.34 (4H, m, cyclopropyl-H), 2.26 (3H, s, Ph-CH)3)，2.27 (3H, s, N-COH3) 2.75-3.58 (8H, m, piperazine-H), 4.36 (1H, m, cyclopropyl-H), 7.56-7.87 (6H, m, 8-H, Ph-H and 2 ʹ -H), 8.28 (1H, d, 5-H), 8.55(1H, d, 3 ʹ -H), 8.87 (1H, s, 2-H); MS (m/z): 474 [ M + H]+Calculating (C)28H28FN3O3)：473.55。
Example 6
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-fluorocinnamoyl) -quinolin-4 (1H) -one (I-6) having the chemical formula:
Figure DEST_PATH_IMAGE011
namely, Ar in the formula I is p-fluoro-phenyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with a dimethylformamide solution, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.2;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.48 g (3.8 mmol) of 4-fluorobenzaldehyde and piperidine, a basic catalyst (0.1 mL) 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-6, wherein the yield is 80.6%, and the m.p. is 238-240 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.26 to 1.46 (4H, m, cyclopropyl-H), 2.32 (3H, s, N-COH)3) 2.88 to 3.67 (8H, m, piperazine-H), 4.36 (1H, m, cyclopropyl-H), 7.87 to 8.08 (6H, m, 8-H, Ph-H and 2 ʹ -H), 8.35 (1H, d, 5-H), 8.62 (1H, d, 3 ʹ -H), 9.11 (1H, s, 2-H); MS (m/z): 478 [ M + H]+Calculating (C)27H25F2N3O3)：477.52。
Example 7
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-chlorocinnamoyl) -quinolin-4 (1H) -one (I-7) having the chemical formula:
Figure DEST_PATH_IMAGE012
namely, Ar in the formula I is p-chlorophenyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with a dimethylformamide solution, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.45 g (3.2 mmol) of 4-chlorobenzaldehyde and piperidine (0.1 mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 20 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-7, wherein the yield is 73.6%, and the m.p. is 227-229 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.24-1.38 (4H, m, cyclopropyl-H), 2.30 (3H, s, N-COH)3) 2.82 to 3.63 (8H, m, piperazine-H), 4.37 (1H, m, cyclopropyl-H), 7.86 to 8.07 (6H, m, 8-H, Ph-H and 2 ʹ -H), 8.34 (1H, d, 5-H), 8.58 (1H, d, 3 ʹ -H), 8.97 (1H, s, 2-H); MS (m/z): 494 [ M + H]+(35Cl), calculating (C)27H25FClN3O3)：493.97。
Example 8
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical formula:
Figure DEST_PATH_IMAGE013
namely, Ar in the formula I is p-bromophenyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.67 g (3.6 mmol) of 4-bromobenzaldehyde and piperidine as a base catalyst (0.1 mL) were added. And (3) refluxing and reacting the mixed reactants for 20 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 74.0%, and the m.p. is 234-236 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.24-1.42 (4H, m, cyclopropyl-H), 2.32 (3H, s, N-COH)3) 2.85-3.67 (8H, m, piperazine-H), 4.36 (1H, m, cyclopropyl-H), 7.88-8.13 (6H, m, 8-H, Ph-H and 2 ʹ -H), 8.38 (1H, d, 5-H), 8.57 (1H, d, 3 ʹ -H), 9.05 (1H, s, 2-H); MS (m/z): 538 and 540 [ M + H]+(79Br and81br), calculating (C)27H25FBrN3O3)：538.42。
Example 9
1-cyclopropyl-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical formula:
Figure DEST_PATH_IMAGE014
namely, Ar in the formula I is p-nitrophenyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.0 g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.54 g (3.6 mmol) of 4-nitrobenzaldehyde and piperidine, a base catalyst (0.1 mL) were added. And (3) refluxing and reacting the mixed reactants for 24 hours, standing at room temperature, filtering and collecting generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-9, wherein the yield is 78.6%, and the m.p. is 253-255 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.31 to 1.46 (4H, m, cyclopropyl-H), 2.32 (3H, s, N-COH)3) 3.07 to 3.68 (8H, m, piperazine-H), 4.45 (1H, m, cyclopropyl-H), 7.86 to 8.17 (6H, m, 8-H, Ph-H and 2 ʹ -H), 8.43 (1H, d, 5-H), 8.62 (1H, d, 3 ʹ -H), 9.16 (1H, s, 2-H); MS (m/z): 505, calculating (C)27H25FN4O5)：504.52。
Example 10
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- (4-hydroxy-cinnamoyl) -quinolin-4 (1H) -one (I-10) having the chemical formula:
Figure DEST_PATH_IMAGE015
namely, Ar in the formula I is 4-hydroxy-phenyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.49g (4.0 mmol) of 4-hydroxy-benzaldehyde and piperidine, a base catalyst (0.1 mL) were added. And carrying out reflux reaction on the mixed reactants for 22h, 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-10, wherein the yield is 64.5%, and the m.p. is 233-235 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.26 to 1.38 (4H, m, cyclopropyl-H), 2.28 (3H, s, N-COH)3) 2.77-3.63 (8H, m, piperazine-H), 4.36 (1H, m, cyclopropyl-H), 7.76-7.88 (6H, m, 8-H, Ph-H and 2 ʹ -H), 8.34 (1H, d, 5-H), 8.57 (1H, d, 3 ʹ -H), 8.87 (1H, s, 2-H), 10.57 (1H, s, OH); MS (m/z): 476, calculating (C)27H26FN4O4)：475.52。
Example 11
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical formula:
Figure DEST_PATH_IMAGE016
namely, Ar in the formula I is 3-pyridyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.37 g (3.6 mmol) of 3-pyridylaldehyde and piperidine, a base catalyst (0.1 mL) were added. The mixed reactants are refluxed and reacted for 15 hours, the mixed reactants are placed at room temperature, the generated solid is collected by filtration, and the absolute ethyl alcohol is recombinedCrystallizing to obtain a yellow crystal shown as a formula I-11, wherein the yield is 87.2 percent and the m.p. is 252-254 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.32 to 1.46 (4H, m, cyclopropyl-H), 2.33 (3H, s, N-COH)3) 3.15 to 3.74 (8H, m, piperazine-H), 4.45 (1H, m, cyclopropyl-H), 7.78 to 8.12 (2H, m, 8-H and 2 ʹ -H), 8.46 to 8.97 (6H, 5-H, 3 ʹ -H and pyridine-H), 9.18 (1H, s, 2-H); MS (m/z): 461, calculating (C)26H25FN4O3)：460.51。
Example 12
1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical formula:
Figure DEST_PATH_IMAGE017
namely, Ar in the formula I is 2-furyl.
(1) Preparation of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, the molar ratio of N-acetylciprofloxacin to carbonyldiimidazole was 1: 1.5;
(2) 1.1g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.38 g (4.0 mmol) of 2-furfural and piperidine (0.1 mL) 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-12, wherein the yield is 67.6%, and the m.p. is 242-244 ℃.1H NMR (400 MHz, CD3Cl) δ: 1.24-1.37 (4H, m, cyclopropyl-H), 2.30 (3H, s, N-COH)3) 2.78-3.65 (8H, m, piperazine-H), 4.46 (1H, m, cyclopropyl-H), 7.12-7.88 (5H, m, 8-H, 2 ʹ -H, and furan-H), 8.36 (1H, d, 5-H), 8.57 (1H, d, 3 ʹ -H), 8.96 (1H, s, 2-H); MS (m/z): 450 [ M + H ]]+Calculating (C)25H24FN3O4)：449.49。
Examples of the effects of the invention
In vitro antitumor activity assays were performed using acrylketone derivatives of N-acetyl ciprofloxacin provided in examples 1-12:
1. test sample
15 samples of the propenone derivative of N-acetyl ciprofloxacin provided by examples 1-12, a classic anti-tumor TOPO inhibitor 10-Hydroxycamptothecin (HC), a chalcone tyrosinase inhibitor Sunitinib (SN), a broad-spectrum anti-cancer drug adriamycin (DOX) and a parent compound N-Acetyl Ciprofloxacin (ACF) are taken as test samples, wherein HC, SN and ACF are used as control experimental groups, and examples 1-12 are used as test experimental groups;
thiazole blue (MTT), HC, SN and ACF 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) first, the 15 kinds of test samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0' 10-4mol∙L-1Stock solution of concentration, and then diluting the stock solution with 10% calf serum RPMI-1640 culture solution to obtain stock solution with 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0mmol ∙ L)-1) The working fluid of (1);
2) taking a 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, a human leukemia cell strain HL60, a human renal clear cell cancer cell sunitinib drug-resistant strain 7SuR and African green monkey kidney VERO in a 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, adding 10 mu L of 5 g.L-1 MTT (thiazole blue) solution in each hole after 48 hours, continuously culturing for 4 hours, and then adding 100 mu L of dodecyl sodium sulfate (SDS) solution with the mass percentage concentration of 10%. 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, linear regression is carried out on the cancer cell inhibition rate corresponding to each concentration by the pair value of each concentration of the test sample to obtain a dose-effect equation, and the half Inhibition Concentration (IC) of the test sample to the experimental cancer cell is calculated from the obtained dose-effect equation50) (ii) a Each data was measured in triplicate and averaged, the results are shown in Table 1.
TABLE 1 antitumor Activity (IC) of the test samples50)
Figure DEST_PATH_IMAGE019
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 N-acetyl ciprofloxacin, 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 is50The value is close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1-12 also showed very strong sensitivity to sunitinib-resistant strain 7SuR, showed strong resistance to drugs, and showed low toxicity to normal cells VERO, having a property of becoming drug-resistant. Thus, following the general approach of drug development, conventional in vitro anti-tumor screening followed by targeted drug discovery is performedThe research shows that the compound of the invention has strong antitumor activity, drug resistance activity and lower cytotoxicity, and the antitumor drug can be prepared by salifying with acid acceptable for human bodies or mixing with a medicinal carrier.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (9)

1. A kind ofN-an propenone derivative of acetyl ciprofloxacin, characterized by having the following general structural formula (i):
Figure 311749DEST_PATH_IMAGE001
wherein Ar is selected from any one of phenyl, p-methoxyphenyl, 3,4- (dioxymethylene) phenyl, 3,4, 5-trimethoxyphenyl, p-methyl-phenyl, p-fluoro-phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 4-hydroxy-phenyl, 3-pyridyl or 2-furyl.
2. The method of claim 1NThe preparation method of the propenone derivative of the acetyl ciprofloxacin is characterized by comprising the following steps:
(1) to be provided withNPerforming water bath stirring reflux reaction on-acetyl ciprofloxacin serving as a raw material and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing with acetone to obtain the (E) -acetyl ciprofloxacinN-acetyl ciprofloxacin imidazole amide compounds;
(2) step (1) ofNCarrying out condensation reaction on an acetyl ciprofloxacin imidazole amide compound and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride, and carrying out reduced pressure evaporation to remove a solvent, extraction, water washing, drying and recrystallization to obtain a C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin;
(3) c-3 Formylacetic acid ethyl ester of N-acetylciprofloxacin of step (2)Hydrolyzing and decarboxylating the compound in sodium hydroxide aqueous solution under the condition of oil bath stirring and refluxing, standing at room temperature, filtering to collect solid, washing with water, drying and recrystallizing to obtain the compoundN-acetyl ciprofloxacin C-3 ethanone;
(4) subjecting the obtained product of step (3)NThe C-3 ethanone of the-acetyl ciprofloxacin and aromatic aldehyde are subjected to Claisen-Schmidt condensation reaction in absolute ethyl alcohol under the catalysis of a base catalyst, and the reaction is complete to obtainN-an propenone derivative of acetyl ciprofloxacin.
3. The method of claim 2NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: the solvent in the step (1) is at least one of anhydrous acetonitrile, tetrahydrofuran, dioxane or dimethylformamide;Nthe mol ratio of the-acetyl ciprofloxacin to the carbonyl diimidazole is 1 (1-2), and the reaction is stirred in a water bath and refluxed for 10 to 24 hours.
4. The method of claim 2NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: in the step (2)NThe mol ratio of the-acetyl ciprofloxacin imidazole amide compound to the potassium salt of the monoethyl malonate is 1 (1-1.5).
5. The method of claim 2NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: and (3) stirring and refluxing the sodium hydroxide aqueous solution with the mass fraction of 3% in the step (3) for 5-10 hours.
6. The method of claim 2NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: in the step (4)NThe molar ratio of the C-3 ethanone of the acetyl ciprofloxacin to the aromatic aldehyde is 1 (1-2).
7. The method of claim 6NA method for preparing an acrylketone derivative of (E) -acetyl ciprofloxacin, which is characterized in thatIn the following steps: the aromatic aldehyde is any one of benzaldehyde, 4-methoxybenzaldehyde, 3, 4-dioxy methylene benzaldehyde, 3,4, 5-trimethoxy benzaldehyde, 4-methyl benzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-nitrobenzaldehyde, 4-hydroxy-benzaldehyde, 3-pyridine aldehyde or 2-furan aldehyde; the base catalyst is at least one of piperidine, pyridine, triethylamine, morpholine, potassium acetate, sodium hydroxide ethanol solution or potassium hydroxide ethanol solution.
8. The method of claim 1NApplication of an acrylketone derivative of-acetyl ciprofloxacin in preparation of antitumor drugs.
9. Use according to claim 8, characterized in that: 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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