CN111646937A - 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 PDFInfo
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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):
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 ofNPropenone derivatives of (E) -acetyl ciprofloxacin for achieving fluoroquinolone bonesThe frame is effectively spliced with the 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 chalcone-like chalcone compound can be used as an anti-tumor active substance to develop an anti-tumor drug with a brand new structure.
Description
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
NThe in vitro antibacterial action of the-acetyl ciprofloxacin belongs to fluoroquinolones is similar to that of norfloxacin and is slightly worse than that of ciprofloxacin, but the in vivo antibacterial activity of the-acetyl ciprofloxacin is obviously better than that of norfloxacin, including the action on escherichia coli, pneumonia bacillus pyocyaneus 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:
a kind ofN-an propenone derivative of acetyl ciprofloxacin having the following general structural formula (i):
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 aboveNThe preparation method of the propenone derivative of the acetyl ciprofloxacin comprises 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; the technical route is as follows:
(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; the technical route is as follows:
(3) the C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin in the step (2) is subjected to hydrolysis decarboxylation reaction in a sodium hydroxide aqueous solution under the condition of oil bath stirring reflux, placed at room temperature, filtered to collect solid, washed with water, dried and recrystallized to obtain the compoundN-acetyl ciprofloxacin C-3 ethanone; the technical route is as follows:
(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; the technical route is as follows:
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 carbonyldiimidazole is 1 (1-2), and the reflux reaction is carried out in a water bath for 10 to 24 hours until the raw materials are reactedNDisappearance of-acetyl ciprofloxacin.
In the step (2)N-acetyl ciprofloxacin imidazole amide compound and malonic acid monoethyl etherThe molar ratio of the ester potassium salt 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.
In the step (4)NThe molar ratio of the C-3 ethanone of the acetyl ciprofloxacin to the aromatic aldehyde 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 aboveNApplication of an acrylketone derivative of-acetyl ciprofloxacin in preparation of 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 fluoroquinolone medicine of the present inventionNDominant pharmacophore of (E) -Acetylciprofloxacin' 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) The-ketone skeleton is used as a substituent of an aryl acrylketone structure, and then a fluoroquinolone 'chalcone-like' derivative with a novel structure is designed. Realizes the effective combination of the fluoroquinolone skeleton and the acrylketone skeleton, and further constructs a novel fluoroquinolone-like chalconeThe ketone compound increases the antitumor activity and the anti-drug resistance of the new compound, reduces the toxic and side effects on normal cells, and can be used as an antitumor active substance to develop an antitumor 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-quinoline-4 (1)H) -a ketone (I-1) of formula:
namely, Ar in the formula I is phenyl.
The preparation method of the compound comprises the following steps:
(1) shown in formula IIN-acetyl ciprofloxacin (purchased commercially) is used as a raw material to react with Carbonyldiimidazole (CDI) to prepare the norfloxacin imidazole amide compound shown as a formula III, and the specific preparation method is as follows:
taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 20 g (54.0mmol) of (E) -ketone-3-carboxylic acid II is dissolved in 500 mL of anhydrous acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole is added, and the mixed reaction 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 a light yellow crystal of formula III, wherein the yield is 87.4%, and m.p. is 237-239 ℃.1H NMR (400 MHz, CD3Cl): 1.26 to 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) Represented by formula IIINThe preparation method comprises the following steps of (1) carrying out condensation reaction on-acetyl ciprofloxacin imidazole amide and malonic acid monoethyl ester potassium salt under the catalysis of triethylamine-magnesium chloride to obtain the C-3 formyl ethyl acetate compound of N-acetyl ciprofloxacin as shown in the formula IV, wherein the specific preparation method comprises the following steps:
taking 1-cyclopropyl-6-fluoro-7- (4-acetyl piperazine-1-yl) -3- (1H-imidazole-1-formyl) -quinoline-4 (1)H) 15g (35.5 mmol) of ketone III, 6.6g (69.1mmol) of magnesium chloride and 8.3g (49.0 mmol) of potassium monoethyl malonate are sequentially added into 600 mL of anhydrous acetonitrile, 12.5g (12.4 mmol) of triethylamine is dropwise added under ice-bath stirring, the mixed reactant is stirred in a water bath and refluxed until the raw material III disappears, the solvent is removed by reduced pressure evaporation, 500 mL of water is added, dichloromethane is used for extraction (3 × 150 mL), organic phases are combined, water is washed (3 × 200 mL), saturated saline water is washed (2 × 150 mL), anhydrous sodium sulfate is dried, dichloromethane is recovered under normal pressure, and the residue is recrystallized by anhydrous ethanol to obtain an off-white crystal of formula IV, wherein the yield is 78.6 percent and the m.p. is 234-236 ℃.1H NMR (400 MHz, CD3Cl): 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) Is shown as formula IVN(ii) mass fraction of C-3 formylethyl acetate compound of (E) -AcetylciprofloxacinThe C-3 ethanone compound of the N-acetyl ciprofloxacin shown in the formula V can be conveniently prepared by carrying out hydrolysis decarboxylation reaction on 3 percent of sodium hydroxide aqueous solution, and the specific preparation method is as follows:
taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 10g (22.6 mmol) of ethyl (E) -ketone-3-formylacetate is suspended in 200mL of 3 percent by mass sodium hydroxide aqueous solution, and the mixture is stirred and refluxed in an oil bath 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): 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) Taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.40 g (3.8 mmol) of benzaldehyde 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 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): 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) -quinoline-4 (1)H) -a ketone (I-2) of formula:
namely, Ar in the formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Keto-3-ethanone V with reference to steps (1) to (3) of example 1, the solvent in step (1) was replaced by tetrahydrofuran,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.0;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.57 g (4.2 mmol) of 4-methoxybenzaldehyde and piperidine (0.1mL) 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-2, wherein the yield is 74.6%, and the m.p. is 232-234 ℃.1H NMR (400 MHz, CD3Cl): 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) -quinoline-4 (1)H) -a ketone (I-3) of the formula:
namely, Ar in the formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Ketone-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with dioxane,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 2.0;
(2) taking 1-ethyl-6, 8-difluoro-7- (3, 4-dimethylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.53 g (3.5 mmol) of 3, 4-dioxytolualdehyde and piperidine (0.1mL) 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)：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) -quinoline-4 (1)H) -a ketone (I-4) of formula:
namely, Ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-keto-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with a mixed solution of dioxane and dimethylformamide with V/V =1:1,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-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 (0.1mL) 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-4, wherein the yield is 68.7%, and the m.p. is 231-233 ℃.1H NMR (400 MHz, CD3Cl): 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) -quinoline-4 (1)H) -a ketone (I-5) of formula:
namely, Ar in the formula I is p-methyl-phenyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of ketone-3-ethanone V referring to steps (1) to (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,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.58 g (4.8 mmol) of 4-methylbenzaldehyde and piperidine (0.1mL) as a base catalyst were added. Refluxing the mixed reactants for 15h, standing at room temperature, and filtering to collect the generated solid and anhydrousRecrystallizing with ethanol to obtain a light yellow crystal shown as formula I-5 with a yield of 63.6% and m.p. of 223-225 ℃.1H NMR (400 MHz, CD3Cl): 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) -quinoline-4 (1)H) -a ketone (I-6) of the formula:
namely, Ar in the formula I is p-fluoro-phenyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Keto-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced by dimethylformamide solution,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.2;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.48 g (3.8 mmol) of 4-fluorobenzaldehyde 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 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): 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) -quinoline-4 (1)H) -a ketone (I-7) of the formula:
namely, Ar in the formula I is p-chlorophenyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Keto-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced by dimethylformamide solution,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.45 g (3.2 mmol) of 4-chlorobenzaldehyde and piperidine (0.1mL) 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): 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) -quinoline-4 (1)H) -a ketone (I-8) of the formula:
namely, Ar in the formula I is p-bromophenyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Ketone-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with anhydrous acetonitrile solution,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.67 g (3.6 mmol) of 4-bromobenzaldehyde and piperidine (0.1mL) 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-8, wherein the yield is 74.0%, and the m.p. is 234-236 ℃.1H NMR (400 MHz, CD3Cl): 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) -quinoline-4 (1)H) -a ketone (I-9) of the formula:
namely, Ar in the formula I is p-nitrophenyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Ketone-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with anhydrous acetonitrile solution,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) -ketones1.0 g (3.0mmol) of (E) -3-ethanone V is dissolved in 20 mL of absolute ethanol, and 0.54 g (3.6 mmol) of 4-nitrobenzaldehyde and piperidine (0.1mL) as a base catalyst are 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): 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) -quinoline-4 (1)H) -a ketone (I-10) of the formula:
namely, Ar in the formula I is 4-hydroxy-phenyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Ketone-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with anhydrous acetonitrile solution,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.49g (4.0 mmol) of 4-hydroxy-benzaldehyde and piperidine (0.1mL) as a base catalyst 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): 1.26 to 1.38(4H, m, cyclopropyl-H), 2.28 (3H, s, N-COH)3) 2.77 to 3.63 (8H, m, piperazine-H), 4.36 (1H, m, cyclopropyl-H), 7.76 to 7.88 (6H, m, 8-H, P)H-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]-quinoline-4 (1)H) -a ketone (I-11) of formula:
namely, Ar in the formula I is 3-pyridyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Ketone-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with anhydrous acetonitrile solution,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.37 g (3.6 mmol) 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, namely a formula I-11, wherein the yield is 87.2%, and the m.p.252-254 ℃.1H NMR (400 MHz, CD3Cl): 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]Quinoline-4 (1)H) -a ketone (I-12) of the formula:
namely, Ar in the formula I is 2-furyl.
(1) 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) Preparation of-Ketone-3-ethanone V referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with anhydrous acetonitrile solution,N-the molar ratio of acetylciprofloxacin to carbonyldiimidazole is 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) 1.1g (3.0mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.38 g (4.0 mmol) of 2-furfural 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-12, wherein the yield is 67.6%, and the m.p. is 242-244 ℃.1H NMR (400 MHz, CD3Cl): 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, the value of each concentration of the sample is used for each pairPerforming linear regression on the cancer cell inhibition rate corresponding to the concentration to obtain a dose-effect equation, and calculating the half Inhibition Concentration (IC) of the test sample on the experimental cancer cells from the 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)
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. 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.
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 (10)
1. A kind ofN-an propenone derivative of acetyl ciprofloxacin, characterized by having the following general structural formula (i):
wherein Ar is any one selected from the group consisting of a benzene ring, a furan ring, a pyridine ring and a substituent thereof.
2. The method of claim 1N-an propenone derivative of acetyl ciprofloxacin characterized in that: 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.
3. The method of claim 1 or 2NThe 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) the C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin in the step (2) is subjected to hydrolysis decarboxylation reaction in a sodium hydroxide aqueous solution under the condition of oil bath stirring reflux, placed at room temperature, filtered to collect solid, washed with water, dried and recrystallized 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.
4. The method of claim 1NA 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.
5. The method of claim 1NA 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).
6. The method of claim 1NA 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.
7. The method of claim 1NA 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).
8. The method of claim 7NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: 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.
9. The method of claim 1 or 2NApplication of an acrylketone derivative of-acetyl ciprofloxacin in preparation of antitumor drugs.
10. Use according to claim 9, 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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