CN111646974A - N-methyl gatifloxacin propenone derivative and preparation method and application thereof - Google Patents

N-methyl gatifloxacin propenone derivative and preparation method and application thereof Download PDF

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CN111646974A
CN111646974A CN202010757567.9A CN202010757567A CN111646974A CN 111646974 A CN111646974 A CN 111646974A CN 202010757567 A CN202010757567 A CN 202010757567A CN 111646974 A CN111646974 A CN 111646974A
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methyl gatifloxacin
methyl
gatifloxacin
cyclopropyl
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姜原
黄帅
崔红艳
胡国强
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Abstract

The invention belongs to the field of drug synthesis, relates to a derivative of N-methyl gatifloxacin, and particularly relates to an propenone derivative of N-methyl gatifloxacin, and a preparation method and application thereof. Has the following structural general formula (I):

Description

N-methyl gatifloxacin propenone derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of medicine synthesis, relates to a derivative of N-methyl gatifloxacin, and particularly relates to an acrylketone derivative of N-methyl gatifloxacin, and a preparation method and application thereof.
Background
N-methyl gatifloxacin belongs to in vitro antibiosis, belongs to fluoroquinolones, has similar in vitro antibacterial action to that of norfloxacin and is slightly inferior to that of ciprofloxacin, but has in vivo antibacterial activity which is obviously superior to that of norfloxacin in the actions 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 gatifloxacin.
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 subject group, in a patent CN201611216638.4, namely an N-methyl gatifloxacin aldehyde thiosemicarbazone derivative, and a preparation method and application thereof, a fluoroquinolone C-3 carboxyl group is converted into a formyl group to form a corresponding fluoroquinolone C-3 aldehyde, and then the aldehyde is condensed with thiosemicarbazone, so that the splicing of a quinoline skeleton and a thiosemicarbazone pharmacophore is realized; preparing the fluoroquinolone medicine for tumor candidates.
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
In order to solve the technical problems, the invention provides an propenone derivative of N-methyl gatifloxacin, and a preparation method and application thereof.
The technical scheme of the invention is realized as follows:
an acrylketone derivative of N-methyl gatifloxacin has the following structural general formula (I):
formula I
Figure 428311DEST_PATH_IMAGE001
Wherein Ar is any one of a benzene ring, a substituted benzene ring, a furan ring or a pyridine ring.
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 N-methyl gatifloxacin comprises the following steps:
(1) carrying out water bath stirring reflux reaction on N-methyl gatifloxacin 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-methyl gatifloxacin imidazole amide compound; the technical route is as follows:
Figure 876609DEST_PATH_IMAGE002
(2) carrying out condensation reaction on the N-methyl gatifloxacin 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-methyl gatifloxacin; the technical route is as follows:
Figure 187505DEST_PATH_IMAGE003
(3) carrying out hydrolysis decarboxylation reaction on the C-3 formyl ethyl acetate compound of the N-methyl gatifloxacin 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 N-methyl gatifloxacin C-3 ethanone; the technical route is as follows:
Figure 317135DEST_PATH_IMAGE004
(4) carrying out Claisen-Schmidt condensation reaction on the N-methyl gatifloxacin C-3 ethanone in the step (3) and aromatic aldehyde in absolute ethyl alcohol under the catalysis of an alkali catalyst, and obtaining an propenone derivative of the N-methyl gatifloxacin after complete reaction; the technical route is as follows:
Figure 662666DEST_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-methyl gatifloxacin to the carbonyldiimidazole is 1 (1-2), and the reaction is stirred and refluxed in a water bath for 10 to 24 hours until the raw material N-methyl gatifloxacin disappears.
The molar ratio of the N-methyl gatifloxacin 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 6%, and the oil bath is stirred and refluxed for reaction for 5 to 10 hours until the C-3 ethyl formylacetate compound of the N-methyl gatifloxacin disappears.
In the step (4), the molar ratio of the N-methyl gatifloxacin C-3 ethanone 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 application of the acrylketone derivative of the N-methyl gatifloxacin 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-methyl gatifloxacin 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 the 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 relates to an acrylketone derivative of N-methyl gatifloxacin, which uses the dominant pharmacophore of fluoroquinolone medicine N-methyl gatifloxacin' 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazine-1-yl) -8-methoxy-quinoline-4 (1)H) -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 fluoroquinolone skeleton and acrylketone skeleton, and constructs new fluoroquinolone chalcone-like chalcone compounds, thereby increasing the anti-tumor activity and the anti-drug resistance of the new compounds, and reducing toxic and side effects on normal cellsHas the functions of developing antitumor medicine with new structure as antitumor active matter.
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- (3, 4-dimethylpiperazin-1-yl) -3-cinnamoyl-8-methoxy-quinoline-4 (1)H) -a ketone (I-1) of formula:
Figure 16287DEST_PATH_IMAGE006
namely, Ar in the formula I is phenyl.
The preparation method of the compound comprises the following steps:
(1) the N-methyl gatifloxacin imidazole amide compound shown in a formula III is prepared by taking N-methyl gatifloxacin shown in a formula II as a raw material and reacting with Carbonyldiimidazole (CDI), and the specific preparation method is as follows:
Figure 814478DEST_PATH_IMAGE002
taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 20g (51.0 mmol) 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 with a yield of 78.5% and m.p. of 228-230 ℃.1H NMR (400 MHz, CD3Cl): 1.25 to 1.47 (7H, m, cyclopropyl-H and CH)3),2.36 (3H,s,N-CH3) 2.76 to 3.55 (8H, m, piperazine-H), 3.87 (s,3H, OCH)3) 4.45 (1H, m, cyclopropyl-H), 6.75-7.35 (2H, m, imidazole-H), 8.14 (1H, d, 5-H), 8.36 (1H, s, imidazole-H), 8.92 (1H, s, 2-H); MS (m/z):440 [M+H]+Calculating (C)23H26FN5O3):439.49。
(2) The method comprises the following steps of carrying out condensation reaction on N-methyl gatifloxacin 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-methyl gatifloxacin shown in a formula IV, wherein the specific preparation method comprises the following steps:
Figure 810116DEST_PATH_IMAGE003
taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (1)H-imidazole-1-formyl) -8-methoxy-quinoline-4 (1)H) 17.0g (39.0 mmol) of ketone formula 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 65.6 percent and the m.p.218-220 ℃.1H NMR (400 MHz, CD3Cl)1.24 to 1.56 (10H, m, cyclopropyl-H and 2 × CH)3),2.35(3H,s,N-CH3) 2.76 to 3.54 (8H, m, piperazine-H), 3.87 (s,3H, OCH)3), 4.10 (2H,s,COCH2CO),4.18 (2H,q,CO2CH2) 4.47 (1H, m, cyclopropyl-H), 8.06 (1H, d, 5-H), 8.92 (1H, s, 2-H); MS (m/z):460 [M+H]+Calculating (C)24H30FN3O5):459.52。
(3) The C-3 ethyl formylacetate compound of the N-methyl gatifloxacin 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 N-methyl gatifloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:
Figure 13083DEST_PATH_IMAGE007
taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 10g (22.0 mmol) of ethyl (E) -ketone-3-formylacetate is suspended in 200mL of 6 mass percent sodium hydroxide aqueous solution, and the mixture is stirred in an oil bath and refluxed 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 73.8%, and m.p. is 220-222 ℃.1H NMR (400 MHz, CD3Cl): 1.23 to 1.58 (7H, m, cyclopropyl-H and CH)3),2.35 (3H,s,N-CH3) 2.76 to 3.57 (8H, m, piperazine-H), 3.89 (s,3H, OCH)3) 4.52 (2H, m, cyclopropyl-H), 8.07 (1H, d, 5-H), 8.91 (1H, s, 2-H); MS (m/z):388[M+H]+Calculating (C)21H26FN3O3):387.46。
(4) Taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) 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 (0.1 mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 18 h, standing at room temperature, filtering and collecting generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-1, wherein the yield is 72.4%, and the m.p. is 221-223 ℃.1H NMR (400 MHz, CD3Cl): 1.22 to 1.56 (7H, m, cyclopropyl-H and CH)3),2.37 (3H,s,N-CH3) 2.82 to 3.60 (8H, m, piperazine-H), 3.88(s, 3H, OCH)3) 4.46 (1H, m, cyclopropyl-H), 7.43-7.86 (6H, m, Ph-H and 2 ʹ -H), 8.12 (1H, d, 5-H), 8.63(1H, d, 3 ʹ -H), 8.88 (1H, s, 2-H); MS (m/z):476 [M+H]+Calculating (C)28H30FN3O3):475.57。
Example 2
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-2) of formula:
Figure 537605DEST_PATH_IMAGE008
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- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Method for the preparation of-keto-3-ethanone v referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with tetrahydrofuran, the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.0;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) 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 (0.1 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-2, wherein the yield is 68.5%, and the m.p. is 230-232 ℃.1H NMR (400 MHz, CD3Cl): 1.25 to 1.58 (7H, m, cyclopropyl-H and CH)3),2.38 (3H,s,N-CH3) 3.05 to 3.68 (8H, m, piperazine-H), 3.88, 3.92 (6H, 2s, 2 × OCH3) 4.47 (1H, m, cyclopropyl-H), 7.46-8.02 (5H, m, Ph-H and 2 ʹ -H), 8.27 (1H, d, 5-H), 8.63(1H, d, 3 ʹ -H), 8.95 (1H, s, 2-H); MS (m/z):506 [M+H]+Calculating (C)29H32FN3O4):505.59。
Example 3
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (3, 4-dioxocinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-3) of the formula:
Figure 823093DEST_PATH_IMAGE009
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- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Method for the preparation of-keto-3-ethanone v referring to steps (1) to (3) of example 1, the solvent in step (1) was replaced with dioxane, the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 2.0;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.53 g (3.5mmol) 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 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 72.6%, and the m.p. is 231-233 ℃.1H NMR (400 MHz,CD3Cl): 1.25 to 1.61 (7H, m, cyclopropyl-H and CH)3),2.36 (3H,s,N-CH3) 2.93 to 3.65 (8H, m, piperazine-H), 3.88 (3H, s, OCH)3) 4.50 (1H, m, cyclopropyl-H), 6.24 (2H, s, OCH)2O), 7.47-8.05 (4H, m, Ph-H and 2 ʹ -H), 8.26 (1H, d, 5-H), 8.67 (1H, d, 3 ʹ -H), 8.93 (1H, s, 2-H); MS (m/z):520[M+H]+Calculating (C)29H30FN3O5):519.58。
Example 4
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (3,4, 5-trimethoxycinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-4) of formula:
Figure 294526DEST_PATH_IMAGE010
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- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Method for preparing 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 dioxane and dimethylformamide with V/V =1:1, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.2;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.63 g (3.2mmol) 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 64.6%, and the m.p. is 216-218 ℃.1H NMR (400 MHz,CD3Cl): 1.23-1.57 (7H, m, cyclopropyl-H and CH)3),2.36 (3H,s,N-CH3) 2.85-3.63 (8H, m, piperazine-H), 3.88, 3.90, 3.96 (12H, 3s, 4' OCH)3) 4.56 (1H, m, cyclopropyl-H), 7.44-7.93 (3H, m, Ph-H and 2 ʹ -H), 8.20 (1H, d, 5-H), 8.65(1H, d, 3 ʹ -H), 8.92 (1H, s, 2-H); MS (m/z):566 [M+H]+Calculating (C)31H36FN3O6):565.65。
Example 5
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (4-methylcinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-5) of formula:
Figure 349070DEST_PATH_IMAGE011
namely, Ar in the formula I is p-methyl-phenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation of (E) -Ketone-3-ethanone V referring to Steps (1) - (3) of example 1, the solvent in step (1) was replaced with V/V of anhydrous acetonitrile and dimethylformamideA mixed solution of =1:1, wherein the molar ratio of the N-methyl gatifloxacin to the carbonyldiimidazole is 1: 1.4;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) 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 (0.1 mL) 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 66.2%, and the m.p. is 216-218 ℃.1H NMR (400 MHz, CD3Cl): 1.23-1.57 (7H, m, cyclopropyl-H and CH)3),2.24 (3H,s,Ph-CH3),2.36 (3H,s,N-CH3) 2.82 to 3.56 (8H, m, piperazine-H), 3.88 (3H, s, OCH)3) 4.57 (1H, m, cyclopropyl-H), 7.45-7.88 (5H, m, Ph-H and 2 ʹ -H), 8.21 (1H, d, 5-H), 8.60 (1H, d, 3 ʹ -H), 8.87 (1H, s, 2-H); MS (m/z):490 [M+H]+Calculating (C)29H32FN3O3):489.60。
Example 6
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (4-fluorocinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-6) of the formula:
Figure 310072DEST_PATH_IMAGE012
namely, Ar in the formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation method of-ketone-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with a dimethylformamide solution, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.7;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Dissolving 1.2g (3.0 mmol) of (E) -keto-3-ethanone in 20 mL of anhydrous ethanol, adding0.48 g (3.8 mmol) of 4-fluorobenzaldehyde and piperidine (0.1 mL) as a base catalyst. And (3) carrying out reflux reaction on the mixed reactants for 16h, 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 75.3%, and the m.p. is 223-225 ℃.1H NMR (400 MHz, CD3Cl): 1.27 to 1.65 (7H, m, cyclopropyl-H and CH)3),2.41 (3H,s,N-CH3) 3.07 to 3.68 (8H, m, piperazine-H), 3.92(3H, s, OCH)3) 4.64 (1H, m, cyclopropyl-H), 7.55-8.17 (5H, m, Ph-H and 2 ʹ -H), 8.36 (1H, d, 5-H), 8.67 (1H, d, 3 ʹ -H), 9.08 (1H, s, 2-H); MS (m/z):494 [M+H]+Calculating (C)28H29F2N3O3):484.56。
Example 7
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (4-chlorocinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-7) of the formula:
Figure 82856DEST_PATH_IMAGE013
namely, Ar in the formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation method of-ketone-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.8;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.45 g (3.2mmol) of 4-chlorobenzaldehyde 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-7, wherein the yield is 65.2%, and the m.p. is 223-225 ℃.1H NMR (400 MHz, CD3Cl): 1.26 to 1.63 (7H, m, cyclopropyl-H and CH)3),2.38 (3H,s,N-CH3) 2.96 to 3.66 (8H, m, piperazine-H), 3.90(3H, s, OCH)3) 4.57 (1H, m, cyclopropyl-H), 7.54-8.07 (5H, m, Ph-H and 2 ʹ -H), 8.32 (1H, d, 5-H), 8.62 (1H, d, 3 ʹ -H), 9.06 (1H, s, 2-H); MS (m/z):510 [M+H]+(35Cl), calculating (C)28H29FClN3O4):510.01。
Example 8
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (4-bromocinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-8) of the formula:
Figure 889138DEST_PATH_IMAGE014
namely, Ar in the formula I is p-bromophenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation method of-ketone-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with tetrahydrofuran solution, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.8;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) 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 (0.1 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-8, wherein the yield is 68.3%, and the m.p. is 234-236 ℃.1H NMR (400 MHz, CD3Cl): 1.26 to 1.63 (7H, m, cyclopropyl-H and CH)3),2.42 (3H,s,N-CH3) 3.11 to 3.67 (8H, m, piperazine-H), 3.93 (3H, s, OCH)3) 4.62 (1H, m, cyclopropyl-H), 7.55-8.07 (5H, m, Ph-H and 2 ʹ -H), 8.32 (1H, d, 5-H), 8.65(1H, d, 3 ʹ -H), 9.06 (1H, s, 2-H); MS (m/z): 554 and 556 [ M + H]+(79Br and81br), calculating (C)28H29FBrN3O3):554.46。
Example 9
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-9) of the formula:
Figure 329347DEST_PATH_IMAGE015
namely, Ar in the formula I is p-nitrophenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation method of-ketone-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with tetrahydrofuran solution, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.8;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.54 g (3.6 mmol) of 4-nitrobenzaldehyde and piperidine (0.1 mL) as a base catalyst 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 70.1%, and the m.p. is 235-237 ℃.1H NMR (400 MHz, CD3Cl): 1.28-1.67 (7H, m, cyclopropyl-H and CH)3),2.44 (3H,s,N-CH3) 3.15 to 3.68 (8H, m, piperazine-H), 3.93 (3H, s, OCH)3) 4.68 (1H, m, cyclopropyl-H), 7.56-8.18 (5H, m, Ph-H and 2 ʹ -H), 8.45 (1H, d, 5-H), 8.65(1H, d, 3 ʹ -H), 9.18 (1H, s, 2-H); MS (m/z): 521, calculating (C)28H29FN4O5):520.57。
Example 10
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- (4-hydroxy-cinnamoyl) -8-methoxy-quinoline-4 (1)H) -a ketone (I-10) of the formula:
Figure 195672DEST_PATH_IMAGE016
namely, Ar in the formula I is 4-hydroxy-phenyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation method of-ketone-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) 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 (0.1 mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 22h, standing at room temperature, filtering and collecting generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-10, wherein the yield is 56.2%, and the m.p. is 227-229 ℃.1H NMR (400 MHz, CD3Cl): 1.25 to 1.58 (7H, m, cyclopropyl-H and CH)3),2.38 (3H,s,N-CH3) 2.94 to 3.62 (8H, m, piperazine-H), 3.89(3H, s, OCH)3) 4.57 (1H, m, cyclopropyl-H), 7.50-7.87 (5H, m, Ph-H and 2 ʹ -H), 8.22 (1H, d, 5-H), 8.62 (1H, d, 3 ʹ -H), 8.93 (1H, s, 2-H), 10.57 (1H, s, OH); MS (m/z): 492, calculate (C)28H30FN4O4):491.57。
Example 11
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl]-8-methoxy-quinoline-4 (1)H) -a ketone (I-11) of formula:
Figure 455752DEST_PATH_IMAGE017
namely, Ar in the formula I is 3-pyridyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation method of-ketone-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) 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 (0.1 mL) 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 78.6%, and the m.p. is 244-246 ℃.1H NMR (400 MHz, CD3Cl): 1.26 to 1.68 (7H, m, cyclopropyl-H and CH)3),2.45 (3H,s,N-CH3) 3.17 to 3.78 (8H, m, piperazine-H), 3.94 (3H, s, OCH)3) 4.66 (1H, m, cyclopropyl-H), 7.56 (1H, d, 2 ʹ -H), 8.36-9.15 (5H, 5-H, 3 ʹ -H and pyridine-H), 9.22 (1H, s, 2-H); MS (m/z): 477 calculating (C)27H29FN4O3):476.56。
Example 12
1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl]Quinoline-4 (1)H) -a ketone (I-12) of the formula:
Figure 268987DEST_PATH_IMAGE018
namely, Ar in the formula I is 2-furyl.
The preparation method of the compound comprises the following steps:
(1) 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) Preparation method of-ketone-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with an anhydrous acetonitrile solution, and the molar ratio of N-methyl gatifloxacin to carbonyldiimidazole was 1: 1.5;
(2) taking 1-cyclopropyl-6-fluoro-7- (3, 4-dimethylpiperazin-1-yl) -8-methoxy-quinoline-4 (1)H) 1.2g (3.0 mmol) of (E) -keto-3-ethanone V was dissolved in 20 mL of anhydrous ethanol, and 0.38 g (4.0 mmol) of 2-furan aldehyde and piperidine (0.1 mL) as a base catalyst were added. And 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 shown as a formula I-12, wherein the yield is 60.2%, and the m.p. is 238-240 ℃.1H NMR (400 MHz, CD3Cl): 1.25 to 1.64 (4H, m, cyclopropyl-H and CH)3),2.38 (3H,s,N-CH3) 2.96 to 3.61 (8H, m, piperazine-H), 3.92(3H, s, OCH)3),4.65 (2H,q,N-CH2) 7.12-7.86 (4H, m, 2 ʹ -H and furan-H), 8.30 (1H, d, 5-H), 8.63(1H, d, 3 ʹ -H), 9.06 (1H, s, 2-H); MS (m/z):466 [M+H]+Calculating (C)26H28FN3O4):465.53。
Examples of the effects of the invention
In vitro antitumor activity assays were performed using the acrylketone derivatives of N-methyl gatifloxacin provided in examples 1-12:
1. test sample
15 samples of the propenone derivative of N-methyl gatifloxacin provided in examples 1 to 12, a classical antitumor TOPO inhibitor 10-Hydroxycamptothecin (HC), a chalcone tyrosinase inhibitor Sunitinib (SN), a broad-spectrum anticancer drug Doxorubicin (DOX) and a parent compound N-Methyl Gatifloxacin (MGF) were used as test samples, wherein HC, SN and MGF are control experimental groups, and examples 1 to 12 are test experimental groups;
thiazole blue (MTT), HC, SN and MGF 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 1.0 × 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.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)
Figure DEST_PATH_IMAGE020
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-methyl gatifloxacin, 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), tyrosine kinase inhibitors Sunitinib (SN) and adriamycin (DOX), and the IC of the compounds is50The 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 toxicity 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.
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. The propenone derivative of the N-methyl gatifloxacin is characterized by having the following structural general formula (I):
Figure DEST_PATH_IMAGE001
in the formula I, Ar is any one of a benzene ring, a substituted benzene ring, a furan ring or a pyridine ring.
2. The propenone derivative of N-methyl gatifloxacin of claim 1, 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 for preparing the propenone derivative of N-methyl gatifloxacin according to claim 1 or 2, comprising the steps of:
(1) carrying out water bath stirring reflux reaction on N-methyl gatifloxacin 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-methyl gatifloxacin imidazole amide compound;
(2) carrying out condensation reaction on the N-methyl gatifloxacin 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-methyl gatifloxacin;
(3) carrying out hydrolysis decarboxylation reaction on the C-3 formyl ethyl acetate compound of the N-methyl gatifloxacin 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 N-methyl gatifloxacin C-3 ethanone;
(4) and (4) carrying out Claisen-Schmidt condensation reaction on the N-methyl gatifloxacin C-3 ethanone in the step (3) and aromatic aldehyde in absolute ethyl alcohol under the catalysis of an alkali catalyst, and completely reacting to obtain the propenone derivative of the N-methyl gatifloxacin.
4. The method for producing an propenone derivative of N-methyl gatifloxacin according to claim 3, characterized in that: the solvent in the step (1) is at least one of anhydrous acetonitrile, tetrahydrofuran, dioxane or dimethylformamide; the molar ratio of the N-methyl gatifloxacin to the carbonyldiimidazole is 1 (1-2), and the reaction is stirred and refluxed in a water bath for 10 to 24 hours.
5. The method for producing an propenone derivative of N-methyl gatifloxacin according to claim 3, characterized in that: the molar ratio of the N-methyl gatifloxacin imidazole amide compound to the potassium monoethyl malonate in the step (2) is 1 (1-1.5).
6. The method for producing an propenone derivative of N-methyl gatifloxacin according to claim 3, characterized in that: the mass fraction of the sodium hydroxide aqueous solution in the step (3) is 6 percent, and the oil bath is stirred and refluxed for 5 to 10 hours.
7. The method for producing an propenone derivative of N-methyl gatifloxacin according to claim 3, characterized in that: in the step (4), the molar ratio of the N-methyl gatifloxacin C-3 ethanone to the aromatic aldehyde is 1 (1-2).
8. The method for producing an propenone derivative of N-methyl gatifloxacin according to claim 7, characterized in that: 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. Use of the propenone derivative of N-methyl gatifloxacin according to claim 1 or 2 for the preparation of an antitumor agent.
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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