CN111647004A - Propenone derivative for removing N-methylofloxacin and preparation method and application thereof - Google Patents
Propenone derivative for removing N-methylofloxacin 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 for removing N-methylofloxacin, and particularly relates to an acrylketone derivative for removing N-methylofloxacin, and a preparation method and application thereof. Has the following structural general formula (I):
Description
Technical Field
The invention belongs to the field of drug synthesis, relates to a derivative for removing N-methylofloxacin, and particularly relates to an acrylketone derivative for removing N-methylofloxacin, and a preparation method and application thereof.
Background
Ofloxacin is an artificially synthesized, broad-spectrum antibacterial fluoroquinolone medicine, is synthesized in 1982, and has the advantages of easy absorption, fast and complete oral administration, high and lasting blood concentration, wide medicine distribution in vivo, etc. The ofloxacin is a high-efficiency broad-spectrum antibacterial agent, has strong effects on gram-positive bacteria (including methicillin-resistant staphylococcus aureus) and gram-negative bacteria (including pseudomonas aeruginosa), and also has certain activity on mycoplasma pneumoniae, neisseria, anaerobic bacteria and mycobacterium tuberculosis. As a lead of new drugs, based on the structure or mechanism of ofloxacin, the research finds that the new drugs are effective methods for new drug innovation.
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 acrylketone derivative for removing N-methylofloxacin and a preparation method and application thereof.
The technical scheme of the invention is realized as follows:
an acrylketone derivative for removing N-methylofloxacin has the following structural general formula (I):
in the formula I, 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 for removing the N-methylofloxacin comprises the following steps:
(1) carrying out water bath stirring reflux reaction on the raw material of de-N-methylofloxacin and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing by acetone to obtain a de-N-methylofloxacin imidazole amide compound; the technical route is as follows:
(2) carrying out condensation reaction on the N-methylofloxacin imidazole amide compound removed 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 formylethyl acetate compound removed with the N-methylofloxacin; the technical route is as follows:
(3) carrying out hydrolysis decarboxylation reaction on the C-3 formyl ethyl acetate compound subjected to N-methylofloxacin removal 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-methylofloxacin-C-3 ethanone; the technical route is as follows:
(4) carrying out Claisen-Schmidt condensation reaction on the N-methylofloxacin-removed C-3 ethanone obtained in the step (3) and aromatic aldehyde in absolute ethyl alcohol under the catalysis of an alkali catalyst, and completely reacting to obtain an propenone derivative for removing the N-methylofloxacin; the technical route is as follows:
the solvent in the step (1) is at least one of anhydrous acetonitrile, tetrahydrofuran, dioxane or dimethylformamide; the molar ratio of the N-methylofloxacin to the carbonyldiimidazole is 1 (1-2), and the temperature of the water bath stirring reflux reaction is 10-24 hours until the N-methylofloxacin serving as the raw material disappears.
The molar ratio of the de-N-methylofloxacin 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%, stirring and refluxing the mixture in an oil bath for 5 to 10 hours to react until the C-3 ethyl formylacetate compound for removing the N-methylofloxacin disappears.
The molar ratio of the N-methylofloxacin C-3 ethanone 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 propenone derivative without the N-methylofloxacin is applied to the preparation of the 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:
the acrylketone derivative for removing N-methylofloxacin is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the split principle of the pharmacophores, realizes the complementation and activity superposition of the pharmacophores with different structures, achieves the effects of synergy, toxicity reduction and drug resistance, and can be developed as an anti-tumor drug with a brand new structure.
The invention uses the advantageous pharmacophore of fluoroquinolone medicine de-N-methylofloxacin "1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) The-ketone skeleton is used as a substituent of an aryl acrylketone structure, so that a fluoroquinolone 'chalcone-like' derivative with a novel structure is designed, the fluoroquinolone skeleton and the acrylketone skeleton are effectively spliced, and a new fluoroquinolone 'chalcone-like' compound is constructed, so that the anti-tumor activity and the anti-drug resistance of the new compound are increased, the toxic and side effects on normal cells are reduced, and the fluoroquinolone 'chalcone-like' derivative can be 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, 8-isopropoxy-6-fluoro-7-piperazin-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) the de-N-methylofloxacin imidazole amide compound shown as a formula III is prepared by taking the de-N-methylofloxacin shown as a formula II as a raw material and reacting with Carbonyldiimidazole (CDI), and the specific preparation method is as follows:
taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 21.0 g (60.0 mmol) of (II) -keto-3-carboxylic acid was dissolved in 500 mL of anhydrous acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole was added, and the reaction mixture was washed with waterThe bath is stirred and the reflux reaction is carried out until the raw material II disappears. Standing at room temperature, filtering to collect the generated solid, and recrystallizing with acetone to obtain the light yellow crystal of de-N-methylofloxacin imidazole amide shown as formula III with the yield of 83.6 percent and the m.p. of 235-237 ℃.1H NMR (400 MHz, CD3Cl)：1.62(3H, d, CH3) 3.05 to 3.65 (8H, m, piperazine-H), 4.38 to 4.82 (3H, m, O-CH)2CH-N), 7.46-7.65 (2H, m, imidazole-H), 8.13 (1H, s, imidazole-H), 8.97 (1H, d, 5-H), 9.14 (1H, s, 2-H); MS (m/z)：398 [M+H]+Calculating (C)20H20FN5O3)：397.41。
(2) The method comprises the following steps of carrying out condensation reaction on N-methylofloxacin 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 shown in a formula IV, wherein the C-3 formyl ethyl acetate compound is obtained by removing N-methylofloxacin, and the specific preparation method comprises the following steps:
taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-3- (1)H-imidazole-1-formyl) - [ quinoline-4 (1)H) 15.5g (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, 12.2g (12.0 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), the 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 formula IV with the yield of 72.6 percent and the m.p. of 228-230 ℃.1HNMR (400 MHz, CD3Cl)：1.26~1.65 (6H，m，2×CH3) 2.97 to 3.66 (8H, m, piperazine-H), 3.43 to 4.85 (7H, m, COCH)2COOCH2And O-CH2CH-N)，8.94 (1H，d，5-H)，9.16 (1H，s, 2-H)；MS (m/z)：418 [M+H]+Calculating (C)21H24FN3O5)：417.44。
(3) The C-3 ethyl formylacetate compound of the de-N-methylofloxacin shown in the formula IV is hydrolyzed and decarboxylated by 6 percent of sodium hydroxide aqueous solution, so as to conveniently prepare the C-3 ethanone compound of the de-N-methylofloxacin shown in the formula V, and the specific preparation method is as follows:
taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 10g (24.0 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, 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 83.2%, m.p. 232-234 deg.C.1H NMR (400 MHz, CD3Cl)：1.63 (3H, d,CH3), 2.40 (3H，s，COCH3) 3.14 to 3.72 (8H, m, piperazine-H), 4.41 to 4.86 (3H, m, O-CH)2CH-N)，8.96 (1H，d，5-H)，9.14 (1H，s, 2-H)；MS (m/z)：346 [M+H]+Calculating (C)18H20FN3O3)：345.38。
(4) Taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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 77.6%, and the m.p. is 233-235 ℃.1H NMR (400 MHz, CD3Cl)：1.64 (3H, d, CH3) 3.15 to 3.68 (8H, m, piperazine-H), 4.45 to 4.87 (3H, m, O-CH)2CH-N), 7.63-8.74 (7H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.95 (1H, d, 5-H), 9.16 (1H, s, 2-H); MS (m/z)：434 [M+H]+Calculating (C)25H24FN3O3)：433.49。
Example 2
1, 8-isopropoxy-6-fluoro-7-piperazin-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, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Process for the preparation of-keto-3-ethanone V with reference to steps (1) to (3) of example 1, the solvent in step (1) was replaced by a tetrahydrofuran solution with a molar ratio of DeN-methylofloxacin to carbonyldiimidazole of 1: 1.0;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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) 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-2, wherein the yield is 80.5%, and the m.p. is 236-238 ℃.1H NMR (400 MHz, CD3Cl)：1.65(3H, d,CH3) 3.15 to 3.70 (8H, m, piperazine-H), 3.89 (3H, s, OCH)3)，4.46~4.86 (3H，m，O-CH2CH-N), 7.63-8.82 (6H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.96 (1H, d, 5-H), 9.13 (1H, s, 2-H); MS (m/z)：464 [M+H]+Calculating (C)26H26FN3O4)：463.51。
Example 3
1, 8-isopropoxy-6-fluoro-7-piperazin-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, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Preparation of-keto-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with dioxane solution, and the molar ratio of de-N-methylofloxacin to carbonyldiimidazole was 1: 1.0;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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 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 83.7%, and the m.p. is 240-242 ℃.1H NMR (400 MHz, CD3Cl)： 1.65 (3H,d, CH3) 3.16 to 3.77 (8H, m, piperazine-H), 4.46 to 4.86 (3H, m, O-CH)2CH-N)，6.23 (2H，s，OCH2O), 7.65-8.86 (5H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.93 (1H, d, 5-H), 9.15 (1H, s, 2-H); MS (m/z)：478 [M+H]+Calculating (C)26H24FN3O5)：477.50。
Example 4
1, 8-Isopropoxy-6-fluoro-7-piperazin-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, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Preparation of-ketone-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 des-methylofloxacin to carbonyldiimidazole was 1: 1.2;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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 72.6%, and the m.p. is 227-229 ℃.1H NMR (400 MHz, CD3Cl)：1.62 (3H, d,CH3) 3.10 to 3.67 (8H, m, piperazine-H), 3.88, 3.93 (9H, 2s, 3 × OCH3)，4.45~4.80 (3H，m，O-CH2CH-N), 7.64-8.86 (4H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.93 (1H, d, 5-H), 9.14 (1H, s, 2-H); MS (m/z)：524 [M+H]+Calculating (C)28H30FN3O6)：523.57。
Example 5
1, 8-isopropoxy-6-fluoro-7-piperazin-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.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Preparation of-ketone-3-ethanone V referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with a mixed solution of tetrahydrofuran and dimethylformamide with V/V =1:1, the molar ratio of des-methylofloxacin to carbonyldiimidazole was 1: 1.7;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-5, wherein the yield is 65.7%, and the m.p. is 223-225 ℃.1H NMR (400 MHz, CD3Cl)：1.61 (3H, d,CH3), 2.26 (3H，s，Ph-CH3) 3.03 to 3.67 (8H, m, piperazine-H), 4.40 to 4.82 (3H, m, O-CH)2CH-N), 7.63-8.86 (6H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.96 (1H, d, 5-H), 9.08 (1H, s, 2-H); MS (m/z)：448 [M+H]+Calculating (C)26H26FN3O3)：447.51。
Example 6
1, 8-isopropoxy-6-fluoro-7-piperazin-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.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Preparation of-ketone-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 des-methylofloxacin to carbonyldiimidazole was 1: 1.5;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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 15h, 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 75.6%, and the m.p. is 235-237 ℃.1H NMR (400 MHz, CD3Cl)：1.66 (3H, d, CH3) 3.18 to 3.85 (8H, m, piperazine-H), 4.47 to 4.86 (3H, m, O-CH)2CH-N), 7.66-8.87 (6H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.98 (1H, d, 5-H), 9.17 (1H, s, 2-H); MS (m/z)：452 [M+H]+Calculating (C)25H23F2N3O3)：451.48。
Example 7
1, 8-isopropoxy-6-fluoro-7-piperazin-1-yl-3- (4-chlorocinnamyl) -quinoline-4 (1)H) -a ketone (I-7) of the formula:
namely, Ar in the formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Preparation of-ketone-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 tetrahydrofuran V/V =1:1, the molar ratio of des-N-methylofloxacin to carbonyldiimidazole was 1: 1.5;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-7, wherein the yield is 76.3%, and the m.p. is 231-233 ℃.1H NMR (400 MHz, CD3Cl)：1.65 (3H, d, CH3) 3.16 to 3.75 (8H, m, piperazine-H), 4.46 to 4.85 (3H, m, O-CH)2CH-N), 7.65-8.87 (6H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 9.03 (1H, d, 5-H), 9.17 (1H, s, 2-H); MS (m/z)：468 [M+H]+Calculating (C)25H23FClN3O3)：467.93。
Example 8
1, 8-isopropoxy-6-fluoro-7-piperazin-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.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Preparation of-keto-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with tetrahydrofuran solution with a molar ratio of de- Λ/-methylofloxacin to carbonyldiimidazole of 1: 1.8;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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) carrying out reflux reaction on the mixed reactants for 24 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-8, wherein the yield is 76.0%, and the m.p. is 233-235 ℃.1H NMR (400 MHz, CD3Cl)：1.67 (3H, d, CH3) 3.18 to 3.82 (8H, m, piperazine-H), 4.45 to 4.87 (3H, m, O-CH)2CH-N), 7.66-8.85 (6H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.96 (1H, d, 5-H), 9.16 (1H, s, 2-H); MS (m/z): 512 and 514 [ M + H]+(79Br and81br), calculating (C)25H23FBrN3O3)：512.38。
Example 9
1, 8-isopropoxy-6-fluoro-7-piperazin-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.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) Preparation of-keto-3-ethanone v referring to steps (1) - (3) of example 1, the solvent in step (1) was replaced with tetrahydrofuran solution with a molar ratio of de- Λ/-methylofloxacin to carbonyldiimidazole of 1: 1.5;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) Dissolving 1.0g (3.0mmol) of (E) -keto-3-ethanone in 20 mL of anhydrous ethanol, and adding 4-nitro-compoundBenzaldehyde 0.54 g (3.6 mmol) and piperidine (0.1mL) as a base catalyst. And (3) carrying out reflux reaction on 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 77.5%, and the m.p. is 240-242 ℃.1H NMR (400 MHz, CD3Cl)：1.67 (3H, d, CH3) 3.28 to 3.87 (8H, m, piperazine-H), 4.46 to 4.90 (3H, m, O-CH)2CH-N), 7.67-8.93 (6H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 9.05 (1H, d, 5-H), 9.18 (1H, s, 2-H); MS (m/z)：479 [M+H]+Calculating (C)25H23FN4O5)：478.48。
Example 10
1, 8-isopropoxy-6-fluoro-7-piperazin-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.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) The preparation of-keto-3-ethanone V is carried out according to the steps (1) to (3) of example 1, with a molar ratio of des-N-methylofloxacin to carbonyldiimidazole of 1: 1.5;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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 (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-10, wherein the yield is 70.2%, and the m.p. is 231-233 ℃.1H NMR (400 MHz, CD3Cl)：1.65 (3H, d, CH3) 3.03 to 3.76 (8H, m, piperazine-H), 4.45 to 4.87 (3H, m, O-CH)2CH-N), 7.65-8.86 (6H, m, Ph-H, 3 ʹ -H and 2 ʹ -H), 8.97 (1H, d, 5-H), 9.11 (1H, s, 2-H), 10.62 (1H, s, OH); MS (m/z): 450, calculate (C)25H24FN3O4)：449.49。
Example 11
1, 8-isopropoxy-6-fluoro-7-piperazin-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.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) The preparation of-keto-3-ethanone V is carried out according to the steps (1) to (3) of example 1, with a molar ratio of des-N-methylofloxacin to carbonyldiimidazole of 1: 1.5;
(2) taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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 shown as a formula I-11, wherein the yield is 80.2%, and the m.p. is 243-245 ℃.1H NMR (400 MHz, CD3Cl)：1.68 (3H, d, CH3) 3.27 to 3.78 (8H, m, piperazine-H), 4.45 to 4.96 (3H, m, O-CH)2CH-N), 7.66 (1H, d, 2 ʹ -H), 8.93-9.13 (6H, 5-H, 3 ʹ -H and pyridine-H), 9.25 (1H, s, 2-H); MS (m/z): 435, calculating (C)24H23FN4O3)：434.47。
Example 12
1, 8-isopropoxy-6-fluoro-7-piperazin-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.
The preparation method of the compound comprises the following steps:
(1) 1, 8-Isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4 (1)H) The preparation of-keto-3-ethanone V is carried out according to the steps (1) to (3) of example 1, with a molar ratio of des-N-methylofloxacin to carbonyldiimidazole of 1: 1.5;
(2) the preparation method of the compound comprises the following steps: taking 1, 8-isopropoxy-6-fluoro-7-piperazine-1-yl-quinoline-4 (1)H) 1.0g (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) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-12, wherein the yield is 67.5%, and the m.p. is 236-238 ℃.1H NMR (400 MHz, CD3Cl)：1.65(3H, d, CH3) 3.17 to 3.78 (8H, m, piperazine-H), 4.45 to 4.87 (3H, m, O-CH)2CH-N), 7.26-8.17 (5H, m, 2 ʹ -H, 3 ʹ -H and furan-H), 8.97 (1H, d, 5-H), 9.15 (1H, s, 2-H); MS (m/z)：424 [M+H]+Calculating (C)23H22FN3O3S)：424.45。
Examples of the effects of the invention
In vitro antitumor Activity assays Using the propenone derivatives with N-methylofloxacin prepared in examples 1-12:
1. test sample
15 of the acrylic ketone derivatives of ofloxacin provided in examples 1-12, the classical antitumor TOPO inhibitor 10-Hydroxycamptothecin (HC), the chalcone tyrosinase inhibitor Sunitinib (SN), the broad-spectrum anticancer drug Doxorubicin (DOX) and the parent compound des-N-methylofloxacin (DMOF) were used as test samples, wherein HC, SN and DMOF are control experimental groups, and examples 1-12 are test experimental groups;
thiazole blue (MTT), HC, SN and DMOF 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)
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 des-N-methylofloxacin, 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 is IC50The value is reached or close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1 to 12 also show extremely strong sensitivity to sunitinib-resistant strain 7SuR, show strong drug-resistant activity, and simultaneously show low cytotoxicity to normal cells VERO, and have the property of becoming drug-resistant. Therefore, according to the general approach of drug development, the conventional antitumor in vitro screening is carried out, and then the targeted research is carried out, so that the compound has strong antitumor activity, drug resistance activity and lower cytotoxicity, and can be used for preparing antitumor drugs by salifying with acid acceptable for human bodies or mixing with medicinal carriers.
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. An acrylketone derivative for removing N-methylofloxacin is characterized by having the following structural general formula (I):
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 des-N-methylofloxacin according to claim 1, wherein: 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 process for preparing the propenone derivative with N-methylofloxacin according to claim 1 or 2, characterized by the following steps:
(1) carrying out water bath stirring reflux reaction on the raw material of de-N-methylofloxacin and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing by acetone to obtain a de-N-methylofloxacin imidazole amide compound;
(2) carrying out condensation reaction on the N-methylofloxacin imidazole amide compound removed 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 formylethyl acetate compound removed with the N-methylofloxacin;
(3) carrying out hydrolysis decarboxylation reaction on the C-3 formyl ethyl acetate compound subjected to N-methylofloxacin removal 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-methylofloxacin-C-3 ethanone;
(4) and (4) carrying out Claisen-Schmidt condensation reaction on the N-methylofloxacin-removed C-3 ethanone obtained 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 with the N-methylofloxacin removed.
4. The process for the preparation of the propenone derivative with de-N-methylofloxacin 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-methylofloxacin 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 process for the preparation of the propenone derivative with de-N-methylofloxacin according to claim 3, characterized in that: the molar ratio of the de-N-methylofloxacin imidazole amide compound to the potassium monoethyl malonate in the step (2) is 1 (1-1.5).
6. The process for the preparation of the propenone derivative with de-N-methylofloxacin 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 for 5 to 10 hours of reflux reaction.
7. The process for the preparation of the propenone derivative with de-N-methylofloxacin according to claim 3, characterized in that: the molar ratio of the N-methylofloxacin C-3 ethanone to the aromatic aldehyde in the step (4) is 1 (1-2).
8. The process for the preparation of the propenone derivative of des-N-methylofloxacin according to claim 7, wherein: 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 with N-methylofloxacin according to claim 1 or 2 for preparing an antitumor medicament.
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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