阅读说明：本技术 一种诺氟沙星的丙烯酮衍生物及其制备方法和应用 (Acrylic ketone derivative of norfloxacin, and preparation method and application thereof ) 是由 武毅君 胡国强 于 2019-11-20 设计创作，主要内容包括：本发明公开了一种诺氟沙星的丙烯酮衍生物及其制备方法和应用,采用如下式Ⅰ化学结构通式：式I中,芳香环Ar为苯环或取代苯环或呋喃环或吡啶环。本发明的一种诺氟沙星的丙烯酮衍生物,实现了氟喹诺酮骨架与丙烯酮骨架的有效拼合,进而构筑了新的氟喹诺酮“类查尔酮”化合物,从而增加了新化合物的抗肿瘤活性及抗耐药性,并降低对正常细胞的毒副作用,可以作为抗肿瘤活性物质开发全新结构的抗肿瘤药物。(The invention discloses an acrylketone derivative of norfloxacin, a preparation method and application thereof, wherein the norfloxacin adopts a chemical structural general formula as shown in the following formula I:)

1. An acrylketone derivative of norfloxacin, which is characterized by being a typical compound with the following structure:

2. the preparation method of the acrylketone derivative of norfloxacin according to claim 1, which comprises the following steps:

1) the norfloxacin compound shown in the formula II is used as a raw material, and is reacted with Carbonyldiimidazole (CDI) to prepare a norfloxacin imidazole amide compound shown in the formula III, and then the norfloxacin imidazole amide compound is subjected to condensation reaction with monoethyl malonate potassium salt to prepare a C-3 formyl ethyl acetate compound of norfloxacin shown in the formula IV; finally, the norfloxacin C-3 ethanone shown in the formula V is prepared by hydrolysis decarboxylation reaction of the formula IV:

2) norfloxacin C-3 ethanone shown in formula V and aromatic aldehyde are subjected to Claisen-Schmidt condensation reaction under the catalysis of alkali to form an acrylketone structure, and the acrylketone derivative of norfloxacin shown in claim 1 can be prepared through post-treatment.

3. The preparation method of the acrylketone derivative of norfloxacin according to claim 2, wherein the molar ratio of norfloxacin represented by the formula II to CDI is 1: 1.0-2.0, the molar ratio of norfloxacin imidazole amide represented by the formula III to monoethyl malonate potassium salt is 1: 1.0-1.5, and the molar ratio of norfloxacin-3 ethanone represented by the formula V to aromatic aldehyde is 1: 1.0-2.0.

4. The use of the acrylketone derivative of norfloxacin as claimed in claim 1 in the preparation of an antitumor medicament.

5. The use of the acrylketone derivative of norfloxacin as claimed in claim 4, wherein the antitumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.

Technical Field

The invention belongs to the technical field of innovative drug synthesis, and particularly relates to an acrylketone derivative of norfloxacin, a preparation method of the acrylketone derivative of norfloxacin, and application of the acrylketone derivative of norfloxacin in antitumor drugs.

Background

New drug innovation stems from the discovery of leads, and rational drug molecular design based on structure or mechanism is an effective method for discovering leads. In the drug effect groups with various structures, the acrylketone structure is not only the characteristic structure of a chalcone compound which is a natural effective component, but also the characteristic drug effect group of a targeted antitumor drug sunitinib. Therefore, compounds constructed with acrylketone as a structural fragment and having various pharmacological activities have been attracting attention. However, most of natural chalcone compounds are multi-hydroxyl benzene ring substituted propenone compounds, and the poor water solubility of the compounds causes low bioavailability and limits clinical application. In addition, the topoisomerase which is an action target point of the antibacterial fluoroquinolone medicine is also an important action target point of the antitumor medicine, the antibacterial activity of the antibacterial fluoroquinolone medicine can be converted into the antitumor activity, and the fluoroquinolone C-3 carboxyl is not a pharmacophore required by the antitumor activity and can be replaced by a biological electron isostere to improve the antitumor activity of the fluoroquinolone medicine. However, the research on the replacement of the C-3 carboxyl group of fluoroquinolone with aryl acrylketone has not been reported. Based on the above, in order to improve the water solubility of chalcone, hydrophilic piperazinyl is introduced to increase the water solubility and improve the bioavailability and the bioactivity of the chalcone, the invention uses the skeleton of the advantageous pharmacophore of the fluoroquinolone drug norfloxacin, namely '1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one', as a substituent of an aryl propenone structure, and further designs the derivatives of the fluoroquinolone 'chalcone-like' with novel structures.

Therefore, the invention aims to provide the acrylketone derivative of norfloxacin, which has the anti-tumor effect and efficacy and also provides a preparation method of the acrylketone derivative of norfloxacin.

In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the acrylic ketone derivative of norfloxacin has a chemical structural formula shown as a general formula I:

in the formula I, Ar is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring, and the compound is a compound with the following specific structure:

the preparation method of the acrylketone derivative of norfloxacin takes the commercially obtained norfloxacin shown in the formula II as a raw material to prepare the norfloxacin derivative;

the preparation method comprises the following specific steps:

1) norfloxacin shown in a formula II is used as a raw material and reacts with Carbonyldiimidazole (CDI) to prepare the norfloxacin imidazole amide compound shown in a formula III, and the specific preparation method is as follows:

dissolving 20g (62.7mmol) of 1-ethyl-6-fluoro-7-piperazine-1-yl-quinoline-4 (1H) -ketone-3-carboxylic acid II in 500mL of anhydrous acetonitrile, adding 15.2g (94.0mmol) of carbonyldiimidazole, and stirring the mixed reactants in a water bath and refluxing to react 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 78.6% and m.p.236-238 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.45(3H，t，CH₃) 2.68 to 3.47(8H, m, piperazine-H), 4.46(2H, q, N-CH)₂) 6.64-7.84 (3H, m, imidazole-H and 8-H), 8.08(1H, d, 5-H), 8.26(1H, s, imidazole-H), 8.86(1H, s, 2-H); MS (m/z): 370[ M + H]⁺Calculating (C)₁₉H₂₀FN₅O₂)：369.40。

As a further improvement, the molar ratio of norfloxacin shown in the formula II to carbonyldiimidazole is 1: 1.0-2.0, and the solvent can be at least one of acetonitrile, tetrahydrofuran, dioxane and dimethylformamide or a mixed solvent of the two.

2) The preparation method comprises the following steps of carrying out condensation reaction on norfloxacin 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 norfloxacin shown in a formula IV, wherein the specific preparation method comprises the following steps:

taking 15g (40.6mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-3- (1H-imidazole-1-formyl) -quinolin-4 (1H) -one formula III, 6.6g (69.1mmol) of magnesium chloride and 8.3g (49.0mmol) of potassium monoethyl malonate, sequentially adding into 600mL of anhydrous acetonitrile, dropwise adding 12.5g (12.4mmol) of triethylamine under stirring in an ice bath, and stirring and refluxing the mixed reaction in a water bath until the raw material III disappears. The solvent was evaporated under reduced pressure, 500mL of water was added, the mixture was extracted with methylene chloride (3X 150mL), the organic phases were combined, washed with water (3X 200mL), washed with saturated brine (2X 150mL), and dried over anhydrous sodium sulfate. And recovering dichloromethane at normal pressure, and recrystallizing the residue with absolute ethyl alcohol to obtain a white crystal shown as a formula IV, wherein the yield is 68.4%, and m.p.218-220 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.26,1.47(6H，2t，2×CH₃) 2.72 to 3.52(8H, m, piperazine-H), 3.96(2H, s, COCH)₂CO)，4.47(2H，q，N-CH₂)，4.26(2H，q，CO₂CH₂)，6.65(1H，d，8-H)，8.06(1H，d，5-H)，8.84(1H，s,2-H)；MS(m/z)：390[M+H]⁺Calculating (C)₂₀H₂₄FN₃O₄)：389.43。

3) The C-3 ethyl formylacetate compound of the norfloxacin 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 norfloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:

taking 10g (26.0mmol) of ethyl 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-formylacetate and suspending the ethyl in 200mL of 6 mass percent oxyhydrogenIn the sodium hydroxide aqueous solution, stirring and refluxing the reaction in an oil bath until the raw material IV disappears. Standing at room temperature, collecting the generated solid by filtration, washing with water to be neutral, drying, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal of formula V, wherein the yield is 84.2%, and m.p.224-226 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.45(3H，t，CH₃)，2.42(3H，s，COCH₃) 2.66 to 3.50(8H, m, piperazine-H), 4.46(2H, q, N-CH)₂)，6.67(1H，d，8-H)，8.07(1H，d，5-H)，8.87(1H，s,2-H)；MS(m/z)：318[M+H]⁺Calculating (C)₁₇H₂₀FN₃O₂)：317.37。

4) C-3 ethanone of norfloxacin shown in a formula V and aromatic aldehyde are subjected to Claisen-Schmidt aldol condensation reaction in absolute ethyl alcohol under the catalysis of alkali, and after the reaction is completed, a target compound is obtained by treatment, wherein the target compound is shown in a formula I, and the specific process is as follows:

wherein Ar in the formula I is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring.

The general synthetic preparation procedure for the target compound of formula i is: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and the aromatic aldehyde (3.2mmol) and the base catalyst piperidine (0.1mL) were added. And (3) refluxing and reacting the mixed reactants for 15-24 h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal shown in the formula I.

As a further improvement, the molar ratio of the norfloxacin C-3 ethanone shown in the formula V to the aromatic aldehyde is 1: 1.0-1.5.

The base catalyst is at least one of piperidine, pyridine, triethylamine, morpholine, potassium acetate, sodium hydroxide ethanol solution or potassium hydroxide ethanol solution.

The application of the acrylketone derivative of norfloxacin 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 acrylketone derivative of norfloxacin is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the split principle of the pharmacophores, realizes the complementation and activity superposition of the pharmacophores with different structures, achieves the effects of synergism, toxicity reduction and drug resistance, and can be developed as an anti-tumor drug with a brand new structure.

Detailed Description

Example 1

1-ethyl-6-fluoro-7-piperazin-1-yl-3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical structure:

namely, Ar in the formula I is phenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.40g (3.8mmol) 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 68.4%, and the m.p.235-237 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.57(3H，t，CH₃) 2.76 to 3.54(8H, m, piperazine-H), 4.26(2H, q, N-CH)₂) 6.77-7.82 (7H, m, 8-H, Ph-H and 2 '-H), 8.16(1H, d, 5-H), 8.43(1H, d, 3' -H),8.62(1H, s, 2-H); MS (m/z): 406[ M + H]⁺Calculating (C)₂₄H₂₄FN₃O₂)：405.48。

Example 2

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical structure:

namely, Ar in the formula I is p-methoxyphenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.57g (4.2mmol) of 4-methoxybenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-2, wherein the yield is 78.3%, and the m.p.238-240 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.56(3H，t，CH₃) 2.78 to 3.56(8H, m, piperazine-H), 3.87(3H, s, OCH)₃),4.28(2H，q，N-CH₂) 6.65-7.86 (6H, m, 8-H, Ph-H and 2 '-H), 8.17(1H, d, 5-H), 8.46(1H, d, 3' -H),8.72(1H, s, 2-H); MS (m/z): 436[ M + H]⁺Calculating (C)₂₅H₂₆FN₃O₃)：435.50。

Example 3

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (3, 4-dioxomethylenecinnamoyl) -quinolin-4 (1H) -one (I-3) having the chemical formula:

namely, Ar in the formula I is 3,4- (dioxymethylene) phenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.53g (3.5mmol) of 3, 4-dioxytolualdehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 22h, 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 82.5%, and the m.p.246-248 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.57(3H，t，CH₃) 2.76 to 3.55(8H, m, piperazine-H), 4.32(2H, q, N-CH)₂)，6.20(2H，s，OCH₂O), 6.68-7.86 (5H, m, 8-H, Ph-H and 2' -H), 8.16(1H, d, 5-H), 8.47(1H，d，3′-H),8.78(1H，s，2-H)；MS(m/z)：450[M+H]⁺Calculating (C)₂₅H₂₄FN₃O₄)：449.49。

Example 4

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (3,4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (I-4) having the chemical structure:

namely, Ar in the formula I is 3,4, 5-trimethoxyphenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.63g (3.2mmol) of 3,4, 5-trioxybenzaldehyde and piperidine (0.1mL) as a 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 80.2%, and the m.p.240-242 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.56(3H，t，CH₃) 2.75 to 3.53(8H, m, piperazine-H), 3.88, 3.92(9H, 2s, 3 XOCH)₃)，4.31(2H，q，N-CH₂) 6.67-7.84 (4H, m, 8-H, Ph-H and 2 '-H), 8.17(1H, d, 5-H), 8.46(1H, d, 3' -H),8.76(1H, s, 2-H); MS (m/z): 496[ M + H]⁺Calculating (C)₂₇H₃₀FN₃O₅)：495.56。

Example 5

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the chemical formula:

namely, Ar in the formula I is p-methyl-phenyl.

The preparation method of the compound comprises the following steps: dissolving 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V in 20mL of anhydrousTo ethanol were added 0.58g (4.8mmol) of 4-methylbenzaldehyde and piperidine (0.1mL) as a base catalyst. 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 73.0%, and m.p.225-227 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.55(3H，t，CH₃)，2.26(3H，s，Ph-CH₃) 2.75 to 3.52(8H, m, piperazine-H), 4.32(2H, q, N-CH)₂) 6.64 to 7.82(6H, m, 8-H, Ph-H and 2 '-H), 8.16(1H, d, 5-H), 8.43(1H, d, 3' -H),8.75(1H, s, 2-H); MS (m/z): 420[ M + H]⁺Calculating (C)₂₅H₂₆FN₃O₂)：419.50。

Example 6

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (4-fluorocinnamoyl) -quinolin-4 (1H) -one (I-6) having the chemical structure:

namely, Ar in the formula I is p-fluoro-phenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.48g (3.8mmol) 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 78.2%, and the m.p.232-234 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.58(3H，t，CH₃) 2.78 to 3.57(8H, m, piperazine-H), 4.35(2H, q, N-CH)₂) 6.68-8.04 (6H, m, 8-H, Ph-H and 2 '-H), 8.21(1H, d, 5-H), 8.48(1H, d, 3' -H),8.82(1H, s, 2-H); MS (m/z): 424[ M + H]⁺Calculating (C)₂₄H₂₃F₂N₃O₂)：423.47。

Example 7

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (4-chlorocinnamoyl) -quinolin-4 (1H) -one (I-7) having the chemical structure:

namely, Ar in the formula I is p-chlorophenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.45g (3.2mmol) of 4-chlorobenzaldehyde and piperidine (0.1mL) as an alkali 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 73.6%, and m.p.217-219 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.57(3H，t，CH₃) 2.76 to 3.57(8H, m, piperazine-H), 4.35(2H, q, N-CH)₂) 6.68-8.00 (6H, m, 8-H, Ph-H and 2 '-H), 8.22(1H, d, 5-H), 8.46(1H, d, 3' -H),8.82(1H, s, 2-H); MS (m/z): 440[ M + H ]]⁺(³⁵Cl), calculating (C)₂₄H₂₃FClN₃O₂)：439.92。

Example 8

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical structure:

namely, Ar in the formula I is p-bromophenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.67g (3.6mmol) of 4-bromobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 24 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-8, wherein the yield is 70.2%, and the m.p.234-236 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.56(3H，t，CH₃) 2.77 to 3.54(8H, m, piperazine-H), 4.36(2H, q, N-CH)₂)，6.72～7.92(6H，m，8-H、Ph-H and 2 '-H), 8.26(1H, d, 5-H), 8.48(1H, d, 3' -H),8.86(1H, s, 2-H); MS (m/z): 484 and 486[ M + H ]]⁺(⁷⁹Br and⁸¹br), calculating (C)₂₄H₂₃FBrN₃O₂)：484.37。

Example 9

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical structure:

namely, Ar in the formula I is p-nitrophenyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.54g (3.6mmol) of 4-nitrobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 24 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-9, wherein the yield is 76.8%, and the m.p.245-247 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.60(3H，t，CH₃) 2.84 to 3.63(8H, m, piperazine-H), 4.46(2H, q, N-CH)₂) 6.87-7.86 (2H, m, 8-H and 2 '-H), 8.31-8.57 (6H, 5-H, 3' -H and Ph-H),8.92(1H, s, 2-H); MS (m/z): 451, calculating (C)₂₄H₂₃FN₄O₄)：450.47。

Example 10

1-ethyl-6-fluoro-7-piperazin-1-yl-3- (4-hydroxy-cinnamoyl) -quinolin-4 (1H) -one (I-10) having the chemical structure:

namely, Ar in the formula I is 4-hydroxy-phenyl.

The preparation method of the compound comprises the following steps: dissolving 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V in 20mL of anhydrous ethanol, and adding 4-0.49g (4.0mmol) of hydroxy-benzaldehyde and the base catalyst piperidine (0.1 mL). 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 58.2%, and the m.p.232-234 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.56(3H，t，CH₃) 2.80 to 3.56(8H, m, piperazine-H), 4.42(2H, q, N-CH)₂) 6.78-7.92 (6H, m, 8-H, Ph-H and 2 '-H), 8.22(1H, d, 5-H), 8.41(1H, d, 3' -H),8.83(1H, s,2-H), 10.52(1H, s, OH); MS (m/z): 422, calculating (C)₂₄H₂₄FN₄O₄)：421.48。

Example 11

1-ethyl-6-fluoro-7-piperazin-1-yl-3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical formula:

namely, Ar in the formula I is 3-pyridyl.

The preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.37g (3.6mmol) of 3-pyridylaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-11, wherein the yield is 80.6%, and the m.p.248-250 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.62(3H，t，CH₃) 2.87 to 3.68(8H, m, piperazine-H), 4.48(2H, q, N-CH)₂) 6.86-7.88 (2H, m, 8-H and 2 '-H), 8.23-8.87 (6H, 5-H, 3' -H and pyridine-H), 9.06(1H, s, 2-H); MS (m/z): 407, calculating (C)₂₃H₂₃FN₄O₂)：406.46。

Example 12

1-ethyl-6-fluoro-7-piperazin-1-yl-3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical formula:

namely, Ar in the formula I is 2-furyl.

The preparation method of the compound comprises the following steps: the preparation method of the compound comprises the following steps: 1.0g (3.2mmol) of 1-ethyl-6-fluoro-7-piperazin-1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.38g (4.0mmol) of 2-furfural and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-12, wherein the yield is 63.2%, and the m.p.241-243 ℃.¹H NMR(400MHz,CD₃Cl)δ：1.56(3H，t，CH₃) 2.76 to 3.57(8H, m, piperazine-H), 4.44(2H, q, N-CH)₂) 6.83-7.82 (5H, m, 8-H, 2 '-H and furan-H), 8.26(1H, d, 5-H), 8.43(1H, d, 3' -H),8.87(1H, s, 2-H); MS (m/z): 396[ M + H]⁺Calculating (C)₂₂H₂₂FN₃O₃)：395.44。

Test examples

One, embodiment 1-12 provides a norfloxacin propenone derivative in vitro anti-tumor activity determination

1. Test sample

15 of the acrylic ketone derivatives of norfloxacin 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 Norfloxacin (NF) were used as test samples, wherein HC, SN and NF are used as control groups, and the samples of examples 1-12 are used as test groups;

thiazole blue (MTT), HC, SN and NF are all products of Sigma company; the RPMI-1640 culture solution is a product of GIBCO company; other used reagents are all domestic analytical pure reagents.

The experimental cancer cell strains are respectively a human non-small cell lung cancer cell strain A549, a human kidney cancer cell strain 769-P, a human hepatoma cell strain Hep-3B, a human gastric cancer cell strain HGC27, a human pancreatic cancer cell strain Panc-1 and a human leukemia cell strain HL60, which are purchased from Shanghai cell banks of Chinese academy of sciences. The human renal clear cell carcinoma cell sunitinib-resistant strain 7SuR was purchased from shanghai zel biotechnology limited, and the normal cell was obtained from african green monkey kidney cell line VERO and purchased from shanghai tong biology limited.

2. Measurement method

The determination method comprises the following specific steps:

1) firstly, the 15 samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0X 10^{- 4}mol·L^-1Stock solution of concentration, then diluting the stock solution with 10% calf serum RPMI-1640 culture solution to have 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0 μmol. L)^-1) The working fluid of (1);

2) taking non-small cell lung cancer cell strain A549, human kidney cancer cell strain 769-P, human liver cancer cell strain Hep-3B, human gastric cancer cell strain HGC27, human pancreatic cancer cell strain Panc-1, human leukemia cell strain HL60, human renal clear cell cancer cell sunitinib drug-resistant strain 7SuR and African green monkey kidney cell strain VERO in logarithmic growth phase, inoculating 6000 cells in each hole to a 96-hole plate, then respectively adding working solution with 5 concentration gradients of the 15 samples, and adding 5 g.L.in each hole after 48 hours^–1mu.L of MTT (thiazole blue) solution was added, and after further culturing for 4 hours, 100. mu.L of a 10% by mass Sodium Dodecyl Sulfate (SDS) solution was added. Culturing for 24 hours, and then measuring an absorbance (OD) value at a wavelength of 570nm by using a microplate reader;

3) the inhibition rate of the test samples with different concentrations on the cancer cells is calculated according to the following formula,

cancer cell inhibition rate ═ [ (1-experimental OD value)/control OD value ] × 100%;

then, linear regression is carried out on the cancer cell inhibition rate corresponding to each concentration by the pair value of each concentration of the test sample to obtain a dose-effect equation, and the half Inhibition Concentration (IC) of the test sample to the experimental cancer cell is calculated from the obtained dose-effect equation₅₀) (ii) a Each data was measured in triplicate and averaged, the results are shown in Table 1.

TABLE 1 antitumor Activity (IC) of the test samples₅₀)

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 norfloxacin, 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 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.