阅读说明：本技术 一种培氟沙星的丙烯酮衍生物及其制备方法和应用 (Propenone derivative of pefloxacin, and preparation method and application thereof ) 是由 曹玉辉 仵钊锋 梁佩芳 黄帅 王爱丽 胡国强 于 2020-07-31 设计创作，主要内容包括：本发明属于药物合成领域,涉及培氟沙星的衍生物,特别是指一种培氟沙星的丙烯酮衍生物及其制备方法和应用。培氟沙星的衍生物,具有如下结构通式(Ⅰ)：<Image he="159" wi="358" file="100004_DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式I中,Ar为苯环、取代苯环、呋喃环或吡啶环中的任意一种。本发明的培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 belongs to the field of drug synthesis, relates to a pefloxacin derivative, and particularly relates to a pefloxacin propenone derivative, and a preparation method and application thereof. A pefloxacin derivative 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.The acrylketone derivative of pefloxacin realizes the effective combination of a fluoroquinolone skeleton and an acrylketone skeleton, and further constructs a novel fluoroquinolone chalcone-like chalcone compound, so that the antitumor activity and the anti-drug resistance of the novel compound are increased, the toxic and side effects on normal cells are reduced, and the pefloxacin acrylketone derivative can be used as an antitumor active substance to develop an antitumor drug with a brand-new structure.)

1. The acrylic ketone derivative of pefloxacin 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 pefloxacin 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 producing an acrylketone derivative of pefloxacin according to claim 1 or 2, which comprises the steps of:

(1) carrying out water bath stirring reflux reaction on pefloxacin serving as a raw material and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing with acetone to obtain a pefloxacin imidazole amide compound;

(2) carrying out condensation reaction on the pefloxacin 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 pefloxacin;

(3) carrying out hydrolysis decarboxylation reaction on the C-3 formyl ethyl acetate compound of the pefloxacin in the step (2) in a sodium hydroxide aqueous solution under the condition of oil bath stirring reflux, placing at room temperature, filtering to collect solid, washing with water, drying and recrystallizing to obtain the pefloxacin C-3 ethanone;

(4) and (4) carrying out a Claisen-Schmidt condensation reaction on the pefloxacin C-3 ethanone in the step (3) and aromatic aldehyde in absolute ethyl alcohol under the catalysis of an alkali catalyst, and obtaining the propenone derivative of the pefloxacin after the reaction is complete.

4. The process for producing an acrylketone derivative of pefloxacin according to claim 3, wherein: the solvent in the step (1) is at least one of anhydrous acetonitrile, tetrahydrofuran, dioxane or dimethylformamide; the molar ratio of the pefloxacin to the carbonyldiimidazole is 1 (1-2), and the mixture is stirred in a water bath and refluxed for reaction for 10 to 24 hours.

5. The process for producing an acrylketone derivative of pefloxacin according to claim 3, wherein: the molar ratio of the pefloxacin imidazole amide compound to the potassium monoethyl malonate in the step (2) is 1 (1-1.5).

6. The process for producing an acrylketone derivative of pefloxacin according to claim 3, wherein: 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 producing an acrylketone derivative of pefloxacin according to claim 3, wherein: the molar ratio of the pefloxacin C-3 ethanone to the aromatic aldehyde in the step (4) is 1 (1-2).

8. The process for producing an acrylketone derivative of pefloxacin 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 acrylketone derivative of pefloxacin as described in 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.

Technical Field

The invention belongs to the field of drug synthesis, relates to a pefloxacin derivative, and particularly relates to a pefloxacin propenone derivative, and a preparation method and application thereof.

Background

Pefloxacin, a novel fluoroquinolone antibacterial agent, has broad-spectrum activity against G-and G + bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter, Haemophilus, Neisseria and Staphylococcus (including methicillin-resistant strains), and has the same action mechanism as norfloxacin; for clinical indications, norfloxacin is used. Intravenous administration is also used in the severe cases of pulmonary infections and in gram-negative sepsis, where often a synergistic antibacterial agent is used in combination. Can be used for treating adult G-bacterium and Staphylococcus severe infection such as septicemia, endocarditis, bacterial meningitis, respiratory tract infection, urinary tract infection, kidney infection, otorhinolaryngological infection, gynecological diseases, abdominal infection, hepatobiliary infection, osteoarthritis, skin infection, etc. 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 pefloxacin.

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 of pefloxacin, and a preparation method and application thereof.

The technical scheme of the invention is realized as follows:

the acrylketone derivative of pefloxacin 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 acrylketone derivative of pefloxacin comprises the following steps:

(1) carrying out water bath stirring reflux reaction on pefloxacin serving as a raw material and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing with acetone to obtain a pefloxacin imidazole amide compound; the technical route is as follows:

；

(2) carrying out condensation reaction on the pefloxacin 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 pefloxacin; the technical route is as follows:

；

(3) carrying out hydrolysis decarboxylation reaction on the C-3 formyl ethyl acetate compound of the pefloxacin in the step (2) in a sodium hydroxide aqueous solution under the condition of oil bath stirring reflux, placing at room temperature, filtering to collect solid, washing with water, drying and recrystallizing to obtain the pefloxacin C-3 ethanone; the technical route is as follows:

；

(4) carrying out Claisen-Schmidt condensation reaction on the pefloxacin C-3 ethanone in the step (3) and aromatic aldehyde in absolute ethyl alcohol under the catalysis of an alkali catalyst, and obtaining an acrylketone derivative of pefloxacin after complete reaction; 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 pefloxacin to the carbonyldiimidazole is 1 (1-2), and the time of stirring and refluxing reaction in a water bath is 10-24 hours until the raw material pefloxacin disappears.

The molar ratio of the pefloxacin imidazole amide compound to the potassium monoethyl malonate in the step (2) is 1 (1-1.5).

The mass fraction of the sodium hydroxide aqueous solution in the step (3) is 6 percent, and the time of the oil bath stirring reflux reaction is 5 to 10 hours until the C-3 formyl ethyl acetate compound of the pefloxacin disappears.

The molar ratio of the pefloxacin C-3 ethanone to the aromatic aldehyde in the step (3) 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 pefloxacin in preparing antitumor drugs.

The anti-tumor medicine is a medicine 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 pefloxacin acrylketone derivative is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the drug pharmacophore split principle, and the complementation and activity superposition of drug pharmacophores with different structures are realized, so that the effects of synergy and toxicity reduction and drug resistance are achieved, and the pefloxacin acrylketone derivative can be developed as an anti-tumor drug with a brand new structure.

2. The invention uses the advantageous pharmacophore of fluoroquinolone drug pefloxacin, namely 1-ethyl-6-fluoro-7- (4-methylpiperazin-1-yl) -quinoline-4 (1)H) The-ketone skeleton is used as a substituent of an aryl acrylketone structure, so that a fluoroquinolone chalcone derivative with a novel structure is designed, the effective splicing of the fluoroquinolone skeleton and the acrylketone skeleton is realized, and a new fluoroquinolone chalcone compound is constructed, so that the antitumor 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 derivative can be used as an antitumor active substance to develop an antitumor drug with a brand new structure.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.