阅读说明：本技术 一种 n-乙酰基环丙沙星的丙烯酮衍生物及其制备方法和应用 (Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof ) 是由 黄帅 曹玉辉 崔红艳 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N-乙酰基环丙沙星的衍生物,特别是指一种N-乙酰基环丙沙星的丙烯酮衍生物及其制备方法和应用。具有如下结构通式(Ⅰ)：<Image he="195" wi="379" file="100004_DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式中,Ar是选自带有苯环、呋喃环或吡啶环及其取代基中的任一种。一种<I>N</I>-乙酰基环丙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 derivative of N-acetyl ciprofloxacin, and particularly relates to an acrylketone derivative of N-acetyl ciprofloxacin and a preparation method and application thereof. Has the following structural general formula (I): wherein Ar is any one selected from the group consisting of a benzene ring, a furan ring, a pyridine ring and a substituent thereof. A kind of N Propenone derivatives of (E) -acetyl ciprofloxacin for achieving fluoroquinolone bonesThe frame is effectively spliced with the acrylketone framework, so that a novel fluoroquinolone chalcone-like chalcone compound is constructed, the anti-tumor activity and the anti-drug resistance of the novel compound are increased, the toxic and side effects on normal cells are reduced, and the fluoroquinolone chalcone-like chalcone compound can be used as an anti-tumor active substance to develop an anti-tumor drug with a brand new structure.)

1. A kind ofN-an propenone derivative of acetyl ciprofloxacin, characterized by having the following general structural formula (i):

wherein Ar is any one selected from the group consisting of a benzene ring, a furan ring, a pyridine ring and a substituent thereof.

2. The method of claim 1N-an propenone derivative of acetyl ciprofloxacin characterized in that: wherein Ar is selected from any one of phenyl, p-methoxyphenyl, 3,4- (dioxymethylene) phenyl, 3,4, 5-trimethoxyphenyl, p-methyl-phenyl, p-fluoro-phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 4-hydroxy-phenyl, 3-pyridyl or 2-furyl.

3. The method of claim 1 or 2NThe preparation method of the propenone derivative of the acetyl ciprofloxacin is characterized by comprising the following steps:

(1) to be provided withNPerforming water bath stirring reflux reaction on-acetyl ciprofloxacin serving as a raw material and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing with acetone to obtain the (E) -acetyl ciprofloxacinN-acetyl ciprofloxacin imidazole amide compounds;

(2) step (1) ofNCarrying out condensation reaction on an acetyl ciprofloxacin imidazole amide compound and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride, and carrying out reduced pressure evaporation to remove a solvent, extraction, water washing, drying and recrystallization to obtain a C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin;

(3) the C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin in the step (2) is subjected to hydrolysis decarboxylation reaction in a sodium hydroxide aqueous solution under the condition of oil bath stirring reflux, placed at room temperature, filtered to collect solid, washed with water, dried and recrystallized to obtain the compoundN-acetyl ciprofloxacin C-3 ethanone;

(4) subjecting the obtained product of step (3)NThe C-3 ethanone of the-acetyl ciprofloxacin and aromatic aldehyde are subjected to Claisen-Schmidt condensation reaction in absolute ethyl alcohol under the catalysis of a base catalyst, and the reaction is complete to obtainN-an propenone derivative of acetyl ciprofloxacin.

4. The method of claim 1NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: the solvent in the step (1) is at least one of anhydrous acetonitrile, tetrahydrofuran, dioxane or dimethylformamide;Nthe mol ratio of the-acetyl ciprofloxacin to the carbonyl diimidazole is 1 (1-2), and the reaction is stirred in a water bath and refluxed for 10 to 24 hours.

5. The method of claim 1NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: in the step (2)NThe mol ratio of the-acetyl ciprofloxacin imidazole amide compound to the potassium salt of the monoethyl malonate is 1 (1-1.5).

6. The method of claim 1NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: and (3) stirring and refluxing the sodium hydroxide aqueous solution with the mass fraction of 3% in the step (3) for 5-10 hours.

7. The method of claim 1NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: in the step (4)NThe molar ratio of the C-3 ethanone of the acetyl ciprofloxacin to the aromatic aldehyde is 1 (1-2).

8. The method of claim 7NA method for producing an acrylketone derivative of (E) -acetylciprofloxacin, characterized by comprising: the aromatic aldehyde is any one of benzaldehyde, 4-methoxybenzene, 3, 4-dioxytoluylene aldehyde, 3,4, 5-trioxybenzaldehyde, 4-methylbenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-nitrobenzaldehyde, 4-hydroxy-benzaldehyde, 3-pyridine aldehyde or 2-furan aldehyde; the base catalyst is at least one of piperidine, pyridine, triethylamine, morpholine, potassium acetate, sodium hydroxide ethanol solution or potassium hydroxide ethanol solution.

9. The method of claim 1 or 2NApplication of an acrylketone derivative of-acetyl ciprofloxacin in preparation of antitumor drugs.

10. Use according to claim 9, characterized in that: the anti-tumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.

Technical Field

The invention belongs to the field of drug synthesis, relates to a derivative of N-acetyl ciprofloxacin, and particularly relates to an acrylketone derivative of N-acetyl ciprofloxacin and a preparation method and application thereof.

Background

NThe in vitro antibacterial action of the-acetyl ciprofloxacin belongs to fluoroquinolones is similar to that of norfloxacin and is slightly worse than that of ciprofloxacin, but the in vivo antibacterial activity of the-acetyl ciprofloxacin is obviously better than that of norfloxacin, including the action on escherichia coli, pneumonia bacillus pyocyaneus and staphylococcus aureus. The action mechanism is the same as that of norfloxacin. At present, the medicine is mainly used for urogenital infection and intestinal infection. As a lead of new drugs, the research finds that the new drugs are effective methods for new drug innovation based on the structure or mechanism of N-methyl lomefloxacin.

The acrylketone structure is not only a characteristic structure of a chalcone compound which is a natural active ingredient, but also a characteristic pharmacophore of a targeted antitumor drug sunitinib. Therefore, compounds constructed with acrylketone as a structural fragment and having various pharmacological activities have been attracting attention. However, most of natural chalcone compounds are multi-hydroxyl benzene ring substituted propenone compounds, and the poor water solubility of the compounds causes low bioavailability and limits the clinical application; in addition, in the preparation and application of CN201811343703.9 bis-fluoroquinolone thiadiazole urea N-acetyl ciprofloxacin derivatives, 2 quinolone skeleton structural units are constructed into the bis-fluoroquinolone thiadiazole urea derivatives by taking thiadiazole urea as a connecting chain; preparing the targeted antitumor drug.

The applicant combines the action target of the antibacterial fluoroquinolone medicine, namely topoisomerase, to be an important action target of the antitumor medicine, can convert the antibacterial activity of the antibacterial fluoroquinolone medicine into the antitumor activity, and finds that the fluoroquinolone C-3 carboxyl is not a pharmacophore required by the antitumor activity and can be replaced by a biological electron isostere to improve the antitumor activity of the fluoroquinolone medicine. However, the effect of substituting the C-3 carboxyl group of fluoroquinolone with a different group cannot be determined. To solve the technical problems and to explore new drugs with good therapeutic effect and no toxicity, a great deal of research and test are carried out in the subject group to improve the water solubility of chalcones and introduce hydrophilic piperazinyl to increase the water solubility, improve the bioavailability and bioactivity of chalcones.

Disclosure of Invention

The invention provides an acrylketone derivative of N-acetyl ciprofloxacin and a preparation method and application thereof, which are used for preparing a new medicament with excellent anti-tumor effect and improving the activity of a primer for inhibiting cancer cells.

The technical scheme of the invention is realized as follows:

a kind ofN-an propenone derivative of acetyl ciprofloxacin having the following general structural formula (i):

wherein Ar is any one selected from the group consisting of a benzene ring, a furan ring, a pyridine ring and a substituent thereof.

Wherein Ar is selected from any one of phenyl, p-methoxyphenyl, 3,4- (dioxymethylene) phenyl, 3,4, 5-trimethoxyphenyl, p-methyl-phenyl, p-fluoro-phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 4-hydroxy-phenyl, 3-pyridyl or 2-furyl.

The aboveNThe preparation method of the propenone derivative of the acetyl ciprofloxacin comprises the following steps:

(1) to be provided withNPerforming water bath stirring reflux reaction on-acetyl ciprofloxacin serving as a raw material and carbonyldiimidazole in a solvent, standing at room temperature, filtering and collecting solid, and recrystallizing with acetone to obtain the (E) -acetyl ciprofloxacinN-acetyl ciprofloxacin imidazole amide compounds; the technical route is as follows:

；

(2) step (1) ofNCarrying out condensation reaction on an acetyl ciprofloxacin imidazole amide compound and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride, and carrying out reduced pressure evaporation to remove a solvent, extraction, water washing, drying and recrystallization to obtain a C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin; the technical route is as follows:

；

(3) the C-3 formyl ethyl acetate compound of the N-acetyl ciprofloxacin in the step (2) is subjected to hydrolysis decarboxylation reaction in a sodium hydroxide aqueous solution under the condition of oil bath stirring reflux, placed at room temperature, filtered to collect solid, washed with water, dried and recrystallized to obtain the compoundN-acetyl ciprofloxacin C-3 ethanone; the technical route is as follows:

；

(4) subjecting the obtained product of step (3)NThe C-3 ethanone of the-acetyl ciprofloxacin and aromatic aldehyde are subjected to Claisen-Schmidt condensation reaction in absolute ethyl alcohol under the catalysis of a base catalyst, and the reaction is complete to obtainN-an propenone derivative of acetyl ciprofloxacin; the technical route is as follows:

。

the solvent in the step (1) is at least one of anhydrous acetonitrile, tetrahydrofuran, dioxane or dimethylformamide;Nthe mol ratio of the-acetyl ciprofloxacin to the carbonyldiimidazole is 1 (1-2), and the reflux reaction is carried out in a water bath for 10 to 24 hours until the raw materials are reactedNDisappearance of-acetyl ciprofloxacin.

In the step (2)N-acetyl ciprofloxacin imidazole amide compound and malonic acid monoethyl etherThe molar ratio of the ester potassium salt is 1 (1-1.5.)

And (3) the mass fraction of the sodium hydroxide aqueous solution in the step (3) is 3%, and the reaction is carried out for 5 to 10 hours under stirring and reflux in an oil bath until the C-3 ethyl formylacetate compound of the reactant N-acetylciprofloxacin disappears.

In the step (4)NThe molar ratio of the C-3 ethanone of the acetyl ciprofloxacin to the aromatic aldehyde is 1 (1-2);

the aromatic aldehyde is any one of benzaldehyde, 4-methoxybenzene, 3, 4-dioxytoluylene aldehyde, 3,4, 5-trioxybenzaldehyde, 4-methylbenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-nitrobenzaldehyde, 4-hydroxy-benzaldehyde, 3-pyridine aldehyde or 2-furan aldehyde; the base catalyst is at least one of piperidine, pyridine, triethylamine, morpholine, potassium acetate, sodium hydroxide ethanol solution or potassium hydroxide ethanol solution.

The aboveNApplication of an acrylketone derivative of-acetyl ciprofloxacin in preparation of antitumor drugs.

The anti-tumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.

The invention has the following beneficial effects:

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

2. The fluoroquinolone medicine of the present inventionNDominant pharmacophore of (E) -Acetylciprofloxacin' 1-cyclopropyl-6-fluoro-7- (4-acetylpiperazin-1-yl) -quinoline-4 (1)H) The-ketone skeleton is used as a substituent of an aryl acrylketone structure, and then a fluoroquinolone 'chalcone-like' derivative with a novel structure is designed. Realizes the effective combination of the fluoroquinolone skeleton and the acrylketone skeleton, and further constructs a novel fluoroquinolone-like chalconeThe ketone compound increases the antitumor activity and the anti-drug resistance of the new compound, reduces the toxic and side effects on normal cells, and can be used as an antitumor active substance to develop an antitumor drug with a brand-new structure.

Detailed Description

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