CN111303189A - A kind of acrylone derivative of rufloxacin and its preparation method and application - Google Patents

Abstract

式I中，芳香环Ar为苯环或取代苯环或呋喃环或吡啶环。本发明的一种芦氟沙星的丙烯酮衍生物，实现了氟喹啉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 a propenone derivative of rufloxacin, a preparation method and application thereof, and adopts the following general chemical structure formula I:

In formula I, the aromatic ring Ar is a benzene ring or a substituted benzene ring, a furan ring or a pyridine ring. The acrylone derivative of rufloxacin of the present invention realizes the effective splicing of the fluoroquinolone skeleton and the acrylone skeleton, thereby constructing a new fluoroquinolone "chalcone-like" compound, thereby adding a new compound Anti-tumor activity and anti-drug resistance, and reduce the toxic and side effects to normal cells, can be used as anti-tumor active substances to develop new structure of anti-tumor drugs.

Description

A kind of acrylone derivative of rufloxacin and its preparation method and application

technical field

The invention belongs to the technical field of innovative drug synthesis, in particular to an acrylone derivative of rufloxacin, a preparation method of an acrylone derivative of rufloxacin, and its application in antitumor drugs .

Background technique

New drug innovation originates from the discovery of leads, and rational drug molecular design based on structure or mechanism is an effective method to discover leads. Among the various pharmacophore structures, the acrylone structure is not only the characteristic structure of the natural active ingredient chalcone compounds, but also the characteristic pharmacophore of the targeted antitumor drug sunitinib. Therefore, compounds with various pharmacological activities constructed with acrylone as structural fragments have attracted attention. However, natural chalcone compounds are mostly polyhydroxybenzene ring-substituted acrylone compounds, which have low bioavailability due to their poor water solubility, which limits their clinical application. In addition, topoisomerase, the target of antibacterial fluoroquinolone drugs, is also an important target of antitumor drugs, which can convert its antibacterial activity into antitumor activity, and found that the C-3 carboxyl group of fluoroquinolone is not an antitumor activity. The necessary pharmacophore can be replaced by bioisosteres to improve its antitumor activity. However, the replacement of the C-3 carboxyl group of fluoroquinolones with arylpropenones has not been reported yet. Based on this, in order to improve the water solubility of chalcones, an attempt is made to introduce a hydrophilic piperazine group to increase water solubility, improve its bioavailability and biological activity, the present invention uses the dominant pharmacophore of the fluoroquinolone drug rufloxacin "1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one" skeleton is used as the substituent of the arylpropenone structure, and further A novel structural fluoroquinolone "chalcone-like" derivative was designed.

Therefore, the purpose of the present invention is to provide an acrylone derivative of rufloxacin, which has antitumor effect and efficacy, and a preparation method of the acrylone derivative of rufloxacin.

In order to achieve the above purpose, the technical scheme adopted in the present invention is: a kind of acrylone derivative of rufloxacin, and its chemical structural formula is as shown in general formula I:

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

A preparation method of acrylone derivative of rufloxacin of the present invention is prepared by using commercially obtained rufloxacin shown in formula II as a raw material;

The specific preparation steps are as follows:

1) using the rufloxacin shown in formula II as a raw material, through reacting with carbonyl diimidazole (CDI), the rufloxacin imidazole amide compound shown in formula III is obtained, and its concrete preparation method is as follows:

Dissolve 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-carboxylic acid II 22.0 g (60.0 mmol) In 500 mL of anhydrous acetonitrile, 15.2 g (94.0 mmol) of carbonyldiimidazole was added, and the mixed reactants were stirred and refluxed in a water bath until the raw material II disappeared. The resulting solids were collected by filtration and recrystallized with acetone to obtain the pale yellow crystals of rufloxacin imidazole amide, formula III, in a yield of 76.4%, mp 239-241°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.35 (3H, s, N-CH ₃ ), 2.86-3.36 (8H, m, piperazine-H), 3.68-4.66 (4H, m, S-CH ₂ CH ₂ -N), 7.46-7.63 (2H, m, imidazole-H), 7.86 (1H, d, 5-H), 8.17 (1H, s, imidazole-H), 8.92 (1H, s, 2-H) ); MS (m/z): 414 [ _{M +} H] ⁺ , calculated for ( _C20H20FN5O2S ): _413.48 .

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

2) condensation reaction takes place with the rufloxacin imidazole amide shown in formula III and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride to obtain the C- of rufloxacin shown in formula IV 3 ethyl formyl acetate compounds, its concrete preparation method is as follows:

Take 1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(1H-imidazole-1-formyl)-[quinoline-4(1H)- Ketone formula III 16.0g (39.0mmol), magnesium chloride 6.6g (69.1mmol) and monoethyl malonate potassium salt 8.3g (49.0mmol) were successively added to 600mL of anhydrous acetonitrile, and triethyl was added dropwise under ice bath stirring Amine 12.2 g (12.0 mmol), mixed reactants in a water bath, stirred and refluxed until the raw material III disappeared. The solvent was evaporated under reduced pressure, 500 mL of water was added, extracted with dichloromethane (3×150 mL), the organic phases were combined, washed with water (3×200 mL), washed with saturated brine (2×150 mL), and dried over anhydrous sodium sulfate. Dichloromethane was recovered at normal pressure, and the residue was recrystallized with absolute ethanol to obtain off-white crystals of formula IV, yield 72.5%, mp 231-233°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 1.25 (3H, t, CH ₃ ), 2.34 (3H, s, N-CH ₃ ), 2.87-3.37 (8H, m, piperazine-H), 3.64 ( 2H, m, S- _CH2 ), 4.16 (2H, s, _COCH2CO ), 4.28 (2H, q, _CO2CH2 ), 4.67 (2H, m, N- _{CH2 )} , 7.84 (1H, d , 5-H), 8.95 (1H, s, 2-H); MS (m/z): 434 [ _{M +} H] ⁺ , calculated for ( _C21H24FN3O4S ): _433.51 .

3) The C-3 formyl ethyl acetate compound of rufloxacin shown in formula IV is subjected to hydrolysis and decarboxylation reaction with an aqueous sodium hydroxide solution whose mass fraction is 6%, so that rufloxacin shown in formula V can be conveniently prepared The C-3 ethyl ketone compound of star, its concrete preparation method is as follows:

Take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-formyl ethyl acetate formula IV 10g (23.0mmol ) was suspended in 200 mL of an aqueous sodium hydroxide solution with a mass fraction of 6%, and the oil bath was stirred and refluxed to react until the raw material IV disappeared. Leave at room temperature, collect the resulting solid by filtration, wash with water until neutral, dry, and recrystallize with absolute ethanol to obtain pale yellow crystals of formula V, yield 71.3%, mp 236-238°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.34 (3H, s, N-CH ₃ ), 2.44 (3H, s, COCH ₃ ), 2.86-3.35 (8H, m, piperazine-H), 3.64- 4.67 (4H, m, S _- CH2CH2 _- N), 7.86 (1H, d, 5-H), 8.94 (1H, s, 2-H); MS (m/z): 362 [M+H ] ⁺ , calculated for (C ₁₈ H ₂₀ FN ₃ O ₂ S): 361.44.

4) C-3 ethyl ketone of rufloxacin shown in formula V and aromatic aldehyde are carried out Claisen-Schmidt aldol condensation reaction in absolute ethanol under the catalysis of alkali, and after the reaction is complete, the target compound is treated as As shown in formula I, the specific process is as follows:

Wherein, Ar in formula I is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring.

The general synthetic preparation operation steps of the target compound formula I are: take 1,8-ethylsulfanyl-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)one-3 -1.1 g (3.0 mmol) of ethyl ketone V was dissolved in 20 mL of absolute ethanol, and an aromatic aldehyde (3.0 mmol) and a base catalyst piperidine (0.1 mL) were added. The mixed reactants were refluxed for 15 to 24 hours, placed at room temperature, and the generated solids were collected by filtration and recrystallized from absolute ethanol to obtain a pale yellow crystal of formula I.

As a further improvement, the mole ratio of rufloxacin C-3 ethyl ketone and aromatic aldehyde represented by formula V is 1:1.0-1.5.

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

The application of the acrylone derivative of rufloxacin in the preparation of antitumor drugs.

The antitumor drug is a drug for treating human non-small cell lung cancer, renal cancer, liver cancer, gastric cancer, pancreatic cancer or leukemia.

The acrylone derivative of rufloxacin of the present invention is based on the splicing principle of pharmacophore, the fluoroquinolone skeleton and the aryl acrylone pharmacophore are effectively combined, and the acrylone derivative of rufloxacin is designed and synthesized. , to achieve the complementation of different structural pharmacophore and the superposition of activities, thus achieving the effect of enhancing efficacy, reducing toxicity and resisting drug resistance, and can be used as a new structure for the development of anti-tumor drugs.

Detailed ways

Example 1

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-cinnamoyl-quinolin-4(1H)-one (I-1), its chemical structural formula for:

That is, Ar in formula I is phenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.40 g (3.8 mmol) of benzaldehyde and a base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 18h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain pale yellow crystals of formula I-1, yield 75.3%, mp 236-238°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.34 (3H, s, N-CH ₃ ), 2.73-3.36 (8H, m, piperazine-H), 3.64-4.67 (4H, m, S-CH ₂ CH ₂ -N), 7.53-7.88 (7H, m, Ph-H, 5-H and 2'-H), 8.56 (1H, d, 3'-H), 8.95 (1H, s, 2-H) ; MS (m/z): 450 [ _{M +} H] ⁺ , calculated for ( _C25H24FN3O2S ): _449.55 .

Example 2

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(4-methoxycinnamoyl)-quinolin-4(1H)-one (I -2), its chemical structural formula is:

That is, Ar in formula I is p-methoxyphenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.57 g (4.2 mmol) of 4-methoxybenzaldehyde and the base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 20h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain light yellow crystals of formula I-2, yield 77.8%, mp 238-240°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.36 (3H, s, N-CH ₃ ), 2.75-3.38 (8H, m, piperazine-H), 3.66-4.68 (7H, m, S-CH _{2 CH2} -N and _OCH3 ), 7.57-7.92 (6H, m, Ph-H, 5-H and 2'-H), 8.58 (1H, d, 3'-H), 8.97 (1H, s, 2 -H); MS (m/z): 480 _{[ M} +H] ⁺ , calculated for ( _C26H26FN3O3S ): _479.58 .

Example 3

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(3,4-dioxymethylenecinnamoyl)-quinoline-4(1H) - Ketone (I-3), its chemical structural formula is:

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

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.53 g (3.5 mmol) of 3,4-dioxymethylene benzaldehyde and a base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 20h, left at room temperature, the generated solids were collected by filtration, and recrystallized from absolute ethanol to obtain pale yellow crystals of formula I-3, yield 80.6%, mp 242-244°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.35 (3H, s, N-CH ₃ ), 2.68-3.38 (8H, m, piperazine-H), 3.67-4.65 (4H, m, S-CH _{2 CH2} -N), 6.23 (2H, s, OCH2O), _7.56-8.03 (5H, m, Ph-H, 5-H and 2'-H), 8.60 (1H, d, 3'-H) , 9.03 (1H, s, 2-H); MS (m/z): 494 [ _{M +} H] ⁺ , calculated for ( _C26H24FN3O4S ): _493.56 .

Example 4

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(3,4,5-trimethoxycinnamoyl)-quinoline-4(1H) - Ketone (I-4), its chemical structural formula is:

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

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.63 g (3.2 mmol) of 3,4,5-trioxybenzaldehyde and a base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 20h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain pale yellow crystals of formula I-4, yield 63.5%, mp 231-233°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.37 (3H, s, N-CH ₃ ), 2.68-3.37 (8H, m, piperazine-H), 3.67-4.66 (13H, S-CH ₂ CH ₂ -N and 3×OCH ₃ ), 7.58-8.11 (4H, m, Ph-H, 5-H and 2'-H), 8.63 (1H, d, 3'-H), 8.96 (1H, s, 2 -H); MS (m/z): 540 [ _M +H] ⁺ , calculated for _{( C28H30FN3O5S} ): _539.63 .

Example 5

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(4-methylcinnamoyl)-quinolin-4(1H)-one (I- 5), its chemical structural formula is:

That is, Ar in formula I is p-methyl-phenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.58 g (4.8 mmol) of 4-methylbenzaldehyde and a base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 15h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain pale yellow crystals of formula I-5, yield 65.2%, mp 226-228°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.28 (3H, s, Ph-CH ₃ ), 2.35 (3H, s, N-CH ₃ ), 2.66-3.36 (8H, m, piperazine-H), 3.65-4.67 (4H, m, S _- CH2CH2 _- N), 7.55-7.93 (6H, m, Ph-H, 5-H and 2'-H), 8.57 (1H, d, 3'-H) ), 8.96 (1H, s, 2-H); MS (m/z): 464 [M+H] ⁺ , calculated for (C ₂₆ H ₂₆ FN ₃ O ₂ S): 463.58.

Example 6

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(4-fluorocinnamoyl)-quinolin-4(1H)-one (I-6 ), its chemical structure is:

That is, Ar in formula I is p-fluoro-phenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.48 g (3.8 mmol) of 4-fluorobenzaldehyde and the base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 15h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain pale yellow crystals of formula I-6, yield 78.6%, mp 240-242°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.41 (3H, s, N-CH ₃ ), 2.78-3.38 (8H, m, piperazine-H), 3.68-4.70 (4H, m, S-CH ₂ CH ₂ -N), 7.61～8.06 (6H, m, Ph-H, 5-H and 2'-H), 8.64 (1H, d, 3'-H), 9.11 (1H, s, 2-H) ; MS (m/z): 468 [ _{M +} H] ⁺ , calculated for _{( C25H23F2N3O2S} ): _467.54 .

Example 7

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(4-chlorocinnamoyl)-quinolin-4(1H)-one (I-7 ), its chemical structure is:

That is, Ar in formula I is p-chlorophenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.45 g (3.2 mmol) of 4-chlorobenzaldehyde and the base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 20h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain pale yellow crystals of formula I-7, yield 76.3%, mp 231-233°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.40 (3H, s, N-CH ₃ ), 2.73-3.37 (8H, m, piperazine-H), 3.67-4.70 (4H, m, S-CH ₂ CH ₂ -N), 7.58～8.04 (6H, m, Ph-H, 5-H and 2'-H), 8.62 (1H, d, 3'-H), 9.07 (1H, s, 2-H) ; MS (m/z): 484 [ _{M +} H] ⁺ ( _35Cl ), calculated for ( ^{C25H23FClN3O2S} ): _484.00 .

Example 8

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(4-bromocinnamoyl)-quinolin-4(1H)-one (I-8 ), its chemical structure is:

That is, Ar in formula I is p-bromophenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.67 g (3.6 mmol) of 4-bromobenzaldehyde and the base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 24h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain pale yellow crystals of formula I-8, yield 75.0%, mp 237-239°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.37 (3H, s, N-CH ₃ ), 2.71-3.38 (8H, m, piperazine-H), 3.66-4.68 (4H, m, S-CH ₂ CH ₂ -N), 7.56～8.06 (6H, m, Ph-H, 5-H and 2'-H), 8.60 (1H, d, 3'-H), 9.05 (1H, s, 2-H) ; MS (m/z): 528 and 530 [ _M +H] ⁺ ( ^79Br and ^81Br ), calculated for ( _{C25H23FBrN3OS} ): _528.45 .

Example 9

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(4-nitrocinnamoyl)-quinolin-4(1H)-one (I- 9), its chemical structural formula is:

That is, Ar in formula I is p-nitrophenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.54 g (3.6 mmol) of 4-nitrobenzaldehyde and the base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 24h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain yellow crystals of formula I-9, yield 78.3%, mp 242-244°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.42 (3H, s, N-CH ₃ ), 3.03-3.41 (8H, m, piperazine-H), 3.70-4.75 (4H, m, S-CH ₂ CH ₂ -N), 7.62～8.17 (6H, m, Ph-H, 5-H and 2'-H), 8.66 (1H, d, 3'-H), 9.15 (1H, s, 2-H) ; MS (m/z): ₄₉₅ , calculated for _{( C25H23FN4O4S} ): _494.55 .

Example 10

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-(4-hydroxy-cinnamoyl)-quinolin-4(1H)-one (I- 10), and its chemical structural formula is:

That is, Ar in formula I is 4-hydroxy-phenyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.49 g (4.0 mmol) of 4-hydroxy-benzaldehyde and the base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 20h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain yellow crystals of formula I-10, yield 66.2%, mp 234-236°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.36 (3H, s, N-CH ₃ ), 2.67-3.35 (8H, m, piperazine-H), 3.67-4.68 (4H, m, S-CH ₂ CH ₂ -N), 7.58～8.02 (6H, m, Ph-H, 5-H and 2'-H), 8.61 (1H, d, 3'-H), 9.03 (1H, s, 2-H) , 10.56 (1H, s, OH); MS ( _m /z): 466, calculated for ( _{C25H24FN3O3S )} : _465.55 .

Example 11

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-[3-(pyridin-3-yl)acryloyl]-quinoline-4(1H) - Ketone (I-11), its chemical structural formula is:

That is, Ar in formula I is 3-pyridyl.

The preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)-one-3-ethanone V1 .1 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, and 0.37 g (3.6 mmol) of 3-pyridine aldehyde and a base catalyst piperidine (0.1 mL) were added. The mixed reactants were refluxed for 15h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain yellow crystals of formula I-11, yield 82.7%, mp 243-245°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.42 (3H, s, N-CH ₃ ), 3.11-3.46 (8H, m, piperazine-H), 3.70-4.73 (4H, m, S-CH ₂ CH ₂ -N), 7.61 (1H, d, 2'-H), 8.64-9.13 (6H, 5-H, 3'-H and pyridine-H), 9.16 (1H, s, 2-H); MS (m/z): 451, calculated for _{( C24H23FN4O2S )} : _450.54 .

Example 12

1,8-Ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-3-[3-(furan-2-yl)acryloyl]quinoline-4(1H)- Ketone (I-12), its chemical structural formula is:

That is, Ar in formula I is 2-furyl.

The preparation method of the compound is as follows: the preparation method of the compound is as follows: take 1,8-ethylthio-6-fluoro-7-(4-methylpiperazin-1-yl)-quinoline-4(1H)- 1.1 g (3.0 mmol) of ketone-3-ethanone V was dissolved in 20 mL of absolute ethanol, and 0.38 g (4.0 mmol) of 2-furanaldehyde and a base catalyst piperidine (0.1 mL) were added. The mixed reactants were reacted under reflux for 18h, left at room temperature, the generated solids were collected by filtration, and recrystallized from anhydrous ethanol to obtain yellow crystals of formula I-12, yield 66.3%, mp 238-240°C. ¹ H NMR (400 MHz, CD ₃ Cl) δ: 2.38 (3H, s, N-CH ₃ ), 2.86-3.41 (8H, m, piperazine-H), 3.68-4.71 (4H, m, S-CH ₂ CH ₂ -N), 7.25～8.03 (5H, m, 2'-H, 5-H and furan-H), 8.64 (1H, d, 3'-H), 9.10 (1H, s, 2-H) ; MS (m/z): 440 _{[ M} +H] ⁺ , calculated for ( _C23H22FN3O3S ): _439.51 .

Test example

1. Determination of in vitro antitumor activity of acrylone derivatives of rufloxacin provided in Examples 1-12

1. Test sample

A kind of acrylone derivative of rufloxacin and classic anti-tumor TOPO inhibitor 10-hydroxycamptothecin (HC), chalcone tyrosinase inhibitor sunitinib provided in Example 1-12 (SN), the broad-spectrum anticancer drug doxorubicin (DOX) and the parent compound rufloxacin (LF) are the test samples, a total of 15 kinds, of which HC, SN and LF are the control experimental groups, Examples 1-12 The sample is the tested experimental group;

Thiazolyl blue (MTT), HC, SN, LF are all products of Sigma company; RPMI-1640 medium is products of GIBCO company; other reagents used are domestic analytical reagents.

The experimental cancer cell lines were human non-small cell lung cancer cell line A549, human kidney cancer cell line 769-P, human liver cancer cell line Hep-3B, human gastric cancer cell line HGC27, human pancreatic cancer cell line Panc-1 and human leukemia cells. Strain HL60 was purchased from Shanghai Cell Bank, Chinese Academy of Sciences. The sunitinib-resistant human clear cell renal cell carcinoma cell line 7SuR was purchased from Shanghai Zeye Biotechnology Co., Ltd., and the normal cells were African green monkey kidney cell line VERO, which was purchased from Shanghai Tongpai Biotechnology Co., Ltd.

2. Measurement method

The specific steps of the determination method are:

1) First, the above 15 test samples were dissolved in dimethyl sulfoxide (DMSO) respectively to prepare a stock solution with a concentration ^of 1.0×10 ^-4 mol·L ^-1 , and then the calf with a concentration of 10% by mass was used. Serum RPMI-1640 culture medium The stock solution was diluted into a working solution with 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0 μmol·L ^-1 );

2) Take the logarithmic growth phase of non-small cell lung cancer cell line A549, human renal cancer cell line 769-P, human liver cancer cell line Hep-3B, human gastric cancer cell line HGC27, human pancreatic cancer cell line Panc-1 and human The leukemia cell line HL60, the sunitinib-resistant human clear cell renal cell carcinoma cell line 7SuR, and the African green monkey kidney cell line VERO were seeded in 96-well plates at 6,000 cells per well, and then added with the above 15 samples. For the working solution with 5 concentration gradients, 10 μL of 5 g·L ^–1 MTT (thiazolyl blue) solution was added to each well after 48 hours, and 100 μL of 10% sodium dodecyl sulfate ( SDS) solution. Incubate for 24 hours, and then measure the absorbance (OD) value at a wavelength of 570 nm with a microplate reader;

3) Calculate the inhibition rate of different concentrations of test samples to cancer cells according to the following formula:

Cancer cell inhibition rate=[(1-OD value of experimental group)/OD value of control group]×100%;

Then use the logarithmic value of each concentration of the test sample to perform a linear regression on the inhibition rate of cancer cells corresponding to each concentration to obtain a dose-response equation, and calculate the half-inhibitory concentration of the test sample on the experimental cancer cells from the obtained dose-response equation ( IC50); each data was measured three times in parallel, and the average value was calculated. The results are shown in Table 1.

Table 1 Antitumor activity (IC ₅₀ ) of each test sample

As can be seen from Table 1, the inhibitory activity of the compounds provided in Examples 1-12 on the experimental 7 cancer cells was significantly stronger than that of the parent compound rufloxacin, especially the inhibitory activity of some compounds on the human non-small cell lung cancer cell line A549 The growth inhibitory activity is stronger than that of the control hydroxycamptothecin (HC), the tyrosine kinase inhibitor sunitinib (SN) and doxorubicin (DOX), and its IC ₅₀ value has reached or is close to nanomolar concentration, with The value of new drug development. More meaningfully, the compounds provided in Examples 1-12 also showed extremely strong sensitivity to sunitinib-resistant strain 7SuR, showed strong anti-resistance activity, and at the same time showed lower VERO in normal cells. cytotoxic, with druggable properties. Therefore, according to the general approach of drug development, routine anti-tumor in vitro screening is carried out first, and then targeted research is carried out. Therefore, the compounds of the present invention have strong anti-tumor activity, anti-drug activity and low cytotoxicity, and can be obtained by The antitumor drug is prepared by forming a salt with a human-acceptable acid or mixing it with a pharmaceutical carrier.

Claims (5)

1. a propenone derivative of rufloxacin is specifically characterized in that it is the typical compound of following structure:

2. the preparation method of the acrylone derivative of a kind of rufloxacin according to claim 1, is characterized in that, concrete preparation step comprises: 1) Using the rufloxacin shown in formula II as a raw material, react with carbonyl diimidazole (CDI) to obtain the rufloxacin imidazole amide compound shown in formula III, and then condense with monoethyl malonate potassium salt The C-3 formyl ethyl acetate compound of rufloxacin shown in formula IV is obtained by the reaction; finally, the C-3 ethyl ketone of rufloxacin shown in formula V is obtained by hydrolysis and decarboxylation reaction of formula IV:

2) Claisen-Schmidt condensation reaction of rufloxacin C-3 ethyl ketone shown in formula V and aromatic aldehyde occurs under the catalysis of alkali to form propylene ketone structure, and a kind of rufloxacin shown in claim 1 can be obtained through post-processing. The acrylone derivative of fluloxacin. 3. the preparation method of the acrylone derivative of a kind of rufloxacin according to claim 2, is characterized in that, the mol ratio of rufloxacin shown in formula II and CDI is 1:1.0～2.0, formula The molar ratio of rufloxacin imidazole amide shown in III to monoethyl malonate potassium salt is 1:1.0～1.5, and the molar ratio of rufloxacin-3 ethyl ketone shown in formula V to aromatic aldehyde is 1 : 1.0 to 2.0. 4. the application of a kind of acrylone derivative of rufloxacin as claimed in claim 1 in the preparation of antitumor drugs. 5. the application of the acrylone derivative of a kind of rufloxacin according to claim 4 in the preparation of antitumor drug, it is characterized in that, described antitumor drug is for the treatment of human non-small cell lung cancer, kidney cancer, liver cancer , gastric cancer, pancreatic cancer or leukemia drugs.