CN112824397B - Lomefloxacin propenone derivative and preparation method and application thereof - Google Patents

Lomefloxacin propenone derivative and preparation method and application thereof Download PDF

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CN112824397B
CN112824397B CN201911139921.5A CN201911139921A CN112824397B CN 112824397 B CN112824397 B CN 112824397B CN 201911139921 A CN201911139921 A CN 201911139921A CN 112824397 B CN112824397 B CN 112824397B
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马云峰
胡国强
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Abstract

The invention discloses an propenone derivative of lomefloxacin, a preparation method and application thereof, and the propenone derivative adopts a chemical structural general formula as shown in the following formula I:

Description

Lomefloxacin propenone derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of innovative drug synthesis, and particularly relates to an propenone derivative of lomefloxacin, and also relates to a preparation method of the propenone derivative of lomefloxacin and application of the propenone derivative in anti-tumor drugs.
Background
New drug innovations stem from the discovery of leads, and rational drug molecular design based on structure or mechanism is an effective method of discovering leads. Among pharmacophores with various structures, the propenone structure is not only the characteristic structure of chalcone compounds which are natural active ingredients, but also the characteristic pharmacophore of targeted antitumor drug sunitinib. Therefore, compounds having various pharmacological activities constructed using propenone as a structural fragment are attracting attention. However, most of natural chalcone compounds are polyhydroxy benzene ring substituted propenone compounds, and the bioavailability is low due to poor water solubility, so that clinical application is limited. In addition, the topoisomerase which is an important action target of the anti-tumor drug is combined with the action target of the anti-bacterial fluoroquinolone drug, so that the anti-bacterial activity of the fluoroquinolone drug can be converted into the anti-tumor activity, and the fluoroquinolone C-3 carboxyl is found to be not a pharmacophore necessary for the anti-tumor activity and can be replaced by a bioelectron isostere to improve the anti-tumor activity of the fluoroquinolone C-3 carboxyl. However, no studies have been reported on the substitution of the fluoroquinolone C-3 carboxyl group with aryl propenone. Based on the above, in order to improve the water solubility of chalcones, hydrophilic piperazinyl is introduced to increase the water solubility and improve the bioavailability and the bioactivity of the chalcones, the invention designs a fluoroquinolone 'chalcone' derivative with a novel structure by using a dominant pharmacophore '1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one' skeleton of the fluoroquinolone drug lomefloxacin as a substituent of an aryl acrylic ketone structure.
Therefore, the invention aims to provide the lomefloxacin propenone derivative which has anti-tumor effect and efficacy, and also provides a preparation method of the lomefloxacin propenone derivative.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: an propenone derivative of lomefloxacin, which has a chemical structural formula shown in a general formula I:
ar in the formula I is benzene ring or substituted benzene ring or furan ring or pyridine ring, and the compound is a compound with the following specific structure:
the invention relates to a preparation method of an acrylic ketone derivative of lomefloxacin, which is prepared by taking the lomefloxacin shown in a commercially obtained formula II as a raw material;
the preparation method comprises the following specific steps:
1) The lomefloxacin shown in the formula II is taken as a raw material and reacts with Carbonyl Diimidazole (CDI) to prepare the lomefloxacin imidazole amide compound shown in the formula III, and the specific preparation method is as follows:
21.0g (60.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-carboxylic acid II is dissolved in 500mL of anhydrous acetonitrile, 15.2g (94.0 mmol) of carbonyldiimidazole is added, and the mixture is stirred in a water bath to reflux until the starting material II disappears. Standing at room temperature, filtering and collecting the generated solid, and recrystallizing with acetone to obtain acetyl lomefloxacin imidazole amide light yellow crystal of formula III, wherein the yield is 74.8%, and the m.p. is 231-233 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.41～1.52(6H,m,2×CH 3 ) 2.85 to 3.57 (7H, m, piperazine-H), 4.68 (2H, q, N-CH) 2 ) 7.46-7.70 (2H, m, imidazole-H), 7.85 (1H, d, 5-H), 8.26 (1H, s, imidazole-H), 8.87 (1H, s, 2-H); MS (m/z): 402[ M+H ]] + Calculation (C) 20 H 21 F 2 N 5 O 2 )：401.42。
As a further improvement, the molar ratio of lomefloxacin shown in the formula II to carbonyl diimidazole 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 solvents.
2) The C-3 formylacetic acid ethyl ester compound of lomefloxacin shown in formula IV is prepared by condensation reaction of lomefloxacin imidazole amide shown in formula III and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride, and the specific preparation method is as follows:
15.6g (39.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) - [ quinolin-4 (1H) -one III, 6.6g (69.1 mmol) of magnesium chloride and 8.3g (49.0 mmol) of monoethyl malonate potassium salt were taken and added successively to 600mL of anhydrous acetonitrile, and 12.2g (12) of triethylamine was added dropwise with stirring in an ice bath.0 mmol), and the mixture is stirred in a water bath and refluxed until the material III disappears. The solvent was distilled off under reduced pressure, 500mL of water was added, the mixture was extracted with methylene chloride (3X 150 mL), the organic phase was combined, washed with water (3X 200 mL), washed with saturated brine (2X 150 mL), and dried over anhydrous sodium sulfate. Recovering dichloromethane at normal pressure, recrystallizing the residue with absolute ethyl alcohol to obtain an off-white crystal compound with the formula IV, the yield of 73.4% and the m.p.226-228 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.32～1.57(9H，m，3×CH 3 ) 2.84-3.55 (7H, m, piperazine-H), 4.16 (2H, s, COCH) 2 CO)，4.28(2H，q，CO 2 CH 2 )，4.67(2H，q，N-CH 2 )，7.84(1H，d，5-H)，8.87(1H，s,2-H)；MS(m/z)：422[M+H] + Calculation (C) 21 H 25 F 2 N 3 O 4 )：421.45。
3) The C-3 formylacetic acid ethyl ester compound of lomefloxacin shown in formula IV is subjected to hydrolysis decarboxylation reaction by using a sodium hydroxide aqueous solution with the mass fraction of 6%, so that the C-3 ethanone compound of lomefloxacin shown in formula V can be conveniently prepared, and the specific preparation method is as follows:
10g (23.0 mmol) of ethyl 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-formylacetate of formula IV was suspended in 200mL of a 6% strength by mass aqueous sodium hydroxide solution, and the mixture was stirred in an oil bath to reflux the reaction until the disappearance of starting material IV. Standing at room temperature, filtering and collecting the generated solid, washing with water to be neutral, drying, and recrystallizing with absolute ethanol to obtain a pale yellow crystal compound of formula V, wherein the yield is 78.2%, and the m.p. is 235-237 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.36～1.55(6H,m,2×CH 3 )，2.45(3H，s，COCH 3 ) 2.88 to 3.56 (7H, m, piperazine-H), 4.68 (2H, q, N-CH) 2 )，7.86(1H，d，5-H)，8.86(1H，s,2-H)；MS(m/z)：350[M+H] + Calculation (C) 18 H 21 F 2 N 3 O 2 )：349.38。
4) C-3 ethanone of lomefloxacin shown in 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, the target compound shown in formula I is obtained through treatment, wherein the specific process is as follows:
wherein Ar in the formula I is benzene ring or substituted benzene ring or furan ring or pyridine ring.
The general synthetic preparation operation steps of the target compound shown in the formula I are as follows: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) one-3-ethanone V was dissolved in 20mL of absolute ethanol, and aromatic aldehyde (3.0 mmol) and base catalyst piperidine (0.1 mL) were added. The mixed reactants are subjected to reflux reaction for 15-24 h, and are placed at room temperature, the generated solid is filtered and collected, and absolute ethyl alcohol is recrystallized, so that a pale yellow crystal of the formula I is obtained.
As a further improvement, the mol ratio of the lomefloxacin 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 lomefloxacin propenone derivative in preparing the anti-tumor medicine.
The antitumor drug is used for treating human non-small cell lung cancer, renal cancer, liver cancer, gastric cancer, pancreatic cancer or leukemia.
The invention relates to a lomefloxacin propenone derivative, which is based on the split principle of pharmacophores, effectively combines a fluoroquinolone skeleton with aryl propenone pharmacophores, designs and synthesizes the lomefloxacin propenone derivative, realizes complementation and activity superposition of pharmacophores with different structures, achieves the effects of synergism, toxicity reduction and drug resistance, and can be used for developing antitumor drugs with brand new structures.
Detailed Description
Example 1
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical structural formula:
that is, ar in formula I is phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.40g (3.8 mmol) of benzaldehyde and 0.1mL of piperidine as a base catalyst were added. The mixed reactants are subjected to reflux reaction for 18 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal compound of the formula I-1, the yield is 68.4%, and the m.p.234-236 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.42～1.57(6H,m,2×CH 3 ) 2.87-3.55 (7H, m, piperazine-H), 4.68 (2H, q, N-CH) 2 ) 7.46 to 8.05 (7H, m, ph-H, 5-H and 2 '-H), 8.55 (1H, d,3' -H), 8.88 (1H, s, 2-H); MS (m/z): 438[ M+H ]] + Calculation (C) 25 H 25 F 2 N 3 O 2 )：437.49。
Example 2
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical structural formula:
that is, ar in formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.57g (4.2 mmol) of 4-methoxybenzaldehyde and 0.1mL of piperidine as a base catalyst were added. The mixed reactants are subjected to reflux reaction for 20 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-2, the yield is 75.6%, and the m.p.238-240 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.42～1.62(6H,m,2×CH 3 ) 3.12 to 3.62 (7H, m, piperazine-H), 3.89 (3H, s, OCH) 3 ),4.71(2H，q，N-CH 2 ) 7.46 to 8.16 (6H, m, ph-H, 5-H and 2 '-H), 8.62 (1H, d,3' -H), 8.95 (1H, s, 2-H); MS (m/z): 468[ M+H ]] + Calculation (C) 26 H 27 F 2 N 3 O 3 )：467.52。
Example 3
1-ethyl-6, 8-difluoro-7- (4-acetylpiperazin-1-yl) -3- (3, 4-dioxomethylcinnamoyl) -quinolin-4 (1H) -one (I-3) having the chemical formula:
that is, ar in formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.53g (3.5 mmol) of 3, 4-dioxomethylenebenzaldehyde and the base catalyst piperidine (0.1 mL) were added. The mixed reactants are subjected to reflux reaction for 20 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-3, the yield is 81.6%, and the m.p.244-246 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.45～1.66(6H,m,2×CH 3 ) 3.17 to 3.65 (7H, m, piperazine-H), 4.70 (2H, q, N-CH) 2 )，6.22(2H，s，OCH 2 O), 7.46 to 8.12 (5H, m, ph-H, 5-H and 2 '-H), 8.62 (1H, d,3' -H), 8.97 (1H, s, 2-H); MS (m/z): 482[ M+H ]] + Calculation (C) 26 H 25 FN 3 O 4 )：481.50。
Example 4
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (3, 4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (I-4) having the chemical structural formula:
that is, ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.63g (3.2 mmol) of 3,4, 5-trioxybenzaldehyde and piperidine (0.1 mL) as a base catalyst were added. The mixed reactants are subjected to reflux reaction for 20 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-4, the yield is 64.7%, and the m.p. is 232-234 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.38～1.62(6H,m,2×CH 3 ) 2.86 to 3.57 (7H, m, piperazine-H), 3.88,3.93 (9H, 2s,3 XOCH) 3 )，4.70(2H，q，N-CH 2 ) 7.48 to 8.07 (4H, m, ph-H, 5-H and 2 '-H), 8.57 (1H, d,3' -H), 8.92 (1H, s, 2-H); MS (m/z): 528[ M+H ]] + Calculation (C) 28 H 31 FN 3 O 5 )：527.57。
Example 5
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the chemical structural formula:
that is, ar in formula I is p-methyl-phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.58g (4.8 mmol) of 4-methylbenzaldehyde and 0.1mL of piperidine as a base catalyst were added. The mixed reactants are subjected to reflux reaction for 15 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-5, the yield is 65.0%, and the m.p.223-225 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.38～1.56(6H,m,2×CH 3 )，2.33(3H，s，Ph-CH 3 ) 2.78 to 3.55 (7H, m, piperazine-H), 4.68 (2H, q, N-CH) 2 ) 7.42 to 7.87 (6H, m, ph-H, 5-H and 2 '-H), 8.57 (1H, d,3'-H),8.86(1H，s，2-H)；MS(m/z)：452[M+H] + Calculation (C) 26 H 27 FN 3 O 2 )：451.52。
Example 6
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (4-fluoro cinnamoyl) -quinolin-4 (1H) -one (I-6) having the chemical structural formula:
that is, ar in formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.48g (3.8 mmol) of 4-fluorobenzaldehyde and 0.1mL of piperidine as a base catalyst were added. The mixed reactants are subjected to reflux reaction for 15 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-6, the yield is 83.6%, and the m.p.242-244 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.45～1.67(6H,m,2×CH 3 ) 3.12 to 3.67 (7H, m, piperazine-H), 4.74 (2H, q, N-CH 2 ) 7.50 to 8.14 (6H, m, ph-H, 5-H and 2 '-H), 8.65 (1H, d,3' -H), 8.97 (1H, s, 2-H); MS (m/z): 456[ M+H ]] + Calculation (C) 25 H 24 F 3 N 3 O 2 )：455.48。
Example 7
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (4-chlorocinnamoyl) -quinolin-4 (1H) -one (I-7) having the chemical structural formula:
that is, ar in formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol and 4-chlorobenzaldehyde 0 was added45g (3.2 mmol) and base catalyst piperidine (0.1 mL). The mixed reactants are subjected to reflux reaction for 20 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-7, the yield is 75.6%, and the m.p.233-235 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.43～1.65(6H,m,2×CH 3 ) 3.15 to 3.63 (7H, m, piperazine-H), 4.71 (2H, q, N-CH) 2 ) 7.48 to 8.10 (6H, m, ph-H, 5-H and 2 '-H), 8.62 (1H, d,3' -H), 8.96 (1H, s, 2-H); MS (m/z): 472[ M+H ]] + ( 35 Cl), calculation (C 25 H 24 F 2 ClN 3 O 2 )：471.94。
Example 8
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical structural formula:
that is, ar in formula I is p-bromophenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.67g (3.6 mmol) of 4-bromobenzaldehyde and 0.1mL of piperidine as a base catalyst were added. The mixed reactants are subjected to reflux reaction for 24 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-8, the yield is 75.5%, and the m.p.238-240 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.43～1.65(6H,m,2×CH 3 ) 3.15 to 3.72 (7H, m, piperazine-H), 4.72 (2H, q, N-CH) 2 ) 7.53 to 8.14 (6H, m, ph-H, 5-H and 2 '-H), 8.65 (1H, d,3' -H), 9.04 (1H, s, 2-H); MS (m/z): 516 and 518[ M+H ]] + ( 79 Br and 81 br), calculation (C 25 H 24 F 2 BrN 3 O 2 )：516.39。
Example 9
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical structural formula:
that is, ar in formula I is p-nitrophenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.54g (3.6 mmol) of 4-nitrobenzaldehyde and 0.1mL of base catalyst piperidine were added. The mixed reactants are subjected to reflux reaction for 24 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-9, the yield is 76.8%, and the m.p.247-249 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.47～1.73(6H,m,2×CH 3 ) 3.15 to 3.78 (7H, m, piperazine-H), 4.76 (2H, q, N-CH) 2 ) 7.48 (1H, d,2 '-H), 8.54-8.87 (5H, 3' -H and Ph-H), 9.17 (1H, s, 2-H); MS (m/z): 483, calculate (C 25 H 24 F 2 N 4 O 4 )：482.49。
Example 10
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- (4-hydroxy-cinnamoyl) -quinolin-4 (1H) -one (I-10) having the chemical structural formula:
that is, ar in formula I is 4-hydroxy-phenyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.49g (4.0 mmol) of 4-hydroxy-benzaldehyde and 0.1mL of piperidine as a base catalyst were added. The mixed reactants are subjected to reflux reaction for 20 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-10, the yield is 68.5%, and the m.p.236-238 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.41～1.66(6H,m,2×CH 3 ) 2.86 to 3.57 (7H, m, piperazine-H), 4.67 (2H, q,N-CH 2 ) 7.44 to 7.86 (6H, m, ph-H, 5-H and 2 '-H), 8.57 (1H, d,3' -H), 8.93 (1H, s, 2-H), 10.62 (1H, s, OH); MS (m/z): 454, calculation (C 25 H 25 F 2 N 3 O 3 )：453.49。
Example 11
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the formula:
that is, ar in formula I is 3-pyridyl.
The preparation method of the compound comprises the following steps: 1.0g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.37g (3.6 mmol) of 3-pyridine aldehyde and 0.1mL of base catalyst piperidine were added. The mixed reactants are subjected to reflux reaction for 15 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-11, the yield is 87.6%, and the m.p.243-245 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.46～1.73(6H,m,2×CH 3 ) 3.16 to 3.77 (7H, m, piperazine-H), 4.76 (2H, q, N-CH) 2 ) 7.56 (1H, d,2 '-H), 8.45-9.16 (6H, 5-H, 3' -H and pyridine-H), 9.17 (1H, s, 2-H); MS (m/z): 439, calculate (C 24 H 24 F 2 N 4 O 2 )：438.48。
Example 12
1-ethyl-6, 8-difluoro-7- (3-methylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the formula:
that is, ar in 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: taking 1-ethyl-6, 8-di1.0g (3.0 mmol) of fluoro-7- (3-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V is dissolved in 20mL of absolute ethanol, and 0.38g (4.0 mmol) of 2-furaldehyde and 0.1mL of base catalyst piperidine are added. The mixed reactants are subjected to reflux reaction for 18 hours, the mixture is placed at room temperature, the generated solid is filtered and collected, and absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-12, the yield is 66.5%, and the m.p.235-237 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.42～1.65(6H,m,2×CH 3 ) 3.06-3.57 (7H, m, piperazine-H), 4.68 (2H, q, N-CH) 2 ) 7.22 to 8.16 (5H, m,2'-H, 5-H and furan-H), 8.62 (1H, d,3' -H), 9.08 (1H, s, 2-H); MS (m/z): 428[ M+H ]] + Calculation (C) 23 H 23 F 2 N 3 O 3 )：427.45。
Test examples
1. In vitro antitumor Activity assay of the propenone derivatives of lomefloxacin provided in examples 1-12
1. Sample for sample
Taking the propenone derivative of lomefloxacin and the 10-Hydroxycamptothecin (HC) which is a classical antitumor TOPO inhibitor, chalcone tyrosinase inhibitor, sunitinib (SN), broad-spectrum anticancer drug, doxorubicin (DOX) and Lomefloxacin (LMF) which are parent compounds provided in examples 1-12 as test samples, wherein HC, SN and LMF are control experiment groups, and the samples in examples 1-12 are test experiment groups;
thiazole blue (MTT) and HC, SN, LMF are all Sigma company products; the RPMI-1640 culture solution is manufactured by GIBCO company; the other reagents used are all domestic analytically pure reagents.
The experimental cancer cell lines are respectively a human non-small cell lung cancer cell line A549, a human kidney cancer cell line 769-P, a human liver cancer cell line Hep-3B, a human gastric cancer cell line HGC27, a human pancreatic cancer cell line Panc-1 and a human leukemia cell line HL60, which are all purchased from Shanghai cell banks of China academy of sciences. Human-derived renal clear cell carcinoma cell sunitinib resistant strain 7SuR was purchased from Shanghai ze leaf biotechnology limited, while normal cells were obtained from african green monkey kidney cell strain VERO, and purchased from Shanghai general derivative technology limited.
2. Measurement method
The measuring method comprises the following specific steps:
1) Firstly, the 15 samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0X10 s - 4 mol·L -1 Stock solution of concentration, which was then diluted with 10% by mass of RPMI-1640 medium of calf serum to 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0. Mu. Mol.L) -1 ) Is a working fluid of (2);
2) Taking a non-small cell lung cancer cell strain A549, a human kidney cancer cell strain 769-P, a human liver cancer cell strain Hep-3B, a human gastric cancer cell strain HGC27, a human pancreatic cancer cell strain Panc-1, a human leukemia cell strain HL60, a human-derived renal clear cell carcinoma cell sunitinib drug-resistant strain 7SuR and an African green monkey kidney cell strain VERO in logarithmic phase, inoculating 6000 cells in each well into a 96-well plate, then respectively adding working solutions with 5 concentration gradients of the 15 samples into each well, and adding 5 g.L into each well after 48 hours –1 10. Mu.L of MTT (thiazole blue) solution was further cultured for 4 hours, and then 100. Mu.L of 10% strength by mass Sodium Dodecyl Sulfate (SDS) solution was added. Culturing for 24 hours, and then measuring the absorbance (OD) value at 570nm wavelength by using an enzyme-labeled instrument;
3) The inhibition ratios of the samples for test with different concentrations to cancer cells were calculated according to the following formula,
cancer cell inhibition ratio = [ (1-experimental group OD value)/control group OD value ] ×100%;
then, the inhibition ratio of the cancer cells corresponding to each concentration is linearly regressed by the logarithmic value of each concentration of the sample to obtain a dose-effect equation, and the half Inhibition Concentration (IC) of the sample to the experimental cancer cells is calculated from the obtained dose-effect equation 50 ) The method comprises the steps of carrying out a first treatment on the surface of the Each data was measured in triplicate and averaged, and the results are shown in table 1.
Table 1 anti-tumor Activity (IC) of each sample 50 )
As can be seen from Table 1, examples 1 to 12 provideThe inhibition activity of the compound on 7 cancer cells is obviously stronger than that of lomefloxacin as a parent compound, especially the growth inhibition activity of part of the compound on a549 cell strain A549 of the non-small cell lung cancer of human beings is stronger than that of the control Hydroxycamptothecin (HC), tyrosine kinase inhibitor Sunitinib (SN) and Doxorubicin (DOX), and the IC thereof 50 The value reaches or approaches nanomolar concentration, and has the value of developing new medicines. More significantly, the compounds provided in examples 1-12 also showed extremely strong sensitivity to sunitinib resistant strain 7SuR, showed strong resistance to drugs, and also showed low toxicity to normal cells VERO, with the property of drug formation. Therefore, according to the general approach of drug development, conventional antitumor in-vitro screening is carried out first, and then targeted research is carried out, so that the compound has strong antitumor activity, drug resistance activity and lower cytotoxicity, and can be prepared into antitumor drugs by salifying with acid acceptable to human bodies or mixing with a medicinal carrier.

Claims (4)

1. An propenone derivative of lomefloxacin, which is specifically characterized by being a typical compound of the following structure:
2. the method for preparing the lomefloxacin propenone derivative according to claim 1, wherein the specific preparation steps comprise:
1) Lomefloxacin shown in a formula II is taken as a raw material, is reacted with Carbonyl Diimidazole (CDI) to prepare a lomefloxacin imidazole amide compound shown in a formula III, and is then condensed with monoethyl malonate potassium salt to prepare a C-3 formylacetic acid ethyl ester compound of lomefloxacin shown in a formula IV; finally, the lomefloxacin C-3 ethanone shown in the formula V is prepared by hydrolysis decarboxylation reaction of the formula IV:
2) Claisen-Schmidt condensation reaction is carried out on lomefloxacin C-3 ethanone shown in formula V and aromatic aldehyde under the catalysis of alkali to form an propenone structure, and the propenone derivative of lomefloxacin shown in claim 1 can be prepared through post-treatment;
the molar ratio of lomefloxacin shown in the formula II to CDI is 1:1.0-2.0, the molar ratio of lomefloxacin imidazole amide shown in the formula III to monoethyl malonate potassium salt is 1:1.0-1.5, and the molar ratio of lomefloxacin-3 ethanone shown in the formula V to aromatic aldehyde is 1:1.0-2.0.
3. Use of a lomefloxacin propenone derivative according to claim 1 for the preparation of an antitumor medicament.
4. The use of a lomefloxacin propenone derivative according to claim 3 for preparing an antitumor drug, wherein the antitumor drug is a drug for treating non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia in humans.
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