CN112824396B - Acrylic ketone derivative of N-acetyl lomefloxacin and preparation method and application thereof - Google Patents

Acrylic ketone derivative of N-acetyl lomefloxacin and preparation method and application thereof Download PDF

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CN112824396B
CN112824396B CN201911139894.1A CN201911139894A CN112824396B CN 112824396 B CN112824396 B CN 112824396B CN 201911139894 A CN201911139894 A CN 201911139894A CN 112824396 B CN112824396 B CN 112824396B
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方东
胡国强
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Abstract

The invention discloses an propenone derivative of N-acetyl 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

Acrylic ketone derivative of N-acetyl lomefloxacin 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 N-acetyl lomefloxacin, and also relates to a preparation method of the propenone derivative of N-acetyl lomefloxacin and application of the propenone derivative in antitumor 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 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-methyl-4-acetyl piperazine-1-yl) -quinoline-4 (1H) -ketone' skeleton of the fluoroquinolone drug N-acetyl lomefloxacin as a substituent of an aryl acrylic ketone structure.
Therefore, the invention aims to provide an propenone derivative of N-acetyl lomefloxacin, which has anti-tumor effect and efficacy, and a preparation method of the propenone derivative of N-acetyl lomefloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: an propenone derivative of N-acetyl lomefloxacin, the chemical structural formula of which is shown as the 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 propenone derivative of N-acetyl lomefloxacin, which is prepared by taking the N-acetyl lomefloxacin shown in a commercial formula II as a raw material;
the preparation method comprises the following specific steps:
1) N-acetyl lomefloxacin shown in formula II is taken as a raw material, and is reacted with Carbonyl Diimidazole (CDI) to prepare the N-acetyl lomefloxacin imidazole amide compound shown in formula III, and the specific preparation method is as follows:
22.0g (60.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -quinoline-4 (1H) -ketone-3-carboxylic acid II is dissolved in 500mL of anhydrous acetonitrile, 15.2g (94.0 mmol) of carbonyldiimidazole is added, and the mixed reactant is stirred in a water bath and refluxed until the raw 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, with yield of 64.5%, and m.p. 226-228 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.36～1.47(6H,m,2×CH 3 )，2.26(3H，s，N-COH 3 ) 2.68 to 3.46 (7H, m, piperazine-H), 4.62 (2H, q, N-CH) 2 ) 7.68 to 7.40 (2H, m, imidazole-H), 7.83 (1H, d, 5-H), 8.24 (1H, s, imidazole-H), 8.86 (1H, s, 2-H); MS (m/z): 444[ M+H ]] + Calculation (C) 22 H 23 F 2 N 5 O 3 )：443.46。
As a further improvement, the mol ratio of the N-acetyl lomefloxacin shown in the formula II to the 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 N-acetyl lomefloxacin imidazole amide shown in the formula III and monoethyl malonate potassium salt are subjected to condensation reaction under the catalysis of triethylamine-magnesium chloride to prepare the C-3 formylacetic acid ethyl ester compound of the N-acetyl lomefloxacin shown in the formula IV, and the specific preparation method is as follows:
17.0g (39.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 to 600mL of anhydrous acetonitrile in this order, 12.2g (12.0 mmol) of triethylamine was added dropwise under ice bath stirring, and the mixed reactant was stirred in a water bath and refluxed until the material III disappeared. 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 in the formula IV, wherein the yield is 70.2%, and m.p.213-215 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.35～1.63(9H，m，3×CH 3 )，2.28(3H，s，N-COH 3 ) 2.66-3.45 (7H, m, piperazine-H), 4.18 (2H, s, COCH) 2 CO)，4.26(2H，q，CO 2 CH 2 )，4.66(2H，q，N-CH 2 )，7.78(1H，d，5-H)，8.84(1H，s,2-H)；MS(m/z)：464[M+H] + Calculation (C) 23 H 27 F 2 N 3 O 5 )：463.49。
3) The C-3 formylacetic acid ethyl ester compound of the N-acetyl lomefloxacin shown in the formula IV is subjected to hydrolysis decarboxylation reaction by using a sodium hydroxide aqueous solution with the mass fraction of 3%, so that the C-3 ethanone compound of the N-acetyl lomefloxacin shown in the 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-methyl-4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-formylacetate of formula IV was suspended in 200mL of 3% strength by mass aqueous sodium hydroxideIn the solution, stirring and refluxing in an oil bath until the raw material IV disappears. 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 68.4%, and the m.p. is 232-234 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.34～1.52(6H,m,2×CH 3 )，2.32(3H，s，N-COH 3 )，2.44(3H，s，COCH 3 ) 2.65 to 3.47 (7H, m, piperazine-H), 4.67 (2H, q, N-CH) 2 )，7.82(1H，d，5-H)，8.87(1H，s,2-H)；MS(m/z)：392[M+H] + Calculation (C) 20 H 23 F 2 N 3 O 3 )：391.42。
4) The method comprises the following steps of carrying out a Claisen-Schmidt aldol condensation reaction on C-3 ethanone of N-acetyl lomefloxacin shown in a formula V and aromatic aldehyde in absolute ethyl alcohol under the catalysis of alkali, and treating to obtain a target compound shown in a formula I after the reaction is completed, 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: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 N-acetyl lomefloxacin C-3 ethanone and the aromatic aldehyde shown in the formula V 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 acrylic ketone derivative of the N-acetyl lomefloxacin in preparing an anti-tumor medicament.
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 an N-acetyl lomefloxacin propenone derivative, which is based on the principle of pharmacophore split, effectively combines a fluoroquinolone skeleton with an aryl propenone pharmacophore, designs and synthesizes the N-acetyl lomefloxacin propenone derivative, realizes complementation and activity superposition of different structural pharmacophores, 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-methyl-4-acetylpiperazin-1-yl) -3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical formula:
that is, ar in formula I is phenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 piperidine as a base catalyst (0.1 mL) 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 61.3 percent, and the m.p.225-227 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.38～1.56(6H,m,2×CH 3 )，2.28(3H，s，N-COH 3 ) 3.05 to 3.61 (7H, m, piperazine-H), 4.66 (2H, q, N-CH) 2 ) 7.42 to 8.03 (7H, m, ph-H, 5-H and 2 '-H), 8.52 (1H, d,3' -H), 8.87 (1H, s, 2-H); MS (m/z): 480[ M+H ]] + Calculation (C) 27 H 27 F 2 N 3 O 3 )：479.53。
Example 2
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical formula:
that is, ar in formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 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 the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal compound of the formula I-2, the yield is 65.2%, and the m.p.232-234 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.40～1.57(6H,m,2×CH 3 )，2.30(3H，s，N-COH 3 ) 3.12 to 3.63 (7H, m, piperazine-H), 3.88 (3H, s, OCH) 3 ),4.67(2H，q，N-CH 2 ) 7.43 to 7.87 (6H, m, ph-H, 5-H and 2 '-H), 8.54 (1H, d,3' -H), 8.87 (1H, s, 2-H); MS (m/z): 519[ M+H ]] + Calculation (C) 28 H 29 F 2 N 3 O 4 )：509.56。
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: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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-dioxymethylene benzaldehyde and base catalyst piperidine (0.1 mL) were added. Reflux reaction of the mixed reactants for 20h, standing at room temperature, and filtering and collecting the generated solid withoutRecrystallizing with water and ethanol to obtain pale yellow crystal of formula I-3 with yield of 74.5%, m.p. 242-244 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.36～1.55(6H,m,2×CH 3 )，2.30(3H，s，N-COH 3 ) 3.05 to 3.62 (7H, m, piperazine-H), 4.68 (2H, q, N-CH) 2 )，6.17(2H，s，OCH 2 O), 7.36 to 7.84 (5H, m, ph-H, 5-H and 2 '-H), 8.56 (1H, d,3' -H), 8.87 (1H, s, 2-H); MS (m/z): 524[ M+H ]] + Calculation (C) 28 H 27 FN 3 O 5 )：523.54。
Example 4
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (3, 4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (I-4) having the chemical formula:
that is, ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 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-4, the yield is 56.3 percent, and the m.p.226-228 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.36～1.55(6H,m,2×CH 3 )，2.28(3H，s，N-COH 3 ) 2.87-3.55 (7H, m, piperazine-H), 3.89,3.91 (9H, 2s,3 XOCH) 3 )，4.68(2H，q，N-CH 2 ) 7.44 to 8.03 (4H, m, ph-H, 5-H and 2 '-H), 8.52 (1H, d,3' -H), 8.87 (1H, s, 2-H); MS (m/z): 570[ M+H ]] + Calculation (C) 30 H 33 FN 3 O 6 )：569.61。
Example 5
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the chemical formula:
that is, ar in formula I is p-methyl-phenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 basic catalyst piperidine (0.1 mL) 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 52.6%, and the m.p. is 217-219 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.35～1.57(6H,m,2×CH 3 )，2.26(3H，s，N-COH 3 )，2.32(3H，s，Ph-CH 3 ) 2.68 to 3.53 (7H, m, piperazine-H), 4.64 (2H, q, N-CH) 2 ) 7.43 to 7.85 (6H, m, ph-H, 5-H and 2 '-H), 8.52 (1H, d,3' -H), 8.87 (1H, s, 2-H); MS (m/z): 494[ M+H ]] + Calculation (C) 28 H 29 FN 3 O 3 )：493.56。
Example 6
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-fluoro-cinnamoyl) -quinolin-4 (1H) -one (I-6) having the chemical formula:
that is, ar in formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 piperidine (0.1 mL) 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 77.3 percent, and the m.p.233-235 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.38～1.62(6H,m,2×CH 3 )，2.32(3H，s，N-COH 3 ) 3.04-3.63 (7H, m, piperazine-H), 4.72 (2H, q, N-CH) 2 ) 7.48 to 8.10 (6H, m, ph-H, 5-H and 2 '-H), 8.61 (1H, d,3' -H), 8.92 (1H, s, 2-H); MS (m/z): 498[ M+H ]] + Calculation (C) 27 H 26 F 3 N 3 O 3 )：497.52。
Example 7
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-chlorocinnamoyl) -quinolin-4 (1H) -one (I-7) having the chemical formula:
that is, ar in formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -1-yl-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.45g (3.2 mmol) of 4-chlorobenzaldehyde and 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 absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-7, the yield is 67.4%, and the m.p.225-227 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.36～1.60(6H,m,2×CH 3 )，2.30(3H，s，N-COH 3 ) 3.03 to 3.65 (7H, m, piperazine-H), 4.68 (2H, q, N-CH) 2 ) 7.46 to 8.07 (6H, m, ph-H, 5-H and 2 '-H), 8.58 (1H, d,3' -H), 8.90 (1H, s, 2-H); MS (m/z): 514[ M+H ]] + ( 35 Cl), calculation (C 27 H 26 F 2 ClN 3 O 3 )：513.98。
Example 8
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical formula:
that is, ar in formula I is p-bromophenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 piperidine (0.1 mL) 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 70.2%, and the m.p.233-235 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.38～1.62(6H,m,2×CH 3 )，2.32(3H，s，N-COH 3 ) 3.13 to 3.68 (7H, m, piperazine-H), 4.71 (2H, q, N-CH) 2 ) 7.48 to 8.08 (6H, m, ph-H, 5-H and 2 '-H), 8.63 (1H, d,3' -H), 8.96 (1H, s, 2-H); MS (m/z): 558 and 560[ M+H ]] + ( 79 Br and 81 br), calculation (C 27 H 26 F 2 BrN 3 O 3 )：558.43。
Example 9
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical formula:
that is, ar in formula I is p-nitrophenyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 piperidine (0.1 mL) 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 absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-9, the yield is 73.5%, and the m.p.244-246 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.45～1.68(6H,m,2×CH 3 )，2.41(3H，s，N-COH 3 )，3.13～3.75(7H，m, piperazine-H), 4.72 (2H, q, N-CH 2 ) 7.43 (1H, d,2 '-H), 8.47-8.84 (5H, 3' -H and Ph-H), 9.15 (1H, s, 2-H); MS (m/z): 525, calculate (C 27 H 26 F 2 N 4 O 5 )：524.53。
Example 10
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-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 basic 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 absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-10, the yield is 61.4%, and the m.p. is 232-234 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.37～1.56(6H,m,2×CH 3 )，2.26(3H，s，N-COH 3 ) 2.77-3.46 (7H, m, piperazine-H), 4.65 (2H, q, N-CH) 2 ) 7.36 to 7.84 (6H, m, ph-H, 5-H and 2 '-H), 8.56 (1H, d,3' -H), 8.86 (1H, s, 2-H), 10.57 (1H, s, OH); MS (m/z): 496, calculate (C 27 H 27 F 2 N 3 O 4 )：495.53。
Example 11
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical formula:
that is, ar in formula I is 3-pyridyl.
The preparation method of the compound comprises the following steps: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.37g (3.6 mmol) of 3-pyridineal and piperidine (0.1 mL) 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 absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-11, the yield is 85.4%, and the m.p.243-245 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.37～1.56(6H,m,2×CH 3 )，2.32(3H，s，N-COH 3 ) 3.11 to 3.63 (7H, m, piperazine-H), 4.72 (2H, q, N-CH) 2 ) 7.52 (1H, d,2 '-H), 8.37-9.10 (6H, 5-H, 3' -H and pyridine-H), 9.13 (1H, s, 2-H); MS (m/z): 481, calculate (C 26 H 26 F 2 N 4 O 3 )：480.52。
Example 12
1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical 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: 1.1g (3.0 mmol) of 1-ethyl-6, 8-difluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.38g (4.0 mmol) of 3-furan aldehyde and piperidine as a base catalyst (0.1 mL) 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 absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-12, the yield is 60.3%, and the m.p.231-233 ℃. 1 H NMR(400MHz,CD 3 Cl)δ：1.38～1.59(6H,m,2×CH 3 )，2.32(3H，s，N-COH 3 ) 3.03 to 3.52 (7H, m, piperazine-H), 4.67 (2H, q, N-CH) 2 ) 7.14 to 7.87 (5H, m,2'-H, 5-H and furan-H), 8.58 (1H, d,3' -H), 9.06 (1H, s, 2-H); MS (m/z): 470[ M+H ]] + Calculation (C) 25 H 25 F 2 N 3 O 4 )：469.49。
Test examples
1. In vitro antitumor Activity assay of the propenone derivatives of N-acetyllomefloxacin provided in examples 1-12
1. Sample for sample
Taking the propenone derivative of the N-acetyl lomefloxacin and the classical antineoplastic TOPO inhibitor 10-Hydroxycamptothecin (HC), chalcone tyrosinase inhibitor Sunitinib (SN), broad-spectrum anticancer drug Doxorubicin (DOX) and parent compound N-Acetyl Lomefloxacin (ALMF) provided in examples 1-12 as test samples, 15 in total, wherein HC, SN and ALMF are control experiment groups, and the samples in examples 1-12 are test experiment groups;
thiazole blue (MTT) and HC, SN, ALMF 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 non-small cell lung cancer cell strain A549 in logarithmic growth phase, human kidney cancer cell strain 769-P, human liver cancer cell strain Hep-3B and human gastric cancer cellThe HGC27, the Panc-1 and HL60, the sunitinib resistant strain 7SuR and the Vero strain are inoculated into 96-well plates with 6000 cells per well, then the working solution with 5 concentration gradients of the 15 samples is respectively added, and 5 g.L is added 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, the compounds provided in examples 1-12 have significantly higher inhibitory activity against 7 cancer cells than the parent compound N-acetyllomefloxacin, especially a portion of the compounds have higher growth inhibitory activity against human non-small cell lung cancer cell line A549 than the control Hydroxycamptothecin (HC), tyrosine kinase inhibitors Sunitinib (SN) and Doxorubicin (DOX), IC 50 The value is close to or reaches 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 a strong resistance to drugs, and at the same time showed low toxicity to normal cells VERO, with adultProperties of the drug. 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 N-acetyl lomefloxacin, which is specifically characterized by being a typical compound of the following structure:
2. the method for preparing the propenone derivative of the N-acetyl lomefloxacin according to claim 1, wherein the specific preparation steps comprise:
1) N-acetyl lomefloxacin shown in a formula II is taken as a raw material, is reacted with Carbonyl Diimidazole (CDI) to prepare an N-acetyl 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 the N-acetyl lomefloxacin shown in a formula IV; finally, the N-acetyl lomefloxacin C-3 ethanone shown in the formula V is prepared through hydrolysis decarboxylation reaction in the formula IV:
2) The method comprises the steps of carrying out a C la is e N-Schmidt condensation reaction on N-acetyl lomefloxacin C-3 ethanone shown in a formula V and aromatic aldehyde under the catalysis of alkali to form an propenone structure, and carrying out post-treatment to obtain the propenone derivative of the N-acetyl lomefloxacin shown in a formula 1;
the molar ratio of the N-acetyl lomefloxacin shown in the formula II to the CDI is 1:1.0-2.0, the molar ratio of the N-acetyl lomefloxacin imidazole amide shown in the formula III to the monoethyl malonate potassium salt is 1:1.0-1.5, and the molar ratio of the N-acetyl lomefloxacin-3 ethyl ketone shown in the formula V to the aromatic aldehyde is 1:1.0-2.0.
3. The use of an propenone derivative of N-acetyl lomefloxacin according to claim 1 in the preparation of an antitumor drug.
4. The use of an propenone derivative of N-acetyl lomefloxacin in 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 human.
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