CN112824401B - Acrylic ketone derivative of N-acetyl gatifloxacin and preparation method and application thereof - Google Patents
Acrylic ketone derivative of N-acetyl gatifloxacin and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an propenone derivative of N-acetyl gatifloxacin, a preparation method and application thereof, and the propenone derivative adopts a chemical structural general formula as shown in the following formula I:
Description
Technical Field
The invention belongs to the technical field of innovative drug synthesis, and particularly relates to an propenone derivative of N-acetyl gatifloxacin, and also relates to a preparation method of the propenone derivative of N-acetyl gatifloxacin 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 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-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-quinolin-4 (1H) -one' skeleton of the fluoroquinolone drug N-acetylgatifloxacin as a substituent of an aryl propenone structure.
Therefore, the invention aims to provide an propenone derivative of N-acetyl gatifloxacin, which has anti-tumor effect and efficacy, and a preparation method of the propenone derivative of N-acetyl gatifloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: an propenone derivative of N-acetyl gatifloxacin 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 propenone derivative of N-acetyl gatifloxacin, which is prepared by taking the N-acetyl gatifloxacin shown in a formula II as a raw material;
the preparation method comprises the following specific steps:
1) The N-acetyl gatifloxacin imidazole amide compound shown in the formula III is prepared by taking N-acetyl gatifloxacin shown in the formula II as a raw material and reacting with Carbonyl Diimidazole (CDI), and the specific preparation method is as follows:
21g (50.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-quinolin-4 (1H) -one-3-carboxylic acid II was dissolved in 500mL of anhydrous acetonitrile, 15.0g (94.0 mmol) of carbonyldiimidazole was added, and the mixture was stirred in a water bath and refluxed until the disappearance of starting material II. Standing at room temperature, filtering and collecting the generated solid, and recrystallizing with acetone to obtain pale yellow crystal of formula III with yield of 82.6%, m.p.234-236 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.27 to 1.52 (7H, m, cyclopropyl-H and CH) 3 )，2.28(3H，s，N-COH 3 ) 3.05 to 3.63 (8H, m, piperazine-H), 3.92 (s, 3H, OCH) 3 ) 4.53 (1H, m, cyclopropyl-H), 6.84-7.42 (2H, m, imidazole-H), 8.17 (1H, d, 5-H), 8.42 (1H, s, imidazole-H), 8.96 (1H, s, 2-H); MS (m/z): 468[ M+H ]] + Calculation (C) 24 H 26 FN 5 O 4 )：467.50。
As a further improvement, the mol ratio of the N-acetylgatifloxacin 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 gatifloxacin 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 gatifloxacin shown in the formula IV, and the specific preparation method is as follows:
18.2g (39.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) -8-methoxy-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 sequence, 12.5g (12.4 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 with the formula IV, the yield of 75.7%, and the m.p.236-238 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.26 to 1.64 (10H, m, cyclopropyl-H and 2 XCH) 3 )，2.30(3H，s，N-COH 3 ) 3.05 to 3.67 (8H, m, piperazine-H), 3.92 (s, 3H, OCH) 3 ),4.13(2H，s，COCH 2 CO)，4.22(2H，q，CO 2 CH 2 ) 4.52 (1H, m, cyclopropyl-H), 8.17 (1H, d, 5-H), 9.03 (1H, s, 2-H); MS (m/z): 488[ M+H ]] + Calculation (C) 25 H 30 FN 3 O 6 )：487.53。
3) The C-3 formylacetic acid ethyl ester compound of N-acetyl gatifloxacin 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 N-acetyl gatifloxacin shown in formula V can be conveniently prepared, and the specific preparation method is as follows:
10g (22.0 mmol) of ethyl 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-quinolin-4 (1H) -one-3-formylacetate formula IV was suspended in 200mL of 3% strength by mass aqueous sodium hydroxide solution and stirred in an oil bath to reflux the solutionRaw 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 69.5%, and the m.p. is 234-236 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.28 to 1.65 (7H, m, cyclopropyl-H and CH) 3 )，2.31(3H，s，N-COH 3 ) 3.11 to 3.67 (8H, m, piperazine-H), 3.91 (s, 3H, OCH) 3 ) 4.58 (2H, m, cyclopropyl-H), 8.13 (1H, d, 5-H), 8.97 (1H, s, 2-H); MS (m/z): 416[ M+H ]] + Calculation (C) 22 H 26 FN 3 O 4 )：415.47。
4) C-3 ethanone of N-acetyl gatifloxacin 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: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and aromatic aldehyde (3.2 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 gatifloxacin 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 propenone derivative of the N-acetyl gatifloxacin 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 gatifloxacin 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 gatifloxacin 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-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-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: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-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 75.8%, and the m.p.235-237 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.25 to 1.66 (7H, m, cyclopropyl-H and CH) 3 )，2.30(3H，s，N-COH 3 ) 3.15 to 3.68 (8H, m, piperazine-H), 3.91 (s, 3H, OCH) 3 ) 4.56 (1H, m, cyclopropyl-H), 7.46-7.88 (6H, m, ph-H and 2 '-H), 8.15 (1H, d, 5-H), 8.67 (1H, d,3' -H), 8.94 (1H, s, 2-H); MS (m/z): 504[ M+H ]] + Calculation (C) 29 H 30 FN 3 O 4 )：503.58。
Example 2
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-2) having the formula:
that is, ar in formula I is p-methoxyphenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-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 as a base catalyst (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-2, the yield is 76.2%, and the m.p.235-237 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.26 to 1.68 (7H, m, cyclopropyl-H and CH) 3 )，2.33(3H，s，N-COH 3 ) 3.15 to 3.72 (8H, m, piperazine-H), 3.89,3.94 (6H, 2s,2 XOCH) 3 ) 4.58 (1H, m, cyclopropyl-H), 7.45-8.06 (5H, m, ph-H and 2 '-H), 8.33 (1H, d, 5-H), 8.65 (1H, d,3' -H), 9.05 (1H, s, 2-H); MS (m/z): 534[ M+H ]] + Calculation (C) 30 H 32 FN 3 O 5 )：533.61。
Example 3
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (3, 4-dioxomethylcinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-3) having the formula:
that is, ar in formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-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 base catalyst piperidine (0.1 mL) were added. The mixed reactants are returnedCarrying out flow reaction for 20h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing by absolute ethyl alcohol to obtain a pale yellow crystal of the formula I-3, wherein the yield is 74.5%, and the m.p.237-239 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.27 to 1.68 (7H, m, cyclopropyl-H and CH) 3 )，2.32(3H，s，N-COH 3 ) 2.96-3.67 (8H, m, piperazine-H), 3.89 (3H, s, OCH) 3 ) 4.56 (1H, m, cyclopropyl-H), 6.23 (2H, s, OCH) 2 O), 7.46 to 8.05 (4H, m, ph-H and 2 '-H), 8.25 (1H, d, 5-H), 8.66 (1H, d,3' -H), 8.97 (1H, s, 2-H); MS (m/z): 548[ M+H ]] + Calculation (C) 30 H 30 FN 3 O 6 )：547.59。
Example 4
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (3, 4, 5-trimethoxycinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-4) having the formula:
that is, ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-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 as a base catalyst (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 72.8%, and the m.p.232-234 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.26 to 1.65 (7H, m, cyclopropyl-H and CH) 3 )，2.30(3H，s，N-COH 3 ) 2.87-3.65 (8H, m, piperazine-H), 3.88,3.91,3.94 (12H, 3s,4 XOCH) 3 ) 4.58 (1H, m, cyclopropyl-H), 7.46 to 8.14 (3H, m, ph-H and 2 '-H), 8.25 (1H, d, 5-H), 8.67 (1H, d,3' -H), 8.98 (1H, s, 2-H); MS (m/z): 594[ M+H ]] + Calculation (C) 32 H 36 FN 3 O 7 )：593.66。
Example 5
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-methylcinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-5) having the formula:
that is, ar in formula I is p-methyl-phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-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 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 a pale yellow crystal of the formula I-5, the yield is 68.4%, and the m.p.225-227 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.25 to 1.62 (7H, m, cyclopropyl-H and CH) 3 )，2.26(3H，s，Ph-CH 3 )，2.31(3H，s，N-COH 3 ) 2.86 to 3.63 (8H, m, piperazine-H), 3.87 (3H, s, OCH) 3 ) 4.55 (1H, m, cyclopropyl-H), 7.43 to 7.84 (5H, m, ph-H and 2 '-H), 8.22 (1H, d, 5-H), 8.63 (1H, d,3' -H), 8.91 (1H, s, 2-H); MS (m/z): 518[ M+H ]] + Calculation (C) 30 H 32 FN 3 O 4 )：517.61。
Example 6
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-fluoro cinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-6) having the formula:
that is, ar in formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-quinolin-4 (1H) -one-3-ethanone V were taken as a solutionTo 20mL of absolute ethanol was added 0.48g (3.8 mmol) of 4-fluorobenzaldehyde and 0.1mL of piperidine as a base catalyst. The mixed reactants are subjected to reflux reaction for 16 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 77.4%, and the m.p.238-240 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.28 to 1.67 (7H, m, cyclopropyl-H and CH) 3 )，2.34(3H，s，N-COH 3 ) 3.15 to 3.74 (8H, m, piperazine-H), 3.95 (3H, s, OCH) 3 ) 4.65 (1H, m, cyclopropyl-H), 7.56-8.15 (5H, m, ph-H and 2 '-H), 8.37 (1H, d, 5-H), 8.66 (1H, d,3' -H), 9.12 (1H, s, 2-H); MS (m/z): 522[ M+H ]] + Calculation (C) 29 H 29 F 2 N 3 O 4 )：521.57。
Example 7
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-chlorocinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-7) having the formula:
that is, ar in formula I is p-chlorophenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-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 the absolute ethyl alcohol is recrystallized to obtain a pale yellow crystal of the formula I-7, the yield is 73.5%, and the m.p.228-230 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.26 to 1.67 (7H, m, cyclopropyl-H and CH) 3 )，2.32(3H，s，N-COH 3 ) 3.05 to 3.72 (8H, m, piperazine-H), 3.91 (3H, s, OCH) 3 ) 4.56 (1H, m, cyclopropyl-H), 7.56-8.11 (5H, m, ph-H and 2 '-H), 8.35 (1H, d, 5-H), 8.64 (1H, d,3' -H), 9.10 (1H, s, 2-H); MS (m/z): 538[ M+H ]] + ( 35 Cl), calculation (C 29 H 29 FClN 3 O 5 )：538.02。
Example 8
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-bromocinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-8) having the formula:
that is, ar in formula I is p-bromophenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.67g (3.6 mmol) of 4-bromobenzaldehyde 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-8, the yield is 73.6%, and the m.p.235-237 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.25 to 1.68 (7H, m, cyclopropyl-H and CH) 3 )，2.33(3H，s，N-COH 3 ) 3.13 to 3.70 (8H, m, piperazine-H), 3.92 (3H, s, OCH) 3 ) 4.61 (1H, m, cyclopropyl-H), 7.56-8.13 (5H, m, ph-H and 2 '-H), 8.35 (1H, d, 5-H), 8.65 (1H, d,3' -H), 9.12 (1H, s, 2-H); MS (m/z): 582 and 584[ M+H ]] + ( 79 Br and 81 br), calculation (C 29 H 29 FBrN 3 O 4 )：582.47。
Example 9
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-9) having the formula:
that is, ar in formula I is p-nitrophenyl.
The preparation method of the compound comprises the following steps: taking 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) o-8-methoxy-quinolin-4 (1H) -one-3-ethanone V1.2 g (3.0 mmol) was dissolved in 20mL of absolute ethanol, and 0.54g (3.6 mmol) of 4-nitrobenzaldehyde and base catalyst piperidine (0.1 mL) 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 67.3 percent, and the m.p.245-247 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.31 to 1.75 (7H, m, cyclopropyl-H and CH) 3 )，2.34(3H，s，N-COH 3 ) 3.17 to 3.76 (8H, m, piperazine-H), 3.94 (3H, s, OCH) 3 ) 4.67 (1H, m, cyclopropyl-H), 7.60 to 8.22 (5H, m, ph-H and 2 '-H), 8.47 (1H, d, 5-H), 8.68 (1H, d,3' -H), 9.23 (1H, s, 2-H); MS (m/z): 549, calculation (C 29 H 29 FN 4 O 6 )：548.58。
Example 10
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- (4-hydroxy-cinnamoyl) -8-methoxy-quinolin-4 (1H) -one (I-10) having the chemical formula:
that is, ar in formula I is 4-hydroxy-phenyl.
The preparation method of the compound comprises the following steps: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-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 base catalyst piperidine (0.1 mL) were added. The mixed reactants are subjected to reflux reaction for 22 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 67.5%, and the m.p. is 232-234 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.26 to 1.65 (7H, m, cyclopropyl-H and CH) 3 )，2.31(3H，s，N-COH 3 ) 2.96-3.68 (8H, m, piperazine-H), 3.90 (3H, s, OCH) 3 ) 4.56 (1H, m, cyclopropyl-H), 7.53-7.96 (5H, m, ph-H and 2 '-H), 8.27 (1H, d, 5-H), 8.63 (1H, d,3' -H), 8.96 (1H, s, 2-H), 10.64 (1H, s, OH); MS (m/z): 520, calculate (C 29 H 30 FN 4 O 5 )：519.58。
Example 11
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -8-methoxy-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: 1.2g (3.0 mmol) of 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-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 as a base catalyst (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 absolute ethyl alcohol is recrystallized to obtain yellow crystals of the formula I-11, the yield is 83.0%, and the m.p.247-249 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.30 to 1.75 (7H, m, cyclopropyl-H and CH) 3 )，2.35(3H，s，N-COH 3 ) 3.18 to 3.76 (8H, m, piperazine-H), 3.95 (3H, s, OCH) 3 ) 4.68 (1H, m, cyclopropyl-H), 7.57 (1H, d,2 '-H), 8.34-9.17 (5H, 5-H, 3' -H and pyridine-H), 9.24 (1H, s, 2-H); MS (m/z): 505, calculate (C 28 H 29 FN 4 O 4 )：504.57。
Example 12
1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] -8-methoxy-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: taking 1-cyclopropyl-6-fluoro-7- (3-methyl-4-acetylpiperazin-1-yl) -8-methoxy-quinolin-4 (1H) -one-3-ethanone V1.2g (3.0 mmol) was dissolved in 20mL absolute ethanol and 0.38g (4.0 mmol) of 2-furaldehyde 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 yellow crystals of the formula I-12, the yield is 66.3%, and the m.p.243-245 ℃. 1 H NMR(400MHz,CD 3 Cl) δ:1.27 to 1.68 (4H, m, cyclopropyl-H and CH) 3 )，2.31(3H，s，N-COH 3 ) 3.06-3.67 (8H, m, piperazine-H), 3.93 (3H, s, OCH) 3 )，4.67(2H，q，N-CH 2 ) 7.18 to 7.88 (4H, m,2'-H and furan-H), 8.32 (1H, d, 5-H), 8.65 (1H, d,3' -H), 9.13 (1H, s, 2-H); MS (m/z): 494[ M+H ]] + Calculation (C) 27 H 28 FN 3 O 5 )：493.54。
Test examples
1. In vitro antitumor Activity assay of propenone derivatives of N-acetylgatifloxacin provided in examples 1-12
1. Sample for sample
Taking the propenone derivative of the N-acetyl gatifloxacin 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 Gatifloxacin (AGF) provided in examples 1-12 as test samples, 15 in total, wherein HC, SN and AGF are control groups, and the samples in examples 1-12 are experimental groups;
thiazole blue (MTT) and HC, SN, AGF 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 rate of the samples for the samples with different concentrations on cancer cells is calculated according to the following formula:
cancer cell inhibition ratio = [ (1-experimental group OD value)/control group OD value ] ×100%;
then, carrying out linear regression on the cancer cell inhibition rate corresponding to each concentration by using the logarithmic value of each concentration of the sample to obtain a dose-effect equation, and calculating the half inhibition concentration (IC 50) of the sample to the experimental cancer cells from the obtained dose-effect equation; 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 )
Slave watch1 it can be seen that the compounds provided in examples 1-12 have significantly stronger inhibitory activity against 7 cancer cells than the parent compound N-acetylgatifloxacin, especially a portion of the compounds have stronger 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 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 N-acetylgatifloxacin characterized by being a typical compound of the structure:
2. the preparation method of the propenone derivative of the N-acetyl gatifloxacin, which is characterized by comprising the following specific preparation steps:
1) N-acetyl gatifloxacin shown in a formula II is taken as a raw material, is reacted with Carbonyl Diimidazole (CDI) to prepare an N-acetyl gatifloxacin imidazole amide compound shown in a formula III, and is condensed with monoethyl malonate potassium salt to prepare a C-3 formylacetic acid ethyl ester compound of N-acetyl gatifloxacin shown in a formula IV; finally, the N-acetyl gatifloxacin C-3 ethanone shown in the formula V is prepared through hydrolysis decarboxylation reaction in the formula IV:
2) The N-acetyl gatifloxacin C-3 ethanone and aromatic aldehyde are subject to Claisen-Schmidt condensation reaction under the catalysis of alkali to form an propenone structure, and the propenone derivative of the N-acetyl gatifloxacin shown in the claim 1 can be prepared through post-treatment;
the molar ratio of the N-acetyl gatifloxacin shown in the formula II to the CDI is 1:1.0-2.0, the molar ratio of the N-acetyl gatifloxacin 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 gatifloxacin-3 ethyl ketone shown in the formula V to the aromatic aldehyde is 1:1.0-2.0.
3. Use of an propenone derivative of N-acetylgatifloxacin in the manufacture of an antitumor medicament according to claim 1.
4. The use of an propenone derivative of N-acetyl gatifloxacin in the manufacture of an anti-tumour medicament according to claim 3, wherein the anti-tumour medicament is a medicament for the treatment of non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukaemia.
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