CN111393453A - Acrylketone derivative of levofloxacin, and preparation method and application thereof - Google Patents
Acrylketone derivative of levofloxacin, and preparation method and application thereof Download PDFInfo
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The invention discloses an acrylketone derivative of levofloxacin, a preparation method and application thereof, wherein the derivative adopts a chemical structure 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 acrylketone derivative of levofloxacin, a preparation method of the acrylketone derivative of levofloxacin, and application of the acrylketone derivative in antitumor drugs.
Background
New drug innovation stems from the discovery of leads, and rational drug molecular design based on structure or mechanism is an effective method for discovering leads. In the drug effect groups with various structures, the acrylketone structure is not only the characteristic structure of a chalcone compound which is a natural effective component, but also the characteristic drug effect group of a targeted antitumor drug sunitinib. Therefore, compounds constructed with acrylketone as a structural fragment and having various pharmacological activities have been attracting attention. However, most of natural chalcone compounds are multi-hydroxyl benzene ring substituted propenone compounds, and the poor water solubility of the compounds causes low bioavailability and limits clinical application. In addition, the topoisomerase which is an action target point of the antibacterial fluoroquinolone medicine is also an important action target point of the antitumor medicine, the antibacterial activity of the antibacterial fluoroquinolone medicine can be converted into the antitumor activity, and the fluoroquinolone C-3 carboxyl is not a pharmacophore required by the antitumor activity and can be replaced by a biological electron isostere to improve the antitumor activity of the fluoroquinolone medicine. However, the research on the replacement of the C-3 carboxyl group of fluoroquinolone with aryl acrylketone has not been reported. Based on the above, in order to improve the water solubility of chalcone, hydrophilic piperazinyl is introduced to increase the water solubility and improve the bioavailability and the bioactivity of the chalcone, the invention uses the skeleton of the advantageous pharmacophore of the fluoroquinolone drug levofloxacin, namely 1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one, as a substituent of an aryl propenone structure, and further designs the fluoroquinolone chalcone derivatives with novel structures.
Therefore, the invention aims to provide the acrylketone derivative of levofloxacin, which has the function and the effect of resisting tumors and simultaneously provides a preparation method of the acrylketone derivative of levofloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the acrylketone derivative of levofloxacin has a chemical structural formula shown as a general formula I:
in the formula I, Ar is a benzene ring or a substituted benzene ring or a furan ring or a pyridine ring, and the compound is a compound with the following specific structure:
the preparation method of the acrylketone derivative of levofloxacin takes the commercially obtained levofloxacin shown in formula II as a raw material to prepare the levofloxacin derivative;
the preparation method comprises the following specific steps:
1) levofloxacin shown in formula II is used as a raw material and reacts with Carbonyldiimidazole (CDI) to prepare the compound shown in formula II
The preparation method of the levofloxacin imidazole amide compound shown in the III comprises the following steps:
dissolving 22.0g (60.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinoline-4 (1H) -ketone-3-carboxylic acid II in 500m L anhydrous acetonitrile, adding 15.2g (94.0mmol) of carbonyldiimidazole, stirring and refluxing the mixed reaction product in water bath until the raw material II disappears, standing at room temperature, filtering to collect the generated solid, and recrystallizing with acetone to obtain a levofloxacin imidazole amide light yellow crystal shown as a formula III, wherein the yield is 68.5 percent, and m.p.232-234 ℃.1H NMR(400MHz,CD3Cl)：1.58(3H,d,CH3),2.36(3H,s,N-CH3) 3.05 to 3.74(8H, m, piperazine-H), 4.36 to 4.87(3H, m, O-CH)2CH-N), 7.46-7.68 (2H, m, imidazole-H), 8.17(1H, s, imidazole-H), 8.96(1H, d, 5-H), 9.13(1H, s, 2-H); MS (m/z): 412[ M + H]+Calculating (C)21H22FN5O3)：411.44。
As a further improvement, the molar ratio of the levofloxacin shown in the formula II to the carbonyldiimidazole 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.
2) The preparation method comprises the following steps of carrying out condensation reaction on levofloxacin imidazole amide shown in a formula III and monoethyl malonate potassium salt under the catalysis of triethylamine-magnesium chloride to obtain a C-3 formyl ethyl acetate compound of levofloxacin shown in a formula IV, wherein the specific preparation method comprises the following steps:
s- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) - [ quinoline-4 (1H) -one formula III 16.0g (39.0mmol), magnesium chloride 6.6g (69.1mmol) and malonic acid monoethyl ester potassium salt 8.3g (49.0mmol) are sequentially added into 600m L anhydrous acetonitrile, 12.2g (12.0mmol) of triethylamine is added dropwise under ice bath stirring, the mixed reaction is stirred in a water bath and refluxed until the raw material III disappears, the solvent is evaporated under reduced pressure, water is added to 500m L, dichloromethane is used for extraction (3 × 150m L), the organic phase is combined, water washing (3 × 200m L), saturated saline washing (2 × 150m L), anhydrous sodium sulfate is dried, dichloromethane is recovered under normal pressure, and the residue is recrystallized by anhydrous ethanol to obtain a white-like crystal formula IV with the yield of 62.6%, m.p.217-219 ℃.1H NMR(400MHz,CD3Cl)：1.27～1.63(6H，m，2×CH3)，2.40(3H,s,N-CH3) 2.97 to 3.66(8H, m, piperazine-H), 3.42 to 4.88(7H, m, COCH)2COOCH2And O-CH2CH-N)，8.95(1H，d，5-H)，9.16(1H，s,2-H)；MS(m/z)：432[M+H]+Calculating (C)22H26FN3O5)：431.47。
3) The C-3 ethyl formylacetate compound of the levofloxacin shown in the formula IV is subjected to hydrolysis decarboxylation reaction by using a sodium hydroxide aqueous solution with the mass fraction of 6 percent, so that the C-3 ethanone compound of the levofloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:
taking 10g (23.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinoline-4 (1H) -ketone-3-formylacetic acid ethyl ester IV and suspending the ethyl ester in 200m L mass percent sodium hydroxide aqueous solution, stirring and refluxing the mixture in an oil bath until the raw material IV disappears, standing the mixture at room temperature, filtering the generated solid, washing the solid with water to be neutral, drying the solid, and recrystallizing the solid with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula V, wherein the yield is 76.2 percent and m.p.227-229 ℃.1H NMR(400MHz,CD3Cl)：1.60(3H,d,CH3),2.38(3H,s,N-CH3)，2.43(3H，s，COCH3) 3.15 to 3.76(8H, m, piperazine-H), 4.42 to 4.86(3H, m, O-CH)2CH-N)，8.93(1H，d，5-H)，9.17(1H，s,2-H)；MS(m/z)：360[M+H]+Calculating (C)19H22FN3O3)：359.40。
4) C-3 ethanone of levofloxacin shown in a 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, a target compound is obtained through treatment, wherein the target compound is shown in a formula I, and the specific process is as follows:
wherein Ar in the 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 shown as the formula I are that S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) one-3-ethanone V1.1 g (3.0mmol) is dissolved in 20m L absolute ethyl alcohol, aromatic aldehyde (3.0mmol) and alkali catalyst piperidine (0.1m L) are added, mixed reactants are refluxed and reacted for 15-24H, the mixture is placed at room temperature, generated solid is filtered, and the absolute ethyl alcohol is recrystallized to obtain a light yellow crystal shown as the formula I.
As a further improvement, the mole ratio of the levofloxacin 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 acrylketone derivative of levofloxacin in preparing antitumor drugs.
The anti-tumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
The acrylketone derivative of levofloxacin is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the split principle of the pharmacophores, realizes the complementation and activity superposition of the pharmacophores with different structures, achieves the effects of synergism, toxicity reduction and drug resistance, and can be developed as an anti-tumor drug with a brand new structure.
Detailed Description
Example 1
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3-cinnamoyl-quinolin-4 (1H) -one (I-1) having the chemical formula:
namely, Ar in the formula I is phenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethanol, adding 0.40g (3.8mmol) of benzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on the mixture for 18H, standing the mixture at room temperature, filtering the generated solid, and recrystallizing the anhydrous ethanol to obtain a light yellow crystal shown as a formula I-1, wherein the yield is 75.6%, and m.p.232-234 ℃.1H NMR(400MHz,CD3Cl)：1.62(3H,d,CH3),2.38(3H,s,N-CH3) 3.14 to 3.68(8H, m, piperazine-H), 4.45 to 4.87(3H, m, O-CH)2CH-N), 7.63-8.67 (7H, m, Ph-H, 3 '-H and 2' -H), 8.93(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 448[ M + H ]]+Calculating (C)26H26FN3O3)：447.51。
Example 2
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-methoxycinnamoyl) -quinolin-4 (1H) -one (I-2) having the chemical formula:
namely, Ar in the formula I is p-methoxyphenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethanol, adding 0.57g (4.2mmol) of 4-methoxybenzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on a mixed reactant for 20 hours, standing at room temperature, filtering generated solid, and recrystallizing with anhydrous ethanol to obtain a light yellow crystal shown as a formula I-2, wherein the yield is 78.5%, and m.p.235-237 ℃.1H NMR(400MHz,CD3Cl)：1.65(3H,d,CH3),2.43(3H,s,N-CH3) 3.16 to 3.75(8H, m, piperazine-H), 3.92(3H, s, OCH)3)，4.46～4.87(3H，m，O-CH2CH-N), 7.65-8.82 (6H, m, Ph-H, 3 '-H and 2' -H), 8.95(1H, d, 5-H),9.17(1H, s, 2-H); MS (m/z): 478[ M + H]+Calculating (C)27H28FN3O4)：477.54。
Example 3
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (3, 4-dioxamethylenecinnamoyl) -quinolin-4 (1H) -one (I-3) having the chemical formula:
namely, Ar in the formula I is 3,4- (dioxymethylene) phenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethyl acetateAdding 0.53g (3.5mmol) of 3, 4-dioxy methylene benzaldehyde and 0.1m L of alkali catalyst piperidine into alcohol, carrying out reflux reaction on the mixed reaction product for 20 hours, standing the reaction product at room temperature, filtering generated solid, and recrystallizing the solid by absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-3, wherein the yield is 82.4%, and m.p.237-239 ℃.1H NMR(400MHz,CD3Cl)：
1.65(3H,d,CH3),2.43(3H,s,N-CH3) 3.16 to 3.78(8H, m, piperazine-H), 4.46 to 4.86(3H, m, O-CH)2CH-N)，6.24(2H，s，OCH2O), 7.66-8.78 (5H, m, Ph-H, 3 '-H and 2' -H), 8.93(1H, d, 5-H),9.15(1H, s, 2-H); MS (m/z): 492[ M + H]+Calculating (C)27H26FN3O5)：491.52。
Example 4
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (3,4, 5-trimethoxycinnamoyl) -quinolin-4 (1H) -one (I-4) having the chemical formula:
namely, Ar in the formula I is 3,4, 5-trimethoxyphenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethanol, adding 0.63g (3.2mmol) of 3,4, 5-trioxybenzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out mixed reaction on the mixture for 20H under reflux, standing the mixture at room temperature, filtering the generated solid, and recrystallizing the anhydrous ethanol to obtain a light yellow crystal, namely a formula I-4, wherein the yield is 73.6%, and m.p.226-228 ℃.1H NMR(400MHz,CD3Cl)：1.66(3H,d,CH3),2.43(3H,s,N-CH3) 3.15-3.77 (8H, m, piperazine-H), 3.89,3.95(9H, 2s,3 × OCH3)，4.45～4.86(3H，m，O-CH2CH-N), 7.63-8.87 (4H, m, Ph-H, 3 '-H and 2' -H), 8.95(1H, d, 5-H),9.15(1H, s, 2-H); MS (m/z): 538[ M + H]+Calculating (C)29H32FN3O6)：537.59。
Example 5
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-methylcinnamoyl) -quinolin-4 (1H) -one (I-5) having the chemical formula:
namely, Ar in the formula I is p-methyl-phenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V in 20m L anhydrous ethanol, adding 0.58g (4.8mmol) of 4-methylbenzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on a mixed reactant for 15 hours, standing at room temperature, filtering generated solid, and recrystallizing with anhydrous ethanol to obtain a light yellow crystal shown as a formula I-5, wherein the yield is 62.3%, and m.p.221-223 ℃.1H NMR(400MHz,CD3Cl)：1.60(3H,d,CH3),2.28(3H，s，Ph-CH3)，2.36(3H,s,N-CH3) 3.07 to 3.65(8H, m, piperazine-H), 4.38 to 4.78(3H, m, O-CH)2CH-N), 7.62-8.85 (6H, m, Ph-H, 3 '-H and 2' -H), 8.97(1H, d, 5-H),9.08(1H, s, 2-H); MS (m/z): 462[ M + H ]]+Calculating (C)27H28FN3O3)：461.54。
Example 6
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-fluorocinnamoyl) -quinolin-4 (1H) -one (I-6) having the chemical formula:
namely, Ar in the formula I is p-fluoro-phenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L absolute ethyl alcohol, adding 0.48g (3.8mmol) of 4-fluorobenzaldehyde and an alkali catalyst piperidine (0.1m L), mixing the reactants, refluxing and reacting for 15H, standing at room temperature, filtering generated solid, and repeating the steps of dissolving the anhydrous ethyl alcohol in absolute ethyl alcoholCrystallizing to obtain a light yellow crystal shown as a formula I-6, wherein the yield is 76.6%, and the m.p.236-238 ℃.1H NMR(400MHz,CD3Cl)：1.66(3H,d,CH3),2.43(3H,s,N-CH3) 3.18 to 3.76(8H, m, piperazine-H), 4.46 to 4.86(3H, m, O-CH)2CH-N), 7.65-8.86 (6H, m, Ph-H, 3 '-H and 2' -H), 9.03(1H, d, 5-H),9.18(1H, s, 2-H); MS (m/z): 466[ M + H]+Calculating (C)26H25F2N3O3)：465.50。
Example 7
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-chlorocinnamyl) -quinolin-4 (1H) -one (I-7) having the chemical formula:
namely, Ar in the formula I is p-chlorophenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethanol, adding 0.45g (3.2mmol) of 4-chlorobenzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on a mixed reactant for 20 hours, standing at room temperature, filtering generated solid, and recrystallizing with anhydrous ethanol to obtain a light yellow crystal shown as a formula I-7, wherein the yield is 78.7%, and m.p.235-237 ℃.1H NMR(400MHz,CD3Cl)：1.64(3H,d,CH3),2.42(3H,s,N-CH3) 3.17 to 3.78(8H, m, piperazine-H), 4.45 to 4.84(3H, m, O-CH)2CH-N), 7.63-8.86 (6H, m, Ph-H, 3 '-H and 2' -H), 8.97(1H, d, 5-H),9.16(1H, s, 2-H); MS (m/z): 482[ M + H ]]+Calculating (C)26H25FClN3O3)：481.96。
Example 8
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-bromocinnamoyl) -quinolin-4 (1H) -one (I-8) having the chemical formula:
namely, Ar in the formula I is p-bromophenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethanol, adding 0.67g (3.6mmol) of 4-bromobenzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on a mixed reactant for 24 hours, standing at room temperature, filtering generated solid, and recrystallizing with anhydrous ethanol to obtain a light yellow crystal, namely a formula I-8, wherein the yield is 74.8%, and m.p.231-233 ℃.1H NMR(400MHz,CD3Cl)：1.65(3H,d,CH3),2.43(3H,s,N-CH3) 3.14 to 3.76(8H, m, piperazine-H), 4.45 to 4.87(3H, m, O-CH)2CH-N), 7.65-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.17(1H, s, 2-H); MS (m/z): 526 and 528[ M + H ]]+(79Br and81br), calculating (C)26H25FBrN3O3)：526.41。
Example 9
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-nitrocinnamoyl) -quinolin-4 (1H) -one (I-9) having the chemical formula:
namely, Ar in the formula I is p-nitrophenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethanol, adding 0.54g (3.6mmol) of 4-nitrobenzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on a mixed reaction product for 24 hours, standing at room temperature, filtering generated solid, and recrystallizing with anhydrous ethanol to obtain a yellow crystal, namely a formula I-9, wherein the yield is 75.7%, and m.p.240-242 ℃.1H NMR(400MHz,CD3Cl)：1.66(3H,d,CH3),2.44(3H,s,N-CH3) 3.23 to 3.87(8H, m, piperazine-H), 4.47 to 4.88(3H, m, O-CH)2CH-N), 7.65-8.88 (6H, m, Ph-H, 3 '-H and 2' -H),9.02(1H，d，5-H),9.24(1H，s，2-H)；MS(m/z)：493[M+H]+calculating (C)26H25FN4O5)：492.51。
Example 10
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- (4-hydroxy-cinnamoyl) -quinolin-4 (1H) -one (I-10) having the chemical formula:
namely, Ar in the formula I is 4-hydroxy-phenyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethanol, adding 0.49g (4.0mmol) of 4-hydroxy-benzaldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on the mixed reaction product for 20 hours, standing the mixture at room temperature, filtering the generated solid, and recrystallizing the anhydrous ethanol to obtain a yellow crystal, namely a formula I-10, wherein the yield is 70.5%, and m.p.233 ℃.1H NMR(400MHz,CD3Cl)：1.62(3H,d,CH3),2.37(3H,s,N-CH3) 3.06 to 3.76(8H, m, piperazine-H), 4.43 to 4.86(3H, m, O-CH)2CH-N), 7.64-8.87 (6H, m, Ph-H, 3 '-H and 2' -H), 8.96(1H, d, 5-H),9.11(1H, s,2-H), 10.62(1H, s, OH); MS (m/z): 464, calculating (C)26H26FN3O4)：463.51。
Example 11
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical formula:
namely, Ar in the formula I is 3-pyridyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone in 20m L anhydrous ethyl acetateAdding 0.37g (3.6mmol) of 3-pyridylaldehyde and a base catalyst piperidine (0.1m L) into alcohol, carrying out reflux reaction on a mixed reaction product for 15 hours, standing at room temperature, filtering to collect generated solid, and recrystallizing by absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-11, wherein the yield is 81.0%, and m.p.243-245 ℃.1H NMR(400MHz,CD3Cl)：1.68(3H,d,CH3),2.45(3H,s,N-CH3) 3.27 to 3.86(8H, m, piperazine-H), 4.46 to 4.95(3H, m, O-CH)2CH-N), 7.66(1H, d, 2 '-H), 8.87-9.13 (6H, 5-H, 3' -H and pyridine-H), 9.23(1H, s, 2-H); MS (m/z): 449, calculating (C)25H25FN4O3)：448.50。
Example 12
S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical formula:
namely, Ar in the formula I is 2-furyl.
The preparation method of the compound comprises the steps of dissolving 1.1g (3.0mmol) of S- (-) -1, 8-isopropoxy-6-fluoro-7- (4-methylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V in 20m L absolute ethyl alcohol, adding 0.38g (4.0mmol) of 2-furan aldehyde and an alkali catalyst piperidine (0.1m L), carrying out reflux reaction on a mixed reaction product for 18H, standing at room temperature, filtering and collecting generated solid, and recrystallizing absolute ethyl alcohol to obtain a yellow crystal of a formula I-12, wherein the yield is 71.5%, and m.p.234-236 ℃.1H NMR(400MHz,CD3Cl)：1.65(3H,d,CH3),2.44(3H,s,N-CH3) 3.18 to 3.84(8H, m, piperazine-H), 4.45 to 4.86(3H, m, O-CH)2CH-N), 7.31-8.17 (5H, m, 2 '-H, 3' -H and furan-H), 8.97(1H, d, 5-H),9.15(1H, s, 2-H); MS (m/z): 438[ M + H]+Calculating (C)24H24FN3O3S)：437.47。
Test examples
One, embodiment 1-12 provide a levofloxacin propenone derivative in vitro anti-tumor activity determination
1. Test sample
15 OF the acrylketone derivatives OF levofloxacin provided in examples 1-12, the classical antitumor TOPO inhibitor 10-Hydroxycamptothecin (HC), the chalcone tyrosinase inhibitor Sunitinib (SN), the broad-spectrum anticancer drug Doxorubicin (DOX) and the parent compound levofloxacin (L OF) were used as test samples, wherein HC, SN and L OF are control groups, and examples 1-12 are test groups;
thiazole blue (MTT), HC, SN and L OF are all products OF Sigma company, RPMI-1640 culture solution is a product OF GIBCO company, and other used reagents are all domestic analytical pure reagents.
The experimental cancer cell strains are respectively a human non-small cell lung cancer cell strain A549, a human kidney cancer cell strain 769-P, a human hepatoma cell strain Hep-3B, a human gastric cancer cell strain HGC27, a human pancreatic cancer cell strain Panc-1 and a human leukemia cell strain H L60, which are purchased from Shanghai cell Bank of China academy of sciences, a human renal clear cell carcinoma cell sunitinib drug-resistant strain 7SuR is purchased from Shanghai leaf Biotech Limited, and normal cells are obtained from African green monkey kidney cell strain VERO and are purchased from Shanghai Patnt Biotech Limited.
2. Measurement method
The determination method comprises the following specific steps:
1) firstly, the 15 samples were dissolved in dimethyl sulfoxide (DMSO) to prepare 1.0 × 10- 4mol·L-1Stock solution of concentration, then diluting the stock solution with 10% calf serum RPMI-1640 culture solution to have 5 concentration gradients (0.1, 1.0, 5.0, 10.0, 50.0 μmol. L)-1) The working fluid of (1);
2) taking non-small cell lung cancer cell strain A549, human kidney cancer cell strain 769-P, human liver cancer cell strain Hep-3B, human gastric cancer cell strain HGC27, human pancreatic cancer cell strain Panc-1 and human leukemia cell strain H L60, human renal clear cell cancer cell sunitinib drug-resistant strain 7SuR and African green monkey kidney cell strain VERO in logarithmic growth phase, inoculating 6000 cells in each well to 96-well plate, and respectively adding the 15 samples with 5 concentration gradientsPreparing liquid, adding 5 g-L per well after 48 hours–1MTT (thiazole blue) solution 10 mu L, continuing to culture for 4 hours, adding Sodium Dodecyl Sulfate (SDS) solution with the mass percentage concentration of 100 mu L percent at 10 percent, culturing for 24 hours, and then measuring the absorbance (OD) value at the wavelength of 570nm by using a microplate reader;
3) the inhibition rate of the test samples with different concentrations on the cancer cells is calculated according to the following formula:
the cancer cell inhibition rate is (1-experimental OD value)/control OD value) × 100%;
then, linear regression is carried out on the cancer cell inhibition rate corresponding to each concentration by the pair value of each concentration of the test sample to obtain a dose-effect equation, and the half Inhibition Concentration (IC) of the test sample to the experimental cancer cell is calculated from the obtained dose-effect equation50) (ii) a Each data was measured in triplicate and averaged, the results are shown in Table 1.
TABLE 1 antitumor Activity (IC) of the test samples50)
As can be seen from Table 1, the inhibitory activity of the compounds provided in examples 1-12 on 7 cancer cells of experiment is significantly stronger than that of the parent compound levofloxacin, especially the growth inhibitory activity of some compounds on human non-small cell lung cancer cell line A549 is stronger than that of the control Hydroxycamptothecin (HC), the tyrosine kinase inhibitors Sunitinib (SN) and adriamycin (DOX), and the IC of the compounds is50The value is reached or close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1 to 12 also show extremely strong sensitivity to sunitinib-resistant strain 7SuR, show strong drug-resistant activity, and simultaneously show low cytotoxicity to normal cells VERO, and have the property of becoming drug-resistant. Therefore, according to the general approach of drug development, the conventional antitumor in vitro screening is carried out, and then the targeted research is carried out, so that the compound of the invention has strong antitumor activity and drug resistance activity and lower cytotoxicity, and can be formed by salifying with acid acceptable for human bodies or forming with a medicinal carrierMixing to prepare the antitumor drug.
Claims (5)
1. The acrylketone derivative of levofloxacin is characterized by being a typical compound with the following structure:
2. the preparation method of the acrylketone derivative of levofloxacin according to claim 1, which comprises the following steps:
1) levofloxacin shown in a formula II is used as a raw material and reacts with Carbonyldiimidazole (CDI) to prepare levofloxacin shown in a formula III
Performing condensation reaction on the ofloxacin imidazole amide compound and monoethyl malonate potassium salt to obtain a C-3 formyl ethyl acetate compound of the levofloxacin shown in a formula IV; finally, the levofloxacin C-3 ethanone shown in the formula V is prepared by hydrolysis decarboxylation reaction of the formula IV:
2) the levofloxacin acrylketone derivative shown in the claim 1 can be prepared by carrying out Claisen-Schmidt condensation reaction on levofloxacin C-3 ethanone shown in the formula V and aromatic aldehyde under the catalysis of alkali to form an acrylketone structure and carrying out post-treatment.
3. The preparation method of the acrylketone derivative of levofloxacin according to claim 2, wherein the molar ratio of levofloxacin and CDI shown in the formula II is 1: 1.0-2.0, the molar ratio of levofloxacin imidazole amide shown in the formula III and monoethyl malonate potassium salt is 1: 1.0-1.5, and the molar ratio of levofloxacin C-3 ethanone shown in the formula V and aromatic aldehyde is 1: 1.0-2.0.
4. The use of the acrylketone derivative of levofloxacin according to claim 1 in the preparation of an antitumor medicament.
5. The use of the acrylketone derivative of levofloxacin according to claim 4 in the preparation of an antitumor drug, wherein the antitumor drug is a drug for treating human non-small cell lung cancer, kidney cancer, liver cancer, stomach cancer, pancreatic cancer or leukemia.
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| US20030045555A1 (en) * | 2001-07-19 | 2003-03-06 | Rivera Nelo R. | Process to chiral integrin antagonist beta-amino acid intermediate |
| CN106317074A (en) * | 2015-06-26 | 2017-01-11 | 河南大学 | Alpha, beta-unsaturated ketone derivatives of ofloxacin, and preparation method and applications thereof |
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