CN111303026A - Propenone derivative of enrofloxacin and preparation method and application thereof - Google Patents
Propenone derivative of enrofloxacin and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses an allyl ketone derivative of enrofloxacin and a preparation method and application thereof, and 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 medicine synthesis, and particularly relates to an acrylketone derivative of enrofloxacin, a preparation method of the acrylketone derivative of enrofloxacin, and application of the acrylketone derivative of enrofloxacin in antitumor medicines.
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 dominant pharmacophore of the fluoroquinolone medicament enrofloxacin, namely 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one, as a substituent of an aryl propenone structure, and further designs the novel structural fluoroquinolone chalcone derivative.
Therefore, the invention aims to provide an acrylketone derivative of enrofloxacin, which has the function and the efficacy of resisting tumors and a preparation method of the acrylketone derivative of enrofloxacin.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the structural formula of the allyl ketone derivative of enrofloxacin is shown as the 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 allyl ketone derivative of enrofloxacin is prepared by taking commercially obtained enrofloxacin shown as a formula II as a raw material;
the preparation method comprises the following specific steps:
1) the method for preparing the norfloxacin imidazole amide compound shown in the formula III by taking enrofloxacin shown in the formula II as a raw material and reacting with Carbonyldiimidazole (CDI) comprises the following steps:
21g (56.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-carboxylic acid II is dissolved in 500mL of anhydrous acetonitrile, 15.2g (94.0mmol) of carbonyldiimidazole is added, and the mixed reaction is stirred in a water bath and refluxed until the raw material II disappears. Standing at room temperature, filtering to collect the generated solid, and recrystallizing with acetone to obtain a light yellow crystal of formula III with a yield of 86.4% and m.p.232-234 ℃.1H NMR(400MHz,CD3Cl)δ：1.15～1.34(7H，m，CH3And cyclopropyl-H), 2.38(2H, q, N-CH)2) 2.87 to 3.55(8H, m, piperazine-H), 4.36(1H, m, cyclopropyl-H), 6.78 to 7.85(3H, m, imidazole-H and 8-H), 8.07(1H, d, 5-H), 8.36(1H, s, imidazole-H), 8.86(1H, s, 2-H); MS (m/z): 410[ M + H]+Calculating (C)22H24FN5O2)：409.47。
As a further improvement, the molar ratio of the enrofloxacin 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 enrofloxacin imidazole amide shown in the formula III and the potassium salt of the monoethyl malonate are subjected to condensation reaction under the catalysis of triethylamine-magnesium chloride to prepare the C-3 formyl ethyl acetate compound of enrofloxacin shown in the formula IV, and the specific preparation method is as follows:
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -3- (1H-imidazole-1-formyl) -quinolin-4 (1H) -one of formula III 15.5g (38.0mmol), magnesium chloride 6.6g (69.1mmol) and monoethyl malonate potassium salt 8.3g (49.0mmol) are sequentially added into 600mL of anhydrous acetonitrile, triethylamine 12.5g (12.4mmol) is added dropwise under stirring in an ice bath, and the mixed reaction is stirred in a water bath and refluxed until the raw material III disappears. The solvent was evaporated under reduced pressure, 500mL of water was added, the mixture was extracted with methylene chloride (3X 150mL), the organic phases were combined, washed with water (3X 200mL), washed with saturated brine (2X 150mL), and dried over anhydrous sodium sulfate. And recovering dichloromethane at normal pressure, and recrystallizing the residue with absolute ethyl alcohol to obtain an off-white crystal shown as a formula IV, wherein the yield is 73.5%, and m.p.223-225 ℃.1H NMR(400MHz,CD3Cl) δ: 1.18 to 1.42(10H, m, cyclopropyl-H and 2 XCH)3)，2.37(2H,q,N-CH2) 2.78 to 3.55(8H, m, piperazine-H), 4.11(2H, s, COCH)2CO)，4.22(2H，q，CO2CH2) 4.36(1H, m, cyclopropyl-H), 7.82(1H, d, 8-H), 8.06(1H, d, 5-H), 8.91(1H, s, 2-H); MS (m/z): 430[ M + H ]]+Calculating (C)23H28FN3O4)：429.50。
3) The C-3 ethyl formyl acetate compound of the enrofloxacin shown in the 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 the enrofloxacin shown in the formula V can be conveniently prepared, and the specific preparation method is as follows:
taking 10g (23.3mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-formylacetic acid ethyl ester IV and suspending the ethyl ester in 200mL of sodium hydroxide aqueous solution with the mass fraction of 6%, and stirring and refluxing the mixture in an oil bath until the raw material IV disappears. Standing at room temperature, collecting the generated solid by filtration, washing with water to be neutral, drying, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal of formula V, wherein the yield is 78.4%, and m.p.221-223 ℃.1HNMR(400MHz,CD3Cl) δ: 1.21 to 1.35(7H, m, cyclopropyl-H and CH)3)，2.38(2H,q,N-CH2),2.42(3H，s，COCH3) 2.76 to 3.55(8H, m, piperazine-H), 4.36(1H, m, cyclopropyl-H), 7.75(1H, d, 8-H), 8.06(1H, d, 5-H), 8.94(1H, s, 2-H); MS (m/z): 358[ M + H]+Calculating (C)20H24FN3O2)：357.43。
4) C-3 ethanone of enrofloxacin 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, a target compound is obtained by treatment, wherein the target compound is shown in 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 procedure for the target compound of formula i is: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and an aromatic aldehyde (3.2mmol) and a base catalyst piperidine (0.1mL) were added. And (3) refluxing and reacting the mixed reactants for 15-24 h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal shown in the formula I.
As a further improvement, the mol ratio of the enrofloxacin 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 allyl ketone derivative of enrofloxacin 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 enrofloxacin is designed and synthesized by effectively combining a fluoroquinolone skeleton and an aryl acrylketone pharmacophore based on the splicing principle of 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
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.40g (3.8mmol) of benzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 18h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-1, wherein the yield is 73.7%, and m.p.226-228 ℃.1H NMR(400MHz,CD3Cl) δ: 1.17 to 1.34(7H, m, cyclopropyl-H and CH)3)，2.38(2H,q,N-CH2) 2.86 to 3.57(8H, m, piperazine-H), 4.38(1H, m, cyclopropyl-H), 7.46 to 7.88(7H, m, 8-H, Ph-H and 2' -H), 8.23(1H, d)，5-H)，8.62(1H，d，3′-H),9.03(1H，s，2-H)；MS(m/z)：446[M+H]+Calculating (C)27H28FN3O2)：445.54。
Example 2
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.57g (4.2mmol) of 4-methoxybenzaldehyde and piperidine, an alkali catalyst (0.1mL) were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-2, wherein the yield is 75.4%, and m.p.232-234 ℃.1H NMR(400MHz,CD3Cl) δ: 1.20 to 1.42(7H, m, cyclopropyl-H and CH)3)，2.38(3H,q,N-CH2) 2.83-3.58 (8H, m, piperazine-H), 3.92(3H, s, OCH)3) 4.42(1H, m, cyclopropyl-H), 7.72 to 7.88(6H, m, 8-H, Ph-H and 2 '-H), 8.27(1H, d, 5-H), 8.65(1H, d, 3' -H),9.05(1H, s, 2-H); MS (m/z): 476[ M + H ]]+Calculating (C)28H30FN3O3)：475.57。
Example 3
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: taking 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quina1.1g (3.0mmol) of lin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.53g (3.5mmol) of 3, 4-dioxytolualdehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 20h, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-3, wherein the yield is 78.3%, and the m.p.235-237 ℃.1H NMR(400MHz,CD3Cl) δ: 1.20 to 1.44(7H, m, cyclopropyl-H and CH)3)，2.40(2H,q,N-CH2) 2.85-3.62 (8H, m, piperazine-H), 4.42(1H, m, cyclopropyl-H), 6.24(2H, s, OCH)2O), 7.76-7.88 (5H, m, 8-H, Ph-H and 2 '-H), 8.36(1H, d, 5-H), 8.65(1H, d, 3' -H),9.07(1H, s, 2-H); MS (m/z): 490[ M + H [ ]]+Calculating (C)28H28FN3O4)：489.55。
Example 4
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.63g (3.2mmol) of 3,4, 5-trioxybenzaldehyde and piperidine (0.1mL) as an alkali catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-4, wherein the yield is 68.6%, and m.p.225-227 ℃.1H NMR(400MHz,CD3Cl) δ: 1.21 to 1.45(7H, m, cyclopropyl-H and CH)3)，2.37(2H,q,N-CH2) 2.84-3.63 (8H, m, piperazine-H), 3.86, 3.90(9H, 2s, 3 XOCH)3) 4.38(1H, m, cyclopropyl-H), 7.84 to 7.93(4H, m, 8-H, Ph-H and 2 '-H), 8.285(1H, d, 5-H), 8.57(1H, d, 3' -H),9.06(1H, s, 2-H); MS (m/z): 536[ M + H]+Calculating (C)30H33FN3O5)：535.62。
Example 5
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.0g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.58g (4.8mmol) of 4-methylbenzaldehyde and piperidine, a basic catalyst (0.1mL) were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-5, wherein the yield is 65.5%, and the m.p.218-220 ℃.1H NMR(400MHz,CD3Cl) δ: 1.18 to 1.37(7H, m, cyclopropyl-H and CH)3)，2.26(3H，s，Ph-CH3)，2.36(2H,q,N-CH2) 2.76 to 3.57(8H, m, piperazine-H), 4.38(1H, m, cyclopropyl-H), 7.53 to 7.87(6H, m, 8-H, Ph-H and 2 '-H), 8.26(1H, d, 5-H), 8.57(1H, d, 3' -H),8.87(1H, s, 2-H); MS (m/z): 460[ M + H ]]+Calculating (C)28H30FN3O2)：459.57。
Example 6
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.48g (3.8mmol) of 4-fluorobenzaldehyde and piperidine (0.1mL) as a basic catalyst were added. Refluxing of the mixed reactantsReacting for 18h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal shown as a formula I-6, wherein the yield is 75.6%, and m.p.225-227 ℃.1HNMR(400MHz,CD3Cl) δ: 1.22 to 1.46(7H, m, cyclopropyl-H and CH)3)，2.45(2H,q,N-CH2) 3.05 to 3.67(8H, m, piperazine-H), 4.46(1H, m, cyclopropyl-H), 7.82 to 8.15(6H, m, 8-H, Ph-H and 2 '-H), 8.37(1H, d, 5-H), 8.64(1H, d, 3' -H),9.08(1H, s, 2-H); MS (m/z): 464[ M + H ]]+Calculating (C)27H27F2N3O2)：463.53。
Example 7
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.45g (3.2mmol) of 4-chlorobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 20 hours, standing at room temperature, filtering and collecting the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-7, wherein the yield is 67.8%, and m.p.226-228 ℃.1HNMR(400MHz,CD3Cl) δ: 1.22 to 1.45(7H, m, cyclopropyl-H and CH)3)，2.41(2H,q,N-CH2) 3.05 to 3.68(8H, m, piperazine-H), 4.45(1H, m, cyclopropyl-H), 7.78 to 8.08(6H, m, 8-H, Ph-H and 2 '-H), 8.36(1H, d, 5-H), 8.64(1H, d, 3' -H),9.07(1H, s, 2-H); MS (m/z): 480[ M + H ]]+(35Cl), calculating (C)27H27FClN3O3)：479.99。
Example 8
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.67g (3.6mmol) of 4-bromobenzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a light yellow crystal, namely a formula I-8, wherein the yield is 67.2%, and the m.p.223-225 ℃.1HNMR(400MHz,CD3Cl) δ: 1.21 to 1.45(7H, m, cyclopropyl-H and CH)3)，2.40(2H,q,N-CH2) 3.07 to 3.68(8H, m, piperazine-H), 4.44(1H, m, cyclopropyl-H), 7.86 to 8.15(6H, m, 8-H, Ph-H and 2 '-H), 8.37(1H, d, 5-H), 8.63(1H, d, 3' -H),9.06(1H, s, 2-H); MS (m/z): 524 and 526[ M + H ]]+(79Br and81br), calculating (C)27H27FBrN3O2)：524.44。
Example 9
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.54g (3.6mmol) of 4-nitrobenzaldehyde and piperidine, a basic catalyst (0.1mL) were added. And (3) carrying out reflux reaction on the mixed reactants for 24 hours, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-9, wherein the yield is 73.2%, and the m.p.241-243 ℃.1HNMR(400MHz,CD3Cl) δ: 1.24 to 1.47(7H, m, cyclopropyl-H and CH)3)，2.42(2H,q,N-CH2) 3.12-3.76 (8H, m, piperazine-H), 4.48(1H, m, cyclopropyl-H), 8.12-8.25 (6H, m, 8-H, Ph-H and 2 '-H), 8.46(1H, d, 5-H), 8.66(1H, d, 3' -H),9.17(1H, s, 2-H); MS (m/z): 491, calculating (C)27H27FN4O4)：490.54。
Example 10
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-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 following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.49g (4.0mmol) of 4-hydroxy-benzaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) refluxing and reacting the mixed reactants for 22h, standing at room temperature, filtering and collecting generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-10, wherein the yield is 57.8%, and the m.p.225-227 ℃.1H NMR(400MHz,CD3Cl) δ: 1.20 to 1.43(4H, m, cyclopropyl-H and CH)3)，2.38(2H,q,N-CH2) 2.96-3.67 (8H, m, piperazine-H), 4.42(1H, m, cyclopropyl-H), 7.76-7.88 (6H, m, 8-H, Ph-H and 2 '-H), 8.38(1H, d, 5-H), 8.62(1H, d, 3' -H),8.97(1H, s,2-H), 10.55(1H, s, OH); MS (m/z): 462, calculating (C)27H28FN4O3)：461.54。
Example 11
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -3- [3- (pyridin-3-yl) acryloyl ] -quinolin-4 (1H) -one (I-11) having the chemical structure:
namely, Ar in the formula I is 3-pyridyl.
The preparation method of the compoundThe method comprises the following steps: 1.1g (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of anhydrous ethanol, and 0.37g (3.6mmol) of 3-pyridylaldehyde and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 15h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal shown as a formula I-11, wherein the yield is 78.6%, and the m.p.243-245 ℃.1H NMR(400MHz,CD3Cl) δ: 1.25 to 1.52(7H, m, cyclopropyl-H and CH)3)，2.44(2H,q,N-CH2) 3.15 to 3.77(8H, m, piperazine-H), 4.48(1H, m, cyclopropyl-H), 7.86 to 8.16(2H, m, 8-H and 2 '-H), 8.42 to 9.05(6H, 5-H, 3' -H and pyridine-H), 9.18(1H, s, 2-H); MS (m/z): 447, calculate (C)26H27FN4O2)：446.53。
Example 12
1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -3- [3- (furan-2-yl) acryloyl ] quinolin-4 (1H) -one (I-12) having the chemical structure:
namely, Ar in the 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 (3.0mmol) of 1-cyclopropyl-6-fluoro-7- (4-ethylpiperazin-1-yl) -quinolin-4 (1H) -one-3-ethanone V was dissolved in 20mL of absolute ethanol, and 0.38g (4.0mmol) of 2-furfural and piperidine (0.1mL) as a base catalyst were added. And (3) carrying out reflux reaction on the mixed reactants for 20h, standing at room temperature, filtering to collect the generated solid, and recrystallizing with absolute ethyl alcohol to obtain a yellow crystal, namely a formula I-12, wherein the yield is 62.5%, and the m.p.236-238 ℃.1H NMR(400MHz,CD3Cl) δ: 1.22 to 1.45(7H, m, cyclopropyl-H and CH)3)，2.41(2H,q,N-CH2) 3.08-3.74 (8H, m, piperazine-H), 4.45(2H, q, N-CH)2) 7.12-7.86 (5H, m, 8-H, 2 '-H and furan-H), 8.42(1H, d, 5-H), 8.63(1H, d, 3' -H),9.12(1H, s, 2-H); MS (m/z): 436[ M + H]+Calculating (C)25H26FN3O3)：435.50。
Test examples
One, embodiment 1-12 provides an in vitro anti-tumor activity assay of an propenone derivative of enrofloxacin
1. Test sample
15 samples of the propenone derivative of N-methyl ciprofloxacin provided by examples 1-12, a classic antitumor TOPO inhibitor 10-Hydroxycamptothecin (HC), a chalcone tyrosinase inhibitor Sunitinib (SN), a broad-spectrum anticancer drug adriamycin (DOX) and a parent compound Enrofloxacin (EOF) are taken as test samples, wherein HC, SN and EOF are control experimental groups, and examples 1-12 are test experimental groups;
thiazole blue (MTT), HC, SN and EOF are all products of Sigma company; the RPMI-1640 culture solution is a product of GIBCO company; 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 HL60, which are purchased from Shanghai cell banks of Chinese academy of sciences. The human renal clear cell carcinoma cell sunitinib-resistant strain 7SuR was purchased from shanghai zel biotechnology limited, and the normal cell was obtained from african green monkey kidney cell line VERO and purchased from shanghai tong biology 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 1.0X 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 hepatoma cell strain Hep-3B, human gastric cancer cell strain HGC27, human pancreatic cancer cell strain Panc-1 and human leukemia cell strain HL60 in logarithmic growth phase, human renal clear cell carcinoma cell SchneiniThe tinib-resistant strain 7SuR and african green monkey kidney cell line VERO were inoculated into a 96-well plate at 6000 cells per well, then working solutions having 5 concentration gradients were added to the 15 samples, and after 48 hours, 5g · L was added per well–1mu.L of MTT (thiazole blue) solution was added, and after further culturing for 4 hours, 100. mu.L of a 10% by mass Sodium Dodecyl Sulfate (SDS) solution was added. Culturing for 24 hours, and then measuring an absorbance (OD) value at a 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:
cancer cell inhibition rate ═ [ (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 enrofloxacin, 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 close to nanomolar concentration, and the method has the value of new drug development. More significantly, the compounds provided in examples 1-12 also showed very strong sensitivity to sunitinib-resistant strain 7SuR, showed strong resistance to drug, and showed low toxicity to normal cell VEROSex, it has the property of becoming a property of property. 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 has strong antitumor activity, drug resistance activity and lower cytotoxicity, and can be used for preparing antitumor drugs by salifying with acid acceptable for human bodies or mixing with medicinal carriers.
Claims (5)
1. An allyl ketone derivative of enrofloxacin, which is characterized by being a typical compound with the following structure:
2. The preparation method of the acrylketone derivative of enrofloxacin as claimed in claim 1, which is characterized by comprising the following steps:
1) the method comprises the following steps of (1) taking enrofloxacin shown as a formula II as a raw material, reacting with Carbonyldiimidazole (CDI) to prepare an enrofloxacin imidazole amide compound shown as a formula III, and then carrying out a condensation reaction with monoethyl malonate potassium salt to prepare a C-3 formyl ethyl acetate compound of enrofloxacin shown as a formula IV; finally, the enrofloxacin C-3 ethanone shown in the formula V is prepared by the hydrolysis decarboxylation reaction of the formula IV:
2) the enrofloxacin C-3 ethanone shown in the formula V and aromatic aldehyde are subjected to Claisen-Schmidt condensation reaction under the catalysis of alkali to form an propenone structure, and the propenone derivative of enrofloxacin shown in the claim 1 can be prepared through post treatment.
3. The method for preparing the acrylketone derivative of enrofloxacin according to claim 2, wherein the molar ratio of enrofloxacin represented by formula II to CDI is 1: 1.0-2.0, the molar ratio of enrofloxacin imidazole amide represented by formula III to monoethyl malonate potassium salt is 1: 1.0-1.5, and the molar ratio of enrofloxacin-3 ethanone represented by formula V to aromatic aldehyde is 1: 1.0-2.0.
4. The use of the acrylketone derivative of enrofloxacin as claimed in claim 1 in the preparation of anti-tumor drugs.
5. The application of the enrofloxacin acrylketone derivative in the preparation of the antitumor drug according to claim 4, 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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111646937A (en) * | 2019-11-20 | 2020-09-11 | 河南大学 | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof |
| CN111646938A (en) * | 2019-11-20 | 2020-09-11 | 河南大学 | Propenone derivative of pefloxacin, and preparation method and application thereof |
| CN111646974A (en) * | 2019-11-20 | 2020-09-11 | 河南大学 | N-methyl gatifloxacin propenone derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045555A1 (en) * | 2001-07-19 | 2003-03-06 | Rivera Nelo R. | Process to chiral integrin antagonist beta-amino acid intermediate |
| CN106279019A (en) * | 2015-06-26 | 2017-01-04 | 河南大学 | A kind of α of enrofloxacin, alpha, beta-unsaturated ketone derivant and its preparation method and application |
-
2019
- 2019-11-19 CN CN201911131815.2A patent/CN111303026A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045555A1 (en) * | 2001-07-19 | 2003-03-06 | Rivera Nelo R. | Process to chiral integrin antagonist beta-amino acid intermediate |
| CN106279019A (en) * | 2015-06-26 | 2017-01-04 | 河南大学 | A kind of α of enrofloxacin, alpha, beta-unsaturated ketone derivant and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| TAKUO KOSUGE: "Synthesis and some reactions of 6-bromooxindole", 《CHEM.PHARM.BULL.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111646937A (en) * | 2019-11-20 | 2020-09-11 | 河南大学 | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof |
| CN111646938A (en) * | 2019-11-20 | 2020-09-11 | 河南大学 | Propenone derivative of pefloxacin, and preparation method and application thereof |
| CN111646974A (en) * | 2019-11-20 | 2020-09-11 | 河南大学 | N-methyl gatifloxacin propenone derivative and preparation method and application thereof |
| CN111646938B (en) * | 2019-11-20 | 2022-01-21 | 河南大学 | Propenone derivative of pefloxacin, and preparation method and application thereof |
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