CN107098895B - Benzoylaminothiazolylmethyl quinolinone derivative and preparation method and application thereof - Google Patents
Benzoylaminothiazolylmethyl quinolinone derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a phenylaminothiazole methyl quinolinone derivative shown as a chemical structural formula I and pharmaceutically acceptable salts thereof:wherein R is selected from: c1～C2An alkyl group; c3～C4Straight chain alkyl or C3～C4A branched alkyl group; x1、X2Selected from: hydrogen, deuterium, C1～C2An alkyl group; x3、X7Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo; x4、X6Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo or trifluoromethyl; x5Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo, nitro or trifluoromethyl; an application of the phenylaminothiazole methyl quinolinone derivative, its pharmaceutically acceptable salts and the pharmaceutical composition in preparing anticancer drugs.
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to an anilinothiazole methylquinolinone derivative and application thereof in preparing an anti-cancer drug.
Background
Holla et al [ Eur Med Chem,2003,38:313-318] describe the preparation and anti-cancer activity of 2-arylamino-4- (2, 4-dichloro-5-fluorophenyl) thiazoles. Huixi et al described the anticancer activity of 5-benzyl-4-alkyl-2-arylaminothiazole hydrobromide [ proceedings of advanced chemistry, 2013, 34 (7): 1646 to 1652 ]; chinese patent (CN 102070556B; CN 102319244B; CN101277692A) describes the preparation and antitumor activity of 5-benzyl-4-alkyl-2-arylaminothiazole.
Disclosure of Invention
The invention aims to provide a class of phenylaminothiazole methyl quinolinone derivatives, a preparation method, a pharmaceutical composition and application thereof.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides phenylaminothiazole methyl quinolinone derivatives shown in a chemical structural formula I and pharmaceutically acceptable salts thereof:
wherein the content of the first and second substances,r is selected from: c1～C2An alkyl group; c3～C4Straight chain alkyl or C3～C4A branched alkyl group; x1、X2Selected from: hydrogen, deuterium, C1～C2An alkyl group; x3、X7Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo; x4、X6Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo or trifluoromethyl; x5Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo, nitro or trifluoromethyl.
Further, preferred compounds are selected from:
3- ((4-tert-butyl-2- (phenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (2-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (3-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (4-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (2-fluoroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -ketone, 3- ((4-tert-butyl-2- (4-fluorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (2-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (3-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (4-bromophenylamino) thiazol-5-yl) methyl) quinolinone 2(1H) -one, 3- ((4-tert-butyl-2- (3-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (4-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (2, 6-dimethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (3, 5-bistrifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, methods of making and using, 3- ((4-tert-butyl-2- (2-fluoro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (3-fluoro-4-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (4-fluoro-3-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (2, 3-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, methods of making and using, 3- ((4-tert-butyl-2- (3, 4-dichloroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, 3- ((4-tert-butyl-2- (3, 5-dichloroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, and 3- ((4-tert-butyl-2- (2-chloro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one.
The second aspect of the technical scheme of the invention provides a preparation method of the phenylamino thiazole methyl quinolinone derivative, which is characterized in that the preparation reaction is as follows:
r is selected from: c1～C2An alkyl group; c3～C4Straight chain alkyl or C3～C4A branched alkyl group; x1、X2Selected from: hydrogen, deuterium, C1～C2An alkyl group; x3、X7Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo; x4、X6Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo or trifluoromethyl; x5Selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo, nitro or trifluoromethyl; x is selected from: chlorine, bromine or iodine.
According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the anilinothiazolylmethylquinolinone derivative of the present invention and a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and the pharmaceutically acceptable salt thereof in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The fourth aspect of the technical scheme of the invention is to provide the phenylaminothiazole methyl quinolinone derivatives and the pharmaceutically acceptable salts thereof of the first aspect of the invention and the application of the pharmaceutical composition of the third aspect in preparing anticancer drugs.
Furthermore, the invention relates to the application of the phenylaminothiazole methyl quinolinone derivative and the pharmaceutically acceptable salts thereof in the first aspect and the pharmaceutical composition in the third aspect in preparing anti-human cervical cancer drugs.
Furthermore, the invention relates to the application of the phenylaminothiazole methyl quinolinone derivative and the pharmaceutically acceptable salts thereof in the first aspect and the pharmaceutical composition in the third aspect in the preparation of the anti-human lung adenocarcinoma drugs.
Furthermore, the invention relates to the application of the phenylaminothiazole methyl quinolinone derivative and the pharmaceutically acceptable salts thereof in the first aspect and the pharmaceutical composition in the third aspect in the preparation of anti-human breast cancer drugs.
The beneficial technical effects are as follows:
the invention relates to a phenylaminothiazole methyl quinolinone derivative which is a compound with a novel structure type and anticancer activity.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 3- ((4-tert-butyl-2- (phenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol, adding 10mmol of phenylthiourea after dissolving, refluxing for 1.5H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (phenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 72.0% and the melting point is 229-232 ℃;1H NMR(400MHz，DMSO-d6)δ：11.92(s，1H，NH)，9.92(s，1H，NH)，7.66(d，J＝7.8Hz，1H)，7.60(d，J＝8.3Hz，2H)，7.56(s，1H)，7.46(s，1H)，7.34～7.25(m，3H)，7.14(s，1H)，6.89(s，1H)，4.00(s，2H，CH2)，1.35(s，9H，3×CH3)。
example 2
Preparation of 3- ((4-tert-butyl-2- (2-toluidino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol, adding 10mmol of 2-methylphenylthiourea after dissolving, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (2-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 80.0% and the melting point is 218-222 ℃;1H NMR(400MHz，CDCl3)δ：12.22(s，1H，NH)，7.69(d，J＝8.2Hz，1H)，7.54(s，1H)，7.50(d，J＝8.3Hz，1H)，7.46(d，J＝7.6Hz，1H)，7.40(d，J＝8.1Hz，1H)，7.23～7.14(m，3H)，6.96(t，J＝7.4Hz，1H)，4.21(s，2H，CH2)，2.31(s，3H，)，1.42(s，9H，3×CH3)；13C NMR(100MHz，CDCl3)δ：158.86，156.31，134.16，132.51，127.84，125.94，124.97，122.58，122.19，118.36，117.71，116.59，115.19，113.67，112.53，110.79，110.39，31.17，26.00，22.61，12.94。
example 3
Preparation of 3- ((4-tert-butyl-2- (3-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinoline-2 (1H) -ketone and 15ml of absolute ethanol, adding 10mmol of 3-methylphenylthiourea, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid,filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (3-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one with the yield of 70% and the melting point of 161-165 ℃;1H NMR(400MHz，CDCl3)δ：12.23(s，1H)，7.54(s，1H)，7.51(d，J＝7.7Hz，1H)，7.47(d，J＝7.3Hz，1H)，7.41(d，J＝8.1Hz，1H)，7.19(dd，J＝18.7，7.5Hz，2H)，7.13(s，2H)，6.85(d，J＝7.2Hz，1H)，4.21(s，2H)，2.31(s，3H)，1.44(s，9H，3×CH3).13C NMR(100MHz，CDCl3)δ：158.76，156.30，134.94，134.58，132.67，132.57，127.28，125.16，124.37，122.65，119.21，117.90，115.10，114.03，110.78，110.21，109.86，31.06，25.88，22.53，16.61。
example 4
Preparation of 3- ((4-tert-butyl-2- (4-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol, adding 10mmol of 4-methylphenylthiourea after dissolving, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (4-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 71.8% and the melting point is 210-212 ℃.1H NMR(400MHz,CDCl3)δ：12.03(s,1H，NH),7.53(s,1H),7.50～7.45(m,2H),7.40(d,J＝8.1Hz,1H),7.22～7.17(m,3H),7.09(d,J＝8.4Hz,2H),4.21(s,2H,CH2),2.28(s,3H,CH3),1.41(s,9H,3×CH3)；13C NMR(100MHz,CDCl3)δ：163.63,160.89,155.73,138.11,137.35,132.76,132.27,129.85,127.49,122.59,120.08,118.13,115.59,114.73,36.03,30.85,27.40,20.71。
Example 5
Preparation of 3- ((4-tert-butyl-2- (2-fluoroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol, adding 10mmol of 2-fluorophenylthiourea after dissolving, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (2-fluorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 84.5% and the melting point is 226-230 ℃.1H NMR(400MHz，CDCl3)δ：11.77(s，1H，NH)，8.11(t，J＝8.1Hz，1H)，7.66(s，1H)，7.54～7.43(m，3H)，7.38(d，J＝8.1Hz，1H)，7.20(t，J＝7.5Hz，1H)，7.10(dd，J＝18.3，10.0Hz，2H)，6.93(dd，J＝13.1，7.2Hz，1H)，4.23(s，2H，CH2)，1.43(s，9H，3×CH3)；13C NMR(100MHz，CDCl3)δ：δ163.42，137.41，137.30，136.13，132.75，129.96，129.73，127.55，124.64，122.70，121.89，120.03，118.03，117.23，116.18，115.49，114.96，114.77，36.09，30.85，27.35。
Example 6
3- ((4-tert-butyl-2- (4-fluorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol, adding 10mmol of 4-fluorophenylthiourea after dissolving, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (4-fluorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 45% and the melting point is 170-173 ℃.1H NMR(400MHz，CDCl3)δ：12.06(s，1H，NH)，7.63(s，1H)，7.56～7.43(m，3H)，7.34(dd，J＝8.5，4.2Hz，2H)，7.19(t，J＝7.5Hz，1H)，6.98(dd，J＝11.9，5.2Hz，2H)，4.19(s，2H，CH2)，1.41(s，9H，3×CH3)；13C NMR(100MHz，CDCl3)δ：166.34，149.23，144.00，138.37，137.52，132.18，131.17，130.94，129.01，127.94，125.83，123.26，119.53，116.80，115.96，115.31，35.20，30.27，27.70。
Example 7
Preparation of 3- ((4-tert-butyl-2- (2-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinoline-2 (1H) -ketone and 15ml of absolute ethanol, adding 10mmol of 2-chlorophenylthiourea after dissolving, refluxing for 2.5H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (2-chloroanilino) thiazol-5-yl) methyl) quinoline-2 (1H) -ketone, wherein the yield is 64.3%, and the melting point is 223-225 ℃.1H NMR(400MHz，DMSO-d6)δ：11.92(s，1H，NH)，9.31(s，1H，NH)，8.46(d，J＝8.2Hz，1H，N＝CH)，7.64(t，J＝8.1Hz，1H)，7.59(s，1H)，7.50～7.39(m，2H)，7.35～7.25(m，2H)，7.15(t，J＝7.5Hz，1H)，6.97(t，J＝7.6Hz，1H)，4.02(s，2H，CH2)，1.35(s，9H，3×CH3)；13C NMR(100MHz，DMSO-d6)δ：161.82，158.89，154.30，138.13，136.46，135.37，133.40，129.98，129.73，127.90，127.83，122.69，122.07，121.56，120.21，119.46，117.29，115.11，36.08，30.92，27.08。
Example 8
Preparation of 3- ((4-tert-butyl-2- (3-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one, 15ml of anhydrous EthaneDissolving the 3-chlorophenyl thiourea in alcohol, adding 10mmol of the 3-chlorophenyl thiourea, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (3-chlorophenylamino) thiazol-5-yl) methyl) quinoline-2 (1H) -ketone, wherein the yield is 75.4%, and the melting point is 271-272 ℃;1H NMR(400MHz，DMSO-d6)δ：11.93(s，1H，NH)，10.21(s，1H，NH)，7.98(t，J＝2.0Hz，1H)，7.66(d，J＝7.3Hz，1H)，7.58(s，1H)，7.46(t，J＝8.4Hz，1H)，7.39(d，J＝7.6Hz，1H)，7.34～7.27(m，2H)，7.14(t，J＝8.0Hz，1H，2-H)，6.95(d，J＝6.7Hz，1H)，4.02(s，2H，CH2)，1.36(s，9H，3×CH3)。
example 9
Preparation of 3- ((4-tert-butyl-2- (4-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol, adding 10mmol of 4-chlorophenylthiourea after dissolving, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (4-chloroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 70.7%, and the melting point is 227-229 ℃;1H NMR(400MHz，DMSO-d6)δ：11.92(s，1H，NH)，10.08(s，1H，NH)，7.65(t，J＝7.9Hz，3H)，7.56(s，1H)，7.46(t，J＝7.7Hz，1H)，7.32(dd，J＝8.2，4.8Hz，3H)，7.14(t，J＝7.5Hz，1H)，4.00(s，2H，CH2)，1.35(s，9H，3×CH3)；
example 10
Preparation of 3- ((4-tert-butyl-2- (4-bromophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol, after dissolving, adding 10mmol of 4-bromophenyl thiourea, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% of ethanol, and drying to obtain 3- ((4-tert-butyl-2- (4-bromophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 70.2%, and the melting point is 150-153 ℃.1H NMR(400MHz，CDCl3)δ：12.16(s，1H，NH)，7.65(s，1H)，7.55～7.48(m，2H)，7.44(d，J＝8.1Hz，1H)，7.39(dd，J＝8.6，1.8Hz，3H)，7.28(s，2H)，4.19(s，2H，CH2)，1.41(s，9H，3×CH3)；13C NMR(100MHz，CDCl3)δ：163.31，139.46，137.58，136.25，132.83，132.21，130.08，129.76，127.60，122.81，121.41，120.00，119.16，117.23，115.52，115.31，36.10，30.82，27.47.
Example 11
Preparation of 3- ((4-tert-butyl-2- (3-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol, adding 10mmol of 3-trifluoromethylphenylthiourea after dissolving, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (3-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 43.7%, and the melting point is 225-228 ℃;1H NMR(400MHz，DMSO-d6)δ：11.93(s，1H，NH)，10.32(s，1H，NH)，7.66(d，J＝7.7Hz，1H)，7.58(d，J＝5.7Hz，2H)，7.50(t，J＝7.8Hz，1H，5-H)，7.45(d，J＝8.1Hz，1H，4-H)，7.32(m，J＝8.2Hz，3H，3-H，4-H，5-H)，7.22(d，J＝7.6Hz，1H，2-H)，7.14(t，J＝7.6Hz，1H，6-H)，4.02(s，2H，CH2)，1.36(s，9H，3×CH3)。
example 12
Preparation of 3- ((4-tert-butyl-2- (4-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethanol are dissolved, 10mmol of 4-trifluoromethylphenylthiourea is added, reflux is carried out for 3.0H, ammonia water is dropwise added to adjust the pH value to 8-9, reflux is carried out for 0.5H, partial solvent is removed by rotation, cooling is carried out, a solid is precipitated, filtering is carried out, 95% ethanol is used for washing, and drying is carried out to obtain 3- ((4-tert-butyl-2- (4-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, the yield is 71.8%, and the melting point is 210-212 ℃.1H NMR(400MHz，CDCl3)δ：11.73(s，1H，NH)，7.93(s，1H)，7.53～7.44(m，4H)，7.39(t，J＝8.0Hz，2H)，7.25～7.17(m，2H)，4.22(s，2H，CH2)，1.43(s，9H，3×CH3).13C NMR(100MHz，CDCl3)δ：158.56，154.00，136.11，132.59，132.40，127.62，125.11，124.78，122.66，117.85，115.13，113.63，111.33，110.63，109.10，31.31，25.91，22.45。
Example 13
Preparation of 3- ((4-tert-butyl-2- (2, 6-dimethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol, after dissolving, adding 10mmol of 2, 6-dimethylphenylthiourea, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid, filtering, washing with 95% of ethanol, and drying to obtain 3- ((4-tert-butyl-2- (2, 6-dimethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 71.6%, and the melting point is 203-205 ℃.1H NMR(400MHz，DMSO-d6)δ：11.85(s，1H，NH)，8.81(s，1H，NH)，7.57(d，J＝7.6Hz，1H)，7.48(s，1H)，7.44(d，J＝8.0Hz，1H)，7.30(d，J＝8.2Hz，1H)，7.14(t，J＝7.5Hz，1H)，7.10～7.04(m，3H)，3.91(s，2H，CH2)，2.22(s，6H，3×CH3)，1.30(s，9H，3×CH3)；13C NMR(100MHz，DMSO-d6)δ：164.09，161.82，154.77，138.74，138.05，136.29，136.04，133.61，129.91，128.67，127.68，126.79，122.13，119.39，115.13，114.11，36.01，31.00，27.36，18.46。
Example 14
Preparation of 3- ((4-tert-butyl-2- (3, 5-bistrifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol, after dissolving, adding 10mmol of 3, 5-bistrifluoromethylphenylthiourea, refluxing for 2.5H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid, filtering, washing with 95% of ethanol, and drying to obtain 3- ((4-tert-butyl-2- (3, 5-bistrifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 51.9% and the melting point is 215-218 ℃.1H NMR(400MHz，CDCl3)δ：11.15(s，1H，NH)，8.08(s，2H)，7.52(s，1H)，7.47(t，J＝9.5Hz，3H)，7.32(d，J＝7.7Hz，1H)，7.20(t，J＝7.2Hz，1H)，4.22(s，2H，CH2)，1.45(s，9H，3×CH3)；13C NMR(100MHz，CDCl3)δ：162.85，150.29，137.62，137.20，132.82，132.50，131.89，130.25，127.66，124.44，122.88，121.73，119.79，117.41，117.34，117.06，115.28，36.02，30.74，27.37。
Example 15
Preparation of 3- ((4-tert-butyl-2- (2-fluoro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
Dissolving 10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinoline-2 (1H) -ketone and 15ml of absolute ethyl alcohol, adding 10mmol of 2-fluoro-4-nitrophenylthiourea, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid, filtering, washing with 95% ethanol, and drying to obtain 3- ((4-tert-butyl-2- (2-fluoro-4-nitrophenylamino) thiazol-5-yl) methyl) quinoline-2 (1H) -ketone, wherein the yield is 64.4%, and the melting point is 270-275 ℃.1H NMR(400MHz，DMSO-d6)δ：11.92(s，1H，NH)，10.03(s，1H，NH)，8.83(d，J＝9.2Hz，1H)，8.28(d，J＝2.3Hz，1H)，8.22(dd，J＝9.4，2.3Hz，1H)，7.65(d，J＝10.2Hz，2H)，7.47(t，J＝7.6Hz，1H)，7.33(d，J＝8.1Hz，1H)，7.15(t，J＝7.5Hz，1H)，4.08(s，2H，CH2)，1.39(s，9H，3×CH3)；13C NMR(100MHz，DMSO-d6)δ：158.72，157.79，132.55，132.45，127.84，127.16，125.01，122.63，120.53，117.69，116.63，116.53，115.13，114.06，112.37，110.67，30.73，25.63，22.90。
Example 16
Preparation of 3- ((4-tert-butyl-2- (4-fluoro-3-chloroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol, after dissolving, adding 10mmol of 4-fluoro-3-chlorophenylthiourea, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, separating out a solid, filtering, washing with 95% of ethanol, and drying to obtain 3- ((4-tert-butyl-2- ((4-fluoro-3-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 63.6% and the melting point is 196-199 ℃.1H NMR(400MHz，DMSO-d6)δ：11.92(s，1H，NH)，10.16(s，1H，NH)，8.13(dd，J＝6.7，2.6Hz，1H)，7.66(d，J＝7.8Hz，1H)，7.58(s，1H)，7.47(t，J＝7.7Hz，1H)，7.44～7.39(m，1H)，7.36～7.30(m，2H)，7.15(t，J＝7.5Hz，1H)，4.02(s，2H，CH2)，1.37(s，9H，3×CH3)；13C NMR(100MHz，DMSO-d6)δ：161.82，158.48，154.81，139.00，138.10，136.38，133.29，129.97，127.84，122.12，119.46，117.81，117.36，117.15，116.79，116.73，116.23，115.11，36.10，30.88，27.02。
3- ((4-tert-butyl-2- (3-fluoro-4-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one was prepared in the same manner.
Example 17
Preparation of 3- ((4-tert-butyl-2- (2, 3-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol are dissolved, 10mmol of 2, 3-dichlorophenyl thiourea is added, reflux is carried out for 3.0H, ammonia water is dropwise added to adjust the pH value to 8-9, reflux is carried out for 0.5H, partial solvent is removed by rotation, cooling is carried out, a solid is separated out, filtering is carried out, 95% of ethanol is used for washing, and drying is carried out to obtain 3- ((4-tert-butyl-2- ((2, 3-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 63.6%, the yield is 71.7%, and the melting point is 228-231 ℃.1H NMR(400MHz，CDCl3)δ：12.13(s，1H，NH)，8.20(d，J＝8.0Hz，1H)，7.51(dd，J＝15.7，7.9Hz，3H)，7.45～7.40(m，1H)，7.19(dd，J＝16.1，8.0Hz，2H)，7.07(d，J＝8.0Hz，1H)，4.25(s，2H，CH2)，1.44(s，9H，3×CH3)；13C NMR(100MHz，CDCl3)δ：158.41，152.83，133.90，132.57，128.04，127.90，127.67，125.10，124.79，122.90，122.62，117.81，117.68，115.12，112.65，110.77，110.32，31.41，25.99，22.54。
Example 18
Preparation of 3- ((4-tert-butyl-2- (3, 4-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol are dissolved, 10mmol of 3, 4-dichlorophenyl thiourea is added, reflux is carried out for 2.5H, ammonia water is dropwise added to adjust the pH value to 8-9, reflux is carried out for 0.5H, partial solvent is removed by rotation, cooling is carried out, a solid is separated out, filtering is carried out, 95% of ethanol is used for washing, and drying is carried out to obtain 3- ((4-tert-butyl-2- ((3, 4-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, the yield is 71.8%, and the melting point is 210-212 ℃.1H NMR(400MHz，DMSO-d6)δ：11.92(s，1H，NH)，10.28(s，1H，NH)，8.22(d，J＝2.5Hz，1H)，7.66(d，J＝7.8Hz，1H)，7.58(s，1H)，7.51(d，J＝8.8Hz，1H)，7.47(t，J＝7.2Hz，1H)，7.39(dd，J＝8.9，2.4Hz，1H)，7.33(d，J＝8.2Hz，1H)，7.15(t，J＝7.5Hz，1H)，4.03(s，2H，CH2)，1.37(s，9H，3×CH3)；13C NMR(101MHz，DMSO-d6)δ：161.81，158.12，154.94，141.62，138.10，136.42，133.25，131.38，130.87，130.00，127.86，122.14，121.75，119.46，117.88，116.92，116.80，115.11，36.11，30.88，27.02。
Example 19
Preparation of 3- ((4-tert-butyl-2- (3, 5-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol are dissolved, 10mmol of 3, 5-dichlorophenyl thiourea is added, reflux is carried out for 2.5H, ammonia water is dropwise added to adjust the pH value to 8-9, reflux is carried out for 0.5H, partial solvent is removed by rotation, cooling is carried out, a solid is separated out, filtering is carried out, 95% of ethanol is used for washing, and drying is carried out to obtain 3- ((4-tert-butyl-2- ((3, 5-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, the yield is 82.9%, and the melting point is 223-226 ℃.1H NMR(400MHz，CDCl3)δ：11.94(s，1H，NH)，7.50(s，1H)，7.48～7.41(m，4H)，7.38(d，J＝8.2Hz，1H)，7.18(t，J＝7.5Hz，1H)，6.92(s，1H)，4.22(s，2H，CH2)，1.41(s，9H，3×CH3)；13C NMR(100MHz，CDCl3)δ：158.71，153.34，151.27，137.64，132.75，132.37，130.41，127.50，125.14，122.64，117.92，116.52，115.16，111.84，110.74，110.35，31.36，25.94，22.48。
Example 20
Preparation of 3- ((4-tert-butyl-2- (2-chloro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one
10mmol of 3- (2-bromo-4, 4-dimethyl-3-oxopentyl) quinolin-2 (1H) -one and 15ml of absolute ethyl alcohol, after dissolving, adding 10mmol of 2-chloro-4-nitrophenylthiourea, refluxing for 2.0H, dropwise adding ammonia water to adjust the pH value to 8-9, refluxing for 0.5H, removing part of the solvent by rotation, cooling, precipitating a solid, filtering, washing with 95% of ethanol, and drying to obtain 3- ((4-tert-butyl-2- ((2-chloro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one, wherein the yield is 65.9%, and the melting point is 273-277 ℃.1H NMR(400MHz，DMSO-d6)δ：11.92(s，1H，NH)，10.22(s，1H，NH)，8.36(d，J＝8.4Hz，1H)，8.06(d，J＝7.6Hz，1H)，7.70(t，J＝4.0Hz，1H)，7.65(d，1H，5-H)，7.61(s，1H)，7.45(t，J＝7.6Hz，1H，7.32(d，J＝8.4Hz，1H)，7.15(t，J＝7.2Hz，1H)，4.05(s，2H，CH2)，1.33(s，9H，3×CH3)。
Example 21
Determination of antitumor activity of phenylaminothiazole methyl quinolinone derivative
1. Principle of antitumor activity
The MTT method is also called MTT colorimetric method, and is a method for detecting cell survival and growth. MTT analysis method uses living cell metabolite reducing agent thiazole blue [3- (4, 5-dimethyl-2-thiazole) -2,5-diphenyl bromide tetrazole; 3- (4, 5-dimethylthiozol-2-yl) -2,5-diphenyltetrazolium bromide, MTT ]. MTT is a dye that can accept hydrogen atoms. NADP-related dehydrogenases in the mitochondria of living cells convert yellow MTT to insoluble blue-violet formazan (formazon) in the cells, whereas dead cells do not. After the formazon is dissolved by DMSO, the optical density value is measured by a microplate reader under a certain wavelength, so that the survival rate of the cells can be quantitatively measured. And observing the inhibition effect of the sample on the tumor cells according to the change of the optical density value.
2. Experiment on antitumor Activity
Sample preparation: EXAMPLES Compounds
Cell line: the cervical cancer cell line HeLa, the lung adenocarcinoma cell line A549 and the breast cancer cell line MCF-7 (provided by Hunan Yao medical college cell Bank, southern China university).
Reagent: thiazole blue (MTT), RPMI 1640 culture medium, newborn bovine serum, antibiotics (invitrogen life technologies, usa); pancreatin (AMRESCO, usa); 96-well culture plates (invitrogen life technologies, usa); dimethyl sulfoxide (Sigma, USA).
The instrument comprises the following steps: HFsafe-1500 model superclean bench, HF151UV model CO2Incubator (Shanghai Li Shen scientific instruments Co., Ltd.); XSP-15C type inverted microscope (Shanghai rectangular optics, Inc.); multiskan MK3 type microplate reader (Thermo corporation, usa); ultrapure water preparation apparatus (Milli-Q, USA).
And (3) experimental operation: test of samples on Hela cells, A549 cells and MCF-7 cells. The procedure was the same for each cell, 5 concentration gradients (0.010. mu. mol/mL, 0.030. mu. mol/mL, 0.100. mu. mol/mL, 0.300. mu. mol/mL and 0.500. mu. mol/mL) were set for each sample during one experiment, four replicates for each concentration were run in parallel 3 times per set of experiments, and the results were compared against a blank set. And detecting the OD value of each hole by using a microplate reader, wherein the detection wavelength is 570 nm.
3. Evaluation of antitumor Activity
(1) Calculating the cell inhibition rate:
(2)IC50value calculation
Linear regression of the logarithmic value of the sample concentration and the cell inhibition rate, and calculating the half inhibition concentration IC of the sample on the cells by using software50The value is obtained. Preferred compounds are IC's on A549 cells, HeLa cells and MCF-7 cells50See tables 1-3.
TABLE 1 inhibitory Activity of anilinothiazolylmethylquinolinone derivatives on A549 cells
| Benzoaminothiazole methyl quinolinone derivatives | IC50，μM |
| 3- ((4-tert-butyl-2- (4-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 20.2±0.3 |
| 3- ((4-tert-butyl-2- (2-fluoro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 3.0±0.8 |
| 3- ((4-tert-butyl-2- (4-fluoro-3-chloroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 19.3±2.2 |
TABLE 2 inhibitory Activity of phenylaminothiazole methyl quinolinone derivatives on Hela cells
| Benzoaminothiazole methyl quinolinone derivatives | IC50，μM |
| 3- ((4-tert-butyl-2- (phenylamino) thiazol-5-yl)) Methyl) quinolin-2 (1H) -ones | 6.4±0.5 |
| 3- ((4-tert-butyl-2- (2-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 18.5±2.2 |
| 3- ((4-tert-butyl-2- (4-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 19.6±3.2 |
| 3- ((4-tert-butyl-2- (4-fluorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 4.4±0.7 |
| 3- ((4-tert-butyl-2- (4-bromophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 11.6±0.2 |
| 3- ((4-tert-butyl-2- (3-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 8.9±0.5 |
| 3- ((4-tert-butyl-2- (4-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 4.6±0.4 |
| 3- ((4-tert-butyl-2- (2-fluoro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 8.6±0.4 |
| 3- ((4-tert-butyl-2- (4-fluoro-3-chloroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 19.5±0.6 |
| 3- ((4-tert-butyl)Butyl-2- (3, 4-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 4.5±0.6 |
| 3- ((4-tert-butyl-2- (3, 5-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 20.7±0.4 |
TABLE 3 inhibitory Activity of anilinothiazolylmethylquinolinone derivatives on MCF-7 cells
| Benzoaminothiazole methyl quinolinone derivatives | IC50，μM |
| 3- ((4-tert-butyl-2- (3-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 0.4±0.1 |
| 3- ((4-tert-butyl-2- (4-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 4.2±1.2 |
| 3- ((4-tert-butyl-2- (4-fluorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 1.8±0.6 |
| 3- ((4-tert-butyl-2- (2-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 13.2±2.6 |
| 3- ((4-tert-butyl-2- (3-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 17.3±1.2 |
| 3- ((4-tert-butyl-2- (4-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 5.6±2.6 |
| 3- ((4-tert-butyl-2- (4-bromophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 13.1±2.5 |
| 3- ((4-tert-butyl-2- (3-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 10.0±0.3 |
| 3- ((4-tert-butyl-2- (3, 4-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 11.7±1.0 |
| 3- ((4-tert-butyl-2- (3, 5-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one | 16.6±0.7 |
The activity test result shows that the phenylaminothiazole methyl quinolinone derivative and the pharmaceutically acceptable salts thereof have good inhibitory activity on human lung adenocarcinoma cells (A549 cells), human cervical carcinoma cells (Hela cells) and human breast cancer cells (MCF-7 cells), and can be used for preparing antitumor drugs.
Claims (8)
1. A phenylamino thiazole methyl quinolinone derivative represented by the chemical structural formula I:
wherein R is selected from: c1～C2An alkyl group; c3～C4Straight chain alkyl or C3～C4A branched alkyl group;
X1、X2selected from: hydrogen, deuterium, C1～C2An alkyl group;
X3、X7selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo;
X4、X6selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo or trifluoromethyl;
X5selected from: hydrogen, deuterium, C1～C2Alkyl, fluoro, chloro, bromo, nitro or trifluoromethyl.
2. The anilinothiazole methylquinolinone derivative of claim 1, and pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of:
3- ((4-tert-butyl-2- (phenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (2-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (3-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (4-methylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (2-fluoroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (4-fluorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (2-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (3-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (4-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (4-bromophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (3-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (4-trifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (2, 6-dimethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (3, 5-bistrifluoromethylphenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (2-fluoro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (3-fluoro-4-chlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (4-fluoro-3-chloroanilino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (2, 3-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (3, 4-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one,
3- ((4-tert-butyl-2- (3, 5-dichlorophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one or
3- ((4-tert-butyl-2- (2-chloro-4-nitrophenylamino) thiazol-5-yl) methyl) quinolin-2 (1H) -one.
3. The process for preparing anilinothiazole methylquinolinone derivatives of claim 1, characterized in that it is prepared by the following reaction:
wherein, R, X1～X7As defined in claim 1; x is selected from: chlorine, bromine or iodine.
4. Use of the anilinothiazole methylquinolinone derivative of claim 1 or 2 and pharmaceutically acceptable salts thereof for the preparation of anticancer drugs.
5. The use of the anilinothiazole methylquinolinone derivative of claim 1 or 2 and its pharmaceutically acceptable salts in the preparation of drugs against human cervical cancer.
6. Use of the anilinothiazole methylquinolinone derivative of claim 1 or 2 and its pharmaceutically acceptable salts in the preparation of a medicament for treating human lung adenocarcinoma.
7. Use of the anilinothiazole methylquinolinone derivative of claim 1 or 2 and its pharmaceutically acceptable salts in the preparation of anti-human breast cancer drugs.
8. A pharmaceutical composition comprising at least one compound of claim 1 or 2 and a pharmaceutically acceptable carrier.
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| US6822097B1 (en) * | 2002-02-07 | 2004-11-23 | Amgen, Inc. | Compounds and methods of uses |
| CN102070556A (en) * | 2010-12-29 | 2011-05-25 | 湖南大学 | 5-benzyl-4-alkyl-2-aminothiazole as well as preparation and application of 5-benzyl-4-alkyl-2-aminothiazole |
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