CN108218847B - Aryloxy phenoxy alkanoic acid derivative and medical application thereof - Google Patents
Aryloxy phenoxy alkanoic acid derivative and medical application thereof Download PDFInfo
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Abstract
The invention discloses aryloxy phenoxy alkanoic acid derivatives and pharmaceutical activity thereof, wherein the chemical structural formula is shown as formula I:
in the formula, R1Is hydrogen or C1～C3Alkyl or C1～C3Any one of haloalkyl groups; x is nitrogen or carbon; x1、X2Is any one of hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano or nitro. The invention also relates to a composition containing the compound and application of the aryloxy phenoxy alkanoic acid derivative in the aspect of tumor resistance.
Description
Technical Field
The invention relates to a compound, in particular to an aryloxyphenoxyalkanoic acid derivative and a medical application thereof.
Background
4-aryloxyphenoxyalkanoic acid derivatives have a wide range of biological activities, and among them, aryloxyphenoxypropionic acid derivatives have been used as a representative thereof, and there are over 20 commercial varieties in agricultural herbicides. Meanwhile, 4-aryloxyphenoxyalkanoic acid derivatives have been reported in many studies on anticancer Drugs [ Investigational New Drugs, 1999, 16: 287-296; investigational New Drugs, 1998, 16: 129-; the pharmaceutical science, 2005, 40(9):814-819], wherein XK469(2- (4- (7-chloroquinoxalin-2-yloxy) phenoxy) propionic acid) is a novel antitumor drug in phase I clinical research under U.S. DuPont, XK469 has a wide antitumor spectrum, less side effects, and is effective for various solid tumor models, such as Colon cancer Colon38 and breast cancer, etc. [ JMed Chem, 2001, 44(11):1758-76 ].
Disclosure of Invention
The invention provides an aryloxy phenoxy alkanoic acid derivative and an isomer thereof, wherein the chemical structural formula of the aryloxy phenoxy alkanoic acid derivative is shown as a formula I:
in the formula, R1Is hydrogen or C1～C3Alkyl or C1～C3Any one of haloalkyl groups; x is nitrogen or carbon; x1、X2Is any one of hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano or nitro.
In the definition of compound I given above, the terms used, whether used alone or in compound words, represent the following substituents:
alkyl groups: refers to straight or branched chain alkyl;
halogenated alkyl groups: refers to straight or branched alkyl groups in which the hydrogen atoms are partially or fully substituted by halogen atoms;
the compounds of the present invention may exist in the form of one or more isomers. Isomers include enantiomers, diastereomers, geometric isomers. The compound shown in the formula I forms stereoisomers (R and S represent different configurations respectively) due to the connection of four different substituents on one carbon atom, and the invention comprises R isomers and S isomers and mixtures of the R isomers and the S isomers in any proportion.
In a preferred scheme, the specific structural formula of the aryloxyphenoxyalkanoic acid derivative is as follows:
the invention provides application of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (5-chloro-3-fluoropyridine-2-oxy) phenoxy) propionyloxy ] -1, 3-oxathiolane-2-carboxylate in preparation of a cervical cancer resistant medicine.
Detailed Description
The invention will be further elucidated with reference to specific embodiments. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
EXAMPLE 1 preparation of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (5-chloro-3-fluoropyridin-2-yloxy) phenoxy) propionyloxy ] -1, 3-oxathiolane-2-carboxylate (1)
N, N-dimethylformamide (40mL), (R) - (+) -2- (4-hydroxyphenoxy) propionic acid (0.02mol, 3.64g), and potassium carbonate (0.02mol, 2.76g), and after stirring at 75 ℃ for 0.5h, the same amount of potassium carbonate was added and stirring was continued for 0.5 h. 2, 3-difluoro-5-chloropyridine (0.02mol, 3.00g) was slowly added dropwise thereto, and after completion of the addition, the reaction temperature was maintained at 75 ℃ overnight. Stopping heating, cooling to room temperature, pouring the reaction solution into 200mL of ice water, adjusting the pH value to 4-5 with dilute hydrochloric acid, filtering, washing with a small amount of ice water for three times, and drying in vacuum to obtain 3.86g of (R) -2- [4- (3-fluoro-5-chloropyridine-2-oxy) phenoxy ] propionic acid white solid with the yield of 62.0%.
40mL of (R) -2- [4- (3-fluoro-5-chloropyridine-2-oxy) phenoxy ] propionic acid (3.3mmol, 1.04g) was added into a 100mL single-neck flask, dissolved by stirring, added with thionyl chloride (20mmol, 2.24g), refluxed for 4 hours, and distilled under reduced pressure to obtain (R) -2- [4- (3-fluoro-5-chloropyridine-2-oxy) phenoxy ] propionyl chloride as a yellow oily liquid which was used in the next reaction without isolation and purification.
The above-mentioned (R) - (+) -2- [4- (3-fluoro-5-chloropyridin-2-yloxy) phenoxy group]Adding propionyl chloride into dichloromethane (40mL), then adding (2R,5R) -5-hydroxy-1, 3-oxathiolane-2-carboxylic acid (1R,2S,5R) -5-methyl-2-isopropylcyclohexyl (0.31g, 3.3mmol), 4-dimethylaminopyridine (DMAP, 0.02g, 0.17mmol), stirring for 15min under ice bath, dropwise adding triethylamine (1.37mL, 10mmol), continuing stirring for 10min after dropwise adding, removing the ice bath, naturally heating to room temperature, stirring for 4h, stopping reaction, pouring the reaction liquid into 150mL of ice water, extracting dichloromethane (40mL x 3), washing an organic phase twice with 50mL of saturated sodium bicarbonate solution, washing three times with 100mL of water, drying with anhydrous sodium sulfate, filtering, evaporating dichloromethane under reduced pressure, separating and purifying a product by silica gel column chromatography, eluent (V)Petroleum ether：VEthyl acetate(1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (5-chloro-3-fluoropyridin-2-yloxy) phenoxy) propionyloxy) yielded a yellow oily liquid]0.27g of 1, 3-oxathiolane-2-carboxylate (1), yield 14.1%;1H NMR(CDCl3,400MHz)δ:0.75(d,3H,J＝6.8Hz,CH3),0.82～1.06(m,11H,cyclohexane-H+CH 3),1.63～1.70(m,5H,CH3+cyclohexane-H),1.93～2.02(m,2H,cyclohexane-H),3.02～3.44(m,2H,CH 2),4.69～4.79(m,2H,OCHCH2+CHCH 2S),5.61(s,1H,SCH),6.81(d,J＝4.0Hz,1H,CHCH2S),6.92(d,J＝9.2Hz,2H,PhH),7.07(d,J＝9.2Hz,2H,PhH),7.49(dd,J＝8.8Hz,2.0Hz,1H,Py-H),7.86(d,J＝2.0Hz,1H,Py-H)；13C NMR(CDCl3,100MHz)δ:16.13,18.37,20.71,21.94,23.25,26.06,31.36,34.09,40.59,47.04,73.09,80.21,100.43,116.29,116.58,122.19,122.34,124.84,136.24,140.06,140.17,147.21,154.77,168.44,170.81.
EXAMPLE 2 preparation of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (3-chloro-5-trifluoromethylpyridine-2-oxy) phenoxy) propionyloxy ] -1, 3-oxathiolane-2-carboxylate (2)
(R) -2- (4-hydroxyphenoxy) propionic acid (3g), DMF (35ml) was added K slowly2CO3(4.55g), heating to 70-80 ℃, stirring for 1h, dropwise adding 2, 3-dichloro-5-trifluoromethylpyridine (3.56g), keeping the temperature at 70-80 ℃, stirring for 8h, stopping the reaction, naturally cooling to room temperature, pouring the mixture into ice water (200mL), adjusting the pH to 4-5 by using dilute hydrochloric acid, extracting by using ethyl acetate, washing an organic phase by using water, drying and desolventizing to obtain (R) -2- [4- (5-trifluoromethyl-3-chloropyridine-2-oxyl) phenoxy]Propionic acid brown liquid 5.03g, yield 84.4%.
(R) -2- [4- (5-trifluoromethyl-3-chloropyridin-2-yloxy) phenoxy]Propionic acid (3.3mmol, 1.08g) was dissolved in toluene (35mL) and SOCl was added dropwise2(20mmol, 2.24g), heating and refluxing, reacting for 4h, and desolventizing to obtain (R) -2- [4- (5-trifluoromethyl-3-chloropyridine-2-oxyl) phenoxy]Propionyl chloride was used directly in the next step.
The resulting acid chloride was dissolved in methylene chloride (35mL), and the intermediate (2R,5R) -5-hydroxy-1, 3-oxathiolane-2-carboxylic acid (1R,2S,5R) -5-methyl-2-isopropylcyclohexyl ester (0.80g) and a catalytic amount of DMAP were added to stir, and triethylamine (0.85g) was slowly added dropwise with stirring to react for 8 hours. The reaction was complete and the mixture was poured into ice water (100mL) and extracted with dichloromethane (80)mL 2), washing the organic phase with water, drying and desolventizing. Purifying by column chromatography to obtain (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (3-chloro-5-trifluoromethylpyridine-2-oxy) phenoxy) propionyloxy]0.38g of (2) -1, 3-oxathiolane-2-carboxylate as a pale brown viscous liquid, yield 22.04%.1H NMR:δ0.76(d,J＝7.2Hz,3H,CHC 3H),0.90-1.10(m,11H,CH2,CH3),1.64-1.71(m,5H,CH,CH2),1.90-2.02(m,2H,CH2),3.03-3.49(m,2H,CH2),4.69-4.80(m,2H,CH,CHCH3),5.62(d,J＝10.0Hz,1H,CH),6.82(d,J＝4.0Hz,1H,CH),6.93-6.98(m,2H,Ph-H),7.06-7.09(m,2H,Ph-H),7.96(d,J＝2.4Hz,1H,Py-H),8.25(s,1H,Py-H)；13C NMR:δ16.16,18.34,20.66,21.92,23.32,26.10,31.37,34.12,40.61,47.08,73.11,80.26,100.47,116.33,116.62,119.17,122.53,122.67,124.21,136.22,142.57,147.03,155.14,161.33,168.44,170.72.
EXAMPLE 3 preparation of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (4-cyano-2-fluorophenoxy) phenoxy) propionyloxy ] -1, 3-oxathiolane-2-carboxylate (3)
Adding (R) -2- (4-hydroxyphenoxy) propionic acid (3.03g, 0.02mol) into N, N-dimethylformamide (DMF,40mL), adding potassium carbonate (5.52g, 0.04mol) in batches, heating to 70-80 ℃, continuously stirring for 1h, adding 3, 4-difluorobenzonitrile (2.38g, 0.02mol) in batches, and continuously stirring for reacting for 6-7 h. Cooling to room temperature, pouring into ice water (250mL), slowly adding dilute hydrochloric acid, adjusting the pH value to 4-5, performing suction filtration, washing with water, and drying in a vacuum drying oven to obtain 3.26g of (R) -2- [4- (4-cyano-2-fluorophenoxy) phenoxy ] propionic acid gray solid (R) -2- [4- (4-cyano-2-fluorophenoxy) phenoxy ] propionic acid, wherein the yield is 65.7%.
(R) -2- [4- (4-cyano-2-fluorophenoxy) phenoxy]Propionic acid (1g, 3.3mmol) was dissolved in toluene (40ml) and SOCl was slowly added2(1.18g, 10mmol), refluxing for 5h, desolventizing with a rotary evaporatorTo obtain (R) -2- [4- (4-cyano-2-fluorophenoxy) phenoxy]Propionyl chloride, directly carrying out the next reaction.
The resulting acid chloride was dissolved in dichloromethane (40ml), and (1R,2S,5R) -5-hydroxy-1, 3-oxathiolane-2-carboxylic acid (1R,2S,5R) -5-methyl-2-isopropylcyclohexyl ester (0.95g, 3.3mmol) and a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added, stirred for 10min under ice bath, and triethylamine (1g, 10mmol) was added dropwise. Stirring was continued for 3 to 10 hours. After the reaction, the reaction mixture was poured into 100ml of ice water, extracted with dichloromethane, the organic phase was collected and washed with water (100 ml. times.2), and the resulting crude product was dried over anhydrous sodium sulfate, desolventized and purified by silica gel column chromatography to give (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (4-cyano-2-fluorophenoxy) phenoxy) propionyloxy group as a pale yellow viscous liquid]1.067g of (3) -1, 3-oxathiolane-2-carboxylate, yield 56.7%.1H NMR:δ0.74(d,J＝6.8Hz,3H,CH3),0.80～1.01(m,11H,CH+CH2+CH3),1.62～1.69(m,5H,CH,CH 2),1.88～1.99(m,2H,CH,CH 2),3.21～3.47(m,2H,CH 2),4.67～4.76(m,2H,CH),5.59(s,1H,S-CH-O),6.80～6.99(m,6H,PhH,CH),7.30～7.34(m,1H,PhH),7.42～7.45(m,1H,PhH)；13C NMR:δ16.14,18.34,20.70,21.93,23.26,26.08,31.35,34.07,40.59,47.06,72.91,80.24,100.02,100.51,116.77,117.09,118.60,120.67,120.97,121.06,129.36,148.77,149.54,152.31,154.80,168.36,170.64.
Example 4 antitumor Activity assay
1. In vitro cell culture
Caski cells were cultured in 10% newborn calf serum5Placing U/L penicillin and 100mg/L streptomycin in RPMI-1640 culture medium at 37 deg.C under CO2Culturing under the saturated humidity condition with the volume fraction of 5 percent, and taking the cells in the logarithmic growth phase for experiment after the cells grow in an adherent manner.
Detecting the inhibition rate of cell growth by MTT method
Preparing cervical cancer CAKSI cells growing in logarithmic phase into cells with the cell density of 1 multiplied by 105Cell suspension/mL, seeded in 96-well plates at 100. mu.L/well, 5% CO2Incubating at 37 ℃, after cells adhere to the wall, replacing culture solution, wherein experimental components are the kava dubia extract groups with different concentrations, adding aryloxyphenoxyalkanoic acid derivatives (6.25, 12.5, 25.0, 50.0 and 100 mu g/mL) with different mass concentrations 100 mu L from low to high in sequence, and each group is provided with 4 compound holes. Transfer the plates to CO2The culture is continued in the incubator, the culture plate is taken out after 24h respectively, 20 mu L of newly prepared 5mg/mL MTT solution is added each time, and the incubation is carried out for 4h at 37 ℃ in the dark, and the culture is stopped. The supernatant was aspirated, 150. mu.L of DMSO was added to each well, and after shaking on a shaker at low speed for 10min, the absorbance (OD) of each well was measured at 490nm using a microplate reader490nm) according to the formula: the cell inhibition rate was (1-dose OD value/blank OD value) × 100%. IC (integrated circuit)50And (3) value 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.
The activity test result shows that (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (5-chloro-3-fluoropyridin-2-oxy) phenoxy) propionyloxy]IC of (E) -1, 3-oxathiolane-2-carboxylate at a concentration of 25.0 μ g/mL for CAKSI in cervical cancer cells50The value was 55.98. mu. mol/L. Other values are as follows, and all other values are data measured at a concentration of 25.0. mu.g/mL.
Claims (1)
1. An application of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (5-chloro-3-fluoropyridine-2-oxy) phenoxy) propionyloxy ] -1, 3-oxathiolane-2-carboxylate in preparing the medicine for treating cervical cancer, characterized in that the structural formula of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl (2R,5R) -5- [ (R) -2- (4- (5-chloro-3-fluoropyridine-2-oxy) phenoxy) propionyloxy ] -1, 3-oxathiolane-2-carboxylate is as follows:
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| CN106632293A (en) * | 2016-12-15 | 2017-05-10 | 三峡大学 | Aryloxyphenoxy alkane acid derivative with biological activity and preparation method thereof |
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| CN103086921A (en) * | 2013-02-01 | 2013-05-08 | 湖南大学 | 2-(4-aryloxyphenoxy)alkylamide and application thereof |
| CN106632293A (en) * | 2016-12-15 | 2017-05-10 | 三峡大学 | Aryloxyphenoxy alkane acid derivative with biological activity and preparation method thereof |
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| N-吡啶基-2-（4-芳氧苯氧基）丙酰胺的合成及抗肿瘤活性;刘祁星 等;《精细化工》;20160228;第33卷(第2期);第176-181、223页 * |
| RN号为2098483-73-7的化合物;STN;《STNEXT》;20170615;正文第1页 * |
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