CN108264506A - Novel isoflavone derivative, preparation method and medical usage - Google Patents

Novel isoflavone derivative, preparation method and medical usage Download PDF

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CN108264506A
CN108264506A CN201810061682.5A CN201810061682A CN108264506A CN 108264506 A CN108264506 A CN 108264506A CN 201810061682 A CN201810061682 A CN 201810061682A CN 108264506 A CN108264506 A CN 108264506A
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preparation
compound
hydrogen
alkyl
pharmaceutically acceptable
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CN108264506B (en
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向华
丘荣茂
陶睿
郑凡
李昊霖
杨启桢
胡伟康
张瑾
刘曼
陈明琪
陈德英
尤启冬
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China Pharmaceutical University
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China Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention relates to medicinal chemistry arts, it is related to isoflavone derivative, preparation method and medical usage, more particularly to a kind of general formula be the isoflavone derivative of (I), their preparation method, the pharmaceutical composition containing these compounds and their medical usage, especially as prevent or treatment hyperlipidemia, type-2 diabetes mellitus, atherosclerosis, nonalcoholic steatohepatitis drug purposes.

Description

Novel isoflavone derivative, preparation method and medical usage
Technical field：
The present invention relates to medicinal chemistry art, more particularly to isoflavone derivative.The invention also discloses their preparations Method and pharmacological activity, the Pharmaceutical composition containing these compounds and their medical usage are especially as preventing or control Treat hyperlipidemia, type-2 diabetes mellitus, atherosclerosis, the purposes of nonalcoholic steatohepatitis drug.
Background technology：
Dyslipidemia is a kind of since fat metabolism or operating exception make the one or more lipids of blood plasma be higher than normal value Systemic disease, shows as T-CHOL in blood (TC) and/or triglycerides (TG) is excessively high or high-density lipoprotein cholesterol (HDL-C) it is too low.Dyslipidemia can cause atherosclerosis, nonalcoholic fatty liver, type-2 diabetes mellitus etc. to be metabolized class disease. The incidence of angiocardiopathy and internal lipoprotein levels are closely related, and TG increases, the increase of LDL-C and the reduction of HDL-C are all It is the Major Risk Factors of angiocardiopathy.
Farnesoid X receptor (FXR) belongs to a member of nuclear receptor superfamily, is the transcription factor of ligand activation, mainly in liver High expression in dirty, enteron aisle, kidney, adrenal gland.FXR is not only involved in regulation and control body bile acid, glycolipid metabolism, and with a variety of metabolism Property disease is related.After FXR activation, the synthesis of induction intestinal cell and secretion human fibroblastic growth factor (FGF) 19, FGF19 The FGF receptor 4 of surface of hepatocytes is activated after entering liver, and then inhibits the expression of 7 hydroxylase 1 of bile acid biosynthesis rate-limiting enzyme cholesterol, Reduce the synthesis of bile acid.Activation FXR can promote the expression of B class I type scavenger receptors, inhibit Sterol regulatory element binding protein 1c is expressed, and induction peroxisome proliferator-activated receptor alpha expression promotes reverse cholesterol transport to enter liver, reduces lipid and close Into promotion fatty acid beta oxidation.
Isoflavone compound is widely present in plant, is one of the active ingredient of many medicinal plants.The study found that Isoflavone compound has a significant effect to cardiovascular system and internal system, has active anticancer, antioxidation, antibacterial The effects that effect, anti-inflammatory effect and hepatoprotective effect.Food and Drug Administration (FDA) just will formally contain in October, 1999 The soybean protein of isoflavones is recommended as blood cholesterol concentration is reduced, to reduce the healthy food for suffering from coronary heart disease risk.
Invention content：
The invention discloses a kind of isoflavone derivatives of general formula I, are proved through experiment in vitro, and the compounds of this invention can be bright The aobvious accumulation of lipid for inhibiting adipocyte.So the compounds of this invention has potential Adjust-blood lipid activity.
Wherein, R1、R2It is independently hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkyl, halogenated C1-3Alkane Oxygroup；
X is O, S, NH；
R3For hydrogen, halogen, C1-6Alkyl, C3-6Cycloalkyl, C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C1-6Alkoxy；
R4For the hydrogen of phenyl ring any position substitution, halogen, hydroxyl, nitro, cyano, methoxyl group, tetrazole base, COOR5、 CONR6R7、OCH2COOR8；
R5、R6、R7、R8It is independently hydrogen, C1-6Alkyl, C3-6Cycloalkyl.
Wherein, R1、R2Independently be preferably hydrogen, chlorine, bromine, fluorine, methoxyl group, a fluorine methoxyl group, difluoro-methoxy, three Fluorine methoxyl group；
X is preferably O；
R3It is preferably isopropyl, cyclopropyl；
R4Be preferably phenyl ring meta or para position substitution hydrogen, halogen, hydroxyl, nitro, cyano, methoxyl group, tetrazole base, COOR5、CONR6R7、OCH2COOR8；
R5、R6、R7、R8Independently be preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
The structure of the part of compounds of the present invention is as follows：
Compound number R1 R2 X R3 R4
A1 -Cl -Cl O -CH(CH3)2 4-F
A2 -Cl -Cl O -CH(CH3)2 4-NO2
A3 -Cl -Cl O -CH(CH3)2 4-OCH3
A4 -Cl -Cl O -CH(CH3)2 4-OH
A5 -Cl -Cl O -CH(CH3)2 4-OCH2CO2CH2CH3
A6 -Cl -Cl O -CH(CH3)2 4-OCH2COOH
A7 -Cl -Cl O -CH(CH3)2 4-COOCH3
A8 -Cl -Cl O -CH(CH3)2 4-COOH
A9 -Cl -Cl O -CH(CH3)2 4-CONHCH3
A10 -Cl -Cl O -CH(CH3)2 4-CONHCH2HC3
A11 -Cl -Cl O -CH(CH3)2 4-CONHCH(CH2)2
A12 -Cl -Cl O -CH(CH3)2 4-CON(CH3)2
The code name of compound is equal to the compound structure corresponding to code name herein in pharmacological evaluation and embodiment below.
The compound A1-A12 of general formula of the present invention can be prepared by following methods：
Reagents and conditions：a)NH2OHHCl, NaOH, EtOH；B) NCS, DMF；c)NaOCH3, CH3OH, THF；D) DIBAL-H, THF；e)SOCl2, DCM；f)BF3·Et2O, Δ；g)BF3·Et2O, DMF, CH3SO2Cl；h) K2CO3, DMF, Δ；i)BBr3, DCM；j)K2CO3, DMF, Δ；K) con HCl, Isosorbide-5-Nitrae-Dioxane, Δ；L) con HCl, Isosorbide-5-Nitrae- Dioxane, Δ；M) EDCI, HOBT, HNR1R2, DMF.
1 3T3-L1 cells induce Analytical Chemical Experiment
1.1 experiment material
DMEM (Dulbecco ' s Modified Eagle ' s Medium) culture medium is purchased from the triumphant base biotechnology stock in Jiangsu Part Co., Ltd；Fetal calf serum (FBS) is purchased from Gibco BRL of Invitrogen Corporation (Carlsbad, CA)； Regular iletin, Jiangsu Wan Bang Pharmaceuticals Ltds；Trypsase, dexamethasone (DEX), 3- isobutyl group -1- methyl yellows are fast Purine (IBMX) and other reagents are that domestic analysis is pure.
1.2 oil red O stains and half-quantitative detection lipid within endothelial cells content
3T3-L1 cells are cultivated in conventional medium, and 2 days (being at this time differentiation the 0th day) changes differentiation after cell converges completely Culture medium I (containing 10%FBS, 0.5mmol/L IBMX, 10mg/L insulin, 1 μm of ol/L DEX DMEM culture solutions) culture 2 My god.Break up the 2nd day, change differential medium II (the DMEM culture solutions containing 10%FBS, 10mg/L insulin) culture cells.Differentiation 4th day and liquid is accordingly changed as the DMEM culture solutions containing 10 μm of ol/L target compounds and 10 μm of ol/L positive drugs GW4064 later, Control group is the complete culture solution of non-dosing.Break up 6d and abandon culture solution in hole, PBS is cleaned twice, and addition is consolidated containing 10% formaldehyde Determine cell 2h.PBS is cleaned twice, and 0.5% oil red dyes 2 hours.PBS is cleaned 3 times.In 37 DEG C of dryings, isopropanol, extraction are added in 10min, extract liquor measure light absorption value in 492nm.Inhibiting rate is calculated as follows：
As a result：Adipocyte inner lipid content is significantly lower than control group after the display administration of oil red decoration method, illustrates new chemical combination Object can significantly inhibit accumulation of lipid.
Experimental result
Compound number Inhibiting rate (%)
GW4064 30.90
A1 33.30
A2 23.45
A3 28.25
A4 24.17
A5 29.04
A6 28.73
A7 32.95
A8 39.46
A9 35.3
A10 19.20
A11 30.65
A12 27.50
The invention further relates to the compound of general formula and the Pharmaceutical compositions of pharmaceutically acceptable carrier composition.
The compounds of this invention can be combined individually or with one or more kinds of pharmaceutically acceptable carriers and be made Preparation is for administration.Oral dosage form can be used, such as conventional tablet and capsule, sustained-release tablet and capsule, Dospan and glue Capsule, dripping pill, dispersible powder, granule etc.；Also ejection preparation can be prepared into.It can contain in these pharmaceutical formulations and vehicle group The active constituent for such as 0.05% to 90% total amount closed, the active constituent of weight between more conventional about 15% to 60%.This hair Bright compound dosage can be 0.001~100mg/kg/ days, can also be deviateed according to the difference of disease degree or the different of dosage form This dosage range.
Specific embodiment
The preparation of part of compounds is implemented as follows：
1H-NMR nuclear magnetic resonance is by Bruker AV300 types (300MHz) nmr determination (TMS is internal standard compound), matter Agilent1100LC-MSD-Trap/SL types mass spectrograph (ESI-MS) is composed to measure.
Column chromatography is 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Haiyang Chemical Plant, Qingdao) with silica gel, is eluted Agent is petroleum ether-ethyl acetate system or methylene chloride-methanol system.Thin-layer chromatography (TLC) GF254 thin layer chromatography board (cigarettes Taijiang friend's silica gel development corporation, Ltd.)；System is unfolded as petroleum ether-ethyl acetate system or methylene chloride-methanol system in TLC, A small amount of acetic acid is added in when necessary；TLC irradiates aobvious under ZF7 types ultraviolet analysis instrument for three purposed (Henan Gongyi Yu Hua Instrument Ltd.) Show.
Embodiment 1
The preparation of 2,6- dichloro benzaldoximes (2)
It is at room temperature that hydroxylamine hydrochloride (10.9g) and sodium hydroxide (6.27g) is soluble in water, it is added drop-wise to 2,6- dichlorobenzaldehydes In ethyl alcohol (200mL) solution of (25g), stirring 24 hours, are cooled to room temperature, are spin-dried for ethyl alcohol under 90 degree, filter, and paint filter is washed with water Cake is placed in infrared lower dry product 26.5g, yield 96.5%.MS(ESI)：M/z=189.9 [M+H]+。
Embodiment 2
The preparation of 2,6- bis- chloro- N- hydroxyls-Chlorobenzaldehyde oxime (3)
2,6- dichloro benzaldoximes (26g) are dissolved in DMF (160mL), NCS (18.5g) is added portionwise at room temperature, are stirred After 1 hour, solution is poured into water (800mL), is extracted with ethyl acetate, eaten respectively with water and saturation after combined ethyl acetate layer Salt water washing, is dried with anhydrous sodium sulfate, is spin-dried for solvent and is obtained water white transparency oily object product 30g, yield 97%.MS(ESI)： M/z=223.9 [M+H]+。
Embodiment 3
The preparation of-isoxazole -4- methyl formates (4) of 3- (2,6- dichlorophenyl) -5- methyl
Sodium (0.21g) is added in absolute methanol (20mL) under ice bath, isobutyl ethyl acetoacetic acid first is added dropwise after stirring half an hour 2,6-, bis- chloro- N- hydroxyls-Chlorobenzaldehyde oxime (1g) is added dropwise after reacting half an hour in tetrahydrofuran (3ml) solution of ester (1.3ml) Tetrahydrofuran (5ml) solution, at room temperature stir 15 hours after be spin-dried for solvent, be extracted with ethyl acetate, washed with saturated common salt It washs, anhydrous magnesium sulfate drying is spin-dried for solvent and obtains grease.Column chromatographic isolation and purification obtains white solid product 0.35g, yield 58%.MS(ESI)：M/z=314.1 [M+H]+。
Embodiment 4
The preparation of-isoxazole (5) of 3- (2,6- dichlorophenyl) -4- methylol -5- methyl
Under nitrogen protection, the toluene solution of diisobutyl aluminium hydride (16.4mL, 1.5M) is added dropwise to 3- (2,6- under ice bath Dichlorophenyl) -5- methyl-isoxazole -4- methyl formates (7g) tetrahydrofuran (50ml) solution in, stirred after restoring to room temperature 15 hours.Under ice bath, first alcohol and water is slowly added dropwise successively, generates gel suspended matter.It is extracted with ethyl acetate after filtering, uses water It is washed successively with saturated salt solution, anhydrous magnesium sulfate drying is spin-dried for solvent and obtains white solid product 5.8g, yield 90%.MS (ESI)：M/z=286.0 [M+H]+。
Embodiment 5
The preparation of-isoxazole (6) of 3- (2,6- dichlorophenyl) -4- chloromethyl 5- methyl
- isoxazole (2.9g) of 3- (2,6- dichlorophenyl) -4- methylol -5- methyl is dissolved in DCM (50mL), under ice bath Thionyl chloride (1mL) is slowly added dropwise, after stirring 4 hours at room temperature, solution is poured into cold saturated sodium bicarbonate aqueous solution, uses Ethyl acetate extracts, and is washed successively with water and saturated salt solution, and anhydrous magnesium sulfate drying is spin-dried for solvent and obtains colorless oil 3.4g, yield 98%.1H-NMR (300MHz, CDCl3)δ：7.46-7.27 (m, 3H), 4.15 (s, 2H), 3.35 (m, 1H), 1.39 (d, 6H)
Embodiment 6
The preparation of 1- (2,4- dihydroxy phenyl) -2- (4- fluorophenyls) ethyl ketones (7a)
Para-fluorophenylacetic acid (7g, 42.1mmol) and resorcinol (6.9g, 63.15mmol) are added in into reaction bulb, is added in 150ml boron trifluoride ether solutions, nitrogen protection.7h is reacted at 80 DEG C.After being cooled to room temperature, 400ml saturated sodium carbonates are added in Solution is extracted with ethyl acetate, with saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, filtering rotation It is dry, dark red liquid is obtained, it is directly lower to throw.MS(ESI)：M/z=245 [M-H]+。
Embodiment 7
The preparation of 1- (2,4- dihydroxy phenyl) -2- (4- nitrobenzophenones) ethyl ketones (7b)
Using the synthetic method identical with compound (7a), red liquid is obtained, it is directly lower to throw.MS(ESI)：M/z=272 [M-H]-。
Embodiment 8
The preparation of 1- (2,4- dihydroxy phenyl) -2- (4- anisyls) ethyl ketones (7c)
Using the synthetic method identical with compound (7a), red liquid is obtained, it is directly lower to throw.MS(ESI)：M/z=257 [M-H]-。
Embodiment 9
The preparation of 4- (2- (2,4- dihydroxy phenyl) -2- oxoethyls) methyl benzoate (7d)
Using the synthetic method identical with compound (7a), red liquid is obtained, it is directly lower to throw.MS(ESI)：M/z=285 [M-H]-。
Embodiment 10
The preparation of 7- hydroxyls -3- (4- fluorophenyls) -4H- benzopyran-4-ones (8a)
By 1- (2,4- dihydroxy phenyl) -2- (4- fluorophenyls) ethyl ketones (5.14g, 19.9mmol) be dissolved in DMF (11.1ml, In 59.7mmol), boron trifluoride ether solution (8.7ml, 99.5mmol) is added under ice bath, 60 degree are warming up under stirring.It will be mixed The DMF solution for closing uniform mesyl chloride is added drop-wise in raw material, and stirring after five minutes, is warming up to 95 degree, the lower reaction 2 of nitrogen protection Hour.Reaction solution is poured into cold saturated sodium carbonate solution after the completion of reaction, there is yellow solid precipitation, is filtered, infrared lower baking It is dry.Silica gel column chromatography obtains white powder solid 3.2g, yield 60.0%.1H-NMR (300MHz, d6-DMSO)δ：10.86 (s, 1H), 8.38 (s, 1H), 7.96 (d, 1H), 7.59 (m, 2H), 7.24 (m, 2H), 6.94 (dd, 1H), 6.85 (d, 1H)
Embodiment 11
The preparation of 7- hydroxyls -3- (4- nitrobenzophenones) -4H- benzopyran-4-ones (8b)
Using the synthetic method identical with compound (8a), yellow solid, yield 50% are obtained.1H-NMR (300MHz, d6- DMSO)δ：10.91 (s, 1H), 8.60 (s, 1H), 8.29 (d, 2H), 8.01 (d, 1H), 7.91 (d, 2H), 6.99 (dd, 1H), 6.90 (d, 1H)
Embodiment 12
The preparation of 7- hydroxyls -3- (4- methoxyphenyls) -4H- benzopyran-4-ones (8c)
Using the synthetic method identical with compound (8a), white solid, yield 58.2% are obtained.MS(ESI)：M/z=269 [M+H]1。
Embodiment 13
The preparation of 4- (7- hydroxyl -4- oxo -4H- chromene -3- alkenyls) methyl benzoate (8d)
Using the synthetic method identical with compound (8a), faint yellow solid, yield 54.2% are obtained.1H-NMR (300MHz, d6-DMSO)δ：10.88 (s, 1H), 8.52 (s, 1H), 8.01 (d, 2H), 8.01 (dd, 3H), 7.77 (d, 2H), 6.99 (dd, 1H), 6.90 (d, 1H), 3.88 (s, 3H)
Embodiment 14
7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -3- (4- fluorophenyls) -4H- benzos The preparation of pyrans (A1)
By-isoxazole of 3- (2,6- dichlorophenyl) -4- chloromethyl 5- methyl and 1- (2,4- dihydroxy phenyl) -2- (4- fluorine Phenyl) ethyl ketone is dissolved in DMF, add in potassium carbonate and potassium iodide, 60 degree reactions 8 hours.It after the completion of reaction, is cooled to room temperature, Enter in water, be extracted with ethyl acetate, anhydrous sodium sulfate drying.It is spin-dried for, column chromatography, obtains white solid, yield 85.6%.1H NMR (300MHz, CDCl3) δ 8.06 (d, J=8.9Hz, 1H), 7.83 (s, 1H), 7.44 (dd, J=8.6,5.5Hz, 2H), 7.35 (d, J=1.9Hz, 1H), 7.32 (s, 1H), 7.25 (dd, J=9.3,6.6Hz, 1H), 7.04 (t, J=8.7Hz, 2H), 6.77 (dd, J=8.9,2.2Hz, 1H), 6.67 (d, J=2.2Hz, 1H), 4.76 (s, 2H), 3.28 (dt, J=13.8, 6.9Hz, 1H), 1.37 (d, J=6.9Hz, 6H)
Embodiment 15
7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -3- (4- nitrobenzophenones) -4H- benzene And the preparation of pyrans (A2)
Using the synthetic method identical with compound (A1), yellow solid, yield 88.7% are obtained.1H NMR (300MHz, d6- DMSO) δ 8.64 (s, 1H), 8.27 (d, J=8.9Hz, 2H), 7.97 (d, J=8.9Hz, 1H), 7.89 (d, J=8.8Hz, 2H), 7.68-7.58 (m, 2H), 7.53 (dd, J=9.3,6.6Hz, 1H), 7.13 (d, J=2.1Hz, 1H), 6.87 (dd, J=8.9, 2.2Hz, 1H), 5.02 (s, 2H), 3.50 (dt, J=14.0,6.9Hz, 1H), 1.34 (t, J=6.7Hz, 6H)
Embodiment 16
7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -3- (4- methoxyphenyls) -4H- The preparation of chromene (A3)
Using the synthetic method identical with compound (A1), white solid, yield 83.2% are obtained.1H NMR (300MHz, d6- DMSO) δ 8.64 (s, 1H), 8.27 (d, J=8.9Hz, 2H), 7.97 (d, J=8.9Hz, 1H), 7.89 (d, J=8.8Hz, 2H), 7.68-7.58 (m, 2H), 7.53 (dd, J=9.3,6.6Hz, 1H), 7.13 (d, J=2.1Hz, 1H), 6.87 (dd, J=8.9, 2.2Hz, 1H), 5.02 (s, 2H), 3.50 (dt, J=14.0,6.9Hz, 1H), 1.34 (t, J=6.7Hz, 6H)
Embodiment 17
4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4- oxo -4H- benzo pyrroles Mutter -3- alkenyls) preparation of carboxylate methyl ester (A7)
Using the synthetic method identical with compound (A1), yellow solid, yield 85.3% are obtained.1H NMR (300MHz, d6- DMSO) δ 8.53 (s, 1H), 7.97 (t, J=7.6Hz, 3H), 7.74 (d, J=8.1Hz, 2H), 7.60 (d, J=7.3Hz, 2H), 7.57-7.48 (m, 1H), 7.10 (s, 1H), 6.86 (d, J=8.9Hz, 1H), 5.03 (s, 2H), 3.86 (s, 3H), 3.51 (dt, J=13.9,6.9Hz, 1H), 1.36 (d, J=6.7Hz, 6H)
Embodiment 18
7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -3- (4- hydroxy phenyls) -4H- benzene And the preparation of pyrans (A4)
By 7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -3- (4- methoxyphenyls) - 4H- chromenes are dissolved in anhydrous methylene chloride, and the dichloromethane solution of 1N Boron tribromides is added under ice bath, and room temperature reaction 4 is small When.After the completion of reaction, saturated sodium bicarbonate solution, ethyl acetate extraction, anhydrous sodium sulfate drying are added dropwise under ice bath.It is spin-dried for molten Agent, column chromatography obtain white solid, yield 85.4%.1H NMR (300MHz, d6- DMSO) δ 9.55 (s, 1H), 8.36 (s, 1H), 7.97 (d, J=8.8Hz, 1H), 7.60 (dd, J=20.2,7.0Hz, 2H), 7.41 (d, J=8.1Hz, 2H), 7.08 (s, 1H), 6.83 (d, J=7.3Hz, 3H), 5.03 (s, 2H), 3.62-3.43 (m, 1H), 1.38 (d, J=6.6Hz, 6H)
Embodiment 19
2- (4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzos Pyrans -3- bases) phenoxy acetic acid ethyl ester (A5) preparation
By 7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -3- (4- hydroxy phenyls) -4H- Chromene and bromoacetate are dissolved in DMF, add in potassium carbonate and potassium iodide, 60 degree of reaction 6h.Reaction terminates, and is cooled to room Temperature, with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.Solvent is spin-dried for, column chromatography obtains white solid 650mg, yield 86.3%.1H NMR (300MHz, CDCl3) δ 8.14 (d, J=8.9Hz, 1H), 7.90 (s, 1H), 7.49 (d, J =8.7Hz, 2H), 7.45-7.37 (m, 2H), 7.32 (dd, J=9.3,6.6Hz, 1H), 6.97 (d, J=8.7Hz, 2H), 6.84 (dd, J=8.9,2.2Hz, 1H), 6.75 (d, J=2.1Hz, 1H), 4.85 (s, 2H), 4.65 (s, 2H), 4.28 (q, J= 7.1Hz, 2H), 3.36 (dt, J=14.0,7.0Hz, 1H), 1.45 (d, J=7.0Hz, 6H), 1.31 (t, J=7.1Hz, 3H)
Embodiment 20
2- (4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzos Pyrans -3- bases) phenoxy acetic acid (A6) preparation
By 2- (4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzene And pyrans -3- bases) phenoxy acetic acid ethyl ester is dissolved in dioxane, concentrated hydrochloric acid, back flow reaction 10 hours is added dropwise.After the completion of reaction, rotation Dry solution, is extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.Solvent is spin-dried for, column chromatography obtains yellowish Color solid, yield 78.2%.1H NMR (300MHz, d6- DMSO) δ 8.41 (s, 1H), 7.95 (d, J=8.9Hz, 1H), 7.62 (d, J=7.2Hz, 2H), 7.58-7.52 (m, 1H), 7.49 (d, J=8.6Hz, 2H), 7.09 (s, 1H), 6.96 (d, J= 8.6Hz, 2H), 6.84 (d, J=8.6Hz, 1H), 5.01 (s, 2H), 4.67 (s, 2H), 3.51 (dt, J=14.2,7.0Hz, 2H), 1.36 (d, J=6.9Hz, 6H)
Embodiment 21
4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzo pyrroles Mutter -3- bases) preparation of benzoic acid (A8)
Using the synthetic method identical with compound (A6), yellow solid, yield 90.0% are obtained.1H NMR (300MHz, d6- DMSO) δ 12.94 (s, 1H), 8.50 (s, 1H), 7.91 (d, J=6.8Hz, 3H), 7.64 (d, J=7.4Hz, 2H), 7.54 (s, 2H), 7.49 (s, 1H), 7.06 (s, 1H), 6.79 (d, J=7.9Hz, 1H), 4.95 (s, 2H), 3.44 (s, 1H), 1.28 (d, J =6.3Hz, 6H)
Embodiment 22
4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzo pyrroles Mutter -3- bases) preparation of-N-methyl-benzamide (A9)
By 4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzo pyrroles Mutter -3- bases) benzoic acid, EDCI, HOBT, triethylamine be dissolved in DMF, add in methylamine hydrochloride, react at room temperature 10 hours.It has reacted Cheng Hou is poured into water, and is extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying.Solvent is spin-dried for, column chromatography obtains To faint yellow solid, yield 83.2%.1H NMR (300MHz, d6- DMSO) δ 8.51 (s, 1H), 8.48 (d, J=4.5Hz, 1H), 7.94 (d, J=8.9Hz, 1H), 7.85 (d, J=8.3Hz, 2H), 7.63 (dd, J=10.0,5.0Hz, 3H), 7.58 (s, 1H), 7.54 (s, 1H), 7.10 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.9,2.1Hz, 1H), 4.99 (s, 2H), 3.49 (dd, J =13.9,6.9Hz, 3H), 2.77 (d, J=4.3Hz, 1H), 1.33 (d, J=6.9Hz, 6H)
Embodiment 23
4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzo pyrroles Mutter -3- bases) preparations of-N- ethyl benzamides (A10)
Using the synthetic method identical with compound (A9), faint yellow solid, yield 83% are obtained.1H NMR (300MHz, CDCl3) δ 8.13 (d, J=8.9Hz, 1H), 7.98 (s, 1H), 7.81 (d, J=8.0Hz, 2H), 7.58 (d, J=7.9Hz, 2H), 7.41 (d, J=7.1Hz, 2H), 7.34 (d, J=6.7Hz, 1H), 6.86 (d, J=8.6Hz, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 4.86 (s, 2H), 3.54-3.42 (t, 2H), 3.37 (dd, J=14.0,7.0Hz, 1H), 1.45 (d, J= 6.9Hz, 6H), 1.27-1.20 (q, 3H)
Embodiment 24
4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzo pyrroles Mutter -3- bases) preparation of-N- cyclopropyl-phenyls formamide (A11)
Using the synthetic method identical with compound (A9), faint yellow solid, yield 80.4% are obtained.1H NMR (400MHz, CDCl3) δ 8.13 (d, J=8.9Hz, 1H), 7.97 (s, 1H), 7.78 (d, J=8.2Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.44-7.37 (m, 2H), 7.33 (dd, J=9.0,7.0Hz, 1H), 6.86 (dd, J=8.9,2.3Hz, 1H), 6.76 (d, J=2.2Hz, 1H), 6.51 (s, 1H), 4.85 (s, 2H), 3.36 (dt, J=14.0,7.0Hz, 1H), 2.90 (dt, J=10.3, 3.4Hz, 1H), 1.45 (d, J=7.0Hz, 6H), 0.86 (d, J=6.3Hz, 2H), 0.63 (d, J=2.0Hz, 2H)
Embodiment 25
4- (7- ((3- (2,6- dichlorophenyl) -5- Yi propyl isoxazole -4-base) oxygen methyl) -4 oxo -4H- benzo pyrroles Mutter -3- bases)-N, the preparation of N- dimethyl benzamides (A12)
Using the synthetic method identical with compound (A9), faint yellow solid, yield 85.3% are obtained.1H NMR (400MHz, CDCl3) δ 8.06 (d, J=8.9Hz, 1H), 7.87 (s, 1H), 7.52 (d, J=8.3Hz, 2H), 7.40 (d, J=8.3Hz, 2H), 7.35-7.29 (m, 2H), 7.25 (dd, J=9.1,6.9Hz, 1H), 6.77 (dd, J=8.9,2.4Hz, 1H), 6.68 (d, J=2.3Hz, 1H), 4.77 (s, 2H), 3.28 (dt, J=14.0,7.0Hz, 1H), 2.99 (d, J=39.7Hz, 6H), 1.37 (d, J=7.0Hz, 6H)

Claims (4)

1. the compound or its pharmaceutically acceptable salt of general formula (I)：
Wherein,
R1、R2It is independently hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkyl, halogenated C1-3Alkoxy；
X is O, S, NH；
R3For hydrogen, halogen, C1-6Alkyl, C3-6Cycloalkyl, C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C1-6Alkoxy；
R4For the hydrogen of phenyl ring any position substitution, halogen, hydroxyl, nitro, cyano, methoxyl group, tetrazole base, COOR5、CONR6R7、 OCH2COOR8；
R5、R6、R7、R8It is independently hydrogen, C1-6Alkyl, C3-6Cycloalkyl.
2. according to the compound of any one in claim 1 or its pharmaceutically acceptable salt, wherein R1、R2Independently For hydrogen, chlorine, bromine, fluorine, methoxyl group, a fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy；
X is O；
R3For isopropyl, cyclopropyl；
R4For the hydrogen of phenyl ring meta or para position substitution, halogen, hydroxyl, nitro, cyano, methoxyl group, tetrazole base, COOR5、 CONR6R7、OCH2COOR8；
R5、R6、R7、R8It is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
3. pharmaceutical composition, it includes according to the compound of any one in claim 1-2 or its pharmaceutically acceptable salt, And pharmaceutically acceptable carrier.
4. according to the compound of any one in claim 1-2 or its pharmaceutically acceptable salt, it is used to prepare prevention or controls Treat hyperlipidemia, type-2 diabetes mellitus, atherosclerosis, nonalcoholic steatohepatitis drug purposes.
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