CN107987116A - A kind of chenodeoxycholic acid derivatives, its preparation method and medical usage - Google Patents
A kind of chenodeoxycholic acid derivatives, its preparation method and medical usage Download PDFInfo
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- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
The present invention relates to medicinal chemistry art, it is related to chenodeoxycholic acid derivatives, its preparation method and medical usage, be the chenodeoxycholic acid derivatives of (I), their preparation method, the pharmaceutical composition containing these compounds and their medical usage more particularly to a kind of general formula, especially as prevent or treatment hyperlipidemia, type ii diabetes, atherosclerosis, nonalcoholic steatohepatitis medicine purposes.
Description
Technical field:
The present invention relates to medicinal chemistry art, more particularly to chenodeoxycholic acid derivatives.The invention also discloses they
Preparation method and pharmacological activity, the Pharmaceutical composition containing these compounds and their medical usage are especially as prevention
Or treatment hyperlipidemia, type ii diabetes, atherosclerosis, the purposes of nonalcoholic steatohepatitis medicine.
Background technology:
Dyslipidemia is a kind of since fat metabolism or operating exception make blood plasma one or more lipid be higher than normal value
Systemic disease, it shows as T-CHOL in blood (TC) and/or triglycerides (TG) is excessive or high-density lipoprotein cholesterol
(HDL-C) it is too low.Dyslipidemia can cause atherosclerosis, nonalcoholic fatty liver, type ii diabetes 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 suppresses 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, suppress Sterol regulatory element binding protein
1c is expressed, and induction peroxisome proliferator-activated receptor alpha expression, promotes reverse cholesterol transport to enter liver, reduce lipid and close
Into promotion fatty acid beta oxidation.
Chenodeoxycholic acid is natural primary bile acid, people, animal, fowl bile in be widely present, be chicken, duck and goose etc.
Main organic principle in poultry bile.Since the 1970s, chenodeoxycholic acid is clinically mainly used for treating courage knot
Stone disease and other diseases in the liver and gallbladder.Chenodeoxycholic acid also has antibacterial, anti-inflammatory, antipyretic and adjust the pharmacological action such as immune, to pancreas
The tolerance of island element also has certain effect.Chenodeoxycholic acid is the native endogenous ligand of FXR.6 α-ethyl-chenodeoxycholic acid
Also known as shellfish cholic acid difficult to understand is a kind of new derivatives of chenodeoxycholic acid, it is the activator of the high affinity degree of the FX R of synthesis, can uses
In treatment primary biliary cirrhosis and non-alcohol fatty liver.
The content of the invention:
The invention discloses a kind of chenodeoxycholic acid derivatives of general formula I, proved through experiment in vitro, the compounds of this invention can
Substantially to suppress the accumulation of adipocyte lipid.So the compounds of this invention has potential Adjust-blood lipid activity.
Wherein,
R1、R2Independently for hydrogen, halogen, C1-3Alkyl, methoxyl group, halogenated methoxy;
X is O, S, NH;
R3For hydrogen, halogen, C1-3Alkyl, methoxyl group, trifluoromethoxy;
R4For OH, COOR5、CONR6R7
R5、R6、R7Independently for hydrogen, C1-6Alkyl, C3-6Cycloalkyl, phenyl, pyridine radicals;Wherein phenyl, pyridine radicals can
Optionally to be substituted by 1 to 3 substituent, the substituent independence selected from hydrogen, halogen, hydroxyl, methoxyl group, acetylamino,
Trifluoromethoxy, C1-3Alkyl.
Wherein, R1、R2Independently be preferably hydrogen, halogen, methyl, methoxyl group, trifluoromethoxy;
X is preferably O;
R3It is preferably hydrogen, methyl, ethyl;
R4It is preferably COOR5、CONR6R7;
R5、R6、R7Independently be preferably hydrogen, C1-6Alkyl, C3-6Cycloalkyl, phenyl;Wherein phenyl can be optionally by 1
Substitute to 3 substituents, the substituent independence is selected from hydrogen, halogen, methoxyl group, acetylamino, trifluoromethoxy, first
Base, hydroxyl.
The structure of the part of compounds of the present invention is as follows:
The code name of compound is equal to the compound structure corresponding to code name herein in pharmacological evaluation and embodiment below.
Compound B-11-the B10 of general formula of the present invention can be prepared by following methods:
Reagents and conditions:A) con HCl, CH3OH, reflux;b)(Ac)2O, TEA, DMAP, DCM;
C) NaClO, AcOH, EA;D) KOH, N2H4·H2O, Δ;E) con HCl, CH3OH, reflux;F) TsCl, Py;g)NaN3, DMF;
h)PPh3, THF, H2O, Δ;I) DCC, HOB T, N2;J) LiOH, CH3OH, H2O;k)RNH2, EDCI, HOBT, DMF or
ClCO2Et, Et3N, then RNH2.
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;Hyclone (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 nutrient solutions) culture 2
My god.Break up the 2nd day, change differential medium II (the DMEM nutrient solutions containing 10%FBS, 10mg/L insulin) culture cells.Differentiation
4th day and accordingly change later liquid be containing 10 μm of ol/L target compound DMEM nutrient solutions, control group for non-dosing complete culture
Liquid.Break up 6d and abandon nutrient solution in hole, PBS cleaning twice, adds and fixes cell 2h containing 10% formaldehyde.PBS cleaning twice,
When 0.5% oil red dyeing 2 is small.PBS cleaning 3 times.In 37 DEG C of dryings, isopropanol is added, extracts 10min, extract is surveyed in 492nm
Determine light absorption value.Inhibiting rate is calculated as follows:
As a result:Adipocyte inner lipid content is substantially lower than control group after the display administration of oil red decoration method, illustrates new chemical combination
Thing can substantially suppress accumulation of lipid.
Experimental result
Compound number | Inhibiting rate (%) |
B1 | 22.60 |
B2 | 22.51 |
B3 | 28.18 |
B4 | 30.94 |
B5 | 22.34 |
B6 | 23.83 |
B7 | 26.17 |
B8 | 24.46 |
B9 | 27.05 |
B10 | 24.70 |
The invention further relates to the compound and the Pharmaceutical composition of pharmaceutically acceptable carrier composition of general formula.
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 ingredient for such as 0.05% to 90% total amount closed, the active ingredient 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 formulation
This dosage range.
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
Compose Agilent1100LC-MSD-Trap/SL types mass spectrograph (ESI-MS) 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.);TLC expansion systems are petroleum ether-ethyl acetate system or methylene chloride-methanol system,
A small amount of acetic acid is added if 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 3 α, 7 α, 12 α-β of trihydroxy-5-cholesteric-24- carboxylic acids formicester (2)
Take raw material cholic acid 10g to be dissolved in 30ml methanol, add 1ml concentrated hydrochloric acids, back flow reaction 1h, is slowly cooled to room temperature, and separates out
Crystal, filters, is dried in vacuo to obtain 10.25g white crystals, yield 96.10%.MS(ESI):M/z=423.3 [M+H]+。
Embodiment 2
The preparation of 3 α, 7 α-- 5 β of the Alpha-hydroxy of diacetoxy-12-cholesteric-24- carboxylic acids formicester (3)
10.25g compounds 2 are dissolved in 40ml dichloromethane, add triethylamine 8ml, acetic anhydride 6ml, 4-dimethylaminopyridine
0.15g, reacts at room temperature 8h.Add water quenching to go out reaction, stir 2h, extracted with dichloromethane, organic layer is washed with saturated common salt, adds nothing
Aqueous sodium persulfate is dried, and re-crystallizing in ethyl acetate is used after being spin-dried for, obtains 5.63 white solids, yield 45.81%.MS(ESI):m/z
=507.3 [M+H]+。
Embodiment 3
The preparation of 3 α, 7 α--5 β of diacetoxy -12- ketone-cholesteric -24- carboxylic acids formicester (4)
5.63g compounds 3 are dissolved in 25ml ethyl acetate, add acetic acid 10ml, 15ml liquor natrii hypochloritis, 40 DEG C of reactions
7h.Standing separates organic layer, is spin-dried for, and filters, and washing, dries to obtain 5.32g white solids, yield 94.50%.MS(ESI):m/z
=505.3 [M+H]+。
Embodiment 4
The preparation of 3 α, 7-5 β of alpha-dihydroxy-cholesteric-24- carboxylic acids (5)
4.06g compounds 4 are dissolved in 20ml diethylene glycols, add 2gKOH, 5ml80% hydrazine hydrates, first 120 DEG C of reflux 2h,
210 DEG C are warming up to again and steams hydrazine hydrate and water with division box, react 3h.Reaction solution is cooled to room temperature, is poured into 50ml water,
With 30% dilute sulfuric acid tune pH to 2-3, there is white solid precipitation, stand, filter, drying, obtains white solid 2.65g, yield
86.6%.MS(ESI):M/z=391.3 [M-H]-。
Embodiment 5
The preparation of 3 α, 7-5 β of alpha-dihydroxy-cholesteric-24- carboxylate methyl esters (6)
10g compounds 5 are dissolved in 30ml methanol, add 1ml concentrated hydrochloric acids, back flow reaction 1h, is slowly cooled to room temperature, and separates out brilliant
Body, filters, is dried in vacuo to obtain 10.10g white crystals, molar yield 97.50%.MS(ESI):M/z=407.3 [M+H]+。
Embodiment 6
The preparation of-7-5 β of Alpha-hydroxy of 3 α-p-methyl benzenesulfonic acid ester group-cholesteric-24- carboxylate methyl esters (7)
2.3g compounds 6 are dissolved in pyridine, add paratoluensulfonyl chloride 2.2g, react at room temperature 6h.Reaction terminates, dichloro
Methane extracts, and successively with water and saturated common salt water washing, anhydrous sodium sulfate drying, is spin-dried for obtaining white solid 2.7g, yield
85%.It is directly lower to throw.MS(ESI):M/z=561.3 [M+H]+。
Embodiment 7
The preparation of 3 β-- 5 β of the Alpha-hydroxy of azido-7-cholesteric-24- carboxylate methyl esters (8)
Compound 7 is dissolved in n,N-Dimethylformamide, is carefully added into sodium azide, 60 DEG C of reaction 18h, nitrogen is protected
Shield.Reaction terminates, and reaction solution is poured into water, and PH is adjusted to 9-10, and ethyl acetate extraction, is washed with water and saturated common salt successively
Wash, anhydrous sodium sulfate drying, is threaded to oily, directly lower to throw.MS(ESI):M/z=432.3 [M+H]+。
Embodiment 8
The preparation of-7-5 β of Alpha-hydroxy of 3 beta-amino-cholesteric-24- carboxylate methyl esters (9)
Compound 8 (0.6g, 1.22mmol), triphenylphosphine (0.63g, 2.44mmol), water are added into reaction bulb
(0.5ml), tetrahydrofuran (10ml), back flow reaction 12h.Reaction terminates, and is spin-dried for reaction solution, and column chromatography obtains white solid 0.41g,
Yield 72.4%.MS(ESI):M/z=406.3 [M+H]+。
Embodiment 9
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24- carboxylate methyl esters (B1)
Prepare
By 3,5- dimethyl isoxazole -4- formic acid (0.53g), dicyclohexylcarbodiimide (1.55g), HOBT (0.675g)
It is dissolved in 30mlTHF, stirring adds 1g compounds 9 after ten minutes, when the lower reaction 12 of nitrogen protection is small.After reaction, filter
Reaction solution is spin-dried for, is extracted with ethyl acetate, successively with water and saturated common salt water washing, anhydrous sodium sulfate drying.Column was spin-dried for obtain
To white solid 0.32g, yield 80%.1H NMR (300MHz, d6- DMSO) δ 7.72 (d, J=5.8Hz, 1H), 4.11 (s,
1H), 3.97 (s, 1H), 3.61 (s, 1H), 3.55 (s, 3H), 2.46 (d, J=13.5Hz, 6H), 0.86 (d, J=6.5Hz,
6H), 0.59 (s, 3H)
Embodiment 10
The preparation of 3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24- carboxylic acids (B2)
1.3g compound B-11s are dissolved in methanol, the aqueous solution 12ml of 2N lithium hydroxides are added dropwise, when room temperature reaction 8 is small.Rotation
Dry solution, is added dropwise 1N hydrochloric acid solutions, adjusts PH to 2, elutriation filtering drying, obtains white solid 1.15g, yield 90%.1H NMR
(300MHz, d6- DMSO) δ 12.01 (s, 1H), 7.74 (s, 1H), 4.14 (s, 1H), 4.02 (s, 1H), 3.66 (s, 1H), 2.50
(d, J=12.8Hz, 6H), 0.91 (s, 6H), 0.64 (s, 3H)
Embodiment 11
The preparation of 3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24- acid amides (B3)
Compound B2 (0.4g) is dissolved in 8ml dichloromethane, sequentially added under ice bath ethyl chloroformate (0.11ml),
Et3N (0.13ml), 0.1ml ammonium hydroxide is added dropwise in reaction after forty minutes, when reaction 8 is small.Reaction end is extracted with ethyl acetate, successively
With water and saturated common salt water washing, anhydrous sodium sulfate drying.It was spin-dried for column and obtains white solid 0.28g, yield 70.2%.1H
NMR (300MHz, d6- DMSO) δ 7.74 (d, J=5.7Hz, 1H), 7.21 (s, 1H), 6.63 (s, 1H), 4.14 (d, J=
2.6Hz, 1H), 3.96 (s, 1H), 3.61 (s, 1H), 2.45 (d, J=14.3Hz, 9H), 0.86 (s, 6H), 0.58 (s, 3H)
Embodiment 12
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24-N- methyl nitrosoureas (B4)
Preparation
Compound B2 (0.15g) is dissolved in 5mlDMF, sequentially adds EDCI (0.11g), HOBT (0.04g), Et3N
(0.2ml) and methylamine hydrochloride (0.06g), nitrogen protection, when room temperature reaction 12 is small.Reaction end is extracted with ethyl acetate, according to
It is secondary to use water and saturated common salt water washing, anhydrous sodium sulfate drying.It was spin-dried for column and obtains white product 0.17g, yield 82.5%.1H
NMR (300MHz, d6- DMSO) δ 7.75 (s, 1H), 7.68 (s, 1H), 4.15 (s, 1H), 3.99 (s, 1H), 3.63 (s, 1H),
2.53 (s, 3H), 2.45 (s, 3H), 2.25 (s, 3H), 0.89 (s, 6H), 0.60 (s, 3H)
Embodiment 13
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24-N- buserelins (B5)
Preparation
Using the synthetic method identical with compound B4, white solid, yield 78.6% are obtained.1H NMR (300MHz, d6-
DMSO) δ 5.94 (d, J=7.0Hz, 1H), 5.72 (t, J=5.2Hz, 1H), 4.25 (s, 1H), 3.84 (s, 1H), 3.33-3.15
(m, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 1.10 (t, J=7.2Hz, 3H), 0.95 (s, 3H), 0.91 (d, J=6.3Hz,
3H), 0.64 (s, 3H)
Embodiment 14
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24-N- amides (B6)
Preparation
Compound B2 (0.25g) is dissolved in 6mlDMF, sequentially adds HBTU (0.27g), triethylamine (0.33ml) and sweet
Propylhomoserin methyl ester hydrochloride (0.12g), nitrogen protection, when room temperature reaction 18 is small.Reaction end is extracted with ethyl acetate, and uses water successively
With saturated common salt water washing, anhydrous sodium sulfate drying.Solvent is spin-dried for, is dissolved in 4ml methanol, 2N lithium hydroxide aqueous solutions are added dropwise
2.5ml, when room temperature reaction 6 is small.Solvent is spin-dried for, adjusts PH to 2, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate is done
It is dry.It is spin-dried for solvent and crosses column obtaining white solid 0.18g, yield 67.5%.1H NMR (300MHz, d6- DMSO) δ 8.03 (s, 1H),
7.70 (d, J=4.0Hz, 1H), 3.97 (s, 1H), 3.68 (d, J=5.8Hz, 2H), 3.61 (s, 1H), 2.43 (s, 3H), 2.23
(s, 3H), 0.87 (s, 6H), 0.59 (s, 3H)
Embodiment 15
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24-N- (4- fluorine) phenyl acyl
The preparation of amine (B7)
Using the synthetic method identical with compound B4, white solid, yield 75.6% are obtained.1H NMR (300MHz,
CDCl3) δ 7.92 (s, 1H), 7.54-7.44 (m, 2H), 6.97 (t, J=8.7Hz, 2H), 5.95 (s, 1H), 5.93 (s, 1H),
4.28 (s, 1H), 3.86 (s, 1H), 2.60 (s, 3H), 2.42 (s, 3H), 0.97 (s, 3H), 0.94 (d, J=6.0Hz, 3H),
0.66 (s, 3H)
Embodiment 16
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24-N- (4- chlorine) phenyl acyl
The preparation of amine (B8)
Using the synthetic method identical with compound B4, white solid, yield 76.2% are obtained.1H NMR (300MHz,
CDCl3) δ 8.00 (s, 1H), 7.46 (d, J=8.5Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 5.92 (s, 1H), 5.90 (s,
1H), 4.24 (s, 1H), 3.82 (s, 1H), 2.56 (s, 3H), 2.39 (s, 3H), 0.93 (s, 3H), 0.89 (d, J=5.5Hz,
3H), 0.62 (s, 3H)
Embodiment 17
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24-N- (4- acetylaminos)
The preparation of phenyl amide (B9)
Using the synthetic method identical with compound B4, white solid, yield 72.3% are obtained.1H NMR (300MHz, d6-
DMSO) δ 9.81 (s, 1H), 9.75 (s, 1H), 7.73 (s, 1H), 7.45 (s, 4H), 4.13 (s, 1H), 3.97 (s, 1H), 3.61
(s, 1H), 2.43 (s, 3H), 2.23 (s, 3H), 1.98 (s, 3H), 0.88 (d, J=7.1Hz, 6H), 0.59 (s, 3H)
Embodiment 18
3 β-- 7-5 β of Alpha-hydroxy of (3,5- dimethyl isoxazole base)-4- formamidos-cholesteric-24-N- (3- chlorine) phenyl acyl
The preparation of amine (B10)
Using the synthetic method identical with compound B4, white solid, yield 73.5% are obtained.1H NMR (300MHz,
CDCl3) δ 8.32 (s, 1H), 7.62 (s, 1H), 7.36 (d, J=8.0Hz, 1H), 7.15 (t, J=8.0Hz, 1H), 6.99 (d, J
=7.9Hz, 1H), 5.95 (s, 1H), 4.23 (s, 1H), 3.81 (s, 1H), 2.55 (s, 3H), 2.38 (s, 3H), 0.92 (s,
3H), 0.88 (d, J=5.7Hz, 3H), 0.61 (s, 3H)
Claims (4)
1. the compound or its pharmaceutically acceptable salt of general formula (I):
Wherein,
R1、R2Independently for hydrogen, halogen, C1-3Alkyl, methoxyl group, halogenated methoxy;
X is O, S, NH;
R3For hydrogen, halogen, C1-3Alkyl, methoxyl group, trifluoromethoxy;
R4For OH, COOR5、CONR6R7;
R5、R6、R7Independently for hydrogen, C1-6Alkyl, C3-6Cycloalkyl, phenyl, pyridine radicals;Wherein phenyl, pyridine radicals can appoint
Choosing is substituted by 1 to 3 substituent, and the substituent independence is selected from hydrogen, halogen, hydroxyl, methoxyl group, acetylamino, trifluoro
Methoxyl group, C1-3Alkyl.
2. according to the compound of any one in claim 1 or its pharmaceutically acceptable salt, wherein R1、R2Independently
For hydrogen, halogen, methyl, methoxyl group, trifluoromethoxy;
X is O;
R3For hydrogen, methyl, ethyl;
R4For COOR5、CONR6R7;
R5、R6、R7Independently for hydrogen, C1-6Alkyl, C3-6Cycloalkyl, phenyl;Wherein phenyl can be optionally by 1 to 3 substitution
Base substitutes, and the substituent independence is selected from hydrogen, halogen, methoxyl group, acetylamino, trifluoromethoxy, methyl, hydroxyl.
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 ii diabetes, atherosclerosis, nonalcoholic steatohepatitis medicine purposes.
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CN110845567A (en) * | 2019-11-21 | 2020-02-28 | 中国药科大学 | Chenodeoxycholic acid derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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