CN109369583A - A kind of PPAR gamma/delta dual agonists, preparation method and its purposes as drug - Google Patents

A kind of PPAR gamma/delta dual agonists, preparation method and its purposes as drug Download PDF

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CN109369583A
CN109369583A CN201811500133.XA CN201811500133A CN109369583A CN 109369583 A CN109369583 A CN 109369583A CN 201811500133 A CN201811500133 A CN 201811500133A CN 109369583 A CN109369583 A CN 109369583A
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alkyl
methyl
naphthenic base
benzofuran
subunit
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张陆勇
李政
周宗涛
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Guangdong Pharmaceutical University
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Priority to CN201910811322.7A priority patent/CN111285829B/en
Priority to PCT/CN2020/100518 priority patent/WO2021036514A1/en
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Abstract

The present invention relates to novel PPAR gamma/delta dual agonists shown in a kind of logical formula (I), preparation method and contain the pharmaceutical composition of the derivative as preparation prevention or/and the medicinal usage for the treatment of abnormal glucose metabolism or/and abnormalities of sugar/lipid metabolism disease.The PPAR gamma/delta dual agonists have excellent internal hypoglycemic activity and regulating blood lipid action, the drug that can be applied to the metabolic syndromes related disease such as preparation prevention or/and treatment diabetes, obesity, hyperlipidemia, atherosclerosis and fatty liver, has broad application prospects.

Description

A kind of PPAR gamma/delta dual agonists, preparation method and its purposes as drug
Technical field
The present invention relates to a kind of PPAR gamma/delta dual agonists, preparation method and its applications, belong to pharmaceutical technology field. Derivant structure involved in the present invention is the field is unique and novelty.
Background technique
Metabolic syndrome is the common disease characterized by glucose and abnormalities of sugar/lipid metabolism, is increased with low-density lipoprotein With high-density lipoprotein cholesterol reduce, common illness be obesity, diabetes, hyperlipemia, atherosclerosis and Fatty liver etc., wherein diabetic is also often accompanied with hyperlipidemia, cardiovascular disease, diabetic nephropathy, diabetic neuropathy Etc. diseases.
It is announced according to the World Health Organization, suffers from diabetes more than 2.2 hundred million people in world wide at present, wherein China has become The most country of global diabetes patient, more than 92,000,000 diabetics, and the current diabetes morbidity in China also in Rising stage, it is estimated that pre-diabetic is about 1.5 hundred million at present for China.The diabetic population of continuous enlargement is brought to society Huge economy and medical burden.The World Health Organization points out, if the development for the diabetes that do not take effective measure to cope with, It is expected that in coming 10 years, only heart disease, apoplexy and diabetes will just bring at least 550,000,000,000 dollars of economic loss to China. Therefore, a kind of serious disease for threatening human health is had become for typical metabolic syndrome with diabetes.Metabolic syndrome can To need to carry out drug therapy when these cannot alleviate symptom by dietary adjustments and exercise treatment.In metabolic syndrome Drug treatment, the effects of antidiabetic drug or lipid-lowering medicine of clinical use, is single at present, is not provided simultaneously with comparatively ideal improvement The effect of metabolic syndrome items pathological index, therefore, for multiple fields improvement metabolic syndrome drug research into Row, to bring safer and more effective newtype drug for metabolic syndrome patient.Wherein peroxisome proliferator-activated receptor The multiple agonist of body PPAR becomes the research hotspot in the recent field.
Peroxisome proliferation-activated receptors (peroxisome proliferator-activated Receptor, PPAR) it is the intranuclear receptor transcription factor superfamily member for adjusting target gene expression, not according to hypotype structure Together, PPAR can be divided into α, β (or δ) and γ three types, and wherein PPAR α is distributed mainly in liver and brown fat, with adjusting Blood lipid level, insulin resistance, that is, inflammatory reaction are closely related；PPAR γ is mainly expressed in adipose tissue and immune system, with rouge Fat cell differentiation, immunity of organism and Relationship between insulin resistance are close, are Studies of The Insulin Sensitizer Thiazolidinediones drugs The target molecule of (troglitazone, TZDs) effect；PPAR δ is distributed mainly in fat, skeletal muscle, heart and liver, mainly Adjust glycolipid metabolism, improve inflammatory reaction etc..Studied confirmation: the multiple agonist of PPAR can activate and regulate and control related gene Expression, plays a significant role in Adipogenesis, glycolipid metabolism, and can regulate and control a variety of diseases includes obesity, diabetes, hyperlipidemia Deng [Azadeh Matin etc., J.Med.Chem.2009,52,6835-6850；Shen etc., J.Nutr.2006,899-905]. PPAR α/δ dual agonists GFT505 is also in nonalcoholic fatty liver III phase clinical research, shows more excellent pharmacology Activity (Bertrand Cariou etc., Expert Opin.Investig.Drugs.2014,23,1441-1448).Currently, PPAR α/γ double excitations, PPAR α/general agonist of gamma/delta and PPAR α/δ dual agonists have lot of documents and report, but by PPAR gamma/delta dual agonists are from having no document report so far.
The present invention relates to the PPAR gamma/delta dual agonists of structure novel, living with excellent PPAR gamma/delta double excitations Property and internal hypoglycemic fat-regulating activity.Therefore the PPAR gamma/delta dual agonists and its officinal salt can potentially be used to treat Or the associated metabolic syndromes such as prevention diabetes, hyperlipidemia and fatty liver, there is wide development prospect.
Summary of the invention
In view of the above-mentioned problems existing in the prior art with unsatisfied clinical demand, the object of the present invention is to provide one kind PPAR gamma/delta dual agonists and its application provide a new class of potential drug to prevent or/and treating metabolic disorder class disease.
One kind PPAR gamma/delta dual agonists of the present invention are containing a effective amount of logical formula (I) compound represented Or its pharmaceutical salt:
Wherein:
R1And R2Be each independently selected from hydrogen, alkyl, wherein the alkyl optionally further by one or more selected from halogen, Hydroxyl, cyano, nitro, alkyl, alkoxy, naphthenic base group replaced；
R3And R4It is each independently selected from hydrogen, alkyl, alkoxy, halogen, naphthenic base；
R5Selected from hydrogen, alkyl, naphthenic base, wherein the alkyl, naphthenic base are optionally further selected from halogen by one or more Element, hydroxyl, cyano, nitro, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) OR6、-OC(O)R6、-C (O)R6、-NHC(O)R6、-NR7R8、-OC(O)NR7R8、-NHC(O)NR7R8Or-S (O)2R7Group replaced；
R6Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, miscellaneous Ring group, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, alkoxy, ring by one or more each independently Alkyl, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced；
R7Or R8It is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkane Base, naphthenic base, heterocycle, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl by one or more each independently Base, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced；
More preferably logical formula (I) compound represented or its pharmaceutical salt:
R1And R2Be each independently selected from hydrogen, alkyl, wherein the alkyl optionally further by one or more selected from hydroxyl, Alkyl, alkoxy, naphthenic base group replaced；
R3And R4It is each independently selected from hydrogen, alkyl, halogen；
R5Selected from hydrogen, alkyl, naphthenic base, wherein the alkyl, naphthenic base are optionally further selected from hydroxyl by one or more Base, cyano, nitro, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) OR6、-OC(O)R6、-C(O)R6、- NHC(O)R6、-NR7R8、-OC(O)NR7R8、-NHC(O)NR7R8Or-S (O)2R7Group replaced；
R6Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, miscellaneous Ring group, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, alkoxy, ring by one or more each independently Alkyl, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced；
R7Or R8It is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkane Base, naphthenic base, heterocycle, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl by one or more each independently Base, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced；
Preferred the compounds of this invention includes, but are not limited to:
2- (4- ((- 2 (3H)-subunit of 6- methoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I-1)；
2- (4- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I-2)；
2- (4- ((- 2 (3H)-subunit of 6- propoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I-3)；
2- (4- ((- 2 (3H)-subunit of 6- isobutoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) second Sour (I-4)；
2- (4- ((- 2 (3H)-subunit of 6- cyclo propyl methoxy -3- oxo benzofuran) methyl) -2,6- dimethyl benzene oxygen Base) acetic acid (I-5)；
2- (the chloro- 4- of 2- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) phenoxy group) acetic acid (I-6)；
2- (4- ((- 2 (3H)-subunit of 6- methoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- Methylpropanoic acid (I-7)；
2- (4- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- Methylpropanoic acid (I-8)；
2- (4- ((- 2 (3H)-subunit of 6- (Carboxvmethoxv) -3- oxo benzofuran) methyl) -2,6- dimethyl benzene oxygen Base) -2 Methylpropionic acid (I-9)；
2- (2,6- dimethyl -4- ((- 2 (3H)-subunit of 3- oxo -6- propoxyl group benzofuran) methyl) phenoxy group) -2- Methylpropanoic acid (I-10)；
2- (4- ((- 2 (3H)-subunit of 6- isobutoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) - 2 Methylpropionic acid (I-11)；
2- (4- ((- 2 (3H)-subunit of 6- butoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- Methylpropanoic acid (I-12)；
2- (4- ((- 2 (3H)-subunit of 6- (cyclo propyl methoxy) -3- oxo benzofuran) methyl) -2,6- dimethyl benzene Oxygroup) -2 Methylpropionic acid (I-13)；
2- (4- ((- 2 (3H)-subunit of 6- (isoamoxy) -3- oxo benzofuran) methyl) -2,6- dimethyl benzene oxygen Base) -2 Methylpropionic acid (I-14)；
2- (2,6- dimethyl -4- ((- 2 (3H)-subunit of 3- oxo -6- propoxyl group benzofuran) methyl) phenoxy group) -2- Methyl sodium propionate (I-15).
Compound of the present invention or its purposes of pharmaceutical salt as PPAR gamma/delta dual agonists.
Another aspect of the present invention relates to a kind of pharmaceutical compositions, the compound containing treatment effective dose or its Pharmaceutical salt and carrier appropriate, diluent or excipient.
Present invention simultaneously relates to the compound or its pharmaceutical salt or its pharmaceutical composition in preparation prevention or/and to control The purposes in the drug of abnormal glucose metabolism or/and abnormalities of sugar/lipid metabolism disease is treated, and in preparation prevention or/and treatment glycosuria The drug of at least one of the metabolic syndromes related disease such as disease, obesity, hyperlipidemia, atherosclerosis and fatty liver disease In purposes.
Detailed description of the invention
Unless otherwise stated, following have following meanings with term in the specification and in the claims.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, straight chain and branched group including 1 to 20 carbon atom.Preferably comprise 1 To the alkyl of 10 carbon atoms, the more preferably alkyl containing 1 to 6 carbon atom, the alkyl of further preferably 1 to 3 carbon atom, Most preferably methyl.Non-limiting embodiment includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tertiary fourth Base, amyl, isopentyl, neopentyl, hexyl etc. and its various branched isomers etc..Alkyl can be substituted or unsubstituted, When substituted, substituent group can be substituted on any workable tie point, preferably one or more following groups, solely Group on the spot selected from halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl is taken Generation.
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferable cycloalkyl ring includes 3 to 10 carbon atoms.The non-limiting reality of monocyclic cycloalkyl Applying example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl Trialkenyl, cyclooctyl etc.
" aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared to adjoin The ring of carbon atom pair) group, preferably 6 to 10 yuan, such as phenyl and naphthalene.The aryl rings can be condensed in heteroaryl, miscellaneous In ring group or cycloalkyl ring, wherein being aryl rings with the ring that precursor structure links together.
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group group replaced.
" heteroaryl " refers to comprising 1 to 4 hetero atom, the heteroaromatic system of 5 to 14 annular atoms, and wherein hetero atom includes Oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.Heteroaryl is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl group, pyrroles Base, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed in aryl, heterocycle On base or cycloalkyl ring, wherein being heteroaryl ring with the ring that precursor structure links together.
Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyanogen Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group group It is replaced.
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted naphthenic base), and wherein alkyl is as defined above.Non- limit Property embodiment processed includes methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy Deng.Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following bases Group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, Naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group group taken Generation.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " is indicated containing one or more compounds of the present invention or its pharmaceutical salt or its prodrug With the mixture of other chemical constituents, for example pharmaceutical carrier of other chemical constituents and excipient.The purpose of pharmaceutical composition It is the absorption for promoting organism to active constituent, plays bioactivity in vivo conducive to active constituent.
Logical formula (I) compound of the present invention can be synthesized by following steps:
Condensation reaction occurs under strongly alkaline conditions for the compound and general formula compound (III) that logical formula (II) indicates, and General formula compound (I) is prepared in hydrolysis in the presence of alkali.
Wherein: R1~R5Definition as described in logical formula (I).
It include inorganic base and organic base as the alkali, the inorganic base can be mentioned that for example, alkali carbonate Class such as sodium carbonate, potassium carbonate, cesium carbonate etc.；Alkali metal hydrogencarbonate class such as saleratus etc.；Alkali metal hydroxide is for example Lithium hydroxide, sodium hydroxide, potassium hydroxide etc.；The organic base can be mentioned that for example triethylamine, pyridine, lutidines, N-BuLi, potassium tert-butoxide, sodium methoxide, sodium ethoxide etc..
The PPAR agonist activity of compound and internal hypoglycemic fat-regulating activity can be by using as described below in the present invention Measure system measurement.
The present invention is explained in following biology testing example description.
The experimental method of actual conditions usually routinely condition or is built according to commodity manufacturer in test case of the present invention The condition of view.The reagent in specific source is not specified, for the common agents of market purchase.
Agonist activity of 1 the compounds of this invention of test case to PPAR
The present invention measures the PPAR agonist activity of the compounds of this invention using following methods:
Transfection: before transfection, HEK293 cell is with 5 × 104The density in/hole is seeded to 96 orifice plates, is placed in 37 DEG C, 5%CO2's Cell incubator culture one day (being transfected for PPAR γ and PPAR δ)；HepG2 cell is with 6 × 104The density in/hole is seeded to 96 Orifice plate is placed in 37 DEG C, 5%CO2Cell incubator culture one day (being transfected for PPAR α)；FuGENE HD transfection is respectively adopted Reagent (being purchased from Roche) is transfected: 25ng/well pBIND-PPAR α or PPAR δ or PPAR γ, 25ng/well PG5Luc and 0.15 μ l/well FuGENE HD.
Agonist activity measurement: after transfection for 24 hours, test-compound being added in Transfected cells orifice plate, and temperature incubates 18h, is added 20 μ l cell pyrolysis liquids carry out cracking and 30 μ l Luciferase Assay reagent II (purchased from Promega company), mix, survey fluorescence, 2 Second delay, reads 10 seconds.Transfection efficiency is corrected using internal reference Renilla uciferase activity.All transfection experiments at least independently weigh Again three times, each experimental group at least two multiple holes.Relative intensity of fluorescence=firefly fluorescence intensity/Shen Shi fluorescence intensity.PPAR swashs Dynamic activity (%)=[(X-Min)/(Max-Min)] × 100%, wherein X indicates that compound group relative intensity of fluorescence, Min indicate Blank control group relative intensity of fluorescence, Max indicate the positive reference compound group relative intensity of fluorescence of 10 μM of concentration.Embodiment It closes object PPAR α, PPAR δ and PPAR γ agonist activity (being 10 μM of concentration) and is shown in Table 1.
Table 1:PPAR α, PPAR δ and PPAR γ agonist activity
Conclusion: all compounds of the present invention have apparent agonist activity to PPAR δ and PPAR γ, and show PPAR α Good selectivity out, wherein I-8, I-10, I-11, I-12, I-13 and I-14 are living with stronger PPAR gamma/delta double excitations Property.
The internal hypoglycemic fat-regulating activity of compound can be by using measurement system as described below in 2 present invention of test case Measurement:
8 week old ob/ob mouse, male, are randomly divided into 4 groups, and every group 6, blank control group (blank solvent: 0.5% carboxylic Methylcellulose sodium solution), blank solvent and tested chemical combination are given in stomach-filling to test-compound group (10mg/kg) respectively twice daily Object, successive administration 15 days, in the 15th day measurement Mouse oral glucose tolerance (OGTT) is administered, mouse was deprived of food but not water before testing 12 hours, docking took blood, measured blood glucose value (being denoted as -30min).Then blank solvent, positive drug and tested are given in stomach-filling respectively Compound, measurement blood glucose value is denoted as 0min after 30min is administered, and 3g/kg glucose solution is given in stomach-filling immediately later, and in 15,30,60,120min measurement blood glucose values.OGTT the results are shown in Table 2.And in the 16th day, mouse blood sampling takes blood plasma, automatically to give birth to It is horizontal to change analysis-e/or determining lipid of mice, the results are shown in Table 3.
Table 2: preferred compound to ob/ob mouse oral sugar tolerance influence (N=6)
Note: P≤0.05 * and P≤0.01 * * are Student ' the s t inspection result relative to blank control group.
It takes orally carbohydrate tolerance test after ob/ob mouse long term administration to show: compound I-10, I-11 and pharmaceutically acceptable sodium salt I-15 energy It is enough obviously improved the oral glucose tolerance of ob/ob mouse, shows preferable hypoglycemic effect.
Table 3: preferred compound to ob/ob lipid of mice level influence (N=6)
Note: P≤0.05 * is Student ' the s t inspection result relative to blank control group.
After ob/ob mouse long term administration blood lipid level influence the result shows that: compound I-10, I-11 and pharmaceutically acceptable sodium salt I-15 The elevated blood lipid levels of ob/ob mouse can be obviously improved, having improves lipid metaboli effect.
Specific embodiment
Below with reference to embodiment, the invention will be further described.It should be noted that following embodiments are only for It is bright, and it is not intended to limit the present invention.The various change that those skilled in the art's training centre according to the present invention is made should all be Within protection scope required by the claim of this application.
Embodiment 1
2- (4- ((- 2 (3H)-subunit of 6- methoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I-1)
6- methoxyl group -3- benzofuranone 1a (1.0g, 6.1mmol) and 2- (4- formoxyl -2,6- dimethyl phenoxy) Methyl acetate 2a (1.3g, 6.1mmol) is dissolved in ethyl alcohol/DMF (20mL, 1: 1, v/v) in the mixed solvent, and 2.3mL is added dropwise at room temperature 50%KOH aqueous solution drips and finishes room temperature reaction 4h, and after TLC detects fully reacting, reaction solution is poured into 30mL water, is vigorously stirred Under pH to 1-2 adjusted with concentrated hydrochloric acid, filtered after cooling, a small amount of cold water washs filter cake, and methanol/DMF (1: 1, v/v) is recrystallized to give Light yellow crystal 1.2g, yield 56%.
1H NMR (300MHz, DMSO-d6) δ: 7.75-7.62 (m, 3H), 7.13 (d, J=1.9Hz, 1H), 6.86,6.83 (dd, J=8.6,2.0Hz, 1H), 6.69 (s, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 2.31 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 181.96,170.43,168.45,167.01,157.19,147.18,132.37,131.50, 128.20,114.31,112.32,110.62,96.51,70.77,55.64,16.63.ESI-MS m/z:353.1 [M-H]- .Anal.calcd.For C20H18O6: C, 67.79；H, 5.12；Found:C, 67.54；H, 5.23.
Embodiment 2
2- (4- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I-2)
Referring to the preparation method of I-1, light yellow crystal 0.64g, yield 50% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.76-7.62 (m, 3H), 7.08 (s, 1H), 6.81 (d, J=8.5Hz, 1H), 6.68 (s, 1H), 4.45 (s, 2H), 4.22 (q, J=6.8Hz, 2H), 2.31 (s, 6H), 1.39 (t, J=6.8Hz, 3H) .13C NMR (75MHz, DMSO-d6) δ: 181.97,170.40,168.41,167.02,157.19,147.18,132.37, 131.50,128.20,114.31,112.32,109.64,100.35,69.37,65.04,16.61,14.78.ESI-MS m/z: 367.1[M-H]-.Anal.calcd.For C21H20O6: C, 68.47；H, 5.47；Found:C, 68.62；H, 5.31.
Embodiment 3
2- (4- ((- 2 (3H)-subunit of 6- propoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I-3)
Referring to the preparation method of I-1, light yellow crystal 0.49g, yield 35% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.76-7.63 (m, 3H), 7.11 (d, J=1.6Hz, 1H), 6.84,6.81 (dd, J=8.5,1.8Hz, 1H), 6.69 (s, 1H), 4.45 (s, 2H), 4.12 (t, J=6.5Hz, 2H), 2.31 (s, 6H), 1.85-1.73 (m, 2H), 1.01 (t, J=7.4Hz, 3H)13CNMR (75MHz, DMSO-d6) δ: 181.93,170.42, 167.20,162.52,157.15,147.20,132.37,131.53,128.32,114.31,112.32,109.64,99.99, 70.77,65.04,22.25,16.63,10.65.ESI-MS m/z:381.1 [M-H]-.Anal.calcd.For C22H22O6: C, 69.10；H, 5.80；Found:C, 69.35；H, 5.71.
Embodiment 4
2- (4- ((- 2 (3H)-subunit of 6- isobutoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) second Sour (I-4)
Referring to the preparation method of I-1, light yellow crystal 0.53g, yield 53% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.68-7.54 (m, 3H), 7.11 (d, J=1.7Hz, 1H), 6.87-6.76 (m, 1H), 6.68 (s, 1H), 4.45 (s, 2H), 3.94 (d, J=6.5Hz, 2H), 2.30 (s, 6H), 2.14-2.03 (m, 1H), 1.01 (d, J=6.7Hz, 6H)13C NMR (75MHz, DMSO-d6) δ: 181.95,170.46,167.23,162.56, 157.17,147.24,132.36,131.51,128.36,114.32,112.35,109.67,99.97,74.65,65.04, 28.36,19.59,16.65.ESI-MS m/z:395.1 [M-H]-.Anal.calcd.For C23H24O6: C, 69.68；H, 6.10；Found:C, 69.84；H, 6.31.
Embodiment 5
2- (4- ((- 2 (3H)-subunit of 6- cyclo propyl methoxy -3- oxo benzofuran) methyl) -2,6- dimethyl benzene oxygen Base) acetic acid (I-5)
Referring to the preparation method of I-1, light yellow crystal 0.37g, yield 45% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 12.85 (s, 1H), 7.66-7.56 (m, 3H), 7.09 (s, 1H), 6.83 (d, J=8.6Hz, 1H), 6.69 (s, 1H), 4.45 (s, 2H), 4.02 (d, J=5.7Hz, 2H), 2.31 (s, 6H), 0.87-0.81 (m, 1H), 0.65-0.58 (m, 2H), 0.42-0.36 (m, 2H)13C NMR (75MHz, DMSO-d6) δ: 181.98,170.38, 168.44,167.17,157.21,147.22,132.38,131.53,128.22,125.75,114.27,113.63,111.18, 97.94,73.89,69.40,16.62,10.28,3.59.ESI-MS m/z:393.1 [M-H]-.Anal.calcd.For C23H22O6: C, 70.04；H, 5.62；Found:C, 70.22；H, 5.43.
Embodiment 6
2- (the chloro- 4- of 2- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) phenoxy group) acetic acid (I-6)
Referring to the preparation method of I-1, light yellow crystal 0.47g, yield 41% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 8.08 (s, 1H), 7.88 (d, J=8.3Hz, 1H), 7.69-7.58 (m, 2H), 7.15 (s, 1H), 6.89-6.82 (m, 2H), 4.89 (s, 2H), 4.24 (q, J=5.9Hz, 2H), 1.39 (t, J= 5.9Hz, 3H)13C NMR (75MHz, DMSO-d6) δ: 181.79,169.75,168.83,166.25,153.73,146.35, 128.26,127.65,124.36,122.69,114.25,112.56,112.07,109.13,97.97,72.59,68.61, 14.82.ESI-MS m/z:373.1 [M-H]-.Anal.calcd.For C19H15ClO6: C, 60.89；H, 4.03；Found:C, 60.64；H, 4.17.
Embodiment 7
2- (4- ((- 2 (3H)-subunit of 6- methoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- Methylpropanoic acid (I-7)
Referring to the preparation method of I-1, light yellow crystal 1.46g, yield 48% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 12.79 (brs, 1H), 7.77-7.52 (m, 3H), 7.10 (s, 1H), 6.83 (d, J=7.4Hz, 1H), 6.67 (s, 1H), 3.93 (s, 3H), 2.25 (s, 6H), 1.42 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 170.30,164.68,154.03,152.84,150.78,140.81,130.14,128.73,128.62, 127.53,116.74,116.68,116.45,111.24,105.16,104.87,66.51,62.94,15.45.ESI-MS m/ Z:381.1 [M-H]-.Anal.calcd.For C22H22O6: C, 69.10；H, 5.80；Found:C, 69.35；H, 5.61.
Embodiment 8
2- (4- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- Methylpropanoic acid (I-8)
Referring to the preparation method of I-1, light yellow crystal 1.57g, yield 52% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 12.78 (brs, 1H), 7.79-7.42 (m, 3H), 7.08 (s, 1H), 6.81 (d, J=7.9Hz, 1H), 6.68 (s, 1H), 4.22 (d, J=6.3Hz, 2H), 2.25 (s, 6H), 1.41-1.21 (m, 9H)13C NMR (75MHz, DMSO-d6) δ: 170.35,164.63,154.05,152.87,150.74,140.85,130.19,128.76, 128.63,127.58,116.76,116.63,116.47,111.25,105.17,104.84,66.51,64.96,15.46, 14.82.ESI-MS m/z:395.1 [M-H]-.Anal.calcd.For C23H24O6: C, 69.68；H, 6.10；Found:C, 69.44；H, 6.25.
Embodiment 9
2- (4- ((- 2 (3H)-subunit of 6- (Carboxvmethoxv) -3- oxo benzofuran) methyl) -2,6- dimethyl benzene oxygen Base) -2 Methylpropionic acid (I-9)
Referring to the preparation method of I-1, light yellow crystal 0.42g, yield 32% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.80-7.59 (m, 3H), 7.14 (s, 1H), 6.87 (d, J=8.4Hz, 1H), 6.71 (s, 1H), 4.90 (s, 2H), 4.45 (s, 2H), 2.31 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 182.04,170.41,169.73,168.13,166.19,157.28,147.13,132.44,131.56,128.17,125.85, 111.44,98.42,98.07,69.40,65.77,16.63.ESI-MS m/z:425.1 [M-H]-.Anal.calcd.For C23H22O8: C, 64.78；H, 5.20；Found:C, 64.54；H, 5.46.
Embodiment 10
2- (2,6- dimethyl -4- ((- 2 (3H)-subunit of 3- oxo -6- propoxyl group benzofuran) methyl) phenoxy group) -2- Methylpropanoic acid (I-10)
Referring to the preparation method of I-1, light yellow crystal 3.05g, yield 47% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.69-7.56 (m, 3H), 7.09 (s, 1H), 6.80 (d, J=8.5Hz, 1H), 6.67 (s, 1H), 4.08 (t, J=6.5Hz, 2H), 2.24 (s, 6H), 1.81-1.68 (m, 2H), 1.38 (s, 6H), 0.98 (t, J=7.4Hz, 3H)13C NMR (75MHz, DMSO-d6) δ: 181.97,175.70,168.37,167.11,155.05, 147.13,133.77,132.11,127.80,125.74,114.25,113.53,111.26,97.79,81.67,70.70, 25.67,22.24,18.19,10.69.ESI-MS m/z:409.1 [M-H]-.Anal.calcd.For C24H26O6: C, 70.23； H, 6.38；Found:C, 70.45；H, 6.31.
Embodiment 11
2- (4- ((- 2 (3H)-subunit of 6- isobutoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) - 2 Methylpropionic acid (I-11)
Referring to the preparation method of I-1, light yellow crystal 1.36g, yield 42% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.68-7.55 (m, 3H), 7.10 (s, 1H), 6.81 (d, J=8.6Hz, 1H), 6.67 (s, 1H), 3.90 (d, J=6.3Hz, 2H), 2.23 (s, 6H), 2.06-1.97 (m, 1H), 1.39 (s, 6H), 0.99 (d, J=6.6Hz, 6H)13C NMR (75MHz, DMSO-d6) δ: 182.00,175.39,168.40,167.21,154.79, 147.19,133.73,132.16,127.98,125.77,114.25,113.57,111.18,97.83,81.26,75.27, 28.01,25.47,19.34,18.13.ESI-MS m/z:423.1 [M-H]-.Anal.calcd.For C25H28O6: C, 70.74； H, 6.65；Found:C, 70.56；H, 6.59.
Embodiment 12
2- (4- ((- 2 (3H)-subunit of 6- butoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- Methylpropanoic acid (I-12)
Referring to the preparation method of I-1, light yellow crystal 0.85g, yield 44% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.69-7.57 (m, 3H), 7.11 (s, 1H), 6.80 (d, J=8.6Hz, 1H), 6.67 (s, 1H), 4.13 (t, J=6.4Hz, 2H), 2.22 (s, 6H), 1.78-1.66 (m, 2H), 1.53-1.41 (m, 2H), 1.38 (s, 6H), 0.93 (t, J=7.5Hz, 3H)13C NMR (75MHz, DMSO-d6) δ: 182.02,175.35, 168.42,167.18,154.78,147.18,133.74,132.16,127.97,125.79,114.21,113.61,111.20, 97.82,81.25,69.03,30.87,25.46,19.09,18.13,14.09.ESI-MS m/z:423.2 [M-H]- .Anal.calcd.For C25H28O6: C, 70.74；H, 6.65；Found:C, 70.85；H, 6.77.
Embodiment 13
2- (4- ((- 2 (3H)-subunit of 6- (cyclo propyl methoxy) -3- oxo benzofuran) methyl) -2,6- dimethyl benzene Oxygroup) -2 Methylpropionic acid (I-13)
Referring to the preparation method of I-1, light yellow crystal 1.62g, yield 53% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.70-7.58 (m, 3H), 7.07 (s, 1H), 6.81 (d, J=8.6Hz, 1H), 6.67 (s, 1H), 3.98 (d, J=6.9Hz, 2H), 2.23 (s, 6H), 1.37 (s, 6H), 1.22-1.15 (m, 1H), 0.64-0.56 (m, 2H), 0.40-0.31 (m, 2H)13C NMR (75MHz, DMSO-d6) δ: 181.99,175.74,168.39, 167.08,147.14,133.79,132.12,127.80,125.74,114.18,113.66,111.28,97.78,81.68, 73.90,25.67,18.18,10.26,3.65.ESI-MS m/z:421.1 [M-H]-.Anal.calcd.For C25H26O6: C, 71.07；H, 6.20；Found:C, 71.15；H, 6.27.
Embodiment 14
2- (4- ((- 2 (3H)-subunit of 6- (isoamoxy) -3- oxo benzofuran) methyl) -2,6- dimethyl benzene oxygen Base) -2 Methylpropionic acid (I-14)
Referring to the preparation method of I-1, light yellow crystal 0.56g, yield 38% are obtained.
1H NMR (300MHz, DMSO-d6) δ: 7.69-7.53 (m, 3H), 7.11 (s, 1H), 6.79 (d, J=8.6Hz, 1H), 6.67 (s, 1H), 4.14 (t, J=6.1Hz, 2H), 2.25 (s, 6H), 1.67-1.58 (m, 2H), 1.32 (s, 6H), 1.21-1.11 (m, 1H), 0.91 (d, J=6.6Hz, 6H)13CNMR (75MHz, DMSO-d6) δ: 181.95,177.52, 174.53,168.33,167.08,156.25,146.91,134.08,131.94,127.08,114.32,113.56,111.68, 97.79,84.24,67.82,37.56,26.71,25.04,23.57,22.82,18.47.ESI-MS m/z:437.1 [M-H]- .Anal.calcd.For C26H30O6: C, 71.21；H, 6.90；Found:C, 71.45；H, 6.79.
Embodiment 15
2- (2,6- dimethyl -4- ((- 2 (3H)-subunit of 3- oxo -6- propoxyl group benzofuran) methyl) phenoxy group) -2- Methyl sodium propionate (I-15)
Compound I-10 (1.5g) is added portionwise into saturated aqueous sodium carbonate (10mL), is stirred at room temperature for 24 hours, filters, A small amount of water washing filter cake, filtration cakes torrefaction obtain faint yellow solid 1.23g.
Embodiment 16
The tablet of the I-8 containing activating agent:
Active constituent, pregelatinized starch and microcrystalline cellulose are sieved, are sufficiently mixed, it is molten that polyvinylpyrrolidone is added Liquid, mixing, softwood processed, sieving, wet granular processed, in 50-60 DEG C of drying, by Sodium carboxymethyl starch, magnesium stearate and talcum powder The compression molding into above-mentioned particle is added in sieving.
Verified, above-mentioned composition also has excellent internal hypoglycemic fat-regulating effect.

Claims (7)

1. a kind of logical formula (I) compound represented or its pharmaceutical salt:
Wherein:
R1And R2Be each independently selected from hydrogen, alkyl, wherein the alkyl optionally further by one or more selected from halogen, hydroxyl, Cyano, nitro, alkyl, alkoxy, naphthenic base group replaced；
R3And R4It is each independently selected from hydrogen, alkyl, alkoxy, halogen, naphthenic base；
R5Selected from hydrogen, alkyl, naphthenic base, wherein the alkyl, naphthenic base are optionally further selected from halogen, hydroxyl by one or more Base, cyano, nitro, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) OR6、-OC(O)R6、-C(O)R6、- NHC(O)R6、-NR7R8、-OC(O)NR7R8、-NHC(O)NR7R8Or-S (O)2R7Group replaced；
R6Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, heterocycle, Aryl or heteroaryl each independently optionally further by one or more selected from alkyl, halogen, hydroxyl, alkoxy, naphthenic base, Heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced；
R7Or R8It is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, ring Alkyl, heterocycle, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, alkane by one or more each independently Oxygroup, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced.
2. having the compound or its pharmaceutical salt of logical formula (I) defined in claim 1:
R1And R2Be each independently selected from hydrogen, alkyl, wherein the alkyl optionally further by one or more selected from hydroxyl, alkyl, Alkoxy, naphthenic base group replaced；
R3And R4It is each independently selected from hydrogen, alkyl, halogen；
R5Selected from hydrogen, alkyl, naphthenic base, wherein the alkyl, naphthenic base are optionally further selected from hydroxyl, cyanogen by one or more Base, nitro, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl ,-C (O) OR6、-OC(O)R6、-C(O)R6、-NHC (O)R6、-NR7R8、-OC(O)NR7R8、-NHC(O)NR7R8Or-S (O)2R7Group replaced；
R6Selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, naphthenic base, heterocycle, Aryl or heteroaryl each independently optionally further by one or more selected from alkyl, halogen, hydroxyl, alkoxy, naphthenic base, Heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced；
R7Or R8It is each independently selected from hydrogen atom, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkyl, ring Alkyl, heterocycle, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, alkane by one or more each independently Oxygroup, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced.
3. leading to formula (I) compound defined in claim 2 or its pharmaceutical salt, the compound being selected from:
2- (4- ((- 2 (3H)-subunit of 6- methoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I- 1)；
2- (4- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I- 2)；
2- (4- ((- 2 (3H)-subunit of 6- propoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I- 3)；
2- (4- ((- 2 (3H)-subunit of 6- isobutoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) acetic acid (I-4)；
2- (4- ((- 2 (3H)-subunit of 6- cyclo propyl methoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) second Sour (I-5)；
2- (the chloro- 4- of 2- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) phenoxy group) acetic acid (I-6)；
2- (4- ((- 2 (3H)-subunit of 6- methoxyl group -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- methyl Propionic acid (I-7)；
2- (4- ((- 2 (3H)-subunit of 6- ethyoxyl -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- methyl Propionic acid (I-8)；
2- (4- ((- 2 (3H)-subunit of 6- (Carboxvmethoxv) -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) - 2 Methylpropionic acid (I-9)；
2- (2,6- dimethyl -4- ((- 2 (3H)-subunit of 3- oxo -6- propoxyl group benzofuran) methyl) phenoxy group) -2- methyl Propionic acid (I-10)；
2- (4- ((- 2 (3H)-subunit of 6- isobutoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- first Base propionic acid (I-11)；
2- (4- ((- 2 (3H)-subunit of 6- butoxy -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- methyl Propionic acid (I-12)；
2- (4- ((- 2 (3H)-subunit of 6- (cyclo propyl methoxy) -3- oxo benzofuran) methyl) -2,6- dimethyl benzene oxygen Base) -2 Methylpropionic acid (I-13)；
2- (4- ((- 2 (3H)-subunit of 6- (isoamoxy) -3- oxo benzofuran) methyl) -2,6- dimethyl phenoxy) -2- Methylpropanoic acid (I-14)；
2- (2,6- dimethyl -4- ((- 2 (3H)-subunit of 3- oxo -6- propoxyl group benzofuran) methyl) phenoxy group) -2- methyl Sodium propionate (I-15).
4. compound defined in claim 1-3 any one or its pharmaceutical salt are as PPAR gamma/delta dual agonists Purposes.
5. a kind of pharmaceutical composition contains compound or pharmaceutically acceptable salt thereof and carrier appropriate described in one of claim 1-3 Or excipient.
6. compound defined in claim 1-5 any one or its pharmaceutical salt or its pharmaceutical composition are prevented in preparation Or/and treatment abnormal glucose metabolism or/and abnormalities of sugar/lipid metabolism disease drug in purposes.
7. compound defined in claim 1-5 any one or its pharmaceutical salt or its pharmaceutical composition are prevented in preparation Or/and in the metabolic syndromes related disease such as treatment diabetes, obesity, hyperlipidemia, atherosclerosis and fatty liver at least A kind of purposes in the drug of disease.
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WO2021036514A1 (en) * 2018-12-07 2021-03-04 广东药科大学 PPAR γ/δ DUAL AGONIST, PREPARATION METHOD THEREOF AND USE THEREOF IN PREPARING A DRUG
CN110240537A (en) * 2019-05-22 2019-09-17 成都阿奇生物医药科技有限公司 A kind of indenes fluoroacetic acid class compound and its preparation method and application
CN110240537B (en) * 2019-05-22 2022-06-21 成都阿奇生物医药科技有限公司 Indene oxyacetic acid compound and preparation method and application thereof
CN112028773A (en) * 2019-06-04 2020-12-04 南昌弘益科技有限公司 Diester compound of PPAR protein activator
CN112028773B (en) * 2019-06-04 2023-08-04 南昌弘益科技有限公司 Diester compounds of PPAR protein activator
CN110452231A (en) * 2019-08-16 2019-11-15 上海应用技术大学 A kind of tryptophan class compound and its preparation method and application
CN110452231B (en) * 2019-08-16 2023-03-28 上海应用技术大学 Tryptophan compound and preparation method and application thereof
CN113801075A (en) * 2020-06-15 2021-12-17 四川大学 1- (3, 4-disubstituted phenyl) piperazine skeleton derivative and application thereof in preparation of medicines
CN114853686A (en) * 2021-08-23 2022-08-05 中国药科大学 Triazole ketone compound and medical application thereof
CN116332887A (en) * 2023-01-19 2023-06-27 天津科技大学 Synthesis method and application of orange ketone derivatives with nonalcoholic steatohepatitis resistance
CN116332887B (en) * 2023-01-19 2024-08-13 天津科技大学 Synthesis method and application of orange ketone derivatives with nonalcoholic steatohepatitis resistance

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