CN107522657B - Compound with PPAR (peroxisome proliferator activated receptor) multiple agonistic activity and preparation method and application thereof - Google Patents

Compound with PPAR (peroxisome proliferator activated receptor) multiple agonistic activity and preparation method and application thereof Download PDF

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CN107522657B
CN107522657B CN201710900298.5A CN201710900298A CN107522657B CN 107522657 B CN107522657 B CN 107522657B CN 201710900298 A CN201710900298 A CN 201710900298A CN 107522657 B CN107522657 B CN 107522657B
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ppar
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郭夫江
李医明
赵圆圆
易婧羽
黄诚
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Shanghai University of Traditional Chinese Medicine
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a compound with PPAR multiple agonistic activity, a preparation method and an application thereof, wherein the compound has a chemical structure shown in a formula I:

Description

Compound with PPAR (peroxisome proliferator activated receptor) multiple agonistic activity and preparation method and application thereof
Technical Field
The invention relates to a compound with PPAR multiple agonistic activity, a preparation method and application thereof, belonging to the technical field of chemical medicine.
Background
The world health organization promulgates that currently about 20% -25% of adults worldwide suffer from metabolic syndrome, 70% -80% of diabetics suffer from metabolic syndrome, and up to 86% of type II diabetics are diagnosed with metabolic disorders. The research shows that: the increase in body weight and immotile lifestyle in humans causes insulin resistance in adipocytes, resulting in an increasing number of people suffering from Metabolic Syndrome (Diabetes & Metabolic Syndrome Research & Reviews [ J ],2015,9(2): 124-. Metabolic syndrome is associated with disturbances of glucose metabolism in the body (Journal of diabetes & Metabolic Disorders [ J ],2014,13(1):1-7), is a risk factor for obesity, central obesity, insulin resistance, dyslipidemia and hypertension (Clinical Laboratory [ J ],2013,59(3-4): 369-. It can be seen that metabolic syndrome has become a serious disease threatening the health of humans.
Peroxisome proliferator-activated receptors (PPARs) are members of The ligand-activated transcription factor nuclear superfamily, and there are 3 subtypes, i.e., PPAR α, β and gamma, different PPARs have different functions due to The specificity of respective tissue distribution, activated ligand and co-cofactor recruitment, and The effects are related to each other and are not completely The same, The study shows that ① PPAR- α is mainly expressed in tissues such as liver, muscle and macrophage (Circulation Research [ J ],2000.87(6): 865) and PPAR- α influences liver lipid metabolism by ligand binding (Journal of Molecular Graphics and modeling [ J ], 201427-36 ], The most classical drug among PPAR- α synthetic agonists is The class of drugs, which is widely used for treating hypertriglyceridemia [ ② -cholesterol and model ] and plays a role in regulating liver lipid metabolism in vivo, and kidney lipid metabolism [ 12: 27-36 ], The study shows that PPAR- α synthetic type drugs are clinically important drugs, i.e. The drugs are clinically relevant drugs for treating hypertriglyceridemia, PPAR-cholesterol, calcium metabolism, calcium.
In the aspect of treatment of metabolic syndrome, the hypoglycemic drugs or lipid-lowering drugs used clinically at present have single effect and cannot simultaneously regulate glycolipid metabolism. The research shows that: double or triple agonists of PPARs act on both lipid metabolism and insulin, and are more effective in ameliorating metabolic syndrome, providing a broader spectrum of therapeutic effects on metabolic syndrome (Cardiovasular diabetes [ J ],2005,4(1): 14). Therefore, screening of compounds with dual or triple PPARs agonistic activity is of great value for prevention and/or treatment of metabolic disorder diseases.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a compound with PPAR multiple agonist activity, a preparation method and an application thereof, and a new drug is screened for preventing and/or treating metabolic disorder diseases.
The compound with PPAR multiple agonistic activity has a chemical structure shown in a formula I:
Figure BDA0001423008820000021
a method for preparing a compound having PPAR multiple agonist activity according to the present invention, comprising the steps of:
a) reacting p-hydroxybenzaldehyde with p-methoxybenzyl chloride in the presence of alkali to obtain a compound shown in a formula II;
b) reacting 3-methoxy-4-bromoaniline with acetonitrile in the presence of a catalyst to obtain a compound of formula III;
c) reacting a compound of formula II with a compound of formula III in the presence of a base to obtain a compound of formula IV;
d) carrying out addition reaction on a compound shown in the formula IV in the presence of a catalyst to obtain a compound shown in the formula V;
e) carrying out Suzuki coupling reaction on a compound shown in a formula V and isopentenyl pinacol borate in the presence of a palladium catalyst and alkali to obtain a compound shown in a formula VI;
f) the compound of formula vi is deprotected under acid catalysis to PMB (i.e.: p-methoxybenzyl) to give the compound of formula i;
the specific reaction route is as follows:
Figure BDA0001423008820000031
preferably, the base in step a) is an inorganic base, preferably a carbonate, such as potassium carbonate, sodium carbonate.
Preferably, the reaction solvent in step a) is a non-alcoholic organic solvent selected from any one of dichloromethane, chloroform, acetonitrile, DMF and THF, preferably DMF.
Preferably, the molar ratio of p-hydroxybenzaldehyde to p-methoxybenzyl chloride in step a) is 1: 1.
Preferably, the reaction temperature in step a) is 0 to 30 ℃, and more preferably 20 to 30 ℃.
Preferably, the catalyst in the step b) is boron trichloride and aluminum trichloride.
As a further preferred scheme, the specific operation of the step b) is as follows: dissolving 3-methoxy-4-bromoaniline in a reaction solvent, slowly adding boron trichloride at 0-5 ℃, slowly adding aluminum trichloride and acetonitrile after the addition is finished, reacting at room temperature for 10-60 minutes after the addition is finished, and then heating to 65-75 ℃ for reaction until the reaction is finished.
As a further preferable scheme, the molar ratio of the boron trichloride to the aluminum trichloride is 1: 1; the molar ratio of the 3-methoxy-4-bromoaniline to the aluminum trichloride is 1: 1-1: 2.
Preferably, the reaction solvent in step b) is dichloromethane or trichloromethane.
Preferably, the molar ratio of the 3-methoxy-4-bromoaniline to the acetonitrile in the step b) is 1:1 to 1: 3.
Preferably, the base in step c) is an inorganic base, preferably sodium hydroxide, potassium hydroxide or lithium hydroxide.
Preferably, the reaction solvent in step c) is an alcoholic organic solvent, such as: methanol, ethanol, propanol, and the like.
Preferably, the reaction temperature in the step c) is 50-70 ℃.
Preferably, the molar ratio of the compound of formula II to the compound of formula III in step c) is 1:2 to 2: 1.
Preferably, the catalyst in step d) is a Lewis acid, and the Lewis acid is preferably antimony trichloride.
Preferably, the reaction solvent in step d) is at least one of acetonitrile, DMF, DMSO, toluene, THF, and chloroform.
Preferably, the reaction temperature in the step d) is 55-85 ℃.
Preferably, the palladium catalyst in step e) is selected from Pd (dppf)2Cl2、PdCl2(PPh3)2、Pd(PPh3)4Any one of (1), preferably Pd (dppf)2Cl2。
Preferably, the base in step e) is an inorganic base, and the inorganic base is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and potassium acetate, preferably cesium carbonate.
Preferably, the reaction solvent in step e) is at least one selected from DMF, DMSO, toluene, THF, dioxane, toluene, methanol, ethanol.
Preferably, the reaction temperature in the step e) is 60-80 ℃.
Preferably, the acid in step f) is p-toluenesulfonic acid.
Preferably, the reaction temperature in the step f) is 50-70 ℃.
The compound with PPAR multiple agonistic activity or at least one of pharmaceutically acceptable salt, tautomer, stereoisomer, precursor compound, hydrate or solvate thereof can be used as an active ingredient for preparing medicines or health-care foods for treating and/or preventing metabolic syndrome.
Further, the metabolic syndrome includes diseases of abnormal glucose metabolism and/or abnormal lipid metabolism.
Further, the metabolic syndrome includes at least one of diabetes, obesity, hyperlipidemia, and atherosclerosis.
In addition, the agents of the present invention may be administered to a patient by a variety of routes of administration, including, but not limited to, oral, transdermal, intramuscular, subcutaneous, and intravenous injection.
The dosage form of the drug of the present invention is not limited as long as it is a dosage form that enables the active ingredient to efficiently reach the body, and includes: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches and the like; oral dosage forms are preferred, such as: capsule, tablet, oral liquid, granule, pill, powder, pellet, and unguent.
The medicine of the invention can contain minor ingredients which do not affect the effective components and/or pharmaceutically acceptable carriers and auxiliary materials necessary for various preparations besides the main active components. For example, when the drug is in an oral dosage form, it may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablets may be coated if necessary. Suitable fillers include cellulose, mannitol, lactose and other similar fillers; suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate; suitable lubricants include, for example, magnesium stearate; suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
The terms described in the present invention are defined as follows:
the term "pharmaceutically acceptable salt" refers to salts of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; such organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, 1, 5-naphthalenedisulfonic acid, sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids; by "pharmaceutically acceptable" is meant a material that is suitable for use in humans without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.
The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in a molecule at two positions, for example: enols and the corresponding ketones.
The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, such as: cis-trans isomers, enantiomers, conformers, and the like.
The term "precursor compound" refers to a compound which is inactive in vitro, but can be converted into the active ingredient of the present invention by metabolic or chemical reaction in vivo, thereby exerting its pharmacological effect.
Compared with the prior art, the invention has the following remarkable beneficial effects:
the research result of the invention shows that the compound of the formula I can obviously improve the transcription activity of PPAR α, β and gamma, has multiple agonist activities of PPAR α, β and gamma, is expected to be used as an active ingredient for preparing a medicament or health-care food for preventing and/or treating metabolic syndrome, is especially expected to be used for preparing a medicament or health-care food for preventing and/or treating glucose metabolism disorder and/or lipid metabolism disorder diseases, and has wide application prospect and obvious medicinal value.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1: preparation of Compounds of formula II
Figure BDA0001423008820000061
Adding p-hydroxybenzaldehyde (3.7g,30.0mmol) and potassium carbonate (12.4g,90.0mmol) into DMF (40mL), stirring at room temperature for dissolving, slowly dropping p-methoxybenzyl chloride (3.5g,30.0mmol), reacting at room temperature (about 20-25 ℃) for 12 hours, finishing the reaction, adding saturated NaCl solution for quenching reaction, adding ethyl acetate for extraction until the extraction is complete, combining organic phases, drying the organic phases with anhydrous sodium sulfate, performing suction filtration, and concentrating under reduced pressure until no solution is distilled off to obtain a white powder substance, namely a compound (named as 4-p-methoxybenzyl hydroxy-benzaldehyde) of a formula II: 6.2g, 25.6mmol, molar yield 85.3%.
Example 2: preparation of Compounds of formula III
Figure BDA0001423008820000062
3-methoxy-4-bromoaniline (6.0g,30.0mmol) was dissolved in dichloromethane (30mL), cooled to 0 ℃ under ice bath conditions, and BCl was slowly added dropwise at 0 ℃3Dichloromethane solution (1.0mol/L, 33mL), stirred for half an hour with heat preservation, then AlCl was added slowly at 0 deg.C3(4.4g,33.0mmol) and CH3CN (3.2mL,60.0mmol), stirring at room temperature for half an hour after the addition is finished, then heating to 70 ℃, keeping the temperature and reacting for 12 hours, finishing the reaction, adding 2N HCL after the reaction liquid is cooled to quench the reaction (the reaction liquid can emit a plurality of white bubbles during the addition of hydrochloric acid and is slowly added under the condition of ice bath at 0 ℃), then stirring at 70 ℃ for 2 hours, cooling to room temperature, adding 1N NaHCO3Adjusting the solution to neutrality, extracting with dichloromethane until extraction is complete, mixing organic phases, drying with anhydrous sodium sulfate, vacuum filtering, concentrating under reduced pressure until no solution is distilled off, and purifying the residue with silica gel column chromatography (cyclohexane/EA 50:1) to obtainTo a brown yellow powder, i.e., a compound of formula III (designated as: 2-amino-4-methoxy-5-bromoacetophenone): 3.7g, 15.2mmol, molar yield 50.7%.
Through the test:
1H NMR(300MHz,CDCl3)δ7.85(s,1H,ArH),6.48(s,2H,NH2),6.10(s,1H,ArH),3.89(s,3H,ArOCH3),2.53(s,3H,COCH3)。
example 3: preparation of Compounds of formula IV
Figure BDA0001423008820000063
Adding a compound (1.7g,6.5mmol) of a compound shown in a formula II and a compound (1.2g,5.0mmol) of a compound shown in a formula III into absolute ethyl alcohol (20mL), then adding sodium hydroxide solid (800.0mg,20.0mmol), after the addition is finished, heating to 60 ℃ for reaction for 12 hours, finishing the reaction, cooling the reaction liquid to room temperature, filtering, washing a filter cake with ethanol, and drying to obtain a yellow powder substance, namely a compound shown in a formula IV (named as 1- (2 '-amino-4' -methoxy-5 '-bromo) -3- (4' -methoxy benzyl anisol) -2E-propylene-1-one): 2.2g, 4.66mmol, molar yield 93.2%.
Through the test:
1H NMR(300MHz,CDCl3)δ8.00(s,1H,ArH),7.70(d,J＝15.3Hz,1H,＝H),7.59(d,J＝8.4Hz,2H,ArH),7.44–7.33(m,3H,＝H/ArH),6.96(dd,J＝21.1,8.3Hz,4H,ArH),6.59(s,2H,NH2),6.13(s,1H,ArH),5.04(s,2H,OCH2),3.89(s,3H,ArOCH3),3.82(s,3H,ArOCH3)。
example 4: preparation of Compounds of formula V
Figure BDA0001423008820000071
Adding a compound (933.0mg,1.99mmol) in the formula IV into anhydrous acetonitrile (15mL), adding antimony trichloride solid (136.8mg,0.6mmol), after the addition is finished, heating to a reflux state for reaction for 6 hours, finishing the reaction, cooling a reaction liquid to room temperature, filtering, washing a filter cake, and drying to obtain a light yellow powder substance, namely the compound (named as 2, 3-dihydro-2- (4' -methoxybenzyl anisole) -6-bromo-7-methoxy-4H-1-quinolin-4-one) in the formula V: 495.0mg, 1.06mmol, 53.3% molar yield.
Through the test:
1H NMR(400MHz,CDCl3)δ8.04(s,1H,ArH),7.35(dd,J＝8.5,5.7Hz,4H,ArH),6.95(dd,J＝22.2,8.7Hz,4H,ArH),6.13(s,1H,ArH),5.00(s,2H,OCH2),4.67(dd,J＝13.6,3.9Hz,1H,H-2),4.54(s,1H,NH),3.87(s,3H,OCH3),3.82(s,3H,OCH3),2.81(dd,J＝16.3,13.5Hz,1H,H-3),2.69(dd,J＝16.4,3.8Hz,1H,H-3)；
13C NMR(125MHz,DMSO-d6)δ190.0,160.1,158.9,157.9,153.4,133.3,130.4,129.4,128.9,127.9,114.8,113.8,112.7,99.2,98.2,68.9,56.2,55.4,55.1,44.5。
example 5: preparation of Compounds of formula VI
Figure BDA0001423008820000081
The compound of formula V (468.0mg,1.0mmol) was dissolved in anhydrous dimethylformamide (15mL), and the palladium catalyst Pd (dppf) was added2Cl2(Chinese name: [1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride dichloromethane complex) solid (245.0mg,0.3mmol) and cesium carbonate solid (977.5mg,3.0mmol), heating the reaction solution to 70 ℃ under anhydrous and oxygen-free conditions, slowly dropping isopentenyl pinacol ester borate (also known as 3-methyl-2-butenyl pinacol ester, CAS #141550-13-2, 0.59mL,2.5mmol), keeping the temperature at 70 ℃ after the addition is finished, reacting for 12 hours, finishing the reaction, cooling the reaction solution to room temperature, adding saturated NaCl solution to quench the reaction, then adding ethyl acetate to extract for multiple times until the extraction is complete, combining organic phases, drying the organic phases with anhydrous sodium sulfate, performing suction filtration, concentrating under reduced pressure until no solution is distilled out, purifying the remainder by silica gel column chromatography (cyclohexane/EA 20:1) to obtain a light yellow powder substance, namely the compound of formula VI (named: 2, 3-dihydro-2- (4' -methoxybenzyl anisole) -6-isopentenyl-7-methoxy-4H-1-quinolin-4-one): 198.0mg,0.43mmol, 43.0% molar yield.
Through the test:
1H NMR(500MHz,CDCl3)δ7.63(s,1H,ArH),7.35(dd,J＝8.6,4.2Hz,4H,ArH),6.94(dd,J＝24.0,8.6Hz,4H,ArH),6.07(s,1H,ArH),5.26(t,J＝7.3Hz,1H,＝H),4.99(s,2H,OCH2),4.64(dd,J＝13.8,3.5Hz,1H,H-2),4.41(s,1H,NH),3.81(s,3H,OCH3),3.80(s,3H,OCH3),3.19(d,J＝7.3Hz,2H,＝CH2),2.78(dd,J＝16.1,13.9Hz,1H,H-3),2.65(dd,J＝16.2,2.7Hz,1H,H-3),1.72(s,3H,＝CH3),1.69(s,3H,＝CH3)；
13C NMR(125MHz,Chloroform-d3)δ191.6,163.2,159.0,158.3,151.8,133.10,132.0,128.7,128.3,127.6,127.3,121.8,121.6,114.7,113.6,112.1,95.7,69.4,57.8,55.0,54.8,45.8,27.3,25.4,17.3。
example 6: preparation of Compounds of formula I
Figure BDA0001423008820000082
The compound of formula VI (110.0mg,0.25mmol) was added (THF: MeOH volume ratio 1:1) to 4mL of the solvent system followed by p-toluenesulfonic acid solid (215.0mg,1.25mmol) and, after the addition was complete, heating the reaction solution to 60 ℃ for reaction for 30 minutes, finishing the reaction, cooling the reaction solution to room temperature, adding saturated NaCl solution to quench the reaction, then adding ethyl acetate for extraction, extracting for multiple times until the extraction is complete, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, performing suction filtration, concentrating under reduced pressure until no solution is distilled off, and purifying the residue by using a silica gel column chromatography to obtain a light yellow powder substance, namely the compound (named as 2, 3-dihydro-2- (4' -hydroxyphenyl) -6-isopentenyl-7-methoxy-4H-1-quinolin-4-one) shown in the formula I: 18.0mg,0.05mmol, molar yield 21.3%.
Through the test:
1H NMR(500MHz,CD3OD)δ7.47(s,1H,ArH),7.31(d,J＝8.5Hz,2H,ArH),6.81(d,J＝8.5Hz,2H,ArH),6.31(s,1H,ArH),5.29–5.22(m,1H,＝H),4.60(dd,J＝13.4,4.1Hz,1H,H-2),3.84(s,3H,OCH3),3.17(d,J＝7.3Hz,2H,＝CH2),2.76(dd,J＝16.2,13.4Hz,1H,H-3),2.58(dd,J＝16.2,4.1Hz,1H,H-3),1.75(s,3H,＝CH3),1.70(s,3H,＝CH3)；
13C NMR(125MHz,CD3OD)δ193.6,164.3,156.9,154.3,132.3,131.8,127.5,126.7,122.2,120.8,114.9,111.2,95.8,57.5,54.6,45.5,27.2,24.5,16.3；
ESI-MS LR(m/z):338.2[M+H]+；ESI-MS HR(m/z):338.1761[M+H]+(ii) a The molecular formula of the corresponding compound is C21H23NO3。
Example 7: analysis of the Effect of Compounds of formula I on PPAR transcriptional Activity Using the Dual luciferase reporter Gene method
The reporter gene measures the effect of the compounds of formula I on PPAR transcriptional activity. The inventor uses two plasmids of PPAR full-length gene and Ligand Binding Domain (LBD) to detect the influence of the compound on the activity of nuclear receptor transcription factor; after the luciferase gene is transfected into 293T cells, the firefly luciferase activity is detected after pharmaceutical intervention for 24 h; and jellyfish luciferase activity was used as a control for transfection efficiency.
(1)293T cell culture
293T cell line (human embryonic kidney cell line) was cultured in DMEM high-sugar medium containing 10% calf serum and 1% diabody at 37 ℃ and 5% CO2Taking 293T cells in logarithmic growth phase and plating, wherein the cell density is 1 × 105～2×105one/mL was plated in 48-well plates.
(2) Plasmid for transfection
pCMX-Gal-mPPARgamma LBD plasmid, PPAR α -LBD plasmid, PPAR β -LBD plasmid, Gal4reportervector MH100 × 4-TK-Luc recombinant plasmid and renilla luciferase internal reference plasmid, PPAR gamma full-length plasmid, PPAR α full-length plasmid and PPAR β full-length plasmid.
The above plasmid construction can be referred to: biochemical and Biophysical research communications2006(348): 571-578; cell metabolism.2(2005) 239-249; j.biol.chem.272(1997) 18779-1878; cell 83(1995) 803-.
(3) Transfection
And (4) standing overnight, and performing transfection when the cells grow to 50-80% of the density. The transfection system was formulated with DMEM (serum-free and double antibody-free): 10 μ g of total plasmid was contained in DMEM per ml, and 15 μ L of transfection reagent-FuGENE HD [ Roche ], then the transfection system was vortexed and left at room temperature for 15min, then the transfection system was co-transfected into 293T cells, and the culture was continued up to 24h with complete medium (DMEM, 10% FBS, 1% double antibody).
(4) Intervention in dosing
After 24h, the intervention was performed with different concentration gradients (0.01, 0.1, 0.3, 1, 3, 10, 30 μ M) of the compound of formula I diluted with complete medium or different concentration gradients (0.001, 0.01, 0.1, 1, 3, 10 μ M) rosiglitazone (specific PPAR γ agonist) or different concentration gradients of the PPAR α agonist fenofibrate (0.001, 0.01, 0.1, 1, 3, 10 μ M) or different concentration gradients of the PPAR β agonist GW7647(0.001, 0.01, 0.1, 1, 3, 10 μ M).
(5) Cell processing
① 24h, washing the cells twice with PBS, and removing the rest cell culture solution;
② adding 65 μ L lysis solution into each well, shaking for 15min, transferring the cell lysis solution into 1.5mL centrifuge tube when the cell lysis is complete;
③ the cell lysate is centrifuged at 1000rpm for 5min, and 10. mu.L of the supernatant is taken to a new centrifuge tube and assayed.
(6) Determination and analysis of luciferase intensity
① Add LARII solution [ purchased from Promega ] 20. mu.l, mix well, measure fluorescence, 2 second delay, read 10 seconds transfection efficiency corrected using internal reference Renilla luciferase activity all transfection experiments were repeated at least three times independently with at least 2 replicate wells per experimental group.
② fluorescence intensity detection of firefly and marine coelenterates is carried out by using Bio-Tek, Synergy HT multifunctional enzyme labeling instrument, the luciferase expression intensity of firefly is expressed by the ratio of the fluorescence intensity of firefly to the fluorescence intensity of marine coelenterates, and the relative fluorescence intensity is the fluorescence intensity of firefly/the fluorescence intensity of marine coelenterates, namely, the relative expression activity of luciferase is mainly used to reflect whether the transcription activity of PPARs is influenced by the functional combination of external drugs and PPARs receptors.
(7) Data analysis
Data analysis was performed using software SPSS16.0, and single factor analysis of variance (ANOVA), p, was used for the differential comparisons between different intervention groups<0.05 statistical differences between groups were considered and EC for each compound intervention group was calculated using the software GraphPad Prism 650The value is obtained.
(8) Results of the experiment
The results of the experiment are shown in tables 1 and 2.
TABLE 1 transcriptional Activity of different compounds on PPARs (activation%; 25. mu.M)
Compound (I) PPAR-α-LBD PPAR-β-LBD PPAR-γ-LBD
Fenofibric acid 12.13±3.42 - -
GW7647 - 55.91±17.17 -
Pioglitazone - - 41.52±4.16
A compound of formula I 9.04±1.43 4.98±0.79 35.45±7.49
TABLE 2 half-value Effective Concentration (EC) of the PPAR transcriptional activity of the compounds of formula I50Value, μ M)
PPAR-α-LBD，EC50(μM) PPAR-β-LBD，EC50(μM) PPAR-γ-LBD，EC50(μM)
22.58±2.35 3.54±1.49 65.33±28.64
As can be seen from table 1 and table 2, the compound of formula I according to the present invention shows significant agonistic activity to PPAR α, β and γ, and has PPAR α, β and γ multiple agonistic activity.
As the existing research shows that: the PPARs multiple agonists can simultaneously act on both lipid metabolism and insulin, can effectively improve metabolic syndrome and provide a wider spectrum of action for treating metabolic syndrome, so that the compound of the formula I or at least one of pharmaceutically acceptable salts, tautomers, stereoisomers, precursor compounds, hydrates or solvates thereof can be used as an active ingredient for preparing medicaments or health-care foods for treating and/or preventing metabolic syndrome, particularly the medicaments and health-care foods for preventing and/or treating glucose metabolism disorder and/or lipid metabolism disorder diseases, and has wide application prospect and obvious medicinal value.
Finally, it should be pointed out here that: the above is only a part of the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention, and the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above description are intended to be covered by the present invention.

Claims (9)

1. A compound having PPAR α, β and gamma triple agonist activities, which is characterized by having a chemical structure shown as a formula I:
Figure FDA0002378877930000011
2. a method for preparing a compound having PPAR α, β and gamma triple agonist activities of claim 1, comprising the steps of:
a) reacting p-hydroxybenzaldehyde with p-methoxybenzyl chloride in the presence of alkali to obtain a compound shown in a formula II;
b) reacting 3-methoxy-4-bromoaniline with acetonitrile in the presence of a catalyst to obtain a compound of formula III;
c) reacting a compound of formula II with a compound of formula III in the presence of a base to obtain a compound of formula IV;
d) carrying out addition reaction on a compound shown in the formula IV in the presence of a catalyst to obtain a compound shown in the formula V;
e) carrying out Suzuki coupling reaction on a compound shown in a formula V and isopentenyl pinacol borate in the presence of a palladium catalyst and alkali to obtain a compound shown in a formula VI;
f) removing the PMB protecting group from the compound shown in the formula VI under the catalysis of acid to obtain a compound shown in the formula I;
the specific reaction route is as follows:
Figure FDA0002378877930000012
3. the method of claim 2, wherein: the base in step a) is an inorganic base.
4. The method of claim 2, wherein: the catalyst in the step b) is boron trichloride and aluminum trichloride.
5. The method of claim 2, wherein: the base in step c) is an inorganic base and the catalyst in step d) is a lewis acid.
6. The method of claim 2, wherein: the palladium catalyst in step e) is selected from Pd (dppf)2Cl2、PdCl2(PPh3)2、Pd(PPh3)4Any one of the above; the acid in step f) is p-toluenesulfonic acid.
7. The application of the compound with PPAR α, β and gamma triple agonistic activity as claimed in claim 1 is characterized in that the compound shown in formula I or the pharmaceutically acceptable salt thereof is used as an active ingredient for preparing the medicines or health-care foods for treating and/or preventing metabolic syndrome.
8. Use according to claim 7, characterized in that: the metabolic syndrome comprises diseases of glucose metabolism disorder and/or lipid metabolism disorder.
9. Use according to claim 8, characterized in that: the metabolic syndrome includes at least one of diabetes, obesity, hyperlipidemia, and atherosclerosis.
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WO2023014861A1 (en) * 2021-08-05 2023-02-09 Flare Therapeutics Inc. Pparg inverse agonists and uses thereof
WO2023078252A1 (en) * 2021-11-02 2023-05-11 Flare Therapeutics Inc. Pparg inverse agonists and uses thereof

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