CN107522657A - A kind of compound with the multiple agonist activities of PPAR and its preparation method and application - Google Patents
A kind of compound with the multiple agonist activities of PPAR and its preparation method and application Download PDFInfo
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- CN107522657A CN107522657A CN201710900298.5A CN201710900298A CN107522657A CN 107522657 A CN107522657 A CN 107522657A CN 201710900298 A CN201710900298 A CN 201710900298A CN 107522657 A CN107522657 A CN 107522657A
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- ppar
- acid
- metabolic syndrome
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a kind of compound with the multiple agonist activities of PPAR and its preparation method and application, the compound has chemical constitution shown in formula I：
Description
Technical field
The present invention is to be related to a kind of compound with the multiple agonist activities of PPAR and its preparation method and application, belonging to
Learn pharmaceutical technology field.
Background technology
The World Health Organization announces, and about 20%-25% adult suffers from metabolic syndrome in world wide at present,
70%-80% diabetic suffers from metabolic syndrome, and up to 86% type ii diabetes patient is diagnosed as metabolic disorder.
Research shows：The increased weight of people and no motion of life style can cause the insulin resistance of adipocyte, cause increasingly
More people suffers from metabolic syndrome (Diabetes＆Metabolic Syndrome Clinical Research＆Reviews
[J],2015,9(2):124-126).Metabolic syndrome (Journal of relevant with internal glucose metabolism disorders
Diabetes&Metabolic Disorders[J],2014,13(1):1-7), it is to cause obesity, central obesity, insulin
Hazards (the Clinical Laboratory [J], 2013,59 (3-4) of resistance, dyslipidemia and hypertension:369-374),
Simultaneously also it is related to the Other diseases such as periodontitis (Journal of Clinical Periodontology [J], 2013,40
(6):599-606).It can be seen that metabolic syndrome turns into a kind of serious disease for threatening human health.
Peroxisome proliferation-activated receptors (peroxisome proliferator-activated
Receptors, PPARs) be ligand activation transcription factor core by superfamily member, 3 kinds of hypotypes be present, i.e.,：PPAR α, β, γ,
The specificity that different PPARs hypotypes are convened due to respective Tissue distribution, activation part and common confactor, its function also have
Difference, their effect are relative to each other, and incomplete same.Research shows：1. PPAR- α are mainly expressed in liver, muscle, huge
(Circulation Research [J], 2000.87 (6) in the tissue such as phagocyte:516-521)；PPAR- α pass through part knot
Close, influence liver lipid-metabolism (Journal of Molecular Graphics and Modelling [J], 2014,51:27-
36)；Medicine the most classical is fibrate in PPAR- α synthesis type activators, and it is high sweet to be clinically used to treatment extensively
Oily three ester diseases.2. PPAR- β/δ distribution is very extensive in vivo, in liver, kidney, skeletal muscle, stomach fat and vascular smooth muscle
Have in cell expression (Biochimica Et Biophysica Acta Molecular Basis of Disease [J],
2005,1740(2):313-317)；So can not be connected with definite clinical disease, therefore clinically there is no at present
PPAR- β/δ excited type ligand drugs；But research finds that disorders of lipid metabolism can be improved, adjust cholesterol by activating PPAR- β/δ
Outflow, Bone m etabolism and insulin sensitivity etc. (The mechanism of protein synthesis [J], 2002,53:
409-435).3. PPAR- γ height is expressed in adipocyte, spleen, adrenal gland and colon, low expression is in liver, skeletal muscle, kidney
In dirty, blood vessel and brain (Endocrinology [J], 1996,137:354-366), it is medicine target the most ripe studied at present
Point, it plays important adjustment effect in the propagation and atomization and its insulin sensitivity of various kinds of cell.
In terms of the treatment of metabolic syndrome, the antidiabetic drug of Clinical practice or lipid-lowering medicine effect are single at present, it is impossible to simultaneously
Adjust glycolipid metabolism.Research shows：Dual or triple PPARs activators can act on lipid-metabolism and the side of insulin two simultaneously
Face, it can more effectively improve metabolic syndrome, there is provided the effect (Cardiovascular of broader spectrum for the treatment of Metabolic Syndrome
Diabetology[J],2005,4(1):14).Therefore, compound pair of the screening with dual or triple PPARs agonist activities
Prevention and/or treatment metabolic disorder class disease have important value.
The content of the invention
In view of the above-mentioned problems existing in the prior art, it is an object of the invention to provide one kind to have the multiple agonist activities of PPAR
Compound and its preparation method and application, screen a kind of new medicine to prevent and/or treating metabolic disorder class disease.
Compound of the present invention with the multiple agonist activities of PPAR, there is chemical constitution shown in formula I：
A kind of method for preparing the compound of the present invention with the multiple agonist activities of PPAR, comprises the following steps：
A) parahydroxyben-zaldehyde is made with reacting mehtoxybenzyl chlorine, to obtain the compound of formula II in the presence of a base；
B) 3- methoxyl group -4- bromanilines are made with acetonitrile reaction, to obtain the compound of formula III in the presence of a catalyst；
C) compound of formula II is reacted in the presence of a base with the compound of formula III, obtain the compound of formula IV；
D) make the compound of formula IV that addition reaction occur in the presence of a catalyst, obtain the compound of formula V；
E) make the compound of formula V that Suzuki occur with isopentene group boric acid pinacol ester in the presence of palladium catalyst and alkali even
Connection reaction, obtains the compound of formula VI；
F) compound of formula VI is made to take off PMB protection groups (i.e. under acid catalysis：To methoxy-benzyl), obtain type I compound；
Its specific reaction scheme is as follows：
Preferably, the alkali in step a) is inorganic base, the preferred carbonate of inorganic base, such as potassium carbonate, carbon
Sour sodium.
Preferably, the reaction dissolvent in step a) is non-alcohols organic solvent, selected from dichloromethane, chloroform, second
Any one in nitrile, DMF, THF, preferably DMF.
Preferably, the parahydroxyben-zaldehyde in step a) is with being 1 to the mol ratio of mehtoxybenzyl chlorine:1.
Preferably, the reaction temperature in step a) is 0~30 DEG C, more preferably 20~30 DEG C.
Preferably, the catalyst in step b) is boron chloride and alchlor.
As further preferred scheme, step b) concrete operations are as follows：It is molten that 3- methoxyl group -4- bromanilines are dissolved in reaction
After agent, boron chloride is first slowly added at 0~5 DEG C, after addition, alchlor and acetonitrile is slow added into, has fed
Bi Hou, first in room temperature reaction 10~60 minutes, 65~75 DEG C of reactions are then heated to until reaction terminates.
As further preferred scheme, the mol ratio of boron chloride and alchlor is 1:1；3- methoxyl group -4- bromanilines
Mol ratio with alchlor is 1:1~1:2.
Preferably, the reaction dissolvent in step b) is dichloromethane or chloroform.
Preferably, the mol ratio of 3- methoxyl group -4- bromanilines and acetonitrile is 1 in step b):1~1:3.
Preferably, the alkali in step c) is inorganic base, inorganic base preferred sodium hydroxide, potassium hydroxide or the hydrogen
Lithia.
Preferably, the reaction dissolvent in step c) is alcohol organic solvent, such as：Methanol, ethanol, propyl alcohol etc..
Preferably, the reaction temperature in step c) is 50~70 DEG C.
Preferably, the mol ratio of the compound of step c) Chinese styles II and the compound of formula III is 1:2~2:1.
Preferably, the catalyst in step d) is lewis acid, the preferred antimony trichloride of lewis acid.
Preferably, the reaction dissolvent in step d) be acetonitrile, DMF, DMSO, toluene, THF, in chloroform at least
It is a kind of.
Preferably, the reaction temperature in step d) is 55~85 DEG C.
Preferably, the palladium catalyst in step e) is selected from Pd (dppf)2Cl2、PdCl2(PPh3)2、Pd(PPh3)4
In any one, preferably Pd (dppf)2Cl2。
Preferably, the alkali in step e) is inorganic base, the inorganic base be selected from sodium carbonate, potassium carbonate, cesium carbonate,
Any one in potassium phosphate, potassium acetate, it is preferable with cesium carbonate.
Preferably, the reaction dissolvent in step e) is selected from DMF, DMSO, toluene, THF, dioxane, toluene, first
At least one of alcohol, ethanol.
Preferably, the reaction temperature in step e) is 60~80 DEG C.
Preferably, the acid in step f) is p-methyl benzenesulfonic acid.
Preferably, the reaction temperature in step f) is 50~70 DEG C.
With the compound of the present invention with the multiple agonist activities of PPAR or its pharmaceutically acceptable salt, mutually variation
At least one of structure body, stereoisomer, precursor compound, hydrate or solvate are used as active component, available for making
The standby medicine or health food treated and/or prevent metabolic syndrome.
Furtherly, the metabolic syndrome includes abnormal glucose metabolism and/or abnormalities of sugar/lipid metabolism disease.
Furtherly, the metabolic syndrome is included in diabetes, obesity, hyperlipemia and atherosclerosis
At least one disease.
In addition, medicine of the present invention can give patient with various methods of administration, including but not limited to oral, transdermal,
Muscle, subcutaneous and intravenous injection.
The formulation of medicine of the present invention is unlimited, all may be used as long as active component can be made effectively to reach internal formulation
With, including：Tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid,
Mouth containing agent, granule, electuary, pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, ointment,
Emplastrum, creme, spray, drops, patch etc.；It is preferred that peroral dosage form, such as：Capsule, tablet, oral liquid, granule, ball
Agent, powder, sublimed preparation, paste etc..
In medicine of the present invention, in addition to containing main active, also containing a small amount of and do not influence effectively
Auxiliary material etc. necessary to the submember and/or pharmaceutically acceptable carrier and various preparations of composition.For example, the medicine
For peroral dosage form when, contain conventional excipient, such as adhesive, filler, diluent, tablet agent, lubricant, disintegration
Agent, colouring agent, flavor enhancement and wetting agent, tablet can be coated if necessary.Suitable filler includes cellulose, mannose
Alcohol, lactose and other similar fillers；Suitable disintegrant includes starch, polyvinylpyrrolidone and starch derivatives, example
Such as sodium starch glycollate；Suitable lubricant includes, such as magnesium stearate；Suitable pharmaceutically acceptable wetting agent includes ten
Sodium dialkyl sulfate.
Heretofore described term is defined as follows：
Term " pharmaceutically acceptable salt " refers to the compound and pharmaceutically acceptable inorganic acid or organic acid institute
The salt of formation, described inorganic acid include but is not limited to：Hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid；Described organic acid includes
But it is not limited to：Formic acid, acetic acid, propionic acid, succinic acid, 1,5- naphthalenedisulfonic acids, asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid,
Benzoic acid, valeric acid, diethacetic acid, malonic acid, butanedioic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, amino
Sulfonic acid, benzenpropanoic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, citric acid, and amino acid；
" pharmaceutically acceptable " refer to be applied to people and without excessive bad side reaction (such as toxicity, stimulation and allergy), i.e.,
Have rational benefit/risk than material.
Term " dynamic isomer " refer to because in molecule a certain atom in two rapid movements in position and caused by functional group
Isomers, such as：Enol and corresponding ketone.
Term " stereoisomer " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule, example
Such as：Cis-trans-isomer, enantiomter, rotamer etc..
Term " precursor compound " refer to it is inactive in vitro, but can be metabolized or be chemically reacted in vivo turn
The active component of the present invention is turned to, so as to play the compound of its pharmacological action.
Compared with prior art, the present invention has following conspicuousness beneficial effect：
The result of study of the present invention is shown：Type I compound of the present invention is remarkably improved PPAR α, β and γ transcription
Activity, there is PPAR α, the multiple agonist activity of β, γ, it is expected to be used to prepare prevention and/or treatment Metabolic syndrome as active component
The medicine or health food of disease, especially it is expected to be used to prepare prevention and/or treatment abnormal glucose metabolism and/or lipid-metabolism is different
The medicine or health food of normal disease, have wide application prospect and notable medical value.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Embodiment 1：The preparation of the compound of formula II
Parahydroxyben-zaldehyde (3.7g, 30.0mmol) and potassium carbonate (12.4g, 90.0mmol) are added in DMF (40mL),
After dissolving is stirred at room temperature, it is slowly dropped into mehtoxybenzyl chlorine (3.5g, 30.0mmol), (about 20~25 DEG C) reactions 12 of room temperature
Hour, terminate reaction, add saturation NaCl solution and reaction is quenched, then add ethyl acetate extraction, until extraction is complete, merge
Organic phase, organic phase anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure into no solution and distillate, obtain white powder material, as formula
II compound (is named as：4- is to mehtoxybenzyl hydroxy-benzaldehyde)：6.2g, 25.6mmol, molar yield 85.3%.
Embodiment 2：The preparation of the compound of formula III
3- methoxyl group -4- bromanilines (6.0g, 30.0mmol) are dissolved in dichloromethane (30mL), cooled down under condition of ice bath
To 0 DEG C, BCl is slowly added dropwise at 0 DEG C3Dichloromethane solution (1.0mol/L, 33mL), insulated and stirred half an hour, then at 0 DEG C
Under be slowly added to AlCl3(4.4g, 33.0mmol) and CH3CN (3.2mL, 60.0mmol), after charging, first stir at room temperature
Reaction half an hour is mixed, then rises to 70 DEG C of insulation reactions 12 hours, terminates reaction, adding 2N HCL after reaction solution cooling is quenched instead
(the process reaction liquid of hydrochloric acid should be added and can be emitted and much steeped in vain, be slowly added to as far as possible under 0 DEG C of condition of ice bath), then stirred in 70 DEG C
Mix 2 hours, after being cooled to room temperature, add 1N NaHCO3Solution adjusts solution to neutrality, then adds dichloromethane extraction, directly
It is complete to extraction, merge organic phase, organic phase anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure into no solution and distillate, residue
With silica gel column chromatography (cyclohexane/EA 50:1) purify, obtain brownish-yellow powder material, the as compound of formula III (name
For：2- amino-4-methoxyl -5- bromoacetophenones)：3.7g, 15.2mmol, molar yield 50.7%.
After tested：
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)。
Embodiment 3：The preparation of the compound of formula IV
The compound of formula II (1.7g, 6.5mmol) and the compound of formula III (1.2g, 5.0mmol) are added into absolute ethyl alcohol
In (20mL), sodium hydrate solid (800.0mg, 20.0mmol) is then added, after charging, it is small to be warming up to 60 DEG C of reactions 12
When, terminate reaction, reaction solution is cooled to room temperature, filters, filter cake washs with ethanol, dry after, obtain yellow powder material, be
The compound of formula IV (is named as：1- (2'- amino -4'- methoxyl group -5'- bromines) -3- (4'- methoxy-benzyls methyl phenyl ethers anisole) -2E- third
Alkene -1- ketone)：2.2g, 4.66mmol, molar yield 93.2%.
After tested：
1H NMR(300MHz,CDCl3) δ 8.00 (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)。
Embodiment 4：The preparation of the compound of formula V
The compound of formula IV (933.0mg, 1.99mmol) is added in anhydrous acetonitrile (15mL), antimony trichloride is then added and consolidates
Body (136.8mg, 0.6mmol), after charging, it is warming up to reflux state and reacts 6 hours, terminate reaction, reaction solution is cooled to
Room temperature, filtering, filter cake use is scrubbed, after drying, obtains pale yellow powder material, the as compound of formula V (is named as：2,3-
The bromo- 7- methoxyl groups -4H-1- quinoline -4- ketone of dihydro -2- (4'- methoxy-benzyls methyl phenyl ethers anisole) -6-)：495.0mg 1.06mmol,
Molar yield is 53.3%.
After tested：
1H NMR(400MHz,CDCl3) δ 8.04 (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。
Embodiment 5：The preparation of the compound of formula VI
The compound of formula V (468.0mg, 1.0mmol) is dissolved in anhydrous dimethyl formamide (15mL), adds palladium chtalyst
Agent Pd (dppf)2Cl2(Chinese name：[double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex) solid
(245.0mg, 0.3mmol) and cesium carbonate solid (977.5mg, 3.0mmol), reaction solution is warming up to 70 under the conditions of anhydrous and oxygen-free
DEG C, it is slowly dropped into isopentene group boric acid pinacol ester (also known as 3- methyl-2-butene ylboronic acid pinacol esters, CAS#141550-
13-2,0.59mL, 2.5mmol), charging is finished after 70 DEG C of insulation reactions 12 hours, terminates reaction, reaction solution is cooled to room
Temperature, adds saturation NaCl solution and reaction is quenched, and then adds ethyl acetate and extracts, and repeatedly extraction is until extraction completely, is associated with
Machine phase, organic phase anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure into no solution and distillate, residue silica gel column chromatography
(cyclohexane/EA 20:1) purify, obtain pale yellow powder material, the as compound of formula VI (is named as：2,3- dihydros-
2- (4'- methoxy-benzyls methyl phenyl ethers anisole) -6- isopentene group -7- methoxyl group -4H-1- quinoline -4- ketone)：198.0mg 0.43mmol,
Molar yield is 43.0%.
After tested：
1H NMR(500MHz,CDCl3) δ 7.63 (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。
Embodiment 6：The preparation of type I compound
The compound of formula VI (110.0mg, 0.25mmol) is added into (THF:MeOH volume ratios 1:1) in dicyandiamide solution 4mL, so
P-methyl benzenesulfonic acid solid (215.0mg, 1.25mmol) is added afterwards, after charging, reaction solution is warming up to 60 DEG C and reacted 30 minutes,
Terminate reaction, reaction solution is cooled to room temperature, adds saturation NaCl solution and reaction is quenched, and then adds ethyl acetate extraction, repeatedly
Extraction is complete up to extraction, merges organic phase, organic phase anhydrous sodium sulfate drying, filters, be concentrated under reduced pressure into no solution and distillate,
Residue is purified with silica gel column chromatography, obtains pale yellow powder material, and as type I compound (is named as：2,3- dihydros -2-
(4'- hydroxy phenyls) -6- isopentene group -7- methoxyl group -4H-1- quinoline -4- ketone)：18.0mg, 0.05mmol, molar yield are
21.3%.
After tested：
1H NMR(500MHz,CD3OD) δ 7.47 (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]+；Corresponding compound point
Minor is C21H23NO3。
Embodiment 7：Utilize influence of the luciferase reporter gene method analysis type I compound to PPAR transcriptional activities
Reporter gene detects influence of the compound of formula I to PPAR transcriptional activities.Inventor is using PPAR full-length genes and matches somebody with somebody
Shadow of the two kinds of plasmid detection compounds of body binding domain (ligand binding domain, LBD) to nuclear receptor transcription factor active
Ring；After being transfected into 293T cells, through pharmaceutical intervention 24h, its firefly luciferase activity is detected；And use jellyfish fluorescent
Plain enzymatic activity does transfection efficiency control.
(1) 293T cell culture
293T cell lines (human embryonic kidney cell line) are used containing 10% calf serum and 1% dual anti-DMEM high glucose mediums in 37
DEG C, 5%CO2Cultivated in incubator.Take the logarithm the 293T plating cells in growth period, cell density is 1 × 105~2 × 105Individual/mL
It is plated in 48 orifice plates.
(2) transfected plasmids are supplied
PCMX-Gal-mPPAR γ LBD plasmids, PPAR α-LBD plasmids, PPAR β-LBD plasmids, Gal4reporter
Vector MH100 × 4-TK-Luc recombinant plasmids and renilla luciferase internal reference plasmids；PPAR γ total length plasmids；
PPAR α total length plasmids；PPAR β total length plasmids.
Above-mentioned plasmid construction refers to document：Biochemical and Biophysical Research
Communications2006(348):571-578；Cell Metabolism.2(2005)239-249；
J.Biol.Chem.272(1997)18779-1878；Cell 83(1995)803-812.
(3) transfect
Overnight, when the density of cell length to 50~80%, transfected.Prepared and transfected with DMEM (serum-free is without dual anti-)
System：Total plasmid containing 10 μ g in every milliliter of DMEM, and 15 μ L transfection reagent-FuGENE HD【Roche】, so
Rotaring redyeing system is vortexed afterwards and mixed, and room temperature places 15min, then by rotaring redyeing system cotransfection in 293T cells, with complete
Culture medium (DMEM, 10%FBS, 1% are dual anti-) continues culture to 24h.
(4) dosing intervention
After 24h, various concentrations gradient (0.01,0.1,0.3,1,3,10,30 μM) that addition complete medium dilutes
Compound of formula I or various concentrations gradient (0.001,0.01,0.1,1, the 3,10 μM) Rosiglitazone diluted with complete medium are (special
Different in nature PPAR gamma agonists) or various concentrations gradient PPAR alfa agonists fenofibrate (0.001,0.01,0.1,1,3,10 μM)
Intervened or the PPAR beta-agonists GW7647 of various concentrations gradient (0.001,0.01,0.1,1,3,10 μM) is intervened.
(5) cell is handled
1. 24h, remove remaining cell culture fluid with PBS cell twice；
2. adding 65 μ L lysate per hole, shaking table vibration 15min, treat that cell cracking is complete, cell pyrolysis liquid is shifted
Into 1.5mL centrifuge tubes；
3. cell pyrolysis liquid is centrifuged into 5min in 1000rpm, the μ L of supernatant 10 are taken in new centrifuge tube, it is to be measured.
(6) measure and analysis of fluorescence element enzyme intensity
1. the plus liquid of LAR II【Purchased from Promega companies】20 μ l, mix, survey fluorescence, postpone within 2 seconds, read 10 seconds.Transfection effect
Rate is corrected using internal reference Renilla uciferase activities.In triplicate, each experimental group is at least for all transfection experiments at least independence
2 secondary orifices.
2. utilizing Bio-Tek, Synergy HT multi-function microplate readers carry out firefly and the detection of ocean coelenteron fluorescence intensity.
Fluc expression intensity represents with the ratio of firefly fluorescent and ocean coelenteron fluorescence intensity, relative intensity of fluorescence=
Firefly fluorescence intensity/ocean coelenteron fluorescence intensity, i.e., it is using the additional medicine of luciferase relative expression's active reaction mainly
It is no by being combined with PPARs acceptor generating functions to influence PPARs transcriptional activities.
(7) data analysis
Data analysis is carried out using software SPSS16.0, the otherness of different intervention groups compares using one-way analysis of variance
(ANOVA), p<0.05 thinks that group difference has statistical significance, and calculates eachization using software GraphPad Prism 6
The EC of compound intervention group50Value.
(8) experimental result
Experimental result is as shown in Table 1 and Table 2.
1 different compounds of table are to PPARs transcriptional activity (activation %, 25 μM)
| Compound | 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 |
| Compound of formula I | 9.04±1.43 | 4.98±0.79 | 35.45±7.49 |
Medium effective concentration value (EC of the compound of formula I of table 2 to PPAR transcriptional activities50Value, μM)
| 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 |
Visible with reference to Tables 1 and 2, compound of formula I of the present invention shows significant excitement to PPAR α, β, γ
Activity, there is PPAR α, the multiple agonist activity of β, γ.
Due to it is existing there are some researches show：The multiple activators of PPARs can act on lipid-metabolism and the aspect of insulin two, energy simultaneously
Effectively improve metabolic syndrome, there is provided the effect of broader spectrum for the treatment of Metabolic Syndrome, therefore, with formula of the present invention
I or its pharmaceutically acceptable salt, dynamic isomer, stereoisomer, precursor compound, hydrate or solvate
At least one of be used as active component, available for prepare treatment and/or prevention metabolic syndrome medicine or health food, especially
It is expected for preparing prevention and/or treatment abnormal glucose metabolism and/or the medicine of abnormalities of sugar/lipid metabolism disease and health care food
Product, there is wide application prospect and notable medical value.
Finally need it is pointed out here that be：It the above is only the part preferred embodiment of the present invention, it is impossible to be interpreted as to this hair
The limitation of bright protection domain, those skilled in the art according to the present invention the above make some it is nonessential improvement and
Adjustment belongs to protection scope of the present invention.
Claims (9)
1. a kind of compound with the multiple agonist activities of PPAR, it is characterised in that there is chemical constitution shown in formula I：
A kind of 2. method for preparing the compound with the multiple agonist activities of PPAR described in claim 1, it is characterised in that bag
Include following steps：
A) parahydroxyben-zaldehyde is made with reacting mehtoxybenzyl chlorine, to obtain the compound of formula II in the presence of a base；
B) 3- methoxyl group -4- bromanilines are made with acetonitrile reaction, to obtain the compound of formula III in the presence of a catalyst；
C) compound of formula II is reacted in the presence of a base with the compound of formula III, obtain the compound of formula IV；
D) make the compound of formula IV that addition reaction occur in the presence of a catalyst, obtain the compound of formula V；
E) make the compound of formula V that Suzuki couplings occur with isopentene group boric acid pinacol ester in the presence of palladium catalyst and alkali anti-
Should, obtain the compound of formula VI；
F) compound of formula VI is taken off PMB protection groups under acid catalysis, obtain type I compound；
Its specific reaction scheme is as follows：
3. according to the method for claim 2, it is characterised in that：Alkali in step a) is inorganic base.
4. according to the method for claim 2, it is characterised in that：Catalyst in step b) is boron chloride and tri-chlorination
Aluminium.
5. according to the method for claim 2, it is characterised in that：Alkali in step c) is inorganic base, the catalysis in step d)
Agent is lewis acid.
6. according to the method for claim 2, it is characterised in that：Palladium catalyst in step e) is selected from Pd (dppf)2Cl2、
PdCl2(PPh3)2、Pd(PPh3)4In any one；Acid in step f) is p-methyl benzenesulfonic acid.
A kind of 7. application of the compound with the multiple agonist activities of PPAR described in claim 1, it is characterised in that：With formula I
Shown compound or its pharmaceutically acceptable salt, dynamic isomer, stereoisomer, precursor compound, hydrate or solvent
At least one of compound is used as active component, for preparing the medicine or health food for the treatment of and/or prevention metabolic syndrome.
8. application according to claim 7, it is characterised in that：The metabolic syndrome include abnormal glucose metabolism and/
Or abnormalities of sugar/lipid metabolism disease.
9. application according to claim 8, it is characterised in that：The metabolic syndrome includes diabetes, obesity, high blood
At least one of fat disease and atherosclerosis disease.
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| CN104109144A (en) * | 2013-04-16 | 2014-10-22 | 上海中医药大学 | PPAR alpha/gamma dual agonist and its application |
| CN105982884A (en) * | 2015-02-25 | 2016-10-05 | 上海中医药大学 | Application of bavachinin and analogs of bavachinin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104109144A (en) * | 2013-04-16 | 2014-10-22 | 上海中医药大学 | PPAR alpha/gamma dual agonist and its application |
| CN105982884A (en) * | 2015-02-25 | 2016-10-05 | 上海中医药大学 | Application of bavachinin and analogs of bavachinin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023172845A1 (en) * | 2022-03-08 | 2023-09-14 | Flare Therapeutics Inc. | Pparg inverse agonists and uses thereof |
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