CN105503856B - A kind of chromone substituted tetrahydrothiazole dione compounds and its application for treating diabetes medicament - Google Patents
A kind of chromone substituted tetrahydrothiazole dione compounds and its application for treating diabetes medicament Download PDFInfo
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Abstract
A kind of application the invention discloses chromone substituted tetrahydrothiazole dione compounds and its for treating diabetes medicament, there is below formula I structure：Wherein, it is benzyl that X, which is selected from NH or O, n=0 or 1, Bn, belongs to medicinal chemistry art.The compound of the present invention confirms through cell experiment and zoopery, can be applied to part activation PPAR gamma activities and has less adverse reaction, to treat the type ii diabetes as target.
Description
Technical field
The present invention relates to medicines technical field, and in particular to a kind of chromone substituted tetrahydrothiazole dione compounds and its
For treating the application of diabetes medicament.
Background technology
Diabetes are common disease in crowd, high morbidity, are with high caused by hypoinsulinism or insulin resistance
The incretion metabolism disease that blood glucose is characterized, turn into the third-largest harm human health for being only second to angiocardiopathy and cancer
Disease.Peroxidase increment activated receptor (PPARs：Peroxisome proliferators-activated
Receptors) it is one of nuclear receptor superfamily member for finding after the 1990s.By with lipophilic small molecule aglucon
With reference to conformational change is caused, as a result these protein complex activate, and can induce or suppress the gene of modulation difference physiology course, such as
Lipid is formed, fat and glycometabolism etc..Therefore PPAR turns into the important target for the treatment of diabetes.PPAR has three kinds of hypotype alpha, gammas,
β/δ.Wherein PPAR γ are mainly expressed in white adipose tissue, also there is a certain amount of expression in skeletal muscle, participate in aliphatic acid
Intake and the transcription of fat storage gene.PPAR γ can promote the differentiation of PECTORAL LIMB SKELETON after being activated, it is thin to increase small fat
The quantity of born of the same parents, so as to strengthen the sensitiveness to insulin, improve insulin resistance, while PPAR gamma agonists can also stimulate fat
The metabolism of free fatty and glucose in fat tissue and skeletal muscle.
Thiazolidinedione (TZD classes) para-insulin sensitizer is the Typical Representative of PPAR γ parts, is controlling for Clinical practice
The common drug of type ii diabetes is treated, is PPAR γ full agonist.But research shows that activation will cause body weight completely for it
Increase, water retention, bone density reduce, pulmonary edema, aggravate or cause the secondary effects such as congestive heart failure.Military field pharmacy is up to
Research in 10 years shows, long-term use of insulin sensitizer Pioglitazone, patients' carcinoma of urinary bladder risk can be caused to raise.Therefore,
Development activity is higher, and safer PPAR gamma portion activators have important clinical significance.
Natural products is the important source that reactive compound is found.Traditional Chinese medicine is the precious deposits that the Nature assigns the mankind, is passed through
The virtual screening discovery to natural products storehouse is crossed, flavone derivative has higher affinity with PPAR γ.Traditional medicine is
Verified, flavone compound possesses relatively low toxicity, is widely present in veterinary antibiotics, red wine and soya bean.Other flavones category
In nuclear receptor family member's activator, the eutectic compound structure of itself and ERs (ER), nuclear receptor (NR) had been taken off already
Show.Nearer research also shows that NASH (NAFLD) and insulin resistance, type ii diabetes etc. are closely related.With
Flavones shows higher PPAR γ agonist activity for the silymarin-group hepatoprotective agent of skeleton.These researchs illustrate flavones pole
PPAR γ activation part may be act as, promotes corresponding regulation mechanism.
At present, research and development of the major drugmaker of the world to PPAR gamma portion activators are not off, and many reports go out successively
Existing, mainly using the afterbody of single or double lipophilic, as basic framework, structural similarity is big on acid head in addition, lacks novelty；Often with
Carboxylic acid as hydrophilic parts, stronger hydrogen bond action easily with H323, H449, Y473 in PPAR γ-LBD (ligand binding domain)
With reference to so as to cause complete excitement, inducing serial toxic side effect, the novel pharmacophore of structure is urgently developed；It is all clinical at present
The PPAR activators to fail in preceding or clinic are simple PPAR gamma agonists, and these activators too activate PPAR γ, from
And induce serial toxic side effect.Consider above mentioned problem, using the flavones of smaller toxic side effect as basic framework, pass through computer
Virtual screening, the chromocor derivative that there is higher affinity with PPAR γ-LBD is searched, is tested by chemical synthesis and inside and outside,
It is that those skilled in the art have the problem of to be solved to seek more safe and efficient PPAR gamma portions activator.
The content of the invention
For the deficiency of existing thiazolidinedione (TZD classes) para-insulin sensitizer, it is an object of the invention to provide one kind
Chromone substituted tetrahydrothiazole dione compounds, and its for treating the application of diabetes medicament.
Specifically, chromone substituted tetrahydrothiazole dione compounds of the present invention, as led to the chromone shown in formula (I)
Substituted tetrahydrothiazole diketone derivative：
Wherein X is selected from nitrogen hydrogen (NH) or oxygen (O), and Bn is benzyl, and n is 0~1 integer.
Preferably, compound of the present invention has the structure shown in formula (II)：
It is furthermore preferred that compound of the present invention has the structure shown in formula (III)：
The invention also discloses the preparation method of such compound.
(1) it is used to prepare important source material 2 used in the present invention, 4- benzyloxy -6- hydroxy acetophenones can be according to classics side
Method is obtained by 2,4,6- trihydroxy-acetophenones and benzyl bromine, in the basic conditions reaction.
(2) it is used to prepare another raw material 5- (4- aminobenzyls) thiazolidine -2,4- diketone, 5- (4- hydroxyls used in the present invention
Benzyl) thiazolidine -2,4- diketone itself is the intermediate of Thiazolidinediones, therefore can also be closed according to classical documents method
Into.
(3) the basic synthesis step of the compound is as follows：
The first step：2,4- benzyloxy -6- hydroxy acetophenones and Ethyl formate reaction are prepared into 5,7- benzyloxy -2- hydroxyls
Base-coumarin-4 -one.Reaction dissolvent is anhydrous tetrahydro furan.Alkali used in reaction is sodium methoxide, caustic alcohol, potassium tert-butoxide, preferably
Alkali is sodium methoxide.Reaction is preferred first to allow anhydrous formic acid ethyl ester and the sodium methoxide of brand-new to carry out premixing stirring at low temperature, preferably
Incorporation time 5-10 minutes.After the completion of mixing, preferably at room temperature, the anhydrous tetrahydrochysene of 2,4- benzyloxy -6- hydroxy acetophenones is added dropwise
Tetrahydrofuran solution is reacted, preferred reaction time 0.5 hour.For reactant mixture after acid neutralizes and post-processes, rotation removes solvent, residual
Thing is stayed to be purified through ethyl acetate quick wash.Without column chromatography for separation, directly can be used after drying in next step.
Second step：Compound 3 preparation.5,7- benzyloxies-2- hydroxyls-coumarin-4 -one that the first step is obtained
Reacted with formaldehyde and prepare 5,7- benzyloxy-3- methylol-4H- coumarin-4 -one.Reaction dissolvent is acetone, and alkali is sodium acetate,
It is preferred that react at room temperature, preferred reaction time 2-3 hours, with thin layer board monitoring reaction end.After the completion of reaction, concentrated hydrochloric acid is added,
Continue room temperature overnight stirring.After reaction completely, ethyl acetate is extractant, solvent repeatedly is evaporated off after extraction, product can
With through chromatographic separation and purification.Chromatographic isolation optimum condition is silicagel column, petroleum ether:Ethyl acetate=1:1-1:2 gradient elutions.
3rd step：5,7- benzyloxy -3- methylol -4H- coumarin-4s the -one (compound 3) that second step is obtained
Reacted with phosphorus tribromide and prepare 5,7- benzyloxy-3- bromomethyl-4H- coumarin-4 -one.It can be closed according to classical documents method
Into.It is preferred that reaction dissolvent is anhydrous tetrahydro furan.Alkali is done with anhydrous pyridine.Reaction is preferred first at low temperature, phosphorus tribromide, anhydrous
Pyridine, anhydrous tetrahydro furan carry out premixing stirring, preferably incorporation time 10-15 minutes, -5-0 DEG C of preferable temperature.Mixing is completed
Afterwards, the tetrahydrofuran solution of 5,7- benzyloxy-3- methylol-4H- coumarin-4 -one is preferably added dropwise at room temperature, continues to stir
React 20-24 hours.After the completion of, reactant mixture filters through diatomite, and after tetrahydrofuran washing, concentrated residues thing can be tied
Crystalline substance, preferably recrystallisation solvent are petroleum ether and dichloromethane mixture, and preferred volume ratio is petroleum ether:Dichloromethane=1:5.
4th step：Compound 1 or Compound 2 preparation.5,7- benzyloxy -3- bromine the first that 3rd step is obtained
Base -4H- coumarin-4s -one and the reactive ketone of 5- (4- aminobenzyls) thiazole -2,4- bis-, or with 5- (4- hydroxybenzyls) thiazole -
The reactive ketones of 2,4- bis-.Reaction preferred catalyst is simple mantoquita, and more preferably catalyst is cuprous iodide；Preferred part is reacted for two
Amine part, more preferably part are (1R, 2R)-cyclohexyl -1,2- diamines.Thiazolidinedione and 5,7- benzyloxy -3- bromine first
Base -4H- coumarin-4s -one preferably reacts mol ratio (ratio of amount of substance) for 1.4:1-1.0:1, more preferably ratio is 1.2.:
1.It is potassium phosphate to react preferred alkali, and mol ratio (ratio of amount of substance) is preferably reacted with thiazolidinedione for 3:1-1:1, more preferably
Ratio is 2:1..Reaction dissolvent is anhydrous 1,4- dioxane.It is 110 DEG C -120 DEG C to react preferable temperature, preferred reaction time
6-10 hours.After reaction completely, ethyl acetate is extractant, solvent repeatedly is evaporated off after extraction, product can be through chromatogram
Isolate and purify.Chromatographic isolation optimum condition is silicagel column, petroleum ether:Ethyl acetate=1:1-1:2 gradient elutions.
The present invention also provides the chromone substituted tetrahydrothiazole cyclohexadione compounds, is adjusted in treatment by PPAR gamma agonists
Disease medicine in application.
And the application in diabetes medicament is treated, the diabetes are Non-Insulin Dependent Diabetes Mellitus.
Compared with prior art, the present invention has the advantages that：
The present invention is to Drugbank databases, Chembl databases, TMC China natural drug database and flavonoid
Thing is derived, based on the leading virtual screening of Libdock score and its DS3.0 score values, to optimal preceding 100 compounds again
Surflex-dock docking are carried out using SybylX-2.0 softwares, select wherein score value the higher person as PPAR gamma agonist candidates
Part.The structure of candidate compound is for example shown below.Tested by chemical synthesis, cell and active animal, confirm such compound
PPAR γ partial agonist is acted on.
The present invention has carried out substantial amounts of cell experiment, including cell transient transfection experiment, PPAR γ protein expression assays, dense
Degree relies on and cooperative experiment, it was demonstrated that chromone substituted tetrahydrothiazole cyclohexadione compounds of the present invention are a kind of new
PPAR gamma portion activators.
Further, the present invention is observed by Wistar rats general state, acute blood sugar reducing function is tested, oral glucose is resistance to
Amount experiment, Biochemical Indices In Serum detection and pathology detection confirm that compound of the invention is to Non-Insulin Dependent Diabetes Mellitus
With therapeutic action and less adverse reaction.Therefore the compound of the present invention is treated to Non-Insulin Dependent Diabetes Mellitus and had
It is significant.
The present invention provides described compound of Formula I to PPAR gamma portion agonisms, does not there is relevant report at present.
Brief description of the drawings
Fig. 1 is that compound 2 docks result with PPAR γ-LBD.
Fig. 2 is Compound 3 nucleus magnetic hydrogen spectrum figure.
Fig. 3 is Compound 3 nuclear-magnetism carbon spectrogram.
Fig. 4 is Compound 3 high resolution mass spectrum figure.
Fig. 5 is Compound 1 nucleus magnetic hydrogen spectrum figure.
Fig. 6 is Compound 1 nuclear-magnetism carbon spectrogram.
Fig. 7 is Compound 1 mass spectrogram.
Fig. 8 is Compound 2 nucleus magnetic hydrogen spectrum figure.
Fig. 9 is Compound 2 nuclear-magnetism carbon spectrogram.
Figure 10 is Compound 2 mass spectrogram.
Figure 11-1 is the concentration dependant figure of Rosiglitazone and compound 2.
Figure 11-2 is compound 2 and Rosiglitazone concentration cooperative figure.
Figure 12 is blank control group rat kidney microscope inspection figure.
Figure 13 is model control group rat kidney microscope inspection figure.
Figure 14 is positive controls rat kidney microscope inspection figure.
Figure 15 is the low dose group rat kidney microscope inspection figures of compound 2.
Figure 16 is the middle dose group rat kidney microscope inspection figures of compound 2.
Figure 17 is blank control group pancreas in rat microscope inspection figure.
Figure 18 is model control group pancreas in rat microscope inspection figure.
Figure 19 is positive controls pancreas in rat microscope inspection figure.
Figure 20 is the low dose group pancreas in rat microscope inspection figures of compound 2.
Figure 21 is the middle dose group pancreas in rat microscope inspection figures of compound 2.
Figure 22 is the high dose group pancreas in rat microscope inspection figures of compound 2.
Specific embodiment
With reference to embodiment, the invention will be further described.
First, virtual screening
PPAR γ albumen is searched for from PDB protein molecular databases, selects PPAR γ albumen PDB structures, it is soft with DS3.0
Part, remove the unnecessary conformation of albumen, then choose all hydrones to be deleted, then choose albumen to be hydrogenated with.Choose
Drugbank databases, chembl databases, TMC China natural drug database.With DS3.0 ADMET modules to data
Absorption, distribution, metabolism, excretion and the toxicity of storehouse small molecular are detected, and are chosen the preferable compound of result and are hydrogenated with, are transported
With Small Molecules | Full Minimization options in Minmize Ligand to molecule minimize excellent
Change.
When Libdock is docked, the active pocket of docking is defined.Radius is set to 10, defines acceptor and active pocket,
Positive ligand molecular is deleted, Max hits to save are changed to 10, Conformation Method selection Best,
Parallel Processing select Ture, are docked, and click on View Results options and check that result selects marking highest
Ligand molecular.High molecular weight protein and micromolecular compound add the CHARMm field of forces, Momany- when CDOCKER is docked in DS3.0
Rone electric fields, acceptor, the definition of active pocket and the processing of smaller ligand are same as above.Selected in CDOCKER Protocol
Dock Ligands (CDOCKER) option, is docked.After the completion of task, click on View Results options and check that result is selected
Go out to give a mark highest ligand molecular.
Surflex-dock docking are carried out using SybylX-2.0 softwares again to optimal preceding 100 compounds, in PDB numbers
According in storehouse, Peroxisome proliferater-activated receptor γ1 (Peroxisome proliferator-activated are chosen
Receptor γ, PPAR γ) albumin crystal structure, PDB numbering：4EMA, its cocrystallization part are Rosiglitazone.Receptor protein
Water, hydrogenation are carried out, after extracting part, preserves file.Flavones series derivates and Pioglitazone, Darglitazone equimolecular pass through
Afterwards plus after the optimization of MMFF94 electric charge Tripos positions, molecular docking is carried out as part database.Surflex-Dock has been calculated
Finish, analyzed according to Total Score scoring functions and preserve result.
As shown in the table, Compound1, Compound 2, Compound 3 are filtered out chromogen ketone derivatives
After chromone substituted tetrahydrothiazole derovatives.Accompanying drawing 1 is that compound 2 docks result with PPAR γ-LBD.
Table 1
Table 2
| 4EMAindex | name | -CDockerEnergy |
| 2 | 794ap | 52.3919 |
| 182 | darglitazone | 49.8545 |
| 72 | 512inv | 44.4463 |
| 172 | rosiglitazone | 43.5102 |
| 162 | pioglitazone | 41.4585 |
| 92 | compound1 | 41.1636 |
| 102 | compound2 | 40.4212 |
| 62 | 429inv | 40.077 |
| 122 | balaglitazone | 39.6947 |
| 112 | compound3 | 38.8405 |
| 152 | metaglidasen | 32.8672 |
| 42 | 334inv | 31.5186 |
| 132 | ciglitazone | 28.814 |
| 22 | 999ap | 26.7133 |
| 142 | INT131 | 24.9574 |
| 12 | 986ap | 20.5434 |
| 52 | 423inv | 17.034 |
| 32 | 1275ap | 13.4208 |
2nd, the preparation of compound
Embodiment 1：5,7- benzyloxy -3- methylol -4H- coumarin-4s -one (compound 3)
Step A：Under argon gas protection, it is anti-that low temperature will be placed in equipped with 30mL anhydrous formic acid ethyl ester 100mL twoport round-bottomed flasks
Answer in device, and be cooled to 0 DEG C, after then sodium methoxide (1.625g, the 30mmol) addition of brand-new and 5min being stirred, return to room temperature and stir
Mix.The anhydrous tetrahydrofuran solution of 2,4- benzyloxy -6- hydroxy acetophenones (3.48 grams, 10mmol) is slowly added dropwise.Drip
Cheng Hou, continues stirring reaction 0.5 hour.Then, 50mL frozen water, 2.25mL acetic acid are added, and stirring reaction 10 minutes.Will reaction
Mixture is placed in liquid separation in separatory funnel, and aqueous phase continues to extract (50ml × 4) with Ethyl formate, merges Ethyl formate with dilute carbon
Sour hydrogen sodium washing, anhydrous sodium sulfate drying, is evaporated in vacuo solvent.Residue is with cold ethyl acetate quick wash.Filtering, vacuum are done
It is dry to obtain first step product 5,7- benzyloxy -2- Hydroxycoumarin -4- ketone (2.79 grams), without being further purified, can directly it make
With Yield:79%.
Step B：By the compound (3.76g, 10mmol) prepared by the first step, sodium acetate (40mg, 0.5mmol), 37%
Formaldehyde (0.128mL, 12mol), the mixing of 40mL acetone, are stirred at room temperature reaction 2 hours.Then add concentrated hydrochloric acid (1mL), solution room
Temperature stirring overnight, TLC monitoring, after reaction completely, add dilute sodium acetate solution and neutralize, vacuum rotation removes solvent.Into residue
50mL water is added, and is extracted (4 × 50mL) with ethyl acetate.Organic phase anhydrous sodium sulfate drying.Vacuum rotation removes solvent, remains
Thing is with silica gel (300-400 mesh) column chromatography (1:1-1:2 petroleum ethers：Ethyl acetate gradient) 5,7- benzyloxies -3- is made
Methylol -4H- coumarin-4s -one (1.51 grams), i.e. Compound 3, yield 39%.1H NMR(400MHz,CDCl3,ppm):δ
=7.70 (1H, s), 7.59 (2H, d, J=7.6Hz), 7.43-7.31 (8H, m), 6.51 (1H, s), 6.49 (1H, s), 5.21
(2H,s),5.07(2H,s),4.51(2H,s),13C NMR(100MHz,CDCl3) δ=177.52,163.14,160.19,
159.88,150.23,136.14,135.54,128.81,128.71,128.53,127.84,127.68,126.67,124.03,
109.82,98.30,94.13,70.78,70.57,59.04..ESIHRMS m/z calcd for[C24H20O5+H]+:
389.1389,found 389.1379.
Embodiment 2：Compound 1 preparation
Step A：Under argon gas protection, it is anti-that low temperature will be placed in equipped with 20mL anhydrous tetrahydro furan 100mL twoport round-bottomed flasks
Answer in device, and be cooled to -5 DEG C.Add phosphorus tribromide (0.32mL, 3.33mmol) and stir 10min at -5 DEG C.Add anhydrous pyridine
The anhydrous tetrahydrofuran solution (0.4mL) of (0.14mL).Then, the benzyloxies of 5,7- bis- of upper step preparation are slowly added dropwise with separatory funnel
The anhydrous tetrahydrofuran solution (20mL) of base -3- methylol -4H- coumarin-4s -one (3.88g, 10mmol), after being added dropwise to complete,
Return to room temperature and continue stirring reaction 20h.Reactant mixture filters through diatomite, after tetrahydrofuran washing, concentrates immediately, uses oil
Ether+dichloromethane (1:5) crystallize and be dried in vacuo to obtain product 5,7- benzyloxy -3- bromomethyl -4H- coumarin-4s -one (4.41
Gram), yield 98%.1H NMR(400MHz,CDCl3,ppm):δ=7.93 (1H, s), 7.62 (2H, d, J=7.6Hz),
7.44-7.33(8H,m),6.53(2H,s),5.22(2H,s),5.11(2H,s),4.34(2H,s).
Step B：Under argon gas protection, by 5,7- benzyloxies-3- bromomethyls-4H- coumarin-4 -one made from upper step
(5mmol, 2.25g), cuprous iodide (0.25mmol, 25mg), (1R, 2R)-cyclohexyl -1,2- diamines ((0.285g, 30 μ l),
5- (4- aminobenzyls) thiazole -2,4- diketone (6mmol, 1.332g), potassium phosphate (10mmol, 2.12g) and anhydrous Isosorbide-5-Nitrae-dioxy
Six rings (40mL) are added sequentially in 100mL neck round bottom flask, are stirred and are warming up to 110 DEG C and react 6 hours.Reaction is completed
Afterwards, it is cooled to room temperature, adds 150mL water, extracted with ethyl acetate (100mL × 3), combined ethyl acetate, vacuum rotation removes solvent, residual
Thing is stayed with petroleum ether：Ethyl acetate (1:1-1:2) gradient elution, compound 1 (2.575 grams), yield 87% can be made.1H NMR(400MHz,CDCl3,ppm):δ=7.56 (2H, d, J=7.6Hz), 7.41-7.31 (8H, m), 7.22 (1H, s),
7.02 (2H, d, J=8.8Hz), 6.63 (2H, d, J=8.0Hz), 6.47 (1H, s), 6.43 (1H, d, J=2.0Hz), 5.20
(2H,s),5.07(2H,s),4.60(2H,dd,J1=15.6Hz, J2=17.2Hz), 4.48 (1H, dd, J1=4.0Hz, J2=
8.4Hz), 3.37 (2H, dd, J1=7.6Hz, J2=14.4H), 3.15 (2H, dd, J1=8.4Hz, J2=14.0Hz)13C
NMR(100MHz,CDCl3) δ=174.84,173.30,170.79,162.92,159.89,159.83,151.62,136.19,
135.60,130.60,128.78,128.65,128.48,127.75,127.59,126.72,118.60,115.65,109.72,
98.41,94.18,70.81,70.53,51.72,37.51,37.30.ESI-MS m/z(relative intensity)
591.28(M-,100).
Embodiment 3：Compound 2 preparation
Argon gas protection under, by 5,7- benzyloxies -3- bromomethyl -4H- coumarin-4s -one made from upper step (5mmol,
2.25g), cuprous iodide (0.25mmol, 25mg), (1R, 2R)-cyclohexyl -1,2- diamines ((0.285g, 30 μ l), 5- (4- hydroxyls
Base benzyl) thiazole -2,4- diketone (6mmol, 1.338g), potassium phosphate (10mmol, 2.12g) and anhydrous Isosorbide-5-Nitrae-dioxane
(40mL) is added sequentially in 100mL neck round bottom flask, is stirred and is warming up to 110 DEG C and reacts 6 hours.It is cold after the completion of reaction
To room temperature, 150mL water is added, is extracted with ethyl acetate (100mL × 3), combined ethyl acetate, vacuum rotation removes solvent, residue
With petroleum ether：Ethyl acetate (1:1-1:2) gradient elution, compound 2 (2.91 grams), yield 98% can be made.1H NMR
(400MHz,CDCl3,ppm):δ=7.50 (2H, d, J=7.2Hz), 7.39-7.25 (8H, m), 7.22 (1H, s), 7.02 (2H,
D, J=8.8Hz), 6.78 (2H, J=8.8Hz), 6.46 (1H, d, J=2.4Hz), 6.43 (1H, d, J=2.0Hz), 5.18
(2H,s),5.00(2H,s),4.62(2H,dd,J1=15.6Hz, J2=22.4Hz), 4.38 (2H, dd, J1=7.6Hz, J2=
8.4Hz),4.14(2H,dd,J1=7.2Hz, J2=14.4H), 3.35 (1H, dd, J1=3.6Hz, J2=14.0Hz), 3.10
(1H,dd,J1=8.4Hz, J2=14.0Hz),13C NMR(100MHz,CDCl3) δ=175.30,173.25,170.93,
163.10,159.89,159.78,156.01,152.10,136.09,135.51,130.74,128.75,128.63,128.47,
127.80,127.66,126.83,126.66,118.42,115.74,109.49,98.47,94.11,70.70,70.50,
60.51,51.68,37.46,37.42.ESI-MS m/z(relative intensity)594.17(M+,100),592.00
(M-,100).
3rd, pharmacological evaluation
Embodiment 4：Compound 1,2,3 pairs of PPAR γ agonist activities-transient transfection studies
Using HEK-293 cell transient transfection PPAR γ plasmids, the screening of luciferase (luciferase) detection method
PPAR activators, wherein PPAR γ positive control drugs are Rosiglitazone, and construction expression PPAR γ, RXR eukaryon expression plasmid carry
Luciferase reporter plasmid carrier (the PPRE- of body and PPAR γ, RXR response element PPRE regulation and control
luciferase).Enter lactation with method cotransfection PPAR γ, RXR, PPRE-luciferase expression plasmid of liposome transfection
Animal cell line HEK-293 cells.3 kinds of plasmid mole ratios of transfection are 1: 1: 2.After HEK-293 cell transfectings 24h, pancreas is used
Enzymic digestion, several pieces are divided into after counting cell, mix with adding the culture medium of sample, continue in suitable culture plate respectively
24h is cultivated, and sets up negative control (solvent dimethyl sulfoxide group 0.1%) and positive control (Rosiglitazone).Each sample is set up
Parallel group.Sample concentration as needed sets gradient.After 24~48h of dosing, with the abundant cell lysis of cell pyrolysis liquid, training is collected
Each hole cell pyrolysis liquid in plate is supported, adds luciferase reaction substrate, fluorescence reading is measured with chemiluminescence detector.Positive drug
The activity that reporter gene expression is activated in the 293ET cells of thing after transfection is set to 100%, the reporter gene activation of test sample
The relative percentage of activity gained compared with positive drug Rosiglitazone 100%, it is the relative activity of test sample.Efficacy
For relative to Rosiglitazone activity ratio.
Shown in following table and Figure 11-1, selected compounds of the present invention are 10 μm of ol/ in concentration for the treatment of compared with positive controls
During L, compound1, compound 2, compound 3 show have partial agonist effect, compound2 to PPAR γ
Preferably, but it is weaker than Rosiglitazone, concentration-dependent relation is as shown in Figure 11-1.Rosiglitazone individualism activity is such as accompanying drawing 11-2 institutes
Show, after compound 2 are added, its activity is substantially partly suppressed, it can be verified that compound 2 is the excitement of PPAR gamma portions
Agent.
Table 3
| Compd. | Efficacy (%) |
| Compound1 | 64±7.5 |
| Compound2 | 78±8.6 |
| Compound3 | 33±4.7 |
| Rosiglitazone | 100 |
Embodiment 5：PPAR γ protein expression assays
Method：Standard items are taken, are diluted to 12ng/ml, 6ng/ml, 3ng/ml, 1.5ng/ml, 0.75ng/ml respectively.It is to be measured
Sample well adds 40 μ l samples per hole, then adds anti-PPAR γ-μ l of antibody 10, Streptavidin-HRP50 μ l；Standard sample wells
Add the μ l of standard items 50 and streptomysin-HRP50 μ l；Blank well is added without anti-the PPAR gamma antibodies and chain of sample, biotin labeling
Mould Avidin-HRP.After sample-adding, shrouding film is covered, gently vibration mixes, and 37 DEG C incubate 60 minutes.By washing, developing the color, terminating
Afterwards, returned to zero with blank, 450nm wavelength sequentially measures the OD values in each hole.Calculated according to the concentration of standard items and corresponding OD values
The regression equation of standard curve, corresponding sample concentration is calculated in the OD values according to sample.
As a result：Model control group PPAR γ protein expressions compare with blank group to be decreased obviously, positive controls PPAR γ eggs
Express in vain significantly raised, the low dose groups of compound 2 are then poor, and the middle dose groups of compound 2 raise compared with model group, high dose
Group is slightly weaker than blank control group and positive controls, further illustrates the partial agonist that compound 2 is PPAR γ
(SPSS13.0 software statistics are analyzed, P<0.05).
Table 4
Embodiment 6：Effects of the Compound 2 to Wistar rats
The foundation of 1 animal model
Take wistar rats 112 (male and female half and half), 200~250g of body weight.Randomly select 12 and be only used as control group；Remaining
100 with high glucose and high fat forage feed 4 weeks.After 4 weeks, each experimental group rats by intraperitoneal injection 35mg/kg Streptozotocins (1%STZ
Solution, it is dissolved in 0.1mol/L citric acid-sodium citrate buffer solutions) induced diabetes；Rat-tail takes hematometry each group rat empty after 72h
Abdomen blood glucose, blood glucose >=11.1mmol/L think modeling success.To diabetes Wistar rats by being randomly divided into 5 groups, respectively mould
Type control group, positive controls, 2 basic, normal, high dosage groups of Compound.Normal group is then pressed per 3, cage, with normal diet
Feed.
According to trial test result, compound 2 is 5mgkg to rat initial effective dose-1·d-1.Above each group is moved
Thing distinguishes gastric infusion, and Normal group and model control group rat give distilled water 10mLkg-1·d-1, positive controls
5mg/kg/d Rosiglitazones are given, the basic, normal, high dosage group of medicine gives drug solution respectively, according to trial test result, to medicament
Amount is respectively 2.5mgkg-1d-1,5mgkg-1d-1,10mgkg-1d-1, administered volume 10mlkg-1, and 1
Secondary/d, continuous 5 weeks.Periodic monitoring rat body weight weekly.(experimental animal and associated materials are by Medical University Of Chongqing's zoopery
The heart provides, and Chongqing in China, citric acid, Streptozotocin, Rosiglitazone are purchased from lark prestige Science and Technology Ltd.).
2 body weight detect
2.1 method：After administration starts, weighed before set time administration weekly, and carrying out when dissected, first determined
The empty body weight of rat.
2.2 result：After modeling, blank control group rat is in good condition, is quick on the draw, no death, and model control group is moved
Thing occurs drinking water and hydrouria, and urine color is deeper, few dynamic, weak, slow movement etc..Positive controls, compound2 be low,
Also there is similar performance, but middle and high its symptom of dosage group animal of compound 2 has clear improvement compared with model control group.Experimental period
Between, the weight of animals is weighed in the set time weekly, there was no significant difference that (SPSS13.0 is soft for the change of each group the weight of animals during administration
Part statistical analysis, P<0.05).The middle and high dosage group the weight of animals of Compound 2 increase it is slower, low dose group body weight increase with
Model control group and positive controls are suitable, and rat body weight situation of change is (table 5) as shown in the table during administration.
Table 5
G/ weeks/only
3 acute blood sugar reducing function experiments
3.1 method：It is administered the 1st day, each group Wistar rat random blood sugars is determined before medicine, blood is determined again after 2h is administered
Sugar, observes whether it has acute hypoglycemic effect (the full vigor type blood glucose meter measure of Roche).
3.2 result：2h blood glucose is respectively 26.2,25.5mmol/L before the low dose group medicines of compound 2, after medicine；Middle dosage
Before group medicine, 2h blood glucose is respectively 24.2,23.0mmol/L after medicine；Before high dose group medicine, after medicine 2h blood glucose be respectively 25.4,
22.8mmol/L.The basic, normal, high dosage each group of positive controls, compound 2 and its model control group compare without significantly before medicine
Sex differernce (P<0.05), 2h each groups blood glucose with being in reduction trend to dosage increase, shows that compound 2 has good drop after medicine
Blood glucose acts on, and relevant with dosage.Obviously, 2 acute blood sugar reducing functions of compound and unobvious, therefore cause in the absence of medication
Acute hypoglycemic risk (every group of 12 Wistar rats).Acute hypoglycemic result as shown in table 6 (software statistics of SPSS 13.0 analyze,
P<0.05)。
Table 6
| Packet | Blood glucose before medicine | Blood glucose (2h) after medicine |
| Blank control group | 9.0±1.7 | 9.0±1.7 |
| Model control group | 25.1±3.2 | 25.1±3.3 |
| Positive controls | 26.1±2.2 | 24.1±2.4 |
| Compound2 low dose groups | 26.2±3.2 | 25.5±4.2 |
| Compound2 middle dose groups | 24.2±3.1 | 23.0±3.1 |
| Compound2 high dose groups | 25.4±3.6 | 22.8±3.1 |
mmol/L
4 oral glucose tolerance tests
4.1 method：After administration the 15th day, Wistar Rat Fasts 12h, tail vein acupuncture takes hematometry fasting blood-glucose to contain
Amount, the intraocular corner of the eyes takes hematometry FPI content, gives glucose 2gkg-1 gavages, setting time (30min,
60min, 120min) tail vein acupuncture take blood survey blood-sugar content.AUC (area under glucose tolerance curve) is calculated, its calculation formula is：
AUC=0.25 × fasting blood-glucose+0.5 × 30min blood glucose+0.75 × 60min blood glucose+120min blood glucose.
4.2 result：In administration the 15th day, positive controls animal fasting blood-glucose was low compared with model control group, gives glucose
Blood glucose value and its AUC are poor different in 30min, 60min blood glucose and AUC and model control group well below model control group afterwards
Significantly (software statistics of SPSS 13.0 are analyzed, P ＜ 0.05)；The low dose groups of compound 2 are slightly worse compared with positive controls, but remote high
In model control group, it is horizontal to show that low dose group has been provided with certain hypoglycemic；The middle dose group hypoglycemic effects of compound 2 are notable,
And high dose group hypoglycemic effect weakens, its blood glucose value and AUC are similar to model control group.The resistance to experimental result of sugar is shown in Table 7 (every group 12
Wistar rats).
Table 7
| Packet | 0min | 30min | 60min | 120min | AUC |
| Blank control group | 6.0±1.8 | 6.1±0.9 | 6.5±0.8 | 5.5±1.4 | 14.9±2.2 |
| Model control group | 13.1±5.3 | 17.8±6.5 | 23.5±5.8 | 19.1±7.6 | 48.9±12.8 |
| Positive controls | 5.2±0.8 | 9.9±3.3 | 11.7±6.5 | 12.4±5.4 | 27.4±9.9 |
| Low dose group | 5.5±3.8 | 11.6±6.8 | 12.6±6.3 | 13.7±7.8 | 30.3±13.3 |
| Middle dose group | 5.3±1.4 | 9.6±2.9 | 11.6±7.3 | 12.5±6.8 | 27.3±11.7 |
| High dose group | 11.4±8.1 | 16.0±6.3 | 19.3±8.1 | 21.4±7.5 | 46.7±14.1 |
mmoL P<0.05
The influence of 5 pairs of rat fats
5.1 method：1h after last time is administered, with 3% yellow Jackets anesthetized rat, abdominal aortic blood is simultaneously put to death dynamic
Thing, centrifuging and taking serum, it is sub-packed in 1.5mL centrifuge tubes, is determined using full automatic biochemical apparatus, determines free-fat in rat blood serum
Sour (FFA), triglycerides (TG), T-CHOL (TC).
5.2 result：It is administered the 30th day, the basic, normal, high dosage group FFA of model control group, positive controls, compound 2
Compared with blank group, increase, but the middle and high dosage group increases of compound 2 are relatively few, illustrate that insulin resistance is present in and remove
In each group outside blank control, but 2 middle and high dosage groups of compound have certain improvement result；Triglycerides (TG) situation class
Seemingly.Compound 2 is low, middle dose group T-CHOL (TC) is compared with model control group, positive controls, hence it is evident that reduces, explanation
Compound 2 has the function that to improve blood lipid metabolism, but the high dose groups of compound 2 then show as TC increase trend.Rat
The influence of blood fat the results are shown in Table 8 (P<0.05).
Table 8
6. pathological examination
6.1 method：Above-mentioned abdominal aortic blood simultaneously puts to death animal, and animal kidney, pancreas are fixed with 4% formalin,
Cut into slices after FFPE, H-E dyeing, carry out histopathologic examination.
6.2 kidney inspection results：In blank control group rat kidney, cortex renis, clear, the renal tubule structure of kidney medulla boundary
Clearly, glomerulus is evenly distributed, and volume is normal, and sacculus is without adhesion, and matrix is without hyperplasia (Figure 12)；And model control group rat ratio
Compared with renal cells is substantially denatured, interstitial proliferation, and blister cavities volume increase, glomerular capillary loop is reduced, and matrix increases
(Figure 13)；Also there is renal cells vacuolar degeneration, the increase of capsula glomeruli blister cavities volume in positive controls rat, matrix increases
It is more, but with model control group rat comparatively, renal tubule degeneration and necrosis Chengdu degree substantially mitigates (Figure 14)；compound 2
Low dose group rat kidney renal tubular epithelial vacuolar degeneration, the increase of capsula glomeruli blister cavities volume, glomerular capillary loop are reduced, mould
Type control group compares degree and mitigates (Figure 15)；Middle dose group rat kidney is shown no obvious abnormalities, and is relatively had no with blank group rat
Notable difference (Figure 16), high dose group situation is similar, no significant difference.Pathology kidney inspection result shows that compound 2 is right
Kidney is lossless to injure murder by poisoning, has certain protective role to kidney.
6.2 pancreas inspection results：Blank control group pancreas islet is mostly elliptical erythrocyte group, is scattered between pancreatic acini, number
Amount is more, and boundary is clear, and no coating, kytoplasm enriches, and core is mostly circular deep dye (Figure 17).Model control group pancreas microscopy result
See, pancreas islet volume reduces, and quantity is reduced drastically, and boundary is smudgy, and islet cell mass is also reduced, cellular swelling, and kytoplasm is shallow
Dye, karyopyknosis (Figure 18).Pancreas islet quantity is reduced in positive controls pancreas, and islet cell mass is reduced, karyopyknosis,
But take a turn for the better (Figure 19) compared with model control group rat.The low dose group pancreas in rat situations of Compound 2 and model control group rat ratio
Compared with the increase of, pancreas islet quantity, other also take an evident turn for the better, but with positive control no significant difference (Figure 20).Agent in Compound 2
Pancreas islet quantity is more obvious than model control group increase in amount group pancreas, but islet cell mass is less (Figure 21) compared with blank group.
Pancreas islet quantity and islet cell mass increase in the high dose group pancreas of Compound 2, injury of pancreas mitigate, with blank group without
Notable difference (Figure 22).Above-mentioned Pancreas Disease Neo-Confucianism inspection result shows that compound 2 is light to injury of pancreas, to recovering pancreas work(
Can and increase stimulates its sensitiveness significant.
The above embodiment of the present invention is only example to illustrate the invention, and is not the implementation to the present invention
The restriction of mode.For those of ordinary skill in the field, other can also be made not on the basis of the above description
With the change and variation of form.It is every to belong to the obvious changes or variations that technical scheme is amplified out and still locate
In the row of protection scope of the present invention.
Claims (4)
1. the preparation method of a kind of chromone substituted tetrahydrothiazole cyclohexadione compounds, it is characterised in that comprise the following steps：
1) 5,7- benzyloxy-3- bromomethyl-4H- coumarin-4 -one is prepared：
2) chromone substituted tetrahydrothiazole cyclohexadione compounds are prepared：
Wherein, X is selected from nitrogen hydrogen (NH) or oxygen (O)；Bn is benzyl；N=1.
2. the preparation method of chromone substituted tetrahydrothiazole cyclohexadione compounds according to claim 1, it is characterised in that specific
Preparation method be：
The first step：By 2,4- benzyloxy -6- hydroxy acetophenones and Ethyl formate reaction prepare 5,7- benzyloxy -2- hydroxyls -
Coumarin-4 -one；Reaction dissolvent is anhydrous tetrahydro furan, and alkali used in reaction is sodium methoxide；Reaction first allows no water beetle at low temperature
Acetoacetic ester and the sodium methoxide of brand-new carry out premixing stirring, incorporation time 5-10 minutes；After the completion of mixing, at room temperature, 2 are added dropwise,
4- benzyloxy -6- hydroxy acetophenone anhydrous tetrahydrofuran solutions are reacted, 0.5 hour reaction time；Reactant mixture passes through
After acid is neutralized and post-processed, rotation removes solvent, and residue purifies through ethyl acetate quick wash；Without column chromatography for separation, through drying
Directly used afterwards in next step；
Second step：5,7- benzyloxies-2- hydroxyls-coumarin-4 -one that the first step is obtained prepares 5,7- bis- with formaldehyde reaction
Benzyloxy-3- methylol-4H- coumarin-4 -one；Reaction dissolvent is acetone, and alkali is sodium acetate, 2-3 hours is reacted at room temperature, with thin
Laminate monitors reaction end；After the completion of reaction, concentrated hydrochloric acid is added, continues room temperature overnight stirring；After reaction completely, with ethyl acetate
For extractant, solvent repeatedly is evaporated off after extraction, product is through chromatographic separation and purification；Chromatographic separation condition is silicagel column, petroleum ether:
Ethyl acetate=1:1-1:2 gradient elutions；
3rd step：5,7- benzyloxies -3- methylols -4H- coumarin-4s the -one that second step is obtained is made with phosphorus tribromide reaction
Standby 5,7- benzyloxy-3- bromomethyl-4H- coumarin-4 -one；Reaction dissolvent is anhydrous tetrahydro furan；Alkali is done with anhydrous pyridine,
First at low temperature, phosphorus tribromide, anhydrous pyridine, anhydrous tetrahydro furan carry out premixing stirring 10-15 minutes, temperature -5-0 for reaction
℃；After the completion of mixing, the tetrahydrofuran solution of 5,7- benzyloxy-3- methylol-4H- coumarin-4 -one is added dropwise at room temperature, after
Continuous stirring reaction 20-24 hours；After the completion of, reactant mixture filters through diatomite, after tetrahydrofuran washing, concentrated residues thing knot
Crystalline substance, recrystallisation solvent are petroleum ether and dichloromethane mixture, and volume ratio is petroleum ether:Dichloromethane=1:5；
4th step：5,7- benzyloxies -3- bromomethyls -4H- coumarin-4s the -one that 3rd step is obtained and 5- (4- aminobenzyls)
The reactive ketone of thiazole -2,4- bis-, or with the reactive ketone of 5- (4- hydroxybenzyls) thiazole -2,4- bis-；Catalysts are cuprous iodide；
Reaction part is (1R, 2R)-cyclohexyl -1,2- diamines；Thiazolidinedione and 5,7- benzyloxy -3- bromomethyl -4H- tonka-beans
Element -4- reactive ketones mol ratio is 1.2:1；Reaction base is potassium phosphate, is 2 with thiazolidinedione reaction mol ratio:1；Reaction dissolvent
For anhydrous 1,4- dioxane；Reaction temperature is 110-120 DEG C, hour in reaction time 6-10；After reaction completely, ethyl acetate is
Extractant, solvent repeatedly is evaporated off after extraction, product is through chromatographic separation and purification；Chromatographic separation condition is silicagel column, petroleum ether:Second
Acetoacetic ester=1:1-1:2 gradient elutions；
3. treatment is by the medicine of the disease of PPAR gamma agonists regulation, it is characterised in that including being obtained by the method for claim 1 or 2
The chromone substituted tetrahydrothiazole cyclohexadione compounds arrived.
4. treat the medicine of Non-Insulin Dependent Diabetes Mellitus, it is characterised in that including what is obtained by the method for claim 1 or 2
Chromone substituted tetrahydrothiazole cyclohexadione compounds.
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