CN106977504A - A kind of 1,2,4 oxadiazole derivatives, preparation method and its medical usage - Google Patents
A kind of 1,2,4 oxadiazole derivatives, preparation method and its medical usage Download PDFInfo
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- CN106977504A CN106977504A CN201710219607.2A CN201710219607A CN106977504A CN 106977504 A CN106977504 A CN 106977504A CN 201710219607 A CN201710219607 A CN 201710219607A CN 106977504 A CN106977504 A CN 106977504A
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- oxadiazole derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to medicinal chemistry art, and in particular to a kind of 1,2,4 oxadiazole derivatives（Shown in Formulas I）,
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of 1,2,4- oxadiazole derivatives shown in formula I, including
The preparation method of the compound and the application in treatment type ii diabetes, obesity and its complication.
Background technology
Type ii diabetes are that the ability that insulin is produced in a kind of common metabolic disorder disease, its patient's body is not lost
Lose, or even produce excessively, but the insulin receptor on cell is reduced to the sensitivity of insulin in patient body, causes diabetes
And trigger obesity（The Lancet, 2014, 383, 1947）.
Protein-tyrosine-phosphatase 1B（protein tyrosine phosphatase 1B, PTP1B）It is first
The protein-tyrosine-phosphatase being successfully separated, is made up of 435 amino acid residues, belongs to typical non-receptor type PTP enzymes
Family（Proc. Natl. Acad. Sci USA, 1990, 87, 5148）.Early stage research has shown that PTP1B can have in vitro
Effect by insulin receptor dephosphorylation（J. Cell. Biol.1996, 134, 801；J. Biol. Chem., 1995,
270, 20503）.Knock out PTP1B genes or suppress internal PTP1B albumen and mRNA expression with GEM 132 (AS0)
Sensitiveness of the test mice to insulin can be not only significantly improved, and can substantially reduce the Expectancy of obesity（Mol. Cell. Biol.2000, 20, 5479；Plos One, 2015, 10, e0126866；Drugs, 2003, 12,
223）.In recent years, increasing research has shown that PTP1B is an active drug action target spot for treating type ii diabetes.
The content of the invention
The present invention discloses a kind of 1,2,4- oxadiazole derivatives shown in formula I, its preparation method and its medical application.Just
Step active testing proves that the compounds of this invention has good PTP1B inhibitory activity, and type ii diabetes, fertilizer are treated available for preparing
Fat disease and its medicine of complication.
The compound of the present invention：5- (5 '-to diethylin phenyl -1 ', 2 ', 4 '-oxadiazoles) -1H- indole -3-formaldehydes,
Structural formula（Formulas I）It is as follows：
。
It is as follows the invention also discloses the preparation method of compound of formula I：
。
The compound of formula 1 obtains Formulas I through formylation reaction, uses acylating reagent for oxalyl chloride, POCl3；Solvent for use
ForN,N- dimethylformamide, dichloromethane, water and its mixture；The reaction temperature is 0 DEG C~80 DEG C, and the reaction time is 1
~24 hours.
Compound of formula I of the present invention has significant PTP1B inhibitory action, can be as preparing II type glycosurias
The medicine or drug leads of disease, obesity and its complication.
Embodiment
With reference to specific embodiment, the present invention is described in further detail.
Embodiment 1：The preparation of compound of formula I
。
2mL POCl3s ice bath is instilled in 4ml DMF, is cooled to 0 degree, rear to add the mixture of 60 mg formulas 1, room temperature reaction
Overnight.After TLC detection display reactions completely, it is slowly added to 10% NaOH solution and adjusts pH value to 9, ethyl acetate extraction, anhydrous sulphur
Sour sodium dries organic phase, and concentration, residue is purified through column chromatography（DCM：MeOH=10：1）After obtain 15mg yellow solid Formulas I, produce
Rate 23%.1H NMR (600 MHz, CDCl3) δ 12.42 (1H, s), 10.00 (1H, s), 8.86 (1H, s),
8.43 (1H, s), 7.98 (1H, d, J = 6 Hz), 7.96 (1H, d, J = 6 Hz), 7.68 (1H, d, J
= 6 Hz), 6.83 (1H, d, J = 6 Hz), 3.43 (4H, t, J = 6 Hz), 1.14 (6H, t, J = 6
Hz). 13C NMR (150 MHz, CDCl3) δ184.7, 175.1, 167.9, 150.1, 139.2, 138.8,
129.1, 123.6, 121.8, 120.1, 119.7, 118.0, 112.6, 110.5, 108.4, 43.3, 11.7.
ESI-MS m/z: 361.2 [M+H]+.
Embodiment 2：Protein-tyrosine-phosphatase 1B（PTP1B）Inhibitory activity is tested
By the compound of formula I and oleanolic acid that are prepared in above-described embodiment 1（Control compound）Dissolved with DMSO, Cord blood,
Concentration controls of the DMSO in final system is not within the scope of detection activity is influenceed, i.e. in the range of 2% DMSO.Inhaled using light
Detection method is received, enzymatic activity is detected in 96 hole flat bottom clear microwell plates.Substrate pNPP hydrolyzes obtained free product through PTP1B and existed
There are very strong light absorbs at 405nm.The change of optical absorption intensity at 405nm is monitored by ELIASA, calculating obtains reacting initial velocity
Degree.Under the single concentration conditions of primary dcreening operation selection（20μg/mL）, the active of sample is tested.For showing under certain condition
The sample of activity, i.e. inhibiting rate are more than 50%, and test agents amount dependence is carried out non-by sample activity to sample concentration
Linear Quasi and obtain IC50, it is GraphpadPrism4 to calculate software used, and model used in fitting is sigmoidaldose-
Response (varible slope), for most of inhibitor screening models, 0 is set as by matched curve bottom and top
With 100.Generally, each sample is respectively provided with multiple holes (n >=3) in testing, in the result with standard error (Standard
Error, SE) represent.As a result it is as follows：
Experiment shows that compound of formula I can suppress protein-tyrosine-phosphatase 1B（PTP1B）, its IC50It is worth for 1.3 μM, it is living
Property be positive control oleanolic acid activity one times.Therefore, compound of formula I of the invention is as PTP1B inhibitor, available for making
The medicine or the lead compound as medicine of standby treatment type ii diabetes, obesity and its complication.
Claims (4)
1. one kind 1,2,4- oxadiazole derivatives, it is characterised in that it be 5- (5 '-to diethylin phenyl -1 ', 2 ', 4 '-dislike
Diazole) -1H- indole -3-formaldehydes, its structural formula is Formulas I：。
2. the preparation method of derivative described in a kind of claim 1：Using the compound of formula 1 as raw material, synthetic compound of formula i；。
3. use of the derivative as protein-tyrosine-phosphatase 1B inhibitor in medicine is prepared described in a kind of claim 1
On the way.
4. a kind of 1,2,4- oxadiazole derivatives described in claim 1 are preparing treatment type ii diabetes, obesity and its simultaneously
Send out the purposes in the medicine of disease.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710219607.2A CN106977504A (en) | 2017-04-06 | 2017-04-06 | A kind of 1,2,4 oxadiazole derivatives, preparation method and its medical usage |
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| CN201710219607.2A CN106977504A (en) | 2017-04-06 | 2017-04-06 | A kind of 1,2,4 oxadiazole derivatives, preparation method and its medical usage |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336719A (en) * | 2020-10-19 | 2021-02-09 | 济南大学 | Thiazole derivative as alpha-glucosidase inhibitor and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101415702A (en) * | 2006-04-03 | 2009-04-22 | 安斯泰来制药有限公司 | Hetero compound |
| WO2009153307A1 (en) * | 2008-06-20 | 2009-12-23 | Glaxo Group Limited | Compounds |
| CN101611033A (en) * | 2006-12-21 | 2009-12-23 | 葛兰素集团有限公司 | Indole derivatives as the S1P1 receptor stimulant |
-
2017
- 2017-04-06 CN CN201710219607.2A patent/CN106977504A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101415702A (en) * | 2006-04-03 | 2009-04-22 | 安斯泰来制药有限公司 | Hetero compound |
| CN101611033A (en) * | 2006-12-21 | 2009-12-23 | 葛兰素集团有限公司 | Indole derivatives as the S1P1 receptor stimulant |
| WO2009153307A1 (en) * | 2008-06-20 | 2009-12-23 | Glaxo Group Limited | Compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336719A (en) * | 2020-10-19 | 2021-02-09 | 济南大学 | Thiazole derivative as alpha-glucosidase inhibitor and application thereof |
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Application publication date: 20170725 |