CN101597216A - Bromo PTP1B inhibitor reaches synthetic and uses in the preparation diabetes medicament - Google Patents
Bromo PTP1B inhibitor reaches synthetic and uses in the preparation diabetes medicament Download PDFInfo
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Abstract
The present invention relates to a kind of chemical total synthesis method and the application in treatment diabetes B medicine of novel bromo PTP1B inhibitor, the chemical structural formula of described PTP1B inhibitor is as above: wherein 2 of phenyl ring, 2 ' and 3,3 ' position group that carbon connected is a bromine atoms; 4,4 ' join with 5,5 ' position carbon and methoxyl group; Chemical name Chinese is: two-(2,3-two bromo-4,5-dimethoxy-phenyl)-methane; English is: and Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane; This compound strengthens insulin receptor susceptibility by the activity of arrestin tyrosine Phospholipid hydrolase 1B, and insulin resistant class diabetes B is had the good curing effect.
Description
Technical field
The present invention relates to biological medicine, specifically a kind of bromo compound is two-chemical total synthesis method, pharmacologically active and the pharmaceutical use of (2,3-two bromo-4,5-dimethoxy-phenyl)-methane.This compound and derivative thereof can be used for treating insulin resistant class diabetes B as euglycemic agent.
Background technology
Diabetes (Diabetes Mellitus, DM) be a kind of chronic incretion metabolism disease, according to IDF (IDF) data in 2007, whole world maturity-onset diabetes patient number was about 2.46 hundred million, and wherein diabetes B (T2DM) patient accounts for total glycosuria patient more than 90%.By 2025, global diabetic subject's number was estimated to reach 3.8 hundred million.The medicine that is used for the treatment of T2DM at present mainly contains biguanides, sulfourea, alpha-glucosidase inhibitor and thiazolidinediones etc., because mostly they be at illness rather than at the design of cause of disease molecular target medicine, thereby has various drawbacks.Therefore, safe and effective, reasonable price of market in urgent need and the ofhypoglycemic medicine can long-term safety taken.
Insulin resistant is the key factor of T2DM morbidity, Regular Insulin is by combining with the outer α subunit of acceptor born of the same parents, β subunit intrinsic tyrosine kinase activity in the activated receptor born of the same parents, cause the tyrosine residues autophosphorylation, thereby activate insulin receptor tyrosine kinase fully, by the phosphorylation IRS signal is handed on again.Tyrosine phosphorylation is the important step that the Regular Insulin effect realizes, being acted on the pair of opposite enzyme is that PTK and PTP regulate.The effect of PTK in the insulin signaling transmission promptly paid close attention to by people very early, but up to date, people just recognize the importance of PTP in onset diabetes gradually.
(Protein tyrosine phosphatase 1B PTP1B), is one of main member in the Protein-tyrosine-phosphatase family to PTP 1B.Human PTP1B gene is positioned at karyomit(e) 20q13.1 zone No. 2, and mouse PTP1B gene is positioned at end of chromosome H2-H3 district No. 2, and the zone at the two place is all relevant with diabetes and obesity.PTP1B plays important negative regulation effect in insulin signaling transduction path.Studies confirm that, using the PTP1B inhibitor in the insulin sensitivity cell can make insulin receptor and substrate phosphorylation level thereof raise, promote the picked-up of glucose transporter transposition and increase glucose etc., the PTP1B inhibitor has played the effect of insulin analog and euglycemic agent.Knock out the PTP1B gene or suppress the expression of PTP1B albumen and mRNA in the body, not only can significantly improve and be tried the susceptibility of mouse, and can obviously reduce patient's probability of obesity Regular Insulin with antisense nucleotide (ASO).Gold-stein studies show that PTP1B and LARPTP express in insulin resistant patient's the insulin target tissue increases, and the expression increase of these two kinds of PTP can be blocked the activation of insulin receptor tyrosine and the signal transduction of Regular Insulin.P387L is a kind of missense mutation of PTP1B, and Echwald etc. confirm that this gene mutation frequency is 1.4% among the diabetes B patient, and the normal control group only is 0.5%, so think that this variation is relevant with diabetes B.Adopt the PTP1B antisense oligonucleotide to handle diabetes type mouse (ob/ob mouse), suppressing its PTP1B expresses, during the down-regulated expression of discovery PTP1B in liver, fat and skeletal muscle, it is normal that the ob/ob mouse blood sugar recovers, the every index relevant with carbohydrate metabolism all is tending towards normal, the experiment of Regular Insulin clamp shows that the liver and the peripheral tissues of diabetic mice strengthen insulin sensitivity.These results confirm the negative regulation effect of PTP1B in the insulin signaling transduction, and its activity increases, and may be an insulin resistant and an impaired paathogenic factor of insulin receptor signal take place.Therefore, seek the novel targets that small molecules PTP1B inhibitor has become treatment T2DM.
Few to the research of PTP1B inhibitor in the world, mainly contain following a few class: (1), peptide class: the peptide class substrate and the PTP1B of phosphorous acidifying tyrosine residues (pTyr) have higher affinity, but its chemistry and biologically stable are poor; (2), naphthoquinones class Naphthnoquinone: the activity of coming inhibitory enzyme by the avtive spot of modifying PTPase; (3), thiazolidinediones Azolidinediones: improve Blood glucose control by the insulin sensitivity that increases target organ, mainly comprise ciglitazone, troglitazone and rosiglitazone, but because serious hepatotoxicity, ciglitazone withdraws from from market; (4), Benzo[b] naphthol[2,3-d] furans and thiophenes class: with benzbromarone (PTP1B inhibitor, IC
50=26 μ M) design synthetic series Benzo[b for lead compound] naphthol[2,3-d] furans and thiophenes compounds, in the mouse body, show good hypoglycemic activity, but to finally become the treatment diabetes medicament and also need to overcome a lot of obstacles, as electronegativity height, permeability of cell membrane difference and selection specificity difference etc., above factor all makes the one-tenth property of medicine of these inhibitor reduce.We have found that from marine alga a series of PTP1B of having suppress active bromo marine natural product, and design has been synthesized strong PTP1B and suppressed active compound-two-(2,3-two bromo-4,5-dimethoxy-phenyl)-methane in view of the above.
Summary of the invention
The object of the invention is to provide a kind of novel PTP1B inhibitor-" two-(2; 3-two bromo-4; 5-dimethoxy-phenyl)-methane ", this compound and derivative thereof are by the activity of arrestin tyrosine Phospholipid hydrolase 1B, strengthen insulin receptor susceptibility, can be used for treating insulin resistant class diabetes B.
For achieving the above object, the technical solution used in the present invention is as follows:
1, the chemical complete synthesis and structure of " two-(2,3-two bromo-4,5-dimethoxy-phenyl)-methane " is identified
(1) Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-the chemical complete synthesis route map of methane 6
Scheme 1 (a) polyphosphoric acid, 75～85 ℃, 50～70min; (b) bromine (bromine: compound 3 mol ratios=2: 1), acetate, room temperature; (c) bromine (bromine: compound 4 mol ratios=4: 1), aluminum chloride, acetate, 75～85 ℃; (d) trifluoroacetic acid, triethyl silicane, room temperature.
(2) Bis-(3,4-dimethoxy-phenyl)-chemosynthesis of methanone 3 and structure identify
According to 1: 1 ratio of mol ratio veratric acid (compound 1), veratrole (compound 2) are joined in the container bottle with polyphosphoric acid, the mass ratio of veratric acid and polyphosphoric acid is 1: 4～1: 5,75～85 ℃ of stirring reaction 50～70min; Be cooled to 60 ℃ and in 30min in reactant the mixture of ice and water of 5 times of volumes of dropwise reaction system, separate out a large amount of water-fast pink solid in the reactant this moment; After filtration dewaters, the solid that obtains is dissolved in the methylene dichloride, the mass ratio of solid and methylene dichloride is 1: 3～1: 5, washs respectively 3～5 times with isopyknic mass concentration 3% sodium hydroxide solution and distilled water successively; The anhydrous sodium sulfate drying methylene dichloride mutually after, concentrating under reduced pressure gets pink solid; Evaporated under reduced pressure gets faint yellow solid behind the petroleum ether solids 3～5 times, through Spectrum Analysis, the conclusive evidence compound be Bis-(3,4-dimethoxy-phenyl)-methanone.
This compound physico-chemical property is as follows: white powder, and fusing point 145.3-146.1 ℃, proton nmr spectra:
1H NMR (500MHz, CDCl
3): δ 3.92 (s, 6H), 3.94 (s, 6H), 6.88 (d, J=8.4Hz, 2H), 7.36 (dd, J=8.4,1.8Hz, 2H), 7.41 (d, J=1.8Hz, 2H); Carbon-13 nmr spectra:
13C NMR (125MHz, CDCl
3): δ 56.03 (q), 109.79 (d), 112.39 (d), 124.69 (d), 130.82 (s), 148.9 (s), 152.61 (s), 194.35 (s).
(3) Bis-(2-bromo-4,5-dimethoxy-phenyl)-chemosynthesis of methanone 4 and structure identify
To react preparation in (2) compound 3Bis-(3,4-dimethoxy-phenyl)-methanone and acetate (mass ratio is 1: 7～1: 9) adds in three mouthfuls of reaction flasks, stir fast under the room temperature and make the solid dissolving; Bromine is added to dilution in the acetate (volume ratio 1: 2), and compd B is-(3,4-dimethoxy-phenyl)-methanone: bromine mol ratio=1: 2, drop to fast under the room temperature in three mouthfuls of reaction flasks, dropwise in the 20min; After bromine dropwises, stir under the room temperature and continue have light-yellow precipitate to separate out behind the reaction 1h, TLC detection reaction terminal point, stopped reaction after raw material point disappears; Reaction solution is poured the separating funnel that fills saturated aqueous common salt into, adds dichloromethane extraction 3～5 times, merges organic phase; Anhydrous sodium sulfate drying gets brown solid behind the concentrating under reduced pressure; Acetone repetitive scrubbing solid, evaporated under reduced pressure gets micro-yellow powder, through Spectrum Analysis, the conclusive evidence compound be Bis-(2-bromo-4,5-dimethoxy-phenyl)-methanone.
This compound physico-chemical property is as follows: pale yellow powder, and fusing point 172.5-173.2 ℃, proton nmr spectra:
1H NMR (500MHz, CDCl
3): δ 3.87 (s, 6H), 3.94 (s, 6H), 7.05 (s, 4H); Carbon-13 nmr spectra:
13C NMR (125MHz, CDCl
3): δ 56.26 (q), 56.33 (q), 113.22 (s), 114.0 (d), 116.36 (d), 131.76 (s), 148.40 (s), 152.01 (s), 194.26 (s).
(4) Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-chemosynthesis of methanone 5 and structure identify
To react the compound 4Bis-(2-bromo-4 of preparation in (3), 5-dimethoxy-phenyl)-methanone and acetate (mass ratio is 1: 18～1: 22) adds in three mouthfuls of reaction flasks, is warming up to 40～50 ℃ and adds an amount of aluminum chlorides (aluminum chloride: the quality of acetic acid ratio is 1: 10～1: 15); Stirring reaction 30min postcooling is to room temperature; Bromine is added to dilution in the acetate (volume ratio 1: 5), compd B is-(2-bromo-4,5-dimethoxy-phenyl)-and methanone: bromine mol ratio=1: 4, drop under the room temperature in three mouthfuls of reaction flasks, dropwise in the 1h, slowly be warming up to 80 ℃ of backflows then, TLC detection reaction terminal point, stopped reaction after raw material point disappears; Reaction solution is poured the separating funnel that fills volume by volume concentration 3% hydrochloric acid soln into, adds dichloromethane extraction 3～5 times, merges organic phase, gets brown solid after the evaporated under reduced pressure; Adopt silica gel column chromatography (sherwood oil: ethyl acetate volume ratio=8: 1 be an eluent) purifying, pale yellow powder, pass through Spectrum Analysis, the conclusive evidence compound be Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methanone.
This compound physico-chemical property is as follows: pale yellow powder, and 120.7～121.4 ℃ of fusing points, proton nmr spectra:
1H NMR (500MHz, CDCl
3): δ 3.87 (s, 6H), 3.91 (s, 6H), 7.03 (s, 2H); Carbon-13 nmr spectra:
13C NMR (125MHz, CDCl
3): δ 56.55 (q), 60.81 (q), 114.01 (d), 115.24 (s), 123.56 (s), 136.34 (s), 150.33 (s), 152.48 (s), 193.55 (s).
(5) Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-chemosynthesis of methane 6 and structure identify
To react the compound 5Bis-(2 of preparation in (4), 3-dibromo-4,5-dimethoxy-phenyl)-methanone and an amount of trifluoroacetic acid (mass ratio 1: 9～1: 11) add in three mouthfuls of reaction flasks, agitation condition adds triethyl silicane (triethyl silicane and trifluoroacetic acid volume ratio are 1: 10), stirring reaction under the room temperature down fast; TLC detection reaction terminal point adds the distilled water termination reaction after raw material point disappears; Reaction solution merges organic phase with dichloromethane extraction 3～5 times, anhydrous sodium sulfate drying, after the evaporated under reduced pressure pale solid, through Spectrum Analysis, the conclusive evidence compound be Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane.
This compound physico-chemical property is as follows: white powder, and fusing point 149.9-150.2 ℃, proton nmr spectra:
1H NMR (500MHz, CDCl
3): δ 3.76 (s, 6H), 3.85 (s, 6H), 4.24 (s, 2H), 6.58 (s, 2H); Carbon-13 nmr spectra:
13C NMR (125MHz, CDCl
3): δ 45.29 (t), 56.30 (q), 60.54 (q), 113.56 (d), 118.02 (s), 122.12 (s), 136.0 (s), 146.66 (s), 152.65 (s).
2, protein-tyrosine Phospholipid hydrolase 1B suppresses determination of activity
Adopt molecular biology method, make up the human PTP1B engineering bacteria of hGST-PTP1B-BL21 E.Coli of gene recombination, with GST affinity chromatography column purification hGST-PTP1B protein, the polypeptide para-Nitrophenyl Phosphate (pNPP) that utilization contains phosphoric acid is fallen a product pNP behind the phosphoric acid has absorption peak at wavelength 405nm place principle by the PTP1B enzymolysis, the scale that generates pNP with PTP1B effect back show that the PTP1B enzymic activity changes and compound to the inhibition situation of enzymic activity, computerized compound PTP1B enzyme activity inhibiting rate.
Described compound is the new compound with PTP1B enzyme inhibition activity, can strengthen insulin receptor susceptibility by negative regulation insulin signaling transduction path, the Regular Insulin physiological function is normally brought into play, and then regulating and controlling blood sugar, reach therapeutic efficiency to insulin resistant class diabetes B; Chemical equivalence things such as acceptable salt, ester or ether can mix with pharmaceutically acceptable pharmaceutical carrier and can be made into tablet, capsule, oral liquid, granule, pill or the injection of treatment to insulin resistant class diabetes B on its compound itself and the pharmacology.
The present invention has following advantage:
Target compound of the present invention is the brand new compound with remarkable PTP1B enzyme inhibition activity, is the treatment new drug of insulin resistant class diabetes B; The present invention has carried out chemical complete synthesis to it, the starting raw material that selection cheaply is easy to get reduces reaction cost, realized the high yield of target compound, synthetic cheaply, and technological operation is simple, has good industrialization prospect of production.
Embodiment
The chemical complete synthesis and structure of embodiment 1 " two-(2,3-two bromo-4,5-dimethoxy-phenyl)-methane " is identified
(1) Bis-(3,4-dimethoxy-phenyl)-chemosynthesis of methanone 3 and structure identify
According to 1: 1 ratio of mol ratio 44.16g (240mmol) veratric acid (compound 1), 33.84g (240mmol) veratrole (compound 2) are joined in three mouthfuls of reaction flasks of 1000ml 80 ℃ of stirring reaction 1h with the 200g polyphosphoric acid; Be cooled to 60 ℃ and in 30min in reactant Dropwise 5 00ml frozen water, separate out a large amount of water-fast pink solid in the reactant this moment; After filtration dewaters, the solid that obtains is dissolved in the 200ml methylene dichloride, uses isopyknic 3% sodium hydroxide solution and distilled water wash three times successively; The anhydrous sodium sulfate drying methylene dichloride mutually after, concentrating under reduced pressure gets pink solid; Evaporated under reduced pressure gets faint yellow solid 3 (61.62g, productive rate 85%) behind the petroleum ether solids three times, through Spectrum Analysis, the conclusive evidence compound be Bis-(3,4-dimethoxy-phenyl)-methanone.
(2) Bis-(2-bromo-4,5-dimethoxy-phenyl)-chemosynthesis of methanone 4 and structure identify
(30.2g 100mmol) adds in three mouthfuls of reaction flasks of 500ml with 240ml acetate, stirs fast under the room temperature solid is dissolved will to react the compound 3 for preparing in (1); The 10.6ml bromine added in the 20ml acetate dilute, drop to fast under the room temperature in three mouthfuls of reaction flasks, dropwise in the 20min; After bromine dropwises, stir under the room temperature and continue have light-yellow precipitate to separate out behind the reaction 1h, TLC detection reaction terminal point, stopped reaction after raw material point disappears.Reaction solution is poured the separating funnel that fills the 240ml saturated aqueous common salt into, adds methylene dichloride (each 200ml) extraction three times, merges organic phase; Anhydrous sodium sulfate drying gets brown solid behind the concentrating under reduced pressure; Washing with acetone solid 4 to 6 times, evaporated under reduced pressure get micro-yellow powder 4 (37.74g, productive rate 82%), through Spectrum Analysis, the conclusive evidence compound be Bis-(2-bromo-4,5-dimethoxy-phenyl)-methanone.
(3) Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-chemosynthesis of methanone 5 and structure identify
(9.2g 20mmol) adds in three mouthfuls of reaction flasks of 500ml with 200ml acetate, is warming up to 45 ℃ and adds the 2.0g aluminum chlorides will to react the compound 4 for preparing in (2); Stirring reaction 30min postcooling is to room temperature; The 4.0ml bromine added in the 20ml acetate dilute, drop under the room temperature in three mouthfuls of reaction flasks, dropwise in the 1h, slowly be warming up to 80 ℃ of backflows then, TLC detection reaction terminal point, the raw material point back stopped reaction that disappears.Reaction solution is poured into and is filled the separating funnel that the 400ml volume by volume concentration is 3% hydrochloric acid soln, adds methylene dichloride (each 200ml) extraction three times, merges organic phase, gets brown solid after the evaporated under reduced pressure; Adopt silica gel column chromatography (sherwood oil: ethyl acetate volume ratio=8: 1 be an eluent) purifying, must white powder 5 (6.34g, productive rate are 51%), through Spectrum Analysis, the conclusive evidence compound be Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methanone.
(4) Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-chemosynthesis of methane 6 and structure identify
(6.2g 10mmol) adds in three mouthfuls of reaction flasks of 250ml with the 40ml trifluoroacetic acid, and quick agitation condition is adding 4ml triethyl silicane down, stirring reaction under the room temperature will to react the compound 5 for preparing in (3); TLC detection reaction terminal point adds 100ml distilled water termination reaction after raw material point disappears.Reaction solution merges organic phase, anhydrous sodium sulfate drying with methylene dichloride (each 100ml) extraction three times, get pale solid 6 (4.4g, productive rate 73%) after the evaporated under reduced pressure, through Spectrum Analysis, the conclusive evidence compound be Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane.
Reaction overall yield=85% * 82% * 51% * 73%=25.9%
Embodiment 2 protein-tyrosine Phospholipid hydrolase 1B suppress determination of activity
With testing compound two-(2,3-two bromo-4,5-dimethoxy-phenyl)-methane is mixed with the need testing solution of different concns with DMSO, get (the 50mM Tris-HCl of survey live body system that 2 μ L need testing solutions join standard respectively, PH6.5,2mM pNPP, 2%DMSO, 30nM hGST-PTP1B), negative control: DMSO, positive control: sodium vanadate, temperature of reaction is 30 ℃, the dynamic measurement wavelength is the photoabsorption at 405nm place, and time 3min is calculated as follows Compound P TP1B enzyme activity inhibiting rate.Inhibiting rate=(experimental group A value-negative control group A value)/(control group A value-negative control group A) * 100% the results are shown in Table 1.
Table 1 protein-tyrosine Phospholipid hydrolase 1B inhibiting rate (%)
Table?1?Inhibitory?Ratio (％)of?PTP1B
Test-results shows: 6 pairs of protein tyrosine phosphatase esterases of compound 1B shows significant inhibitory effect, has good anti-diabetes B potential applicability in clinical practice.
Claims (5)
1. bromo PTP1B inhibitor, it is characterized in that: described protein-tyrosine Phospholipid hydrolase 1B inhibitor is compound " two-(2,3-two bromo-4,5-dimethoxy-phenyl)-methane ", and its chemical structural formula is as follows:
Wherein 2,2 of phenyl ring ' and 3,3 ' position group that carbon connected be bromine atoms; 4,4 ', 5 and 5 ' position carbon and methoxyl group join; Chemical name Chinese is: two-(2,3-two bromo-4,5-dimethoxy-phenyl)-methane; English is: and Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane.
2. described inhibitor chemical synthesis process of claim 1 is characterized in that: the synthetic route of described compound is,
Scheme 1 (a) polyphosphoric acid, 75～85 ℃, 50～70min; (b) bromine (bromine: compound 3 mol ratios=2: 1), acetate, room temperature; (c) bromine (bromine: compound 4 mol ratios=4: 1), aluminum chloride, acetate, 75～85 ℃; (d) trifluoroacetic acid, triethyl silicane, room temperature.
3. according to the described chemical synthesis process of claim 2, it is characterized in that: the concrete preparation process of described inhibitor is as follows,
(1) according to 1: 1 ratio of mol ratio veratric acid, veratrole and polyphosphoric acid are joined in the container bottle, the mass ratio of veratric acid and polyphosphoric acid is 1: 4～1: 5,75～85 ℃ of stirring reaction 50～70min; Be cooled to 60 ℃ and in 30min in reactant the mixture of ice and water of 5 times of volumes of dropwise reaction system, separate out a large amount of water-fast pink solid in the reactant this moment; After filtration dewaters, the solid that obtains is dissolved in the methylene dichloride, the mass ratio of solid and methylene dichloride is 1: 3～1: 5, washs respectively 3～5 times with isopyknic mass concentration 3% sodium hydroxide solution and distilled water successively; The anhydrous sodium sulfate drying methylene dichloride mutually after, concentrating under reduced pressure gets pink solid; Evaporated under reduced pressure gets faint yellow solid behind the petroleum ether solids 3～5 times, through Spectrum Analysis, the conclusive evidence compound be Bis-(3,4-dimethoxy-phenyl)-methanone;
(2) (3,4-dimethoxy-phenyl)-methanone and acetate adds in the reaction flask, stirs fast under the room temperature and makes the solid dissolving, their mass ratio is 1: 7～1: 9 will to react the compd B is-of preparation in (1); Bromine added in the acetate dilute, their volume ratio 1: 2, compd B is-(3,4-dimethoxy-phenyl)-methanone: bromine mol ratio=1: 2, drop to fast in the reaction flask under the room temperature, dropwise in the 20min; After bromine dropwises, stir under the room temperature and continue have light-yellow precipitate to separate out behind the reaction 1h, TLC detection reaction terminal point, stopped reaction after raw material point disappears; Reaction solution is poured the separating funnel that fills saturated aqueous common salt into, adds dichloromethane extraction 3～5 times, merges organic phase; Anhydrous sodium sulfate drying gets brown solid behind the concentrating under reduced pressure; Acetone repetitive scrubbing solid, evaporated under reduced pressure gets micro-yellow powder, through Spectrum Analysis, the conclusive evidence compound be Bis-(2-bromo-4,5-dimethoxy-phenyl)-methanone;
(3) will react the compd B is-(2-bromo-4 for preparing in (2), 5-dimethoxy-phenyl)-methanone and acetate adds in the reaction flask, their mass ratio is 1: 18～1: 22, be warming up to 40～50 ℃ and add aluminum chloride, aluminum chloride: the quality of acetic acid ratio is 1: 10～1: 15; Stirring reaction 30min postcooling is to room temperature; Bromine added in the acetate dilute, their volume ratio 1: 5, compd B is-(2-bromo-4,5-dimethoxy-phenyl)-and methanone: bromine mol ratio=1: 4, drop in the reaction flask under the room temperature, dropwise in the 1h, slowly be warming up to 80 ℃ of backflows then, TLC detection reaction terminal point, stopped reaction after raw material point disappears; Reaction solution is poured the separating funnel that fills volume by volume concentration 3% hydrochloric acid soln into, adds dichloromethane extraction 3～5 times, merges organic phase, gets brown solid after the evaporated under reduced pressure; Adopt silica gel chromatography, sherwood oil: ethyl acetate volume ratio=8: 1 be an eluent, pale yellow powder, pass through Spectrum Analysis, the conclusive evidence compound be Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methanone;
(4) will react the compd B is-(2 for preparing in (3), 3-dibromo-4,5-dimethoxy-phenyl)-methanone and trifluoroacetic acid add in the reaction flask, their mass ratio 1: 9～1: 11, agitation condition adds triethyl silicane down fast, triethyl silicane and trifluoroacetic acid volume ratio are 1: 10, stirring reaction under the room temperature; TLC detection reaction terminal point adds the distilled water termination reaction after raw material point disappears; Reaction solution merges organic phase with dichloromethane extraction 3～5 times, anhydrous sodium sulfate drying, after the evaporated under reduced pressure pale solid, through Spectrum Analysis, the conclusive evidence compound be Bis-(2,3-dibromo-4,5-dimethoxy-phenyl)-methane.
4. the application of the described inhibitor of claim 1 in preparation treatment diabetes B medicine, the described compound of claim 1 is the new compound with PTP1B enzyme inhibition activity, can be by negative regulation insulin signaling transduction path, strengthen insulin receptor susceptibility, the Regular Insulin physiological function is normally brought into play, and then regulating and controlling blood sugar, reach therapeutic efficiency to insulin resistant class diabetes B.
5. according to the described application of claim 1, it is characterized in that: the described compound of claim 1 has PTP1B and suppresses active, and chemical equivalence things such as acceptable salt, ester or ether can mix with pharmaceutically acceptable pharmaceutical carrier and can be made into tablet, capsule, oral liquid, granule, pill or the injection of treatment to insulin resistant class diabetes B on its compound itself and the pharmacology.
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| CN102020545A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B inhibitor, synthesis and application thereof |
| CN102020547A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor as well as chemical synthesis method and application thereof |
| CN102020539A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor, synthesis and application thereof in preparation of drugs for treating type 2 diabetes mellitus |
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| CN102020541A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | Protein tyrosine phosphatase 1B (PTP1B) inhibitor as well as chemical synthesis method and application thereof |
| CN102020546A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B inhibitor and preparation and application in preparing drug for treating type 2 diabetes mellitus thereof |
| CN105777505A (en) * | 2016-03-31 | 2016-07-20 | 中国科学院海洋研究所 | Novel fluorinated PTP1B (protein tyrosine phosphatase 1B) inhibitor as well as synthesis method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020547B (en) * | 2010-04-13 | 2012-09-19 | 中国科学院海洋研究所 | PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor as well as chemical synthesis method and application thereof |
| CN102020541B (en) * | 2010-04-13 | 2012-09-12 | 中国科学院海洋研究所 | Protein tyrosine phosphatase 1B (PTP1B) inhibitor as well as chemical synthesis method and application thereof |
| CN102020539A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor, synthesis and application thereof in preparation of drugs for treating type 2 diabetes mellitus |
| CN102020546B (en) * | 2010-04-13 | 2013-07-24 | 中国科学院海洋研究所 | PTP1B inhibitor and preparation and application in preparing drug for treating type 2 diabetes mellitus thereof |
| CN102020541A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | Protein tyrosine phosphatase 1B (PTP1B) inhibitor as well as chemical synthesis method and application thereof |
| CN102020546A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B inhibitor and preparation and application in preparing drug for treating type 2 diabetes mellitus thereof |
| CN102020547A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor as well as chemical synthesis method and application thereof |
| CN102020539B (en) * | 2010-04-13 | 2012-09-12 | 中国科学院海洋研究所 | PTP1B (Protein Tyrosine Phosphatase 1B) inhibitor, synthesis and application thereof in preparation of drugs for treating type 2 diabetes mellitus |
| CN102020545B (en) * | 2010-04-13 | 2012-09-12 | 中国科学院海洋研究所 | PTP1B inhibitor, synthesis and application thereof |
| CN102020545A (en) * | 2010-04-13 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B inhibitor, synthesis and application thereof |
| CN102018688B (en) * | 2010-08-06 | 2012-10-10 | 中国科学院海洋研究所 | PTP1B inhibitor and synthesis and application thereof in preparation of medicine used for treating type II diabetes |
| CN102018688A (en) * | 2010-08-06 | 2011-04-20 | 中国科学院海洋研究所 | PTP1B inhibitor and synthesis and application thereof in preparation of medicine used for treating type II diabetes |
| CN105777505A (en) * | 2016-03-31 | 2016-07-20 | 中国科学院海洋研究所 | Novel fluorinated PTP1B (protein tyrosine phosphatase 1B) inhibitor as well as synthesis method and application thereof |
| CN105777505B (en) * | 2016-03-31 | 2018-01-09 | 中国科学院海洋研究所 | A kind of fluoro PTP1B inhibitor and its synthesis and application |
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