CN101143869A - Aldose reductase inhibitor structure and synthesis method thereof - Google Patents
Aldose reductase inhibitor structure and synthesis method thereof Download PDFInfo
- Publication number
- CN101143869A CN101143869A CNA200710121326XA CN200710121326A CN101143869A CN 101143869 A CN101143869 A CN 101143869A CN A200710121326X A CNA200710121326X A CN A200710121326XA CN 200710121326 A CN200710121326 A CN 200710121326A CN 101143869 A CN101143869 A CN 101143869A
- Authority
- CN
- China
- Prior art keywords
- compound
- aldose reductase
- reductase inhibitor
- formula
- synthesis method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses the structure of a class of hydantoin type aldose reductase (AR) inhibitor and a synthesis method, and the structure of the present invention is shown as the formula on the upper right. In the preparation method, according to the molar equivalent ratio of 1:1.2, a compound <1><2> and phenylenediamine are catalyzed by DCC, so that a coupling reaction occurs, and therefore the aldose reductase (AR) inhibitor is generated. The preparation process is expressed by a molecular structure reaction formula which is shown as the formula on the lower right, and the compound (1) in the reaction formula is (2S, 4S)-6-fluorin-2', 5'-dioxaspiro[chroman-4, 4' imidazole alkane]-2-carboxylic acid.
Description
Technical field
The present invention relates to novel aldose reductase inhibitor, its preparation method and to the restraining effect of aldose reductase (AR) is applied to chemicobiology, biomedicine and bioengineering field.
Background technology
A large amount of animals and clinical experiment have proved that aldose reductase inhibitor (ARIs) is very effective to the treatment diabetic complication.In past 30 years, have at least 14 kinds of ARIs to be proved to be very effectively and by the II phase clinical.The Epalrestat that has the most effectively gone on the market in Japan and entered clinical Fidarestat and AS-3201 of III phase wherein.And wherein Fidarestat is proved to be more effective than the Epalrestat that has gone on the market, and its inhibition effect in vivo will be higher than Epalrestat far away.The ARIs of all discoveries at present mainly is combined in the known catalytic activity position of AR.It is reported
[1], may have the active combining site of on-catalytic near the catalytic activity position of enzyme, not only can strengthen inhibition to the combination at these nonactive positions, and selection of inhibitors can strengthen greatly also.Based on above-mentioned background, the present invention as precursor structure, has designed and synthesized a class novel cpd with Fidarestat, and estimates, determined the restraining effect of compound to AR.
Summary of the invention
The object of the present invention is to provide a class new aldose reductase (AR) is had compound that suppresses ability more by force and preparation method thereof.
Compound provided by the present invention is a compound 2, and its structural formula is:
The synthetic method of compound 2 is with compound 1
[2](for prior art) makes than linked reaction takes place under DCC catalysis with 1: 1.2 molar equivalent with Ursol D.This preparation process can be expressed as follows with the molecular structure reaction formula:
In the reaction formula compound 1 be (2S, 4S)-6-fluoro-2 ', 5 '-dioxy spiral shell [chroman-4,4 '-imidazolidine]-2-carboxylic acid.
The title of compound 2a of the present invention, structure and molecular weight are as shown in table 1.
Title, structure and the molecular weight of table 1 compound 2a
To the aldose reductase inhibition activity measuring method: the AR that proposes from the mouse eyes is partly purified, tested new synthetic compound 2a then,, use fidarestat compound in contrast in the active ability of vitro inhibition AR (as shown in table 2).Test in the variation that 340nm (for the absorption of AR coenzyme NADP 11) locates absorbancy with ultraviolet spectrophotometer monitoring reaction liquid.
Table 2 compound 2a and fidarestat are in external inhibition ability to mouse lens AR
| Compound | Suppress percentage ratio (%) | IC 50 a (μM) | |||||
| 10 -8M | 3.3× 10 -8M | 5×10 -8 M | 10 -7M | 10 -6M | 10 -5M | ||
| 2a | 13 | --- b | --- b | 36 | 40 | 81 | 0.42 |
| fidarestat | 26 | --- b | 42 | 88 | --- b | --- b | 0.034 |
aIC
50(μ M) is value measured in the experimental system of implementing in the present invention (95%C.L.)
bUnder this concentration, do not measure
Compound provided by the present invention and inhibition activity can be used for the synthetic of aldose reductase inhibitor and reach the inhibiting research of aldose reductase, can be used as aldose reductase inhibitor uses in the treatment diabetic complication, and in chemicobiology, biomedicine and bioengineering field are with a wide range of applications.
Embodiment
Embodiment 1
The preparation of compound 2:
According to former document
[2]In method can get raw material 1, make compound 2 with raw material 1 again
The preparation method of compound 2 is approximate, with compound (2S, 4S)-6-fluoro-2 ', 5 '-dioxy spiral shell [chroman-4,4 '-imidazolidine]-2-amide group-to the example that is prepared as of aniline 2a.
1, (100mg 0.36mmol), dissolves in THF, adds HOBt (59mg, 0.50mmol), adds DCC (152mg 0.72mmol) then with raw material 1.
2, the reaction stirring at room is 20 minutes, and (46.7mg 0.43mmol), stirs after 5 hours, and TLC checks (chloroform/methanol=10/1), finds Rf=0.60 (corresponding product 2a) under the ultraviolet, and reaction mixture is filtered, and filters white precipitate DCU to add Ursol D.
3, column chromatography (methylene chloride=25/1) carries out purifying to thick product and obtains product 2a (64mg, 46/%), pale yellow powder.
Institute's synthetic compound all passes through ESI mass spectrum (MS) in the enforcement, and nuclear magnetic resonance spectrum (1HNMR) is analyzed and ultimate analysis is identified.
Implement The compounds of this invention to aldose reductase inhibition activity
1, preparation buffered soln: compound concentration is NaH2P04 and the Na2HP04 solution of 0.2mol/L respectively earlier, gets the two 81.5ml then respectively, and it is 200ml that 18.5ml is diluted with water to final volume, promptly obtains the phosphate buffer soln of 0.1mol/L pH=6.2.
2, compound concentration is 0.104 mM NADPH solution (with a buffered soln as solvent).
3, compound concentration is 10 mM D, L-Glycerose solution (with buffered soln as solvent).
4, from the mouse eyeball that normally kills, take out lens rapidly, in the Glas-Potter homogenizer, add 3 times (0.4ml/lens) then in cold deionized water (0-4 ℃) homogenate of its volume.Homogenate in refrigerated centrifuge with 12000 * g rotating speed, 0-4 ℃ temperature, centrifugal 30min. gets supernatant liquor at last, is the aqueous solution of AR, is used for the enzyme test of living.
5, under the temperature of 30 ° of C, in 1ml test cuvette, add 0.25mL 0.104mM NADPH respectively, 0.25mL0.1M phosphate buffer soln (pH=6.2), the enzyme liquid that 0.1mL extracted, 0.15mL deionized water.With reference to adding 0.25mL 0.104mM NADPH, 0.50mL 0.1M phosphate buffer soln (pH=6.2), the enzyme liquid that 0.1mL extracted, 0.15mL deionized water in the cuvette.Then two cuvettes that contain above-mentioned mixed solution are placed under 30 ℃ of conditions insulation 10min.Adding 0.25mL 10mM substrate at last in the test cuvette is D, and L-Glycerose begins reaction, monitors 5min with ultraviolet spectrophotometer at 340nm.From the gained data, be the longitudinal axis with the absorbancy, the time is horizontal state, can get a straight line, tries to achieve this collinear slope, is designated as I
0, represent enzyme to live.The active optimum value of enzyme is to be in the NADPH absorbancy to change in the scope of 0.011 ± 0.0010 absorbance unit/min, if not in this scope, makes it reach this scope by dilution enzyme liquid.Will add the contrast cuvette to the test cuvette is in order to proofread and correct because non-enzyme factor the oxidation of the NADPH that (also can oxidation NADPH such as oxygen in the air) be caused.
6, the compound test that suppresses percentage ratio is similar with surveying the method that enzyme lives, just when not adding substrate, and be at the test cuvette and respectively add the test compound solution of 5 μ L in reference to cuvette.Gained collinear slope is designated as Ix.Calculate inhibition percentage ratio under can this concentration according to following formula then.
I％＝(|I
0-I
x|/|I
0|)×100％
The compound solution of replicate measurement different concns, calculate the inhibition percentage ratio of respective concentration respectively, can obtain " inhibition percentage ratio " straight line, read from figure then that to suppress percentage ratio be the concentration logarithm of 50% correspondence " concentration logarithm ", antilogarithm get final product IC
50
Claims (2)
1. aldose reductase inhibitor structure and synthetic method is characterized in that:
The structure of compound 2 is:
2. the synthetic method of compound 2 as claimed in claim 1 is characterized in that: be with compound 1
[2]Than taking place under DCC catalysis, linked reaction makes with 1: 1.2 molar equivalent with phenylenediamine;
This preparation process is expressed as follows with the molecular structure reaction formula:
In the reaction formula compound 1 be (2S, 4S)-6-fluoro-2 ', 5 '-dioxy spiral shell [chroman-4,4 ' imidazolidine]-2-carboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710121326XA CN101143869A (en) | 2007-09-04 | 2007-09-04 | Aldose reductase inhibitor structure and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710121326XA CN101143869A (en) | 2007-09-04 | 2007-09-04 | Aldose reductase inhibitor structure and synthesis method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101143869A true CN101143869A (en) | 2008-03-19 |
Family
ID=39206619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710121326XA Pending CN101143869A (en) | 2007-09-04 | 2007-09-04 | Aldose reductase inhibitor structure and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101143869A (en) |
-
2007
- 2007-09-04 CN CNA200710121326XA patent/CN101143869A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liao et al. | A novel acylhydrazone-based derivative as dual-mode chemosensor for Al3+, Zn2+ and Fe3+ and its applications in cell imaging | |
| CN101143868A (en) | Aldose reductase inhibitor structure and use | |
| Nocentini et al. | 7-Aryl-triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrase IX and XII | |
| Zianna et al. | Zinc complexes of salicylaldehydes: synthesis, characterization and DNA-binding properties | |
| Chen et al. | Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold | |
| Günsel et al. | Comparison of novel tetra-substituted phthalocyanines with their quaternized derivatives: Antioxidant and antibacterial properties | |
| Yu et al. | A supramolecular bifunctional artificial enzyme with superoxide dismutase and glutathione peroxidase activities | |
| Shang et al. | The effect of 7, 8, 4‐trihydroxyflavone on tyrosinase activity and conformation: Spectroscopy and docking studies | |
| CN104774607B (en) | The fluorescent probe of single-minded identification bivalent cupric ion and application in a kind of aqueous phase | |
| Gao et al. | A “reactive” turn-on fluorescence probe for hypochlorous acid and its bioimaging application | |
| CN108484582A (en) | A kind of cumarin hydroxyacyl hydroxyacyl hydrazine class schiff bases Al3+Fluorescence probe prepares and application | |
| Eğlence-Bakır et al. | Dioxomolybdenum (VI) complexes with 3-methoxy salicylidene-N-alkyl substituted thiosemicarbazones. Synthesis, characterization, enzyme inhibition and antioxidant activity | |
| CN102426157B (en) | Method for analyzing tyrosinase activity based on functional Au nanoparticles | |
| CN107365830A (en) | A kind of oxidoreductase activity method of testing | |
| CN105968098B (en) | A kind of quinoline substituted containing carbazole, benzimidazole and its preparation method and application | |
| CN101143869A (en) | Aldose reductase inhibitor structure and synthesis method thereof | |
| US20170057986A1 (en) | Magnetic resonance imaging contrast agent capable of detecting hydrogen peroxide and reducing reactive oxygen species | |
| Wu et al. | Light-responsive benzobisthiazole as oxidase mimic for rapid determination of glutathione in food and vegetable | |
| US11499094B1 (en) | Ratiometric fluorescent probe, preparation method thereof, and application in detection of hydrogen peroxide | |
| CN110330505A (en) | A kind of two-photon Ratiometric fluorescent probe compound and preparation method thereof for Aminopeptidase N detection | |
| Karlık et al. | Microwave‐assisted synthesis of 1‐substituted‐1H‐benzimidazolium salts: Non‐competitive inhibition of human carbonic anhydrase I and II | |
| CN104946244A (en) | Fluorescent molecular probe for detecting O2.<-> as well as synthesis method and application thereof | |
| CN101417989B (en) | Anion receptor based on nitrofuran formyl hydrazone and phenolic hydroxyl and preparation and use of organagel thereof | |
| CN101493417B (en) | Simple method for detecting concentration of oxalic acid | |
| CN103588727A (en) | 2-mercapto-1,3,4-thiadiazole derivative, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080319 |