CN1990481A - Scutellarein derivative, its preparing process and application - Google Patents
Scutellarein derivative, its preparing process and application Download PDFInfo
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Abstract
The invention discloses a novel scutellarein derivative, the method for preparing the same and the application. It is proved through pharmacological test that the compound possesses obvious effect against lipid peroxidation, effect against cell damage induced by H2O2 and cell apoptosis induced by A beta, it can also inhibit Cu2+ from inducing oxidation and modification for low density lipoprotein. The compound can be used to prepare medicine that can prevent or treat neurodegenerative diseases such as Alzheimer's disease caused by free radical oxidation, and medicine that can treat inflammation, reduce blood fat and treat atherosclerosis.
Description
Technical field
The present invention relates to the novel Scutellarein derivative of a class, be specifically related to the application in nerve degenerative diseases, anti-inflammatory, reducing blood-fat, the treatment atherosclerosis medicine such as class treatment Alzheimer.
Background technology
The relation of free radical and disease is very close.The generation of free radical and removing overbalance in body, excessive free radical can cause damage to DNA, carbohydrate, protein and lipid, thereby cause a series of diseases such as astogeny, cardiovascular disorder or the like, so the compound with excellent antioxidant character is effective with treatment to the prevention of these diseases probably.Seek, screen the drug research that has the formation of blocking-up free radical or remove free radical and more and more be subjected to people's attention.
Scutellarin is a kind of main active ingredient of baikal skullcap root, has multiple physiologically active and pharmacological actions such as anti-oxidant, anti-inflammatory, antibiotic, resistance attitude, decreasing cholesterol.Most pharmacologically actives of scutellarin are based on its antioxygenation, but its effect is not very strong, and solubility property is bad, has limited its application in field of medicaments.In order to improve these shortcomings and to enlarge its range of application, people transform it, are intended to seek novel active compound.Bibliographical information (J.Med.Chem, 2004,47,5555-5566),, the A ring obtained a series of Scutellarein derivatives by being carried out alkylation, and strengthen it and suppressed P-glycoprotein 170 activity, the active testing result shows that these compounds have certain cytotoxicity; Other have bibliographical information (Acta Pharmaceutica Sinica, 1997,32,140-143) two benzyl oxide analog derivatives have certain HIV (human immunodeficiency virus)-resistant activity.The methylamine class Scutellarein derivative that also has patent (Chinese patent application number 02111185.5) to report that the 8-position replaces has the activity of stronger arrestin kinase c (PKC) and inhibition virus of AIDS HIV/IIIB.But Shang Weijian is about carrying out structure of modification to obtain stronger bibliographical information with lipoid peroxidization resistant and control because of disease that radical damage is caused to scutellarin.
The present invention is in order to strengthen its antioxygenation and to improve its solubility property, the effective group of difference is introduced scutellarin, obtain the novel Scutellarein derivative of a class, and then find new biological activity, can be developed further into associated nerve degenerative diseases such as treatment Alzheimer, and anti-inflammatory, reducing blood-fat, the atherosclerotic medicine of treatment, to satisfy the needs of clinical application.
Summary of the invention
The purpose of this invention is to provide the novel Scutellarein derivative of a class;
Another object of the present invention is several preparation methods that disclose this compounds;
The 3rd purpose of the present invention is to disclose the application of this compounds in nerve degenerative diseases, anti-inflammatory, reducing blood-fat, the atherosclerotic medicines of treatment such as preparation treatment Alzheimer.
The present invention has synthesized the Scutellarein derivative that following general structure is arranged:
(I) in the formula: R1, R2, R3 can be identical or different, and R1, R2, R3 represent hydrogen, alkyl, aryl, electron-donating group such as F or electron-withdrawing group such as OCH
3The cycloalkyl that replaces of substituted aryl, alkynyl, thiazolinyl, cycloalkyl, heteroatoms, fatty acyl group, aromaticacyl radical ,-RNR``R` ,-RCOOR```;
Wherein, R is an alkyl, R`, R`` can be identical or different, and R`, R`` and R``` represent hydrogen, alkyl, thiazolinyl, alkynyl, aryl.
Scutellarein derivative of the present invention can prepare by the following method:
Reaction formula 1
Reaction formula 1 has provided the synthetic method of 7-position Scutellarein derivative.
Scutellarin (1) obtains compound (2) under catalyzer and solvent action, temperature of reaction is 70～80 ℃, and the reaction times is 7-24 hour; Said solvent is an aceticanhydride, and said catalyzer comprises Na
2CO
3Or pyridine;
Compound (2) obtains compound (3) with allyl bromide 98 or chlorallylene reaction under catalyzer and solvent action, temperature of reaction is 60～75 ℃, and the reaction times is 8～24 hours; Said solvent comprises acetone, DMF, and said catalyzer comprises K
2CO
3, KI;
Compound (3) obtains compound (4) under catalyzer and solvent action, temperature of reaction is 60～90 ℃, and the reaction times is 3～12 hours; Said solvent comprises methyl alcohol, ethanol, acetone, and said catalyzer comprises dense HCl;
Compound (4) obtains compound (5) with cylite or Benzyl Chloride reaction under catalyzer and solvent action, temperature of reaction is 60～80 ℃, and the reaction times is 6～36 hours; Said solvent comprises acetone, DMF, and said catalyzer comprises K
2CO
3, KI;
Compound (5) obtains compound (6) under catalyzer and solvent action, temperature of reaction is a room temperature, and the reaction times is 0.5～3 hour; Said solvent comprises THF, and said catalyzer comprises Pd (Ph
3)
4And NaBH
4
Compound (6) obtains compound (7) with bromo-derivative and chloro thing or acyl chloride reaction under catalyzer and solvent action, temperature of reaction is room temperature or 60～80 ℃, and the reaction times is 1～12 hour; Said solvent comprises pyridine and acetone, DMF or CHCl
3And CH
2Cl
2, said catalyzer comprises Ag
2CO
3And K
2CO
3, KI and triethylamine;
Compound (7) obtains compound (I) under catalyzer and solvent action, temperature of reaction is a room temperature, and the reaction times is 4～36 hours; Said solvent comprises THF, and said catalyzer comprises Pd/C.
Compound (2) obtains compound (8) with cylite or Benzyl Chloride and allyl bromide 98 or chlorallylene reaction under catalyzer and solvent action, temperature of reaction is 60～75 ℃, and the reaction times is 8～24 hours; Said solvent comprises acetone, DMF, and said catalyzer comprises K
2CO
3, KI;
Compound (8) obtains compound (9) under catalyzer and solvent action, temperature of reaction is 60～90 ℃, and the reaction times is 3～12 hours; Said solvent comprises methyl alcohol, ethanol, acetone, and said catalyzer comprises K
2CO
3, NaOH or KOH;
Compound (9) obtains compound (10) with bromo-derivative and chloro thing under catalyzer and solvent action, 60～80 ℃ of temperature of reaction, and the reaction times is 8～36 hours; Said solvent comprises acetone, DMF, and said catalyzer comprises K
2CO
3, KI;
Compound (10) obtains compound (I) under catalyzer and solvent action, temperature of reaction is a room temperature, and the reaction times is 0.5～36 hour; Said solvent comprises THF, and said catalyzer comprises Pd/C or Pd (PPh
3)
4And NaBH
4
Reaction formula 3
Reaction formula 3 has provided the synthetic method of 6-position ester bond Scutellarein derivative.
Scutellarin (1) obtains compound (I) with aromatic acid or fatty acid response under catalyzer and solvent action, temperature of reaction is a room temperature, and the reaction times is 0.5-2 hour; Said solvent is DMF, said catalyzer comprise benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (blocking special condensing agent),
Triethylamine;
Compound (I) under catalyzer and solvent action with CH
3The I reaction obtains compound (11), and temperature of reaction is a room temperature, and the reaction times is 2-12 hour; Said solvent is DMF, acetone, and said catalyzer comprises K
2CO
3, with the position of NOE conclusive evidence replacement.
Scutellarein derivative of the present invention has been carried out following biological activity determination:
By certain bioactivity screening (as anti peroxidation of lipid, the antagonism H
2O
2Methods such as inductive cell injury) find that this analog derivative shows tangible activity, be better than scutellarin, associated disease treatment will be applicable to, as nerve degenerative diseases, anti-inflammatory, reducing blood-fat, treatment atherosclerosiss etc. such as treatment Alzheimers.
1, anti peroxidation of lipid
The MDA assay is got the fresh rat liver, and is clean with the physiological saline rinsing, puts to wipe away driedly on the thieving paper, takes by weighing 1g, puts in the small beaker to shred for a short time with ophthalmology, adds 20mL physiological saline, transfers in the homogenate pipe ice bath homogenate 7～8 minutes.Get the 10mL centrifuge tube, every pipe adds homogenate 1mL, adds soup, mixing, 37 ℃ of water-baths 90 minutes.After the taking-up, every pipe adds 10% trichoroacetic acid(TCA) and each 1mL of 0.67% thiobarbituricacid, and mixing was put in the boiling water bath 15 minutes.The flowing water cooling, centrifugal 10 minutes of 4000rpm gets supernatant 532nm colorimetric estimation.Calculate MDA content with following formula.
MDA content (nmol/mg prot)={ [(A
Sample-A
Blank) ÷ (A
Standard-A
Blank)] * 10nmol/ml} ÷ protein content
Being determined in the small test tube of protein content adds above-mentioned liver homogenate liquid 0.05mL, the pipe of writing in reply, and other gets 0.05mL distilled water and 0.05mL standard protein (1mg/mL) respectively as blank and standard control.Each pipe adds examines blue solution (0.1g/L) 3mL of Ma Shi, mixing, after 10 minutes in 595nm place its absorbancy of mensuration.With following formula calculation sample protein content
Sample protein content (mg/ml)=[(A
Sample-A
Blank) ÷ (A
Standard-A
Blank)] * 1mg/ml
MDA content with not administration liver homogenate is 100%, and the reduction percentage ratio of MDA content is inhibiting rate after the calculating administration, and by the MDA content reduction inhibiting rate of different concns dosage, statistical study draws IC
50Value.
Experimental result sees Table 1
Table 1 explanation: indicate in the table
*P＜0.01 representative has remarkable effect.
2, antagonism H
2O
2The inductive cell injury
The PC12 cell is with the DMEM nutrient solution that contains 10% calf serum, with 1 * 10
5Individual/mL density is inoculated on 96 well culture plates, and the inoculation volume is 100 μ L/ holes, puts into subsequently to contain 5%CO
237 ℃ of constant incubators in cultivate.Cultivate after 24 hours, add the compound 10 μ L/ holes of respective concentration in the administration group, final concentration is 10
-5, 10
-6M preincubate 2 hours (control group and damage group add 10 μ L/ hole PBS respectively, make its volume keep equating).After the PC12 cell is hatched 2 hours, in administration group and damage group, add 200 μ M H respectively
2O
2Damage agent 10 μ L/ holes (control group adds 10 μ L/ hole PBS).After 30 minutes, the RPMI RPMI-1640 that all changes the nutrient solution of each group into no calf serum continues to put into constant incubator to be cultivated 24 hours, and the nutrient solution volume still is 100 μ L/ holes.Continue to cultivate after 24 hours, add 5mg/mL MTT 10 μ L/ holes in each group, carry out viable cell dyeing.After treating 4 hours, add 20%SDS stop buffer 100 μ L/ holes in each group, ambient temperature overnight.Under the dual wavelength of 570/630nm, measure the OD value of each group.Test result repeats 3 times, and with One way ANOVA and Duncan`s test method statistic, each organizes numeric representation is mean ± SEM, is 100% with control group, and administration group and damage class value are represented with the per-cent of control group.
Experimental result sees Table 1
3, antagonism H
2O
2The apoptosis that causes
With the PC12 cell with 1 * 10
5The density of individual/ml is inoculated in 96 orifice plates, medicine and H
2O
2Handle back (treatment process is with the mtt assay unanimity), cell conditioned medium liquid is removed, clean 1 time with PBS, adding is through 37 ℃ of 4% Paraformaldehyde 96 stationary liquid, and room temperature 15 minutes is removed the Paraformaldehyde 96 stationary liquid, PBS cleans 3 times, with 1 μ g/ml DAPI staining agent room temperature dyeing 30 minutes, clean 3 times with PBS, fluorescent microscope is observed down.Antagonism H
2O
2The apoptosis test result figure that causes.Three compounds all show stronger anti-apoptotic activity.Experimental result is seen accompanying drawing.
Description of drawings
Fig. 1-A is blank figure.
Fig. 1-B is H
2O
2(300 μ M) figure.
Fig. 1-E is the positive hexyloxy scutellarin+H of 7-
2O
2Apoptosis figure.
Fig. 2-A is blank figure.
Fig. 2-B is H
2O
2(300 μ M) figure.
Fig. 2-F is 7-(4-methoxyl group) benzyloxy scutellarin+H
2O
2Apoptosis figure.
Embodiment
The preparation of the positive hexyloxy scutellarin of embodiment 1 7-
1-a:5,6,7-triacetyl oxygen base scutellarin are with 5.40g (20mmol) scutellarin, aceticanhydride 31.8mL (300mmol), sodium acetate, anhydrous 2.25g (28.0mmol) puts in the 100mL reaction flask, and 80 ℃ of reactions are to there not being raw material, pour in the 150mL frozen water, separate out gray solid, filter and collect, with ethanol flush away impurity, get the 7.21g pale solid, productive rate 91.1%.
1HNMR(400MHz，CDCl
3)：δ2.35(s，3H)，2.36(s，3H)，2.45(s，3H)，6.66(s，1H)，7.51-7.55(m，4H)，7.85-7.87(m，2H)；MS(EI)：m/z?396(M
+)，354，312，270(100％)
1-b:5,6-diacetyl-7-allyloxy scutellarin is with 3.96g (10mmol) 5,6,7-triacetyl oxygen base scutellarin, anhydrous K
2CO
35.52g (40mmol), allyl bromide 98 2.54mL (30mmol), anhydrous propanone 250mL puts in the 500mL reaction flask, reflux under the drying regime, to reacting completely filtered while hot, evaporate to dryness, get pale solid, wash impurity, get the 3.64g white solid, productive rate 92.4% with ethyl acetate.
1HNMR(400MHz，CDCl
3)：δ2.35(s，3H)，2.45(s，3H)，4.68-4.70(m，2H)，5.34-5.46(m，2H)，5.97-6.07(m，1H)，6.60(s，1H)，6.95(s，1H)，7.50-7.53(m，3H)，7.84-7.86(m，2H)；MS(EI)m/z：394(M
+)，310(100％)，270，241，69；
NOE shows that the H at 4.68-4.70 place is relevant with 6.95 H of place, illustrates that allyl group is substituted in the 7-position.
1-c:7-allyloxy scutellarin is with 5.52g (14.01mmol) 5,6-diacetyl-7-allyl group oxygen base scutellarin, 200mL ethanol, the dense HCl of 6mL puts in the 500mL reaction flask, reflux, to reacting completely, add 50mL water, be evaporated to a large amount of yellow solids and occur, collect, with small amount of ethanol flush away impurity, get the 3.94g yellow solid, productive rate 90.7%.
1HNMR(400MHz，CDCl
3)：84.73-4.75(m，2H)，5.38-5.51(m，3H)，6.06-6.16(m，1H)，6.62(s，1H)，6.69(s，1H)，7.50-7.58(m，3H)，7.88-7.91(m，2H)，12.52(s，1H)；MS(EI)m/z310(M
+)，296(100％)，241，139，69；
1-d:5,6-benzyloxy-7-allyloxy scutellarin is with 4.65g (15mmol) 7-allyloxy scutellarin, cylite 14.28mL (120mmol), anhydrous K
2CO
316.56g (120mmol), anhydrous propanone 200mL puts in the 500mL reaction flask, reflux under the drying regime, to reacting completely, filtered while hot, evaporated under reduced pressure, gray solid, wash impurity with ethanol, the 6.06g white solid, productive rate 82.4%.
1HNMR(400MHz，CDCl
3)：84.65-4.67(m，2H)，5.06(s，2H)，5.14(s，2H)，5.36-5.40(m，1H)，5.45-5.51(m，1H)，6.04-6.13(m，1H)，6.70(s，2H)，6.82(s，2H)，7.32-7.40(m，6H)，7.44-7.46(m，2H)，7.50-7.54(m，3H)，7.66-7.68(m，2H)，7.88-7.90(m，2H)；MS(EI)m/z：490(M
+)，399，309，91(100％)；
1-e:5,6-benzyloxy scutellarin are with 3.12g (6.37mmol) 5,6-benzyloxy-7-allyl group oxygen base scutellarin, Pd (Ph
3P)
40.172g (0.149mmol), heavily steam THF 80mL, behind stirring at room 5min, add NaBH
40.378g (9.99mmol), continue reaction to there not being raw material.With rare HCl solution adjust pH to 4～5, collect the lead solid, with the post fast purifying, take off with ethyl acetate and the drip washing of sherwood oil mixed solution, get the 2.72g white solid, productive rate 95.0%.
1HNMR(400MHz，DMSO-d
6)：85.00(s，4H)，6.77(s，1H)，6.95(s，1H)，7.30-7.37(m，6H)，7.40-7.43(m，2H)，7.54-7.58(m，5H)，8.01-8.04(m，2H)，11.00(s，1H)；MS(EI)m/z：450(M
+)，359，269，241，91(100％)；
The positive hexyloxy scutellarin of 1-f:5,6-benzyloxy-7-is 0.252g (0.56mmol) 5,6-benzyloxy scutellarin, 0.178g (1.68mmol) anhydrous Na
2CO
3, 65mL anhydrous propanone, 5mL dry DMF, 0.236mL (1.68mmol) 1-Bromohexane, put in the 100mL reaction flask, reflux under the drying regime, reaction is filtered to there not being raw material, with column purification,, get the 0.208g white solid, productive rate 69.7% with ethyl acetate and sherwood oil mixed solution wash-out.
1HNMR(400MHz，CDCl
3)：δ0.91-0.95(m，3H)，1.36-1.56(m，4H)，1.87-1.94(m，4H)，4.09(t，2H，J＝6.46)，5.04(s，2H)，5.14(s，2H)，6.81(s，1H)，6.84(s，1H)，7.33-7.40(m，6H)，7.45-7.47(m，2H)，7.51-7.54(s，3H)，7.66-7.68(m，2H)，7.89-7.92(m，2H)；MS(EI)m/z：534(M
+)，443(100％)，353，269，91；
The positive hexyloxy scutellarin of 1-g:7-is the positive hexyloxy scutellarin of 0.094g (0.176mmol) 5,6-benzyloxy-7-, 10%Pd/C 47mg, and THF 60mL puts in the 100mL reaction flask, at H
2Under the state, room temperature reaction filters to there not being raw material, with column purification, uses CH
2Cl
2And CH
3OH mixed solution wash-out gets the 0.039g yellow solid, productive rate: 62.6%
1HNMR(400MHz，CDCl
3)：δ0.88-0.94(m，3H)，1.33-1.40(m，4H)，1.46-1.52(m，2H)，1.87-1.94(m，2H)，4.13-4.16(m，2H)，5.38(s，1H)，6.60(s，1H)，6.70(s，1H)，7.50-7.56(m，3H)，7.88-7.91(m，2H)；12.50(s，1H)；MS(EI)m/z：354(M
+)，283，270(100％)，168；
The preparation of embodiment 2 7-n-Hexadecane oxygen base scutellarins
2-a:5,6-benzyloxy-7-n-Hexadecane oxygen base scutellarin is 0.121g (0.269mmol) 5,6-benzyloxy scutellarin, 0.133g (1.25mmol) anhydrous Na
2CO
3, 0.458mL (1.50mmol) 1-Bromohexadecane, 65mL anhydrous propanone, 5mL dry DMF, put in the 100mL reaction flask, reflux under the drying regime, reaction is filtered to there not being raw material, with column purification,, get the 0.152g white solid, productive rate 83.9% with ethyl acetate and sherwood oil mixed solution wash-out
1HNMR(400MHz，CDCl
3)：δ0.86-0.90(m，3H)，1.18-1.57(m，26H)，1.87-1.94(m，2H)，4.08(t，2H)，5.05(s，2H)，5.15(s，2H)，6.70(s，1H)，6.84(s，1H)，7.32-7.41(m，6H)，7.45-7.54(m，5H)，7.68-7.70(m，2H)，7.88-7.90(m，2H)；MS(EI)m/z：674(M
+)，583(100％)，493，359，269，91；
2-b:7-n-Hexadecane oxygen base scutellarin is 0.150g (0.222mmol) 5,6-benzyloxy-7-n-Hexadecane oxygen base scutellarin, 10%Pd/C 75mg, and THF 60mL puts in the 100mL reaction flask, at H
2Under the state, room temperature reaction filters to there not being raw material, with column purification, uses CH
2Cl
2And CH
3OH mixed solution wash-out gets the 0.077g yellow solid, and productive rate is 70.0%
1HNMR(400MHz，CDCl
3)：δ0.86-0.89(m，3H)，1.25-1.52(m，26H)，1.87-1.94(m，2H)，4.14(t，J＝6.71，2H)，5.34(s，1H)，6.58(s，1H)，6.64(s，1H)，7.50-7.57(m，3H)，7.88-7.90(m，2H)，12.45(s，1H)；MS(EI)m/z：494(M
+)，283，270(100％)，168，57；
The preparation of embodiment 3 7-(4`-methoxyl group) benzyloxy scutellarin
3-a:5,6-diacetyl-7-(4`-methoxyl group) benzyloxy scutellarin is with 0.277g (0.70mmol) 5,6,7-triacetyl oxygen base scutellarin, 0.483g (3.50mmol) anhydrous K
2CO
3, 0.24mL (1.75mmol) 4-methoxybenzyl chloride, 0.015g (0.09mmol) KI, anhydrous propanone 40mL, reflux under the drying regime, to reacting completely filtered while hot, evaporate to dryness, get pale solid, wash impurity, get the 0.269g white solid, productive rate 81.0%. with ethyl acetate
1HNMR(400MHz，CDCl
3)：δ2.28(s，3H)，2.45(s，3H)，3.82(s，3H)，5.12(s，2H)，6.60(s，1H)，6.92-6.94(m，2H)，7.01(s，1H)，7.32-7.34(d，2H)，7.49-7.54(m，3H)，7.83-7.85(m，2H)；MS(EI)m/z：474(M
+)，432，390，270，121(100％)，84；
3-b:7-(4`-methoxyl group) benzyloxy scutellarin: with 0.160g (0.338mmol) 5,6-diacetyl-7-(4-methoxyl group) phenoxy group scutellarin, 2mL5%NaOH, 30mL acetone is at N
2Under the gas shiled, 40～50 ℃ of reactions are transferred pH to 5～6 to complete with rare HCl liquid, add 10mL water, are evaporated to a large amount of yellow solids and occur, and collect, and with small amount of ethanol flush away impurity, get the 0.114g yellow solid, productive rate 86.4%.
1HNMR(300MHz，DMSO-d
6)：δ3.75(s，3H)，5.20(s，2H)，6.94-7.00(m，3H)，7.06(s，1H)，7.44-7.47(m，2H)，7.55-7.62(m，3H)，8.07-8.10(m，2H)；MS(EI)m/z：390(M
+)，375，270，121(100％)
Preparation method by embodiment 3 also can prepare 7-(4`-fluorine) benzyloxy scutellarin, 7-(3`, the inferior fork base of 4`-dioxy) benzyloxy scutellarin or the like compound.
Embodiment 4 7-[1`-(ethoxycarbonyl)] preparation of propoxy-scutellarin
4-a:5,6-benzyloxy-7-[1`-(ethoxycarbonyl)] the propoxy-scutellarin is 0.127g (0.282mmol) 5,6-benzyloxy scutellarin, anhydrous pyridine 10mL, Ag
2CO
30.320g (1.16mmol), put in the 25mL reaction flask, sealing is injected 62 μ L (0.423mmol) 2-bromo ethyl butyrates with syringe, and room temperature reaction is poured 150mL CHCl into to there not being raw material
3In, it is inferior to give a baby a bath on the third day after its birth with rare HCl solution, CHCl
3Liquid is with anhydrous Na
2SO
4Drying with column purification, with ethyl acetate and sherwood oil mixed solution wash-out, gets the unformed solid of 0.116g, productive rate 73.0%.
1HNMR(400MHz，CDCl
3)：δ1.14(t，3H，J＝7.28)，1.26(t，3H，J＝7.14)，2.08-2.15(m，2H)，4.26(q，J＝7.14，2H)，4.77(t，J＝5.90，1H)，5.02-5.17(m，4H)，6.72(s，1H)，6.88(s，1H)，7.31-7.40(m，6H)，7.47-7.54(m，5H)，7.64-7.66(m，2H)，7.88-7.90(m，2H)；MS(EI)m/z：564(M
+)，473，383，269，91(100％)；
4-b:7-[1`-(ethoxycarbonyl)] the propoxy-scutellarin is 0.113g (0.200mmol) 5,6-benzyloxy-7-[1`-ethyl-2`-(ethoxycarbonyl)] the oxyethyl group scutellarin, 10%Pd/C 56.5mg, THF 60mL puts in the 100mL reaction flask, at H
2Under the state, room temperature reaction filters to there not being raw material, with column purification, uses CH
2Cl
2And CH
3OH mixed solution wash-out gets the 0.046g yellow solid, productive rate 60.0%
1HNMR(400MHz，CDCl
3)：δ1.14(t，J＝7.42，3H)，1.26(t，J＝7.15，3H)，2.05-2.13(m，1H)，4.24(q，J＝7.14，2H)，4.70(t，J＝5.36，1H)，6.54(s，1H)，6.68(s，1H)，7.48-7.55(m，3H)，7.85-7.87(m，2H)；MS(EI)m/z：384(M
+)，338，311，281，270(100％)，254，241，168；
Embodiment 5 7-[2`-(to chlorophenoxy)] preparation of isobutyl acyloxy scutellarin
5-a:5,6-benzyloxy-7-[2`-(to chlorophenoxy)] isobutyl acyloxy scutellarin is 0.115g (0.256mmol) 5,6-benzyloxy scutellarin, 0.089g (0.382mmol) 2-methyl-2-(4-chlorophenoxy) propionyl chloride, 84 μ L (0.60mmol) triethylamines heavily steam CH
2Cl
250mL puts in the 100mL reaction flask, and room temperature reaction is poured 150mL CH into to there not being raw material
2Cl
2In, with washing, saturated NaCl liquid is washed, and uses anhydrous Na
2SO
4Drying is filtered, and evaporate to dryness with amount of ethyl acetate flush away impurity, gets the 0.138g white solid, productive rate 83.6%
1HNMR(400MHz，CDCl
3)：1.60(s，6H)，5.10(s，2H)，5.17(s，2H)，6.75(s，1H)，6.87-6.90(m，2H)，7.02(s，1H)，7.13-7.16(m，2H)，7.29-7.40(m，8H)，7.51-7.64(m，5H)，7.88-7.90(m，2H)；MS(EI)：646(M
+)，555，359，269，91(100％)；
5-b:7-[2`-(to chlorophenoxy)] isobutyl acyloxy scutellarin is 0.129g (0.200mmol) 5,6-benzyloxy-7-[2`-methyl-2`-(4-chlorophenoxy)] the propionyloxy scutellarin, 10%Pd/C 64.5mg, THF 60mL puts in the 100mL reaction flask, at H
2Under the state, room temperature reaction filters to there not being raw material, with column purification, uses CH
2Cl
2And CH
3OH mixed solution wash-out gets 0.073g deep yellow solid, productive rate 78.2%
1HNMR(400MHz，CDCl
3)：δ1.82(s，6H)，6.57(s，1H)，6.65(s，1H)，6.98-7.08(m，2H)，7.26-7.30(m，2H)，7.50-7.56(m，3H)，7.85-7.87(d，2H)，12.98(s，1H)；MS(EI)m/z：466(M
+)，270(100％)，168；
The preparation of the positive hexyloxy scutellarin of embodiment 6 6-
6-a:5,6-diacetoxy-7-benzyloxy scutellarin is with 1.98g (5mmol) 5,6,7-triacetyl oxygen base scutellarin, 2.26g (20mmol) anhydrous K
2CO
3, benzyl bromine 1.78mL (15mmol), 5mgKI, anhydrous propanone 200mL puts in the 500mL reaction flask, reflux under the drying regime, to reacting completely, filtered while hot, evaporate to dryness, pale solid, wash impurity with ethyl acetate, the 1.88g white solid, productive rate 84.8%.
1HNMR(400MHz，CDCl
3)：2.32(s，3H)，2.46(s，3H)，5.22(s，2H)，6.60(s，1H)，7.00(s，1H)，7.36-7.43(m，5H)，7.48-7.54(m，3H)，7.83-7.85(m，2H)；MS(EI)m/z：444(M
+)，402，360，269，91(100％)；
NOE shows that the H at 5.22 places is relevant with the H at 7.00 places, shows that benzyl replaces the 7-position.
6-b:7-benzyloxy scutellarin is 5.33g (12.00mmol) 5,6-diacetoxy-7-benzyloxy scutellarin, 37.4mL5%NaOH, and 150mL acetone is put in the 250mL reaction flask, at N
2Under the gas shiled, 40～50 ℃ of reactions are transferred pH to 5～6 to complete with rare HCl liquid, add 50mL water, are evaporated to a large amount of yellow solids and occur, and collect, and with small amount of ethanol flush away impurity, get the 4.32g yellow solid, productive rate 96.8%.
1HNMR(400MHz，CDCl
3)：δ5.27(s，2H)，5.43(s，1H)，6.67(s，1H)，6.69(s，1H)，7.36-7.73(m，8H)，7.87-7.89(m，2H)，12.54(s，1H)；MS(EI)m/z：360(M
+)，269(100％)，241，139，91，69；
The positive hexyloxy of 6-c:6--7-benzyloxy scutellarin is with 0.180g (0.5mmol) 7-benzyloxy scutellarin, 0.166g (1.20mmol) anhydrous K
2CO
3, 87 μ L (0.625mmol) 1-Bromohexane, anhydrous propanone 50mL refluxes under the drying regime, to reacting completely, filtered while hot gets gray solid, with column purification, with the mixed solution drip washing of ethyl acetate and sherwood oil, get the shallow white solid of 0.133g, productive rate 59.9%.
1HNMR(300MHz，CDCl
3)：0.85-0.90(m，3H)，1.25-1.35(m，4H)，1.40-1.49(m，2H)，1.73-1.82(m，2H)，4.04-4.10(m，2H)，5.20(s，2H)，6.61(s，1H)，6.67(s，1H)，7.35-7.56(m，8H)，7.86-7.89(m，2H)，12.66(s，1H)；MS(EI)m/z：444(M
+)，373，269(100％)，241，91；
The positive hexyloxy scutellarin of 6-d:6-is the positive hexyloxy of 0.124g (0.28mmol) 6--7-benzyloxy scutellarin, 10%Pd/C62.0mg, and THF 60mL puts in the 100mL reaction flask, at H
2Under the state, room temperature reaction filters to there not being raw material, with column purification, uses CH
2Cl
2And CH
3OH mixed solution wash-out gets the 0.085g yellow solid, productive rate 86.1%
1HNMR(300MHz，CDCl
3)：0.86-0.93(m，3H)，1.22-1.50(m，6H)，1.74-1.83(m，2H)，4.25(t，J＝6.7，2H)，6.55(s，1H)，6.62(s，1H)，6.66(s，1H)，7.49-7.57(m，3H)，7.87-7.90(m，2H)，13.01(s，1H)；MS(EI)m/z：354(M
+)，270(100％)，241，168；
Embodiment 7 6-are to the preparation of fluorine benzyloxy scutellarin
7-a:7-allyloxy-6-to fluorine benzyloxy scutellarin with 0.465g (1.5mmol) 7-allyloxy scutellarin, anhydrous K
2CO
30.414g (3mmol), to fluorobenzyl bromide 0.213mL (1.725mmol), anhydrous propanone 50mL puts in the 100mL reaction flask, reflux under the drying regime, to reacting completely, filtered while hot gets gray solid, with column purification, with the mixed solution drip washing of ethyl acetate and sherwood oil, get the shallow white solid of 0.458g, productive rate 73.0%.
1HNMR(300MHz，CDCl
3)：4.62-4.65(m，2H)，5.09(s，2H)，5.33-5.47(m，2H)，5.99-6.12(m，1H)，6.51(s，1H)，6.68(s，1H)，6.98-7.06(m，2H)，7.47-7.59(m，5H)，7.87-7.91(m，2H)，12.75(s，1H)；MS(EI)m/z：418(M
+)，309(100％)，253，109；
7-b:6-to fluorine benzyloxy scutellarin with 0.200g (0.478mmol) 6-to fluorine benzyloxy-7-allyloxy scutellarin, Pd (PPh
3)
40.014g (0.012mmol), heavily steam THF 50mL, behind stirring at room 5min, add NaBH
40.029g (0.77mmol), continue reaction to there not being raw material.With rare HCl solution adjust pH to 4～5, collect the lead solid, with the post fast purifying,, get the 0.162g light yellow solid, productive rate 89.5% with ethyl acetate and sherwood oil mixed solution wash-out
1HNMR(300MHz，CDCl
3)：5.20(s，2H)，6.41(s，1H)，6.54(s，1H)，6.67(s，1H)，7.02-7.09(m，2H)，7.39-7.44(m，2H)，7.49-7.58(m，3H)，7.86-7.90(m，2H)，13.2(s，1H)；MS(EI)m/z：378(M
+)，269(100％)，241，91；
Preparation method by embodiment 7 also can prepare 6-to methoxyl group benzyloxy base scutellarin, 6-benzyloxy scutellarin or the like compound.
Embodiment 8
The preparation of 8-a:6-(2`-phenoxy group) propionyloxy scutellarin
With 0.135g (0.5mmol) scutellarin, 0.083g (0.5mmol) 2-phenoxy propionic acid, Bop reagent 0.275g (0.6mmol), triethylamine 0.17mL (1.2mmol) heavily steams DMF 5.0mL, puts in the 10mL reaction flask, room temperature reaction is to there not being raw material, pour in the 100mL ethyl acetate, wash, use cold saturated NaHCO then with cold 1MHCl liquid
3Liquid is washed, and washes with saturated NaCl liquid again, uses anhydrous Na
2SO
4Drying, with column purification, the mixed solution flushing with ethyl acetate and sherwood oil gets 0.139g light yellow solid 8, productive rate 66.7%
1HNMR(400MHz，CDCl
3)δppm：1.88(d，J＝6.7，3H)，5.14(q，J＝6.7，1H)，5.48(s，1H)，6.52(s，1H)，6.65(s，1H)，7.04-7.09(m，3H)，7.36-7.40(m，2H)，7.49-7.51(m，3H)，7.84-7.87(m，2H)，12.98(b，1H)；MS(EI)：m/z?418(M
+)，270(100％)，168；
Preparation method by embodiment 8 also can prepare 6-benzoyloxy scutellarin, 6-(3`-trifluoromethyl) benzoyloxy scutellarin, 6-(4`-methoxyl group) benzoyloxy scutellarin or the like compound.
Embodiment 9: biological activity test anti peroxidation of lipid and antagonism H
2O
2Inductive rat suprarenal gland pheochromocytoma cell injury measurement result
Table 1
Claims (6)
1, a class has the Scutellarein derivative of following general formula (I):
It is characterized in that R
1, R
2, R
3Can be identical or different, R
1, R
2, R
3Represent cycloalkyl that the substituted aryl, alkynyl, thiazolinyl, cycloalkyl, heteroatoms of hydrogen, alkyl, aryl, electron-donating group or electron-withdrawing group replace, fatty acyl group, aromaticacyl radical ,-RNR " R ' ,-RCOOR ; Wherein, R is alkyl, R ', R " can be identical or different, R ', R " and R represents hydrogen, alkyl, thiazolinyl, alkynyl, aryl.
2, Scutellarein derivative according to claim 1 is characterized in that, works as R
2, R
3During for H, R
1Can be C
4-C
25Alkyl, C
3-C
16Alkynyl, thiazolinyl, C
3-C
9The C that replaces of cycloalkyl, heteroatoms
3-C
9Cycloalkyl, aryl, substituted aryl, fatty acyl group, aromaticacyl radical, substituted aroma acyl group.
3, Scutellarein derivative according to claim 1 is characterized in that, works as R
1, R
3During for H, R
2Be C
4-C
25Alkyl, C
3-C
16Alkynyl, thiazolinyl, C
3-C
9The C that replaces of cycloalkyl, heteroatoms
3-C
9Cycloalkyl, aryl, substituted aryl, fatty acyl group, aromaticacyl radical, substituted aroma acyl group.
4, the preparation method of Scutellarein derivative as claimed in claim 1 is characterized in that the preparation of compound comprises the steps:
The synthetic method of reaction formula 1 7-position Scutellarein derivative:
A) with scutellarin 1 at catalyst n a
2CO
3Or the effect of pyridine is following and aceticanhydride reacted 7-24 hour under 70～80 ℃ of conditions, obtains compound 2;
B) compound 2 obtained compound 3 in 8～24 hours reacting under 60～75 ℃ of conditions with allyl bromide 98 or chlorallylene under catalyzer and the solvent action; Wherein solvent is acetone, DMF, and catalyzer is K
2CO
3, KI;
C) compound 3 obtained compound 4 in 3～12 hours 60～90 ℃ of reactions under catalyzer and solvent action; Wherein solvent is methyl alcohol, ethanol, acetone, and catalyzer is dense HCl;
D) compound 4 was obtaining compound 5 in 6～36 hours with cylite or Benzyl Chloride reaction under catalyzer and the solvent action under 60～80 ℃ of conditions; Wherein solvent is acetone, DMF, and said catalyzer is K
2CO
3, KI;
E) compound 5 obtained compound 6 in 0.5～3 hour in room temperature reaction under catalyzer and solvent action, and wherein solvent is THF, and catalyzer is Pd (Ph
3)
4And NaBH
4
F) compound 6 obtained compound 7 with bromo-derivative and chloro thing or acyl chlorides in 1～12 hour in room temperature or 60～80 ℃ of reactions under catalyzer and solvent action, and wherein solvent comprises pyridine and acetone, DMF, CHCl
3Or CH
2Cl
2, catalyzer comprises Ag
2CO
3, K
2CO
3, KI or triethylamine;
G) compound 7 obtained general formula compound (I) in 4～36 hours in room temperature reaction under the effect of catalyst P d/C and solvent THF:
The synthetic method of reaction formula 2 6-position ehter bond Scutellarein derivatives:
A) compound 2 obtained compound 8 in 8～24 hours with cylite or Benzyl Chloride and allyl bromide 98 or chlorallylene in 60～75 ℃ of reactions under catalyzer and solvent action, and wherein solvent comprises acetone, DMF, and catalyzer comprises K
2CO
3, KI;
B) compound 8 obtained compound 9 in 3～12 hours at catalyzer and solvent action in 60～90 ℃ of reactions, and wherein solvent comprises methyl alcohol, ethanol, acetone, and catalyzer comprises K
2CO
3, NaOH or KOH;
C) compound 9 obtained compound 10 in 8～36 hours with bromo-derivative or chloro thing in 60～80 ℃ of reactions under catalyzer and solvent action, and wherein solvent comprises acetone, DMF, and catalyzer comprises K
2CO
3, KI;
D) compound 10 acts on room temperature reaction at catalyzer and solvent THF and obtained compound (I) in 0.5～36 hour, and wherein catalyzer comprises Pd/C, Pd (PPh
3)
4Or NaBH
4
The synthetic method of reaction formula 3 6-position ester bond Scutellarein derivatives:
A) scutellarin 1 at room temperature reacts with aromatic acid or lipid acid under catalyzer and solvent DMF effect and obtained compound (I) in 0.5-2 hour, and wherein catalyzer is card special condensing agent BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate)
B) compound (I) is at catalyzer K
2CO
3Following and the CH with solvent action
3I obtained 6-position ester bond compound (11) in room temperature reaction 2-12 hour, and wherein solvent is DMF, acetone.
5, the purposes of Scutellarein derivative as claimed in claim 1, the application in preparation treatment nerve degenerative diseases medicine.
6, the purposes of Scutellarein derivative according to claim 5, the application in preparing treatment Alzheimer relevant and anti-inflammatory, reducing blood-fat, atherosclerosis medicine with nerve degenerative diseases.
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