CN101870684A - Scutellarin aglycone derivative for treating vascular dementia and preparation method and application thereof - Google Patents
Scutellarin aglycone derivative for treating vascular dementia and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a scutellarin aglycone derivative which can treat vascular dementia and has structures shown in the following structural formulas I and II, and pharmacologically acceptable inorganic or organic acid salt, a preparation method and application thereof. A pharmacological test proves that the scutellarin aglycone derivative has obvious activity of resisting nerve cell damage caused by induction of hydrogen peroxide and can be used for the application in the preparation of a medicament for resisting vascular dementia.
Description
Technical field
The present invention relates to the synthetic and area of pharmacology of medicine.Particularly, relate to Scutellarein L-amino acid ester or ether derivant and Scutellarein N, N-is two to replace aminomethyl phenyl manthanoate or ether and preparation of compositions method thereof, and this compounds is in the anti-angiogenic dementia of preparation (vascular dementia, VD) purposes in the medicine.
Background technology
Vascular dementia (vascular dementia, VD) be the one group of clinical syndrome (Castro that on the brain tissue damage basis that cerebrovascular disease causes, produces based on the higher nerve cognition dysfunction, J Curr Alzheimer Res, 2008,5 (1): 61).The sickness rate of VD and mortality ratio rise year by year in recent years, have worldwide become the 3rd fatal disease (rehabilitation of Luo Nan duckweed tcm clinical practice, 2004,8 (25): 5338) after heart trouble, cancer.Clinical common vascular dementia type comprises: (Tian Jinzhou Beijing University of Chinese Medicine journals such as dementia and hemorrhagic dementia due to multi-infarct dementia, Big Area Cerebral Infarction dementia, subcortical arteriosclerotic encephalopathy (Binswager disease), the privileged sites infraction, 2000,23 (5): 24).According to epidemiology survey, account for 60% of senile dementia at China VD.The elderly's health and life quality in the VD serious threat, caused great burden for family and society.
The treatment of vascular dementia at present is divided into prophylactic treatment and symptomatic treatment two classes.Prophylactic treatment is conceived to the control of vascular risk factors, i.e. the firsts and seconds of cerebral apoplexy prevention.Symptomatic treatment relates to multiple pharmacological Mechanism, comprise cholinesterase inhibitor (cholinesterase inhibitor, ChEI), neurotrophy and neuroprotective drug, N-methyl-D-aspartate (N-methyl-D-aspartate, NMDA) (Desmond such as receptor antagonist, antioxidant, microcirculation improvement medicine, nootropics, hormone replacement therapy and anti-inflammatory therapy, D.W.Clinical Neuroscience Research, 2004,3,437; Wei Jurui, Chinese medical science of recovery therapy magazine, 2009,24 (1): 92).
Though the research of relevant VD treatment is still actively being carried out, and up to now, also is approved for the treatment of VD without any medicine.Therefore further investigate the pathogenesis of VD,, become the important subject of international medical community in the hope of seeking effective medicine.
Recent study is found, oxidative damage is vascular dementia (Vascular dementia, VD) and alzheimer's disease (Alzheimer ' s disease, the key factor that forms of nervus centralis degenerative disease such as AD), its reason is that the endogenous radical damage defensive substance content of cerebral tissue is lower, thereby to the oxidative damage of free-radical generating very responsive (Shima, Y.S.Journal of the Neurological Sciences 2009,283,240; Lethem, R.The Lancet 1997,349,1189; Ihara, Y.Journal of Neurological Sciences 1997,153,76).Discover that the superoxide-dismutase (SOD) of VD and AD patient's frontal cortex and hippocampus and the level of gsh Green Tea Extract materials such as (GSH) obviously are reduced to the normal people.Because the endogenous antioxidant level of VD patient's cerebral tissue is lower, cause the accumulation of excessive active oxygen (ROS) in the brain cell, produce lipid peroxidation, the latter can change the flowability and the ability of seeing through of neuron membrane, thereby enzyme or function of receptors (Danuta R.Journal of the Neurological Sciences 2002 that infringement cell function or cytolemma connect, 203,195).Discover that simultaneously because brain cell Mitochondrial DNA (mtDNA) lacks the histone protection, therefore extremely sensitive to the oxidative damage that ROS causes, this has quickened the process of nerve degenerative diseases.Therefore, suppress the generation of oxyradical, promote it to remove, and suppress its neurocyte that causes infringement, VD is significant to treatment.
Herba Erigerontis is the herb of composite family bitter fleabane platymiscium Erigeron breviscapus (Vant.) Hand.-Mazz. (Erigerm breviscapus), mainly is distributed in the ground such as Yunnan, the west and south, Guizhou of China, has effects such as promoting blood circulation and removing blood stasis, clearing and activating the channels and collaterals.Scutellarin is topmost activeconstituents in Herba Erigerontis.Pharmacodynamics test shows that scutellarin can be by significantly reducing the content of cerebral tissue peroxidation product mda (MDA), rising superoxide-dismutase (SOD) level, suppress the generation of ROS, and significantly improve the neuronic form of hippocampus, alleviate peroxide injury (Xiong Z.Biol.Pharm.Bull.2006,29 (9): 1880 of cerebral tissue; Hong H.Life Sciences 2004,74,2959).Therefore developing the scutellarin series derivates can promote it to remove by the generation of system oxyradical, and suppresses its neurocyte that causes infringement, thereby treatment has higher value for VD.
At present, the various preparations of scutellarin are widely used in the treatment cardiovascular and cerebrovascular diseases clinically, have very high pharmaceutical use and economic worth.But, its advantage is fully utilized and brings into play because the oral administration biaavailability of scutellarin is extremely low.Its reason is the water-soluble and fat-soluble all not good of scutellarin, and conventional tablet and granule exist oral administration biaavailability extremely low, and metabolism extensively waits the deficiency of medicine for character soon with eliminating; And normal injection and powder injection injection administration exist the transformation period short, eliminate rapidly in the body, and patient compliance is poor, use deficiencies such as inconvenience.Modern study is the result show, interior real absorption and the drug effect form of its body is its aglycon behind the oral scutellarin, but the absolute bioavailability of Scutellarein is still very low, only is 7.0% (Shao Yun, Chinese natural drug, 2007,5 (3): 229; Che Qingming, Chinese Pharmaceutical Journal, 2007,42 (18): 1418).Therefore be lead compound with the Scutellarein, design its prodrug type that absorbs improvement and just seem very urgent, it is extremely low that this may become solution scutellarin oral administration biaavailability, the key breakthrough mouth that drug effect is more weak, but do not see domestic and international relevant report at the optimization prodrug design of Scutellarein so far.
The deficiency that this patent is low at the scutellarin oral administration biaavailability, drug effect is more weak, with Guizhou Province's real estate herbal medicine Herba Erigerontis is main raw material, adopting modern extraction and separation technology to obtain highly purified Scutellarein is lead compound, according to active transport principle and L-L-threonine derivatives of high therapeutic index layout strategy the successful experience (Isabel oral antiviral bioavailability improve on of small intestinal mucosa peptide transporter 1 (hPepT1) to L-amino acids prodrug, Rubio-A.Trends in Pharmacological Sciences, 2003,23, (9): 434; Xiaozhong Fu.Bioorganic ﹠amp; Medicinal Chemistry Letters, 2007,17 (2): 465); Use for reference N simultaneously, two influence (Bundgaard, H.Pharmacological Research, 1991,8 (9): 1087) that replace aminomethyl phenyl manthanoate structural modification for oral pharmaceutical stability and internal metabolism stability of N-.On 4 '-hydroxyl of Scutellarein structure, introduce L-amino acid and N, the two aminomethyl phenyl manthanoate structures that replace of N-, design, synthetic new oral bioavailability and active Scutellarein 4 '-L-amino acid ester and the N that improves of Green Tea Extract oxidative damage with independent intellectual property rights, the two aminomethyl phenyl formate ester prodrugs that replace of N-.Adopt PC12 cellular oxidation damage model to carry out the anti-neurocyte oxidative damage of compound effect assessment.
This patent is intended to utilize L-amino acid ester and the N in the Scutellarein prodrug structure, the two aminomethyl phenyl manthanoate fragments that replace of N-improve its oral administration biaavailability, anti-angiogenic dementia activity and effect selectivity, adopt L-amino acid and N, the two replacement of N-aminomethyl phenyl formic acid prodrug layout strategy is lower as solving the oral administration biaavailability that exists in the scutellarin clinical application, undesirable these two the insufficient breaches of drug effect, thus important theory and practical basis established for formulating novel anti vascular dementia Scutellarein prodrug with independent intellectual property right.
Summary of the invention
The purpose of this invention is to provide a class and have on active Scutellarein prodrug of anti-angiogenic dementia and the pharmacology thereof the inorganic or organic salt crystalline hydrate of acceptable, solvate.
Another object of the present invention provides the preparation method of above-claimed cpd
A further object of the present invention provides the pharmaceutical composition that comprises above-claimed cpd
A further object of the present invention provides the medicinal use of above-claimed cpd
A further object of the present invention provides the medicinal use of above-mentioned composition
The invention provides a class and have following structural formula I, the inorganic or organic salt crystalline hydrate of acceptable, solvate on the Scutellarein prodrug of structure shown in the II and the pharmacology thereof.
Wherein,
R1 is the C1-4 alkyl;
R2 is a nitrogen heterocyclic ring;
N is 0,2,3
Preferably, representative compounds of the present invention can be following compound:
1) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-L-valine ester
2) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-alanine ester
3) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine ester
4) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine ester
5) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine ester
6) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-proline ester
7) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-methionine(Met) ester
8) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Xie Ansuan ethyl ether
9) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine ethyl ether
10) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine ethyl ether
11) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine ethyl ether
12) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine propyl ether
13) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine propyl ether
14) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine propyl ether
15) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) benzoic ether
16) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((benzamido group) methyl) benzoic ether
17) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(morpholinyl methyl) benzoic ether
18) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(pyrroles-1-ylmethyl) benzoic ether
19) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((4-methylpiperazine-1-yl) methyl) benzoic ether
20) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((4-piperidines-1-yl) methyl) benzoic ether
21) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) phenylformic acid propyl ether
22) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((benzamido group) methyl) phenylformic acid propyl ether
23) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(morpholinyl methyl) phenylformic acid propyl ether
24) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) phenylformic acid ethyl ether
25) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(morpholinyl methyl) phenylformic acid ethyl ether
26) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(pyrroles-1-ylmethyl) phenylformic acid ethyl ether
The structural formula of representation compound of the present invention sees Table 1
Table 1 representation compound 1-14 of the present invention structural formula
Table 1 representation compound 15-26 of the present invention structural formula
The present invention also provides the method for preparing above-claimed cpd
The method for preparing above-claimed cpd may further comprise the steps:
(1) preparation of Scutellarein
According to patent report method (Che Qingming, CN1657042A), be raw material with the scutellarin work in-process, system is back hydrolysis 20h under 8% sulphuric acid soln condition, put cold back suction filtration, the filter cake acetone extraction merges the acetone layer, anhydrous magnesium sulfate drying, filtration, steaming desolventizes, obtain the Scutellarein crude product, gains are used solvent recrystallization again, obtain purity and are higher than 90% Scutellarein:
(2) Scutellarein ketal protection intermediate preparation
According to literature method (Chen Zhiwei etc.; Acta Pharmaceutica Sinica 2005; 40 (11) 1001) Scutellarein and catalytic amount 4-dimethylamino pyridine (DMAP) are dissolved in an amount of N; in the dinethylformamide (DME), add and the equimolar dichloro diphenyl methane of aglycon, system is warming up to 160 ℃-180 ℃; reaction 2h; put and solvent is steamed after cold, the resistates silica gel column chromatography separating purification obtains Scutellarein ketal protection intermediate:
(3) Scutellarein 4 '-L-amino acid ester analog derivative is synthetic
The Scutellarein of N-Boc-L-amino acid and ketal protection is at N; N-dicyclohexylcarbodiimide (DCC) exists down with 4-dimethylamino pyridine (DMAP); condensation forms Scutellarein 4 ' N-Boc-L-amino acid ester derivative under with the reaction conditions of tetrahydrofuran solvent, and products therefrom is through CH
3COCl/MeOH system low-temp reaction slough simultaneously hexichol ketal protected with N-Boc (N-tertbutyloxycarbonyl) protecting group obtain the ultimate aim compound:
(4) Scutellarein 4 '-L-amino acid ether derivative is synthetic
With N-Boc L-amino acid is substrate, obtains N-Boc L-amino acid-2-bromine ethyl ester or 3-bromopropyl ester by itself and ethylene bromohyrin or the condensation under the DMAP/DCC condition of 3-bromo-1-propyl alcohol, and the Scutellarein of gained compound and ketal protection is at cesium carbonate, 4
MS exists condensation down to obtain ketal protection scutellarin glycosides former 4 '-N-Boc-L-amino acid ethyl ether and propyl ether, products therefrom process CH
3COCl/MeOH system low-temp reaction slough simultaneously hexichol ketal protected with N-Boc (N-tertbutyloxycarbonyl) protecting group obtain the ultimate aim compound:
(5) Scutellarein 4 '-aminomethyl benzoate derivatives is synthetic
To chloromethyl benzoic acid and the condensation under the dehydrated alcohol condition of replacement amine; separate out post precipitation with concentrated hydrochloric acid regulation system pH 3.4; the precipitation isopropanol extraction; resistates separated acquisition substituted amine methyl phenylformic acid through silica gel column chromatography after isopropanol layer steamed solvent; gains and ketal protection Scutellarein are being solvent with the tetrahydrofuran (THF); with DMAP/DCC is under the condensation reagent condition, obtains ketal protection Scutellarein 4 '-replacement aminomethyl phenyl manthanoate through room temperature reaction, and gains are after CH
3COCl/MeOH system low-temp reaction is sloughed ketal protected, obtains target compound:
(6) Scutellarein 4 '-aminomethyl phenyl formic acid ether derivative is synthetic
The substituted amine methyl phenylformic acid that the last step obtains, gains and ethylene bromohyrin or the condensation under the DMAP/DCC condition of 3-bromo-1-propyl alcohol obtain substituted amine methyl phenylformic acid 2-bromo-ethyl ester or 3 bromopropyl esters, and the latter and ketal protection Scutellarein are at cesium carbonate, 4
Condensation condensation reaction under the molecular sieve existence condition is after CH
3COCl/MeOH system low-temp reaction is sloughed ketal protected, obtains target compound:
The preparation method of target compound 1-14 is shown in flow process (I) particularly:
Wherein, a:N, N-dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP), 20～65 ℃; B:N, N-dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP), 20～65 ℃; C:Cs
2CO
3, N-Methyl pyrrolidone (NMP), 4
Molecular sieve, 40～100 ℃; D: Acetyl Chloride 98Min./methyl alcohol, ethyl acetate ,-5 ℃～25 ℃.
The preparation method of target compound 15-26 is shown in flow process (II) particularly
Wherein, a: dehydrated alcohol, 25～80 ℃; B:N, N-dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP), 20～65 ℃; C:N, N-dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP), 20～65 ℃; D:Cs
2CO
3, N-Methyl pyrrolidone (NMP), 4
Molecular sieve, 40～100 ℃; E: Acetyl Chloride 98Min./methyl alcohol, ethyl acetate ,-5 ℃～25 ℃.
The embodiment of flow process (I) is described in detail as follows:
1, be reaction raw materials with ketal protection Scutellarein and N-tertbutyloxycarbonyl-L-amino acid, according to bibliographical information method (Tetrahedron Lett.1979,20, (40), 3811-3814; J.Chem.Res.1991,10,292-302) at N, N-dicyclohexylcarbodiimide (DCC) is synthetic ketal protection Scutellarein 4 '-N-tertbutyloxycarbonyl L-amino acid ester intermediate under the condensation reagent condition with 4-dimethylamino pyridine (DMAP);
2, the condensation under the DCC/DMAP condition of N-tertbutyloxycarbonyl-L-amino acid and 3-bromo-1 propyl alcohol or ethylene bromohyrin forms N-tertbutyloxycarbonyl-L-amino acid-2-bromo-ethyl ester and 3-bromopropyl ester (Tetrahedron Lett.1979; 20; (40); 3811-3814); products therefrom and ketal protection Scutellarein reference report method (Bioorg.Med.Chem.Lett.2007; 17,959-963) in cesium carbonate/4
The molecular sieve existence condition, 40～100 ℃ of reactions 2～24 hours, optimum reaction condition is that N-tertbutyloxycarbonyl-L-amino acid 3-bromopropyl ester or 2-bromo-ethyl ester and ketal protection Scutellarein prorate are 1.5～2.0: 1mol, be that acid binding agent, N-Methyl pyrrolidone are under the solvent condition with the cesium carbonate, reacted 4～10 hours down at 60～80 ℃, obtain ketal protection Scutellarein 4 '-N-tertbutyloxycarbonyl L-amino acid ethyl and propyl ether intermediate;
3, protect Scutellarein 4 '-N-tertbutyloxycarbonyl L-amino acid ethyl and propyl ether in polarity or non-polar solvent, to use Acetyl Chloride 98Min./methanol system ketal protection the Scutellarein 4 '-N-tertbutyloxycarbonyl L-amino acid ester intermediate and the ketal that obtain, under-10～25 ℃, reacted 0.2～16 hour, optimum reaction condition be in Acetyl Chloride 98Min./methanol system 0 ℃～25 ℃ the reaction 4～8 hours, obtain target compound 1-14;
The embodiment of flow process (II) is described in detail as follows:
1, be reaction raw materials with the 4-chloromethyl benzoic acid with replacing amine or heterocycle, (J.G.Lombardino, US 4623486) is being under the reaction solvent condition with the dehydrated alcohol according to the bibliographical information method, and condensation obtains 4-and replaces aminomethyl phenyl formic acid intermediate;
2,4-replacement aminomethyl phenyl formic acid intermediate and ketal protection Scutellarein are according to bibliographical information method (J.Chem.Res.1991,10,292-302) at N, N-dicyclohexylcarbodiimide (DCC) is synthetic ketal protection Scutellarein 4 '-aminomethyl phenyl manthanoate intermediate under the condensation reagent condition with 4-dimethylamino pyridine (DMAP);
3,4-replaces aminomethyl phenyl formic acid and 3-bromo-1 propyl alcohol or ethylene bromohyrin condensation under DCC/DMAP condition formation 4-replacement aminomethyl phenyl formic acid-2-bromo-ethyl ester and 3-bromopropyl ester (Tetrahedron Lett.1979; 20; (40); 3811-3814); products therefrom and ketal protection Scutellarein reference report method (Bioorg.Med.Chem.Lett.2007; 17,959-963) in cesium carbonate/4
The molecular sieve existence condition, 40～100 ℃ of reactions 2～24 hours, optimum reaction condition is that 4-replaces aminomethyl phenyl formic acid 3-bromopropyl ester or 2-bromo-ethyl ester to protect the Scutellarein prorate with ketal be 1.5～2.0: 1mol, be that acid binding agent, N-Methyl pyrrolidone are under the solvent condition with the cesium carbonate, reacted 4～10 hours down at 60～80 ℃, obtain ketal protection Scutellarein 4 '-aminomethyl phenyl formic acid ethyl ether and propyl ether intermediate;
3, protect Scutellarein 4 '-aminomethyl phenyl formic acid ethyl ether and propyl ether intermediate in polarity or non-polar solvent, to use Acetyl Chloride 98Min./methanol system ketal protection the Scutellarein 4 '-aminomethyl phenyl manthanoate intermediate and the ketal that obtain; under-10～25 ℃; reacted 0.2～16 hour; optimum reaction condition be in Acetyl Chloride 98Min./methanol system 0 ℃～25 ℃ the reaction 4～8 hours, obtain target compound 15-26.
The present invention also provides the pharmaceutical composition that comprises above-mentioned flavonoid glycoside derivative, and described composition comprises the compound of the present invention as active ingredient for the treatment of effective dose, and assistant agent.
The present invention also provides above-mentioned flavonoid glycoside derivative to be used for the treatment of application in the vascular dementia in preparation.
The present invention also provide said medicine be combined in the treatment vascular dementia medicine in application.
Unless dated especially, term used herein has to give a definition:
Straight chain, the branched alkane hydrocarbon chain of " alkyl " saturated or undersaturated, replacement of expression or non-replacement, concrete enumerates as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl butyl, 2-methyl-propyl, hexyl, isohexyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 2-methyl butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl etc.In these groups, being that the individual alkyl of 1-4 is good with carbonatomss such as methyl, ethyl, propyl group, sec.-propyl, butyl, is the best with methyl, ethyl, propyl group.
" pharmacy acceptable salt " can enumerate the salt with mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphonic acids particularly, with organic acid and the acid salt of acidic amino acids such as aspartic acid, L-glutamic acid or the salt that form with basic aminoacidss such as Methionin, arginine, ornithines such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acids.
Embodiment
Preparation embodiment 1:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-L-valine ester
The Scutellarein (30mg, 67 μ mol) of ketal protection is dissolved in the 5ml tetrahydrofuran (THF) (THF), and the back adds N-Boc-L-Xie Ansuan (18.6mg, 81 μ mol) and 4-dimethylamino pyridine (DMAP) (4mg, 33 μ mol).Add 3mL N then, the tetrahydrofuran solution of N-dicyclohexylcarbodiimide (DCC) (17mg, 81 μ mol), reaction is 14 hours under the stirring at room condition.TLC monitor to feedstock conversion fully after; the concentrating under reduced pressure resistates is with sherwood oil: ethyl acetate: methylene dichloride=7: 1: 5 is an eluent; silica gel column chromatography separates to such an extent that the yellow oily target product is the Scutellarein 4 '-L-L-valine ester derivative 30.6mg of ketal protection, productive rate 83%.
1H-NMR(400MHz，CDCl
3)δ：7.93(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.82-7.80(m，4H，Ph-4H)，7.64-7.61(m，4H，Ph-6H)，6.98(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.62(s，1H，Ar-H
8)，6.57(s，1H，Ar-H
3)，5.08(d，J＝6.4Hz，1H，NHBoc)，4.21-4.18(m，1H，CHNH)，3.11-3.09(m，1H，CH(CH
3)
2)，1.41(d，J＝6.4Hz，6H，2×CH
3).
Under the cryosel bath condition; successively with methyl alcohol (27 μ L; 667 μ mol) and Acetyl Chloride 98Min. (39 μ L; 556 μ mol) join in the ethyl acetate of 2ml; keep cryosel to bathe stirring reaction 3 as a child; Scutellarein 4 '-L-L-valine ester derivative (30.6mg with the protection of the ketal that obtains before; 55.6 μ mol) be dissolved in the 1.5ml ethyl acetate after, be added in the above-mentioned reaction system, continue to keep cryosel to bathe reaction after 2 hours; gradually temperature of reaction is risen to room temperature; reacted 12 hours, and had safran to precipitate attached wall, reaction system is through ultrasonic; after centrifugal; the gained precipitation gets safran oily target product 12mg, productive rate 56.1% three times with the ethyl acetate washing.
1H-NMR(400MHz，DMSO-d6)δ：12.59(brs，1H，5-OH)，10.61(brs，1H，7-OH)，8.65(brs，1H，6-OH)，8.18(d，J＝8.4Hz，2H，Ar’-H
3，5)，7.42(d，J＝8.4Hz，2H，Ar’-H
3，6)，6.95(s，1H，Ar-H
8)，6.65(s，1H，Ar-H
3)，4.20(d，J＝4.4Hz，1H，COCHNH
2)，2.38-2.33(m，1H，CH(CH
3)
2)，1.12(d，J＝7.2Hz，3H，CH
3)，1.10(d，J＝7.2Hz，3H，CH
3)
Preparation embodiment 2:5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-alanine ester
Scutellarein and N-Boc L-L-Ala with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get safran oily target product, productive rate 63.3%.
1H-NMR(400MHz，DMSO-d6)δ：12.62(brs，1H，5-OH)，10.74(brs，1H，7-OH)，8.73(brs，1H，6-OH)，8.29(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.42(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.98(s，1H，Ar-H
8)，6.67(s，1H，Ar-H
3)，4.43(m，1H，COCHNH
2)，1.33(d，J＝6.8Hz，3H，CH
3).
Preparation embodiment 3:5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine ester
Scutellarein and N-Boc L-leucine with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get safran oily target product, productive rate 76.5%.
1H-NMR(400MHz，DMSO-d6)δ：12.57(brs，1H，5-OH)，10.76(brs，1H，7-OH)，8.74(brs，1H，6-OH)，8.17(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.42(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.93(s，1H，Ar-H
8)，6.71(s，1H，Ar-H
3)，4.27(m，1H，COCHNH
2)，1.96-1.79(m，3H，CH
2CH(CH
3)
2)，1.05-1.01(m，6H，2×CH
3).
Preparation embodiment 4:5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine ester
Scutellarein and N-Boc L-Isoleucine with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get safran oily target product, productive rate 69.8%.
1H-NMR(400MHz，DMSO-d6)δ：12.57(brs，1H，5-OH)，10.78(brs，1H，7-OH)，8.76(brs，1H，6-OH)，8.17(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.41(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.94(s，1H，Ar-H
8)，6.65(s，1H，Ar-H
3)，4.25(m，1H，COCHNH
2)，2.07(m，1H，CH(CH
3)C
2H
5)，1.62-1.59(m，1H，CH
2CH
3-1H)，1.41-1.37(m，1H，CH
2CH
3-1H)，1.06(d，J＝6.8Hz，3H，CH(CH
3))，0.97(t，J＝7.6Hz，3H，CH
2CH
3).
Preparation embodiment 5:5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine ester
Scutellarein and N-Boc L-phenylalanine with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get safran oily target product, productive rate 75.4%.
1H-NMR(400MHz，DMSO-d6)δ：12.58(brs，1H，5-OH)，10.69(brs，1H，7-OH)，8.83(brs，1H，6-OH)，8.17(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.41-7.32(m，5H，Ph-5H)，7.18(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.90(s，1H，Ar-H
8)，6.63(s，1H，Ar-H
3)，4.59(t，J＝6.8Hz，1H，COCH)，3.25-3.20(m，2H，CH
2Ph).
Preparation embodiment 6:5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-proline ester
Scutellarein and N-Boc L-proline(Pro) with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get safran oily target product, productive rate 50.7%.
1H-NMR(400MHz，DMSO-d6)δ：12.58(brs，1H，5-OH)，10.48(brs，1H，7-OH)，8.68(brs，1H，6-OH)，8.16(d，J＝8.0Hz，2H，Ar’-H
3，5)，6.93(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.83(s，1H，Ar-H
8)，6.56(s，1H，Ar-H
3)，4.23-4.18(m，1H，COCH)，2.29-2.23(m，2H，NHCH
2)，2.01-1.88(m，4H，NHCHCH
2CH
2)
Preparation embodiment 7:5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-methionine(Met) ester
Scutellarein and N-Boc L-methionine(Met) with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 1 method.Get safran oily target product, productive rate 64.5%.
1H-NMR(400MHz，DMSO-d6)δ：12.80(brs，1H，5-OH)，10.41(brs，1H，7-OH)，8.85(brs，1H，6-OH)，8.24(d，J＝9.2Hz，2H，Ar’-H
3，5)，7.57(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.98(s，1H，Ar-H
8)，6.67(s，1H，Ar-H
3)，4.46(t，J＝6.0Hz，1H，COCH)，2.73-2.67(m，2H，CH
2SCH
3)，2.34-2.29(m，2H，CH
2CH
2S)，2.11(s，3H，CH
3).
Preparation embodiment 8:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Xie Ansuan ethyl ether
The Scutellarein (50mg, 111 μ mol) of ketal protection is dissolved in the 3mlN-methyl-2-pyrrolidone (NMP), adds N-tertbutyloxycarbonyl-L-Xie Ansuan 3-bromo-ethyl ester (43.5mg, 167 μ mol) then, cesium carbonate (36.2mg, 111 μ mol), 4
Molecular sieve number, 80 ℃ of following stirring reactions 4 hours, reaction system removes 4
Add an amount of trichloromethane behind the molecular sieve; wash 5 times with 0.5% hydrochloric acid soln then; remove N-Methyl pyrrolidone; trichloromethane layer anhydrous magnesium sulfate drying; solution decompression concentrates; resistates is with sherwood oil: ethyl acetate: methylene dichloride=7: 1: 5 is an eluent, silica gel column chromatography separate the Scutellarein 4 '-L-Xie Ansuan ethyl ether derivative 23mg of ketal protection, yield 30%.
1H-NMR(400MHz，CDCl
3)δ：7.82(d，J＝8.4Hz，2H，Ar’-H
3，5)，7.63-7.60(m，4H，Ph-4H)，7.44-7.37(m，4H，Ph-6H)，7.02(d，J＝8.4Hz，2H，Ar’-H
2，6)，6.63(s，1H，Ar-H
8)，6.57(s，1H，Ar-H
3)，5.04(d，J＝8.8Hz，1H，NHBoc)，4.57-4.48(m，2H，CH
2OCO)，4.28-4.25(m，3H，Ar’OCH
2，CHNH)，1.87-1.83(m，1H，CH(CH
3)
2)，0.98(d，J＝6.8Hz，3H，CH
3)，0.91(d，J＝6.8Hz，3H，CH
3).
Under the cryosel bath condition; successively with methyl alcohol (16 μ L; 400 μ mol) and Acetyl Chloride 98Min. (20 μ L; 333 μ mol) join in the ethyl acetate of 2ml; keep cryosel to bathe stirring reaction after 3 hours; Scutellarein 4 '-L-Xie Ansuan ethyl ether derivative (23mg with the protection of the ketal that obtains before; 33.1 μ mol) be dissolved in the 1.5ml ethyl acetate after; be added in the above-mentioned reaction system, continue to keep cryosel to bathe reaction after 2 hours, gradually temperature of reaction is risen to room temperature; reacted 12 hours; have safran to precipitate attached wall, reaction system is through ultrasonic; centrifugal back gained precipitation gets safran oily target product 8mg, yield 56.3% three times with the ethyl acetate washing.
1H-NMR(400MHz，DMSO-d6)δ：12.71(brs，1H，5-OH)，10.62(brs，1H，7-OH)，8.48(brs，1H，6-OH)，8.13(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.13(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.83(s，1H，Ar-H
8)，6.62(s，1H，Ar-H
3)，4.66-4.63(m，1H，CH
2OCO-1H)，4.49-4.46(m，1H，CH
2OCO-1H)，4.34(m，2H，Ar’OCH
2)，3.95(m，1H，COCH)，2.18-2.14(m，1H，CH(CH
3)
2)，0.98(d，J＝6.0Hz，3H，CH
3)，0.94(d，J＝6.8Hz，3H，CH
3).
Preparation embodiment 9:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine ethyl ether
Scutellarein and N-Boc L-leucine-2-bromine ethyl ester with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 8 methods.Get safran oily target product, productive rate 47.3%.
1H-NMR(400MHz，DMSO-d6)δ：12.70(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.52(brs，1H，6-OH)，8.03(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.11(d，J＝8.8Hz，2H，Ar’-H
3，6)，6.84(s，1H，Ar-H
8)，6.63(s，1H，Ar-H
3)，4.59-4.57(m，1H，CH
2OCO-1H)，4.49-4.45(m，1H，CH
2OCO-1H)，4.35-4.33(m，2H，Ar’OCH
2)，3.99(m，1H，COCH)，1.72-1.70(m，1H，CH(CH
3)
2)，1.64-1.59(m，2H，CH
2CH(CH
3)
2)，0.83(d，J＝8.0Hz，6H，2×CH
3).
Preparation embodiment 10:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine ethyl ether
Scutellarein and N-Boc L-Isoleucine-2-bromine ethyl ester with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 8 methods.Get safran oily target product, productive rate 58.8%.
1H-NMR(400MHz，DMSO-d6)δ：12.75(brs，1H，5-OH)，10.75(brs，1H，7-OH)，8.53(brs，1H，6-OH)，8.03(d，J＝8.0Hz，2H，Ar’-H
3，5)，7.11(d，J＝8.0Hz，2H，Ar’-H
3，6)，6.83(s，1H，Ar-H
8)，6.64(s，1H，Ar-H
3)，4.66-4.63(m，1H，CH
2OCO-1H)，4.47-4.44(m，1H，CH
2OCO-1H)，4.33(m，2H，Ar’OCH
2)，3.98(m，1H，COCH)，1.89(m，1H，CH(CH
3)C
2H
5)，1.47-1.44(m，1H，CH
2CH
3-1H)，1.30-1.23(m，1H，CH
2CH
3-1H)，1.05(t，J＝6.8Hz，3H，CH(CH
3))，0.90(d，J＝6.8Hz，3H，CH
2CH
3).
Preparation embodiment 11:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine ethyl ether
Scutellarein and N-Boc L-phenylalanine-2-bromine ethyl ester with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 8 methods.Get safran oily target product, productive rate 67.5%.
1H-NMR(400MHz，DMSO-d6)δ：12.71(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.56(brs，1H，6-OH)，8.04(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.23(m，5H，Ph-5H)，7.10(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.84(s，1H，Ar-H
8)，6.62(s，1H，Ar-H
3)，4.51-4.10(m，2H，CH
2OCO)，4.35-4.32(m，1H，COCH)，4.24-4.17(m，2H，OCH
2CH
2)，3.24-3.16(m，1H，CH
2Ph-1H)，3.09-3.04(m，1H，CH
2Ph-1H).
The preparation of 1-chromene-4-L-leucine propyl ether
Scutellarein and N-Boc L-leucine 3-bromopropyl ester with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 8 methods.Get safran oily target product, productive rate 45.3%.
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，10.58(brs，1H，7-OH)，8.44(brs，1H，6-OH)，8.03(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.13(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.84(s，1H，Ar-H
8)，6.61(s，1H，Ar-H
3)，4.33(m，2H，CH
2OCO)，4.18(m，2H，PhOCH
2)，3.98(m，1H，COCH)，2.13-2.10(m，2H，OCH
2CH
2CH
2O)，1.71-1.58(m，3H，CH
2CH(CH
3)
2)，0.87(d，J＝6.4Hz，6H，2×CH
3).
Preparation embodiment 13:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine propyl ether
Scutellarein and N-Boc L-Isoleucine 3-bromopropyl ester with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 8 methods.Get safran oily target product, productive rate 51.7%.
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，10.58(brs，1H，7-OH)，8.44(brs，1H，6-OH)，8.13(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.13(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.83(s，1H，Ar-H
8)，6.61(s，1H，Ar-H
3)，4.37(m，2H，CH
2OCO)，4.17(m，2H，PhOCH
2)，3.97(m，1H，COCH)，2.13-2.10(m，2H，OCH
2CH
2CH
2O)，1.45-1.40(m，1H，CH(CH
3))，1.27-1.21(m，2H，CH
2CH
3)，0.89-0.83(m，6H，2×CH
3).
Preparation embodiment 14:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine propyl ether
Scutellarein and N-Boc L-phenylalanine-3,4-quinone-bromopropyl ester with the ketal protection are that reaction raw materials is according to being similar to the preparation of embodiment 8 methods.Get safran oily target product, productive rate 58.1%.
1H-NMR(400MHz，DMSO-d6)δ：12.70(brs，1H，5-OH)，10.57(brs，1H，7-OH)，8.61(brs，1H，6-OH)，8.12(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.31-7.27(m，5H，Ph-5H)，7.13(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.85(s，1H，Ar-H
8)，6.64(s，1H，Ar-H
3)，4.30-4.23(m，3H，CH
2OCO，COCH)，3.99-3.97(m，2H，PhOCH
2)，3.22-3.16(m，1H，CH
2Ph-1H)，3.09-3.03(m，1H，CH
2Ph-1H)，2.08-1.98(m，2H，OCH
2CH
2CH
2O).
Preparation embodiment 15:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) benzoic ether
With diethylamine tolyl acid (20mg; 95 μ mol) be dissolved in a small amount of methyl-sulphoxide; be settled to 5ml with tetrahydrofuran (THF); get the Scutellarein (30mg of ketal protection; 67 μ mol) be dissolved in the 5ml tetrahydrofuran (THF) (THF); the THF solution 5ml and 4-dimethylamino pyridine (the DMAP) (4mg that add the diethylamine tolyl acid successively; 33 μ mol); contain N to the reaction system dropping; N-dicyclohexylcarbodiimide (DCC) (17mg; 81 μ mol) 3mL tetrahydrofuran solution drips and finishes, and reaction is 14 hours under the stirring at room condition.TLC monitor to feedstock conversion fully after; the system concentrating under reduced pressure is removed tetrahydrofuran (THF); the back extracts 3 times with chloroform-aqueous systems; wash out DMSO solvent in the system, collect chloroform layer, add anhydrous magnesium sulfate drying 1h after-filtration; filtrate is concentrated; with chloroform: methyl alcohol=30: 1 is eluent, silica gel column chromatography separate hexichol ketal protection Scutellarein-4 '-to diethylamine methyl benzoic acid ester 37.8mg, productive rate 80%.
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，8.12(d，J＝8.0Hz，2H，Ar’-H
3，5)，7.95(d，J＝8.4Hz，2H，Ar’-H
2，6)，7.63-7.61(m，2H，Ar”-H
3，5)，7.58-7.56(m，2H，Ar”-H
2，6)，7.41-7.37(m，10H，2×Ph-5H)，6.67(s，2H，Ar-H
3，8)，3.84(s，2H，Ar”-CH
2N)，2.73(q，J＝7.2Hz，4H，2×NCH
2CH
3)，1.15(t，J＝6.8Hz，6H，2×CH
3).
In 25ml exsiccant eggplant-shape bottle; add the 3ml ethyl acetate; cryosel is bathed (5 ℃) and is stirred down; add methyl alcohol (0.03ml successively; 0.7mmol); Acetyl Chloride 98Min. (0.028ml; 0.4mmol), insulation reaction 3h, in reaction system, drip contain hexichol ketal protection Scutellarein-4 '-to diethylamine methyl benzoic acid ester (26mg; 0.04mmol) the 2ml ethyl acetate solution; rise to room temperature reaction 12h behind the insulation reaction 2h, have yellow mercury oxide to be attached to wall, add ultrasonic, the washing of an amount of ethyl acetate; get yellow solid target compound 10mg, yield 52.6%.
1H-NMR(400MHz，DMSO-d6)δ：12.67(brs，1H，5-OH)，10.67(brs，1H，7-OH)，8.68(brs，1H，6-OH)，8.29-8.17(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.89(d，J＝8.0Hz，Ar’-H
2，6)，7.53(d，J＝8.4Hz，Ar”-H
2，6)，6.97(s，1H，Ar-H
8)，6.65(s，1H，Ar-H
3)，3.76(s，2H，Ar”-CH
2N)，3.06(m，4H，2×NCH
2CH
3)，1.25-1.23(m，6H，2×CH
3).
Preparation embodiment 16:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((benzamido group) methyl) benzoic ether
With the benzylamine tolyl acid, to be reaction raw materials be prepared into the yellow solid target product, yield 46.7% according to the method for similar example 15 to the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.63(brs，1H，5-OH)，10.70(brs，1H，7-OH)，8.83(brs，1H，6-OH)，8.28-8.23(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.79(d，J＝8.8Hz，Ar’-H
2，6)，7.57-7.55(m，5H，Ph-5H)，7.51(d，J＝8.8Hz，Ar”-H
2，6)，6.97(s，1H，Ar-H
8)，6.66(s，1H，Ar-H
3)，4.29(s，2H，Ar”-CH
2N)，4.18(s，2H，CH
2Ph).
Preparation embodiment 17:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((morpholinyl) methyl) benzoic ether
With the morpholine methyl phenylformic acid, to be reaction raw materials be prepared into deep yellow solid target product, yield 56.4% according to the method for similar example 15 to the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.63(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.31(brs，1H，6-OH)，8.31-8.17(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.83(d，J＝7.2Hz，Ar’-H
2，6)，7.52(d，J＝8.8Hz，Ar”-H
2，6)，6.98(s，1H，Ar-H
8)，6.65(s，1H，Ar-H
3)，3.92(s，2H，Ar”-CH
2N)，3.75(m，4H，2×CH
2O)，2.52(m，4H，2×CH
2N).
Preparation embodiment 18:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((Pyrrolidine base) methyl) benzoic ether
With the Pyrrolidine tolyl acid, to be reaction raw materials be prepared into pale brown look solid target product, yield 32.1% according to the method for similar example 15 to the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.65(brs，1H，5-OH)，10.70(brs，1H，7-OH)，8.24-8.19(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.88(d，J＝8.8Hz，Ar’-H
2，6)，7.52(d，J＝8.8Hz，Ar”-H
2，6)，6.99(s，1H，Ar-H
8)，6.68(s，1H，Ar-H
3)，4.50(s，2H，Ar”-CH
2N)，2.54-2.50(m，4H，2×CH
2N)，1.69-1.51(m，4H，2×NCH
2CH
2).
Preparation embodiment 19:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((4-methylpiperazine-1-yl) methyl) benzoic ether
With (to methylpiperazine-1-yl) tolyl acid, to be reaction raw materials be prepared into pale brown look solid target product, yield 17.6% according to the method for similar example 15 to the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.68(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.17(d，J＝8.0Hz，2H，Ar’-H
3，5)，7.94(d，J＝8.4Hz，2H，Ar”-H
3，5)，7.63-7.61(m，4H，Ar’-H
2，6，Ar”-H
2，6)，6.97(s，1H，Ar-H
8)，6.59(s，1H，Ar-H
3)，3.61(s，2H，Ar”-CH
2N)，2.52-2.32(m，8H，4×CH
2N)，2.30(s，3H，CH
3).
Preparation embodiment 20:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((piperidyl) methyl) benzoic ether
With the piperidine methyl phenylformic acid, to be reaction raw materials be prepared into pale brown look solid target product, yield 37.6% according to the method for similar example 15 to the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.68(brs，1H，5-OH)，10.65(brs，1H，7-OH)，8.19(d，J＝8.4Hz，Ar’-H
3，5)，7.98(d，J＝8.4Hz，2H，Ar”-H
3，5)，7.56-7.46(m，4H，Ar’-H
2，6，Ar”-H
2，6)，6.97(s，1H，Ar-H
8)，6.64(s，1H，Ar-H
3)，3.71(s，2H，Ar”-CH
2N)，2.59-2.39(m，4H，2×CH
2N)，1.84-1.57(m，6H，3×CH
2).
Preparation embodiment 21:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) phenylformic acid propyl ether
Get dry diethylamine tolyl acid (0.1g, 0.48mmol), place 50ml eggplant type bottle, it is fixed molten to 15ml to add the short molten back adding of a small amount of dimethyl sulfoxide (DMSO) (DMSO) methylene dichloride, make system be settled solution, after add successively 3-bromo-1-propyl alcohol (0.07g, 0.48mmol), to Dimethylamino pyridine (DMAP) (0.025g, 0.24mmol), drip under the stirring at room and contain N, N '-dicyclohexyl carbimide (DCC) (0.069g, 10ml dichloromethane solution 0.33mmol), drip and finish, room temperature reaction 12h, the TLC monitoring reaction is complete, concentrates, adopt chloroform: methyl alcohol=30: 1 is eluent, through purification by silica gel column chromatography get the cured shape of off-white color to diethylamine tolyl acid bromine propyl ester, 85mg, yield 71%.
1H-NMR(400MHz，CDCl
3)δ：7.98(d，J＝8.0Hz，2H，Ar-H
2，6)，7.43(d，J＝8.0Hz，2H，Ar-H
3，5)，4.4(t，J＝6.4Hz，2H，CH
2OCO)，3.71-3.57(m，4H，BrCH
2，Ar-CH
2N)，2.55-2.51(q，J＝6.4Hz，4H，2×NCH
2)，2.32-2.29(m，2H，OCH
2CH
2CH
2Br)，1.07(t，6H，J＝6.4Hz，2×CH
3).
Get exsiccant ketal protection Scutellarein (50mg; 0.11mmol), to diethylamine tolyl acid bromine propyl ester (50mg, 0.15mmol); place the 25ml eggplant-shape bottle; add 4ml N-Methyl pyrrolidone (NMP), fully dissolving adds cesium carbonate (24mg; 0.07mmol); add several molecular sieves (4A) then, under 100 ℃ of conditions, stirring reaction 6h.Reaction is finished, reaction system places chloroform, wash 4-6 time with 0.5M dilute hydrochloric acid the back, flush away reaction solvent N-Methyl pyrrolidone (NMP) is told organic layer, and is dry, concentrated, separate through silica gel column chromatography, eluent: chloroform: methyl alcohol=30: 1 gets yellow oily target product 33mg, yield 42.9%.
1H-NMR(400MHz，CDCl
3)δ：12.54(brs，1H，5-OH)，7.98-7.88(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.80(d，J＝8.8Hz，2H，Ar’-H
2，6)，7.41-7.37(m，10H，2×Ph-5H)，7.23(d，J＝8.8Hz，2H，Ar”-H
2，6)，6.92(s，1H，Ar-H
8)，6.82(s，1H，Ar-H
3)，4.77(t，J＝6.0Hz，2H，Ar’-OCH
2)，4.37(s，2H，Ar”-CH
2N)，4.30(t，J＝6.8Hz，2H，CH
2OCO)，3.15-3.09(m，4H，2×NCH
2)，2.43-2.36(m，2H，OCH
2CH
2CH
2O)，1.66(t，J＝7.6Hz，2×CH
3).
In 25ml exsiccant eggplant-shape bottle; add the 3ml ethyl acetate; cryosel is bathed (5 ℃) and is stirred down; add methyl alcohol (0.03ml successively; 0.7mmol); Acetyl Chloride 98Min. (0.028ml; 0.4mmol), insulation reaction 3h, in reaction system, drip contain hexichol ketal protection Scutellarein-4 '-to diethylamine tolyl acid propyl ether (28mg; 0.04mmol) the 2ml ethyl acetate solution; rise to room temperature reaction 12h behind the insulation reaction 2h, have yellow mercury oxide to be attached to wall, add ultrasonic, the washing of an amount of ethyl acetate; get brown oily target compound 10mg, yield 47.6%.
1H-NMR(400MHz，DMSO-d6)δ：12.64(brs，1H，5-OH)，10.68(brs，1H，7-OH)，8.36(brs，1H，6-OH)，8.04-7.98(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.76(d，J＝8.8Hz，2H，Ar’-H
2，6)，7.13(d，J＝8.8Hz，2H，Ar”-H
2，6)，6.82(s，1H，Ar-H
8)，6.61(s，1H，Ar-H
3)，4.47(t，J＝6.0Hz，2H，Ar’-OCH
2)，4.44(s，2H，Ar”-CH
2N)，4.26(t，J＝6.8Hz，2H，CH
2OCO)，3.05-2.99(m，4H，2×NCH
2)，2.23-2.16(m，2H，OCH
2CH
2CH
2O)，1.23(t，J＝7.6Hz，2×CH
3).
Preparation embodiment 22:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((benzamido group) methyl) phenylformic acid propyl ether
With the benzylamine tolyl acid, to be reaction raw materials be prepared into the yellow oily target product, yield 44.9% according to the method for similar example 21 for 3-bromo-1-propyl alcohol, the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.68(brs，1H，5-OH)，10.64(brs，1H，7-OH)，8.32(brs，1H，6-OH)，8.22(d，J＝8.8Hz，2H，Ar’-H
3，5)，8.13(d，J＝8.8Hz，2H，Ar”-H
3，5)，7.62-7.47(m，5H，Ph-5H)，7.38-7.31(m，4H，Ar’-H
2，6，Ar”-H
2，6)，6.97(s，1H，Ar-H
8)，6.61(s，1H，Ar-H
3)，4.54(d，J＝6.4Hz，2H，Ar’-OCH
2)，4.32(d，J＝6.4Hz，2H，CH
2OCO)，3.83(s，2H，PhCH
2N)，3.72(s，2H，NCH
2Ph)，2.19(m，2H，OCH
2CH
2CH
2O).
Preparation embodiment 23:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((morpholinyl) methyl) phenylformic acid propyl ether
With the morpholine methyl phenylformic acid, to be reaction raw materials be prepared into the yellow oily target product, yield 44.3% according to the method for similar example 21 for 3-bromo-1-propyl alcohol, the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.85(s，1H，5-OH)，10.65(s，1H，7-OH)，8.05-7.98(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.37(d，J＝8.8Hz，2H，Ar’-H
2，6)，7.13(d，J＝8.8Hz，2H，Ar”-H
2，6)，6.82(s，1H，Ar-H
8)，6.61(s，1H，Ar-H
3)，4.47(t，J＝6.4Hz，2H，Ar’-OCH
2)，4.40(s，2H，PhCH
2N)，4.25(t，J＝6.0Hz，2H，CH
2OCO)，3.78-3.66(m，4H，2×OCH
2CH
2)，3.17-3.14(m，4H，2×NCH
2CH
2)，2.21-2.18(m，2H，OCH
2CH
2CH
2O).
Preparation embodiment 24:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) phenylformic acid ethyl ether
With the diethylamine tolyl acid, to be reaction raw materials be prepared into pale brown look oily target product, yield 41.9%. according to the method for similar example 21 for bromoethanol, the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.74(brs，1H，5-OH)，10.68(brs，1H，7-OH)，8.36(brs，1H，6-OH)，8.09-8.03(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.74(d，J＝8.8Hz，2H，Ar’-H
2，6)，7.18(d，J＝8.8Hz，2H，Ar”-H
2，6)，6.85(s，1H，Ar-H
8)，6.62(s，1H，Ar-H
3)，4.67(t，J＝6.0Hz，2H，Ar’-OCH
2)，4.48(s，2H，Ar”-CH
2N)，4.38(t，J＝6.8Hz，2H，CH
2OCO)，3.18-3.05(m，4H，2×NCH
2CH
3)，1.21(t，J＝7.6Hz，6H，2×CH
3).
Preparation embodiment 25:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((morpholinyl) methyl) phenylformic acid ethyl ether
With the morpholine methyl phenylformic acid, to be reaction raw materials be prepared into brown oily target product, yield 13.6% according to the method for similar example 21 for bromoethanol, the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.65(s，1H，5-OH)，10.65(s，1H，7-OH)，8.76(brs，1H，6-OH)，8.02-7.98(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.70(d，J＝8.0Hz，2H，Ar’-H
2，6)，7.14(d，J＝8.8Hz，2H，Ar”-H
2，6)，6.81(s，1H，Ar-H
8)，6.58(s，1H，Ar-H
3)，4.63(m，2H，Ar’-OCH
2)，4.44(s，2H，PhCH
2N)，4.37(m，2H，CH
2OCO)，3.51-3.28(m，4H，2×OCH
2CH
2)，3.26-3.13(m，4H，2×NCH
2CH
2).
Preparation embodiment 26:5,6, the preparation of 7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((pyrryl) methyl) phenylformic acid ethyl ether
With the Pyrrolidine tolyl acid, to be reaction raw materials be prepared into brown oily target product, yield 45.5% according to the method for similar example 21 for bromoethanol, the Scutellarein of ketal protection
1H-NMR(400MHz，DMSO-d6)δ：12.72(brs，1H，5-OH)，10.81(brs，1H，7-OH)，9.16(brs，1H，6-OH)，8.03-7.99(m，4H，Ar’-H
3，5，Ar”-H
3，5)，7.94(d，J＝8.4Hz，Ar’-H
2，6)，7.16(d，J＝8.8Hz，Ar”-H
2，6)，6.83(s，1H，Ar-H
8)，6.62(s，1H，Ar-H
3)，4.65(s，2H，Ar”-CH
2N)，4.20(m，2H，Ar’-OCH
2)，4.05-4.01(m，2H，CH
2OCO)，3.15-3.04(m，4H，2×CH
2N)，2.54-2.50(m，4H，2×CH
2N)，1.89-1.83(m，4H，2×NCH
2CH
2).
EXPERIMENTAL EXAMPLE
1, experiment material and instrument
PC 12 cell strains are provided by Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences; Test compounds is provided by Guiyang Medical College pharmaceutical college; Vitamin-E is available from Sigma company; The DMEM high glucose medium is available from Gibco company; Foetal calf serum is available from Hangzhou Sijiqing Biological Engineering Material Co., Ltd.; MTT is available from Sigma company; LDH mensuration test kit is purchased to Nanjing and is built up Science and Technology Ltd.; Microplate reader is Bole 680Model.
2, test method
(1) cell toxicity test
Adopt the tetrazole reduction method, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, MTT) detection of drugs is to the restraining effect of PC12 cell growth itself.With the PC12 cell dissociation is the individual cells suspension, and adjusting cell density is 5 * 10
4Individual/ml, be inoculated in 96 orifice plates (100 μ l/ hole), 37 ℃, 5%CO
2The incubator overnight incubation.Supernatant is removed in suction after treating cell attachment, adds the nutrient solution that contains concentration gradient dilution medicine (1 μ M, 10 μ M, 50 μ M, 100 μ M), puts and continues in the incubator to cultivate.24h after dosing inhales and removes supernatant, adds and contains MTT (0.25mg/ml) serum free medium, cultivates 4 hours, inhales and removes nutrient solution, adds 100 μ l DMSO vibration and makes Formazan crystallization dissolving, and 490nm measures each hole light absorption value to calculate cell survival rate.Test-results sees Table-1.
(2) the PC12 cytoprotection of hydrogen peroxide damage is tested
Choose logarithmic phase PC12 cell, with every hole 100 μ l, 5～10 * 10
4Individual/ml kind is planted in 96 well culture plates, and culture plate is put 37 ℃, 5%CO
2Hatch 24h in the incubator.Experiment is divided into normal control group, positive controls, dosing group.After filtering substratum, get cell plate, the careful suction removed nutrient solution, changes the liquid dosing.The every hole of normal control group adds the DMEM nutrient solution of 100 μ l; The every hole of model group adds contains 1000 μ MH
2O
2Nutrient solution 100 μ l, the every hole of positive controls adds contains 1000 μ M H
2O
2And the nutrient solution 100 μ l of 20 μ M vitamin-Es; The every hole of dosing group adds contains 1000 μ M H
2O
2And the nutrient solution 100 μ l of 1,10,20 μ M test-compounds, detect with the LDH release rate behind the effect PC12 cell 6h.Get 10 μ l cell culture fluids and survey the activity of LDH in the cell culture fluid supernatant, add the 1%Triton X-100 of 100 μ l again discarding nutrient solution then, 4 ℃ leave standstill 10min, and lysing cell is got the activity that 10 μ l cell pyrolysis liquids are measured LDH in the cell.The active measuring method of LDH builds up LDH test kit illustration method by Nanjing to carry out, and detects 490nm wavelength place every hole absorbancy OD value with microplate reader, parallel 4 holes of each concentration, and experiment repeats 3 times.Test-results sees Table-2.
3, test-results
(1) compound is to PC12 cell toxicity test result
The experimental result explanation, Scutellarein and series compound thereof are with 1-100 μ M effect PC12 cell 24h, and be less to its growth effect.Wherein SC-AG and WX-13,15,16, WZ-3,4,5,8～13 cell growth do not make significant difference.(table-1)
(2) compound is to the provide protection of the PC12 cell of hydrogen peroxide damage
By investigating the provide protection of LDH burst size evaluation Scutellarein and series compound thereof to the PC12 cell of hydrogen peroxide damage.The experimental result explanation, the Scutellarein of 1-20 μ M and series compound and H
2O
2With effect PC12 cell 6h, test-compound all can be protected the oxidative damage of superoxide to the generation of PC12 cell in the mode of acellular poison jointly.Wherein SC-AG, WX-3,4,7,9, WZ-1,3,11,12,13 effect are better than the positive drug vitamin-E.(table-2)
Claims (9)
1. a class has the organic and inorganic salt crystalline hydrate of acceptable, solvate on the scutellarin aglycone derivative of following structural formula (I) shown in (II) and the pharmacology thereof.
Wherein,
R1 is the C1-4 alkyl;
R2 is a nitrogen heterocyclic ring;
N is 0,2,3.
2. purine compound as claimed in claim 1, its feature again in, described compound is:
1) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-L-valine ester
2) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-alanine ester
3) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine ester
4) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine ester
5) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine ester
6) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-proline ester
7) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-methionine(Met) ester
8) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Xie Ansuan ethyl ether
9) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine ethyl ether
10) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine ethyl ether
11) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine ethyl ether
12) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-leucine propyl ether
13) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-Isoleucine propyl ether
14) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-L-phenylalanine propyl ether
15) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) benzoic ether
16) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((benzamido group) methyl) benzoic ether
17) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(morpholinyl methyl) benzoic ether
18) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(pyrroles-1-ylmethyl) benzoic ether
19) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((4-methylpiperazine-1-yl) methyl) benzoic ether
20) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((4-piperidines-1-yl) methyl) benzoic ether
21) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) phenylformic acid propyl ether
22) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((benzamido group) methyl) phenylformic acid propyl ether
23) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(morpholinyl methyl) phenylformic acid propyl ether
24) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-((diethylin) methyl) phenylformic acid ethyl ether
25) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(morpholinyl methyl) phenylformic acid ethyl ether
26) 5,6,7-trihydroxy--4-oxygen-2-(4-hydroxy phenyl)-4H-1-chromene-4-(pyrroles-1-ylmethyl) phenylformic acid ethyl ether.
3. method that is used to prepare the scutellarin aglycone derivative of claim 1 is characterized in that said method comprising the steps of:
(1) Scutellarein 4 '-L-amino acid ester analog derivative is synthetic
The Scutellarein of N-Boc-L-amino acid and ketal protection is at N; N-dicyclohexylcarbodiimide (DCC) exists down with 4-dimethylamino pyridine (DMAP); condensation forms Scutellarein 4 ' N-Boc-L-amino acid ester derivative under with the reaction conditions of tetrahydrofuran solvent, and products therefrom is through CH
3COCl/MeOH system low-temp reaction slough simultaneously hexichol ketal protected with N-Boc (N-tertbutyloxycarbonyl) protecting group obtain the ultimate aim compound:
(2) Scutellarein 4 '-L-amino acid ether derivative is synthetic
With N-Boc L-amino acid is substrate, obtains N-Boc L-amino acid-2-bromine ethyl ester or 3-bromopropyl ester by itself and ethylene bromohyrin or the condensation under the DMAP/DCC condition of 3-bromo-1-propyl alcohol, and the Scutellarein of gained compound and ketal protection is at cesium carbonate, 4
MS exists condensation down to obtain ketal protection scutellarin glycosides former 4 '-N-Boc-L-amino acid ethyl ether and propyl ether, products therefrom process CH
3COCl/MeOH system low-temp reaction slough simultaneously hexichol ketal protected with N-Boc (N-tertbutyloxycarbonyl) protecting group obtain the ultimate aim compound:
(3) Scutellarein 4 '-aminomethyl benzoate derivatives is synthetic
To chloromethyl benzoic acid and the condensation under the dehydrated alcohol condition of replacement amine; separate out post precipitation with concentrated hydrochloric acid regulation system pH 3.4; the precipitation isopropanol extraction; resistates separated acquisition substituted amine methyl phenylformic acid through silica gel column chromatography after isopropanol layer steamed solvent; gains and ketal protection Scutellarein are being solvent with the tetrahydrofuran (THF); with DMAP/DCC is under the condensation reagent condition, obtains ketal protection Scutellarein 4 '-replacement aminomethyl phenyl manthanoate through room temperature reaction, and gains are after CH
3COCl/MeOH system low-temp reaction is sloughed ketal protected, obtains target compound:
(4) Scutellarein 4 '-aminomethyl phenyl formic acid ether derivative is synthetic
The substituted amine methyl phenylformic acid that the last step obtains, gains and ethylene bromohyrin or the condensation under the DMAP/DCC condition of 3-bromo-1-propyl alcohol obtain substituted amine methyl phenylformic acid 2-bromo-ethyl ester or 3 bromopropyl esters, and the latter and ketal protection Scutellarein are at cesium carbonate, 4
Condensation condensation reaction under the molecular sieve existence condition is after CH
3COCl/MeOH system low-temp reaction is sloughed ketal protected, obtains target compound:
4. method as claimed in claim 3 is characterized in that, N-tertbutyloxycarbonyl in step (2)-L-amino acid-2-bromo-ethyl ester and 3-bromopropyl ester and ketal protection Scutellarein are in cesium carbonate/4
The molecular sieve existence condition; 40～100 ℃ of reactions 2～24 hours; optimum reaction condition is that N-tertbutyloxycarbonyl-L-amino acid 3-bromopropyl ester or 2-bromo-ethyl ester and ketal protection Scutellarein prorate are 1.5～2.0: 1mol; be that acid binding agent, N-Methyl pyrrolidone are under the solvent condition with the cesium carbonate, reacting 4～10 hours down at 60～80 ℃.
5. method as claimed in claim 3 is characterized in that, 4-replaces aminomethyl phenyl formic acid-2-bromo-ethyl ester and 3-bromopropyl ester and ketal protection Scutellarein in cesium carbonate/4 in step (4)
The molecular sieve existence condition; 40～100 ℃ of reactions 2～24 hours; optimum reaction condition is that 4-replaces aminomethyl phenyl formic acid 3-bromopropyl ester or 2-bromo-ethyl ester to protect the Scutellarein prorate with ketal be 1.5～2.0: 1mol; be that acid binding agent, N-Methyl pyrrolidone are under the solvent condition with the cesium carbonate, reacting 4～10 hours down at 60～80 ℃.
6. method as claimed in claim 3; it is characterized in that; solvent can be selected chloroform, methylene dichloride, tetrahydrofuran (THF) or ethyl acetate for use in step (1)～(4) deprotection base process; perhaps in Acetyl Chloride 98Min./methanol system; reacted 0.2～16 hour down at-10～25 ℃; be under the solvent condition in ethyl acetate preferably, system was reacted 5-12 hour for 0 ℃～25 ℃ with Acetyl Chloride 98Min./methanol system.
7. drug regimen is characterized in that comprising the scutellarin aglycone derivative and the assistant agent of the claim 1 of dose therapeutically effective.
8. the described scutellarin aglycone derivative of claim 1 is used for the treatment of application in the medicine of vascular dementia in preparation.
9. the application of the described scutellarin aglycone derivative of claim 1 in the medicine of treatment vascular dementia.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087024A (en) * | 2013-01-15 | 2013-05-08 | 四川大学 | Flavone alkylamine compounds as well as preparation method and application thereof |
| CN103739642A (en) * | 2013-10-10 | 2014-04-23 | 贵阳医学院 | Carbamate derivates of scutellarin and seutellarein, and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101337956A (en) * | 2008-08-22 | 2009-01-07 | 四川大学 | Scutellarein carbamate derivates, preparation method and application thereof |
| WO2009026166A2 (en) * | 2007-08-17 | 2009-02-26 | Herbalscience Group Llc | Antiinfective flavonol compounds and methods of use thereof |
-
2010
- 2010-06-30 CN CN201010213663A patent/CN101870684A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009026166A2 (en) * | 2007-08-17 | 2009-02-26 | Herbalscience Group Llc | Antiinfective flavonol compounds and methods of use thereof |
| CN101337956A (en) * | 2008-08-22 | 2009-01-07 | 四川大学 | Scutellarein carbamate derivates, preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087024A (en) * | 2013-01-15 | 2013-05-08 | 四川大学 | Flavone alkylamine compounds as well as preparation method and application thereof |
| CN103739642A (en) * | 2013-10-10 | 2014-04-23 | 贵阳医学院 | Carbamate derivates of scutellarin and seutellarein, and application thereof |
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Application publication date: 20101027 |