CN101337956A - Scutellarein carbamate derivates, preparation method and application thereof - Google Patents
Scutellarein carbamate derivates, preparation method and application thereof Download PDFInfo
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- CN101337956A CN101337956A CNA2008100458692A CN200810045869A CN101337956A CN 101337956 A CN101337956 A CN 101337956A CN A2008100458692 A CNA2008100458692 A CN A2008100458692A CN 200810045869 A CN200810045869 A CN 200810045869A CN 101337956 A CN101337956 A CN 101337956A
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Abstract
The invention relates to a novel scutellarin aglycon 4 (1)-position carbamate derivant (1), a preparation method and the application thereof. A pharmacological experiment proves that the compounds have obvious inhibitory activity of acetylcholinesterase and have protective effect with different degrees on PC12 cell trauma induced by H2O2, so the compounds can be used for preparing the drugs for treating neurodegenerative diseases such as vascular dementia, AD (presenile dementia), etc.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the novel scutellarin aglycone derivative of a class, be specifically related to Scutellarein 4 '-bit amino formate ester derivative, its preparation method and the application in preparation treatment vascular dementia, Alzheimer nerve degenerative diseases medicines such as (presenile dementias).
Background technology
Vascular dementia (Vascular Dementia, VD) be by the intelligence due to various types of cerebrovascular diseases (comprising ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, acute and chronic hypoxia cerebrovascular disease etc.) and the clinical syndrome of cognition dysfunction, its main clinical manifestation comprises: going down and the change of emotion, personality of cognitive ability, memory and social life ability is a kind of chronic progressive disease.In Asian countries's vascular dementias such as China, Japan is first reason of senile dementia; Along with the continuous propelling of world population to aging, cerebro-vascular diseases is increasing, and the vascular dementia sickness rate has the trend that rises gradually, has a strong impact on the elderly's work and quality of life, and brings heavy economy and mental burden for society and family.Therefore, VD has become important research focus in current geriatrics and the psychologic medicine field.Vascular dementia is not because the pathogenesis complexity still has the medicine that can block disease progression, and clinical treatment is to improve brain blood circulation and brain metabolism at present, and it is main strengthening brain nutrition.
In recent years, studies show that also frequent unusual with cholinergic system when VD patient shows cognitive function damage both at home and abroad.VD patient's hippocampus ChAT positive neuron and fibre density attenuating, the ChAT of the interior different sites of brain is active to descend, and the ACh concentration in VD patient's cerebrospinal fluid is starkly lower than normal level, and the severity of the degree of its concentration reduction and dementia is proportionate; Acetylcholine esterase active rises in the brain and cerebral ischemia can cause; Simultaneously, also find some acetylcholinesterase depressant as HuperzineA and Revastigmine, the neuronal damage that can protect ischemic to cause, and can promote the recovery of nerve injury and brain function after the cerebral ischemia.This shows that acetylcholinesterase depressant also can be used for the treatment of vascular dementia.
Herba Erigerontis is the herb of composite family bitter fleabane platymiscium Erigeron breviscapus (Vant.) Hand.-Mazz. Erigeron Breviscapine (vant) Hand Mass, has another name called Herba Erigerontis, oil lamp chrysanthemum etc., mainly is distributed in various places, China south.Twentieth century seventies is through clinical verification, proof Herba Erigerontis crude extract has obvious curative effects to hypertension, Intracerebral hemorrhage, cerebral thrombosis, cerebral embolism polyneuritis, chronic Intraventricular membrane inflammation and sequela thereof, causes the extensive interest of people to the research of Herba Erigerontis crude extract effective constituent thus.Through research for many years, from Herba Erigerontis isolation identification the number of chemical composition, as: pyranone, flavonoid, lactone, amino acids, polyose etc., and find that (have another name called: scutellarin) be the main active ingredient of Herba Erigerontis extract, its crude extract has been used for clinical as the cardiovascular and cerebrovascular medicine scutellarin; Studies show that that scutellarin also has is antitumor, extensive pharmacologically active such as anti HIV-1 virus, anti-hepatic fibrosis, anti-senile dementia, neuroprotective.
Discover, adopt Breviscarpine treatment VD after 20 days, simple intelligent status checking table (MMSE), vital function scale (ADL), Chang Gu river Dementia scale (HDS), dementia severity clinical assessment scale (WMS) scoring all is significantly improved, and hemorheology indexs such as whole blood viscosity, plasma viscosity, erythrocyte aggregation index, Fibrinogen all descend, with control group significant difference is arranged relatively, simultaneously, superoxide dismutase (SOD) obviously rises, and mda (MDA) obviously descends.Show that Breviscarpine may increase the blood confession by improving cerebral circulation to the treatment of VD, suppresses to pour into the activation of protein kinase again and suppresses Ca
2+Overload, reduce free radical, the approach such as release that reduce excitatory amino acid stop apoptosis, alleviate cerebral ischemia re-pouring injured and work; Histological stain finds that Breviscarpine has reduced hippocampus CA1 district cell pathology and changed simultaneously; as: karyopyknosis, intracellular edema and centrum cellular layer fall into disarray etc.; proved that Breviscarpine improves the symptom of vascular dementia rats; prevented that the neuronal damage and the calcium ion that are caused by free radical from increasing, and has neuroprotective for the cerebrovascular and vascular dementia.
In addition, Breviscarpine also can be used for treating senile dementia.Treat senile dementia with Herba Erigerontis tablet, treatment group total effective rate 62.85%, there were significant differences for 36%, two group of contrast of control group (hydergine) total effective rate; And find that Breviscarpine can obviously improve mouse study, the dysmnesia due to the Scopolamine, obviously improve the large and small mouse memory represents obstacle due to the ethanol, and the learning capacity of the two is obviously strengthened, compare with brain multiple plain (cerebrolysin, Cerebrolysin Vial), act on close or strong slightly.
Because problems such as that scutellarin exists is poorly soluble, bioavailability is low, short and toxic side effect of transformation period is serious in the body, with the scutellarin for guide's thing carries out structure of modification, in the hope of finding that the better medicine of pharmacologically active and curative effect is with significant.Internal metabolism to scutellarin is discovered; Scutellarein is its active metabolite; have than strong biological activity; therefore; with the Scutellarein is guide's thing; modify by chemical structure; introduce inhibiting activity of acetylcholinesterase, pharmacophoric group---carbamate in its 4 '-position; designed a series of Scutellareins 4 '-bit amino carbamate derivatives, hope can be from antithrombotic; expansion of cerebral vascular; Green Tea Extract; multiaction target spots such as neuroprotective and enhancing maincenter acetylcholine neural function reach the Synergistic treatment vascular dementia; Alzheimer (presenile dementia).
Summary of the invention
The object of the present invention is to provide the novel scutellarin aglycone derivative of a class (Scutellarein 4 '-bit amino carbamate derivatives);
Another object of the present invention is the preparation method who discloses this compounds;
The 3rd purpose of the present invention is to disclose the application of this compounds in treatment vascular dementia, Alzheimer nerve degenerative diseases medicines such as (presenile dementias).
The chemical structure of general formula of Scutellarein 4 ' provided by the present invention-bit amino carbamate derivatives is:
In the formula: R
1, R
2Can be identical or different, R
1, R
2Represent H, C
1～C
12Fat alkane, C
3～C
7The C of cycloaliphatic ring alkane, replacement
3～C
7Aryl, C that cycloaliphatic ring alkane, aryl, power supply or electrophilic replace
1～C
6Fatty Alcohol(C12-C14 and C12-C18) and ester thereof, C
1～C
6Carboxylic acid and ester thereof, or R
1, R
2Form tetra-atomic ring, five-ring, six-ring or seven-membered ring with C, O and the cyclization of N atom respectively.
Scutellarin aglycone derivative proposed by the invention can prepare by the following method:
Above-mentioned chemical equation has provided the synthetic method of Scutellarein 4 '-bit amino carbamate derivatives.
With Scutellarein (1) is starting raw material, with the reaction of itself and phenylbenzene methylene dichloride (2), 6,7-(phenylbenzene methylene radical dioxy)-5,4 '-dihydroxyflavone (3), 6, the protected aglycon of 7-position hydroxyl respectively with urea chloride or isocyanic ester (R
1During=H) derivative (4) condensation, get 6, the protected Scutellarein 4 ' of 7-position hydroxyl-bit amino carbamate derivatives (5), gained intermediate remove protecting group through catalytic hydrogenolysis again, get Scutellarein 4 '-bit amino carbamate derivatives (I).
Its concrete preparation method is described below:
Scutellarein (1) gets intermediate (3) with phenylbenzene methylene dichloride (2) through condensation reaction, need not to add organic solvent in the reaction, wherein, the molar feed ratio when react with (2) (1) is 1.0: 1.0～3.0, and preferred molar feed ratio is 1.0: 1.2～2.0; Temperature of reaction is 100～230 ℃, and preferable reaction temperature is 150 ℃～200 ℃; Reaction times is 10 minutes～120 minutes, and the preferred reaction time is 10 minutes～1 hour;
Intermediate (3) alkalescence and the inert solvent condition under respectively with urea chloride or isocyanic ester (R
1During=H) derivative (4) condensation, get 6,7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-carbamate-flavone derivative (5), wherein, intermediate (3) is 1.0: 1.0～3.0 with the molar feed ratio of (4), and preferred molar feed ratio is 1.0: 1.2～1.5; Reacting used alkali is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl-α-Ben Yian, 4-methylmorpholine, TBAH), preferred bases is: sodium bicarbonate, salt of wormwood, triethylamine, pyridine; The molar feed ratio of alkali consumption and raw material (4) is 1.0～4.5: 1.0, and preferred molar feed ratio is 1.0～2.0: 1.0; Reacting used inert solvent is: ether, tetrahydrofuran (THF), N, dinethylformamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C
3～C
8Aliphatic ketone, benzene, normal heptane, toluene, pyridine, preferred solvent are N, dinethylformamide, acetone, pyridine, tetrahydrofuran (THF); Temperature of reaction is 0～130 ℃, and preferable reaction temperature is room temperature～80 ℃; Condensation reaction time is 2 hours～7 days, and the preferred reaction time is 24～48 hours;
Intermediate (5) gets Scutellarein 4 '-bit amino carbamate derivatives (I) under catalyzer and solvent action, wherein, catalyst system therefor is 5% Pd/C, 10% Pd/C, 10% Pd (OH)
2/ C, preferred catalyst are 10% Pd (OH)
2/ C; Solvent for use is: C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), N, dinethylformamide, tetrahydrofuran (THF), preferred solvent is an ethanol; Temperature of reaction is room temperature～100 ℃, and preferable reaction temperature is a room temperature.
Scutellarein 4 ' provided by the invention-bit amino carbamate derivatives (I) can obtain its pharmacy acceptable salt by conventional salifying method pharmaceutically with suitable mineral alkali, and described mineral alkali is that basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates all can be used.
Scutellarein 4 ' of the present invention-bit amino carbamate derivatives has carried out following bioactivity screening:
1, inhibiting activity of acetylcholinesterase,
Acetylcholinesterase (AChE) enzyme source adopts rat layer 5% homogenate (to use 75mmol, pH 7.4,4 ℃ of phosphoric acid buffers are made the homogenate medium), experiment is preceding by the selective depressant tetra isopropyl pyrophosphoramide (iso-OMPA) that adds 4mmol butyrylcholine esterase (BuChE) at 10: 1,37 ℃ are incubated 5 minutes, with colorimetric method for determining AChE vigor.Add acetylthiocholine iodide 0.3mmol in pear-shaped tube, 0.1mol/L pH 7.4 sodium phosphate buffer 1.0ml and concentration are 10
-4The target compound DMSO solution 0.1ml of mol/L, add water mend to 4ml (comprise the back enzyme-added liquid measure, the reaction final concentration of each compound is 2.5 * 10
-6Mol/L), add enzyme liquid 0.1ml after 5 minutes in 37 ℃ of insulations, be incubated sodium laurylsulfonate (SDS) the solution 1.0ml termination reaction of adding 3% after 8 minutes again, add at last 0.2% 5,5 '-Lian sulphur-2,2 '-nitro-phenylformic acid (DTNB, Ellman ' s reagent) solution 1.0ml colour developing, produce yellow 5-sulphur-2-nitrobenzoyl acid anion, measure optical density(OD) (A in 440nm with 752C type ultraviolet-visible pectrophotometer
n), all samples is all surveyed two-tube and is measured three times, with the mensuration pipe optical density(OD) that do not add compound as 100% (A
Control), compound determination pipe optical density(OD) compares with it, and the percentage of reduction is enzyme inhibition rate (A
n/ A
Control* 100%); In the test with 10% and 20%DMSO 0.1ml as solvent control, done the contrast of corresponding medicine color simultaneously, measurement result has all been deducted the influence of solvent control and color contrast.The part target compound is to inhibiting activity of acetylcholinesterase, as shown in Table 1:
2, compound is to H
2O
2The provide protection screening of inductive PC12 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
-5Mol/L, 10
-6Mol/L, 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 100 μ MH respectively
2O
2Damage agent 10 μ L/ holes (control group adds 10 μ L/ hole PBS), after 30 minutes, the RPMI RPMI-1640 that the nutrient solution of each group is all changed into no calf serum continues to put into constant incubator cultivation 24 hours, and the nutrient solution volume still is 100 μ L/ holes.Continue to cultivate after 24 hours, add 5mg/mL MTT 100 μ L/ holes in each group, carry out viable cell dyeing.After treating 3 hours, add 100%DMSO stop buffer 100 μ L/ holes in each group, fully dissolve mixing.Under the wavelength of 490nm, measure the OD value of each group.Test result repeats 3 times, use Duncan ' s test method statistic, and each organizes numeric representation is mean ± S.E.M., is 100% with control group, administration group and damage class value and represent, test result with the per-cent of control group as shown in Table 2:
Embodiment
Can further describe the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
Embodiment 1
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5,4 '-dihydroxyflavone (3)
In reaction flask, add Scutellarein 13.3g (0.047mol) and phenylbenzene methylene dichloride 16.7g (0.070mol) successively; mix; under noble gas protection, be warming up to 170 ℃ of reactions 1 hour, be cooled to room temperature after, add an amount of chloroform; suction filtration while hot; filtrate decompression is steamed and is desolventized, and resistates chloroform recrystallization gets light brown needle crystal 13.83g; mp:250～252 ℃, yield 65.9%.
1H NMR (DMSO-d
6, 400MHz) δ: 13.18 (brs, 1H, 5-OH), 10.41 (brs, 1H, 4 '-OH), 7.95 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.61 (s, 1H, Ar-H
8), 7.59～7.56 (m, 4H, Ph-H), 7.51～7.47 (m, 6H, Ph-H), 6.94 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.88 (s, 1H, Ar-H
3); HR-TOFMS m/z:449.1036 ([C
28H
18O
6-H]
+Calculated value: 449.1025).
Embodiment 2
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N-Pyrrolidine methanoyl)-flavones (5a)
With 1.0g (2.21mmol) intermediate 3,0.35mmol Pyrrolidine formyl chloride, 30ml N, dinethylformamide and 5ml anhydrous pyridine add in the reaction flask, 15 hours (reaction process is followed the tracks of with TLC) of stirring at room reaction; After reaction finishes, add an amount of frozen water, suction filtration, a small amount of frozen water washing leaching cake, the gained crude product through column chromatography purification (elutriant: chloroform-ethyl acetate), pale yellow powder solid 0.593g, mp:226～228 ℃, yield 49.0%.
1H?NMR(CDCl
3，400MHz)δ：7.86(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.64～7.61(m，4H，Ph-H)，7.41～7.37(m，6H，Ph-H)，7.31(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.65(s，1H，Ar-H
8)，6.62(s，1H，Ar-H
3)，3.56(t，J＝6.8Hz，2H，NCH
2-H
α)，3.53(t，J＝6.8Hz，2H，NCH
2-H
β)，1.92(t，J＝6.8Hz，2H，β-CH
2-H
α)，1.87(t，J＝6.8Hz，2H，β-CH
2-H
β)。
Embodiment 3
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N, N-dimethylamino methanoyl)-flavones (5b)
Operating process is with embodiment 2, and just with Pyrrolidine formyl chloride N, the N-dimethylcarbamyl chloride substitutes, get 6, the pale yellow powder solid of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N, N-dimethylamino methanoyl)-flavones, mp:230～232 ℃, yield 71.2%.
1H?NMR(CDCl
3，400MHz)δ：7.86(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.64～7.61(m，4H，Ph-H)，7.41～7.37(m，6H，Ph-H)，7.28(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.65(s，1H，Ar-H
8)，6.62(s，1H，Ar-H
3)，3.13(s，3H，CH
3)，3.04(s，3H，CH
3)。
Embodiment 4
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N, N-diethylamino methanoyl)-flavones (5c)
Operating process is with embodiment 2, and just with Pyrrolidine formyl chloride N, N-diethylamino formyl chloride substitutes, get 6, the pale yellow powder solid of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N, N-diethylamino methanoyl)-flavones, mp:216～218 ℃, yield 67.9%.
1H?NMR(CDCl
3，400MHz)δ：7.86(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.64～7.60(m，4H，Ph-H)，7.43～7.37(m，6H，Ph-H)，7.29(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.66(s，1H，Ar-H
8)，6.63(s，1H，Ar-H
3)，3.46(q，J＝6.8Hz，2H，NCH
2)，3.41(q，J＝6.8Hz，2H，NCH
2)，1.27(t，J＝6.8Hz，3H，CH
3)，1.22(t，J＝6.8Hz，3H，CH
3)。
Embodiment 5
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N, N-diisopropylaminoethyl methanoyl)-flavones (5d)
Operating process is with embodiment 2, just with Pyrrolidine formyl chloride N, N-diisopropylaminoethyl formyl chloride substitutes, get 6,7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N, N-diisopropylaminoethyl methanoyl)-and the pale yellow powder solid of flavones, mp:239～241 ℃, yield 50.4%.
1H?NMR(CDCl
3，400MHz)δ：7.86(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.64～7.61(m，4H，Ph-H)，7.42～7.38(m，6H，Ph-H)，7.29(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.66(s，1H，Ar-H
8)，6.63(s，1H，Ar-H
3)，4.11(q，J＝6.8Hz，1H，NCH)，3.99(q，J＝6.8Hz，1H，NCH)，1.35(d，J＝6.8Hz，6H，2×CH
3)，1.32(d，J＝6.8Hz，6H，2×CH
3)。
Embodiment 6
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N-morpholine methanoyl)-flavones (5e)
Operating process just substitutes the Pyrrolidine formyl chloride with embodiment 2 with N-morpholine formyl chloride, get 6, the pale yellow powder solid of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N-morpholine methanoyl)-flavones, and mp:＞242 ℃, yield 52.5%.
1H?NMR(CDCl
3，400MHz)δ：7.87(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.63～7.61(m，4H，Ph-H)，7.42～7.38(m，6H，Ph-H)，7.28(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.65(s，1H，Ar-H
8)，6.63(s，1H，Ar-H
3)，3.70(t，J＝4.8Hz，2H，NCH
2)，3.60(t，J＝4.8Hz，2H，NCH
2)，3.77(t，J＝4.8Hz，4H，2×OCH
2)。
Embodiment 7
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N-methyl-N-ethylamino methanoyl)-flavones (5f)
Operating process is with embodiment 2, just the Pyrrolidine formyl chloride is substituted with N-methyl-N-ethylamino formyl chloride, get 6, the pale yellow powder solid of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N-methyl-N-ethylamino methanoyl)-flavones, mp:192～194 ℃, yield 80.8%.
1H?NMR(CDCl
3，400MHz)δ：7.86(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.64～7.60(m，4H，Ph-H)，7.42～7.36(m，6H，Ph-H)，7.28(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.65(s，1H，Ar-H
8)，6.62(s，1H，Ar-H
3)，3.50(q，J＝7.2Hz，1H，NCH
2)，3.43(q，J＝7.2Hz，1H，NCH
2)，3.09(s，1.5H，NCH
3)，3.01(s，1.5H，NCH
3)，1.26(t，J＝7.2Hz，1.5H，CH
3)，1.21(t，J＝7.2Hz，1.5H，CH
3)。
Embodiment 8
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N-piperidine formyl oxygen base)-flavones (5g)
Operating process is with embodiment 2, just the Pyrrolidine formyl chloride is substituted with N-piperidine formyl chlorine, get 6, the pale yellow powder solid of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(N-piperidine formyl oxygen base)-flavones, mp:220～222 ℃, yield 86.7%.
1H?NMR(CDCl
3，400MHz)δ：7.88(d，J＝8.8Hz，2H，Ar’-H
3，5)，7.66～7.62(m，4H，Ph-H)，7.43～7.40(m，6H，Ph-H)，7.29(d，J＝8.8Hz，2H，Ar’-H
2，6)，6.67(s，1H，Ar-H
8)，6.64(s，1H，Ar-H
3)，3.64(m，2H，NCH
2)，3.55(m，2H，NCH
2)，1.68(m，6H，3×CH
2)。
Embodiment 9
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-[N-(4-benzyl) piperidine formyl oxygen base]-flavones (5h)
Operating process is with embodiment 2, just the Pyrrolidine formyl chloride is substituted with N-(4-benzyl) piperidine formyl chlorine, get 6, the pale yellow powder solid of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-[N-(4-benzyl) piperidine formyl oxygen base]-flavones, mp:98～100 ℃, yield 71.5%.
1H?NMR(CDCl
3，400MHz)δ：7.92(d，J＝8.8Hz，1H，Ar’-H
3，5)，7.85(d，J＝8.8Hz，1H，Ar’-H
3，5)，7.64～7.59(m，4H，Ph-H)，7.43～7.38(m，6H，Ph-H)，7.33～7.19(m，5H，Ph-H)，7.17(d，J＝8.8Hz，1H，Ar’-H
2，6)，7.14(d，J＝8.8Hz，1H，Ar’-H
2，6)，6.65(s，0.5H，Ar-H
8)，6.62(s，0.5H，Ar-H
3)，6.58(s，0.5H，Ar-H
8)，6.50(s，0.5H，Ar-H
3)，4.27(t，J＝15.2Hz，2H，PhCH
2)，2.95(m，1H，NCH
2)，2.74(m，1H，NCH
2)，2.61(m，1H，NCH
2)，2.59(m，1H，NCH
2)，1.76(m，1.5H，CHCH
2)，1.73(m，1.5H，CHCH
2)，1.33(m，1H，CH
2)，1.27(m，1H，CH
2)。
Embodiment 10
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-[N-(4-methyl) piperazine methanoyl]-flavones (5i)
Operating process is with embodiment 2, just the Pyrrolidine formyl chloride is substituted with 4-methyl isophthalic acid-piperazine formyl chloride hydrochloride, get 6, the pale yellow powder solid of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-[N-(4-methyl) piperazine methanoyl]-flavones, yield 67.5%.
Embodiment 11
6, the preparation of 7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-(third carbamoyloxy)-flavones (5j)
In reaction flask, add 1.0g (2.21mmol) intermediate 3, anhydrous tetrahydro furan 30ml and anhydrous triethylamine 0.46ml (3.31mmol), after the stirring at room 5 minutes, drip the third amino isocyanic ester 0.225g (2.65mmol) and be dissolved in the solution of 5ml tetrahydrofuran (THF), 6 hours (reaction process is monitored with TLC) of 40～50 ℃ of insulated and stirred reactions; Reaction removes solvent under reduced pressure after finishing, and the gained crude product is through column chromatography purification (elutriant: methylene dichloride-ethyl acetate), get pale yellow powder solid 1.053g, yield 89.0%.
Embodiment 12
5,6,7-trihydroxy--4 '-preparation of (N-Pyrrolidine methanoyl)-flavones (Ia)
Add intermediate 5a 0.547g (1.00mmol) and ethanol 25ml in reaction flask, the back that stirs adds 10% Pd (OH)
2/ C 40mg, logical then hydrogen room temperature stirring reaction 48 hours after reaction finishes, filters, the small amount of ethanol washing leaching cake, filtrate decompression is steamed and is desolventized, resistates is through acetone recrystallization, pale yellow powder solid 0.268g, mp:212～24 ℃, yield 70.0%.
1H NMR (DMSO-d
6, 400MHz) δ: 12.68 (brs, 1H, 5-OH), 10.59 (brs, 1H, 7-OH), 8.63 (brs, 1H, 6-OH), 8.09 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.34 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.93 (s, 1H, Ar-H
8), 6.63 (s, 1H, Ar-H
3), 3.53 (t, J=6.8Hz, 2H, NCH
2-H
α), 3.36 (t, J=6.8Hz, 2H, NCH
2-H
β), 1.92 (t, J=6.8Hz, 2H, β-CH
2-H
α), 1.87 (t, J=6.8Hz, 2H, β-CH
2-H
β); HR-TOFMS (+Q) m/z:384.1080 ([C
20H
17NO
7+ H]
+Calculated value: 384.1083).
Embodiment 13
5,6,7-trihydroxy--4 '-preparation of (N, N-dimethylamino methanoyl)-flavones (Ib)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5b, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of (N, N-dimethylamino methanoyl)-flavones, mp:＞242 ℃, yield 62.5%.
1HNMR (DMSO-d
6, 400MHz) δ: 12.68 (brs, 1H, 5-OH), 10.61 (brs, 1H, 7-OH), 8.85 (brs, 1H, 6-OH), 8.10 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.33 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.94 (s, 1H, Ar-H
8), 6.63 (s, 1H, Ar-H
3), 3.07 (s, 3H, CH
3), 2.94 (s, 3H, CH
3); HR-TOFMS (+Q) m/z:358.0900 ([C
18H
15NO
7+ H]
+Calculated value: 358.0927).
Embodiment 14
5,6,7-trihydroxy--4 '-preparation of (N, N-diethylamino methanoyl)-flavones (Ic)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5c, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of (N, N-diethylamino methanoyl)-flavones, mp:182～184 ℃, yield 47.7%.
1H NMR (DMSO-d
6, 400MHz) δ: 12.68 (brs, 1H, 5-OH), 10.60 (brs, 1H, 7-OH), 8.85 (brs, 1H, 6-OH), 8.10 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.33 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.94 (s, 1H, Ar-H
8), 6.63 (s, 1H, Ar-H
3), 3.43 (q, J=6.8Hz, 2H, NCH
2), 3.13 (q, J=6.8Hz, 2H, NCH
2), 1.22 (t, J=6.8Hz, 3H, CH
3), 1.13 (t, J=6.8Hz, 3H, CH
3); HR-TOFMS (+Q) m/z:386.1231 ([C
20H
19NO
7+ H]
+Calculated value: 386.1240).
Embodiment 15
5,6,7-trihydroxy--4 '-preparation of (N, N-diisopropylaminoethyl methanoyl)-flavones (Id)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5d, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of (N, N-diisopropylaminoethyl methanoyl)-flavones, mp:206～208 ℃, yield 63.0%.
1H NMR (DMSO-d
6, 400MHz) δ: 12.67 (brs, 1H, 5-OH), 10.56 (brs, 1H, 7-OH), 8.81 (brs, 1H, 6-OH), 8.09 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.30 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.92 (s, 1H, Ar-H
8), 6.63 (s, 1H, Ar-H
3), 4.01 (q, J=6.8Hz, 2H, 2 * NCH), 1.27 (d, J=6.8Hz, 12H, 4 * CH
3); HR-TOFMS (+Q) m/z:414.1507 ([C
22H
23NO
7+ H]
+Calculated value: 414.1553).
Embodiment 16
5,6,7-trihydroxy--4 '-preparation of (N-morpholine methanoyl)-flavones (Ie)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5e, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of (N-morpholine methanoyl)-flavones, mp:＞242 ℃, yield 47.2%.
1H NMR (DMSO-d
6, 400MHz) δ: 12.66 (brs, 1H, 5-OH), 10.57 (brs, 1H, 7-OH), 8.81 (brs, 1H, 6-OH), 8.10 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.36 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.93 (s, 1H, Ar-H
8), 6.63 (s, 1H, Ar-H
3), 3.67 (t, J=4.8Hz, 4H, 2 * NCH
2), 3.61 (m, 2H, OCH
2), 3.44 (m, 2H, OCH
2); HR-TOFMS (+Q) m/z:400.1002 ([C
20H
17NO
8+ H]
+Calculated value: 400.1032).
Embodiment 17
5,6,7-trihydroxy--4 '-preparation of (N-methyl-N-ethylamino methanoyl)-flavones (If)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5f, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of (N-methyl-N-ethylamino methanoyl)-flavones, mp:200～202 ℃, yield 50.0%.
1H NMR (DMSO-d
6, 400MHz) δ: 12.67 (brs, 1H, 5-OH), 10.56 (brs, 1H, 7-OH), 8.81 (brs, 1H, 6-OH), 8.09 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.32 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.92 (s, 1H, Ar-H
8), 6.63 (s, 1H, Ar-H
3), 3.45 (q, J=7.2Hz, 1H, NCH
2), 3.38 (q, J=7.2Hz, 1H, NCH
2), 3.05 (s, 1.5H, NCH
3), 2.92 (s, 1.5H, NCH
3), 1.20 (t, J=7.2Hz, 1.5H, CH
3), 1.12 (t, J=7.2Hz, 1.5H, CH
3); HR-TOFMS (+Q) m/z:372.1049 ([C
19H
17NO
7+ H]
+Calculated value: 372.1083).
Embodiment 18
5,6,7-trihydroxy--4 '-preparation of (N-piperidine formyl oxygen base)-flavones (Ig)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5g, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of (N-piperidine formyl oxygen base)-flavones, mp:196～198 ℃, yield 55.4%.
1H NMR (DMSO-d
6, 400MHz) δ: 12.69 (brs, 1H, 5-OH), 10.60 (brs, 1H, 7-OH), 8.86 (brs, 1H, 6-OH), 8.09 (d, J=8.8Hz, 2H, Ar '-H
3,5), 7.33 (d, J=8.8Hz, 2H, Ar '-H
2,6), 6.94 (s, 1H, Ar-H
8), 6.63 (s, 1H, Ar-H
3), 3.58 (m, 2H, NCH
2), 3.42 (m, 2H, NCH
2), 1.60 (m, 6H, 3 * CH
2); HR-TOFMS (+Q) m/z:398.1204 ([C
21H
19NO
7+ H]
+Calculated value: 398.1240).
Embodiment 19
5,6,7-trihydroxy--4 '-preparation of [N-(4-benzyl) piperidine formyl oxygen base]-flavones (Ih)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5h, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of [N-(4-benzyl) piperidine formyl oxygen base]-flavones, mp:176～178 ℃, yield 44.3%.
1H NMR (CDCl
3, 400MHz) δ: 7.72 (d, J=8.8Hz, 1H, Ar '-H
3,5), 7.68 (d, J=8.8Hz, 1H, Ar '-H
3,5), 7.34～7.17 (m, 5H, Ph-H), 7.19 (d, J=8.8Hz, 1H, Ar '-H
2,6), 7.13 (d, J=8.8Hz, 1H, Ar '-H
2,6), 6.51 (s, 0.5H, Ar-H
8), 6.50 (s, 0.5H, Ar-H
3), 6.42 (s, 0.5H, Ar-H
8), 6.13 (s, 0.5H, Ar-H
3), 4.29 (t, J=15.2Hz, 2H, PhCH
2), 2.97 (m, 1H, NCH
2), 2.85 (m, 1H, NCH
2), 2.63 (m, 1H, NCH
2), 2.61 (m, 1H, NCH
2), 1.78 (m, 1.5H, CHCH
2), 1.75 (m, 1.5H, CHCH
2), 1.32 (m, 1H, CH
2), 1.29 (m, 1H, CH
2); HR-TOFMS (+Q) m/z:488.1687 ([C
28H
25NO
7+ H]
+Calculated value: 488.1709).
Embodiment 20
5,6,7-trihydroxy--4 '-preparation of [N-(4-methyl) piperazine methanoyl]-flavones (Ii)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5i, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of [N-(4-methyl) piperazine methanoyl]-flavones, yield 48.7%.HR-TOFMS (+Q) m/z:413.1340 ([C
21H
20N
2O
7+ H]
+Calculated value: 413.1349).
Embodiment 21
5,6,7-trihydroxy--4 '-preparation of (third carbamoyloxy)-flavones (Ij)
Operating process is with embodiment 12, just intermediate 5a is substituted with intermediate 5j, 5,6,7-trihydroxy--4 '-the pale yellow powder solid of (third carbamoyloxy)-flavones, yield 72.8%.HR-TOFMS (+Q) m/z:372.1068 ([C
19H
17NO
7+ H]
+Calculated value: 372.1083).
Embodiment 22 biological activity test results
Table one: the part target compound suppresses percentage to acetylcholinesterase
Conclusion: the part target compound has significant inhibitory effect to acetylcholinesterase, and suppresses active in the positive control medicine---Rivastigmine is strong.
Table two: part target compound antagonism H
2O
2Inductive PC12 cell injury measurement result
Conclusion: target compound all has in various degree provide protection to the PC12 cell injury of hydrogen peroxide-induced.
The invention is not restricted to the foregoing description
Claims (7)
1. a class has the scutellarin aglycone derivative of following general formula (I), and pharmacy acceptable salt:
It is characterized in that R
1, R
2Can be identical or different, R
1, R
2Represent H, C
1～C
12Fat alkane, C
3～C
7The C of cycloaliphatic ring alkane, replacement
3～C
7Aryl, C that cycloaliphatic ring alkane, aryl, power supply or electrophilic replace
1～C
6Fatty Alcohol(C12-C14 and C12-C18) and ester thereof, C
1～C
6Carboxylic acid and ester thereof, or R
1, R
2Form tetra-atomic ring, five-ring, six-ring or seven-membered ring with C, O and the cyclization of N atom respectively.
2. compound or its pharmacy acceptable salt according to claim 1 is characterized in that the preparation of compound comprises the steps:
With Scutellarein (1) is starting raw material, with the reaction of itself and phenylbenzene methylene dichloride (2), 6,7-(phenylbenzene methylene radical dioxy)-5,4 '-dihydroxyflavone (3), 6, the protected aglycon of 7-position hydroxyl respectively with urea chloride or isocyanic ester (R
1During=H) derivative (4) condensation, get 6, the protected Scutellarein 4 ' of 7-position hydroxyl-bit amino carbamate derivatives (5), gained intermediate remove protecting group through catalytic hydrogenolysis again, get Scutellarein 4 '-bit amino carbamate derivatives (I).
3. the preparation method of compound according to claim 1, it is characterized in that Scutellarein (1) and phenylbenzene methylene dichloride (2) get intermediate (3) through condensation reaction, need not to add organic solvent in the reaction, wherein, the molar feed ratio when react with (2) (1) is 1.0: 1.0～3.0; Temperature of reaction is 100～230 ℃; Reaction times is 10 minutes～120 minutes.
4. the preparation method of compound according to claim 1 is characterized in that, intermediate (3) under alkalescence and inert solvent condition respectively with urea chloride or isocyanic ester (R
1During=H) derivative (4) condensation, get 6,7-(phenylbenzene methylene radical dioxy)-5-hydroxyl-4 '-carbamate-flavone derivative (5), wherein, intermediate (3) is 1.0: 1.0～3.0 with the molar feed ratio of (4); Reacting used alkali is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl-α-Ben Yian, 4-methylmorpholine, TBAH); The molar feed ratio of alkali consumption and raw material (4) is 1.0～4.5: 1.0; Reacting used inert solvent is: ether, tetrahydrofuran (THF), N, dinethylformamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C
3～C
8Aliphatic ketone, benzene, normal heptane, toluene, pyridine; Temperature of reaction is 0～130 ℃; Condensation reaction time is 2 hours～7 days.
5. the preparation method of compound according to claim 1, it is characterized in that, intermediate (5) gets Scutellarein 4 '-bit amino carbamate derivatives (I) under catalyzer and solvent action, wherein, catalyst system therefor is 5%Pd/C, 10%Pd/C, 10%Pd (OH)
2/ C; Solvent for use is: C
1～C
6Fatty Alcohol(C12-C14 and C12-C18), N, dinethylformamide, tetrahydrofuran (THF); Temperature of reaction is room temperature～100 ℃.
6. compound or its pharmacy acceptable salt according to claim 1, it is characterized in that described pharmacy acceptable salt is (I) and basic metal or the formed salt of alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates.
7. scutellarin aglycone derivative as claimed in claim 1, the application in treatment vascular dementia, Alzheimer nerve degenerative diseases medicines such as (presenile dementias).
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| CN101845034A (en) * | 2010-06-11 | 2010-09-29 | 贵阳医学院 | Preparation and application method of scutellarin |
| CN101870684A (en) * | 2010-06-30 | 2010-10-27 | 贵阳医学院 | Scutellarin aglycone derivative for treating vascular dementia and preparation method and application thereof |
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