CN1106391C - Magnolol series of compounds, synthesizing process thereof, and medicinal composition using same as active component - Google Patents
Magnolol series of compounds, synthesizing process thereof, and medicinal composition using same as active component Download PDFInfo
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Abstract
The R is the following group: ***, wherein R1 can adopt-(-CH2-)n-CH2-CH2-R2-(CH2)n-***-(CH2)n-***, ***; R2 can adopt-(CH2)n-*** ***. The present invention discloses a structure of a magnolol series compound, a synthetic method and activity thereof, wherein a structural formula is two series disclosed in a formula I and a formula II (disclosed in the right formula); R3 can adopt halogen, a hydrogen group, methyloxyl, ethyloxyl, propyloxyl and NO2; a n value is natural numbers of 0, 1, 2 and 3. The present invention also reveals a synthetic method of the compound, a medicinal composition using the compound as active components and an application of the compound of the present invention and the medicinal composition to blood pressure reduction, anti-oxidative activity and antiradical activity.
Description
The present invention relates to the structural formula of magnolol series compound and synthetic method thereof and be the pharmaceutical composition of active ingredient, and they are in the application of hypotensive, anti-oxidant activity, the active pharmaceutical composition of Green Tea Extract with this compound.
The bark of official magnolia belongs to Magnoliacea plant, originates in ground such as Sichuan, Guizhou, North of Hunan, Shaanxi, Fujian, and Shennong Bencaojing is carried: [bark of official magnolia cures mainly that apoplexy, cold headache, heat are cold, palpitation with fear, qi and blood numbness, dead flesh, go three worms].The grand scape Mingyi Bielu of Liang Tao claims [bark of official magnolia Wen Zhongyi gas, the dissolving phlegm therapeutic method to keep the adverse qi flowing downward, treatment cholera and stomachache turgor, cold in the stomach is contrary, vomits incessantly, lets out the dysentery pouring in the heart and reveal].
Magnolol (magnolol) is in nineteen thirty, is gone out with the medicinal part bark extracting of the Chinese Sichuan bark of official magnolia by the kind Xiong Shi of Japanese scholar Shan Jing, and the contained magnolol content of the Chinese medicinal materials bark of official magnolia is very high, accounts for 1/10th of dry weight.In traditional medication among the people, the bark of official magnolia is used for the treatment of anxiety, nerve and cardiovascular disorder.Nineteen ninety Teng, the mechanism of action that people such as C.M point out its main component magnolol in the 1153rd～1161 page of the 47th phase of Life Sci flows for suppressing intracellular calcium ion, vascular smooth muscle loosens, anti-platelet aggregation and suppress thrombotonin secretion etc.
Fujita in 1994, S. wait the people to disclose the bark of official magnolia and contain a small amount of different magnolol (honokiol) as shown in Figure 3 in addition in the 273rd～277 page of the 17th phase of Biol.Med., its structure also belongs to the bis-phenol structure, with the pass of magnolol be isomers, different magnolol was through LO in 1994, Y.C. proof also has powerful anti peroxidation of lipid ability, but its activity slightly is inferior to magnolol.A series of being starting raw material magnolol synthetic method as shown in Figure 4 to propylene phenylmethylether (p-allylanisole) people such as Feringa B. in 1976 in the 98th phase of J.Org.Chem the 3372nd～3373 page of report; Other 1978 people such as Kupchan S.M. also disclose a series of being starting raw material magnolol synthetic method as shown in Figure 5 to propylene phenylmethylether (p-allylanisole) in the 4076th～4080 page of the 43rd phase of J.Org.Chem; 1985 by people such as He Dongying in the 40th phase of Taiwan science the 31st～35 page of announcement two direction synthetic methods as shown in Figure 6; At nineteen ninety-five Agharahimi, M.R. wait the people in the 60th phase of J.Org.Chem the 1856th～1863 page of announcement synthetic method as shown in Figure 7, this method reaches 40% than people's such as He Dongying synthetic method productivity is higher, and produce than no coupling product, so purifying is easier, can make from above-mentioned proof magnolol that can be explicit, its basic structure is that two phenol rings connections form, and belongs to bis-phenol (biphenol) compound.The anti peroxidation of lipid ability of reported in literature magnolol in 1994 is 1000 times of vitamin-E, the structure of magnolol is real compared with many known antioxidants to be simple, therefore, this research efficiently reaches the lead compound of the magnolol of easy structure as structural modification with this.The resistance of oxidation of magnolol via the method for measuring " eliminator ", shows that the resistance of oxidation of magnolol far is inferior to vitamin-E from the research in past.But it is, stronger 1000 times than vitamin-E if, show that magnolol possesses powerful antioxygenation with the method for measuring " chain reaction interrupter (chain breaker) ".Because the oxidative damage of cell, relate to a succession of reaction of free radical at the cell paste adventitia, so magnolol should be the antioxidant of a kind of [chain reaction interrupter] type, by accompanying drawing 8, accompanying drawing 9, accompanying drawing 10 as can be known, the anti peroxidation of lipid ability of magnolol is significantly strong than vitamin-E, be the chain reaction interrupter of brute force, magnolol institute's role in accompanying drawing 10, accompanying drawing 11, accompanying drawing 12 is removing person, can know that by accompanying drawing the resistance of oxidation of finding out its stage far is inferior to vitamin-E.
Oxidative pressure (oxidative stress) is the noun of a complexity, is meant that briefly the degree of oxidation is better than anti-oxidant under oxidation and oxidation resistant equilibrium system.This is because most cells all need oxygen just to be survived, and active oxygen causes the reason of oxidation just.Though the antioxidant of many physiology self-defences is arranged in the human body, the antioxidant component that comprises many ferment and non-ferment, because the prosperity of industry, pollution to human habitat is serious day by day, thereby impel the probability of oxygenizement also to increase day by day, when the antioxidant system of physiology self-defence can't resist, the injury that oxidation caused promptly can be accumulated in vivo.Report in AM.J.Med the 91st phase the 14S～23S page or leaf in 1991 according to HalliwellB., the existing at present disease that surpasses more than 50 kinds, its cause of disease is because the injury that oxidation caused, therefore, further seek and this type of antioxidant of research, comprising synthetic or natural antioxidant, is present problem demanding prompt solution.
The object of the present invention is to provide the new magnolol series compound of a class and the synthetic method of this compound thereof with pharmaceutical use; Another object of the present invention be carry a kind of have bring high blood pressure down, anti-oxidant activity, the active pharmaceutical composition of Green Tea Extract.
Technical conceive of the present invention:
According to purpose of the present invention, provide magnolol two big series compound and synthetic methods thereof, thereby further provide with this compound be activeconstituents multiple have bring high blood pressure down, anti-oxidant activity, the active pharmaceutical composition of Green Tea Extract.
The synthetic method of magnolol is a series of being starting raw material magnolol synthetic method as shown in Figure 4 to propylene phenylmethylether (p-allylanisole) in the 98th phase of J.Org.Chem. the 3372nd～3373 page of report people such as Feringa B. in 1976, it is propylene phenylmethylether (p-allylanisole) and boron tribromide methyl sulfide (boron tribromide-methylsulfide complex) to be removed the methyl reaction, to generate anol (p-allylphenol; Chavicol); Under alkaline environment, again with the Tripotassium iron hexacyanide (potassium ferricyanide; K
3Fe (CN)
6) carry out redox reaction, generate 2-[2-hydroxyl-5-(2-propenyl) phenyl]-4-(2-propenyl) phenol (2-[2-hydroxy-5-(2-propenyl) phenyl]-4-(2-propenyl) phenol; Magnolol); Disclose a series of being starting raw material magnolol synthetic method as shown in Figure 5 to propylene phenylmethylether (p-allylanisole) in the 4076th～4080 page of the 43rd phase of J.Org.Chem. people such as Kupchan S.M in 1978, it is to be solvent with methylene dichloride, adds trifluoracetic acid (trifluororacetic acid; TFA) and trifluoroacetic anhydride (TFAA) (trifluororacetic acid anhydride; TFAA), at oxygen vanadium fluoride (vanadium oxytrifluoride; VOF
3) redox reaction under, generate 1-methoxyl group-2-[2-methoxyl group-5-(2-propenyl) phenyl]-4-(2-propenyl) benzene (1-methoxy-2-[2-methoxy-5-(2-propenyl) phenyl]-4-(2-propenyl) benzene); Remove the methyl reaction with boron tribromide methyl sulfide (boron tribromide-methyl sulfide complex) again, generate 2-[2-hydroxyl-5-(2-propenyl) phenyl]-4-(2-propenyl) phenol (2-[2-hydroxy-5-(2-propenyl) phenyl]-4-(2-propenyl) phenol; Magnolol); In the 40th phase of Taiwan science the 31st～35 page of announcement two direction synthetic methods as shown in Figure 6, the advantage of present method was that route of synthesis is short people such as He Dongying in 1985, and reagent is more cheap; Shortcoming is productivity too low (0.25%), and the physico-chemical property of end product and by product is too similar, causes the separation and purification difficulty, can't mass production; At nineteen ninety-five Agharahimi, people such as M.R are in the 60th phase of J.Org.Chem the 1856th～1863 page of announcement synthetic method as shown in Figure 7, present method advantage is higher than the productivity of people's such as He Dongying synthetic method, can reach 40%, and produce than no coupling product, purifying is easier, but manufacturing process is long, used reagent costliness, and reaction conditions all need anhydrous, keep away under oxygen and the cold condition and carry out, therefore do not have industrial utilization and be worth; The comprehensive above-mentioned relative merits of the present invention, the retrosynthesis of detailed analysis magnolol are learnt, can set about synthetic magnolol from two directions, the one, and earlier synthetic anol joins together it again; The 2nd, in the contraposition of bis-phenol, import propenyl.It is the compound of skeleton that the present invention synthesizes two serial magnolols, selects two kinds of methods for use: the one, get magnolol (magnolol) and formaldehyde, and after adding second sulfonamide derivatives heated and stirred fully being reacted under acidic conditions, concentrating under reduced pressure carries out purifying and recrystallize again; Can obtain neat (Mannich) alkali of agate pears, suc as formula 2-[3-substituent methyl-2-hydroxyl-5-(2-propenyl) phenyl of I]-4-(2-propenyl) phenol (2-[3-substitutedmethyl-2-hydroxy-5-(2-propenyl) phenyl]-4-(2-propenyl) Pbenols); Another serial synthetic method is that magnolol is dissolved in tetrahydrofuran (THF), under alkaline condition, the chloromethyl methyl ether is added reaction; Evenly stir the 1-chloro-2 that ground adds fore-distillation, 3-propylene oxide, reflux; Add six hydrogen pyrrole hydrazine derivative reflux respectively, concentrating under reduced pressure carries out purifying and recrystallize, gets each intermediate product; With the silica gel column chromatography purifying, can obtain 2-[2-(3-replaces 2-hydroxyl propoxy-)-5-(2-propenyl) phenyl of formula II]-4-(2-propenyl) phenol (2-[2-(3-substituted-2-hydroxypropoxy)-5-(2-propenyl) phenyl-4-(2-propenyl)-phenols]); Most active oxygens are oxyradical, but exception is also arranged, as singlet oxygen molecule (Singlet oxygen;
1O
2) and hydrogen peroxide (H
2O
2), different oxygen all has different half lifes, and wherein hydroxyl radical free radical (OH) is the free radical that activity is the highest and half life is the shortest, so it is also the most serious to the injury of human body, peroxy radical (RO
2) half life the longest, this is to cause peroxy radical can diffuse to the reason of elsewhere, its generation is because other free radical is attacked unsaturated fatty acids (Polyunsaturated fatty acids; PUFAs) forming, when peroxy radical is born, is exactly the beginning of lipid peroxidation; Lipid peroxidation is the main mechanism that oxyradical damages human body, so on pathology, occupy very important role, as aspect the central nervous system, lipid peroxidation can make brain and spinal cord sustain damage, and cause the generation of degenerative disorders, as apoplexy (stroke), Parkinson's disease (Parkinson ' s disease) etc.Aspect cardiovascular, can destroy endotheliocyte (endothelial cell), make the function of blood vessel impaired, and produce many cardiovascular disordeies, as hypertension.The blood vessel infraction causes that myocardial ischemia (ischemia) reaches the injury that perfusion (reperfusion) is caused again, and is also relevant with lipid peroxidation; Aspect blood, the after birth of blood cell is broken, produce hemolytic phenomenon, the cause of disease of many serious diseases is all lipid peroxidation; When histocyte sustains damage, for example: wound, inflammation etc., can cause necrocytosis.When after birth breaks, transition metal ion (transition metal ions) promptly discharges from cell, and these transition metal ion tool redox abilities can cause the generation of free radical, and then causes lipid peroxidation.These damages also can activate cyclooxygenase (cyclooxygenase) and lipoxidase (lipoxygenase) in addition, and these two ferment can act on the unsaturated fatty acids, produce free radical, also can cause lipid peroxidation; Work as arteriosclerosis, the undesired extreme of infraction or blood vessel is shunk, make normally perfusion (Perfusion) of blood, cause myocardial ischemia (myocardial ischemia), myocardial ischemia can cause fatal arrhythmia and cause death, many results of study think because the cell peroxidation injury (peroxidation damage) that oxyradical (oxygen free radical) causes, when myocardial ischemia, adenosine triphosphate (ATP) can be degraded into inferior xanthine (hypoxanthine) and purine (purine), effect via XOD (xanthine oxidase), then produce superoxide anion (superoxide anion), pass through the redox ability of transition metal again and produce hydroxyl radical free radical (hydroxyl radical), these two free radicals all can be attacked after birth, and then generation lipid peroxidation, enlarge histiocytic injury scope, when blood normally during perfusion, usually administered agents is nothing more than being vasodilator, thrombolytic agent or give surgical operation, make it perfusion again, though perfusion can make the anoxybiotic cell obtain oxygen again, but a large amount of as shown in Figure 1 oxygen enter and make lipid peroxidation more serious, since free radical can be direct or indirect the phosphatide of attack after birth, produce lipid peroxidation, attack C especially easily
20:4And C
22:6Unsaturated fatty acids, change the structure of after birth, and then disintegrate the function of cell, by finding out in the accompanying drawing 2, lipid peroxidation is chain reaction, if can't stop the generation of reaction in good time, the injury that then causes also is chain, when free radical is attacked unsaturated fatty acids, lipid molecule promptly can be reset, and the structure of formation conjugated dienes (conjugated diene), form two kinds of lipid peroxide through two different pathways metabolisms again, the one, ring texture endoperoxide (endoperoxide) and hydroperoxide (hydroperoxide), the end product of last lipid peroxidation are the third two vinegar dialdehyde (malondialdehyde, MDA), so to calculate the content of the third two vinegar dialdehyde (MDA) be the index that generally is used for assessing level of lipid peroxidation; At nineteen ninety-five Uko, E.A. wait the people to point out in the 159th～163 page of the 671st phase of Brain Res, at cardiovascular patient, the complication that comprises the disease that takes a disease is the cardiovascular pathological changes person, all can measure a large amount of the third two vinegar dialdehyde (MDA) in its blood plasma and the vascular tissue, as diabetes, hypertension and arteriosclerotic, the content of the third two vinegar dialdehyde (MDA) is also than general cell height in aged cells, discover that the third two vinegar dialdehyde can produce reaction with some important molecules in the body, as Amino acid, protein and nucleic acid etc., human body is damaged, the The compounds of this invention good antioxidant activity, the Green Tea Extract activity makes it have the effect that brings high blood pressure down, can develop into cardiovascular agent, above-mentioned disease is had therapeutic action.
Reach caption content of the present invention and embodiment in conjunction with the accompanying drawings:
Fig. 1 but makes lipid peroxidation more serious for entering of a large amount of oxygen.
Fig. 2 is lipid peroxidation.
Fig. 3 is the structure of magnolol (magnolol) and different magnolol (honokiol).
Fig. 4 is the method for the synthetic magnolol of people such as Feringa B..
Fig. 5 is the method for the synthetic magnolol of people such as Kupchan S.M..
Fig. 6 is the method for the synthetic magnolol of people such as eastern English why.
Fig. 7 is Agharahimi, the method for the synthetic magnolol of people such as M.R..
Fig. 8 be magnolol (magnolol, ●) press down with vitamin-E (α-Tocopherol, ▲)
The ability (n=6) of system cardiac muscle grain line body oxygen-consumption.
Fig. 9 be magnolol (magnolol, ●) press down with vitamin-E (α-Tocopherol, ▲)
System cardiac muscle grain line body produces the ability (n=6) of the third two vinegar dialdehyde (MDA).
Figure 10 be magnolol (magnolol, ●) press down with vitamin-E (α-Tocopherol, ▲)
System cardiac muscle grain line body produces the ability (n=3) of conjugated dienes.
Figure 11 be magnolol (magnolol, ●) with vitamin-E (α-Tocopherol, ▲) with
Hexichol nitro hydrazine (DPPH) reaction was removed hexichol nitro hydrazine free radical after 90 minutes
Ability (n=3).
Figure 12 be magnolol (magnolol, ●) clear with vitamin-E (α-Tocopherol, ▲)
Remove the ability of hexichol nitro hydrazine free radical, the concentration of test compounds is 200 μ M,
(n＝3)。
Figure 13 removes the ability (n=3) of hexichol nitro hydrazine free radical for The compounds of this invention.
Figure 14 removes the ability (n=3) of hexichol nitro hydrazine free radical for The compounds of this invention.
Figure 15 produces the ability (n=3) of the third two vinegar dialdehyde (MDA) for The compounds of this invention.
Table 1 is 2-[3-substituent methyl-2-hydroxyl-5-(2-propenyl) phenyl]-4-(2-propenyl)
The rerum natura of phenol series compound, voltinism data.
Table 2 is 2-[2-(3-replaces 2-hydroxyl propoxy-)-5-(2-propenyl) phenyl]-4-(2-
Propenyl) rerum natura of phenol series compound, voltinism data.
Table 3 is the resistance of oxidation of hexichol nitro hydrazine (DPPH) test come clear free radical.
Table 4 is a hypotensive activity.
Main contents of the present invention can be divided into the explanation of three parts, and one is the new synthetic side of magnolol Method; It two is magnolol two big series compounds; It three is the bark of official magnolia of new synthetic method preparation Phenol two big series compounds, the good resistance oxidation activity that has, the Green Tea Extract activity reduces blood The effect of pressing can this compound be the application of the pharmaceutical composition of active component also.
The synthetic method one that magnolol is new is to synthesize earlier the anol, it is tied again; Two Be that contraposition at bis-phenol imports acrylic, according to Singh in 1992, the people such as B were in J.Med.Chem. The 35th phase the 4858th～4865 page of report, synthetic a series of agate pears neat (Mannich) alkali of containing Amphyl, wherein hydrochlorinate 1-(1-Pyrrolizidine methyl-naphthols) ((1-pyrrolldine-activity of powerful β type step-down 1-yl)-methyl-2-naphtholHCl) arranged. Will The magnolol that is synthesized is the compound of skeleton, imports a series ofly may have hypotensive isoreactivity Neat (Mannich) alkali of agate pears, expect this compound except having good antioxidation activity, More have the hypotensive cardiac vascular activity of Denging concurrently.
It is the compound of skeleton that the present invention synthesizes two serial magnolols, is to select two methods, one Be to get magnolol (magnolol) and formaldehyde, add second amine derivative and under acid condition, heat After stirring fully reaction, reduced pressure concentration carries out purifying and recrystallization again; It is neat to have obtained the agate pears (Mannich) alkali, the 2-[3-substituent methyl suc as formula 1-2-hydroxyl-5-(2-acrylic) phenyl]-4-(2-acrylic) phenol (2-[3-substituted methyl-2-hydroxy-5-(2-propenyl) phenyl]-4-(2-propenyl) phenols); In addition a series of Synthetic method is that magnolol is dissolved in oxolane, under alkali condition, with the chloromethyl methyl ether Add reaction; Uniform stirring ground adds the 1-chloro-2 of pre-distillation, 3-expoxy propane, heating Reflux; Add respectively six hydrogen pyrrole hydrazine derivates and add hot reflux, reduced pressure concentration carries out purifying and reaches Crystallization gets each intermediate product; With the silica gel column chromatography purifying, can obtain the 2-[2-of formula II (3-replaces 2-hydroxyl propoxyl group)-5-(2-acrylic) phenyl]-4-(2-acrylic) Phenol (2-[2-(3-Substituted-2-hydroxypropoxy)-5-(2-Propenyl) phenyl-4-(2-propenyl) phenols]).
The structure of the formula I that the present invention synthesized and formula II magnolol two big series compounds is as follows:
Above-mentioned R refers to following groups
And R wherein1Can select: 
And R wherein2Can select:
And R wherein3Can select: halogen, hydrogen base, methyl oxygen base, ethyl oxygen base, propyl group oxygen base, NO2, the n value is that natural number is 0,1,2,3. Therefore R Shang Ke represents following groups:
The compound that the present invention is prepared, measure respectively after purified method or the crystallization fusing point (mp), ultimate analysis, mass spectrum (MS), infrared spectrum (IR), NMR (Nuclear Magnetic Resonance) spectrum (
1H-NMR,
13CH-NMR), ultraviolet radiation absorption physical chemistry data such as (UV).
Synthetic formula I of institute of the present invention and formula II magnolol two big series compounds, test through embodiment 24,25,26 pharmacologically actives, the Green Tea Extract of its result compd E C-2 shown in accompanying drawing 13, accompanying drawing 14, accompanying drawing 15 and table 3 is active good, outclass magnolol, also stronger than clinical medicine Talus (Trolox) and Pu Luohe (Probucol).
Compound of the present invention adds various vehicle, as Magnesium Stearate, Semen Maydis powder, starch, lactose, the hydroxy acid methylcellulose gum is received, ethanol, glycerine etc., or thinner (diluents), lubricant (lubricants), correctives, collapse powder (disintegrants), tackiness agent (binders), or tinting material, sweeting agent is made lozenge or other solid preparations, can be made into injection or other liquors and various formulation and adjust potential of hydrogen (PH) value with the phosphoric acid salt damping fluid, wherein solid dosage is to comprise tablet, lozenge, powder, capsule, Sublingual tablet, formulations such as particle.Pharmacy tolerable acid salt of the present invention, and the pharmacy goods of this pharmacy tolerable acid salt, except that for oral administration, rectum are thrown with it solid dosage, also can be prepared as the injection type of injection type, liquid dosage form or the parenteral use of significant quantity, or directly apply the ointment dosage form in affected part.General dispensing dosage can need be allocated with symptom, is generally everyone each 50mg to 300mg, every day 3 times.
Embodiments of the invention are as follows:
Get 18.6g (0.100mol) 2,2 '-Lian phenol places the 500ml reaction flask, adds 24.2g (0.200mol) propylene bromine and 0.20g (1.500mmol) chlorination mace (II), adds 30ml water again, and inflated with nitrogen, after the reflux 10 hours, add saturated sodium bicarbonate aqueous solution again, the bromic acid that neutralization reaction produced, with vinyl acetic monomer and water extracting, be evaporated to dried, with silica gel column chromatography (ether: hexane=1: 2) purifying gets the white crystals product, weigh 5.3g (28.5%).This product magnolol fusing point is identical with the pure product of physico-chemical property and natural origin.
EC-2、EC-3、EC-4、EC-5、EC-9、EC-10、EC-11
2-[3-substituent methyl-2-hydroxyl-5-(2-propenyl) phenyl]-the general synthesis method of 4-(2-propenyl) phenol (2-[3-substituted methyl-2-hydroxy-5-(2-propenyl) phenyl]-4-(2-propenyl) phenols).
Getting 0.200g (0.752mmol) magnolol is dissolved among the ethanol 10ml, add 0.83mmol second sulfonamide derivatives respectively, heated and stirred 5 hours, concentrating under reduced pressure, carry out purifying and recrystallize and get each product EC-2, EC-4, EC-5, EC-9, EC-10, EC-11, the analytical data of each product sees table 1 for details.
2-[2-methoxymethoxy-5-(2-propenyl) phenyl]-4-(2-propenyl) phenol (2-[2-methoxymethoxy-5-(2-propenyl) phenyl-4-(2-Propenyl) phenol, EC-7).
Get 0.200g (0.752mmol) magnolol and be dissolved in the 10ml tetrahydrofuran (THF), place reaction flask, get 0.020g (0.830mmol) sodium hydride and be dissolved in the 1ml tetrahydrofuran (THF), slowly add this solution in the reaction flask, at room temperature stirred 15 minutes, left standstill 5 minutes, restir 1 hour, slowly add 60.5mg (0.752mmol) chloromethyl methyl ether at last, stirred 12 hours under the room temperature, be evaporated to dried, dry back with silica gel column chromatography (EA: Hexane=1: 5) purifying, weigh product 0.162g productive rate 81%.
Analytical data is as follows:
UV(EtOH)λmax：290，214nm.
MS(EI，70eV)：m/z(％)＝310[M
+](100％)
IR(KBr)：3320，3210，2924，1644，1589，1504，1410，1200，1010，
912，820cm
-1。
1-NMR(300MHz，CDCl
3)δ：3.42(3H，s，CH
3OCH
2)，3.45(4H，d，J＝
5.2Hz，2×CH
2CH＝CH
2)，5.12(4H，m，2×CH
2CH＝CH
2)，
5.16(2H，s，OCH
2O)，6.05(2H，m，2×CH
2CH＝CH
2)，6.20(1H，
s，OH)，7.00-7.23(6H，m，6×Ar-H)
13C-NMR(75MHz，CDCl
3)δ：40.5，57.0，96.6，116.1，116.6，117.2，
117.8，126.6，129.0，130.0，131.8，132.9，135.8，137.90，152.5。
Rf(EA∶Hexane?＝1∶5)＝0.50
Ultimate analysis: molecular formula C
20H
22O
3
Theoretical value C, 77.39; H, 7.14
Actual value C, 77.11; H, 7.19.
1-(oxyethane-2-ylmethoxy)-2-[(2-methoxymethoxy-5-(2-propenyl) phenyl]-4-(2-propenyl) benzene (1-(oxirah-2-ylmethoxy)-2-[2-methoxy methoxy-5-(2-propenyl) phenyl]-4-(2-propenyl) benzene, EC-8).
Get 0.200g (0.64mmol) embodiment 9 product EC-7 and be dissolved in 10ml ethanol, place reaction flask, 476.5mg (5.1mmol) the 1-chloro-2 that adds fore-distillation, the 3-propylene oxide stirs, reflux 2 hours, leave standstill, be evaporated to dried, with silica gel column chromatography (EA: Hexane=1: 5) purified product, weigh product 0.21g productive rate 100%.
Analytical data is as follows:
UV(EtOH)λmax：285，217nm.
MS(EI，70eV)：m/z(％)＝366[M
+](100％)
IR(KBr)：3289，3081，2950，1640，1504，1410，1350，1270，1010，
912，840，820cm
-1。
1H-NMR(300MHz，CDCl
3)δ：2.76(2H，d，J＝2.8Hz，CH
2OCH)，3.36
(3H，s，CH
3OCH
2)，3.39(4H，d，J＝8.7Hz，2×CH
2CH＝CH
2)，
5.05(4H，m，2×CH
2CH＝CH
2)，5.07(2H，s，OCH
2O)，6.01
(2H，m，2×CH
2CH＝CH
2)，6.91-7.15(6H，m，6×Ar-H)
13C-NMR(75MHz，CDCl
3)δ：40.0，50.8，56.4，69.9，96.2，113.7，
116.1，116.3，129.3，129.0，132.4，133.2，138.3，154.0，
154.99。
Rf(EA∶Hexane＝1∶5)＝0.40
Ultimate analysis: molecular formula C
23H
26O
4
Theoretical value C, 75.38; H, 7.15
Actual value C, 75.39; H, 7.28.
Embodiment 11 to 23 is:
2-[2-(3-replaces 2-hydroxyl propoxy-)-5-(2-propenyl) phenyl]-4-(2-propenyl) phenol [2-[2-(3-substituted2-hydroxypropoxy)-5-(2-propenyl) phenyl]-4-(2-propenyl) phenols, EC-130～EC-250).
Getting 1.2g (3.28mmol) embodiment 10 product EC-8 is dissolved in the 50ml methyl alcohol, add 6.56mmol six hydrogen pyrrole hydrazine derivative (if hydrochlorinate derivatives respectively, the sodium bicarbonate that then need add equivalent, to remove hydrochloric acid), reflux 5 hours, concentrating under reduced pressure, carry out purifying and recrystallize, get each intermediate product, identify through structure at this intermediate product end, directly descends step reaction:
Get the above-mentioned intermediate product of 3.10mmol respectively, be dissolved in THF: i-PrOH=1: in 1 the solvent, add 1.2ml concentrated hydrochloric acid (37%), after at room temperature stirring 18 hours, add in the saturated sodium bicarbonate solution and after, be allocated in water and the vinyl acetic monomer, the organic layer concentrating under reduced pressure, with the silica gel column chromatography purifying, promptly get following second series product EC-130, EC-140, EC-150, EC-160, EC-170, EC-180, EC-190, EC-200, EC-210, EC-220, EC-230, EC-240, EC-250, analytical data sees table 2 for details.
Embodiment 24 is hexichol nitro hydrazine (DPPH) test anti-oxidant activity:
According to Mellors in 1966, people such as A. were in J.Biol.Chem, and the 241st phase the 4353rd page of revealing method is dissolved in ethanol with hexichol nitro hydrazine (DPPH), is configured to 100 μ M.With the molten ethanol of a corpse or other object for laboratory examination and chemical testing to be measured, be configured to 100 μ M, 50 μ M, 20 μ M and 10 μ M respectively, a corpse or other object for laboratory examination and chemical testing to be measured is added hexichol nitro hydrazine (1,1-diphenyl-2-picryhydrazyl.DPPH) in, evenly stir, left standstill 30 minutes, under wavelength 517nm, survey its light absorption value, by the light absorption value of measuring, can estimate to remove the activity of free radical, analytical data sees table 3 for details.
Embodiment 25 is the anti peroxidation of lipid activity.
The method that discloses in Eur.J.Pharmarco. the 303rd phase 129-139 page or leaf according to people such as Teng.C.M in 1966, get the whole brain tissue of 8 all SD mouse in age in week, remove cerebellum, with ice-cold Krebs damping fluid flushing, and it is homogenized with Dow clarifixator (Dounce homogenizer), low-speed centrifugal is 10 minutes under the low temperature, add 100 μ M desires and test active compound, standing and reacting 10 minutes, add 200 μ M ferrous ions, and under 37 ℃, reacted 30 minutes, to bring out lipid peroxidation, add the ice-cold trichloroacetic acid solution of 10 μ M and the bathyran of 200 μ M (thiobarbituric acid) is done photoghraphic coupler, in boiling water reaction taking-up after 15 minutes down, wait its cooling, the propyl carbinol that adds 1ml again, centrifugal 5 minutes, take out organic layer, under wavelength 532nm, survey its light absorption value, can estimate its anti peroxidation of lipid activity, its result shows compd E C-5, EC-6, EC-9, EC-10, the anti peroxidation of lipid specific activity magnolol of EC-170 and EC-250 is strong, and EC-150 and magnolol are suitable, its blood pressure, the variation of heartbeat is as shown in table 4.
Embodiment 26 is the hypotensive test of peripheral administration:
According to Tao in 1993, P.L. wait the method for people in the 135th page of announcement of the 243rd phase of Eur.J.Pharmarco., get 10 weeks of age week, the male congenital hypertensive big white mouse of the about 250-300g of body weight, after abdominal injection 50mg/kg Ben Tababita (pentobarbital) anesthesia, make femoral artery and femoral venous catheter respectively, polyethylene (polyethylene) conduit (PE-50) that will be filled with 100 μ g/ml heparin (heparin) inserts femoral artery, and be connected in sensator (Gould statham P23ID) with the detecting blood pressure, heartbeat then utilizes the blood pressure pollex to be connected in heartbeat monitor (Tachometer, Grass Co) records, write down its variation via the multinomial tracer of high formula (GrassModel) 7D physiology again, the conduit that will be filled with normal saline solution in addition inserts femoral vein, the usefulness of doing administration and replenishing body fluid, do trachea cannula (PE-240), prevent that tracheae from being blocked and supplying with the usefulness of oxygen by phlegm.After operation is finished, treat that the blood pressure, heartbeat of animal is stable and reach 30 minutes that the beginning administration is squeezed into the medicine to be measured of 0.4mg/200g via venous cannula, simultaneously with 01ml normal saline solution flushing line tube wall residual medicine, the variation of writing down its heartbeat and blood pressure.
Mean blood pressure (mean blood pressure; MBP) computing method:
[(systolic pressure-diastolic pressure)/3]+diastolic pressure.
Table 1
Table .2
0.690 ± 0.140 table 4 compound Δ mean blood pressure Δ HR Heart Rate action time of table 3Compound Concentration (μ M) at Δ A=2Magnolol 65.450 ± 10.542Probucol 4.796 ± 0.309Trolox 3.04 ± 1.022EC-2
(mmHg) (bpm) (divide) Magnolol---EC-2---EC-3-66.6 ± 17.5 45 ± 8 2EC-4---EC-5---EC-6-23.3 ± 10-8 2EC-9---EC-10---EC-130-49.2 ± 17.5 4 ± 5.3 35 ± 5EC-140-31.7 ± 5-24 ± 8 35 ± 15EC-150---EC-160-75.0 ± 17.5 81 ± 0.3EC-170-48.3,60 ± 4 6EC-180---EC-190-30-24 ± 8 12 ± 3EC-200---EC-210---EC-220---EC-230-20 ± 5-24 ± 6 0.5EC-240---EC-250+68.4 ± 5+75 ± 5 12.5 ± 2.5Carvedilol-83.4-24,70 ± 10-to represent without effect
Claims (9)
1, a kind of magnolol series compound, its structure is suc as formula I and formula II
Wherein R is meant following groups:
R
1Can select for use:
And R wherein
2Can select for use:
And R wherein
3Can select for use halogen, hydrogen base, methyl oxygen base, ethyl oxygen base, propyl group oxygen its, NO
2, n is natural number 0,1,2,3.
2, the preparation method of magnolol series compound shown in the formula I as claimed in claim 1, it is characterized in that, this method may further comprise the steps: a) get magnolol (magnolol) and formaldehyde, after adding second sulfonamide derivatives heated and stirred fully being reacted under acidic conditions; B) concentrating under reduced pressure; C) carry out purifying and recrystallize again, get magnolol series compound shown in the formula I.
3, the preparation method of magnolol series compound shown in the formula II as claimed in claim 1 is characterized in that, this method may further comprise the steps: a) magnolol is dissolved in tetrahydrofuran (THF), under alkaline condition, the chloromethyl methyl ether is added reaction; B) evenly stir and add the 1-chloro-2 of fore-distillation, 3-propylene oxide, reflux; C) adding six hydrogen pyrrole hydrazine derivative reheat respectively refluxes; D) concentrating under reduced pressure; E) carry out purifying and recrystallize, get each intermediate product; F), obtain magnolol series compound shown in the formula II with the silica gel column chromatography purifying.
4, a kind of have a pharmaceutical composition that brings high blood pressure down, and it is characterized in that the magnolol series compound with claim 1 Chinese style I structure is a major ingredient, adds various vehicle with the needs of various formulations.
5, a kind of have a pharmaceutical composition that brings high blood pressure down, and it is characterized in that the magnolol series compound with claim 1 Chinese style II structure is a major ingredient, adds various vehicle with the needs of various formulations.
6, a kind of pharmaceutical composition with anti-oxidant activity is characterized in that the magnolol series compound with claim 1 Chinese style I structure is a major ingredient, adds various vehicle with the needs of various formulations.
7, a kind of pharmaceutical composition with anti-oxidant activity is characterized in that the magnolol series compound with claim 1 Chinese style II structure is a major ingredient, adds various vehicle with the needs of various formulations.
8, a kind of have an active pharmaceutical composition of Green Tea Extract, it is characterized in that the magnolol series compound with claim 1 Chinese style I structure is a major ingredient, adds various vehicle with the needs of various formulations.
9, a kind of have an active pharmaceutical composition of Green Tea Extract, it is characterized in that the magnolol series compound with claim 1 Chinese style II structure is a major ingredient, adds various vehicle with the needs of various formulations.
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| CN100374107C (en) * | 2003-12-11 | 2008-03-12 | 陈世忠 | Preparation of honokiol, magnolol or their admixture and usage in preparing medication for treating cardiovascular and cerebrovascular diseases |
| CN101293816B (en) * | 2008-06-24 | 2011-09-28 | 江南大学 | Magnolol synthesizing method |
| EP2423181A1 (en) | 2010-07-28 | 2012-02-29 | Prous Institute For Biomedical Research S.A. | Multitarget substituted biphenyl diol derivatives |
| US9000231B2 (en) | 2011-12-20 | 2015-04-07 | Colgate-Palmolive Company | Processes for making magnolol and derivatives thereof |
| BR112014015031A2 (en) | 2011-12-20 | 2017-06-13 | Colgate Palmolive Co | process for manufacturing magnolol analogs |
| CN103113264B (en) * | 2013-01-22 | 2015-01-14 | 北京红惠新医药科技有限公司 | Magnolol derivative, honokiol derivative and preparation method and application thereof |
| CN103724223B (en) * | 2013-12-23 | 2015-10-21 | 西北农林科技大学 | Azo magnolol/Honokiol and nitrated magnolol analog derivative and prepare the application of plant insecticide |
| CN110343033B (en) * | 2018-04-02 | 2021-09-07 | 四川大学 | Magnolol series derivatives, and preparation method and application thereof |
| CN109053387B (en) * | 2018-09-19 | 2021-07-09 | 九江学院 | Method for synthesizing magnolol |
| CN110615742B (en) * | 2019-09-20 | 2021-11-19 | 广东省禾基生物科技有限公司 | Magnolol derivative and preparation method and application thereof |
| CN112806364A (en) * | 2019-11-15 | 2021-05-18 | 兰州大学 | Application of magnolol and derivatives thereof in preparation of medicines for preventing and treating or resisting plant diseases |
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