CN104231013B - A kind of gastrodine Glehnilae and preparation method thereof and application - Google Patents
A kind of gastrodine Glehnilae and preparation method thereof and application Download PDFInfo
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Abstract
The present invention relates to gastrodine Glehnilae and preparation method thereof and application, effectively solve to combine gastrodine ferulic acid to make gastrodine Glehnilae, and preparation improves and treatment neurasthenia, the medication problem of neurasthenia syndrome and angioneurotic headache, method is, anhydrous glucose acetic anhydride is carried out acetylation, hemiacetal hydroxyl bromo again, then with hydroxy benzaldehyde condensation, hydro-reduction, obtain acegastrodine, the protection of ferulic acid acetylating hydroxyl groups is obtained 3-(4 '-acetyl group-3 '-methoxyphenyl)-2-acrylic acid, prepare Acetylferuloyl Chloride again；Acegastrodine is dissolved in dry solvent, adds nucleophilic acylation catalyst and acid binding agent；Acetylferuloyl Chloride is dissolved in dry solvent, two solution mixing, obtain ester type compound, then deacetylation in the basic conditions, obtain gastrodine Glehnilae；The gastrodine Glehnilae of the present invention has calmness, hypnosis, improves effect of brain blood circulation.
Description
Technical field
The present invention relates to field of medicine and chemical technology, particularly a kind of gastrodine Glehnilae and preparation method thereof and application.
Background technology
Sedative hypnotic English name is sedative-hypnotic, normally takes the favourable health in sedative hypnotic.Sedative hypnotic helps avoid insomnia infringement health and orthobiosis.Sedative hypnotic is the good medicine effectively helping for sleep and being effectively improved sleep.Sedative hypnotic is avoided that the insomnia serious harm to human body, and sedative hypnotic treatment insomnia disease, sleep quality is improved in sedative hypnotic.Most sedative hypnotic belong to healthy medicine, are not belonging to psychotropic substances.Obvious boundary, the difference only measured is not had between Hypnotics and sedatives.Low dose of hypnotic has sedation effect.Tranquilizer can make people quiet down.Tranquilizer is suitably used to be conducive to patient to recuperate.
The effect of central nervous system is had by the change of quantitative change to qualitative change by sedative hypnotic.Excessive excitement can be made to return to normally time low dose of, be called sedation；Can induce, deepen and extend sleep during middle dosage, be called syngignoscism；The tic that skeletal muscle is strong can be released during larger dose, be called anticonvulsant action；Consciousness anesthesia can be made time heavy dose of, but easily recover, be called anesthetic action；Functional activity can be made during toxic dose to stop not easily recovering, be called paralysis effect.The mechanism of action: blocking-up reticular formation of brain stem ascending activating system swashs, to corticocerebral, the effect of waking up, it is suppressed that dispersivity spreads, with drug dose size, it is suppressed that the shallow of degree calmness, hypnosis, convulsion, anesthesia and paralysis effect occurs deeply.Also it is believed that also have and directly suppress corticocerebral effect.Clinic is mainly used in calmness, hypnosis, convulsion, anxiety neurosis, hysteria, neurasthenia etc..
Along with increasingly sharpening of all sectors of society competition, neurasthenia and angioneurotic headache class disease remain problem to be solved.
Function of nervous system's sexual disorders that symptom is feature such as neurasthenia is owing to cerebral nerve activity is chronically at tense situation, causes that brain excitement and a group suppressing functional disorder and producing are easily excited with spirit, mental fatiguability, emotional instability.Normally behave as clinically: mental deficiency, tired mind, internal external stimulus sensitivity, anxious state of mind, shortage patience, insomnia, dreaminess, psychophysiological disorders, work efficiency drop etc., but exist without organic disease.
Current Most scholars thinks that Nervous and Mental Factors is to cause neurasthenic main cause.Every some factors that can cause lasting buck fever and long-term intrapsychic conflict, make strong and lasting in tension of neural activity process, exceed the tolerance limit of nervous system tension force, namely may occur in which neurasthenia syndrome, neurasthenia occurs.
Vascular headache is a kind of type the most common in outpatient service headache patient, because causing the reason of this kind of headache both to be from blood vessel, therefore is referred to as vascular headache.Vascular headache is divided into constitutional and the big class of Secondary cases two.Because of the headache that head vasomotor dysfunction causes, it is called constitutional vascular headache, also known as migraine, it it is a kind of functional headache, different manifestations according to headache, can be classified as again 5 kinds of main Types such as classical migraine, common migraine, cluster migraine, hemiplegia type migraine and ophthalmoplegic migraine；Another kind is to have the clear and definite headache caused by cerebrovascular disease (such as apoplexy, intracranial hematoma, cerebral vasculitis etc.), is called secondary headache.
Existing major part calmness, hypnosis, improve brain blood circulation medicine market and occupied by Western medicine, clinical application proves that, majority controls neurasthenic Western medicine, especially pain relieving class Western medicine, easily causing dependency, and Chinese medicine has the advantage of its uniqueness in treatment headache, form of Chinese drug can nurse one's health function on the whole, treatment headache, reaches treating both the principal and secondary aspects of a disease.
Gastrodine is the principle active component of Chinese medicine Rhizoma Gastrodiae, can regulate the dysequilibrium between cerebral cortex excitement and process of inhibition, have tranquilizing soporific, epilepsy, analgesic activity, be used for treating neurasthenia and neurasthenia syndrome；Blood vessel can be expanded again, improve brain blood circulation, increase vertebra one basilar arterial blood supply, improve vertebra one basilar artery insufficiency, treat vascular headache.Also there is now a lot of report to gastrodine structural modification, reach better effect with expectation.
Wearing is familiar with waits the chemical synthesis process at gastrodine and phenolic glycosides thereof to study [J]. Yunnan Institute for nationalities's journal (natural science edition), mention the similar phenol glucosides of multiple gastrodine in 2004,13 (2): 83-85:
Wherein A glycosyl part can be not only monosaccharide, and can be disaccharidase even trisaccharide etc., monosaccharide can be pentose, hexose or substituted monosaccharide, for instance: ribose, deoxyribose, xylose, arabinose, glucose, allose, mannose, galactose, glucosamine, lactose, maltose, cottonseed sugar etc..To glycoside unit, R1 can be C1～C6 alkylol or aldehyde, hydrogen atom, it is also possible at ortho position, a position, para-position.R2 can be C2～C6 alkyl, C1～C6 haloalkyl, C3～C6 cycloalkyl, aryl, hydrogen atom, amino, substituted-amino, halogen, hydroxyl, it is also possible at ortho position, a position, para-position.
Other many sections of documents and Li Huilan etc. at acegastrodine at the spasmolysis [J] to vascular smooth muscle. Acta Pharmaceutica Sinica, in 1986,21 (7): 539-541, mention another gastrodin derivative acegastrodine of gastrodine:
Wherein R is acetyl group.
Zhang Aiwu etc. are at Liang Qi Medical Colleges of the Inner Mongol journal, 2005,27 (2): 99-10 and 2007, two several gastrodine amino-acid ester schiff base compounds are proposed, it is desirable to filter out the gastrodin derivative of higher pharmacologically active in 29 (2): 110-112:
Wherein R is selected from serine ethyl ester base, methionine ethoxycarbonyl, ethycysteine base, phenylalanine ethyl ester base, glycine ethyl ester base, methyl methionine base, valine methyl ester base, phenyalanine methyl ester base, leucine methyl ester base, methyl lactamine base.
Gastrodine and acegastrodine have good clinical efficacy in improving and treating neurasthenia, neurasthenia syndrome and angioneurotic headache, but both to obtain good therapeutic effect, and patient medication every time must more than 100mg, comparatively inconvenience.
Ferulic acid (Ferulic acid) has antiplatelet aggregation, it is suppressed that platelet 5-HT discharges, it is suppressed that the generation of platelet thrombus element A2 (TXA2), strengthens the effects such as prostaglandin activity, analgesia, alleviating vascular spasm.There is bibliographical information ferulic acid to have the migrainous effect of radical cure, again because its toxicity is extremely low, be produce the base stock for treating the disease medicine such as cardiovascular and cerebrovascular disease and leukopenia.
There is presently no and gastrodine ferulic acid is combined into lipoid substance is used for improving and treating the open report of neurasthenia, neurasthenia syndrome and angioneurotic headache.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the purpose of the present invention is just to provide a kind of gastrodine Glehnilae and preparation method thereof and application, can effectively solve to combine gastrodine ferulic acid and make gastrodine Glehnilae (also known as 4-hydroxymethyl phenyl-β-D-pyranglucoside esters derivative), and preparation improves and the medication problem for the treatment of neurasthenia, neurasthenia syndrome and angioneurotic headache.
The technical scheme that this invention address that is, a kind of its molecular structural formula of gastrodine Glehnilae is:
Wherein:
R1=R2=R3=R4For acetyl group or hydrogen；
R5For hydrogen or acetyl group or C1～C4Alkyl；
R5C1～C4Alkyl is appointed and is substituted by phenyl；
R5For C1～C4The aromatic hydrocarbons that alkyl is substituted by phenyl, wherein said aromatic hydrocarbons is by halogen, C1～C4Alkyl, C1～C4The substituent group of alkoxyl, amino, nitro and cyano group replaces；
Described gastrodine Glehnilae includes the compound described in following structural formula:
The preparation method of this formula I compound is to comprise the following steps:
(1) acegastrodine (4-methylol benzene-2 ', 3 ', 4 ', 6 '-four acetyl-β-D-Glucopyranose .s), is prepared:
This acegastrodine molecular formula:
First anhydrous glucose acetic anhydride is carried out acetylation, the hemiacetal hydroxyl bromo of the full acetyl sugar of generation, obtain Bromotetraacetylgluc,se；Bromotetraacetylgluc,se and hydroxy benzaldehyde condensation obtain condensation substance 4-formyl benzene-2 ', 3 ', 4 ', 6 '-four acetyl-β-D-Glucopyranose .s；Then then through hydro-reduction, acegastrodine shown in formula (II) (4-methylol benzene-2 ', 3 ', 4 ', 6 '-four acetyl-β-D-Glucopyranose .s) is obtained；
(2), the protection of ferulic acid acetylating hydroxyl groups is obtained 3-(4 '-acetyl group-3 '-methoxyphenyl)-2-acrylic acid, then prepare the Acetylferuloyl Chloride (3-(4 '-acetyl group-3 '-methoxyphenyl)-2-acryloyl chloride) shown in formula (III)；
(3), by aspirin and vanillin under benzene sulfonyl chloride exists, being obtained by reacting 3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] benzaldehyde, then the 3-methoxyl group-4-obtained [(2-acetoxyl group) benzoyloxy] benzaldehyde is obtained by reacting 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl shown in formula (IV) with malonic acid } acrylic acid:
(4), by the compound shown in the formula (II) that obtains with dry solvent with w/v 1:15～20; w/v refers to that solid is in g; in the w/v that descends to the mortal world, liquid (each means that solid is with g in ml; liquid is in ml); it is dissolved in dry solvent, adds nucleophilic acylation catalyst and acid binding agent；Compound shown in formula (III) and dry solvent are dissolved in dry solvent with w/v 1:15～20 times; the solution that compound shown in dropping formula (III) is made in the solution that compound shown in formula (II) is made, is obtained by reacting the ester type compound of acetyl group protection；
Molar ratio: formula (II) compound: formula (III) compound: nucleophilic acylation catalyst: acid binding agent=1:1.05～1.6:0.05～0.5:0.3～1.5；
Described dry solvent is the one in toluene, chloroform, dichloromethane, ethyl acetate or its mixed solvent；
Described nucleophilic acylation catalyst is DMAP (DMAP), pyridine or other acylation catalysts；
Described acid binding agent is the one of trimethylamine, pyridine, triethylamine or other organic bases；
(5), the protection of the ester type compound deacetylation in the basic conditions protected by the acetyl group obtained obtains the gastrodine Glehnilae shown in formula (I)；
Wherein refer to addition alkali in basic solvent or in solvent under alkali condition；
Basic solvent is the one of diethylamine, triethylamine, pyrrolidine or its mixed solvent；
The protection ester type compound of charged material weight volume ratio acetyl group: basic solvent=1:8～20；
Solvent is the one in methanol, ethanol or its mixed solvent；
The ester type compound of acetyl group protection is 1:1～30 with the w/v of solvent；
Alkali is the one in liquid methanol sodium, tert-butylamine, barium hydroxide, potassium tert-butoxide or its mixed solvent；
The addition of alkali is 0.2～1 times of the ester type compound weight of acetyl group protection；
Or the solution that the solvent that formula (II) and formula (IV) compound are separately added into w/v 1:2～5 is made mixes, add condensing agent and be obtained by reacting the ester type compound of acetyl group protection；
Wherein molar ratio formula (II) compound: formula (IV) compound: condensing agent=1:1.0～1.2:1.0～1.5；
Solvent is the one of dichloromethane, chloroform or its mixed solvent；
Described condensing agent is the one of N, N '-dicyclohexylcarbodiimide (DCC), DMAP (DMAP) or its mixing；
The ester type compound deacetylation in the basic conditions protection protected by acetyl group again obtains the gastrodine Glehnilae shown in formula (I)；
The preparation method of formula (Ic) compound, comprises the following steps: with w/v 1:15～20, acegastrodine shown in formula (II) is dissolved in dry solvent, adds nucleophilic acylation catalyst and acid binding agent, stirring, becomes reactant liquor；Separately the Acetylferuloyl Chloride shown in formula (III) is dissolved in dry solvent with w/v 1:15～20, and it is added drop-wise in reactant liquor, room temperature reaction disappears to formula (II) compound, then respectively with the hydrochloric acid of mass concentration 3% and saturated ammonium chloride solution washing, desiccant dryness, filter, solvent is evaporated off, ethyl acetate-light petrol mixes recrystallization with volume ratio 1:1 and obtains the compound shown in formula (Ic), molar ratio acegastrodine: Acetylferuloyl Chloride: nucleophilic acylation catalyst: acid binding agent=1:1.05～1.6:0.05～0.5:0.3～1.5；
Described solvent is the one in toluene, chloroform, dichloromethane, ethyl acetate or its mixed solvent；
Described nucleophilic acylation catalyst is DMAP (DMAP), pyridine or other acylation catalysts；
Described acid binding agent is the one of trimethylamine, pyridine, triethylamine or other organic bases；
Described desiccant is anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster or other common solvent desiccant；
The preparation method of described formula (Ib) compound, comprises the following steps:
Compound shown in formula (Ic) is put in basic solvent, 10～60 DEG C of stirrings, to be dissolved complete, add solvent dilution, then respectively with 1M sulphuric acid and saturated ammonium chloride washing, desiccant dryness, filter, solvent is evaporated off, and chromatographic isolation obtains compound shown in formula (Ib), the compound shown in charged material weight volume ratio formula (Ic): basic solvent=1:8～20；Chromatographic isolation is preferably used silicagel column, and ethyl acetate-light petrol mixes with volume ratio 1:1 makes mobile phase；
Described basic solvent is the one of diethylamine, triethylamine, pyrrolidine or its mixed solvent；
Described retarder thinner is the one of ethyl acetate, toluene, dichloromethane, chloroform or its mixed solvent；
Described desiccant is anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster or other common solvent desiccant；
The preparation method of described formula (Ia) compound, comprises the following steps:
Compound shown in formula (Ic) is put in solvent, the w/v of the compound shown in formula (Ic) and solvent is 1:1～30, it is stirred at room temperature, the alkali of chemical combination weight 0.2～1 times shown in addition formula (Ic), question response is complete, neutralizing with diluted acid, solvent is then evaporated off, recrystallization obtains the compound shown in formula (Ia)；
Described solvent and recrystallization solvent are the one in methanol, ethanol or its mixed solvent；
Described alkali is the one in liquid methanol sodium, tert-butylamine, barium hydroxide, potassium tert-butoxide；
The preparation method of described formula (Id) compound:
By 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl shown in formula (IV) } acegastrodine shown in acrylic acid and formula (II) mixes with solvent, 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl shown in formula (IV) } w/v of the acegastrodine shown in acrylic acid and formula (II) and solvent is 1:2～5, add condensing agent reaction, filter, filtrate is washed with mass concentration 20% sodium carbonate and saturated nacl aqueous solution respectively, dry, solvent evaporated, obtain compound shown in formula (Id)；
Described formula (II) compound: formula (IV) compound: the mol ratio of condensing agent is 1:1.0～1.2:1.0～1.5；
Described solvent is the one of dichloromethane, chloroform or its mixed solvent；
Described condensing agent is the one of N, N '-dicyclohexylcarbodiimide (DCC), DMAP (DMAP) or its mixing；
The preparation method of described formula (Ie) compound, comprises the following steps:
Compound shown in formula (Id) and basic solvent are mixed, the w/v of compound and basic solvent is 1:8～20 times, 10～60 DEG C of stirrings, to be dissolved completes, add solvent dilution, then respectively with 1M sulphuric acid and saturated ammonium chloride washing, desiccant dryness, filter, solvent is evaporated off, chromatographic isolation obtains compound shown in formula (Ie), and chromatographic isolation uses silicagel column, ethyl acetate as mobile phase；
Described basic solvent is the one of diethylamine, triethylamine, pyrrolidine or its mixed solvent；
Described retarder thinner is the one of ethyl acetate, toluene, dichloromethane, chloroform or its mixed solvent；
Described desiccant is anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster or other common solvent desiccant.
The gastrodine Glehnilae of the present invention has calmness, hypnosis, improves effect of brain blood circulation, it is effective to the medicine of preparation neurasthenia, neurasthenia syndrome and angioneurotic headache, open up gastrodine and the new application of ferulic acid medical value, have huge economic and social benefit.
Detailed description of the invention
Below in conjunction with embodiment, the specific embodiment of the present invention is elaborated.
The present invention can be provided by following example in being embodied as.
Embodiment 1
A kind of gastrodine Glehnilae, the preparation of compound shown in described formula II, is realized by following steps:
(1) at 32 DEG C; anhydrous glucose is added catalyst perchloric acid acetic anhydride and carries out acetylation; generate full acetyl sugar; TLC detects reaction end; acetylation passes into hydrogen bromide (gas) after completing, control the temperature hemiacetal hydroxyl bromo at 28 DEG C, to full acetyl sugar; synthesis Bromotetraacetylgluc,se, molar ratio anhydrous glucose: acetic anhydride: perchloric acid: hydrogen bromide=1:7.5:0.04:0.76；
(2) in the two-phase system that volume ratio is 1:1 chloroform and water composition, phase transfer catalyst tetrabutyl ammonium bromide is added, carbonate and hydroxy benzaldehyde, control temperature at 55 DEG C, Bromotetraacetylgluc,se drips after being dissolved in chloroform, the weight ratio of Bromotetraacetylgluc,se and hydroxy benzaldehyde is 1:1, TLC monitors reaction end, obtain condensation substance 4-formyl benzene-2 ', 3 ', 4 ', 6 '-four acetyl-β-D-Glucopyranose .s, again with 95% ethyl alcohol recrystallization, molar ratio is Bromotetraacetylgluc,se: hydroxy benzaldehyde: carbonate: tetrabutyl ammonium bromide=1:1:1.1:0.3；
(3) add 4-formyl benzene-2 ', 3 ', 4 ', 6 '-four acetyl-β-D-Glucopyranose .s are in inhaling hydrogen solvent, add Raney's nickel or the palladium charcoal of in step (2) the 25% of condensation substance weight, logical hydrogen is forced into 0.5MPa, hydrogenating, temperature is 37 DEG C of reaction 6h, feeds intake with w/v for condensation substance: inhale hydrogen solvent=1:6, w/v refers to that liquid is in ml, solid in g, obtain acegastrodine shown in formula (II) (4-methylol benzene-2 ', 3 ', 4 ', 6 '-four acetyl-β-D-Glucopyranose .s)；
The preparation of compound shown in described formula (III), is realized by following steps:
(1) ferulic acid 38.8g (or 0.2mol) is put in the 200ml aqueous solution containing sodium hydroxide 25.4g (or 0.52mol); it is cooled to less than 10 DEG C; acetic anhydride 25.4g (or 0.25mol) is joined in coolant; stir 10 minutes at 20 DEG C; then stir 20 minutes under room temperature; pH to 4～5 is adjusted followed by dilute sulfuric acid; precipitate out solid; filter; washing; ethyl alcohol recrystallization obtains 3-(4 '-acetyl group-3 '-methoxyphenyl)-2-acrylic acid (37.7g, 77%): mp197-200 DEG C；1HNMR (DMSO-d6) δ 12.45 (s, 1H), 7.61 (d, 1H, J=15.6Hz), 7.12-7.49 (m, 3H), 6.61 (d, 1H, J=15.6Hz), 3.84 (s, 3H), 2.28 (s, 3H)；13CNMR(DMSO-d6) δ 168.6,167.8,151.3,143.5,141.0,133.4,123.4,121.5,119.7,11 2.0,56.2,20.6；
(2) 3-(4 '-acetyl group-3 '-methoxyphenyl)-2-acrylic acid 23.6g (or 0.1mol) is put in 100ml chloroform; it is subsequently adding the DMF of catalytic amount; and add thionyl chloride 8.5mL (or 0.12mol); stir 4 hours under room temperature; finally decompression steams solvent and excessive thionyl chloride; obtain the Acetylferuloyl Chloride shown in light yellow formula (III), mp129-131 DEG C；1HNMR (CDCl3) δ 7.79 (d, 1H, J=15.6Hz), 7.09-7.12 (m, 3H), 6.59 (d, 1H, J=15.6Hz), 3.88 (s, 3H), 2.35 (s, 3H)；13CNMR(CDCl3)δ168.5,165.9,151.7,149.8,142.8,131.8,123.6,122.5,122.4,111.9,56.0,20.6.Anal.CalcdforC12H11ClO4: C, 56.60；H, 4.35.Found:C, 56.56；H, 4.28.
Embodiment 2
The present invention in being embodied as, a kind of gastrodine Glehnilae, this described gastrodine Glehnilae is the compound shown in formula I, and its preparation method is:
The preparation of formula (Ic) compound
By the acegastrodine 4.6g (i.e. 10.13mmol) shown in formula (II), pyridine 1.2g (i.e. 15.20mmol), DMAP0.4g (i.e. 3.04mmol) and 100ml dichloromethane put in reactor, stirring, separately the Acetylferuloyl Chloride 3.9g (i.e. 15.20mmol) shown in formula (III) is dissolved in 100ml dichloromethane, then Acetylferuloyl Chloride dichloromethane solution is instilled in reactor, it is stirred at room temperature 2 hours, then respectively with the hydrochloric acid of mass concentration 3% and saturated ammonium chloride solution washing, anhydrous magnesium sulfate dries, filter, decompression steams solvent and obtains the compound (5.9g shown in formula (Ic), 93%),1HNMR(400MHz,CDCl3) δ 7.66 (d, J=16.0Hz, 1H), 7.36 (d, J=8.6Hz, 2H), 7.06 (ddd, J=24.8,13.4,5.2Hz, 5H), 6.40 (d, J=16.0Hz, 1H), 5.36 5.21 (m, 2H), 5.21 5.02 (m, 4H), 4.29 (dd, J=12.3,5.3Hz, 1H), 4.22 4.06 (m, 1H), 3.91 3.78 (m, 4H), 2.32 (s, 3H), 2.06 (dd, J=10.1,6.7Hz, 12H)；
13CNMR(100MHz,CDCl3)δ170.45,170.13,169.30,169.18,168.64,166.47,156.77,151.34,144.40,141.47,133.18,130.96,129.98,123.20,121.19,117.95,116.99,111.19,98.95,72.62,72.01,71.10,68.22,65.82,61.86,55.82,20.60,20.53.
MS(ES/+): m/z=690.2 [M+NH4]+；
Or by the acegastrodine 4.6g (10.13mmol) shown in formula (II), triethylamine 0.3g (3.04mmol), DMAP0.06g (0.51mmol) and 100ml chloroform put in reactor, stirring, separately the Acetylferuloyl Chloride 2.8g (11.14mmol) shown in formula (III) is dissolved in 100ml chloroform, then Acetylferuloyl Chloride chloroform soln is instilled in reactor, it is stirred at room temperature 2 hours, then respectively with the hydrochloric acid of mass concentration 3% and saturated ammonium chloride solution washing, anhydrous sodium sulfate dries, filter, decompression steams solvent and obtains the compound (5.7g shown in formula (Ic), 90%)；
Or by the acegastrodine 4.6g (10.13mmol) shown in formula (II), trimethylamine 0.5g (8.61mmol), DMAP0.3g (2.53mmol) and 100ml ethyl acetate put in reactor, stirring, separately the Acetylferuloyl Chloride 3.3g (13.17mmol) shown in formula (III) is dissolved in 100ml ethyl acetate, then Acetylferuloyl Chloride ethyl acetate solution is instilled in reactor, it is stirred at room temperature 2 hours, then respectively with the hydrochloric acid of mass concentration 3% and saturated ammonium chloride solution washing, dead plaster dries, filter, decompression steams solvent and obtains the compound (5.8g shown in formula (Ic), 91%).
Embodiment 3
One gastrodine Glehnilae of the present invention, this described compound is the compound shown in formula (1b), and its preparation method is:
Compound 2.0g (2.97mmol) shown in formula (Ic) is put in 40ml diethylamine, 60 DEG C of stirrings, to be dissolved complete, add toluene 40ml dilution, then respectively with 1M sulphuric acid and saturated ammonium chloride washing, anhydrous sodium sulfate dries, filtering, toluene is evaporated off, chromatography silica gel post ethyl acetate-light petrol volume ratio 1:1 mixes and makes mobile phase, separate to obtain compound 428mg shown in formula (Ib)1HNMR (400MHz, DMSO) δ 9.60 (s, 1H), 7.57 (d, J=15.9Hz, 1H), 7.41 7.28 (m, 3H), 7.12 (d, J=8.2Hz, 1H), 7.04 (d, J=8.5Hz, 2H), 6.79 (d, J=8.2Hz, 1H), 6.51 (d, J=15.9Hz, 1H), 5.31 (d, J=4.7Hz, 1H), 5.14 (s, 2H), 5.08 (d, J=4.4Hz, 1H), 5.02 (d, J=5.2Hz, 1H), 4.88 (d, J=7.2Hz, 1H), 4.55 (t, J=5.7Hz, 1H), 3.81 (s, 3H), 3.78 3.62 (m, 1H), 3.46 (dt, J=11.8, 6.0Hz, 1H), 3.30 3.20 (m, 2H), 3.17 (dt, J=13.9, 7.0Hz, 1H), 2.32 (s, 3H).
13CNMR(100MHz,DMSO)δ179.96,166.75,157.47,149.59,148.14,145.50,130.00,129.84,125.78,123.43,116.40,115.70,114.57,111.42,100.51,77.26,76.84,73.44,69.93,65.33,60.92,55.90,40.33,40.12,39.91,39.70,39.49,39.28,39.07,28.94.
MS(ES/+): m/z=527.15 [M+Na]+；
Or the compound 2.0g (2.97mmol) shown in formula (Ic) is put in 16ml pyrrolidine, it is stirred at room temperature, to be dissolved complete, adding dichloromethane 16ml dilution, then wash with 1M sulphuric acid and saturated ammonium chloride respectively, anhydrous magnesium sulfate dries, filter, dichloromethane is evaporated off, and chromatography silica gel post ethyl acetate-light petrol volume ratio 1:1 mixes and makes mobile phase, separates to obtain compound 546mg shown in formula (Ib)；
Or the compound 2.0g (2.97mmol) shown in formula (Ic) is put in 30ml triethylamine, 40 DEG C of stirrings, to be dissolved complete, adding ethyl acetate 30ml dilution, then wash with 1M sulphuric acid and saturated ammonium chloride respectively, dead plaster dries, filter, ethyl acetate is evaporated off, and chromatography silica gel post ethyl acetate-light petrol volume ratio 1:1 mixes and makes mobile phase, separates to obtain compound 519mg shown in formula (Ib)；
Or the compound 2.0g (2.97mmol) shown in formula (Ic) is put in 30ml triethylamine, 40 DEG C of stirrings, to be dissolved complete, adding chloroform 30ml dilution, then wash with 1M sulphuric acid and saturated ammonium chloride respectively, anhydrous magnesium sulfate dries, filter, chloroform is evaporated off, and chromatography silica gel post ethyl acetate-light petrol volume ratio 1:1 mixes and makes mobile phase, separates to obtain compound 527mg shown in formula (Ib).
Embodiment 4
One gastrodine Glehnilae of the present invention, this described compound is the compound shown in formula (1a), and its preparation method is:
Compound 1.5g (2.23mmol) shown in formula (Ic) is put in 5ml methanol, it is stirred at room temperature, it is subsequently adding 0.3g liquid methanol sodium, react completely after 20 hours, with in dilute hydrochloric acid and after, solvent is evaporated off, and residue adds recrystallizing methanol and obtains formula (Ia) compound 761mg1HNMR (400MHz, DMSO) δ 9.60 (s, 1H), 7.57 (d, J=15.9Hz, 1H), 7.41 7.28 (m, 3H), 7.12 (d, J=8.2Hz, 1H), 7.04 (d, J=8.5Hz, 2H), 6.79 (d, J=8.2Hz, 1H), 6.51 (d, J=15.9Hz, 1H), 5.31 (d, J=4.7Hz, 1H), 5.14 (s, 2H), 5.08 (d, J=4.4Hz, 1H), 5.02 (d, J=5.2Hz, 1H), 4.88 (d, J=7.2Hz, 1H), 4.55 (t, J=5.7Hz, 1H), 3.81 (s, 3H), 3.78 3.62 (m, 1H), 3.46 (dt, J=11.8, 6.0Hz, 1H), 3.35 (s, 1H), 3.30 3.20 (m, 2H), 3.17 (dt, J=13.9, 7.0Hz, 1H).13CNMR(100MHz,DMSO)δ166.75,157.47,149.59,148.14,145.50,130.00,129.84,125.78,123.43,116.40,115.70,114.57,111.42,100.51,77.26,76.84,73.44,69.93,65.33,60.92,55.90,40.33,40.12,39.91,39.70,39.49,39.28,39.07.
MS(ES/+): m/z=485.14 [M+Na]+；
Or the compound 1.5g (2.23mmol) shown in formula (Ic) is put in 30ml ethanol, it is stirred at room temperature, it is subsequently adding 1.5g liquid methanol sodium, react completely after 16 minutes, with in dilute hydrochloric acid and after, solvent is evaporated off, and residue adds recrystallizing methanol and obtains formula (Ia) compound 838mg；
Or the compound 1.5g (2.23mmol) shown in formula (Ic) is put in 45ml methanol, it is stirred at room temperature, it is subsequently adding 1.1g liquid methanol sodium, react completely after 5 hours, with in dilute hydrochloric acid and after, solvent is evaporated off, and residue adds recrystallizing methanol and obtains formula (Ia) compound 786mg.
Embodiment 5
One gastrodine Glehnilae of the present invention, this described compound is the compound shown in formula (Id), and its preparation method is:
(1) aspirin 18.0g (0.1mol) is dissolved in 100ml pyridine, with 0 DEG C at dropping benzene sulfonyl chloride 13ml (0.1mol), drip vanillin 16.7g (0.11mol) after 30 minutes and be dissolved in pyridine 50ml, react 4 hours, pouring in trash ice, dilute hydrochloric acid is adjusted to neutrality, precipitates out solid, ethyl alcohol recrystallization obtains 3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] benzaldehyde, mp120～122 DEG C；
(2) 3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] benzaldehyde 15.7g (50mmol) sum upper step obtained drips aniline, and propylene glycol 10.0g (0.1mol) in 300ml ethanol 70 DEG C react 12 hours, it is concentrated into dry, column chromatography, obtain white 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl } acrylic acid, mp155～157 DEG C, ESI-MS:355.1 [M-H]-。1HNMR(CDCl3300MHz) δ: 2.30 (s, 3H), 3.86 (s, 3H), 6.40 (d, J=19.6Hz, lH), 7.15～7.19 (m, 4H), 7.36～7.41 (m, lH), 7.61～7.67 (m, lH), 7.78 (d.J=15.9Hz, 1H), 8.23 (m, 1H).IRV:2983.1753,1679,1627,1510cm-1.；
(3) by 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl } the acegastrodine 22.7g (50mmol) shown in acrylic acid 17.8g (50mmol) and formula (II) joins in 150ml dichloromethane, add condensing agent DCC10.3g reaction, filter, filtrate is washed with 20% sodium carbonate and saturated nacl aqueous solution respectively, dry, solvent evaporated, obtains compound shown in formula (Id)1HNMR(400MHz,CDCl3) δ 7.66 (d, J=16.0Hz, 1H), 7.36 (d, J=8.6Hz, 2H), 7.15-7.21 (m, 4H), 7.06 (ddd, J=24.8,13.4,5.2Hz, 5H), 6.40 (d, J=16.0Hz, 1H), 5.36 5.21 (m, 2H), 5.21 5.02 (m, 4H), 4.29 (dd, J=12.3,5.3Hz, 1H), 4.22 4.06 (m, 1H), 3.91 3.78 (m, 4H), 2.28 (s, 3H), 2.06 (dd, J=10.1,6.7Hz, 12H).
13CNMR(100MHz,CDCl3)δ170.45,170.13,169.30,169.18,168.64,166.47,156.77,154.71,151.34,144.40,141.47,134.13,133.18,130.96,130.50,129.98,125.22,123.50,123.20,121.34,121.19,117.95,116.99,111.19,98.95,72.62,72.01,71.10,68.22,65.82,61.86,55.82,20.60,20.53,16.9.
MS(ES/+): m/z=815.22 [M+Na]+。
Embodiment 6
One gastrodine Glehnilae of the present invention, this described compound is the compound shown in formula (Ie), and its preparation method is:
Compound 2.0g (2.5mmol) shown in formula (Id) is put in 18ml pyrrolidine, it is stirred at room temperature, to be dissolved complete, adding dichloromethane 18ml dilution, then wash with 1M sulphuric acid and saturated ammonium chloride respectively, anhydrous magnesium sulfate dries, filter, dichloromethane is evaporated off, and chromatography silica gel post ethyl acetate as mobile phase separates to obtain compound 623mg shown in formula (Ie)1HNMR (400MHz, DMSO) δ 9.60 (s, 1H), 7.57 (d, J=15.9Hz, 1H), 7.41 7.28 (m, 3H), 7.14-7.17 (m, 4H), 7.12 (d, J=8.2Hz, 1H), 7.04 (d, J=8.5Hz, 2H), 6.79 (d, J=8.2Hz, 1H), 6.51 (d, J=15.9Hz, 1H), 5.31 (d, J=4.7Hz, 1H), 5.14 (s, 2H), 5.08 (d, J=4.4Hz, 1H), 5.02 (d, J=5.2Hz, 1H), 4.88 (d, J=7.2Hz, 1H), 3.81 (s, 3H), 3.78 3.62 (m, 1H), 3.46 (dt, J=11.8, 6.0Hz, 1H), 3.35 (s, 1H), 3.30 3.20 (m, 2H), 3.17 (dt, J=13.9, 7.0Hz, 1H), 2.28 (s, 3H).
13CNMR(100MHz,DMSO)δ168.01,166.75,164.03,157.47,154.71,149.59,148.14,145.50,134.10,130.52,130.00,129.84,125.78,125.25,123.56,123.43,121.34,116.40,115.70,114.57,111.42,100.51,77.26,76.84,73.44,69.93,65.33,60.92,55.90,40.33,40.12,39.91,39.70,39.49,39.28,39.07,16.90.
MS(ES/+): m/z=647.17 [M+Na]+。
Gastrodine Glehnilae of the present invention, for improving and treat the medicine of neurasthenia, neurasthenia syndrome and angioneurotic headache, this medicine includes giving the effective dosage form of described patient treatment and dosage, and described dosage form includes capsule, tablet, injection, wherein:
Described capsule is made up of formula (I) compound 50.0mg, starch 3.0mg, microcrystalline Cellulose 250.0mg, cross-linking sodium carboxymethyl cellulose 7.5mg, magnesium stearate 2.0mg, formula (I) compound mixes with other excipient, mixture can be used to fill gelatine capsule or be pressed into tablet with suitable stamping machine, and tablet can carry out coating with routine techniques and coating material；
Described tablet is made up of formula (I) compound 50.0mg, lactose 250.0mg, microcrystalline Cellulose 90.0mg, polyvinylpyrrolidone 35.0mg, cross-linking sodium carboxymethyl cellulose 7.5mg and magnesium stearate 2.0mg, formula (I) compound mixes with lactose, microcrystalline Cellulose, partial cross-linked sodium carboxymethyl cellulose, mixture is dispersed in medical solvent (such as water), add polyvinylpyrrolidone and form granule, after particle drying is pulverized, mix with remaining excipient, making tablet with pelleter again, tablet can carry out coating with routine techniques and coating material；
Described injection is added to 1ml made by formula (I) compound 2～70mg/ml, sodium phosphate 1.0～50.0mg/ml, water for injection, and preparation can be contained in glass peace and cut open bottle or bottle, injects with syringe；May also be fabricated which infusion solution, this infusion solution is added mass concentration 0.9% sodium chloride solution by formula (I) compound or mass concentration 5% glucose solution is made, the mass concentration of formula (I) compound is 2～70mg/ml, is contained in infusion bottle or transfusion bag.
The present invention is through animal experiment and clinical trial, fully prove that gastrodine Glehnilae has calmness, hypnosis, improves effect of brain blood circulation, effect is strong, good effect, and the prominent effect not easily recurred, being effective to the medicine of preparation treatment neurasthenia, neurasthenia syndrome and angioneurotic headache, it is achieved the application in preparation treatment neurasthenia, neurasthenia syndrome and angioneurotic headache medicine, relevant testing data is as follows:
The substantial amounts of drug study of the present invention, demonstrate the compound shown in formula provided by the invention (I) to there is calmness, hypnosis, improve brain blood circulation effect, have good effect to improving and treating the diseases such as neurasthenia, neurasthenia syndrome and angioneurotic headache.
Described neurasthenia and the performance of neurasthenia syndrome include but not limited to debilitating symptoms main manifestations for often feel like deficient in energy, dispirited, can not require mental skill, or mental retardation, limb adynamia, sleepy drowsy；Agitation main manifestations for patient book or newspaper reading or watch TV wait movable time spirit easily excited, memory and association increase in spite of oneself, directivity thinking is felt painstaking, and the thinking lacking sensing is very active, loses control of；Emotional symptoms, main manifestations is easy worried and easy excitation；Tonicity pain；Sleep disorder；Other psychophysiological disorderses, more typically as: giddy, dim eyesight, tinnitus, cardiopalmus, have palpitation, breathe hard, uncomfortable in chest, abdominal distention, dyspepsia, frequent micturition, hyperhidrosis, sexual impotence, premature ejaculation or menoxenia etc..
Described angioneurotic headache includes but not limited to the following aspects: acute ischemic cerebrovascular disease, intracranial hematoma, subarachnoid hemorrhage, uncracked vascular malformation, arteritis, carotid artery or vertebral artery pain, venous thrombosis, arterial hypertension, also includes other the relevant headaches because brain blood circulation obstacle causes.
Present invention also offers a kind of formula (I) compound giving bacterium with pharmaceutical composition, described medicine comprises pharmaceutically acceptable carrier and formula (I) compound.The inventive method also includes the preparation of use formula (I) compound and improves and treat the medicine of neurasthenia, neurasthenia syndrome and angioneurotic headache.
Pharmaceutical composition provided by the invention, except formula (I) compound containing therapeutically effective amount, also containing other medicinal compound, can make compound formulation.
Formula (I) compound or its Pharmaceutical composition can include but not limited to be administered orally by the route of administration medication of any routine, pulmonary, intraperitoneal, intravenous, intramuscular, subcutaneous, transdermal, buccal, per nasal, Sublingual, eye, rectum and vagina medicinal.It addition, the mode that nervous system is directly administered can include but not limited to use or do not use pump installation to pass through in cranium brain or spinal column in the brain of pin or conduit, in ventricle, the administration of Intraventricular, spinal cord peripheral route.Those skilled in the art be it is evident that, and any dosage that can produce curative effect described herein or administration frequency are suitable for the present invention.
The therapeutically effective amount of formula (I) compound or its Pharmaceutical composition can be about 0.01mg/kg/ agent to 100mg/kg/ agent.Preferred therapeutically effective amount can be about 10mg/kg/ agent to 100mg/kg/ agent.Most preferred therapeutically effective amount can be about 30mg/kg/ agent to 100mg/kg/ agent.It is thus possible, for instance for the patient of average weight 70kg, therapeutically effective amount active component contained by above-mentioned every dosage unit (such as tablet, capsule, granule, injection, suppository etc.) can be about 1mg/ days to about 7000mg/ days.
But, dosage can change according to the needs (including the various factors relevant to the particular patient treated, including the age of patient, body weight, diet, preparation specification, PD and administering mode and time) of patient.
Those skilled in the art can be easily determined best dosage, and this makes to need to adjust dosage and reaches suitable treatment level.Can be administered every day can also cyclical administration afterwards.Preferred oral or parenteral giving construction (I) compound or its Pharmaceutical composition.
Can be administered respectively at the different time of the course for the treatment of according to the inventive method, above-mentioned formula (I) compound or its Pharmaceutical composition, it is also possible to be administered with combination medicine form separately or a kind of combination medicine form mixed simultaneously.Formula (I) compound or its Pharmaceutical composition can be administered by potion every day easily, it is also possible to by total daily dose successive administration or with the divided dose of twice, three times or four times administration every day.It is to be understood that the present invention has included all such schemes either simultaneously or alternately treated and medication, also should correspondingly understand term " administration ".
Term " patient " used refers to the animal becoming treatment, observation or subjects, it is preferable that mammal, it is most preferred that the mankind.
Term " therapeutically effective amount " used refers to that researcher, veterinary, doctor or other clinical staff reactive compound to be determined or medicine are tissue system (preferred animal；More preferably mammal；Optimum is chosen) in cause the dosage of biology or medical response, described reaction includes the symptom slowing down treated disease or disease.
Term " compositions " used refers to the product containing specified quantitative special component and any product directly or indirectly obtained by various special components with specified quantitative combination.
In order to prepare Pharmaceutical composition of the present invention, being combined closely with pharmaceutical carrier conventionally medicinal formulation technology by formula (I) compound as active component, wherein according to route of administration (such as oral or parenteral medication), carrier can require that dosage form adopts various different form.Suitable pharmaceutically acceptable carrier is generally well-known in the art.
Preferred Pharmaceutical composition is unit dosage form, such as tablet, pill, capsule, wafer, capsule ingot, lozenge, granule, powder, sterile parenteral solutions or suspensoid, the aerosol of metering or liquid spray, drop, peace cut open, automatic injector or suppository, are administered by the mode of oral, intranasal, Sublingual, ophthalmic, transdermal, parenteral, rectum, vagina, suction or suction.Or, compositions can be suitable for dosage form that is per week or that be monthly administered once, it is also possible to for the preparation of applicable intramuscular injection.
When the Pharmaceutical composition of solid dosage forms such as tablet, pill that preparation is administered orally, capsule, wafer, capsule ingot, granule or powder (every kind all includes release, time controlled released and slow releasing preparation immediately), suitable carrier and additive include but not limited to diluent, lubricant, binding agent, fluidizer, disintegrating agent etc..If it is required, tablet changes the coating that can carry out various ways according to standard technique.
For preparing solid preparation, it is possible to main active is mixed with pharmaceutical carrier (such as conventional composition such as diluent, binding agent, disintegrating agent, lubricant and the fluidizer preparing tablet).Masticable solid dosage forms can add sweeting agent and flavoring agent to improve mouthfeel.It addition, in order to medicine is readily identified or attractive in appearance, solid dosage forms can add or apply coloring agent and coating.These carriers are prepared together with active medicinal matter and there is therapeutics release characteristic obtains the accurate and suitable dosage of active medicinal matter to provide.
When preparing the liquid dosage form Pharmaceutical composition of oral, local and parenteral, any common pharmaceutical media or excipient can be used.Therefore, for fluid unit dosage form, such as suspensoid (colloidal state agent, Emulsion and dispersant) and solution, suitable carrier and additive include but not limited to pharmaceutically acceptable wetting agent, dispersant, flocculant, thickening agent, pH adjusting agent, penetrating agent, coloring agent, flavoring agent, preservative, and can use liquid excipient.It not that every kind of liquid dosage form is required for all the components listed above.The new compositions of the present invention can be added include but not limited to aqueous solution, the suspension through suitably seasoned syrup, aqueous or oiliness and the emulsion with edible oil seasoning for the liquid form of oral or injection administration, also include elixir and similar pharmaceutical media.
One, animal experiment
The impact on mice autonomic activities of A, intraperitoneal administration
Male mice in kunming, 18～20g, 125, it is randomly divided into five groups, often organizes each 25, wherein 25 intraperitoneal injection of saline 0.1mg/kg of matched group, all the other respectively organize lumbar injection to tested material；Observe and record each number of times organizing mice autonomic activities in 30min.Result is in Table 1.
The impact (n=25, x ± SE) on mice autonomic activities of table 1 intraperitoneal administration
Compare with matched group, * p < 0.05, * * p < 0.01, * * * p < 0.005, t-test.
The impact on mice autonomic activities of B, gastric infusion
Male mice in kunming, 18～20g, 100, it is randomly divided into four groups, often organizes each 25, wherein matched group gavage normal saline 0.1mg/kg, all the other respectively organize gavage to tested material；Observe and record each number of times organizing mice autonomic activities in 30min.
Result is in Table 2.
The impact (n=25, x ± SE) on mice autonomic activities of table 2 gastric infusion
Compare with matched group, * p < 0.05.
The collaborative pentobarbital sodium inducing mouse of C, intraperitoneal administration is fallen asleep and is tested
Male mice in kunming, 18～20g, 120, it is randomly divided into five groups, often group 25, matched group intraperitoneal injection of saline 0.1mg/kg, all the other respectively organize lumbar injection to tested material；30min after administration, dosage 23mg/kg under each group lumbar injection pentobarbital sodium sleep maximal valve, observe and each group mice sleep situation in 20 minutes in recording.Result is in Table 3.
The collaborative pentobarbital sodium inducing mouse of table 3 intraperitoneal administration is fallen asleep and is tested (n=25, x ± SE)
Compare with matched group, * * * p < 0.005.
The collaborative pentobarbital sodium inducing mouse of D, gastric infusion is fallen asleep and is tested
Male mice in kunming, 18～20g, 120, it is randomly divided into four groups, often group 30, matched group gavage is to normal saline 0.1mg/kg, and all the other respectively organize gavage to tested material；30min after administration, dosage 23mg/kg under each group lumbar injection pentobarbital sodium sleep maximal valve, observe and each group mice sleep number of elements in 20 minutes in recording.Result is in Table 4.
The collaborative pentobarbital sodium inducing mouse of table 4 gastric infusion is fallen asleep and is tested (n=30, x ± SE)
Compare with matched group, * * p < 0.01.
E, formula (I) compound, gastrodine and the impact on mice autonomic activities of the acegastrodine intraperitoneal administration
Male mice in kunming 150, every 18～20g, it is divided into six groups at random, matched group abdominal cavity normal saline 0.1mg/kg, all the other respectively organize abdominal cavity to tested material；Observe and record each number of times organizing mice autonomic activities in 30min.Result is in Table 5.
The impact (n=25, x ± SE) on mice autonomic activities of table 5 formula (I) compound, gastrodine and acegastrodine intraperitoneal administration
Compare with matched group, * p < 0.05, * * * p < 0.005, t-test.
In actual tests, also formula (Id) compound, formula (Ie) compound have been done above-mentioned same test, all achieve same or like with above-mentioned test like result, no longer describe in detail one by one here.
By above-mentioned test it should be apparent that, gastrodine Glehnilae of the present invention has calmness, hypnosis, improve the effect of brain blood circulation, can be effectively used for preparation treatment neurasthenia, the medicine of neurasthenia syndrome and angioneurotic headache, and obtain through clinical trial and fully to prove, through clinic to suffering from neurasthenia, each 60 of the patient of neurasthenia syndrome and angioneurotic headache, by 0.1mg/kg/ days every day, 100mg/kg/ days, with the gastrodine Glehnilae of the present invention, for the patient of average weight 70kg, above-mentioned every dosage unit is (such as tablet, capsule, granule, injection, suppository etc.) contained by therapeutically effective amount active component be 7 7000mg, divide 1-3 time and use, it within 10 days, it is a course for the treatment of, curative effect is added up after three courses for the treatment of, neurasthenia, the symptom of neurasthenia syndrome and angioneurotic headache all has improvement in various degree, and do not find untoward reaction, show drug safety, effectively, curative effect is high, wherein, the symptom of neurasthenia's clinical manifestation feels more tired after requiring mental skill, it is often accompanied by professional achievements or deals with a degree of decline of routine matter efficiency, or namely feel weak and extremely tired after slight physical work, accompany by myalgia and can not loosen phenomenon eliminator or substantially eliminator up to 30, account for 50%, symptom is clearly better 28, account for 46.7%；The giddy of neurasthenia syndrome clinical manifestation, headache, insomnia, forgetful, difficult concentrating, anxiety, anxiety, agitation, tired, work efficiency reduces, fearness sound, tinnitus, general malaise and lethargy etc., can with transference cure person 12 people of vegetative nerve and sexual disorder, account for 20%, 45 people that symptom is clearly better, account for 75%；Angioneurotic headache is many to be caused by psychentonia, anger, and cardinal symptom is the vexed pain of head of persistence, constriction, sense of heaviness, and some patient's private prosecutions are that head has " lock ring " to feel.Most patients is amphicrania, mostly is two temporo sides, rear pillow part and head or full head.Headache character is dull pain, distending pain, constriction, feeling of numbness and band sample lock ring sense, and after treating by the present invention, its symptom all has clear improvement and improvement in various degree.
Above-mentioned animal experiment and clinical trial are tested through repeatedly (more than 12 times), all achieve same or like like result, concrete test situation no longer describes in detail one by one.
By above-mentioned data it should be apparent that, the gastrodine Glehnilae of the present invention has calmness, hypnosis, improve effect of brain blood circulation, it is effective to preparation treatment neurasthenia, the medicine of neurasthenia syndrome and angioneurotic headache, efficiently solve the preparation of gastrodine Glehnilae, and preparation treatment neurasthenia, application in neurasthenia syndrome and angioneurotic headache medicine, open up the medical value new application of gastrodine and ferulic acid, there is very strong practical value and clinical meaning, economic and social benefit is huge.
Claims (9)
1. a gastrodine Glehnilae, its feature is in, the described compound that gastrodine Glehnilae is following structural formula:
2. the preparation method of the gastrodine Glehnilae described in claim 1, its feature in, comprise the following steps:
(1), acegastrodine is prepared:
This acegastrodine molecular formula:
First anhydrous glucose acetic anhydride is carried out acetylation, the hemiacetal hydroxyl bromo of the full acetyl sugar of generation, obtain Bromotetraacetylgluc,se；Bromotetraacetylgluc,se and hydroxy benzaldehyde condensation obtain condensation substance 4-formyl benzene-2 ', 3 ', 4 ', 6 '-four acetyl-β-D-Glucopyranose .s；Then then through hydro-reduction, the acegastrodine shown in formula (II) is obtained；
(2), the protection of ferulic acid acetylating hydroxyl groups is obtained 3-(4 '-acetyl group-3 '-methoxyphenyl)-2-acrylic acid, then prepares the Acetylferuloyl Chloride shown in formula (III):
(3), by aspirin and vanillin under benzene sulfonyl chloride exists, be obtained by reacting 3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] benzaldehyde, be then obtained by reacting 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl shown in formula (IV) with malonic acid acrylic acid:
(4), by the compound shown in formula (II) and dry solvent with w/v 1:15～20, w/v refers to that solid is in g, and liquid, in ml, is dissolved in dry solvent, adds nucleophilic acylation catalyst and acid binding agent；Compound shown in formula (III) and dry solvent are dissolved in dry solvent with w/v 1:15～20 times; the solution that compound shown in dropping formula (III) is made in the solution that compound shown in formula (II) is made, is obtained by reacting the ester type compound of acetyl group protection；
Molar ratio: formula (II) compound: formula (III) compound: nucleophilic acylation catalyst: acid binding agent=1:1.05～1.6:0.05～0.5:0.3～1.5；
Described dry solvent is the one in toluene, chloroform, dichloromethane, ethyl acetate or its mixed solvent；
Described nucleophilic acylation catalyst is DMAP or pyridine；
Described acid binding agent is the one of trimethylamine, pyridine, triethylamine；
(5), the protection of the ester type compound deacetylation in the basic conditions protected by acetyl group obtains gastrodine Glehnilae；
Wherein refer to addition alkali in basic solvent or in solvent under alkali condition；
Basic solvent is the one of diethylamine, triethylamine, pyrrolidine or its mixed solvent；
The ester type compound of charged material weight volume ratio acetyl group protection: basic solvent=1:8～20；
Solvent is the one in methanol, ethanol or its mixed solvent；
The ester type compound of acetyl group protection is 1:1～30 with the w/v of solvent；
Alkali is the one in liquid methanol sodium, tert-butylamine, barium hydroxide, potassium tert-butoxide or its mixed solvent；
The addition of alkali is 0.2～1 times of the ester type compound weight of acetyl group protection；
Or the solution that the solvent that formula (II) and formula (IV) compound are separately added into w/v 1:2～5 is made mixes, add condensing agent and be obtained by reacting the ester type compound of acetyl group protection；
Wherein ratio: formula (II) compound: formula (IV) compound: condensing agent=1:1.0～1.2:1.0～1.5；
Solvent is the one of dichloromethane, chloroform or its mixed solvent；
Described condensing agent is the one of N, N '-dicyclohexylcarbodiimide, DMAP or its mixing；
The ester type compound deacetylation in the basic conditions protection protected by acetyl group again obtains gastrodine Glehnilae.
3. the preparation method of gastrodine Glehnilae according to claim 2; it is characterized in that, acegastrodine shown in formula (II) is dissolved in dry solvent with w/v 1:15～20, add nucleophilic acylation catalyst and acid binding agent; stirring, becomes reactant liquor；Separately the Acetylferuloyl Chloride shown in formula (III) is dissolved in dry solvent with w/v 1:15～20, and it is added drop-wise in reactant liquor, room temperature reaction disappears to formula (II) compound, then respectively with the hydrochloric acid of mass concentration 3% and saturated ammonium chloride solution washing, desiccant dryness, filter, solvent is evaporated off, ethyl acetate-light petrol mixes recrystallization with volume ratio 1:1 and obtains the compound shown in formula (Ic), molar ratio acegastrodine: Acetylferuloyl Chloride: nucleophilic acylation catalyst: acid binding agent=1:1.05～1.6:0.05～0.5:0.3～1.5；
Described solvent is the one in toluene, chloroform, dichloromethane, ethyl acetate or its mixed solvent；
Described nucleophilic acylation catalyst is DMAP, pyridine；
Described acid binding agent is the one of trimethylamine, pyridine, triethylamine；
Described desiccant is anhydrous sodium sulfate, anhydrous magnesium sulfate or dead plaster.
4. the preparation method of gastrodine Glehnilae according to claim 2, it is characterized in that, compound shown in formula (Ic) is put in basic solvent, 10～60 DEG C of stirrings, to be dissolved complete, add solvent dilution, then respectively with 1M sulphuric acid and saturated ammonium chloride washing, desiccant dryness, filter, solvent is evaporated off, and chromatographic isolation obtains compound shown in formula (Ib), the compound shown in charged material weight volume ratio formula (Ic): basic solvent=1:8～20；Chromatographic isolation uses silicagel column, and ethyl acetate-light petrol mixes with volume ratio 1:1 makes mobile phase；
Described basic solvent is the one of diethylamine, triethylamine, pyrrolidine or its mixed solvent；
Described retarder thinner is the one of ethyl acetate, toluene, dichloromethane, chloroform or its mixed solvent；
Described desiccant is anhydrous sodium sulfate, anhydrous magnesium sulfate or dead plaster.
5. the preparation method of gastrodine Glehnilae according to claim 2, it is characterized in that, compound shown in formula (Ic) is put in solvent, the w/v of the compound shown in formula (Ic) and solvent is 1:1～30, is stirred at room temperature, and adds the alkali of compound by weight 0.2～1 times shown in formula (Ic), question response is complete, neutralizing with diluted acid, solvent is then evaporated off, recrystallization obtains the compound shown in formula (Ia)；
Described solvent and recrystallization solvent are the one in methanol, ethanol or its mixed solvent；
Described alkali is the one in liquid methanol sodium, tert-butylamine, barium hydroxide, potassium tert-butoxide.
6. the preparation method of gastrodine Glehnilae according to claim 2, it is characterized in that, by 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl shown in formula (IV) } acegastrodine shown in acrylic acid and formula (II) mixes with solvent, 3-{3-methoxyl group-4-[(2-acetoxyl group) benzoyloxy] phenyl shown in formula (IV) } w/v of the acegastrodine shown in acrylic acid and formula (II) and solvent is 1:2～5, add condensing agent reaction, filter, filtrate is washed with mass concentration 20% sodium carbonate and saturated nacl aqueous solution respectively, dry, solvent evaporated, obtain compound shown in formula (Id)；
Described formula (II) compound: formula (IV) compound: the mol ratio of condensing agent is 1:1.0～1.2:1.0～1.5；
Described solvent is the one of dichloromethane, chloroform or its mixed solvent；
Described condensing agent is the one of N, N '-dicyclohexylcarbodiimide, DMAP or its mixing.
7. the preparation method of gastrodine Glehnilae according to claim 2, it is characterized in that, compound shown in formula (Id) and basic solvent are mixed, the w/v of compound and basic solvent is 1:8～20 times, 10～60 DEG C of stirrings, to be dissolved complete, add solvent dilution, then respectively with 1M sulphuric acid and saturated ammonium chloride washing, desiccant dryness, filter, solvent is evaporated off, chromatographic isolation obtains compound shown in formula (Ie), and chromatographic isolation uses silicagel column, ethyl acetate as mobile phase；
Described basic solvent is the one of diethylamine, triethylamine, pyrrolidine or its mixed solvent；
Described retarder thinner is the one of ethyl acetate, toluene, dichloromethane, chloroform or its mixed solvent；
Described desiccant is anhydrous sodium sulfate, anhydrous magnesium sulfate or dead plaster.
8. the gastrodine Glehnilae described in claim 1 is in preparation calmness, hypnosis, the application that improves in brain blood circulation medicine.
9. the application in preparation treatment neurasthenia, neurasthenia syndrome and angioneurotic headache medicine of the gastrodine Glehnilae described in claim 1.
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| CN1428345A (en) * | 2002-11-22 | 2003-07-09 | 云大科技股份有限公司 | Chemical synthesis process for preparing gastrodin and its analogous henolic glycoside formula (I) |
| KR20040080783A (en) * | 2003-03-13 | 2004-09-20 | 학교법인 한림대학교 | Anticonvulsant material isolated from Gastrodia elata |
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