CN105837541A - Pharmaceutical composition of benproperine phosphate and application of pharmaceutical composition in biological medicines - Google Patents
Pharmaceutical composition of benproperine phosphate and application of pharmaceutical composition in biological medicines Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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Abstract
The invention discloses a pharmaceutical composition of benproperine phosphate and application of the pharmaceutical composition in biological medicines. The pharmaceutical composition of benproperine phosphate contains benproperine phosphate and a novel-structure natural product compound (I) separated from dried bulbs of fritillaria cirrhosa. By virtue of the independent action of benproperine phosphate and the compound (I), the learning and memory capacities of a rat with synthetic vascular dementia can be obviously improved; and by virtue of the combined action of benproperine phosphate and the compound (I), the improvement effect is more obvious, so that the benproperine phosphate and the compound (I) can be developed into drugs for treating the synthetic vascular dementia. Compared with the prior art, the pharmaceutical composition has the outstanding substantive characteristics and remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of benproperine phosphate, be specifically related to the medicine of benproperine phosphate
Composition and the application in biological medicine thereof.
Background technology
Benproperine phosphate is non-narcotic anti-tussive agents, has dual antitussive effect, and mechanism of action mainly blocks the stretching of lung-pleura
Lung-vagus reflex that receptor produces, also has an inhibitory action simultaneously to respiratory center, thus its antitussive effect have concurrently central and
Peripheral double mechanism.It acts on strong compared with codeine 2-4 times.Pharmacological experiments proves, orally available or intravenous this product 2mg/kg
The cough that multiple stimulation causes can be completely inhibited.This product is oral to come into force soon, within after clothes 15-20 minute, i.e. comes into force, duration length (4-7
Hour).This product does not suppress to breathe, and without additive, do not cause biliary tract and duodenum spasm or contraction, will not cause constipation.
Vascular dementia (vascular dementia, VD) is to occur at lacking with memory, cognitive function on the basis of cranial vascular disease
Damage is main, or damages with the continuation of language, visual space technical ability and the acquired intelligence of emotion or personality disorder.
Up to now, there is not yet the correlation report of benproperine phosphate and pharmaceutical composition thereof and vascular dementia.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of benproperine phosphate, containing phosphoric acid phenylpropyl alcohol in this pharmaceutical composition
Piperazine woods and the natural products of a kind of novel structure, benproperine phosphate and this natural products can be with Synergistic treatment vascular dementias.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of benproperine phosphate, including benproperine phosphate, compound as claimed in claim 1 (I)
Pharmaceutically acceptable carrier, is prepared as the formulation needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, adhesive, wetting agent, collapses
Solve agent, sorbefacient, surfactant, absorption carrier or lubricant.
Further, described formulation include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, spray, drops or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: the dry bulb of Bulbus Fritillariae Cirrhosae is pulverized by (a), uses
85～95% alcohol heat reflux extract, merge extract, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturated successively
Extracting n-butyl alcohol, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butanol takes thing macroreticular resin removal of impurities, first with 8 column volumes of 35% ethanol elution, then with 12 cylinders of 90% ethanol elution
Long-pending, collect 90% eluent, reduced pressure concentration obtains 90% ethanol elution concentrate；C in () step (b), 90% ethanol elution is dense
Contracting thing purification on normal-phase silica gel separates, successively with the methylene chloride-methanol gradient elution that volume ratio is 120:1,60:1,30:1 and 15:1
Obtain 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 40:1,30:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 10:1；Component 2 octadecylsilane key in (e) step (d)
The reverse phase silica gel closed separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collects 14～18 column volumes and washes
De-liquid, eluent is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 90% alcohol heat reflux, merges extract.
Further, in the preparation method of compound (I), described macroreticular resin is D101 type macroporous absorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation treatment vascular dementia.
The application in the medicine of preparation treatment vascular dementia of the pharmaceutical composition of above-mentioned benproperine phosphate.
Advantages of the present invention: in the pharmaceutical composition of the benproperine phosphate that the present invention provides containing benproperine phosphate and a kind of from
The natural products of the novel structure of isolated in the dry bulb of Bulbus Fritillariae Cirrhosae, benproperine phosphate and this natural products independent role
Time, vascular dementia is had therapeutic action；During the two synergy, the result for the treatment of of vascular dementia is improved further,
The medicine for the treatment of vascular dementia can be developed into.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: the dry bulb (2kg) of Bulbus Fritillariae Cirrhosae is pulverized by (a), extracts (15L × 3 time) with 90% alcohol heat reflux,
Merge extract, be concentrated into without alcohol taste (3L), successively use petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and
Water saturated n-butanol (3L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and extracting n-butyl alcohol
Thing；B acetic acid ethyl ester extract D101 type macroreticular resin removal of impurities in () step (a), first with 8 posts of 35% ethanol elution
Volume, then with 12 column volumes of 90% ethanol elution, collect 90% eluent, reduced pressure concentration obtains 90% ethanol elution concentrate；
C in () step (b), 90% ethanol elution concentrate purification on normal-phase silica gel separates, be 120:1 (11 cylinders by volume ratio successively
Long-pending), 60:1 (9 column volumes), 30:1 (9 column volumes) and the methylene chloride-methanol gradient of 15:1 (8 column volumes)
Afford 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 40:1 by volume ratio successively
The methylene chloride-methanol gradient elution of (6 column volumes), 30:1 (8 column volumes) and 10:1 (6 column volumes) obtains 3
Individual component；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and by concentration expressed in percentage by volume is
The methanol aqueous solution isocratic elution of 85%, collects 14～18 column volume eluents, and eluent is concentrated under reduced pressure to give compound (I)
(308mg, HPLC normalization purity is more than 98%).
Structural identification: buff powder, HRAPCIMS shows [M+H]+For m/z 241.0831, can score in conjunction with nuclear-magnetism feature
Minor is C15H12O3, degree of unsaturation is 10.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1 (3.52,
D, J=6.2Hz, 2H), H-2 (6.24, dd, J=10.3,6.2Hz), H-3 (5.82, dd, J=10.3,7.1Hz),
H-4 (3.73, m), H-8 (8.03, s), H-12 (8.43, s), H-13 (9.74, s), H-14 (10.38, s),
H-15 (1.47, q, J=7.6Hz)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 27.3 (CH2,
1-C), 124.6 (CH, 2-C), 128.3 (CH, 3-C), 29.8 (CH, 4-C), 125.8 (C, 5-C), 161.3
(C, 6-C), 120.4 (C, 7-C), 124.1 (CH, 8-C), 133.4 (C, 9-C), 134.2 (C, 10-C),
129.8 (C, 11-C), 161.3 (CH, 12-C), 185.1 (CH, 13-C), 193.8 (CH, 14-C), 18.8
(CH3, 15-C).Infrared spectrum shows that this compound contains carbonyl (1765cm-1), alkene (1647cm-1) and aromatic rings
(1612cm-1, 1564m-1, 1463m-1) group.13C-NMR, DEPT and hsqc spectrum show 15 carbon signals,
Including a methyl δC18.8, a methylene δC27.3, seven methines (two carbonyl carbon, three alkene carbon and companies
Oxygen alkene carbon) δC124.6,128.3,29.8,124.1,161.3,185.1,193.8 and six quaternary carbons (six alkene carbon)
δC125.8、161.3、120.4、133.4、134.2、129.8；In conjunction with insatiable hunger sum, function above structure shows that this compound is
Tricyclic structure.1H-NMR spectrum one methyl proton signal δ of displayH1.47 (3H, q, J=7.6Hz), one group of ring internal olefin matter
Subsignal δH6.24 (1H, dd, J=10.3,6.2Hz) and δH5.82 (1H, dd, J=10.3,7.1Hz), connect in a ring
Oxygen olefinic proton signals δH8.43 (1H, s), an aromatic protons signal δH8.03 (1H, s), two aldehyde radical proton signals
δH9.74 (1H, s) and δH10.38 (1H, s).In HMBC spectrum, H-13 (δH9.74) with C-7 (δC120.4) and
C-12(δC161.3) correlation shows C-11 (δC129.8) position is connected with an aldehyde radical, H-14 (δH10.38) with C-10 (δC 134.2)
With C-8 (δC124.1) correlation shows that another aldehyde radical is connected to C-9 (δC133.4) position, H3-15(δH1.47) and C-3
(δC128.3) and C-5 (δC125.8) correlation understands C-4 (δC29.8) position is connected with a methyl.Additionally, analyze HMBC
H in spectrum2-1 with C-2 and C-10, H-3 and C-2 and C-4, H-8 and C-7 and C-9, H-12 and C-6 and C-11 and
H3-15 with the correlation of C-3 with C-5 combining1H-1H in H COSY spectrum2-1/H-2/H-3 and H-12/H-8/H-13's is relevant
Property can construct the connected mode of this compound, and then confirms the structure of this compound.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum
Compose with NOESY, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is shown below, three-dimensional structure
Type is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 animal
SD rat, male and female half and half, body weight (250 ± 20) g (Medical University Of Anhui's Experimental Animal Center).
1.2 medicines and reagent
Benproperine phosphate is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
Dihydroergotoxine methanesulfonate spansule (trade name: Perenan, 2.5mg, Sanofi-Aventis)；Adenosine diphosphate (ADP) (ADP,
Sigma company)；Fibrin ferment (Sigma company)；Epinephrine injection (Shanghai Hefeng Pharmaceutical Co., Ltd.)；Kang Paite
Medical adhesive (Beijing Shunkang Medical Adhesive Co., Ltd)；Benzylpenicillin sodium for injection (middle promise medicine company Shijiazhuang Co., Ltd)；Celebrating is big
Mycin parenteral solution (Nanjing Jinling Pharmaceutical Factory)；Acetylcholine (Ach) measures kit (R&D company).
1.3 instrument
RM-200 eight arm labyrinth (Chengdu Tai Meng science and technology)；OLYMPUSBX51 microscope (OLYMPUS company of Japan)；
RM2125 type slicer (LEICA company of Germany)；ELX808 ELIASA, ELX60 wash trigger (U.S. Bio-TEK).
The preparation of 1.4 mixed thrombus derivants
With sterile water for injection, ADP is diluted to 1.25mmol L before modeling-1, fibrin ferment is diluted to 12.5U mL-1, on kidney
Parathyrine is lmg mL-1, mixing according to the ratio of 100:200:5, lucifuge is standby in putting ice chest.
The preparation of 1.5VD model
After 3.5% chloraldurate lumbar injection (ip) rat anesthesia, neck median incision of lying on the back, on the right side of blunt separation exposure, neck is total
Artery (CCA), internal carotid (ICA), external carotid artery (ECA), ligature each branch of ECA, temporary transient with micro vessel clamp
Folder closes CCA, drives in the wrong direction having installed Thrombus inducer syringe to the insertion of arteria carotis communis crotch through ECA, and slowly injection is standby
Good mixed thrombus derivant, then opens arteria carotis communis folder, causes multiple cerebral to replicate and intends VD model.Pin hole is cured
Be glued, then inside and outside sew up the incision, routine disinfection otch, lumbar injection gentamicin with prevent infect.In whole modelings
In journey, holding animal heat is at about 37 DEG C, to prevent the low temperature effect to cerebral ischemia.The anesthesia of sham-operation group and operation method
Ibid, but CCA on the right side of only exposing, do not ligature ECA, inject equal-volume physiological saline to arteria carotis communis.
1.6 animal used as test packet and administrations
70 modelings of experimental rat, are shortlisted for the rat surviving 54 after modeling and are grouped, be randomly divided into 5 groups, its middle mold
Type control group 11, benproperine phosphate group (80mg kg-1), compound (I) group (80mg kg-1), phosphoric acid phenylpropyl alcohol
Piperazine woods and compound (I) composition [40mg kg-1Benproperine phosphate+40mg kg-1Compound (I)] organize each 11,
Positive drug 10.Separately arranging Sham-operated control group 10, do not give outside mixed thrombus derivant, remaining processes and at modeling
Reason is consistent.Removing rat cadavers during gastric infusion, final result is benproperine phosphate and compound (I) composition group
7, compound (I) group 8, benproperine phosphate group 8,8 (5mg kg of positive drug group-1), sham-operation group
9, model control group 8, model control group, sham-operation group give distilled water according to equivalent.Every day 1 time, continuous gavage
21d。
The collection of 1.7 samples
With 3.5% chloraldurate lumbar injection rat anesthesia, after abdominal aortic blood, quick sacrificed by decapitation on ice platform, takes immediately
Brain tissue, separates Cerebral cortex and hippocampus, weighs.Cerebral cortex is placed in homogenizer, adds ice physiological saline, grind homogenate,
Stand, 4 DEG C, 3000r min-1, centrifugal 10min, take supernatant, the Cerebral cortex physiological saline homogenate of preparation 10%, for enzyme
Linked immunosorbent adsorption test (ELISA) measures the content of Ach.Residual blood in normal saline flushing hippocampal tissue, is placed in 10%
Formalin is fixed, dyes for HE.
1.8 behaviouristics detections
Use radial eight arm labyrinths.Radial eight arm labyrinths are a kind of maze for studying animal spatial memory.Animal
Learning and memory self and bait (being placed in the white little food ball of labyrinth arm end) is come by observing some fixing objects of reference around
Position relatively.Before training, rat is first at labyrinth endoadaptation 2d, every day 1 time, each 10min, and rat can freely movable and picked-up
Food.Fasting subsequently carries out 1 training every day, each 10min, altogether 7d.It is respectively provided with in eight arms only 4 arms during training every time
(1,3,5,7 arm) is placed with food, for working arm, remaining for reference arm.Continuous 5 times training wrong choice number of times be 1 time or
Less than 1 time, working memory error (WME) is necessary for zero simultaneously, it is believed that train successfully.During experiment, rat is placed in labyrinth
Centre district, opens surrounding wicket after 15s, and rat may select any 1 arm pickuping food.Rat enters working arm and pickuping food is
1 time correct, otherwise for wrong choice.Reenter and put bait arm and claim WME, enter for the first time and do not put bait arm to be referred to as reference memory wrong
By mistake (RME).
1.9 statistical procedures
Using SPSS12.0 statistical software to carry out one-way analysis of variance, data mean ± standard deviation (x ± s) represents, conspicuousness
Level of difference P ＜ 0.05 is standard.
2, experimental result
2.1 impacts on VD rat learning and remembering ability
After VD rat continuous gastric infusion 21d, compared with sham-operation group, the WME of model control group rat, RME number
Significantly increase (P ＜ 0.01)；Can substantially reduce after giving benproperine phosphate, compound (I) VD rat WME,
RME number (P ＜ 0.05), gives WME, RME after benproperine phosphate and compound (I) composition and positive drug
Number of times significantly reduces (P < 0.01).The results are shown in Table 1.
Table 1 is on VD Working Memory in Rats mistake (WME), the impact of reference memory mistake (RME) number of times
| Group | WME | RME |
| Sham-operation group | 0.67±0.47 | 1.44±0.50 |
| Model control group | 2.50±0.71 | 4.25±0.83 |
| Positive controls | 0.88±0.60 | 2.13±0.60 |
| Benproperine phosphate group | 1.60±0.71 | 2.75±0.66 |
| Compound (I) group | 1.67±0.75 | 2.83±0.62 |
| Benproperine phosphate and compound (I) composition group | 0.86±0.64 | 1.91±0.70 |
2.2 impacts on VD rat brain cortex Ach content
Compared with sham-operation group, in model control group rat brain cortex, the content of Ach is in substantially reducing (P ＜ 0.01)；With model
Control group is compared, benproperine phosphate and the content of Ach in compound (I) composition group and positive controls rat brain cortex
Significantly improve, there is significant difference (P ＜ 0.01)；Benproperine phosphate group, compound (I) group is also in improving trend
(P<0.05).The results are shown in Table 2.
The table 2 impact on VD rat brain cortex Ach content
| Group | Ach/μg·mL-1 |
| Sham-operation group | 750.80±13.90 |
| Model control group | 704.75±19.30 |
| Positive controls | 753.86±17.97 |
| Benproperine phosphate group | 728.89±17.79 |
| Compound (I) group | 724.00±13.76 |
| Benproperine phosphate and compound (I) composition group | 748.66±14.22 |
VD due to cerebral ischemia or hemorrhagic cerebrovascular disease cause, brain function decline disease with dementia as main clinical manifestation
Sick.Mainly show as hypophrenia.Intelligence generally includes abstract thinking ability, comprehension, judgment, learning and memory, adaptation
The ability etc. of social environment, wherein learning and memory is the key element that intelligence is most basic, it is easy to measures and analyzes, therefore the most often study note
Recall achievement as the leading indicator evaluating intelligence.Central cholinergic system plays very important effect in learning and memory,
Central cholinergic system path is the major avenues of approach constituting learning and memory, and wherein Ach is important neurotransmitter.Generally believe VD at present
The damage of frontal cortex and hippocampus cholinergic neuron is probably the morphological base of cognitive impairment evil.VD rat hippocampus courage
Alkali serotonergic neuron reduces and causes spatial memory capacity to decline.
Above-mentioned result of the test shows, when benproperine phosphate, compound (I) are used alone, can be obviously improved plan vascular and be crazy about
The learning and remembering ability of slow-witted rat；When benproperine phosphate and compound (I) synergy, improve effect and become apparent from,
The medicine for the treatment of Rat VD model can be developed into.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.
It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a benproperine phosphate, it is characterised in that: include benproperine phosphate, such as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier, be prepared as the formulation needed.
The pharmaceutical composition of benproperine phosphate the most according to claim 2, it is characterised in that: pharmaceutically acceptable
Carrier include diluent, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surfactant,
Absorption carrier or lubricant.
The pharmaceutical composition of benproperine phosphate the most according to claim 2, it is characterised in that: described formulation include tablet,
Capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution
Agent, injection, suppository, spray, drops or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dry bulb of Bulbus Fritillariae Cirrhosae is pulverized, with 85～95% alcohol heat reflux extract, merging extract, be concentrated into without alcohol taste, use successively
Petroleum ether, ethyl acetate and water saturated extracting n-butyl alcohol, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and positive fourth
Alcohol extract；B in () step (a), n-butanol takes thing macroreticular resin removal of impurities, first with 8 column volumes of 35% ethanol elution,
Again with 12 column volumes of 90% ethanol elution, collecting 90% eluent, reduced pressure concentration obtains 90% ethanol elution concentrate；(c)
In step (b), 90% ethanol elution concentrate purification on normal-phase silica gel separates, and is 120:1,60:1,30:1 and 15:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel,
3 components are obtained successively with the methylene chloride-methanol gradient elution that volume ratio is 40:1,30:1 and 10:1；(e) step (d)
The reverse phase silica gel that middle component 2 is bonded by octadecylsilane separates, and washes with the methanol aqueous solution that concentration expressed in percentage by volume is 85% is isocratic
De-, collect 14～18 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) 90% second
Alcohol circumfluence distillation, merges extract.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroreticular resin is D101
Type macroporous absorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
9. the application in the medicine of preparation treatment vascular dementia of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described benproperine phosphate of claim 2～4 is at the medicine of preparation treatment vascular dementia
In application.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924490A (en) * | 2016-04-23 | 2016-09-07 | 徐月苗 | Candesartan cilexetil medicinal composition and application thereof in biomedicines |
| CN107929504A (en) * | 2018-01-10 | 2018-04-20 | 四川省自然资源科学研究院 | Fritillaria total alkaloids are preparing the new application in treating vascular dementia medicine |
| CN108752290A (en) * | 2018-06-27 | 2018-11-06 | 大连万福制药有限公司 | A kind of method of green syt benproperine phosphate intermediate |
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| CN105924490A (en) * | 2016-04-23 | 2016-09-07 | 徐月苗 | Candesartan cilexetil medicinal composition and application thereof in biomedicines |
| CN107929504A (en) * | 2018-01-10 | 2018-04-20 | 四川省自然资源科学研究院 | Fritillaria total alkaloids are preparing the new application in treating vascular dementia medicine |
| CN108752290A (en) * | 2018-06-27 | 2018-11-06 | 大连万福制药有限公司 | A kind of method of green syt benproperine phosphate intermediate |
| CN108752290B (en) * | 2018-06-27 | 2021-05-28 | 大连万福制药有限公司 | Green synthesis method of benproperine phosphate intermediate |
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