CN105884741A - Drug composition of bisoprolol fumarate and pharmaceutical application thereof - Google Patents
Drug composition of bisoprolol fumarate and pharmaceutical application thereof Download PDFInfo
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- CN105884741A CN105884741A CN201610263999.8A CN201610263999A CN105884741A CN 105884741 A CN105884741 A CN 105884741A CN 201610263999 A CN201610263999 A CN 201610263999A CN 105884741 A CN105884741 A CN 105884741A
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- JZFWEQKAKPTYBL-CXKWOXBZSA-N CC(C)(C(CC1)C2[C@@]1(C)Oc1cc(/C=C/Cc3ccccc3)c3O)[C@@]2(C=C)c1c3OC Chemical compound CC(C)(C(CC1)C2[C@@]1(C)Oc1cc(/C=C/Cc3ccccc3)c3O)[C@@]2(C=C)c1c3OC JZFWEQKAKPTYBL-CXKWOXBZSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Abstract
The invention discloses a drug composition of bisoprolol fumarate and a pharmaceutical application thereof. The drug composition of the bisoprolol fumarate contains the bisoprolol fumarate and a novel-structured natural product compound (I) separated from dried loquat leaves, wherein a compound of the bisoprolol fumarate and the compound (I) has obvious anti-inflammation and cough-reliving effects which is better than the independent anti-inflammation and cough-reliving effects of the bisoprolol fumarate or the compound (I), and can be developed into an anti-inflammation and cough-reliving drug. Compared with the prior art, the drug composition has prominent substantive features and remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of bisoprolol fumarate, be specifically related to fumaric acid peso
The pharmaceutical composition of Luo Er and the application in antiinflammatory cough-relieving thereof.
Background technology
Bisoprolol fumarate is beta-blocker, and the β1-receptor of bronchus and vascular smooth muscle is had high-affinity,
So that vasodilation, blood pressure reduces.It is applicable to hypertension, coronary heart disease and moderate to severe chronic stable heart failure etc.
Disease.
Bisoprolol fumarate is a kind of high selective β 1-adrenergic receptor antagonist, without intrinsic sympathomimetic acitivity with
Film stabilizing active.Bisoprolol fumarate has high-affinity to the β1-receptor of bronchus and vascular smooth muscle, to bronchus and blood
The beta 2-receptor of pipe smooth muscle and regulation metabolism only has the lowest affinity.Therefore, bisoprolol fumarate does not generally interfere with and exhales
Inhale road resistance and the metabolic effect of beta 2-receptor regulation.Bisoprolol fumarate still has β1-receptor choosing when beyond therapeutic dose
The effect of selecting property.
Up to now, there is not yet the dependency report of bisoprolol fumarate and pharmaceutical composition thereof and antiinflammatory cough-relieving.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of bisoprolol fumarate, this pharmaceutical composition contains
Bisoprolol fumarate and a kind of natural product, bisoprolol fumarate and this natural product can work in coordination with antiinflammatory cough-relieving.
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 bisoprolol fumarate, including bisoprolol fumarate, changes as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, binding agent, wetting agent,
Disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: dry Folium Eriobotryae is pulverized by (a), with 70～
80% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, ethyl acetate and water saturated just
Butanol, before immunoassay, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；N-butyl alcohol in (b) step (a)
Extract macroporous resin remove impurity, first with 6 column volumes of 15% ethanol elution, then with 10 column volumes of 70% ethanol elution, receives
Collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate is with just
Phase silica gel separates, and obtains 4 groups with the methylene chloride-methanol gradient elution that volume ratio is 80:1,30:1,15:1 and 5:1 successively
Point；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be the dichloromethane of 25:1,15:1 and 2:1 by volume ratio successively
Alkane-methanol elution gradient obtains 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates,
With the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 8～14 column volume eluents, eluent decompression is dense
Contracting obtains pure compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 75% alcohol heat reflux, united extraction
Liquid.
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane
Take, obtain dichloromethane extract.
The above-claimed cpd (I) application in the medicine preparing antiinflammatory cough-relieving.
The application in the medicine preparing antiinflammatory cough-relieving of the pharmaceutical composition of above-mentioned bisoprolol fumarate.
Advantages of the present invention:
The pharmaceutical composition of the bisoprolol fumarate that the present invention provides contains bisoprolol fumarate and a kind of from dry
The natural product of the novel structure of isolated in dry Folium Eriobotryae, bisoprolol fumarate and this natural product independent role
Time, there is antiinflammatory antitussive action；During the two synergy, antiinflammatory cough suppressing effect is more preferable, can develop into the medicine of antiinflammatory cough-relieving.
The present invention compared with prior art has prominent substantive distinguishing features and significantly progress.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit the present invention with this and protect model
Enclose.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, can be right
Technical scheme is modified or equivalent, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, insults peaking purchased from Shanghai
Learning reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: dry Folium Eriobotryae (2kg) is pulverized by (a), extracts (20L × 3 time) with 75% alcohol heat reflux, closes
And extracting solution, be concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated just
Butanol (4L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) step
A n-butyl alcohol extract D101 type macroporous resin remove impurity in (), first with 6 column volumes of 15% ethanol elution, then uses 70% ethanol
10 column volumes of eluting, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；70% second in (c) step (b)
Alcohol eluting concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 80:1 (8 column volumes), 30:1 (8 column volumes), 15:1
The methylene chloride-methanol gradient elution of (8 column volumes) and 5:1 (10 column volumes) obtains 4 components；Group in (d) step (c)
Points 3 separate further by purification on normal-phase silica gel, successively with volume ratio be 25:1 (8 column volumes), 15:1 (10 column volumes) and 2:1 (5
Individual column volume) methylene chloride-methanol gradient elution obtain 3 components；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 72%, collects 8～14 column volumes and washes
De-liquid, eluent is concentrated under reduced pressure to give compound (I) (259mg, HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 405.2027, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C26H28O5, degree of unsaturation is 13.Hydrogen nuclear magnetic resonance modal data δH(ppm, CD3OD, 500MHz): H-6 (6.62, s), H-7
(7.95, d, J=15.4Hz), H-8 (6.84, d, J=15.4Hz), H-10 (7.52, d, J=7.1Hz), H-11 (7.33, t, J
=7.3Hz), H-12 (7.24, t, J=7.3Hz), H-13 (7.33, t, J=7.3Hz), H-14 (7.52, d, J=7.1Hz), H-
1 ' (3.18, d, J=9.8Hz), H-2 ' (2.62, dd, J=9.8,7.6Hz), H-4 ' (1.42, s), H-5 ' (1.67,
Overlap), and H-5 ' (1.97, m), H-6 ' (1.68, overlap), H-6 ' (1.70, overlap), H-7 ' (2.45, m), H-9 '
(1.42, s), H-10 ' (0.83, s), 3-OMe (3.85, s)；Carbon-13 nmr spectra data δC(ppm, CD3OD, 125MHz):
141.6 (C, 1-C), 103.7 (C, 2-C), 160.4 (C, 3-C), 112.1 (C, 4-C), 158.4 (C, 5-C), 109.3 (CH, 6-
C), 131.2 (CH, 7-C), 130.4 (CH, 8-C), 139.3 (C, 9-C), 127.4 (CH, 10-C), 129.5 (CH, 11-C),
128.2 (CH, 12-C), 129.5 (CH, 13-C), 127.4 (CH, 14-C), 175.3 (C, 15-C), 37.3 (CH, 1 '-C), 38.2
(CH, 2 '-C), 85.6 (C, 3 '-C), 27.2 (CH3, 4 '-C), 39.5 (CH2, 5 '-C), 26.3 (CH2, 6 '-C), 47.5 (C, 7 '-
C), 39.8 (C, 8 '-C), 33.6 (CH3, 9 '-C), 17.8 (CH3, 10 '-C), 63.1 (CH3, 3-OMe).Infrared spectrum shows this
Compound contains carbonyl (1748cm-1), aromatic rings (1618cm-1, 1557m-1, 1445cm-1) group.13C-NMR, DEPT and
Hsqc spectrum shows 26 carbon signals, including four methyl (methoxyl group), two methylene, 11 methines (two
Individual alkene carbon, six aromatic carbon), and nine quaternary carbons (six aromatic carbon, an alkene carbon, two carbonyls)；Function above is tied
In conjunction with insatiable hunger sum, structure shows that this compound is five ring structures.1There is one group of unsubstituted phenyl ring proton signal δ in H-NMR spectrumH
7.52 (2H, d, J=7.1Hz), 7.33 (2H, t, J=7.3Hz) and 7.24 (1H, t, J=7.3Hz) and one group of trans olefins matter
Subsignal δH7.95 (1H, d, J=15.4Hz) have trans stilbene sheet in 6.84 (1H, d, J=15.4Hz) hint structure
Section, three methine proton signal δH3.18 (1H, d, J=9.8Hz), 2.62 (1H, d, J=9.8,7.6Hz) and 2.45 (1H,
M), two methene proton signal δH1.67 (1H, overlap) with 1.97 (1H, m) and δH1.68 (1H, overlap) with
1.70 (1H, overlap), three methyl proton signal δH1.42 (3H, s), 1.42 (3H, s) with 0.83 (3H, s), a first
Epoxide proton signal δH3.85 (3H, s).By13The chemical shift δ of C-3 Yu C-5 in C-NMR spectrumC-3160.9 and δC-5158.6 can
Knowing that C-3, C-5 are all even oxygen carbon, in another HMBC spectrum, the coherent signal of methoxyl group proton and C-3 indicates C-3 position and is connected with methoxy
Base, and H-1 ', H-2 ', H3-4’、H2-5 ' and C-3 ' exists coherent signal, the chemical shift of C-3 ' is δC-3’80.7 prompting C-3 '
Also for even oxygen carbon.H in HMBC spectrum3-9 ' and H3-10 ' and the coherent signal of C-1 ', C-7 ' and C-8 ' and1H-1In H COSY spectrum
H-1 ' and H-2 ' and H-2 ' and H-7 ' coherent signal hint compound contain dimethylcyclobutane structure, and H-1 ' and C-4 phase
OFF signal is confirmed dimethylcyclobutane and is connected by C-4-C-1 ' key with trans stilbene.Another HMBC spectrum exists H-1 ' with
C-4, C-2 ' and C-3 ', H3-4 ' and C-2 ' and C-3 ' coherent signal and1H-1H-1 ' and H-2 ' coherent signal in H COSY spectrum,
It is all even oxygen carbon in conjunction with C-5, C-3 ' and C-1 '-C-2 '-C-3 ' chain and the phenyl ring C-4 in trans stilbene unit can be speculated,
It is benzopyran structure that C-5 position is joined directly together with carbon-oxygen-carbon phase concatemerization by carbon-to-carbon respectively.Additionally,1H-1In H COSY spectrum
H2-5’/H2-6 ' H-2 ' and C-3 ' and C-7 ', H in/H-7 '/H-2 ' coherent signal, and HMBC spectrum2-5 ' and C-2 ', C-3 ', C-
4 ', C-6 ' and C-7 ' coherent signal understand C-2 '-C-3 '-C-5 '-C-6 '-C-7 ' and form a cyclopentane structure unit.HMBC
Spectrum also confirms the coherent signal of H-6 Yu C-7 and H-8 Yu C-1, thus understands and trans stilbene unit connection side
Formula.In HMBC spectrum, the coherent signal of H-6 with C-2 and C-15 has then known that in structure, carboxyl is connected with C-2.Comprehensive hydrogen is composed, carbon is composed,
HMBC spectrum and ROESY compose, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is shown below, vertical
Body configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.This compound chemical formula and carbon atoms numbered
As follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 medicines and reagent
Bisoprolol fumarate is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in enforcement
Example 1.Glacial acetic acid, Nanning chemical reagent factory produces；Dimethylbenzene, Solution on Chemical Reagents in Shanghai company of Chinese Medicine group produces；She
The train of thought is blue, and Solution on Chemical Reagents in Shanghai purchasing and supply station subpackage factory produces.Aspirin tablet (100mg/ sheet), Baeyer drugmaker is raw
Produce；GUILONG KECHUANNING JIAONANG, Guilong Medicine Co., Ltd., Shanxi produces；Exocarpium Citri Rubrum electuary, Nanchang Kang Zhengde pharmaceutical Co. Ltd is raw
Produce.
1.2 laboratory animal
Kun Ming mice 90, weight (20 ± 2) g, male and female half and half；Wistar rat 60, weight (200 ±
20) g, male and female half and half, provided by Hubei Province's Experimental Animal Center.
1.3 equipment
1.80-2 type centrifuge, Shanghai Surgical Operation Equipment Factory produces；721 type spectrophotometers, Shanghai the 3rd analytical tool factory
Produce；AEU-210 type electronic balance, Japan's Shimadzu produces.
1.4 antiinflammatory experiments
1.4.1 xylol causes the impact of mice auricle swelling degree
Taking mice 50, be randomly divided into 5 groups, often group 10, is respectively as follows: normal saline group, aspirin group (300mg/
Kg), bisoprolol fumarate's group (80mg/kg), compound (I) group (80mg/kg), bisoprolol fumarate and compound (I)
Compositions group [40mg/kg bisoprolol fumarate's+40mg/kg compound (I)] respectively group is administered by corresponding dosage, normal saline group
Gavage normal saline.The equal gastric infusion of each group, every day 1 time, continuous 5d.After last is administered 1h, each group mouse right ear is coated with
Only, left ear is not coated with makees self-blank comparison to dimethylbenzene 0.05ml/.After smearing dimethylbenzene 30min, mice dislocation of cervical vertebra is put to death,
Lay the disk of left and right ears same area with the card punch of internal diameter 6mm, claim quality respectively, with auris dextra quality and left ear quality
Difference is swelling, the swelling of relatively more each group.
1.4.2 Dichlorodiphenyl Acetate causes the effect that mouse peritoneal capillary permeability increases
Take mice 50, be grouped and be administered same 1.4.1.Each group gives medicine every day 1 time, continuous 3d.After last is administered 1h,
After the normal saline 0.1ml/10g of mouse tail vein injection 0.5% Evans blue, inject 0.6% acetic acid in mouse peritoneal immediately
Only, after 20min, break end 0.2ml/ sacrificed by exsanguination mice, with 5ml normal saline flushing abdominal cavity 3 times, collects cleaning mixture, centrifugal
(1000rpm) 5min, measures trap (OD value) at 721 type spectrophotometer 590nm.
1.5 cough-relieving experiments
1.5.1, SO2 causes to cough the impact of mice
Take mice 50, be randomly divided into 5 groups, often group 10, i.e. normal saline group, bisoprolol fumarate group (80mg/
Kg), compound (I) group (80mg/kg), bisoprolol fumarate and compound (I) compositions group [40mg/kg fumaric acid peso
Luo Er+40mg/kg compound (I)], GUILONG KECHUANNING group (5g/kg).Each group is administered by corresponding dosage, and normal saline group gavages
Normal saline, every day 1 time, altogether 7d.1h after last administration, puts into mice in the wide mouthed bottle of 500ml, is passed through SO26ml draws
Cough, occur significantly dehiscing to pant for cough index with mice, observe and record mice and put in bottle to hiding that cough occurs
Cough number of times in phase and 3min.
1.5.2 the impact on rat expectoration amount
Take Wistar rat 50, be randomly divided into 5 groups, often group 10, i.e. normal saline group, bisoprolol fumarate's group
(80mg/kg), compound (I) group (80mg/kg), bisoprolol fumarate and compound (I) compositions group [40mg/kg richness horse
Acid bisoprolol+40mg/kg compound (I)], Exocarpium Citri Rubrum electuary group (5g/kg).Each group is administered by corresponding dosage, normal saline group
Gavage normal saline, every day 1 time, altogether 7d.Before experiment, water 12h is can't help in fasting, after last is administered 30min, uses pentobarbital
Sodium 30mg/kg anaesthetizes, and dorsal position fixes, and cuts off neck center skin, separates trachea, thyroid cartilage lower edge hit exactly two cartilaginous rings it
In, prick an aperture with injection needle, be inserted into one, the capillary tube of the known quality (G1) of diameter 0.5ml, long 10cm.Make hair
Thin glass tube just contacts surface, trachea portion, to draw the sputum in trachea, if a glass-tube is filled, changes a glass-tube at once, receives
The expectoration amount of collection rat 60min, then collects the weight (G2) of the glass-tube having sputum with electronic scale weighing, and G2-G1 is rat
The expectoration amount of 60min, calculates the drain mg number of 60min/100g as index of eliminating the phlegm.
1.6 statistical method
Application SPSS11.5 software kit carries out data process.Measurement data represents with x ± s, compares employing t inspection between group.P
< 0.05 is that difference is statistically significant.
2, experimental result
2.1 xylol cause mice auricle swelling and Dichlorodiphenyl Acetate causes the effect that mouse peritoneal capillary permeability increases
Impact
Compare with normal saline group, bisoprolol fumarate and compound (I) compositions group and the swelling of aspirin group
Degree and OD value the most substantially reduce, difference statistically significant (P < 0.01), and bisoprolol fumarate's group, compound (I) group also may be used
Significantly reduce swelling and OD value (P < 0.05), the antiinflammation of bisoprolol fumarate and compound (I) compositions is described relatively
Substantially, and can significantly reduce OD value, more apparent suppression acetic acid causes mouse peritoneal capillary permeability to be increased.
Result of the test is shown in Table 1.
Table 1 anti-inflammation test result (x ± s, n=10)
| Group | Swelling | Trap (OD value) |
| Normal saline group | 1.91±0.35 | 0.556±0.112 |
| Positive controls | 1.41±0.23 | 0.401±0.079 |
| Bisoprolol fumarate's group | 1.60±0.31 | 0.422±0.045 |
| Compound (I) group | 1.59±0.42 | 0.428±0.072 |
| Bisoprolol fumarate and compound (I) compositions group | 1.37±0.36 | 0.404±0.068 |
2.3 couples of mice SO2Cause the antitussive action coughed
Compare with normal saline group, bisoprolol fumarate and compound (I) compositions group and the equal energy of GUILONG KECHUANNING group
Reduce mice SO2Cause the cough number of times coughed, extend cough latent period, difference statistically significant (P < 0.01), fumaric acid peso
Luo Er group, compound (I) group also can reduce cough number of times, extends cough latent period (P < 0.05).
Result of the test is shown in Table 2.
Table 2 is to mice SO2Cause the antitussive action (x ± s, n=10) coughed
| Group | Cough number of times (secondary) | Incubation period (s) |
| Normal saline group | 59.7±6.3 | 41.97±7.76 |
| Positive controls | 38.8±5.9 | 69.66±8.67 |
| Bisoprolol fumarate's group | 46.3±4.5 | 51.57±7.25 |
| Compound (I) group | 44.2±7.5 | 52.92±7.13 |
| Bisoprolol fumarate and compound (I) compositions group | 32.2±2.4 | 70.34±8.42 |
2.4 impacts on rat expectoration amount
Bisoprolol fumarate's group, compound (I) group and the mg number of Exocarpium Citri Rubrum electuary group 60min/100g drain be 3.21 ±
0.57,3.25 ± 0.37 and 3.28 ± 0.42 be above normal saline group (2.24 ± 0.43), difference statistically significant (P <
0.05), bisoprolol fumarate and compound (I) compositions group are 3.54 ± 0.68, be significantly higher than normal saline group (P <
0.01)。
In sum, the bisoprolol fumarate that the present invention provides and compound (I) compositions only have obvious antiinflammatory
Cough effect, and be better than bisoprolol fumarate or compound (I) individually antiinflammatory antitussive action.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a bisoprolol fumarate, it is characterised in that: include bisoprolol fumarate, such as claim
Compound (I) described in 1 and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of bisoprolol fumarate the most according to claim 2, it is characterised in that: pharmaceutically can accept
Carrier include diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, suction
Appendix body or lubricant.
The pharmaceutical composition of bisoprolol fumarate the most according to claim 2, it is characterised in that: described dosage form includes sheet
Agent, capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, note
Penetrate agent, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a) will be dry
Dry Folium Eriobotryae is pulverized, with 70～80% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use successively petroleum ether,
Ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butanol extraction
Thing；B n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 6 column volumes of 15% ethanol elution, then with 70%
10 column volumes of ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b)
70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with the dichloromethane that volume ratio is 80:1,30:1,15:1 and 5:1-
Methanol elution gradient obtains 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, by volume ratio be successively
The methylene chloride-methanol gradient elution of 25:1,15:1 and 2:1 obtains 3 components；E in () step (d), component 2 uses octadecyl
The reverse phase silica gel of silane group separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collects 8～14 posts
Volume eluent, eluent is concentrated under reduced pressure to give pure compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is returned by 75% ethanol heat
Stream extracts, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is D101 type
Macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) uses dichloromethane generation
Extract for ethyl acetate, obtain dichloromethane extract.
9. the application in the medicine preparing antiinflammatory cough-relieving of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described bisoprolol fumarate of claim 2～4 is in the medicine preparing antiinflammatory cough-relieving
Application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610263999.8A CN105884741A (en) | 2016-04-23 | 2016-04-23 | Drug composition of bisoprolol fumarate and pharmaceutical application thereof |
Applications Claiming Priority (1)
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| CN105837449A (en) * | 2016-04-18 | 2016-08-10 | 镇江高海生物药业有限公司 | Pharmaceutical composition for L-tert-leucine and application thereof in biological medicine |
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| CN105663138A (en) * | 2016-04-23 | 2016-06-15 | 贺玉皓 | Clonazepam medicinal composition and medicinal application thereof |
| CN105837449A (en) * | 2016-04-18 | 2016-08-10 | 镇江高海生物药业有限公司 | Pharmaceutical composition for L-tert-leucine and application thereof in biological medicine |
| CN106146601A (en) * | 2016-06-23 | 2016-11-23 | 崔坤峰 | The pharmaceutical composition of azithromycin and the medical usage of cough-relieving thereof |
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| CN105837449A (en) * | 2016-04-18 | 2016-08-10 | 镇江高海生物药业有限公司 | Pharmaceutical composition for L-tert-leucine and application thereof in biological medicine |
| CN106146601A (en) * | 2016-06-23 | 2016-11-23 | 崔坤峰 | The pharmaceutical composition of azithromycin and the medical usage of cough-relieving thereof |
| WO2017220050A3 (en) * | 2016-06-23 | 2018-02-15 | 赵吉永 | Azithromycin pharmaceutical composition and medical use thereof for cough relief |
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