CN1345727A - Aqueous soluble steroid compound alkaloid salt, preparation process and medicinal composition containing same - Google Patents
Aqueous soluble steroid compound alkaloid salt, preparation process and medicinal composition containing same Download PDFInfo
- Publication number
- CN1345727A CN1345727A CN 00129507 CN00129507A CN1345727A CN 1345727 A CN1345727 A CN 1345727A CN 00129507 CN00129507 CN 00129507 CN 00129507 A CN00129507 A CN 00129507A CN 1345727 A CN1345727 A CN 1345727A
- Authority
- CN
- China
- Prior art keywords
- acid
- nhch
- compound
- general formula
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to sterides alkaloid water soluble salts, their preparation method and compositions containing them. Said invention also provides their general formulae. These alkaloid mainly can be used for curing angiocardiopathy and cerebrovascular diseases, but they have the defects of poor solubility and low bioavailability. In said invention, they react with acid to produce water soluble salts, raiser ther water solubility so as to raise their bioavailability and therapeutic effect.
Description
The present invention relates to aqueous soluble steroid compound alkaloid salt salt, its preparation method and contain their pharmaceutical composition.
The present invention be specifically related to water-soluble general formula (I) and general formula (II steroid compound alkaloid salt salt,
General formula (I)
General formula (II)
Be singly-bound between 6,7 in its formula of (I), R=H or OH, R
1=CH
3Or H, R
2=CH
3Or H or CH
2OH, R
3=R
4==O or NH
2Or NHCH
3Or N (CH
3)
2,
Or be two keys between 6,7, R=H or OH, R
1=CH
3, R
2=CH
2OH, R
3=R
4=NH
2Or NHCH
3Or N (CH
3)
2,
General formula (II), R '=H or OH, R '
1=CH
3Or H, R '
2=CH
3Or H or CH
2OH, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid.
Free general formula (I) and general formula (II) steroid compound alkaloid salt and activity thereof have been reported in the prior art, it mainly extracts from the Buxus plant, separate and obtain, and has wherein introduced in the general formula (I) part free steroid alkaloid to the provide protection of cerebral ischemia at " herbal medicine " 1997 the 28th volumes the 7th phase 413-414 page or leaf; " journal of shanghai traditional Chinese medicine " 1992 the 3rd phase 13-15 page or leaf has been introduced the middle part free steroid alkaloid of general formula (I) to coronary heart disease, anginal therapeutic action; " Journal of naturalproducts " 1999 the 62nd volumes the 5th phase 665-669 has introduced general formula (I) and the middle part free steroid alkaloid of general formula (II) has the effect of antimalarial, tuberculosis, anti-HIV.
" pharmacy circular " 1981 the 16th volumes the 4th phase 3-4 page or leaf; " Botany Gazette " 1996 the 38th volume the 6th phase 183-188 page or leaf has introduced how part free steroid alkaloid is separated in the general formula of the present invention (I) from the Buxus plant, and the evaluation that finishes structure.
" Journal of natural products " 1999 the 62nd volumes the 5th phase 665-669; " Journal ofnatural products " 1999 the 51st volume the 2nd phase 309-310 has reported the separating of general formula of the present invention (I) and the middle part free steroid alkaloid of general formula (II), preparation and authentication method thereof." Phytochemistry " Vol.35 NO.4 pp.993-1000 1994; " Phytochemistry " Vol.27 NO.10 pp3342-3343 1988; " Phytochemistry " Vol.29 NO.4pp.12930-1296 1990; " Phytochemistry " Vol.28 NO.10 pp.2848-50 1989; " Phytochemistry " Vol.30 NO.4 pp.1295-98 1991; Deng also having other periodicals, as " Heterocycles " Vol.49 1998 pp481-488; Also all report the part-structure of free steroid compound alkaloid salt in general formula of the present invention (I) and the general formula (II) respectively, and disclose its method for separating and preparing and activity thereof.
CN1064869 disclose a kind of from little leaf boxwood wherein a kind of alkaloid cyclovirobuxinum D of separation and Extraction (be singly-bound, R=OH, R between 6,7
1=R
2=CH
3, R
3=R
4=NHCH
3Compound of Formula I) production technique and preparation thereof, this method can extract the pure product of cyclovirobuxinum D, and are made into tablet.
Though above-mentioned document and other documents have all been reported the free steroid compound alkaloid salt of the part in general formula of the present invention (I) and the general formula (II) respectively, do not find its salifiable report document.Be actually used in the application process of patient, it is found that general formula (I) and general formula (II) steroid compound alkaloid salt extract are insoluble in water, only can by oral route award general formula (I) or general formula (II) compound alkaloid salt, as with tablet form, but dissolution rate is slower in vivo to contain the oral preparations of general formula (I) or general formula (II) steroid alkaloid, the activeconstituents dissolution rate is low, is unfavorable for absorption by human body, and the active ingredient bioavailability is relatively poor.
It is water-soluble to the present invention seeks to improve the free alkaloid of general formula I and general formula I I steroid compound, accelerates its dissolution rate in vivo, thus improve its in vivo bioavailability and enlarge route of administration.
The inventor finds after deliberation, steroid alkaloid and organic acid, mineral acid or amino acid salify with general formula (I) and general formula (II), can obviously improve the water-soluble of general formula (I) and general formula (II) steroid alkaloid, improved its dissolution rate, improve bioavailability, and enlarged their route of administration thus.
First aspect present invention relates to water-soluble general formula (I) and general formula (II) steroid compound alkaloid salt salt,
General formula (I)
General formula (II)
Its formula of (I) is singly-bound between 6,7, R=H or OH, R
1=CH
3Or H, R
2=CH
3Or H or CH
2OH, R
3=R
4==O or NH
2Or NHCH
3Or N (CH
3)
2Or
When being two key between 6,7, R=H or OH, R
1=CH
3, R
2=CH
2OH, R
3=R
4=NH
2Or NHCH
3Or N (CH
3)
2, or
General formula (II), R '=H or OH, R '
1=CH
3Or H, R '
2==CH
3Or H or CH
2OH, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid can be selected from: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid can be selected from: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid can be selected from: Methionin, aspartic acid.
The present invention relates to the pharmaceutical composition that contains at least a water-soluble general formula (I) and/or general formula (II) steroid compound alkaloid salt salt and pharmaceutical carrier or vehicle on the other hand.
Further aspect of the present invention relates to the purposes that contains at least aspect a kind of water-soluble general formula (I) and/or general formula (II) steroid compound alkaloid salt salt is used for the treatment of coronary heart disease, stenocardia, premature ventricular beat disease in preparation the medicine.
Further aspect of the present invention relates to the purposes that contains at least aspect a kind of general formula (I) and/or general formula (II) steroid compound alkaloid salt water-soluble salt be used for the immunodeficiency type viral infectious disease in preparation the medicine.
The water-soluble general formula of the present invention (I) can prepare by free general formula (I) is contacted to react with acid with general formula (II) steroid compound alkaloid salt with general formula (II) steroid compound alkaloid salt salt, and wherein free general formula (I) can separate, produce (as: " pharmacy circular " 1981 the 16th volumes the 4th phase 3-4 page or leaf) of acquisition by open reported method on the document with general formula (II) steroid compound alkaloid salt.
General formula (I)
General formula (II)
Be singly-bound between 6,7 in its formula of (I) compound, R=H or OH, R
1=CH
3Or H, R
2=CH
3Or H or CH
2OH, R
3=R
4==O or NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid, or
Two keys between 6,7 in general formula (I) compound, R=H or OH, R
1=CH
3, R
2=CH
2OH, R
3=R
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid; Or
In general formula (II) compound, R '=H or OH, R '
1=CH
3Or H, R '
2=CH
3Or H or CH
2OH, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid;
According to the present invention, preferred following general formula (I) alkaloid water-soluble salt is a singly-bound between 6,7 in its formula of (I) compound, R=H, R
1=CH
3, R
2=CH
3, R
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid, or
Be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=CH
3, R
2=CH
3, R
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is Methionin, aspartic acid; Or
Be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=CH
3, R
2=H, R
3=NHCH
3, R
4=N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is Methionin, aspartic acid; Or
Be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=CH
2OH, R
2=H; R
3=NH
2, R
4=NH
2M is mineral acid, organic acid or amino acid, and wherein mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is Methionin, aspartic acid; Or
Be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=H, R
2=CH
3, R
3=NHCH
3, R
4==O, M are mineral acid, organic acid or amino acid, and wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid; Or
In its formula of (I) compound two keys, R=H or OH, R
1=CH
3, R
2=CH
2OH, R
3=R
4=N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid;
According to the present invention, preferred following general formula (II) alkaloid water-soluble salt:
R '=H in general formula (II) compound, R '
1=CH
3, R '
2=CH
3, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid, or
R '=H in general formula (II) compound, R '
1=CH
3, R '
2=CH
2OH, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2,
M is mineral acid, organic acid or amino acid, and wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid, or
R '=H in general formula (II) compound, R '
1=H, R '
2=CH
2OH, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid, or
R '=OH in general formula (II) compound, R '
1=CH
3, R '
2=CH
3, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid, or
R '=OH in general formula (II) compound, R '
1=H, R '
2=CH
2OH, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid,
According to the present invention, more preferably Xia Mian general formula (I) alkaloid water-soluble salt:
Be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=CH
3, R
2=CH
3R
3=NH
2Or NHCH
3Or N (CH
3)
2R
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is Methionin, aspartic acid, or
Be singly-bound between 6,7 in its formula of (I) compound, R=H, R
1=CH
3, R
2=CH
3R
3=NH
2Or NHCH
3Or N (CH
3)
2R
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid,
According to the present invention, more preferably Xia Mian general formula (II) alkaloid water-soluble salt: R '=H in general formula (II) compound, R '
1=CH
3, R '
2=CH
3, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid, or
R '=H in general formula (II) compound, R '
1=CH
3, R '
2=CH
2OH, R '
3=NH
2, → R '
4=N (CH
3)
2, or
R '=OH in general formula (II) compound, R '
1=CH
3, R '
2=CH
3, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2, M is mineral acid, organic acid or amino acid, wherein mineral acid is: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is: Methionin, aspartic acid.
The preparation method of water-soluble general formula of the present invention (I) and general formula (II) steroid compound alkaloid salt salt is: with free general formula (I) and (II) compound alkaloid salt water or alcohol or water and pure solution dissolving, dropping is with the solution dissolved acid solution of water or alcohol or water and alcohol, stirred 0.5-3 hour, temperature is that 20-80 ℃, decolouring, filtration or underpressure distillation steam solvent, recrystallization, promptly gets product.Wherein alcohol is: methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol.
According to the present invention, pharmaceutical composition of the present invention contains at least a general formula (I) and/or general formula (II) steroid compound alkaloid salt water-soluble salt and pharmaceutical carrier or vehicle.
According to the present invention, pharmaceutical composition of the present invention can pass through oral or parenterai administration administration, and the formulation of oral administration can be tablet, capsule, granule; The formulation of parenterai administration can be injection, lyophilized injectable powder, injection liquid, transfusion.
Used carrier or vehicle can be thinner, tackiness agent, disintegrating agent, lubricant, glidant in the preparation according to the present invention.
Can select starch, Icing Sugar, lactose, dextrin, microcrystalline cellulose for use for the operable thinner of oral preparations; Tackiness agent can be selected starch, syrup, jelly for use; Disintegrating agent can be selected dry starch, Walocel MT 20.000PV etc. for use; Glidant can select for use micropowder silica gel, correctives can select soluble saccharin for use; Perfume compound can be selected peppermint for use.
For injection used carrier and vehicle can select water for injection for use, stablizer can be selected creatinine, glycine for use, oxidation inhibitor such as S-WAT, bisulfite are received, Sodium Pyrosulfite, isotonic solution.
Water-soluble general formula (I) and/or general formula (II) steroid compound alkaloid salt salt or the pharmaceutical composition that contains them can be treated diseases such as coronary heart disease, stenocardia, premature ventricular beat and immunodeficiency type virus infection according to the present invention.
Because general formula of the present invention (I) and general formula (II) steroid compound alkaloid salt water-soluble salt have improved the water-soluble of its free alkali, enlarged route of administration, accelerated the free alkaloidal dissolution rate of general formula (I) and general formula (II) steroid compound, improve bioavailability of medicament, increased curative effect such as rapid-action, dosage reduction.
The following examples, experimental example are used to further specify the present invention, but and do not mean that any limitation of the invention.
Experimental example 1
Adopt the cuvette method to measure hydrochloric acid Buxine dissolution rate in vitro:
Instrument: 2R58 intelligence stripping experiment instrument (Tianjin radio factory of Nankai University)
Sample: hydrochloric acid cyclovimbuxine D (also claims the hydrochloric acid Buxine, i.e. R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The compound of Formula I hydrochloride); Cyclovirobuxinum D (also claims Buxine, i.e. R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The compound of Formula I alkaloid).
Method: get 100ml solution respectively and put in 1,2 cuvettes, Buxine and each two in hydrochloric acid Buxine tablet are added on respectively in the cuvette, rotating speed is 50 rev/mins, the sampling respectively in 30,45 minutes.The accurate respectively two sample solution 5ml that draw add in the separating funnel, add 2ml methyl alcohol, 2ml matching stain, 10ml chloroform, and jolting 15min left standstill 1 hour.Get two sample subnatant 5ml respectively.Respectively add dehydrated alcohol 1ml, after 15 minutes, measure the optical density at 620nm place respectively.
The result is as follows:
From experimental result as can be seen: salifiable alkaloidal dissolution rate significantly is higher than not salifiable alkaloid.
Title | ????30min | ????45min |
Hydrochloric acid cyclovimbuxine D | ????75% | ????96% |
Cyclovirobuxinum D | ????23% | ????35% |
Embodiment 1
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) hydrochloride
2.5g (0.62mmol) Buxine is added to makes it dissolving in the dehydrated alcohol of 80ml, under agitation drip 0.71ml hydrochloric acid, be dissolved in the ethanol solution of 20ml, continue to stir 2 hours, filtration, filtrate decompression steam solvent, obtain white solid, with propyl carbinol-ethyl acetate recrystallization, obtain the needle-like crystal of title compound.MP:324 ℃, optically-active [α]
D 25=31.2.
Embodiment 2,
R=OH; R
1=R
2=CH
3R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) hydrochloride
The 20g Buxine is added in 80% ethanolic soln of 300ml, obtains suspension, under agitation, drip 80% ethanolic soln of 95ml 1mol/L HCL, Buxine all dissolves, and continues to stir 30min, add the 0.3g gac,, filter in 80 ℃ of heating 10min, filtrate decompression steams solvent, obtain white solid,, get title compound 9.4g with propyl carbinol-ethyl acetate recrystallization, MP:324 ℃, optically-active [α]
D 25=31.2.
Embodiment 3
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) hydrochloride
The 1g Buxine is added in the 50ml water, the suspension that stirs, the aqueous hydrochloric acid of the 1.0mol/L of the 5.0ml that under agitation progressively increases treats that Buxine all dissolves, continue to stir 30min, filtration, filtrate decompression steam solvent, get white solid, dry weight 1.14g, with using Virahol-acetate one ester recrystallization, get the title compound crystalline material, MP:324 ℃, optically-active [α]
D 25=31.2.
Embodiment 4
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) vitriol
402mg (1mmol) Buxine is dissolved in the 40ml dehydrated alcohol, under agitation, drips 100mg (0.05mol) vitriol oil in the ethanol solution of 10ml, separate out precipitation, continue to stir 2 hours, placement is spent the night, filtration drying, get the 400mg title compound, white bulk solids, optically-active [α]
D 25=18.0
Embodiment 5
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) hydrobromate.
Get 310mg (0.77mmol) Buxine, make it under agitation to drip the solution of the Hydrogen bromide 10ml Virahol of 0.5ml (content 40%) in dissolving and the 30ml Virahol, separate out white precipitate, continue to stir 2 hours, place and filter, drying, get title compound 0.37 gram, white solid, optically-active [α]
D 25=25.7
Embodiment 6
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) acetate.
2.5g (0.62mmol) Buxine is dissolved in the 80ml dehydrated alcohol, under agitation, adds 0.71ml acetic acid and be dissolved in the 20ml dehydrated alcohol, continue agitation and filtration, the filtrate decompression distillation desolventizes, and vacuum-drying must get title compound, white solid.
Embodiment 7
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) succinate
Get 0.42g (10mmol) Buxine and join in the 250ml dehydrated alcohol, make it dissolving, filter and to obtain Buxine alkali ethanol solution.Other gets 1.22g (10.03mmol) succsinic acid, adds the 50ml dehydrated alcohol, makes it dissolving, obtains the succsinic acid ethanol solution.Under agitation, be added drop-wise in the Buxine ethanol solution the succsinic acid ethanolic soln is very long in 70 degree, continue to stir 2 hours in room temperature, placement is spent the night, vacuum-drying, title compound 4.62g, white solid.Optically-active [α]
D 25=28.9
Embodiment 8
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) fumaric acid hydrochlorate.
3.1g (7.7mmol) Buxine alkali is added in the 200ml Virahol, makes it dissolving, obtain fumaric acid Buxine aqueous isopropanol, get 1.0g (8.6mmol) fumaric acid again and be added in the 50ml Virahol, make it dissolving, obtain the fumaric acid aqueous isopropanol.Under agitation, in 70 ℃ the fumaric acid aqueous isopropanol slowly is added drop-wise in the Buxine aqueous isopropanol, continues to stir 2 hours in room temperature, placement is spent the night, and filters vacuum-drying, gets title compound 3.92g, white solid.Optically-active [α]
D 25=30.2
Embodiment 9
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) maleate
Get 4.02g (10mml) Buxine alkali, be added in the 250ml dehydrated alcohol, make it dissolving, obtain the Buxine ethanol solution.Other gets 1.22g (10.03mmol) toxilic acid and is added in the 50ml dehydrated alcohol, make it dissolving and obtain the toxilic acid ethanol solution, under agitation, with 70 ℃ the toxilic acid ethanol solution is added in the Buxine ethanol solution, room temperature continues to stir 2 hours, places filtration, underpressure distillation solvent, gets title compound, white solid, optically-active [α]
D 25=23.1.
Embodiment 10
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) oxalate
Get 310mg (0.77mmol) Buxine, make it to be dissolved in the Virahol of 30ml, obtain the Buxine aqueous isopropanol, other gets oxalic acid, is dissolved in the 100ml Virahol, obtains the oxalic acid aqueous isopropanol, under the stirring at room, the oxalic acid aqueous isopropanol is added drop-wise in the Buxine aqueous isopropanol, continues to stir 2 hours, filter, 60 ℃ of dryings 4 hours, must get title compound 2.4g, white solid, optically-active [α]
D 25=24.5.
Embodiment 11
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) tartrate
Get 0.31 gram (0.77mmol) Buxine, make it to be dissolved in the methanol solution of 50ml, obtain in the Buxine methanol solution, other gets 120mg tartrate and makes it to be dissolved in the 25ml methyl alcohol, obtains the tartrate methanol solution, slowly drip the tartrate methanol solution under the stirring at room to the Buxine methanol solution, continue to stir evaporated under reduced pressure solvent, 80 ℃ of evaporates to dryness 2 hours 30 minutes, get title compound 340mg, white solid.Optically-active [α]
D 25=30.9.
Embodiment 12
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) tartrate.
Get 0.31 gram (0.77mmol) Buxine, make it to be dissolved in 50% the ethanolic soln of 50ml, obtain in the Buxine ethanol suspension solution, other gets 160mg tartrate and makes it to be dissolved in the ethanolic soln of 25ml 50%, obtains tartrate ethanol suspension solution, and it is molten in Buxine ethanol suspension solution slowly to drip tartrate ethanol suspendible under the stirring at room, continue to stir 2 hours, filter, with the filtrate decompression solvent evaporated, drying, title compound 340mg, white solid.Optically-active [α]
D 25=30.9
Embodiment 13
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) citrate.
Get 0.402g (1.0mmol) Buxine and make it to be dissolved in the 40ml dehydrated alcohol, obtain the Buxine ethanol solution.Other gets the 210mg Citric Acid, make it to be dissolved in the 10ml dehydrated alcohol, to citric acid anhydrous ethanol.Room temperature slowly is added drop-wise to the citric acid anhydrous ethanolic soln in the Buxine ethanol solution under stirring, and continues to stir 2 hours, filters, and with the filtrate decompression evaporate to dryness, placement is spent the night, and obtains precipitation, and 60 ℃ of filtrations get title compound 0.51g white solid.Optically-active [α]
D 25=21.3
Embodiment 14
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
30.31g (0.77mmol) Buxine is got in the preparation of general formula (I) compound (Buxine) aspartate, make it to be dissolved in 50% the ethanolic soln of 50ml, obtain in the Buxine ethanol suspension solution, other gets 210mg L-aspartic acid, make it to be dissolved in the 20ml water, obtain the aspartic acid suspension solution.Slowly drip the aspartic acid suspension solution under the stirring at room in Buxine ethanol suspension solution, continue to stir 2 hours, filter, filtrate decompression solvent evaporated, drying.Get white solid, the Virahol recrystallization with 80% must get title compound white crystals 85mg.Optically-active [α]
D 25=13.1
Embodiment 15
R=OH, R
1=R
2=CH
3, R
3=R
4=NHCH
3The preparation of general formula (I) compound (Buxine) ferulate
Take by weighing the stirring of 402mg (1.0mmol) Buxine and make it to dissolve the 50ml dehydrated alcohol, obtain the Buxine ethanol solution.Other gets 430mg (2.2mmol) forulic acid and is dissolved in the 25ml dehydrated alcohol, filter the forulic acid ethanol solution.Under agitation, in room temperature, the forulic acid ethanolic soln is added drop-wise in the Buxine ethanolic soln, stirred 2 hours, placement is spent the night, and reaction is evaporated to dried.Get title compound 0.6g, little yellow solid.
Embodiment 16,
R '=H, R '
1=CH
3, R '
2=CH
2OH, R '
3=NH
2, R '
4=N (CH
3)
2The preparation of general formula (II) compound hydrochloride
The free alkaloid of this title compound of 20g is added in 80% dehydrated alcohol of 300ml, obtain suspension, under agitation, drip 80% ethanolic soln of 95ml 1mol/L HCL, Buxine all dissolves, continue to stir 30min, add the 0.3g gac, in 80 ℃ of heating 10min, filter, filtrate decompression steams solvent, and obtaining title compound is white solid, gets 9.0g with the propyl carbinol recrystallization.
Embodiment 17,
R '=H, R '
1=CH
3, R '
2=CH
2OH, R '
3=NH
2, R '
4=N (CH
3)
2The preparation of general formula (II) compound tartrate
Get the free alkaloid of this title compound of 0.5g, make it to be dissolved in 50% the ethanolic soln of 50ml, obtain in the Buxine ethanol suspension solution, other gets 160mg tartrate and makes it to be dissolved in the ethanolic soln of 25ml 50%, obtains tartrate ethanol suspension solution.It is molten in Buxine ethanol suspension solution slowly to drip tartrate ethanol suspendible under the stirring at room, continue to stir 2 hours, filters, with filtrate decompression solvent evaporated, drying.Getting title compound is white solid.
Embodiment 18
The preparation of Buxine hydrochloride injection liquid
Get hydrochloric acid Buxine 1g, add injection water 3000ml, stir, make it to dissolve fully, add gac 0.05g, in 80 ℃ of insulation 20min, put and be chilled to 40 ℃, with 0.22 μ m filtering with microporous membrane, water for injection is diluted to 1000ml and regulates PH=5.8 with NaOH solution, with 0.22 μ m filtering with microporous membrane, embedding is sterilized promptly.
Embodiment 19
The preparation of Buxine maleate injection liquid
Get toxilic acid Buxine 1g, add injection water 300ml, stir, make it to dissolve fully, get NaS
2O
30.1g, be dissolved in the 100ml water for injection, toxilic acid Buxine solution and EDTA-2Na solution are mixed.Add gac 0.05g, boil 25min and put and be chilled to 42 ℃, with 0.22 μ m filtering with microporous membrane.Be diluted to 1000ml with water for injection, regulate pH value 5.8,0.22 μ m filtering with microporous membrane with NaOH solution, embedding, 100 ℃ of flowing steam sterilization 30min, promptly.
Embodiment 20
The preparation of Buxine succinate injection liquid
Get succsinic acid Buxine 1g, add injection water 300ml, stirring makes it to dissolve fully, get EDTA-2Na0.05g, be dissolved in the 100ml water for injection, succsinic acid Buxine solution and EDTA-2Na solution are mixed, add gac 0.05g in 85 ℃ of insulation 20min, put and be chilled to 40 ℃, with 0.22 μ m filtering with microporous membrane, water for injection is diluted to 1000ml, regulates PH=6.0 with NaOH solution, filter with 0.22 μ m filtering with microporous membrane, embedding, sterilization are promptly.
Embodiment 21
The preparation of Buxine aspartic acid saline injection
Get aspartic acid Buxine 1g, add injection water 300ml, stir, make it perfect solution.Add gac 0.1g, be heated to 85 ℃, insulation 25min is put cold 40 ℃, 0.22 μ m filtering with microporous membrane, and filtrate adds injection and is diluted with water to 1000ml, regulates pH value to 6.1,0.22 μ m filtering with microporous membrane, embedding, inflated with nitrogen seals, and sterilization is promptly.
Embodiment 22
N.F,USP MANNITOL 50g is got in the preparation of Buxine hydrochloride lyophilized injectable powder, is dissolved in 1000ml water for injection, and other gets hydrochloric acid Buxine 1g, be dissolved in the 300ml water for injection, stir, make it to dissolve fully, two solution are mixed the adding gac, and 0.05g is in 80 ℃ of insulation 30min, place 40 ℃, 0.22 μ m filtering with microporous membrane, water for injection is diluted to 2000ml, regulate pH value to 5.8 with NaOH solution, 0.22 μ m filtering with microporous membrane, packing (2ml/ props up), freeze-drying is promptly.
Embodiment 23
The preparation of Buxine maleate lyophilized injectable powder
Get low molecular dextran 25g, be dissolved in the 500ml water for injection, other gets toxilic acid Buxine 1g, is dissolved in the 500ml water for injection, stir, make it to dissolve fully, two solution are mixed, add gac 0.05g, boil 30min, put and be chilled to 45 ℃, 0.22 μ m filtering with microporous membrane.Water for injection is diluted to 2000ml, regulates PH=5.60 with NaOH solution, and with 22 μ m filtering with microporous membrane, freeze-drying promptly in packing (2ml/ only).
Embodiment 24
Lactose 20g is got in the preparation of Buxine aspartic acid salt freeze-dried powder-injection, be dissolved in the 500ml water for injection, other gets aspartic acid Buxine 1g, is dissolved in stirring in the 500ml water for injection making it dissolving, and two solution are mixed, add gac 0.05g, boil 30min, put and be chilled to 40 ℃, with 0.22 μ m filtering with microporous membrane, packing (2ml/ props up), freeze-drying promptly.
Embodiment 25
Buxine hydrochloride 10mg is got in the preparation of Buxine hydrochloride transfusion, adds the proper amount of water for injection dissolving, and other gets sodium-chlor, adds the proper amount of water for injection dissolving.With sodium-chlor Buxine hydrochloric acid soln, add an amount of water for injection to requirement, tame gac 0.05% (w/v) is in 80 ℃, and heating 30min uses G
4Funnel filters, and filtrate is transferred PH=4.6-6.5, and 0.22 μ m filtering with microporous membrane is clarification extremely, embedding, and every bottle of 100ml is with 112 degree pressure sterilizing 30min promptly.
Embodiment 26
The preparation of Buxine fumarate transfusion
Get fumaric acid Buxine 20mg, be dissolved in an amount of water for injection, other gets glucose 50g, is dissolved in merging two solution in an amount of water for injection, add to required with water for injection, add gac 0.15% (w/v) stirring and boil 30min, filter, filtrate is transferred PH=4.6-6.5, with the extremely clarification of 0.22 μ m filtering with microporous membrane, every bottle of 100ml of embedding is with 110 ℃ of pressure sterilizing 30min, promptly.
Embodiment 27
The capsular preparation of Buxine hydrochloride
Preparation 5%PVP50% ethanolic soln 10ml, getting Buxine hydrochloride 0.59g adds among the 5%PVP% ethanolic soln 10ml, stirring and dissolving, take by weighing starch 20g, Icing Sugar 30g, Microcrystalline Cellulose 50g, 5 usefulness %PVP% ethanolic soln 10ml make softwood, cross 20 mesh sieves, 60 ℃ of oven dry, the whole grain of 20 mesh sieves, encapsulated, promptly.
Embodiment 28
The capsular preparation of Buxine fumarate
Preparation 5%PVP aqueous solution 8ml gets Buxine fumarate 0.59g and adds among the 5%PVP aqueous solution 8ml, and stirring and dissolving takes by weighing Icing Sugar 30g, Microcrystalline Cellulose 30g, the low 50g of replacement, and 5%PVP aqueous solution 10ml makes softwood.Cross 20 mesh sieves, 60 ℃ of oven dry, whole grain, encapsulated, promptly.
Embodiment 29
The capsular preparation of Buxine aspartate
Configuration 2%PVP80% ethanolic soln, getting Buxine aspartate 0.5g adds among the 2%PVP80% alcoholic solution 8ml, stirring and dissolving claims Microcrystalline Cellulose 50g, the low 40g of replacement of sodium starch glycolate 20g, pregelatinized Starch 30g, and 8ml makes softwood with the 2%PVP80% ethanolic soln.Cross 20 mesh sieves, 60 ℃ of oven dry, the whole grain of 20 mesh sieves, encapsulated, promptly.
Embodiment 30
The preparation of Buxine hydrochloride tablet:
Take by weighing Buxine hydrochloride 0.5g, starch 50g, Microcrystalline Cellulose 50g, mix, make softwood, cross 18 mesh sieves with the 3%PVP70% ethanolic soln by the equivalent incremental method, 60 ℃ of oven dry, the whole grain of 16 orders, the recessed stamping of 60mm is promptly.
Embodiment 31
The preparation of Buxine succinate tablet
Take by weighing Buxine succinate 0.5g, lactose 70g, ethyl cellulose 30g, mix, make softwood, cross 18 mesh sieves with the 1%PVP50% ethanolic soln by the equivalent incremental method, 60 ℃ of oven dry, the whole grain of 16 orders, the recessed stamping of 60mm is promptly.
Embodiment 32
The preparation of Buxine aspartic acid salt tablets
Be mixed with the 1%PVP50% ethanolic soln, get Buxine aspartate 0.5g, add in the 1%PVP50% ethanolic soln, stir and make it dissolving, take by weighing lactose 70g, gram micropowder silica gel 30g, be mixed, make soft, cross 20 mesh sieves with the 1%PVP50% ethanol liquid that contains the Buxine aspartate, 65 ℃ of oven dry, the whole grain of 20 mesh sieves adds Magnesium Stearate, and the flat stamping of 5.5mm promptly gets makes 1000.
Embodiment 33
The preparation of Buxine maleate tablet
Take by weighing hydroxypropylcellulose 75g, glycolic acid Starch Sodium 50g, lactose 145g, aspartame 1g, mint flavouring 30g, cross 80 mesh sieves, mix, increase progressively addition with equivalent and add Buxine toxilic acid 5g, mix, cross 100 mesh sieves from branch, for several times, gained direct powder compression.
Claims (17)
1, general formula (I) and (II) steroid alkaloid water-soluble salt,
General formula (I)
General formula (II)
Its formula of (I) is singly-bound between 6,7, R=H or OH, R
1=CH
3Or H, R
2=CH
3Or H or CH
2OH, R
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R
4==O or NH
2Or NHCH
3Or N (CH
3)
2,
Or be two keys between 6,7, R=H or OH, R
1=CH
3, R
2=CH
2OH, R
3=R
4=NH
2Or NHCH
3Or N (CH
3)
2, or
General formula (II), R '=H or OH, R '
1=CH
3Or H, R '
2=CH
3Or H or CH
2OH, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2,
M is mineral acid, organic acid or amino acid, and wherein mineral acid is selected from: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Organic acid is selected from: acetic acid, oxalic acid, fumaric acid, toxilic acid, succsinic acid, tartrate, Citric Acid, lactic acid, forulic acid; Amino acid is selected from: Methionin, aspartic acid.
2, according to the described water-soluble salt of claim 1, be singly-bound between 6,7 in its formula of (I) compound, R=H or OH, R
1=R
2=CH
3, R
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R
4=NH
2Or NHCH
3Or N (CH
3)
2, wherein M as defined in claim 1.
3, according to the described water-soluble salt of claim 1, be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=CH
3, R
2=H; R
3=NHCH
3, R
4=N (CH
3)
2, wherein M as defined in claim 1.
4, according to the described water-soluble salt of claim 1, be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=CH
2OH, R
2=H, R
3=NH
2, R
4=NH
2, wherein M such as in 1 definition.
5, according to the described water-soluble salt of claim 1, be singly-bound between 6,7 in its formula of (I) compound, R=OH, R
1=H, R
2=CH
3, R
3=NHCH
3, R
4=O, wherein M such as in 1 definition.
6, according to the described water-soluble salt of claim 1,6,7 positions are two keys in its formula of (I) compound, R=H or OH, R
1=CH
3, R
2=CH
2OH, R
3=R
4=N (CH
3)
2, wherein M as defined in claim 1.
7, according to the described water-soluble salt of claim 2, be singly-bound between 6,7 in its formula of (I) compound, R=OH or H, R
1=R
2=CH
3, R
3=R
4=NH
2Or NHCH
3Or N (CH
3)
2, wherein M as defined in claim 1.
8, according to the described water-soluble salt of claim 1, R '=H or OH in its formula of (II) compound, R '
1=R '
2=CH
3, R '
3==O or NH
2Or NHCH
3Or N (CH
3)
2, R '
4=NH
2Or NHCH
3Or N (CH
3)
2, wherein M as defined in claim 1.
9, according to the described water-soluble salt of claim 1, R '=H in its formula of (II) compound, R '
1=CH
3, R '
2=CH
2OH, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2, wherein M as defined in claim 1.
10, according to the described water-soluble salt of claim 1, R '=R ' in its formula of (II) compound
1=H, R '
2=CH
2OH, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2, wherein M as defined in claim 1.
11, according to the described water-soluble salt of claim 1, R '=OH in its formula of (II) compound, R '
1=H, R '
2=CH
2OH, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2, wherein M as defined in claim 1.
12, described according to Claim 8 water-soluble salt, R '=OH or H in its formula of (II) compound, R '
1=CH
3, R '
2=CH
3, R '
3=R '
4=NH
2Or NHCH
3Or N (CH
3)
2, wherein M as defined in claim 1.
13, according to the described water-soluble salt of claim 9, R '=H in its formula of (II) compound, R '
1=CH
3, R '
2=CH
2OH, R '
3=NH
2, R '
4=N (CH
3)
2, wherein M is by being defined in the claim 1.
14, pharmaceutical composition wherein contains a kind of according to claims 1-13 described general formula of described arbitrary claim (I) and/or general formula (II) steroid alkaloid water-soluble salt and pharmaceutical carrier or vehicle at least.
15, according to the described pharmaceutical composition of claim 14, it can be tablet, capsule, granule, injection, transfusion, lyophilized injectable powder.
16, according to the described general formula of the arbitrary claim of claim 1-13 (I) and (II) the steroid alkaloid water-soluble salt in the purposes aspect preparation treatment coronary heart disease, stenocardia, premature ventricular beat, the immunodeficiency type medicine for treating viral infections.
17, according to the described general formula of the arbitrary claim of claim 1-13 (I) and (II) preparation method of steroid alkaloid water-soluble salt, it comprises: with general formula (I) or (II) free alkaloid water or alcohol or the water and the pure solution dissolving of compound, drip the solution dissolved acid solution of water or alcohol or water and alcohol, stirred 0.5-3 hour, temperature is that 20-80 ℃, decolouring, filtration or underpressure distillation steam solvent, recrystallization, promptly get product, wherein alcohol is: methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, acid is by M and as in the claim 1 M being defined.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 00129507 CN1118473C (en) | 2000-09-29 | 2000-09-29 | Aqueous soluble steroid compound alkaloid salt, preparation process and medicinal composition containing same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 00129507 CN1118473C (en) | 2000-09-29 | 2000-09-29 | Aqueous soluble steroid compound alkaloid salt, preparation process and medicinal composition containing same |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1345727A true CN1345727A (en) | 2002-04-24 |
CN1118473C CN1118473C (en) | 2003-08-20 |
Family
ID=4593548
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 00129507 Expired - Fee Related CN1118473C (en) | 2000-09-29 | 2000-09-29 | Aqueous soluble steroid compound alkaloid salt, preparation process and medicinal composition containing same |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1118473C (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018076568A1 (en) * | 2016-10-25 | 2018-05-03 | 合肥合源药业有限公司 | Cycloartane tetracyclic triterpenoid compound, preparation method therefor and use thereof |
CN110105561A (en) * | 2016-06-22 | 2019-08-09 | 中国药科大学 | A kind of tanshinone IIA high-molecular compound and its preparation and application |
-
2000
- 2000-09-29 CN CN 00129507 patent/CN1118473C/en not_active Expired - Fee Related
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110105561A (en) * | 2016-06-22 | 2019-08-09 | 中国药科大学 | A kind of tanshinone IIA high-molecular compound and its preparation and application |
WO2018076568A1 (en) * | 2016-10-25 | 2018-05-03 | 合肥合源药业有限公司 | Cycloartane tetracyclic triterpenoid compound, preparation method therefor and use thereof |
CN110177555A (en) * | 2016-10-25 | 2019-08-27 | 合肥合源药业有限公司 | Cycloartane tetracyclic triterpenoid, Its Preparation Method And Use |
US10568892B2 (en) * | 2016-10-25 | 2020-02-25 | Hefei Cosource Pharmaceuticals Inc. | Cycloartane tetracyclic triterpenoid compound, preparation method therefor and use thereof |
CN110177555B (en) * | 2016-10-25 | 2022-09-30 | 合肥合源药业有限公司 | Cyclobornane tetracyclic triterpenoid compound, preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN1118473C (en) | 2003-08-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1358184A (en) | New medicine | |
CN1084408A (en) | Cyclic adhesion inhibitors | |
CN1615133A (en) | Crystalline solids of carvedilol and processes for their preparation | |
CN1505614A (en) | Process for making amlodipine maleate | |
CN1792362A (en) | Intravenous administration preparation of arbidol and salt thereof and preparation method | |
FR2650504A1 (en) | HYDROCHLORIDE MONOHYDRATE OF 6-BROMO-5-HYDROXY-4-DIMETHYLAMINOMETHYL-1-METHYL-2-PHENYLTHIOMETHYLINDOLE-3-CARBONIC ACID ETHYL ETHER, PROCESS FOR OBTAINING THE SAME, AND ANTIVIRAL MEDICINAL PRODUCT COMPRISING THE SAME | |
CN1210469A (en) | Mixtures derived from eugenia jambolana lamarck, preparation and use of said mixtures and some of their constituents as medicaments | |
CN1245398C (en) | Extraction technology of baicalein, medicinal composition and preparation technology of medicine | |
CN1296052C (en) | Non-injection preparation containing medium and/or low molecular weight chondroitin sulfate | |
CN101074189A (en) | Styrene acid derivative and use in preparation of various blood-vessels target agent medicine | |
CN1118473C (en) | Aqueous soluble steroid compound alkaloid salt, preparation process and medicinal composition containing same | |
CN1225464C (en) | Extraction technology of Hanbaicalein, medicinal composition and preparation technology of medicine | |
CN1915986A (en) | High purified tanshinone IIA sodium sulfonate, fabricating method, and preparation | |
CN1256090C (en) | Application in antidepressants preparation of asiatic acid and derivation | |
CN1568960A (en) | High purity chlorogenic acid prescription | |
CN1726221A (en) | Process for producing hop glume polyphenol | |
CN1826318A (en) | Stable modifications of tegaserod hydrogen maleate | |
EP2996688A1 (en) | Composition comprising a complex of (+)-catechin and amino acid for the treatment and prevention of cancer | |
RU2256451C1 (en) | Medicinal agent for treatment of atypical pneumonia | |
CN113214207A (en) | Hesperetin and betaine eutectic compound A, preparation method, composition and application thereof | |
CN1438225A (en) | Ginger-yellow pigment metal-ion complex, its preparation method and use | |
CN1723030A (en) | Remedies or preventing for allergic diseases comprising processed peanut seed coat | |
CN1903869A (en) | Tibifudine derivative salt and its preparation method and pharmaceutical application | |
CN1887906A (en) | Hypoglycemic polypeptide from silkworm and its prepn and use | |
CN113214206B (en) | Hesperetin and betaine eutectic substance B, preparation method, composition and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C06 | Publication | ||
PB01 | Publication | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee |
Owner name: SHANDONG LUYE PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME OR ADDRESS: SHANDONG GREEN LEAF PHARMACEUTICAL CO., LTD. |
|
CP01 | Change in the name or title of a patent holder |
Address after: 264003, No. 9, Po Yuen Road, Laishan District, Shandong, Yantai Patentee after: Shandong Luye Pharma Co., Ltd. Address before: 264003, No. 9, Po Yuen Road, Laishan District, Shandong, Yantai Patentee before: Luye Pharmaceutical Co., Ltd., Shandong |
|
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |