CN107198683A - A kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition and its production and use - Google Patents
A kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition and its production and use Download PDFInfo
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- CN107198683A CN107198683A CN201710453014.2A CN201710453014A CN107198683A CN 107198683 A CN107198683 A CN 107198683A CN 201710453014 A CN201710453014 A CN 201710453014A CN 107198683 A CN107198683 A CN 107198683A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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Abstract
A kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition and its production and use, described pharmaceutical composition is made up of farnesylacetic acid spiceleaf alcohol ester active component and pharmaceutically acceptable carrier, and the farnesylacetic acid spiceleaf alcohol ester active component is no more than 2% (4Z/8E) farnesylacetic acid spiceleaf alcohol ester containing (4E/8E) farnesylacetic acid spiceleaf alcohol ester and by active component gross weight meter；Described pharmaceutical composition has the advantages that toxicity is low, peptic ulcer protective effect is strong, relative bioavailability is high.
Description
Technical field
The present invention relates to a kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition and its production and use.
Background technology
Farnesylacetic acid spiceleaf alcohol ester is gefarnate, and trade name favour is strengthened, and is that flourish foster medicine strain formula meeting is shaken in Osaka, Japan life
The isoprene class compound gastric mucosa protective agent of society's production, is mainly used in acute or chronic gastritis, peptic ulcer, non-ulcerative
Acute gastric mucosal injury caused by dyspeptic treatment and prevention other factors.Its pharmacological action is by increasing before endogenous
Mucosa for Protective Effect is played in the generation of row parathyrine.Promote to burst in addition, farnesylacetic acid spiceleaf alcohol ester can improve aminohexose content
Ulcer healing；Suppress neutrophil leucocyte and monocyte infiltration and relevant inflammatory factors release, so as to mitigate gastric mucosa tissue
The inflammatory reactions such as hyperemia, oedema, erosion.Except in addition to the application in terms of gastric mucosa, also having pertinent literature to report method both at home and abroad
Guanidine-acetic acid spiceleaf alcohol ester is in colitis, the application of dry eye treatment.
Farnesylacetic acid spiceleaf alcohol ester is initially isolated by cabbage, and later adami et al. is obtained by synthetic method,
Structural formula is as indicated with 1.Commercially available farnesylacetic acid spiceleaf alcohol ester is the mixture of two kinds of geometric isomers, be respectively (4E/8E)-
The farnesylacetic acid spiceleaf alcohol ester [trienic acids of (4E, 8E)-5,9,13- trimethyls-4,8,12- 14-(2 ' E)-3 ', 7 '-diformazan
Base -2 ', 6 '-octadiene alcohol ester] and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester [(4Z, 8E) -5,9,13- trimethyl -4,8,
The trienic acids of 12- 14-(2 ' E)-3 ', 7 '-dimethyl-2 ', 6 '-octadiene alcohol ester], both proportion of composing Japanese Pharmacopoeia requirements
It is 70%~80% to 20%~30%, as a result the extracted rear gas chromatography analysis of marketed tablet shows the two proportion
Respectively 70% and 30%.
Existing gefarnate medicine still suffers from more as toxicity is higher, Relative biological is utilized in terms of disease of digestive system is treated
The problem of spending low.
The content of the invention
The purpose of the present invention is toxicity height, the peptic ulcer protective effect existed for gefarnate medicine in the prior art
It is weak, there is provided a kind of new farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition, its preparation side the problem of relative bioavailability is low
Method, purposes and formulation, so as to provide the method that a kind of toxicity is low, peptic ulcer protective effect is strong, relative bioavailability is high
Guanidine-acetic acid spiceleaf alcohol ester pharmaceutical composition.
To achieve these goals, the present invention provides following technical scheme：
The present invention provides a kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition, it is characterised in that described pharmaceutical composition
It is made up of farnesylacetic acid spiceleaf alcohol ester active component and pharmaceutically acceptable carrier, and the farnesylacetic acid geraniol
Ester active component containing (4E/8E)-farnesylacetic acid spiceleaf alcohol ester and by active component gross weight meter no more than 2% (4Z/8E)-
Farnesylacetic acid spiceleaf alcohol ester；Preferably, the content of described (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester is 0.1~1%.
(4E/8E)-farnesylacetic acid spiceleaf alcohol ester of the present invention, chemistry entitled [(4E, 8E) -5,9,13- trimethyls
- 4,8,12- ten four trienic acid-(2 ' E) -3 ', 7 '-dimethyl -2 ', 6 '-octadiene alcohol ester], its chemical structural formula is as shown in 2：
(4Z/8E)-farnesylacetic acid spiceleaf alcohol ester of the present invention, chemistry entitled [(4Z, 8E) -5,9,13- trimethyls
- 4,8,12- ten four trienic acid-(2 ' E) -3 ', 7 '-dimethyl -2 ', 6 '-octadiene alcohol ester], its chemical structural formula is as shown in 3：
Alternatively, above-mentioned pharmaceutical composition, it is characterised in that the farnesylacetic acid spiceleaf alcohol ester active component and medicine
The percentage by weight of acceptable carrier is 1 on:19~3:7, preferably 1:10~1:4.
Alternatively, above-mentioned pharmaceutical composition, it is characterised in that the pharmaceutically acceptable carrier include diluent,
One or more in excipient, adhesive, filler, disintegrant, flavouring agent, sweetener.
Alternatively, above-mentioned pharmaceutical composition, it is characterised in that described pharmaceutical composition include starch, microcrystalline cellulose,
One or more in magnesium stearate, Almasilate, calcium monohydrogen phosphate, vegetable oil, beeswax, gelatin polyethylene glycol, glycerine.
Alternatively, the formulation of above-mentioned pharmaceutical composition includes granula, pulvis, tablet, capsule, syrup, suppository, injection
Agent, emulsion, tincture, suspension, the form oral or non-oral administration formulation of solution.
Preferably, the formulation includes tablet, capsule, dripping pill.
The present invention also provides the method for preparing above-mentioned pharmaceutical composition, it is characterised in that including farnesylacetic acid is fragrant
The step of leaf-alcohol ester active component is mixed with pharmaceutically acceptable carrier, the wherein preparation process of farnesylacetic acid spiceleaf alcohol ester
Middle use L-Aspartic acid is used as catalyst.
Alternatively, above-mentioned method, it is characterised in that comprise the following steps：
(1) using trans nerolidol and ortho-acetate as raw material, L-Aspartic acid is catalyst, is reset through Claisen anti-
Farnesylacetic acid ester should be obtained；
(2) farnesylacetic acid ester hydrolysis, crystallization, acidifying are obtained into farnesylacetic acid；
(3) farnesylacetic acid and geraniol are condensed to yield farnesylacetic acid spiceleaf alcohol ester active component；
(4) farnesylacetic acid spiceleaf alcohol ester active component and pharmaceutically acceptable carrier are mixed to prepare the medicine group
Compound.
Alternatively, above-mentioned method, it is characterised in that comprise the following steps：
(1) using trans nerolidol and ortho-acetate as raw material, L-Aspartic acid is catalyst, is entered at 90~150 DEG C
Row reaction, is cooled to 60~90 DEG C of vacuum distillations, is warming up to 90~130 DEG C of vacuum distillations, obtains farnesylacetic acid ester；
(2) farnesylacetic acid ester is mixed into generation hydrolysis with alkali, reaction solution is extracted with organic solvent (preferably petroleum ether)
Take, adjust reaction solution pH to 3~4, organic solvent extraction merges organic phase, plus alkali, concentration, add organic solvent (preferred acetic acid second
Ester), filtering, filter cake adds water and adjusts pH to 3~4, and organic solvent (preferably petroleum ether) extraction merges organic phase, saturated aqueous common salt
Washing, dry farnesylacetic acid；
(3) by farnesylacetic acid, geraniol, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC-
HCl), DMAP (DMAP) hybrid reaction, water, saturated common salt water washing are used by reaction solution respectively, are dried, and cross silicon
Silica gel is crossed in glue, concentration, vacuum distillation, is dried, and the farnesylacetic acid spiceleaf alcohol ester active component is made；
(4) farnesylacetic acid spiceleaf alcohol ester active component and pharmaceutically acceptable carrier are mixed to prepare the medicine group
Compound.
Alternatively, the synthetic route of above-mentioned preparation method is as shown in Figure 8：
The present invention also provides above-mentioned pharmaceutical composition and is preparing the purposes in treating or preventing disease of digestive system medicine.
The present invention also provides purposes of the above-mentioned pharmaceutical composition in disease of digestive system is treated or prevented.
Alternatively, the disease of digestive system includes acute and chronic gastritis mucosa injury；Alternatively, the disease of digestive system bag
Include acute or chronic gastritis, peptic ulcer, non-ulcer dyspepsia.
The application method of pharmaceutical composition of the present invention has no particular limits, for example, can be applied by oral way
Patient for needing this treatment.
Pharmaceutically acceptable carrier of the present invention refers to the conventional carrier of pharmaceutical field, including various excipient and dilute
Release agent.The term refers to some such medicament carriers：Themselves it is not necessary active component, and does not have undue after administration
Toxicity.Suitable carrier is well known to those of ordinary skill in the art.In Remington's Pharmaceutical
Discussing fully on pharmaceutically acceptable excipient can be found in Sciences (Mack Pub.Co., N.J.1991).
The upper acceptable carrier of combination of traditional Chinese medicine may include liquid, such as water, salt solution, glycerine and ethanol.In addition, may be used also in these carriers
There is complementary material, for example：Adhesive such as starch, dextrin, sucrose, cellulose derivative, gelatin, polyethylene glycol, poly-
Vinylpyrrolidone etc.；Filler for example lactose, microcrystalline cellulose, calcium dihydrogen phosphate, calcium monohydrogen phosphate, calcium sulfate, calcium silicates carbonic acid
Magnesium, Almasilate, Hydrotalcite, superfine silica gel powder etc.；Disintegrant for example sodium carboxymethyl starch, PVPP, carboxymethyl cellulose,
Calcium carbonate, sodium acid carbonate etc.；Furthermore it is also possible to add in the composition other adjuvants for example flavouring agent, sweetener, wetting agent,
Emulsifying agent, pH buffer substance etc..
Beneficial effects of the present invention：
Farnesylacetic acid is fragrant in specific farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention, described pharmaceutical composition
2% is no more than by weight of active ingredient (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester in leaf-alcohol ester active component, with toxicity
The low, advantage that peptic ulcer protective effect is strong, relative bioavailability is high.
When the content of (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester is 0.1%~1.0%, with (4Z/8E)-farnesyl- second
Sour geraniol ester content is compared when being less than 0.1%, the toxicity of described pharmaceutical composition is lower, peptic ulcer protective effect more
By force, relative bioavailability is higher, with unexpected technique effect.
Brief description of the drawings
Fig. 1 is the protective effect photo that farnesylacetic acid spiceleaf alcohol ester causes rat acute mucosal lesion to absolute ethyl alcohol,
Wherein：A is normal group；B is model group；C is (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；D is gefarnate treatment group；
E is farnesylacetic acid spiceleaf alcohol ester medicine composite for curing group of the present invention；F is Lansoprazole control group.
Fig. 2 is that farnesylacetic acid spiceleaf alcohol ester causes rat acute mucosal lesion ulcer area to absolute ethyl alcohol than statistics post
Shape figure, wherein：Model is model group；4Z is (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；Gefarnate is lucky method
Ester treatment group, 4E is farnesylacetic acid spiceleaf alcohol ester medicine composite for curing group of the invention；Lansoprazole is Lan Suola
Azoles randomized controlled treatment group, * represented compared with model group, p<0.05.
Fig. 3 is that farnesylacetic acid spiceleaf alcohol ester causes rat acute mucosal lesion ulcer inhibition rate to count post absolute ethyl alcohol
Shape figure, wherein：4Z is (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；Gefarnate is gefarnate treatment group, and 4E is this
The farnesylacetic acid spiceleaf alcohol ester medicine composite for curing group of invention；Lansoprazole is Lansoprazole randomized controlled treatment group. *
Represent compared with model group, p<0.05.
Fig. 4 is rat stomach tissue pathologies change figure under light microscopic, wherein：A is normal group；B is model group；C is (4Z/
8E)-farnesylacetic acid spiceleaf alcohol ester treatment group；D is gefarnate treatment group；E is farnesylacetic acid spiceleaf alcohol ester medicine of the invention
Compositions treatment group；F is Lansoprazole randomized controlled treatment group.
Fig. 5 is cylindricality of the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition to rat gastric ulcer inhibiting rate of different purity
Figure, wherein：Ordinate is inhibiting rate, and abscissa is the farnesylacetic acid of different content (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester
Spiceleaf alcohol ester pharmaceutical composition.
Fig. 6 is influence cylindricality of the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of different purity to rat gastric ulcer area
Figure, wherein：Ordinate is gastric ulcer area ratio, and abscissa is the method for different content (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester
Guanidine-acetic acid spiceleaf alcohol ester pharmaceutical composition.
Fig. 7 is drug concentration versus time curve after farnesylacetic acid spiceleaf alcohol ester gastric infusion, wherein：4E is this
The farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition group of invention；Gefarnate is gefarnate group；4Z is (4Z/8E)-farnesyl- second
Sour spiceleaf alcohol ester treatment group.
Fig. 8 is the synthetic route chart of (4E/8E)-farnesylacetic acid spiceleaf alcohol ester, wherein, aspartic acid are L- days
Winter propylhomoserin.
Embodiment
The embodiment to the present invention is described in detail below.It should be appreciated that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to limit the invention.
(1) preparation of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
Farnesylacetic acid spiceleaf alcohol ester in following embodiments in obtained farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
The content of active component is obtained by gas chromatography detection；Geometric configuration is normal by the coupling of gas chromatography and nuclear magnetic resonance
Numerical value is determined.
Embodiment 1
1) synthesis of farnesylacetic acid ethyl ester
Trans nerolidol 500g (2.25mol), triethly orthoacetate 546g (3.37 are sequentially added in 2L round-bottomed flasks
Mol), L-Aspartic acid 30g (0.22mol), is heated to 120 DEG C and is reacted.TLC (petroleum ethers:Ethyl acetate=30:1) supervise
Reaction process is surveyed, is stopped when reacting complete to trans nerolidol.Reaction temperature is set to be down to 80 DEG C, decompression is steamed in reaction and generated
Coproduct ethanol；Then heat to 120 DEG C, decompression steam unreacted triethly orthoacetate, obtain farnesylacetic acid ethyl ester
520g, yield 80%.
2) preparation of farnesylacetic acid
Addition method ethyl 480g (1.6 0mol), sodium hydroxide 70.4g (1.76 in 5000ml round-bottomed flasks
Mol), water 480ml, ethanol 960ml, are stirred overnight at room temperature, and obtain yellow clear liquid.Stop reaction, use 800ml petroleum ethers
Extractive reaction liquid 3 times.Reaction solution adjusts pH to 3~4 with concentrated hydrochloric acid, then uses 320ml petroleum ether extractions, is extracted twice, and merges stone
Oily ether layer is washed 3 times, and anhydrous sodium sulfate drying is evaporated to obtain 404.8g yellow, clear grease, yield 96.1%.
Obtained grease farnesylacetic acid 396g (1.5mol), potassium hydroxide 82. are added in 3000ml round-bottomed flasks
5g (1.5mol), methanol 1000ml, are stirred at room temperature 1h and obtain yellow clear liquid, stop stirring, reaction solution is concentrated to dryness, plus
Enter 2000mL ethyl acetate, stir 2h, separate out white solid, suction filtration, filter cake 1000mL water dissolves, and adjusts pH extremely with concentrated hydrochloric acid
3~4,1000ml petroleum ether extractions are then used, are extracted twice, merge petroleum ether layer, are washed 1 time with saturated common salt, anhydrous slufuric acid
Sodium is dried, be evaporated 249g is faint yellow, clear grease, i.e. farnesylacetic acid, yield 63%.
3) preparation of farnesylacetic acid spiceleaf alcohol ester active component
Farnesylacetic acid 185g (0.7mol) obtained above, geraniol 107g are added in 5000ml round-bottomed flasks
(0.71mol), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC-HCl) 151g (0.83mol), DMAP
12.2g (0.1mol) dichloromethane 2000ml, is stirred at room temperature reaction, raw material reaction is complete during TLC monitoring about 6h, stops reaction,
Reaction solution washed once with water, saturated aqueous common salt respectively, dry, and cross silica gel, be concentrated to give light yellow, clarification, transparent oily liquid；
The grease through vacuum distillation remove impurity, again cross silica gel remove origin at impurity, be evaporated colourless, clarification, transparent, oily
Thing farnesylacetic acid spiceleaf alcohol ester active component 229g, yield 82%, ((the 4Z/8E)-farnesylacetic acid spiceleaf of purity 99.5%
Alcohol ester content is 0.3%) [gas chromatography：GC-14B gas chromatographs (Japanese Shimadzu), SE-54 posts (0.53mm × 30m),
Column temperature：30 DEG C/min-160 DEG C of 80 DEG C (5min) (3min) 30 DEG C/min-260 DEG C 250 DEG C of (20min) injection port, detector
260 DEG C, nitrogen flow rate 20ml/min].
4) preparation of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
(1) farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition 1
Composition is：
Exemplified by preparing 1000 farnesylacetic acid spiceleaf alcohol ester medicinal composition tablets, specific preparation method is：Will place
The above-mentioned farnesylacetic acid spiceleaf alcohol ester active component of side's amount is dissolved in absolute ethyl alcohol, and calcium monohydrogen phosphate is pressed after being mixed with Almasilate
Farnesylacetic acid spiceleaf alcohol ester ethanol solution is added according to equal increments method, after fully mixing, plus starch stirs, and is formed sediment with 15%
Softwood is made in slurry, and granulation, drying, whole grain add recipe quantity microcrystalline cellulose, magnesium stearate, talcum powder, pressure into particle
Piece, is coated with 8% Opadry ethanol solution.
(2) farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition 2
Composition is：
Exemplified by preparing 1000 farnesylacetic acid spiceleaf alcohol ester medicinal composition soft capsules, specific preparation method is：Claim
The above-mentioned farnesylacetic acid spiceleaf alcohol ester active component of recipe quantity is taken to be dissolved in the soybean oil of equivalent, stirring makes it fully mix,
The soybean oil for adding remaining recipe quantity is well mixed, and is ground three times by colloid mill, vacuum outgas steep 2 hours it is standby.Weigh place
The gelatin of side's amount, is fully swelled with the water of recipe quantity 80%.By glycerine and the water of surplus, 70 DEG C are heated to, gelatin solution is added,
1.5 hours, addition titanium dioxide uniform to melting of stirring, stirs.Made glue is put into incubator, and temperature is maintained at 80
Film is suppressed between~90 DEG C.Film and content decoction are pressed into soft capsule by automatic rotary transformation of ownership capsule machine, it is setting, whole
Shape, shampooing ball, drying, packaging.
Embodiment 2
1) synthesis of farnesylacetic acid methyl esters
Trans nerolidol 400g (1.80mol), trimethyl orthoacetate 324g (2.70 are sequentially added in 2L round-bottomed flasks
Mol), L-Aspartic acid 24g (0.18mol), is heated to 100 DEG C and is reacted.TLC (petroleum ethers:Ethyl acetate=30:1) supervise
Reaction process is surveyed, is stopped when reacting complete to trans nerolidol.Reaction temperature is set to be down to 70 DEG C, decompression is steamed in reaction and generated
Coproduct ethanol；Then heat to 100 DEG C, decompression steam unreacted triethly orthoacetate, obtain farnesylacetic acid methyl esters
425g, yield 85%.
2) preparation of farnesylacetic acid
Addition method acetic acid methyl ester 50g (0.18mol), sodium hydroxide 7.9g (0.20 in 250ml round-bottomed flasks
Mol), water 50ml, ethanol 100ml, are stirred overnight at room temperature, and obtain orange clear liquid.Stop reaction, extracted with 100ml petroleum ethers
Extract reaction solution 3 times.Reaction solution adjusts pH to 3~4 with concentrated hydrochloric acid, then uses 100ml petroleum ether extractions, is extracted twice, and merges oil
Ether layer is washed 3 times, and anhydrous sodium sulfate drying is evaporated to obtain 45.2g yellow, clear grease, i.e. farnesylacetic acid, yield
95.2%.
Obtained farnesylacetic acid 26g (0.10mol), potassium hydroxide 5.5g (0.1 are added in 250ml round-bottomed flasks
Mol), methanol 80ml, is stirred at room temperature 1h and obtains yellow clear liquid, stop stirring, reaction solution is concentrated to dryness, add 150mL
Ethyl acetate, stirs 2h, separates out white solid, suction filtration, filter cake 80mL water dissolves, and adjusts pH to 3~4 with concentrated hydrochloric acid, then
80ml petroleum ether extractions are used, are extracted twice, merge petroleum ether layer, are washed 1 time with saturated common salt, anhydrous sodium sulfate drying is evaporated
15.6g is faint yellow, clear grease, i.e. farnesylacetic acid, yield 60%.
3) preparation of farnesylacetic acid spiceleaf alcohol ester active component
Farnesylacetic acid 12.3g (0.05mol) obtained above, geraniol 7.1g are added in 250ml round-bottomed flasks
(0.047mol), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC-HCl) 10.1g (0.055mol),
DMAP 1.22g (0.01mol) dichloromethane 100ml, is stirred at room temperature reaction, raw material reaction is complete during TLC monitoring about 5h, stops
Reaction, reaction solution washed once with water, saturated aqueous common salt respectively, dry, and cross silica gel, be concentrated to give light yellow, clarification, clear oil
Liquid；The grease removes impurity through vacuum distillation, and silica gel is crossed again and removes impurity at origin, is evaporated colourless, clarifies, thoroughly
Bright, grease farnesylacetic acid spiceleaf alcohol ester active component 16.6g, yield 83%, ((the 4Z/8E)-farnesyl- of purity 99.4%
Geranyl alcohol ester content is 0.5%) gas-chromatography detection method be the same as Example 1.
4) preparation of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
Composition is：
(a) farnesylacetic acid spiceleaf alcohol ester active component 5mg/ balls
(b) Macrogol 6000 45mg/ balls
Exemplified by preparing 1000 farnesylacetic acid spiceleaf alcohol ester medicament composition dropping pills, specific preparation method is：Will place
Side's amount Macrogol 6000 is put in aluminum pot, in being heated to 90 DEG C~100 DEG C in oil bath, after after all meltings, adds recipe quantity
Above-mentioned farnesylacetic acid spiceleaf alcohol ester active component is stirred, and is transferred in reservoir, it is closed and be incubated 80 DEG C~
90 DEG C, dropping liquid quantitative valve is adjusted, from top to bottom, in the methyl-silicone oil for instilling 10 DEG C~15 DEG C, dripping pill is taken out, exhausts dripping pill table
Face cooling agent, dries, produces.
Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition in following (two), (three), (five) is prepared by embodiment 1
Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition 1, the purity of wherein farnesylacetic acid spiceleaf alcohol ester active component is
99.5%.
Following (4Z/8E)-farnesylacetic acid spiceleaf alcohol esters：(Zhou Xunrong waits geometric isomer in gefarnates to bibliography
Research, chemical reagent, 2012,34 (3):266-268) prepared by method, purity 99.8%.
Following gefarnates：Bibliography (Zhou Xunrong, waits the research of geometric isomer in gefarnates, chemical reagent, and 2012,
34(3):266-268) method extract from commercially available tablet (gastric infusion is needed by extracting raw material and removing the auxiliary material of tablet, with
Just dosage is calculated).
Following Lansoprazoles are marketable material medicine.
(2) toxicity test of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
Pass through document《Pharmacological experimental methodology》(Wei Wei chief editors) recommends method fragrant to the farnesylacetic acid of the present invention respectively
Leaf-alcohol ester pharmaceutical composition, gefarnate, acute toxicity, result of the test are detected by way of oral, intraperitoneal injection, intravenous injection
Show, the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition LD of the Oral Administration in Rats administration present invention50For 12555mg/kg, (4Z/
The LD of 8E)-farnesylacetic acid spiceleaf alcohol ester50For 3826mg/Kg, the LD of gefarnate50For 8455mg/Kg；Rats by intraperitoneal injection is given
The farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition LD of the medicine present invention50For 7426mg/kg, (4Z/8E)-farnesylacetic acid geraniol
The LD of ester50For 2522mg/Kg, the LD of gefarnate50For 4688mg/Kg；The farnesylacetic acid of the rat intravenous injection administration present invention
Spiceleaf alcohol ester pharmaceutical composition LD50For 3894mg/kg, the LD of (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester50For 1498mg/Kg,
The LD of gefarnate50For 2855mg/Kg.The toxicity of the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the experimental result prompting present invention
Less than (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester and the two 7:3 scalemic thereof gefarnates.
(3) the peptic ulcer protective effect experiment of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
(main component is that (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester and (4E/8E)-farnesylacetic acid are fragrant to commercially available gefarnate
Leaf-alcohol ester presses 3:7 ratios are mixed) as gastric mucosa protective agent, ulcer healing can be promoted, strengthen gastric mucosal barrier, stomach is expanded
Mucous membrane microcirculation, improves blood distribution.Pass through document (Hajrezaie M, Salehen N, Karimian H, et al.
Biochanin A Gastroprotective Effects in Ethanol-Induced Gastric Mucosal
Ulceration in Rats. PLoS One,2015,10(3):E0121529.) method recommended, is induced using absolute ethyl alcohol
Rat, sets up acute gastric ulcer model, and the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the oral administration gavage present invention, (4Z/8E)-
Farnesylacetic acid spiceleaf alcohol ester, gefarnate, Lansoprazole, are calculated ulcer index and ulcer inhibition rate by software, are contaminated using HE
Color observes gastric tissue morphology, can reflect that medicine causes the protective effect of gastric mucosa of rat to absolute ethyl alcohol.
1 experimental method
1.1 experiment packets and dose design
SD rats are divided into Normal group, model group, positive controls (Lansoprazole 20mg/kg), administration group ((4E/
8E)-farnesylacetic acid spiceleaf alcohol ester 200mg/kg, (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester 200mg/kg, gefarnate
200mg/kg), totally 5 groups, every group of animal 8.
1.2 absolute ethyl alcohols cause rat acute gastric ulcer
Take SD rats 40,180~220g of body weight.Daily gastric infusion 1 time, continuous 7 days.24h before modeling, rat needs to prohibit
Food can't help water, and in after 1h after last dose, every rat oral gavage absolute ethyl alcohol 1mL causes acute gastric mucosal lesion.Gavage is anhydrous
10% chloral hydrate anesthesia after ethanol 1h, using vacuum venous blood-sampling pipe by abdominal aorta 5 mL of blood sampling, stands 4000r/ after 2h
Min centrifuges 10min, separates serum, is placed in -80 DEG C of refrigerators and preserves to be measured.
The measuring and calculating of 1.3 stomach lining ulcer areas and ulcer inhibition rate
Put to death after rat extracting blood, it is rapid to take out mouse stomach, cut off along greater curvature, cleaned in stomach and remained with the physiological saline of precooling
Thing, deploys and gastric tissue is fixed between two pieces of glass plates for taking pictures.Calculate ulcer surface with Image J image analysis softwares
Product, and calculate inhibiting rate.Inhibiting rate (%)=(control group ulcer area-administration group ulcer area)/control group ulcer index x
100%.
1.4 rat stomach histopathology histological observations
HE (Haematoxylin andeosin) dyeing is in the presence of different dye liquors, by the different material in section
Dye different colours and show, then by the various structures in observation by light microscope tissue, it is dye the most conventional
Color, can aid in and make diagnosis to gastric ulcer degree.Histopathology operation includes drawing materials fixed, dehydration thoroughly in gastric tissue
Bright, waxdip is embedded, section is dyed with paster, dewaxing dyeing, HE, is dehydrated the several steps of transparent and sealing.
1.5 data inputtings and Treatment Analysis
As a result represented, and analyzed using the statistical softwares of SPSS 17.0 with mean ± standard error (Mean ± S.E.M.),
Not comparison in difference one-way analysis of variance (One-way ANOVA) (not assuming that homogeneity of variance Dunnett's T3) between each group. P<
0.05 represents difference tool statistical significance.
2 experimental results
2.1 farnesylacetic acid spiceleaf alcohol ester pharmaceutical compositions cause the protection of rat acute mucosal lesion to make to absolute ethyl alcohol
With
Absolute ethyl alcohol causes gastric mucosa damage observation result to show (Fig. 1) that normal group stomach lining finishing is intact, in dark red
Color, mucus is more, no hyperemia, the anomalous variation such as oedema, ulcer and cicatricial tissue hyperplasia.Model group and (4Z/8E)-farnesyl- second
Sour spiceleaf alcohol ester treatment group gastric mucosa has an extensive injuries, oedema, hyperemia, erosion, in kermesinus, and sees and be largely dispersed in bleeding
And bleeding band.Remaining each group blutpunkte and bleeding bar carry different degrees of reduction, wherein gefarnate and the method for the present invention
Guanidine-acetic acid spiceleaf alcohol ester medicine composite for curing group compares, and the former rotten to the corn situation is more serious, and bleeding band is more；The method of the present invention
Guanidine-acetic acid spiceleaf alcohol ester medicine composite for curing group and Lansoprazole control group stomach lining are in kermesinus, for a sheet bleeding,
Most of stomach lining has no inflammatory reaction and damage.
Test result indicates that the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the present invention is to acute caused by absolute ethyl alcohol
The protective effect of mucosal lesion is better than (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester and gefarnate, and with the blue rope of positive control drug
Draw azoles suitable.
Influence of the 2.2 farnesylacetic acid spiceleaf alcohol ester pharmaceutical compositions to rat gastric ulcer area and ulcer inhibition rate
The ulcer area of experimental rat/itself stomach area result is as shown in Fig. 2 gastric ulcer area is damaged wherein in model group
Maximum explanation absolute ethyl alcohol causes the success of rat gastric ulcer model.Test result indicates that, farnesylacetic acid spiceleaf alcohol ester of the invention
Pharmaceutical composition can substantially suppress the ulcerative lesions that absolute ethyl alcohol is caused to gastric mucosa tissue with control group Lansoprazole, drop
Low ulcer area, improves pathomorphism and inflammatory reaction.Gefarnate group suppression ulcerative lesions effect is not obvious enough, and (4Z/
8E)-farnesylacetic acid spiceleaf alcohol ester confrontation absolute ethyl alcohol causes mucosal lesion substantially to no effect.
Experimental rat ulcer inhibition rate is shown in Fig. 3.Test result indicates that, farnesylacetic acid spiceleaf alcohol ester medicine group of the invention
Compound ulcer inhibition rate is up to 78.20%, and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester ulcer inhibition rate is then 35.56%,
Gefarnate ulcer inhibition rate is 37.60%, and farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition ulcer inhibition rate of the invention is obvious,
It is more or less the same with control group Lansoprazole (ulcer inhibition rate is 81.10%).
Rat stomach tissue pathologies change under 2.3 light microscopics
Liver histopathological analysis such as Fig. 4 shows that rat normal gastric mucosa structural integrity, mucous membrane surface foveolae gastricae clearly may be used
See, the close rule of body of gland arrangement in mucous membrane, epithelium, which has no, to come off, body of gland has no damage, lamina propria has no bleeding and inflammatory cell leaching
Profit (0 degree of damage)；Model group is deeper with (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester treatment group mucosal lesion, and area is larger,
Foveolae gastricae structure is destroyed, and oedema and inflammatory infiltration occurs, a large amount of epithelial cells denaturation, is come off, rotten to the corn, and gland structure is disorderly, has
Missing, lamina propria is shown in moderate bleeding (damage of IV degree)；Gefarnate treatment group stomach lining is kept than more complete, body of gland degree of injury
Smaller (damage of III degree)；The present invention farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition treatment group have to above-mentioned pathology damage compared with
Be obviously improved effect, stomach lining gastric mucosa minor injury, epithelium, which has no, to come off, and body of gland has no damage, the rare bleeding of lamina propria and
Cell infiltration (damage of I degree damage-II degree)；Positive group stomach lining minor injury, epithelium, which has no, to come off, and body of gland has no damage,
Lamina propria has no bleeding and cell infiltration (damage of I degree damage-II degree).
(4) the peptic ulcer protective effect research of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition
Pass through document (Hajrezaie M, Salehen N, Karimian H, et al.Biochanin A
Gastroprotective Effects in Ethanol-Induced Gastric Mucosal Ulceration in
Rats.PLoS One,2015,10(3):E0121529.) method recommended, using absolute ethyl alcohol induced rat, sets up acute
Gastric ulcer model, oral administration gavage farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition calculates ulcer index by software and ulcer presses down
Rate processed.
1.1 prepare for reagent product
By embodiment 1 and bibliography (Zhou Xunrong, waits the research of geometric isomer in gefarnates, chemical reagent, 2012,
34(3):Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition 266-268) prepared by method, (4E/8E)-farnesylacetic acid spiceleaf
Alcohol ester and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester, blended preparation (4Z/8E)-farnesylacetic acid geraniol ester content is
0.05%th, 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10% farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition test sample.
1.2 experiments and detection method are with described in (three).
1.3 experimental result
1.3.1 influence result of (the 4Z/8E)-farnesylacetic acid spiceleaf alcohol ester of different purity to rat gastric ulcer inhibiting rate
See Fig. 5.
1.3.2 influence result of (the 4Z/8E)-farnesylacetic acid spiceleaf alcohol ester of different purity to rat gastric ulcer area is shown in
Fig. 6.
From Fig. 5 and Fig. 6：When (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester concentration be less than or equal to 2% and more than etc.
When 0.1%, farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention, ulcer inhibition rate substantially, can substantially suppress nothing
The ulcerative lesions that water-ethanol is caused to gastric mucosa tissue, reduce ulcer area, improve pathomorphism and inflammatory reaction, with compared with
Consistent unexpected technique effect；But when the concentration of (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester is more than 2% or small
When 0.1%, farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition is substantially reduced to gastric ulcer inhibiting rate, to suppressing absolute ethyl alcohol
Effect is poor in terms of the damage caused to mucosa tissue.
(5) farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition characteristics of pharmacokinetics is investigated
The farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the present invention, gefarnate, (4Z/8E)-farnesylacetic acid geraniol
Ester causes the protective effect of gastric mucosa of rat to there is notable difference absolute ethyl alcohol.The present invention sets up superelevation liquid-high resolution mass spectrum connection
With technique study three by after gastric infusion enter rat body in after difference, investigate three characteristics of pharmacokinetics.
Instrument：Waters Acquity H UPLC, Waters Xevo G2-XS QTof
Chromatographic condition：Chromatographic column (Waters BEH C18(2.1mm × 50mm, 1.7 μm m) post, 40 DEG C of column temperature)；Mobile phase
(0.1% formic acid water-methanol-acetonitrile (1:54:45) isocratic elution, flow velocity 0.3mLmin-1)；The μ L of sample size 2；Sample injection time
6min。
Mass Spectrometry Conditions：Electron spray ionisation source (ESI)；Holotype gathers (Negative mode)；Capillary voltage 2kV, from
120 DEG C of component, 400 DEG C of desolvation temperature, desolventizing gas flow 800Lh-1, taper hole throughput 50Lh-1；Mass spectrometric data
Collection and processing software MassLynx V4.1 work stations, scan mode MS patterns.
Linearly：Take standard sample to be configured to 20,40,80,200,400,1000,2000ngmL series standard liquid.Take
The μ L of blank plasma 100, are placed in 2mL Ep pipes, sequentially add the μ L of above-mentioned standard liquid 100, add 400 μ L methanol and add 800 μ L
Ethyl acetate, vortex mixed 15min, 10000rmin-110min is centrifuged, upper organic layer is drawn, nitrogen drying, residue is added
100 μ L methanol dissolve, 13000rmin-110min sample introductions are centrifuged to determine.With mass concentration (c) for abscissa, sample peak area
(y) carries out linear regression with weighted least-squares method for ordinate, weight coefficient is 1/c, drafting standard curve, obtain (4E/8E)-
Farnesylacetic acid spiceleaf alcohol ester calibration curve equation is the (r of Y=256.5086C- 11.00392=0.998 9), Gefarnate
Calibration curve equation is Y=224.C-10.0189 (r2=0.997 8), and (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester standard is bent
Line equation is Y=188.4582C-6.8258 (r2=0.998 1) result show, detection mass concentration the range of linearity be 20
~2000ngmL, quantitative limit is 20ngmL.
Sample is determined：18 male and female half and half of rat are taken, weight 200-230g is divided into three groups every group 6, fasting before experiment
12h, normal water.Rat claim after quality by common dose conversion gavage give gavage solution, dosage is 200 mg/kg, in
0.25 after gastric infusion, 0.5,1,2.5,3.5,4.5,6,7.5,9,10.5,12,14,24,30h docking take blood 0.3ml, be placed in
In test tube of hepari 1.5ml centrifuge tubes, 4500r/min centrifugation 10min take the μ l of plasma sample 100 to be placed in 2mL Ep pipes, add 400
μ L methanol adds 800 μ L ethyl acetate, vortex mixed 15min, 10000 rmin-110min is centrifuged, upper strata is drawn organic
Layer, nitrogen drying, residue adds the dissolving of 100 μ L methanol, 13000rmin-110min sample introductions are centrifuged to determine.
Experimental result：Farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition, gefarnate, (the 4Z/8E)-farnesyl- second of the present invention
Drug-time curve is as shown in Figure 7 after sour spiceleaf alcohol ester difference gastric infusion.After pharmacokinetic parameters, rat oral gavage administration originally
The farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of invention, gefarnate, (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester peak time
About 6 hours, but the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the present invention, gefarnate, (4Z/8E)-farnesylacetic acid
The AUC of spiceleaf alcohol ester0-tRespectively 19126.58 (ngh/ml), 14656.05 (ngh/ml), 8785.62 (ngh/ml).
Illustrate that the relative bioavailability of the farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the present invention is more than (4Z/8E)-farnesyl- second
Sour spiceleaf alcohol ester and gefarnate.
In summary, farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition of the invention has that toxicity is low, peptic ulcer is protected
Shield effect is strong, the advantage that relative bioavailability is high.
The preferred embodiment of the present invention is described in detail above in association with accompanying drawing, still, the present invention is not limited to above-mentioned reality
The detail in mode is applied, in the range of the technology design of the present invention, a variety of letters can be carried out to technical scheme
Monotropic type, this simple variant belongs to protection scope of the present invention.
Claims (10)
1. a kind of farnesylacetic acid spiceleaf alcohol ester pharmaceutical composition, it is characterised in that described pharmaceutical composition is by farnesylacetic acid
Spiceleaf alcohol ester active component and pharmaceutically acceptable carrier are constituted, and the farnesylacetic acid spiceleaf alcohol ester active component contains
(4E/8E)-farnesylacetic acid spiceleaf alcohol ester and (4Z/8E)-farnesylacetic acid perfume by active component gross weight meter no more than 2%
Leaf-alcohol ester；Preferably, the content of described (4Z/8E)-farnesylacetic acid spiceleaf alcohol ester is 0.1~1%.
2. pharmaceutical composition according to claim 1, it is characterised in that the farnesylacetic acid spiceleaf alcohol ester active component
Percentage by weight with pharmaceutically acceptable carrier is 1:19~3:7, preferably 1:10~1:4.
3. pharmaceutical composition according to claim 1 or 2, it is characterised in that the pharmaceutically acceptable carrier includes
One or more in diluent, excipient, adhesive, filler, disintegrant, flavouring agent, sweetener.
4. the pharmaceutical composition according to any one of claim 1-3, it is characterised in that described pharmaceutical composition includes forming sediment
One in powder, microcrystalline cellulose, magnesium stearate, Almasilate, calcium monohydrogen phosphate, vegetable oil, beeswax, gelatin polyethylene glycol, glycerine
Plant or more than one.
5. the pharmaceutical composition according to any one of claim 1-4, it is characterised in that the formulation of described pharmaceutical composition
Form including granula, pulvis, tablet, capsule, syrup, suppository, injection, emulsion, tincture, suspension, solution is oral or non-
Oral administered dosage form；Preferably, the formulation includes tablet, capsule, dripping pill.
6. prepare the method for the pharmaceutical composition any one of claim 1-5, it is characterised in that including by farnesyl- second
The step of sour spiceleaf alcohol ester active component is mixed with pharmaceutically acceptable carrier, the wherein preparation of farnesylacetic acid spiceleaf alcohol ester
During catalyst is used as using L-Aspartic acid.
7. method according to claim 6, it is characterised in that comprise the following steps：
(1) using trans nerolidol and ortho-acetate as raw material, L-Aspartic acid is catalyst, is obtained through Claisen rearrangement reactions
To farnesylacetic acid ester；
(2) farnesylacetic acid ester hydrolysis, crystallization, acidifying are obtained into farnesylacetic acid；
(3) farnesylacetic acid and geraniol are condensed to yield farnesylacetic acid spiceleaf alcohol ester active component；
(4) farnesylacetic acid spiceleaf alcohol ester active component and pharmaceutically acceptable carrier are mixed to prepare the drug regimen
Thing.
8. the method according to claim 6 or 7, it is characterised in that comprise the following steps：
(1) using trans nerolidol and ortho-acetate as raw material, L-Aspartic acid is catalyst, is carried out at 90~150 DEG C anti-
Should, 60~90 DEG C of vacuum distillations are cooled to, 90~130 DEG C of vacuum distillations is warming up to, obtains farnesylacetic acid ester；
(2) farnesylacetic acid ester is mixed into generation hydrolysis with alkali, reaction solution is extracted with organic solvent (preferably petroleum ether), is adjusted
Reaction solution pH to 3~4, organic solvent extraction merges organic phase, plus alkali, and concentration adds organic solvent (ethyl acetate),
Filtering, filter cake is added water and adjusts pH to 3~4, and organic solvent (preferably petroleum ether) is extracted, merging organic phase, saturated common salt water washing,
Dry farnesylacetic acid；
(3) by farnesylacetic acid, geraniol, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC-HCl),
DMAP (DMAP) hybrid reaction, water, saturated common salt water washing are used by reaction solution respectively, are dried, and cross silica gel, dense
Silica gel is crossed in contracting, vacuum distillation, is dried, and the farnesylacetic acid spiceleaf alcohol ester active component is made；
(4) farnesylacetic acid spiceleaf alcohol ester active component and pharmaceutically acceptable carrier are mixed to prepare the drug regimen
Thing.
9. the pharmaceutical composition any one of claim 1-5 is in treatment or prevention disease of digestive system medicine is prepared
Purposes.
10. purposes according to claim 9, it is characterised in that the disease of digestive system is damaged including acute and chronic gastritis mucous membrane
Wound；Alternatively, the disease of digestive system includes acute or chronic gastritis, peptic ulcer, non-ulcer dyspepsia.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370731A (en) * | 2013-08-15 | 2015-02-25 | 南京瑞尔医药有限公司 | Gefarnate key intermediate refining or reaction solution direct post-processing method |
| CN105272854A (en) * | 2014-05-27 | 2016-01-27 | 重庆圣华曦药业股份有限公司 | Preparation method of gefarnate |
-
2017
- 2017-06-15 CN CN201710453014.2A patent/CN107198683B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370731A (en) * | 2013-08-15 | 2015-02-25 | 南京瑞尔医药有限公司 | Gefarnate key intermediate refining or reaction solution direct post-processing method |
| CN105272854A (en) * | 2014-05-27 | 2016-01-27 | 重庆圣华曦药业股份有限公司 | Preparation method of gefarnate |
Non-Patent Citations (3)
| Title |
|---|
| 周训蓉等: "吉法酯中几何异构体的研究", 《化学试剂》 * |
| 朱高峰等: "吉法酯合成工艺研究", 《化学试剂》 * |
| 陈文章等: "4,8-E-法呢基乙酸香叶酯的合成", 《广州化工》 * |
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