CN103864638A - Benzoic acid compound, and preparation method and application thereof - Google Patents
Benzoic acid compound, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a novel benzoic acid compound which is named 2-lactacylaminobenzoic acid in chemistry. The structural formula of the compound is described in the specification. The compound is extracted and separated from secondary metabolite of a microbe and can be obtained through chemical synthesis. Pharmacological experiments show that the compound has analgesia and anti-inflammatory activity, causes small irritation to gastrointestinal tracts and is expected to be a novel non-steroid anti-inflammatory drug.
Description
Technical field
The invention belongs to Natural Medicine Chemistry and medicine and synthesize and area of pharmacology, be specifically related to a kind of new benzoic acid derivative and preparation method thereof and medical use.
Background technology
Microorganism is the important sources of natural active matter, people have found many special, novel biologically active substances in microorganism and metabolite thereof, comprise antitumor, antibacterial, anti-inflammatory, antiviral compound, biotoxin, enzyme inhibitors, immunosuppressor, unsaturated fatty acids etc., there is bioactive microbial metabolites and can be widely used in food and medicine industry.
At present, although benzoic acid derivative is a lot, large multipair gi tract have larger hormesis.2-lacto phenylformic acid is to extract and separate the new compound obtaining from the meta-bolites of microorganism, and can obtain by the method for chemosynthesis, non-stimulated to gi tract, has gratifying medical use.
In recent years, column chromatography and preparative liquid chromatography in the extraction of microbial metabolites, separate, there has been applied research more widely the aspect such as purifying, and has clearly demonstrated the effect of its uniqueness; And the method for chemosynthesis not only can be carried out commercial scale production according to needs, and can shorten the production time, raise the efficiency, promote the development of new drug research.
Summary of the invention
The object of the present invention is to provide a kind of new benzoic acid derivative.
Another object of the present invention is to provide the preparation method of above-mentioned benzoic acid derivative, comprises microbe fermentation method and chemical synthesis.
A further object of the present invention is to provide the medical use of this compound.
Benzoic acid derivative provided by the present invention, carboxyl is positioned at C
1position, lacto is positioned at C
2position, belongs to benzoic acid derivative, and has following general structure:
The invention provides chemical structure and the title of one of them benzoic acid derivative, i.e. 2-lacto phenylformic acid, English 2-lactoylaminobenzoic acid by name, its concrete structure formula is as follows:
This compound has following spectroscopy feature:
1h-NMR and
13c-NMR spectrum is as shown in table 1.
Table 1. 2-lacto is benzoic
1h-NMR and
13c-NMR spectrum
| Position | 1H | 13C |
| 1 | - | 120.0 |
| 2 | - | 138.8 |
| 3 | 7.74(d,7.8) | 121.0 |
| 4 | 7.47 (m) | 131.9 |
| 5 | 7.12 (m) | 122.5 |
| 6 | 8.57 (d) | 128.6 |
| 1′-OH | 11.91(s) | - |
| 1′′-NH | 8.16(s) | - |
| 1′′ | - | 174.2 |
| 2′′ | 4.10 (m) | 68.0 |
| 3′′ | 1.30 (d, 6.6) | 20.9 |
MS data: for this compound, its high resolution mass spectrum provides molecular ion peak ESI-MS (positive ion mode): 232.0582 [M+Na]
+, molecular formula: C
10h
11o
4n.
Benzoic acid derivative provided by the present invention is to separate and obtain from the meta-bolites of Penicillium fungi Penicillium chrysogenum or P. notatum bacterial strain, and its preparation method concrete steps are as follows:
(1) preparation solid medium and fermention medium; (2) get Penicillium chrysogenum or P. notatum inoculation on solid medium, 28 ℃ of constant temperature culture were forwarded in fermention medium after 5 days, and 28 ℃ of constant temperature culture obtain fermented liquid for 14 days; (3) fermented liquid is after extracting solvent extraction, and concentrating under reduced pressure obtains paste crude extract; (4) by paste crude extract with dissolve with methanol, octadecylsilane chemically bonded silica (ODS) is mixed sample, upper prop, 40%-100% methyl alcohol gradient elution, wherein gained stream part Fr 1 ~ 4 is through preparative liquid chromatography (chromatographic column: octadecylsilane chemically bonded silica (ODS); Moving phase: methanol-water (40:60 ~ 80:20)) separate and obtain new compound 2-lacto phenylformic acid.
In the present invention, cultivating bacterial strain is Penicillium fungi Penicillium chrysogenum or P.notatum.
In the present invention, extraction solvent is ethyl acetate.
In the present invention, while adopting ODS column chromatography to separate, dry method loading, methanol-water system gradient elution, methyl alcohol initial proportion is 40%-100%; While adopting preparative liquid chromatography purifying, moving phase adopts methanol-water system, and the two ratio is 40:60 ~ 80:20.
Benzoic acid derivative provided by the present invention can also obtain by the method for chemosynthesis, and its synthetic method concrete steps are as follows:
(a) Pfansteihl (II) acts on and obtains intermediate (IV), 10 ~ 40 ℃ of temperature of reaction, 2 ~ 15 hours reaction times with Acetyl Chloride 98Min. (III) in anhydrous tetrahydro furan or diacetyl oxide;
(b) intermediate (IV) obtains intermediate (V), 40 ~ 80 ℃ of temperature of reaction, 1 ~ 4 hour reaction times with sulfur oxychloride effect;
(c) intermediate (V) reacts and generates intermediate (VII), 10 ~ 40 ℃ of temperature of reaction, 1 ~ 24 hour reaction times with methyl o-aminobenzoate (VI) in anhydrous diethyl ether;
(d) intermediate (VII) reacts in methyl alcohol with solution of potassium carbonate and obtains intermediate (VIII), and intermediate (VIII) reacts in tetrahydrofuran (THF) with sodium hydroxide solution and obtains 2-lacto phenylformic acid (I); Or intermediate (VII) reacts in tetrahydrofuran (THF) and methyl alcohol with sodium hydroxide solution and directly obtains 2-lacto phenylformic acid (I); 15 ~ 35 ℃ of the former temperature of reaction, 1 ~ 20 hour reaction times, 10 ~ 40 ℃ of latter reaction's temperature, 1 ~ 24 hour reaction times.
Above-mentioned steps (a) is to react in anhydrous tetrahydrofuran (THF) or diacetyl oxide, and the amount of substance ratio of Pfansteihl and Acetyl Chloride 98Min. is 0.3 ~ 0.5:1.
In above-mentioned steps (b), temperature of reaction is 40 ~ 80 ℃.
In above-mentioned steps (c), the amount of substance ratio of formula V compound and formula (VI) compound is 1 ~ 3:5,10 ~ 40 ℃ of temperature of reaction, 1 ~ 24 hour reaction times.
In above-mentioned steps (d), there are two kinds of methods can obtain 2-lacto phenylformic acid; Two kinds of method organic solvents used are tetrahydrofuran (THF) and methyl alcohol, and the former reacts with solution of potassium carbonate, and the latter reacts with sodium hydroxide solution.
In above-mentioned steps (d), formula (VII) compound is 1 ~ 2:5 with the amount of substance ratio of salt of wormwood; Formula (VII) compound is 1 ~ 2:5 with the amount of substance ratio of sodium hydroxide.
In above-mentioned steps (d), after reacting completely, also use salt acid for adjusting pH to 1 ~ 4 with dichloromethane extraction.
In above-mentioned synthetic method, related raw material, intermediate and reaction scheme are as follows:
In the present invention, the pharmacological action of described benzoic acid derivative is to have significant antalgic and inflammation relieving activity.
In the present invention, the new benzoic acid derivative obtaining has significant antalgic and inflammation relieving activity, and its raw materials wide material sources, cost is not high, stomach is had no stimulation, compare and there is stronger advantage with existing nonsteroidal anti-inflammatory compound, have very gratifying application prospect.
Accompanying drawing explanation
Fig. 1 is the benzoic high resolution mass spectrum of 2-lacto (TOF-MS) figure.
Fig. 2 be the benzoic hydrogen of 2-lacto spectrum (
1h-NMR) figure.
Fig. 3 be the benzoic carbon of 2-lacto spectrum (
13c-NMR) figure.
Embodiment
Be described more specifically the present invention with specific embodiment below, but and do not mean that restriction the present invention.
The benzoic microorganism fermentation of embodiment 1. 2-lacto separates preparation
1.1 materials:
1.1.1 bacterial classification: Penicillium chrysogenum or P. notatum bacterial classification.
1.1.2 the preparation of substratum (1) solid medium: yeast soaks powder 0.09g, and Fructus Hordei Germinatus soaks powder 0.09g, peptone 0.15g, glucose 0.3g, agar 0.45g, sodium-chlor 0.015g, distilled water 30ml, 121 ℃, 111MPa high-temperature sterilization 30 min.
(2) fermention medium: yeast soaks powder 2.1g, Fructus Hordei Germinatus soaks powder 2.1g, peptone 3.5g, glucose 7.0g, sodium-chlor 0.35g and distilled water 700ml, 121 ℃, 111MPa high-temperature sterilization 30 min.
Fermentation process:
Get Penicillium chrysogenum or P.notatum bacterial strain, be inoculated on the solid medium in φ 10cm culture dish, 28 ℃ of constant incubators are cultivated after 5 days and are forwarded in the 2L triangular flask that fermention medium is housed, 28 ℃ of constant temperature culture 14 days.Be total to obtain fermented liquid 21L through repeatedly fermenting.
Separation and purification:
Get fermented liquid (700ml), add ethyl acetate 200ml, jolting 2min, filtering mycelium, filtrate leaving standstill makes layering, divides and gets ethyl acetate layer, and water layer adds ethyl acetate 200ml, and jolting 2min leaves standstill and makes layering, divides and gets ethyl acetate layer; Combined ethyl acetate layer, the 100ml that adds water, jolting 2min, staticly makes layering, discards water layer, and ethyl acetate layer filters, the concentrated paste crude extract 2g that to obtain of filtrate decompression.By paste crude extract with dissolve with methanol, get ODS(4g) mix sample, pack the sample of mixing into ODS post (20g) cylinder top that pre-treatment is good, 40% methyl alcohol is as initial solvent, with 40%-100% methyl alcohol gradient elution, obtain 61 streams part, wherein stream part Fr 1 ~ 4 is through preparative liquid chromatography (permaphase ODS; Moving phase: methanol-water (60:40); Detect wavelength: 220nm) separate and obtain new compound 2-lacto phenylformic acid.
[0032] chemosynthesis of embodiment 2. 2-lacto phenylformic acid and methyl esters thereof preparation
2.1 reagent: Pfansteihl, methyl o-aminobenzoate, Acetyl Chloride 98Min., sulfur oxychloride, tetrahydrofuran (THF), anhydrous diethyl ether, methyl alcohol, methylene dichloride, ethyl acetate
2.2 synthetic methods:
2.2.1 intermediate (IV) is synthetic
Get Pfansteihl 12.0g(133.3 mmol) in tri-mouthfuls of reaction flasks of 250ml, add anhydrous tetrahydro furan 24ml, under-10 ~ 0 ℃ of stirring, drip Acetyl Chloride 98Min. 19.2ml(266.6mmol) after, stirring at room temperature 5h, 35 ℃ of concentrating under reduced pressure obtain colourless oil liquid 14.6g, yield 83.2%.
2.2.2 intermediate (V) is synthetic
Get intermediate (IV) 14.6g(110.6 mmol) in 250ml reaction flask, add sulfur oxychloride 48ml, 50 ℃ of reaction 2h, 40 ℃ of concentrating under reduced pressure obtain pale yellow oily liquid body 15.6g, yield 93.7%.
2.2.3 intermediate (
) synthetic
Get methyl o-aminobenzoate (
) 60.0g(395.8 mmol) in 500ml reaction flask, add anhydrous diethyl ether 150ml, under-10 ~ 0 ℃ of stirring, add intermediate (V) 15.6g(103.7mmol), after stirring at room temperature 3h, suction filtration, filtrate is successively with hydrochloric acid, water, saturated sodium-chloride washing, and concentrating under reduced pressure obtains faint yellow crystallization 24.7g, yield 89.9%.
2.2.4 2-lacto phenylformic acid (I) is synthetic
Get intermediate (
) 12.0g(45.28mmol) in 250ml reaction flask, add methyl alcohol 60ml, room temperature drips after solution of potassium carbonate and stirs 2h, ethyl acetate 150ml extraction 3 times, merges organic phase, concentrating under reduced pressure obtain intermediate (
i), i.e. 2-lactic amide yl benzoic acid methyl esters 9.0g, yield 89.1%, MS(ESI): m/z=223.0624; Get intermediate (
i) 9.0g(40.36mmol) in 250ml reaction flask, add tetrahydrofuran (THF) 60ml, room temperature stirs 1.5h after dripping sodium hydroxide solution, and methylene dichloride 150ml extraction 3 times, discards dichloromethane extraction liquid, water is used salt acid for adjusting pH to 1 ~ 4, leave standstill crystallization, suction filtration, dry, obtain 2-lactic acid benzaminic acid 7.51g, yield 88.9%.
Get intermediate (
) 12.7g(47.92mmol) in 500ml reaction flask, add tetrahydrofuran (THF) 60ml, methyl alcohol 40ml, room temperature stirs 3h after dripping sodium hydroxide solution, and methylene dichloride 200ml extraction 3 times, discards dichloromethane extraction liquid, water is used salt acid for adjusting pH to 1 ~ 4, leave standstill crystallization, suction filtration, dry, obtain 2-lactic acid benzaminic acid 8.79g, yield 87.8%.
1H-NMR（600 MHz，DMSO）：δ1.30（d，3H，CH
3），4.10 (m，1H，2’’-OH), 7.12 (m, 1H，Ar-H)，7.47 (m，1H，Ar-H)，7.74(d, 1H，Ar-H)，8.16(s，1H，NH)，8.57 (m，1H，Ar-H)，11.91(s，1H，OH)；
13C-NMR（600 MHz）：δ 20.9，68.0，120.0, 121.0，122.5，128.6，131.9, 138.8, 170.3，174.2；
MS（ESI）：m/z = 232.0582 [M+Na]
+ 。
Embodiment 3. 2-lacto phenylformic acid analgesic activities researchs
3.1 reagent
Glacial acetic acid, sodium cellulose glycolate, acetylsalicylic acid (ASA), 2-lacto phenylformic acid (Compound I) (self-control, HPLC purity > 99.5%), 2-lactic amide yl benzoic acid methyl esters (compound VI II) (self-control, HPLC purity > 99.5%).
Laboratory animal
KM kind mouse, female, SPF level, body weight 22～28g, SCXK2010-0001.
Experimental technique
Get 40 of KM kind female mices, be divided at random four groups, be respectively solvent control group, positive controls, Compound I group and compound VI II group, 10 every group, weigh, number.Before all experimentation on animalies, fasting be can't help water 12 hours, control group gavage gives 1% sodium cellulose glycolate solution, positive controls gives 0.2g/kg acetylsalicylic acid 1% sodium cellulose glycolate suspension, Compound I group gives the 2-lacto phenylformic acid 1% sodium cellulose glycolate suspension of 0.2g/kg, and compound VI II group gives the 2-lacto methyl benzoate 1% sodium cellulose glycolate suspension of 0.2g/kg.30min pneumoretroperitoneum is injected 0.6 ﹪ acetic acid timing, shrinks with abdominal cavity, and hind leg is stretched to writhing to start, and recovers initial equilibrium state for finishing, and is designated as writhing one time.Record writhing number of times in 15min, and record the writhing time for the first time.
Average statistical, standard deviation and by the writhing latent period of positive controls, Compound I group (writhing time for the first time) and writhing number of times do T check with solvent control group respectively.SPSS 15.0 for windows statistical softwares processing for data analysis.
Experimental result
Experimental result is in table 2.
The restraining effect of table 2. 2-lacto phenylformic acid to the caused pain of 0.6% acetic acid
| Group | Writhing latent period (s) | Writhing number of times |
| Contrast | 3.89±2.39 | 31.90±12.63 |
| ASA | 9.94±4.25** | 7.30±8.99** |
| Compound I | 7.57±4.57* | 12.60±9.89** |
| Compound VI II | 6.47±4.65* | 11.90±8.29** |
*
p<0.05
vscontrol group
*
p<0.01
vscontrol group
As can be seen from Table 2, the writhing number of times of Compound I group and the compound VI II group utmost point significant difference of having compared with control group, Compound I group and compound VI II organize writhing and compare that there were significant differences latent period with control group.
This invention experimental result shows, compound 2-lacto phenylformic acid and 2-lacto methyl benzoate all have certain analgesic activity.
Embodiment 4. 2-lacto phenylformic acid anti-inflammatory activity researchs
4.1 reagent
Sodium cellulose glycolate, dimethylbenzene, acetylsalicylic acid (ASA), 2-lacto phenylformic acid (self-control, HPLC purity > 99.5%), 2-lacto methyl benzoate (self-control, HPLC purity > 99.5%).
Laboratory animal
KM kind mouse, male, SPF level, body weight 22～28g, conformity certification: SCXK2010-0001.
Experimental technique
Get 40 of KM kind male mices, be divided at random four groups, be respectively solvent control group, positive controls, Compound I group and compound VI II group, 10 every group, weigh, number.Before all experimentation on animalies, fasting be can't help water 12 hours, control group gavage gives 1% sodium cellulose glycolate solution, positive controls gives 0.2 g/kg acetylsalicylic acid 1% sodium cellulose glycolate suspension, Compound I group gives the 2-lacto phenylformic acid 1% sodium cellulose glycolate suspension of 0.2 g/kg, and compound VI II group gives the 2-lacto methyl benzoate 1% sodium cellulose glycolate suspension of 0.2 g/kg.Once a day, 3d administration continuously, feeding feedwater immediately after administration.After last administration 1 h, draw dimethylbenzene 50 μ l with micropipet, be evenly applied in mouse right ear exterior feature, the each 25 μ l in interior outside.After mouse is placed in to the mouse cage without bedding and padding, feeding feedwater.After 50min, de-mouse cervical vertebra is put to death, get immediately bilateral ear, by overlapping bilateral ear placement, lay two disks at same position rapidly with 6mm punch tool, weigh respectively with analytical balance.Calculate auricle swelling degree (mg) and swelling rate.
Swelling=auris dextra tablet quality-left auricle quality; Swelling rate=(auris dextra tablet quality/left auricle quality) × 100%.Average statistical, standard deviation are also done T check with solvent control group respectively by the swelling of positive controls and Compound I group.SPSS 15.0 for windows statistical softwares processing for data analysis.
4.4 experimental result
Experimental result is in table 3.
The restraining effect of the mice ear that table 3. 2-lacto phenylformic acid p-Xylol causes
| Group | Swelling (mg) | Swelling rate (%) |
| Contrast | 5.5±1.7 | 242.56±31.57 |
| ASA | 4.0±1.0* | 193.65±27.40** |
| Compound I | 3.6±1.8* | 191.04±47.65** |
| Compound VI II | 4.2±1.7* | 201.54±41.64* |
*
p<0.05
vscontrol group
*
p<0.01
vscontrol group
As can be seen from Table 3, the ear swelling rate of the Compound I group utmost point significant difference of having compared with control group, there were significant differences with control group comparison for the ear swelling rate of the ear swelling degree of Compound I group and compound VI II group and swelling.
This invention experimental result shows, compound 2-lacto phenylformic acid and methyl esters thereof all have significant anti-inflammatory action.
Embodiment 5. researchs of 2-lacto phenylformic acid to gastric irritation effect
5.1 reagent
Sodium cellulose glycolate, acetylsalicylic acid (ASA), 2-lacto phenylformic acid (self-control, HPLC purity > 99.5%).
Laboratory animal
KM kind mouse, male and female half and half, SPF level, body weight 22～28g, conformity certification: SCXK2010-0001.
Experimental technique
Get 20 of KM kind mouse, be divided at random two groups, 10 every group, male and female half and half, weigh, number.Before all experimentation on animalies, fasting be can't help water 12 hours, is respectively positive controls and new compound group.Positive controls gives 0.2 g/kg acetylsalicylic acid 1% sodium cellulose glycolate suspension, and Compound I group gives the 2-lacto phenylformic acid 1% sodium cellulose glycolate suspension of 0.2 g/kg.Once a day, 3d administration continuously, feeding feedwater immediately after administration.Within the 4th day, adopt cervical vertebra dislocation method that mouse is put to death, rapidly its stomach is taken out, and after stomach being cut open along greater gastric curvature, in observed under electron microscope, record stomach degree of injury.(0=not damaged, 0.5=mild hyperaemia, 1=1-2 slight ulcer point, the serious ulcer of 3=, the whole ulcer of 5=).Damage index is evaluated by the mean value of scoring.Average statistical, standard deviation the degree of injury by positive controls and new compound group do T check.SPSS 15.0 for windows statistical softwares processing for data analysis.
Experimental result
Experimental result is in table 4.
The stimulation degree of table 4. compound 2-lacto phenylformic acid to stomach
| Group | Minor injury | Major injury |
| ASA | 0.83±0.21 | 4.0±0.5 |
| Compound I | 0*** | 0*** |
* *
p<0.001
vsacetylsalicylic acid (ASA) group
As can be seen from Table 4, the Compound I group utmost point significant difference of having compared with positive controls (ASA group).
This invention experimental result shows, compound 2-lacto phenylformic acid to Mouse Stomach without obvious hormesis.
Claims (14)
1. there is the benzoic acid derivative of following general formula:
。
2. there is the 2-lacto phenylformic acid of following structure:
3. a pharmaceutical composition, comprises compound and pharmaceutically acceptable carrier described in claim 1 or 2.
4. the preparation method of compound as claimed in claim 1, comprises the following steps:
(1) preparation solid medium and fermention medium; (2) get Penicillium fungi Penicillium chrysogenum or P.notatum inoculation and on solid medium, cultivate to obtain fermented liquid; (3) fermented liquid is after extracting solvent extraction, and concentrating under reduced pressure obtains paste crude extract; (4) by paste crude extract with dissolve with methanol, octadecylsilane chemically bonded silica is mixed sample, upper prop, 40%-100% methyl alcohol gradient elution, wherein gained stream part Fr 1 ~ 4 separates and obtains compound 2-lacto phenylformic acid through preparative liquid chromatography.
5. the preparation method of compound as claimed in claim 1, is characterized in that comprising the following steps:
(a) Pfansteihl (II) obtains intermediate (IV) with Acetyl Chloride 98Min. (III) effect;
(b) intermediate (IV) obtains intermediate (V) with sulfur oxychloride effect;
(c) intermediate (V) reacts and generates intermediate (VII) with methyl o-aminobenzoate (VI) in organic solvent;
(d) intermediate (VII) reacts with alkali carbonate solution and obtains intermediate (VIII), or intermediate (VII) obtains 2-lacto phenylformic acid (I) with alkali hydroxide solution reaction;
6. chemical synthesis process according to claim 5, is characterized in that step (a) is to react in anhydrous tetrahydrofuran (THF) or diacetyl oxide, and the mol ratio of Pfansteihl and Acetyl Chloride 98Min. is 0.3 ~ 0.5:1.
7. chemical synthesis process according to claim 5, is characterized in that step (c) intermediate (V) and the mol ratio of methyl o-aminobenzoate (VI) are 1 ~ 3:5, and described organic solvent is anhydrous diethyl ether.
8. chemical synthesis process according to claim 5, is characterized in that in step (d), (VII) reacts in methyl alcohol and carry out with solution of potassium carbonate, and intermediate (VII) reacts in tetrahydrofuran (THF) and methyl alcohol and carries out with sodium hydroxide solution.
9. chemical synthesis process according to claim 5, is characterized in that step (d) Chinese style (VII) compound and the amount of substance ratio of salt of wormwood are 1 ~ 2:5.
10. chemical synthesis process according to claim 5, is characterized in that step (d) Chinese style (VII) compound and the amount of substance ratio of sodium hydroxide are 1 ~ 2:5.
11. chemical synthesis process according to claim 5, after it is characterized in that reacting completely in step (d) with dichloromethane extraction and regulate pH to 1 ~ 4.
12. the compound described in claim 1 or 2 or composition claimed in claim 3 are in the purposes of preparing in antalgic and inflammation relieving medicine.
13. purposes according to claim 12, wherein said analgesic activity comprises treatment headache, migraine, arthrodynia, neurodynia, dysmenorrhoea, shoulder pain, myalgia, pain in the back, biliary colic, cancer pain and postoperative pain.
14. purposes according to claim 12, wherein said anti-inflammatory action comprises treatment acute and chronic rheumatic arthritis, osteoarthritis, urarthritis, property childhood sacroiliitis, bursitis, tenosynovitis, articular capsulitis, gastritis and gastric and duodenal ulcer.
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| CN106831475A (en) * | 2017-01-19 | 2017-06-13 | 沈阳药科大学 | The preparation method of 2 lacto benzoic acid and application |
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| CN104257644A (en) * | 2014-09-15 | 2015-01-07 | 崔银方 | Pharmaceutic preparation for treating arrhythmia |
| CN104257644B (en) * | 2014-09-15 | 2016-06-01 | 烟台市华文欣欣医药科技有限公司 | A kind of pharmaceutical preparation treating irregular pulse |
| CN104434947B (en) * | 2014-11-07 | 2016-11-09 | 滨州医学院附属医院 | The pharmaceutical composition of a kind of anti-cholangiocarcinoma and application thereof |
| CN106831475A (en) * | 2017-01-19 | 2017-06-13 | 沈阳药科大学 | The preparation method of 2 lacto benzoic acid and application |
| WO2018133765A1 (en) * | 2017-01-19 | 2018-07-26 | 沈阳药科大学 | Method for preparing lactamide-based benzoic acid and applications thereof |
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| CN103864638B (en) | 2015-12-09 |
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