CN103864638B - A kind of benzoic acid derivative and its preparation method and application - Google Patents
A kind of benzoic acid derivative and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of new benzoic acid derivative, chemistry 2-lacto phenylformic acid by name, its structural formula is as follows.This compound is extraction and isolation from the secondary metabolite of microorganism, and can be obtained by the method for chemosynthesis.It is active that pharmacological evaluation shows that it has good antalgic and inflammation relieving, and less to GI hormesis, is expected to become new NSAID (non-steroidal anti-inflammatory drug).
Description
Technical field
The invention belongs to Natural Medicine Chemistry and pharmaceutical synthesis 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 the new compound that extraction and isolation obtains from the meta-bolites of microorganism, and can be obtained by the method for chemosynthesis, non-stimulated to gi tract, has gratifying medical use.
In recent years, column chromatography and preparative liquid chromatography have had applied research more widely in the extracting and developing, purifying etc. of microbial metabolites, and clearly demonstrate the effect of its uniqueness; And the method for chemosynthesis not only can carry out commercial scale production according to needs, and can the production time be shortened, 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 the preparation method providing above-mentioned benzoic acid derivative, comprises microbe fermentation method and chemical synthesis.
Another object of the present invention is the medical use providing this compound.
Benzoic acid derivative provided by the present invention, carboxyl is positioned at C
1position, lacto is positioned at C
2position, namely 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-lactoylaminobenzoicacid by name, its concrete structure formula is as follows:
This compound has following spectroscopic properties:
1h-NMR and
13c-NMR spectrum is as shown in table 1.
Table 1.2-lacto is benzoic
1h-NMR and
13c-NMR composes
| 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 (positiveionmode): 232.0582 [M+Na]
+, molecular formula: C
10h
11o
4n.
Benzoic acid derivative provided by the present invention is separated to obtain from the meta-bolites of Penicillium fungi Penicilliumchrysogenum or P.notatum bacterial strain, and its preparation method concrete steps are as follows:
(1) solid medium and fermention medium is prepared; (2) get Penicilliumchrysogenum or P.notatum inoculation on solid medium, 28 DEG C of constant temperature culture were forwarded in fermention medium after 5 days, and 28 DEG C of constant temperature culture obtain fermented liquid in 14 days; (3), after fermentation liquor extracts solvent extraction, concentrating under reduced pressure obtains paste crude extract; (4) by paste crude extract with dissolve with methanol, octadecylsilane chemically bonded silica (ODS) mixes sample, upper prop, 40%-100% methanol elution gradient, and wherein gained stream part Fr1 ~ 4 are through preparative liquid chromatography (chromatographic column: octadecylsilane chemically bonded silica (ODS); Moving phase: methanol-water (40:60 ~ 80:20)) be separated obtain new compound 2-lacto phenylformic acid.
In the present invention, cultivating bacterial strain is Penicillium fungi Penicilliumchrysogenum or P.notatum.
In the present invention, extraction solvent is ethyl acetate.
In the present invention, when adopting ODS pillar layer separation, dry method loading, methanol-water system gradient elution, methyl alcohol initial proportion is 40%-100%; When 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 be obtained by the method for chemosynthesis, and its synthetic method concrete steps are as follows:
A () Pfansteihl (II) and Acetyl Chloride 98Min. (III) act on and obtain intermediate (IV), temperature of reaction 10 ~ 40 DEG C, 2 ~ 15 hours reaction times in anhydrous tetrahydro furan or diacetyl oxide;
B () intermediate (IV) and sulfur oxychloride effect obtain intermediate (V), temperature of reaction 40 ~ 80 DEG C, 1 ~ 4 hour reaction times;
C () intermediate (V) and methyl o-aminobenzoate (VI) react and generate intermediate (VII), temperature of reaction 10 ~ 40 DEG C, 1 ~ 24 hour reaction times in anhydrous diethyl ether;
D () intermediate (VII) and solution of potassium carbonate are obtained by reacting intermediate (VIII) in methyl alcohol, intermediate (VIII) and sodium hydroxide solution are obtained by reacting 2-lacto phenylformic acid (I) in tetrahydrofuran (THF); Or intermediate (VII) and sodium hydroxide solution react and directly obtain 2-lacto phenylformic acid (I) in tetrahydrofuran (THF) and methyl alcohol; The former temperature of reaction 15 ~ 35 DEG C, 1 ~ 20 hour reaction times, latter reaction's temperature 10 ~ 40 DEG C, 1 ~ 24 hour reaction times.
Above-mentioned steps (a) is reacted 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 DEG C.
In above-mentioned steps (c), the amount of substance ratio of formula V compound and formula (VI) compound is 1 ~ 3:5, temperature of reaction 10 ~ 40 DEG C, 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 and solution of potassium carbonate react, and the latter and sodium hydroxide solution react.
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, involved raw material, intermediate and reaction scheme are as follows:
In the present invention, the pharmacological action of described benzoic acid derivative has significant antalgic and inflammation relieving activity.
In the present invention, it is active that the new benzoic acid derivative obtained has significant antalgic and inflammation relieving, and its raw materials wide material sources, cost is not high, stomach is had no stimulation, compares with existing nonsteroidal anti-inflammatory compound and there is stronger advantage, 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 2-lacto benzoic hydrogen spectrum (
1h-NMR) figure.
Fig. 3 be 2-lacto benzoic carbon spectrum (
13c-NMR) figure.
Embodiment
Further illustrate the present invention with specific embodiment below, but and do not mean that restriction the present invention.
The benzoic fermentable of embodiment 1.2-lacto is separated preparation
1.1 materials:
1.1.1 bacterial classification: Penicilliumchrysogenum or P.notatum bacterial classification.
1.1.2 preparation (1) solid medium of substratum: yeast leaching powder 0.09g, Fructus Hordei Germinatus leaching powder 0.09g, peptone 0.15g, glucose 0.3g, agar 0.45g, sodium-chlor 0.015g, distilled water 30ml, 121 DEG C, 111MPa high-temperature sterilization 30min.
(2) fermention medium: yeast leaching powder 2.1g, Fructus Hordei Germinatus leaching powder 2.1g, peptone 3.5g, glucose 7.0g, sodium-chlor 0.35g and distilled water 700ml, 121 DEG C, 111MPa high-temperature sterilization 30min.
Fermentation process:
Get Penicilliumchrysogenum or P.notatum bacterial strain, be inoculated on the solid medium in φ 10cm culture dish, be forwarded to after 28 DEG C of constant incubators cultivate 5 days and be equipped with in the 2L triangular flask of fermention medium, 28 DEG C of constant temperature culture 14 days.Fermented liquid 21L is total to obtain through repeatedly fermenting.
Separation and purification:
Get fermented liquid (700ml), add ethyl acetate 200ml, jolting 2min, filtering mycelium, filtrate leaving standstill makes layering, and divide and get ethyl acetate layer, water layer adds ethyl acetate 200ml, jolting 2min, leaves standstill and makes layering, divides and gets ethyl acetate layer; Combined ethyl acetate layer, add water 100ml, jolting 2min, staticly makes layering, discards water layer, and ethyl acetate layer filters, and filtrate reduced in volume obtains paste crude extract 2g.By paste crude extract with dissolve with methanol, get ODS(4g) mix sample, the sample mixed is loaded good ODS post (20g) the cylinder top of pre-treatment, 40% methyl alcohol is as initial solvent, with 40%-100% methanol elution gradient, obtain 61 stream parts, wherein flow part Fr1 ~ 4 through preparative liquid chromatography (permaphase ODS; Moving phase: methanol-water (60:40); Determined wavelength: 220nm) be separated obtain new compound 2-lacto phenylformic acid.
The chemosynthesis preparation of embodiment 2.2-lacto phenylformic acid and methyl esters thereof
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 the synthesis of intermediate (IV)
Get Pfansteihl 12.0g(133.3mmol) in 250ml tri-mouthfuls of reaction flasks, add anhydrous tetrahydro furan 24ml ,-10 ~ 0 DEG C is stirred lower dropping Acetyl Chloride 98Min. 19.2ml(266.6mmol) after, stirring at room temperature 5h, 35 DEG C of concentrating under reduced pressure obtain colourless oil liquid 14.6g, yield 83.2%.
2.2.2 the synthesis of intermediate (V)
Get intermediate (IV) 14.6g(110.6mmol) in 250ml reaction flask, add sulfur oxychloride 48ml, 50 DEG C of reaction 2h, 40 DEG C of concentrating under reduced pressure obtain pale yellow oily liquid body 15.6g, yield 93.7%.
2.2.3 intermediate (
) synthesis
Get methyl o-aminobenzoate (
) 60.0g(395.8mmol) in 500ml reaction flask, add anhydrous diethyl ether 150ml, intermediate (V) 15.6g(103.7mmol is added) under-10 ~ 0 DEG C of stirring, 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 pale yellow crystals 24.7g, yield 89.9%.
2.2.42-the synthesis of lacto phenylformic acid (I)
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, and ethyl acetate 150ml extracts 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 extracts 3 times, discards dichloromethane extraction liquid, aqueous phase 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 extracts 3 times, discards dichloromethane extraction liquid, aqueous phase 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（600MHz，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（600MHz）：δ20.9，68.0，120.0,121.0，122.5，128.6，131.9,138.8,170.3，174.2；
MS（ESI）：m/z=232.0582[M+Na]
+。
Embodiment 3.2-lacto phenylformic acid analgesic activities is studied
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 KM kind female mice 40, be divided into four groups at random, be respectively solvent control group, positive controls, Compound I group and compound VI II group, often organize 10, weigh, number.Before all experimentation on animalies, fasting 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 injects 0.6 ﹪ acetic acid and timing, and shrink with abdominal cavity, hindlimb extension is that writhing starts, and recovering initial equilibrium state for terminating, being designated as a writhing.Writhing number of times in record 15min, and record writhing time first time.
Average statistical, standard deviation writhing latent period of positive controls, Compound I group (writhing time first time) and writhing number of times are T with solvent control group respectively check.Data analysis SPSS15.0forwindows statistical software process.
Experimental result
Experimental result is in table 2.
Table 2.2-lacto phenylformic acid is to the restraining effect of the pain caused by 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, Compound I group has pole significant difference with the writhing number of times of compound VI II group compared with control group, and there were significant differences compared with control group latent period for Compound I group and compound VI II group writhing.
This invention experimental result shows, compound 2-lacto phenylformic acid and 2-lacto methyl benzoate all have certain analgesic activity.
The research of embodiment 4.2-lacto phenylformic acid anti-inflammatory activity
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 KM kind male mice 40, be divided into four groups at random, be respectively solvent control group, positive controls, Compound I group and compound VI II group, often organize 10, weigh, number.Before all experimentation on animalies, fasting 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.Once a day, continuous 3d administration, feeding feedwater immediately after administration.After last administration 1h, draw dimethylbenzene 50 μ l with micropipet, uniform application is wide in mouse right ear, each 25 μ l in interior outside.After mouse is placed in mouse cage without bedding and padding, feeding feeds water.After 50min, mouse is taken off cervical vertebra to put to death, get bilateral ear immediately, bilateral ear overlap is placed, lays 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 the swelling of positive controls and Compound I group is T with solvent control group respectively checks.Data analysis SPSS15.0forwindows statistical software process.
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 Compound I group has pole significant difference compared with control group, and the ear swelling degree of Compound I group and the ear swelling rate of compound VI II group and swelling compare with control group that there were significant differences.
This invention experimental result shows, compound 2-lacto phenylformic acid and methyl esters thereof all have significant anti-inflammatory action.
Embodiment 5.2-lacto phenylformic acid is to the research of 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 KM kind mouse 20, be divided into two groups at random, often organize 10, male and female half and half, weigh, number.Before all experimentation on animalies, fasting can't help water 12 hours, is respectively positive controls and new compound group.Positive controls gives 0.2g/kg acetylsalicylic acid 1% sodium cellulose glycolate suspension, and Compound I group gives the 2-lacto phenylformic acid 1% sodium cellulose glycolate suspension of 0.2g/kg.Once a day, continuous 3d administration, feeding feedwater immediately after administration.Within 4th day, adopt cervical dislocation by sacrifice, 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, 3=severe ulceration, the whole ulcer of 5=).Damage index is evaluated by the mean value of scoring.Average statistical, standard deviation the degree of injury of positive controls and new compound group is T checks.Data analysis SPSS15.0forwindows statistical software process.
Experimental result
Experimental result is in table 4.
Table 4. compound 2-lacto phenylformic acid is to the stimulation degree of 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, Compound I group has pole significant difference 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 the compound described in claim 1 or 2 and pharmaceutically acceptable carrier.
4. the preparation method of compound as claimed in claim 2, comprises the following steps:
(1) solid medium and fermention medium is prepared; (2) Penicillium fungi Penicilliumchrysogenum is got or P.notatum inoculation cultivates to obtain fermented liquid on solid medium; (3), after fermentation liquor extracts solvent extraction, concentrating under reduced pressure obtains paste crude extract; (4) by paste crude extract with dissolve with methanol, octadecylsilane chemically bonded silica mixes sample, upper prop, 40%-100% methanol elution gradient, wherein gained stream part Fr1 ~ 4 through preparative liquid chromatography be separated obtain compound 2-lacto phenylformic acid.
5. the preparation method of compound as claimed in claim 2, is characterized in that comprising the following steps:
A () Pfansteihl (II) and Acetyl Chloride 98Min. (III) act on and obtain intermediate (IV);
B () intermediate (IV) and sulfur oxychloride effect obtain intermediate (V);
C () intermediate (V) and methyl o-aminobenzoate (VI) react in organic solvent and generate intermediate (VII);
D () intermediate (VII) and alkali carbonate solution are obtained by reacting intermediate (VIII), or intermediate (VII) obtains 2-lacto phenylformic acid (I) with alkali hydroxide solution reaction;
。
6. chemical synthesis process according to claim 5, it is characterized in that step (a) is reacted in anhydrous tetrahydrofuran (THF) or diacetyl oxide, the mol ratio of Pfansteihl and Acetyl Chloride 98Min. is 0.3 ~ 0.5:1.
7. chemical synthesis process according to claim 5, it is characterized in that step (c) intermediate (V) is 1 ~ 3:5 with the mol ratio of methyl o-aminobenzoate (VI), described organic solvent is anhydrous diethyl ether.
8. chemical synthesis process according to claim 5, to it is characterized in that in step (d) that (VII) and solution of potassium carbonate reacts and carry out in methyl alcohol, intermediate (VII) and sodium hydroxide solution react and carry out in tetrahydrofuran (THF) and methyl alcohol.
9. chemical synthesis process according to claim 5, is characterized in that step (d) Chinese style (VII) compound is 1 ~ 2:5 with the amount of substance ratio of salt of wormwood.
10. chemical synthesis process according to claim 5, is characterized in that step (d) Chinese style (VII) compound is 1 ~ 2:5 with the amount of substance ratio of sodium hydroxide.
11. chemical synthesis process according to claim 5, regulate pH to 1 ~ 4 with dichloromethane extraction after it is characterized in that reacting completely in step (d).
12. the compound described in claim 1 or 2 or composition according to claim 3 are preparing the purposes in antalgic and inflammation relieving medicine.
13. purposes according to claim 12, wherein said analgesic activity comprises treatment headache, 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, juvenile arthritis, bursitis, tenosynovitis, articular capsulitis, gastritis and gastric and duodenal ulcer.
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| 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 |
| CN106831475B (en) * | 2017-01-19 | 2018-11-27 | 沈阳药科大学 | The preparation method and application of 2- lacto benzoic acid |
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| JPS57136519A (en) * | 1982-01-19 | 1982-08-23 | Kureha Chem Ind Co Ltd | Antidiabetic containing aminobenzoic acid derivative |
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