CN1315845C - Methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide, preparation method and application - Google Patents
Methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide, preparation method and application Download PDFInfo
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- CN1315845C CN1315845C CNB200410050908XA CN200410050908A CN1315845C CN 1315845 C CN1315845 C CN 1315845C CN B200410050908X A CNB200410050908X A CN B200410050908XA CN 200410050908 A CN200410050908 A CN 200410050908A CN 1315845 C CN1315845 C CN 1315845C
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Abstract
The present invention relates to methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide, a preparation method and application, which discloses the chemical structure general formula of a methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide. The preparation method uses 7-amido-3-methylene containing aminobeterocycle substitution-cephalosporanic acid generates reaction with bromo-acetyl bromide and double-substitution thiourea to prepare the methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide. The obtained product has good antibacterial activity to Gram-positive bacteria.
Description
Technical field
The invention relates to new cynnematin, amidine sulphur acetamido cephalosporins derivatives that particularly a kind of new C3 methylene radical nitrogen heterocyclic ring that therapeutic activity is arranged replaces and synthetic and application thereof.
Technical background
Therefore the cephem microbiotic has good antimicrobial acivity and hypotoxicity to Mammals, and is the medicine of very useful treatment Mammals transmissible disease.
Cephalosporin analog antibiotic along with its resistance of wide clinical application also produces immediately, particularly become present serious clinical problem by the streptococcus aureus (MRSA) of Staphcillin resistance, the streptococcus pneumoniae (PRSP) of penicillin resistance and the transmissible disease that the resistance faecalis causes.Just because of this, strong request obtains new cephem microbiotic, to strengthen the microorganism active of these bacteriums of antagonism.
Transform on 7 side chains in the structure of modification of cynnematin and mainly contain cefotaxime acetic acid side chain series, as cefotaxime, rocephin;
Phenylglycine series is as Cephalexin Monohydrate Micro/Compacted, cefradine.And mainly concentrating on the C-3 position, the transformation of pharmacokinetics aspect introduces various functional groups.Current cynnematin structure of modification research field is comparatively active is modification to the C-3 position, the C3-of cephalosporin-group that the OAc group is contained S or N replaces, can improve and widen antibiotic effect, as sulfo-heterocyclic substituted on the 7-ACA3 position, can obviously strengthen cynnematin to the activity (Chinese microbiotic magazine, Vol.252 in 1988) of gram-positive microorganism and negative bacterium and improve stability to β-Nei Xiananmei.For example 3 be the tetrazole sulfydryl as cefoperazone, cefmetazole, 3 be the triazine sulfydryl as rocephin.3 be the thiadiazoles sulfydryl as Cephazolin, cefuzonam etc.C3 then can prolong metabolic half life for introducing acid functional group, reaches long-acting, and result of treatment efficiently is as rocephin, cefonicid.
Functional group is introduced in the C3 position of cephalosporin mother nucleus 7-ACA, obtain different intermediates, as these intermediates of 7-ACT, 7-TACS are commercial pharmaceutical intermediates in the prior art, the free amine group and the various thiocarbamide of these intermediates are carried out condensation, obtain the activity that a series of cephalosporins derivatives have anti-G+, G-, and to β-Nei Xiananmei stability and the wider drug metabolism phase.
C-3 substituting group used in the The compounds of this invention is known in the cephem field, but does not see in the past with C-7 substituting group among the present invention and combine.C-3 and the substituent combination of C-7 that the applicant finds in the The compounds of this invention to be provided have enlarged the cynnematin antimicrobial spectrum, have strengthened its activity to positive bacteria, thereby have had commercial viability.
Summary of the invention
The purpose of this invention is to provide the cepham streptozotocin derivative
Another object of the present invention provides the method for preparing cephalosporins derivatives
A further object of the present invention has provided pharmaceutical composition, the especially injection that this kind cephalosporins derivatives is made activeconstituents
A further object of the present invention has provided cephalosporins derivatives and has been used for the treatment of the gram positive bacteria infection purposes.
Technical solution of the present invention
Sulphur amidine acetamido cynnematin and/or its pharmacy acceptable salt that a kind of C3 methylene radical nitrogen heterocyclic ring replaces is characterized in that representing with following general formula
Wherein R1 is
Above-mentioned cynnematin is characterized in that a kind of unbound state, a kind of solvated compounds state.
Above-mentioned cynnematin, it is preferably the compound that following structural formula is represented:
Its chemistry 7a-((N, N-di-isopropyl) amidine sulphur acetamido) by name-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) methyl)-Cephalosporanic acid (cephalo piperazine amidine).
Above-described cephalo piperazine amidine can be its hydrobromate or amine salt.
The compound of general formula I also can be the compound of following structure:
The preparation method of the cynnematin of general formula I is characterized in that comprising:
1, the amino C-3 methyne of 7-nitrogen heterocyclic ring is replaced the dissolving of 4-carboxyl Cephalosporanic acid or be suspended in the appropriate solvent system; And, make solution molten fully clear with organic bases or mineral alkali regulator solution PH;
2, the settled solution with step 1 gained reacts with bromoacetyl bromide;
3, with the solution acidifying of step 2 gained;
4, with the same N of the product of step 3 gained, the two substituting thioureidos of N react;
5, the product that step 4 is obtained separates.
Described solvent is meant alkyl ketone, alkyl alcohol, the mixture of halogenated alkane or above-mentioned solvent.
Described alkyl ketone is meant acetone, methyl iso-butyl ketone (MIBK), and alkyl alcohol is meant methyl alcohol, ethanol, Virahol, and halogenated alkane is meant methylene dichloride.
The preparation method of described cynnematin, its organic bases is triethylamine, diethylamine, Tributylamine, tetramethyl guanidine, mineral alkali is sodium bicarbonate, yellow soda ash, NH
3Water etc.
The preparation method of described cynnematin, wherein hydrochloric acid, sulfuric acid, Glacial acetic acid, phosphoric acid are adopted in acidifying.
The preparation method of described cynnematin, wherein the amino C-3 methyne of 7-nitrogen heterocyclic ring replacement 4-carboxyl Cephalosporanic acid is selected from following compounds:
Described in the definition such as general formula I of R1.
N, the two substituting thioureidos of N are selected from following compounds:
The present invention also provides the preparation method of the cynnematin cephalo piperazine amidine with preferred construction formula II.It is characterized in that 7-amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) methyl sulphur))-reaction of Cephalosporanic acid and bromoacetyl bromide makes 7-acetobrom amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as triazine-3-yl) methyl sulphur))-Cephalosporanic acid, with N, the reaction of N di-isopropyl thiourea makes a kind of cynnematin with anti-microbial activity again.Its reaction formula is as follows:
Detailed preparation method may further comprise the steps
1, with 7-amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) sulphur) methyl)-Cephalosporanic acid (7ACT) dissolves or is suspended in the appropriate solvent system.
Described solvent can be moisture or aqueous solvent system not, as ketone C1-C6 alkyl ketone particularly, as acetone, methyl iso-butyl ketone (MIBK).Diethyl ketone; The alcohols of C1-C6: methyl alcohol, ethanol, Virahol etc., nitrile: as acetonitrile; The mixed solvent of acid amides such as N,N-DIMETHYLACETAMIDE, dimethyl formamide etc. or above-mentioned solvent.
2, step 1 is obtained solution and make the solution clarification with organic amine or mineral alkali adjusting PH.
Described amine is triethylamine, diethylamine, Tributylamine, and mineral alkali is yellow soda ash, sodium bicarbonate, ammoniacal liquor etc.
3, step 2 being obtained solution reacts with bromoacetyl bromide.
Every mole of 7-ACT needs the bromoacetyl bromide of 0.5-3.0ml, preferred 1.2-2.4ml.
Its temperature of reaction is 0-50 ℃ of preferred 10-40 ℃,
Its reaction times is 10-60 minute, obtains settled solution
4, the reaction solution acidifying that step 3 is obtained also separates.Wherein hydrochloric acid, sulfuric acid, Glacial acetic acid, phosphoric acid are adopted in acidifying.
5, the product that step 4 is obtained dissolves or is suspended in the solvent, and with N, the N di-isopropyl thiourea reacts;
The mol ratio of acetobrom 7ACT and thiocarbamide is the 1.0-4.0 mole, and preferred 1-2.5 mole more preferably pulls out the 1.2-1.8 mole, temperature of reaction 0-42 ℃, and reaction times 30-300 minute.
Described solvent is the halo alkanes, ketone, alcohols or their mixed solvent.
6, the product separation that step 5 is obtained.Separation adopts certain methods commonly used to make it the precipitation byproduct of reaction as the adding solvent and impurity then is dissolved in the solvent, and the product purity Gao Keda of gained is more than 90%.
Described solvent is a ketone, alcohols, nitrile or their mixture.Ketone such as acetone, methyl iso-butyl ketone (MIBK), alcohols such as methyl alcohol, ethanol, nitrile such as acetonitrile or their mixture
The present invention also comprises provides a kind of cephalosporin intermediate, and available following general formula is represented:
The R1 definition is the same.
Above-mentioned intermediates preparation is characterized in that general formula VI and bromoacetyl bromide reaction are made.Specifically finish by 1 to 4 step among the detailed preparation method.
The present invention also comprises a kind of pharmaceutical composition, and the described compound that it comprises general formula I or II is activeconstituents and pharmaceutically acceptable carrier.
Aforementioned pharmaceutical compositions is as antiseptic-germicide.
Experimental technique commonly used is adopted in the external antimicrobial experiment of The compounds of this invention, and its minimum inhibitory concentration MIC (mg/l) is as shown in the table.
| Compound I I | Compound III | Compound IV | Compound V | |
| Gold Portugal bacterium | 1-4 | ?0.25-0.5 | 0.25-2 | |
| Form staph | 0.0312-2 | 0.5-2 | ||
| A organizes Hemolytic streptococcus | 2-8 | 0.125-1 | ||
| B organizes Hemolytic streptococcus | ?0.25-4 | 0.5-1 | ||
| Streptococcus viridans | 0.125-4 | |||
| Faecalis | 4-8 | ?4-8 | 2-8 | |
| Micrococcus scarlatinae | ?0.125-1 | 0.0312-0.5 | ||
| Streptococcus pneumoniae | 0.125-0.5 | 0.25-0.5 | ||
| Salmonella | 8-16 | 2-8 | ||
| Shigella | ?＞64 | 16-256 | ||
| Pseudomonas aeruginosa | ＞512 | ?＞256 | ＞512 | |
| Hemophilus influenzae | 8-16 | ?8-64 | ＞256 |
As seen from the above table, The compounds of this invention is to golden Portugal bacterium, form staph, micrococcus scarlatinae, streptococcus pneumoniae, Hemolytic streptococcus equal altitudes sensitivity, to the faecalis sensitivity, to Salmonella, Shigella, hemophilus influenzae medium sensitivity or resistance, Pseudomonas aeruginosa there is not antibiotic activity, show that above-claimed cpd has strong or stronger anti-microbial activity to G+, G-has activity to part.
Above-claimed cpd is obtained by third generation cephalosporin such as rocephin, Cefodizime, cefonicid, ceforanide transformation, at the C3 that keeps them is that functional group is constant down, N is introduced in the C7 position, the N di-isopropyl thiourea, described third generation cephalosporin has good susceptibility to G-, as intestinal bacteria, hemophilus influenzae etc., but, most of G+ is comprised the susceptibility of faecalis is poor to the Pseudomonas aeruginosa resistance.
The invention has the beneficial effects as follows by 7 of cephalo parent nucleus and introduce N, the synthetic a series of cephem microbiotic of the two substituting thioureidos of N, this class cephem is compared with third generation cephalosporin, has obviously increased the anti-microbial activity to gram-positive microorganism, particularly golden Portugal bacterium, resistance enterococcus spp have enlarged antimicrobial spectrum.
Specific embodiment
The preparation of 7a-((N, N-di-isopropyl) amidine sulphur acetamido)-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) methyl)-Cephalosporanic acid (cephalo piperazine amidine)
One, the preparation of intermediate
Example 1
With 50ml toluene, 50ml water adds in the there-necked flask, add 5 gram C-21 (0) 7-amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl] sulphur] methyl]-Cephalosporanic acid (having another name called 7-ACT), drip the 3.4ml triethylamine, stirring makes it dissolving, adds bromoacetyl bromide 3ml, the 30m15%NaHCO3 aqueous solution, reacted 2 hours, leave standstill phase-splitting, organic phase discards, water is transferred PH=3 with hydrochloric acid, 0-10 ℃ of growing the grain 2 hours, suction filtration, vacuum-drying gets 4 gram 7-acetobrom amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl] sulphur] methyl]-Cephalosporanic acid.
Example 2
Vinyl acetic monomer, each 60ml of water, 5 gram 7-ACT are added in the there-necked flasks, and 0-10 ℃ adds triethylamine 3.4ml to be stirred to solid molten entirely, adds bromoacetyl bromide 4.0ml, adds the 2ml triethylamine, reaction is finished, and adds hydrochloric acid and transfers PH=3, separates out solid, growing the grain body 2 hours, suction filtration, vacuum-drying gets 3.3 grams.
Example 3
Acetonitrile, each 60-60ml of water, 5 gram 7-ACT add in the there-necked flask, and 0-10 ℃ adds triethylamine 3.6ml, is stirred to the solid dissolving, adds the 4ml bromoacetyl bromide, mends 30ml5%NaHCO
3The aqueous solution, reaction is finished, and adds hydrochloric acid and transfers PH=3, separates out solid, growing the grain 2 hours, suction filtration, vacuum-drying gets 4.9 gram products.
Example 4
Methylene dichloride, each 250ml of water, 5 gram 7-ACT go in the there-necked flask, and the dropping triethylamine is molten clear to solid, adds bromoacetyl bromide 4ml, there are a large amount of solids to separate out, reacted 2 hours, standing demix is finished in reaction, and organic phase discards, water is transferred PH=3 with hydrochloric acid, growing the grain 2 hours, suction filtration, the product water is washed and starched, vacuum-drying gets 3.2 grams to moisture 2.0%.
Example 5
Acetone, each 50ml of water, 5 gram 7-ACT drip triethylamine and make it molten clear, add bromoacetyl bromide 4.0ml, add 5%NaHCO simultaneously
3Water 100ml reacted 1 hour, and reaction is finished, and transferred PH to 3 with hydrochloric acid, and a large amount of solids are separated out, growing the grain 2 hours, and suction filtration, product washes vacuum-drying with water, draws 4 grams.
Two, the preparation of product cephalo piperazine amidine
Example 1
There-necked flask adds methylene dichloride 200ml, C-21 (1) 2.0 restrains, drips a triethylamine 16ml and makes it to dissolve, add N, N-di-isopropyl thiourea 0.6 gram, back flow reaction is to reacting completely, and solid is separated out, cooling growing the grain 1 hour, suction filtration, vacuum-drying get 1.5 gram title compounds, PH=5.4, turbidity＜No. 1 (1 gram is dissolved in the 10ml water), product is very easily water-soluble.
HNMR (DMSO-d
6, 500Hz): 1.13 (m, 12H ,-CH-CH
3), 3.03 (q, 2H, J=22.0,7.0Hz ,-S-NH-CH-), 3.04,3.61 (d, 2H, the AB type, J=17.5Hz, C2-H), 3.58 (s, 3H ,-N-CH3), 3.88 (m, 4H ,-S-CH2-CO-,-CH-CH3), 4.15,4.35 (d, the 2H.AB type, J=12.5Hz ,-CH2-S-), 5.02 (d, 1H, J=5.0Hz, C6-H), 5.54 (d, 1H, J=4.5Hz, C7-H), 9.38 (s, 1H ,-NH-).
Example 2
Add 100ml methylene dichloride 100ml acetone 2 gram C-21 (1) in the there-necked flask, 0-10 ℃ drips diethylamine 1.4ml and makes it dissolving control PH5.0-7.5, adds thiocarbamide 0.8 gram, and back flow reaction is to reacting completely, growing the grain, suction filtration, vacuum-drying, 2.3 gram title compounds.HNMR result is with example 1.
N, N-diisopropylamidinateand sulphur acetamido-3-(5-carboxymethyl-4-methyl isophthalic acid, 3-thiazole-2-thiopurine methyltransferase) Cephalosporanic acid synthetic
One, the preparation of intermediate
5 gram TACS (7-amino-3-(5-carboxymethyl-4-methyl isophthalic acid, 3-thiazole-2-thiopurine methyltransferase) Cephalosporanic acid) (0.0124mole) add 50ml acetone and 80ml water, stir 0-5 ℃ of temperature control, drip 1.8ml triethylamine (0.013mole), finish.0.5 hour solid is molten clear, adds solid sodium bicarbonate 3.5 grams, drips 2.3ml bromoacetyl bromide (0.026mole) simultaneously, finishes reaction 1.5 hours in batches.Add 1 gram gac, stir decolouring 0.5 hour, suction filtration is washed carbon-coating with 10ml.Merge water, transfer PH=2-2.5 with 3N hydrochloric acid, separate out solid, 0-5 ℃ was stirred growing the grain 1 hour, and suction filtration, solid wash with water to PH=3,50 ℃ of vacuum-drying (＜0.08MPa ", acetobrom TACS5 gram, yield 77%.
Two, the preparation of product
In the 50ml methylene dichloride, add 5 gram acetobrom TACS (0.0096mole), stir temperature control and drip 1 for 0-5 ℃.The 6ml triethylamine, molten clear after 0.5 hour, add 1.9 gram N, N-di-isopropyl thiourea (0.0118mole), be warming up to 38-40 ℃ and be back to thiocarbamide and dissolve fully, refluxed about 0.5 hour and separate out yellow solid, insulation reaction 1.5 hours, lower the temperature then 0-5 ℃ and stirred growing the grain 1 hour, suction filtration, product washes twice with the 10ml methylene dichloride, and 75ml acetone is washed 2 times, 35 ℃ of vacuum-drying (＜0.08MPa〉target compound 4.2 grams, yield 75%.
Following compounds III, IV are, and to be starting raw material with commercial intermediate VI make according to the preparation method of cephalo piperazine amidine.
Wherein R1 is
Structural formula is as follows:
Nuclear magnetic resonance data is:
3.03,3.60 (d, 2H, the AB type, J=17.5Hz, C2-H)
5.00(d，1H，J＝5.9Hz，C6-H)
5.56(d，1H，J＝4.5Hz，C7-H)
9.36(s，1H，-NH-)
Nuclear magnetic resonance data is:
3.05,3.63 (d, 2H, the AB type, J=17.5Hz, C2-H)
5.04(d，1H，J＝5.9Hz，C6-H)
5.56(d，1H，J＝4.5Hz，C7-H)
9.40(s，1H，-NH-)。
Claims (10)
1, a kind of amidine sulphur acetamido cynnematin or its pharmacy acceptable salt of C3 methylene radical nitrogen heterocyclic ring replacement is characterized in that representing with following general formula:
Wherein R1 is
2, the amidine sulphur acetamido cynnematin of the described C3 methylene radical nitrogen heterocyclic ring replacement of claim 1 is characterized by following structural formula and represents:
Or
Or
Or
3, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 1 nitrogen heterocyclic ring replacement is characterized in that comprising:
(1), the amino C-3 methylene radical of 7-nitrogen heterocyclic ring is replaced the dissolving of 4-carboxyl Cephalosporanic acid or be suspended in the appropriate solvent system; And, make solution molten fully clear with organic bases or mineral alkali regulator solution PH;
(2), step 1 gained settled solution is reacted with bromoacetyl bromide;
(3), with the solution acidifying of step 2 gained;
(4), with the same N of product of step 3, the two substituting thioureidos of N react;
(5), the product that step 4 is obtained separates.
4, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, its solvent is meant the mixture of alkyl ketone, alkyl alcohol, haloalkane or above-mentioned solvent.
5, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, its organic bases is triethylamine, diethylamine, Tributylamine, tetramethyl guanidine, mineral alkali is yellow soda ash, sodium bicarbonate, ammoniacal liquor etc.
6, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, wherein hydrochloric acid, sulfuric acid, Glacial acetic acid, phosphoric acid are adopted in acidifying.
7, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, wherein the amino C-3 methylene radical of 7-nitrogen heterocyclic ring replacement 4-carboxyl Cephalosporanic acid is selected from following compounds:
The definition of R1 is described with claim 1;
N, the two substituting thioureidos of N are selected from following compounds:
8, a kind of cephalosporin intermediate, available following general formula is represented:
The definition of R1 is described with claim 1.
9, the preparation method of the described cephalosporin intermediate of claim 8 is characterized in that general formula VI and bromoacetyl bromide reaction are made.
10, a kind of antibacterial combination, the described compound that it comprises claim 1 or 2 is activeconstituents and pharmaceutically acceptable carrier.
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| CN101434611B (en) * | 2007-11-12 | 2013-01-09 | 广州市医药工业研究所 | Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof |
| CN111116610A (en) * | 2019-12-27 | 2020-05-08 | 广药白云山化学制药(珠海)有限公司 | Production method of cefoperazone sodium |
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| US7700581B2 (en) * | 2007-01-31 | 2010-04-20 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. | Cephalosporin compounds comprising a C3 thio-methyl moiety substituted with N-containing heterocyclic group, and a C7 thiourea acetamido group, their preparations and uses thereof |
| CN101555463B (en) * | 2008-04-08 | 2012-05-30 | 中国科学院上海生命科学研究院湖州工业生物技术中心 | Recombinant escherichia coli strain expressing cephalosporin deacetylase and construction method thereof |
| US20110118462A1 (en) * | 2009-11-18 | 2011-05-19 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory | N-heterocyclic substituent-containing antibiotic, preparation and use thereof |
| CN105461739B (en) * | 2014-09-09 | 2019-03-29 | 广州白云山医药集团股份有限公司白云山制药总厂 | Crystalline cephem piperazine amidine sodium and its preparation method and application |
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| CN1431211A (en) * | 2003-01-28 | 2003-07-23 | 广州白云山制药股份有限公司 | Amine salt of cefathiamiding, its preparing method and application |
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| CN1431211A (en) * | 2003-01-28 | 2003-07-23 | 广州白云山制药股份有限公司 | Amine salt of cefathiamiding, its preparing method and application |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101434611B (en) * | 2007-11-12 | 2013-01-09 | 广州市医药工业研究所 | Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof |
| CN111116610A (en) * | 2019-12-27 | 2020-05-08 | 广药白云山化学制药(珠海)有限公司 | Production method of cefoperazone sodium |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160418 Address after: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the same road No. 78 Patentee after: White Cloud Mountain chemical pharmaceutical factory of Guangzhou Baiyunshan Pharmaceutical Group Co., Ltd. Patentee after: Guangzhou Baiyun Mountain Pharmaceutical Group Limited by Share Ltd Address before: Baiyun District of Guangzhou City, Guangdong province 510515 and Yunxiang Road No. 88 Patentee before: Baiyuanshan Pharmaceutical Co Ltd, Guangzhou |