CN101265214B - Methylophtocillin ester and its salts, and preparation method, application and pharmaceutical composition thereof - Google Patents
Methylophtocillin ester and its salts, and preparation method, application and pharmaceutical composition thereof Download PDFInfo
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- CN101265214B CN101265214B CN200810097818.4A CN200810097818A CN101265214B CN 101265214 B CN101265214 B CN 101265214B CN 200810097818 A CN200810097818 A CN 200810097818A CN 101265214 B CN101265214 B CN 101265214B
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Abstract
The invention relates to methyl chrysogenin ester as well as salts thereof, a preparation method thereof as well as the application on tuberculosis resistance, and a medicine compound.
Description
Technical field
The present invention relates to new p-dimethylamino-azo-benzene penicillin ester and salt compounds, its preparation method and application and pharmaceutical composition.
Background technology
Tuberculosis is a kind of disease of serious harm people life and health, and incidence of tuberculosis is obvious ascendant trend in recent years.
Resistance especially multidrug resistance tubercule bacillus increases fast.Mycobacterium tuberculosis drug-resistant rate reaches 20%-50%, and multidrug resistance rate reaches 5%-20%.Drug Resistance for Tuberculosis situation is very serious.China's tubercule bacillus initial drug resistant rates is 28.1%, and secondary resistant rate is 41.1%, and wherein the ratio of Multidrug resistant bacteria, up to 15%, has exceeded the barrier line that WHO specifies.In addition, the HIV patient of China increases sharply, and HIV and tuberculosis accompanying infection have increased the weight of tuberculosis epidemic situation.
The first-line drug using in current clinical antituberculosis therapy is still some traditional antitubercular agents, comprises vazadrine, Rifampin, Streptomycin sulphate etc.But along with being widely used of these medicines, the continuous increase of resistance and Multidrug resistant bacteria, these traditional antitubercular agents have lost their original curative effects gradually, according to statistics, the resistant rate of vazadrine, Rifampin, Streptomycin sulphate, EMB, TH has reached respectively 14.4%, 10.6%, 21.1%, 2.4%, 3.7% at present; That develops in recent years has also reached 30-40% as novel carbostyril medicine Ciprofloxacin, the ofloxacin of tuberculotherapy two wires medicine and the resistant rate of sparfloxacin.Existing antitubercular agent has been difficult to the tuberculosis of the resistant organism initiation of controlling continuous appearance
DNA gyrase B subunit is a very significant target spot in research antitubercular agent.DNA gyrase is distinctive a kind of topoisomerase in bacterium, is made up of A subunit and B subunit, and respectively by gyrA and gyrB genes encoding, natural organized enzyme is by two A subunits and two tetramers that B subunit forms.The A of DNA gyrase, B subunit all contain its specific structure and function district, are jointly determining the biological function of enzyme.This enzyme catalysis utilizes closed hoop double-stranded DNA negative supercoiling reaction of ATP etc. a series of about the conversion reaction between DNA molecular and topological isomer, by bacteria live necessary.
Known quinolones and coumarins medicine are the inhibitor of DNA gyrase, and the former acts on A subunit, and the latter acts on B subunit.Coumarin kind compound is as Vulkamycin. PA-93, there is high-affinity with the B subunit of DNA gyrase, and only have B subunit to have the binding site of Vulkamycin. PA-93, their combination changes the conformation of enzyme molecule, forming a kind ofly stable has the conformation compared with low-affinity with ATP, disturb the energy coupling of ATP in negative supercoiling reaction, thereby suppress the activity of gyrase.
The inventor has carried out taking DNA gyrase B subunit as target spot and has set up screening model, sets up the research of the medicaments sifting model that DNA gyrase B subunit is target spot with mycobacterium.
It is target spot that the present invention adopts mycobacterium DNA gyrase B subunit, the antitubercular agent screening model of target resistance tubercule bacillus, (for example from 7200 parts of microorganisms, find excellent aspergillus Aspergillus clavatus, purchased from the microorganism of preserving number CGMCC 3.1290) fungal fermented filtrate crude extract there is significant anti-tubercle bacillus activity, its mechanism of action is to suppress DNA gyrase activity, and action target spot is DNA gyrase B subunit.Rod aspergillus Aspergillus clavatus crude extract shows stronger activity specific to mycobacterium, and gram negative bacterium, yeast and fungi are not had to activity (Chinese microbiotic magazine 2004; 29 (12): 742-745.).Excellent aspergillus Aspergillus clavatus crude extract is separated and structural research shows, its anti-tubercle bacillus activeconstituents is new p-dimethylamino-azo-benzene penicillin xanthocillin X monomethyl ether compounds.
The known p-dimethylamino-azo-benzene penicillins compound obtaining from nature has xanthocillin X monomethyl ether at present, xanthocillin X dimethyl ether, methoxy-xanthocillin X dimethyl ether are external has anti-microbial activity, antitumor and antivirus action (J Antibiot (Tokyo) .1968Dec to part gram positive bacterium; 21 (12): 671-5., J Antibiot (Tokyo) .1968 Dec; 21 (12): 676-80.); MK4588 have the resisting gram-positive of narrow spectrum and negative bacterium activity (
j antibiot (Tokyo).1990May; 43 (5): 456-61.); BU-4704 has resisting gram-positive and weak anti-Gram-negative bacteria activity (J Antibiot (Tokyo) .1993Apr; 46 (4): 687-88.).What BU-4704 provided is two dimensional structure, and two isonitrile base configurations are uncertain.Compound structure shown in Chinese style 1 of the present invention is molecule relative configuration, and two isonitrile bases are at heteropleural.Its fusing point and spectral data and BU-4704 have different.P-dimethylamino-azo-benzene penicillin and derivative thereof have produced multinomial patent at anti-microbial activity, antitumor and anti-virus aspect:
1. xanthocillin extraction and separation technology patent:
(1) nineteen sixty Production Flow Chart patent that April 12, Gerhard Barwald applied for xanthocillin, the publication number NO.:GB898.198 of EUROPEAN PATENT OFFICE (esp@cenet), application number: GB19600013099 19600412. priority numbers: GB19600013099 19600412
(2) 1966 years R.Bergkvist have obtained the patent of xanthocillin separation and extraction technology, the patent No.: the No.US3 of EUROPEAN PATENT OFFICE (esp@cenet), 281,331 October 25 1966 date, other publication numbers of same Patent: CH441198,, FI42062B
2. compound patent:
(1) 1993 year May 11, everyday the people such as this scientist Kurihara obtained the compound patent of xanthocillin (XME, XDE and XTE), the patent No.: United States PatentNO.5,210,097 dates: on May 11st, 1993
The patent that (2) 2005 years Japanese Nissan Miyaji et al of Chemical Co., Ltd. have applied for xanthocillin derivative (structural formula is as Fig. 3), patent publication No.: US Patent Pub NO.US2005/02822730 A1 (Thrombopoetin Receptor Activator and Processfor Producing the Same)
3. antitumor Patents
May 17 in 1994, everyday the people such as this scientist Tsutomu Tsuruoka obtained the patent that xanthocillin is used for the treatment of tumour, in experiment, be surprised to find that to be recognized to there is the xanthocillin of anti-microbial effect and its derivative compound and have the blocking-up activity of high aromatizing enzyme always, can be used for the treatment of hormone-dependent diseases.Comprising treatment mammary cancer, men and women's diseases such as prostatitis, US Patent[19] No.5,312,833 dates: on May 17th, 1994
4. the patent of thrombocytopoiesis receptor activators
The Miyaji et al of Nissan Chemical Co., Ltd. in 2005 has applied for that xanthocillin derivative has the active patent of thrombocytopoiesis receptor activators, the patent No.: US Patent PubNO.US 2005/02822730 A1 (Thrombopoetin Receptor Activator andProcess for Producting the Same)
5. xanthocillin is as the Patents of aromatase inhibitor
Nineteen ninety-five Japan scientist NAKAYAMA MASAJI at el has applied for the patent of xanthocillin as aromatase inhibitor, application number: JP19930237140 19930831; Priority number: JP19930237140 19930831 date of publications: March 14 nineteen ninety-five
6. xanthocillin X is as the patent of wormer
The high wood of nineteen ninety Mingzhi pharmaceutical Co. Ltd of Japan has been applied for the patent of xanthocillin X as wormer, is mainly to act on globefish, horse, ox, sheep, dog, the meeting in the poultry bodies such as cat causes host's anaemia, malnutritive, body void, the multiple parasites such as the low inferior blood sucker of Fertility, EUROPEAN PATENT OFFICE, patent publication No.: JP2040324. application number: JP1988018672019880728. priority number: JP19880186720 19880728 Japanese patent gazette, NO. Unexamined Patent 2-40324
Do not find p-dimethylamino-azo-benzene penicillin sulfuric ester and its esters compound and preparation method thereof, with and there is the pertinent literature of anti-tubercle bacillus and the report of patent.
The p-dimethylamino-azo-benzene penicillin ester that the object of the invention is to provide new and salt compounds thereof and preparation method thereof, with and the application in anti-tubercle bacillus and the pharmaceutical composition that contains p-dimethylamino-azo-benzene penicillin ester and salt compounds thereof.
Summary of the invention
A first aspect of the present invention, relate to be new compound p-dimethylamino-azo-benzene penicillin ester and pharmacy acceptable salt class thereof structure as shown in Equation 1.
Formula 1
Wherein, R represents C
2-C
10containing ring or containing ring acyl group, C
1-C
5alkylsulfonyl, (C
1-C
6alkyl or halogen) replace or unsubstituted benzenesulfonyl, amino acid acyl ,-HSO
3,-H
2pO
3, and the salt of they and metal or nonmetal formation.
The present invention be more particularly directed to as p-dimethylamino-azo-benzene penicillin sulfuric ester and pharmacy acceptable salt thereof, the particularly sodium of p-dimethylamino-azo-benzene penicillin sulfuric ester, potassium or ammonium salt one of in above-mentioned formula 1.
A second aspect of the present invention, relating to and containing p-dimethylamino-azo-benzene penicillin ester and the salt compounds thereof for the treatment of significant quantity is the pharmaceutical composition of effective constituent and one or more pharmaceutical carriers.
A third aspect of the present invention, relates to a kind of p-dimethylamino-azo-benzene penicillin ester and salt compounds thereof in the application of preparing in antitubercular agent.
A fourth aspect of the present invention, relates to the preparation method of a kind of p-dimethylamino-azo-benzene penicillin sulfuric ester and salt compounds thereof, mainly comprises the following steps:
A: cultivate: the fungi microbe of cultivating the excellent aspergillus Aspergillus clavatus with generation p-dimethylamino-azo-benzene penicillin sulfuric ester ability in substratum makes it to generate in culture and accumulation.
Substratum in step a is the nutrition source that adopts microorganism used therefor to utilize, and wherein carbon source can adopt glucose, sucrose, starch, glycerine, can be used in combination; Nitrogenous source is used in combination peptone, soybean cake powder, cottonseed meal, blood and freezes, and can suitably add sodium salt, sylvite, phosphoric acid salt, polyoxyethylene glycol in addition; Cultural method is the liquid cultivating method of concussion, aeration-agitation; Medium liquid pH=6.0 in step a in addition; Substratum temperature remains on 25-30 DEG C of incubation time 3-5 days.
B: separate
From fermented liquid, extract the crude extract that separates the salt that contains p-dimethylamino-azo-benzene penicillin sulfuric ester according to the general extraction and separation method of tunning.
General extraction and separation method described in step b comprises solvent extraction, macroporous adsorbent resin, chromatography.First filter or the centrifugal mycelium of removing, fermented liquid adopts absorption with macroporous adsorbent resin, by p-dimethylamino-azo-benzene penicillin sulfuric ester absorption macroporous adsorbent resin, then is eluted as elutriant with the organic solvent that comprises ethyl acetate-acetone.Elutriant adds respectively appropriate Potassium ethanoate, sodium-acetate or ammonium acetate according to salt such as the required sodium obtaining, potassium, ammoniums, under 0-25 DEG C of condition, stir 2-5h, reclaim under reduced pressure ethyl acetate-acetone under 0-25 DEG C of condition, residuum carries out lyophilize, obtains potassium, the sodium of p-dimethylamino-azo-benzene penicillin sulfuric ester, the crude extract of ammonium salt class.
C: refining
Further the salt of separation and purification p-dimethylamino-azo-benzene penicillin sulfuric ester, adopts general micromolecular compound separation and refining method.
Process for purification described in step c is to adopt silica gel adsorption chromatography, taking ethyl acetate-acetone as eluent, can add in right amount a small amount of DMSO; And the reversed phase chromatography of ODS bonding type silica gel, taking acetonitrile-water or methanol-water as eluent.In treating process, the confirmation of the salt of p-dimethylamino-azo-benzene penicillin sulfuric ester adopts bioassay method and the high performance liquid chromatography (HPLC) coupling of p-dimethylamino-azo-benzene penicillin sulfuric ester microbiostatic activity.
D.: the preparation of p-dimethylamino-azo-benzene penicillin sulfuric ester
The salt obtaining from above-mentioned steps is dissolved in DMSO, adds rare acid for adjusting pH to obtain p-dimethylamino-azo-benzene penicillin sulfuric ester.
P-dimethylamino-azo-benzene penicillin sulfuric ester structural identification and data:
P-dimethylamino-azo-benzene penicillin sulfuric ester is white crystal, the iodine vapor color reaction positive.Fusing point: 157-162 DEG C (decomposition); High resolution mass spectrum ESI-MS
-show that molecular weight is: 382.05480, molecular formula is: C19H14N205S.
1hNMR,
13cNMR shows to contain in molecule two A
2b
2fragrance Coupling System, two isolated double bonds and methoxyl group signal,
13cNMR data show in molecule simultaneously and contain and replace the unsaturated phenylpropyl alcohol isonitrile of α, β feature.
ESI-MS-：381.05480(M-1)，301.09831M-SO3)，286.07503(M-SO3-CH3)，274.08770(M-SO3-HCN)，259.06417(M-SO3-CH3-HCN)。
1HNMR：7.87(2H，d，J＝9.0Hz，2″、6″)，7.80(2H，d，J＝9.0Hz，2′、6′)，7.31(1H，S，4-H)，7.30(1H，S，1-H)，7.19(2H，d，J＝9.0Hz，3″、5″)，7.11(2H，d，J＝9.0Hz，3′、5′)，3.83(3H，s，Ar-OCH
3)。
13cNMR data are in table 1.
Table 1 p-dimethylamino-azo-benzene penicillin sulfuric ester
13cNMR data
Anti-tubercle bacillus determination of activity
1. materials and methods
(1) tested medicine: as compound of the present invention: the sodium salt of p-dimethylamino-azo-benzene toximycin sulfuric ester, p-dimethylamino-azo-benzene toximycin sulfuric ester and the sylvite of p-dimethylamino-azo-benzene toximycin sulfuric ester;
Contrast drug isoniazid (INH) and Rifampin (RFP) are Sigma company product.
(2) experimental strain: mycobacterium tuberculosis type strain H
37rv is for preserving bacterial strain in this chamber.
(3) substratum: 7H9 liquid nutrient medium (Difco company product).
(4) method: aseptic 96 orifice plate (Falcon3072; Becton Dickinson, LincolnPark, N.J.), 200 μ l aqua sterilisas add in each hole of surrounding of 96 orifice plates, to prevent the composition evaporation of each experimental port in culturing process.INH is with aseptic distillation water dissolution, compound of the present invention and RFP are with dmso solution, and making concentration is the first solution of 6.4mmg/ml, and diluting with 7H9 substratum (not containing tween-80) is required each two times of concentration, add 96 orifice plate 100 μ l, compound final concentration is: 0.5,1,2,4,8,16,32 μ g/ml.0.006,0.0125,0.025,0.05,0.1,0.2, μ g/ml, INH and RFP final concentration are:.Mycobacterium tuberculosis H37Rv, 100 μ l are inoculated in every hole, and the final concentration of bacterium is 1 × 10
5cFU/ml.On every plate, all establish 2 not containing the growth control hole of antimicrobial drug, 96 orifice plates are hatched in 37 DEG C.After 7 days, add the mixed solution of growth control hole 20 μ l 10 × Alamar Blue (Setotec company product) and 5% Tween80 50 μ l, 37 hatch 24 hours, if color becomes pink colour from blueness, in the hole of each Experimental agents, add Alamar Blue and the Tween80 mixed solution of above-mentioned amount, hatch the color in the 24 each holes of hour record for 37 DEG C, MIC is defined as the minimal inhibitory concentration that stops colour-change (becoming pink from blueness).
2. result
The minimal inhibitory concentration (MIC) that MABA method is measured is as table 2.
The minimal inhibitory concentration (MIC) that table 2 MABA method is measured
Under this experiment condition, the sodium salt of p-dimethylamino-azo-benzene toximycin sulfuric ester, p-dimethylamino-azo-benzene toximycin sulfuric ester and the sylvite of p-dimethylamino-azo-benzene toximycin sulfuric ester are to mycobacterium tuberculosis type strain H
37the MIC of Rv is respectively 1 μ g/ml, 4 μ g/ml and 2 μ g/ml, and the MIC of INH and RFP is respectively 0.025 μ g/ml and 0.0125 μ g/ml.
Brief description of the drawings
The high resolution mass spectrum of Fig. 1 p-dimethylamino-azo-benzene penicillin sulfuric ester
The high resolution multi-stage ms of Fig. 2 p-dimethylamino-azo-benzene penicillin sulfuric ester
Fig. 3 p-dimethylamino-azo-benzene penicillin sulfuric ester
1hNMR collection of illustrative plates
Fig. 4 p-dimethylamino-azo-benzene penicillin sulfuric ester
13cNMR collection of illustrative plates
Fig. 5 p-dimethylamino-azo-benzene penicillin sulfuric ester
1h-
1h COSPY collection of illustrative plates
Specific embodiments
Example is below applicable to further illustrate the present invention, but does not mean that the present invention only limits to this.
The concrete preparation method of the sodium salt of p-dimethylamino-azo-benzene penicillin sulfuric ester and p-dimethylamino-azo-benzene penicillin sulfuric ester, the sylvite of p-dimethylamino-azo-benzene penicillin sulfuric ester is as follows:
Prepare example 1: substratum composition
A. slant medium
Sabouraud substratum: glucose 4%, peptone 1%, agar 1.5%, pH5.6.
B. first order seed substratum
Glycerine 1%, KH
2pO
40.03%, glucose 1%, Zulkovsky starch 1%, sucrose 1%, analysis for soybean powder 0.2%, polyethylene glycol 6000 0.25%, NaNO
30.3%, peptone 1%, (NH
4)
2sO
40.03%, pH6.0 (generally cultivate basigamy is complete reaches 6.0 naturally).
C. secondary seed medium (with one-level seed culture medium)
D. fermention medium (with one-level seed culture medium, tank top fermentation adds 3/10000ths defoamers again)
Prepare example 2: cultural method
Bacterium access first order seed substratum (20% loading amount of picking appropriate (picking nail cover size in general 500ml shaking flask) from the good excellent aspergillus Aspergillus clavatus fungi inclined-plane of fresh culture, 500ml shaking flask), in first order seed shaking flask, need to add appropriate granulated glass sphere, agglomerating in order to prevent mycelium, cultivate 48 hours shaking speed 200rpm/s for 28 DEG C.First order seed substratum proceeds to secondary seed medium (20% loading amount, 500ml shaking flask), and inoculum size 5% without adding granulated glass sphere, is cultivated 24 hours shaking speed 200rpm/s for 28 DEG C in current shaking flask.Secondary seed medium proceeds to fermention medium, inoculum size 10%, and dissolved oxygen remains on more than 30%, cultivates about 78-80 hour for 28 DEG C, and fermentation pH approaches at 7.7 o'clock and puts tank.
Prepare example 3: the preparation of the sylvite of p-dimethylamino-azo-benzene penicillin sulfuric ester
Get fungi rod aspergillus Aspergillus clavatus fermented product 50L, refrigeration 12h, filter, filtrate is flow through the chromatography column that packs in advance 2L HP20 macroporous adsorbent resin into the speed of 20ml/min under 4 DEG C of conditions, after having adsorbed, adopt successively 20L water, 10L 30% acetone drip washing HP20 resin, then adopt 6L ethyl acetate-acetone 3: 7 (V/V) mixing solutions wash-out, substep is collected elutriant, 100ml/ bottle.Merge contain p-dimethylamino-azo-benzene penicillin sulfuric ester elutriant, add Potassium ethanoate 0.6g, stir 3h, then at 5 DEG C of following decompression ethyl acetate-acetone, reclaim the residuum lyophilize after ethyl acetate-acetone, obtain the crude extract of the potassium salt compound that 20g contains p-dimethylamino-azo-benzene penicillin sulfuric ester.
The crude extract of the potassium salt compound that 18g is contained to p-dimethylamino-azo-benzene penicillin sulfuric ester is dissolved in 200ml ethyl acetate, under subzero 16-18 DEG C condition, carry out silica gel column chromatography, use successively ethyl acetate 500ml, ethyl acetate-acetone (9: 1, V/V) 300ml, ethyl acetate-acetone (8: 2, V/V) 1000ml wash-out, 8: 2 wash-out positions of the ethyl acetate-acetone of the potassium salt compound that contains p-dimethylamino-azo-benzene penicillin sulfuric ester are merged, 5 DEG C are evaporated to 1/10 of original volume below, the concentrated silica gel column chromatography repeatedly that carries out of liquid, the elutriant of the potassium salt compound that contains p-dimethylamino-azo-benzene penicillin sulfuric ester is concentrated, crystallization under refrigerated condition, obtain the potassium salt compound crystal of p-dimethylamino-azo-benzene penicillin sulfuric ester, by ethyl acetate washing several for the potassium salt compound crystal of p-dimethylamino-azo-benzene penicillin sulfuric ester, filter, obtain the potassium salt compound sterling 100mg of white p-dimethylamino-azo-benzene penicillin sulfuric ester.
Prepare the preparation of the sodium salt of example-4 p-dimethylamino-azo-benzene penicillin sulfuric ester
Get fungi rod aspergillus Aspergillus clavatus fermented product 50L, refrigeration 12h, filter, filtrate is flow through the chromatography column that packs in advance 2L HP20 macroporous adsorbent resin into the speed of 20ml/min under 4 DEG C of conditions, after having adsorbed, adopt successively 20L water, 10L 30% acetone drip washing HP20 resin, then adopt 6L ethyl acetate-acetone 3: 7 (V/V) mixing solutions wash-out, substep is collected elutriant, 100ml/ bottle.Merge contain p-dimethylamino-azo-benzene penicillin sulfuric ester elutriant, add sodium-acetate 0.8g, stir 3h, then at 5 DEG C of following decompression ethyl acetate-acetone, reclaim the residuum lyophilize after ethyl acetate-acetone, obtain the crude extract of the sodium salt compound that 20g contains p-dimethylamino-azo-benzene penicillin sulfuric ester.
The sodium salt crude extract of 18g p-dimethylamino-azo-benzene penicillin sulfuric ester is dissolved in 400ml ethyl acetate, under subzero 16-18 DEG C condition, carry out silica gel column chromatography, use successively ethyl acetate 500ml, ethyl acetate-acetone (9: 1, V/V) 300ml, ethyl acetate-acetone (8: 2, V/V) 1000ml wash-out, 8: 2 wash-out positions of the ethyl acetate-acetone of the sodium salt compound that contains p-dimethylamino-azo-benzene penicillin sulfuric ester are merged, be concentrated into 1/10 of original volume, the concentrated silica gel column chromatography repeatedly that carries out of liquid, the elutriant of the sodium salt compound that contains p-dimethylamino-azo-benzene penicillin sulfuric ester is concentrated, crystallization under refrigerated condition, obtain the sodium salt compound crystal of p-dimethylamino-azo-benzene penicillin sulfuric ester, by ethyl acetate washing several for the sodium salt compound crystal of p-dimethylamino-azo-benzene penicillin sulfuric ester, filter, obtain the sodium salt pure compounds 80mg of white p-dimethylamino-azo-benzene penicillin sulfuric ester.
Prepare the preparation of example-5 p-dimethylamino-azo-benzene penicillin sulfuric ester
The sylvite 25mg of p-dimethylamino-azo-benzene penicillin sulfuric ester, be dissolved in 10ml ethyl acetate-methyl-sulphoxide=9: in 1 mixed solvent, under-5 DEG C of conditions, drip 0.1M hydrochloric acid 0.6ml, maintain the temperature at-5 DEG C and stir after 15min, add to be in advance refrigerated to the ethyl acetate 50ml of-10 DEG C, ice-water mixture 50ml, after violent jolting, separates ethyl acetate layer fast, after ice for ethyl acetate layer-water mixture 50ml washs fast, 4 DEG C of conditions add anhydrous sodium sulfate drying to spend the night.The dry ethyl acetate solution of filtering sodium sulfate fast decompression under-10 DEG C of conditions is concentrated into dry, obtains p-dimethylamino-azo-benzene penicillin sulfuric ester 8mg.
Claims (2)
1. p-dimethylamino-azo-benzene penicillin ester as shown in Equation 1 and pharmacy acceptable salt class thereof are for the preparation of suppressing tubercule bacillus and preventing and treating the application in the medicine in tuberculosis;
Wherein, represent-HSO of R
3.
2. the application of claim 1, wherein said p-dimethylamino-azo-benzene penicillin ester and pharmacy acceptable salt class thereof are sodium, potassium or the ammonium salts of p-dimethylamino-azo-benzene penicillin sulfuric ester.
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