CN101152195B - Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection - Google Patents
Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection Download PDFInfo
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- CN101152195B CN101152195B CN2007101328564A CN200710132856A CN101152195B CN 101152195 B CN101152195 B CN 101152195B CN 2007101328564 A CN2007101328564 A CN 2007101328564A CN 200710132856 A CN200710132856 A CN 200710132856A CN 101152195 B CN101152195 B CN 101152195B
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- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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Abstract
The invention provies an application of an aminoglycoside antibiotic in preparing drug combination to treat drug-resistant bacteria infection, belonging to the aminoglycoside antibiotic application technical field. The invention provides the application method of 2'-NH<SUB>2</SUB>-3',4'-dideoxy aminoglycoside antibiotic1-N-acyl derivatives and the preparation methods of the derivatives and agentsof the product.
Description
Technical field
The application of a kind of aminoglycoside antibiotics in the Pharmaceutical composition of preparation treatment drug-fast bacteria infection belongs to the aminoglycoside antibiotics applied technical field.The present invention relates to have 2 '-NH
2-3 ', the 1-N-acylated derivatives and the application in preparation antimicrobial agent Pharmaceutical composition thereof of the aminoglycoside antibiotics of 4 '-two deoxidation structures.
Background technology
Document 1CN1420120A,
Document 2ZL93112412.3,
Document 3ZL01133701.X,
Document 4USP4117221,
Document 5USP4230847,
Document 6USP5442047.
Since the aminoglycoside antibiotics listing, its broad spectrum antibiotic activity is especially to the show strong antibacterial action of gram negative bacteria, to have good synergism and their main ears, nephrotoxicity to have predictable with widely used beta-lactam antibiotic clinically, thereby becomes an indispensable clinically class antibiotic.
In order to reduce toxicity and enhancing to the activity of fastbacteria, also developed some semi-synthetic aminoglycoside antibioticss, as arbekacin, isepamicin, etimicin, netilmicin, their structural formula is as follows:
AHB=(s)-4-amino-2-maloyl group,
AHP=(s)-3-amino-2-hydroxyl propiono,
Arbekacin (1-N-AHB-dibekacin):
Isepamicin (1-N-AHP-Gentamicin B):
Etimicin (1-N-ethyl gentamicinC la):
Netilmicin (1-N-Netilmicin):
In recent years, along with being extensive use of of all kinds of antibacterials, induce many Resistant strains, cause producing many clinicians of order and be difficult to the effectively infection disease of treatment, especially the coagulase negative staphylococcus (MRCNS) etc. that various antibacterial is shown height, multidrug resistant methicillin-resistant staphylococcus aureus (MRSA), methicillin resistance becomes and infects the very big obstacle of disease in treating clinically.
The semi-synthetic aminoglycoside antibiotics of above-mentioned exploitation, except arbekacin has the clear and definite effect MRSA, all the other products are all undesirable to the antibacterial effect of MRSA.
Disclose acyl derivatives such as many 1-N-gentamycins and sisomicin in the document 4, reported that also these acylated derivatives have good antibacterial activity to fastbacteria, can make the antibiotic formulations of commercial usefulness.But document and unexposed these derivants are to the antibacterial activity of MRSA and MRCNS equal altitudes fastbacteria, and not all chemical compound all has good antibacterial activity to MRSA in the disclosed derivant of document, and for example 1-N-AHP Gentamicin B (isepamicin) does not just have good antibacterial activity to MRSA.Therefore, above-mentioned patent documentation can not cover the inventive concept of this patent.
Document 5 discloses employing bivalent metal ion complex protection, the synthetic 1-NH that removes
2The position is the protection intermediate of free state, further carries out the method for specificity derivatization in the 1-N position, and document 6 discloses uses the zinc ion complexation, formoxyl protection intermediate, the new method of synthetic isepamicin.But do not cover synthetic method of the present invention.
Summary of the invention
The purpose of this invention is to provide the application of a kind of aminoglycoside antibiotics as preparation treatment drug-fast bacteria infection medicine, the problem that solve is to provide has powerful antibiotic and aminoglycoside antibiotics that production cost is low to MRSA and MRCNS.
In order to address this problem, the inventor has carefully compared the antibacterial activity of the aminoglycoside antibiotics with different structure feature of clinical practice to clinical isolating pathogen.Wherein,
The architectural feature of etimicin: the 1-N-ethyl, 2 '-NH
2, 3 ', 4 '-two deoxidations, 3 " N-CH
3,
The architectural feature of isepamicin: 1-N-AHP, 2 '-hydroxyl, 3 ', 4 '-dihydroxy, 3 " N-CH
3,
The architectural feature of amikacin: 1-N-AHB, 2 '-hydroxyl, 3 ', 4 '-dihydroxy, 3 " NH
2,
The architectural feature of arbekacin: 1-N-AHB, 2 '-NH
2, 3 ', 4 '-two deoxidations, 3 " NH
2,
The architectural feature of netilmicin: the 1-N-ethyl, 2 '-NH
2, 3 ', 4 '-two deoxidations, 3 " N-CH
3, 4 '=5 ' double bond structure,
SK-701=1-N-(S)-3-amino-2-hydroxyl propionyl gentamicinC la;
SK-702=1-N-(S)-3-amino-2-hydroxyl propiono-3 " N-demethylation gentamicinC la.
The architectural feature of SK-701: 1-N-AHP, 2 '-NH
2, 3 ', 4 '-two deoxidations, 3 " N-CH
3,
The architectural feature of SK-702: 1-N-AHP, 2 '-NH
2, 3 ', 4 '-two deoxidations, 3 " NH
2
The antibiotic of the various different structure features of table 1. is to the antibacterial activity of MRSA and MRCNS
By comparing, can see:
1.4 '=5 ' double bond structure (netilmicin) be not the necessary structure that antibiotic has anti-MRSA;
2.1-N acidylate (amikacin, isepamicin) neither have the unique necessary structure of anti-MRSA by antibiotic;
3.1-N the anti-MRSA effect of alkylating product (netilmicin, etimicin) is little.
Thus, we be surprised to find with have 2 '-NH
2-3 ', the antibiotic of 4 '-two deoxidation architectural features is that the synthetic 1-N acyl derivative of precursor has significant anti-MRSA and MRCNS activity, thereby finished the present invention.
The invention provides have 2 '-NH
2-3 ', the aminoglycoside antibiotics 1-N-acyl derivative of 4 '-two deoxidation architectural features is as the application of preparation treatment drug-fast bacteria infection pharmaceutical formulation.
Technical scheme of the present invention: the application of a kind of aminoglycoside antibiotics in the Pharmaceutical composition of preparation treatment drug-fast bacteria infection, this aminoglycoside antibiotics has following 1-N acylated derivatives structure
R=CH
3CO, (S)-CH
2(NH
2) CH (OH) CO, or (S)-CH
2(NH
2) CH
2CH (OH) CO,
R
1=H or CH
3, R
2=H or CH
3
This aminoglycoside antibiotics is R=(S)-CH
2(NH
2) CH (OH) CO, R
1=H, R
2=CH
3, structure is as follows:
Be the application of 1-N-(s)-3-amino-2-hydroxyl propionyl gentamicinC la in the Pharmaceutical composition of preparation treatment drug-fast bacteria infection.Or this aminoglycoside antibiotics is R=(S)-CH
2(NH
2) CH (OH) CO, R
1=R
2=H, structure is as follows:
" the application of N-demethylation gentamicinC la in the Pharmaceutical composition of preparation treatment drug-fast bacteria infection that be 1-N-(s)-3-amino-2-hydroxyl propionyl-3.
Described fastbacteria is a methicillin-resistant staphylococcus aureus, or fastbacteria is the methicillin-resistant coagulase negative staphylococcus.
Described Pharmaceutical composition; by forming, and be 0.01%～99.99% to be that 99.99%～0.01% weight proportion is formed with containing medicinal carrier by this 1-N acylated derivatives or its pharmaceutical salts as this 1-N acylated derivatives of active component or its pharmaceutical salts and pharmaceutical carrier.
The preparation method of described Pharmaceutical composition is that the 1-N acylated derivatives of effective dose or its pharmaceutical salts is mixed mutually with pharmaceutical carrier, makes through the packing of routine, sterilization.
Described Pharmaceutical composition is tablet, aqueous injection, injectable powder, collyrium, aerosol, cream or aerosol agent.
The preparation method of the aminoglycoside antibiotics chemical compound of following structure
R=CH
3CO, (S)-CH
2(NH
2) CH (OH) CO, or (S)-CH
2(NH
2) CH
2CH (OH) CO
R
1=H or CH
3,
Comprise the steps:
1) carrying out formylation reaction after making parent nucleus compound 1 bit amino be complex state with bivalent metal ion, is zinc ion, cobalt ion or nickel ion as the bivalent metal ion of complexation;
2) remove metal ion;
3) carry out R base derivative reaction in the 1-N position;
4) specificity is removed the formylated protecting group;
5) target product is carried out purification, product purification adopts the cation exchange resin column chromatography method, carries out eluting with the ammonia spirit of variable concentrations; Or product purification employing adsorbent resin column chromatography method, carry out eluting with Different concentrations of alcohol, methanol or aqueous acetone solution.
The preparation method of the aminoglycoside antibiotics chemical compound of following structure
R=CH
3CO, (S)-CH
2(NH
2) CH (OH) CO, or (S)-CH
2(NH
2) CH
2CH (OH) CO,
R
1=H or CH
3,
Comprise the steps:
1) parent nucleus compound is realized 3 " obtaining 3 after the N demethylating reaction is also purified "-N-demethylation products with iodine or iodide;
2) carrying out formylation reaction after making 1 bit amino be complex state with bivalent metal ion, is zinc ion, cobalt ion or nickel ion as the bivalent metal ion of complexation;
3) remove metal ion;
4) carry out R base derivative reaction in the 1-N position;
5) specificity is removed the formylated protecting group;
6) target product is carried out purification, product purification adopts the cation exchange resin column chromatography method, carries out eluting with the ammonia spirit of variable concentrations; Or product purification employing adsorbent resin column chromatography method, carry out eluting with Different concentrations of alcohol, methanol or aqueous acetone solution.
Beneficial effect of the present invention:
Arbekacin has same architectural feature, and significant anti-MRSA activity is also arranged.But arbekacin is a kanamycin class aminoglycoside antibiotics, and its adopt complicated chemical method carry out 3 ', 4 '-two deoxidations, synthetic route is long, complex process, cost height.
For realizing the present invention cost-effectively, the present invention with natural origin, economy be easy to get have 2 '-NH
2-3 ', the antibiotic of 4 '-two deoxidation architectural features is as the synthetic 1-N-acylated derivatives of raw material, make the present invention have good industrial applications and be worth.
The present invention selects natural origin has 2 '-NH
2-3 ', the gentamicinC la of 4 '-two deoxidation architectural features is that the synthetic 1-N-acylated derivatives of raw material is:
SK-701=1-N-(S)-3-amino-2-hydroxyl propionyl gentamicinC la;
SK-702=1-N-(S)-3-amino-2-hydroxyl propiono-3 " N-demethylation gentamicinC la.
But be not limited only to this, 1-N-(S)-4-amino-2-maloyl group radical derivative and 1-N-acetyl derivative also can adopt method provided by the invention to synthesize.
The structure determination data of SK-701 and SK-702 are as follows:
1.MS:SK-701 M+1=537, its molecular weight are 536
SK-702, M+1=523, its molecular weight are 522
2.
13The C-NMR measurement result sees Table 2.
Table 2
3.
1The H-NMR characteristic sees Table 3
Table 3
Disclosed by the inventionly have 2 '-NH
2-3 ', the aminoglycoside antibiotics 1-N-acyl derivative of 4 '-two deoxidation architectural features not only demonstrates that MRSA and MRCNS are had the excellent antibiotic effect, but also demonstrate gram negative bacteria is also had good antibacterial action.
The drug sensitive detection method of antibacterial: press the double dilution method of agar that CLSI (Clinical and Laboratory Standards Institute) recommends, carry out the mensuration of sample to the minimum inhibitory concentration (MIC) of clinical isolates.Antibacterials concentration is 12 double dilution factors of concentration of 128mg/L-0.06mg/L.Bacterial load is 10
4The CFU/ point.The Quality Control bacterial strain is: the susceptibility criterion of golden yellow Fructus Vitis viniferae ball ATCC29213 (MSSA), escherichia coli ATCC25922, the false unit cell ATCC27853. of Aerugo amikacin is pressed CLSI2007 version standard.The outstanding table of result of the test 4-8.
Table 4 SK-701, investigational agents such as SK-702 are to the susceptibility (MICmg/L) of aerobic gram-positive cocci
Table 5 SK-701, investigational agents such as SK-702 are to the susceptibility (MICmg/L) of aerobic gram negative bacilli
Investigational agents such as table 6-1 SK-701 and SK-702 are to the accumulative total bacteriostasis rate (%) to clinical isolates 300 strains
Investigational agents such as table 6-2 SK-701 and SK-702 are to the accumulative total bacteriostasis rate (%) to clinical isolates 300 strains
Preliminary acute toxicity (the LD of SK-701 and SK-702
50) result of the test shows the LD of SK-701 and SK-702
50Close, be 50-75mg/Kg, in the scope of the clinical usage license of aminoglycoside antibiotics.
Can see that SK-701 and SK-702 have significant anti-MRSA and MRCNS activity, LD
50Therefore the result can be used for preparation to the medicative medicament of drug-fast bacteria infection in the scope of aminoglycoside antibiotics clinical practice permission.
Synthetic method 1
R=CH
3CO, (S)-CH
2(NH
2) CH (OH) CO (AHP) or (S)-CH
2(NH
2) CH
2CH (OH) CO (AHB)
R1=H or CH3
Synthetic method 2
R＝CH
3CO，(S)-CH
2(NH
2)CH(OH)CO(AHP)，(S)-CH
2(NH
2)CH
2CH(OH)CO(AHB)
R1=H or CH
3
Synthetic method 3
R＝CH
3CO，(S)-CH
2(NH
2)CH(OH)CO(AHP)，(S)-CH
2(NH
2)CH
2CH(OH)CO(AHB)
R
1=H or CH
3
The present invention carries out the modification of target side chain for specificity in the 1-N position, adopts formoxyl protection intermediate, and the donor of formoxyl is a 2-formyl thyroidan, and its structural formula is as follows:
The present invention is when being used for these derivants preparation drug-fast bacteria infection treated effective Pharmaceutical composition, be neutralized into salt soluble in water with acid earlier, wherein acid can be mineral acid example hydrochloric acid, phosphoric acid, sulphuric acid etc., also can be organic acid such as maleic acid, lactic acid, tartaric acid, the most frequently used be the sulfate made from sulphuric acid.
The preparation method of these pharmaceutical formulations disclosed by the invention, concrete method be with have 2 '-NH
2-3 ', the aminoglycoside antibiotics 1-N-acyl derivative of 4 '-two deoxidation architectural features or their pharmaceutical salts be as applicable carrier such as buffer agent, lubricant, disintegrating agent, binding agent, surfactant, antiseptic, sweeting agent, isotonic agent etc. on active component and the medicine; be that active component accounts for the ratio preparation that 0.01-99.99% and carrier account for 99.99-0.01% with the weight ratio, and form through encapsulation, sterilization.
The occupation mode of pharmaceutical formulation of the present invention, dosage are similar to other aminoglycoside antibiotics, and for example, the most frequently used application mode is an injection, and its dosage is 50-800mg/ days, divides 1-3 use.
The specific embodiment
Embodiment 1:1-N-(S)-3-amino-2-hydroxyl propionyl gentamicinC la's is synthetic
1) 3,2 ', 6 '-three-N-formoxyl gentamicinC la synthetic
25 gram gentamicinC la (GMCla) stir dissolving down with 500mL dimethyl sulfoxine (DMSO), are cooled to room temperature, add 100mL dichloromethane, 32 gram four hydration cobalt acetates, at room temperature stirring and dissolving and complexations.Add 40 gram 2-formyl thyroidans in batches, stir reaction down 1 hour.500mL5 ℃ of cold water mix of adding is even in the reactant liquor, and separatory adds 5 gram active carbons and stirs filtration in 20 minutes in the liquid of upper strata, and filtrate extracts secondary with the dichloromethane extraction of 1/10 filtrate volume.
The upper strata water after washing eliminates DMSO, is used 0.4N ammonia eluting with 800mL HD-2 resin (ammonium type) post dynamic adsorption, begin fraction collection during to pH9.5, merge same composition, be concentrated into dried, with 100mL dissolve with methanol, evaporate to dryness dehydration, repeat once, obtain solid 20.5 grams.
Get above-mentioned solid 5 gram 200mL HD-2 resin column (height/diameter＞10) purification; with 0-0.4N ammonia gradient elution; the fraction collection eluent; merge same composition; be concentrated into dried; with the dehydration of dissolve with methanol, evaporate to dryness, repeat once, obtain solid product 3,2 ', 6 '-three-N-formoxyl gentamicinC la, 2.8 grams.[α]
DT=154 °; Elementary analysis: C:44.32 H:7.41 O:12.35 (moisture: 5.6%, theoretical value: C:44.22 H:7.56 O:12.31).
2) 1-N-(S)-3-amino-2-hydroxyl propionyl gentamicinC la's is synthetic
Solid 15 grams that obtain the above-mentioned first time are added in the 300mL methanol and dissolve, add 10.5 gram phthalyl amido-α-Qiang Jibingsuans (PHPA), 5 gram I-hydroxybenzotriazole monohydrate (HOBT) stirring and dissolving under the room temperature, add 8.4 gram dicyclohexylcarbodiimides (DCC) in batches, reacted 1 hour.
Reacting liquid filtering, filtrate decompression is concentrated into dried, adds 300mL ethanol, 80mL hydrazine hydrate, hydrazinolysis 6 hours.Reduction vaporization reclaims ethanol, is dissolved in water, and with the absorption of HD-2 resin column, purification, 0-0.4N ammonia eluting, fraction collection merges same composition, is concentrated into dried solid 7.2 grams that obtain.
Get above-mentioned solid 2 grams, use the 50mL water dissolution, microporous filter membrane (0.45 micron) filters, the filtrate lyophilization, and obtaining 1.7 gram solids is 1-N-(S)-3-amino-2-hydroxyl propionyl gentamicinC la alkali.
Other gets above-mentioned solid 5 grams and uses the 80mL water dissolution, adds 6N H
2SO
4Transfer pH4.5～7, add 2 gram activated carbon decolorizings, filter, the filtrate lyophilization obtains 7.1 gram 1-N-(S)-3-amino-2-hydroxyl propionyl gentamicinC la sulfate.
" N-demethylation gentamicinC la's is synthetic for embodiment 2:1-N-(S)-3-amino-2-hydroxyl propiono-3
" N-demethylation gentamicinC la adds 20mL water, 100mL DMSO to 5 grams 3, and stirring and dissolving adds 10 gram zinc acetate stirring and dissolving, adds 8.5 gram 2-formyl thyroidan stirring reactions under the room temperature in batches.Reactant liquor adds 150mL cold water, and mix homogeneously filters.Filtrate begins fraction collection with acidulous cation resin D151 dynamic adsorption, washing back with 0.4N ammonia eluting during pH9.5, merge same composition, and reduction vaporization obtains solid 3.5 grams to doing.
Above-mentioned solid is with step 2 among the embodiment 1) method carry out the 1-N acylation reaction and purification obtains 1-N-(S)-3-amino-2-hydroxyl propiono-3 " N-demethylation gentamicinC la alkali 1.8 grams.
Get the wherein above-mentioned solid of 1.5 grams 30mL water dissolution, 6N H
2SO
4Transfer pH4.5～7.0, add activated carbon decolorizing, filter, the filtrate lyophilization obtains 2.1 gram 1-N-(S)-3-amino-2-hydroxyl propiono-3 " N-demethylation gentamicinC la sulfate.
" N-demethylation gentamicinC la's is synthetic for embodiment 3:1-N-(S)-3-amino-2-hydroxyl propiono-3
1-N-(S)-3-amino-2-hydroxyl propionyl gentamicinC la sulfate 8 grams add the 100mL water dissolution, add 10 gram sodium acetates, drip 10 gram iodine (dissolving of 100mL dimethyl formamide), 50～70 ℃ of stirring reactions 12 hours.The reactant liquor thin up is to 400mL, and with 100mL D151 resin dynamic adsorption, the washing back begins fraction collection with 0.4N ammonia eluting during pH9.5, merge same composition, and reduction vaporization is to doing.Add the 50mL water dissolution, with HD-2 (acidulous cation resin) resin column (height/diameter＞10) purification, 0-0.4N ammonia eluting, fraction collection.Merge same composition, be concentrated into driedly, use the 30mL water dissolution, add 6N H
25O
4Transfer pH4.5～7, add 1 gram activated carbon decolorizing, filter, the filtrate lyophilization obtains 3.1 gram 1-N-(S)-3-amino-2-hydroxyl propiono-3 " N-demethylation gentamicinC la sulfate.
Embodiment 4. antibiotic aqueous injection
Prescription:
SK-701 10 grams
Anhydrous sodium sulfite 0.4 gram
Water for injection adds to 200 milliliters
pH 4.5～7.0
Technology: take by weighing main ingredient by prescription, be dissolved in the 160mL water for injection, adjust that to add active carbon behind the pH an amount of, add water to standardize solution 200mL, remove charcoal after the microporous filter membrane fine straining to clean, logical nitrogen embedding, 100 ℃ of flowing steam sterilizations 30 minutes.
Claims (6)
1. the application of aminoglycoside antibiotics in the Pharmaceutical composition of preparation treatment methicillin-resistant staphylococcus aureus and/or the infection of methicillin-resistant coagulase negative staphylococcus is characterized in that this aminoglycoside antibiotics has following 1-N acylated derivatives structure
R=CH
3CO, (S)-CH
2(NH
2) CH (OH) CO, or (S)-CH
2(NH
2) CH
2CH (OH) CO,
R
1=H or CH
3, R
2=H or CH
3
2. application according to claim 1 is characterized in that this aminoglycoside antibiotics is R=(S)-CH
2(NH
2) CH (OH) CO, R
1=H, R
2=CH
3, structure is as follows:
Be 1-N-(s)-3-amino-2-hydroxyl propionyl gentamicinC la.
3. application according to claim 1 is characterized in that this aminoglycoside antibiotics is R=(S)-CH
2(NH
2) CH (OH) CO, R
1=R
2=H, structure is as follows:
" the N-demethylation gentamicinC la that is 1-N-(s)-3-amino-2-hydroxyl propionyl-3.
4. according to the described application of one of claim 1-3; it is characterized in that described Pharmaceutical composition by forming, and be 0.01%～99.99% to be that 99.99%～0.01% weight proportion is formed with containing medicinal carrier by this 1-N acylated derivatives or its pharmaceutical salts as this 1-N acylated derivatives of active component or its pharmaceutical salts and pharmaceutical carrier.
5. application according to claim 4 is characterized in that the preparation method of described Pharmaceutical composition is: the 1-N acylated derivatives of effective dose or its pharmaceutical salts is mixed mutually with pharmaceutical carrier, make through the packing of routine, sterilization.
6. application according to claim 4 is characterized in that described Pharmaceutical composition is tablet, aqueous injection, injectable powder, collyrium, aerosol, cream or aerosol agent.
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|---|---|---|---|
| CN2007101328564A CN101152195B (en) | 2007-10-09 | 2007-10-09 | Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection |
| PCT/CN2008/001677 WO2009049490A1 (en) | 2007-10-09 | 2008-09-28 | Use of aminoglycoside antibiotic in the preparation of pharmaceutical composition for treating drug-resistant bacterial infection |
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| CN101152195B (en) * | 2007-10-09 | 2010-09-08 | 常州方圆制药有限公司 | Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection |
| CN101928310B (en) * | 2010-03-26 | 2012-09-05 | 常州方圆制药有限公司 | 3,2',6'-tri-N-acetyl gentamicin C1aprepn |
| CN102190690B (en) * | 2011-04-01 | 2015-01-21 | 福州博立医药科技有限公司 | Convenient high-yield Arbekacin synthesis method |
| CN115838388A (en) * | 2022-12-16 | 2023-03-24 | 无锡济煜山禾药业股份有限公司 | Preparation method of 3-N-acetyl etimicin |
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| PH12960A (en) * | 1974-03-19 | 1979-10-19 | Scherico Ltd | Derivatives of 4,6-di-(aminoglycosyl)-1,3-diaminocy-clitols and pharmaceutical compositions thereof |
| US5900406A (en) * | 1991-07-09 | 1999-05-04 | Nzym, Inc. | Use of antibiotics of the type 2-deoxystreptamine substituted with aminosugars to inhibit growth of microorganisms containing group I introns |
| CN101152195B (en) * | 2007-10-09 | 2010-09-08 | 常州方圆制药有限公司 | Application of aminoglycoside antibiotic in preparing pharmaceutical composition for treating drug-fast bacteria infection |
| CN101139371A (en) * | 2007-10-09 | 2008-03-12 | 无锡苏科生物科技有限公司 | Aminoglycoside antibiotics |
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- 2008-09-28 WO PCT/CN2008/001677 patent/WO2009049490A1/en active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| J.J. Wright, etc..selective N-acylation of gentamicin antibiotics-synthesis of 1-N-acyl derivatives.The journal of antibiotics.1976,714-719. * |
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| CN101152195A (en) | 2008-04-02 |
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