CN101225093A - Aminoglycoside derivatives - Google Patents

Aminoglycoside derivatives Download PDF

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CN101225093A
CN101225093A CNA2007100132316A CN200710013231A CN101225093A CN 101225093 A CN101225093 A CN 101225093A CN A2007100132316 A CNA2007100132316 A CN A2007100132316A CN 200710013231 A CN200710013231 A CN 200710013231A CN 101225093 A CN101225093 A CN 101225093A
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gentamicinc
vitriol
salt
compounds
gentamicinb
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CN101225093B (en
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黄振华
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Jilin Jinsheng Pharmaceutical Co Ltd
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Abstract

The invention relates to a new aminoglycoside compound and the salt, belonging to technical field of drugs. The preparation method of the compounds comprises necessary drug combination of active component for the compound and the salt and the application of the compound and the salt in preparing drugs used for treating and / or preventing infectious diseases. The preparation method of the new aminoglycoside compounds has the advantages of wide antibacterial spectrum, high antibacterial activity, higher antibacterial activity in particular to drug-resistant bacteria compared with prior aminoglycoside antibiotics, good clinical value when used for treating and / or preventing infectious diseases. The new aminoglycoside compounds can be prepared with a vector acceptable pharmaceutically into certain dosage form, preferred injection or oral preparation which are accepted clinically or pharmaceutically.

Description

Aminoglycoside derivatives
1, technical field
The present invention relates to new aminoglycoside compounds and salt thereof, the preparation method of these compounds, contain the pharmaceutical composition of these compound or its salts as essential activeconstituents, and these compound or its salts preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application, belong to medical technical field.
2, background technology
Since nineteen forty-four is found Streptomycin sulphate (streptomycin), found Xin Meisu (neomycin) in 1949,, found or semi-synthetic a series ofly can be used for clinical aminoglycoside antibiotics through the time of over half a century.The development of aminoglycoside antibiotics was roughly experienced with the next stage: Streptomycin sulphate-Xin Meisu period, kantlex period, celebrate big mould rope (tobramycin, sisomicin, micronomicin) period, semisynthetic aminoglycoside antibiotics derivative period (netilmicin, Arbekacin, isepamicin etc.).In recent years, though the aminoglycoside antibiotics development is fast not as beta-lactam, but still be infection of treatment gram-negative bacteria and the indispensable medicine of tuberculosis.
Because the aminoglycoside antibiotics of the natural origin of early stage listing is Streptomycin sulphate, kantlex, gentamicin etc. for example, serious ototoxicity and renal toxicity is arranged, and be easy to generate resistance.Be ototoxicity and the renal toxicity that reduces this type of medicine, and reduce its chemical sproof incidence, researched and developed some semi-synthetics, for example amikacin, dibekacin, Arbekacin, isepamicin, netilmicin, Etimicin etc.The appearance of these semi-synthetic derivatives overcomes and part has overcome the bacterial drug resistance that occurs clinically and ear, kidney toxic side effect.Efficiently, low toxicity, to the appearance of the effectively new derivative of resistant organism, brought into play vital role clinically, simultaneously, also opened up a valid approach for the development of aminoglycoside antibiotics.
3, summary of the invention
Because aminoglycoside antibiotics has been important clinically anti-infectives since coming out, and infects indispensable medicine for treating gram-negative bacteria clinically always, determined curative effect is cheap.Now so that in the future this type of medicine still be clinical necessary medicine, still will be in China's widespread use.But, very easily produce resistant organism after this type of drug use, simultaneously itself have untoward reactions such as ototoxicity, renal toxicity again, bring great inconvenience to clinical application, in order to address these problems, our pharmaceuticals researcher has carried out many useful explorations, seeks the new derivative of aminoglycoside antibiotics of high-efficiency low-toxicity, antimicrobial agent.
We study and have synthesized some new aminoglycoside compounds, the new compound of surprised discovery the present invention is compared with existing aminoglycoside antibiotics, have has a broad antifungal spectrum, anti-microbial activity height, especially resistant organism had higher anti-microbial activity, have the total stable physico-chemical property of aminoglycoside and higher water-soluble simultaneously, have higher clinical use value.
The present invention's claimed 1-N-Z-aminoglycoside compounds and salt thereof are selected from:
1-N-Z-gentamicin A, 1-N-Z-gentamicinB, 1-N-Z-gentamicinB 1, the 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2a, the 1-N-Z-gentamicinC 2b(being the 1-N-Z-micronomicin), 1-N-Z-gentamicinX, 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanamycin A, 1-N-Z-kanendomycin, 1-N-Z-kanamycin C, 1-N-Z-3 ' 4 '-dibekacin B (being the 1-N-Z-dibekacin), 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin, or its pharmacy acceptable salt;
Wherein, Z is for replacing or unsubstituted-COCH 2NHC (CH 3) 3Or-COCH (NH 2) CH 2CH 2CH 2CH 2NH 2, described substituting group is selected from-NH 2,-OH, F, Cl, Br, I.
Preferred compound is selected from:
1-N-Z-gentamicin A, 1-N-Z-gentamicinB, 1-N-Z-gentamicinB 1, the 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2a, the 1-N-Z-gentamicinC 2b(being the 1-N-Z-micronomicin), 1-N-Z-gentamicinX, 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanamycin A, 1-N-Z-kanendomycin, 1-N-Z-kanamycin C, 1-N-Z-3 ', 4 '-dibekacin B (being the 1-N-Z-dibekacin), 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin, or its pharmacy acceptable salt;
Wherein, Z is-COCH 2NHC (CH 3) 3Or-COCH (NH 2) CH 2CH 2CH 2CH 2NH 2
Further preferred compound is selected from:
1-N-Z-gentamicin A, 1-N-Z-gentamicinB, 1-N-Z-gentamicinB 1, the 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2a, the 1-N-Z-gentamicinC 2b(being the 1-N-Z-micronomicin), 1-N-Z-gentamicinX, 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanamycin A, 1-N-Z-kanendomycin, 1-N-Z-kanamycin C, 1-N-Z-3 ', 4 '-dibekacin B (being the 1-N-Z-dibekacin), 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin;
Wherein, Z is-COCH 2NHC (CH 3) 3
Further preferred compound is:
1-N-Z-gentamicinB, 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2b(being the 1-N-Z-micronomicin), 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanendomycin, 1-N-Z-3 ', 4 '-dibekacin B (being the 1-N-Z-dibekacin), 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin;
Wherein, Z is-COCH 2NHC (CH 3) 3
Most preferred is:
1-N-Z-gentamicinB, 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2b(being the 1-N-Z-micronomicin), 1-N-Z-3 ', 4 '-dibekacin B (being the 1-N-Z-dibekacin); Wherein, Z is-COCH 2NHC (CH 3) 3That is:
Uncle's 1-N-fourth glycyl-gentamicinB (hereinafter to be referred as compd A), structural formula is as follows:
Figure A20071001323100061
Uncle's 1-N-fourth glycyl-gentamicinC 1a(hereinafter to be referred as compd B), structural formula is as follows:
Figure A20071001323100062
Uncle's 1-N-fourth glycyl-gentamicinC 2b, i.e. uncle's 1-N-fourth glycyl-micronomicin (hereinafter to be referred as Compound C), structural formula is as follows:
Figure A20071001323100063
Uncle's 1-N-fourth glycyl-3 ', 4 '-dibekacin B, i.e. uncle's 1-N-fourth glycyl-dibekacin (hereinafter to be referred as Compound D), structural formula is as follows:
Figure A20071001323100071
In order to improve water-soluble or stability etc., to adapt to the needs of storage, preparation manufacturing or clinical application, the all right salify of above-claimed cpd comprises: vitriol, hydrochloride, hydrobromate, phosphoric acid salt, mesylate, fumarate, maleate, Lactobionate, citrate, tartrate, bitartrate, aspartate, acetate.Discover that through the inventor vitriol of above-claimed cpd of the present invention has well water-soluble and stable.The vitriol of most preferred compound is respectively:
Uncle's 1-N-fourth glycyl-gentamicinB vitriol (hereinafter to be referred as compd A vitriol), structural formula is as follows:
Figure A20071001323100072
Uncle's 1-N-fourth glycyl-gentamicinC 1aVitriol (hereinafter to be referred as compd B vitriol), structural formula is as follows:
Figure A20071001323100073
Uncle's 1-N-fourth glycyl-gentamicinC 2bVitriol, i.e. uncle's 1-N-fourth glycyl-micronomicin vitriol (hereinafter to be referred as Compound C vitriol), structural formula is as follows:
Uncle's 1-N-fourth glycyl-3 ', 4 '-dibekacin B vitriol, i.e. uncle's 1-N-fourth glycyl-dibekacin vitriol (hereinafter to be referred as Compound D vitriol), structural formula is as follows:
Figure A20071001323100082
The compounds of this invention can be by following prepared, but is not limited only to following technology:
The preparation of step 1:Z-OH active ester
In the exsiccant there-necked flask, add anhydrous acetonitrile, stir adding Z-OH down, after the stirring and dissolving, add 1-hydroxy benzo triazole (HOBT), be warming up to suitable temp with water-bath, stirring reaction, reduce to room temperature then, add the dicyclohexyl carbimide, the stirring at room reaction is reduced to reaction solution under 0 ℃ in batches, leave standstill after-filtration, filtrate for later use.
Step 2: the preparation of silanization aminoglycoside antibiotics
In three mouthfuls of reaction flasks of drying of the reflux condensing tube that the band drying tube is housed, whipping appts, add acetonitrile, glycol dimethyl ether, stir and add aminoglycoside antibiotics, hexamethyldisilazane, trimethylchlorosilane down, temperature rising reflux reaction then, reaction finishes, and filters, and filtrate decompression is to doing, and then with acetonitrile dissolving, refrigeration is placed standby.
Step 3: the preparation of The compounds of this invention
Under the ice bath in the exsiccant there-necked flask, the acetonitrile liquid of the silanization aminoglycoside antibiotics that the step prepares in the adding slowly drips active ester acetonitrile solution, stirring reaction then, rise to room temperature, dilute with water is slowly regulated pH, stirring reaction with dilute hydrochloric acid then, filter, filtrate decompression concentrates to remove and desolvates, and residuum dehydrated alcohol recrystallization gets The compounds of this invention.
Step 4: The compounds of this invention vitriol preparation
The compounds of this invention is dissolved in the dehydrated alcohol, and ice bath is slowly regulated pH with 2N sulfuric acid down, separates out a large amount of white solids, filters, and the solid ethyl alcohol recrystallization gets The compounds of this invention vitriol.
In the aforesaid method, the implication of Z is same as above among the Z-OH; Aminoglycoside antibiotics comprises gentamicin A, gentamicinB, gentamicinB 1, gentamicinC 1, gentamicinC 1a, gentamicinC 2, gentamicinC 2a, gentamicinC 2b(being micronomicin), gentamicinX, 3 ', 4 '-two deoxidation gentamicinBs, kanamycin A, kanendomycin, kanamycin C, 3 ', 4 '-dibekacin B (being dibekacin), tobramycin, sisomicin, sisomycin etc.
Further claimed above-claimed cpd of the present invention and salt thereof treat and/or prevent application in the medicine of infectious diseases in preparation.The compounds of this invention and salt thereof have has a broad antifungal spectrum, and anti-microbial activity is strong, resistant organism are also had the advantage of higher anti-microbial activity.Pharmacological evaluation shows, the various aerobic gram negative bacillis of The compounds of this invention and salt pair thereof comprise that escherichia coli, klebsiella spp, enterobacter, proteus, Citrobacter, Serratia and Morganella all have the height anti-microbial activity, have stronger anti-microbial effect to acinetobacter, Pseudomonas aeruginosa and hemophilus; Aerobic gram positive organism is comprised that streptococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, Streptococcus viridans, streptococcus pyogenes also have stronger anti-microbial activity.The compounds of this invention and salt thereof escherichia coli, Klebsiella Pneumoniae, the streptococcus aureus to anti-gentamicin when lower concentration has significant anti-microbial activity, is better than going on the market aminoglycoside antibiotics.The compounds of this invention and salt thereof have significant antibacterial activity in vivo, all have significant provide protection to infecting escherichia coli, Klebsiella Pneumoniae in the mouse body.The toxicity of The compounds of this invention and salt thereof is lower, and clinical application is safer.
The present invention also further claimed above-claimed cpd and the salt thereof of comprising as the essential activeconstituents and the pharmaceutical composition of pharmaceutically acceptable carrier, for clinically or pharmaceutically acceptable arbitrary formulation; Can parenteral, mode such as oral is applied to the patient who needs this treatment, is preferably oral preparations or injection.Containing of the present invention arbitrary compound or its salt (in The compounds of this invention) 0.01～5g of physiology significant quantity in the aforementioned pharmaceutical compositions, for example can be 10mg, 20mg, 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 0.1g, 0.125g, 0.15g, 0.175g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.7g, 0.75g, 0.8g, 0.9g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g etc.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The compounds of this invention and salt thereof compared with prior art have the following advantages:
(1) provides and had broad-spectrum antimicrobial especially active new aminoglycoside compounds of resistant organism and salt thereof, for example uncle's 1-N-fourth glycyl-gentamicinB, uncle's 1-N-fourth glycyl-gentamicinC 1a, uncle's 1-N-fourth glycyl-gentamicinC 2b, uncle's 1-N-fourth glycyl-3 ', 4 '-dibekacin B and vitriol thereof, for clinical application provides new microbiotic kind.
(2) pharmacological evaluation shows, The compounds of this invention and salt thereof have the broad-spectrum high efficacy anti-microbial activity, various aerobic gram negative bacillis are comprised that escherichia coli, klebsiella spp, enterobacter, proteus, Citrobacter, Serratia and Morganella all have the height anti-microbial activity, have stronger anti-microbial effect to acinetobacter, Pseudomonas aeruginosa and hemophilus; Aerobic gram positive organism is comprised that streptococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, Streptococcus viridans, streptococcus pyogenes also have stronger anti-microbial activity.
(3) pharmacological evaluation shows, The compounds of this invention and salt pair resistant organism thereof also have stronger anti-microbial activity, escherichia coli, Klebsiella Pneumoniae, streptococcus aureus to anti-gentamicin when lower concentration have significant anti-microbial activity, are better than going on the market aminoglycoside antibiotics.
(4) pharmacological evaluation shows, The compounds of this invention and salt thereof have significant antibacterial activity in vivo, all has significant provide protection to infecting escherichia coli, Klebsiella Pneumoniae in the mouse body.
(5) pharmacological evaluation shows, the acute toxicity of The compounds of this invention and salt thereof is lower, and clinical application is safer.
(6) The compounds of this invention and salt thereof have the potent anti-microbial activity of wide spectrum, and resistant organism is also had very high anti-microbial activity, and toxicity is lower, have the good clinical using value.
Below example is further set forth the beneficial effect of new aminoglycoside compounds of the present invention by experiment, and these experimental examples comprise pharmacodynamics test, the toxicology test of The compounds of this invention.The compounds of this invention has following beneficial effect, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
Replace uncle's 1-N-fourth glycyl-gentamicinB vitriol with compd A vitriol in the following experimental example, compd B vitriol replaces uncle's 1-N-fourth glycyl-gentamicinC 1aVitriol, Compound C vitriol replace uncle's 1-N-fourth glycyl-gentamicinC 2bVitriol, Compound D vitriol replacement uncle 1-N-fourth glycyl-3 ', 4 '-dibekacin B vitriol.
Experimental example 1: the antibacterial activity in vitro of The compounds of this invention
Trial-product: The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol are self-control; Gentamicin sulphate, sulphuric acid kanamycin, Isepamicin sulfate are commercial.
Strains tested:
(1) experimental strain: the clinical separation pathogenic bacterium of 1274 strains, gram-negative bacteria comprises: escherichia coli 125 strains, Klebsiella Pneumoniae 112 strains, Pseudomonas aeruginosa 97 strains, shigella dysenteriae 82 strains, enterobacter cloacae 78 strains, enteroaerogen 78 strains, Proteus mirabilis 76 strains, 39 strains of Fei Shi citric acid bacillus, 39 strains of difference citric acid bacillus, serratia marcesens 38 strains, morganella morganii 38 strains, acinetobacter calcoaceticus 37 strains, hemophilus influenzae 36 strains, haemophilus parainfluenzae 32 strains; Gram positive organism comprises: streptococcus aureus 123 strains, staphylococcus epidermidis 83 strains, streptococcus pneumoniae 72 strains, Streptococcus viridans 45 strains, streptococcus pyogenes 44 strains.
(2) standard Quality Control bacterial strain: select escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853, streptococcus aureus ATCC25923 for use.
Substratum:
MH (Mueller-Hinton Broth) broth culture, brain heart infusion (brain heart infusion) substratum, MH nutrient agar, nutrient broth are commercial.HTM substratum (Haemophilus Test Medium) promptly on MH nutrient agar basis, adds 15 μ g/ml nadide, 15 μ g/ml ox blood red pigment and 5mg/ml yeast powders, pH7.4 according to the preparation of NCCLS prescriptive procedure.Blood meida is made for add 5% defiber rabbit blood in the MH broth culture, is used for streptococcic drug sensitive experiment.
Experimental technique:
The mensuration of minimum inhibitory concentration (MIC):, adopt plate doubling dilution and Denley multiple spot inoculator to carry out drug sensitive experiment with reference to the NCCLS standard.Experimental bacteria is cultivated and is increased bacterium.Medicine becomes various desired concns with the doubling dilution of MH broth culture, add respectively in right amount in plate, MH nutrient agar fusing back is quantitatively injected and is contained mixing in the soup plate, and the final concentration of medicine is respectively 0.0075,0.015,0.03,0.06 ... 128 μ g/ml (in compound).Hemophilus influenzae and haemophilus parainfluenzae are adopted the HTM substratum, and suis is used blood meida.(inoculum size is about 10 on the plate surface of different pharmaceutical concentration with microbionation with multiple spot inoculation instrument 4The CFU/ point) after, (hemophilus influenzae and haemophilus parainfluenzae are put 5%CO to put 37 ℃ of constant temperature culture 18h 2Incubator is cultivated 24h) the back observations is the minimum inhibitory concentration (MIC) of medicine to this bacterium with the minimum concentration of contained drug in the no bacterial growth plate substratum.
Table 1 The compounds of this invention is to the anti-microbial activity (μ g/ml) of 1274 strain clinical isolates strains
Figure A20071001323100121
Table 1 The compounds of this invention is to the anti-microbial activity (μ g/ml) (continuous 1) of 1274 strain clinical isolates strains
Figure A20071001323100131
Table 1 The compounds of this invention is to the anti-microbial activity (μ g/ml) (continuous 2) of 1274 strain clinical isolates strains
Figure A20071001323100141
Table 1 The compounds of this invention is to the anti-microbial activity (μ g/ml) (continuous 3) of 1274 strain clinical isolates strains
Experimental result: The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol all have stronger anti-microbial effect to the clinical gram positive organism that separates of clinical separation gram-negative bacteria of 907 strains and 367 strains, the results are shown in Table 1.
Anti-microbial activity to gram-negative bacteria: The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol have height anti-microbial activity, MIC to escherichia coli, Klebsiella Pneumoniae genus, shigella dysenteriae, enterobacter cloacae, enteroaerogen, Proteus mirabilis, Fei Shi citric acid bacillus, difference citric acid bacillus, serratia marcesens, morganella morganii 50In 0.125～1 μ g/ml, MIC 90In 4～32 μ g/ml scopes; Pseudomonas aeruginosa, acinetobacter calcoaceticus, hemophilus influenzae and haemophilus parainfluenzae also there are stronger anti-microbial effect, MIC 50In 1～4 μ g/ml, MIC 90In 8～64 μ g/ml scopes.The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol significantly are better than gentamicin sulphate and sulphuric acid kanamycin to the anti-microbial activity of gram-negative bacteria, slightly are better than Isepamicin sulfate or suitable.
Anti-microbial activity to gram positive organism: The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol all have stronger anti-microbial activity, MIC to streptococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, Streptococcus viridans, streptococcus pyogenes 50In 0.125～2 μ g/ml, MIC 90In 8～32 μ g/ml scopes.The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol significantly are better than gentamicin sulphate and sulphuric acid kanamycin to the anti-microbial activity of gram positive organism, slightly are better than Isepamicin sulfate or suitable.
Conclusion: The above results shows, The compounds of this invention comprises that to various aerobic gram negative bacillis escherichia coli, klebsiella spp, enterobacter, proteus, Citrobacter, Serratia and Morganella all have the height anti-microbial activity, have stronger anti-microbial effect to acinetobacter, Pseudomonas aeruginosa and hemophilus; Aerobic gram positive organism is comprised that streptococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, Streptococcus viridans, streptococcus pyogenes also have stronger anti-microbial activity.The compounds of this invention significantly is better than gentamicin and kantlex to the anti-microbial activity of various strains testeds, slightly is better than isepamicin or suitable.
Experimental example 2: The compounds of this invention compares the anti-microbial activity of resistant organism
Trial-product: gentamicin sulphate, sulphuric acid kanamycin, Micronomicin Sulfate, dibekacin sulfate, amikacin sulfate, Isepamicin sulfate, netilmicin sulfate, 8 kinds of aminoglycoside antibioticss of Etimicin sulfate provide by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol, self-control.
Strains tested:
(1) experimental strain: paper disk method is measured gentamicin resistance (antibacterial circle diameter≤escherichia coli 40 strains 12cm), Klebsiella Pneumoniae 18 strains, streptococcus aureus 38 strains.
(2) standard Quality Control bacterial strain: escherichia coli ATCC25922, streptococcus aureus ATCC25923, administrative center provides by the preservation of Chinese medicine bacterium.
The mensuration of minimum inhibitory concentration (MIC): the same, with reference to the NCCLS standard, adopt plate doubling dilution and Denley multiple spot inoculator to carry out drug sensitive experiment.The final concentration of medicine is respectively 0.0075,0.015,0.03,0.06 ... 128,256 μ g/ml (in compound).
Table 2 The compounds of this invention is to the anti-microbial activity (μ g/ml) of gentamicin resistant organism
Figure A20071001323100171
Experimental result: the results are shown in Table 2.Measure the drug-fast escherichia coli of gentamicin as can be seen by clinical isolating paper disk method to the MIC value result of The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol and contrast medicine, compd A vitriol of the present invention, B vitriol, C vitriol, D vitriol are the strongest to the anti-microbial activity of the drug-fast escherichia coli of gentamicin, Klebsiella Pneumoniae, streptococcus aureus, MIC 50In 2～8 μ g/ml, MIC 90In 16～32 μ g/ml scopes, slightly be better than amikacin sulfate and Isepamicin sulfate or suitable, be better than netilmicin sulfate and Etimicin sulfate, significantly be better than dibekacin sulfate, Micronomicin Sulfate, gentamicin sulphate and sulphuric acid kanamycin.
Conclusion: escherichia coli, Klebsiella Pneumoniae are to cause the modal gram-negative bacteria of clinical infection, and streptococcus aureus is to cause the modal gram positive organism of clinical infection.Experimental result shows that The compounds of this invention escherichia coli, Klebsiella Pneumoniae, streptococcus aureus to anti-gentamicin when lower concentration has significant anti-microbial activity, is better than going on the market aminoglycoside antibiotics, can be used for the clinical drug-resistant bacterium and infects.
Experimental example 3: the protection of The compounds of this invention to infecting in the mouse body
Laboratory animal: healthy Kunming kind small white mouse, body weight 20～25g, female half and half, random packet, 20 every group.
Trial-product: The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol are self-control; Gentamicin sulphate, sulphuric acid kanamycin, Isepamicin sulfate are commercial.Above medicine is all standby with the physiological saline preparation.
Route of administration and administration volume: intramuscularly, 25ml/kg (in compound).
For trying bacterium liquid: with 5% gastric Mucin dilution escherichia coli, Klebsiella Pneumoniae suspension, bacteria containing amount is 10 10Individual/ml.
Experimental technique: every mouse peritoneal injection bacterium liquid 0.5ml infects, and infects back 1h and presses table 3 intramuscularly administration, and the blank group gives physiological saline, infects back 24h and observes the animal survival number, judges the provide protection of trial-product.
The provide protection (n=20) of table 3 The compounds of this invention to infecting in the mouse body
Experimental result: The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol all have significant provide protection to infecting escherichia coli, Klebsiella Pneumoniae in the mouse body; and the effect that significantly is better than gentamicin sulphate or sulphuric acid kanamycin; slightly be better than Isepamicin sulfate or suitable, see Table 3.
Conclusion: experimental result shows that The compounds of this invention has significant antibacterial activity in vivo, and the antibacterial effect of comparing with existing aminoglycoside antibiotics is stronger.
Experimental example 4: the acute toxicity of The compounds of this invention
Laboratory animal: healthy Kunming kind small white mouse, body weight 20～25g, female half and half, random packet, 10 every group.
Trial-product: The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol are self-control; Gentamicin sulphate, sulphuric acid kanamycin, Isepamicin sulfate are commercial.Above medicine is all standby with the physiological saline preparation.
Route of administration and administration volume: intramuscularly, 25ml/kg (in compound).
Experimental technique: in the scope of trial test acquisition 0% and 100% lethal dose, animal subject is divided into 5 dosage groups (totally 15 groups), 10 every group of each trial-products at random.Intramuscularly administration respectively, the toxic reaction symptom of observing each dosage treated animal after the administration is dissected immediately to dead animal, the pathology in each internal organs of visual inspection.Calculate its mld LD according to seven days animal dead numbers after the administration 50Value.
Experimental result: mouse intramuscularly aminoglycoside antibiotics is after 15 hours, and the high dose group mouse begins symptoms such as struggle, dystaxia to occur, occurs death in 24 hours in succession, and all the other each groups were generally replied normally after 24 hours by dead animal.Dead animal is dissected each internal organs of back visual inspection, and not seeing has obvious pathology.The compounds of this invention A vitriol, B vitriol, C vitriol, D vitriol are to the LD of mouse intramuscularly administration 50Value is respectively: 218.32mg/kg, 225.70mg/kg, 226.42mg/kg, 212.53mg/kg (in compound), gentamicin sulphate, sulphuric acid kanamycin, Isepamicin sulfate are to the LD of mouse intramuscularly administration 50Value is respectively: 146.87mg/kg, 123.52mg/kg, 216.94mg/kg (in compound).
Conclusion: above-mentioned experimental result shows that The compounds of this invention significantly is lower than gentamicin and kantlex to the acute toxicity of mouse intramuscularly administration, and is approaching with isepamicin, shows that the acute toxicity of The compounds of this invention is lower, and clinical application is safer.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Replace uncle's 1-N-fourth glycyl-gentamicinB vitriol with compd A vitriol in the following experimental example, compd B vitriol replaces uncle's 1-N-fourth glycyl-gentamicinC 1aVitriol, Compound C vitriol replace uncle's 1-N-fourth glycyl-gentamicinC 2bVitriol, Compound D vitriol replacement uncle 1-N-fourth glycyl-3 ', 4 '-dibekacin B vitriol.
The preparation of embodiment 1 uncle's 1-N-fourth glycyl-gentamicinB and vitriol thereof
Step 1: the preparation of tertiary butyl Padil active ester
Figure A20071001323100201
In the exsiccant there-necked flask, add anhydrous acetonitrile 100ml, stir adding uncle fourth Padil 4g (30.5mmol) down, after the stirring and dissolving, add 1-hydroxy benzo triazole (HOBT) 4.8g (35.5mmol), be warming up to 40 ℃ with water-bath, stirring reaction 1 hour, reduce to room temperature then, add dicyclohexyl carbimide 7.4g (36mmol), stirring at room reaction 2 hours is reduced to reaction solution under 0 ℃ in batches, leave standstill after-filtration, filtrate for later use.
Step 2: the preparation of silanization gentamicinB
In three mouthfuls of reaction flasks of drying of the reflux condensing tube that the band drying tube is housed, whipping appts, add acetonitrile 30ml, glycol dimethyl ether 60ml stirs adding gentamicinB1 2g (25mmol) down, hexamethyldisilazane 30ml, trimethylchlorosilane 0.1ml, temperature rising reflux reacts 1h then, and reaction finishes, filter, filtrate decompression is extremely done, and then dissolves with acetonitrile, and refrigeration is placed standby.
The preparation of step 3:1-N-uncle fourth glycyl-gentamicinB
In the exsiccant there-necked flask, the acetonitrile liquid of the silanization gentamicinB that the step prepares in the adding slowly drips tertiary butyl Padil active ester acetonitrile solution then under the ice bath; stirring reaction 2h; rise to room temperature, dilute with water is slowly regulated pH1～2 with dilute hydrochloric acid then; stirring reaction 20min; filter, filtrate decompression concentrates to remove desolvates residuum dehydrated alcohol recrystallization; get off-white color uncle 1-N-fourth glycyl-gentamicinB 10.8g, yield: 72.3%.
The vitriol preparation of step 4:1-N-uncle fourth glycyl-gentamicinB
10.8g (18.1mmol) uncle N-1-fourth glycyl-gentamicinB is dissolved in the 100ml dehydrated alcohol; ice bath is slowly regulated about pH6 with 2N sulfuric acid down; separate out a large amount of white solids; filter; solid is with 85% ethyl alcohol recrystallization; get the vitriol 9.8g of uncle's 1-N-fourth glycyl-gentamicinB, yield: 72.9%.
Molecular formula: C 25H 49N 5O 111.5H 2SO 4
Molecular weight: 742.80
Ultimate analysis: measured value: C, 40.33%; H, 7.17%; N, 9.35%; S, 6.39%
Theoretical value: C, 40.42%; H, 7.06%; N, 9.43%; S, 6.48%
Mycin C is removed in embodiment 2 uncle's 1-N-fourth glycyl-celebratings 1a And the preparation of vitriol
Reference example 1, gentamicinC feeds intake 1a11.2g (25mmol), get uncle's 1-N-fourth glycyl-gentamicinC 1aVitriol 11.2g, total recovery: 59.1%.
Molecular formula: C 25H 50N 6O 82H 2SO 4
Molecular weight: 758.86
Ultimate analysis: measured value: C, 39.48%; H, 7.30%; N, 11.15%; S, 8.41%
Theoretical value: C, 39.57%; H, 7.17%; N, 11.07%; S, 8.45%
Embodiment 3 uncle's 1-N-fourth glycyl-gentamicinCs 2b Preparation
Reference example 1, gentamicinC feeds intake 2b11.6g (25mmol), get uncle's 1-N-fourth glycyl-gentamicinC 2bVitriol 10.5g, total recovery: 54.3%.
Molecular formula: C 26H 52N 6O 82H 2SO 4
Molecular weight: 772.88
Ultimate analysis: measured value: C, 40.26%; H, 7.45%; N, 10.79%; S, 8.24%
Theoretical value: C, 40.40%; H, 7.30%; N, 10.87%; S, 8.30%
Embodiment 4 uncle's 1-N-fourth glycyl-3 ', 4 '-preparation of dibekacin B
Reference example 1, feed intake 3 ', 4 '-dibekacin B 11.3g (25mmol), uncle's 1-N-fourth glycyl-3 ', 4 '-dibekacin B vitriol 10.9g, total recovery: 57.5%.
Molecular formula: C 24H 48N 6O 92H 2SO 4
Molecular weight: 760.83
Ultimate analysis: measured value: C, 37.76%; H, 6.97%; N, 10.95%; S, 8.38%
Theoretical value: C, 37.89%; H, 6.89%; N, 11.05%; S, 8.43%
The preparation of embodiment 5 The compounds of this invention liquid drugs injections
1, prescription:
Prescription 1:
The vitriol 50g of compd A, B, C or D (in compd A, B, C or D)
Sorbyl alcohol 10g
EDTA disodium salt 1g
Water for injection 1000ml
Prepare 1000 altogether
Prescription 2:
The vitriol 100g of compd A, B, C or D (in compd A, B, C or D)
Sorbyl alcohol 20g
EDTA disodium salt 2g
Water for injection 1000ml
Prepare 1000 altogether
Prescription 3:
The vitriol 200g of compd A, B, C or D (in compd A, B, C or D)
Sorbyl alcohol 20g
EDTA disodium salt 2g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 4:
The vitriol 500g of compd A, B, C or D (in compd A, B, C or D)
Sorbyl alcohol 50g
EDTA disodium salt 5g
Water for injection 2000ml
Prepare 1000 altogether
2, preparation technology:
To produce with the ampoule dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription; Get the water for injection that sorbyl alcohol adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal; Add raw material in solution, stirring and dissolving adds the EDTA disodium salt, and stirring and dissolving is measured the also pH value of regulator solution, and benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity, the inspection of semifinished product through the smart filter of the millipore filtration of 0.22 μ m; Soup is loaded in the ampoule 100 ℃ of flowing steam sterilization 30min, leak detection, lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 The compounds of this invention freeze-dried powders
1, prescription:
Prescription 1:
The vitriol 25g of compd A, B, C or D (in compd A, B, C or D)
N.F,USP MANNITOL 50g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 2:
The vitriol 75g of compd A, B, C or D (in compd A, B, C or D)
N.F,USP MANNITOL 100g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 3:
The vitriol 150g of compd A, B, C or D (in compd A, B, C or D)
N.F,USP MANNITOL 150g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 4:
The vitriol 300g of compd A, B, C or D (in compd A, B, C or D)
N.F,USP MANNITOL 300g
Water for injection 3000ml
Prepare 1000 altogether
2, preparation technology:
To produce used cillin bottle, plug and dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription; N.F,USP MANNITOL is added dosing amount 80% water for injection, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% then stirs 15min, filters, and takes off charcoal; Add bulk drug in solution, stirring and dissolving is measured the also pH value of regulator solution, and benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m; The inspection of semifinished product; Soup is sub-packed in the cillin bottle, half tamponade; Freeze-drying, tamponade, Zha Gai; Finished product is examined entirely, the packing warehouse-in.
The preparation of the aseptic subpackaged powder pin of embodiment 7 The compounds of this invention
1, prescription:
Prescription 1:
The vitriol 10g of compd A, B, C or D (in compd A, B, C or D)
Prepare 1000 altogether
Prescription 2:
The vitriol 100g of compd A, B, C or D (in compd A, B, C or D)
Prepare 1000 altogether
Prescription 3:
The vitriol 250g of compd A, B, C or D (in compd A, B, C or D)
Prepare 1000 altogether
Prescription 4:
The vitriol 500g of compd A, B, C or D (in compd A, B, C or D)
Prepare 1000 altogether
2, preparation technology:
Carry out aseptically process with producing used antibiotic glass bottle, plug etc.; Take by weighing raw material by prescription, aseptic powder is placed the portioning machine packing, detect loading amount at any time; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 The compounds of this invention sodium chloride injections
1, prescription:
Prescription 1:
The vitriol 125g of compd A, B, C or D (in compd A, B, C or D)
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
The vitriol 250g of compd A, B, C or D (in compd A, B, C or D)
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 3:
The vitriol 400g of compd A, B, C or D (in compd A, B, C or D)
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 4:
The vitriol 1000g of compd A, B, C or D (in compd A, B, C or D)
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
With dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription; Get the water for injection that sodium-chlor adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal; In solution, add bulk drug, stirring and dissolving; Measure the also pH value of regulator solution; Benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m; The inspection of semifinished product; Soup is loaded in the infusion bottle 250ml/ bottle; 115 ℃ of pressure sterilizing 30min; Leak detection, the lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 The compounds of this invention glucose injections
1, prescription:
Prescription 1:
The vitriol 175g of compd A, B, C or D (in compd A, B, C or D)
Glucose 5000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
The vitriol 750g of compd A, B, C or D (in compd A, B, C or D)
Glucose 12500g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 3:
The vitriol 1000g of compd A, B, C or D (in compd A, B, C or D)
Glucose 12500g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 4:
The vitriol 2000g of compd A, B, C or D (in compd A, B, C or D)
Glucose 12500g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
With dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription; Get the water for injection that glucose adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal; In solution, add bulk drug, stirring and dissolving; Measure the also pH value of regulator solution; Benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m; The inspection of semifinished product; Packing; 115 ℃ of pressure sterilizing 30min; Leak detection, the lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 The compounds of this invention sheets
1, prescription:
Prescription 1:
The vitriol 40g of compd A, B, C or D (in compd A, B, C or D)
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 2:
The vitriol 125g of compd A, B, C or D (in compd A, B, C or D)
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVPK30 alcohol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
2, preparation technology:
It is standby that raw material and auxiliary material separated pulverizing are crossed 80 mesh sieves; Granulation solution preparation: getting PVP K30, to add concentration be that 30～95% medicinal alcohols are made 5～10% solution; Get raw material and auxiliary materials and mixing, add granulation solution and make softwood in right amount, 20 orders are granulated, and after 50～70 ℃ of dryings, the whole grain of 18 orders adds the Magnesium Stearate mixing; Measure granule content, compressing tablet, detection lug is heavy at random; Finished product is examined entirely, the packing warehouse-in.
The capsular preparation of embodiment 11 The compounds of this invention
1, prescription:
Prescription 1:
The vitriol 100g of compd A, B, C or D (in compd A, B, C or D)
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 2:
The vitriol 250g of compd A, B, C or D (in compd A, B, C or D)
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
2, preparation technology:
It is standby that raw material and auxiliary material separated pulverizing are crossed 80 mesh sieves; Granulation solution preparation: getting PVP K30, to add concentration be that 30～95% medicinal alcohols are made 5～10% solution; Get raw material and auxiliary materials and mixing, add granulation solution and make softwood in right amount, 20 orders are granulated, and after 50～70 ℃ of dryings, the whole grain of 18 orders adds the Magnesium Stearate mixing; Measure granule content, capsule is filled, with the machine testing loading amount; Finished product is examined entirely, the packing warehouse-in.

Claims (10)

1.1-N-Z-aminoglycoside compounds and salt thereof are selected from:
1-N-Z-gentamicin A, 1-N-Z-gentamicinB, 1-N-Z-gentamicinB 1, the 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2a, the 1-N-Z-gentamicinC 2b, 1-N-Z-gentamicinX, 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanamycin A, 1-N-Z-kanendomycin, 1-N-Z-kanamycin C, 1-N-Z-3 ', 4 '-dibekacin B, 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin, or its pharmacy acceptable salt;
Wherein, Z is for replacing or unsubstituted-COCH 2NHC (CH 3) 3Or-COCH (NH 2) CH 2CH 2CH 2CH 2NH 2, described substituting group is selected from-NH 2,-OH, F, Cl, Br, I.
2. 1-N-Z aminoglycoside compounds as claimed in claim 1 and salt thereof are selected from:
1-N-Z-gentamicin A, 1-N-Z-gentamicinB, 1-N-Z-gentamicinB 1, the 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2a, the 1-N-Z-gentamicinC 2b, 1-N-Z-gentamicinX, 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanamycin A, 1-N-Z-kanendomycin, 1-N-Z-kanamycin C, 1-N-Z-3 ', 4 '-dibekacin B, 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin, or its pharmacy acceptable salt;
Wherein, Z is-COCH 2NHC (CH 3) 3Or-COCH (NH 2) CH 2CH 2CH 2CH 2NH 2
3. 1-N-Z aminoglycoside compounds as claimed in claim 2 and salt thereof are selected from:
1-N-Z-gentamicin A, 1-N-Z-gentamicinB, 1-N-Z-gentamicinB 1, the 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2a, the 1-N-Z-gentamicinC 2b, 1-N-Z-gentamicinX, 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanamycin A, 1-N-Z-kanendomycin, 1-N-Z-kanamycin C, 1-N-Z-3 ', 4 '-dibekacin B, 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin, or its pharmacy acceptable salt;
Wherein, Z is-COCH 2NHC (CH 3) 3
4. 1-N-Z aminoglycoside compounds as claimed in claim 3 and salt thereof are selected from:
1-N-Z-gentamicinB, 1-N-Z-gentamicinC 1, the 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2, the 1-N-Z-gentamicinC 2b, 1-N-Z-3 ', 4 '-two deoxidation gentamicinBs, 1-N-Z-kanendomycin, 1-N-Z-3 ', 4 '-dibekacin B, 1-N-Z-tobramycin, 1-N-Z-sisomicin, 1-N-Z-sisomycin, or its pharmacy acceptable salt;
Wherein, Z is-COCH 2NHC (CH 3) 3
5. 1-N-Z aminoglycoside compounds as claimed in claim 4 and salt thereof are selected from:
1-N-Z-gentamicinB, 1-N-Z-gentamicinC 1a, the 1-N-Z-gentamicinC 2b, 1-N-Z-3 ', 4 '-dibekacin B, or its pharmacy acceptable salt;
Wherein, Z is-COCH 2NHC (CH 3) 3
6. as described arbitrary 1-N-Z aminoglycoside compounds of claim 1～5 and salt thereof, it is characterized in that described pharmacy acceptable salt is vitriol, hydrochloride, hydrobromate, phosphoric acid salt, mesylate, fumarate, maleate, Lactobionate, citrate, tartrate, bitartrate, aspartate or acetate.
As the described arbitrary 1-N-Z-aminoglycoside compounds of claim 1～5 and salt thereof preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application.
As the described arbitrary 1-N-Z-aminoglycoside compounds of claim 1～5 and salt thereof as the essential activeconstituents and the pharmaceutical composition of pharmaceutically acceptable carrier.
9. pharmaceutical composition as claimed in claim 8 is injection or oral preparations.
10. the described arbitrary 1-N-Z-aminoglycoside compounds of claim 1～5 and the salt 0.01～5g thereof that contain the physiology significant quantity in the pharmaceutical composition as claimed in claim 8.
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Cited By (4)

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CN102321131A (en) * 2011-06-03 2012-01-18 常州方圆制药有限公司 Semi-synthetic aminoglycoside antibiotic, preparation method and medicine composition thereof
CN104546699A (en) * 2014-12-19 2015-04-29 成都天台山制药有限公司 Pharmaceutical composition of sisomicin sulphate injection and preparation method
CN106432382A (en) * 2015-08-12 2017-02-22 武汉大学 Preparation and applications of a series of novel aminoglycoside compounds, and construction method of high-yield engineering strain for producing novel aminoglycoside compounds
CN107987111A (en) * 2017-07-07 2018-05-04 朱孝云 The deuterated aminoglycoside derivatives of antibiotic property

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
CN1040177C (en) * 1993-04-23 1998-10-14 江苏省微生物研究所 1-N-ethyl gentamicin derivative and its preparing method
CN1156488C (en) * 2001-12-18 2004-07-07 国家药品监督管理局四川抗菌素工业研究所 Derivative of micronomycine and its preparing process and medical application

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102321131A (en) * 2011-06-03 2012-01-18 常州方圆制药有限公司 Semi-synthetic aminoglycoside antibiotic, preparation method and medicine composition thereof
CN104546699A (en) * 2014-12-19 2015-04-29 成都天台山制药有限公司 Pharmaceutical composition of sisomicin sulphate injection and preparation method
CN104546699B (en) * 2014-12-19 2017-06-09 成都天台山制药有限公司 Sisomicin sulfate injection pharmaceutical composition and preparation method
CN106432382A (en) * 2015-08-12 2017-02-22 武汉大学 Preparation and applications of a series of novel aminoglycoside compounds, and construction method of high-yield engineering strain for producing novel aminoglycoside compounds
CN106432382B (en) * 2015-08-12 2019-01-04 武汉大学 The preparation and application of a series of new glucoside-containing component and its construction method of high production bacteria
CN107987111A (en) * 2017-07-07 2018-05-04 朱孝云 The deuterated aminoglycoside derivatives of antibiotic property

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