CN102432647A - Aminoglycoside compound and extracting separation method thereof - Google Patents
Aminoglycoside compound and extracting separation method thereof Download PDFInfo
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- CN102432647A CN102432647A CN2010102969825A CN201010296982A CN102432647A CN 102432647 A CN102432647 A CN 102432647A CN 2010102969825 A CN2010102969825 A CN 2010102969825A CN 201010296982 A CN201010296982 A CN 201010296982A CN 102432647 A CN102432647 A CN 102432647A
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Abstract
The invention relates to an aminoglycoside compound and an extracting separation method thereof. The compound is separated from etimicin sulfate and has a following structural formula. The invention also relates to a separating method for the aminoglycoside compound.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, a kind of aminoglycoside compound chemical structure and extraction and separation method thereof.
Background technology
Aminoglycoside compounds (Aminoglycosides) is the glycoside that is formed by connecting through oxo bridge aminosugar and aminocyclitol.Have from the Streptomycin sulphate of streptomycete etc., from the natural aminoglycosides such as qingfengmeisu qiong of micromonospora, also have semi-synthetic aminoglycosides such as Etimicin, all belong to Broad spectrum antibiotics.
Aminoglycoside antibiotics mainly is suppress bacterioprotein synthetic for the effect of bacterium, and point of application is at the aminoacyl site of the 16SrRNA area decoder of cell 30S ribosomal subunit.Research shows that this type of medicine can influence bacterioprotein synthetic whole process, hinders the synthetic of initial recombination thing, induces bacterium resultant fault albumen and prevents the release of synthetic proteins, thereby cause bacterial death.
Aminoglycoside antibiotics is mainly used in the systemic infection due to the responsive aerobic gram negative bacilli.Though multiple cephalosporins and quinolones medicine are arranged in recent years in wide clinical application; But because aminoglycoside antibiotics is longer to the PAE of common gram negative bacillis such as Pseudomonas aeruginosa, pneumobacillus, intestinal bacteria; So; Still be used to treat the severe infections due to the aerobic gram negative bacilli, like meningitis, respiratory tract, urinary tract, skin soft tissue, gi tract, burn, wound and bone joint infection etc.
Etimicin sulfate (Etimicin sulfate) is that China scientific research personnel develops voluntarily; Having efficient, the low toxicity of independent intellectual property right, the of new generation semi-synthetic aminoglycoside antibiotics of antimicrobial agent, is the anti-infectives of unique acquisition first class national new drug certificate.
The Etimicin sulfate injection liquid is applicable to the various infection that its responsive intestinal bacteria, Cray Bai Shi pneumobacillus, Serratia genus, citrobacter, enterobacter, acinetobacter, proteus, bloodthirsty hemophilus influenza, Pseudomonas aeruginosa and staphylococcus etc. are caused.These article of clinical studies show have curative effect preferably to following infection: respiratory tract infection: like acute bronchitis, acute episode of chronic bronchitis, community's pulmonary infection etc.Kidney and urogenital infections: like acute pyelonephritis, urocystitis, chronic pyelonephritis or chronic cystitis acute attack etc.Skin soft tissue and other infection: like skin and soft tissue infection, infection and other sensitive organisms in wound, wound and operation postpartum infect.
At present, the technology of production Etimicin sulfate use is the technology (application number: 93112412.3) of patent report.Its key step is: Gentamicin C1a alkali adds Cobaltous diacetate, diacetyl oxide in solvent, generates 3,2; 6 ,-three-N-ethanoyl Gentamicin C1a (P1) concentrates through extracting, and liquid concentrator feeds hydrogen sulfide and removes cobalt ion; Obtain the P1 that purity is 90%-95%, add acetaldehyde then, in 0-5 ℃ of ice-water bath, use reductive agent hydrogenation, obtain 3; 2,, 6 ,-three-N-ethanoyl-1-N ethyl Gentamicin C1a (P2); After the adsorptive macroporous resin separates, obtain the higher P2 of purity, the higher P2 of purity adds the sodium hydroxide solution of 1N, and hydrolysis refluxed 48 hours, and it is 1-N-ethyl Gentamicin C1a (Etimicin) solution more than 90% that hydrolyzed solution obtains purity through the separation of adsorptive macroporous resin; Add sour salify, activated carbon decolorizing, lyophilize promptly gets Etimicin salt.
Etimicin sulfate is a kind of many infrastructure products, is difficult in the production it is purified, and the present invention is a kind of new compound of unexpected discovery in purge process, and this compound finds to have patent or reported in literature up to now as yet.Find that through in-vitro antibacterial test this compound can effectively be killed Gram-negative bacteria such as escherichia coli, Cray Bai Shi pneumobacillus, Serratia genus, Citrobacter Freundii, enterobacter, acinetobacter, proteus, hemophilus influenzae, Pseudomonas aeruginosa and staphylococcus etc. under conventional concentration.
Summary of the invention
The present invention's purpose is the aminoglycoside compounds is furtherd investigate, and seeks MRSA to its sensitivity with it, the new aminoglycoside antibiotics that the ear renal toxicity is low.
The present invention provides the following compound of a kind of structural formula or its pharmacy acceptable salt.
Formula (I)
Formula of the present invention (I) compound can form pharmaceutically acceptable non-toxic salt.These salt comprise the salt with mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc.; Salt with organic carboxyl acid such as acetate, trifluoroacetic acid, Hydrocerol A, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, racemic melic acid, xitix or oxysuccinic acid; Or with the salt of sulfonic acid such as methylsulfonic acid, tosic acid etc., and with common known and conventional other sour salt that is applied in the quinolone compounds technical field.Can be by these acid salt of conventional conversion processes.
The present invention can adopt following preparing method's preparation:
Get the Etimicin sulfate bullion in the production process, be dissolved in water, be splined on HD-2 weakly acidic cation-exchange resin post, respectively water; The ammoniacal liquor gradient elution, (developping agent: chloroform-methanol-ammoniacal liquor, 1: 1: 1 is known in the TLC inspection; Lower layer I2) also merges stream part, obtains impurity enriched stream part.(chloroform: methyl alcohol: ammoniacal liquor (2: 1: 1, lower layer) and CM-Sephadex C-25 carry out column chromatography for separation, are collected into the 5th component, are this compound respectively an impurity enriched stream part warp to be used silica gel H repeatedly.
NMR spectrum is resolved, this material
1H,
13C-NMR data such as following table.
This material
1H,
13C NMR data
Annotate: data in literature is the hydrogen spectrum and the carbon spectrum data of Gentamicin C1a.
The low field of hydrogen spectrum occur chemical shift be respectively 4.99 with the doublet of 5.29ppm, possibly be the terminal hydrogen of sugar, point out and contain two sugar in this compound.Chemical shift has the unimodal of three hydrogen at the 2.57ppm place, possibly be the substituent methyl on the amino.Low field has the unimodal of three hydrogen at the 1.23ppm place, show to have a methyl that is connected on the quaternary carbon.The triplet that three hydrogen are arranged respectively at 1.10ppm and 1.11ppm place shows to have two ethyls.Document [1] value of hydrogen spectrum data and Gentamicin C1a compares, and the hydrogen on discovery B encircles 1 and 3 has the ethyl replacement respectively to high field displacement on 1 and 3 nitrogen of prompting B ring.
Compare with the carbon spectrum data of Gentamicin C1a in the document [2], find to have more four carbon signals, chemical shift is 42.92ppm, 16.11ppm, and 42.62ppm and 16.53ppm possibly be two ethyls that are connected on the amino.In addition, 1 on B ring and 3 carbon signals are respectively to low field displacement 6ppm and 5ppm, and 2 carbon signals are to high field displacement 7ppm, and 4 and 6 carbon are respectively to high field displacement 4ppm and 2ppm, explain that ethyl is substituted on 1 and 3 bit aminos.Remainder data and literature value basically identical.
Further analyze the coupling constant of this compound, the coupling constant of C ring 3 ' position hydrogen is 10.8Hz, thus 2 ' with the hydrogen of 3 ' position all at axial bond, 1 ' with the coupling constant of 2 ' position be 3.6Hz, so a 1 ' hydrogen is at horizontal key.The coupling constant of last 4,5,6 hydrogen of B ring is 9.2Hz all, explains 1,3,4,5, and 6 hydrogen is all on axial bond, and is consistent with the relative configuration of Gentamicin C1a.This related substance is the homologue of Etimicin, the by product when being the synthetic Etimicin of selectivity, and the source is clear and definite, so this material of preliminary evaluation is 1,3-N, N-diethylammonium Gentamicin C1a is a new compound.Interpretation of mass spectra (ESI-MS)
ESI-MSn determination data and analysis result:
ESI-MS?m/e?506.3[M+H]+；
ESI-MS2m/e(506.3)：378，330，243，219。
Ion source is an electrospray ionization mass spectrum, and positive ion mode mainly provides the molion hydrogenation peak of sample.The lytic pathway See Figure of the second order ms that positive ion mode provides.ESI-MS2 information proves sample and infers that structure conforms to.
The cleavage of mass spectrum approach of this material
Comprehensive above NMR resolves and the interpretation of mass spectra result, and proving conclusively this material is 1,3-N, and N-diethylammonium Gentamicin C1a belongs to aminoglycoside derivatives, is a new compound, and structure and compound information are following
Compound information:
Chinese name: 1,3-N, N-diethylammonium Gentamicin C1a
English name: 1,3-N, N-DiEthylgentamicin C1a
Chemical name: O-3-deoxy-4-C-methyl-3-(methylamino)-β-L-arabinopyranosyl-(1 → 6)-O-[2; 6-diamino-2,3,4; 6-tetradeoxy-α-D-erythro-hexopyranosyl-(1 → 4)]-2-deoxy-N1, N3-diethyl-D-Streptamine
Molecular formula: C
23H
43N
5O
7
Molecular weight: 505
The present invention also provides and contains as above defined compound, or on its pharmacodynamics acceptable salt as the pharmaceutical composition of activeconstituents.The weight ratio of the The compounds of this invention that pharmaceutical composition contains in compsn is 0.01-99.9%, and the weight ratio of medicine acceptable carrier in compsn is 0.01-99.9%.Pharmaceutical composition exists to be fit to medicinal dosage form.Medicinal preparation is tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, oral liquid, mixture, sucks agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, powder injection, lyophilized injectable powder, suppository, ointment, plaster, creme, sprays, aerosol, drops, patch.
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the invention compound that contains in every dose is 0.1mg-1000mg; Said every dose refers to, and each preparation unit is like every of tablet; Capsular every, also can refer to each taking dose, as take 100mg at every turn.
But pharmaceutical composition of the present invention can use solid carrier when solid that is prepared into pulvis, tablet dispersion powder, capsule, cachet, suppository and ointment or semisolid pharmaceutical formulation.Spendable solid carrier is preferably one or more materials that are selected from thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, the swelling agent etc., or can be encapsulating substance.In powderous preparations, in carrier, contain 5% to 70% micronize activeconstituents.Suitable solid carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose gum, Xylo-Mucine, lower boiling wax, theobroma oil etc.Because they are easy to administration, tablet, pulvis, cachet and capsule are represented best oral solid formulation.
Liquid preparation of the present invention comprises solution, suspension and emulsion.For example, the injection formulations of parenteral administration can be water or water-propylene glycol solution form, regulates its degree of oozing such as grade, and pH etc. make the physiological condition that is suitable for live body.Liquid preparation also can be made into the solution form in polyoxyethylene glycol, the aqueous solution.Can add an amount of tinting material, seasonings, stablizer and thickening material again through activeconstituents is dissolved in the water, prepare oral aqueous solution.Can micronized activeconstituents be dispersed in to prepare in viscous substance such as natural and synthetical glue, methylcellulose gum, Xylo-Mucine and other the known suspension agent and be suitable for oral aqueous suspensions.
In order to be easy to administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, and each unit contains the activeconstituents of the good predetermined amount of the calculating that produces desired result of treatment.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis, be contained in the pipe or the bottle in ointment, gel or creme.
Though the amount of contained activeconstituents can change in the dosage unit form, generally, be adjusted in the 1-800mg scope according to the effectiveness of selected activeconstituents.
When formula of the present invention (I) active compound during as the medicine of treatment infectation of bacteria, dosage can change along with the seriousness of the infection of patient's needs, desire treatment, selected compounds etc.
Those skilled in the art can confirm to be suitable for the preferred dose of certain situation by ordinary method.Generally, the amount of begin treatment is lower than the optimal dose of activeconstituents, increases dosage then gradually, up to reaching optimum therapeuticing effect.For simplicity, total per daily dose can be divided into several parts, divides administration for several times.
Anti-microbial activity test-results of the present invention is following:
Mouse and rat muscle injection LD50
Compare with Etimicin sulfate, the stronger toxicity of activity of the present invention is lower.
Description of drawings:
Fig. 1: the ESI-MS collection of illustrative plates of this compound
Fig. 2: this compound
1The H-NMR collection of illustrative plates
Fig. 3: this compound
1H-NMR amplifies collection of illustrative plates (1.0-3.0ppm)
Fig. 4: this compound
1H-NMR amplifies collection of illustrative plates (3.0-5.5ppm)
Fig. 5: this compound
13C NMR collection of illustrative plates
Fig. 6: this compound
13C NMR amplifies collection of illustrative plates (10-50ppm)
Fig. 7: this compound
13C NMR amplifies collection of illustrative plates (50-110ppm)
Fig. 8: HPLC-ELSD color atlas
Embodiment:
Below further specify the present invention through embodiment, but not as limitation of the present invention.
Embodiment 1
Take the Etimicin sulfate bullion that prior art is produced, be dissolved in water, be splined on HD-2 weakly acidic cation-exchange resin post; The difference water, the ammoniacal liquor gradient elution, (developping agent: chloroform-methanol-ammoniacal liquor is known in the TLC inspection; 1: 1: 1; Lower layer I2) also merges stream part, obtains impurity enriched stream part.(chloroform: methyl alcohol: ammoniacal liquor (2: 1: 1, lower layer) and CM-Sephadex C-25 carry out column chromatography for separation, are collected into the 6th component, are compound 1,3-N, N-diethylammonium Gentamicin C1a respectively an impurity enriched stream part warp to be used silica gel H repeatedly.
Take the Etimicin sulfate bullion that prior art is produced, be dissolved in water, be splined on HD-2 weakly acidic cation-exchange resin post; The difference water, the ammoniacal liquor gradient elution, (developping agent: chloroform-methanol-ammoniacal liquor is known in the TLC inspection; 1: 1: 1; Lower layer I2) also merges stream part, obtains impurity enriched stream part.(chloroform: methyl alcohol: ammoniacal liquor (2: 1: 1, lower layer) and CM-Sephadex C-25 carry out column chromatography for separation, are collected into the 6th component respectively an impurity enriched stream part warp to be used silica gel H repeatedly; Be concentrated into 200-500mg/ml, regulate PH to 4.0-5.0, add the gac of 2%-5% again with the hydrochloric acid of 10mol/L; 60-80 ℃ is stirred decolouring 30 minutes; Filter, the filtrating freeze-drying promptly gets the hydrochloride solid of this material.
Take the Etimicin sulfate bullion that prior art is produced, be dissolved in water, be splined on HD-2 weakly acidic cation-exchange resin post; The difference water, the ammoniacal liquor gradient elution, (developping agent: chloroform-methanol-ammoniacal liquor is known in the TLC inspection; 1: 1: 1; Lower layer I2) also merges stream part, obtains impurity enriched stream part.(chloroform: methyl alcohol: ammoniacal liquor (2: 1: 1, lower layer) and CM-Sephadex C-25 carry out column chromatography for separation, are collected into the 6th component respectively an impurity enriched stream part warp to be used silica gel H repeatedly; Be concentrated into 200-500mg/ml, regulate PH to 4.0-5.0, add the gac of 2%-5% again with the sulfuric acid of 5mol/L; 60-80 ℃ is stirred decolouring 30 minutes; Filter, the filtrating freeze-drying promptly gets the vitriol solid of this material.
Embodiment 4, the preparation of tablet:
Get 5 to 20 parts of vitriol solid or the hydrochloride solids of this material, add 5 to 10 parts talcum powder or other, add 5 to 10 parts of Xylo-Mucines, powder is granulated, and compressing tablet promptly gets.
Embodiment 5, the preparation of injection:
Get the vitriol solid or the hydrochloride solid of this material, add the water for injection that 10-25 doubly measures, add ten thousand/ gac, stir half a hour, filtration, with 1ml, 2ml, 5ml or the embedding of 10ml ampoule, sterilizing promptly gets to 5/1000ths.
Claims (8)
1. compound or its pharmacy acceptable salt that structural formula is following.
2. compound as claimed in claim 1 or its pharmacy acceptable salt; Wherein said or its pharmacy acceptable salt salt comprises the salt with mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc.; Salt with organic carboxyl acid such as acetate, trifluoroacetic acid, Hydrocerol A, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, racemic melic acid, xitix or oxysuccinic acid; Or with the salt of sulfonic acid such as methylsulfonic acid, tosic acid etc., and with common known and conventional other sour salt that is applied in the quinolone compounds technical field.Can be by these acid salt of conventional conversion processes.
3. the preparation method of compound as claimed in claim 1 is characterized in that, through following steps, gets the Etimicin sulfate bullion; Use water dissolution, last HD-2 weakly acidic cation-exchange resin post, water respectively; The ammoniacal liquor gradient elution, TLC examines knowledge, and merges stream part; Obtain impurity enriched stream part, respectively an impurity enriched stream part warp is carried out column chromatography for separation with silica gel H and CM-Sephadex C-25 repeatedly, obtain this compound.
4. preparation method as claimed in claim 2 is characterized in that, through following steps, takes the Etimicin sulfate bullion that prior art is produced; Be dissolved in water, be splined on HD-2 weakly acidic cation-exchange resin post, respectively water; The ammoniacal liquor gradient elution, (developping agent: chloroform-methanol-ammoniacal liquor, 1: 1: 1 is known in the TLC inspection; Lower layer I2) also merges stream part, obtains impurity enriched stream part.(chloroform: methyl alcohol: ammoniacal liquor (2: 1: 1, lower layer) and CM-Sephadex C-25 carry out column chromatography for separation, are collected into the 6th component, are this compound respectively an impurity enriched stream part warp to be used silica gel H repeatedly.
5. the pharmaceutical composition that contains the described compound of claim 1.
6. compsn as claimed in claim 4 is any pharmaceutically useful dosage form.
7. compsn as claimed in claim 5 wherein also contains the medicine acceptable carrier.
8. compsn as claimed in claim 6, containing weight percent is the described compound of claim 1 of 0.01-99.9% and the medicine acceptable carrier that weight percent is 0.01-99.9%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665069A (en) * | 2013-12-17 | 2014-03-26 | 无锡济民可信山禾药业股份有限公司 | Aminoglycoside compound and extraction separation method thereof |
| CN108129527A (en) * | 2018-01-11 | 2018-06-08 | 中国医药集团总公司四川抗菌素工业研究所 | Etimicin derivative and preparation method thereof, its pharmaceutical composition and application |
| WO2022222249A1 (en) * | 2021-04-24 | 2022-10-27 | 无锡济煜山禾药业股份有限公司 | Method for obtaining 1-n-ethyl gentamicin c1a by using pipeline reaction hydrolysis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100467A (en) * | 1993-04-23 | 1995-03-22 | 江苏省微生物研究所 | 1-N-ethyl gentamicin derivative and its preparing method |
-
2010
- 2010-09-29 CN CN201010296982.5A patent/CN102432647B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100467A (en) * | 1993-04-23 | 1995-03-22 | 江苏省微生物研究所 | 1-N-ethyl gentamicin derivative and its preparing method |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665069A (en) * | 2013-12-17 | 2014-03-26 | 无锡济民可信山禾药业股份有限公司 | Aminoglycoside compound and extraction separation method thereof |
| CN103665069B (en) * | 2013-12-17 | 2016-05-11 | 无锡济民可信山禾药业股份有限公司 | A kind of glucoside-containing component and extraction separation method thereof |
| CN108129527A (en) * | 2018-01-11 | 2018-06-08 | 中国医药集团总公司四川抗菌素工业研究所 | Etimicin derivative and preparation method thereof, its pharmaceutical composition and application |
| CN108129527B (en) * | 2018-01-11 | 2020-03-20 | 中国医药集团总公司四川抗菌素工业研究所 | Etimicin derivative, preparation method thereof, pharmaceutical composition thereof and application thereof |
| WO2022222249A1 (en) * | 2021-04-24 | 2022-10-27 | 无锡济煜山禾药业股份有限公司 | Method for obtaining 1-n-ethyl gentamicin c1a by using pipeline reaction hydrolysis |
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Address after: 214028 Changjiang South Road, new Wu District, Wuxi, Jiangsu Province, No. 12 Patentee after: Wuxi Jiyu Shanhe Pharmaceutical Co., Ltd Patentee after: JINGXI JIMIN KEXIN GROUP Co.,Ltd. Address before: 214028 No. 12 Changjiang South Road, New District, Jiangsu, Wuxi Patentee before: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. Patentee before: JINGXI JIMIN KEXIN GROUP Co.,Ltd. |