CN103848986A - New compound containing cephalosporin structure as well as preparation method and application thereof - Google Patents
New compound containing cephalosporin structure as well as preparation method and application thereof Download PDFInfo
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- CN103848986A CN103848986A CN201310614888.3A CN201310614888A CN103848986A CN 103848986 A CN103848986 A CN 103848986A CN 201310614888 A CN201310614888 A CN 201310614888A CN 103848986 A CN103848986 A CN 103848986A
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterized by the type of post-polymerisation functionalisation
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- C08G2650/38—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type containing oxygen in addition to the ether group
- C08G2650/40—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type containing oxygen in addition to the ether group containing ketone groups, e.g. polyarylethylketones, PEEK or PEK
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Abstract
The invention discloses a new compound containing a cephalosporin structure as well as a preparation method and application thereof. Drugs prepared from the new compound containing the cephalosporin structure have better effects on treating entophthalmia diseases than drugs or medicaments in other forms.
Description
Technical field
The invention discloses the new compound that contains cynnematin structure and preparation method and the purposes of this compound.
Background technology
Cynnematin sterilization has identical reaction pattern with beta-lactam class microbiotic (as penicillin).Cynnematin destroys the synthetic of bacteria cell wall peptidoglycan.Peptidoglycan is to bacterium, and especially the structural integrity of gram-positive bacteria cell wall plays an important role.
Endophthalmitis is a kind of inflammation of involving eyeball internal layer, vitreum, sclera, and most endophthalmitis are due to bacterium or fungi infestation.Bacterium route of infection can be wound, and the eyeball wound that operation causes can be also haematogenous (bacterium menses spread and cast to intraocular).The symptom of endophthalmitis is usually heavier, mainly contains ophthalmodynia, hyperemia, serious photophobia and eyesight and sharply declines.The symptom of endophthalmitis is usually heavier, mainly contains ophthalmodynia, hyperemia, serious photophobia and eyesight and sharply declines.
The new compound that contains cynnematin of preparing at this patent directly wraps up the nanometer formulation that cynnematin makes and compares with polymkeric substance is simple when endophthalmitis in treatment, the medicine that this patent is invented medication effect in the time of the eye disease model for the treatment of endophthalmitis and severe infections is very good, and effect far surmounts the nanometer formulation of the simple directly parcel of polymkeric substance cynnematin.
Summary of the invention
Of the present invention theing contents are as follows:
The segmented copolymer that the invention discloses the cynnematin coupling shown in following formula I, its structure is as follows:
Wherein PEG refers to polyoxyethylene glycol, and molecular weight is 100-100000, the integer between n=1-200; The preferably integer between n=1-100.
The preparation method of multipolymer of the present invention, is characterized in that:
1) obtain compd A with methoxy poly (ethylene glycol) amine and citric acid reactions;
2) reaction of the sebacic acid of compd A and ethanoyl obtains polymer B, the wherein integer of n=1-200, preferably 1-100;
3) polymer B is reacted and is obtained final product with cephalosporin;
polymer B;
Cephalosporin
Wherein cephalosporin is purchased.The required solvent of described chemical step of the final product of the synthetic new compound that contains cynnematin is selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.
The compound of new system can be prepared into the nanometer formulation that is suitable for topical, microball preparation.Purposes is the medicine of preparation treatment endophthalmitis.
Preparation method of the present invention is specific as follows:
1) sebacic acid is refluxed in diacetyl oxide, form ethanoyl-sebacic acid;
2) methoxy poly (ethylene glycol) amine and citric acid are dissolved in solvent, and hybrid reaction is spent the night, the dry compd A that obtains;
3) ethanoyl-sebacic acid is mixed to reaction at 100-200 ℃, reaction times 10min to 10h with compd A; After question response mixture is cooling, washing, the dry polymer B that obtains;
4) by cephalosporin and polymer B as for 1-96 hour in solvent, after ultrasonic reaction 1-30 minute, in baking oven, foster and obtain formula I polymkeric substance, then homogenizer high-speed stirring 1-10 minute in subzero 30 ℃ of 0-, rotation volatilization obtains crude product, and aftertreatment obtains the nanometer formulation of end product formula I polymkeric substance.
Its reaction equation is as follows:
The polymkeric substance that what the present invention obtained contain cynnematin structure, is easy to dissolve in water, and its transformation period extend much than cynnematin, such new compound effect in the time of the model for the treatment of endophthalmitis is splendid.
The nanometer formulation that the end product of preparing at this patent is made treatment eye disease relatively in, the medication effect of this patent new compound is very good, surmounts the nanometer formulation that is directly wrapped up cynnematin (not with cynnematin coupling) by polymkeric substance completely.
accompanying drawing explanation:
fig. 1the nuclear magnetic resonance map of the end product of embodiment 1.
fig. 2the nuclear magnetic resonance map of the end product of embodiment 2.
fig. 3the nuclear magnetic resonance map of the end product of embodiment 3.
fig. 4the nuclear magnetic resonance map of the end product of embodiment 4.
fig. 5nanoparticle, the sebacic acid-glycol copolymer that embodiment 1 makes directly wraps up medicine accumulative releasing degree and the time chart of cynnematin nanoparticle and cynnematin ordinary preparation.
fig. 6nanoparticle, the sebacic acid-glycol copolymer that embodiment 2 makes directly wraps up medicine accumulative releasing degree and the time chart of cynnematin nanoparticle and cynnematin ordinary preparation.
fig. 7nanoparticle, the sebacic acid-glycol copolymer that embodiment 3 makes directly wraps up medicine accumulative releasing degree and the time chart of cynnematin nanoparticle and cynnematin ordinary preparation.
fig. 8nanoparticle, the sebacic acid-glycol copolymer that embodiment 4 makes directly wraps up medicine accumulative releasing degree and the time chart of cynnematin nanoparticle and cynnematin ordinary preparation.Medicine accumulative releasing degree and the time chart of agent.
Embodiment
Specific embodiment is described in further detail the present invention below, but the present invention not only limits to following examples.
Preparation Example is as follows:
embodiment 1
1) mixture of sebacic acid 47g in 600ml diacetyl oxide refluxes, to form ethanoyl-sebacic acid;
2) methoxy poly (ethylene glycol) amine 6.0g, citric acid 73mg, dicyclohexylcarbodiimide 162mg and pyridine 8.0mg mix and add 32ml methylene dichloride, at room temperature stir and spend the night; Then wash with ether, and dry under vacuum, obtain polymkeric substance;
3) by the 1st) step and the 2nd) step Product mix puts into flask, and at 180 ℃, decompression contains intermingle with reaction 1 hour; Treat that polymkeric substance is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
4) the 850mg polymkeric substance of 150mg Cephradine and step 3 is put into the dichloromethane solution 48 hours of 8ml dimethyl sulfoxide (DMSO) and 14ml; Ultrasonic 5 minutes; Then insert in baking oven 1 hour; In subzero 10-20 degree, homogenizer ultra-high speed stirs 3 minutes, then puts into 2% polyvinyl alcohol solution 600 and turns and stir 3 hours; Freeze-drying after centrifugal collection, obtains the nanoparticle of end product.
embodiment 2
1) mixture of sebacic acid 35g in 500ml diacetyl oxide refluxes, to form ethanoyl-sebacic acid;
2) methoxy poly (ethylene glycol) amine 6.5g, citric acid 70mg, dicyclohexylcarbodiimide 168mg and pyridine 8.2mg mix and add 32ml methylene dichloride, at room temperature stir and spend the night; Then wash with ether, and dry under vacuum, obtain polymkeric substance;
3) by the 1st) step and the 2nd) step Product mix puts into flask, and at 180 ℃, decompression contains intermingle with reaction 1 hour; Treat that polymkeric substance is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
4) the 700mg polymkeric substance of 180mg cefroxadine and step 3 is put into the dichloromethane solution 24 hours of 8ml dimethyl sulfoxide (DMSO) and 12ml; Ultrasonic 5 minutes; Then insert in baking oven 2 hours; In subzero 10-20 degree, homogenizer ultra-high speed stirs 3 minutes, then puts into 1% polyvinyl alcohol solution 600 and turns and stir 3 hours; Freeze-drying after centrifugal collection, obtains the nanoparticle of end product.
1) mixture of sebacic acid 50g in 500ml diacetyl oxide refluxes, to form ethanoyl-sebacic acid;
2) methoxy poly (ethylene glycol) amine 6.5g, citric acid 73mg, dicyclohexylcarbodiimide 168mg and pyridine 8.2mg mix and add 32ml methylene dichloride, at room temperature stir and spend the night; Then wash with ether, and dry under vacuum, obtain polymkeric substance;
3) by the 1st) step and the 2nd) step Product mix puts into flask, and at 180 ℃, decompression contains intermingle with reaction 1 hour; Treat that polymkeric substance is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
4) the 800mg polymkeric substance of 120mg cefaclor and step 3 is put into the dichloromethane solution 48 hours of 8ml dimethyl sulfoxide (DMSO) and 12ml; Ultrasonic 5 minutes; Then insert in baking oven 1 hour; In subzero 10-20 degree, homogenizer ultra-high speed stirs 3 minutes, then puts into 8% cholic acid solution 600 and turns and stir 3 hours; Freeze-drying after centrifugal collection, obtains the nanoparticle of end product.
embodiment 4
1) methoxy poly (ethylene glycol) amine 3g, citric acid 45mg, dicyclohexylcarbodiimide 200mg and pyridine 6mg mix and add 20ml methylene dichloride, at room temperature stir and spend the night; Then wash with ether, and dry under vacuum;
2) ethanoyl-sebacic acid 20g(is purchased) and the 1st step Product mix put into flask, at 170 ℃, react 1.5 hours; Treat that polymkeric substance is cooled to room temperature chloroform and dissolves, and with petroleum ether the dry polymkeric substance (structure or with homemade slightly different, molecular weight or different because being purchased quality) that obtains;
3) 50mg Cephalonium and this polymkeric substance 150mg are put into the solution being mixed by 1ml methyl alcohol and 1ml methylene dichloride; Ultrasonic 2 minutes; Then insert in baking oven 24 hours; In subzero 10-20 degree, homogenizer high-speed stirring 2 minutes, product is put into 3% cholic acid solution 600 and is turned and stir 4 hours; Freeze-drying after centrifugal collection, obtains the microballoon of new compound.
effect experiment is as follows:
Sample prepared by embodiment 1-4 and and sebacic acid-glycol copolymer directly the nanoparticle medicine group of the cynnematin of parcel (there is not chemical coupling reaction, cynnematin does not have structural changes), cynnematin ordinary preparation (powder injection) carries out respectively the drug action test of stability test, drug release in vitro test and endophthalmitis.
Stability test:
By the nanoparticle medicine group of the cynnematin of 1 group of sample of preparing of embodiment and sebacic acid-glycol copolymer parcel, cynnematin ordinary preparation is got with amount (in cynnematin) and is measured respectively absorbance.Then put into 20 degree incubator 3 months for three groups, take out subsequently and measure nanometer absorbance, the absorbance front and back of the cynnematin of the visible embodiment 1-4 group of result and ordinary preparation group are without changing, and the nanoparticle group absorbancy of parcel declines respectively 26%, 22%, 21%, 17%.
Drug release in vitro test:
By embodiment 1-4 group, sebacic acid-glycol copolymer directly the nanoparticle medicine group of the cynnematin of parcel and cynnematin ordinary preparation component have another name called get equivalent medicine (in cynnematin, every group containing 10mg cynnematin), then by each group of medicine as in test tube, after soaking with PBS damping fluid, 37 degrees Celsius of lower joltings in shaking table, after timing sampling, under ultraviolet spectrophotometer, measure the content of medicine, and the medicament contg per-cent that after record, calculating discharges, do releasing curve diagram, X-coordinate be the time (my god), ordinate zou be discharge per-cent.See Fig. 2, the medicine that visible embodiment discharges is more permanent, makes drug half-life longer.
Solubility test in water:
By embodiment 1-4 group, sebacic acid-glycol copolymer directly the nanoparticle medicine group of the cynnematin of parcel and cynnematin ordinary preparation component have another name called get equivalent medicine (in cynnematin, every group containing 100mg cynnematin), put into respectively test tube, with the dissolving of 10mlPBS damping fluid jolting, situation is dissolved in static rear observation.The dissolved state that records 3 minutes and 20 minutes, result is as follows.
The comparison of table 1 solubleness
| Group | 3 minutes | 20 minutes |
| Sebacic acid-glycol copolymer directly wraps up nanoparticle prepared by Cephradine | Muddy white suspension solution | At the bottom of nanoparticle is deposited to bottle (layering) |
| Sebacic acid-glycol copolymer directly wraps up nanoparticle prepared by cefroxadine | Muddy white suspension solution | At the bottom of nanoparticle is deposited to bottle (layering) |
| Sebacic acid-glycol copolymer directly wraps up nanoparticle prepared by cefaclor | Muddy white suspension solution | At the bottom of nanoparticle is deposited to bottle (layering) |
| Sebacic acid-glycol copolymer directly wraps up nanoparticle prepared by Cephalonium | Muddy white suspension solution | At the bottom of nanoparticle is deposited to bottle (layering) |
| Embodiment 1 | Stabilizing solution | Stabilizing solution (not layering) |
| Embodiment 2 | Stabilizing solution | Stabilizing solution (not layering) |
| Embodiment 3 | Stabilizing solution | Stabilizing solution (not layering) |
| Embodiment 4 | Stabilizing solution | Stabilizing solution (not layering) |
| Cephradine ordinary preparation | At the bottom of medicine is deposited to bottle | At the bottom of medicine is deposited to bottle (layering) |
| Cefroxadine ordinary preparation | At the bottom of medicine is deposited to bottle | At the bottom of medicine is deposited to bottle (layering) |
| Cefaclor ordinary preparation | At the bottom of medicine is deposited to bottle | At the bottom of medicine is deposited to bottle (layering) |
| Cephalonium ordinary preparation | At the bottom of medicine is deposited to bottle | At the bottom of medicine is deposited to bottle (layering) |
The therapeutic action of medicine to eye inflammation
1 laboratory animal
Healthy Wistar rat, male and female are not limit, and body weight is at 220g, observes intraocular in good condition and carry out this test without other eye illness person under slit lamp.
2 experimental techniques
2.1 modeling method
Carry out eyeground trauma infection contamination model, rat sucks etherization, on simple fixing and mouse plate, uses ophthalmology micro-surgical instrument on right eye temporo centered by 10 positions after elongation limbus of sclera 2 millimeters, does the arc incision parallel with corneoscleral junction, is about 3.0mm.Cut wall of eyeball holostrome, deeply reach vitreous space.Incision causes pigmented film incarceration, and pigmented film exposed parts is parallel with cutting edge, and otch will not be sewed up, and allows it produce and infects.
2.2 clustering method
Modeling success laboratory animal is divided into model group, embodiment 1-4 group, cynnematin ordinary preparation group at random, polymkeric substance directly wraps up nanoparticle subgroup prepared by cynnematin, the equal intravitreal 50 μ l medicines of each group, model group gives isopyknic PBS solution.
3 inspection items and method
Conventional fundoscopy
Every daily slit lamp, indirect ophthalmoscope inspection.After intervening, each treated animal was carried out to the scoring of endophthalmitis clinical scale in 1,4,7 day, primary part observation anterior chamber scintillation, aqueous cell and vitreous opacity degree, for anterior chamber's scintillation classification marking, (inflammatory exudate enters aqueous humor to its grade scale, under the narrow light belt of slit lamp casts oblique rays on, visible light flash and ooze out particle float, this phenomenon is called aqueous flare): 0 grade, without aqueous flare (light beam is transparent shinny); 1 grade, slight aqueous flare (the faint light beam that turns white); 2 grades, moderate aqueous flare (the milky white light beam of moderate can be distinguished iris and lens details); 3 grades, significantly aqueous flare (obvious milky white light beam, impalpable iris and lens details); 4 grades, serious anterior chamber's scintillation, aqueous humor becomes curdled appearance, with a large amount of fibrinous exudates.
4 statistical procedures
Data represent with x ± s, t check between relatively employing group between two groups.P < 0.05, for there being significant difference, has statistical significance.
5 results
Clinical inflammation scoring
24h after sudden and violent leakage wound, there is palpebral edema in all rats, and corneal edema is obvious, and conjunctiva is congested, oedema obviously, anterior chamber's scintillation (+), exudation of anterior chamber (+).After intervening, within 4,7 days, carry out clinical inflammation scoring, model group inflammatory symptom increases the weight of day by day, and treatment group laboratory animal cornea is all transparent gradually, and anterior chamber's scintillation alleviates gradually, oozes out and is tending towards absorbing, and vitreous opacity alleviates in various degree.Each treatment group and model group more all have significant difference (table 1).
The clinical inflammation scoring of the each group of the postoperative different time points of table 1 situation (n>10 x ± s)
| Group | 4d | 7d |
| Model group | 3.75±0.17 | 3.84±0.19 |
| Cephradine ordinary preparation administration group | 3.20±0.26* | 2.98±0.20* |
| Cefroxadine ordinary preparation administration group | 3.19±0.25* | 2.99±0.23* |
| Cefaclor ordinary preparation administration group | 3.17±0.26* | 2.95±0.23* |
| Cephalonium ordinary preparation administration group | 3.22±0.24* | 2.96±0.22* |
| Polymkeric substance directly wraps up Cephradine administration group | 3.09±0.21* | 2.90±0.22** |
| Polymkeric substance directly wraps up cefroxadine administration group | 2.99±0.22* | 2.96±0.21** |
| Polymkeric substance directly wraps up cefaclor administration group | 3.03±0.22* | 2.97±0.21** |
| Polymkeric substance directly wraps up Cephalonium administration group | 3.04±0.21* | 2.93±0.19** |
| Embodiment 1 | 1.08±0.20** | 0.82±0.19** |
| Embodiment 2 | 1.07±0.23** | 0.78±0.16** |
| | 1.11±0.21** | 0.79±0.19** |
| Embodiment 4 | 1.13±0.22** | 0.85±0.18** |
With relatively * p<0.05 of model group, * * p<0.01.
Claims (10)
1. in the structure being shown below, contain the new compound of cynnematin, its structure is as follows:
Wherein R is alkane, aromatic hydrocarbon or undersaturated alkane or unsaturated hydrocarbons, can be alkoxyl group, and halogen family or halogen family alkane, containing alkane or the unsaturated hydrocarbons of fat key, also can be pyridyl, furyl, pyrryl, thienyl or pyranyl.
2. the multipolymer of claim 1, wherein PEG refers to polyoxyethylene glycol, and molecular weight is 100-100000, the integer between n=1-200; The preferably integer between n=1-100.
The preferred CH of 3.R
3, CH
3o, CH
3cOOCH
2, Cl, Br, OH etc.
4. the structure of the part new compound in claim 1 is as follows:
Containing the new compound of Cephradine
Containing the new compound of cefroxadine
Containing the new compound of cefaclor
Containing the new compound of Cephalonium
。
5. the preparation method of multipolymer as claimed in claim 1, is characterized in that:
1) obtain compd A with methoxy poly (ethylene glycol) amine and citric acid reactions;
2) reaction of the sebacic acid of compd A and ethanoyl obtains polymer B, the wherein integer of n=1-200, preferably 1-100;
3) polymer B is reacted and is obtained final product with cephalosporin;
Cephalosporin
。
6. the method for claim 4, wherein said chemical step 1-3 selects solvent to be selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.
7. the compound of claim 1 can be prepared into the nanometer formulation that is suitable for topical, microball preparation.
8. described in claim 6, part is intravitreal injection administration, dosing eyes.
9. the purposes of the compound of claim 1, purposes is the medicine of preparation treatment eye disease.
10. the purposes of the compound of claim 1, purposes is the medicine of preparation treatment endophthalmitis or ocular infection.
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| CN103848852A (en) * | 2012-11-28 | 2014-06-11 | 杨子剑 | New compound containing cephalosporin structure as well as preparation method and application thereof |
| CN107445978A (en) * | 2017-08-24 | 2017-12-08 | 艾美科健（中国）生物医药有限公司 | A kind of synthesis of cefalonium and purification process |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578325A (en) * | 1993-07-23 | 1996-11-26 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
| CN1879639A (en) * | 2005-06-17 | 2006-12-20 | 张晴龙 | A nanometer 'Xue Shuan Tong' injection and preparation method thereof |
| CN101259106A (en) * | 2006-06-30 | 2008-09-10 | 伊兰公开公司 | Nano controlled release compositions comprising a cephalosporin |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2003248624B2 (en) * | 2002-06-05 | 2006-04-06 | University Of Florida | Opthalmic drug delivery system |
| EP1698329A4 (en) * | 2003-12-24 | 2009-10-28 | Ltt Bio Pharma Co Ltd | Drug-containing nanoparticle, process for producing the same and parenterally administered preparation from the nanoparticle |
| US20060105941A1 (en) * | 2004-11-12 | 2006-05-18 | Allergan, Inc. | Mixed antibiotic codrugs |
| CN1965802B (en) * | 2006-11-09 | 2010-04-14 | 复旦大学 | Injectable hydrogel preparation of pegylated medicament and preparing method thereof |
| EP2538929A4 (en) * | 2010-02-25 | 2014-07-09 | Univ Johns Hopkins | Sustained delivery of therapeutic agents to an eye compartment |
| CN103848986B (en) * | 2012-11-28 | 2019-10-11 | 杨子剑 | Compound and preparation method and purposes containing cephalosporin structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578325A (en) * | 1993-07-23 | 1996-11-26 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
| CN1879639A (en) * | 2005-06-17 | 2006-12-20 | 张晴龙 | A nanometer 'Xue Shuan Tong' injection and preparation method thereof |
| CN101259106A (en) * | 2006-06-30 | 2008-09-10 | 伊兰公开公司 | Nano controlled release compositions comprising a cephalosporin |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848852A (en) * | 2012-11-28 | 2014-06-11 | 杨子剑 | New compound containing cephalosporin structure as well as preparation method and application thereof |
| CN107445978A (en) * | 2017-08-24 | 2017-12-08 | 艾美科健（中国）生物医药有限公司 | A kind of synthesis of cefalonium and purification process |
| CN107445978B (en) * | 2017-08-24 | 2019-06-18 | 艾美科健（中国）生物医药有限公司 | A kind of synthesis of cefalonium and purification process |
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| CN103848852B (en) | 2019-02-19 |
| CN103848986B (en) | 2019-10-11 |
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