CN104004003B - Cefixime derivative and its production and use - Google Patents
Cefixime derivative and its production and use Download PDFInfo
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- CN104004003B CN104004003B CN201310056746.XA CN201310056746A CN104004003B CN 104004003 B CN104004003 B CN 104004003B CN 201310056746 A CN201310056746 A CN 201310056746A CN 104004003 B CN104004003 B CN 104004003B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D501/22—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D501/02—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
Abstract
The invention discloses a class and there are the two salt hydrate of good water miscible Cefixime or the two salt solvent compounds of Cefixime and its preparation method and application. Such Compound Phase has good water-soluble and stability for cefixime trihydrate, can use separately, also can combine other beta-lactamase inhibitor and combine use, or form compound preparation with beta-lactamase inhibitor etc., with injection form administration, there is higher bioavilability and good stability.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to the two salt hydrate of Cefixime or Cefixime pair that a class is newSalt solvent compound and preparation method thereof and the application in treatment bacterial infection disease medicine.
Background technology
Cefixime is the oral cephalosporin analog antibiotic of the third generation, and by Japanese rattan pool Developed, 1987 by JapanFujisawa Pharmaceutical Co., Ltd is first in Japan's listing, and commodity are called cefixime. Cefixime chemistry is by name: (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxymethoxyl) imido grpup] acetamido)-3-vinyl-8-oxo-5-Thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid trihydrate. China started imported raw material and preparation in 1994,This product clinical effectiveness is remarkable, and determined curative effect and bad reaction are little, and dosage is in rising trend.
Cefixime, as the third generation cephalosporin of wide spectrum, has many outstanding features: 1. steady to beta-lactamaseFixed, because Cefixime is stable to beta-lactamase, therefore Cefixime has effectively overcome the drug resistance of bacterium, become resistance resistance toThe important kind (soup boil etc., Shandong chemical industry .2009,38 (2), 19-21.) that medicine bacterium infects. 2. has a broad antifungal spectrum, cephalo gramOxime has the antibacterial action of wide spectrum to gram-positive bacteria and negative bacterium, particularly stronger to Gram-negative bacteria effect, antibacterialSpectrum comprises streptococcus, the pneumococcus etc. in gram-positive bacteria; Gonococcus in Gram-negative bacteria, Escherichia coli, pneumoniaBacillus, proteus mirabilis, influenza Pseudomonas etc. 3. long half time, this product half-life 3.7h, be in current oral cephalosporinLong one. 4. indication is wide, good effect, and Cefixime is clinically for respiratory tract infection, urinary tract infection, infection of biliary tract, littleThe acute atypical bacterial forms dysentery of youngster, Er Bi section etc., evident in efficacy. 5. dosage is little, and Cefixime is for making clinically at presentWith the Cephalosporins of dosage minimum.
The bulk drug that this medicine is applied in clinical treatment is cefixime trihydrate, and in water, solubility is very little, formulationThe form administration with oral solid formulation, as tablet, capsule, dispersing tablet and granule etc., simultaneously owing to dissolving in waterSpend very littlely, cause the bioavilability of these oral formulations low. Oral solid formulation is for injection in addition, and medicine risesImitate slowlyer, be not suitable for severe infection patient or MDR patient's emergency treatment, therefore clinical in by oral headA spore gram oxime solid pharmaceutical preparation converts injection to using the demand as emergency treatment, but uses as injection, and medicine must toolThere is good water-soluble and stability.
Summary of the invention
The object of this invention is to provide and there are the two salt hydrate of good water miscible Cefixime or the two salt of Cefixime is moltenAgent compound.
Another object of the present invention is to provide has the two salt hydrate of good water miscible Cefixime or CefiximeThe preparation method of two salt solvent compounds.
A further object of the present invention is to provide the two salt hydrate of Cefixime or prepared by the two salt solvent compounds of CefiximeBe used for the treatment of or prevent by bacterium infect cause or the medicine of the disease that causes in application.
The object of the invention is to realize by following concrete technical scheme:
The two salt hydrate of Cefixime or solvate that a kind of general formula (I) is following:
Wherein M is Na or K;
X is selected from 0,0.25,0.5,0.75,1,1.25,1.50,1.75,2,2.25,2.50,2.75,3,3.25,3.50,3.75 or 4;
Y is selected from 0,0.25,0.5,0.75,1,1.25,1.50,1.75,2,2.25,2.50,2.75,3,3.25,3.50,3.75 or 4;
X, Y can not be 0 simultaneously;
R is the alkyl that C1～C10 is direct-connected or side chain replaces.
Alkyl R refers to the saturated hydrocarbyl of the straight or branched with 1 to 10 carbon atom, and wherein R has and is selected from: methyl,Ethyl, propyl group, the straight or branched groups such as butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl; Preferred: methyl, ethyl,Propyl group, butyl.
The two salt hydrate of Cefixime or the solvate of above formula (I) statement, the compound that can list has:
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid sodium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium trihydrate;
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid potassium trihydrate;
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid potassium one methyl alcohol compound;
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium one ethanol compound;
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid potassium one ethanol compound;
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium one and 1/2nd isopropylsAlcohol adduct.
Wherein highly preferred compound is:
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid sodium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium trihydrate;
(6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup] acetamideBase) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid potassium trihydrate.
Its X diffracting spectrum shows that it is a kind of amorphous powder.
The method of preparing the compounds of this invention is: cefixime trihydrate is dissolved in to alcoholic solvent, then adds alkaline sodiumOr the compound of potassium to reconcile pH value be neutral, add again afterwards precipitating reagent, crystallization, separation, obtains corresponding Cefixime pair saltThe two salt solvent compounds of hydrate or Cefixime.
" precipitating reagent " mentioned in the method for the invention, i.e. crystallization solvent, can be regarded as with this product sl. sol. at the mostSolvent. According to the technical field under the method, dilution crystallization method (or solvent crystallization) is that solute is dissolved in to water or otherIn organic solvent, then in crystalline solid, add certain anti-phase solvent that the solubility of solute in former solvent is reduced, thus moltenThe method for crystallising that matter is separated out fast. The anti-phase solvent adding is known as precipitating reagent, i.e. crystallization solvent.
Cefixime trihydrate and counter ion counterionsl gegenions M+Salt-forming reaction between source is to carry out under conventional salt-forming condition, for example, in the alcoholic solvent such as methyl alcohol or ethanol, after mixing with the alkali of sodium or potassium, cefixime trihydrate reacts salify, thenAdd precipitating reagent, obtain formula (I) compound through crystallization. Suitable precipitating reagent is ether solvent, and alcohols solvent or ketones solvent are excellentThe precipitating reagent of choosing is ether, ethanol, acetone, isopropyl alcohol, n-butanol or two kinds and two or more mixed solvents.
Dissolve the alcoholic solvent that cefixime trihydrate uses, be generally the aliphatic alcohol of carbon containing 1-10, particular methanol orEthanol.
Counter ion counterionsl gegenions M can be provided+Suitable alkali be the compound of alkaline sodium or potassium, for example NaOH, sodium carbonate, carbonAcid hydrogen sodium, sodium methoxide, caustic alcohol, sodium isopropylate, sodium tert-butoxide, potassium hydroxide, potash, saleratus, potassium methoxide, ethanolPotassium, potassium isopropoxide or potassium tert-butoxide etc.; Particular methanol sodium, caustic alcohol, sodium isopropylate, sodium tert-butoxide, potassium methoxide, potassium ethoxide, differentPotassium propoxide or potassium tert-butoxide.
Formula of the present invention (I) compound is being infected the medicine of the disease causing or cause for the preparation for the treatment of or prevention by bacteriumIn thing, apply. Formula (I) compound can be applied separately, and also can combine other beta-lactamase inhibitor associating and use together,Or use together with the composition compound preparations such as beta-lactamase inhibitor.
The two salt hydrate of Cefixime of the present invention or solvate are being infected and are being led by bacterium for the preparation for the treatment of or preventionIn the medicine of the disease causing or cause, apply, bacterium wherein infects and comprises by gram-positive bacteria, Gram-negative bacteria, anaerobismBacterium, mycoplasma, Chlamydia, the infection that Legionella or mycobacterium cause.
The present invention also provides a kind of pharmaceutical composition, comprises the two salt hydrate of Cefixime or solvate for effectively becomingPoint and/or one or more pharmaceutically suitable carrier, excipient, diluent. Said composition can list various concrete forms: injectionAgent is as powder-injection, and oral formulations is as tablet, capsule, granule etc.
The solubility of the compounds of this invention can record by the solubility test method of standard, for example at room temperature water solution orIn neutral physiological buffer solution, formula (I) compound solubility is greater than 500mg/ml, more water-soluble in room temperature than cefixime trihydrateIn liquid or neutral physiological buffer solution, the numerical value of solubility increases more than 500 times.
Beneficial effect of the present invention is: compared with the oral solid formulation of cefixime trihydrate, and chemical combination of the present inventionThe solid pharmaceutical preparation bioavilability of thing is high, has a broad antifungal spectrum, antibacterial activity is higher than cefixime trihydrate preparation, have wide spectrum,Efficiently, resistance to enzyme, the features such as low toxicity; The good water-soluble aqueous solution that is conducive to be prepared into, for example, can be prepared into intravenous injection,The simultaneously good water-soluble bioavilability that can improve this compound or its compound preparation.
Compound of the present invention also has good heat-resisting, resistance to high humility performance, and stability is high, and these advantages are convenient to makeThe injection that quality is higher.
Brief description of the drawings
Figure 1 shows that the X-ray powder diffraction spectrogram of Cefixime two sodium trihydrates prepared by the embodiment of the present invention 4.
Figure 2 shows that the X-ray powder diffraction spectrogram of Cefixime dipotassium trihydrate prepared by the embodiment of the present invention 6.
Detailed description of the invention
Embodiment 1 (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid sodium methoxyl group) imido grpup]Acetamido) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium trihydrateThe preparation of (Cefixime two sodium trihydrates)
Get (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxymethoxyl) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid trihydrate (10.0g) is molten in room temperatureIn methyl alcohol, be cooled to afterwards 10 DEG C, slowly add the methanol solution (1mol/L) of sodium methoxide, reconcile pH to 7.0, then be cooled to5 DEG C, slowly add absolute ethyl alcohol (200ml), equality of temperature stirs 1h, filters, absolute ethanol washing, vacuum drying obtains solid4.59g, productive rate 42%.
1HNMR(400MHz,DMSO-d6)δ:11.80(d,J=8.5Hz,1H),7.16(s,2H),7.04(dd,J=17.8,11.2Hz,1H),6.84(s,1H),5.59(dd,J=8.5,4.9Hz,1H),5.11(d,J=17.6Hz,1H),5.03(d,J=4.9Hz,1H),4.90(d,J=11.7Hz,1H),4.25(s,2H),3.44(s,1H),3.39(s,1H)。
Elementary analysis (C16H19N5Na2O10S2) measured value (calculated value, %): C34.64(34.85), H3.80(3.47),N12.37（12.70）。
Na＋Assay measured value (calculated value, %): 7.88(8.34).
Embodiment 2 (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid sodium methoxyl group) imido grpup]Acetamido) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium trihydrateThe preparation of (Cefixime two sodium trihydrates)
Get (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxymethoxyl) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid trihydrate (10.0g) is molten in room temperatureIn methyl alcohol, be cooled to afterwards 10 DEG C, slowly add the methanol solution (1mol/L) of sodium methoxide, reconcile pH to 7.0, then be cooled to5 DEG C, slowly add absolute ether (200ml), equality of temperature stirs 1h, filters, absolute ether washing, vacuum drying obtains solid8.51g, productive rate 78%.
1HNMR(400MHz,DMSO-d6)δ:11.82(d,J=8.5Hz,1H),7.14(s,2H),7.06(dd,J=17.8,11.2Hz,1H),6.88(s,1H),5.57(dd,J=8.5,4.9Hz,1H),5.12(d,J=17.6Hz,1H),5.06(d,J=4.9Hz,1H),4.92(d,J=11.7Hz,1H),4.23(s,2H),3.47(s,1H),3.38(s,1H)。
Elementary analysis (C16H19N5Na2O10S2) measured value (calculated value, %): C34.02(34.85), H3.90(3.47), N12.12（12.70）。
Na＋Assay measured value (calculated value, %): 8.22(8.34).
Embodiment 3 (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid sodium methoxyl group) imido grpup]Acetamido) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium trihydrateThe preparation of (Cefixime two sodium trihydrates)
Get (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxymethoxyl) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid trihydrate (10.0g) is molten in room temperatureIn methyl alcohol, be cooled to afterwards 10 DEG C, slowly add the ethanolic solution (1mol/L) of caustic alcohol, reconcile pH to 7.0, then be cooled to5 DEG C, slowly add acetone (200ml), equality of temperature stirs 1h, filters, ethanol washing, vacuum drying obtains solid 3.85g, productive rate35%。
1HNMR(400MHz,DMSO-d6)δ:11.79(d,J=8.5Hz,1H),7.15(s,2H),7.03(dd,J=17.8,11.2Hz,1H),6.83(s,1H),5.58(dd,J=8.5,4.9Hz,1H),5.10(d,J=17.6Hz,1H),5.07(d,J=4.9Hz,1H),4.94(d,J=11.7Hz,1H),4.23(s,2H),3.45(s,1H),3.40(s,1H)。
Elementary analysis (C16H19N5Na2O10S2) measured value (calculated value, %): C35.92(34.85), H3.69(3.47), N12.64（12.70）。
Na＋Assay measured value (calculated value, %): 8.11(8.34).
Embodiment 4 (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid sodium methoxyl group) imido grpup]Acetamido) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium trihydrateThe preparation of (Cefixime two sodium trihydrates)
Get (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxymethoxyl) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid trihydrate (10.0g) is molten in room temperatureIn methyl alcohol, be cooled to afterwards 10 DEG C, slowly add the ethanolic solution (1mol/L) of caustic alcohol, reconcile pH to 7.0, then be cooled to5 DEG C, slowly add isopropyl alcohol (200ml), equality of temperature stirs 1h, filters, washed with isopropyl alcohol, vacuum drying obtains solid 9.06g, producesRate 83%.
1HNMR(400MHz,DMSO-d6)δ:11.83(d,J=8.5Hz,1H),7.19(s,2H),7.03(dd,J=17.8,11.2Hz,1H),6.85(s,1H),5.60(dd,J=8.5,4.9Hz,1H),5.12(d,J=17.6Hz,1H),5.08(d,J=4.9Hz,1H),4.91(d,J=11.7Hz,1H),4.27(s,2H),3.44(s,1H),3.37(s,1H)。
Elementary analysis (C16H19N5Na2O10S2) measured value (calculated value, %): C36.01(34.85), H3.82(3.47),N12.52（12.70）。
Na＋Assay measured value (calculated value, %): 8.20(8.34).
Embodiment 5 (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup]Acetamido) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid potassium trihydrateThe preparation of (Cefixime dipotassium trihydrate)
Get (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxymethoxyl) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid trihydrate (10.0g) is molten in room temperatureIn methyl alcohol, be cooled to afterwards 10 DEG C, slowly add the methanol solution (1mol/L) of potassium methoxide, reconcile pH to 7.0, then be cooled to5 DEG C, slowly add absolute ethyl alcohol (200ml), equality of temperature stirs 1h, filters, absolute ethanol washing, vacuum drying obtains solid5.06g, productive rate 44%.
1HNMR(400MHz,DMSO-d6)δ:11.81(d,J=8.5Hz,1H),7.15(s,2H),7.03(dd,J=17.8,11.2Hz,1H),6.85(s,1H),5.58(dd,J=8.5,4.9Hz,1H),5.12(d,J=17.6Hz,1H),5.04(d,J=4.9Hz,1H),4.92(d,J=11.7Hz,1H),4.26(s,2H),3.46(s,1H),3.36(s,1H)。
Elementary analysis (C16H19K2N5O10S2) measured value (calculated value, %): C32.99(32.92), H3.46(3.28), N11.87（12.00）。
K＋Assay measured value (calculated value, %): 13.18(13.40).
Embodiment 6 (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup]Acetamido) }-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid potassium trihydrateThe preparation of (Cefixime dipotassium trihydrate)
Get (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxymethoxyl) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid trihydrate (10.0g) is molten in room temperatureIn methyl alcohol, be cooled to afterwards 10 DEG C, slowly add the methanol solution (1mol/L) of potassium methoxide, reconcile pH to 7.0, then be cooled to5 DEG C, slowly add isopropyl alcohol (200ml), equality of temperature stirs 1h, filters, washed with isopropyl alcohol, vacuum drying obtains solid 9.85g, producesRate 86%.
1HNMR(400MHz,DMSO-d6)δ:11.83(d,J=8.5Hz,1H),7.12(s,2H),7.04(dd,J=17.8,11.2Hz,1H),6.86(s,1H),5.57(dd,J=8.5,4.9Hz,1H),5.11(d,J=17.6Hz,1H),5.03(d,J=4.9Hz,1H),4.90(d,J=11.7Hz,1H),4.23(s,2H),3.48(s,1H),3.38(s,1H)。
Elementary analysis (C16H19K2N5O10S2) measured value (calculated value, %): C33.06(32.92), H3.49(3.28), N11.91（12.00）。
K＋Assay measured value (calculated value, %): 13.26(13.40).
The test of embodiment 7X-ray powder diffraction
Get Cefixime two sodium trihydrates (embodiment 4 samples) and Cefixime dipotassium trihydrate (embodiment 6 samplesProduct), to measure with sharp shadow (Empyrean) x-ray diffractometer, testing conditions is: Cu target K ɑ1Ray, voltage 40kV, electric current40mA, 1/32 ° of divergent slit, 1/16 ° of anti-scatter slit, anti-scatter slit 7.5mm, 2 θ scopes: 3 °-50 °, 0.02 ° of step-length,Every step time of staying 40S. Detect foundation: turn target polycrystal X-ray diffraction method general rule JY/T009-1996. X-ray powderDiffraction spectrogram is shown in accompanying drawing 1 and accompanying drawing 2, and result shows Cefixime two sodium trihydrates (embodiment 4 samples) and Cefixime twoPotassium trihydrate (embodiment 6 samples) is unformed powder.
Embodiment 8 Cefixime two sodium trihydrate solubility experiments
Get four parts of Cefixime two sodium trihydrates (embodiment 4 samples), every part of 1.500g, respectively at 10 DEG C, 20 DEG C, 30DEG C and 40 DEG C at add purified water 3.0ml, sway and all obtain clear solution, therefore Cefixime two sodium trihydrates dissolveDegree is 500mg/ml.
Table 1. Cefixime two sodium trihydrate solubility tables
。
Embodiment 9 Cefixime two sodium trihydrate accelerated stability research experiments
Cefixime two sodium trihydrates (embodiment 4 samples) and Cefixime disodium are carried out (with reference to Chinese patentThe method preparation of ZL200410040017.6) accelerated stability research experiment (40 DEG C, 75% relative humidity), result shows cephaloGram oxime two sodium trihydrates have better stability in accelerated stability test.
Table 2. Cefixime two sodium trihydrate accelerated test stability tables
。
From the stability data of upper table, can draw, under the environment such as high temperature, high humility, Cefixime two of the present inventionSodium trihydrate was compared Cefixime disodium after 30 days, high 6% left and right of the purity of its active ingredient; After 60 days, it effectively becomesPoint high 8% left and right of purity, above data show Cefixime two sodium trihydrates with respect to Cefixime disodium hot and humidDegradation speed under condition is slower, and bulk drug stability is better. The most basic requirement of pharmaceutical preparation is safety, effective, stable.Pharmaceutical preparation, in production, storage, use procedure, can go bad because the impact of various factors occurs to decompose, thereby cause medicine to be treatedEffect reduces or side effect increases, and cephalosporins medicine even can produce noxious material, increases patient's allergic reaction probability, also may makeBecome larger economic loss. Cefixime two sodium trihydrates of the present invention have good stability, can ensure formulation productsQuality, can reduce again the economic loss causing because preparation is unstable.
The embodiment 10 Cefixime two sodium trihydrate tests of pesticide effectiveness
Cefixime two sodium trihydrates (embodiment 4 samples) of getting injection are trial target, with Cefixime three waterIn contrast, in-vitro antibacterial experiment shows compound, Cefixime two sodium trihydrates of injection to Gram-negative bacteria asThe antibacterial activity of Escherichia coli CMCC44113 and Pseudomonas aeruginosa CMCC10211 and this medicine to gram-positive bacterium as goldThe antibacterial activity of staphylococcus aureus CMCC26112 is higher than the antibacterial activity of cefixime trihydrate.
Table 3. Cefixime two sodium trihydrate test of pesticide effectiveness tables of data
。
From the activity data of upper table, can draw, Cefixime two sodium trihydrates of the present invention are compared Cefixime threeHydrate is high 16 times to the activity of staphylococcus aureus; Compare vancomycin hydrochloride high 128 times to colibacillary activity, tableReveal extremely strong antibacterial activity. Compared with cefixime trihydrate, Cefixime two sodium trihydrates do not have biological utilisationSpend low problem, its has a broad antifungal spectrum, antibacterial activity is higher than cefixime trihydrate, has wide spectrum, efficient, resistance to enzyme, low toxicity etc.Feature.
Embodiment 11 Cefixime two sodium trihydrate pharmaceutical composition preparations
Take Sodium Benzoate 1g, add Cefixime two sodium trihydrate 1000g, after mixing, then press powder pin normalThe packing of rule production technology makes injection Cefixime two sodium trihydrate powder-injection.
Above-described embodiment is preferably embodiment of the present invention, but embodiments of the present invention are not subject to above-described embodimentRestriction, other any do not deviate from change, the modification made under Spirit Essence of the present invention and principle, substitutes, combination, simplification,All should be equivalent replacement mode, within being included in protection scope of the present invention.
Claims (10)
1. the two salt hydrate of Cefixime or a solvate, it is: (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid sodium methoxyl group) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid sodium trihydrate.
2. the two salt hydrate of Cefixime or a solvate, it is: (6R, 7R)-7-{ ((Z)-2-(thiazolamine-4-yl)-2-[(carboxylic acid potassium methoxyl group) imido grpup] acetamido)-3-vinyl-8-oxo-5-thia-1-azabicyclic (4,2,0)-2-octene-2-carboxylic acid potassium trihydrate.
3. the two salt hydrate of Cefixime according to claim 1 and 2 or solvate, is characterized in that for amorphous powderEnd.
4. prepare two salt hydrate of Cefixime described in claim 1 or 2 or a method for solvate, described method spyLevy and be: cefixime trihydrate is dissolved in to alcoholic solvent, then adds the compound of alkaline sodium or potassium to reconcile pH value for neutral,Add afterwards precipitating reagent, crystallization, separates again, and obtains the two salt hydrate of corresponding Cefixime or Cefixime pair salt solvents and closesThing.
5. the preparation method of the two salt hydrate of Cefixime according to claim 4 or solvate, wherein alcohol usedSolvent is selected from methyl alcohol or ethanol.
6. the preparation method of the two salt hydrate of Cefixime according to claim 4 or solvate, wherein precipitating reagent choosingFrom ether, ethanol, acetone, isopropyl alcohol, one of n-butanol or its mixture.
7. the preparation method of the two salt hydrate of Cefixime according to claim 4 or solvate, wherein alkali usedThe compound of property sodium or potassium is selected from sodium methoxide, caustic alcohol, sodium isopropylate, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide orPotassium tert-butoxide.
The two salt hydrate of Cefixime described in claim 1 or 2 or solvate for the preparation for the treatment of or prevention by carefullyBacterium infect cause or the medicine of the disease that causes in application.
9. pharmaceutical composition, comprises in claim 1,2 the two salt hydrate of the Cefixime described in any one or solvate and isActive ingredient and/or one or more pharmaceutically suitable carrier, excipient, diluent.
10. pharmaceutical composition according to claim 9, is characterized in that for injection.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4487927A (en) * | 1979-11-19 | 1984-12-11 | Fujisawa Pharmaceutical Co., Ltd. | 3-Phosphonium and 3-phosphoranylidenecephems |
| CN1594322A (en) * | 2004-06-18 | 2005-03-16 | 余安国 | Cefixime sodium pharmaceutical composition and its preparation and application |
| CN1696134A (en) * | 2005-05-20 | 2005-11-16 | 天津市医药集团技术发展有限公司 | Method for preparing cefixime |
| WO2006119844A2 (en) * | 2005-05-11 | 2006-11-16 | The Jordanian Pharmaceutical Manufacturing Co. | Controlled release oral drug delivery system |
| CN101220040A (en) * | 2008-01-30 | 2008-07-16 | 四川方向药业有限责任公司 | Preparation of cefixime cephalosporin and fine purification method |
| CN101591347A (en) * | 2009-05-25 | 2009-12-02 | 漆又毛 | Cefixime acid type double salt compound and preparation method thereof |
| CN102079751A (en) * | 2010-12-10 | 2011-06-01 | 湖北楚阳科技股份有限公司 | Method for preparing cefixime trihydrate |
| CN102268018A (en) * | 2010-06-03 | 2011-12-07 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Crystallization method of cefixime |
| CN102516262A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Method for crystallizing cefixime trihydrate |
-
2013
- 2013-02-22 CN CN201310056746.XA patent/CN104004003B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4487927A (en) * | 1979-11-19 | 1984-12-11 | Fujisawa Pharmaceutical Co., Ltd. | 3-Phosphonium and 3-phosphoranylidenecephems |
| CN1594322A (en) * | 2004-06-18 | 2005-03-16 | 余安国 | Cefixime sodium pharmaceutical composition and its preparation and application |
| WO2006119844A2 (en) * | 2005-05-11 | 2006-11-16 | The Jordanian Pharmaceutical Manufacturing Co. | Controlled release oral drug delivery system |
| CN1696134A (en) * | 2005-05-20 | 2005-11-16 | 天津市医药集团技术发展有限公司 | Method for preparing cefixime |
| CN101220040A (en) * | 2008-01-30 | 2008-07-16 | 四川方向药业有限责任公司 | Preparation of cefixime cephalosporin and fine purification method |
| CN101591347A (en) * | 2009-05-25 | 2009-12-02 | 漆又毛 | Cefixime acid type double salt compound and preparation method thereof |
| CN102268018A (en) * | 2010-06-03 | 2011-12-07 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Crystallization method of cefixime |
| CN102079751A (en) * | 2010-12-10 | 2011-06-01 | 湖北楚阳科技股份有限公司 | Method for preparing cefixime trihydrate |
| CN102516262A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Method for crystallizing cefixime trihydrate |
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