CN104788470A - Cefetamet pivoxil hydrochloride compound for treating sensitive bacteria infectious diseases - Google Patents
Cefetamet pivoxil hydrochloride compound for treating sensitive bacteria infectious diseases Download PDFInfo
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- CN104788470A CN104788470A CN201510215460.0A CN201510215460A CN104788470A CN 104788470 A CN104788470 A CN 104788470A CN 201510215460 A CN201510215460 A CN 201510215460A CN 104788470 A CN104788470 A CN 104788470A
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- pivoxil hydrochloride
- cefetamet pivoxil
- hydrochloride compound
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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
-
- 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
- C07D501/12—Separation; Purification
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention belongs to technical field of medicine, and relates to a cefetamet pivoxil hydrochloride compound for treating sensitive bacteria infectious diseases. An X-ray powder diffraction pattern of the cefetamet pivoxil hydrochloride compound measured by virtue of a Cu-Kalpha ray is shown in a figure 1. The cefetamet pivoxil hydrochloride compound is a novel crystal form compound, and is different from cefetamet pivoxil hydrochloride reported in the prior art. An experiment proves that compared with the prior art, the novel crystal form compound of the cefetamet pivoxil hydrochloride has relatively low high-molecular polymer content and good stability; the increase of the content of the high-molecular polymer is reduced along with prolonging of the storage time; and meanwhile, the compound has relatively significant antibacterial activity on pneumococcus and hemophilus influenza, and has relatively high antibacterial activity on enterococcus and staphylococcus.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of cefetamet pivoxil hydrochloride compound for the treatment of sensitive organism infectious diseases.
Background technology
Ro 15-8075 is third generation broad-spectrum cephalosporin class microbiotic.The cefetamet being hydrolyzed to rapidly anti-microbial activity after oral in vivo plays germicidal action.Ro 15-8075 is to gram positive organisms such as streptococcus (except streptococcus faecium), streptococcus pneumoniae, and have very strong anti-microbial activity to intestinal bacteria, klebsiella spp, hemophilus influenza, Diplococcus gonorrhoeae, especially obvious to the anti-microbial activity of the low Serratia of cynnematin susceptibility, indole-positive Bacillus proteus, enterobacter and citric acid Pseudomonas.Bacteriogenic β-lactamase is stablized.Ro 15-8075 is invalid to Pseudomonas, mycoplasma, chlamydozoan, faecalis and resistance staphylococcus.
But because its basic structure is the same with microbiotic in the many semisynthetic beta-lactam gone on the market, Ro 15-8075 also can form high molecular polymer, also can cause type Ⅰ hypersensitivity reaction in Clinical practice, very harmful to patient.Prior art improves its stability from aspects such as raising content, reduction impurity mostly.
Research proves, the anaphylactogen causing β-lactam antibitics type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.Reduce the high molecular polymer content existed in Ro 15-8075 bulk drug, improve stability, make it can ensure the lower effective way being the reaction of reduction anaphylactic shock and occurring of the content of its high molecular polymer existed in long term storage.Therefore, be necessary to provide the cefetamet pivoxil hydrochloride compound that a kind of high molecular polymer content is low, performance is more superior.
Summary of the invention
The first object of the present invention is just to provide a kind of cefetamet pivoxil hydrochloride compound crystal, this compound crystal comparatively prior art is compared, there is lower high molecular polymer content, good stability, and increase seldom along with its high molecular polymer content of prolongation of period of storage.
The second object of the present invention is the preparation method providing a kind of above-mentioned cefetamet pivoxil hydrochloride compound, and the method technique is simple, and yield is high, products obtained therefrom high purity 99.9%.
For realizing object of the present invention, the present invention adopts following technical scheme:
Treat a cefetamet pivoxil hydrochloride compound for sensitive organism infectious diseases, it is characterized in that, described compound has X-ray powder diffraction pattern as shown in Figure 1.
A preparation method for above-claimed cpd, comprises the following steps:
Get Ro 15-8075 bulk drug, add in mixed solvent A, obtain solution; Then in the horizontal direction of the liquid level of gained solution, apply stationary magnetic field, and in solution, drip the mixed solvent of acetone, ethyl acetate, ether under the condition of this stationary magnetic field; After being added dropwise to complete, leave standstill, filter, filter cake washing with alcohol, vacuum-drying 2-4 hour, obtains described cefetamet pivoxil hydrochloride compound.
In preparation method of the present invention, described mixed solvent A is the mixed solvent of methyl alcohol, dimethyl formamide, and volume ratio is 1:2.5.
In preparation method of the present invention, the volume of described mixed solvent A is 6-8 times of Ro 15-8075 weight.
In preparation method of the present invention, the temperature of described mixed solvent A is 15-25 DEG C.
In preparation method of the present invention, the magneticstrength of described stationary magnetic field is 0.8T-1.5T.
In preparation method of the present invention, the mixed solvent volume of described acetone, ethyl acetate, ether is Ro 15-8075 weight 8-10 times.
In preparation method of the present invention, the volume ratio of described acetone, ethyl acetate and ether is 2:3:5.
In preparation method of the present invention, described time of repose is 3-5 hour.
The polymorphism of solid chemical is the spontaneous phenomenon that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " paramorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physico-chemical property may be different.For " paramorphism medicine " that physico-chemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
Because the basic structure of Ro 15-8075 is the same with microbiotic in the many semisynthetic beta-lactam gone on the market, also type Ⅰ hypersensitivity reaction can be caused in Clinical practice, very harmful to patient.Research proves, the anaphylactogen causing β-lactam antibitics type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.But prior art improves its stability from aspects such as raising content, reduction impurity mostly, does not propose any improvement to high molecular polymer content wherein.
The present inventor obtains a kind of Ro 15-8075 new crystal structure being different from prior art through a large amount of tests, and by test, show that this new crystal structure not only has lower high molecular polymer content, and increase seldom along with its high molecular polymer content of prolongation of period of storage.
Simultaneously, the present inventor passes through In vitro Bactericidal Experiments, surprisingly find, cefetamet pivoxil hydrochloride compound provided by the present invention has more significant anti-microbial activity to streptococcus pneumoniae, hemophilus influenza, and also has stronger anti-microbial activity to the Ro 15-8075 of prior art report without the faecalis of anti-microbial activity, staphylococcus.
Compared with prior art, tool of the present invention has the following advantages:
(1) cefetamet pivoxil hydrochloride compound provided by the present invention is crystal compound, it is a kind of cefetamet pivoxil hydrochloride compound being different from prior art report, find through test, this Ro 15-8075 crystal compound is compared compared with the cefetamet pivoxil hydrochloride compound of prior art, not only there is lower high molecular polymer content, and increase seldom along with its high molecular polymer content of prolongation of period of storage;
(2) cefetamet pivoxil hydrochloride compound provided by the present invention has more significant anti-microbial activity to streptococcus pneumoniae, hemophilus influenza, and also has stronger anti-microbial activity to the Ro 15-8075 of prior art report without the faecalis of anti-microbial activity, staphylococcus.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of the cefetamet pivoxil hydrochloride compound that the embodiment of the present invention 1 obtains.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
embodiment 1:the preparation of cefetamet pivoxil hydrochloride compound
Get Ro 15-8075 bulk drug, the volume adding 15 DEG C is that in the mixed solvent A of the methyl alcohol of Ro 15-8075 weight 6 times, dimethyl formamide, methyl alcohol and dimethyl formamide volume ratio are 1:2.5, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magneticstrength is 0.8T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent that volume is Ro 15-8075 weight 8 times of acetone, ethyl acetate, ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:5; After being added dropwise to complete, leave standstill 3 hours, filter, filter cake washing with alcohol, vacuum-drying 2 hours, obtains described cefetamet pivoxil hydrochloride compound.
The cefetamet pivoxil hydrochloride compound of gained uses powder X-ray diffraction assay method to measure, and obtains X-ray powder diffraction pattern as shown in Figure 1.
embodiment 2:the preparation of cefetamet pivoxil hydrochloride compound
Get Ro 15-8075 bulk drug, the volume adding 20 DEG C is that in the mixed solvent A of the methyl alcohol of Ro 15-8075 weight 7 times, dimethyl formamide, methyl alcohol and dimethyl formamide volume ratio are 1:2.5, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magneticstrength is 1.15T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent that volume is Ro 15-8075 weight 9 times of acetone, ethyl acetate, ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:5; After being added dropwise to complete, leave standstill 4 hours, filter, filter cake washing with alcohol, vacuum-drying 3 hours, obtains described cefetamet pivoxil hydrochloride compound.
The cefetamet pivoxil hydrochloride compound of gained uses powder X-ray diffraction assay method to measure, and the X-ray powder diffraction pattern obtained is similar to embodiment 1.
embodiment 3:the preparation of cefetamet pivoxil hydrochloride compound
Get Ro 15-8075 bulk drug, the volume adding 25 DEG C is that in the mixed solvent A of the methyl alcohol of Ro 15-8075 weight 8 times, dimethyl formamide, methyl alcohol and dimethyl formamide volume ratio are 1:2.5, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magneticstrength is 1.5T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent that volume is Ro 15-8075 weight 10 times of acetone, ethyl acetate, ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:5; After being added dropwise to complete, leave standstill 5 hours, filter, filter cake washing with alcohol, vacuum-drying 4 hours, obtains described cefetamet pivoxil hydrochloride compound.
The cefetamet pivoxil hydrochloride compound of gained uses powder X-ray diffraction assay method to measure, and the X-ray powder diffraction pattern obtained is similar to embodiment 1.
test example 1:high molecular polymer comparision contents is tested
(1) accelerated test
By following each sample temperature 40 DEG C, place 6 months under relative humidity 75% condition, respectively at the 1st, 2,3, sampling in June, according to " related substance in HPLC method mensuration Ro 15-8075 and polymkeric substance ", [king builds, and wangdan is red, the related substance in big vast sharp Na .HPLC method mensuration Ro 15-8075 and polymkeric substance (J), pharmaceutical analysis magazine, 2015, (2)] measure the content of polymkeric substance in each sample, and with 0 day results contrast.Test-results is shown in Table 1:
Trial target: the Ro 15-8075 crystal that the embodiment of the present invention 1 is obtained;
Reference substance: commercially available Ro 15-8075 raw material, is provided by Zhuhai United Laboratories Ltd.
The content of high molecular polymer in table 1, accelerated test each sample
(2) test of long duration
Each sample at room temperature, respectively at the 3rd, sampling in 6,9,12 months, according to " related substance in HPLC method mensuration Ro 15-8075 and polymkeric substance ", [king builds, wangdan is red, Hong Lina. the related substance in HPLC method mensuration Ro 15-8075 and polymkeric substance (J), pharmaceutical analysis magazine, 2015, (2)] measure the content of polymkeric substance in each sample, and with 0 day results contrast.Test-results is shown in Table 2:
The assay result of polymkeric substance in table 2, test of long duration each sample
Find out from above-mentioned test-results, compared with commercially available prod, the polymer content of cefetamet pivoxil hydrochloride compound crystal of the present invention is lower, good stability, and the content of polymkeric substance is along with the prolongation of period of storage, and it increases seldom.
Also carried out above-mentioned test to the cefetamet pivoxil hydrochloride compound prepared by other embodiment of the present invention, its result obtained is similar.
test example 2:anti-microbial activity is tested
1, materials and methods
1.1 bacterium
Certain clinical laboratory of institute is collected in the blood of clinical patient, phlegm, secretory product, Urine specimens and isolates 82 strain clinical bacterias, through the qualification of VITEK-AMS microbiological analysis instrument, has 19 strain streptococcus pneumoniae, 21 influenzae strain bacillus, 20 strain faecalis, 22 strain staphylococcuses.Quality-control strains is provided by Ministry of Health's Clinical Laboratory center.
1.2 substratum
Isolation medium is 5% blood agar, and drug test MH agar is purchased from Oxoid company.
1.3 antibacterials
Trial target: the Ro 15-8075 crystal that the embodiment of the present invention 1 is obtained;
Reference substance: commercially available Ro 15-8075 raw material, is provided by Zhuhai United Laboratories Ltd.
1.4 judging criterion
Standard bacteria and tested bacterium drug sensitivity tests judge by NCCLS standard in 2000.
1.5 statistical method
Calculate Sensitivity rate, medium sensitivity rate, the resistant rate of various antibacterials to different bacterium, and use χ
2check the Sensitivity rate of more each Ro 15-8075.
2, the results are shown in Table 3, table 4, table 5, table 6
Table 3, antibacterials are to the pneumococcal antibacterial activity in vitro of 19 strain
Table 4, antibacterials are to the antibacterial activity in vitro of 21 influenzae strain bacillus
Table 5, antibacterials are to the enterococcal antibacterial activity in vitro of 20 strain
Table 6, antibacterials are to the staphylococcic antibacterial activity in vitro of 22 strain
As can be seen from above-mentioned test-results, the cefetamet pivoxil hydrochloride compound prepared by the present invention has more significant anti-microbial activity to streptococcus pneumoniae, hemophilus influenza; Commercially available Ro 15-8075 is to faecalis, staphylococcus without anti-microbial activity, and Ro 15-8075 provided by the invention has stronger anti-microbial activity to faecalis, staphylococcus.
Above-mentioned test is also carried out to cefetamet pivoxil hydrochloride compound prepared by other embodiment of the present invention, has obtained similar test-results.
Claims (9)
1. treat a cefetamet pivoxil hydrochloride compound for sensitive organism infectious diseases, it is characterized in that, described compound has X-ray powder diffraction pattern as shown in Figure 1.
2. cefetamet pivoxil hydrochloride compound as claimed in claim 1, it is characterized in that, the preparation method of described compound comprises the following steps: get Ro 15-8075 bulk drug, adds in mixed solvent A, obtains solution; Then in the horizontal direction of the liquid level of gained solution, apply stationary magnetic field, and in solution, drip the mixed solvent of acetone, ethyl acetate, ether under the condition of this stationary magnetic field; After being added dropwise to complete, leave standstill, filter, filter cake washing with alcohol, vacuum-drying 2-4 hour, obtains described cefetamet pivoxil hydrochloride compound.
3. cefetamet pivoxil hydrochloride compound according to claim 2, is characterized in that, described mixed solvent A is the mixed solvent of methyl alcohol, dimethyl formamide, and volume ratio is 1:2.5.
4. cefetamet pivoxil hydrochloride compound according to claim 2, is characterized in that, the volume of described mixed solvent A is 6-8 times of Ro 15-8075 weight.
5. cefetamet pivoxil hydrochloride compound according to claim 2, is characterized in that, the temperature of described mixed solvent A is 15-25 DEG C.
6. cefetamet pivoxil hydrochloride compound according to claim 2, is characterized in that, the magneticstrength of described stationary magnetic field is 0.8T-1.5T.
7. cefetamet pivoxil hydrochloride compound according to claim 2, is characterized in that, the mixed solvent volume of described acetone, ethyl acetate, ether is Ro 15-8075 weight 8-10 times.
8. cefetamet pivoxil hydrochloride compound according to claim 2, is characterized in that, the volume ratio of described acetone, ethyl acetate and ether is 2:3:5.
9. cefetamet pivoxil hydrochloride compound according to claim 2, is characterized in that, described time of repose is 3-5 hour.
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| CN201510215460.0A CN104788470A (en) | 2015-04-30 | 2015-04-30 | Cefetamet pivoxil hydrochloride compound for treating sensitive bacteria infectious diseases |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974177A (en) * | 2015-07-29 | 2015-10-14 | 成都倍特药业有限公司 | Cefetamet pivoxil hydrochloride crystal form II and preparation method thereof |
| CN105030697A (en) * | 2015-09-15 | 2015-11-11 | 青岛华之草医药科技有限公司 | Anti-infective drug cefetamet pivoxil hydrochloride composite capsule |
| CN105078902A (en) * | 2015-09-24 | 2015-11-25 | 青岛华之草医药科技有限公司 | Cefetamet pivoxil hydrochloride composite granules for treating bacterial infection |
| CN105106120A (en) * | 2015-09-17 | 2015-12-02 | 青岛华之草医药科技有限公司 | Antibacterial agents cefetamet pivoxil hydrochloride composition |
| CN105168147A (en) * | 2015-09-11 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical cefetamet pivoxil hydrochloride composite granule for treating bacterial infection |
| CN106432281A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Preparation method of pharmaceutical ceftazidime crystal compound for treating surgical infection |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974177A (en) * | 2015-07-29 | 2015-10-14 | 成都倍特药业有限公司 | Cefetamet pivoxil hydrochloride crystal form II and preparation method thereof |
| CN105168147A (en) * | 2015-09-11 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical cefetamet pivoxil hydrochloride composite granule for treating bacterial infection |
| CN105030697A (en) * | 2015-09-15 | 2015-11-11 | 青岛华之草医药科技有限公司 | Anti-infective drug cefetamet pivoxil hydrochloride composite capsule |
| CN105106120A (en) * | 2015-09-17 | 2015-12-02 | 青岛华之草医药科技有限公司 | Antibacterial agents cefetamet pivoxil hydrochloride composition |
| CN105078902A (en) * | 2015-09-24 | 2015-11-25 | 青岛华之草医药科技有限公司 | Cefetamet pivoxil hydrochloride composite granules for treating bacterial infection |
| CN106432281A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Preparation method of pharmaceutical ceftazidime crystal compound for treating surgical infection |
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