CN100396688C - Cephems phosphate and preparation process and use thereof - Google Patents
Cephems phosphate and preparation process and use thereof Download PDFInfo
- Publication number
- CN100396688C CN100396688C CNB2004100423623A CN200410042362A CN100396688C CN 100396688 C CN100396688 C CN 100396688C CN B2004100423623 A CNB2004100423623 A CN B2004100423623A CN 200410042362 A CN200410042362 A CN 200410042362A CN 100396688 C CN100396688 C CN 100396688C
- Authority
- CN
- China
- Prior art keywords
- compound
- salt
- phosphoric acid
- acid ester
- pharmacy acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention relates to a cephem compound phosphate represented in a general formula (I) and salt thereof, which has wide antibiotic action to various pathogenesis bacteria. The compound has good antibacterial activity in bodies, high dissolution, high stability, easy storage, easy treatment, etc.
Description
Technical field
The present invention relates to cephalosporanic olefinic compound, particularly various pathogenic bacterium are had the cephem compounds phosphoric acid ester of broad-spectrum antibacterial action or its salt and its production and use.
Background technology
During the last ten years, the research that various gram-positive microorganisms and Gram-negative bacteria are had a cephem compounds of effective anti-microbial activity concentrate on the 7-side chain by aminothiazole or amino thiadiazoles replaces and the 3-position by the methyl substituted cephem compounds of ring-like quaternary ammonium.For example, known 7-aminothiazole type comprises cefepime Hydrochloride (US 4,406,899), Cefpirome Sulfate (US 4,609,653) and cefoselis sulfate (WO97/41128), the amino thiadiazoles type of 7-comprises cefclidin (US 4,748,171) and hydrochloric acid.
Cefozopran (EP0319856, US4864022) etc.Japanese Patent JP2002187896 discloses Cefozopran phosphoric acid ester active compound of amino thiadiazoles type and preparation method thereof; The Cefozopran phosphoric acid ester has broad-spectrum antibacterial action to various pathogenic bacterium, and anti-microbial activity in vivo, solvability, and stability, easy storage property, easily aspect such as property handled is good.
Cefepime Hydrochloride, Cefpirome Sulfate, cefoselis sulfate are the aminothiazole type compounds that has better anti-microbial activity in this class antibacterial active compounds.The present inventor is on the basis of further investigation; structure to above-mentioned cephalosporanic olefinic compound is transformed; on the thiazole ring amino of 7-position side chain, introduced phosphono; obtained having good antibiotic active prodrug, discovered that these medicines are anti-microbial activity in vivo; solvability; stability, easy storage property, easily aspect such as property handled is good.
Summary of the invention
The object of the present invention is to provide phosphoric acid ester and the pharmacy acceptable salt or the hydrate of the cephalosporanic olefinic compound of a kind of general formula (I) expression,
The group of array structure under the R representative in the formula:
In other words, phosphoric acid ester and the pharmacy acceptable salt or the hydrate of the cephalosporanic olefinic compound of general formula of the present invention (I) expression, wherein the R representative is selected from 1-methylpyrrole alkyl, and 2,3-cyclopentenes-1-pyridyl and 3-amino-2-(2-hydroxyethyl)-1-pyrazolyl.
In the phosphoric acid ester and pharmacy acceptable salt or hydrate of the cephalosporanic olefinic compound of above-mentioned general formula (I) expression, wherein pharmacy acceptable salt is meant the pharmaceutically acceptable mineral acid of this compound, organic acid, mineral alkali, salt and inner salt that organic bases or halogen ion form; Organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, tosic acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid; Mineral alkali comprises basic metal such as sodium, potassium, and alkaline-earth metal comprises barium, calcium, magnesium, and organic bases comprises meglumine, amido glucose.
In the phosphoric acid ester of the cephalosporanic olefinic compound of general formula of the present invention (I) expression and pharmacy acceptable salt or hydrate, can contain the additional salt of Methionin, arginine, Histidine or an alkali metal salt, alkaline earth salt.
The invention still further relates to a kind of preparation and have the method for cephalosporanic olefinic compound or its salt of following formula, the comprising of this method:
Make compound or its salt with (II) formula and compound or its carboxyl position activated derivatives or its reactant salt with (III) formula,
Compound or its salt with (I) formula
Wherein, R representative
The invention still further relates to a kind of phosphoric acid ester and pharmacy acceptable salt or medicinal compound of hydrate of cephalosporanic olefinic compound of general formula (I) expression that contains medicine effective dose, comprising pharmaceutically acceptable carrier.The dosage form of this pharmaceutical composition comprises big or small-volume injection, freeze-dried powder, aseptic powder packing.
In addition, the invention still further relates to the application of the phosphoric acid ester of cephalosporanic olefinic compound of general formula (I) expression and pharmacy acceptable salt thereof or hydrate at the preparation antiseptic-germicide.
The preparation route of the object of the invention compound is as shown in the formula expression:
Details are as follows for the preparation method of the object of the invention compound:
Compound (III) or its salt can obtain by making the reaction of aminothiazole oxime acid (ATA) and phosphorus pentachloride.Be reflected in the non-active solvent and carry out.Non-active solvent has ethers, nitrile, ketones such as tetrahydrofuran (THF), dioxane, ether, acetonitrile, acetone, ethyl acetate, toluene, chloroform, methylene dichloride, ester class, halogenated hydrocarbon, hydro carbons etc., more preferably ethers, ester class; These solvents can use separately, also can mix use.In general, in order to improve speed of response and to make reaction carry out fully PCl
5Should be suitably excessive, it is to the about 1.2-4 of mol ratio of aminothiazole oxime acid, more preferably 1.5-2.5 ,-20 ℃～35 ℃ approximately of temperature of reaction, preferred-10 ℃～20 ℃, about 1 hour～24 hours of reaction times, preferred 1～5 hour.
Purpose compound (I) or its salt are prepared by compound (II) and compound (III) condensation reaction.Compound (II) is a known compound, and when R represented 1-methylpyrrole alkyl, its preparation method was referring to US659812 (1987); When R represents base 2, during 3-cyclopentenes-1-pyridyl, its preparation method is referring to J.Antibiotic.1988, XLI (10), 1374-1388; When R represents 3-amino-2-(2-hydroxyethyl)-1-pyrazolyl, its preparation method is referring to Bioorg.Med.Chem.19975 (8), 1685-94. condensation reaction is carried out in conventional solvent, the example of solvent for use has water, ethanol, methyl alcohol, acetone, acetonitrile, N, dinethylformamide, tetrahydrofuran (THF), pyridine etc.These conventional solvents can also can mix use separately, perhaps mix use with water with arbitrary proportion.
Temperature of reaction is normally carried out under the situation of normal temperature.-10 ℃～60 ℃ approximately of range of reaction temperature, are preferably in about 5 ℃～25 ℃ scopes and react by preferred 0-40 ℃.Reaction times is by the kind of (II), solvent types, and the decision of factors such as the ratio of mixture of mixed solvent, temperature of reaction, the reaction times was not waited from 1-6 hour, preferred 1-3 hour.The aftertreatment of reaction can be carried out according to a conventional method.Generally need to adopt extract, concentrate, dash analyse, methods such as macroporous resin chromatography, crystallization or lyophilize obtain product.
The example of the pharmacy acceptable salt of compound (I) comprises salt and the inner salt that mineral acid, organic acid, mineral alkali and organic bases or halogen ion etc. form.Representative examples of mineral pigments comprises, haloid acid, sulfuric acid etc.; The organic acid example comprises formic acid, acetate, trifluoroacetic acid, methylsulfonic acid, benzene sulfonate, tosic acid etc.; The example of mineral alkali comprises basic metal such as Na, K etc.; The example of organic bases comprises meglumine, amido glucose etc.
Compound (I) demonstrates very wide antimicrobial spectrum, can be used for the various diseases that is caused by pathogenic micro-organism of prevention or treatment Mammals (comprising the people), as respiratory tract infection and urinary tract infection.
The present invention also provides a kind of pharmaceutical composition, contains above-mentioned antibiotic cephalosporanic olefinic compound phosphoric acid ester or salt and medicine auxiliarys such as pharmaceutically acceptable carrier, vehicle or thinner as activeconstituents.
Described pharmaceutical composition is by after method for preparing being obtained antibiotic cephalosporanic olefinic compound phosphoric acid ester or salt and pharmaceutically acceptable medicine auxiliary mixing, according to the conventional preparation method of preparation to prepare required dosage form.
Said composition can be dosage forms such as freeze-dried powder, aseptic powder packing.For parenteral admin, injection particularly, can be with active ingredient according to special process and sterile carrier or vehicle mixing, also activeconstituents and sterile carrier or vehicle can be dissolved in water for injection and filtration sterilization, be filled in bottle or the ampoule afterwards and freeze-drying and sealing.Also can in said composition, comprise tensio-active agent or wetting agent, be beneficial to the uniform distribution of this compound.
Route of administration, dosage and administration number of times can suitably be adjusted according to patient age, body weight and disease.
According to different medications, composition can contain 20～100% weight, the active substance of preferred 40～100% weight.
Another object of the present invention is to provide above-mentioned antibiotic cephalosporanic olefinic compound phosphoric acid ester or salt and composition thereof to be used for preparing the application of the medicine that eliminates the phlegm, and the application that is used for useful in preparing drug formulations.
Embodiment
Explain the present invention in more detail below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
The preparation of embodiment 1. side chain compounds [III]
In the 500ml there-necked flask, drop into ethyl acetate 150ml, PCl
538g (182mmol), ice bath (0 ℃-5 ℃) stirred 5 minutes, add aminothiazole oxime acid 16.7g (ATA, 83mmol), temperature is no more than 5 ℃ in the control, and stirring reaction 3 hours, reaction is finished, and adds the saturated brine 100ml of an amount of precooling, and stirring 5mins, tell organic layer, 40ml of salt washing is with anhydrous Na
2SO
4Dry back concentrates, and solidifies, and lyophilized solid gets [3] 25.7g, yield 92%.
The preparation of embodiment 2. phosphoric acid cepham compounds [Ia]
In the 50ml reaction flask, throw [IIa] hydrochloride 1.8g (5.4mmol), add THF (18ml), water (9ml) is regulated PH to 8～9 with triethylamine, and compound [III] 1.7g (8.5mmol) is dissolved in (10ml) among the THF in addition, splash in the above-mentioned cooling solution, reaction is 2 hours in cryosel is bathed, and concentrates to remove THF, splashes in the acetone under stirring, filter, get faint yellow solid 2.7g,, cross HP this solid (10ml) soluble in water
20Macroporous resin, with Virahol: water=1: 20 wash-out, collect positive component freeze-drying, lyophilized powder 1.9g, this lyophilized powder is added deionized water (5ml) stirring at room, separate out crystal, filter, white product 1.13g, yield 37.4%.
IR(KBr)cm
-1：3296，2977，2948，1774，1656，1569，1389，1041，905.
The preparation of the full compound [Ib] of embodiment 3. phosphoric acid heads
In the 50ml reaction flask, drop into compound [IIb] hydrochloride 1.5g (4.1mmol), tetrahydrofuran (THF) (18ml), water (9ml) stirs and makes dissolving, cooling drips compound [III] (1.3g down, 6.46mmol) THF solution (10ml), regulating PH with triethylamine is 8～9, control 0～5 ℃ and reacts 2 hours, be added dropwise to (50ml) in the acetone, filter solid 2.13g.Solid is dissolved in the water (6ml), crosses HP
20Macroporous resin, with Virahol: water=1: 20 wash-out, collect positive component freeze-drying, lyophilized powder 1.8g, again through C
18Preparative column separates, with acetonitrile: water=do moving phase at 25: 75, collect positive component, the high vacuum cryoconcentration is to about 4～5ml, stirs down to splash in the acetone, separates out white precipitate, filters, and gets white solid product 1.2g, yield 49.3%).
IR(KBr)cm
-1：3424，3202，2984，1796，1645，1547，1364，1115，1036，797.
The preparation of embodiment 4. cepham compounds [Ic]
In the 50ml reaction flask, throw [IIIc] hydrochloride 2g (5.3mmol), add THF (20ml), water (10ml), regulate PH to 8-9 with triethylamine, other gets compound [II] 1.6g (7.96mmol) and is dissolved in (8ml) among the THF, drip in the cold above-mentioned solution, and in ice bath stirring reaction 2 hours, concentrate and remove THF, splash into (60ml) in the acetone, filter white solid 1.9g, cross HP
20Macroporous resin column, with Virahol: water=3: 97 wash-outs, collect positive component, the high vacuum cryoconcentration stirs and separates out crystal to 5ml, filter, off-white color crystallized product 0.97g.Yield 30.4%.
IR(KBr)cm
-1：3219，3060，1774，1656，1571，1354，11117，775.
The preparation of embodiment 5. cefepime phosphoric acid ester [Ia] sterile powders
Under aseptic condition, be prepared into aseptic cefepime phosphoric acid ester crystalline powder by example 2 described methods. in aseptic weighing room, take by weighing aseptic cefepime phosphoric acid ester 50g, L-arginine 35.5g, cross 80～100 mesh sieves by the prescription proportioning, mix, packing adds the sterilization plug and rolls enclosing cover, promptly.
The preparation of the aseptic freeze-dried pulvis of embodiment 6. cefpirome phosphoric acid ester [Ib]
Under aseptic condition, take by weighing cefpirome phosphoric acid ester 10g, add injection water 100ml, temperature remains on 10～15 ℃, under agitation, transfers pH5.8～6.0 with 1% sodium hydrogen carbonate solution, stirring and dissolving, the solution clarification adds 0.1% gac, stirred 15 minutes, behind the filtering decarbonization,, be sub-packed in the aseptic dish with 0.22 μ m millipore filtration Sterile Filtration, lyophilize gets aseptic cefpirome sodium phosphate lyophilized powder.
The preparation of the aseptic freeze-dried pulvis of embodiment 7. Wincef phosphoric acid ester [Ic]
Under aseptic condition, take by weighing Wincef phosphoric acid ester 10g, add injection water 100ml, temperature remains on 10～15 ℃, under agitation, transfers pH5.8～6.0 with 1% sodium hydrogen carbonate solution, stirring and dissolving, the solution clarification adds 0.1% gac, stirred 15 minutes, behind the filtering decarbonization,, be sub-packed in the aseptic dish with 0.22 μ m millipore filtration Sterile Filtration, lyophilize gets aseptic cefpirome sodium phosphate lyophilized powder.
The effect of experimental example 1. The compounds of this invention (I) aspect inhibition intestinal bacteria and golden Portugal bacterium.
Test compound:
Compound (Ia): cefepime phosphoric acid ester
Compound (Ib): cefpirome phosphoric acid ester
Reference substance: cefepime
Adopt ability technician known method to test.Test-results sees Table 1.
Table 1: compound (Ia), compound (Ib), the ED of cefepime
50Relatively
Experiment shows:
[1] compound (Ia), compound (Ib), the cefepime intravenously administrable is suitable substantially to the interior curative effect of golden Portugal bacterium infecting mouse.There was no significant difference between the three.
[2] compound (Ia), compound (Ib), the cefepime intravenously administrable is better than interior curative effect to golden Portugal bacterium infecting mouse to the interior curative effect of coli-infection.Suitable substantially between the three, there was no significant difference.
Claims (9)
1. phosphoric acid ester and the pharmacy acceptable salt or the hydrate of the cephalosporanic olefinic compound of a general formula (I) expression,
Wherein, the R representative contains five yuan or the substituted radical of hexa-member heterocycle of nitrogen heteroatom, and nitrogen heteroatom directly links to each other with 3-position methylene radical.
2. according to phosphoric acid ester and the pharmacy acceptable salt or the hydrate of the cephalosporanic olefinic compound of claim 1 general formula (I) expression, wherein the R representative is selected from 1-methylpyrrole alkyl, 2,3-cyclopentenes-1-pyridyl and 3-amino-2-(2-hydroxyethyl)-1-pyrazolyl.
3. phosphoric acid ester and the pharmacy acceptable salt or the hydrate of the cephalosporanic olefinic compound of general formula according to claim 1 (I) expression, wherein pharmacy acceptable salt is meant the pharmaceutically acceptable mineral acid of this compound, organic acid, mineral alkali, salt and inner salt that organic bases or halogen ion form; Organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, tosic acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid; Mineral alkali comprises basic metal, and alkaline-earth metal comprises barium, calcium, magnesium, and organic bases comprises meglumine, amido glucose.
4. phosphoric acid ester and the pharmacy acceptable salt or the hydrate of the cephalosporanic olefinic compound of general formula according to claim 3 (I) expression, wherein said basic metal is sodium or potassium.
5. according to phosphoric acid ester and the pharmacy acceptable salt or the hydrate of the cephalosporanic olefinic compound of claim 1 general formula (I) expression, wherein contain the additional salt of Methionin, arginine, Histidine or an alkali metal salt, alkaline earth salt.
6. one kind prepares the cephalosporanic olefinic compound with following formula or the method for its salt, and this method comprises:
Make compound or its salt with (II) formula and compound or its carboxyl position activated derivatives or its reactant salt with (III) formula,
Compound or its salt with (I) formula
Wherein, R representative
7. phosphoric acid ester and the pharmacy acceptable salt or the medicinal compound of hydrate of the cephalosporanic olefinic compound of general formula (I) expression that contains medicine effective dose are comprising pharmaceutically acceptable carrier.
8. pharmaceutical composition according to claim 7, its dosage form comprise big or small-volume injection, freeze-dried powder, aseptic powder packing.
9. according to of the application of the arbitrary described compound of claim 1-5 at the preparation antiseptic-germicide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100423623A CN100396688C (en) | 2004-05-20 | 2004-05-20 | Cephems phosphate and preparation process and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100423623A CN100396688C (en) | 2004-05-20 | 2004-05-20 | Cephems phosphate and preparation process and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1699384A CN1699384A (en) | 2005-11-23 |
| CN100396688C true CN100396688C (en) | 2008-06-25 |
Family
ID=35475650
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100423623A Expired - Fee Related CN100396688C (en) | 2004-05-20 | 2004-05-20 | Cephems phosphate and preparation process and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100396688C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4406899A (en) * | 1982-03-04 | 1983-09-27 | Bristol-Myers Company | Cephalosporins |
-
2004
- 2004-05-20 CN CNB2004100423623A patent/CN100396688C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4406899A (en) * | 1982-03-04 | 1983-09-27 | Bristol-Myers Company | Cephalosporins |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1699384A (en) | 2005-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2478643C2 (en) | Macrocyclic polymorphs, compositions containing such polymorphs, and methods for using and preparing them | |
| KR0180798B1 (en) | Crystalline penicillin derivative, and its production and use | |
| KR101626506B1 (en) | Hydrates of erythromycin salts, the preparation and the use thereof | |
| KR880002087B1 (en) | Process for preparing salts of antimicrobial naphthyridine and quinoline compounds | |
| WO2011113361A1 (en) | Ceftizoxime sodium crystalline hydrate, preparation methods and uses thereof | |
| CN102180890A (en) | Cefathiamidine hydrate and preparation method and application thereof | |
| JP6957807B2 (en) | Type 2 crystals of right-handed oxyracetam, preparation method and application | |
| WO2018177218A1 (en) | Preparing method for and uses of 3,5-disubstituted methylpyrazolo[1,5-a] pyrimidin-7-phenolate analogues and derivatives | |
| NZ227872A (en) | Ionic zinc/ceftiofur complexes: pharmaceutical compositions and methods of treatment | |
| CN100396688C (en) | Cephems phosphate and preparation process and use thereof | |
| CN110393720B9 (en) | Pharmaceutical preparation of compound of trisufen ceftriaxone sodium and new indication for treating infection of patients with low immune function | |
| JP2022506957A (en) | Antibiotic compounds, methods of producing them, pharmaceutical compositions containing them and their use | |
| NZ213741A (en) | Crystalline cephalosporin hydrohalide compounds and pharmaceutical compositions | |
| CN101676271B (en) | Tetracycline derivatives containing unsaturated heterocyclic amine | |
| CN101772506B (en) | Macrocycles and their uses | |
| CN101418015B (en) | Ceftriaxone phosphorylation derivates | |
| CN101945866B (en) | Aminothiazoles and their uses | |
| CN102731530B (en) | Cephalosporin compound and synthetic method thereof and application | |
| CN102212074A (en) | Cefonicid sodium hydrate and preparation method and application thereof | |
| US20110118462A1 (en) | N-heterocyclic substituent-containing antibiotic, preparation and use thereof | |
| CZ292565B6 (en) | Use of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine for preparing a pharmaceutical preparation for treating cognitive dysfunction | |
| CN111499658B (en) | Cefoperazone compound medicinal preparation and new indication for treating endometritis and other gynecological genital tract infection | |
| US20140128359A1 (en) | N-Heterocyclic Substituent-Containing Antibiotic, Preparation and Use Thereof | |
| CN110396103B (en) | Cefazolin sodium or composition thereof, preparation method and preparation thereof, and new indications of reproductive system infection | |
| CN115650996B (en) | Preparation method of cefepime impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080625 Termination date: 20150520 |
|
| EXPY | Termination of patent right or utility model |