CN101418015A - Ceftriaxone phosphorylation derivates - Google Patents
Ceftriaxone phosphorylation derivates Download PDFInfo
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- CN101418015A CN101418015A CN 200810170397 CN200810170397A CN101418015A CN 101418015 A CN101418015 A CN 101418015A CN 200810170397 CN200810170397 CN 200810170397 CN 200810170397 A CN200810170397 A CN 200810170397A CN 101418015 A CN101418015 A CN 101418015A
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- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 title abstract description 24
- 229960004755 ceftriaxone Drugs 0.000 title description 12
- 230000026731 phosphorylation Effects 0.000 title description 4
- 238000006366 phosphorylation reaction Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
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- 238000002360 preparation method Methods 0.000 claims abstract description 39
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- 150000004677 hydrates Chemical class 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 4
- -1 benzyloxymethyl Chemical group 0.000 claims description 116
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
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- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to novel phosphorylated derivatives of ceftriaxone, pharmaceutically acceptable salts, easily hydrolyzable esters, isomers and hydrates of the phosphorylated derivatives, hydrates of the salts and the esters, methods for preparing the compounds, pharmaceutical compositions containing the compounds and use of the compounds for the preparation of medicines for treating and/or preventing infectious diseases, and belongs to the technical field of medicine. Researches show that the phosphorylated derivatives of ceftriaxone and the pharmaceutically acceptable salts, the easily hydrolyzable esters, the isomers and the hydrates of the phosphorylated derivatives and the hydrates of the salts and the esters have advantages of wide antimicrobial spectrum, strong antimicrobial activities, small drug resistance and so on and have good clinical value. R<1>, R<2>, R<3>, R<4> and Z are as defined in the specification.
Description
1. Field of the invention
The invention relates to a novel phosphorylated derivative of ceftriaxone, pharmaceutically acceptable salts, easily hydrolyzed esters, isomers, hydrates and hydrates of salts or esters thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds, and application of the compounds in preparation of drugs for treating and/or preventing infectious diseases, and belongs to the technical field of medicines.
2. Background of the invention
Ceftriaxone, also known as ceftriaxone, is a semi-synthetic third-generation cephalosporin antibiotic, which has the characteristics of long-acting effect, broad-spectrum effect and strong effect on gram-negative bacteria, has strong antibacterial activity on most gram-positive bacteria and gram-negative bacteria, and has an antibacterial spectrum comprising pseudomonas aeruginosa, escherichia coli, pneumobacillus, haemophilus influenzae, enteroaerobacter aerogenes, proteus spp, diplococcus spp, staphylococcus aureus and the like. The product is stable to beta-lactamase. The traditional Chinese medicine composition is mainly used for treating meningitis, pneumonia, skin and soft tissue infection caused by sensitive bacteria infection, infection of patients with low immune mechanism, peritonitis, urinary system infection, gonorrhea, hepatobiliary infection, surgical trauma, septicemia, genital infection and the like in clinic, and is currently used as a first-line medicine for treating gonorrhea. The half-life period is 8h, and the bactericidal activity is 24 hours, and the penetrating power to tissues is strong.
However, ceftriaxone is a white crystalline powder, and it must be dissolved in a predetermined injection for injection, and clinical use is unstable, which brings great inconvenience to clinical use.
3. Summary of the invention
In order to solve the above problems, the present inventors have conducted extensive studies and, as a result, have modified ceftriaxone to introduce a phosphoryl group into the 7-position thiazole ring, and have obtained phosphorylated derivatives of ceftriaxone that are excellent in antibacterial activity, solubility, stability, storage stability and handling property.
The technical scheme of the invention is as follows:
the invention provides a compound shown in a general formula (I), pharmaceutically acceptable salt, easily hydrolysable ester, isomer, hydrate and hydrate of salt or ester thereof:
wherein:
R1and R2May be the same or different and each independently represents a hydroxyl group or C1-4An alkoxy group;
R3represents a hydrogen atom, a straight chain or branched C substituted or unsubstituted by a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a nitro group, a cyano group1-4An alkyl group;
R4represents a hydrogen atom or a carboxyl protecting group;
z represents N or CR5，R5Represents a hydrogen atom or a halogen atom.
Preferred compounds are:
wherein,
R1and R2May be the same or different and each independently represents a hydroxyl group or C1-4An alkoxy group;
R3represents a hydrogen atom, a methyl group, an ethyl group, a fluoromethyl group, a fluoroethyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, an acetoxy group or an isobutyric acid group;
R4represents a hydrogen atom or a carboxyl-protecting group,
wherein said carboxyl protecting group is selected from methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, phenacyl, ethyl, t-butyl, allyl, benzyl, p-nitrobenzyl, p-methoxybenzyl or diphenylmethyl;
z represents N or CR5，R5Represents a hydrogen atom or a chlorine atom.
Further preferred compounds are:
wherein,
R1and R2May be the same or different and each independently represents a hydroxyl group, a methoxy group, an ethoxy group or an isopropoxy group;
R3represents a hydrogen atom, a methyl group or an isobutyric acid group;
R4represents a hydrogen atom or a carboxyl-protecting group,
wherein said carboxyl protecting group is selected from methyl, t-butyl, allyl, benzyl, p-nitrobenzyl, p-methoxybenzyl or diphenylmethyl;
z represents CH.
The "halogen" in the invention includes fluorine atom, chlorine atom, bromine atom and iodine atom.
"C" according to the invention1-4Alkoxy "includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
The "carboxyl protecting group" as used herein refers to a protecting group conventionally used for substituting an acidic proton of a carboxylic acid. Examples of such groups include: methyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethyl, allyl, benzyloxymethyl, phenacyl, p-bromobenzoylmethyl, α -methylbenzoylmethyl, p-methoxybenzoylmethyl, diacylmethyl, N-phthalimidomethyl, ethyl, 2, 2, 2-trichloroethyl, 2-haloethyl, ω -chloroalkyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 2- (p-nitrophenylthio) ethyl, 2- (p-tolylthio) ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, bis (o-nitrophenyl) methyl, 9-fluorenylmethyl, 2- (9, 10-dioxo) fluorenylmethyl, 5-diphenylthio, Benzyl, 2, 4, 6-trimethylbenzyl, p-bromobenzyl, O-nitrobenzyl, p-methoxybenzyl, piperonyl, 4-picolyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, S-t-butyl, S-phenyl, S-2-pyridyl, N-hydroxypiperidinyl, N-hydroxysuccinimidyl, N-hydroxyphthalimidyl, N-hydroxybenzotriazolyl, O-acyloxime, 2, 4-dinitrophenylthio, 2-alkyl-2, 5-dihydrooxazolyl, 4-alkyl-5-oxo-2, 5-dihydrooxazolyl, 5-alkyl-4-oxo-1, 2, 3-oxadiazolyl, triethylstannyl, tri-N-butylstannyl, N' -diisopropylhydrazide, etc.
Further preferred individual compounds are selected from:
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [ [2- (2-phosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]2-oct-2-ene-2-carboxylic acid,hereinafter referred to as compound 1-1:
structural formula (xvi):
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [2- [2- (diethylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]2-oct-2-ene-2-carboxylic acid,hereinafter referred to as compound 2-1:
structural formula (xvi):
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-trisOxazin-3-yl) sulfur]Methyl radical]-7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]2-oct-2-ene-2-carboxylic acid,hereinafter referred to as compound 3-1:
structural formula (xvi):
pharmaceutically acceptable salts of any of the above compounds of the invention include acetate, mesylate, maleate, succinate, tartrate, citrate, fumarate, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, sodium, potassium, calcium, magnesium, and zinc salts. Through extensive studies by the present inventors, it was found that the sodium salts thereof all have good properties for easily preparing injections. The chemical name and structural formula are as follows:
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [ [2- (2-phosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]2-alkene-2-carboxylic acid disodium salt,hereinafter referred to as compound 1-2:
structural formula (xvi):
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [2- [2- (diethylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]2-alkene-2-carboxylic acid disodium salt,hereinafter referred to as compound 2-2:
structural formula (xvi):
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]2-alkene-2-carboxylic acid disodium salt,hereinafter referred to as compound 3-2:
structural formula (xvi):
the compound shown in the general formula (I), the pharmaceutically acceptable salt and the easily hydrolysable ester thereof can be in the form of hydrates. Hydration may be accomplished during the manufacturing process or may be gradual using the hygroscopic properties of the original anhydrous product. The present inventors have further studied the hydrate of the above compound and found that the trissesquihydrate has excellent stability. The chemical name and structural formula are as follows:
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [ [2- (2-phosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Octa-2-ene-2-carboxylic acid disodium salt triple hemihydrate,hereinafter referred to as compounds 1-3:
structural formula (xvi):
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [2- [2- (diethylphosphoramido) -4-thiazolyl]-2-(Methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Octa-2-ene-2-carboxylic acid disodium salt triple hemihydrate,hereinafter referred to as compound 2-3:
structural formula (xvi):
chemical name: 6R [6 alpha, 7 beta (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-7- [2- [2- (diisopropylphosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Octa-2-ene-2-carboxylic acid disodium salt triple hemihydrate,hereinafter referred to as compound 3-3:
structural formula (xvi):
the invention also provides a preparation method for preparing the preferable compound and the sodium salt and the hydrate thereof, which comprises the following steps:
step 1: preparation of intermediate 1
Adding the raw material 1 and carbon tetrachloride or toluene into a four-mouth bottle, controlling the temperature in an ice-water bath, and dropwise adding phosphorus trichloride while stirring. Heating to continue the reaction, and simultaneously decompressing and extracting hydrogen chloride gas generated in the system. Concentrating under reduced pressure, rectifying the concentrated liquid, and collecting appropriate fraction.
Step 2: preparation of Compound A
Controlling the temperature to be about 0 ℃ in a salt-freezing bath, adding the raw material 2 into a four-mouth bottle, adding water, stirring, adjusting the pH value with 25% sodium hydroxide solution, and completely dissolving the solid. Tetrabutylammonium bromide and the intermediate 1 are added, and a sodium hypochlorite solution is added dropwise. The reaction was continued after the addition. Stopping reaction, adding ether for extraction once, adjusting pH of the water layer with hydrochloric acid in ice bath, freezing for crystallization, filtering, washing the filter cake with ethanol, filtering, and drying the filter cake under reduced pressure to obtain the compound A.
And step 3: preparation of sodium salt of Compound A
Compound a was suspended in deionized water, then adjusted to pH with sodium carbonate and stirred to a clear solution. Then adding ethanol, stirring uniformly, freezing and crystallizing. Filtering, and drying the filter cake at 40 ℃ under reduced pressure for 6h to obtain the sodium salt of the compound A.
And 4, step 4: preparation of compound a hydrate
And drying the sodium salt of the compound A at normal temperature under reduced pressure to obtain a hydrate of the compound A.
R in the above reaction equation1、R2、R3Z is as described above, the carboxyl group on the cephalosporin nucleus of the compound of the invention may be protected by a carboxyl protecting group or may be formed into an easily hydrolysable ester, i.e. a compound of formula (I).
The easily hydrolysable ester in the present invention is understood to mean that one or more carboxyl groups present in formula (I) are present as easily hydrolysable ester groups. Examples of conventional forms of such esters include: including alkanoyloxyalkyl esters such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, isovaleryloxymethyl ester, pivaloyloxymethyl ester, 2-dimethylvaleryloxymethyl ester, octanoyloxymethyl ester, decanoyloxymethyl ester, etc.; alkoxycarbonyloxyalkyl esters such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, isopropoxycarbonyloxyethyl, hexyloxycarbonyloxyethyl, octyloxycarbonyloxyethyl, decyloxycarbonyloxyethyl, dodecyloxycarbonyloxyethyl and the like; alkoxymethyl esters such as methoxymethyl ester, 1-isopropoxymethyl ester and the like; alkanoylmethyl esters such as formamidomethyl ester, acetamidomethyl ester, and the like; cycloalkanoyloxyalkyl esters such as cyclohexylformyloxymethyl ester, cyclohexylformyloxyethyl ester, 1-methylcyclohexylcarbonyloxyethyl ester, 4-methylcyclohexylcarbonyloxymethyl ester and the like; cycloalkoxyacyl esters such as cyclopentanyloxycarbonyloxyethyl ester, cyclohexanyloxycarbonyloxyethyl ester and the like; (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, 2- [ (2-methylpropoxy) carbonyl ] -2-pentenyl ester, etc. Preferably propionyloxymethyl ester, butyryloxymethyl ester, t-butylformyloxymethyl ester, isopropyloxomethyl ester, isopropyloxoethylformyloxy ester, cyclohexyloxoethylformyloxy ester, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, etc.
The isomers referred to in the present invention are meant to be all enantiomeric, diastereomeric and tautomeric forms thereof. When a key is represented by a wedge, this indicates that the key will come out of the paper in three dimensions, and when a key is shaded, this indicates that the key will come back into the paper in three dimensions. The compounds of formula (I) have a number of stereogenic centres, e.g. in the 6-position, in the 7-position.
The invention comprises a pharmaceutical composition of any compound, pharmaceutically acceptable salt, easily hydrolysable ester, hydrate and hydrate of the salt or ester and other medicinal active ingredients, such as sulbactam and sodium salt thereof, sulbactam pivoxil, tazobactam and sodium salt thereof, and clavulanate potassium.
The invention further claims a pharmaceutical composition comprising any of the compounds described above, pharmaceutically acceptable salts thereof, easily hydrolysable esters thereof, hydrates thereof and hydrates of salts or esters thereof, together with one or more pharmaceutically acceptable carriers and/or diluents, wherein 0.05g to 5g (based on the compound of formula (I)) of any of the compounds of formula (I), pharmaceutically acceptable salts thereof, easily hydrolysable esters thereof, hydrates thereof and salts or esters thereof, as an essential active ingredient, may be 0.05g, 0.075g, 0.1g, 0.125g, 0.25g, 0.5g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, etc., for preferred compounds A to D and derivatives thereof, may be 0.1g, 0.125g, 0.25g, 0.5g, 0.75g, 1.75g, 1.25g, 1.75g, 2.75 g, 1.75g, 1., 2.5g, 3g, 4g, 5g, etc., preferably 0.25g, 0.5g, 1g, 2 g. As will be appreciated by those of ordinary skill in the art: the dosage of the drug also depends on the age, condition and kind of the disease to be prevented or/and treated of the mammal. The pharmaceutical composition can be administered to a patient in need of treatment by parenteral administration, oral administration, etc., preferably injection or oral preparation.
For parenteral administration, it can be made into injection. The injection is a sterile preparation of solution, emulsion or suspension for injection into the body and powder or concentrated solution for preparation or dilution into solution or suspension before use, and can be divided into injection, sterile powder for injection and concentrated solution for injection. The injection is sterile solution type injection, emulsion type injection or suspension type injection prepared from the medicine for injection into human body, and can be used for intramuscular injection, intravenous drip, etc.; the standard of the injection is 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml and the like, wherein the large-volume (generally not less than 100ml) injection for intravenous drip is also called intravenous infusion. The sterile powder for injection is sterile powder or sterile block which is prepared by proper sterile solution to be prepared into clear solution or uniform suspension before use, can be prepared by proper solvent for injection and then injected, and can also be prepared by intravenous infusion and then is subjected to intravenous drip; the sterile powder is prepared by solvent crystallization, spray drying or freeze drying. Concentrated solution for injection refers to sterile concentrated solution of the drug for dilution before use for intravenous drip.
The injection can be prepared by conventional method in pharmaceutical field, and can be aqueous solvent or non-aqueous solvent. The most commonly used aqueous solvent is water for injection, and 0.9% sodium chloride solution or other suitable aqueous solution can also be used; the common non-aqueous solvent is vegetable oil, which is mainly soybean oil for injection, and other aqueous solutions of ethanol, propylene glycol, polyethylene glycol and the like. When preparing injection, appropriate additives such as osmotic pressure regulator, pH regulator, solubilizer, filler, antioxidant, bacteriostatic agent, emulsifier, suspending agent, etc. can be added according to the properties of the medicine. Commonly used osmo-regulators include sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, etc., preferably sodium chloride or glucose; common pH regulator includes acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate, etc.; commonly used solubilizers include polysorbate 80, propylene glycol, lecithin, polyoxyethylene castor oil, and the like; common fillers include lactose, mannitol, sorbitol, dextran, and the like; common antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, and the like; common bacteriostats are phenol, cresol, chlorobutanol and the like. The common containers for injections include glass ampoules, glass bottles, plastic ampoules, plastic bottles and the like.
For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. The tablet is a round or special-shaped tablet solid preparation prepared by uniformly mixing and pressing the medicament and proper auxiliary materials, mainly takes an oral common tablet as a main part, and also comprises a buccal tablet, a sublingual tablet, an oral patch, a chewable tablet, a dispersible tablet, a soluble tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet, an enteric-coated tablet and the like. The capsule refers to a solid preparation prepared by filling a drug or an adjuvant into an empty capsule or sealing in a soft capsule material, and can be divided into hard capsules (generally called capsules), soft capsules (capsules), sustained-release capsules, controlled-release capsules, enteric capsules and the like according to the dissolution and release characteristics of the solid preparation. The pill refers to a spherical or spheroidal solid preparation prepared by uniformly mixing the medicament and appropriate auxiliary materials and preparing the mixture by a proper method, and comprises a dropping pill, a sugar pill, a pellet and the like. The granules refer to dry granular preparations with certain granularity prepared by the medicines and proper auxiliary materials, and can be divided into soluble granules (generally called granules), suspension granules, effervescent granules, enteric granules, sustained-release granules, controlled-release granules and the like. Oral solution means that the drug is dissolved in a suitable solvent to make into a clear liquid preparation for oral administration. Oral suspensions refer to poorly soluble solid drugs dispersed in a liquid medium to form a suspension formulation for oral administration, including dry suspensions or concentrated suspensions. Syrup refers to a concentrated aqueous solution of sucrose containing the drug.
When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. Common fillers include starch, sugar powder, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, and the like; common adhesives include sodium carboxymethylcellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch, etc.; common disintegrants include dry starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and the like; common lubricants include magnesium stearate, talc, sodium lauryl sulfate, aerosil, and the like.
The invention also provides the application of the ceftriaxone phosphorylation derivative in preparing the medicaments for treating and/or preventing infectious diseases. The ceftriaxone phosphorylation derivative has good antibacterial activity on gram-positive bacteria and gram-negative bacteria, can be used for treating and/or preventing various diseases of mammals (including human beings) caused by pathogenic microorganisms, such as respiratory tract infection, urinary tract infection, biliary tract infection, abdominal cavity infection, pelvic infection, skin soft tissue infection, bone and joint infection, septicemia, meningitis and the like, and can be used for preventing infection in an operative period, and can also be used for treating simple gonorrhea.
Compared with the closest prior art, the phosphorylated derivatives of ceftriaxone of the invention have the following advantages:
(1) the novel phosphorylated derivatives of ceftriaxone are provided for the first time, have broad-spectrum and high-efficiency antibacterial action, have good protective action on infected experimental animals, and have stronger antibacterial activity and small side effect;
(2) the invention further researches the preferable compound and the derivative thereof, and finds that the sodium salt has better characteristic of being easy to prepare into injection;
(3) the compound has good stability to beta-lactamase and long half-life period;
(4) the compound has the advantages of low toxicity, good stability and the like;
(5) the compound of the invention has simple preparation process, high medicine purity, high yield, easy treatment, stable quality, easy storage and easy large-scale industrial production.
The beneficial effects of the phosphorylated derivatives of ceftriaxone according to the present invention are further illustrated by the following experimental examples, which include pharmacodynamic and toxicological experiments of the phosphorylated derivatives of ceftriaxone according to the present invention. The phosphorylated derivatives of ceftriaxone of the present invention have the following advantageous effects, but it should not be understood that the phosphorylated derivatives of ceftriaxone of the present invention have only the following advantageous effects.
Experimental examples the antibacterial spectrum and antibacterial activity of the compound of the present invention
Test strains: the following clinical isolates were purchased at public institutions.
15 strains of staphylococcus aureus, 10 strains of methicillin-resistant staphylococcus aureus, 13 strains of streptococcus pneumoniae, 18 strains of enterococcus faecalis, 19 strains of klebsiella pneumoniae, 10 strains of escherichia coli, 10 strains of proteus mirabilis, 8 strains of enterobacter cloacae, 15 strains of pseudomonas aeruginosa, 10 strains of haemophilus influenzae and 10 strains of gonococcus are all clinical isolated strains.
The experimental method comprises the following steps: agar dilution method, referred to pharmacological test methodology P1659-1660, national institutes of health Press: xu tert cloud, etc., edition: print 5 th time 8/1/2002/1/3/1982.
The test drugs are:
ceftriaxone: purchasing in market;
the compounds 1-1, 2-1 and 3-1 are prepared by the method.
Experimental results and conclusions: the results are shown in Table 1.
TABLE 1 antibacterial spectra and antibacterial Activity of the Compounds of the invention
As can be seen from Table 1, the compounds 1-1, 2-1 and 3-1 of the invention have good bacteriostatic action on all tested strains, and the antibacterial activity is obviously stronger than that of ceftriaxone.
The experimental results show that the phosphorylated derivatives of ceftriaxone have the advantages of wide antibacterial spectrum and high antibacterial activity, and are novel compounds with good clinical application potential.
4. Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The auxiliary materials of each dosage form in the following examples can be replaced by pharmaceutically acceptable auxiliary materials, or reduced or increased.
EXAMPLE 1 preparation of diethyl phosphite
Adding 230ml of absolute ethyl alcohol and 50ml of carbon tetrachloride into a 1000ml four-mouth bottle, controlling the temperature in an ice-water bath to be below 15 ℃, and dropwise adding 88ml of phosphorus trichloride (PCl) while stirring3) The addition was completed within 4 hours. Heating to 50-60 ℃, continuously reacting for 6 hours, and simultaneously decompressing and pumping out hydrogen chloride gas generated in the system. And (3) carrying out reduced pressure concentration, rectifying the concentrated liquid, and collecting 89-93 ℃/0.095MP fraction.
Example 26R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [2- [2- (diethylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo
[4.2.0]Preparation of oct-2-ene-2-carboxylic acid (i.e., Compound 2-1)
In a salt bath, the temperature is controlled to be about 0 ℃, 30g (52mmol) of ceftriaxone acid is added into a 1000ml four-mouth bottle, 200ml of water is added, stirring is carried out, the pH value is adjusted to 9.5 by 25% sodium hydroxide solution, and the solid is completely dissolved. 130mg of tetrabutylammonium bromide and 7.9g of diethyl phosphite (57mmol) were added and 29ml of a 12% strength sodium hypochlorite solution were added dropwise. The reaction was continued for 4 hours after the addition was completed. Stopping reaction, adding ether for extraction once, adjusting the pH of a water layer to 3 with hydrochloric acid in an ice bath, freezing, crystallizing, filtering, washing a filter cake with ethanol, filtering, and drying the filter cake at 40 ℃ under reduced pressure for 8 hours to obtain light brown yellow powder 27.7 g. Yield: 68.6 percent.
1H-NMR(600MHz，DMSO)δ：1.24(m，6H)，3.56(m，3H)，3.75(d，2H)，3.86(s，3H)，4.09(d，2H)，4.38(d，2H)，5.15(d，2H)，5.79(m，2H)，6.79(s，1H)，7.64(w，3H)，9.66(d，1H).
IR(KBr)cm-1：3315，3103，2941，1772，1658，1535，1413，1367，1180，1097，1041，676，509.
The molecular formula is as follows: c22H27N8O10PS3
Molecular weight: 690.7
Mass Spectrum (m/e): 691(M +1)
Elemental analysis:
experimental values: c: 38.15%, H: 4.12%, N: 16.18%, P: 4.39%, S: 13.84 percent
Theoretical value: c: 38.26%, H: 3.94%, N: 16.22%, P: 4.48%, S: 13.93 percent
Example 36R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [2- [2- (diethylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azaDouble ring
[4.2.0]Preparation of Oct-2-ene-2-Carboxylic acid disodium salt (i.e., Compound 2-2)
10g of the product obtained in example 2 is suspended in 100ml of deionized water, then the pH value is adjusted to 7-8 by 10% of sodium carbonate, and the mixture is stirred to obtain a clear solution. Then 200ml of ethanol is added, and after uniform stirring, the mixture is frozen and crystallized. Filtering, drying the filter cake at 40 ℃ for 6h under reduced pressure to obtain 8.5g of 6R [6 alpha, 7 beta (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diethylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt, yield: 79.9 percent.
Example 46R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [2- [2- (diethylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo
[4.2.0]Preparation of Oc-2-ene-2-Carboxylic acid disodium salt triple hemihydrate (Compound 2-3)
10g of the filter cake obtained in example 3 (wet weight before drying) was dried at room temperature under reduced pressure at 75% RH for 2 days to obtain 5.8g of 6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diethylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt triple hemihydrate.
EXAMPLE 5 preparation of diisopropyl phosphite
Adding 240ml of anhydrous isopropanol and 40ml of toluene into a 500ml four-mouth bottle, controlling the temperature in an ice water bath to be below 15 ℃, and dropwise adding 70ml of phosphorus trichloride (PCl) under stirring3) The addition was completed within 4 hours. Heating to 50-60 ℃, continuously reacting for 6 hours, and simultaneously decompressing and pumping out hydrogen chloride gas generated in the system. And (3) carrying out reduced pressure concentration, rectifying the concentrated liquid, and collecting the fraction at 62-67 ℃/0.095 MPa.
Example 66R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo
[4.2.0]Preparation of oct-2-ene-2-carboxylic acid (i.e., Compound 3-1)
In an ice salt bath, the temperature is controlled to be about 0 ℃, 30g (0.052mol) of ceftriaxone acid is added into a 1000ml four-mouth bottle, 200ml of water is added, stirring is carried out, the pH value is adjusted to 9.5 by 25 percent of sodium hydroxide solution, and the solid is completely dissolved. 9.5g diisopropyl phosphite (57mmol) and 166mg tetrabutylammonium bromide were added in one portion. 30ml of a 12% strength sodium hypochlorite solution are added dropwise. The reaction was continued for 4 hours after the addition was completed. Stopping reaction, adding ether for extraction once, adjusting the pH of a water layer to 4 with hydrochloric acid in an ice bath, freezing, crystallizing, filtering, washing a filter cake with ethanol, filtering, and drying the filter cake at 40 ℃ under reduced pressure for 8 hours to obtain yellowish powder 29.5 g. Yield: 78.9 percent.1H-NMR(600MHz，DMSO)δ：1.24(m，12H)，3.59(m，3H)，3.72(d，2H)，3.83(s，3H)，4.10(d，1H)，4.37(d，1H)，5.13(d，2H)，5.79(m，2H)，6.74(s，1H)，7.24(w，3H)，9.60(d，1H).
IR(KBr)cm-1：3330，2939，1772，1659，1608，1535，1407，1369，1250，1043，858，507.
The molecular formula is as follows: c24H31N8O10PS3
Molecular weight: 718.7
Mass Spectrum (m/e): 719(M +1)
Elemental analysis:
experimental values: c: 40.02%, H: 4.56%, N: 15.45%, P: 4.27%, S: 13.32 percent
Theoretical value: c: 40.11%, H: 4.35%, N: 15.59%, P: 4.31%, S: 13.38 percent
Practice ofExample 76R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo
[4.2.0]Preparation of Oct-2-ene-2-carboxylic acid disodium salt (i.e., Compound 3-2)
10g of the product obtained in example 6 is suspended in 100ml of deionized water, then the pH value is adjusted to 7-8 by 10% of sodium carbonate, and the mixture is stirred to obtain a clear solution. Then 200ml of ethanol is added, and after uniform stirring, the mixture is frozen and crystallized. Filtering, drying the filter cake at 40 ℃ for 6h under reduced pressure to obtain 8.4g of 6R [6 alpha, 7 beta (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt, yield: 79.1 percent.
Example 86R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [2- [2- (diisopropylphosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo
[4.2.0]Preparation of Oc-2-ene-2-Carboxylic acid disodium salt triple hemihydrate (Compound 3-3)
10g of the filter cake obtained in example 7 (wet weight before drying) was dried at room temperature under reduced pressure at 75% RH for 2 days to obtain 5.5g of 6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diisopropylphosphoramido-4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt triple hemihydrate.
Example 96R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [ [2- (2-phosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Xin-2-
Preparation of ene-2-carboxylic acid (i.e., Compound 1-1)
Controlling the temperature to be about 0 ℃ in an ice salt bath, adding 30g (0.052mol) of ceftriaxone acid into a 1000ml four-mouth bottle, adding 200ml of water, stirring, adjusting the pH to 9-10 by using 25% sodium hydroxide solution, dissolving the solid completely, adding 108mg of tetrabutylammonium bromide and 5.0g (0.06mol) of phosphorous acid, and dropwise adding 25ml of sodium hypochlorite solution with the concentration of 12%. The reaction was continued for 4 hours after the addition was completed. Stopping the reaction, adding ether for extraction once, adjusting the pH of a water layer to 3 with hydrochloric acid in an ice bath, freezing, crystallizing, filtering, washing a filter cake with ethanol, filtering, and drying the filter cake at 40 ℃ under reduced pressure for 8 hours to obtain yellowish powder 25.3g, wherein the yield is as follows: 76.7 percent.
The molecular formula is as follows: c18H19N8O10PS3
Molecular weight: 634.56
Mass Spectrum (m/e): 635(M +1)
Elemental analysis:
measured value: c: 33.94%, H: 3.24% N: 17.61% P: 4.79% S: 15.32 percent
Theoretical value: c: 34.07%, H: 3.02% N: 17.66% P: 4.88% S: 15.16 percent
1H-NMR(600MHz，DMSO)δ：2.10(w，2H)，3.59(m，3H)，3.72(d，2H)，3.83(s，3H)，5.13(d，2H)，5.79(m，2H)，6.74(s，1H)，7.24(w，3H)，9.60(d，1H).
IR(KBr)cm-1：3316，2946，1785，1662，1610，1533，1412，1372，1254，1046，863，511.
Example 106R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [ [2- (2-phosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Octa-2-
Ene-2-carboxylic acid disodium salt (i.e., sodium salt)Preparation of Compound 1-2)
Dissolving 10g of the product obtained in the previous step into 100ml of deionized water, adjusting the pH value to 5.5-7.5 by using 10% sodium carbonate, stirring to obtain a clear solution, adding 300ml of ethanol, uniformly stirring, and freezing and crystallizing. Filtering, drying the filter cake for 6h at 40 ℃ under reduced pressure to obtain 8.5g of 6R [6 alpha, 7 beta (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [2- (2-phosphonamido-4-thiazolyl) ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt, yield: 79.2 percent.
Example 116R [6 α, 7 β (Z) ]]-3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio]Methyl radical]-
7- [ [2- (2-phosphoramido-4-thiazolyl)]-2- (methoxyimino) acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Octa-2-
Preparation of ene-2-carboxylic acid disodium salt triple hemihydrate (i.e., Compounds 1-3)
10g of the filter cake obtained in example 10 (wet weight before drying) was dried at room temperature under reduced pressure at 75% RH for 2 days to obtain 5.2g of triple hemihydrate of disodium 6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [2- (2-phosphonamido-4-thiazolyl) ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate.
EXAMPLE 12 preparation of sterile injectable powder of the Compound of the present invention
1. Prescription:
prescription 1:
prescription 2:
prescription 3:
2. the preparation process comprises the following steps:
(1) performing aseptic treatment on antibiotic glass bottles, rubber plugs and the like used for preparation;
(2) weighing raw materials and adjuvants (sterile raw materials can be prepared by sterilizing crystallization or spray drying), pulverizing, mixing, packaging, and detecting the content at any time;
(3) and (4) plugging, capping, fully inspecting finished products, packaging and warehousing.
EXAMPLE 13 preparation of tablets of the Compound of the invention
1. Prescription:
prescription 1:
prescription 2:
2. the preparation process comprises the following steps:
(1) weighing raw materials and auxiliary materials according to a prescription, crushing the raw materials, sieving the crushed raw materials with a 100-mesh sieve, and respectively sieving the rest auxiliary materials with the 100-mesh sieve;
(2) mixing the raw materials, starch, hydroxypropyl cellulose and microcrystalline cellulose uniformly, adding into a mixing granulator, adding 50% ethanol water solution of 1% HPMC, stirring for 15 min, and granulating;
(3) drying the granules at a temperature lower than 60 ℃;
(4) adding superfine silica gel powder and magnesium stearate into the dried granules, granulating and uniformly mixing;
(5) sampling and testing a semi-finished product;
(6) tabletting the tablets according to the assay;
(7) and (6) fully inspecting the finished product, and packaging and warehousing.
EXAMPLE 14 preparation of capsules of the Compound of the invention
1. Prescription
Prescription 1:
2. the preparation process comprises the following steps:
(1) respectively crushing the raw materials and the auxiliary materials and sieving the crushed raw materials and the auxiliary materials with a 100-mesh sieve for later use;
(2) weighing raw materials and auxiliary materials according to the prescription amount;
(3) dissolving hydroxypropyl methylcellulose in water to prepare a 2% 50% ethanol water solution for later use;
(4) mixing the raw materials, low-substituted hydroxypropyl cellulose and microcrystalline cellulose uniformly, adding 2% HPMC 50% ethanol water solution, and stirring uniformly to obtain soft material;
(5) sieving with 20 mesh sieve, granulating, oven drying at 60 deg.C, adding magnesium stearate and silica gel micropowder into the dried granules, sieving with 18 mesh sieve, grading, and mixing;
(6) sampling and testing a semi-finished product;
(7) filling into capsules according to the filling amount determined by the test;
(8) and (6) fully inspecting the finished product, and packaging and warehousing.
Claims (10)
1. A compound represented by the general formula (I), pharmaceutically acceptable salts thereof, easily hydrolysable esters thereof, isomers thereof, hydrates thereof, and hydrates of the salts or esters thereof:
wherein:
R1and R2May be the same or different and each independently represents a hydroxyl group or C1-4An alkoxy group;
R3represents a hydrogen atom, a straight chain or branched C substituted or unsubstituted by a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a nitro group, a cyano group1-4An alkyl group;
R4represents a hydrogen atom or a carboxyl protecting group;
z represents N or CR5，R5Represents a hydrogen atom or a halogen atom.
2. The compound, pharmaceutically acceptable salts thereof, easily hydrolysable esters thereof, isomers thereof, hydrates thereof, and hydrates of the salts or esters thereof according to claim 1, wherein:
R1and R2May be the same or different and each independently represents a hydroxyl group or C1-4An alkoxy group;
R3represents a hydrogen atom, a methyl group, an ethyl group, a fluoromethyl group, a fluoroethyl group, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, an acetoxy group or an isobutyric acid group;
R4represents a hydrogen atom or a carboxyl-protecting group,
wherein said carboxyl protecting group is selected from methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, phenacyl, ethyl, t-butyl, allyl, benzyl, p-nitrobenzyl, p-methoxybenzyl or diphenylmethyl;
z represents N or CR5，R5Represents a hydrogen atom or a chlorine atom.
3. The compound, its pharmaceutically acceptable salt, its easily hydrolyzable ester, its isomer, its hydrate and its hydrate of salt or ester according to claim 2, wherein
R1And R2May be the same or different and each independently represents a hydroxyl group, a methoxy group, an ethoxy group or an isopropoxy group;
R3represents a hydrogen atom, a methyl group or an isobutyric acid group;
R4represents a hydrogen atom or a carboxyl-protecting group,
wherein said carboxyl protecting group is selected from methyl, t-butyl, allyl, benzyl, p-nitrobenzyl, p-methoxybenzyl or diphenylmethyl;
z represents CH.
4. The compound, its pharmaceutically acceptable salt, its easily hydrolyzable ester, its isomer, its hydrate and its hydrate of salt or ester according to claim 3, wherein the compound is:
6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [2- (2-phosphonamido-4-thiazolyl) ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid,
6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [2- (2-phosphonamido-4-thiazolyl) ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt,
6R [6 alpha, 7 beta (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [2- (2-phosphonamido-4-thiazolyl) ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid triple hemihydrate,
6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diethylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid,
6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diethylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt,
6R [6 alpha, 7 beta (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diethylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid triple hemihydrate,
6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid,
6R [6 α, 7 β (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt, and
6R [6 alpha, 7 beta (Z) ] -3- [ [ (1, 2, 5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [2- [2- (diisopropylphosphoramido) -4-thiazolyl ] -2- (methoxyimino) acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid triple hemihydrate.
5. A compound according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt thereof comprises acetate, mesylate, maleate, succinate, tartrate, citrate, fumarate, hydrochloride, hydrobromide, nitrate, sulphate, phosphate, sodium, potassium, calcium, magnesium, zinc.
6. A compound according to any one of claims 1 to 4, wherein the hydrolysable ester is one or more of the carboxyl groups present in formula (I) in the form of a hydrolysable ester group, and comprises: alkanoyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkoxymethyl esters, alkanoylmethyl esters, cycloalkanoyloxyalkyl esters, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, 2- [ (2-methylpropoxy) carbonyl ] -2-pentenyl ester.
7. A pharmaceutical composition comprising the compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, an isomer thereof, a hydrate thereof, and a hydrate of the salt or ester, and other pharmaceutically active ingredients, wherein the other pharmaceutically active ingredients comprise a beta-lactamase inhibitor selected from one or more of sulbactam, sulbactam sodium, sulbactam pivoxil, tazobactam sodium, and clavulanate potassium.
8. A pharmaceutical composition comprising the compound of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a hydrolyzable ester thereof, an isomer thereof, a hydrate thereof, and a hydrate of the salt or ester thereof, and/or one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.
9. The pharmaceutical composition according to claim 8, which comprises 0.05g to 5g of the compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, an easily hydrolyzable ester thereof, an isomer thereof, a hydrate thereof, and a hydrate of the salt or ester thereof as an essential active ingredient.
10. Use of the compound, the pharmaceutically acceptable salt thereof, the easily hydrolyzable ester thereof, the isomer thereof, the hydrate thereof, and the hydrate of the salt or ester thereof according to any one of claims 1 to 4 for the preparation of a medicament for the treatment and/or prevention of infectious diseases.
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| CN103864851A (en) * | 2014-03-25 | 2014-06-18 | 华润赛科药业有限责任公司 | Ceftobiprole derivatives as prodrug and preparation method and use of ceftobiprole derivatives |
| CN106659718A (en) * | 2014-04-18 | 2017-05-10 | 沃克哈特有限公司 | Pharmaceutical compositions comprising antibacterial agents |
| CN106822147A (en) * | 2016-11-03 | 2017-06-13 | 湘北威尔曼制药股份有限公司 | A kind of Ceftriaxone Sodium and sulbactam sodium composition, the pharmaceutical preparation comprising said composition and its application |
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| CH641468A5 (en) * | 1978-05-30 | 1984-02-29 | Hoffmann La Roche | CEPHEM DERIVATIVES. |
| DE3165922D1 (en) * | 1980-03-28 | 1984-10-18 | Biochemie Gmbh | New process for the production of cephalosporin antibiotics, and novel intermediates used in such process and their production |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103864851A (en) * | 2014-03-25 | 2014-06-18 | 华润赛科药业有限责任公司 | Ceftobiprole derivatives as prodrug and preparation method and use of ceftobiprole derivatives |
| CN103864851B (en) * | 2014-03-25 | 2016-08-17 | 华润赛科药业有限责任公司 | Ceftobiprole derivant as prodrug and its production and use |
| CN106659718A (en) * | 2014-04-18 | 2017-05-10 | 沃克哈特有限公司 | Pharmaceutical compositions comprising antibacterial agents |
| CN106822147A (en) * | 2016-11-03 | 2017-06-13 | 湘北威尔曼制药股份有限公司 | A kind of Ceftriaxone Sodium and sulbactam sodium composition, the pharmaceutical preparation comprising said composition and its application |
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