CN101245081B - Novel cephalosporin derivative - Google Patents

Novel cephalosporin derivative Download PDF

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CN101245081B
CN101245081B CN2008100742631A CN200810074263A CN101245081B CN 101245081 B CN101245081 B CN 101245081B CN 2008100742631 A CN2008100742631 A CN 2008100742631A CN 200810074263 A CN200810074263 A CN 200810074263A CN 101245081 B CN101245081 B CN 101245081B
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acetoxyl
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CN101245081A (en
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黄振华
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Beijing Ruiye Drugs Manufacture Co ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract

The invention belongs to the technical field of medicine, in particular to a novel cephalosporin derivative shown in the general formula (I), the pharmacologically acceptable salt, the easily hydrolysable ester, the isomer, the hydrate, and the hydrate of the ester or the salt; wherein, R<1>, R<2>, R<3>, R<4> and X are defined in the instruction book; the invention further relates to the preparation methods of the compounds, the medicine combinations containing the compounds, and the application of the compounds in the preparation of medicines for treating and/ or preventing infectious diseases.

Description

Cephalosporins derivatives
1, technical field
The present invention relates to the hydrate of ester, its isomer, its hydrate and the ester or the salt of cephalosporins derivatives, its pharmacy acceptable salt, its facile hydrolysis, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes, belong to medical technical field.
2, background technology
Cynnematin has developed very soon since coming out the forties in 20th century, and according to the age of its research and development, antimicrobial spectrum, antibiotic characteristics, pharmacokinetic characteristics and to the stability and the renal toxicity of β-Nei Xiananmei can be divided into it for one, two, three, four generations.
Present the 4th generation cephalo majority of compounds have 2-(thiazolamine-4-yl)-2-hydroxyl (or the hydroxyl that replaces) imino-kharophen or 2-(5-amino-1 at its 7,2,4-thiadiazoles-3-yl)-2-hydroxyl (or the hydroxyl that replaces) imino-kharophen, 3 contain a level Four ammonia structure, for example monocycle pyridyl or condensed ring pyridyl do not have substituting group or one or more substituting groups are arranged on its ring.These compounds can be used for some bacterium of Chinese People's Anti-Japanese Military and Political College's enterobacter, some bacterium of citric acid Pseudomonas and the bacterium that great majority belong to proteus, can also resist some bacterium of Staphylococcus and streptococcus, has good activity, but effect can not be satisfactory when the clinical isolated bacterial of antagonism for these compounds, and the effect of especially resisting bacteriums such as MRSA is unsatisfactory.
And be that the cephalosporin compound that pyrrole derivative replaces is reported seldom on 3, once reported at CN94104429.7.Compare with existing cephalosporin analog antibiotic, the antimicrobial spectrum of these compounds and anti-microbial activity have all had progress, but the fungistatic effect for clinical isolated bacterial is not greatly improved, so research has very strong active medicine to become the focus of domestic and international concern for clinical separation of bacterial especially MRSA.
3, summary of the invention
The invention provides cephalosporins derivatives, have wide spectrum, characteristics of high efficiency.
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its isomer, its hydrate and the ester or the salt of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Figure B2008100742631D00011
Wherein: R 1Expression hydrogen atom or amino protecting group;
R 2Expression hydrogen atom or the low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, low-grade cycloalkyl, phenyl or the heterocyclic radical that are not substituted or are replaced by 1～3 substituting group, described substituting group is selected from halogen atom, hydroxyl, amino, cyano group or carboxyl;
R 3Expression hydrogen atom or carboxyl-protecting group;
R 4The expression hydrogen atom, halogen atom, hydroxyl, amino, cyano group, carboxyl or the low alkyl group, lower alkoxy, low-grade alkenyl, alkynyl of low-grade chain, low-grade cycloalkyl, phenyl or the heterocyclic radical that are not substituted or are replaced by 1～3 substituting group, described substituting group is selected from halogen atom, hydroxyl, amino, cyano group or carboxyl;
X represents CH or N.
Preferred compound is:
Wherein: R 1Expression hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, 3-acetoxyl group propyl group or diazo;
R 2Expression hydrogen atom or the low alkyl group or the low-grade cycloalkyl that are not substituted or are replaced by 1～3 substituting group, described substituting group is selected from hydroxyl, amino or carboxyl;
R 3Expression hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R 4The expression hydrogen atom, halogen atom, hydroxyl, amino, carboxyl or the low alkyl group, lower alkoxy or the low-grade cycloalkyl that are not substituted or are replaced by 1～3 substituting group, described substituting group is selected from hydroxyl, amino or carboxyl;
X represents CH or N.
Further preferred compound is:
Wherein: R 1Expression hydrogen atom or amino protecting group,
Described amino protecting group is selected from diazo, methyl, the tertiary butyl, formyl radical, tert-butoxycarbonyl, allyloxy carbonyl, to the nitro benzyloxycarbonyl or to methoxyl group benzyloxy base carbonyl;
R 2The expression hydrogen atom, methyl, ethyl, propyl group, methylol, hydroxyethyl, aminomethyl, aminoethyl, acetoxyl, propionyloxy, cyclopropyl or cyclobutyl;
R 3Expression hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R 4The expression hydrogen atom, halogen atom, methyl, ethyl, propyl group, hydroxyl, methylol, hydroxyethyl, amino, aminomethyl, aminoethyl, carboxyl, acetoxyl, propionyloxy, methoxyl group, oxyethyl group, cyclopropyl or cyclobutyl;
X represents CH or N.
Particularly preferred compound is:
Wherein: R 1Expression hydrogen atom or amino protecting group,
Described amino protecting group is selected from diazo, methyl, the tertiary butyl, formyl radical, tert-butoxycarbonyl or allyloxy carbonyl;
R 2Expression hydrogen atom or methyl;
R 3Expression hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, to nitrobenzyl, allyl group or benzyl;
R 4The expression hydrogen atom, methyl, ethyl, hydroxyl, methylol, amino, aminomethyl, carboxyl, acetoxyl, propionyloxy;
X represents CH or N.
" low alkyl group " mentioned above is C 1-6The alkyl of straight or branched comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
" lower alkoxy " mentioned above is C 1-6The alkoxyl group of straight or branched comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.
" low-grade alkenyl " mentioned above is C 2-6The alkenyl of straight or branched comprises vinyl, 1-propenyl, pseudoallyl, 1-butylene base, crotyl, 3-butenyl, methylallyl or 1,1-dimethylallyl etc.
" alkynyl of low-grade chain " mentioned above is C 2-6The alkynyl group of straight or branched comprises ethynyl, 1-proyl, different proyl, ethyl acetylene base, 2-butyne base, 3-butynyl, first for propargyl or 1,1-diformazan propargyl etc.
" low-grade cycloalkyl " mentioned above is C 3-7Alicyclic hydrocarbon radical, comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.
" halogen atom " mentioned above comprises fluorine, chlorine, bromine, iodine.
" heterocyclic radical " mentioned above is meant and contains 1～4 heteroatoms, as nitrogen-atoms, 5～8 yuan of rings of Sauerstoffatom or sulphur atom, or its thick and ring, for example: 2-or 3-pyrryl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-imidazolyl, 1,2,3-or 1,2,4-triazolyl, 1H-or 2H-tetrazyl, 2-or 3-furyl, 2-or 3-thienyl, 2-, 4-or 5-oxazolyl, 3-, different-oxazolyls of 4-or 5-, 1,2,3-oxadiazole-4-or-the 5-base, 1,2,3-thiazolyl-4-or-the 5-base, 1,2,4-thiazolyl-3-or-the 5-base, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 1-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 2-, 3-or 4-piperazinyl, pyrazinyl, piperazinyl, 2-, 3-or 4-pyranyl, 2-, 3-or 4-thiapyran base etc.
" amino protecting group " mentioned above refers to that routine is used for the blocking group of substituted-amino acid proton, their example comprises: diazo, methyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, ethyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Allyl group; allyloxy carbonyl; tert-butoxycarbonyl; to the nitro benzyloxycarbonyl; to methoxyl group benzyloxy base carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; (N '; N '-dimethylaminomethylene); N; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; the acyl group vinyl; 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; diethyl phosphonyl; the dibenzyl phosphono; the diphenylphosphine acyl group; phosphono; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; phenacyl alkylsulfonyl etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methyl, methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, allyl group, benzyloxymethyl, phenacyl, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, ethyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
The chemical name and the structural formula of special preferred compound are as follows:
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, be called for short compound 1.
Structural formula:
Figure B2008100742631D00051
Chemical name: (6R, 7R)-7-[[(2-amino-thiazolyl--4-yl)-Z-2-methoxy oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, be called for short compound 2.
Structural formula:
Figure B2008100742631D00052
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, be called for short compound 3.
Structural formula:
Figure B2008100742631D00061
Chemical name: (6R, 7R)-7-[[(2-amino-thiazolyl--4-yl)-the 2-oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, be called for short compound 4.
Structural formula:
Figure B2008100742631D00062
The present invention also provides the preparation method of preparation above-claimed cpd, but is not limited only to following preparation method, also can make by additive method:
Reaction equation: the R in the equation 1, R 2, R 3, R 4, X representative group as previously described.
Reactions steps:
Step 1, in reaction flask, add raw material 1, raw material 2, triethylamine and DMF stir.React the postcooling that finishes, pour in the frozen water, with chloroform extraction for several times, merge organic layer, washing, drying, concentrating under reduced pressure.Residuum gets intermediate 1 with methyl alcohol and ethyl acetate mixed solution recrystallization.
Add raw material 3 in step 2, the four-hole bottle, add dimethyl sulfoxide (DMSO), be heated to dissolving.Add raw material 4, stirring reaction.After being cooled to room temperature, add entry, separate out faint yellow solid after the stirring.Filter, filtrate is used CHCl 3Extracting twice.Organic layer and filter cake merge solution, concentrating under reduced pressure, resistates dissolves with chloroform, uses purification by silica gel column chromatography, with chloroform and methyl alcohol mixed liquor gradient elution, collects required component, is concentrated into driedly, promptly gets intermediate 2.
Step 3, with intermediate 2, sodium iodide and dry acetone stirring reaction.Reaction Bi Huishou acetone adds ethyl acetate in the residue, use hypo solution and saturated common salt water washing successively, uses anhydrous sodium sulfate drying, filters the back and reclaims ethyl acetate, gets jelly.Use the acetic acid ethyl dissolution jelly, stir adding triphenylphosphine down.Finish stirring reaction.Filter, filtrate decompression concentrates, and the cooling back adds isopropyl ether, stirs after-filtration.Filter cake washs with isopropyl ether, and drying promptly gets intermediate 3.
Step 4, add intermediate 3 in reaction flask, methylene dichloride adds intermediate 1 after the stirring and dissolving, promptly get The compounds of this invention.
Raw material 4 in the step 2 is represented active ester, described active ester comprises (Z)-2-(2-triphen methylamino-thiazole-4-yl)-2-methoxyimino thioacetic acid (S-2-benzene isothiazole) ester, α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester, or α-(2-amino-thiazolyl--4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester etc.
Carboxyl on the The compounds of this invention cephalo parent nucleus also can be protected by carboxyl-protecting group, perhaps can adult in the ester of facile hydrolysis, the i.e. described The compounds of this invention of general formula (I).
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention, comprise acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt; Preferred mesylate, hydrochloride and sodium salt.
The ester of the claimed compound facile hydrolysis of the present invention, comprise the alkyloyloxyethyl alkyl ester, for example acetyl oxygen methyl esters, propionyl oxygen methyl esters, butyryl oxygen methyl esters, sec.-propyl methanoyl methyl esters, tertiary butyl methanoyl methyl esters, neo-pentyl methanoyl methyl esters, isobutyl-methanoyl methyl esters, new penta acetyl oxygen methyl esters, decoyl oxygen methyl esters, caprinoyl oxygen methyl esters etc.; The alkyl oxy carbonyl oxygen alkyl ester, for example methoxy methyl acyl-oxygen methyl esters, (ethoxymethyl) acyl-oxygen methyl esters, isopropoxy methanoyl-1-ethyl ester, hexyloxy methanoyl-1-ethyl ester, octyloxy methanoyl-1-ethyl ester, the last of the ten Heavenly stems oxygen base methanoyl-1-ethyl ester, dodecyloxy methanoyl-1-ethyl ester etc.; Alkoxyl group methyl esters, for example methoxy methyl esters, the different third oxygen methyl esters of 1-etc.; Alkyl amido methyl esters, for example formamido group methyl esters, kharophen methyl esters etc.; Cycloalkanes acyloxyalkyl group ester, for example cyclohexyl methanoyl methyl esters, cyclohexyl methanoyl-1-ethyl ester, 1-methyl-cyclohexyl alkyl methanoyl-1-ethyl ester, 4-methyl-cyclohexyl alkyl methanoyl methyl esters etc.; Cycloalkyloxy acyloxyalkyl group ester, for example pentamethylene oxygen base methanoyl-1-ethyl ester, hexamethylene alkoxyl group methanoyl-1-ethyl ester etc.; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester, 2-[(2-methyl propoxy-) carbonyl]-2-amylene ester etc.Be preferably propionyl oxygen methyl ester, butyroxymethyl ester, tertiary butyl methanoyl methyl ester, the different third oxygen methanoyl methyl ester, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester, (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester etc.
Isomer of the present invention is meant that its all differences are to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.
The ester of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis, its isomer can be hydrate forms.Hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of other active pharmaceutical ingredients, as cilastatin and sodium salt, Betamipron etc.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.01g～5g shown in the general formula (I) of physiology significant quantity, can be 0.01g, 0.025g, 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.
The hydrate of the ester of the arbitrary compound of the present invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate or its ester or salt, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Described arbitrary compound above the present invention is further claimed; its pharmacy acceptable salt; the ester of its facile hydrolysis; its isomer; the hydrate of its hydrate and ester thereof or salt; preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes; cephalosporins derivatives of the present invention is to clinical isolates; the coprodaecum coccus; escherichia coli; Klebsiella Pneumoniae; Acinetobacter baumannii; Pseudomonas aeruginosa; bacteriums such as standard clostridium perfringens all have good antibacterial activity; can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism of Mammals (comprising the people); as respiratory tract infection and urinary tract infection, also can be used for septicemia; meningitis etc.
Cephalosporins derivatives of the present invention is compared with immediate prior art, has the following advantages:
(1) cephalosporins derivatives of the present invention has has a broad antifungal spectrum, and anti-microbial activity is strong, the advantage that toxicity is low, can by safety be used for the treatment of and/or prevent various Mammalss (comprising the people) by the caused various diseases of germ.
When (2) cephalosporins derivatives of the present invention was as antiseptic-germicide, target bacteria had no particular limits, and bacteriums such as gram-positive microorganism and Gram-negative bacteria and anerobe can be as target bacteria.
(3) cephalosporins derivatives of the present invention all has good especially anti-microbial activity to Staphylococcus, streptococcus, Pseudomonas aeruginosa, methicillin-resistant staphylococcus aureus (MRSA) and MSSA (MSSA).
(4) cephalosporins derivatives excellent in stability of the present invention, especially The compounds of this invention 1～4, comprises the hydrate of ester, its isomer, its hydrate and the ester or the salt of its pharmacy acceptable salt, its facile hydrolysis.
(5) preparation technology of cephalosporins derivatives of the present invention is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below routine by experiment beneficial effect of further setting forth cephalosporins derivatives of the present invention.Cephalosporins derivatives of the present invention has following beneficial effect, but this should be interpreted as that cephalosporins derivatives of the present invention only has following beneficial effect.
Experimental example 1: the antimicrobial spectrum of The compounds of this invention and anti-microbial activity
For trying bacterial classification: clinical isolated M RSA 21 strains, MSSA 18 strains, streptococcus pneumoniae 18 strains, Streptococcus viridans 22 strains, faecalis 24 strains, Haemophilus influenzae 20 strains, 13 strains of mucositis micrococci, streptococcus pyogenes 17 strains, intestinal bacteria 16 strains, pneumobacillus 13 strains, enterobacter cloacae 21 strains, Proteus mirabilis 13 strains, proteus vulgaris 14 strains, Pseudomonas aeruginosa 16 strains, 15 strains of Fu Shi citric acid bacterium, clostridium perfringens 12 strains.
Trial-product:
The compounds of this invention 1～4, chemical name and structural formula are made by oneself as previously described;
Contrast medicine D: vancomycin, commercial;
Contrast medicine E: with reference to disclosed compound K (chemical name: [6R-[3 (E) in CN94104429.7,6 α, 7 β (Z)]]-7-[[(2-amino-4-thiazolyl) (oximino) ethanoyl] amino]-8-oxo-3-[[2-oxo-1-(3-pyridyl)-3-pyrrolidylidene] methyl]-5-thia-1-azabicyclo [4.2.0]-oct-2-ene-2-carboxylic acid) method make;
Experimental technique:
Agar dilution.
Table 1 The compounds of this invention minimum inhibitory concentration MIC (μ g/ml)
Figure B2008100742631D00111
Table 2 The compounds of this invention minimum inhibitory concentration MIC (μ g/ml)
Figure B2008100742631D00112
Experimental result and conclusion: the results are shown in Table 1,2.
From table 1,2 as can be seen, The compounds of this invention all has good effect to all gram-positive microorganism and Gram-negative bacterias for examination.E compares with the contrast medicine, and The compounds of this invention 1～4 has has a broad antifungal spectrum, the advantage that anti-microbial activity is strong, and especially the fungistatic effect to bacteriums such as MRSA, MSSA, Pseudomonas aeruginosa and anerobes has obtained than much progress; Compare with contrast medicine vancomycin, better or suitable to the bacteriostatic activity of clinical isolated M RSA, MSSA, but toxicity reduces greatly.Experimental result shows, cephalosporins derivatives of the present invention has has a broad antifungal spectrum, anti-microbial activity height, advantage that toxicity is little, for having the new compound of good clinical application potential.
Experimental example 2: the resistance research of The compounds of this invention
Experimental strain: experiment is mainly derived from bacterial strain and comprises phlegm, secretory product, throat swab, blood, urine, hydrothorax, seroperitoneum etc.Isolate 652 strain escherichia colis altogether, 629 strain Klebsiella Pneumoniaes, pseudomonas aeruginosa 616 strains are totally three kinds of gram negative bacilluses, and all the other strain separated do not take statistics.
Trial-product:
Cefepime is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
The disodium salt of The compounds of this invention 1～4, chemical name and structural formula are made by oneself as previously described;
Method: adopt the MIC method of disk diffusion method, Microscam system to carry out drug sensitive experiment, operate and interpretation in strict accordance with the rule that the stdn council of U.S. clinical labororatory (NCCLS) formulated in 2005.
Quality control: every batch of experiment is measured the corresponding microbiotic scraps of paper with standard escherichia coli ATCC25922, standard Klebsiella Pneumoniae ATCC700603, standard verdigris aeruginosa atcc 27853 simultaneously.
The resistance situation of table 3 The compounds of this invention
Figure B2008100742631D00121
Annotate: S: sensitivity; R: resistance.
Experimental result and conclusion: the results are shown in Table 3.Escherichia coli to the resistant rate of cefepime all more than 30%, and to the resistant rate of The compounds of this invention disodium salt between 8.74%～9.36%, illustrate The compounds of this invention to escherichia coli anti-microbial activity be higher than cefepime; Klebsiella Pneumoniae to the resistant rate of cefepime all more than 40%, and to the resistant rate of The compounds of this invention disodium salt between 7.63%～8.27%, illustrate that The compounds of this invention all is higher than cefepime to the anti-microbial activity of Klebsiella Pneumoniae; Pseudomonas aeruginosa to the resistant rate of cefepime all more than 40%, and to the resistant rate of The compounds of this invention disodium salt between 8.77%～9.09%, illustrate that The compounds of this invention all is higher than cefepime to the anti-microbial activity of pseudomonas aeruginosa.Experimental result shows that The compounds of this invention and disodium salt thereof are having beyond thought advantage aspect the anti-Gram-negative bacteria resistance.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation of embodiment 1 2-[5-(2,3-dioxo-pyrroles-1-yl) thiophene [2,3-d] isoxazole-3-base] tert.-butyl acetate
In reaction flask, add 2,3-dioxo-tetramethyleneimine 10g (0.1mol), 2-[5-bromo-thiophene [2,3-d] isoxazole-3-base] tert.-butyl acetate 31.8g (0.1mol), triethylamine 15g (0.15mol) and DMF 200ml, in stirring at room 3h, 60 ℃ are stirred 24h.Reaction finishes postcooling to room temperature, pours among the frozen water 1000ml, with chloroform extraction for several times, merges organic layer, washing, drying, concentrating under reduced pressure.Residuum gets 2-[5-(2,3-dioxo-pyrroles-1-yl) thiophene [2,3-d] isoxazole-3-base] tert.-butyl acetate 22g, yield: 65.3% with methyl alcohol and ethyl acetate mixed solution recrystallization.
Embodiment 2 (6R, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3- The preparation of chloromethyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester
Figure B2008100742631D00131
(6R, 7R)-7-amino-3-chloromethyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester adds in the four-hole bottle, adds dimethyl sulfoxide (DMSO) 200ml, water-bath is heated to dissolving for 50 ℃ to get 20.7g (0.05mol).Take by weighing (Z)-2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-2-methoxyimino thioacetic acid (S-2-benzene isothiazole) ester 32.7g (0.055mol), add stirring reaction 6h in batches.After reaction solution is cooled to room temperature, add 100ml water, separate out faint yellow solid after the stirring.Filter, filtrate is used 100ml CHCl 3Extracting twice.Organic layer and filter cake merge solution, concentrating under reduced pressure, resistates dissolves with chloroform, uses purification by silica gel column chromatography, with chloroform and methyl alcohol mixed liquor gradient elution, collects required component, is concentrated into dried yellow solid 35.9g, yield: 85.4%.
Embodiment 3 (6R, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] ethanamide Base]-system of 3-(triphenyl phosphorus base) methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester iodide Be equipped with
Figure B2008100742631D00132
With (6R, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-chloromethyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester 33.6g (0.04mol), sodium iodide (20g, 0.13mol) and dry acetone 500ml react 4h in stirring at room.Reclaim under reduced pressure acetone is finished in reaction, adds ethyl acetate (500ml) in the residue, uses 10% hypo solution and saturated common salt water washing successively, uses anhydrous sodium sulfate drying, filters back reclaim under reduced pressure ethyl acetate, gets jelly.With 400ml acetic acid ethyl dissolution jelly, stir adding 20g triphenylphosphine (0.08mol) down, finish stirring at room reaction 3h.Filter, it is surplus about 1/2 that filtrate decompression is concentrated into, and the cooling back adds the 500ml isopropyl ether, stirs after-filtration.Filter cake washs with isopropyl ether, drying under reduced pressure under room temperature, get (6R, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-(triphenyl phosphorus base) methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester iodide 29.8g, yield: 62.3%.
Embodiment 4 (6R, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] ethanamide Base]-3-[[[1-[3-(2-tert.-butyl acetate) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-sulphur The preparation of assorted-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester
Figure B2008100742631D00141
In reaction flask, with (6R, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-(triphenyl phosphorus base) methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester iodide 29.8g (0.025mol), methylene dichloride 500ml, after the stirring and dissolving, add 2-[5-(2,3-dioxo-pyrroles-1-yl) thiophene [2,3-d] isoxazole-3-base] tert.-butyl acetate 10.1g (0.03mol), get (6R, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[[1-[3-(2-tertiary butyloxycarbonyl ethyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester 10.9g, yield: 38.9%.
Embodiment 5 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] ethanamide]-3-[[1-[3-(2-second Acidic group) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] The preparation of oct-2-ene-2-formic acid (compound 1)
In reaction flask, add 50ml methylene dichloride, 50ml trifluoroacetic acid and 15ml phenylmethylether, stir and add (6R down, 7R)-7-[[2-(5-triphen methylamino--1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[1-[3-(2-tertiary butyloxycarbonyl ethyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid benzhydryl ester 11.25g (10mmol), stirring at room reaction 30min.Decompression and solvent recovery adds ethanol (80ml) and water (100ml) in the residue, ice bath stirs down and drips saturated sodium bicarbonate solution to pH 6.5～7.0, stirring at room 30min.Filter, filter cake washs with less water successively, after the reduced pressure at room temperature, with ethanol-re-crystallizing in ethyl acetate, (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] ethanamide]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid 3.66g, yield: 55.4%.
Molecular weight: 660.66
Molecular formula: C 24H 20N 8O 9S 3
Ultimate analysis: measured value: C, 43.59%; H, 3.12%; N, 16.90%; S, 14.51%
Theoretical value: C, 43.63%; H, 3.05%; N, 16.96%; S, 14.56%
Prepared following compound according to the foregoing description:
(6R, 7R)-and 7-[[2-(2-amino-thiazolyl--4-yl)-Z-2-methoxy oximido] ethanamide]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid (compound 2)
Molecular weight: 659.67
Molecular formula: C 25H 21N 7O 9S 3
Ultimate analysis: measured value: C, 45.55%; H, 3.29%; N, 14.78%; S, 14.52%
Theoretical value: C, 45.52%; H, 3.21%; N, 14.86%; S, 14.58%
MS(ISP)：M+H +＝660.67
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl) 2-oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid (compound 3)
Molecular weight: 646.63
Molecular formula: C 23H 18N 8O 9S 3
Ultimate analysis: measured value: C, 42.61%; H, 2.88%; N, 17.30%; S, 14.75%
Theoretical value: C, 42.72%; H, 2.81%; N, 17.33%; S, 14.88%
(6R, 7R)-and 7-[[2-(2-amino-thiazolyl--4-yl)-2-oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles 3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid (compound 4)
Molecular weight: 645.64
Molecular formula: C 24H 19N 7O 9S 3
Ultimate analysis: measured value: C, 44.57%; H, 3.11%; N, 15.20%; S, 14.79%
Theoretical value: C, 44.65%; H, 2.97%; N, 15.19%; S, 14.90%
Embodiment 6 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] ethanamide]-3-[[[1-[3-(2-second Acidic group) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] The preparation of oct-2-ene-2-formic acid disodium salt (disodium salt of compound 1)
Figure B2008100742631D00151
In reaction flask, add (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] ethanamide]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid 3.96g (6mmol), dehydrated alcohol 100ml, add the 1g gac after the stirring and dissolving and stir decolouring, filtrate adds the saturated solution that contains the 0.6g sodium bicarbonate down in the ice bath cooling, finish, behind the stirring at room 0.5h, filter a spot of absolute ethanol washing of filter cake, room temperature vacuum-drying, get (6R, 7R)-and 7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] ethanamide]-3-[[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid disodium salt 3.6g, yield: 85.2%.
The sodium salt that has prepared following compound according to the foregoing description:
(6R, 7R)-and 7-[[2-(2-amino-thiazolyl--4-yl)-Z-2-methoxy oximido] ethanamide]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid disodium (disodium salt of compound 2)
Figure B2008100742631D00161
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid disodium salt (disodium salt of compound 3)
Figure B2008100742631D00162
(6R, 7R)-and 7-[[2-(2-amino-thiazolyl--4-yl)-2-oximido] ethanamide]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid disodium salt (disodium salt of compound 4)
Figure B2008100742631D00163
The preparation of embodiment 7 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in compound 1～4 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in compound 1～4 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in compound 1～4 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in compound 1～4 or derivatives thereof
Prepare 1000 altogether
2, preparation technology:
(1) will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process;
(2) take by weighing raw material (feeding intake after the conversion) by prescription, sterilized powder is placed the portioning machine packing, detect loading amount at any time;
(3) jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in compound 1～4 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 2:
Any one 125g (in compound) in compound 1～4 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
2, preparation technology:
(1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
(2) take by weighing raw material and auxiliary material according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) The compounds of this invention, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
(5) cross 20 mesh sieve system particles.
(6) particle is dried under 60 ℃ condition.
(7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes.
(8) sampling, the work in-process chemical examination.
(9) the sheet weight sheet of determining according to chemical examination.
(10) finished product is examined entirely, the packing warehouse-in.
The capsular preparation of embodiment 9 The compounds of this invention
1, prescription
Prescription 1:
Any one 250g (in compound) in compound 1～4 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Prepare 1000 altogether
Prescription 2:
Any one 125g (in compound) in compound 1～4 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Prepare 1000 altogether
2, preparation technology:
(1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
(2) take by weighing raw material and auxiliary material according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) The compounds of this invention, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
(5) cross 20 mesh sieve system particles.
(6) particle is dried under 60 ℃ condition.
(7) dry good particle adds Magnesium Stearate, micropowder silica gel, crosses the whole grain of 18 mesh sieves, mixes.
(8) sampling, the work in-process chemical examination.
(9) loading amount of determining according to chemical examination incapsulates.
(10) finished product is examined entirely, the packing warehouse-in.

Claims (7)

1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Figure F2008100742631C00011
Wherein: R 1The expression hydrogen atom;
R 2The expression hydrogen atom, methyl, ethyl or propyl group;
R 3The expression hydrogen atom;
R 4Expression carboxyl, acetoxyl or propionyloxy;
X represents CH or N.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein: R 1The expression hydrogen atom;
R 2Expression hydrogen atom or methyl;
R 3The expression hydrogen atom;
R 4Expression acetoxyl or propionyloxy;
X represents CH or N.
3. compound as claimed in claim 2, for:
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid
(6R, 7R)-7-[[(2-amino-thiazolyl--4-yl)-Z-2-methoxy oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, or (6R, 7R)-7-[[(2-amino-thiazolyl--4-yl)-the 2-oximido] acetamido]-3-[[1-[3-(2-acetoxyl) thiophene [2,3-d] isoxazole-5-base]-2-oxo-pyrroles-3-thiazolinyl] methylene radical]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, and pharmacy acceptable salt.
4. as the described compound of the arbitrary claim of claim 1～3, its pharmacy acceptable salt is selected from acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt.
5. the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner is characterized in that described pharmaceutical composition is pharmaceutically acceptable arbitrary formulation.
6. pharmaceutical composition as claimed in claim 5 contains the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt 0.01g～5g.
As the described compound of claim 1～4, its pharmacy acceptable salt preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application.
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