CN101210020B - Cephalosporin compound - Google Patents

Cephalosporin compound Download PDF

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CN101210020B
CN101210020B CN2007103009101A CN200710300910A CN101210020B CN 101210020 B CN101210020 B CN 101210020B CN 2007103009101 A CN2007103009101 A CN 2007103009101A CN 200710300910 A CN200710300910 A CN 200710300910A CN 101210020 B CN101210020 B CN 101210020B
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amino
oxo
thiomethyl
thia
thiazol
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CN101210020A (en
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黄振华
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Jilin Zhenao Pharmaceutical 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a novel cephalosporin compound with a general formula (I), pharmaceutically acceptable salt(s) thereof, easy hydrolysable ester(s) thereof, isomer(s) thereof, hydrate(s) thereof, and hydrate(s) of the salt(s) or ester(s) thereof, wherein, R <1>, R<2>, R<3>, R<4>, R<5> and X are defined in the specification. The invention also relates to preparation methods of these compounds, the medicine compositions containing these compounds, and applications of these compounds in preparing medicines for treatment and/or prevention of infective diseases, pertaining to medicine technique field.

Description

Novel cephalosporin compounds
1, technical field
The ester, its isomer, its hydrate that the present invention relates to a kind of novel cephalosporin compounds, its pharmacy acceptable salt, its facile hydrolysis with and the hydrate of salt or ester, 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
Cephalosporin antibiotic is to be widely used in clinical antibacterials, developed into for the 4th generation, but because prolonged application clinically causes bacterium that cephalosporin analog antibiotic is produced resistance, influence the antibiotic curative effect of cephalosporin analog antibiotic greatly, influenced its application clinically.Particularly the transmissible disease that is caused by methicillin-resistant staphylococcus aureus, penicillin resistant streptococcus pneumoniae and resistance faecalis has become serious clinical problem, makes that seeking new antibiotic becomes urgent clinical needs.
Cefepime Hydrochloride be the 4th generation cynnematin, has a broad antifungal spectrum, anti-microbial effect is strong, and Gram-negative bacteria is had good antibacterial activity, yet its effect for the clinical isolates strain can not be satisfactory, structural formula is as follows:
Figure S2007103009101D00011
3, summary of the invention
In order to overcome clinically resistance widely, infectious diseases is better treated, the invention provides novel cephalosporin compounds, it has wide spectrum, efficient, characteristics that resistance is little.
Technical scheme of the present invention is as follows:
The ester, its isomer, its hydrate that the invention provides the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis with and the hydrate of salt or ester:
Figure S2007103009101D00012
Wherein: R 1, R 2Independently represent hydrogen atom or amino protecting group respectively;
R 3Represent hydrogen atom, replaced or unsubstituted C by halogen atom, carboxyl, amino or hydroxyl 1-6Alkyl is by C 1-4Alkyl replacement or unsubstituted 3～6 yuan of cycloalkyl, aryl or aralkyl, alkenyl or alkynyl;
R 4Represent hydrogen atom or carboxyl-protecting group;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Figure S2007103009101D00021
Described substituting group is selected from carboxyl, amino, hydroxyl, C 1-6Alkyl or the C that is replaced by hydroxyl 1-6Alkyl;
X represents CH or N.
Be preferably:
Wherein: R 1, R 2Independently represent hydrogen atom or amino protecting group respectively,
Described amino protecting group is selected from diazo, methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, tert-butoxycarbonyl, allyloxy carbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, phenacyl or 3-acetoxyl group propyl group;
R 3Represent hydrogen atom, methyl, ethyl, carboxymethyl, propyloic, isobutyl acidic group, aminomethyl, aminoethyl, methylol, hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, phenmethyl or benzyl;
R 4Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, methoxymethyl, first thiomethyl, methoxyethyl methyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl or to nitrobenzyl;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Figure S2007103009101D00022
Described substituting group is selected from carboxyl, amino, hydroxyl, C 1-4Alkyl or the C that is replaced by hydroxyl 1-4Alkyl;
X represents CH or N.
More preferably:
Wherein: R 1, R 2Independently represent hydrogen atom or amino protecting group respectively,
Described amino protecting group is selected from diazo, methyl, ethyl, the tertiary butyl, formyl radical, tert-butoxycarbonyl, allyloxy carbonyl, to the nitro benzyloxycarbonyl or to methoxyl group benzyloxy base carbonyl;
R 3Represent hydrogen atom, methyl, ethyl or isobutyl acidic group;
R 4Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, methoxymethyl, first thiomethyl, methoxyethyl methyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl or to nitrobenzyl;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Figure S2007103009101D00031
Described substituting group is selected from carboxyl, amino, hydroxyl, methyl, ethyl or hydroxyethyl;
X represents CH or N.
Further be preferably:
Wherein: R 1, R 2Independently represent hydrogen atom or amino protecting group respectively,
Described amino protecting group is selected from methyl, the tertiary butyl or formyl radical;
R 3Represent hydrogen atom, methyl, ethyl or isobutyl acidic group;
R 4Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, allyl group or benzyl;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Figure S2007103009101D00032
Described substituting group is selected from amino, methyl, ethyl or hydroxyethyl;
X represents CH or N.
" C of the present invention 1-6Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, neo-pentyl, hexyl etc.
" 3～6 yuan of cycloalkyl " of the present invention comprises cyclopropyl, cyclobutyl, cyclopentyl, ring ethyl etc.
" aryl " of the present invention comprises phenyl, naphthyl etc.
" aralkyl " of the present invention comprises benzyl, styroyl etc.
" alkenyl " of the present invention comprises vinyl, allyl group, 1-propenyl, pseudoallyl, 1-butylene base, crotyl, 3-butenyl, methylallyl or 1,1-dimethylallyl etc.
" alkynyl " of the present invention comprises ethynyl, proyl or fourth propyl group etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups 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.
Particularly preferred compound is:
Its chemical name and structural formula are as follows:
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. With Under be called for short compound 1:
Structural formula:
Figure S2007103009101D00051
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 2:
Structural formula:
Figure S2007103009101D00052
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 3:
Structural formula:
Figure S2007103009101D00061
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 4:
Structural formula:
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 5:
Structural formula:
Figure S2007103009101D00063
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 6:
Structural formula:
Figure S2007103009101D00071
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and the 2-oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as change Compound 7:
Structural formula:
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and the 2-oximido] acetamido]-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 8:
Structural formula:
Figure S2007103009101D00073
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and the 2-oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as Compound 9:
Structural formula:
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Below Be called for short compound 10:
Structural formula:
Figure S2007103009101D00081
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 11:
Structural formula:
Figure S2007103009101D00082
Chemical name: (6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Following letter Claim compound 12:
Structural formula:
Figure S2007103009101D00083
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 13:
Structural formula:
Figure S2007103009101D00091
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 14:
Structural formula:
Figure S2007103009101D00092
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and the 2-oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 15:
Structural formula:
Figure S2007103009101D00093
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 16:
Structural formula:
Figure S2007103009101D00094
Chemical name: (6R, 7R)-7-[2-(2-amino-1,3-thiazole-4-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 17:
Structural formula:
Figure S2007103009101D00101
Chemical name: (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 18:
Structural formula:
Figure S2007103009101D00102
Chemical name: (6R, 7R)-7-[2-(2-amino-1,3-thiazole-4-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 19:
Structural formula:
Chemical name: (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 20:
Structural formula:
Figure S2007103009101D00111
Chemical name: (6R, 7R)-7-[2-(2-amino-1,3-thiazole-4-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 21:
Structural formula:
Figure S2007103009101D00112
Chemical name: (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 22:
Structural formula:
Chemical name: (6R, 7R)-7-[2-(2-amino-1,3-thiazole-4-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 23:
Structural formula:
Figure S2007103009101D00121
Chemical name: (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt. Hereinafter to be referred as compound 24:
Structural formula:
Figure S2007103009101D00122
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt.
The ester of the compound facile hydrolysis that the present invention is claimed, 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, acetamido 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.
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following preparation method, also can make by additive method:
Reaction equation:
Figure S2007103009101D00131
Experimental procedure:
Step 1: the preparation of intermediate A
In the dry reaction bottle, add acetic anhydride and formic acid, stir cooling, add raw material 1, slowly heat up, stir.Reaction finishes to steam and desolventizes, and adds entry in the residuum, uses the saturated sodium bicarbonate solution adjust pH, uses ethyl acetate extraction.Merge organic layer, anhydrous magnesium sulfate drying.Filter, filtrate vacuum-evaporation gets intermediate A to doing.
Step 2: the preparation of intermediate B
In the dry reaction bottle, add raw material 2, the N-bromo-succinimide, benzoyl peroxide, tetracol phenixin, heated and stirred refluxes, and reaction is finished, and is cooled to room temperature, filters, and filtrate decompression reclaims solvent.Add concentrated hydrochloric acid in the residuum, freezing crystallization after the insulated and stirred gets crude product, and ether-sherwood oil recrystallization gets intermediate B.
Step 3: the preparation of intermediate C
In the exsiccant reaction flask, add top gained intermediate B, dimethyl formamide, the back that stirs adds nitrogenous heterocyclic group raw material 3 and is R in the general formula 5Shown group, the intensification stirring reaction.With in the reaction solution impouring water, use ethyl acetate extraction then.Merge organic phase, successively with deionized water and saturated sodium chloride solution washing.Tell organic layer, be evaporated to dried, intermediate C.
Step 4: the preparation of intermediate D
Step intermediate C and raw material 4 add methylene dichloride and DMA then on adding in three-necked bottle, drip triethylamine and transfer pH, stirring reaction.Add distilled water after reaction finishes and stir, standing demix, organic phase washes with water, the merging water, and use the washed with dichloromethane water, and regulate water pH with dilute hydrochloric acid under the cooling, crystallization filters, and filter cake gets intermediate D with a small amount of Virahol and washing with acetone.
Step 5: the preparation of intermediate E
To go up step gained intermediate D and add methylene dichloride, cryosel is bathed cooling, adds phosphorus pentachloride and pyridine, insulated and stirred, stirring at room.Bathe down slowly adding methyl alcohol in cryosel,, add entry and stir decompression and solvent recovery in stirring at room.Residuum is dissolved in the deionized water, and cryosel is used NaHCO under bathing 3The solution adjust pH is used dichloromethane extraction, merges organic phase, washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, and drying gets intermediate E.
Step 6: the preparation of intermediate F
Step gained intermediate E and active ester add methylene dichloride and DMA then on adding in reaction flask, drip the triethylamine adjust pH, stirring reaction.Add distilled water after reaction finishes and stir, standing demix, organic phase washes with water, merges water, and uses the washed with dichloromethane water.Cooling is regulated aqueous pH values with hydrochloric acid down, and crystallization filters, and filter cake gets intermediate F with Virahol and washing with acetone.
Step 7: the preparation of The compounds of this invention
In there-necked flask, add acetonitrile, reduce temperature, under constantly stirring, add step gained intermediate F to zero degrees celsius.Stir and slowly add anhydrous formic acid, stirring down.Then at interior dense HCl, the continuation stirring reaction of splashing into.Filter filter cake second eyeball washed twice.Filter cake is dissolved in the deionized water, uses NaHCO under the cooling and stirring 3Regulate the pH value, separate out solid, promptly get The compounds of this invention.
In the reactions steps in the The compounds of this invention protecting group on the carboxyl can also select above mentioned substituting group, be the compound shown in the The compounds of this invention general formula (I)
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises alkali metallic sodium, potassium, lithium, and alkaline-earth metal comprises barium, calcium, magnesium, zinc.
The ester that the claimed compound of the present invention is easy to hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis.These esters can be conventional, lower alkane acyloxyalkyl group ester for example, acetoxyl methyl ester, pivalyl oxygen methyl ester, 1-acetoxyl ethyl ester, 1-pivalyl oxygen ethyl ester; The lower alkoxycarbonyl alkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, 1-sec.-propyl ketonic oxygen ethyl ester; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; The lower alkoxy methyl ester, methoxymethyl ester; Lower alkane acyl amino methyl ester, the acetamidomethyl ester.The ester that also can use other is for example: benzyl ester and cyano methyl ester.Other examples of these esters are as follows: (2,2-dimethyl-1-oxygen propoxy-) methyl ester; (1RS)-1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-the pentenyl ester; The 1-[[(1-methyl ethoxy) carbonyl] oxygen] ethyl ester; 1-(acetoxyl) ethyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester; The 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester; 3,3-dimethyl-2-oxo butyl ester.It is evident that for the professional of this area the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy place of this compound, for example at 4 carboxyl place.。
The ester, its isomer, its hydrate that the present invention includes arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis with and the hydrate of salt or ester and the pharmaceutical composition of other active pharmaceutical ingredients, as Sulbactam and sodium salt or Unasyn Oral, Tazobactam Sodium and sodium salt thereof, clavulanic acid and sylvite thereof.
The present invention is further claimed to comprise arbitrary compound recited above; its pharmacy acceptable salt; the ester of its facile hydrolysis; its isomer; its hydrate with and the hydrate of salt or ester and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner; wherein contain active ingredient by the described compound 0.01g～5g of formula (I); 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., preferred 0.25g; 0.5g; 1g; 2g.Aforementioned pharmaceutical compositions can be applied to the patient who needs treatment, preferred oral preparation or injection in modes such as oral, administered parenterallys.
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.
The present invention also provide new cephalosporin compound preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.Novel cephalosporin compounds Gram-positive of the present invention and negative, aerobic and anerobe and hospital clinical pathogenic bacteria such as Pseudomonas aeruginosa and acinetobacter bacterium all have better antibacterial activity, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
Cephalosporins derivatives of the present invention is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention has good anti-microbial activity and shows hypotoxicity, can being used for the treatment of and/or preventing various Mammalss (comprising the mankind) by the caused various diseases of sensitive organism by safety;
(2) The compounds of this invention has a broad antifungal spectrum all has better antibacterial activity to Gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria, and has lower resistance;
(3) The compounds of this invention preparation technology 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.Novel cephalosporin compounds of the present invention has following beneficial effect, but this should be interpreted as that novel cephalosporin compounds of the present invention only has following beneficial effect.
The antimicrobial spectrum of experimental example The compounds of this invention and antibacterial activity in vitro
For trying bacterial classification:
Be the clinical isolates strain:
Gram positive organism: MSSA (MSSA) 15 strains, methicillin-resistant staphylococcus aureus (MRSA) 17 strains, streptococcus pneumoniae 13 strains, enterococcus faecalis 18 strains;
Gram-negative bacteria: intestinal bacteria 15 strains, Proteus mirabilis 15 strains, Klebsiella Pneumoniae 15 strains, enterobacter cloacae 10 strains, hemophilus influenzae 15 strains, clostridium perfringens 10 strains;
Trial-product:
Compound 1-24: self-control, the preparation method sees embodiment for details;
Cefepime Cefepime: commercial.
Experimental technique:
Agar dilution.
Experimental result and conclusion: the results are shown in Table 1.
By table 1 as seen, The compounds of this invention 1-24 all has good bacteriostatic action to all strains testeds, show that The compounds of this invention all has better antibacterial activity to resisting gram-positive, negative bacterium, clinical separation MRSA, MSSA also there is better antibacterial activity, have has a broad antifungal spectrum, advantage that anti-microbial activity is high, for having the microbiotic of good clinical application potential.
The vitro antibacterial activity of table 1 The compounds of this invention
Bacterial strain MIC 90(mg/L)
MRSA MSSA Streptococcus pneumoniae Enterococcus faecalis Intestinal bacteria Proteus mirabilis Klebsiella Pneumoniae Enterobacter cloacae Hemophilus influenzae Clostridium perfringens
Cefepime compound 1 compound 2 compounds 3 compounds 4 compounds 5 compounds 6 compounds 7 compounds 8 compounds 9 compounds 10 compounds 11 compounds 12 compounds 13 compounds 14 compounds 15 compounds 16 compounds 17 compounds 18 compounds 19 compounds 20 compounds 21 compounds 22 compounds 23 compounds 24 64 8 4 8 16 4 4 4 8 8 8 4 4 16 4 4 4 2 2 4 8 2 2 4 8 4 2 1 2 1 0.5 1 1 2 1 2 1 2 0.5 1 0.5 0.5 0.5 1 1 2 0.5 0.5 1 2 2 0.5 0.25 0.25 0.25 1 0.25 0.5 0.5 1 0.25 0.25 0.5 0.5 0.5 1 1 1 0.5 0.5 1 1 0.5 0.5 1 16 4 4 8 4 2 4 4 8 2 8 2 2 2 4 4 4 8 4 2 4 8 4 2 4 0.25 0.064 0.064 0.125 0.125 0.064 0.064 0.032 0.064 0.064 0.125 0.064 0.032 0.064 0.125 0.125 0.125 0.064 0.064 0.032 0.125 0.125 0.064 0.032 0.125 0.125 0.125 0.064 0.032 0.032 0.016 0.064 0.032 0.064 0.032 0.064 0.032 0.064 0.032 0.016 0.032 0.032 0.032 0.032 0.064 0.064 0.032 0.064 0.064 0.064 0.25 0.125 0.064 0.125 0.125 0.125 0.064 0.032 0.032 0.064 0.125 0.125 0.032 0.064 0.064 0.125 0.064 0.064 0.032 0.032 0.125 0.064 0.032 0.064 0.125 32 8 16 16 16 8 4 4 8 16 16 4 8 4 8 8 8 4 4 16 8 4 4 8 8 0.25 0.125 0.125 0.064 0.064 0.125 0.25 0.125 0.125 0.064 0.125 0.125 0.064 0.25 0.125 0.032 0.064 0.125 0.125 0.064 0.032 0.125 0.064 0.064 0.032 2 0.5 1 1 0.25 0.5 0.5 0.5 1 1 0.25 0.25 0.5 1 0.25 0.5 0.25 0.5 0.25 0.5 0.5 0.5 0.25 0.25 0.25
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.
Embodiment 1 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(1-methyl pyrrole Cough up-the 1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-system of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt Be equipped with (compound 1)
1, the preparation of 4-methyl-2-formyl sulfo--1,3-thiazoles
In the dry reaction bottle, add acetic anhydride 50ml and formic acid 30ml, stirring is cooled to below 0 ℃, adds 4-methyl-2-sulfydryl-1, and 4-thiazole 13.1g (0.1mol) slowly is warming up to 60 ℃, stirs 1h.Reaction finishes to steam and desolventizes, and adds 100ml water in the residuum, transfers to pH with saturated sodium bicarbonate solution and is about 7, uses ethyl acetate extraction 3 times.Merge organic layer, anhydrous magnesium sulfate drying.Filter, filtrate vacuum-evaporation gets 4-methyl-2-formyl sulfo--1,3-thiazoles 13.7g, yield: 86.3% to doing.
2, the preparation of 4-brooethyl-2-sulfydryl-1,3-thiazoles
In the dry reaction bottle, add 4-brooethyl-2-formyl sulfo--1,3-thiazoles 12.7g (0.08mol), N-bromo-succinimide 17.8g (0.1mol), benzoyl peroxide 4.0g, tetracol phenixin 200ml, heated and stirred backflow 2h.Reaction is finished, and is cooled to room temperature, filters, and filtrate decompression reclaims solvent.Add concentrated hydrochloric acid in the residuum, freezing crystallization behind 40 ℃ of stirring 0.5h gets crude product.Ether-sherwood oil recrystallization gets 4-brooethyl-2-sulfydryl-1,3-thiazoles 10.5g, yield: 62.5%.
3, the preparation of 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1,3-thiazoles bromide
In the exsiccant reaction flask, add 4-brooethyl-2-sulfydryl-1,3-thiazoles 10.5g (0.05mol), dimethyl formamide 100ml, the back that stirs adds 1-methylpyrrole 5.1g (0.06mol), is warming up to 50 ℃ of stirring reaction 24h.Then with in the reaction solution impouring 100ml water, with ethyl acetate 50ml * 3 extractions.Merge organic phase, successively with deionized water and saturated sodium chloride solution washing.Tell organic layer, be evaporated to dried, 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1,3-thiazoles bromide 10.3g, yield: 70.1%.
4, (6R, 7R)-7-phenylacetyl amido-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to the preparation of methoxybenzyl ester bromide
In the dry reaction bottle, 14.6g (30mmol) 7-phenylacetyl amido-3-chloromethyl cephalosporanic is dissolved in the 200ml dry acetone methoxybenzyl ester, cryosel is bathed and is added NaI15g (100mmol) down, add 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1 then, 3-thiazole bromide 8.9g (30mmol) bathes stirring reaction 4h down in cryosel.Add ethyl acetate 200ml and water 200ml and fully stir, water layer extracts with ethyl acetate (100ml * 2), merges organic layer, washing, and saturated NaCl solution is washed anhydrous sodium sulfate drying.Filter, concentrate and remove organic solvent.(6R, 7R)-7-phenylacetyl amido-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester bromide 13.5g, yield: 60.5%.
5, (6R, 7R)-7-amino-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to the preparation of methoxybenzyl ester bromide
With (6R, 7R)-7-phenylacetyl amido-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid adds the 100ml methylene dichloride to methoxybenzyl ester bromide 13.5g (18mmol), cryosel is bathed and is cooled to about-15 ℃, add phosphorus pentachloride 7g and pyridine 2.5ml, insulated and stirred 15min, stirring at room 15min.Bathe down slowly adding methyl alcohol 50ml in cryosel,, add entry 30ml and stir 15min, decompression and solvent recovery at stirring at room 15min.Residuum is dissolved in the 20ml deionized water, and cryosel is used 5%NaHCO under bathing 3Solution is transferred pH to 5.With dichloromethane extraction 50ml * 3 time, merge organic phase, washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, drying, get (6R, 7R)-and 7-amino-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester bromide 6.3g, yield: 55.6%.
6, (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to the preparation of methoxybenzyl ester bromide
Step (6R in reaction flask, adding, 7R)-7-amino-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester bromide 6.3g (10mmol) and α-(thiazolamine-4-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester 3.8g (11mmol), add 30ml methylene dichloride and 3 DMA then, drip triethylamine and transfer about pH to 6～7 stirring reaction 2h.Add distilled water 30ml after reaction finishes and stir 5min, standing demix.Organic phase merges water with 50ml water washing 2 times, and with 30ml washed with dichloromethane water 2 times.Cooling is regulated water pH to 4～5, crystallization with dilute hydrochloric acid down.Filter, filter cake is with a small amount of Virahol and washing with acetone 2 times, get (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester bromide 6.9g, yield about 84.8%.
7, (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-preparation of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
In the 500ml there-necked flask, add the 100ml acetonitrile, reduce temperature to zero degrees celsius, under constantly stirring, add (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester bromide 6.9g (8.5mmol).Stir the slow down 30ml of adding anhydrous formic acid, stir 2h down at 0 ℃.In 5min, splash into the dense HCl of 15ml then, continue 0 ℃ of following stirring reaction 3h.Filter filter cake second eyeball washed twice.Filter cake is dissolved in the deionized water, uses 5%NaHCO under the cooling and stirring 3Regulate pH to 7, separate out solid.(6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 2.8g, yield: 53.4%.
Molecular formula: C 23H 27N 7O 5S 4
Molecular weight: 609.76
Results of elemental analyses:
Measured value: C, 45.12%; H, 3.53%; N, 15.98%; S, 20.93%
Theoretical value: C, 45.30%; H, 4.46%; N, 16.08%; S, 21.03%
Embodiment 2 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(6, the 7-dihydro -5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] suffering-2- The preparation (compound 2) of alkene-2-formic acid inner salt
Reference implementation 1 operation, quaternary ammonium salt is 4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl-2-sulfydryl-1,3-thiazoles bromide.Get target compound 2.6g.
Molecular formula: C 26H 25N 7O 5S 4
Molecular weight: 643.78
Results of elemental analyses:
Measured value: C, 48.45%; H, 3.97%; N, 15.20%; S, 19.85%
Theoretical value: C, 48.51%; H, 3.91%; N, 15.23%; S, 19.92%
Embodiment 3 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] ethanamide Base]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt Preparation (compound 3)
Reference implementation 1 operation, used quaternary ammonium salt is 4-(imidazo [1, a 2-b] pyridazine) methyl-2-sulfydryl-1,3-thiazoles bromide.Get target compound 2.3g.
Molecular formula: C 24H 21N 9O 5S 4
Molecular weight: 643.74
Results of elemental analyses:
Measured value: C, 44.59%; H, 3.45%; N, 19.36%; S, 19.86%
Theoretical value: C, 44.78%; H, 3.29%; N, 19.58%; S, 19.92%
Embodiment 4 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(1-first Base pyrroles-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 4)
Reference implementation 1 operation, used quaternary ammonium salt is 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 2.4g.
Molecular formula: C 22H 26N 8O 5S 4
Molecular weight: 610.75
Results of elemental analyses:
Measured value: C, 43.19%; H, 4.38%; N, 18.26%; S, 20.97%
Theoretical value: C, 43.26%; H, 4.29%; N, 18.35%; S, 21.00%
Embodiment 5 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(6,7- Dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] The preparation (compound 5) of oct-2-ene-2-formic acid inner salt
Reference implementation 1 operation, used quaternary ammonium salt is 4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl-2-sulfydryl-1,3-thiazole bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 1.9g.
Molecular formula: C 25H 24N 8O 5S 4
Molecular weight: 644.77
Results of elemental analyses:
Measured value: C, 44.52%; H, 3.84%; N, 17.32%; S, 19.70%
Theoretical value: C, 44.57%; H, 3.75%; N, 17.38%; S, 19.89%
Embodiment 6 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(imidazoles And [1,2-b] pyridazine) methyl isophthalic acid, 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid in The preparation of salt (compound 6)
Reference implementation 1 operation, used quaternary ammonium salt is 4-(imidazo [1, a 2-b] pyridazine) methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 2.2g.
Molecular formula: C 23H 20N 10O 5S 4
Molecular weight: 644.73
Results of elemental analyses:
Measured value: C, 42.73%; H, 3.24%; N, 21.65%; S, 19.82%
Theoretical value: C, 42.85%; H, 3.13%; N, 21.72%; S, 19.89%
Embodiment 7 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) Methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 7)
Reference implementation 1 operation, used quaternary ammonium salt is 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 2.0g.
Molecular formula: C 22H 25N 7O 5S 4
Molecular weight: 595.74
Results of elemental analyses:
Measured value: C, 44.25%; H, 4.16%; N, 16.29%; S, 21.47%
Theoretical value: C, 44.35%; H, 4.23%; N, 16.46%; S, 21.53%
Embodiment 8 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[4-(6,7-dihydro-5H-ring Amyl group is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-first The preparation (compound 8) of acid inner salt
Reference implementation 1 operation, used quaternary ammonium salt is 4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.9g.
Molecular formula: C 25H 23N 7O 5S 4
Molecular weight: 629.75
Results of elemental analyses:
Measured value: C, 47.58%; H, 3.78%; N, 15.46%; S, 20.29%
Theoretical value: C, 47.68%; H, 3.68%; N, 15.57%; S, 20.37%
Embodiment 9 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[4-(rattle away by imidazo [1,2-b] Piperazine) methyl isophthalic acid, 3-thiazol-2-yl] thiomethyl]-preparation of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (changes Compound 9)
Reference implementation 1 operation, used quaternary ammonium salt is 4-(imidazo [1, a 2-b] pyridazine) methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 2.6g.
Molecular formula: C 23H 19N 9O 5S 4
Molecular weight: 629.71
Results of elemental analyses:
Measured value: C, 43.79%; H, 3.09%; N, 19.98%; S, 20.32%
Theoretical value: C, 43.87%; H, 3.04%; N, 20.02%; S, 20.37%
Embodiment 10 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(1-methylpyrrole -1-yl) methyl isophthalic acid 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 10)
Reference implementation 1 operation, used quaternary ammonium salt is 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 2.2g.
Molecular formula: C 21H 24N 8O 5S 4
Molecular weight: 596.73
Results of elemental analyses:
Measured value: C, 42.19%; H, 4.20%; N, 18.67%; S, 21.42%
Theoretical value: C, 42.27%; H, 4.05%; N, 18.78%; S, 21.49%
Embodiment 11 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(6, the 7-dihydro -5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] suffering-2- The preparation (compound 11) of alkene-2-formic acid inner salt
Reference implementation 1 operation, used quaternary ammonium salt is 4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl-2-sulfydryl-1,3-thiazole bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 2.1g.
Molecular formula: C 24H 22N 8O 5S 4
Molecular weight: 630.74
Results of elemental analyses:
Measured value: C, 45.55%; H, 3.67%; N, 17.70%; S, 20.26%
Theoretical value: C, 45.70%; H, 3.52%; N, 17.77%; S, 20.33%
Embodiment 12 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-the hot 2-alkene of 8-oxo-5-thia-1-azabicyclic [4.2.0]-2-formic acid inner salt Preparation (compound 12)
Reference implementation 1 operation, used quaternary ammonium salt is 4-(imidazo [1, a 2-b] pyridazine) methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.7g.
Molecular formula: C 22H 18N 10O 5S 4
Molecular weight: 630.7
Results of elemental analyses:
Measured value: C, 44.82%; H, 3.02%; N, 22.15%; S, 20.23%
Theoretical value: C, 41.90%; H, 2.88%; N, 22.21%; S, 20.34%
Embodiment 13 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(2-(5-ammonia Base-1H-pyrazol-1-yl) methyl isophthalic acid ethanol), the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2- The preparation of formic acid inner salt (compound 13)
1, the preparation of 5-formamido group-1-(2-methanoyl ethyl) pyrazoles
In the dry reaction bottle, add acetic anhydride 40ml and formic acid 20ml, at room temperature stir 10min.Be cooled to below 0 ℃, add 5-amino-1-(2-hydroxyethyl) pyrazoles 12.8g (0.1mol), be warming up to 40 ℃, stir 1h.In reaction solution, add 100ml water after reaction finishes, transfer to pH with saturated sodium bicarbonate solution and be about 6, use ethyl acetate extraction 3 times.Merge organic layer, anhydrous magnesium sulfate drying.Filter, filtrate vacuum-evaporation gets 5-formamido group-1-(2-methanoyl ethyl) pyrazoles 10.6g, yield: 57.9% to doing.
2,4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] preparation of methyl-2-sulfydryl-1,3-thiazoles bromide
Add 4-brooethyl-2-sulfydryl-1,3-thiazoles 10.5g (0.05mol) in the exsiccant reaction flask, the preparation method is referring to embodiment 1), dimethyl formamide 100ml.Add 5-formamido group-1-(2-methanoyl ethyl) pyrazoles 10.1g (0.055mol) after stirring 10min, be warming up to 40 ℃ of stirring reaction 24h.With in the reaction solution impouring 200ml water, use ethyl acetate extraction then.Merge organic subtract each other to press be concentrated into driedly, in residuum, add concentrated hydrochloric acid, 50 ℃ are stirred 0.5h, with ethyl acetate 50ml * 3 extractions.Merge organic phase, successively with deionized water and saturated sodium chloride solution washing.Tell organic layer, be evaporated to dried 4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] methyl-2-sulfydryl-1,3-thiazoles bromide 10.9g, yield: 58.9%.
3, (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-preparation of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
With reference to 4 of embodiment 1,5,6,7 operations, feed intake 7-phenylacetyl amido-3-chloromethyl cephalosporanic to methoxybenzyl ester 14.6g (30mmol), 4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] methyl-2-sulfydryl-1,3-thiazole bromide 10.1g (30mmol), get target compound (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(2-(5-amino-1H-pyrazol-1-yl) ethanol)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 1.8g.
Molecular formula: C 23H 25N 9O 6S 4
Molecular weight: 651.76
Results of elemental analyses:
Measured value: C, 42.21%; H, 3.98%; N, 19.18%; S, 19.52%
Theoretical value: C, 42.38%; H, 3.87%; N, 19.34%; S, 19.68%
Embodiment 14 (6R 7R)-7-[2-[5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(2-(5- Amino-1H-pyrazol-1-yl) methyl isophthalic acid ethanol), the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene The preparation of-2-formic acid inner salt (compound 14)
Reference implementation 13 operations, used quaternary ammonium salt is 4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 1.6g.
Molecular formula: C 22H 24N 10O 6S 4
Molecular weight: 652.75
Results of elemental analyses:
Measured value: C, 44.37%; H, 3.92%; N, 21.39%; S, 19.59%
Theoretical value: C, 44.48%; H, 3.71%; N, 21.46%; S, 19.65%
Embodiment 15 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[4-(2-(5-amino-1H- Pyrazol-1-yl) methyl isophthalic acid ethanol), 3-thiazol-2-yl] thiomethyl]-the hot 2-alkene of 8-oxo-5-thia-1-azabicyclic [4.2.0]-2-formic acid in The preparation of salt (compound 15)
Reference implementation 13 operations, used quaternary ammonium salt is 4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.5g.
Molecular formula: C 22H 23N 9O 6S 4
Molecular weight: 637.73
Results of elemental analyses:
Measured value: C, 44.35%; H, 3.73%; N, 19.62%; S, 19.99%
Theoretical value: C, 41.43%; H, 3.64%; N, 19.77%; S, 20.11%
Embodiment 16 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(2-(5-amino -1H-pyrazol-1-yl) methyl isophthalic acid ethanol), the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-first The preparation (compound 16) of acid inner salt
Reference implementation 13 operations, used quaternary ammonium salt is 4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] methyl-2-sulfydryl-1,3-thiazoles bromide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.6g.
Molecular formula: C 21H 22N 10O 6S 4
Molecular weight: 638.72
Results of elemental analyses:
Measured value: C, 39.36%; H, 3.62%; N, 21.87%; S, 19.98%
Theoretical value: C, 39.49%; H, 3.47%; N, 21.93%; S, 20.08%
Embodiment 17 (6R, 7R)-7-[2-(2-amino-1,3-thiazoles-4-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene The preparation of-2-formic acid inner salt (compound 17)
Reference implementation 1 operation, quaternary ammonium salt is 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1,3-thiazoles bromide, α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and 2-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt crude product.Crude product is dropped in the 100ml exsiccant reaction flask, add the acetonitrile of 50ml, be cooled to 0 ℃, the anhydrous formic acid of 7ml 0 ℃ of stirring reaction 2 hours, drips 98% the vitriol oil of 2ml then, react 3 hours, and filtration, filter cake washs with acetonitrile.Filter cake is dissolved in the small amount of deionized water, and the sodium hydrogen carbonate solution with 5% is slowly regulated about pH7.0 down in ice bath, adds the acetone of 10 times of amounts then, and stirring and crystallizing gets target compound 2.9g.
Molecular formula: C 26H 25N 7O 5S 4
Molecular weight: 643.78
Results of elemental analyses:
Measured value: C, 45.52%; H, 4.83%; N, 14.22%; S, 18.54%
Theoretical value: C, 45.80%; H, 4.58%; N, 14.38%; S, 18.81%
Embodiment 18 (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene The preparation of-2-formic acid inner salt (compound 18)
Reference implementation 17 operations, 4-(1-methylpyrrole-1-yl) methyl-2-sulfydryl-1,3-thiazoles bromide, α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get target compound 2.7g.
Molecular formula: C 26H 25N 7O 5S 4
Molecular weight: 643.78
Results of elemental analyses:
Measured value: C, 43.72%; H, 4.69%; N, 16.22%; S, 18.54%
Theoretical value: C, 43.97%; H, 4.43%; N, 16.41%; S, 18.78%
Embodiment 19 (6R, 7R)-7-[2-(2-amino-1,3-thiazoles-4-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azepine The preparation (compound 19) of two ring [4.2.0] oct-2-ene-2-formic acid inner salts
Reference implementation 17 operations, quaternary ammonium salt is 4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl-2-sulfydryl-1,3-thiazoles bromide, α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get target compound 2.5g.
Molecular formula: C 26H 25N 7O 5S 4
Molecular weight: 643.78
Results of elemental analyses:
Measured value: C, 48.48%; H, 4.34%; N, 13.53%; S, 17.75%
Theoretical value: C, 48.66%; H, 4.08%; N, 13.70%; S, 17.92%
Embodiment 20 (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azepine The preparation (compound 20) of two ring [4.2.0] oct-2-ene-2-formic acid inner salts
Reference implementation 17 operations, quaternary ammonium salt is 4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl-2-sulfydryl-1,3-thiazole bromide, α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get target compound 2.4g.
Molecular formula: C 26H 25N 7O 5S 4
Molecular weight: 643.78
Results of elemental analyses:
Measured value: C, 46.77%; H, 4.18%; N, 15.42%; S, 17.65%
Theoretical value: C, 46.91%; H, 3.94%; N, 15.63%; S, 17.89%
Embodiment 21 (6R, 7R)-7-[2-(2-amino-1,3-thiazoles-4-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] suffering-2- The preparation (compound 21) of alkene-2-formic acid inner salt
Reference implementation 17 operations, quaternary ammonium salt is 4-(imidazo [1, a 2-b] pyridazine) methyl-2-sulfydryl-1,3-thiazoles bromide, α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get target compound 2.2g.
Molecular formula: C 26H 25N 7O 5S 4
Molecular weight: 643.78
Results of elemental analyses:
Measured value: C, 45.14%; H, 3.79%; N, 17.45%; S, 17.72%
Theoretical value: C, 45.30%; H, 3.52%; N, 17.61%; S, 17.92%
Embodiment 22 (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] suffering-2- The preparation (compound 22) of alkene-2-formic acid inner salt
Reference implementation 17 operations, quaternary ammonium salt is 4-(imidazo [1, a 2-b] pyridazine) methyl-2-sulfydryl-1,3-thiazoles bromide, α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get target compound 2.1g.
Molecular formula: C 26H 25N 7O 5S 4
Molecular weight: 643.78
Results of elemental analyses:
Measured value: C, 43.32%; H, 3.55%; N, 19.29%; S, 17.61%
Theoretical value: C, 43.57%; H, 3.37%; N, 19.54%; S, 17.89%
Embodiment 23 (6R, 7R)-7-[2-(2-amino-1,3-thiazoles-4-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic The preparation (compound 23) of [4.2.0] oct-2-ene-2-formic acid inner salt
Reference implementation 17 operations, used quaternary ammonium salt is 4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] methyl-2-sulfydryl-1,3-thiazole bromide, α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get target compound 2.0g.
Molecular formula: C 22H 23N 9O 6S 4
Molecular weight: 637.73
Results of elemental analyses:
Measured value: C, 42.98%; H, 4.25%; N, 17.19%; S, 17.43%
Theoretical value: C, 43.14%; H, 4.04%; N, 17.42%; S, 17.72%
Embodiment 24 (6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido -3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic The preparation (compound 24) of [4.2.0] oct-2-ene-2-formic acid inner salt
Reference implementation 17 operations, used quaternary ammonium salt is 4-[5-amino-1-(2-hydroxyethyl) pyrazoles-2-yl] methyl-2-sulfydryl-1,3-thiazoles bromide, α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetate sulfydryl benzene isothiazole ester.Get target compound 1.9g.
Molecular formula: C 22H 23N 9O 6S 4
Molecular weight: 637.73
Results of elemental analyses:
Measured value: C, 41.21%; H, 4.05%; N, 19.42%; S, 17.51%
Theoretical value: C, 41.43%; H, 3.89%; N, 19.32%; S, 17.70%
The preparation of embodiment 25 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 125g (in compound) of compound 1-24 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 250g (in compound) of compound 1-24 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 500g (in compound) of compound 1-24 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 1000g (in compound) of compound 1-24 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 26 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) of compound 1-24 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) of compound 1-24 or derivatives thereof
Pregelatinized Starch 30g
Low-substituted hydroxypropyl cellulose 20g
Microcrystalline Cellulose 20g
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) with compound 1-24 or derivatives thereof any one, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, it is an amount of to add the 2%HPMC aqueous solution, 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.

Claims (9)

1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Figure FSB00000112606100011
Wherein: R 1, R 2Independently represent hydrogen atom respectively;
R 3Represent hydrogen atom, replaced or unsubstituted C by halogen atom, carboxyl, amino or hydroxyl 1-6Alkyl is by C 1-4Alkyl replaces or unsubstituted 3～6 yuan of cycloalkyl;
R 4Represent hydrogen atom;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Described substituting group is selected from carboxyl, amino, hydroxyl, C 1-6Alkyl or the C that is replaced by hydroxyl 1-6Alkyl; X represents CH or N.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein: R 1, R 2Independently represent hydrogen atom respectively;
R 3Represent hydrogen atom, methyl, ethyl, carboxymethyl, propyloic, isobutyl acidic group, aminomethyl, aminoethyl, methylol, hydroxyethyl, cyclopropyl, cyclobutyl or cyclopentyl;
R 4Represent hydrogen atom;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Figure FSB00000112606100013
Described substituting group is selected from carboxyl, amino, hydroxyl, C 1-4Alkyl or the C that is replaced by hydroxyl 1-4Alkyl;
X represents CH or N.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein: R 1, R 2Independently represent hydrogen atom respectively;
R 3Represent hydrogen atom, methyl, ethyl or isobutyl acidic group;
R 4Represent hydrogen atom;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Figure FSB00000112606100021
Described substituting group is selected from carboxyl, amino, hydroxyl, methyl, ethyl or hydroxyethyl;
X represents CH or N.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
R 1, R 2Independently represent hydrogen atom respectively;
R 3Represent hydrogen atom, methyl, ethyl or isobutyl acidic group;
R 4Represent hydrogen atom;
R 5Be selected from the group shown in the following structural that replaced by one or more substituting groups or unsubstituted:
Figure FSB00000112606100022
Described substituting group is selected from amino, methyl, ethyl or hydroxyethyl;
X represents CH or N.
5. compound as claimed in claim 4 is:
(6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt;
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt,
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[4-(6,7 dihydros-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt,
(6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and the 2-oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(2-amino-1,3-thiazole-4-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(1-methylpyrrole-1-yl) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(2-amino-1,3-thiazole-4-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(2-amino-1,3-thiazoles-4-yl)-2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(imidazo [1,2-b] pyridazine) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(2-amino-1,3-thiazole-4-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
(6R, 7R)-7-[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-[(isopropyl oxygen imino)-the 2-carboxylic acid] acetyl] amido-3-[[4-(2-(5-amino-1H-pyrazol-1-yl) ethanol) methyl isophthalic acid, the 3-thiazol-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, and pharmacy acceptable salt.
6. as the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt comprises acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt.
7. as the pharmaceutical composition of the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner, for clinically or pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 7 wherein contains the active ingredient of the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt 0.01g～5g.
Described compound of the arbitrary claim of claim 1～5 and pharmacy acceptable salt thereof preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application.
CN2007103009101A 2006-12-31 2007-12-07 Cephalosporin compound Active CN101210020B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN85106532A (en) * 1984-10-29 1986-10-01 住友制药株式会社 The preparation of Cephem Derivative
CN1043717A (en) * 1988-12-29 1990-07-11 田边制药株式会社 Cephalosporin compound
EP0556768A2 (en) * 1992-02-20 1993-08-25 Biochemie Gesellschaft M.B.H. New process for the production of ceftriaxone
US6599893B2 (en) * 2000-08-29 2003-07-29 Essential Therapeutics, Inc. Cephalosporin antibiotics and prodrugs thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN85106532A (en) * 1984-10-29 1986-10-01 住友制药株式会社 The preparation of Cephem Derivative
CN1043717A (en) * 1988-12-29 1990-07-11 田边制药株式会社 Cephalosporin compound
EP0556768A2 (en) * 1992-02-20 1993-08-25 Biochemie Gesellschaft M.B.H. New process for the production of ceftriaxone
US6599893B2 (en) * 2000-08-29 2003-07-29 Essential Therapeutics, Inc. Cephalosporin antibiotics and prodrugs thereof

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