CN101230069A - Novel cephalosporin derivant - Google Patents

Novel cephalosporin derivant Download PDF

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CN101230069A
CN101230069A CNA200710196897XA CN200710196897A CN101230069A CN 101230069 A CN101230069 A CN 101230069A CN A200710196897X A CNA200710196897X A CN A200710196897XA CN 200710196897 A CN200710196897 A CN 200710196897A CN 101230069 A CN101230069 A CN 101230069A
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amino
ester
thiazine
salt
oxo
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CN101230069B (en
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黄振华
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Jilin Zhenao Pharmaceutical 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 derivative shown in general formula (I), the pharmaceutically acceptable salt, the easily hydrolysable ester, the isomer, the hydrate and the hydrate of the salt or ester thereof, wherein, R1, R2, R3, R4, and X are defined as in the instruction; the preparation method of the compound, the medicine composition containing the compound and the use of the compound in preparing medicines for treating and/or preventing infectious diseases belong to the medicament technical field.

Description

New cephalosporins derivatives
1, technical field
The present invention relates to the hydrate of ester, its isomer, its hydrate and the salt or the ester of new cephalosporins derivatives, pharmacy acceptable salt, 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
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.
Wincef be the 4th generation cynnematin, has a broad antifungal spectrum, anti-microbial effect is strong, and Gram-negative bacteria is had good antibacterial activity, especially Pseudomonas aeruginosa is had good antibacterial activity, structural formula adds down:
Figure S200710196897XD00011
But because the continuous appearance of resistant organism, be used for clinical microbiotic now and can not satisfy patient demand, so be badly in need of the new antibacterials of exploitation.
3, summary of the invention
In order to overcome clinically resistance widely, infectious diseases is better treated, the invention provides new cephalosporins derivatives, it has wide spectrum, efficient, characteristics that resistance is little.
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its isomer, its hydrate and the salt or the ester of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Wherein: R 1, R 2Independently represent hydrogen atom or amino protecting group respectively;
R 3Represent hydrogen atom, be not substituted or by halogen atom, hydroxyl, carboxyl, the amino C that replaces 1-6Alkyl, C 3-7Cycloalkyl is not substituted or by halogen atom, hydroxyl, carboxyl or the amino phenyl that replaces;
R 4Representative is not substituted or by R 5The following groups that replaces:
Figure S200710196897XD00021
Described R 5The C that representative is not substituted or is replaced by carboxyl, hydroxyl, halogen atom, amino or nitro 1-6Alkyl, C 3-7Cycloalkyl or phenyl;
X represents CH or N.
Preferred compound is:
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, be not substituted or by halogen atom, hydroxyl, carboxyl or the amino C that replaces 1-6Alkyl;
R 4Representative is not substituted or by a R 5The following groups that replaces,
Figure S200710196897XD00022
Described R 5Representative is not substituted or by carboxyl, hydroxyl or the amino C that replaces 1-6Alkyl;
X represents CH or N.
Further preferred compound is:
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 or C 1-4Alkyl;
R 4Representative is not substituted or by R 5The following groups that replaces
Figure S200710196897XD00031
Described R 5The C that representative is not substituted or is replaced by hydroxyl 1-4Alkyl;
X represents CH or N.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" 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.
" C of the present invention 3-7Cycloalkyl " comprise cyclopropyl, cyclobutyl, cyclopentyl, ring ethyl 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.
Further be preferably:
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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 1, structural formula:
Chemical name: (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.Hereinafter to be referred as compound 2, structural formula:
Figure S200710196897XD00042
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-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 S200710196897XD00051
Chemical name: (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-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:
Figure S200710196897XD00052
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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:
Chemical name: (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-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.Hereinafter to be referred as compound 6, structural formula:
Figure S200710196897XD00054
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-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 7, structural formula:
Figure S200710196897XD00061
(6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-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:
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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:
(6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and the 2-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.Hereinafter to be referred as compound 10, structural formula:
Figure S200710196897XD00064
(6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and the 2-oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-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 S200710196897XD00071
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-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 12, structural formula:
Figure S200710196897XD00072
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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 S200710196897XD00073
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-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.Hereinafter to be referred as compound 14, structural formula:
Figure S200710196897XD00081
6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-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 S200710196897XD00082
(6R, 7R)-and 7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-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 S200710196897XD00083
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, 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, along anti-geometrical isomer, 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 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 S200710196897XD00101
Experimental procedure:
Step 1: the preparation of intermediate 1
In the exsiccant reaction flask, add raw material 1, dimethyl formamide, sodium iodide.Stir the back and add raw material 2, heat up 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 driedly, promptly get intermediate 1
Step 2: the preparation of intermediate 3
In the dry reaction bottle raw material 2 is dissolved in the dry acetone, cryosel is bathed down and is added NaI, adds intermediate 1 then, bathes stirring reaction down in cryosel.Add ethyl acetate and water, fully stir, the water layer ethyl acetate extraction merges organic layer, washing, and saturated NaCl solution is washed anhydrous sodium sulfate drying.Filter, concentrate and remove organic solvent.Residuum dehydrated alcohol recrystallization promptly gets intermediate 2.
The preparation of step 3 intermediate 3
Intermediate 2 is added methylene dichloride, and 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 bathed downward modulation pH.Use dichloromethane extraction, merge organic phase, washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, and after ether solidified, drying promptly got intermediate 3.
The preparation of step 4 intermediate 4
Step intermediate 3 and raw material 4 add methylene dichloride and DMA then on adding in three-necked bottle, drip the triethylamine adjust pH, and stirring reaction adds distilled water after reaction finishes and stirs standing demix.Organic phase washes with water, merges water, and uses the washed with dichloromethane water, and cooling is regulated aqueous pH values with dilute hydrochloric acid, crystallization down.Filter, filter cake gets intermediate 4 with a small amount of Virahol and washing with acetone.
The preparation of step 5 The compounds of this invention
Add acetonitrile in the 500ml there-necked flask, reduce temperature, step gained intermediate 4 in the adding under constantly stirring stirs down slowly adding anhydrous formic acid, stirring down, is splashing into then, continues stirring reaction, filters filter cake second eyeball washed twice.Filter cake is dissolved in the deionized water, uses 5%NaHCO under the cooling and stirring 3Regulate pH, separate out solid.Get The compounds of this invention.
R in the above reaction equation 1, R 3, R 4, R 5, X representative group as mentioned before, R 4*Represent following group:
Figure S200710196897XD00111
The present invention includes the pharmaceutical composition of ester, hydrate, solvate or its isomer and other active pharmaceutical ingredients of arbitrary compound recited above, pharmacy acceptable salt, its facile hydrolysis, as Sulbactam and sodium salt or Unasyn Oral, Tazobactam Sodium and sodium salt thereof, clavulanic acid and sylvite thereof.
The present invention is claimed ester, hydrate, solvate or its isomer of arbitrary compound recited above, pharmacy acceptable salt, facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner of comprising further; 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.Modes such as aforementioned pharmaceutical compositions can be oral, administered parenterally are applied to the patient who needs treatment, preferred oral preparation or injection.
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 ester of the also further claimed new cephalosporins derivatives of the present invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate with and the hydrate of salt or ester preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes; cephalosporin derivative of the present invention all has good antibacterial activity to gram-negative bacteria, positive bacteria; 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.
The new cephalosporins derivatives of the present invention is compared with immediate prior art, has the following advantages:
(1) provides new cephalosporins derivatives first, had better antibacterial activity, lower resistance;
(2) further The compounds of this invention is carried out pharmacodynamic experiment, the result shows that it has wide spectrum, anti-microbial effect efficiently; Resistance is little;
(3) preparation technology of above-claimed cpd of the present invention is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below by experiment example further set forth the present invention new the beneficial effect of cephalosporins derivatives.New cephalosporins derivatives of the present invention has following beneficial effect, but this should be interpreted as that new cephalosporins derivatives 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, staphylococcus epidermidis 15 strains, streptococcus pneumoniae 13 strains, Pseudomonas aeruginosa 10 strains,
Gram-negative bacteria: intestinal bacteria 15 strains, Proteus mirabilis 15 strains, serratia marcesens 15 strains, Klebsiella Pneumoniae 15 strains, enterobacter cloacae 10 strains, morganella morganii 10 strains, hemophilus influenzae 15 strains;
Trial-product:
Compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16: self-control; Wincef: commercial.
Experimental technique:
Agar dilution.
Experimental result and conclusion:
The antibacterial activity in vitro of table 1 The compounds of this invention
The bacterium pearl MIC 90(μg/ml)
Wincef Compound 1 Compound 2 Compound 3 Compound 4 Compound 5
MSSA MRSA staphylococcus epidermidis streptococcus pneumoniae intestinal bacteria Pseudomonas aeruginosa serratia marcesens Klebsiella pneumonia enterobacter cloacae Proteus mirabilis morganella morganii hemophilus influenzae 16 128 8 2 8 4 2 2 64 0.125 2 0.25 1 16 2 0.25 1 1 0.25 0.5 8 0.032 0.25 0.125 1 16 1 0.5 0.5 0.5 0.25 0.25 2 0.063 0.25 0.125 2 4 1 0.5 1 1 0.25 0.5 4 0.063 0.25 0.5 2 16 1 0.5 1 1 0.25 0.5 4 0.063 0.25 0.5 1 8 2 1 1 2 0.5 0.5 4 0.016 0.5 0.125
The antibacterial activity in vitro of table 1 (continuing) The compounds of this invention
The bacterium pearl MIC 90(μg/ml)
Compound 6 Compound 7 Compound 8 Compound 9 Compound 10 Compound 11
MSSA MRSA staphylococcus epidermidis streptococcus pneumoniae intestinal bacteria Pseudomonas aeruginosa serratia marcesens Klebsiella pneumonia enterobacter cloacae Proteus mirabilis morganella morganii hemophilus influenzae 1 8 1 1 1 2 0.5 0.25 4 0.125 0.5 0.125 1 4 1 0.5 1 1 0.25 0.5 4 0.031 0.25 0.125 1 4 2 0.5 0.5 0.5 0.25 0.25 8 0.063 0.25 0.125 2 8 1 0.5 1 1 0.25 0.5 4 0.063 0.25 0.5 2 16 1 0.5 1 1 0.25 0.5 4 0.063 0.25 0.5 1 8 2 1 1 2 0.5 0.5 4 0.125 0.5 0.125
The antibacterial activity in vitro of table 1 (continuing) The compounds of this invention
The bacterium pearl MIC 90(μg/ml)
Compound 12 Compound 13 Compound 14 Compound 15 Compound 16
MSSA MRSA staphylococcus epidermidis streptococcus pneumoniae intestinal bacteria Pseudomonas aeruginosa serratia marcesens Klebsiella pneumonia enterobacter cloacae Proteus mirabilis morganella morganii hemophilus influenzae 2 16 1 0.5 1 1 0.25 0.5 4 0.063 0.25 0.5 1 8 0.5 0.5 1 1 0.25 0.5 8 0.031 0.25 0.125 1 16 1 0.5 0.5 0.5 0.25 0.25 4 0.063 0.25 0.125 2 16 1 1 1 1 0.25 0.5 4 0.063 0.25 0.25 2 8 1 0.5 1 1 0.25 0.5 4 0.063 0.25 0.5
Experimental result and conclusion: the results are shown in Table 1.
By table 1 as seen, 1～16 pair of all strains tested of The compounds of this invention all have good bacteriostatic action, show that The compounds of this invention all has better antibacterial activity to resisting gram-positive, negative bacterium, clinical separation MRSA also there is better antibacterial activity, have has a broad antifungal spectrum, advantage that anti-microbial activity is high, use the microbiotic of diving and adding for having good clinical.
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-[[5-(1-methyl pyrrole Cough up-the 1-yl)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (chemical combination Thing 1) preparation
1,5-(1-methylpyrrole-1-yl)-2H-2-sulfydryl-1, the preparation of 4-thiazine iodide
In the exsiccant reaction flask, add 5-chloro-2H-2-sulfydryl-1,4-thiazine 16.5g (0.1mol), dimethyl formamide 200ml, sodium iodide 23g.Add 1-methylpyrrole 9.4g (0.11mol) after stirring 10min, be warming up to 40 ℃ of stirring reaction 24h.Then with in the reaction solution impouring 400ml water, with ethyl acetate 100ml * 3 extractions.Merge organic phase, successively with deionized water and saturated sodium chloride solution washing.Tell organic layer, be evaporated to dried, 5-(1-methylpyrrole-1-yl)-2H-2-sulfydryl-1,4-thiazine iodide 25.7g, yield: 75.2%.
2, (6R, 7R)-7-phenylacetylamino-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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 iodide
In the dry reaction bottle with 14.6g (30mmol) 7-phenylacetyl amido-3-chloromethyl cephalosporanic to methoxybenzyl ester (GCLE: molecular weight 487) be dissolved in the 250ml dry acetone, cryosel is bathed and is added NaI15g (100mmol) down, add 5-(1-methylpyrrole-1-yl)-2H-2-sulfydryl-1 then, 4-thiazine iodide 10.3g (30mmol) bathe stirring reaction 4h down in cryosel.Add ethyl acetate 400ml and water 300ml and fully stir, water layer extracts with ethyl acetate (150ml * 2), merges organic layer, washing, and saturated NaCl solution is washed anhydrous sodium sulfate drying.Filter, concentrate and remove organic solvent.Residuum dehydrated alcohol recrystallization, get (6R, 7R)-and 7-phenylacetylamino-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester iodide 12.9g, yield: 54.4%.
3, (6R, 7R)-7-amino-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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 iodide
With (6R, 7R)-7-phenylacetylamino-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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 10.3g (13mmol), cryosel is bathed and is cooled to about-15 ℃, add phosphorus pentachloride 5.4g and pyridine 1.8ml, insulated and stirred 0.5h, stirring at room 0.5h.Bathe down slowly adding methyl alcohol 50ml in cryosel,, add entry 30ml and stirred decompression and solvent recovery 0.5 hour at stirring at room 0.5h.Residuum is dissolved in the 20ml deionized water, and cryosel is used 5%NaHCO under bathing 3Solution transfers pH to 6-7.With dichloromethane extraction 50ml * 3 time, merge organic phase, washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims solvent, after ether solidifies, dry, get (6R, 7R)-and 7-amino-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester iodide 4.5g, yield: 51.2%.
4, (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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 iodide
Step intermediate 4.4g (6.5mmol) and α-(thiazolamine-4-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester 2.45g (7.0mmol) in three-necked bottle, adding, 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-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid is to methoxybenzyl ester iodide 5.0g, yield about 90.2%.
5, (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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, under constantly stirring, add step gained intermediate 4.3g (5mmol) to zero degrees celsius.Stir the slow down 20ml of adding anhydrous formic acid, stir 2h down at 0 ℃.In 5min, splash into the dense HCl of 10ml 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 pH8, separate out solid.Get (6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 1.90g, yield: 63.1%.
Molecular formula: C 23H 27N 7O 5S 4
Molecular weight: 609.76
Results of elemental analyses:
Theoretical value: C, 45.30%; H, 4.46%; N, 16.08%; S, 21.03%
Measured value: C, 45.07%; H, 3.57%; N, 15.94%; S, 20.84%
Embodiment 2 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(2-(5-amino -1H-pyrazol-1-yl) ethanol)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2- The preparation of formic acid inner salt (compound 2)
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.
2,5-[5-formamido group-1-(2-methanoyl ethyl) pyrazoles-2-yl]-2H-2-sulfydryl-1, the preparation of 4-thiazine iodide
In the exsiccant reaction flask, add 5-chloro-2H-2-sulfydryl-1,4-thiazine 8.3g (0.05mol), dimethyl formamide 100ml, sodium iodide 12g.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.Then with in the reaction solution impouring 200ml 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, 5-[5-formamido group-1-(2-methanoyl ethyl) pyrazoles-2-yl]-2H-2-sulfydryl-1,4-thiazine iodide 15.1g, yield: 68.7%.
3, (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]-preparation of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
With reference to 2 of embodiment 1,3,4,5 operations, feed intake 7-phenylacetyl amido-3-chloromethyl cephalosporanic to methoxybenzyl ester 14.6g (30mmol), 5-[5-formamido group-1-(2-methanoyl ethyl) pyrazoles-2-yl]-2H-2-sulfydryl-1,4-thiazine iodide 13.2g (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 2.15g.
Molecular formula: C 23H 25N 9O 6S 4
Molecular weight: 651.76
Results of elemental analyses:
Theoretical value: C:C, 42.38%; H, 3.87%; N, 19.34%; S, 19.68%
Measured value: C:C, 42.21%; H, 3.98%; N, 19.18%; S, 19.52%
Embodiment 3 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(6, the 7-dihydro -5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] suffering-2- The preparation of alkene-2-formic acid inner salt (compound 3)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-2-sulfydryl-1,4-thiazine iodide.Get target compound 1.53g.
Molecular formula: C26H25N7O5S4
Molecular weight: 643.78
Results of elemental analyses:
Theoretical value: C, 48.51%; H, 3.91%; N, 15.43%; S, 19.92%
Measured value: C, 48.38%; H, 4.02%; N, 15.25%; S, 19.63%
Embodiment 4 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(imidazo [1,2-b] pyridazine)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt The preparation of (compound 4)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(imidazo [1,2-b] pyridazine)-2H-2-sulfydryl-1,4-thiazine iodide.Get target compound 1.68g.
Molecular formula: C24H21N9O5S4
Molecular weight: 643.74
Results of elemental analyses:
Theoretical value: C, 44.78%; H, 3.29%; N, 19.58%; S, 19.92%
Measured value: C, 44.63%; H, 3.51%; N, 19.27%; S, 19.78%
Embodiment 5 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(1-first Base pyrroles-1-yl)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt The preparation of (compound 5)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(1-methylpyrrole-1-yl)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 1.76g.
Molecular formula: C22H26N8O5S4
Molecular weight: 610.75
Results of elemental analyses:
Theoretical value: C, 43.26%; H, 4.29%; N, 18.35%; S, 21.00%
Measured value: C, 43.14%; H, 4.42%; N, 18.18%; S, 20.86%
Embodiment 6 (6R, 7R)-7-[2-[(5-amino-1,2,4 ,-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(2-(5- Amino-1H-pyrazol-1-yl) ethanol)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene The preparation of-2-formic acid inner salt (compound 6)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-[5-formamido group-1-(2-methanoyl ethyl) pyrazoles-2-yl]-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 1.50g.
Molecular formula: C22H24N10O6S4
Molecular weight: 652.75
Results of elemental analyses:
Theoretical value: C, 40.48%; H, 3.71%; N, 21.46%; S, 19.65%
Measured value: C, 44.32%; H, 3.85%; N, 21.34%; S, 19.52%
Embodiment 7 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(6,7- Dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] The preparation of oct-2-ene-2-formic acid inner salt (compound 7)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 1.85g.
Molecular formula: C25H24N8O5S4
Molecular weight: 644.77
Results of elemental analyses:
Theoretical value: C, 46.57%; H, 3.75%; N, 17.38%; S, 19.89%
Measured value: C, 44.41%; H, 3.93%; N, 17.20%; S, 19.75%
Embodiment 8 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(miaow Azoles is [1,2-b] pyridazine also)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid in The preparation of salt (compound 8)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(imidazo [1,2-b] pyridazine)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(methoxyimino) acetate sulfydryl benzene isothiazole ester.Get target compound 1.76g.
Molecular formula: C23H20N10O5S4
Molecular weight: 644.73
Results of elemental analyses:
Theoretical value: C, 42.85%; H, 3.13%; N, 21.72%; S, 19.89%
Measured value: C, 42.69%; H, 3.34%; N, 21.61%; S, 19.71%
Embodiment 9 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[5-(1-methylpyrrole-1- Base)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 9) Preparation
Examine and implement 1 operation, used doped quaternary ammonium salt is 5-(1-methylpyrrole-1-yl)-2H-2-sulfydryl-1,4-thiazine iodide, and active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.37g.
Molecular formula: C22H25N7O5S4
Molecular weight: 595.74
Results of elemental analyses:
Theoretical value: C, 44.35%; H, 4.23%; N, 16.46%; S, 21.53%
Measured value: C, 44.18%; H, 4.45%; N, 16.33%; S, 21.42%
Embodiment 10 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[5-(2-(5-amino-1H-pyrrole Azoles-1-yl) ethanol)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt The preparation of (compound 10)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-[5-formamido group-1-(2-methanoyl ethyl) pyrazoles-2-yl]-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.24g.
Molecular formula: C22H23N9O6S4
Molecular weight: 637.73
Results of elemental analyses:
Theoretical value: C, 41.43%; H, 3.64%; N, 19.77%; S, 20.11%
Measured value: C, 44.28%; H, 3.79%; N, 19.54%; S, 19.96%
Embodiment 11 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[5-(6,7-dihydro-5H- Cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2- The preparation of formic acid inner salt (compound 11)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.52g.
Molecular formula: C25H23N7O5S4
Molecular weight: 629.75
Results of elemental analyses:
Theoretical value: C, 47.68%; H, 3.68%; N, 15.57%; S, 20.37%
Measured value: C, 47.50%; H, 3.82%; N, 15.43%; S, 20.19%
Embodiment 12 (6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[5-(imidazo [1,2-b] Pyridazine)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 12) preparation
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(imidazo [1,2-b] pyridazine)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(thiazolamine-4-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.44g.
Molecular formula: C23H19N9O5S4
Molecular weight: 629.71
Results of elemental analyses:
Theoretical value: C, 43.87%; H, 3.04%; N, 20.02%; S, 20.37%
Measured value: C, 43.66%; H, 3.18%; N, 19.87%; S, 20.21%
Embodiment 13 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[5-(1-methyl pyrrole Cough up-the 1-yl)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (chemical combination Thing 13) preparation
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(1-methylpyrrole-1-yl)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.28g.
Molecular formula: C 21H 24N 8O 5S 4
Molecular weight: 596.73
Results of elemental analyses:
Theoretical value: C, 42.27%; H, 4.05%; N, 18.78%; S, 21.49%
Measured value: C, 42.13%; H, 4.25%; N, 18.59%; S, 21.31%
Embodiment 14 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[5-(2-(5-amino -1H-pyrazol-1-yl) ethanol)-and 2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-first The preparation of acid inner salt (compound 14)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-[5-formamido group-1-(2-methanoyl ethyl) pyrazoles-2-yl]-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.34g.
Molecular formula: C21H22N10O6S4
Molecular weight: 638.72
Theoretical value: C, 39.49%; H, 3.47%; N, 21.93%; S, 20.08%
Measured value: C, 39.24%; H, 3.57%; N, 21.84%; S, 19.95%
Embodiment 15 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[5-(6, the 7-dihydro -5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] suffering-2- The preparation of alkene-2-formic acid inner salt (compound 15)
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 1.12g.
Molecular formula: C24H22N8O5S4
Molecular weight: 630.74
Theoretical value: C, 45.70%; H, 3.52%; N, 17.77%; S, 20.33%
Measured value: C, 45.64%; H, 3.73%; N, 17.64%; S, 20.18%
Embodiment 16 (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-the 2-oximido] acetamido]-3-[[5-(imidazo [1, 2-b] pyridazine)-2H-1,4-thiazine-2-yl] thiomethyl]-(change of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt Compound 16) preparation
Reference implementation 1 operation, used doped quaternary ammonium salt is 5-(imidazo [1,2-b] pyridazine)-2H-2-sulfydryl-1,4-thiazine iodide, active ester is α-(5-amino-1,2,4-thiadiazoles-3-yl)-α-(oximido) acetate sulfydryl benzene isothiazole ester.Get target compound 0.95g.
Molecular formula: C 21H 18N 10O 5S 4
Molecular weight: 630.7
Theoretical value: C, 41.90%; H, 2.88%; N, 22.21%; S, 20.34%
Measured value: C, 44.63%; H, 3.51%; N, 19.27%; S, 19.78%
The preparation of embodiment 17 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 125g (in compound) of compound 1-16 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 250g (in compound) of compound 1-16 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 500g (in compound) of compound 1-16 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 1000g (in compound) of compound 1-16 or derivatives thereof
Prepare 1000 altogether
Prescription 5:
Any one 2000g (in compound) of compound 1-16 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) of compound 1-16 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 1-16 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 1-16 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.
The capsular preparation of embodiment 9 The compounds of this invention
1, prescription
Prescription 1:
Any one 250g (in compound) of compound 1-16 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 500g (in compound) of compound 1-16 or derivatives thereof
Pregelatinized Starch 80g
Low-substituted hydroxypropyl cellulose 50g
Microcrystalline Cellulose 50g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 8.0g
Magnesium Stearate 8.0g
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 1-16 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, 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 (10)

1. the hydrate of the ester of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and salt or ester:
Wherein: R 1, R 2Independently represent hydrogen atom or amino protecting group respectively;
R 3Represent hydrogen atom, be not substituted or by halogen atom, hydroxyl, carboxyl, the amino C that replaces 1-6Alkyl, C 3-7Cycloalkyl is not substituted or by halogen atom, hydroxyl, carboxyl or the amino phenyl that replaces;
R 4Representative is not substituted or by R 5The following groups that replaces:
Figure S200710196897XC00012
Described R 5The C that representative is not substituted or is replaced by carboxyl, hydroxyl, halogen atom, amino or nitro 1-6Alkyl, C 3-7Cycloalkyl or phenyl;
X represents CH or N.
2. the hydrate of the ester of compound as claimed in claim 1, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and salt or ester:
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, be not substituted or by halogen atom, hydroxyl, carboxyl or the amino C that replaces 1-6Alkyl;
R 4Representative is not substituted or by R 5The following groups that replaces,
Described R 5Representative is not substituted or by carboxyl, hydroxyl or the amino C that replaces 1-6Alkyl;
X represents CH or N.
3. the hydrate of the ester of compound as claimed in claim 2, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and salt or ester:
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 or C 1-4Alkyl;
R 4Representative is not substituted or by R 5The following groups that replaces
Figure S200710196897XC00021
Described R 5The C that representative is not substituted or is replaced by hydroxyl 1-4Alkyl;
X represents CH or N.
4. compound as claimed in claim 3 is selected from:
(6R, 7R)-7-[2-[(2-amino-1,3-thiazole-4-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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-[[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
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-Z-2-methoxy oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-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-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-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-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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-[[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
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-methoxy oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-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-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-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-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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-[[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
(6R, 7R)-7-[2-[(2-amino-1,3-thiazoles-4-yl)-the 2-oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-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-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-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-oximido] acetamido]-3-[[5-(1-methylpyrrole-1-yl)-2H-1,4-thiazine-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-[[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
6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[5-(6,7-dihydro-5H-cyclopentyl is [b] pyridine-1-yl also)-2H-1,4-thiazine-2-yl] thiomethyl]-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, or
(6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-[[5-(imidazo [1,2-b] pyridazine)-2H-1,4-thiazine-2-yl] thiomethyl]-hydrate of ester, its isomer, its hydrate and the salt or the ester of 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt and pharmacy acceptable salt thereof, its facile hydrolysis.
5. as the described compound of the arbitrary claim of claim 1～4, the ester of its facile hydrolysis comprises the alkyloyloxyethyl alkyl ester, the alkyl oxy carbonyl oxygen alkyl ester, the alkoxyl group methyl esters, alkyl amido methyl esters, cycloalkanes acyloxyalkyl group ester, cycloalkyloxy acyloxyalkyl group ester, (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester, 2-[(2-methyl propoxy-) carbonyl]-2-amylene ester.
6. as the described compound of the arbitrary claim of claim 1～4, 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. comprise the hydrate of ester, its isomer, its hydrate or its salt or ester of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner.
8. pharmaceutical composition as claimed in claim 7 wherein contains the active ingredient of hydrate 0.01g～5g of ester, its isomer, its hydrate or its salt or the ester of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis.
9. pharmaceutical composition as claimed in claim 7 is for clinically or pharmaceutically acceptable arbitrary formulation.
The hydrate of the ester of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and salt or ester preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application.
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Co-patentee after: Langfang high Bojing State Pharmaceutical Co. Ltd.

Patentee after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd.

Address before: 250101 Block A, 2518 Tianchen Street, Jinan High-tech Development Zone, Shandong Province

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Effective date of registration: 20210929

Address after: 134000 No. 68, Xiangjiang Road, Meihekou City, Tonghua City, Jilin Province

Patentee after: Jilin Zhen Ao Pharmaceutical Co.,Ltd.

Address before: 101113 Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing (in Beijing Sihuan Pharmaceutical Co., Ltd.)

Patentee before: Beijing Aohe Pharmaceutical Research Institute Co.,Ltd.

Patentee before: Langfang high Bojing State Pharmaceutical Co.,Ltd.

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