CN103275081A - Carbapenems antibiotics - Google Patents

Carbapenems antibiotics Download PDF

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CN103275081A
CN103275081A CN2007101137779A CN200710113777A CN103275081A CN 103275081 A CN103275081 A CN 103275081A CN 2007101137779 A CN2007101137779 A CN 2007101137779A CN 200710113777 A CN200710113777 A CN 200710113777A CN 103275081 A CN103275081 A CN 103275081A
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methyl
oxygen
ester
acid
azabicyclo
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黄振华
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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
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention belongs to the field of medicine technology, more specifically relates to carbapenems antibiotics, and pharmaceutically acceptable salt, hydrolyzed ester, isomer, hydrate, hydrate of ester or salt thereof shown in the general formula (I), wherein, R1, R2, R3 and ring A are defined in the specification; the invention also relates to the preparation method of compounds, and pharmaceutical composition containing the compounds, and purposes of the compounds in preparation of medicaments for infectious disease treatment and/or prevention.

Description

Train southern antibiotics
1, technical field
The invention belongs to medical technical field, be specifically related to train the hydrate of ester, its isomer, its hydrate and ester or the salt of southern antibiotics, its pharmacy acceptable salt, its facile hydrolysis, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are for the preparation of the purposes in the medicine that treats and/or prevents infectious diseases.
2, background technology
Training southern antibiotics is the class β-Nei Xiananleikangshengsu that the seventies grows up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stable to β-Nei Xiananmei, and receives much concern.Its constructional feature is, the sulphur that the penam parent nucleus is 1 is replaced by carbon, and 2 have two keys, the effect of the five-ring of compound penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.
This similar drug that has gone on the market at present has imipenum, panipenem, meropenem, S-4661, biapenem, ertapenem etc.Imipenum is by Merck exploitation, separately during medication, is subject to the degraded of dehydropeptidase of kidney (DHP-I) in vivo and loses anti-microbial activity, needs and the coupling of DHP-I inhibitor cilastatin; Panipenem is the training south class microbiotic of the 2nd listing, by the development of Japanese Sankyo Co., Ltd, also unstable to DHP-I, need the coupling Betamipron, to the anti-microbial activity of methicillin-sensitivity staphylococcus, streptococcus pneumoniae, streptococcus and enterococcus faecalis and imipenum is similar or slightly strong, outstanding to the acinetobacter effect, anerobes such as bacteroides fragilis, clostridium difficile all there is good action, its structural formula is as follows:
Figure B2007101137779D000011
Ertapenem sodium is the long-acting injection carbapenem by the Merck exploitation, (PBP-2 and PBP-3) has high avidity to penicillin-binding protein, the activity of anti-gram positive organism is a little less than imipenum, and the activity of anti-gram-negative bacteria is better than imipenum, and its structural formula is as follows:
Figure B2007101137779D000012
And train southern class microbiotic because the increase of clinical application, cause the continuous increase of bacterial drug resistance, and because the limitation that digestive tube absorbs, the training of listing south class clinically can only be as the injection administration at present, clinical availability is not high, can not meet clinical needs.Therefore, be badly in need of research and development and have better antibacterial activity, and have the southern class microbiotic of long-acting training of good chemical stability and DHP-I stability.
3, summary of the invention
The inventor carries out a large amount of discovering to training southern class microbiotic, compares with microbiotic in the past, and the The compounds of this invention anti-microbial activity is stronger, be used for the treatment of and/or prophylaxis against infection diseases very effective, thereby finished the present invention.
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its isomer, its hydrate and ester or the salt of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Figure B2007101137779D000021
Wherein, R 1Represent hydrogen atom or C 1-4Alkyl;
R 2Representation carboxy ,-COOR 4Or the ester of facile hydrolysis, described R 4The representation carboxy protecting group;
Ring A is selected from following groups:
Figure B2007101137779D000022
R 3Be selected from following groups:
Figure B2007101137779D000023
R wherein 5Representation carboxy or by the C of carboxyl substituted 1-4Alkyl, R 6And R 7Independently represent hydrogen atom, carboxyl respectively or by the C of carboxyl substituted 1-4Alkyl,
Above-mentioned cyclic group can further be replaced by 1～2 following substituting group, and described substituting group is selected from halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, sulfonic group, formamyl, C 1-4Alkyl, the C that is replaced by hydroxyl 1-4Alkyl, the amino C that replaces of quilt 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Carbalkoxy, C 1-4Alkylamidoalkyl, C 1-4Alkyl sulphonyl or C 1-4Alkylsulfonamido.
Preferred compound is:
Wherein, R 1Represent hydrogen atom or methyl;
R 2Representation carboxy ,-COOR 4Or the ester of facile hydrolysis,
Described R 4The representation carboxy protecting group is selected from methyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis is selected from alkyloyloxyethyl alkyl ester, alkoxyl group acyloxyalkyl group ester, cycloalkanes acyloxyalkyl group ester, cycloalkyloxy acyloxyalkyl group ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
Ring A is selected from following groups:
Figure B2007101137779D000031
R 3Be selected from following groups:
R wherein 5Representation carboxy or by the C of carboxyl substituted 1-4Alkyl, R 6And R 7Independently represent hydrogen atom, carboxyl respectively or by the C of carboxyl substituted 1-4Alkyl,
Above-mentioned cyclic group can further be replaced by 1～2 following substituting group, and described substituting group is selected from fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, sulfonic group, formamyl, hydroxymethyl, amino methyl, methoxyl group, oxyethyl group, methoxycarbonyl, acetamido, methyl sulphonyl or methylsulfonyl amido.
Further preferred compound is:
Wherein, R 1Represent methylidene;
R 2Representation carboxy ,-COOR 4Or the ester of facile hydrolysis,
Described R 4The representation carboxy protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis is selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, isopropyl oxygen methanoyl methyl esters, isopropyl oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
Ring A is selected from following groups:
Figure B2007101137779D000033
R 3Be selected from following groups:
Figure B2007101137779D000034
R wherein 5Representation carboxy, R 6And R 7Independently represent hydrogen atom or carboxyl respectively,
Above-mentioned cyclic group can further be replaced by 1～2 following substituting group, and described substituting group is selected from fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, sulfonic group, formamyl, hydroxymethyl, amino methyl, methoxyl group, oxyethyl group, methoxycarbonyl, acetamido, methyl sulphonyl or methylsulfonyl amido.
" C of the present invention 1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl etc.
Of the present invention " by the C of carboxyl substituted 1-4Alkyl " comprise carboxymethyl, propyloic, carboxylic propyl group, carboxylic butyl etc.
" the C that is replaced by hydroxyl of the present invention 1-4Alkyl " comprise methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl etc.
Of the present invention " by the amino C that replaces 1-4Alkyl " comprise aminomethyl, aminoethyl, aminopropyl, ammonia butyl etc.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention 1-4Alkoxyl group " comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy etc.
" C of the present invention 1-4Carbalkoxy " comprise methoxycarbonyl, ethoxycarbonyl, the positive third oxygen carbonyl, isopropyl oxygen carbonyl, butoxy carbonyl etc.
" C of the present invention 1-4Alkylamidoalkyl " comprise formamido-, acetamido, propionamido-, Isopropamide base, amide-based small, t-butyl carboxamide base etc.
" C of the present invention 1-4Alkyl sulphonyl " comprise methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, isopropyl alkylsulfonyl, fourth alkylsulfonyl, uncle's fourth alkylsulfonyl etc.
" C of the present invention 1-4Alkylsulfonamido " comprise methylsulfonyl amido, ethanesulfonamide group, third sulfoamido, isopropyl sulfoamido, fourth sulfoamido, uncle's fourth sulfoamido etc.
" carboxyl-protecting group " of the present invention refers to the conventional blocking group that is used for the 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, diphenyl methyl, 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-isoxazoline, 4-alkyl-5-oxo-1, the 3-isoxazole alkyl, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
Further preferred compound is as follows:
Chemical name: (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-azepine butane-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 1, structural formula is as follows:
Figure B2007101137779D000051
Chemical name: (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 2, structural formula is as follows:
Figure B2007101137779D000052
Chemical name: (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 3, structural formula is as follows:
Figure B2007101137779D000053
Chemical name: (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 4, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 5, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 6, structural formula is as follows:
Figure B2007101137779D000056
Chemical name: (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 7, structural formula is as follows:
Figure B2007101137779D000061
Chemical name: (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 8, structural formula is as follows:
Figure B2007101137779D000062
Chemical name: (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 9, structural formula is as follows:
Figure B2007101137779D000063
Chemical name: (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxylic acid, be called for short compound 10, structural formula is as follows:
Figure B2007101137779D000064
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 11, structural formula is as follows:
Figure B2007101137779D000065
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 12, structural formula is as follows:
Figure B2007101137779D000071
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 13, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 14, structural formula is as follows:
Figure B2007101137779D000073
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxylic acid, be called for short compound 15, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxylic acid, be called for short compound 16, structural formula is as follows:
Figure B2007101137779D000075
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 17, structural formula is as follows:
Figure B2007101137779D000076
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 18, structural formula is as follows:
Figure B2007101137779D000081
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 19, structural formula is as follows:
Figure B2007101137779D000082
Chemical name: (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxylic acid, be called for short compound 20, structural formula is as follows:
Figure B2007101137779D000083
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method, and reaction equation is as follows:
Figure B2007101137779D000084
Reactions steps:
The preparation of step 1 intermediate 1
In the reaction flask of drying, add raw material 1, methylene dichloride, triethylamine, splash into the dichloromethane solution of raw material 2 then, the stirring at room reaction, reaction finishes, and adds water, and tells organic layer, drying, concentrating under reduced pressure steams and desolventizes, and residuum adds methylene dichloride, stirring and dissolving, add hydrochloric acid soln then, heat up stirring reaction, reaction finishes, and tells organic layer, the organic layer drying, remove solvent under reduced pressure, residuum gets intermediate 1 with ethyl acetate-hexanaphthene recrystallization.
The preparation of step 2 intermediate 2
Add the acetonitrile solution cooling of raw material 3 in the dry reaction bottle, the acetonitrile solution of adding diisopropylethylamine and intermediate 1 stirs, and after reaction finishes, adds the ethyl acetate dilution, water, saturated salt washing successively, and organic layer drying, concentrated gets intermediate 2.
The preparation of step 3 The compounds of this invention
Intermediate 2 is dissolved in the methylene dichloride, add methyl-phenoxide and Nitromethane 99Min., in-50 ℃ of Nitromethane 99Min. solution that drip the 1mol/L aluminum chloride down,-40 ℃ of stirrings add water, and separate out solid, filter, filter cake is dissolved in the mixed solution of THF and water, adds 10% palladium-charcoal, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation.Water merges, and 0 ℃ slowly splashes into methyl alcohol, and-10 ℃ of stirrings are filtered, and filter cake water-Virahol recrystallization gets The compounds of this invention.
R in the above reaction equation 1, R 3, ring A representative group as mentioned before, the carboxyl on the The compounds of this invention carbapenem parent nucleus can be protected by carboxyl-protecting group, perhaps can adult in the ester of facile hydrolysis, the i.e. described compound of 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 acetic acid, 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 the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
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, 1-isopropyl oxygen methyl esters 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, isopropyl oxygen methanoyl methyl ester, isopropyl 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 refers to that its all differences are to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (I) compound has many three-dimensional centers, for example on the 4-position, on the 5-position, on the 6-position, first-class in the 8-position.
The ester of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis, its isomer can be hydrate forms.Hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
The present invention is the hydrate of claimed ester, its isomer, its hydrate or its ester or the salt that comprises arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of other active pharmaceutical ingredients further, as cilastatin and sodium salt, Betamipron etc.
The present invention is the hydrate of claimed ester, its isomer, its hydrate or its ester or the salt that comprises arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner further; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.01g～10g shown in the general formula (I) of physiology significant quantity, can be 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.04g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g etc.
The hydrate of the ester of the arbitrary compound of the present invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate or its ester or salt, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection mean that medicine makes for inject in the body solution, emulsion or suspension and for facing with preceding preparation or being diluted to solution or the sterile preparation of the powder of suspension or strong solution, 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 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 water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is 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 not add additives, also 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 can be made into conventional solid preparation, as tablet, capsule, pill, granule etc. when oral; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape that medicine and suitable auxiliary materials and mixing compacting form or the solid preparation of special-shaped sheet, 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 is 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 that medicine evenly mixes with the auxiliary material that suits, 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 provides and has trained southern antibiotics for the preparation of the purposes in the medicine that treats and/or prevents infectious diseases.The present invention trains southern antibiotics all has better antibacterial activity to gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria, can be used for treating and/or preventing the various diseases that is caused by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
Usually, have been found that the southern antibiotics of training is nontoxic to warm-blooded animal, and this general rule also is applicable to The compounds of this invention.Preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria to the mouse administration, is not observed by the caused tangible poisoning aura of The compounds of this invention or side effect.
The southern antibiotics of training 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 is strong to PBPs avidity, has a broad antifungal spectrum, the anti-microbial activity height all has better antibacterial activity to gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria, especially gram-positive and negative resistant organism is demonstrated outstanding anti-microbial activity;
(3) The compounds of this invention is stable to β-Nei Xiananmei and people's kidney DHP-I, can single medicine administration;
(4) The compounds of this invention has long transformation period and post antibiotic effect, and anti-microbial effect is lasting, and medication is convenient;
(5) 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 further set forth the beneficial effect of the southern antibiotics of training of the present invention by antibacterial experiment in external and the body, but this should be interpreted as that the southern antibiotics of training of the present invention only has following beneficial effect.
Antimicrobial spectrum and the antibacterial activity in vitro of experimental example 1 The compounds of this invention
For trying bacterial classification:
1, reference culture
Streptococcus aureus ATCC25923, escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853.
2, clinical isolates strain
Gram positive organism: MSSA (MSSA) 18 strains, methicillin-resistant staphylococcus aureus (MRSA) 20 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 15 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 15 strains, responsive streptococcus pneumoniae (PSSP) 20 strains of penicillin, penicillin resistant streptococcus pneumoniae (PRSP) 16 strains, enterococcus faecalis 15 strains;
Gram-negative bacteria: responsive Pseudomonas aeruginosa 20 strains of imipenum, 15 strains of imipenem-resistant Pseudomonas aeruginosa, anti-ceftazime Pseudomonas aeruginosa 16 strains, escherichia coli 20 strains, Klebsiella Pneumoniae 25 strains, enterobacter cloacae 20 strains, hemophilus influenzae 18 strains;
Anerobe: bacteroides fragilis 8 strains.
Trial-product:
Preferred compound 1～20 of the present invention, self-control, its chemical name and structural formula are as mentioned before;
Imipenum: commercial;
Panipenem: commercial;
Meropenem: commercial;
Ertapenem: commercial.
Experimental technique:
Agar dilution.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of reference culture
Figure B2007101137779D000121
Figure B2007101137779D000131
By table 1 experimental result as seen, compare with imipenum, panipenem, meropenem and ertapenem, 1～20 pair of streptococcus aureus of the preferred compound of the present invention and escherichia coli have better antibacterial activity, and 11～15 pairs of Pseudomonas aeruginosa reference cultures of the preferred compound of the present invention have good antibacterial activity.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Figure B2007101137779D000132
Figure B2007101137779D000141
By table 2 experimental result as seen, compare with imipenum, panipenem, meropenem and ertapenem, the gram-positive bacterial strain of 1～20 pair of clinical separation of the preferred compound of the present invention has the excellent antibiotic activity.
Table 3 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Figure B2007101137779D000142
By table 3 experimental result as seen, compare with imipenum, panipenem, meropenem and ertapenem, escherichia coli, Klebsiella Pneumoniae, enterobacter cloacae, the hemophilus influenzae of 1～20 pair of clinical separation of the preferred compound of the present invention have the excellent antibiotic activity, and the responsive Pseudomonas aeruginosa of the imipenum of 11～15 pairs of clinical separation of the preferred compound of the present invention, imipenem-resistant Pseudomonas aeruginosa, anti-ceftazime Pseudomonas aeruginosa have the excellent antibiotic activity.
Table 4 The compounds of this invention is to the anti-microbial activity of clinical separation anerobe
Figure B2007101137779D000151
By table 4 experimental result as seen, compare with imipenum, panipenem, meropenem and ertapenem, the bacteroides fragilis of 1～20 pair of clinical separation of the preferred compound of the present invention has good antibacterial activity.
Above-mentioned experimental result shows, The compounds of this invention is compared with immediate prior art, gram positive organism, negative bacterium and resistant organism thereof and anerobe are had potent anti-microbial effect, have has a broad antifungal spectrum, advantage that anti-microbial activity is high, for having the new compound of good clinical application potential.
Experimental example 2 The compounds of this invention are to the antibacterial activity in vivo of mouse
For trying bacterial classification:
Streptococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), escherichia coli, Pseudomonas aeruginosa.
Trial-product:
Preferred compound 1～20 of the present invention, self-control, its chemical name and structural formula see before civilian described;
Imipenum: commercial;
Panipenem: commercial;
Meropenem: commercial;
Ertapenem: commercial;
Cilastatin: commercial.
For trying animal: mouse
Experimental technique: systemic infection test, all give drug compound all with the cilastatin coupling.
Microbemia mouse model: mouse, body weight 18～22g, peritoneal injection bacteria suspension (5% mucoitin) 0.5ml.After bringing out infection 60min, each of subcutaneous injection single dose is for the reagent thing, and the infecting mouse of survival continues to observe 7 days, uses the probability-weighted method to calculate median effective dose (ED 50).
Experimental result and conclusion:
Table 5 The compounds of this invention is to the provide protection of mouse systemic infection
Figure B2007101137779D000161
By table 5 as seen, The compounds of this invention is better than the provide protection of mouse systemic infection or is equivalent to imipenum and meropenem.Show that The compounds of this invention compares with immediate prior art, effect is more good, but better application is in 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 The preparation of 3-sulfydryl-N-(ethyl benzoate-3-yl) methyl-azepine butane
In the reaction flask of drying, add 3-acetylthio-azepine butane 13.1g (100mmol), methylene dichloride 100ml, triethylamine 20ml splashes into the 100ml dichloromethane solution of 3-brooethyl-ethyl benzoate 24.3g (100mmol) then, stirring at room reaction 6h, reaction finishes, add 100ml water, tell organic layer, drying, concentrating under reduced pressure steams and desolventizes, residuum adds methylene dichloride 100ml, and stirring and dissolving adds the hydrochloric acid soln 50ml of 4mol/L then, be warming up to 40 ℃, stirring reaction 2h, reaction finishes, and tells organic layer, the organic layer drying, remove solvent under reduced pressure, residuum gets faint yellow solid product 21.8g, yield: 86.8% with ethyl acetate-hexanaphthene recrystallization.
The preparation of embodiment 2 3-sulfydryl-N-(ethyl benzoate-3-yl) methyl-tetramethyleneimine
Preparation method's reference example 1 is thrown 3-acetylthio-tetramethyleneimine 14.5g (100mmol), and 3-brooethyl-ethyl benzoate 24.3g (100mmol) gets product 23.5g, yield: 88.4%.
The preparation of embodiment 3 3-sulfydryl-N-(ethyl benzoate-3-yl) methyl-piperidines
Preparation method's reference example 1 is thrown 3-acetylthio-piperidinyl-1 5.9g (100mmol), and 3-brooethyl-ethyl benzoate 24.3g (100mmol) gets product 22.8g, yield: 81.6%.
Embodiment 4 5-sulfydryl-N-(ethyl benzoate-3-yl) methyl isophthalic acid, the preparation of 4,5,6-tetrahydropyrimidine
Preparation method's reference example 1 is thrown 5-acetylthio-1,4,5,6-tetrahydropyrimidine 15.8g (100mmol), and 3-brooethyl-ethyl benzoate 24.3g (100mmol) gets product 22.2g, yield: 79.5%.
Embodiment 5 The preparation of 3-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-azetidine
Preparation method's reference example 1 is thrown 3-acetylthio-azepine butane 13.1g (100mmol), and 5-brooethyl-thiophene-2-carboxylic acid ethyl ester 24.9g (100mmol) gets product 20.7g, yield: 80.3%.
The preparation of embodiment 6 3-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-tetramethyleneimine
Preparation method's reference example 1 is thrown 3-acetylthio-tetramethyleneimine 14.5g (100mmol), and 5-brooethyl-thiophene-2-carboxylic acid ethyl ester 24.9g (100mmol) gets product 22.7g, yield: 83.8%.
The preparation of embodiment 7 3-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-piperidines
Preparation method's reference example 1 is thrown 3-acetylthio-piperidinyl-1 5.9g (100mmol), and 5-brooethyl-thiophene-2-carboxylic acid ethyl ester 24.9g (100mmol) gets product 23.3g, yield: 81.6%.
Embodiment 8 5-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl isophthalic acid, the preparation of 4,5,6-tetrahydropyrimidine
Preparation method's reference example 1 is thrown 5-acetylthio-1,4,5,6-tetrahydropyrimidine 15.8g (100mmol), and 5-brooethyl-thiophene-2-carboxylic acid ethyl ester 24.9g (100mmol) gets product 21.4g, yield: 75.2%.
Embodiment 9 3-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) preparation of methyl-azetidine
Preparation method's reference example 1 is thrown 3-acetylthio-azepine butane 13.1g (100mmol), and 5-brooethyl-isoxazoles-3-ethyl formate 23.4g (100mmol) get product 19.4g, yield: 80.2%.
Embodiment 10 3-sulfydryl-N-(isoxazole-5-base) preparation of methyl-azetidine
Preparation method's reference example 1 is thrown 3-acetylthio-azepine butane 13.1g (100mmol), and 5-brooethyl-isoxazole 16.2g (100mmol) get product 14.9g, yield: 87.8%.
Embodiment 11 3-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) preparation of methyl-tetramethyleneimine
Preparation method's reference example 1 is thrown 3-acetylthio-tetramethyleneimine 14.5g (100mmol), and 5-brooethyl-isoxazoles-3-ethyl formate 23.4g (100mmol) get product 20.8g, yield: 81.1%.
Embodiment 12 3-sulfydryl-N-(isoxazole-5-base) preparation of methyl-tetramethyleneimine
Preparation method's reference example 1 is thrown 3-acetylthio-tetramethyleneimine 14.5g (100mmol), and 5-brooethyl-isoxazole 16.2g (100mmol) get product 16.2g, yield: 88.1%.
Embodiment 13 3-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) preparation of methyl-piperidines
Preparation method's reference example 1 is thrown 3-acetylthio-piperidinyl-1 5.9g (100mmol), and 5-brooethyl-isoxazoles-3-ethyl formate 23.4g (100mmol) get product 22.2g, yield: 82.2%.
Embodiment 14 3-sulfydryl-N-(isoxazole-5-base) preparation of methyl-piperidines
Preparation method's reference example 1 is thrown 3-acetylthio-piperidinyl-1 5.9g (100mmol), and 5-brooethyl-isoxazole 16.2g (100mmol) get product 16.5g, yield: 83.1%.
Embodiment 15 5-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) methyl isophthalic acid, the preparation of 4,5,6-tetrahydropyrimidine
Preparation method's reference example 1 is thrown 5-acetylthio-1,4,5,6-tetrahydropyrimidine 15.8g (100mmol), and 5-brooethyl-isoxazoles-3-ethyl formate 23.4g (100mmol) get product 21.2g, yield: 78.9%.
Embodiment 16 5-sulfydryl-N-(isoxazole-5-base) methyl isophthalic acid, the preparation of 4,5,6-tetrahydropyrimidine
Preparation method's reference example 1 is thrown 5-acetylthio-1,4,5,6-tetrahydropyrimidine 15.8g (100mmol), and 5-brooethyl-isoxazole 16.2g (100mmol) get product 16.5g, yield: 83.4%.
The preparation of embodiment 17 5-acetylthio-N-(ethyl benzoate-3-yl) methyl-hexahydropyrimidine
In the reaction flask of drying, add 5-acetylthio-hexahydropyrimidine 16.0g (100mmol), methylene dichloride 100ml, triethylamine 20ml splashes into the 100ml dichloromethane solution of 3-brooethyl-ethyl benzoate 24.3g (100mmol) then, stirring at room reaction 5h, reaction finishes, add 100ml water, tell organic layer, drying, concentrating under reduced pressure steams and desolventizes, residuum gets faint yellow solid product 29.2g, yield: 90.6% with ethyl acetate-hexanaphthene recrystallization.
The preparation of embodiment 18 5-acetylthio-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-hexahydropyrimidine
Preparation method's reference example 17 is thrown 5-acetylthio-hexahydropyrimidine 16.0g (100mmol), and 5-brooethyl-thiophene-2-carboxylic acid ethyl ester 24.9g (100mmol) gets product 28.5g, yield: 86.8%.
Embodiment 19 5-acetylthio-N-(isoxazole-3-ethyl formate-5-yl) preparation of methyl-hexahydropyrimidine
Preparation method's reference example 17 is thrown 5-acetylthio-hexahydropyrimidine 16.0g (100mmol), and 5-brooethyl-isoxazoles-3-ethyl formate 23.4g (100mmol) get product 27.1g, yield: 86.4%.
Embodiment 20 5-acetylthio-N-(isoxazole-5-base) preparation of methyl-hexahydropyrimidine
Preparation method's reference example 17 is thrown 5-acetylthio-hexahydropyrimidine 16.0g (100mmol), and 5-brooethyl-isoxazole 16.2g (100mmol) get product 22.5g, yield: 93.4%.
The preparation of embodiment 21 5-sulfydryl-3-tertbutyloxycarbonyl-N-(ethyl benzoate-3-yl) methyl-hexahydropyrimidine
In reaction flask, add 5-acetylthio-N-(ethyl benzoate-3-yl) methyl-hexahydropyrimidine 32.2g (100mmol), methylene dichloride 100ml, triethylamine 20ml stirs then and is cooled to 10 ℃, drips (Boc) 2The dichloromethane solution 100ml of O32.7g (150mmol), insulated and stirred reaction 5h, reaction finishes, add the hydrochloric acid soln 60ml of 5mol/L, be warming up to 40 ℃, stirring reaction 2h, reaction finishes, tell organic layer, washing, organic layer drying, remove solvent under reduced pressure, residuum gets faint yellow solid product 35.3g, yield: 92.8% with ethyl acetate-hexanaphthene recrystallization.
The preparation of embodiment 22 5-sulfydryl-3-tertbutyloxycarbonyl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-hexahydropyrimidine
Preparation method's reference example 21 is thrown 5-acetylthio-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-hexahydropyrimidine 32.8g (100mmol), gets product 34.5g, yield: 89.2%.
Embodiment 23 5-sulfydryl-3-tertbutyloxycarbonyl-N-(isoxazole-3-ethyl formate-5-yl) preparation of methyl-hexahydropyrimidine
Preparation method's reference example 21 is thrown 5-acetylthio N-(isoxazole-3-ethyl formate-5-yl) methyl-hexahydropyrimidine 31.3g (100mmol), get product 32.8g, yield: 88.4%.
Embodiment 24 5-sulfydryl-3-tertbutyloxycarbonyl-N-(isoxazole-5-base) preparation of methyl-hexahydropyrimidine
Preparation method's reference example 21 is thrown 5-acetylthio-N-(isoxazole-5-base) methyl-hexahydropyrimidine 24.1g (100mmol), get product 27.6g, yield: 92.1%.
Embodiment 25 (4R, 5S, 6S)-and 3-[N-(ethyl benzoate-3-yl) methyl-azepine butane-3-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the dry reaction bottle, with (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol) be dissolved in the 120ml acetonitrile solution cold in, be chilled to below-10 ℃, the acetonitrile solution 80ml that adds diisopropylethylamine 5ml and 3-sulfydryl-N-(ethyl benzoate-3-yl) methyl-azepine butane 5.5g (22mmol), 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 300ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets product 8.1g, yield: 67.8%.
Embodiment 26 (4R, 5S, 6S)-and 3-[N-(ethyl benzoate-3-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(ethyl benzoate-3-yl) methyl-tetramethyleneimine 5.8g (22mmol).Get product 8.1g, yield: 66.8%.
Embodiment 27 (4R, 5S, 6S)-and 3-[N-(ethyl benzoate-3-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4- Methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(ethyl benzoate-3-yl) methyl-piperidines 6.1g (22mmol).Get product 8.1g, yield: 65.2%.
Embodiment 28 (4R, 5S, 6S)-and 3-[N-(ethyl benzoate-3-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl N-(ethyl benzoate-3-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine 6.1g (22mmol).Get product 7.3g, yield: 58.9%.
Embodiment 29 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-azetidine-3-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-azetidine 5.7g (22mmol).Get product 7.3g, yield: 61.5%.
Embodiment 30 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyl Ethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-tetramethyleneimine 6.0g (22mmol).Get product 8.2g, yield: 66.4%.
Embodiment 31 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-piperidines 6.3g (22mmol).Get product 7.5g, yield: 60.8%.
Embodiment 32 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine 6.3g (22mmol).Get product 7.2g, yield: 57.2%.
Embodiment 33 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl-azetidine-3-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) methyl-azetidine 5.3g (22mmol).Get product 7.4g, yield: 63.1%.
Embodiment 34 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(isoxazole-5-base) methyl-azetidine 3.7g (22mmol).Get product 7.1g, yield: 69.1%.
Embodiment 35 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-1- Hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) methyl-tetramethyleneimine 5.6g (22mmol).Get product 7.6g, yield: 63.2%.
Embodiment 36 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-first Base-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(isoxazole-5-base) methyl-tetramethyleneimine 4.1g (22mmol).Get product 7.3g, yield: 69.5%.
Embodiment 37 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyl Ethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) methyl-piperidines 5.9g (22mmol).Get product 7.2g, yield: 58.4%.
Embodiment 38 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-methyl -7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 3-sulfydryl-N-(isoxazole-5-base) methyl-piperidines 4.4g (22mmol).Get product 7.4g, yield: 67.8%.
Embodiment 39 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl-N-(isoxazole-3-ethyl formate-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine 5.9g (22mmol).Get product 6.8g, yield: 55.1%.
Embodiment 40 (4R, 5S, 6S))-3-[N-(isoxazole-5-base) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyl Ethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl-N-(isoxazole-5-base) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine 4.3g (22mmol).Get product 7.2g, yield: 66.3%.
Embodiment 41 (4R, 5S, 6S)-and 3-[3-tertbutyloxycarbonyl-N-(ethyl benzoate-3-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl-3-tertbutyloxycarbonyl-N-(ethyl benzoate-3-yl) methyl-hexahydropyrimidine 8.4g (22mmol).Get product 9.1g, yield: 62.5%.
Embodiment 42 (4R, 5S, 6S)-3-[3-tertbutyloxycarbonyl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-hexahydropyrimidine-5-yl] Sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl-3-tertbutyloxycarbonyl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-hexahydropyrimidine 8.5g (22mmol).Get product 9.3g, yield: 63.5%.
Embodiment 43 (4R, 5S, 6S)-and 3-[3-tertbutyloxycarbonyl-N-(isoxazole-3-ethyl formate-5-yl) methyl-hexahydropyrimidine-5-yl] Sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl-3-tertbutyloxycarbonyl-N-(isoxazole-3-ethyl formate-5-yl) methyl-hexahydropyrimidine 8.2g (22mmol).Get product 8.5g, yield: 59.2%.
Embodiment 44 (4R, 5S, 6S)-3-[3-tertbutyloxycarbonyl-N-is (different
Figure B2007101137779D000221
Azoles-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 25, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), 5-sulfydryl-3-tertbutyloxycarbonyl N-(isoxazole-5-base) methyl-hexahydropyrimidine 6.6g (22mmol).Get product 8.3g, yield: 64.8%.
Embodiment 45 (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-azepine butane-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4- The preparation of methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
With (4R, 5S, 6S)-and 3-[N-(ethyl benzoate-3-yl) methyl-azepine butane-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-the 50ml methylene dichloride of 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.0g (10mmol) in, add methyl-phenoxide 10ml and Nitromethane 99Min. 20ml, in-50 ℃ of Nitromethane 99Min. solution 100ml that drip the 1mol/L aluminum chloride down,-40 ℃ are stirred 2h, add water 200ml, separate out solid, filter, filter cake is dissolved in the mixed solution of 400ml THF and water 30ml, adds 10% palladium-charcoal 2g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF150ml in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 20ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 30ml, and-10 ℃ are stirred 1h, filter, and filter cake water-Virahol recrystallization gets white crystal 2.5g, yield: 58.5%.
Molecular formula: C 21H 24N 2O 6S molecular weight: 432.49
Ultimate analysis: C, 58.15%; H, 5.79%; N, 6.41%; S, 7.55%
(calculate: C, 58.32%; H, 5.59%; N, 6.48%; S, 7.41%)
Embodiment 46 (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-first The preparation of base-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(ethyl benzoate-3-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.1g (10mmol).Get target product 2.5g, yield: 54.9%.
Molecular formula: C 22H 26N 2O 6S molecular weight: 446.52
Ultimate analysis: C, 59.01%; H, 6.05%; N, 6.12%; S, 7.03%
(calculate: C, 59.18%; H, 5.87%; N, 6.27%; S, 7.18%)
Embodiment 47 (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-methyl The preparation of-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(ethyl benzoate-3-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.2g (10mmol).Get target product 2.6g, yield: 56.5%.
Molecular formula: C 23H 28N 2O 6S molecular weight: 460.54
Ultimate analysis: C, 59.73%; H, 6.28%; N, 5.92%; S, 6.79%
(calculate: C, 59.98%; H, 6.13%; N, 6.08%; S, 6.96%)
Embodiment 48 (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyl Ethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-3-[N-(ethyl benzoate-3-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.2g (10mmol).Get target product 2.3g, yield: 49.6%.
Molecular formula: C 22H 25N 3O 6S molecular weight: 459.52
Ultimate analysis: C, 57.33%; H, 5.81%; N, 9.06%; S, 6.79%
(calculate: C, 57.50%; H, 5.48%; N, 9.14%; S, 6.98%)
Embodiment 49 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyl Ethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.0g (10mmol).Get target product 2.2g, yield: 51.2%.
Molecular formula: C 19H 22N 2O 6S 2Molecular weight: 438.52
Ultimate analysis: C, 51.84%; H, 5.28%; N, 6.19%; S, 14.71%
(calculate: C, 52.04%; H, 5.06%; N, 6.39%; S, 14.62%)
Embodiment 50 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-first The preparation of base-7-oxygen-1-azabicyclo-[2,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.2g (10mmol).Get target product 2.6g, yield: 56.5%.
Molecular formula: C 20H 24N 2O 6S 2Molecular weight: 452.54
Ultimate analysis: C, 52.97%; H, 5.54%; N, 6.02%; S, 14.02%
(calculate: C, 53.08%; H, 5.35%; N, 6.19%; S, 14.17%)
Embodiment 51 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4- The preparation of methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.3g (10mmol).Get target product 2.4g, yield: 52.1%.
Molecular formula: C 21H 26N 2O 6S 2Molecular weight: 466.57
Ultimate analysis: C, 53.86%; H, 5.84%; N, 5.91%; S, 13.62%
(calculate: C, 54.06%; H, 5.62%; N, 6.00%; S, 13.74%)
Embodiment 52 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-3-[N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.3g (10mmol).Get target product 2.3g, yield: 48.6%.
Molecular formula: C 20H 23N 3O 6S 2Molecular weight: 465.54
Ultimate analysis: C, 51.42%; H, 5.17%; N, 8.85%; S, 13.54%
(calculate: C, 51.60%; H, 4.98%; N, 9.03%; S, 13.78%)
Embodiment 53 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-1- Hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 5.9g (10mmol).Get target product 2.1g, yield: 50.1%.
Molecular formula: C 18H 21N 3O 7S molecular weight: 423.44
Ultimate analysis: C, 49.69%; H, 5.32%; N, 9.62%; S, 7.51%
(calculate: C, 51.06%; H, 5.00%; N, 9.92%; S, 7.57%)
Embodiment 54 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 5.1g (10mmol).Get target product 2.2g, yield: 58.9%.
Molecular formula: C 17H 21N 3O 5S molecular weight: 379.43
Ultimate analysis: C, 53.73%; H, 5.76%; N, 10.95%; S, 8.24%
(calculate: C, 53.81%; H, 5.58%; N, 11.07%; S, 8.45%)
Embodiment 55 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.0g (10mmol).Get target product 2.3g, yield: 52.6%.
Molecular formula: C 19H 23N 3O 7S molecular weight: 437.47
Ultimate analysis: C, 52.03%; H, 5.54%; N, 9.43%; S, 7.48%
(calculate: C, 52.16%; H, 5.30%; N, 9.61%; S, 7.33%)
Embodiment 56 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-first The preparation of base-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 5.3g (10mmol).Get target product 2.3g, yield: 58.9%.
Molecular formula: C 18H 23N 3O 5S molecular weight: 393.46
Ultimate analysis: C, 54.83%; H, 6.03%; N, 10.52%; S, 8.22%
(calculate: C, 54.95%; H, 5.89%; N, 10.68%; S, 8.15%)
Embodiment 57 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.1g (10mmol).Get target product 2.3g, yield: 51.2%.
Molecular formula: C 20H 25N 3O 7S molecular weight: 451.49
Ultimate analysis: C, 53.02%; H, 5.75%; N, 9.22%; S, 6.90%
(calculate: C, 53.20%; H, 5.58%; N, 9.31%; S, 7.10%)
Embodiment 58 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-methyl The preparation of-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 5.4g (10mmol).Get target product 2.2g, yield: 55.2%.
Molecular formula: C 19H 25N 3O 5S molecular weight: 407.48
Ultimate analysis: C, 55.84%; H, 6.41%; N, 10.22%; S, 8.01%
(calculate: C, 56.00%; H, 6.18%; N, 10.31%; S, 7.87%)
Embodiment 59 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[N-(isoxazole-3-ethyl formate-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.1g (10mmol).Get target product 2.2g, yield: 49.4%.
Molecular formula: C 19H 22N 4O 7S molecular weight: 450.47
Ultimate analysis: C, 50.45%; H, 5.14%; N, 12.26%; S, 7.02%
(calculate: C, 50.66%; H, 4.92%; N, 12.44%; S, 7.12%)
Embodiment 60 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyl Ethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45 is thrown (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 5.4g (10mmol).Get target product 2.3g, yield: 55.9%.
Molecular formula: C 18H 22N 4O 5S molecular weight: 406.46
Ultimate analysis: C, 53.05%; H, 5.64%; N, 13.53%; S, 7.70%
(calculate: C, 53.19%; H, 5.46%; N, 13.78%; S, 7.89%)
Embodiment 61 (4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4- The preparation of methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[3-tertbutyloxycarbonyl-N-(ethyl benzoate-3-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 7.2g (10mmol).Get target product 2.4g, yield: 52.3%.
Molecular formula: C 22H 27N 3O 6S molecular weight: 461.53
Ultimate analysis: C, 57.15%; H, 6.18%; N, 9.19%; S, 6.82%
(calculate: C, 57.25%; H, 5.90%; N, 9.10%; S, 6.95%)
Embodiment 62 (4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-1-hydroxyl second Base]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[3-tertbutyloxycarbonyl-N-(thiophene-2-carboxylic acid ethyl ester-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 7.3g (10mmol).Get target product 2.3g, yield: 48.5%.
Molecular formula: C 20H 25N 3O 6S 2Molecular weight: 467.56
Ultimate analysis: C, 51.25%; H, 5.52%; N, 8.78%; S, 13.54%
(calculate: C, 51.38%; H, 5.39%; N, 8.99%; S, 13.72%)
Embodiment 63 (4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyl Ethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[3-tertbutyloxycarbonyl-N-(isoxazole-3-ethyl formate-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 7.2g (10mmol).Get target product 2.2g, yield: 48.2%.
Molecular formula: C 19H 24N 4O 7S molecular weight: 452.48
Ultimate analysis: C, 50.26%; H, 5.56%; N, 12.13%; S, 7.02%
(calculate: C, 50.43%; H, 5.35%; N, 12.38%; S, 7.09%)
Embodiment 64 (4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4- The preparation of methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Concrete preparation method's reference example 45, throw (4R, 5S, 6S)-and 3-[3-tertbutyloxycarbonyl-N-(isoxazole-5-base) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 6.4g (10mmol).Get target product 2.3g, yield: 56.1%.
Molecular formula: C 18H 24N 4O 5S molecular weight: 408.47
Ultimate analysis: C, 52.79%; H, 6.13%; N, 13.56%; S, 7.67%
(calculate: C, 52.93%; H, 5.92%; N, 13.72%; S, 7.85%)
The preparation of embodiment 65 The compounds of this invention aseptic powder injections
1, prescription:
Figure B2007101137779D000271
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; 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; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 66 The compounds of this invention tablets
1, prescription:
Figure B2007101137779D000281
2, preparation technology: raw material pulverizing is crossed 100 mesh sieves, and all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby; Take by weighing raw material and auxiliary material according to recipe quantity; Hypromellose 2% the aqueous solution made soluble in water is standby; With in the compound 1-20 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; Cross 20 mesh sieves particle processed; Particle is dried under 60 ℃ condition; Dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; 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 ester or salt:
Figure F2007101137779C000011
Wherein, R 1Represent hydrogen atom or C 1-4Alkyl;
R 2Representation carboxy ,-COOR 4Or the ester of facile hydrolysis, described R 4The representation carboxy protecting group;
Ring A is selected from following groups:
Or
Figure F2007101137779C000013
R 3Be selected from following groups:
Figure F2007101137779C000015
Or
Figure F2007101137779C000016
R wherein 5Representation carboxy or by the C of carboxyl substituted 1-4Alkyl, R 6And R 7Independently represent hydrogen atom, carboxyl respectively or by the C of carboxyl substituted 1-4Alkyl,
Above-mentioned cyclic group can further be replaced by 1～2 following substituting group, and described substituting group is selected from halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, sulfonic group, formamyl, C 1-4Alkyl, the C that is replaced by hydroxyl 1-4Alkyl, the amino C that replaces of quilt 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Carbalkoxy, C 1-4Alkylamidoalkyl, C 1-4Alkyl sulphonyl or C 1-4Alkylsulfonamido.
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 ester or salt:
Wherein, R 1Represent hydrogen atom or methyl;
R 2Representation carboxy ,-COOR 4Or the ester of facile hydrolysis,
Described R 4The representation carboxy protecting group is selected from methyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis is selected from alkyloyloxyethyl alkyl ester, alkoxyl group acyloxyalkyl group ester, cycloalkanes acyloxyalkyl group ester, cycloalkyloxy acyloxyalkyl group ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
Ring A is selected from following groups:
Figure F2007101137779C000021
R 3Be selected from following groups:
Figure F2007101137779C000022
R wherein 5Representation carboxy or by the C of carboxyl substituted 1-4Alkyl, R 6And R 7Independently represent hydrogen atom, carboxyl respectively or by the C of carboxyl substituted 1-4Alkyl,
Above-mentioned cyclic group can further be replaced by 1～2 following substituting group, and described substituting group is selected from fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, sulfonic group, formamyl, hydroxymethyl, amino methyl, methoxyl group, oxyethyl group, methoxycarbonyl, acetamido, methyl sulphonyl or methylsulfonyl amido.
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 ester or salt:
Wherein, R 1Represent methylidene;
R 2Representation carboxy ,-COOR 4Or the ester of facile hydrolysis,
Described R 4The representation carboxy protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis is selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, isopropyl oxygen methanoyl methyl esters, isopropyl oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
Ring A is selected from following groups:
Figure F2007101137779C000023
Or
R 3Be selected from following groups:
Or
Figure F2007101137779C000026
R wherein 5Representation carboxy, R 6And R 7Independently represent hydrogen atom or carboxyl respectively,
Above-mentioned cyclic group can further be replaced by 1～2 following substituting group, and described substituting group is selected from fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, sulfonic group, formamyl, hydroxymethyl, amino methyl, methoxyl group, oxyethyl group, methoxycarbonyl, acetamido, methyl sulphonyl or methylsulfonyl amido.
4. compound as claimed in claim 3, for:
(4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-azepine butane-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(phenylformic acid-3-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(thiophene-2-carboxylic acid-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-5-base) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-azetidine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-piperidines-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl-hexahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, or
(4R, 5S, 6S)-and 3-[N-(isoxazole-3-formic acid-5-yl) methyl isophthalic acid, 4,5,6-tetrahydropyrimidine-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
And the hydrate of ester, its isomer, its hydrate and ester or the salt of pharmacy acceptable salt, its facile hydrolysis.
5. as the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetic acid, 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 the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
6. 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.
7. comprise the hydrate of ester, its isomer, its hydrate or its ester or salt 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 is pharmaceutically acceptable arbitrary formulation.
9. pharmaceutical composition as claimed in claim 7 contains the hydrate 0.01g～10g of ester, its isomer, its hydrate or its ester or salt of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis as essential activeconstituents.
10. as the hydrate of ester, its isomer, its hydrate and ester or the salt of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis, for the preparation of the application in the medicine that treats and/or prevents infectious diseases.
CN2007101137779A 2007-09-12 2007-09-12 Carbapenems antibiotics Pending CN103275081A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019232053A1 (en) * 2018-05-30 2019-12-05 VenatoRx Pharmaceuticals, Inc. Broad-spectrum carbapenems

Citations (2)

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Publication number Priority date Publication date Assignee Title
JP2003183280A (en) * 2001-12-21 2003-07-03 Wyeth Lederle Japan Ltd Carbapenem compound
CN1946724A (en) * 2004-08-31 2007-04-11 韩国化学研究院 2-arylmethylazetidine carbapenem derivatives and preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003183280A (en) * 2001-12-21 2003-07-03 Wyeth Lederle Japan Ltd Carbapenem compound
CN1946724A (en) * 2004-08-31 2007-04-11 韩国化学研究院 2-arylmethylazetidine carbapenem derivatives and preparation thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019232053A1 (en) * 2018-05-30 2019-12-05 VenatoRx Pharmaceuticals, Inc. Broad-spectrum carbapenems
CN112513043A (en) * 2018-05-30 2021-03-16 维纳拓尔斯制药公司 Broad spectrum carbapenems

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