CN101372490B - Penem derivative containing sulfhydryl nitrogen heterocyclic ring and vinyl nitrogen heterocyclic ring - Google Patents
Penem derivative containing sulfhydryl nitrogen heterocyclic ring and vinyl nitrogen heterocyclic ring Download PDFInfo
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- CN101372490B CN101372490B CN2008102104654A CN200810210465A CN101372490B CN 101372490 B CN101372490 B CN 101372490B CN 2008102104654 A CN2008102104654 A CN 2008102104654A CN 200810210465 A CN200810210465 A CN 200810210465A CN 101372490 B CN101372490 B CN 101372490B
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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
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- 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 belongs to the technical field of medicine, and more particularly relates to ertapenem derivatives which are shown in general formula (I) and contain hydrosulphonyl nitrogen heterocyclic ring ethylene azacyclonol, salt which can be accepted by the derivatives on pharmacy, ester of the derivatives that is easy to hydrolyze, and isomer of the derivatives; wherein, R1, R2, R3, R4, m, nand are defined as instruction; the invention also relates to a method used for preparing the compounds, medicine combinations containing the compounds, and the application of the compounds in the preparation of the medicine for treating and/or preventing infectious diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to contain Pennem derivates, its pharmacy acceptable salt, the ester of its facile hydrolysis, its isomer of sulfhydryl nitrogen heterocyclic ring and vinyl nitrogen heterocyclic ring, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are in the purposes that is used for preparing the medicine that treats and/or prevents infectious diseases.
2, background technology
Training southern class microbiotic is the New-type wide-spectrum that grows up the seventies in 20th century, anti-enzyme, efficient β-Nei Xiananleikangshengsu.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.This similar drug that has gone on the market at present has imipenum, panipenem, meropenem, S-4661, biapenem, ertapenem etc.
First listing be imipenum, gram-positive and negative, aerobic and anerobe all there is very strong activity, stable to various β-Nei Xiananmeis, there is not cross resistance with other microbiotic, but easily by dehydropeptidase of kidney-I (DHP-I) degraded rapidly, must share with dehydropeptidase of kidney inhibitor cilastatin clinically in vivo.Meropenem is introduced 1 Beta-methyl, has strengthened to train the stability of southern compounds to DHP-I, and is all responsive to gram positive organism, gram-negative bacteria, especially gram-negative bacteria had very strong anti-microbial activity.
The imipenum meropenem
P-91022 (Kyung Seok Lee, Yong Koo Kang, Kyung Ho Yoo et al.Novel1 β-methylcarbapenems with isoxazoloethenyl moieties containing carboxylic acid sodium salt, Bioorganic﹠amp; Medicinal Chemistry Letters15 (2005) 231-234) be new training south class microbiotic, by the exploitation of Korea S S. Korea and the USA company, in external activity with resisting gram-positive and negative bacterium.Structural formula is as follows:
Because the training of clinical application at present south class microbiotic too much causes the continuous increase of bacterial drug resistance, owing to the limitation of drug administration by injection, can not meet clinical needs simultaneously.Therefore seek the emphasis that penem compound new, that have high PBPs (penicillin-binding protein) avidity and DHP-I resistance becomes such drug development.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides ester, its isomer of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Wherein, R
1Represent hydrogen atom or C
1-4Alkyl;
R
2Representation carboxy ,-COOR
5Or the ester of facile hydrolysis, described R
5The representation carboxy protecting group;
R
3Represent hydrogen atom, C
1-4Alkyl or amino protecting group;
R
4Represent hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkyl amine group, C
1-4Alkylamidoalkyl, C
1-4Alkyl sulphonyl, C
1-4The alkyl sulfonamide base, carbamyl or C
1-4The alkylamine formyl radical;
M represents 1～4 integer;
N represents 0～4 integer;
Preferred compound is:
Wherein, R
1Represent hydrogen atom or methyl;
R
2Representation carboxy ,-COOR
5Or the ester of facile hydrolysis, described R
5The representation carboxy protecting group;
R
3Represent hydrogen atom, methyl, ethyl or amino protecting group;
R
4Represent hydrogen atom, fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group or trifluoromethyl;
M represents 1 or 2;
N represents 0,1 or 2;
Represent singly-bound or two key.
Further preferred compound is:
Wherein, R
1Represent methylidene;
R
2Representation carboxy ,-COOR
5Or the ester of facile hydrolysis, described R
5The representation carboxy protecting group;
R
3Represent hydrogen atom, methyl, ethyl or amino protecting group;
R
4Represent hydrogen atom;
M is 1 or 2;
N is 0 or 1;
Part of compounds of the present invention
Further preferred compound is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 1, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 2, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 3, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-2-[2-(tetramethyleneimine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 4, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 5, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 6, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 7, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 8, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 9, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 10, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 11, structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, be called for short compound 12, structural formula is as follows:
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl etc.
" C of the present invention
1-4Alkoxyl group " comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy etc.
" C of the present invention
1-4Alkyl amine group " comprise methyl amido, ethyl amido, propyl group amido, sec.-propyl amido, butyl amido, tertiary butyl amido 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, different third alkylsulfonyl, fourth alkylsulfonyl, uncle's fourth alkylsulfonyl etc.
" C of the present invention
1-4Alkylsulfonamido " comprise methylsulfonyl amido, ethanesulfonamide group, third sulfoamido, different third sulfoamido, fourth sulfoamido, uncle's fourth sulfoamido etc.
" C of the present invention
1-4The alkylamine formyl radical " comprise methylamine formyl radical, ethamine formyl radical, propylamine formyl radical, Isopropylamine formyl radical, butylamine formyl radical, TERTIARY BUTYL AMINE formyl radical 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: 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, 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, 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, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, 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; Tert-butoxycarbonyl; allyloxy 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 '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; (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; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; 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; the phenacyl alkylsulfonyl; diazo etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, allyl group, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, methyl, ethyl, diphenyl methyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
The 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:
Reactions steps:
The preparation of step 1 compound 1
In the dry reaction bottle, add dioxane, Zinc Chloride Anhydrous, POTASSIUM BOROHYDRIDE is after the stirring at room, add raw material 1, stir down and slowly be warming up to back flow reaction, be chilled to room temperature, add the hydrochloric acid dilution, ethyl acetate extraction, organic phase is washed with saturated salt, drying, concentrate compound 1.
The preparation of step 2 compound 2
In the dry reaction bottle, add compound 1 and thioacetic acid potassium, DMF (dimethyl formamide), be heated with stirring to dissolving after, insulation reaction, be cooled to room temperature after, thin up, ethyl acetate extraction, organic phase washes with water, drying concentrates, compound 2.
The preparation of step 3 compound 3
Under nitrogen protection, add compound 2, dry acetone; splash into TMSI (Iodotrimethylsilane), vigorous stirring reaction under the room temperature, ice-water bath cooling; stir, decompress filter, filtrate decompression reclaims acetone; add ethyl acetate in the residue, use hypo solution and saturated common salt water washing successively, use anhydrous sodium sulfate drying; filter back reclaim under reduced pressure ethyl acetate; get jelly, use the acetic acid ethyl dissolution jelly, stir adding triphenylphosphine down; potassiumiodide; finish the stirring at room reaction; filter, filtrate decompression concentrates, and the cooling back adds isopropyl ether; stir after-filtration; filter cake washs with isopropyl ether, and drying under reduced pressure under room temperature gets compound 3.
The preparation of step 4 compound 4
In reaction flask, with compound 3, methylene dichloride, after the stirring and dissolving, add raw material 2, transfer pH with saturated sodium bicarbonate, back flow reaction under the vigorous stirring after reaction finishes, is regulated pH with concentrated hydrochloric acid, tell organic layer, anhydrous sodium sulfate drying, decompression and solvent recovery, residuum refluxes in ether, filter, get compound 4.
The preparation of step 5 compound 5
In the dry reaction bottle, add the acetonitrile solution of raw material 3, cooling, the acetonitrile solution of adding diisopropylethylamine and compound 4, low temperature stirs, and after reaction finishes, adds the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets compound 5.
The preparation of step 6 compound 6
Compound 5 is dissolved in the mixed solution of THF and water, adds Lin Dela Pd-C, stirring reaction under the room temperature hydrogen pressure, filtering palladium charcoal adds THF, layering in the filtrate, collect water layer, in THF, add magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation, water merges, low temperature slowly splashes into methyl alcohol, stirs, and filters, the filter cake acetone recrystallization gets compound 6.
R in the above reaction equation
1, R
3, R
4The group of representative and m, n,
Civilian as defined above described, the carboxyl on compound 6 parent nucleus also can be protected by carboxyl-protecting group, perhaps can adult in the ester of facile hydrolysis.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises 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, 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 its all differences to stereoisomerism, diastereo-isomerism.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, that is: on the 4-position; On the 5-position; On the 6-position.When containing olefinic double bonds, comprise cis and trans geometrical isomer.
The present invention is the claimed ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its isomer and other active pharmaceutical ingredients of comprising further, as cilastatin and sodium salt, Betamipron etc.
The present invention is the claimed ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its isomer and one or more pharmaceutical carriers and/or thinner of comprising further; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.01g～5g shown in the general formula (I) of physiology significant quantity, can be 0.01g, 0.015g, 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 etc.
The ester of the arbitrary compound of the present invention, its pharmacy acceptable salt, its facile hydrolysis or its isomer, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The present invention also provide the Pennem derivates that contains sulfhydryl nitrogen heterocyclic ring and vinyl nitrogen heterocyclic ring preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.Pennem derivates of the present invention all has better antibacterial activity to gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria such as MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), Pseudomonas aeruginosa and acinetobacter bacterium, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
Usually, have been found that the southern class 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 tangible poisoning aura or side effect.
Pennem derivates 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 present invention has carried out in the body and external antibacterial tests, show that The compounds of this invention is strong to PBPs avidity, has a broad antifungal spectrum, the anti-microbial activity height, gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria all there are better antibacterial activity, especially gram-positive and negative resistant organism are demonstrated outstanding anti-microbial activity;
(3) The compounds of this invention is stable to β-Nei Xiananmei and DHP-1, can single medicine administration;
(4) The compounds of this invention has longer 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 Pennem derivates of the present invention, but this should be interpreted as that Pennem derivates of the present invention only has following beneficial effect by antibacterial experiment in external and the body.
The 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 is purchased in public institution.
Gram positive organism: MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), methicillin-sensitivity staphylococcus epidermidis (MSSE), methicillin-resistant staphylococcus epidermidis (MRSE), the responsive streptococcus pneumoniae (PSSP) of penicillin, penicillin resistant streptococcus pneumoniae (PRSP), micrococcus scarlatinae, enterococcus faecalis;
Gram-negative bacteria: the responsive Pseudomonas aeruginosa of imipenum, imipenem-resistant Pseudomonas aeruginosa, anti-ceftazime Pseudomonas aeruginosa, escherichia coli, Proteus mirabilis, Klebsiella Pneumoniae, enterobacter cloacae, Fei Shi citric acid bacillus, hemophilus influenzae;
Anerobe: bacteroides fragilis.
Trial-product:
Compound 1-12, structural formula and chemical name are as indicated above, self-control;
Imipenum, meropenem: commercial;
P-91022: by literature method self-control (structural formula pass away scape technology).
Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of reference culture
By table 1 experimental result as seen, compare with imipenum, meropenem and P-91022, The compounds of this invention 1-12 has good antibacterial activity to the reference culture of streptococcus aureus, escherichia coli and Pseudomonas aeruginosa.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Table 2 (continuing) The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
By table 2 experimental result as seen, The compounds of this invention 1-12 has the excellent antibiotic activity to clinical isolating gram-positive bacterial strain, and is stronger or suitable than the anti-microbial activity of imipenum, meropenem and P-91022.
Table 3 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Table 3 (continuing) The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
By table 3 experimental result as seen, The compounds of this invention 1-12 has the excellent antibiotic activity to clinical isolating Grain-negative bacterial strain, and is stronger or suitable than the anti-microbial activity of imipenum, meropenem and P-91022.
Table 4 The compounds of this invention is to the anti-microbial activity of clinical separation anerobe
By table 4 experimental result as seen, The compounds of this invention 1-12 has good antibacterial activity to clinical isolating bacteroides fragilis, is better than the anti-microbial activity of P-91022, is better than or is equivalent to the anti-microbial activity of imipenum and meropenem.
Above-mentioned experimental result shows that The compounds of this invention is compared with immediate prior art, and effect is more excellent, has 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, methicillin-resistant staphylococcus aureus, escherichia coli, Pseudomonas aeruginosa.
Trial-product:
Compound 1-12: structural formula and chemical name are made by oneself as mentioned before;
Imipenum, meropenem, cilastatin: commercial;
P-91022: by literature method self-control (structure pass away scape technology).
For trying animal: mouse
Experimental technique: systemic infection test, imipenum and cilastatin coupling.
Microbemia mouse model: male mice, 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
The continuous The compounds of this invention of table 5 is to the provide protection of mouse systemic infection
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, meropenem and P-91022.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 (2S, 4R)-preparation of 1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol
In the dry reaction bottle, add dioxane 100ml, add Zinc Chloride Anhydrous 6.8g (50mmol) then, POTASSIUM BOROHYDRIDE 5.4g (100mmol), behind the stirring at room 2h, add (2S, 4R)-1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl-formiate 8.1g (25mmol).Stir down and slowly be warming up to back flow reaction 2h, be chilled to room temperature, add the hydrochloric acid 100ml dilution of 1mol/L, ethyl acetate extraction.Organic phase is washed with saturated salt, drying, concentrate (2S, 4R)-1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 6.3g, yield: 85.2%.
Embodiment 2 (2S, 4R)-preparation of 1-methyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol
With reference to embodiment 1 preparation method, throw (2S, 4R)-1-methyl-4-mesyloxy tetramethyleneimine-2-methyl-formiate 5.9g (25mmol).Get product: 4.6g, yield: 87.9%.
The preparation of embodiment 3 1-tertbutyloxycarbonyl-5-mesyloxy piperidines-2-methyl alcohol
With reference to embodiment 1 preparation method, throw 1-tertbutyloxycarbonyl-5-mesyloxy piperidines-2-methyl-formiate 8.4g (25mmol).Get product: 7.0g, yield: 83.5%.
The preparation of embodiment 4 1-methyl-5-mesyloxy piperidines-2-methyl alcohol
With reference to embodiment 1 preparation method, throw 1-methyl-5-mesyloxy piperidines-2-methyl-formiate 6.3g (25mmol).Get product: 6.8g, yield: 84.3%.
Embodiment 5 (2S, 4R)-preparation of 4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol
In the dry reaction bottle, add (2S 4R)-1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 11.7g (40mmol) and thioacetic acid potassium 9.2g (80mmol), adds DMF150ml then, be heated with stirring to dissolving after, insulation reaction 10h.After being cooled to room temperature, add water 100ml dilution, ethyl acetate extraction, organic phase washes with water, and drying concentrates, and gets product 9.9g, yield: 90.2%.
Embodiment 6 (2S, 4R)-preparation of 4-acetylthio-1-methyl-tetramethyleneimine-2-methyl alcohol
With reference to embodiment 5 preparation methods, throw (2S, 4R)-1-methyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 8.4g (40mmol), thioacetic acid potassium 9.2g (80mmol).Get product: 7.0g, yield: 93.1%.
The preparation of embodiment 7 5-acetylthio-1-tertbutyloxycarbonyl-piperidines-2-methyl alcohol
With reference to embodiment 5 preparation methods, throw 1-tertbutyloxycarbonyl-5-mesyloxy piperidines-2-methyl alcohol 12.4g (40mmol), thioacetic acid potassium 9.2g (80mmol).Get product: 10.1g, yield: 87.5%.
The preparation of embodiment 8 5-acetylthio-1-methyl-piperidines-2-methyl alcohol
With reference to embodiment 5 preparation methods, throw 1-methyl-5-mesyloxy piperidines-2-methyl alcohol 8.9g (40mmol), thioacetic acid potassium 9.2g (80mmol).Get product: 7.3g, yield: 89.2%.
Embodiment 9 (2S, 4S)-preparation of 4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-tetramethyleneimine iodide
Under nitrogen protection, add (2S, 4R)-4-acetylthio-1-tertbutyloxycarbonyl-tetramethyleneimine-2-methyl alcohol 11g (40mmol); dry acetone 100ml splashes into TMSI 8ml (60mmol), vigorous stirring reaction 4h under the room temperature; ice-water bath is cooled to 0 ℃, stirs 30min, decompress filter.Filtrate decompression reclaims acetone, adds the 500ml ethyl acetate in the residue, uses 10% hypo solution and saturated common salt water washing successively, uses anhydrous sodium sulfate drying, filters back reclaim under reduced pressure ethyl acetate, gets jelly.Use the 400ml acetic acid ethyl dissolution, stir adding 20g triphenylphosphine (0.08mol) down, potassiumiodide 5g.Finish stirring at room reaction 3h, filter, it is surplus about 1/2 that filtrate decompression is concentrated into, and the cooling back adds the 500ml isopropyl ether, stirs after-filtration.Filter cake washs with isopropyl ether, and drying under reduced pressure under room temperature gets product 17.3g, yield: 66.7%.
Embodiment 10 (2S, 4S)-preparation of 4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-tetramethyleneimine iodide
With reference to embodiment 9 preparation methods, throw (2S, 4R)-4-acetylthio-1-methyl-tetramethyleneimine-2-methyl alcohol 7.6g (40mmol).Get product: 15.5g, yield: 68.8%.
The preparation of embodiment 115-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-piperidines iodide
With reference to embodiment 9 preparation methods, throw 5-acetylthio-1-tertbutyloxycarbonyl-piperidines-2-methyl alcohol 11.6g (40mmol).Get product: 16.4g, yield: 62.1%.
The preparation of embodiment 125-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-piperidines iodide
With reference to embodiment 9 preparation methods, throw 5-acetylthio-1-methyl-piperidines-2-methyl alcohol 7.6g (40mmol).Get product: 14.8g, yield: 64.5%.
Embodiment 13 (2S, 4S, E)-preparation of 4-sulfydryl-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-tetramethyleneimine
In reaction flask, add (2S, 4S)-4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-tetramethyleneimine iodide 64.7g (100mmol); methylene dichloride 1.0L; after the stirring and dissolving, be added dropwise to the dichloromethane solution 100ml of 1-carbonyl pyrrolidine 20g (200mmol), regulate pH9 with saturated sodium bicarbonate solution; stir 2h in 35 ℃; transfer to pH5 with concentrated hydrochloric acid, tell organic layer, anhydrous sodium sulfate drying; filter, filtrate decompression reclaims solvent.It is an amount of that residuum adds ethyl acetate, separates out solid, filters, and drying gets product 20.4g, yield: 68.5%.
Embodiment 14 (2S, 4S, E)-preparation of 4-sulfydryl-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-tetramethyleneimine
With reference to embodiment 13 preparation methods, throw (2S, 4S)-4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-tetramethyleneimine iodide 56.1g (100mmol), 1-carbonyl pyrrolidine 20g (200mmol).Get product: 14.9g, yield: 70.4%.
The preparation of embodiment 15 (E)-5-sulfydryl-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-piperidines
With reference to embodiment 13 preparation methods, throw 5-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-piperidines iodide 66.1g (100mmol), 1-carbonyl pyrrolidine 20g (200mmol).Get product: 20.5g, yield: 65.6%.
The preparation of embodiment 16 (E)-5-sulfydryl 2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-piperidines
With reference to embodiment 13 preparation methods, throw 5-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-piperidines iodide 57.5g (100mmol), 1-carbonyl pyrrolidine 20g (200mmol).Get product: 15.7g, yield: 69.2%.
Embodiment 17 (2S, 4S, E)-4-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-preparation of 1-tertbutyloxycarbonyl-tetramethyleneimine
With reference to embodiment 13 preparation methods, throw (2S, 4S)-4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-tetramethyleneimine iodide 64.7g (100mmol), 2,5-dihydro-1H-pyrroles 19.4g (200mmol).Get product: 20.3g, yield: 68.5%.
Embodiment 18 (2S, 4S, E)-4-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-preparation of 1-methyl-tetramethyleneimine
With reference to embodiment 13 preparation methods, throw (2S, 4S)-4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-tetramethyleneimine iodide 56.1g (100mmol), 2,5-dihydro-1H-pyrroles 19.4g (200mmol).Get product: 14.9g, yield: 70.8%.
Embodiment 19 (E)-5-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-preparation of 1-tertbutyloxycarbonyl-piperidines
With reference to embodiment 13 preparation methods, throw 5-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-piperidines iodide 66.1g (100mmol), 2,5-dihydro-1H-pyrroles 19.4g (200mmol).Get product: 20.6g, yield: 66.2%.
Embodiment 20 (E)-5-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-preparation of 1-methyl-piperidines
With reference to embodiment 13 preparation methods, throw 5-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-piperidines iodide 57.5g (100mmol), 2,5-dihydro-1H-pyrroles 19.4g (200mmol).Get product: 15.3g, yield: 68.4%.
Embodiment 21 (2S, 4S, E)-4-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-preparation of 1-tertbutyloxycarbonyl-tetramethyleneimine
With reference to embodiment 13 preparation methods, throw (2S, 4S)-4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-tetramethyleneimine iodide 64.7g (100mmol), azetidine 11.4g (200mmol).Get product: 20.3g, yield: 71.2%.
Embodiment 22 (2S, 4S, E)-4-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-preparation of 1-methyl-tetramethyleneimine
With reference to embodiment 13 preparation methods, throw (2S, 4S)-4-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-tetramethyleneimine iodide 56.1g (100mmol), azetidine 11.4g (200mmol).Get product: 14.7g, yield: 73.9%.
Embodiment 23 (E)-5-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-preparation of 1-tertbutyloxycarbonyl-piperidines
With reference to embodiment 13 preparation methods, throw 5-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-tertbutyloxycarbonyl-piperidines iodide 66.1g (100mmol), azetidine 11.4g (200mmol).Get product: 20.8g, yield: 69.7%.
Embodiment 24 (E)-5-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-preparation of 1-methyl-piperidines
With reference to embodiment 13 preparation methods, throw 5-acetylthio-2-(triphenyl phosphorus base) methylene radical-1-methyl-piperidines iodide 57.5g (100mmol), azetidine 11.4g (200mmol).Get product: 15.4g, yield: 72.7%.
Embodiment 25 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-1-hydroxyethyl]-the acetonitrile solution 150ml of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), be chilled to below-10 ℃, add diisopropylethylamine 6ml and (2S, 4S, E)-and the acetonitrile solution 100ml of 4-sulfydryl-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-tetramethyleneimine 7.5g (25mmol), 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 300ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets solid 8.9g, yield: 55.2%.
Embodiment 26 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (2S, 4S, E)-4-sulfydryl-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-tetramethyleneimine 5.3g (25mmol).Get product: 8.2g, yield: 58.7%.
Embodiment 27 (4R, 5S, 6S)-3-[(E)-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (E)-5-sulfydryl-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-piperidines 7.8g (25mmol).Get product: 8.9g, yield: 54.3%.
Embodiment 28 (4R, 5S, 6S)-3-[(E)-2-[2-(tetramethyleneimine-1-yl) vinyl]-1-methyl-piperazine
Pyridine-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (E)-5-sulfydryl-2-[2-(tetramethyleneimine-1-yl) vinyl]-1-methyl-piperidines 5.7g (25mmol).Get product: 8.5g, yield: 59.4%.
Embodiment 29 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-tertbutyloxycarbonyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (2S, 4S, E)-4-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-tertbutyloxycarbonyl-tetramethyleneimine 7.4g (25mmol).Get product: 9.1g, yield: 57.1%.
Embodiment 30 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (2S, 4S, E)-4-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-tetramethyleneimine 5.3g (25mmol).Get product: 8.3g, yield: 59.6%.
Embodiment 31 (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-tertbutyloxycarbonyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (E)-5-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-tertbutyloxycarbonyl-piperidines 7.8g (25mmol).Get product: 9.2g, yield: 56.2%.
Embodiment 32 (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (E)-5-sulfydryl-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-piperidines 5.6g (25mmol).Get product: 8.2g, yield: 57.7%.
Embodiment 33 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-1-tertbutyloxycarbonyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (2S, 4S, E)-4-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-1-tertbutyloxycarbonyl-tetramethyleneimine 7.1g (25mmol).Get product: 9.5g, yield: 60.4%.
Embodiment 34 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (2S, 4S, E)-4-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-1-methyl-tetramethyleneimine 5.0g (25mmol).Get product: 8.6g, yield: 63.7%.
Embodiment 35 (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-1-tertbutyloxycarbonyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (E)-5-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-1-tertbutyloxycarbonyl-piperidines 7.5g (25mmol).Get product: 9.5g, yield: 59.2%.
Embodiment 36 (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With reference to embodiment 25 preparation methods, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), (E)-5-sulfydryl-2-[2-(azetidine-1-yl) vinyl]-1-methyl-piperidines 5.3g (25mmol).Get product: 8.5g, yield: 60.8%.
Embodiment 37 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 1)
With (4R, 5S, 6S)-and 3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 12.9g (20mmol) is dissolved in the mixed solution of THF 300ml and water 30ml, add 10% Lin Dela palladium charcoal 4g, stirring reaction 2h under the room temperature 2MPa hydrogen pressure, filtering palladium charcoal adds THF 150ml 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 100ml, and-10 ℃ are stirred 1h, filters, and the filter cake acetone recrystallization gets target compound 4.2g, yield: 51.2%.
[0229]Molecular formula: C
20H
29N
30
4S molecular weight: 407.53
Ultimate analysis: C, 58.72%; H, 7.32%; N, 10.19%; S, 7.75%
[0231](calculate: C, 58.94%; H, 7.17%; N, 10.31%; S, 7.87%)
Embodiment 38 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 2)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(2S, 4S, E)-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.1g (20mmol).Get product: 4.4g, yield: 52.6%.
[0234]Molecular formula: C
21H
31N
3O
4S molecular weight: 421.55
Ultimate analysis: C, 59.75%; H, 7.62%; N, 9.78%; S, 7.39%
(calculate: C, 59.83%; H, 7.41%; N, 9.97%; S, 7.61%)
Embodiment 39 (4R, 5S, 6S)-3-[(E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 3)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-(2-(tetramethyleneimine-1-yl) vinyl)-1-tertbutyloxycarbonyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 13.1g (20mmol).Get product: 4.2g, yield: 49.4%.
[0239]Molecular formula: C
21H
31N
3O
4S molecular weight: 421.55
Ultimate analysis: C, 59.72%; H, 7.65%; N, 9.73%; S, 7.48%
(calculate: C, 59.83%; H, 7.41%; N, 9.97%; S, 7.61%)
Embodiment 40 (4R, 5S, 6S)-3-[(E)-2-[2-(tetramethyleneimine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 4)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-[2-(tetramethyleneimine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.4g (20mmol).Get product: 4.2g, yield: 48.2%.
[0244]Molecular formula: C
22H
33N
3O
4S molecular weight: 435.58
Ultimate analysis: C, 60.53%; H, 7.88%; N, 9.38%; S, 7.23%
(calculate: C, 60.66%; H, 7.64%; N, 9.65%; S, 7.36%)
Embodiment 41 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 5)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-tertbutyloxycarbonyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 12.8g (20mmol).Get product: 4.2g, yield: 51.3%.
[0249]Molecular formula: C
20H
27N
3O
4S molecular weight: 405.51
Ultimate analysis: C, 59.11%; H, 6.89%; N, 10.13%; S, 7.76%
(calculate: C, 59.24%; H, 6.71%; N, 10.36%; S, 7.91%)
Embodiment 42 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 6)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.1g (20mmol).Get product: 4.4g, yield: 52.5%.
[0254]Molecular formula: C
21H
29N
3O
4S molecular weight: 419.54
Ultimate analysis: C, 59.95%; H, 7.18%; N, 9.81%; S, 7.37%
(calculate: C, 60.12%; H, 6.97%; N, 10.02%; S, 7.64%)
Embodiment 43 (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 7)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-tertbutyloxycarbonyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 13.1g (20mmol).Get product: 4.0g, yield: 48.2%.
[0259]Molecular formula: C
21H
29N
3O
4S molecular weight: 419.54
Ultimate analysis: C, 59.95%; H, 7.23%; N, 9.84%; S, 7.38%
(calculate: C, 60.12%; H, 6.97%; N, 10.02%; S, 7.64%)
Embodiment 44 (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 8)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.4g (20mmol).Get product: 4.4g, yield: 50.7%.
[0264]Molecular formula: C
22H
31N
3O
4S molecular weight: 433.56
Ultimate analysis: C, 60.78%; H, 7.52%; N, 9.81%; S, 7.27%
(calculate: C, 60.94%; H, 7.21%; N, 9.69%; S, 7.40%)
Embodiment 45 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 9)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-1-tertbutyloxycarbonyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 12.6g (20mmol).Get product: 4.1g, yield: 51.5%.
[0269]Molecular formula: C
19H
27N
3O
4S molecular weight: 393.5
Ultimate analysis: C, 57.78%; H, 7.07%; N, 10.42%; S, 8.01%
(calculate: C, 57.99%; H, 6.92%; N, 10.68%; S, 8.15%)
Embodiment 46 (4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 10)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 10.9g (20mmol).Get product: 4.3g, yield: 52.9%.
[0274]Molecular formula: C
20H
29N
3O
4S molecular weight: 407.53
Ultimate analysis: C, 58.76%; H, 7.34%; N, 10.08%; S, 7.55%
(calculate: C, 58.94%; H, 7.17%; N, 10.31%; S, 7.87%)
Embodiment 47 (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 11)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-1-tertbutyloxycarbonyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 12.9g (20mmol).Get product: 3.9g, yield: 47.4%.
[0279]Molecular formula: C
20H
29N
3O
4S molecular weight: 407.53
Ultimate analysis: C, 58.73%; H, 7.36%; N, 10.44%; S, 7.56%
(calculate: C, 58.94%; H, 7.17%; N, 10.31%; S, 7.87%)
Embodiment 48 (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being The compounds of this invention 12)
With reference to embodiment 37 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.1g (20mmol).Get product: 4.3g, yield: 50.5%.
Molecular formula: C
21H
31N
3O
4S molecular weight: 421.55
Ultimate analysis: C, 59.75%; H, 7.64%; N, 10.16%; S, 7.47%
(calculate: C, 59.83%; H, 7.41%; N, 9.97%; S, 7.61%)
The preparation of embodiment 49 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Prescription 2:
Prescription 3:
Prescription 4:
2, preparation technology:
(1) will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process;
(2) take by weighing raw material 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 50 The compounds of this invention tablets
1, prescription:
Prescription 1:
Prescription 2:
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 among the compound 1-12 any one, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, it is an amount of to add the 2%HPMC aqueous solution, stirs, and makes suitable softwood;
(5) cross 20 mesh sieve system particles;
(6) particle is dried under 60 ℃ condition;
(7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes;
(8) sampling, the work in-process chemical examination;
(9) the sheet weight sheet of determining according to chemical examination;
(10) finished product is examined entirely, the packing warehouse-in.
Claims (9)
1. the compound shown in the general formula (I), its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom or C
1-4Alkyl;
R
2Representation carboxy;
R
3Represent hydrogen atom or C
1-4Alkyl;
R
4Represent hydrogen atom;
M represents 1 or 2;
N represents 0 or 1;
2. compound as claimed in claim 1, its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom or methyl;
R
2Representation carboxy;
R
3Represent hydrogen atom, methyl or ethyl;
R
4Represent hydrogen atom;
M represents 1 or 2;
N represents 0 or 1;
3. compound as claimed in claim 2, its pharmacy acceptable salt:
Wherein, R
1Represent methylidene;
R
2Representation carboxy;
R
3Represent hydrogen atom, methyl or ethyl;
R
4Represent hydrogen atom;
M is 1 or 2;
N represents 0 or 1;
Represent singly-bound or two key.
4. compound as claimed in claim 3, its pharmacy acceptable salt, described compound is selected from:
(4R, 5S, 6S)-and 3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[(2S, 4S, E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(E)-and 2-(2-(tetramethyleneimine-1-yl) vinyl)-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(E)-2-[2-(tetramethyleneimine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(E)-2-[2-(2,5-dihydro-1H-pyrroles-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, or
(4R, 5S, 6S)-3-[(E)-2-[2-(azetidine-1-yl) vinyl]-1-methyl-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
5. as the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its pharmacy acceptable salt is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts.
6. the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner.
7. pharmaceutical composition as claimed in claim 6 is pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 6 contains the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt 0.01g～5g as essential activeconstituents.
As the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt in the application that is used for preparing the medicine that treats and/or prevents gram positive organism and the microbial infectious diseases of Grain-negative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008102104654A CN101372490B (en) | 2007-08-15 | 2008-08-14 | Penem derivative containing sulfhydryl nitrogen heterocyclic ring and vinyl nitrogen heterocyclic ring |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710016522 | 2007-08-15 | ||
| CN200710016522.0 | 2007-08-15 | ||
| CN2008102104654A CN101372490B (en) | 2007-08-15 | 2008-08-14 | Penem derivative containing sulfhydryl nitrogen heterocyclic ring and vinyl nitrogen heterocyclic ring |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019070A1 (en) * | 1992-03-26 | 1993-09-30 | Zeneca Limited | Carbapenem derivatives as antibiotics and intermediates thereof |
| CN1821248A (en) * | 2001-09-26 | 2006-08-23 | 麦克公司 | Process for making carbapenem compounds |
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- 2008-08-14 CN CN2008102104654A patent/CN101372490B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019070A1 (en) * | 1992-03-26 | 1993-09-30 | Zeneca Limited | Carbapenem derivatives as antibiotics and intermediates thereof |
| CN1821248A (en) * | 2001-09-26 | 2006-08-23 | 麦克公司 | Process for making carbapenem compounds |
Non-Patent Citations (5)
| Title |
|---|
| Kyung Seok Lee.et al.Novel 1β-methylcarbapenems with isoxazoloethenyl moieties containing carboxylic acid sodium salt.《Bioorganic & Medicinal Chemistry Letters》.2004,第15卷第231-234页. |
| Kyung Seok Lee.et al.Novel 1β-methylcarbapenems with isoxazoloethenyl moieties containing carboxylic acid sodium salt.《Bioorganic & * |
| Makoto Sunagawa.et al.Structural Features Resulting in Convulsive Activity of Carbapenem Compounds:Effect of C-2 Side Chain.《The Journal of Antibiotics》.1995,第48卷(第5期),第408-416页. * |
| Medicinal Chemistry Letters》.2004,第15卷第231-234页. * |
| 孔漫.碳青霉烯类抗生素的研究进展.《中国新药杂志》.2003,第12卷(第9期),第700-703页. * |
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