CN101412720B - Carbapenem compound containing mercapto nitrogen heterocyclic vinyl - Google Patents
Carbapenem compound containing mercapto nitrogen heterocyclic vinyl Download PDFInfo
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- CN101412720B CN101412720B CN2008102158368A CN200810215836A CN101412720B CN 101412720 B CN101412720 B CN 101412720B CN 2008102158368 A CN2008102158368 A CN 2008102158368A CN 200810215836 A CN200810215836 A CN 200810215836A CN 101412720 B CN101412720 B CN 101412720B
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- 0 C[C@]([C@]([C@]([C@]1C=I)N2C(*)=C1S[C@@](C1)CN(C)[C@@]1C=CNc1cccc(C(O)=O)c1)C2=O)O Chemical compound C[C@]([C@]([C@]([C@]1C=I)N2C(*)=C1S[C@@](C1)CN(C)[C@@]1C=CNc1cccc(C(O)=O)c1)C2=O)O 0.000 description 1
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Abstract
The invention belongs to the technical field of medicine, in particular to a mercapto-heterocyclic vinyl containing carbapenems compound shown in a general formula (1), pharmaceutically acceptable salts, easily hydrolysable esters or isomers thereof, wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, X and n are defined in the specification. The invention also relates to a method for preparing the compounds, medical compositions containing the compounds, and application of the compounds to the preparation of medicines for treating and/ preventing infectious diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to contain carbapenem compounds, its pharmacy acceptable salt of mercapto nitrogen heterocyclic vinyl, ester or its isomer of its facile hydrolysis, 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
Carbapenem antibiotic, because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stable to β-Nei Xiananmei, and receives much concern.Clinical have imipenum, meropenem, panipenem, biapenem and ertapenem etc. have been applied to.Ertapenem sodium belongs to the long-acting injection carbapenem, by the Merck exploitation, is used for infectation of bacteria, comprises that intra-abdominal infection, skin and skin soft-tissue infection, urinary tract infection, Obstetric and Gynecologic Department infect and pneumonia.Its structural formula is as follows:
Ertapenem has the excellent antibiotic activity to aerophil, anerobe especially enterobacter bacterium, the activity of anti-gram positive organism is a little less than imipenum, the activity of anti-gram-negative bacteria is better than imipenum, anti-wide spectrum and extended spectrum produce bacterium such as intestinal bacteria and Klebsiella Pneumoniae effect surpass the third generation and the 4th generation cynnematin.But, owing to the limitation of drug administration by injection, can not meet clinical needs simultaneously because clinical application too much causes the continuous increase of bacterial drug resistance.
Therefore seek new, (dehydropeptidase of kidney-I) carbapenem compounds of stability becomes the emphasis of such drug development to have high PBPs (penicillin-binding protein) avidity and DHP-I.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides ester or its isomer of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Wherein, R
1Representation carboxy ,-COOR
7Or the ester of facile hydrolysis, described R
7The representation carboxy protecting group;
R
2Represent hydrogen atom, low alkyl group, the ester of amino protecting group or facile hydrolysis;
R
3Represent hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, low alkyl group or lower alkoxy;
R
4And R
5Represent identical or different group, be selected from hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, low alkyl group, lower alkoxy, lower alkoxycarbonyl, amino-sulfonyl, low alkyl group amido alkylsulfonyl, formamyl, sulfonic group or low alkyl group amido;
R
6Represent hydrogen atom or low alkyl group;
N is 0～4 integer;
X represents NH, S or O.
Preferred compound is:
Wherein, R
1Representation carboxy ,-COOR
7Or the ester of facile hydrolysis,
Described R
7The 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;
R
2Represent hydrogen atom, methyl, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group is selected from benzyl, formyl radical, and ethanoyl, tert-butoxycarbonyl, allyloxy carbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy carbonyl, diazo, phenacyl or 3-acetoxyl group propyl group,
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;
R
3Represent hydrogen atom, fluorine atom, hydroxyl, amino, carboxyl, methyl, trifluoromethyl, ethyl, methoxy or ethoxy;
R
4And R
5Represent identical or different group, be selected from hydrogen atom, fluorine atom, hydroxyl, amino, carboxyl, cyano group, nitro, methyl, trifluoromethyl, ethyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxy carbonyl, amino-sulfonyl, methyl amido alkylsulfonyl, formamyl, sulfonic group or methyl amido;
R
6Represent hydrogen atom or methyl;
N is 0,1 or 2;
X represents NH.
Further preferred compound is:
Wherein, R
1Representation carboxy ,-COOR
7Or the ester of facile hydrolysis,
Described R
7The 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, be selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R
2Represent hydrogen atom, methyl, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group is selected from benzyl, formyl radical, and allyloxy carbonyl, to the nitro benzyloxycarbonyl, tertbutyloxycarbonyl or 3-acetoxyl group propyl group,
The ester of described facile hydrolysis, be selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R
3Representation carboxy;
R
4And R
5Represent similar and different group, and be selected from hydrogen atom, carboxyl, methyl or methyl amido;
R
6Represent methylidene;
N is 1 or 2;
X represents NH.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" low alkyl group " of the present invention is C
1-6The alkyl of straight or branched is as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
" lower alkoxy " of the present invention is C
1-6The alkoxyl group of straight or branched is as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.
" lower alkoxycarbonyl " of the present invention is C
1-6The carbalkoxy of straight or branched is as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, secondary butoxy carbonyl, penta oxygen carbonyl, new penta oxygen carbonyl, own oxygen carbonyl etc.
" low alkyl group amido alkylsulfonyl " of the present invention is C
1-6The alkyl amine group alkylsulfonyl of straight or branched is as methyl amido alkylsulfonyl, ethyl amido alkylsulfonyl, propyl group amido alkylsulfonyl, sec.-propyl amido alkylsulfonyl, butyl amido alkylsulfonyl, isobutyl-amido alkylsulfonyl, tertiary butyl amido alkylsulfonyl, sec-butyl amido alkylsulfonyl, amyl group amido alkylsulfonyl, neo-pentyl amido alkylsulfonyl, hexyl amido alkylsulfonyl etc.
" low alkyl group amido " of the present invention is C
1-6The alkyl amine group of straight or branched is as methyl amido, ethyl amido, propyl group amido, sec.-propyl amido, butyl amido, isobutyl-amido, tertiary butyl amido, sec-butyl amido, pentyloxy amido, neo-pentyl amido, hexyloxy amido etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methyl, methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, allyl group, benzyloxymethyl, phenacyl, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, ethyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: diazo, 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, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, N '-piperidino carbonyl, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Allyl group; allyloxy carbonyl; tert-butoxycarbonyl; to the nitro benzyloxycarbonyl; to methoxyl group benzyloxy base carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; (N '; N '-dimethylaminomethylene); N; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; the acyl group vinyl; 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; 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; phenacyl alkylsulfonyl etc.
Further preferred compound is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid is called for short compound 1, and structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 is called for short compound 2, and structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-piperidines-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid is called for short compound 3, and structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 is called for short compound 4, and structural formula is as follows:
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 compound shown in step 1 formula 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 shown in the formula 1.
The preparation of compound shown in step 2 formula 2
In the dry reaction bottle, compound and thioacetic acid potassium shown in the step gained formula 1 in the adding, DMF, 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 shown in the formula 2.
The preparation of compound shown in step 3 formula 3
Under nitrogen protection, compound shown in the step gained formula 2 in the adding, dry acetone; splash into TMSI, 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 10% 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 shown in the formula 3.
The preparation of compound shown in step 4 formula 4
In reaction flask, will go up compound shown in the step gained formula 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 acetone, filter compound shown in dry the formula 4.
The preparation of compound shown in step 5 formula 5
In the dry reaction bottle, raw material 3 is chilled in acetonitrile solution below-10 ℃, add compound shown in diisopropylethylamine and the last step gained formula 4, stir, after reaction finishes, add the ethyl acetate dilution, water, saturated brine washing successively, organic layer drying, concentrated gets compound shown in the formula 5.
The preparation of compound shown in step 6 formula 6
Compound shown in the gained formula 5 of last step is dissolved in the mixed solution of THF and water, adds 10% woods moral and draw Pd-C, stirring reaction under the room temperature 2MPa hydrogen pressure, filtering palladium charcoal adds THF, layering in the filtrate, collect water layer, in THF, add 5% magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation, water merges, 0 ℃ slowly splashes into methyl alcohol, and-10 ℃ of stirrings are filtered, the filter cake acetone recrystallization gets compound shown in the formula 6.
R in the above reaction equation
2, R
3, R
4, R
5, R
6, R
7Civilian as defined above described with the group of X representative and n, the i.e. described The compounds of this invention of general formula (I).
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention 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 that its all differences are to stereoisomerism, along anti-geometrical isomer, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (I) compound has many three-dimensional centers, for example on the 4-position, on the 5-position, first-class in the 6-position.The compounds of this invention contains olefinic double bonds, comprises cis and trans geometrical isomer when not specializing.
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 0.01～5g 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 carbapenem compounds that contains mercapto nitrogen heterocyclic vinyl preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.The carbapenem compounds that contains mercapto nitrogen heterocyclic vinyl 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), 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 carbapenems is nontoxic to warm-blooded animal, and this general rule also is applicable to The compounds of this invention.With preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria, not to be noted by caused tangible poisoning aura of The compounds of this invention or side effect to the mouse administration.
The carbapenem compounds that contains mercapto nitrogen heterocyclic vinyl 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 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 that contains the carbapenem compounds of mercapto nitrogen heterocyclic vinyl of the present invention by antibacterial experiment in external and the body, but this should be interpreted as that the carbapenem compounds that contains mercapto nitrogen heterocyclic vinyl of the present invention only has following beneficial effect.
The antimicrobial spectrum and the antibacterial activity in vitro of experimental example 1 The compounds of this invention
For trying bacterial classification: all purchase in clinical public institution.
1, reference culture
Streptococcus aureus ATCC25923, escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853.
2, clinical isolates strain
Gram positive organism: MSSA (MSSA) 20 strains, methicillin-resistant staphylococcus aureus (MRSA) 25 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 15 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 18 strains, responsive streptococcus pneumoniae (PSSP) 12 strains of penicillin, penicillin resistant streptococcus pneumoniae (PRSP) 19 strains, micrococcus scarlatinae 22 strains, enterococcus faecalis 25 strains;
Gram-negative bacteria: escherichia coli 18 strains, Proteus mirabilis 20 strains, Klebsiella Pneumoniae 26 strains, enterobacter cloacae 25 strains, 20 strains of Fei Shi citric acid bacillus, hemophilus influenzae 20 strains;
Trial-product:
Compound 1-4: self-control, its chemical name sees embodiment for details; Imipenum: imipenem for injection, commercial; Meropenem: the injection meropenem, commercial; Ertapenem: the injection ertapenem, commercial.
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 as seen, compare with imipenum, meropenem and ertapenem, the anti-microbial activity of 1-4 pairs of streptococcus aureuses of The compounds of this invention, escherichia coli reference culture is than imipenum or meropenem is good or quite, and is suitable to activity and the ertapenem of Pseudomonas aeruginosa.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Table 2 shows that 1-4 pairs of clinical isolating gram-positive bacterial strains of The compounds of this invention have the excellent antibiotic activity, and the anti-microbial activity of joining south than imipenum, meropenem and E Ta is slightly strong or suitable.
Table 3 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
By table 3 as seen, 1-4 pairs of clinical isolating Grain-negative bacterial strains of The compounds of this invention have the excellent antibiotic activity, and are slightly stronger or suitable than the anti-microbial activity of imipenum, meropenem and ertapenem.
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.
Trial-product:
Compound 1-4: its chemical name sees embodiment for details; Imipenum: imipenem for injection, commercial; Meropenem: the injection meropenem, commercial; Ertapenem: the injection ertapenem, commercial; Cilastatin: commercial.
Laboratory 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).
Table 4 The compounds of this invention is to the provide protection of mouse systemic infection
Experimental result and conclusion:
By table 4 as seen, the provide protection of 1-4 pairs of mouse systemic infections of The compounds of this invention is better than or is equivalent to imipenum, meropenem and ertapenem.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, Zinc Chloride Anhydrous 6.8g (50mmol) and POTASSIUM BOROHYDRIDE 5.4g (100mmol), behind the stirring at room 2h, add (2S, 4R)-and 1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl-formiate 8.1g (25mmol), stir and slowly be warming up to back flow reaction 2h down.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, 4S)-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, 4S)-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, 4S)-4-acetylthio-1-tertbutyloxycarbonyl-tetramethyleneimine-2-methyl alcohol 11g (40mmol); dry acetone 100ml splashes into TMSI8ml (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, 4S)-4-acetylthio-1-methyl-tetramethyleneimine-2-methyl alcohol 7.6g (40mmol).Get product: 15.5g, yield: 68.8%.
The preparation of embodiment 11 5-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 12 5-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)-4-sulfydryl-2-[2-(phenylformic acid-3-yl) vinyl amino]-preparation of 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 3-formamido group phenylformic acid 18.2g (110mmol), regulate pH9 with saturated sodium bicarbonate solution, stir 2h in 40 ℃, 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 acetone, separates out solid, filters, and drying gets product 25.0g, yield: 68.5%.
Embodiment 14 (2S, 4S, E)-4-sulfydryl-2-[2-(phenylformic acid-3-yl) vinyl amino]-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), 3-formamido group phenylformic acid 18.2g (110mmol).Get product: 19.5g, yield: 70.2%.
Embodiment 15 (E)-5-sulfydryl-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 66.2g (100mmol), 3-formamido group phenylformic acid 18.2g (110mmol).Get product: 25.1g, yield: 66.3%.
Embodiment 16 (E)-5-sulfydryl-2-[2-(phenylformic acid-3-yl) vinyl amino]-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), 3-formamido group phenylformic acid 18.2g (110mmol).Get product: 20.1g, yield: 68.8%.
Embodiment 17 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] the acetonitrile 150ml of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), solution is chilled to below-10 ℃, adds diisopropylethylamine 6ml and (2S, 4S, E)-4-sulfydryl-2-[2-(phenylformic acid-3-yl) vinyl amino]-the acetonitrile solution 100ml of 1-tertbutyloxycarbonyl-tetramethyleneimine 9.1g (25mmol), 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 300ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets solid 9.9g, yield: 55.6%.
Embodiment 18 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 17 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-(phenylformic acid-3-yl) vinyl amino]-1-methyl-tetramethyleneimine 7.0g (25mmol).Get product: 9.0g, yield: 58.1%.
Embodiment 19 (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 17 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-(phenylformic acid-3-yl) vinyl amino]-1-tertbutyloxycarbonyl-piperidines 9.5g (25mmol).Get product: 10.0g, yield: 55.4%.
Embodiment 20 (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 17 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-(phenylformic acid-3-yl) vinyl amino]-1-methyl-piperidines 7.3g (25mmol).Get product: 9.2g, yield: 57.8%.
Embodiment 21 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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)
Will (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 14.2g (20mmol) is dissolved in the mixed solution of 300mlTHF and water 30ml, add 10% woods moral and draw Pd-C4g, stirring reaction 2h under the room temperature 2MPa hydrogen pressure, filtering palladium charcoal adds 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 100ml, and-10 ℃ are stirred 1h, filters, and the filter cake acetone recrystallization gets target compound 5.8g, yield: 61.3%.
Molecular formula: C
23H
27N
3O
6S
Molecular weight: 473.542
Ultimate analysis: C, 58.15%; H, 5.94%; N, 8.55%; S, 6.92%
(calculate: C, 58.34%; H, 5.75%; N, 8.87%; S, 6.77%)
Embodiment 22 (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-1-methyl-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 21 preparation methods, throw (4R, 5S, 6S)-3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 12.5g (20mmol).Get product: 6.2g, yield: 63.9%.
Molecular formula: C
24H
29N
3O
6S
Molecular weight: 487.569
Ultimate analysis: C, 58.93%; H, 6.27%; N, 8.43%; S, 6.69%
(calculate: C, 59.12%; H, 6.00%; N, 8.62%; S, 6.58%)
Embodiment 23 (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 21 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 14.5g (20mmol).Get product: 5.7g, yield: 58.5%.
Molecular formula: C
24H
29N
3O
6S
Molecular weight: 487.569
Ultimate analysis: C, 59.03%; H, 6.30%; N, 8.48%; S, 6.76%
(calculate: C, 59.12%; H, 6.00%; N, 8.62%; S, 6.58%)
Embodiment 24 (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 21 preparation methods, throw (4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 12.7g (20mmol).Get product: 6.1g, yield: 60.7%.
Molecular formula: C
25H
31N
3O
6S
Molecular weight: 501.595
Ultimate analysis: C, 59.74%; H, 6.56%; N, 8.19%; S, 6.57%
(calculate: C, 59.86%; H, 6.23%; N, 8.38%; S, 6.39%)
The preparation of embodiment 25 The compounds of this invention aseptic powder injections
1, prescription: prescription 1
Prescription 2
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing raw material 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 26 The compounds of this invention tablets
1, prescription:
Prescription 1
Prescription 2
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; Compound, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, and the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood; Cross 20 mesh sieve system particles; 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 (9)
1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Wherein, R
1Representation carboxy;
R
2Represent hydrogen atom or C
1-6The alkyl of straight or branched;
R
3Represent halogen atom, hydroxyl, amino, carboxyl, cyano group or nitro;
R
4And R
5Represent identical or different group, be selected from hydrogen atom, trifluoromethyl, C
1-6The alkyl of straight or branched or C
1-6The alkoxyl group of straight or branched;
R
6Represent hydrogen atom or C
1-6The alkyl of straight or branched;
N is 1 or 2;
X represents NH.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R
1Representation carboxy;
R
2Represent hydrogen atom or methyl;
R
3Represent fluorine atom, hydroxyl, amino or carboxyl;
R
4And R
5Represent identical or different group, be selected from hydrogen atom, methyl, trifluoromethyl, ethyl, methoxy or ethoxy;
R
6Represent hydrogen atom or methyl;
N is 1 or 2;
X represents NH.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R
1Representation carboxy;
R
2Represent hydrogen atom or methyl;
R
3Representation carboxy;
R
4And R
5Represent similar and different group, and be selected from hydrogen atom or methyl;
R
6Represent methylidene;
N is 1 or 2;
X represents NH.
4. compound as claimed in claim 3 or its pharmacy acceptable salt, described compound is selected from:
(4R, 5S, 6S)-and 3-[(2S, 4S, E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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-(phenylformic acid-3-yl) vinyl amino]-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-(phenylformic acid-3-yl) vinyl amino]-piperidines-5-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid and
(4R, 5S, 6S)-3-[(E)-2-[2-(phenylformic acid-3-yl) vinyl amino]-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 or 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 or 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 or its pharmacy acceptable salt 0.01g～5g as essential activeconstituents.
9. treat and/or prevent application in the medicine of infectious diseases as the described compound of the arbitrary claim of claim 1～4 and pharmacy acceptable salt thereof in preparation.
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| CN2008102158368A CN101412720B (en) | 2007-08-27 | 2008-08-26 | Carbapenem compound containing mercapto nitrogen heterocyclic vinyl |
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| CN200710017102 | 2007-08-27 | ||
| CN200710017102.4 | 2007-08-27 | ||
| CN2008102158368A CN101412720B (en) | 2007-08-27 | 2008-08-26 | Carbapenem compound containing mercapto nitrogen heterocyclic vinyl |
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| CN101412720B true CN101412720B (en) | 2011-05-18 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0747381A1 (en) * | 1994-02-25 | 1996-12-11 | Banyu Pharmaceutical Co., Ltd. | Carbapenem derivative |
| US20050209212A1 (en) * | 1992-02-04 | 2005-09-22 | Astrazeneca Uk Limited | Antibiotic compounds |
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2008
- 2008-08-26 CN CN2008102158368A patent/CN101412720B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050209212A1 (en) * | 1992-02-04 | 2005-09-22 | Astrazeneca Uk Limited | Antibiotic compounds |
| EP0747381A1 (en) * | 1994-02-25 | 1996-12-11 | Banyu Pharmaceutical Co., Ltd. | Carbapenem derivative |
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