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CN101376656A - Penem derivative - Google Patents

Penem derivative Download PDF

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Publication number
CN101376656A
CN101376656A CNA2007100148598A CN200710014859A CN101376656A CN 101376656 A CN101376656 A CN 101376656A CN A2007100148598 A CNA2007100148598 A CN A2007100148598A CN 200710014859 A CN200710014859 A CN 200710014859A CN 101376656 A CN101376656 A CN 101376656A
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Prior art keywords
ester
methyl
group
oxygen
acid
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黄振华
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Priority to CNA2007100148598A priority Critical patent/CN101376656A/en
Priority to CN200880020521.6A priority patent/CN101711250B/en
Priority to PCT/CN2008/001532 priority patent/WO2009030107A1/en
Priority to JP2010522167A priority patent/JP2010536888A/en
Publication of CN101376656A publication Critical patent/CN101376656A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention belongs to the pharmaceutical technical field, and particularly relates to a penem derivative, and pharmaceutically acceptable salts thereof, easily-hydrolyzed esters thereof, isomers thereof, hydrate thereof and hydrates of esters or salts thereof shown as a formula (I), wherein R1, R2, R3, R4 and R5 are defined as in the description, and can be further substituted on a benzene ring. The invention also relates to the preparation method of the compounds and the pharmaceutical compound containing the same, and the application thereof on the preparation of pharmaceuticals for treating and/or preventing infection diseases.

Description

Pennem derivates
1, technical field
The invention belongs to medical technical field, be specifically related to the hydrate of ester, its isomer, its hydrate and the ester or the salt of Pennem derivates, its pharmacy acceptable salt, 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 S-4661 etc. have been applied to.S-4661 is used for the treatment of urinary tract infection and respiratory tract infection by the exploitation of the wild adopted Co., Ltd. of Japanese salt.Went on the market in Japan first in 2005.What S-4661 had obtained U.S. FDA examines treatment fast, is used for the treatment of Nosocomial Pneumonia, comprises ventilator associated pneumonia.Its inhalation just carries out I phase clinical study in Britain, carries out preclinical study in this year day, and its structural formula of pulmonary infection that is used for cystic fibrosis patient is as follows:
Figure A200710014859D00051
S-4661 generally all is better than imipenum to the anti-microbial activity of Gram-negative bacteria; To the germ resistance of gram-positive microorganism and Meropenem quite or stronger, poor than imipenum, the carbapenem compounds of therefore seeking new potent Gram-negative and positive anti-microbial activity and DHP-I resistance becomes the emphasis of such drug development.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its isomer, its hydrate and the ester or the salt of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Figure A200710014859D00052
Wherein, R 1Representation carboxy ,-COOR 6Or the ester of facile hydrolysis, described R 6The representation carboxy protecting group;
R 2And R 3Represent hydrogen atom respectively independently, the ester of amino protecting group or facile hydrolysis;
R 4Represent hydrogen atom, low alkyl group or carboxyl;
And phenyl ring can further be replaced by 1-2 substituting groups, and described substituting group is selected from hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, low alkyl group, lower alkoxy, lower alkoxycarbonyl, amino-sulfonyl, the low-grade alkyl amino alkylsulfonyl, formamyl, sulfonic group or low-grade alkyl amino;
R 5Represent hydrogen atom or low alkyl group.
Preferred compound is:
Wherein, R 1Representation carboxy ,-COOR 6Or the ester of facile hydrolysis,
Described R 6The 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 2And R 3Represent hydrogen atom respectively independently, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group; be selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, 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 4Represent hydrogen atom, methyl or carboxyl;
And phenyl ring can further be replaced by 1-2 substituting groups, and described substituting group is selected from hydrogen atom, fluorine atom, hydroxyl, amino, carboxyl, cyano group, nitro, methyl, trifluoromethyl, ethyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxy carbonyl, amino-sulfonyl, the methylamino alkylsulfonyl, formamyl, sulfonic group or methylamino;
R 5Represent hydrogen atom or methyl.
Further preferred compound is:
Wherein, R 1Representation carboxy ,-COOR 6Or the ester of facile hydrolysis,
Described R 6The 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 2And R 3Represent hydrogen atom respectively separately, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group is selected from methyl, the tertiary butyl, benzyl, formyl radical, allyloxy carbonyl, to nitro benzyloxycarbonyl 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 4Represent methylidene or carboxyl;
And phenyl ring can further be replaced by 1-2 substituting groups, and described substituting group is selected from hydrogen atom, fluorine atom, hydroxyl, amino, carboxyl, cyano group, nitro, methyl, trifluoromethyl, ethyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxy carbonyl, amino-sulfonyl, the methylamino alkylsulfonyl, formamyl, sulfonic group or methylamino;
R 5Represent methylidene.
" 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-grade alkyl amino alkylsulfonyl " of the present invention is C 1-6The alkyl amino sulfonyl of straight or branched is as methylamino alkylsulfonyl, ethylamino alkylsulfonyl, propyl group amino-sulfonyl, sec.-propyl amino-sulfonyl, butyl amino-sulfonyl, isobutylamino alkylsulfonyl, tertiary butyl amino-sulfonyl, sec-butyl amino-sulfonyl, amyl group amino-sulfonyl, neo-pentyl amino-sulfonyl, hexyl amino-sulfonyl etc.
" low-grade alkyl amino " of the present invention is C 1-6The alkylamino of straight or branched is as methylamino, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, isobutylamino, tertiary butyl amino, sec-butyl amino, pentyloxy amino, neo-pentyl amino, hexyloxy amino 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, methyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, ethyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, 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)-and 2-[4-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 1, structural formula is as follows:
Figure A200710014859D00091
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 2, structural formula is as follows:
Figure A200710014859D00092
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 3, structural formula is as follows:
Figure A200710014859D00093
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, be called for short compound 4, structural formula is as follows:
Figure A200710014859D00094
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 intermediate 1
In the dry reaction bottle, raw material 1 and methanol mixed are even, and dripping thionyl chloride solution stirs, and white crystal is separated out in cooling, filters, and filtration cakes torrefaction gets intermediate 1.
The preparation of step 2 intermediate 2
In the dry reaction bottle, triethylamine solution is added in the dichloromethane solution of intermediate 1, adding triethylamine and methylsulfonyl chloride after stirring, reaction is after washing, dry, concentrated gets intermediate 2.
The preparation of step 3 intermediate 3
In the dry reaction bottle, Zinc Chloride Anhydrous and POTASSIUM BOROHYDRIDE are dropped in the diox, stirring at room adds intermediate 2 in batches, stirs slowly to be warming up to back flow reaction down, be chilled to room temperature again, filter, add hydrochloric acid cancellation reaction, dilution is extracted, washing, drying concentrates, and gets intermediate 3.
The preparation of step 4 intermediate 4
In the dry reaction bottle, the thioacetic acid potassium solution of adding intermediate 3 is dissolved among the DMF, and reacting by heating is chilled to room temperature again, and dilution is extracted, washing, and drying concentrates, and gets intermediate 4.
The preparation of step 5 intermediate 5
Raw material 2 and triphenylphosphine are added in the THF solution of intermediate 4, drip diethyl azodiformate, add toluene after reaction finishes, concentrate, separate out solid, filter, filtrate concentrates, residuum dissolves with methylene dichloride, add hydrochloric acid soln, tell organic phase after the reaction, through washing, dry, concentrated, residuum gets intermediate 5 with ethyl acetate-hexanaphthene recrystallization.
The preparation of step 6 intermediate 6
In the dry reaction bottle, adding intermediate 5, acetonitrile, diisopropylethylamine and raw material 3 stir, dilution, water, saturated salt washing successively, organic layer drying, concentrated gets intermediate 6.
The preparation of step 7 The compounds of this invention
Intermediate 6 is dissolved in the methylene dichloride, adds methyl-phenoxide and Nitromethane 99Min. solution, add the Nitromethane 99Min. solution stirring of aluminum chloride, add elutriation and go out solid, filter, filter cake is dissolved in the mixed solution of THF and water, add 10% Lin Dela palladium-charcoal, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering Lin Dela palladium-charcoal adds THF in the filtrate, layering, collect water layer, in THF, add 5% magnesium chloride solution again, leave standstill, divide water-yielding stratum, repetitive operation, water merges, and 0 ℃ slowly splashes into methyl alcohol,-10 ℃ of stirrings, filter, filter cake water-Virahol recrystallization gets The compounds of this invention.
R in the above reaction equation 2, R 3, R 4, R 5The group of representative as mentioned before, and phenyl ring can be further replaces by 1-2 substituting groups, the described substituting group literary composition that sees before; Carboxyl on the The compounds of this invention carbapenem parent nucleus also can be protected by carboxyl-protecting group, perhaps can adult in the ester of facile hydrolysis, 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, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (I) compound has many three-dimensional centers, for example on the 4-position, on the 5-position, on the 6-position, first-class in the 8-position.
The ester of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis, its isomer can be hydrate forms.Hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of other active pharmaceutical ingredients, as cilastatin and sodium salt, Betamipron etc.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.01g～10g shown in the general formula (I) of physiology significant quantity, can be 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.04g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g etc.
The hydrate of the ester of the arbitrary compound of the present invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate or its ester or salt, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection 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 new Pennem derivates 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) etc., 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.
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-I, can single medicine administration;
(4) The compounds of this invention has long transformation period and post antibiotic effect, and anti-microbial effect is lasting, and medication is convenient;
(5) The compounds of this invention preparation technology is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of 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
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, pseudomonas aeruginosa 20 strains;
Trial-product:
Compound 1:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Compound 2:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Compound 3:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Compound 4:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Imipenum: commercial;
Meropenem: commercial;
S-4661: commercial.
Experimental technique:
Agar dilution.
Experimental result and conclusion:
By table 1 as seen, compare with imipenum, meropenem and S-4661,1-2 pairs of streptococcus aureuses of The compounds of this invention, escherichia coli, pseudomonas aeruginosa anti-microbial activity are good or suitable than imipenum, meropenem and S-4661,3-4 pairs of streptococcus aureuses of compound, escherichia coli anti-microbial activity are good or suitable than imipenum, meropenem and S-4661, and be slightly poor to the pseudomonas aeruginosa anti-microbial activity.
Table 1 The compounds of this invention is to the anti-microbial activity of reference culture
Figure A200710014859D00151
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Figure A200710014859D00152
By table 2 as seen, 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 Duo Ni 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, 1-2 pairs of clinical isolating Grain-negative bacterial strains of The compounds of this invention have the excellent antibiotic activity, anti-microbial activity than imipenum, meropenem and S-4661 is slightly strong or suitable, other gram-negative bacterias except 3-4 pairs of pseudomonas aeruginosas of compound have the excellent antibiotic activity, and are slightly stronger or suitable than the anti-microbial activity of imipenum, meropenem and S-4661.Above-mentioned experimental result shows, each compound of the present invention is compared with immediate prior art, gram positive organism, negative bacterium and resistant organism thereof and anerobe are had potent anti-microbial effect, have has a broad antifungal spectrum, advantage that anti-microbial activity is high, for having the new compound of good clinical application potential.
Experimental example 2 The compounds of this invention are to the antibacterial activity in vivo of mouse
For trying bacterial classification:
Streptococcus aureus, methicillin-resistant staphylococcus aureus, escherichia coli.
Trial-product:
Compound 1:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Compound 2:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Compound 3:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Compound 4:(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid;
Imipenum: commercial;
Meropenem: commercial;
S-4661: commercial;
Cilastatin: commercial.
Laboratory animal: mouse
Experimental technique:
Systemic infection test, all give drug compound all with the 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 4 The compounds of this invention is to the provide protection of mouse systemic infection
Figure A200710014859D00171
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 S-4661.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 4-hydroxyl-2-methoxycarbonyl pyrrolidine hydrochloride
In the dry reaction bottle, trans-4-hydroxy-l-proline 13.1g (100mmol) and methyl alcohol 50ml mix, 0 ℃ adds sulfur oxychloride 8ml down, drip Bi Shengzhi stirring at room 20min, rise to 40 ℃ again and stir 14h, cooling, separate out white crystal, filter, filtration cakes torrefaction gets product 13.9g, yield 95.6%.
Embodiment 2 (2S, 4R)-preparation of 1-tertbutyloxycarbonyl-4-mesyloxy-2-methoxycarbonyl tetramethyleneimine
Will (2S 4R)-the dichloromethane solution 50ml ice bath of 4-hydroxyl-2-methoxycarbonyl pyrrolidine hydrochloride 7.3g (50mmol) is chilled to 0 ℃, adds triethylamine 8ml, drips (Boc) after stirring 10min 2The dichloromethane solution 50ml of O 13g (60mmol) stirs 1h, adds triethylamine 8ml again, drips methylsulfonyl chloride 4.0ml (51mmol), in 8～10 ℃ of reaction 2h.Through washing, dry, concentrated, get white solid product 15g, yield: 92.5%.
Embodiment 3 (2S, 4R)-preparation of 1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol
Zinc Chloride Anhydrous 6.8g (50mmol) and POTASSIUM BOROHYDRIDE 5.4g (100mmol) are dropped among the diox 100ml, stirring at room 2h, add (2S in batches, 4R)-1-tertbutyloxycarbonyl-4-mesyloxy-2-methoxycarbonyl tetramethyleneimine 8.1g (22.4mmol), slowly be warming up to back flow reaction 2h. under stirring and be chilled to room temperature, filter, add 5mol/L hydrochloric acid 10ml cancellation reaction, add water 100ml dilution, extract ethyl acetate 100ml * 2, and organic phase is washed with saturated salt, dry, concentrate, get product 13.3g, yield: 90.1%.
Embodiment 4 (2S, 4S)-preparation of 4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol
With (2S, 4R)-1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 8.9g (30mmol) and thioacetic acid potassium 6.9g (60mmol) be dissolved among the DMF100ml, be heated to 65 ℃ of reaction 10h. and be chilled to room temperature, add water 200ml dilution, extract ethyl acetate 100ml * 2, and organic phase washes with water, dry, concentrated, get yellow oil 7.9g, yield: 95.6%.
Embodiment 5 (2S, 4S)-4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-4-methyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) The preparation of tetramethyleneimine
With (2S, 4S)-add triphenylphosphine 7.8g (30mmol) and N-(tertbutyloxycarbonyl)-4-methyl-benzsulfamide 9.0g (33mmol) among the THF solution 40ml of 4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol 5.5g (20mmol), 0 ℃ slowly drips diethyl azodiformate 5.4g (30mmol), drip and finish 0～2 ℃ of reaction 6h, add toluene 50ml, add toluene 80ml again after concentrating, separate out solid, filter, filtrate concentrates, and residuum dissolves with the 30ml methylene dichloride, the hydrochloric acid soln that adds 100ml5mol/L, be warming up to 40 ℃, stirring reaction 2h tells organic phase, through washing, dry, concentrate, residuum gets white solid 5.8g, yield: 60.0% with ethyl acetate-hexanaphthene recrystallization.
Embodiment 6 (2S, 4S)-4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-3-methyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) The preparation of tetramethyleneimine
With reference to embodiment 5 preparation methods, throw (2S, 4S)-4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol 5.5g (20mmol), N-(tertbutyloxycarbonyl)-3-methyl-benzsulfamide 9.0g (33mmol), get (2S, 4S)-and 4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-3-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine 5.3g, yield: 54.6%.
Embodiment 7 (2S, 4S)-4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-4-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) The preparation of tetramethyleneimine
With reference to embodiment 5 preparation methods, throw (2S, 4S)-4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol 5.5g (20mmol), N-(tertbutyloxycarbonyl)-4-carboxyl-benzsulfamide 10.5g (35mmol), get (2S, 4S)-and 4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-4-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine 5.5g, yield: 53%.
Embodiment 8 (2S, 4S)-4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-3-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) The preparation of tetramethyleneimine
With reference to embodiment 5 preparation methods, throw (2S, 4S)-4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol 5.5g (20mmol), N-(tertbutyloxycarbonyl)-3-carboxyl-benzsulfamide 10.5g (35mmol), get (2S, 4S)-and 4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-3-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine 5.3g, yield: 51.6%.
Embodiment 9 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-4-methyl-benzene sulfonamido] methylene radical-1-(uncle's fourth The oxygen carbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid is to nitre The preparation of base benzyl ester
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 solution 120ml of 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol) is chilled to below-10 ℃, add diisopropylethylamine 5ml and (2S, 4S)-and 4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-4-methyl-benzene sulfonamido] the acetonitrile solution 80ml of methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine 10.7g (22mmol), 0 ℃ is stirred 15h, after reaction finishes, add ethyl acetate 300ml dilution, successively water, the saturated salt washing, the organic layer drying, concentrate, get yellow solid 11.3g, yield: 68.1%.
Embodiment 10 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-3-methyl-benzene sulfonamido] methylene radical-1-(uncle's fourth The oxygen carbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid is to nitre The preparation of base benzyl ester
With reference to embodiment 9 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]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (2S, 4S)-and 4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-3-methyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine 10.7g (22mmol), get product 10.6g, yield: 61.3%.
Embodiment 11 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-4-carboxyl-benzene sulfonamido] methylene radical-1-(uncle's fourth The oxygen carbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid is to nitre The preparation of base benzyl ester
With reference to embodiment 9 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]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (2S, 4S)-4-sulfydryl-2-[N-(tertbutyloxycarbonyl)-4-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine 11.4g (22mmol).Get product 10.9g, yield: 63.5%.
Embodiment 12 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-3-carboxyl-benzene sulfonamido] methylene radical-1-(uncle's fourth The oxygen carbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid is to nitre The preparation of base benzyl ester
With reference to embodiment 9 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]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-oxazole-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 11.4g (22mmol), get product 10.6g, yield: 64.8%.
Embodiment 13 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid (being The compounds of this invention 1)
With (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-4-methyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-the 50ml methylene dichloride of 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 8.3g (10mmol) in, add methyl-phenoxide 10ml and Nitromethane 99Min. 20ml, in-50 ℃ of Nitromethane 99Min. solution 100ml that drip the 1mol/L aluminum chloride down ,-40 ℃ are stirred 2h, add entry 200ml, separate out solid, filter, filter cake is dissolved in the mixed solution of 400mlTHF and water 30ml, add 10% Lin Dela palladium-charcoal 2g, stirring reaction 2h under the room temperature 5MPa 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 30ml, and-10 ℃ are stirred 1h, filters, and filter cake water-Virahol recrystallization gets white crystal 2.5g, yield: 49.6%.
Molecular formula: C 22H 29N 3O 6S 2
Molecular weight: 495.61
Ultimate analysis: C, 53.20%; H, 6.16%; N, 8.31%; S, 12.77%
(calculate: C, 53.31%; H, 5.90%; N, 8.48%; S, 12.94%)
Embodiment 14 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid (being The compounds of this invention 2)
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-3-methyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 8.6g (10mmol), get target product 2.5g, yield: 48.1%.
Molecular formula: C 22H 29N 3O 6S 2
Molecular weight: 495.61
Ultimate analysis: C, 50.39%; H, 5.39%; N, 7.65%; S, 12.11%
(calculate: C, 50.27%; H, 5.18%; N, 7.99%; S, 12.20%)
Embodiment 15 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid (being The compounds of this invention 3)
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-4-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 8.6g (10mmol), get target product 2.7g, yield: 51.7%.
Molecular formula: C 22H 27N 3O 8S 2
Molecular weight: 525.60
Ultimate analysis: C, 50.11%; H, 5.35%; N, 8.07%; S, 12.05%
(calculate: C, 50.27%; H, 5.18%; N, 7.99%; S, 12.20%)
Embodiment 16 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid (being The compounds of this invention 4)
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-[N-(tertbutyloxycarbonyl)-3-carboxyl-benzene sulfonamido] methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 8.6g (10mmol), get target product 2.5g, yield: 48.1%.
Molecular formula: C 22H 27N 3O 8S 2
Molecular weight: 525.60
Ultimate analysis: C, 50.39%; H, 5.39%; N, 7.65%; S, 12.11%
(calculate: C, 50.27%; H, 5.18%; N, 7.99%; S, 12.20%)
The preparation of embodiment 17 The compounds of this invention aseptic powder injections
1, prescription:
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing raw material (feeding intake after the conversion) by prescription, sterilized powder is placed the portioning machine packing, detect loading amount at any time; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 18 The compounds of this invention tablets
1, prescription:
Figure A200710014859D00212
2, preparation technology: raw material pulverizing is crossed 100 mesh sieves, and all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby; Take by weighing raw material and auxiliary material according to recipe quantity; Hypromellose 2% the aqueous solution made soluble in water is standby; With in compound 1～4 or derivatives thereof any one, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, it is an amount of to add the 2%HPMC aqueous solution, stirs, and makes suitable softwood; Cross 20 mesh 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 (10)

1, the hydrate of the ester of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and ester or salt:
Figure A200710014859C00021
Wherein, R 1Representation carboxy ,-COOR 6Or the ester of facile hydrolysis, described R 6The representation carboxy protecting group;
R 2And R 3Represent hydrogen atom respectively independently, the ester of amino protecting group or facile hydrolysis;
R 4Represent hydrogen atom, low alkyl group or carboxyl;
And phenyl ring can further be replaced by 1-2 substituting groups, and described substituting group is selected from hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, nitro, trifluoromethyl, low alkyl group, lower alkoxy, lower alkoxycarbonyl, amino-sulfonyl, the low-grade alkyl amino alkylsulfonyl, formamyl, sulfonic group or low-grade alkyl amino;
R 5Represent hydrogen atom or low alkyl group.
2, the hydrate of the ester of compound as claimed in claim 1, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and ester or salt:
Wherein, R 1Representation carboxy ,-COOR 6Or the ester of facile hydrolysis,
Described R 6The 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 2And R 3Represent hydrogen atom respectively independently, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group; be selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, 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 4Represent hydrogen atom, methyl or carboxyl;
And phenyl ring can further be replaced by 1-2 substituting groups, and described substituting group is selected from hydrogen atom, fluorine atom, hydroxyl, amino, carboxyl, cyano group, nitro, methyl, trifluoromethyl, ethyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxy carbonyl, amino-sulfonyl, the methylamino alkylsulfonyl, formamyl, sulfonic group or methylamino;
R 5Represent hydrogen atom or methyl.
3, the hydrate of the ester of compound as claimed in claim 2, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and ester or salt:
Wherein, R 1Representation carboxy ,-COOR 6Or the ester of facile hydrolysis,
Described R 6The 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 2And R 3Represent hydrogen atom respectively separately, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group is selected from methyl, the tertiary butyl, benzyl, formyl radical, allyloxy carbonyl, to nitro benzyloxycarbonyl 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 4Represent methylidene or carboxyl;
And phenyl ring can further be replaced by 1-2 substituting groups, and described substituting group is selected from hydrogen atom, fluorine atom, hydroxyl, amino, carboxyl, cyano group, nitro, methyl, trifluoromethyl, ethyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxy carbonyl, amino-sulfonyl, the methylamino alkylsulfonyl, formamyl, sulfonic group or methylamino;
R 5Represent methylidene.
4, compound as claimed in claim 3 is selected from:
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-methyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[4-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, or
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-[3-carboxyl-benzene sulfonamido] methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid,
And the hydrate of ester, its isomer, its hydrate and the ester or the salt of pharmacy acceptable salt, its facile hydrolysis.
5, as the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises 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.
6, as the described compound of the arbitrary claim of claim 1～4, the ester of its facile hydrolysis is for being hydrolyzed into the ester of corresponding carboxylic acid in vivo.
7, comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner.
8, pharmaceutical composition as claimed in claim 7 is pharmaceutically acceptable arbitrary formulation.
9, pharmaceutical composition as claimed in claim 7, the hydrate 0.01g～10g of ester, its isomer, its hydrate or its ester or salt that contains the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis is as essential activeconstituents.
10, as the hydrate of ester, its isomer, its hydrate and the ester or the salt of the described compound of the arbitrary claim of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis, in the application that is used for preparing the medicine that treats and/or prevents infectious diseases.
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