CN101333217A - 1-methyl carbapenem antibiotics - Google Patents

1-methyl carbapenem antibiotics Download PDF

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CN101333217A
CN101333217A CNA2007100166079A CN200710016607A CN101333217A CN 101333217 A CN101333217 A CN 101333217A CN A2007100166079 A CNA2007100166079 A CN A2007100166079A CN 200710016607 A CN200710016607 A CN 200710016607A CN 101333217 A CN101333217 A CN 101333217A
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ester
methyl
acid
hydrogen atom
hydrate
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黄振华
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Priority to JP2010513622A priority patent/JP2010531308A/en
Priority to PCT/CN2008/001238 priority patent/WO2009000163A1/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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Abstract

The invention belongs to the field of medical technology, particularly relating to a 1 - methyl carbapenem antibiotic as shown in the general formula (1), and also relating to the pharmaceutical acceptable salts of the antibiotic, the easy hydrolysis esters of the antibiotic, the isomers of the antibiotic, the hydrates of the antibiotic, as well as the hydrates of the esters or salts of the antibiotic; wherein, R1, R2, R3, R4, R5, R6 and n are defined in the instruction book; the invention also relates to the preparation methods for the compounds, the drug combinations containing the compounds, as well as the applications of the compounds in the preparation of drugs for curing and/or preventing infectious diseases.

Description

The 1-beta-methyl carbapenem antibiotic
1, technical field
The invention belongs to medical technical field, be specifically related to beta-methylcarbapenem antibiotics, its pharmacy acceptable salt, its facile hydrolysis ester, its isomer, its hydrate, with and the hydrate of ester or salt, 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 is the class β-Nei Xiananleikangshengsu that the seventies grows up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stable to β-Nei Xiananmei, and receives much concern.Its constructional feature is, the sulphur that the penam parent nucleus is 1 is replaced by carbon, and 2 have two keys, the effect of the five-ring of compound penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.
This similar drug that has gone on the market at present has imipenum, meropenem, S-4661, biapenem, ertapenem etc.Because antibiotic abuse causes the continuous increase of bacterial drug resistance, and because the limitation that digestive tube absorbs, the carbapenems of listing clinically can only be as the injection administration at present, clinical availability is not high, and except that S-4661 the transformation period all shorter, can not meet clinical needs.
Therefore, be badly in need of research and development and have better antibacterial activity, and have the long-acting carbapenem antibiotic of good chemical stability and DHP-I stability.
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 (1), its pharmacy acceptable salt, its facile hydrolysis:
Figure A20071001660700041
Wherein, R 1Represent hydrogen atom or carboxyl-protecting group;
R 2Represent hydrogen atom or amino protecting group;
R 3Represent hydrogen atom or low alkyl group;
R 4, R 5Independently represent hydrogen atom respectively, low alkyl group, perhaps R 4, R 5Link to each other and form 5-8 unit ring;
R 6Represent hydrogen atom, halogen atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl, by amino, hydroxyl, carboxyl substituted or unsubstituted low alkyl group, lower alkoxy, low-grade alkyl amino alkylsulfonyl, elementary alkyl amido methanoyl, low alkyl group sulfonamido, perhaps low alkyl group amido;
N represents 1,2 or 3.
Preferred compound is:
Wherein, R 1Represent hydrogen atom or carboxyl-protecting group;
R 2Represent hydrogen atom or amino protecting group;
R 3Represent hydrogen atom, methyl or ethyl;
R 4, R 5Independently represent hydrogen atom respectively, methyl, ethyl, perhaps R 4, R 5Link to each other and form 5-6 unit ring;
R 6Represent hydrogen atom, fluorine atom, chlorine atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl, low alkyl group, lower alkoxy, methylamino formyl radical, methanesulfonamido or kharophen;
N represents 1 or 2.
Further preferred compound is:
Wherein, R 1Represent hydrogen atom;
R 2Represent hydrogen atom;
R 3Represent hydrogen atom or methyl;
R 4, R 5Independently represent hydrogen atom respectively, methyl, ethyl, perhaps R 4, R 5Link to each other and form 5 yuan of rings;
R 6Dai Ji represents hydrogen atom, low alkyl group;
N represents 2.
" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms or 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 comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.
" low-grade alkyl amino alkylsulfonyl " of the present invention is C 1-6Alkyl amino sulfonyl comprises first sulfamyl, second sulfamyl etc.
" elementary alkyl amido methanoyl " of the present invention is C 1-6Alkyl-carbamoyl comprises methylamino formyl radical, ethylamino formyl radical etc.
" low alkyl group sulfonamido " of the present invention is C 1-6Alkyl sulfonyl amino comprises methanesulfonamido, ethanesulfonamido etc.
" low alkyl group amido " of the present invention is C 1-6Alkyl amido comprises kharophen, propionamido 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: 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, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; The N-formyl radical, the N-ethanoyl, N-ethanoyl-pyridine, N-(N '-the dithio benzyloxycarbonyl amino) ethanoyl, N-3-phenyl propionyl, N-3-(to hydroxyphenyl) propionyl, N-3-(ortho-nitrophenyl base) propionyl, N-2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, N-2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, N-4-chloro butyryl radicals, the N-isobutyryl, the adjacent nitro cinnamoyl of N-, N-pyridine formyl radical, N-(N '-the acetyl methionyl), N-(N '-benzoyl-phenylalkyl), the N-benzoyl, N-is to the phenyl benzoyl, N-is to anisoyl, the N-o-nitrobenzoyl, N-neighbour's (benzoyloxy methyl) benzoyl and N-be right-acid amides of P-benzoyl; N-phthaloyl, N-2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and N-dithio succinyl; The N-allyl group; the N-allyloxy carbonyl; the N-phenacyl; N-3-acetoxyl group propyl group; N-(4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-yl); quaternary ammonium salt; the N-methoxymethyl; N-2-chloroethoxy methyl; the N-benzyloxymethyl; N-valeryl methyl; N-[1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; N-[1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the N-2-THP trtrahydropyranyl; N-2; the 4-dinitrophenyl; the N-benzyl; N-3; the 4-dimethoxy-benzyl; the adjacent nitrobenzyl of N-; N-two (p-methoxyphenyl) methyl; the N-trityl; N-(p-methoxyphenyl) diphenyl methyl; N-phenylbenzene-4-pyridylmethyl; N-2-picolyl N '-oxide compound; N-5-two phenylpropyl alcohol suberane bases; N-(N '; N '-dimethylaminomethylene); N; N '-isopropylidene; the N-benzylidene; N-is to the methoxyl group benzylidene; N-is to the nitro benzylidene; the N-salicylidene; N-5-chlorine salicylidene; the N-diphenylmethylene; N-(5-chloro-2-hydroxyphenyl) phenylmethylene; N-(acyl group vinyl); N-(5; 6-dimethyl-3-oxo-1-cyclohexenyl); the N-borine; N-[phenyl (pentacarbonyl chromium or tungsten)] carbonyl; N-copper or N-chelates of zinc; the N-nitro; the N-nitroso-group; the N-oxide compound; the N-diphenylphosphino; N-diformazan sulfenyl phosphinyl; N-hexichol sulfenyl phosphinyl; N-diethyl phosphoryl; N-dibenzyl phosphoryl; N-diphenylphosphine acyl group; phosphoryl; the N-trimethyl silyl; the N-thiophenyl; N-ortho-nitrophenyl sulfenyl; N-2; 4-dinitrobenzene sulfenyl; N-2-nitro-4-anisole sulfenyl; N-three benzylthios; the N-benzenesulfonyl; N-is to the anisole alkylsulfonyl; N-2; 4,6-Three methyl Benzene alkylsulfonyl; the N-methyl sulphonyl; N-benzene methylsulfonyl; N-is to the toluene methylsulfonyl; the N-trifluoromethyl sulfonyl; N-phenacyl alkylsulfonyl etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, 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, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
The chemical name and the structural formula of particularly preferred compound are as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-[2-(3 for the 2-formyl, 4-dimethoxy-benzene-1-yl)-N-methyl-ethylamino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 1, structural formula is as follows:
Figure A20071001660700071
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-[4-(1 for the 2-formyl, 1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 2, structural formula is as follows:
The present invention also provides the preparation method of above-claimed cpd:
Reaction equation:
Figure A20071001660700081
Reactions steps:
The preparation of step 1 intermediate B
In the exsiccant reaction flask, add raw material 1, anhydrous tetrahydro furan.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles (CDI), reaction adds raw material 2, continues reaction.Dripping hydrochloric acid is used ethyl acetate extraction then, and organic phase is water, saturated nacl aqueous solution washing successively, concentrating under reduced pressure, resistates adds hydrochloric acid, stirs, and is adjusted to pH with dilute alkaline soln, separate out solid, solid gets intermediate B with ethyl acetate-hexanaphthene mixed solution recrystallization.
The preparation of step 2 intermediate C
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]-and 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's (raw material 3) acetonitrile solution, cooling, the acetonitrile solution that adds diisopropylethylamine and intermediate B stirs.After reaction finishes, add the ethyl acetate dilution, tell organic layer, organic layer is water, saturated salt washing successively, and drying concentrates, and gets intermediate C.
The preparation of step 3 The compounds of this invention
To go up step gained intermediate C and be dissolved in the methylene dichloride, add methyl-phenoxide and Nitromethane 99Min., in-50 ℃ of Nitromethane 99Min. solution that drip aluminum chloride down, stir, add entry, separate out solid, filter, filter cake is dissolved in the mixed solution of THF and water, adds 10% palladium-charcoal, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF in the filtrate, water layer is collected in layering.In THF, add magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and slowly splashes into methyl alcohol, stirs, and filters, and filter cake water-Virahol recrystallization promptly gets The compounds of this invention.
R in the above reaction equation 3, R 4, R 5, R 6The representative group and the n numeric value represented as mentioned before, the carboxyl in the invention compound of the present invention can be protected by carboxyl-protecting group, the hydrogen atom on the nitrogen-atoms can be protected by amino protecting group, is compound shown in the general formula (1).
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 that the claimed compound of the present invention is easy to hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis.These esters can be conventional, lower alkane acyloxyalkyl group ester for example, acetoxyl methyl ester, pivalyl oxygen methyl ester, 1-acetoxyl ethyl ester, 1-pivalyl oxygen ethyl ester; The lower alkoxycarbonyl alkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, 1-sec.-propyl ketonic oxygen ethyl ester; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; The lower alkoxy methyl ester, methoxymethyl ester; Lower alkane acyl amino methyl ester, the acetylamino methyl ester.The ester that also can use other is for example: benzyl ester and cyano methyl ester.Other examples of these esters are as follows: (2,2-dimethyl-1-oxygen propoxy-) methyl ester; (1RS)-1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-the pentenyl ester; The 1-[[(1-methyl ethoxy) carbonyl] oxygen] ethyl ester; 1-(acetoxyl) ethyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester; The 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester; 3,3-dimethyl-2-oxo butyl ester.It is evident that for the professional of this area the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy place of this compound, for example at 4 carboxyl place.
Isomer of the present invention is meant its all differences 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 (1) compound has many three-dimensional centers, that is: on the 4-position; On the 5-position; On the 6-position; On the 8-position.
The ester of the compound shown in the general formula (1), 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 includes the hydrate of ester, its isomer, its hydrate and the ester or the salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis, with the pharmaceutical composition of other active pharmaceutical ingredients, as cilastatin and sodium salt thereof, Betamipron.
The present invention is the claimed hydrate that comprises ester, its isomer, its hydrate and the ester or the salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis further; pharmaceutical composition with 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 (1) 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 compounds of this invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and 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.
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 present invention also provide new beta-methylcarbapenem antibiotics preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.Beta-methyl carbapenem antibiotic of the present invention all has better antibacterial activity to Gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria such as Pseudomonas aeruginosa and acinetobacter bacterium, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
Beta-methylcarbapenem antibiotics of the present invention compared with prior art has the following advantages:
(1) The compounds of this invention has good anti-microbial activity and shows hypotoxicity, can being used for the treatment of and/or preventing various Mammalss (comprising the mankind) by the caused various diseases of sensitive organism by safety;
(2) The compounds of this invention has a broad antifungal spectrum all has better antibacterial activity to Gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria;
(3) The compounds of this invention has high stability to β-Nei Xiananmei and DHP-I, can be used for β-Nei Xiananmei and produces bacterium, and do not need to share with other medicines;
(4) long half time in the The compounds of this invention body can reduce administration number of times, improves patient's tolerance;
(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.
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, 4S)-4-sulfydryl-2-formyl [2-(3,4-dimethoxy-benzene-1-yl)-N-methyl-ethylamino]-1-(tertiary butyloxycarbonyl Base) preparation of tetramethyleneimine
In the exsiccant reaction flask, add (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 14.5g (50mmol), anhydrous tetrahydro furan 100ml.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles 13.1g (80mmol), reaction 1h is adding 17.6g (90mmol) 2-(3,4-dimethoxy-benzene-1-yl)-N-methyl-ethylamine below 0 ℃, continue reaction 1h.Drip 1mol/l hydrochloric acid 40ml then, extract with ethyl acetate (50ml * 2), organic phase is water, saturated nacl aqueous solution washing successively, concentrating under reduced pressure, and resistates adds the hydrochloric acid 100ml of 5mol/L, stir 2h, be adjusted to pH8 with dilute alkaline soln, separate out solid, solid is with ethyl acetate-hexanaphthene mixed solution recrystallization, get solid 16.5g, yield: 77.6%.
Embodiment 2 (2S, 4S)-4-sulfydryl-2-formyl [2-(3,4-methylene-dioxy-benzene-1-yl)-ethylamino]-1-(tertbutyloxycarbonyl) pyrrole Cough up the preparation of alkane
Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 14.5g (50mmol), 2-(3,4-methylene-dioxy-benzene-1-yl)-ethylamine 14.5g (90mmol), (2S, 4S)-[2-(3 for 4-sulfydryl-2-formyl, 4-methylene-dioxy-benzene-1-yl)-ethylamino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 16.3g, yield: 82.6%.
Embodiment 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [2-(3,4-dimethoxy-benzene-1-yl)-N-methyl-ethylamino]-1-(uncle Butoxy carbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-the 2-carboxylic acid is right The preparation of nitrobenzyl 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 200ml of 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 23.8g (40mmol), be chilled to below-10 ℃, add diisopropylethylamine 10ml and (2S, 4S)-[2-(3 for 4-sulfydryl-2-formyl, 4-dimethoxy-benzene-1-yl)-N-methyl-ethylamino]-the acetonitrile solution 100ml of 1-(tertbutyloxycarbonyl) tetramethyleneimine 19.1g (45mmol), 0 ℃ is stirred 15h.After reaction finishes, add the dilution of 400ml ethyl acetate, tell organic layer, organic layer is water, saturated salt washing successively, and drying concentrates, and gets solid 21.9g, yield: 71.3%.
Embodiment 4 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [2-(3,4-methylene-dioxy-benzene-1-yl)-ethylamino]-1-(tertiary butyloxycarbonyl Base) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid is to nitrobenzyl The preparation of ester
Concrete preparation method's reference example 3.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 23.8g (40mmol), (2S, 4S)-4-sulfydryl-2-formyl [2-(3,4-methylene-dioxy-benzene-1-yl)-ethylamino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 17.8g (45mmol).Get product 22.9g, yield: 77.4%.
Embodiment 5 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [2-(3,4-dimethoxy-benzene-1-yl)-N-methyl-ethylamino]-pyrroles Alkane-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
With (4R, 5S, 6S)-3-[(2S, 4S)-[2-(3 for the 2-formyl, 4-dimethoxy-benzene-1-yl)-N-methyl-ethylamino]-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 15.4g (20mmol) is dissolved in the 100ml methylene dichloride, adds methyl-phenoxide 20ml and Nitromethane 99Min. 30ml, in-50 ℃ of Nitromethane 99Min. solution 200ml 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, adds 10% palladium-charcoal 4g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF150ml in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 30ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 50ml, and-10 ℃ are stirred 1h, filters, and filter cake water-Virahol recrystallization gets white crystal 5.8g, yield: 54.6%.
Molecular formula: C 26H 35N 3O 7S
Molecular weight: 533.64
Ultimate analysis:
Measured value: C, 58.45%; H, 6.87%; N, 7.69%; S, 5.85%
Theoretical value: C, 58.52%; H, 6.61%; N, 7.87%; S, 6.01%
Embodiment 6 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]- Tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid
Preparation method's reference example 5.Throw (4R, 5S, 6S)-3-[(2S, 4S)-[2-(3 for the 2-formyl, 4-methylene-dioxy-benzene-1-yl)-ethylamino]-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 14.8g (20mmol).Get white crystal 5.2g, yield: 52.1%.
Molecular formula: C 24H 29N 3O 7S
Molecular weight: 503.57
Ultimate analysis:
Measured value: C, 57.05%; H, 6.09%; N, 8.12%; S, 6.27%
Theoretical value: C, 57.24%; H, 5.80%; N, 8.34%; S, 6.37%
The preparation of embodiment 7 The compounds of this invention aseptic powder injections
1, prescription:
Any one 10～10000g in compound 1～2 or derivatives thereof
Prepare 1000 altogether
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 8 The compounds of this invention tablets
1, prescription:
Any one 10～10000g in compound 1～2 or derivatives thereof
Pregelatinized Starch is an amount of
Low-substituted hydroxypropyl cellulose is an amount of
Microcrystalline Cellulose is an amount of
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel is an amount of
Magnesium Stearate is an amount of
Carboxymethylstach sodium is an amount of
Prepare 1000 altogether
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 1～2 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 (1), its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and ester or salt:
Figure A2007100166070002C1
Wherein, R 1Represent hydrogen atom or carboxyl-protecting group;
R 2Represent hydrogen atom or amino protecting group;
R 3Represent hydrogen atom or low alkyl group;
R 4, R 5Independently represent hydrogen atom respectively, low alkyl group, perhaps R 4, R 5Link to each other and form 5-8 unit ring;
R 6Represent hydrogen atom, halogen atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl, by amino, hydroxyl, carboxyl substituted or unsubstituted low alkyl group, lower alkoxy, low-grade alkyl amino alkylsulfonyl, elementary alkyl amido methanoyl, low alkyl group sulfonamido, perhaps low alkyl group amido;
N represents 1,2 or 3.
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:
R 1Represent hydrogen atom or carboxyl-protecting group;
R 2Represent hydrogen atom or amino protecting group;
R 3Represent hydrogen atom, methyl or ethyl;
R 4, R 5Independently represent hydrogen atom respectively, methyl, ethyl, perhaps R 4, R 5Link to each other and form 5-6 unit ring;
R 6Represent hydrogen atom, fluorine atom, chlorine atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl, low alkyl group, lower alkoxy, methylamino formyl radical, methanesulfonamido or kharophen;
N represents 1 or 2.
3, the hydrate of the ester of compound as claimed in claim 2, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate and ester or salt:
Wherein, R 1Represent hydrogen atom;
R 2Represent hydrogen atom;
R 3Represent hydrogen atom or methyl;
R 4, R 5Independently represent hydrogen atom respectively, methyl, ethyl, perhaps R 4, R 5Link to each other and form 5 yuan of rings;
R 6Dai Ji represents hydrogen atom, low alkyl group;
N represents 2.
4, compound as claimed in claim 3 is selected from:
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [2-(3,4-dimethoxy-benzene-1-yl)-N-methyl-ethylamino]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, perhaps
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-(1,1-diketo-thiomorpholine-4-yl) methyl-phenyl amino]-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, its ester or the salt of pharmacy acceptable salt, its facile hydrolysis.
5, the described arbitrary compound 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, the described arbitrary compound 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 arbitrary compound of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner.
8, pharmaceutical composition as claimed in claim 7 is pharmaceutically acceptable arbitrary formulation.
9, pharmaceutical composition as claimed in claim 7 contains the hydrate 0.01g～10g of ester, its isomer, its hydrate or its ester or salt of the described arbitrary compound of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis as essential activeconstituents.
10, the hydrate of ester, its isomer, its hydrate and the ester or the salt of the described arbitrary compound of claim 1～4, its pharmacy acceptable salt, its facile hydrolysis is in the application that is used for preparing the medicine that treats and/or prevents infectious diseases.
CNA2007100166079A 2007-06-26 2007-06-26 1-methyl carbapenem antibiotics Pending CN101333217A (en)

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