CN101362759B - Dihydropyrrole methano substituted carbapenem derivates - Google Patents

Dihydropyrrole methano substituted carbapenem derivates Download PDF

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CN101362759B
CN101362759B CN2008101454985A CN200810145498A CN101362759B CN 101362759 B CN101362759 B CN 101362759B CN 2008101454985 A CN2008101454985 A CN 2008101454985A CN 200810145498 A CN200810145498 A CN 200810145498A CN 101362759 B CN101362759 B CN 101362759B
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CN101362759A (en
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黄振华
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Xuanzhu Biopharmaceutical Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention pertains to the technical field of medicine and particularly relates to a carbon-substituted penem derivative which contains dihydro pyrrole methylene substitution and is shown as general formula (I), and pharmaceutically acceptable salts, easily hydrolysable ester and isomers of the derivative; wherein, R<1>, R<2> and R<3> are defined as the specification. The invention also relates to a preparation method of the compounds, medicine composition containing the compounds as well as application of the compounds to the preparation of medicines treating and/or preventing infectious diseases.

Description

Contain the carbapeneme derivatives that the pyrrolin methylene radical replaces
1, technical field
The invention belongs to medical technical field, be specifically related to contain the ester and the isomer thereof of carbapeneme derivatives that the pyrrolin methylene radical replaces, its pharmacy acceptable salt, its facile hydrolysis, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent purposes in the medicine of infectious diseases in preparation.
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.
Figure G2008101454985D00011
Meropenem
This similar drug that has gone on the market at present has imipenum, meropenem, S-4661, biapenem, ertapenem etc.Meropenem is the microbiotic of first 1 Beta-methyl carbapenem of present listing, along with the rising of clinical frequency of utilization, has demonstrated resistance gradually.Because antibiotic abuse causes the continuous increase of bacterial drug resistance, and except that ertapenem the transformation period all shorter, can not meet clinical needs.
Therefore, be badly in need of research and development and have better antibacterial activity, effective to resistant organism, and the carbon substituted penems antibiotics with good chemical stability and dehydropeptidase of kidney-I (DHP-I) stability.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides the ester and the isomer thereof of the compound shown in the general formula (1), its pharmacy acceptable salt, its facile hydrolysis:
Figure G2008101454985D00012
Wherein, R 1Representation carboxy ,-COOR 4Or the ester of facile hydrolysis, wherein R 4The representation carboxy protecting group;
R 2Represent hydrogen atom, by halogen atom, hydroxyl or carboxyl substituted or unsubstituted C 1-6Alkyl, the ester of amino protecting group or facile hydrolysis;
R 3Represent hydrogen atom, hydroxyl, carboxyl, amino, or by amino, hydroxyl or carboxyl substituted or unsubstituted C 1-6Alkyl, C 1-6Alkoxyl group.
Preferred compound is:
Wherein, R 1Representation carboxy ,-COOR 4Or the ester of facile hydrolysis,
R 4The representation carboxy protecting group is selected from methyl, methoxymethyl, first thiomethyl, methoxyethyl methyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl or to nitrobenzyl,
The ester of described facile hydrolysis is selected from lower alkane acyloxyalkyl group ester, cycloalkanes acyloxyalkyl group ester, lower alkane acyloxyalkyl group ester, cycloalkanes acyloxyalkyl group ester, lower alkoxycarbonyl oxyalkyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester;
R 2Represent hydrogen atom, C 1-4Alkyl, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group is selected from benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl or 3-acetoxyl group propyl group, tertbutyloxycarbonyl,
The ester of described facile hydrolysis is selected from lower alkanols alkanoyloxymethyl oxygen carbonyl ester, cycloalkanes acyloxy methyl oxygen carbonyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methoxycarbonyl ester;
R 3Represent hydrogen atom, hydroxyl, carboxyl, amino, C 1-4Alkyl or C 1-4Alkoxyl group.
Further preferred compound is:
Wherein, R 1Representation carboxy ,-COOR 4Or the ester of facile hydrolysis,
R wherein 4The representation carboxy protecting group is selected from methyl, allyl group, benzyl or to nitrobenzyl,
The ester of described facile hydrolysis is selected from 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 or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester;
R 2Represent hydrogen atom, methyl, ethyl, the ester of amino protecting group or facile hydrolysis,
Described amino protecting group is selected from formyl radical, tertbutyloxycarbonyl,
The ester of described facile hydrolysis is selected from propionyl oxygen methoxycarbonyl ester, butyryl oxygen methoxycarbonyl ester, tertiary butyl methanoyl methoxycarbonyl ester, the different third oxygen methanoyl methoxycarbonyl ester, different third oxygen methanoyl-1-ethoxycarbonyl ester, hexamethylene alcoxyl methanoyl-1-ethoxycarbonyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methoxycarbonyl ester;
R 3Represent hydrogen atom, hydroxyl, carboxyl or amino.
Part of compounds of the present invention is listed below:
Figure G2008101454985D00021
Compound number R 2 R 3
1 H H
2 -CH 3 H
Compound number R 2 R 3
3 -CH 2CH 3 H
4 H 2-OH
5 -CH 3 4-OH
6 -CH 2CH 3 3-OH
7 H 5-COOH
8 -CH 3 2-COOH
9 -CH 2CH 3 3-COOH
10 H 4-NH 2
11 -CH 3 5-NH 2
12 -CH 2CH 3 2-NH 2
" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" C of the present invention 1-6Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
" C of the present invention 1-6Alkoxyl group " comprise methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N '-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Tert-butoxycarbonyl; allyloxy carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl-N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; N '; N '-dimethylaminomethylene; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; (acyl group vinyl); 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; the phenacyl alkylsulfonyl; diazo etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: 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.
The chemical name and the structural formula of particularly preferred compound are as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 1, structural formula is as follows:
Figure G2008101454985D00051
(4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 2, structural formula is as follows:
Figure G2008101454985D00052
The present invention also provides the preparation method of above-claimed cpd, reaction equation:
Figure G2008101454985D00053
Reactions steps:
The preparation of step 1 compd A
In the dry reaction bottle, add dioxane, add Zinc Chloride Anhydrous then, POTASSIUM BOROHYDRIDE after the stirring at room, adds raw material 1.Stir and slowly be warming up to back flow reaction down.Be chilled to room temperature, add the hydrochloric acid dilution, ethyl acetate extraction.Organic phase is washed with saturated salt, and drying concentrates, and promptly gets compd A.
The preparation of step 2 compd B
In the dry reaction bottle, step gained compd A and thioacetic acid potassium adds DMF then in the adding, be heated with stirring to dissolving after, insulation reaction.After being cooled to room temperature, thin up, ethyl acetate extraction, organic phase washes with water, and drying concentrates, and promptly gets compd B.
The preparation of step 3 Compound C
Under nitrogen protection, step gained compd B in the adding, methylene dichloride splashes into TMSI, vigorous stirring reaction under the room temperature, decompress filter is stirred in cooling.The filter cake washed with dichloromethane, filtrate collection is in the flask of precooling.Under nitrogen protection, in this solution, drip the tetrahydrofuran solution that contains dimethylamine, dropwise, reaction, the reaction solution decolouring, suction filtration, filtrate decompression is concentrated into dried, adds hydrochloric acid then, and stirring reaction is chilled to room temperature, suction filtration, drying promptly gets Compound C.
The preparation of step 4 Compound D
In the dry reaction bottle, add the acetonitrile solution of raw material 3, cooling, the acetonitrile solution of adding diisopropylethylamine and last step gained Compound C stirs.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated promptly gets Compound D.
The preparation of step 5 compd E
Gained Compound D of last step is dissolved in the mixed solution of THF and water, adds Lin Dela palladium charcoal, stirring reaction under the room temperature 2MPa hydrogen pressure, filtering palladium charcoal adds THF in the filtrate, and 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 the filter cake acetone recrystallization promptly gets compd E.
R in the above reaction equation 2, R 3The representative group as mentioned before, the carboxyl in the compd E can be protected by carboxyl-protecting group, also can form the ester of facile hydrolysis, 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 that contains sodium, potassium, barium, calcium, magnesium, zinc, lithium.
The ester of the compound facile hydrolysis that the present invention is claimed is meant the ester of hydrolysis in vivo.For example, the ester of the facile hydrolysis that forms with carboxyl, for example lower alkane acyloxyalkyl group ester comprises sec.-propyl methanoyl methyl esters, tertiary butyl methanoyl methyl esters, neo-pentyl methanoyl methyl esters, isobutyl ester methanoyl methyl esters, new penta acetyl oxygen methyl esters, decoyl oxygen methyl esters, caprinoyl oxygen methyl esters; Cycloalkanes acyloxyalkyl group ester comprises cyclohexyl methanoyl methyl esters, cyclohexyl methanoyl-1-ethyl ester, 1-methyl-cyclohexyl alkyl methanoyl-1-ethyl ester, 4-methyl-cyclohexyl alkyl methanoyl methyl esters; Lower alkanols alcoxyl base acyloxyalkyl group ester comprises (ethoxymethyl) acyl-oxygen methyl esters, isopropoxy methanoyl-1-ethyl ester, hexyloxy methanoyl-1-ethyl ester, octyloxy methanoyl-1-ethyl ester, last of the ten Heavenly stems oxygen base methanoyl-1-ethyl ester, dodecyloxy methanoyl-1-ethyl ester; Cycloalkyloxy acyloxyalkyl group ester comprises pentamethylene oxygen base methanoyl-1-ethyl ester, hexamethylene alkoxyl group methanoyl-1-ethyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester etc.The ester of the facile hydrolysis that the nitrogen-atoms place on tetramethyleneimine forms, for example lower alkanols alkanoyloxymethyl oxygen carbonyl ester comprises propionyl oxygen methoxycarbonyl ester, butyryl oxygen methoxycarbonyl ester, tertiary butyl methanoyl methoxycarbonyl ester, sec.-propyl methanoyl methoxycarbonyl ester, different third oxygen methanoyl-1-ethoxycarbonyl ester; Cycloalkanes acyloxy methyl oxygen carbonyl ester comprises hexamethylene alcoxyl methanoyl-1-ethoxycarbonyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester; Allyloxycarbonyl ester etc.Be preferably: the ester that is become with carboxyl: 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.The ester that N atom place on tetramethyleneimine becomes: propionyl oxygen methoxycarbonyl ester, butyryl oxygen methoxycarbonyl ester, tertiary butyl methanoyl methoxycarbonyl ester, the different third oxygen methanoyl methoxycarbonyl ester, different third oxygen methanoyl-1-ethoxycarbonyl ester, hexamethylene alcoxyl methanoyl-1-ethoxycarbonyl ester, (5-methyl-2-oxo-1,3-dioxole-4-yl) methoxycarbonyl ester.
Isomer of the present invention is meant its all differences to stereoisomerism, diastereo-isomerism.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (1) compound has many three-dimensional centers, that is: on the 4-position; On the 5-position; On the 6-position.
The present invention includes ester or its isomer 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 ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its isomer and one or more pharmaceutical carriers and/or thinner of comprising further; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.01g～5g shown in the general formula (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 etc.
The ester and the isomer thereof of The compounds of this invention, its pharmacy acceptable salt, its facile hydrolysis, 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.Preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria to the mouse administration, is not observed by caused tangible poisoning aura of The compounds of this invention or side effect.
The present invention also provides and has contained carbapeneme derivatives that the pyrrolin methylene radical replaces and treat and/or prevent purposes in the medicine of infectious diseases in preparation.The carbapeneme derivatives that contains the replacement of pyrrolin methylene radical of the present invention all has better antibacterial activity to Gram-positive and feminine gender, can be used for treating and/or preventing the various diseases that is caused by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
The carbapeneme derivatives that contains the replacement of pyrrolin methylene radical of the present invention is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention has good anti-microbial activity and shows hypotoxicity, can being used for the treatment of and/or preventing various Mammalss (comprising the mankind) by the caused various diseases of sensitive organism by safety;
(2) The compounds of this invention 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) The compounds of this invention has long post antibiotic effect, 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.
Below further set forth the beneficial effect that the present invention contains the carbapeneme derivatives that the pyrrolin methylene radical replaces by in-vitro antibacterial experiment, but this should be interpreted as that carbapenem antibiotics of the present invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For the examination bacterial classification: below be the clinical isolates strain, purchase in public institution.
Gram positive organism: MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), methicillin-sensitivity staphylococcus epidermidis (MSSE), methicillin-resistant staphylococcus epidermidis (MRSE), the responsive streptococcus pneumoniae (PSSP) of penicillin, penicillin resistance streptococcus pneumoniae (PRSP), streptococcus pyogenes, enterococcus faecalis.
Gram-negative bacteria: hemophilus influenzae, escherichia coli, klepsiella pneumoniae, Proteus mirabilis, enterobacter cloacae, Grain-negative anerobe: bacteroides fragilis.
Trial-product:
Preferred compound 1 of the present invention and compound 2, self-control, its chemical name and structural formula are as mentioned before;
Imipenum, meropenem: commercial.
Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Figure G2008101454985D00101
By table 1 experimental result as seen, compare with meropenem with imipenum, 2 pairs of clinical isolating examination gram positive organisms that supply of The compounds of this invention 1 and compound all have the excellent antibiotic activity.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Figure G2008101454985D00102
By table 2 experimental result as seen, compare with meropenem with imipenum, 2 pairs of The compounds of this invention 1 and compounds are clinical isolating for the examination gram-negative bacteria, comprise that the Grain-negative anerobe has the excellent antibiotic activity.
Above-mentioned experimental result shows that The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium and anerobe, compare with immediate prior art, anti-microbial activity quite or better, and has a broad antifungal spectrum has the good clinical application potential.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 1 (2S, 4R)-preparation of 1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol
In the dry reaction bottle, add dioxane 100ml, add Zinc Chloride Anhydrous 6.8g (50mmol) then, POTASSIUM BOROHYDRIDE 5.4g (100mmol), behind the stirring at room 2h, add (2S, 4R)-1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl-formiate 8.1g (25mmol).Stir and slowly be warming up to back flow reaction 2h down.Be chilled to room temperature, add the hydrochloric acid 100ml dilution of 1mol/L, ethyl acetate extraction.Organic phase is washed with saturated salt, drying, concentrate (2S, 4R)-1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 6.5g, yield: 88.5%.
Embodiment 2 (2S, 4R)-preparation of 4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol
In the dry reaction bottle, add (2S 4R)-1-tertbutyloxycarbonyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 11.8g (40mmol) and thioacetic acid potassium 9.2g (80mmol), adds DMF150ml then, be heated with stirring to dissolving after, insulation reaction 10h.After being cooled to room temperature, add water 100ml dilution, ethyl acetate extraction, organic phase washes with water, and drying concentrates, and gets yellow oil 10.3g, yield: 93.2%.
Embodiment 3 (2S, 4S)-4-sulfydryl-2-(preparation of 2H-pyrroles-1 (5H)-yl) methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine
Under nitrogen protection, add (2S, 4R)-4-acetylthio-1-tertbutyloxycarbonyl tetramethyleneimine-2-methyl alcohol 5.5g (20mmol); methylene dichloride 100ml splashes into TMSI4ml (30mmol), vigorous stirring reaction 4h under the room temperature; ice-water bath is cooled to 0 ℃, stirs 30min, decompress filter.The a small amount of washed with dichloromethane of filter cake, filtrate collection is in the flask of precooling.Under 0 ℃ of nitrogen protection, dropping contains 2, the 20ml tetrahydrofuran solution of 5-dihydro-1H-pyrroles 3.5g (50mmol) in this solution; dropwise, in 0～5 ℃ of reaction 4h, reaction solution decolouring; suction filtration, filtrate decompression is concentrated into dried, adds the 5mol/L hydrochloric acid of 50ml then; 50 ℃ of stirring reaction 1h; be chilled to room temperature, suction filtration, drying; get product 5.1g, yield is 89.5%.
Embodiment 4 (4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine-4- Base] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-1-hydroxyethyl]-the acetonitrile solution 150ml of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), be chilled to below-10 ℃, add diisopropylethylamine 6ml and (2S, 4S)-(the acetonitrile 100ml solution of 2H-pyrroles-1 (5H)-yl) methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine 7.1g (25mmol), 0 ℃ is stirred 15h to 4-sulfydryl-2-.After reaction finishes, add ethyl acetate 300ml dilution, water successively, the saturated salt washing, concentrates the organic layer drying, solid 9.7g, yield: 61.5%.
Embodiment 5 (4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
With (4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 12.6g (20mmol) is dissolved in the mixed solution of 300mlTHF and water 30ml, adds 10% Lin Dela palladium carbon 4g, stirring reaction 2h under the room temperature 2MPa hydrogen pressure, filtering palladium charcoal, add THF150ml in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 20ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 100ml, and-10 ℃ are stirred 1h, filters, and the filter cake acetone recrystallization gets target compound 4g, yield: 50.2%.
Molecular formula: C 19H 27N 3O 4S
Molecular weight: 393.17
Ultimate analysis:
Measured value: C, 58.12%; H, 7.31%; N, 10.47%; S, 8.02%
Theoretical value: C, 57.99%; H, 6.92%; N, 10.68%; S, 8.15%
Embodiment 6 (2S, 4R)-preparation of 1-methyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol
In the dry reaction bottle, add dioxane 100ml, add Zinc Chloride Anhydrous 6.8g (50mmol) then, POTASSIUM BOROHYDRIDE 5.4g (100mmol), behind the stirring at room 2h, add (2S, 4R)-1-methyl-4-mesyloxy tetramethyleneimine-2-methyl-formiate 8.1g (25mmol).Stir and slowly be warming up to back flow reaction 2h down.Be chilled to room temperature, add the hydrochloric acid 100ml dilution of 1mol/L, ethyl acetate extraction.Organic phase is washed with saturated salt, drying, concentrate (2S, 4R)-1-methyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 4.8g, yield: 91.6%.
Embodiment 7 (2S, 4R)-preparation of 4-acetylthio-1-methyl-tetramethyleneimine-2-methyl alcohol
In the dry reaction bottle, add (2S 4R)-1-methyl-4-mesyloxy tetramethyleneimine-2-methyl alcohol 11.8g (40mmol) and thioacetic acid potassium 9.2g (80mmol), adds DMF150ml then, be heated with stirring to dissolving after, insulation reaction 10h.After being cooled to room temperature, add water 100ml dilution, ethyl acetate extraction, organic phase washes with water, and drying concentrates, and gets solid 6.6g, yield: 87.3%.
Embodiment 8 (2S, 4S)-4-sulfydryl-2-(preparation of 2H-pyrroles-1 (5H)-yl) methylene radical-1-methyl-tetramethyleneimine
Under nitrogen protection, add (2S, 4R)-4-acetylthio-1-methylpyrrolidin-2-methyl alcohol 3.8g (20mmol); methylene dichloride 100ml splashes into TMSI4ml (30mmol), vigorous stirring reaction 4h under the room temperature; ice-water bath is cooled to 0 ℃, stirs 30min, decompress filter.The a small amount of washed with dichloromethane of filter cake, filtrate collection are in the flask of precooling, under 0 ℃ of nitrogen protection; dropping contains 2 in this solution, and the 20ml tetrahydrofuran solution of 5-dihydro-1H-pyrroles 3.5g (50mmol) dropwises; in 0～5 ℃ of reaction 4h, reaction solution decolouring, suction filtration; filtrate decompression is concentrated into dried, adds the 5mol/L hydrochloric acid of 50ml then, 50 ℃ of stirring reaction 1h; be chilled to room temperature, suction filtration, drying; get product 3.6g,, yield is 91.4%.
Embodiment 9 (4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-1-methyl-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-1-hydroxyethyl]-the acetonitrile solution 150ml of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 14.9g (25mmol), be chilled to below-10 ℃, add diisopropylethylamine 6ml and (2S, 4S)-(the acetonitrile 100ml solution of 2H-pyrroles-1 (5H)-yl) methylene radical-1-methyl-tetramethyleneimine 5.9g (25mmol), 0 ℃ is stirred 15h to 4-sulfydryl-2-.After reaction finishes, add ethyl acetate 300ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets solid 8.6g, yield: 63.4%.
Embodiment 10 (4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-1-1 methyl-tetramethyleneimine-4-yl] sulphur Base-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] The preparation of hept-2-ene"-2-carboxylic acid
With (4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 10.9g (20mmol) is dissolved in the mixed solution of 300mlTHF and water 30ml, adds 10% Lin Dela palladium carbon 4g, stirring reaction 2h under the room temperature 2MPa hydrogen pressure, filtering palladium charcoal, add THF150ml in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 20ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 100ml, and-10 ℃ are stirred 1h, filters, and the filter cake acetone recrystallization gets target compound 4.5g, yield: 54.6%.
Molecular formula: C 20H 29N 3O 4S
Molecular weight: 407.53
Ultimate analysis:
Measured value: C, 58.76%; H, 7.33%; N, 10.05%; S, 7.59%
Theoretical value: C, 58.94%; H, 7.17%; N, 10.31%; S, 7.87%
The preparation of embodiment 11 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in compound 1,2 or derivatives thereofs
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in compound 1,2 or derivatives thereofs
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in compound 1,2 or derivatives thereofs
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in compound 1,2 or derivatives thereofs
Prepare 1000 altogether
2, preparation technology:
(1) will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process;
(2) 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;
(3) jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 12 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in compound 1,2 or derivatives thereofs
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 2:
Any one 125g (in compound) in compound 1,2 or derivatives thereofs
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 70g
Microcrystalline Cellulose 50g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
2, preparation technology:
(1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby;
(2) take by weighing raw material and auxiliary material according to recipe quantity;
(3) hypromellose 2% the aqueous solution made soluble in water is standby;
(4) with in compound 1,2 or derivatives thereofs any one, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, it is an amount of to add the 2%HPMC aqueous solution, stirs, and makes suitable softwood;
(5) cross 20 mesh sieve system particles;
(6) particle is dried under 60 ℃ condition;
(7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes;
(8) sampling, the work in-process chemical examination;
(9) the sheet weight sheet of determining according to chemical examination;
(10) finished product is examined entirely, the packing warehouse-in.

Claims (5)

1. compound as described below or its pharmacy acceptable salt:
(4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, or
(4R, 5S, 6S)-3-[(2S, 4S)-2-(2H-pyrroles-1 (5H)-yl) methylene radical-1-methyl-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
2. the described compound of claim 1 or its pharmacy acceptable salt, its pharmacy acceptable salt is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts.
3. the pharmaceutical composition that comprises the described compound of claim 1 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner.
4. pharmaceutical composition as claimed in claim 3, this pharmaceutical composition are pharmaceutically acceptable arbitrary formulation.
5. the described compound of claim 1 or its pharmacy acceptable salt are in the application that is used for preparing the medicine that treats and/or prevents infectious diseases.
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