CN101367811B - Carbon substituted penems antibiotics - Google Patents

Carbon substituted penems antibiotics Download PDF

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CN101367811B
CN101367811B CN2008101293451A CN200810129345A CN101367811B CN 101367811 B CN101367811 B CN 101367811B CN 2008101293451 A CN2008101293451 A CN 2008101293451A CN 200810129345 A CN200810129345 A CN 200810129345A CN 101367811 B CN101367811 B CN 101367811B
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CN101367811A (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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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention belongs to the technical field of medicine, in particular to a carbapenem antibiotic with antibiotic activity shown in the formula (I) and a pharmaceutically acceptable salt, an easily hydrolyzed ester, a hydrate and a hydrate of the ester or the salt thereof: wherein, R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are defined in the description. Moreover, the present invention also provides preparation methods of the compounds, drug combinations containing the compounds and applications of the compounds in the preparation of drugs for treating and/or preventing infective diseases.

Description

Carbon substituted penems antibiotics
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 carbon substituted penems antibiotics, 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 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.Disclose compound as follows among the patent documentation JP1999071277, this compound has the excellent antibiotic activity to Pseudomonas aeruginosa, and is relatively poor but it has other bacterial activities, and the transformation period is very short, can not oral administration.
Figure S2008101293451D00011
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 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, 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 (I), its pharmacy acceptable salt, its facile hydrolysis:
Figure S2008101293451D00021
Wherein, R 1Represent hydrogen atom or carboxyl-protecting group;
R 2Represent hydrogen atom or amino protecting group;
R 3Represent hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, nitro, cyano group is replaced or unsubstituted low alkyl group by halogen atom, hydroxyl, carboxyl, amino, nitro or cyano group;
R 4, R 5, R 6Independently represent hydrogen atom or low alkyl group respectively.
Preferred compound is:
Wherein, R 1Represent hydrogen atom or carboxyl-protecting group;
R 2Represent hydrogen atom or amino protecting group;
Wherein, R 3Represent hydrogen atom, fluorine atom, the chlorine atom, hydroxyl, carboxyl, amino is by halogen atom, hydroxyl, carboxyl or amino the replacement or unsubstituted low alkyl group;
R 4, R 5, R 6Independently represent hydrogen atom, methyl, ethyl or propyl group respectively.
Further preferred compound is:
Wherein, R 1, R 2, R 3, R 4Independently represent hydrogen atom respectively;
R 5, R 6Independently represent hydrogen atom, methyl or ethyl respectively.
Part of compounds of the present invention
Numbering R 1 R 2 R 3 R 4 R 5 R 6
1 H H Hydrogen atom H H H
2 H H Fluorine atom H H H
3 H H The chlorine atom H H H
4 H H Hydroxyl H H H
5 H H Carboxyl H H H
6 H H Trifluoromethyl H H H
7 H H Hydrogen atom H CH 3 H
8 H H Fluorine atom H CH 3 H
9 H H The chlorine atom H CH 3 H
10 H H Hydroxyl H CH 3 H
11 H H Carboxyl H CH 3 H
12 H H Trifluoromethyl H CH 3 H
" 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.
" 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, ethyl, 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, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Tert-butoxycarbonyl; allyloxy carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl-N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; N '; N '-dimethylaminomethylene; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; (acyl group vinyl); 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; the phenacyl alkylsulfonyl; diazo etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, 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.
Further preferred compound is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-guanidine radicals carbonyl-piperidines-1-yl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid, be called for short compd A, structural formula is as follows:
The present invention also provides the preparation method of above-claimed cpd:
Reaction equation:
Figure S2008101293451D00051
Reactions steps:
The preparation of step 1 intermediate (I)
In the exsiccant reaction flask, add (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine (being raw material 1), anhydrous tetrahydro furan.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles (being CDI) reaction, the acetone soln of adding raw material 2 continues reaction.Drip 1mol/L hydrochloric acid then, with ethyl acetate extraction, organic phase is water, saturated nacl aqueous solution washing successively, and concentrating under reduced pressure, solid get intermediate (I) with acetonitrile-hexanaphthene mixing solutions recrystallization.
The preparation of step 2 intermediate (II)
In reaction flask, add under the dichloromethane solution ice bath cooling of intermediate (I), add triethylamine, stir the back and drip (Boc) 2The dichloromethane solution of O stirs.Add entry under the frozen water cooling, divide water-yielding stratum, water layer is used dichloromethane extraction again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, resistates adds the hydrochloric acid of 5mol/L, stir, be adjusted to alkalescence, separate out solid with dilute alkaline soln, solid gets intermediate (II) with acetonitrile and acetone mixing solutions recrystallization.
The preparation of step 3 intermediate (III)
In the reaction flask, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's (being raw material 3) acetonitrile solution, cooling, the acetonitrile solution that adds diisopropylethylamine and intermediate (II) stirs.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets intermediate (III).
The preparation of step 4 compound (IV)
(III) dissolves in the methylene dichloride with intermediate, adds methyl-phenoxide and Nitromethane 99Min., drips the Nitromethane 99Min. solution of 1mol/L aluminum chloride, 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 5% magnesium chloride brine again, leave standstill, divide water-yielding stratum, repetitive operation.Water merges, and slowly splashes into methyl alcohol, stirs, and filters, and the filter cake recrystallization gets compound (IV).
R in the above reaction equation 3, R 4, R 5, R 6The representative group as mentioned before, the carboxyl on the invention compound (IV) 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 (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 that the claimed compound of the present invention is easy to hydrolysis is there is and can be hydrolyzed in vivo corresponding carboxylic acid in carboxyl with the ester group form that is easy to hydrolysis a ester.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; Lower alkoxycarbonyl oxyalkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, the different third oxygen ketonic oxygen ethyl ester of 1-; 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.
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 (I) compound has many three-dimensional centers, that is: on the 4-position; On the 5-position; On the 6-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; can be preferably oral preparations or injection for clinically or pharmaceutically acceptable arbitrary formulation.Wherein contain the compound 0.01g～5g shown in the general formula (I) of physiology significant quantity, can be 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.04g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g etc.
The hydrate of the ester of The compounds of this 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.
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 provide carbon substituted penems antibiotics preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.Carbon substituted penems antibiotics 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.
Carbon substituted penems antibiotics 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, especially Pseudomonas aeruginosa is had activity preferably;
(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, 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 carbon substituted penems antibiotics of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that carbon substituted penems 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, Pseudomonas aeruginosa; Grain-negative anerobe: bacteroides fragilis.
Trial-product:
Preferred compound A of the present invention, self-control, its chemical name and structural formula are as mentioned before;
The compound of coming into the open among the JP1999071277: structure shown in background technology, the preparation of reference literature method;
Imipenum: 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 S2008101293451D00091
By table 1 experimental result as seen, compare with the compound of coming into the open among imipenum and the JP1999071277, The compounds of this invention A isolatingly all has the excellent antibiotic activity for the examination gram positive organism to clinical.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Figure S2008101293451D00101
By table 2 experimental result as seen, compare with the compound of coming into the open among imipenum and the JP1999071277, The compounds of this invention A comprises that to clinical isolating for the examination gram-negative bacteria Grain-negative anerobe has the excellent antibiotic activity.
Above-mentioned experimental result shows, The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium and resistant organism thereof and anerobe, compares with immediate prior art, and 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, 4S)-system of 4-acetylthio-2-formyl [4-guanidine radicals carbonyl-piperidines-1-yl]-1-(tertbutyloxycarbonyl) tetramethyleneimine Be equipped with
In the exsiccant reaction flask, add (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 14.5g (50mmol), anhydrous tetrahydro furan 200ml.Under nitrogen protection, add 1 in room temperature, 1-carbonyl dimidazoles 9.8g (60mmol), reaction 1h at the acetone soln that adds 10.2g (60mmol) 4-formyl guanidino-piperidines below 0 ℃, continues reaction 0.5h.Drip 1mol/L hydrochloric acid 100ml then, extract with ethyl acetate (50ml * 2), organic phase is water, saturated nacl aqueous solution washing successively, and concentrating under reduced pressure, solid get solid 21g, yield: 95.3% with acetonitrile-hexanaphthene mixing solutions recrystallization.
Embodiment 2 (2S, 4S)-4-sulfydryl-2-formyl [4-(N, N '-two tertbutyloxycarbonyl) guanidine radicals carbonyl-piperidines-1-yl]-1-(uncle's fourth oxygen Carbonyl) preparation of tetramethyleneimine
In reaction flask, add (2S, 4S)-the dichloromethane solution 80ml of 4-acetylthio-2-formyl [4-guanidine radicals carbonyl-piperidines-1-yl]-1-(tertbutyloxycarbonyl) tetramethyleneimine 17.7g (40mmol), ice bath is chilled under 5 ℃, adds triethylamine 10ml, drips 20g (Boc) behind the stirring 5min 2The dichloromethane solution 100ml of O stirs 1h.The frozen water cooling adds 100ml water down, divide water-yielding stratum, water layer is used the dichloromethane extraction of 50ml * 3 again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, resistates adds the hydrochloric acid 200ml of 5mol/L, stirs 2h, is adjusted to alkalescence with dilute alkaline soln, separate out solid, solid gets product 22.1g, yield: 92.3% with acetonitrile and acetone mixing solutions recrystallization.
Embodiment 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(N, N '-two tertbutyloxycarbonyl) guanidine radicals carbonyl-piperidines-1- Base]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0 ,] hept-2-ene" -2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the reaction flask, 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 150ml of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 17.9g (30mmol), be chilled to below-10 ℃, add diisopropylethylamine 8ml and (2S, 4S)-4-sulfydryl-2-formyl [4-(N, N '-two tertbutyloxycarbonyl) guanidine radicals carbonyl-piperidines-1-yl]-the acetonitrile solution 100ml of 1-(tertbutyloxycarbonyl) tetramethyleneimine 18g (31mmol), 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 400ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets product 17.9g, yield: 63.2%.
Embodiment 4 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-guanidine radicals carbonyl-piperidines-1-yl]-tetramethyleneimine-4-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid preparation
With (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [4-(N, N '-two tertbutyloxycarbonyl) guanidine radicals carbonyl-piperidines-1-yl]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 18.9g (20mmol) dissolves in the 100ml methylene dichloride, adds methyl-phenoxide 20ml and Nitromethane 99Min. 30ml, in-50 ℃ of Nitromethane 99Min. solution 150ml 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 5g, 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 20ml 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 the filter cake recrystallization gets white crystal 4.1g, yield: 40.2%.
Molecular formula: C 22H 32N 6O 6S
Molecular weight: 508.59
Ultimate analysis:
Measured value: C, 51.81%; H, 6.58%; N, 16.31%; S, 6.22%
Theoretical value: C, 51.95%; H, 6.34%; N, 16.52%; S, 6.30%
The preparation of embodiment 5 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compd A or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in the compd A or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in the compd A or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in the compd A or derivatives thereof
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 6 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compd A or derivatives thereof
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 the compd A or derivatives thereof
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
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) The compounds of this invention A or derivatives thereof, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood;
(5) cross 20 mesh sieve system particles;
(6) particle is dried under 60 ℃ condition;
(7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes;
(8) sampling, the work in-process chemical examination;
(9) the sheet weight sheet of determining according to chemical examination;
(10) finished product is examined entirely, the packing warehouse-in.

Claims (9)

1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Figure FSB00000127320500011
Wherein, R 1Represent hydrogen atom;
R 2Represent hydrogen atom;
R 3Represent hydrogen atom, halogen atom, hydroxyl, amino, cyano group or C 1-6The straight or branched alkyl;
R 4, R 5, R 6Independently represent hydrogen atom or C respectively 1-6The straight or branched alkyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R 3Represent hydrogen atom, fluorine atom, chlorine atom, hydroxyl, amino or C 1-6The straight or branched alkyl;
R 4, R 5, R 6Independently represent hydrogen atom, methyl, ethyl or propyl group respectively.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R 1, R 2, R 3, R 4Independently represent hydrogen atom respectively;
R 5, R 6Independently represent hydrogen atom, methyl or ethyl respectively.
4. compound as claimed in claim 3, be (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [4-guanidine radicals carbonyl-piperidines-1-yl]-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid, and pharmacy acceptable salt.
5. the described compound of each claim of claim 1～4, its pharmacy acceptable salt is inorganic acid salt, organic acid salt, organic alkali salt or inorganic base salts.
6. the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～4 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner.
7. pharmaceutical composition as claimed in claim 6 is characterized in that being pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 6 is characterized in that containing the described compound of the arbitrary claim of claim 1～4 or its pharmacy acceptable salt 0.01g～5g as essential activeconstituents.
9. the described compound of the arbitrary claim of claim 1～4 or its pharmacy acceptable salt treat and/or prevent application in the medicine of infectious diseases in preparation.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053566A1 (en) * 2000-12-27 2002-07-11 Sumitomo Pharmaceuticals Company, Limited Novel carbapenem compounds
WO2002094829A1 (en) * 2001-05-21 2002-11-28 Kyoto Pharmaceutical Industries, Ltd. Carbapenem compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053566A1 (en) * 2000-12-27 2002-07-11 Sumitomo Pharmaceuticals Company, Limited Novel carbapenem compounds
WO2002094829A1 (en) * 2001-05-21 2002-11-28 Kyoto Pharmaceutical Industries, Ltd. Carbapenem compound

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