CN101328181B - Novel penem compounds - Google Patents

Novel penem compounds Download PDF

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CN101328181B
CN101328181B CN2008101248460A CN200810124846A CN101328181B CN 101328181 B CN101328181 B CN 101328181B CN 2008101248460 A CN2008101248460 A CN 2008101248460A CN 200810124846 A CN200810124846 A CN 200810124846A CN 101328181 B CN101328181 B CN 101328181B
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ester
methyl
hydrate
alkyl
oxygen
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CN101328181A (en
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黄振华
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a novel penem compound as shown in a general formula (I), an easily hydrolyzed ester thereof, a salt thereof acceptable in pharmacology, an isomer thereof, a hydrate thereof, a hydrate of the ester or the salt thereof, a preparation method of the compounds as shown in the formula (I), an application of the compounds as medicine active substances, particularly application of the compounds in preparing medicines used to treat and/or prevent infectious diseases as well as a medicine combination containing the compounds as shown in the formula (I), wherein the definition of each group is detailed in a specification.

Description

New penem compound
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 new penem compound, 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
Can be used for treating the communicable disease that comprises gram-positive and negative, aerobic and anaerobic infection by having isolated carbapeneme in the fermentation media and having found that it has broad spectrum antibiotic activity in 1974.
This similar drug that has gone on the market at present has imipenum, meropenem, S-4661, biapenem, ertapenem etc.First listing be imipenum, gram-positive microorganism, negative bacterium, aerophil, anerobe all there is very strong activity, stable to various β-Nei Xiananmeis, there is not cross resistance with other microbiotic, but easily by dehydropeptidase of kidney-I (DHP-I) degraded rapidly, must share with kidney peptidase inhibitors-cilastatin clinically in vivo.
Further discover, introduce 1 Beta-methyl, can strengthen the chemical stability of carbapenem and to the stability of DHP-I, 1 Beta-methyl carbapenem of first listing is a meropenem.
Figure S2008101248460D00011
PZ-601 is the carbapenem antibiotic by the exploitation of SUMITOMO CHEMICAL Pharmaceutical Co., Ltd, has the thyroidan structure, staphylococcus and suis (comprising resistant organism) had anti-microbial activity, moraxelle catarrhalis, escherichia coli, Klebsiella Pneumoniae, Proteus mirabilis are also had anti-microbial activity, and its structural formula is as follows:
Figure S2008101248460D00012
Compound P Z-601 with top structure, antimicrobial spectrum is compared with the microbiotic in early stage with anti-microbial activity and has been obtained large increase, 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, and clinical availability is not high, the inventor modifies above the structure at this, it is wider to have obtained antimicrobial spectrum, and anti-microbial activity is stronger, the class penem compound that stability is higher.
3, summary of the invention
The inventor is through a large amount of research and practice, synthesized new Carbpenem derivants, gram-positive and negative, aerobic and anaerobic bacterium had the excellent antibiotic activity, β-Nei Xiananmei and DHP-I had satisfactory stability, and have long post antibiotic effect, provide a new channel to clinical application.Comparing with immediate prior art more has novelty and superiority.
Technical scheme of the present invention is as follows:
The invention provides ester, its pharmacy acceptable salt, its isomer, its hydrate of the compound shown in the general formula (I), its facile hydrolysis, and the hydrate of ester or salt:
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group;
R 2Expression hydrogen atom or C 1-6Alkyl;
R 3The expression hydrogen atom, halogen atom, cyano group, hydroxyl, carboxyl, amino, formamyl, amino-sulfonyl, C 1-6Alkoxyl group is not substituted or by amino, hydroxyl, halogen atom, carboxyl, cyano group, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1 -6Alkyl sulphinyl, formamyl, C 1-6The C that alkyl sulphonyl replaces 1-6Alkyl;
R 4The expression hydrogen atom, cyano group, amino, hydroxyl, carboxyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl is not substituted or by the C of halogen atom, carboxyl substituted 1-6Alkyl ,-C (R 6)=NR 7, R 6, R 7Independently represent hydrogen atom, amino, C 1-6Alkyl or R 6And R 7Former and the carbon atom of the nitrogen that can mutually combine and connect with their constitutes the heterocycle of 5-7 unit;
X represents CH 2, NH, O or S;
Y represents CH or N;
N represents 0,1 or 2.
Preferred compound is
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group,
Described carboxyl-protecting group is selected from methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis is selected from alkyloyloxyethyl alkyl ester, alkoxyl group acyloxyalkyl group ester, cycloalkanes acyloxyalkyl group ester, cycloalkyloxy acyloxyalkyl group ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R 2Expression hydrogen atom or C 1-4Alkyl
R 3The expression hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, formamyl, amino-sulfonyl, the C that is not substituted or is replaced by halogen atom, hydroxyl 1-6Alkyl;
R 4Expression hydrogen atom or C 1-6Alkyl;
X represents CH 2, NH, O or S;
Y represents CH or N;
N represents 0 or 1.
Further preferred compound is
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group,
Described carboxyl-protecting group is selected from the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis, be selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R 2Expression hydrogen atom, methyl, ethyl, sec.-propyl;
R 3Expression hydrogen atom or C 1-4Alkyl;
R 4Expression hydrogen atom or C 1-4Alkyl;
X represents O or S;
Y represents CH or N;
N represents 0 or 1.
Further preferred compound is
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, to nitrobenzyl, allyl group or benzyl,
The ester of described facile hydrolysis is selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R 2The expression methyl;
R 3Expression hydrogen atom or C 1-3Alkyl;
R 4The expression hydrogen atom;
X represents O or S;
Y represents CH or N;
N represents 0 or 1.
Low alkyl group mentioned above is C 1-6The alkyl of straight or branched comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
Halogen atom mentioned above comprises fluorine atom, chlorine atom, bromine atoms.
Lower alkoxy mentioned above 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.
Lower alkylthio mentioned above is C 1-6The alkylthio of straight or branched comprises methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, uncle's butylthio, positive penta sulfenyl, own sulfenyl etc. just.
Elementary alkyl amido methanoyl mentioned above is C 1-6Alkyl-carbamoyl comprises methylamino formyl radical, ethylamino formyl radical etc.
Low alkyl group sulfinyl mentioned above is C 1-6Alkyl sulphinyl comprises methanesulfinyl, second sulfinyl etc.
Low alkyl group alkylsulfonyl mentioned above is C 1-6Alkyl sulphonyl comprises methylsulfonyl, ethylsulfonyl etc.
5-7 mentioned above unit heterocycle is meant and removes a hydrogen atom that links to each other with the heterocycle carbon atom and the group that forms, this heterocycle be meant contain one arrive several, 1-4 heteroatoms preferably, 5-7 unit ring example as nitrogen-atoms (can be oxidized), Sauerstoffatom or sulphur atom has: 3,4-dihydro-2-H-pyrrole ring, 2,3,4, the 5-tetrahydro pyridine ring, 3,4,5,6-tetrahydrochysene-2-H-heptan is because of ring etc.
Carboxyl-protecting group mentioned above is meant that routine is used for the blocking group of substituted carboxylic acid character.The example comprises: allyl group, benzyl, diphenyl methyl, 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.
The chemical name and the structural formula of particularly preferred compound are as follows:
Chemical name: (4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-thiadiazoles-5-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:
Figure S2008101248460D00051
Chemical name: (4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-oxadiazole-5-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:
Figure S2008101248460D00052
Chemical name: (4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-isoxazole-5-bases] 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 3:
Structural formula:
Figure S2008101248460D00053
Chemical name: (4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-thiadiazoles-5-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 4:
Structural formula:
Figure S2008101248460D00054
Chemical name: (4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-oxadiazole-5-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 5
Structural formula:
Figure S2008101248460D00061
Chemical name: (4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-isoxazole-5-bases] 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 6
Structural formula:
Isomer of the present invention is meant that its all differences are to stereoisomerism and diastereo-isomerism 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 claimed compound facile hydrolysis of the present invention, comprise the alkyloyloxyethyl alkyl ester, for example acetyl oxygen methyl esters, propionyl oxygen methyl esters, butyryl oxygen methyl esters, sec.-propyl methanoyl methyl esters, tertiary butyl methanoyl methyl esters, neo-pentyl methanoyl methyl esters, isobutyl-methanoyl methyl esters, new penta acetyl oxygen methyl esters, decoyl oxygen methyl esters, caprinoyl oxygen methyl esters etc.; The alkyl oxy carbonyl oxygen alkyl ester, for example methoxy methyl acyl-oxygen methyl esters, (ethoxymethyl) acyl-oxygen methyl esters, isopropoxy methanoyl-1-ethyl ester, hexyloxy methanoyl-1-ethyl ester, octyloxy methanoyl-1-ethyl ester, the last of the ten Heavenly stems oxygen base methanoyl-1-ethyl ester, dodecyloxy methanoyl-1-ethyl ester etc.; Alkoxyl group methyl esters, for example methoxy methyl esters, the different third oxygen methyl esters of 1-etc.; Alkyl amido methyl esters, for example formamido group methyl esters, kharophen methyl esters etc.; Cycloalkanes acyloxyalkyl group ester, for example cyclohexyl methanoyl methyl esters, cyclohexyl methanoyl-1-ethyl ester, 1-methyl-cyclohexyl alkyl methanoyl-1-ethyl ester, 4-methyl-cyclohexyl alkyl methanoyl methyl esters etc.; Cycloalkyloxy acyloxyalkyl group ester, for example pentamethylene oxygen base methanoyl-1-ethyl ester, hexamethylene alkoxyl group methanoyl-1-ethyl ester etc.; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester, 2-[(2-methyl propoxy-) carbonyl]-2-amylene ester etc.Be preferably propionyl oxygen methyl ester, butyroxymethyl ester, tertiary butyl methanoyl methyl ester, the different third oxygen methanoyl methyl ester, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester, (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester etc.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention, comprise acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt; Preferred mesylate, hydrochloride and sodium salt.
The ester of general formula (I) compound, its pharmacy acceptable salt, its facile hydrolysis can be a 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 also provides the preparation method of preparation above-claimed cpd, but is not limited only to following preparation method, also can make by additive method:
Reaction equation:
Experimental procedure:
Step 1, in reaction flask, add the dichloromethane solution of material 1, ice bath is cold, adds triethylamine, stirs the back and drips (Boc) 2The dichloromethane solution of O stirs.Frozen water cooling adds entry down, divides water-yielding stratum, and water layer is used dichloromethane extraction again, and the merging organic layer, is concentrated into driedly at anhydrous sodium sulfate drying, promptly gets intermediate A.
Step 2, in the dry reaction bottle, add the acetonitrile solution of material 2, cooling adds the acetonitrile solution of diisopropylethylamine and last step gained intermediate A, stirs.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated promptly gets intermediate B.
Step 3, will go up step gained intermediate B and be dissolved in the methylene dichloride, add methyl-phenoxide and Nitromethane 99Min., the following Nitromethane 99Min. solution that drips the 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 1 time.Water merges, and slowly splashes into methyl alcohol, stirs, and filters, and filter cake promptly gets The compounds of this invention with acetonitrile-Virahol recrystallization.
Each substituting group in the reaction equation is as indicated above, and the hydrogen atom of carboxyl can be replaced by carboxyl-protecting group in the step 3, and the hydrogen atom on the N also can be by R mentioned above 4Substituting group replaces.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.05g～5g shown in the general formula (I) of physiology significant quantity, can be 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.
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 add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The present invention is claimed arbitrary compound of the present invention further; the ester of its facile hydrolysis; its pharmacy acceptable salt; its isomer; its hydrate; and the hydrate of ester or salt preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes; carbapenem compounds of the present invention is to clinical isolating gram-positive; aerobic or anerobe such as feminine gender all has good antibacterial activity; can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism of Mammals (comprising the people); as respiratory tract infection and urinary tract infection, also can be used for septicemia; meningitis 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 compounds of this invention is to various gram positive organisms, negative bacterium, the fungistatic effect of anerobe, aerophil is fine, wherein especially isolated M RSA clinically had good especially antibacterial effect, β-Nei Xiananmei and DHP-I are had satisfactory stability, show that The compounds of this invention has had new progress on the basis of prior art; Show that carbapenem compounds of the present invention has has a broad antifungal spectrum, advantage that anti-microbial activity is high, for having the new compound of good clinical application potential.
Carbpenem derivants of the present invention is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention (I) has good anti-microbial activity and broad-spectrum antibacterial activity and demonstration hypotoxicity, so its can by safety be used for the treatment of and/or to prevent various Mammalss (for example mouse, rat, rabbit, dog, cat, ox, pig etc.) to comprise human by the caused various diseases of germ, as pulmonary infection and urinary tract infections etc.
When (2) The compounds of this invention (I) is as antiseptic-germicide, target bacteria has no particular limits, as long as compound (I) shows anti-microbial activity to it, bacteriums such as various gram positive organisms and gram-negative bacteria and aerophil and anerobe can be as target bacteria.
(3) The compounds of this invention (I) is to having good activity to Staphylococcus, streptococcus etc.
(4) The compounds of this invention (I) excellent in stability is effective to the germ of anti-β-Nei Xiananmei, and DHP-I is had special advantages of excellent stability.
(5) The compounds of this invention (I) has long post antibiotic effect, and anti-microbial effect is lasting, and medication is convenient.
(6) preparation technology of The compounds of this invention (I) 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 the new penem compound of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that the new penem compound of the present invention only has following beneficial effect.
The antimicrobial spectrum of experimental example The compounds of this invention and anti-microbial activity
For trying bacterial classification: the clinical isolates strain
Gram positive organism: MSSA (MSSA) 17 strains, methicillin-resistant staphylococcus aureus (MRSA) 22 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 13 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 15 strains, responsive streptococcus pneumoniae (PSSP) 12 strains of penicillin, penicillin medium sensitivity streptococcus pneumoniae (PISP) 15 strains, penicillin resistance streptococcus pneumoniae (PRSP) 16 strains, streptococcus pyogenes 13 strains, streptococcus agalactiae 16 strains, enterococcus faecalis 15 strains;
Gram-negative bacteria: 16 strains of ampicillin sensitive hemophilus influenzae, Ampicillin Trihydrate resistance hemophilus influenzae 15 strains, escherichia coli 23 strains, klepsiella pneumoniae 25 strains, Proteus mirabilis 14 strains, enterobacter cloacae 17 strains, moraxelle catarrhalis 18 strains; Grain-negative anerobe: bacteroides fragilis 8 strains.
Trial-product:
Compound 1～6: self-control, chemical name and structural formula are as previously described;
Meropenem: commercial; Imipenum: commercial; PZ-601: self-control, its chemical name and structural formula are as mentioned before.
Experimental technique: agar dilution.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Figure S2008101248460D00111
Table 1 (continuing) The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Figure S2008101248460D00112
By table 1 experimental result as seen, compare with imipenum, meropenem and PZ-601,1～6 pair of clinical isolating examination gram positive organism that supplies of preferred compound of the present invention all has the excellent antibiotic activity.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Table 2 (continuing) The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Figure S2008101248460D00122
By table 2 experimental result as seen, compare with imipenum, meropenem and PZ-601,1～6 pair of preferred compound of the present invention is clinical isolating for the examination gram-negative bacteria, comprises that the 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, anti-microbial activity to positive bacteria obviously is better than imipenum, meropenem and PZ-601, and the anti-microbial activity of negative bacterium is better than or is equivalent to the best medicine meropenem of present anti-negative bacterium.
Compare with immediate prior art, the The compounds of this invention anti-microbial activity is better, and antimicrobial spectrum compares greatly with medicine in the past and increase, and 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 (R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-1,2, the system of 4-thiadiazoles Be equipped with
Add (R)-3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-1,2 in reaction flask, the dichloromethane solution 120ml of 4-thiadiazoles 19.9g (100mmol), ice bath are chilled under 5 ℃, add triethylamine 18ml, drip 33g (Boc) behind the stirring 5min 2The methylene dichloride 100ml solution of O (150mmol) stirs 1h.Frozen water cooling adds 250ml water down, divides water-yielding stratum, and water layer is used the dichloromethane extraction of 100ml * 2 again, merges organic layer, anhydrous sodium sulfate drying, be concentrated into dried, solid 26.8g, yield: 89.4%.
Embodiment 2 (R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-1,2, the system of 4-oxadiazole Be equipped with
With reference to embodiment 1 operation, throw (R)-3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-1,2,4-oxadiazole 18.3g (100mmol).Get product 23.9g, yield: 84.5%.
The preparation of embodiment 3 (R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-oxazoles
With reference to embodiment 1 operation, throw (R)-3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-oxazole 18.2g (100mmol).Get product 24.7g, yield: 87.6%.
Embodiment 4 (R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-1,2, the system of 4-thiadiazoles Be equipped with
With reference to embodiment 1 operation, throw (R)-3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-1,2,4-thiadiazoles 21.3g (100mmol).Get product 27.8g, yield: 88.7%.
Embodiment 5 (R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-1,2, the system of 4-oxadiazole Be equipped with
With reference to embodiment 1 operation, throw (R)-3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-1,2,4-oxadiazole 19.7g (100mmol).Get product 25.5g, yield: 85.8%.
The preparation of embodiment 6 (R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-oxazoles
With reference to embodiment 1 operation, throw (R)-3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-1,2,4-oxadiazole 19.6g (100mmol).Get product 24.2g, yield: 81.6%.
Embodiment 7 (4R, 5S, 6S)-3-[(R)-and 3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-thiophene two Azoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy Preparation
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] the acetonitrile solution 360ml of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 35.8g (60mmol) is chilled to-below the 1O ℃, adds diisopropylethylamine 16ml and (R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-1,2, the acetonitrile solution 200ml of 4-thiadiazoles 21g (70mmol), 0 ℃ is stirred 15h.After reaction finishes, add the dilution of 600ml ethyl acetate, water, saturated salt washing successively, organic layer drying, concentrated gets yellow solid 29.8g, yield: 77.1%.
Embodiment 8 (4R, 5S, 6S)-3-[(R)-and 3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-Evil two Azoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy Preparation
Concrete preparation method's reference example 7.Throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 35.8g (60mmol), (R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-1,2,4-oxadiazole 19.8g (70mmol).Get product 28.1g, yield: 74.7%.
Embodiment 9 (4R, 5S, 6S)-3-[(R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-oxazoles-5-yl] Sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 7.Throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 35.8g (60mmol), (R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-5-sulfydryl-oxazole 19.8g (70mmol).Get product 26.8g, yield: 71.3%.
Embodiment 10 (4R, 5S, 6S)-3-[(R)-and 3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-thiophene two Azoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy Preparation
Concrete preparation method's reference example 7.Throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 35.8g (60mmol), (R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-1,2,4-thiadiazoles 21.9g (70mmol).Get product 29.1g, yield: 73.8%.
Embodiment 11 (4R, 5S, 6S)-3-[(R)-and 3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-Evil two Azoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy Preparation
Concrete preparation method's reference example 7.Throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 35.8g (60mmol), (R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-1,2,4-oxadiazole 20.8g (70mmol).Get product 26.9g, yield: 69.6%.
Embodiment 12 (4R, 5S, 6S)-3-[(R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-oxazoles-5-yl] Sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 7.Throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 35.8g (60mmol), (R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-5-sulfydryl-oxazole 20.7g (70mmol).Get product 25.6g, yield: 66.7%.
Embodiment 13 (4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-thiadiazoles-5-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-[(R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-thiadiazoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] the 200ml dichloromethane solution of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 25.7g (40mmol), add benzene 20ml methyl ether and 30ml Nitromethane 99Min., in-50 ℃ of Nitromethane 99Min. solution 200ml that drip the 1mol/L aluminum chloride down ,-40 ℃ are stirred 2h, add 500ml water, separate out solid, filter, filter cake is dissolved in the mixed solution of 1000mlTHF and 60ml water, add 10% palladium-charcoal 8g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds 300mlTHF in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 70ml 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 filter cake gets white crystal 7.6g, yield: 46.5% with acetonitrile-Virahol recrystallization.
Molecular formula: C 17H 20N 4O 4S 2
Molecular weight: 408.5
Ultimate analysis:
Measured value: C, 49.67%; H, 5.15%; N, 13.52%; S, 15.59%
Theoretical value: C, 49.98%; H, 4.93%; N, 13.72%; S, 15.70%
Embodiment 14 (4R, 5S, 6S)-3-[(R)-3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1, 2,4-oxadiazole-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 13.Throw (4R, 5S, 6S)-3-[(R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-oxadiazole-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 25.1g (40mmol).Get target product 7.0g, yield: 44.6%.
Molecular formula: C 17H 20N 4O 5S
Molecular weight: 392.43
Ultimate analysis:
Measured value: C, 52.16%; H, 5.37%; N, 14.09%; S, 8.05%
Theoretical value: C, 52.03%; H, 5.14%; N, 14.28%; S, 8.17%
Embodiment 15 (4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-oxazoles-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 13.Throw (4R, 5S, 6S)-3-[(R)-3-(N-tertbutyloxycarbonyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-oxazoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 25.1g (40mmol).Get target product 6.5g, yield: 41.6%.
Molecular formula: C 18H 21N 3O 5S
Molecular weight: 391.44
Ultimate analysis:
Measured value: C, 55.06%; H, 5.67%; N, 10.89%; S, 8.06%
Theoretical value: C, 55.23%; H, 5.41%; N, 10.73%; S, 8.19%
Embodiment 16 (4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-thiadiazoles-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 13.Throw (4R, 5S, 6S)-3-[(R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-thiadiazoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 26.3g (40mmol).Get target product 7.3g, yield: 43.4%.
Molecular formula: C 18H 22N 4O 4S 2
Molecular weight: 422.52
Ultimate analysis:
Measured value: C, 51.05%; H, 5.42%; N, 13.55%; S, 15.03%
Theoretical value: C, 51.17%; H, 5.25%; N, 13.26%; S, 15.18%
Embodiment 17 (4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-oxadiazole-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 13.Throw (4R, 5S, 6S)-3-[(R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-oxadiazole-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 25.7g (40mmol).Get target product 6.4g, yield: 39.3%.
Molecular formula: C 18H 22N 4O 5S
Molecular weight: 406.46
Ultimate analysis:
Measured value: C, 53.06%; H, 5.71%; N, 13.91%; S, 7.75%
Theoretical value: C, 53.19%; H, 5.46%; N, 13.78%; S, 7.89%
Embodiment 18 (4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-oxazoles-5-yl] sulfenyl -6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Preparation method's reference example 13.Throw (4R, 5S, 6S)-3-[(R)-3-(N-tertbutyloxycarbonyl-2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-oxazoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 25.6g (40mmol).Get target product 6.3g, yield: 38.8%.
Molecular formula: C 19H 23N 3O 5S
Molecular weight: 405.57
Ultimate analysis:
Measured value: C, 56.12%; H, 5.94%; N, 10.19%; S, 7.76%
Theoretical value: C, 56.28%; H, 5.72%; N, 10.36%; S, 7.91%
The preparation of embodiment 19 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compound 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in the compound 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in the compound 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in the compound 1-6 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 20 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compound 1-6 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 compound 1-6 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) with in the The compounds of this invention 1-6 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;
(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 (10)

1. the ester of the compound shown in the formula (I), its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, and the hydrate of ester or salt:
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group;
R 2Expression hydrogen atom or C 1-6Alkyl;
R 3The expression hydrogen atom, halogen atom, cyano group, hydroxyl, carboxyl, amino, formamyl, amino-sulfonyl, C 1-6Alkoxyl group is not substituted or by amino, hydroxyl, halogen atom, carboxyl, cyano group, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, formamyl, C 1-6The C that alkyl sulphonyl replaces 1-6Alkyl;
R 4The expression hydrogen atom, cyano group, amino, hydroxyl, carboxyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl is not substituted or by the C of halogen atom, carboxyl substituted 1-6Alkyl ,-C (R 6)=NR 7, R 6, R 7Independently represent hydrogen atom, amino, C 1-6Alkyl or R 6And R 7Former and the carbon atom of the nitrogen that can mutually combine and connect with their constitutes the heterocycle of 5-7 unit;
X represents CH 2, NH, O or S;
Y represents CH or N;
N represents 0,1 or 2.
2. the ester of compound as claimed in claim 1, its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, and the hydrate of ester or salt,
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group,
Described carboxyl-protecting group is selected from methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis is selected from alkyloyloxyethyl alkyl ester, alkoxyl group acyloxyalkyl group ester, cycloalkanes acyloxyalkyl group ester, cycloalkyloxy acyloxyalkyl group ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R 2Expression hydrogen atom or C 1-4Alkyl
R 3The expression hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, formamyl, amino-sulfonyl, the C that is not substituted or is replaced by halogen atom, hydroxyl 1-6Alkyl;
R 4Expression hydrogen atom or C 1-6Alkyl;
X represents CH 2, NH, O or S;
Y represents CH or N;
N represents 0 or 1.
3. the ester of compound as claimed in claim 2, its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, and the hydrate of ester or salt,
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group,
Described carboxyl-protecting group is selected from the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis, be selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R 2Expression hydrogen atom, methyl, ethyl, sec.-propyl;
R 3Expression hydrogen atom or C 1-4Alkyl;
R 4Expression hydrogen atom or C 1-4Alkyl;
X represents O or S;
Y represents CH or N;
N represents 0 or 1.
4. the ester of compound as claimed in claim 3, its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, and the hydrate of ester or salt,
Wherein: R 1Representation carboxy ,-COOR 5Or the ester of facile hydrolysis, described R 5The representation carboxy protecting group,
Described carboxyl-protecting group is selected from the tertiary butyl, to nitrobenzyl, allyl group or benzyl,
The ester of described facile hydrolysis is selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R 2The expression methyl;
R 3Expression hydrogen atom or C 1-3Alkyl;
R 4The expression hydrogen atom;
X represents O or S;
Y represents CH or N;
N represents 0 or 1.
5. compound as claimed in claim 4 is selected from:
(4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-thiadiazoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-1,2,4-oxadiazole-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(R)-and 3-(5-methyl-2,5-dihydro-1H-pyrroles-3-yl)-isoxazole-5-bases] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-thiadiazoles-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(R)-and 3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-1,2,4-oxadiazole-5-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, perhaps
(4R, 5S, 6S)-3-[(R)-3-(2-methyl isophthalic acid, 2,5,6-tetrahydropyridine-4-yl)-isoxazole-5-bases] sulfenyl-6-[(1R)-1-hydroxyethyl]-hydrate of ester, its pharmacy acceptable salt, its isomer, its hydrate or its ester or the salt of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid and facile hydrolysis thereof.
6. as the described compound of the arbitrary claim of claim 1～5, the ester of its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, and the hydrate of ester or salt, the ester of its facile hydrolysis is selected from the alkyloyloxyethyl alkyl ester, alkyl oxy carbonyl oxygen alkyl ester, alkoxyl group methyl esters, the alkyl amido methyl esters, cycloalkanes acyloxyalkyl group ester, cycloalkyloxy acyloxyalkyl group ester, (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester, 2-[(2-methyl propoxy-) carbonyl]-2-amylene ester.
7. as the described compound of the arbitrary claim of claim 1～5, the ester of its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, and the hydrate of ester or salt, its pharmacy acceptable salt is selected from acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt.
8. comprise the described compound of the described arbitrary claim of claim 1～5, the ester of its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, or the pharmaceutical composition of the hydrate of its ester or salt and one or more pharmaceutical carriers and/or thinner.
9. pharmaceutical composition as claimed in claim 8, wherein contain the described compound of the described arbitrary claim of claim 1～5, the ester of its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, or the hydrate 0.05g～5g of its ester or salt is as essential active ingredient.
10. comprise the described compound of the arbitrary claim of claim 1～5, the ester of its facile hydrolysis, its pharmacy acceptable salt, its isomer, its hydrate, or the hydrate of its ester or salt preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application.
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US4640915A (en) * 1982-03-29 1987-02-03 Fujisawa Pharmaceutical Co., Ltd. 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives

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Publication number Priority date Publication date Assignee Title
US4640915A (en) * 1982-03-29 1987-02-03 Fujisawa Pharmaceutical Co., Ltd. 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives

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