CN101323616A - Carbpenem derivates containing sulfhydryl thiazole - Google Patents
Carbpenem derivates containing sulfhydryl thiazole Download PDFInfo
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Abstract
The invention relates to a carbapenem derivative containing thyroidan as showed in a general formula (I), easily hydrolyzable ester thereof, a pharmaceutically acceptable nontoxic salt thereof, hydrate thereof and hydrate of the ester or salt thereof as well as a preparation method of the compound in the general formula (I). The invention also relates to medicine compositions containing the compounds and the application of the medicine compositions as active substances of medicines, in particular to the application of the compounds in preparing medicines for curing and/or preventing infectious diseases, wherein, the detailed definitions of each group refer to a specification.
Description
1, technical field
The present invention relates to contain carbapenem derivative, the ester of its facile hydrolysis, its pharmaceutically acceptable non-toxic salt, its hydrate of thyroidan, and the hydrate of ester or salt, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes, belong to medical technical field.
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.Because antibiotic widespread use constantly increases drug-resistance of bacteria, in addition owing to the limitation of digestive tube absorption, clinically can only be as the injection administration, clinical availability is not high, can not meet clinical needs.
3, summary of the invention
The inventor is through a large amount of research and practice, a series of carbapenem derivatives that contain thyroidan have been synthesized, gram-positive and negative, aerobic and anaerobic bacterium especially resistant organism had the excellent antibiotic activity, β-Nei Xiananmei had satisfactory stability, and the transformation period is longer, have long post antibiotic effect, provide a new channel to clinical application.
Technical scheme of the present invention is as follows:
The invention provides ester, its pharmaceutically acceptable non-toxic salt, its hydrate of the compound shown in the general formula (I), its facile hydrolysis, and the hydrate of ester or salt:
Wherein: R
1Expression hydrogen atom or carboxyl-protecting group;
R
2Expression hydrogen atom or low alkyl group;
A represents group shown in the following formula,
R
3, R
4Independent respectively expression hydrogen atom, halogen atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl is by amino, hydroxyl, carboxyl substituted or unsubstituted low alkyl group, lower alkoxy, elementary alkyl amido methanoyl, low-grade alkyl amino alkylsulfonyl, low alkyl group amido, low alkyl group sulfonamido;
X represents NH or CH
2
W represents the integer of 0-6; M represents the integer of 0-6; N represents 0,1 or 2.
Preferred compound is:
Wherein: R
1Expression hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, ethyl, the tertiary butyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Expression hydrogen atom or low alkyl group;
A represents group shown in the following formula,
R
3, R
4Independent respectively expression hydrogen atom, fluorine atom, chlorine atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl, low alkyl group, lower alkoxy, methylamino formyl radical, kharophen or methanesulfonamido;
X represents NH or CH
2
W represents the integer of 0-3; M represents the integer of 0-3; N represents 0 or 1.
Further preferred compound is:
Wherein: R
1Expression hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Expression hydrogen atom or methyl;
A represents group shown in the following formula,
R
3, R
4Independent respectively expression hydrogen atom or low alkyl group;
X represents NH or CH
2
W represents 0 or 1; M represents 0 or 1; N represents 0 or 1.
Table 1 part of compounds of the present invention
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.
Low-grade alkyl amino alkylsulfonyl mentioned above is C
1-6Alkyl amino sulfonyl comprises first sulfamyl, second sulfamyl, third sulfamyl, fourth sulfamyl, penta sulfamyl, own sulfamyl etc.
Elementary alkyl amido methanoyl mentioned above is C
1-6Alkyl-carbamoyl comprises methylamino formyl radical, ethylamino formyl radical, propyl group formamyl, butyl formamyl, amyl group formamyl, hexyl formamyl etc.
Low alkyl group sulfonamido mentioned above is C
1-6Alkyl sulfonyl amino comprises methanesulfonamido, ethanesulfonamido, third sulfoamido, fourth sulfoamido, penta sulfoamido, own sulfoamido etc.
Low alkyl group amido mentioned above is C
1-6Alkyl amido comprises kharophen, propionamido, butyrylamino, valeryl amino, hexanamido, heptanamido 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, allyl group, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, methyl, ethyl, diphenyl methyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
The chemical name and the structural formula of particularly preferred compound are as follows:
Chemical name: (4R, 5S, 6S)-and 3-[4-methyl-5-acetoxyl-thiazol-2-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:
Chemical name: (4R, 5S, 6S)-and 3-[7-carboxyl-4,7-dihydrobenzo [d] thiazol-2-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:
Chemical name: (4R, 5S, 6S)-and 3-[7-carboxyl-4H-thiazole [4,5-b] pyridine-2-yl also] 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:
Chemical name: (4R, 5S, 6S)-3-[6-oxo-4,5-pyrrolin alkane is [3,4-d] thiazol-2-yl also] 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:
Chemical name: (4R, 5S, 6S)-3-[6-oxo 4, the 5-thiazoline is [4,5-c] pyridine-2-yl also] 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:
The ester that the claimed compound of the present invention is easy to hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis.These esters can be conventional, lower alkane acyloxyalkyl group ester for example, acetoxyl group ethyl ester, pivalyl oxygen methyl ester, 1-acetoxyl ethyl ester, 1-pivalyl oxygen ethyl ester; The lower alkoxycarbonyl alkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, 1-sec.-propyl ketonic oxygen ethyl ester; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; The lower alkoxy methyl ester, methoxymethyl ester; Lower alkane acyl amino methyl ester, the acetylamino methyl ester.The ester that also can use other is for example: benzyl ester and cyano methyl ester.Other examples of these esters are as follows: (2,2-dimethyl-1-oxygen propoxy-) methyl ester; (1RS)-1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-the pentenyl ester; The 1-[[(1-methyl ethoxy) carbonyl] oxygen] ethyl ester; 1-(acetoxyl) ethyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester; The 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester; 3,3-dimethyl-2-oxo butyl ester.It is evident that for the professional of this area the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy place of this compound, for example at 4 carboxyl place.
The pharmaceutically acceptable non-toxic salt of compound mentioned above (I) comprises inorganic acid salt, example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, the salt of phosphoric acid etc.; Organic acid salt, as acetate, trifluoroacetic acid, citric acid, formic acid, toxilic acid, oxalic acid, Succinic Acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix, the salt of oxysuccinic acid etc. or methylsulfonic acid or toluenesulphonic acids etc.; These acid salt can be according to any universal method preparation.In addition, compound (I) also can form non-toxic salt with alkali, comprises by metal deutero-salt, ammonium salt, by organic bases deutero-doped quaternary ammonium salt and amino acid salts.The example of preferred metal-salt has by basic metal deutero-salt, for example lithium (Li
+), sodium (Na
+), potassium (K
+); With by alkaline-earth metal deutero-salt, for example calcium (Ca
2+), magnesium (Mg
2+) and other metallic cation salt such as iron (Fe
2+Or Fe
3+), aluminium (Al
3+) and zinc (Zn
2+) ionic salt is also included within the scope of the present invention; Example by organic bases deutero-doped quaternary ammonium salt comprises general methylamine salt, glucosamine salt, trismethylamine salt, triethyl amine salt, tetramethyl ammonium, tetraethyl-ammonium salt, phenmethyl leptodactyline, phenyl triethyl ammonium salt etc.; Comprise and pyridine, morpholine, picoline, N-methyl piperidine, N-ethylpiperidine, dicyclohexylamine, PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N the salt that N '-dibenzyl-ethylene diamines, alkylamine or dialkylamine form by amine deutero-salt; Amino acid salts is as arginic acid salt, aspartate, glutaminate, Methionin.
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 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 the exsiccant reaction flask, add material 1 and methyl alcohol mixing, slowly splash into sulfur oxychloride, drip the Bi Shengzhi stirring at room, heat up again and stir, cooling, crystallization is filtered, filtration cakes torrefaction promptly gets intermediate 1.
Step 2, in the dry reaction bottle, the dichloromethane solution ice bath that adds material 2 is cold, adds triethylamine, stirs the back and drips (Boc)
2The dichloromethane solution of O stirs.Add entry under the frozen water cooling, divide water-yielding stratum, water layer adds dichloromethane extraction again, merges organic layer, and anhydrous sodium sulfate drying, concentrated promptly gets intermediate 2.
Step 3, in the dry reaction bottle, the acetonitrile solution that adds step 1 and 2 products therefroms is chilled to below-10 ℃, adds the acetonitrile solution of diisopropylethylamine and material 2,0 ℃ of stirring.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated promptly gets intermediate 3.
Step 4, step 3 products therefrom is dissolved in the mixed solution of THF and water, adds palladium-charcoal, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF in the filtrate, and 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 0 ℃ slowly splashes into methyl alcohol, and-10 ℃ of stirrings are filtered, and filter cake water-Virahol recrystallization promptly gets The compounds of this invention.
R in the reaction equation
2, R
3, R
4, w, m and n representative group as indicated above.
The present invention is further claimed to comprise arbitrary compound recited above; the ester of its facile hydrolysis; its pharmaceutically acceptable non-toxic salt; its hydrate; or the pharmaceutical composition of the hydrate of its ester or salt and one or more pharmaceutical carriers and/or thinner; wherein contain the arbitrary compound shown in the formula (I); the ester of its facile hydrolysis; its pharmaceutically acceptable non-toxic salt; its hydrate; or the hydrate 0.05g～5g of its ester or salt (by compound shown in the formula I) can be 0.05g as necessary active ingredient; 0.075g; 0.1g; 0.125g; 0.25g; 0.3g; 0.5g; 0.75g; 1g; 1.25g; 1.5g; 1.75g; 2g; 2.5g; 3g; 4g; 5g etc.
Aforementioned pharmaceutical compositions can be applied to the patient who needs treatment, preferred oral preparation or injection or external preparation in modes such as oral, administered parenterally or external applications.
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 pharmaceutically acceptable non-toxic salt; 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 purposes; the carbapenem derivative of thyroidan that contains 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 carbapenem derivative that contains thyroidan 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, 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) was as antiseptic-germicide, target bacteria had no particular limits, as long as compound (I) shows anti-microbial activity to it.
(3) The compounds of this invention (I) has good especially anti-microbial activity to Staphylococcus, streptococcus, Pseudomonas aeruginosa genus.
(4) The compounds of this invention (I) excellent in stability, especially The compounds of this invention 1-5 and derivative thereof.
(5) The compounds of this invention (I) has long transformation period and 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.
(7) The compounds of this invention (I) has good activity in digestive tube, can be through the gi system administration.
Below further set forth the beneficial effect that contains the carbapenem derivative of thyroidan of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that the southern antibiotics of training of the present invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For trying bacterial classification: following clinical isolates strain
Gram positive organism: MSSA (MSSA) 13 strains, methicillin-resistant staphylococcus aureus (MRSA) 17 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 14 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 15 strains, responsive streptococcus pneumoniae (PSSP) 17 strains of penicillin, penicillin resistance streptococcus pneumoniae (PRSP) 16 strains, streptococcus pyogenes 17 strains, enterococcus faecalis 13 strains;
Gram-negative bacteria: hemophilus influenzae 17 strains, escherichia coli 16 strains, klebsiella pneumoniae 16 strains, Proteus mirabilis 13 strains, enterobacter cloacae 15 strains, Pseudomonas aeruginosa 15 strains; Grain-negative anerobe: bacteroides fragilis 13 strains.
Trial-product:
The compounds of this invention 1-5, self-control, chemical name and structural formula are as mentioned before;
Imipenum: commercial; Meropenem: commercial.
Experimental technique: agar dilution.
Experimental result and conclusion:
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
By table 2 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention 1-5 all has the excellent antibiotic activity to the clinical isolating examination gram positive organism that supplies.
Table 3 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
By table 3 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention 1-5 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 12-sulfydryl-6-oxo-6,7-thiazoline be the preparation of [4,5-c] pyridine also
1, the preparation of 2-acetylthio-4-methyl-5-thiazole Acetyl Chloride 98Min.
In the dry reaction bottle, add 19g (0.1mol) 2-sulfydryl-4-methyl-5-thiazole acetate, add the 100ml diacetyl oxide then, stir and be warming up to backflow, remove excessive acetic anhydride via under reduced pressure behind the reaction 2h.Add the 150ml methylene dichloride in the residuum, respectively with 1N NaOH solution, deionized water, saturated nacl aqueous solution washing.Add after the organic layer drying in the reaction flask, add triethylamine 20g, 0.5mlDMF is heated with stirring to backflow.Slow then dripping thionyl chloride 8ml (0.11mol) continues stirring reaction 0.5h.Reaction is finished, and removes methylene dichloride under reduced pressure, and residuum continues to add methylene dichloride 50ml, removes under reduced pressure after stirring.Add the 100ml methylene dichloride again, respectively with 1NNaOH solution, deionized water, saturated nacl aqueous solution washing.Organic layer with anhydrous sodium sulfate drying after the sealing standby.
2, the preparation of 2-acetylthio-4-methyl-5-thiazole ethanamide
The dichloromethane solution that adds 2-acetylthio-4-methyl-5-thiazole Acetyl Chloride 98Min. of going up the step preparation in the dry reaction bottle feeds exsiccant ammonia, stirring reaction 5h in solution under the ice bath.Reaction is finished, and solution is filtered, and filtrate is used deionized water wash, and the organic layer concentrating under reduced pressure gets solid 10.3g, first two steps total recovery: 44.8%.
3, the preparation of 2-acetylthio-4-brooethyl-5-thiazole ethanamide
In the reaction flask, add the dichloromethane solution 100ml of 2-acetylthio-4-methyl-5-thiazole ethanamide 9.2g (40mmol), add N-bromo-succinimide 10.7g (60mmol) and Diisopropyl azodicarboxylate 0.1g, reflux 12h.After reaction finished, organic layer is water, saturated salt washing successively, and organic layer drying, concentrating under reduced pressure get solid 6.1g, yield: 49.6%.
4,2-sulfydryl-6-oxo-6,7-thiazoline be the preparation of [4,5-c] pyridine also
Add 2-acetylthio-4-brooethyl-5-thiazole ethanamide 15.5g (0.05mol) in reaction flask, the 100ml methylene dichloride adds triethylamine 15g, is heated with stirring to backflow.Stirring reaction 10h.Reaction is finished, and reaction solution is respectively with deionized water, saturated nacl aqueous solution washing.Organic layer with anhydrous sodium sulfate drying after concentrating under reduced pressure get solid 5.3g, yield: 56.6%.
Embodiment 22-sulfydryl-6-oxo-4H-tetramethyleneimine is the preparation of [3,4-d] thiazole also
Preparation method's reference example 1, the raw material of throwing are 2-sulfydryl-4-methyl-5-thiazole formic acid ethyl ester.
Embodiment 32-sulfydryl-4, the preparation of 7-dihydrobenzo [d] thiazole-7-formic acid
In reaction flask, add 2-chloro-3-nitro-phenylformic acid 12.1g (0.06mol), dissolve with 1N NaOH solution 80ml, stirring is warming up to 50 ℃, the suspension that slowly adds the 70ml water of sodium sulphite 8.3g (0.15mol) and sulphur powder 13.1g (0.41mol) then, oil bath is heated to 120 ℃ then, and insulated and stirred reaction 2h is chilled to room temperature and places 2h, add 7ml dithiocarbonic anhydride again, slowly be warming up to 50 ℃, insulated and stirred 18h stops to stir, be chilled to the ethyl acetate that adds 100ml after the room temperature, filter, filter cake washes with water, and filter cake is dissolved in the sodium carbonate solution that 100ml contains 16.6g (0.20mol), transfer pH3.3 with the HCl of 6N down in ice bath, separate out solid, filter, washing, obtain light gray solid 9.4g after the vacuum-drying, yield: 73.4%.
Embodiment 42-sulfydryl-4,7-thiazoline be the preparation of [4,5-b] pyridine-7-formic acid also
Preparation method's reference example 3 is thrown 2-chloro-3-nitro-pyridine carboxylic acid 12.2g (0.06mol), gets 2-sulfydryl-4, and the 7-thiazoline is [4,5-b] pyridine-7-formic acid 8.8g also, yield: 68.8%.
Embodiment 52-sulfydryl-4, the preparation of 7-dihydrobenzo [d] thiazole-7-methyl-formiate
In reaction flask, add 2-sulfydryl-4,7-dihydrobenzo [d] thiazole-7-formic acid 10.7g (50mmol) and methyl alcohol 50ml mixing, 0 ℃ slowly splashes into sulfur oxychloride 4ml, drip Bi Shengzhi stirring at room 20min, rise to 40 ℃ again and stir 14h, cooling, separate out white crystal, filter, filtration cakes torrefaction gets 10.5g, yield: 92.5%.
Embodiment 62-sulfydryl-4,7-thiazoline be the preparation of [4,5-b] pyridine-7-methyl-formiate also
With reference to embodiment 5 operations, throw 2-sulfydryl-4, the 7-thiazoline is [4,5-b] pyridine-7-formic acid 10.7g (50mmol) also.Get product 9.9g, yield: 86.3%.
The preparation of embodiment 72-sulfydryl-4-methyl-thiazole-5-methyl acetate
With reference to embodiment 5 operations, throw 2-sulfydryl-4-methyl-thiazole-5-acetate 9.5g (50mmol).Get product 9.2g, yield: 90.2%.
Embodiment 82-sulfydryl-4-tertbutyloxycarbonyl-7-methoxycarbonyl thiazole is the preparation of [4,5-b] pyridine also
Add 2-sulfydryl-4 in reaction flask, the 7-thiazoline is the dichloromethane solution 50ml of [4,5-b] pyridine-7-methyl-formiate 9.1g (40mmol) also, and ice bath is chilled to 0 ℃, adds triethylamine 7ml, drips 10.9g (Boc) behind the stirring 5min
2The dichloromethane solution 50ml of O (50mmol) stirs 1h.Add 100ml water under frozen water cools off, divide water-yielding stratum, water layer adds the 100ml dichloromethane extraction again, merges organic layer, and anhydrous sodium sulfate drying, concentrated gets white solid 11.1g, yield: 85.0%.
Embodiment 92-sulfydryl-5-tertbutyloxycarbonyl-6-oxo-4H-tetramethyleneimine is the preparation of [3,4-d] thiazole also
With reference to embodiment 8 operations, throw 2-sulfydryl-6-oxo-4,5-pyrrolin alkane is [3,4-b] thiazole 6.9g (40mmol) also.Get product 9.7g, yield: 89.5%.
Embodiment 102-sulfydryl-5-tertbutyloxycarbonyl-6-oxo-6,7-thiazoline be the preparation of [4,5-c] pyridine also
With reference to embodiment 8 operations, throw 2-sulfydryl-6-oxo-4, the 5-thiazoline is [4,5-c] pyridine 7.5g (40mmol) also.Get product 9.4g, yield: 82.3%.
Embodiment 11 (4R, 5S, 6S)-and 3-[7-methoxycarbonyl-4,7-dihydrobenzo [d] thiazol-2-yl] sulfenyl-6-[(1R)-1-hydroxyl second
Base]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-1-hydroxyethyl]-the acetonitrile solution 180ml of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 17.9g (30mmol), be chilled to below-10 ℃, add diisopropylethylamine 8ml and 2-sulfydryl-4, the acetonitrile solution 120ml of 7-dihydrobenzo [d] thiazole-7-methyl-formiate 8.0g (35mmol), 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 400ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets yellow solid 12.4g, yield: 72.1%.
Embodiment 12 (4R, 5S, 6S)-and 3-[4-tertbutyloxycarbonyl-7-methoxycarbonyl thiazole [4,5-b] pyridine-2-yl also] 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
Concrete preparation method's reference example 11.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 17.9g (30mmol), 2-sulfydryl-4-tertbutyloxycarbonyl-7-methoxycarbonyl thiazole is [4,5-b] pyridine 11.5g (35mmol) also.Get product 13.9g, yield: 68.7%.
Embodiment 13 (4R, 5S, 6S)-and 3-[4-methyl-5-methoxy carbonyl methyl-thiazol-2-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-first
Base-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 11.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 17.9g (30mmol), 2-sulfydryl-4-methyl-thiazole-5-methyl acetate 7.1g (35mmol).Get product 13.7g, yield: 71.6%.
Embodiment 14 (4R, 5S, 6S)-and 3-[5-tertbutyloxycarbonyl-6-oxo-4H-tetramethyleneimine [3,4-d] thiazol-2-yl also] 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
Concrete preparation method's reference example 11.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 17.9g (30mmol), 2-sulfydryl-5-tertbutyloxycarbonyl-6-oxo-4H-tetramethyleneimine is [3,4-b] thiazole 9.5g (35mmol) also.Get product 12.1g, yield: 65.4%.
Embodiment 15 (4R, 5S, 6S)-3-[5-tertbutyloxycarbonyl-6-oxo-6, the 7-thiazoline is [4,5-c] pyridine-2-yl also] 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
Concrete preparation method's reference example 11.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 17.9g (30mmol), 2-sulfydryl-5-tertbutyloxycarbonyl-6-oxo-6, the 7-thiazoline is [4,5-c] pyridine 10.0g (35mmol) also.Get product 12.6g, yield: 66.8%.
Embodiment 16 (4R, 5S, 6S)-and 3-[7-carboxyl-4,7-dihydrobenzo [d] thiazol-2-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-
The preparation of methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
With (4R, 5S, 6S)-3-[7-methoxycarbonyl-4,7-dihydrobenzo [d] thiazol-2-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 11.4g (20mmol) is dissolved in the mixed solution of 800mlTHF and water 50ml, adds 10% palladium-charcoal 4g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal, add THF300ml in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 40ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 50ml, and-10 ℃ are stirred 1h, filters, and filter cake water-Virahol recrystallization gets white crystal 4.1g, yield: 48.6%.
Molecular formula: C
18H
18N
2O
6S
2
Molecular weight: 422.48
Ultimate analysis:
Measured value: C, 51.02%; H, 4.53%; N, 6.48%; S, 15.02%
Theoretical value: C, 51.17%; H, 4.29%; N, 6.63%; S, 15.18%
Mass spectrum: m/e 423.1 (M+1)
Hydrogen spectrum: δ/ppm, D
2O
δ(1.11，d，3H)δ(1.24，d，3H)δ(2.96，m，1H)δ(3.14，t，1H)δ(3.21，s，1H)δ(3.24，t，1H)δ(3.40，d，1H)δ(3.61，q，1H)δ(4.33，s，1H)δ(5.65，s，2H)
Embodiment 17 (4R, 5S, 6S)-and 3-[4-methyl-5-acetoxyl-thiazol-2-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-
The preparation of oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 16.Throw (4R, 5S, 6S)-and 3-[4-methyl-5-methoxy carbonyl methyl-thiazol-2-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 11g (20mmol).
Get target product 3.5g, yield: 43.7%.
Molecular formula: C
16H
18N
2O
6S
2
Molecular weight: 398.45
Ultimate analysis:
Measured value: C, 47.11%; H, 4.65%; N, 6.95%; S, 16.04%
Theoretical value: C, 47.23%; H, 4.55%; N, 7.03%; S, 16.09%
Mass spectrum: m/e 399.8 (M+1)
Hydrogen spectrum: δ/ppm, D
2O
δ(1.00，d，3H)δ(1.19，d，3H)δ(2.93，s，3H)δ(3.24，q，1H)δ(3.45，d，d，1H)δ(3.69，s，2H)δ(4.23，m，2H)
Embodiment 18 (4R, 5S, 6S)-and 3-[7-carboxyl-4H-thiazole [4,5-b] pyridine-2-yl also] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-the 4-first
The preparation of base-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
With (4R, 5S, 6S)-3-[4-tertbutyloxycarbonyl-7-methoxycarbonyl thiazole also [4,5-b] pyridine-2-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] in the 100ml methylene dichloride of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 13.5g (20mmol), add methyl-phenoxide 20ml and Nitromethane 99Min. 30ml, in-50 ℃ of Nitromethane 99Min. solution 200ml that drip the 1mol/L aluminum chloride down ,-40 ℃ are stirred 2h, add entry 300ml, separate out solid, filter, filter cake is dissolved in the mixed solution of 800mlTHF and water 50ml, add 10% palladium-charcoal 4g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF300ml in the filtrate, water layer is collected in layering.In THF, add 5% magnesium chloride brine 40ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 50ml, and-10 ℃ are stirred 1h, filters, and filter cake water-Virahol recrystallization gets white crystal 4.4g, yield: 52.1%.
Molecular formula: C
17H
17N
3O
6S
2
Molecular weight: 423.46
Ultimate analysis:
Measured value: C, 48.10%; H, 4.31%; N, 9.78%; S, 15.02%
Theoretical value: C, 48.22%; H, 4.05%; N, 9.92%; S, 15.14%
Mass spectrum: m/e 424.3 (M+1)
Hydrogen spectrum: δ/ppm, D
2O
δ(1.16，d，3H)δ(1.21，d，3H)δ(2.91，m，1H)δ(3.05，t，1H)δ(3.40，d，1H)δ(3.65，q，1H)δ(4.39，s，1H)δ(4.95，m，1H)δ(6.36，d，1H)
Embodiment 19 (4R, 5S, 6S)-3-[6-oxo-4,5-pyrrolin alkane is [3,4-d] thiazol-2-yl also] sulfenyl-6-[(1R)-1-hydroxyl second
Base]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 18.Throw (4R, 5S, 6S)-and 3-[5-tertbutyloxycarbonyl-6-oxo-4H-tetramethyleneimine [3,4-d] thiazol-2-yl also] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 12.3g (20mmol).Get target product 3.6g, yield: 47.6%.
Molecular formula: C
15H
15N
3O
5S
2
Molecular weight: 381.43
Ultimate analysis:
Measured value: C, 47.11%; H, 4.15%; N, 11.15%; S, 16.68%
Theoretical value: C, 47.23%; H, 3.96%; N, 11.02%; S, 16.81%
Mass spectrum: m/e 382.5 (M+1)
Hydrogen spectrum: δ/ppm, D
2O
δ(1.19，d，3H)δ(1.27，d，3H)δ(3.01，m，1H)δ(3.18，t，1H)δ(3.51，t，1H)δ(3.68，t，1H)δ(4.32，s，2H)
Embodiment 20 (4R, 5S, 6S)-3-[6-oxo-4, the 5-thiazoline is [4,5-c] pyridine-2-yl also] sulfenyl-6-[(1R)-1-hydroxyl second
Base]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 18.Throw (4R, 5S, 6S)-3-[5-tertbutyloxycarbonyl-6-oxo-6,7-thiazoline also [4,5-c] pyridine-2-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 12.6g (20mmol).Get target product 3.6g, yield: 45.5%.
Molecular formula: C
16H
17N
3O
5S
2
Molecular weight: 395.45
Ultimate analysis:
Measured value: C, 48.45%; H, 4.61%; N, 10.55%; S, 16.10%
Theoretical value: C, 48.60%; H, 4.33%; N, 10.63%; S, 16.22%
Mass spectrum: m/e 396.3 (M+1)
Hydrogen spectrum: δ/ppm, D
2O
δ(1.19，d，3H)δ(1.26，d，3H)δ(3.05，m，1H)δ(3.20，t，1H)δ(3.42，t，1H)δ(3.49，t，2H)δ(3.61，m，1H)δ(4.49，s，2H)
The preparation of embodiment 21 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compound 1-5 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in the compound 1-5 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in the compound 1-5 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in the compound 1-5 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 22 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compound 1-5 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 1-5 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 1-5 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 pharmaceutically acceptable non-toxic salt, its hydrate, and the hydrate of ester or salt:
Wherein: R
1Expression hydrogen atom or carboxyl-protecting group;
R
2Expression hydrogen atom or low alkyl group;
A represents group shown in the following formula,
R
3, R
4Independent respectively expression hydrogen atom, halogen atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl is by amino, hydroxyl, carboxyl substituted or unsubstituted low alkyl group, lower alkoxy, elementary alkyl amido methanoyl, low-grade alkyl amino alkylsulfonyl, low alkyl group amido, low alkyl group sulfonamido;
X represents NH or CH
2
W represents the integer of 0-6;
M represents the integer of 0-6;
N represents 0,1 or 2.
2, the ester of compound as claimed in claim 1, its facile hydrolysis, its pharmaceutically acceptable non-toxic salt, its hydrate, and the hydrate of ester or salt,
Wherein: R
1Expression hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, ethyl, the tertiary butyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Expression hydrogen atom or low alkyl group;
A represents group shown in the following formula,
R
3, R
4Independent respectively expression hydrogen atom, fluorine atom, chlorine atom, cyano group, hydroxyl, carboxyl, amino, trifluoromethyl, formamyl, amino-sulfonyl, low alkyl group, lower alkoxy, methylamino formyl radical, kharophen or methanesulfonamido;
X represents NH or CH
2
W represents the integer of 0-3;
M represents the integer of 0-3;
N represents 0 or 1.
3, the ester of compound as claimed in claim 2, its facile hydrolysis, its pharmaceutically acceptable non-toxic salt, its hydrate, and the hydrate of ester or salt,
Wherein: R
1Expression hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2Expression hydrogen atom or methyl;
A represents group shown in the following formula,
R
3, R
4Independent respectively expression hydrogen atom or low alkyl group;
X represents NH or CH
2
W represents 0 or 1;
M represents 0 or 1;
N represents 0 or 1.
4, compound as claimed in claim 3 is selected from:
(4R, 5S, 6S)-and 3-[4-methyl-5-acetoxyl-thiazol-2-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)-and 3-[7-carboxyl-4,7-dihydrobenzo [d] thiazol-2-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)-and 3-[7-carboxyl-4H-thiazole [4,5-b] pyridine-2-yl also] 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-[6-oxo-4,5-pyrrolin alkane is [3,4-d] thiazol-2-yl also] 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-[6-oxo-4, the 5-thiazoline is [4,5-c] pyridine-2-yl also] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid; And the hydrate of the ester of facile hydrolysis, its pharmaceutically acceptable non-toxic salt, its hydrate or its ester or salt.
5, the described compound of the arbitrary claim of claim 1～4; the ester of its facile hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis; described ester comprises lower alkane acyloxyalkyl group ester; lower alkoxycarbonyl oxyalkyl ester; the lactone group ester, lower alkoxy methyl ester, lower alkane acyl amino methyl ester; benzyl ester, the cyano methyl ester.
6, the described compound of the arbitrary claim of claim 1～4, its pharmaceutically acceptable non-toxic salt comprises organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, citric acid, formic acid, toxilic acid, oxalic acid, Succinic Acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix, oxysuccinic acid, methylsulfonic acid, toluenesulphonic acids; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises general methylamine salt, glucosamine salt, trismethylamine salt, triethyl amine salt, tetramethyl ammonium, tetraethyl-ammonium salt, phenmethyl leptodactyline, phenyl triethyl ammonium salt; The amino acid hydrochlorate comprises arginic acid salt, aspartate, glutaminate, Methionin; Mineral alkali comprises the basic cpd of lithium, sodium, potassium, calcium, magnesium, iron, aluminium, zinc.
7, comprise the hydrate of ester, its pharmaceutically acceptable non-toxic salt, its hydrate or its ester or salt of the described compound of the arbitrary claim of claim 1～4, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner.
8, pharmaceutical composition as claimed in claim 7, the hydrate 0.05g～5g of ester, its pharmaceutically acceptable non-toxic salt, its hydrate or its ester or salt that wherein contains the described compound of the arbitrary claim of claim 1～4, its facile hydrolysis is as essential active ingredient.
9, pharmaceutical composition as claimed in claim 7 is for clinically or pharmaceutically acceptable arbitrary formulation.
10, comprise the described compound of the arbitrary claim of claim 1～4, its facile hydrolysis ester, its pharmaceutically acceptable non-toxic salt, its hydrate or its ester or salt hydrate preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application.
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