CN102190656B - Oxazolidinone bacteriophage containing azaheterocycle - Google Patents

Oxazolidinone bacteriophage containing azaheterocycle Download PDF

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CN102190656B
CN102190656B CN201110074920.4A CN201110074920A CN102190656B CN 102190656 B CN102190656 B CN 102190656B CN 201110074920 A CN201110074920 A CN 201110074920A CN 102190656 B CN102190656 B CN 102190656B
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methyl
hydrogen atom
triazole
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oxazolidine
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CN102190656A (en
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黄振华
宋运涛
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Beijing Ao He Research Institute Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicaments and in particular relates to oxazolidinone bacteriophage containing azaheterocycle, pharmaceutically-acceptable salts or stereoisomeride thereof, wherein the oxazolidinone bacteriophage is shown as a general formula (I) in the specification, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y and Z are defined as a description. The invention also relates to a preparation method of the compound, a medicinal composition containing the compound as well as application of the compound or the medicinal compound thereof to preparation of medicines for treating and/or preventing infectious diseases.

Description

Contain five-membered ring oxazolidone antibiotic
1, technical field
The invention belongs to medical technical field, be specifically related to contain five-membered ring oxazolidone antibiotic and pharmacy acceptable salt thereof or its steric isomer, and their preparation method, the pharmaceutical composition that contains described compound, and described compound or its pharmaceutical composition treat and/or prevent the application in the medicine of infectious diseases in preparation.
2, background technology
Oxazolidine ketone antimicrobial drug is the complete synthesis antimicrobial drug of a class new chemical of developing after sulfamido and fluoroquinolones, has the effect that suppresses multidrug resistant gram-positive microorganism.
Linezolid is first listing oxazolidone antibiotics,
Figure BSA00000460462300011
It has stronger restraining effect to gram-positive microorganism, with other antimicrobial drugs without cross resistance.Its mechanism of action is unique, the commitment of energy anti-bacteria protein synthesis.Linezolid is mainly used in the infectious diseases that treatment is caused by resistance gram-positive microorganism, also can be used for the treatment of surgical infection disease.
Yet the clinical application kind of the more and more serious ， oxazolidone antibiotics of the resistance situation of gram-positive microorganism is single clinically, can not meet clinical demand, and the resistance situation of Linezolid also constantly occurs.Therefore, be badly in need of developing the effective antibacterials of drug tolerant bacteria height.
3, summary of the invention
The invention provides the anti-infective compounds with better anti-microbial activity that a class is new, there is structure shown in following general formula (I):
Figure BSA00000460462300012
Wherein, R 1for acetamido, hydroxyl, amino, C 1-6alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3be hydrogen atom or halogen atom independently;
R 4for hydrogen atom or C 1-6alkyl;
R 5for the saturated or undersaturated nitrogen heterocyclic of 5-6 unit;
R 6, R 7, R 8, R 9be hydrogen atom or C independently 1-6alkyl;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, halogen atom or C 1-6alkyl.
Be preferably:
Wherein, R 1for acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3be hydrogen atom or halogen atom independently;
R 4for hydrogen atom or methyl;
R 5for 5-6 unit unsaturated nitrogen heterocycle;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, halogen atom or C 1-4alkyl.
More preferably:
Wherein, R 1for acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3be hydrogen atom or fluorine atom independently;
R 4for hydrogen atom;
R 5be 1,2,3-triazol radical, 1,2,4-triazol radical, pyrazolyl, imidazolyl, pyrrotriazole base, pyridyl or pyrazinyl;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, fluorine atom, chlorine atom or methyl.
More preferably:
Wherein, R 1for acetamido;
R 2, R 3be hydrogen atom or fluorine atom independently;
R 4for hydrogen atom;
R 5it is 1,2,3-triazol radical;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, fluorine atom, chlorine atom or methyl.
Another technical scheme of the present invention is as follows:
Figure BSA00000460462300031
Wherein, R 1for acetamido, hydroxyl, amino, C 1-6alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3be hydrogen atom or halogen atom independently;
R 4for hydrogen atom or C 1-6alkyl;
R 5for the saturated or undersaturated nitrogen heterocyclic of 5-6 unit;
R 6, R 7, R 8, R 9be hydrogen atom or C independently 1-6alkyl;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, halogen atom or C 1-6alkyl.
Be preferably:
Wherein, R 1for acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3be hydrogen atom or halogen atom independently;
R 4for hydrogen atom or methyl;
R 5for 5-6 unit unsaturated nitrogen heterocycle;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, halogen atom or C 1-4alkyl.
More preferably:
Wherein, R 1for acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3be hydrogen atom or fluorine atom independently;
R 4for hydrogen atom;
R 5be 1,2,3-triazol radical, 1,2,4-triazol radical, pyrazolyl, imidazolyl, pyrrotriazole base, pyridyl or pyrazinyl;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, fluorine atom, chlorine atom or methyl.
More preferably:
Wherein, R 1for acetamido;
R 2, R 3be hydrogen atom or fluorine atom independently;
R 4for hydrogen atom;
R 5it is 1,2,3-triazol radical;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S, O or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom, fluorine atom, chlorine atom or methyl.
" halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" C of the present invention 1-6alkyl, C 1-6alkyl amine group " in " C 1-6alkyl " expression straight chain, the alkyl that contains 1-6 carbon atom of side chain or ring-type, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" the saturated or undersaturated nitrogen heterocyclic of 5-6 unit " of the present invention comprises pyrryl, Pyrrolidine base, imidazolidyl, pyrazolidine, imidazolyl, pyrazolyl, 4,5-pyrazoline, 1,2,3-triazol radical, 1,2,4-triazol radical, 1,2,3,4-tetrazyl, 1,2,3,5-tetrazyl, pyridyl, piperidyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazines base, 1,2,4,5-tetrazine base etc.
Particularly preferred compound comprises:
Figure BSA00000460462300041
Figure BSA00000460462300051
The present invention also provides the preparation method of above-claimed cpd:
Work as R 7during for hydrogen atom, can be prepared with reference to following method.
Reaction equation:
Reactions steps:
The preparation of step 1 intermediate 1
In dry reaction flask, add mixed solvent (dioxane/EtOH/H 2o), then add raw material 1, raw material 2, solid Cs 2cO 3, after dissolving, under nitrogen protection, add Pd (PPh 3) 2cl 2, reaction solution reacting by heating, filters, except desolventizing, and filter cake water and ethyl acetate extraction, organic layer water and saturated sodium-chloride washing, anhydrous magnesium sulfate drying, obtains intermediate 1.
The preparation of step 2 formula I ' compound
In dry reaction flask, add intermediate 1 to be dissolved in ethanol, drip raw material 3 under nitrogen protection, cryosel is bathed cooling, adds sodium cyanoborohydride in batches, and keeps temperature of reaction low temperature, continues reaction, and concentrating under reduced pressure, separates out white solid, obtains formula I ' compound.
R in above reaction equation 1, R 2, R 3, R 4, R 5, R 6, R 8, R 9, X, Y and Z be as defined above.
Work as R 7for C 1-6during alkyl, can be prepared with reference to aforesaid method.
The compounds of this invention " pharmacy acceptable salt " refers to by the salt of pharmaceutically acceptable, non-toxic bases or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.Organic acid salt comprises formate, acetate, propionic salt, benzene sulfonate, benzoate, tosilate, 2, 3-dyhydrobutanedioic acid salt, camsilate, Citrate trianion, mesylate, esilate, propanesulfonic acid salt, fumarate, gluconate, glutaminate, isethionate, lactic acid salt, maleate, malate, mandelate, mucate, embonate, pantothenate, succinate, tartrate etc., benzoate particularly preferably, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate.Inorganic acid salt comprises hydrogen chlorate, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate etc., particularly preferably hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt.Organic alkali salt comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylin ethanol, 2-dimethylamino-ethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, polyamides resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, the salt that Trometamol etc. form.Inorganic base salts comprises the basic cpd of ammonium salt and lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, barium salt, aluminium salt, molysite, mantoquita, ferrous salt, manganese salt, manganous salt etc., particularly preferably ammonium salt and sodium salt, sylvite, calcium salt, magnesium salts.
The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and each will produce two optical isomers independently this class asymmetric center, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.
If compound of the present invention contains olefinic double bonds, unless stated otherwise, the present invention includes cis-isomeride and trans-isomer(ide).
Compound of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shifts.Each tautomer and composition thereof is all included in compound of the present invention.
For example compound and the intermediate in preparation process thereof shown in formula of the present invention (I), R 5representative time, can there is change, when having prepared one of them, be equivalent to prepare its tautomer.Allly relate to the compounds of this invention of above-mentioned situation and prepare intermediate, be considered as being equal to, be all included in the scope of the invention.
Figure BSA00000460462300072
That is:
Figure BSA00000460462300073
For example prepare compound 1, be equivalent to prepare compound 1 '.
Figure BSA00000460462300074
Compound 1 '
The present invention is the claimed pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner further.Described composition can be made clinically or pharmaceutically acceptable arbitrary formulation, is preferably oral preparations, injection.
The compounds of this invention, its pharmacy acceptable salt or its steric isomer can be oral or the mode such as administered parenterally be applied to the patient who needs this treatment.
During for administered parenterally, can be made into injection.Injection means the solution that confession is injected in vivo, emulsion or suspension that medicine is made and for preparing or be diluted to the powder of solution or suspension or the sterile preparation of strong solution before use, injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid mean that medicine makes for the sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid that are injected in 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 (being generally the not less than 100mL) injection liquid for intravenous drip also claims intravenous infusion.Injectable sterile powder means that the sterile solution for suitable before use that medicine is made is mixed with settled solution or evenly sterilized powder or the aseptic block of suspension, injection after available suitable solvent for injection preparation, also available intravenous infusion preparation posterior vein instils; For sterilized powder, solvent crystallization, spray-drying process or freeze-drying etc. make.Concentrated solution for injection mean that medicine makes for the aseptic strong solution of diluting before use for intravenous drip.
While making injection, can adopt the ordinary method in existing pharmacy field to produce, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Conventional non-aqueous solvent is vegetables oil, is mainly injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During preparation injection, can not add additives, also 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.Conventional osmotic pressure regulator comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferably sodium-chlor or glucose; Conventional pH value conditioning agent comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-sodium carbonate etc.; Conventional solubilizing agent comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Conventional weighting agent comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Conventional oxidation inhibitor has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Conventional fungistat is phenol, cresols, trichloro-butyl alcohol etc.The conventional container of injection has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
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 disc-shaped that medicine and the compacting of suitable auxiliary materials and mixing form or the solid preparation of special-shaped sheet, take oral ordinary tablet as main, separately have 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 auxiliary material filling in Capsules or is sealed in the solid preparation in 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 that medicine evenly mixes with suitable auxiliary material, and the spherical or near-spherical solid preparation made from proper method, 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 insoluble solid pharmaceutical, is dispersed in 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.
While making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Conventional weighting agent 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.; Conventional disintegrating agent 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 also provides and has contained five-membered ring oxazolidone antibiotic for the preparation of the purposes treating and/or preventing in the medicine of infectious diseases.Oxazolidone antibiotic of the present invention has good anti-microbial activity to gram-positive microorganism, and Gram-positive resistant organism is also had to good anti-microbial activity, can be used for treating and/or preventing the various diseases being caused by gram-positive microorganism.
By antibacterial activity test, further set forth the compounds of this invention beneficial effect below, but this should be interpreted as to the compounds of this invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example the compounds of this invention
For examination bacterial classification: following clinical isolates Zhu Jun public institution buys.
Methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), vancomycin-resistant enterococcus (VRE)
Trial-product: part of compounds of the present invention, its chemical name and preparation method are shown in the Preparation Example of each compound;
Experimental technique: agar dilution, with reference to National Committee for Clinical Laboratory Standards.2006.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard--Seventh Edition M7-A7.
Experimental result and conclusion:
The anti-microbial activity of table 1 the compounds of this invention
Figure BSA00000460462300091
The anti-microbial activity of table 1 the compounds of this invention
Figure BSA00000460462300092
From experimental result, the compounds of this invention has good anti-microbial activity to above strains tested, and the compounds of this invention has good clinical application potentiality.
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 to the scope of the above-mentioned theme of the present invention only limits to following examples.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
embodiment 1 (S)-N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-2- tang Ji oxazolidine-5-yl] methyl] preparation of acetamide hydrochloride (compound 1 hydrochloride)
Figure BSA00000460462300101
(1) N-[(5-bromothiophene-2-yl) methyl] preparation of propine-2-base-1-amine
In dry reaction flask, add propargylamine 9.5g (172mmol), 5-bromothiophene-2-formaldehyde 30g (158mmol) and 1,2-ethylene dichloride 450mL after stirring at room 2h, adds triethoxy sodium borohydride 43.3g (203mmol) in batches, stirred overnight at room temperature, reaction solution washes with water, and organic phase, without further processing, is directly used in next step.
(2) preparation of the tertiary butyl (5-bromothiophene-2-yl) methyl (propine-2-yl) carbamate
Figure BSA00000460462300103
In organic solution obtained in the previous step, add triethylamine 14.5g (143mmol), be cooled to 0 ℃, drip (Boc) 20 acid anhydrides 26.4g (121mmol), after dropwising, reaction solution is in stirring at room 3h, after end, in system, add water 200mL, organic phase is after anhydrous sodium sulfate drying, and solvent is removed in decompression, column chromatography purification (ethyl acetate: sherwood oil=1: 30), obtain faint yellow oily matter 28.1g.
(3) preparation of the tertiary butyl (1H-1,2,3-triazole-5-yl) methyl [(5-bromothiophene-2-yl) methyl] carbamate
Figure BSA00000460462300104
In the there-necked flask of 250mL, add the tertiary butyl (5-bromothiophene-2-yl) methyl (propine-2-yl) carbamate 8.6g (26mmol), TMSN 34.4g (38mmol), DMF 72mL and methyl alcohol 8mL, reaction system nitrogen protection; add fast cuprous iodide 0.97g (5.1mmol), be warming up to 100 ℃, reaction 4h; pour mixture into frozen water 300mL; by extracted with diethyl ether, merge organic phase, saturated common salt water washing; dried over sodium sulfate; solvent, column chromatography purification (ethyl acetate: sherwood oil=1: 1), obtain yellow oil 5.0g are removed in decompression.
(4) preparation of the tertiary butyl (5-bromothiophene-2-yl) methyl [(1-trityl-1H-1,2,3-triazole-5-yl) methyl] carbamate
Figure BSA00000460462300111
In dry reaction flask, add the tertiary butyl (1H-1, 2, 3-triazole-5-yl) methyl [(5-bromothiophene-2-yl) methyl] carbamate 5.0g (13.4mmol), triethylamine 1.8g (17.4mmol) and methylene dichloride 25mL, under ice-water bath, drip the dichloromethane solution of TrtCl 4.3g (15.5mmol), and keep the temperature of reaction system lower than 5 ℃, after dropwising, mixture rises to room temperature, reaction 2h, reaction solution 10mL water washing, organic phase is after anhydrous sodium sulfate drying, solvent is removed in decompression, column chromatography purification (ethyl acetate: sherwood oil=1: 8), obtain faint yellow oily matter 7.1g.
(5) (S)-tertiary butyl [5-[4-[5-(acetylamino methylene radical)-2-Tang Ji oxazolidine-3-yl]-3-fluorophenyl] thiophene-2-yl] preparation of methyl [(1-trityl-1H-1,2,3-triazole-5-yl) methyl] carbamate
Figure BSA00000460462300112
In tri-mouthfuls of reaction flasks of dry 100mL, add the tertiary butyl (5-bromothiophene-2-yl) methyl [(1-trityl-1H-1,2,3-triazole-5-yl) methyl] carbamate 2.0g (3.3mmol), the fluoro-4-(4 of (S)-N-[[3-[3-, 4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide 1.4g (3.6mmol), Cs 2cO 33.2g (9.8mmol), is dissolved in mixed solvent (dioxane/ethanol/water=9mL: 3mL: 3mL), under nitrogen protection, add Pd (dppf) 2cl 20.12g (0.16mmol), is heated to 90 ℃, reacts 2 hours, reaction solution is cooled to room temperature, filters, and the ethanol in filtrate is removed in decompression, in residuum, add frozen water, with dichloromethane extraction, merge organic phase, saturated common salt water washing, dried over sodium sulfate, solvent, column chromatography purification (ethyl acetate: sherwood oil=4: 1), obtain colorless oil 1.3g are removed in decompression.
(6) (S)-N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] preparation of ethanamide
Figure BSA00000460462300113
In dry reaction flask; throw (S)-tertiary butyl [5-[4-[5-(acetylamino methylene radical)-2-Tang Ji oxazolidine-3-yl]-3-fluorophenyl] thiophene-2-yl] methyl [(1-trityl-1H-1; 2; 3-triazole-5-yl) methyl] carbamate 1.0g (1.3mmol); be dissolved in 3mL methylene dichloride, add trifluoroacetic acid 3mL, mixture stirred overnight at room temperature; add 3mL water, use saturated Na 2cO 3solution adjust pH to 9, filters collecting precipitation, and with ether washing, vacuum-drying, obtains pale solid 266mg.
Molecular formula: C 20h 21fN 6o 3s molecular weight: 444.48
1H-NMR(DMSO-d 6，300MHz)：δ15.02(1H，br)，9.75(2H，br)，8.28(1H，t)，7.84(1H，t)，7.64(1H，dd)，7.53(1H，d)，7.43(1H，dd)，7.36(1H，d)，4.78-4.74(1H，m)，4.46(2H，s)，4.31(2H，s)，4.15(1H，t)，3.79(1H，t)，3.30-3.42(2H，m)，1.84(3H，s).
(7) (S)-N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] preparation of acetamide hydrochloride
Figure BSA00000460462300121
By (S)-N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] ethanamide 564mg (1.27mmol) is dissolved in 0.5mL methyl alcohol and 1mL methylene dichloride, the dioxane solution that adds the saturated hydrochloric acid of 1mL, stirs, reaction 1h, after end, collecting precipitation, with ether washing, obtains white solid 280mg.
embodiment 2 (5R)-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorobenzene base]-5-(preparation of methylol) oxazolidine-2-ketone (compound 4)
Figure BSA00000460462300122
(1) tertiary butyl [the fluoro-4-[(R of 5-[2-)-5-(methylol)-2-oxo-3-oxazolidinyl] phenyl] thiophene-2-yl] preparation of carbamate
By the fluoro-4-of (R)-3-[3-(4,4,5,5-tetramethyl--1,3,2-dioxy boron, penta ring-2-yl) phenyl]-5-(methylol) oxazolidine-2-ketone 8g (23.7mmol), the tertiary butyl (5-bromothiophene-2-yl) carbamate 6.9g (23.7mmol), sodium carbonate 5g (47.5mmol), Pd (dppf) Cl 20.8g is dissolved in dioxane, is heated to 90 ℃ of reactions and spends the night under nitrogen protection, and reaction solution is cooled to room temperature; add water and be extracted with ethyl acetate, salt solution washing three times for organic layer, merges organic layer; concentrated by column chromatography for separation (DCM: MeOH=20: 1), obtain product 6g.
(2) (R)-3-[4-[5-(aminomethyl) thiophene-2-yl]-3-fluorophenyl]-5-(preparation of methylol) oxazolidine-2-ketone
By the tertiary butyl [the fluoro-4-[(R of 5-[2-)-5-(methylol)-2-oxo-3-oxazolidinyl] phenyl] thiophene-2-yl] carbamate (6g, 14.2mmol) be dissolved in methylene dichloride, add 20mL trifluoroacetic acid, under room temperature, stir 20h, solvent evaporate to dryness is obtained to oily matter, and this oily matter is directly used in next step reaction without purification.
(3) the fluoro-4-[5-[[[1-of (R)-3-[3-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] phenyl]-5-(preparation of methylol) oxazolidine-2-ketone
By (R)-3-[4-[5-(aminomethyl) thiophene-2-yl]-3-fluorophenyl]-5-(methylol) oxazolidine-2-ketone (87mg, 0.27mmol) be dissolved in ethanol, add 1-(4-methoxybenzyl)-1H-1, 2, 3-triazole-5-formaldehyde (59mg, 0.27mmol), be heated to 50 ℃ of reaction 1h, then add itrile group sodium borohydride (67mg, 1.07mmol) stirring reaction spends the night, use dilute hydrochloric acid cancellation, with saturated sodium bicarbonate, adjust pH to 10, be extracted with ethyl acetate three times, organic layer evaporate to dryness is by column chromatography for separation (DCM: MeOH=20: 1) obtain the fluoro-4-[5-[[[1-of yellow solid (R)-3-[3-(4-methoxybenzyl)-1H-1, 2, 3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] phenyl]-5-(methylol) oxazolidine-2-ketone 1.2g.
(4) (R)-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-5-(preparation of methylol) oxazolidine-2-ketone
Figure BSA00000460462300133
By the fluoro-4-[5-[[[1-of (R)-3-[3-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] phenyl]-5-(methylol) oxazolidine-2-ketone (560mg, 1.07mmol) be dissolved in 10mL trifluoroacetic acid, under room temperature, stirring reaction spends the night, and solvent is transferred, with sodium bicarbonate, adjust pH to 10, filter, dry, concentrate to obtain solid.Crude product obtains white solid (R)-3-[4-[5-[[(1H-1 for three times by washed with dichloromethane, 2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-5-(methylol) oxazolidine-2-ketone 220mg.
Molecular formula: C 18h 18fN 5o 3s molecular weight: 403.43
1H-NMR(DMSO-d 6，400MHz)：δ7.73-7.70(2H，m)，7.60(1H，dd)，7.40(1H，dd)，7.34(1H，d)，6.98(1H，d)，5.21(1H，br)，4.71(1H，t)，4.10(1H，t)，3.89-3.82(2H，m)，3.80(2H，s)，3.72-3.64(1H，m)，3.59-3.52(1H，m).
embodiment 3 (5R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl] preparation of-3-fluorophenyl] oxazolidine-2-ketone (compound 5)
Figure BSA00000460462300141
(1) (R)-[3-(the bromo-3-fluorobenzene of 4-)-2-carbonyl-oxazolidines-5-yl] methyl 4-toluene sulfonic acide ester
Figure BSA00000460462300142
By (R)-3-(the bromo-3-fluorobenzene of 4-)-5-(methylol) oxazolidine-2-ketone (20g, 69.2mol) be dissolved in DCM, add triethylamine (21g, 207.6mmol) and TosCl (15.8g, 83.1mmol), under reaction solution room temperature, stirring reaction spends the night.Reaction solution washs with saturated sodium bicarbonate, and organic layer concentrates and to obtain solid, uses washed with dichloromethane three times, and filtration drying obtains white solid (R)-[3-(the bromo-3-fluorobenzene of 4-)-2-carbonyl-oxazolidines-5-yl] methyl 4-toluene sulfonic acide ester 24g.
(2) (R)-5-(azido-methyl)-3-(the bromo-3-fluorobenzene of 4-) oxazolidine-2-ketone
Figure BSA00000460462300143
By (R)-[3-(the bromo-3-fluorobenzene of 4-)-2-carbonyl-oxazolidines-5-yl] methyl 4-toluene sulfonic acide ester (5g, 11.3mmol) be dissolved in DMF, add sodiumazide (1.5g in batches, 22.6mmol), reaction solution is heated to 70 ℃ of reactions and spends the night, reaction solution is washed three times with ethyl acetate diluting water and salt, organic layer is concentrated to be obtained white solid (R)-5-(azido-methyl)-3-(the bromo-3-fluorobenzene of 4-) oxazolidine-2-ketone 3.5g, this product is directly used in next step reaction without purification.
(3) (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-(the bromo-3-fluorobenzene of 4-) oxazolidine-2-ketone
Figure BSA00000460462300144
By (R)-5-(azido-methyl)-3-(the bromo-3-fluorobenzene of 4-) oxazolidine-2-ketone (6g, 19.1mmol) be dissolved in dioxane, under room temperature, add tetrahydroindene (13.8g, 114.6mmol), reaction solution heating reflux reaction spends the night, and solvent is shifted, and residuum is through column chromatography (PE: EA=1: 1) separated yellow solid (the R)-5-[(1H-1 that obtains, 2,3-triazole-1-yl) methyl]-3-(the bromo-3-fluorobenzene of 4-) oxazolidine-2-ketone 4.8g.
(4) (R)-5-[(1H-1,2,3-triazole-1-yl) methyl] preparation of the fluoro-4-of-3-[3-(4,4,5,5-tetramethyl--1,3,2-dioxy boron, penta ring-2-yl) phenyl] oxazolidine-2-ketone
Figure BSA00000460462300151
By (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-(4-bromine-3-fluorophenyl) oxazolidine-2-ketone (2g, 5.88mmol), two valeryl two boron (1.8g, 7.06mmol), Potassium ethanoate (1.2g, 11.76mmol) and Pd (dppf) 2cl 2under nitrogen protection, be dissolved in DMSO, reaction solution is heated to 90 ℃ of reaction 4h.By ethyl acetate, dilute, organic phase water and salt solution washing, dry, concentrated by column chromatography for separation (DCM: MeOH=20: 1) obtain yellow solid (R)-5-[(1H-1,2,3-triazole-1-yl) methyl] the fluoro-4-(4 of-3-[3-, 4,5,5-tetramethyl--1,3,2-dioxy boron, penta ring-2-yl) phenyl] oxazolidine-2-ketone 1.5g.
(5) tertiary butyl [5-[4-[(R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl] thiophene-2-yl] preparation of carbamate
Figure BSA00000460462300152
(1) in reference example 2, throw (R)-5-[(1H-1,2,3-triazole-1-yl) methyl] the fluoro-4-(4,4 of-3-[3-, 5,5-tetramethyl--1,3,2-dioxy boron, penta ring-2-yl) phenyl] oxazolidine-2-ketone 578mg (1.49mmol), the tertiary butyl (5-bromothiophene-2-yl) carbamate 435mg (1.49mmol), obtains product 0.5g.
(6) (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-(aminomethyl) thiophene-2-yl] preparation of-3-fluorophenyl] oxazolidine-2-ketone
Figure BSA00000460462300153
(2) in reference example 2, the throwing tertiary butyl [5-[4-[(R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl] thiophene-2-yl] carbamate 6.7g (14.2mmol), obtain product 4.5g.This product is directly used in next step reaction without purification.
(7) (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-[[[1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] preparation of-3-fluorophenyl] oxazolidine-2-ketone
(3) in reference example 2, throw (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-(aminomethyl) thiophene-2-yl]-3-fluorophenyl] oxazolidine-2-ketone 2g (5.15mmol), 1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-formaldehyde (1.1g, 5.15mmol) obtains product 1g.
(8) (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl] preparation of-3-fluorophenyl] oxazolidine-2-ketone
Figure BSA00000460462300161
(4) in reference example 2, (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-[[[1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl]-3-fluorophenyl] oxazolidine-2-ketone 1.2g (2.11mmol), obtain product 700mg.
Molecular formula: C 20h 19fN 8o 2s molecular weight: 454.48
1H-NMR(DMSO-d 6，400MHz)：δ8.17(1H，d)，7.97(1H，b)，7.79-7.74(2H，m)，7.56(1H，d)，7.49(1H，d)，7.37(1H，d)，7.30(1H，d)，5.14-5.20(1H，m)，4.85(2H，d)，4.38(2H，s)，4.29-4.22(3H，m)，3.95-3.91(1H，m).
embodiment 4 (5R)-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorobenzene base]-5-[(isoxazole-3-base oxygen base) preparation of methyl] oxazolidine-2-ketone (compound 6)
(1) (R)-5-[(isoxazole-3-base oxygen base) methyl]-3-[4-[5-[[[1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] preparation of-3-fluorophenyl] oxazolidine-2-ketone
Figure BSA00000460462300163
By the fluoro-4-[5-[[[1-of (R)-3-[3-(4-methoxybenzyl)-1H-1; 2; 3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] phenyl]-5-(methylol) oxazolidine-2-ketone (0.8g; 1.53mmol); 5-hydoxyisoxazole (0.2g; 2.29mmol); triphenylphosphine (0.8g; 3.06mmol) under room temperature nitrogen protection, be dissolved in THF; at 0 ℃, drip DEAD (532mg, 3.06mmol), rise to room temperature reaction and spend the night; by evaporate to dryness under solvent vacuum, thick product is through the HPLC yellow solid 900mg that purifies to obtain.
(4) (R)-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-5-[(isoxazole-3-base oxygen base) preparation of methyl] oxazolidine-2-ketone
(4) in reference example 2, throw ((R)-5-[(isoxazole-3-base oxygen base) methyl]-3-[4-[5-[[[1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl]-3-fluorophenyl] oxazolidine-2-ketone 0.7g (1.25mmol), obtain product 213mg.
Molecular formula: C 21h 19fN 6o 4s molecular weight: 470.48
1H-NMR(DMSO-d 6，400MHz)δ9.50(1H，br)，8.68(1H，d)，7.99(1H，br)，7.82(1H，t)，7.62(1H，d)，7.50(1H，d)，7.44(1H，d)，7.30(1H，d)，6.38(1H，d)，5.10-5.12(1H，m)，4.49-4.47(2H，m)，4.47(2H，s)，4.30(2H，s)，4.23(1H，t)，3.95(1H，dd).
embodiment 5N-[[(S)-3-[4-[2-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiazole-5-yl]-3-fluorobenzene base]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide (compound 8)
Figure BSA00000460462300171
(1) preparation of the tertiary butyl (5-bromo thiazole-2-yl) methyl [[1-(3,4-dimethoxy-benzyl)-1H-1,2,3-triazole-5-yl] methyl] carboxylicesters
Figure BSA00000460462300172
By 1-(5-bromo thiazole-2-yl)-N-[[1-(3,4-dimethoxy-benzyl)-1H-1,2,3-triazole-5-yl] methyl] methylamine (42g, 100mmol) is dissolved in 30mL DCM, then adds Boc 2o (44g, 200mmol) and triethylamine (20g, 200mmol), stir and spend the night under room temperature, and mixture is through the separated product 2.2g that obtains of post.
(2) (S)-tertiary butyl [5-[4-[5-(acetyl aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl] thiazol-2-yl] methyl [[1-(3,4-dimethoxy-benzyl)-1,2,3-triazole-5-yl] methyl] carboxylicesters
Figure BSA00000460462300173
(5) in reference example 1, throw the tertiary butyl (5-bromo thiazole-2-yl) methyl [[1-(3,4-dimethoxy-benzyl)-1H-1,2,3-triazole-5-yl] methyl] carboxylicesters 52g (100mmol) and the fluoro-4-(4 of (S)-N-[[3-[3-, 4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide (4g, 110mmol), obtain product 1.2g.
(3) N-[[(S)-3-[4-[2-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiazole-5-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
Figure BSA00000460462300181
(6) in reference example 1, throw (S)-tertiary butyl [5-[4-[5-(acetyl aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl] thiazol-2-yl] [[1-(3 for methyl, 4-dimethoxy-benzyl)-1,2,3-triazole-5-yl] methyl] carboxylicesters 14g (20mmol), obtain product 250mg.
Molecular formula: C 19h 20fN 7o 3s molecular weight: 445.47
1H-NMR(CD 3OD，400MHz)：δ8.20(1H，s)，8.02(1H，s)，.7.75(1H，t)，7.70(1H，d)，7.41(1H，d)，4.88-4.82(1H，m)，4.70(2H，s)，4.57(2H，s)，4.20(1H，t)，3.87(1H，dd)，3.60(2H，d)，1.96(3H，s).
With reference to above-mentioned preparation method, can also prepare following compound.
Figure BSA00000460462300182
Figure BSA00000460462300191

Claims (7)

1. the compound shown in general formula (I), its pharmacy acceptable salt:
Figure FSB0000116944160000011
Wherein, R 1for acetamido, hydroxyl Huo isoxazole oxygen base;
R 2, R 3be hydrogen atom or fluorine atom independently;
R 4for hydrogen atom;
R 5be 1,2,3-triazol radical, 1,2,4-triazol radical, pyrrotriazole base;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom.
2. compound as claimed in claim 1, its pharmacy acceptable salt:
Wherein, R 1for acetamido;
R 2, R 3be hydrogen atom or fluorine atom independently;
R 4for hydrogen atom;
R 5it is 1,2,3-triazol radical;
R 6, R 7, R 8, R 9be hydrogen atom independently;
X is S or NH;
Y, Z are N or CR independently 10, R wherein 10for hydrogen atom.
3. compound as described below:
(S)-N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] ethanamide,
(5R)-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-5-(methylol) oxazolidine-2-ketone,
(5R)-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl]-5-[(isoxazole-3-base oxygen base) methyl] oxazolidine-2-ketone,
N-[[(S)-3-[4-[2-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiazole-5-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
4. the compound as described in claim 1～3 any one, its pharmacy acceptable salt, its pharmacy acceptable salt is benzoate, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate, hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt, ammonium salt, sodium salt, sylvite, calcium salt or magnesium salts.
5. the pharmaceutical composition that comprises compound, its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner described in claim 1～3 any one, is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.
6. pharmaceutical composition as claimed in claim 5, is characterized in that for oral preparations or injection.
7. the compound described in claim 1～3 any one, its pharmacy acceptable salt treat and/or prevent the application in the medicine of infectious diseases in preparation.
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WO2003035648A1 (en) * 2001-10-25 2003-05-01 Astrazeneca Ab Aryl substituted oxazolidinones with antibacterial activity
WO2008143649A2 (en) * 2006-12-04 2008-11-27 Dr. Reddy's Laboratories Limited Novel oxazolidinone compounds as antiinfective agents

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