CN102190656A - Oxazolidinone bacteriophage containing azaheterocycle - Google Patents
Oxazolidinone bacteriophage containing azaheterocycle Download PDFInfo
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- CN102190656A CN102190656A CN2011100749204A CN201110074920A CN102190656A CN 102190656 A CN102190656 A CN 102190656A CN 2011100749204 A CN2011100749204 A CN 2011100749204A CN 201110074920 A CN201110074920 A CN 201110074920A CN 102190656 A CN102190656 A CN 102190656A
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- methyl
- hydrogen atom
- triazole
- independently
- fluorophenyl
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- 0 C*1C(c2cnn[n]2)=C*C1 Chemical compound C*1C(c2cnn[n]2)=C*C1 0.000 description 9
- PFADKXNBIJFTQL-CYBMUJFWSA-N OC[C@@H](CN1c(cc2)cc(F)c2-c2ccc(CNCc3cnn[nH]3)[s]2)OC1=O Chemical compound OC[C@@H](CN1c(cc2)cc(F)c2-c2ccc(CNCc3cnn[nH]3)[s]2)OC1=O PFADKXNBIJFTQL-CYBMUJFWSA-N 0.000 description 1
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
1, technical field
The invention belongs to medical technical field, be specifically related to contain five-membered ring De 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 application in the medicine of infectious diseases in preparation.
2, background technology
Oxazolidine ketone antimicrobial drug is the complete synthesis antimicrobial drug of developing after sulfamido and fluoroquinolones of a class new chemical, has the effect that suppresses the multidrug resistant gram-positive microorganism.
Linezolid is first listing De oxazolidone antibiotics,
It has stronger restraining effect to gram-positive microorganism, does not have cross resistance with other antimicrobial drugs.Its mechanism of action uniqueness can suppress bacterioprotein synthetic commitment.Linezolid is mainly used in the infectious diseases that treatment is caused by the resistance gram-positive microorganism, also can be used for the surgical infection treatment of diseases.
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 satisfy clinical demand, and the resistance situation of Linezolid occurs constantly also.Therefore, be badly in need of developing to the effective antibacterials of drug tolerant bacteria height.
3, summary of the invention
The invention provides the new anti-infective compounds of a class, have structure shown in the following general formula (I) with better anti-microbial activity:
Wherein, R
1Be 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
4Be hydrogen atom or C
1-6Alkyl;
R
5Be 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
10Be hydrogen atom, halogen atom or C
1-6Alkyl.
Be preferably:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3Be hydrogen atom or halogen atom independently;
R
4Be hydrogen atom or methyl;
R
5Be 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
10Be hydrogen atom, halogen atom or C
1-4Alkyl.
More preferably:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3Be hydrogen atom or fluorine atom independently;
R
4Be 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
10Be hydrogen atom, fluorine atom, chlorine atom or methyl.
More preferably:
Wherein, R
1Be acetamido;
R
2, R
3Be hydrogen atom or fluorine atom independently;
R
4Be hydrogen atom;
R
5Be 1,2, the 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
10Be hydrogen atom, fluorine atom, chlorine atom or methyl.
Another technical scheme of the present invention is as follows:
Wherein, R
1Be 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
4Be hydrogen atom or C
1-6Alkyl;
R
5Be 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
10Be hydrogen atom, halogen atom or C
1-6Alkyl.
Be preferably:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3Be hydrogen atom or halogen atom independently;
R
4Be hydrogen atom or methyl;
R
5Be 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
10Be hydrogen atom, halogen atom or C
1-4Alkyl.
More preferably:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3Be hydrogen atom or fluorine atom independently;
R
4Be 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
10Be hydrogen atom, fluorine atom, chlorine atom or methyl.
More preferably:
Wherein, R
1Be acetamido;
R
2, R
3Be hydrogen atom or fluorine atom independently;
R
4Be hydrogen atom;
R
5Be 1,2, the 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
10Be hydrogen atom, fluorine atom, chlorine atom or methyl.
" halogen atom " of the present invention is meant 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 " the expression straight chain; side chain or cyclic contain the alkyl of 1-6 carbon atom; as methyl; ethyl; n-propyl; sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 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:
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 the exsiccant reaction flask, add mixed solvent (dioxane/EtOH/H
2O), add raw material 1, raw material 2, solid Cs then
2CO
3, after the dissolving, under nitrogen protection, add Pd (PPh
3)
2Cl
2, the reaction solution reacting by heating is filtered, and remove and desolvate, filter cake water and ethyl acetate extraction, organic layer water and saturated sodium-chloride washing, anhydrous magnesium sulfate drying gets intermediate 1.
The preparation of step 2 formula I ' compound
Add intermediate 1 and be dissolved in ethanol in the exsiccant reaction flask, drip raw material 3 under nitrogen protection, cryosel bath cooling adds sodium cyanoborohydride in batches, and keeps temperature of reaction low temperature, continues reaction, and concentrating under reduced pressure is separated out white solid, gets formula I ' compound.
R in the above reaction equation
1, R
2, R
3, R
4, R
5, R
6, R
8, R
9, X, Y and Z such as preamble define.
Work as R
7Be C
1-6During alkyl, can be prepared with reference to aforesaid method.
The compounds of this invention " pharmacy acceptable salt " is meant 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., preferred especially benzoate, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate.Inorganic acid salt comprises hydrogen chlorate, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate etc., preferred especially 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, the 2-dimethylamino-ethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the 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., preferred especially 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.
Compound of the present invention unless stated otherwise, the present invention includes cis-isomeride and trans-isomer(ide) if contain olefinic double bonds.
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 all is included in the compound of the present invention.
Compound and the intermediate in preparation process thereof shown in the formula for example of the present invention (I), R
5Representative
The time, change can take place, when having prepared one of them, be equivalent to prepare its tautomer.The compounds of this invention and preparation intermediate thereof that all relate to above-mentioned situation are considered as being equal to, and all are included in the scope of the invention.
That is:
For example prepare compound 1, be equivalent to prepare compound 1 '.
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 mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1mL, 2mL, 5mL, 10mL, 20mL, 50mL, 100mL, 200mL, 250mL, 500mL etc., and wherein large volume (generally the being not less than 100mL) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The present invention also provides and has contained the purposes that five-membered ring De oxazolidone antibiotic is used for preparing the medicine that treats and/or prevents infectious diseases.De oxazolidone antibiotic of the present invention has good antibacterial activity to gram-positive microorganism, and the Gram-positive resistant organism is also had good antibacterial activity, can be used for treating and/or preventing the various diseases that is caused by gram-positive microorganism.
Below further set forth the The compounds of this invention beneficial effect by antibacterial activity test, but this should be interpreted as that The compounds of this 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 is all bought in public institution.
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 seen the preparation embodiment 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
The anti-microbial activity of table 1 The compounds of this invention
By experimental result as seen, The compounds of this invention all has better antibacterial activity to above strains tested, and The compounds of this invention has clinical application potentiality preferably.
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.
Embodiment 1 (S)-N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-
Tang Ji oxazolidine-5-yl] methyl] preparation of acetamide hydrochloride (compound 1 hydrochloride)
(1) methyl N-[(5-bromothiophene-2-yl)] preparation of propine-2-base-1-amine
In the exsiccant reaction flask, add propargylamine 9.5g (172mmol), 5-bromothiophene-2-formaldehyde 30g (158mmol) and 1,2-ethylene dichloride 450mL behind the 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 need not further processing, is directly used in next step.
(2) preparation of the tertiary butyl (5-bromothiophene-2-yl) methyl (propine-2-yl) carbamate
In the organic solution that previous step obtains, 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 the end, add entry 200mL in system, organic phase is behind anhydrous sodium sulfate drying, solvent is removed in decompression, column chromatography purification (ethyl acetate: sherwood oil=1: 30), get faint yellow oily thing 28.1g.
(3) preparation of the tertiary butyl (1H-1,2,3-triazole-5-yl) methyl [(5-bromothiophene-2-yl) methyl] carbamate
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 cuprous iodide 0.97g (5.1mmol) fast, be warming up to 100 ℃, reaction 4h; pour mixture into frozen water 300mL; use extracted with diethyl ether, merge organic phase, the saturated common salt water washing; dried over sodium sulfate; solvent is removed in decompression, column chromatography purification (ethyl acetate: sherwood oil=1: 1), get yellow oil 5.0g.
(4) preparation of the tertiary butyl (5-bromothiophene-2-yl) methyl [(1-trityl-1H-1,2,3-triazole-5-yl) methyl] carbamate
In the exsiccant 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 to be lower than 5 ℃, after dropwising, mixture rises to room temperature, reaction 2h, reaction solution 10mL water washing, organic phase are behind anhydrous sodium sulfate drying, and solvent is removed in decompression, column chromatography purification (ethyl acetate: sherwood oil=1: 8), get faint yellow oily thing 7.1g.
(5) (S)-and the 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
In three mouthfuls of reaction flasks of exsiccant 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), (S)-N-[[3-[3-fluoro-4-(4,4,5,5-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), be dissolved in mixed solvent (dioxane/ethanol/water=9mL: 3mL: 3mL), under the nitrogen protection, add Pd (dppf)
2Cl
20.12g (0.16mmol), be heated to 90 ℃, reacted 2 hours, reaction solution is cooled to room temperature, filters, and the ethanol in the filtrate is removed in decompression, in residuum, add frozen water, use dichloromethane extraction, merge organic phase, the saturated common salt water washing, dried over sodium sulfate, solvent is removed in decompression, column chromatography purification (ethyl acetate: sherwood oil=4: 1), get colorless oil 1.3g.
(6) (S)-and N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] preparation of ethanamide
In the exsiccant 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 the 3mL methylene dichloride, add trifluoroacetic acid 3mL, the mixture stirred overnight at room temperature; add 3mL water, use saturated Na
2CO
3Solution adjust pH to 9 filters collecting precipitation, and with the ether washing, vacuum-drying gets 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)-and N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] preparation of acetamide hydrochloride
With (S)-N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] ethanamide 564mg (1.27mmol) is dissolved in 0.5mL methyl alcohol and the 1mL methylene dichloride, the dioxane solution that adds the saturated hydrochloric acid of 1mL stirs, reaction 1h, after the end, collecting precipitation with the ether washing, gets white solid 280mg.
Embodiment 2 (5R)-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorobenzene
Base]-5-(preparation of methylol) oxazolidine-2-ketone (compound 4)
(1) tertiary butyl [5-[2-fluoro-4-[(R)-5-(methylol)-2-oxo-3-oxazolidinyl] phenyl] thiophene-2-yl] preparation of carbamate
With (R)-3-[3-fluoro-4-(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), yellow soda ash 5g (47.5mmol), Pd (dppf) Cl
20.8g be dissolved in the dioxane, be heated to 90 ℃ of reactions under the nitrogen protection and spend the night, reaction solution is cooled to room temperature; add the water ethyl acetate extraction, organic layer merges organic layer with salt solution washing three times; concentrate after column chromatography for separation (DCM: MeOH=20: 1), get product 6g.
(2) (R)-3-[4-[5-(aminomethyl) thiophene-2-yl]-the 3-fluorophenyl]-5-(preparation of methylol) oxazolidine-2-ketone
With the tertiary butyl [5-[2-fluoro-4-[(R)-5-(methylol)-2-oxo-3-oxazolidinyl] phenyl] thiophene-2-yl] carbamate (6g, 14.2mmol) be dissolved in the methylene dichloride, add the 20mL trifluoroacetic acid, stir 20h under the room temperature, the solvent evaporate to dryness is got oily matter, and this oily matter is directly used in next step reaction without purification.
(3) (R)-and 3-[3-fluoro-4-[5-[[[1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] phenyl]-5-(preparation of methylol) oxazolidine-2-ketone
With (R)-3-[4-[5-(aminomethyl) thiophene-2-yl]-the 3-fluorophenyl]-5-(methylol) oxazolidine-2-ketone (87mg, 0.27mmol) be dissolved in the ethanol, add 1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-formaldehyde (59mg, 0.27mmol), be heated to 50 ℃ of reaction 1h, add itrile group sodium borohydride (67mg then, 1.07mmol) stirring reaction spends the night, use the dilute hydrochloric acid cancellation, transfer pH to 10 with saturated sodium bicarbonate, use ethyl acetate extraction three times, the organic layer evaporate to dryness is after column chromatography for separation (DCM: MeOH=20: 1) get yellow solid (R)-3-[3-fluoro-4-[5-[[[1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-yl] methylamino] methyl] thiophene-2-yl] phenyl]-5-(methylol) oxazolidine-2-ketone 1.2g.
(4) (R)-and 3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-5-(preparation of methylol) oxazolidine-2-ketone
With (R)-3-[3-fluoro-4-[5-[[[1-(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 the 10mL trifluoroacetic acid, stirring reaction spends the night under the room temperature, and solvent is transferred, transfer pH to 10 with sodium bicarbonate, filter, drying, concentrate solid.Crude product obtains white solid (R)-3-[4-[5-[[(1H-1 for three times with washed with dichloromethane, and 2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 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)
(1) (R)-[3-(4-bromo-3-fluorobenzene)-2-carbonyl-oxazolidines-5-yl] methyl 4-toluene sulfonic acide ester
With (R)-3-(4-bromo-3-fluorobenzene)-5-(methylol) oxazolidine-2-ketone (and 20g 69.2mol) is dissolved among the DCM, add triethylamine (21g, 207.6mmol) and TosCl (15.8g, 83.1mmol), stirring reaction spends the night under the reaction solution room temperature.Reaction solution washs with saturated sodium bicarbonate, organic layer concentrate solid, with washed with dichloromethane three times, filtration drying gets white solid (R)-[3-(4-bromo-3-fluorobenzene)-2-carbonyl-oxazolidines-5-yl] methyl 4-toluene sulfonic acide ester 24g.
(2) (R)-5-(azido-methyl)-3-(4-bromo-3-fluorobenzene) oxazolidine-2-ketone
With (R)-[3-(4-bromo-3-fluorobenzene)-2-carbonyl-oxazolidines-5-yl] methyl 4-toluene sulfonic acide ester (5g, 11.3mmol) be dissolved among the DMF, add sodiumazide (1.5g in batches, 22.6mmol), reaction solution is heated to 70 ℃ of reactions and spends the night, reaction solution is given a baby a bath on the third day after its birth time with ethyl acetate diluting water and salt solution, and organic layer concentrates and obtains white solid (R)-5-(azido-methyl)-3-(4-bromo-3-fluorobenzene) oxazolidine-2-ketone 3.5g, this product is directly used in next step reaction without purification.
(3) (R)-and 5-[(1H-1,2,3-triazole-1-yl) methyl]-3-(4-bromo-3-fluorobenzene) oxazolidine-2-ketone
With (R)-5-(azido-methyl)-3-(4-bromo-3-fluorobenzene) oxazolidine-2-ketone (6g, 19.1mmol) be dissolved in the dioxane, add tetrahydroindene (13.8g under the room temperature, 114.6mmol), the reaction solution heating reflux reaction spends the night, solvent is shifted, residuum through column chromatography (PE: EA=1: 1) separate yellow solid (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-(4-bromo-3-fluorobenzene) oxazolidine-2-ketone 4.8g.
(4) (R)-and 5-[(1H-1,2,3-triazole-1-yl) methyl]-preparation of 3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl] oxazolidine-2-ketone
With (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-(4-bromo-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
2Be dissolved in DMSO under nitrogen protection, reaction solution is heated to 90 ℃ of reaction 4h.Dilute with ethyl acetate, organic phase water and salt solution washing, drying concentrates after column chromatography for separation (DCM: MeOH=20: 1) get yellow solid (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[3-fluoro-4-(4,4,5,5-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]-the 2-fluorophenyl] thiophene-2-yl] preparation of carbamate
(1) in the reference example 2, throw (R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[3-fluoro-4-(4,4,5,5-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) gets product 0.5g.
(6) (R)-and 5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-(aminomethyl) thiophene-2-yl]-preparation of 3-fluorophenyl] oxazolidine-2-ketone
(2) in the reference example 2, the throwing tertiary butyl [5-[4-[(R)-5-[(1H-1,2,3-triazole-1-yl) methyl]-2-oxo-3-oxazolidinyl]-the 2-fluorophenyl] thiophene-2-yl] carbamate 6.7g (14.2mmol), get product 4.5g.This product is directly used in next step reaction without purification.
(7) (R)-and 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 the 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, (1.1g 5.15mmol) gets product 1g to 3-triazole-5-formaldehyde.
(8) (R)-and 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
(4) in the 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), get 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]-the 3-fluorobenzene
Base]-5-[(isoxazole-3-base oxygen base) preparation of methyl] oxazolidine-2-ketone (compound 6)
(1) (R)-and 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
With (R)-3-[3-fluoro-4-[5-[[[1-(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) be dissolved in THF under the room temperature nitrogen protection; dropping DEAD under 0 ℃ (532mg, 3.06mmol), rising to room temperature reaction spends the night; with evaporate to dryness under the solvent vacuum, thick product through HPLC purify yellow solid 900mg.
(4) (R)-and 3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-5-[(isoxazole-3-base oxygen base) preparation of methyl] oxazolidine-2-ketone
(4) in the 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), get 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)-and 3-[4-[2-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiazole-5-yl]-the 3-fluorobenzene
Base]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide (compound 8)
(1) preparation of the tertiary butyl (5-bromo thiazole-2-yl) methyl [[1-(3, the 4-dimethoxy-benzyl)-1H-1,2,3-triazole-5-yl] methyl] carboxylicesters
With 1-(5-bromo thiazole-2-yl)-N-[[1-(3, the 4-dimethoxy-benzyl)-1H-1,2,3-triazole-5-yl] methyl] (42g 100mmol) is dissolved among the 30mL DCM methylamine, adds Boc then
2O (44g, 200mmol) with triethylamine (20g 200mmol), stirs under the room temperature and spends the night, mixture through post separate product 2.2g.
(2) (S)-and the tertiary butyl [5-[4-[5-(acetyl aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl] thiazol-2-yl] methyl [[1-(3, the 4-dimethoxy-benzyl)-1,2,3-triazole-5-yl] methyl] carboxylicesters
(5) in the reference example 1, throw the tertiary butyl (5-bromo thiazole-2-yl) methyl [[1-(3, the 4-dimethoxy-benzyl)-1H-1,2,3-triazole-5-yl] methyl] carboxylicesters 52g (100mmol) and (S)-N-[[3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] (4g 110mmol), gets product 1.2g to ethanamide.
(3) N-[[(S)-and 3-[4-[2-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiazole-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
(6) in the reference example 1, throw (S)-tertiary butyl [5-[4-[5-(acetyl aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl] thiazol-2-yl] methyl [[1-(3, the 4-dimethoxy-benzyl)-1,2,3-triazole-5-yl] methyl] carboxylicesters 14g (20mmol), get 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.
Claims (9)
1. the compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be 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
4Be hydrogen atom or C
1-6Alkyl;
R
5Be 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
10Be hydrogen atom, halogen atom or C
1-6Alkyl.
2. compound as claimed in claim 1, its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3Be hydrogen atom or halogen atom independently;
R
4Be hydrogen atom or methyl;
R
5Be 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
10Be hydrogen atom, halogen atom or C
1-4Alkyl.
3. compound as claimed in claim 2, its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3Be hydrogen atom or fluorine atom independently;
R
4Be 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
10Be hydrogen atom, fluorine atom, chlorine atom or methyl.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be acetamido;
R
2, R
3Be hydrogen atom or fluorine atom independently;
R
4Be hydrogen atom;
R
5Be 1,2, the 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
10Be hydrogen atom, fluorine atom, chlorine atom or methyl.
5. compound as claimed in claim 4, its pharmacy acceptable salt or its steric isomer, described compound is:
(S)-and N-[[3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Tang Ji oxazolidine-5-yl] methyl] ethanamide,
N-[[(S)-and 3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl]-1H-pyrroles-2-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide,
N-[[(S)-and 3-[4-[5-[[N-methyl-N-[(1H-1,2,3-triazole-5-yl) methyl] amino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide,
(5R)-and 3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 3-fluorophenyl]-5-(methylol) oxazolidine-2-ketone,
(5R)-and 5-[(1H-1,2,3-triazole-1-yl) methyl]-3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-3-fluorophenyl] oxazolidine-2-ketone,
(5R)-and 3-[4-[5-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiophene-2-yl]-the 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] oxazole-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide and
N-[[(S)-and 3-[4-[2-[[(1H-1,2,3-triazole-5-yl) methylamino] methyl] thiazole-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
6. as each described compound of claim 1~5, its pharmacy acceptable salt or its steric isomer, 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.
7. the pharmaceutical composition that comprises each described compound of claim 1~5, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 7 is characterized in that being oral preparations or injection.
9. each described compound of claim 1~5, its pharmacy acceptable salt and steric isomer thereof is characterized in that preparing the application in the medicine that treats and/or prevents infectious diseases.
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WO2013044865A1 (en) * | 2011-09-30 | 2013-04-04 | 山东轩竹医药科技有限公司 | Oxazolidinone antibiotics containing fused ring |
WO2013044845A1 (en) * | 2011-09-29 | 2013-04-04 | 山东轩竹医药科技有限公司 | Biaryl heterocycle substituted oxazolidinon antibacterial drug |
CN103420995A (en) * | 2013-09-07 | 2013-12-04 | 吉首大学 | Oxazolidinone-alkyl amine group-furanone type compound and preparation method and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1261889A (en) * | 1997-07-11 | 2000-08-02 | 法玛西雅厄普约翰美国公司 | Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agent |
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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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 |
Cited By (6)
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---|---|---|---|---|
WO2013044845A1 (en) * | 2011-09-29 | 2013-04-04 | 山东轩竹医药科技有限公司 | Biaryl heterocycle substituted oxazolidinon antibacterial drug |
US9359344B2 (en) | 2011-09-29 | 2016-06-07 | Xuanzhu Pharma Co., Ltd. | Biaryl heterocycle substituted oxazolidinone antibacterial agents |
WO2013044865A1 (en) * | 2011-09-30 | 2013-04-04 | 山东轩竹医药科技有限公司 | Oxazolidinone antibiotics containing fused ring |
US9487545B2 (en) | 2011-09-30 | 2016-11-08 | Xuanzhu Pharma Co., Ltd. | Fused ring-containing oxazolidinones antibiotics |
CN103420995A (en) * | 2013-09-07 | 2013-12-04 | 吉首大学 | Oxazolidinone-alkyl amine group-furanone type compound and preparation method and application thereof |
CN103420995B (en) * | 2013-09-07 | 2015-07-01 | 吉首大学 | Oxazolidinone-alkyl amine group-furanone type compound and preparation method and application thereof |
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