CN107400126A - Novel oxazolidinone class compound and preparation method thereof and application medically - Google Patents

Novel oxazolidinone class compound and preparation method thereof and application medically Download PDF

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CN107400126A
CN107400126A CN201610338563.0A CN201610338563A CN107400126A CN 107400126 A CN107400126 A CN 107400126A CN 201610338563 A CN201610338563 A CN 201610338563A CN 107400126 A CN107400126 A CN 107400126A
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compound
acid
pharmaceutically acceptable
alkyl
acceptable salt
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陆华龙
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Shaanxi Synthetic Pharmaceutical Co ltd
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Jiangsu Tiandirenhe Pharmaceutical Co Ltd
SHAANXI HECHENG PHARMACEUTICAL CO Ltd
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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Abstract

Application the present invention relates to a kind of novel oxazolidinone class compound and preparation method thereof and medically, specifically, the present invention relates to a kind of formula（I）Shown novel oxazolidinone class compound, its preparation method and the pharmaceutical composition containing the compound, as well as therapeutic agent, the particularly purposes in the medicine for preparing treatment microorganism infection, its formula of（I）In each substituent definition it is identical with the definition in claims.

Description

Novel oxazolidinone compound, preparation method and medical application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a novel oxazolidinone derivative, a preparation method, a pharmaceutical composition containing the derivative, and application of the derivative in anti-infective diseases.
Background
The development of drug-resistant bacteria of various antibiotics and antibacterial drugs is rapid, the life health of infectious disease patients is seriously threatened, and the exploration of new drugs of the drug-resistant gram-positive bacteria becomes a research hotspot in the medical field at home and abroad. The oxazolidinone antibacterial drugs are novel chemically fully-synthesized antibacterial drugs developed after sulfonamides and fluoroquinolones in about 30 years, can kill gram-positive pathogens by inhibiting protein synthesis at an extremely early stage, and have the effect of inhibiting multi-drug-resistance gram-positive bacteria.
In the prior art, various oxazolidinone derivatives have been disclosed, but until now, only linezolid (ZYVOX), which is a single antibacterial agent of the oxazolidinone class, has been approved for the treatment of microbial infections, but reversible thrombocytopenia and other myelosuppressive reactions have occurred in part after a long period of use, and the antibacterial spectrum of the drug does not sufficiently cover upper respiratory tract infections caused by haemophilus influenzae and moraxella catarrhalis and atypical pathogens, so there is still a great demand for new anti-infective agents.
The invention content is as follows:
the invention provides a novel oxazolidinone compound shown as the following formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof in a first aspect.
In a second aspect, the present invention provides a process for preparing oxazolidinones, stereoisomers or pharmaceutically acceptable salts thereof according to the first aspect of the invention.
In a third aspect, the present invention provides oxazolidinones, stereoisomers or pharmaceutically acceptable salts thereof according to the first aspect of the present invention.
In a fourth aspect, the invention provides an oxazolidinone compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, and an application thereof in preparing a medicament for treating microbial infection.
In a fifth aspect, the present invention provides a pharmaceutical composition, which comprises a clinically effective dose of the oxazolidinone compound of the first aspect, a stereoisomer or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
Detailed Description
In order to achieve the above purpose, the present invention provides a series of novel oxazolidinone compounds represented by the following general formula (I), and also provides a series of oxazolidinone compounds represented by the following general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, wherein:
wherein:
R1is selected from、、、、、
、、、、、、、、、；
R2Selected from hydrogen, hydroxy, methyl, halogen, hydroxymethyl, C1-C10Alkyl radical, C1-C10Alkenyl radical, C1-C10Alkoxy, aryl C1-C10Alkyl, hydroxy trifluoromethyl, difluoromethyl, fluoromethyl;
R3selected from OH, NH (C ═ O) CH3、-NR4R5、-OR6Hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, carboxyl or carboxylate, triazole, alkyl phosphate, phosphite, phosphate, or a metal salt of a phosphate;
wherein,
R4and R5The same or different, each represents hydrogen, alkyl of 1 to 4 carbon atoms or acetyl;
R6is hydrogen, alkyl of 1 to 3 carbon atoms or an acylated amino acid; when R is6In the case of an acylated amino acid, the amino acid is alanine, glycine, proline, isoleucine, leucine, phenylalanine, β -alanine, or valine.
Preferably, the oxazolidinone compound, stereoisomer or pharmaceutically acceptable salt thereof is shown as formula (II):
R1、R2and R3As defined in claim 1.
The invention provides oxazolidinone compounds, stereoisomers or pharmaceutically acceptable salts thereof, wherein the oxazolidinone compounds comprise the following compounds:
。
in a second aspect, the present invention provides a process for preparing oxazolidinones, stereoisomers or pharmaceutically acceptable salts thereof according to the first aspect of the invention. The method comprises the following steps:
in the above formulae, R1、R2、R3As defined above.
And (2) reacting the compound A and the compound B in a polar solvent in the presence of a protective agent and an organic base for 1-12 hours to obtain the compound (I).
The compound comprises a racemate, an S configuration and an R configuration.
The invention also provides an application of the oxazolidinone compound or the medicinal salt thereof in preparing a microbial infection medicament.
The invention also provides a pharmaceutical composition containing the oxazolidinone compound and a stereoisomer or a pharmaceutically acceptable salt, which comprises a clinically effective dose of the oxazolidinone compound, the stereoisomer or the pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier. The oxazolidinone compound, the stereoisomer or the medicinal salt thereof can be singly administered or administered in the form of medicinal combination. The pharmaceutical composition can be prepared into various suitable dosage forms according to the administration route. The use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration chosen and may be manufactured according to common general knowledge in the art.
The administration route can be oral, parenteral or topical, preferably oral and injectable. The oral administration preparation comprises capsules, granules, tablets and the like. Sublingual tablets or other non-swallowing forms of administration may also be used when the patient has difficulty swallowing. The compounds of the invention may also be formulated for parenteral or transdermal administration or transmucosal administration. Or by means of suppositories or implants. It will be appreciated by those skilled in the art that the compounds of the present invention may be employed with suitable drug delivery systems to achieve more beneficial effects.
It is further noted that the dosage and method of administration of the compounds of the present invention will depend upon a variety of factors including the age, weight, sex, health, nutritional status, activity intensity of the compound, time of use, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferable dosage is 2-1200 mg/kg; preferably, the dosage of the medicine is 0.2-100 mg per kg in 24 hours, and multiple times of administration can also be adopted.
The present invention will be described in further detail with reference to examples, but it should be understood that the scope of the present invention is not limited to these examples.
Example 1: preparation of N- (((S) -3- (3-fluoro-4- ((4 aR, 7 aR) -octahydropyrrolo [3,4-b ] pyridin-6-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound A)
Compound A
Taking 10g of (4 aR, 7 aR) -6- (4-bromo-2-fluorophenyl) -octahydro-1H-pyrrolo [3,4-b ] pyridine, adding 200ml of ethyl acetate to dissolve the pyridine, then reducing the temperature of the solution to below 5 ℃, then adding 6.5g of N- (((S) -2-oxooxazolidin-5-yl) methyl) acetamide in batches, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring the mixture to react for 8 hours, then filtering insoluble substances, washing a small amount of chloroform, then combining chloroform solutions, washing the chloroform solutions twice, drying anhydrous sodium sulfate and concentrating the dried solution. The residue was subjected to HPLC separation system to obtain 3.5g of Compound A.
Example 2: preparation of (S) -3- (3-fluoro-4- ((4 aR, 7 aR) -octahydropyrrolo [3,4-B ] pyridin-6-yl) phenyl) -5- ((methylamino) methyl) oxazolidine 2-one (Compound B)
Compound B
Prepared by the method of example 1, except that N- (((S) -2-oxooxazolidin-5-yl) methyl) acetamide is replaced with (S) -5- ((dimethylamino) methyl) oxazolidin-2-one.
Example 3: preparation of N- (((S) -3- (4- ((R) -3-Aminoazepan-1-yl) -3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound C)
Compound C
Taking 10g of (R) -1- (4-bromo-2-fluorophenyl) azepane-3-amine, adding 200ml of dichloromethane for dissolving, then reducing the temperature of the solution to be below 5 ℃, then adding 7.5g of N- (((S) -2-oxo oxazolidine-5-yl) methyl) acetamide in batches, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring for reacting for 8 hours, then filtering out insoluble substances, washing by a small amount of chloroform, combining chloroform solutions, then washing twice by water, drying by anhydrous sodium sulfate, and concentrating to be dry. The residue was subjected to HPLC separation system to obtain 4.2g of compound C.
Example 4: preparation of N- (((S) -3- (3- (trifluoromethyl) -4- (3-methyl-1H-pyrrol-1-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound D)
Compound D
Taking 10g of 1- (4-bromo-2- (trifluoromethyl) phenyl) -3-methyl-1H-pyrrole, adding 200ml of dichloromethane for dissolving, then reducing the temperature of the solution to be below 5 ℃, then adding 7.5g of N- (((S) -2-oxo oxazolidine-5-yl) methyl) acetamide in batches, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring for reacting for 8H, then filtering out insoluble substances, washing with a small amount of chloroform, then combining chloroform liquid, washing with water twice, drying with anhydrous sodium sulfate, and concentrating to be dry. The residue was subjected to HPLC separation system to obtain 1.7g of compound D.
Example 5: : preparation of N- (((S) -3- (3-fluoro-4- (3-methyl-1H-pyrrol-1-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound E)
Compound E
Taking 10g of 1- (4-bromo-2-fluorophenyl) -3-methyl-1H-pyrrole, adding 200ml of dichloromethane for dissolving, then reducing the temperature of the solution to be below 5 ℃, then adding 7.5g of N- (((S) -2-oxo oxazolidine-5-yl) methyl) acetamide in batches, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring for reacting for 8 hours, then filtering out insoluble substances, washing by a small amount of chloroform, combining chloroform solutions, then washing twice by water, drying by anhydrous sodium sulfate, and concentrating to be dry. The residue was subjected to HPLC separation system to obtain 2.5g of compound E.
Example 6: preparation of (R) -3- (3-fluoro-4- (3-methylpiperazin-1-yl) phenyl) -5- (hydroxymethyl) oxazolidin-2-one (Compound F)
Compound F
Taking 10g of 1- (4-bromo-2-fluorophenyl) -3-methylpiperazine, adding 200ml of dichloromethane for dissolving, then reducing the temperature of the solution to below 5 ℃, then adding 3.5g of (R) -5- (hydroxymethyl) oxazolidine-2-ketone in batches, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring for reacting for 8 hours, then filtering out insoluble substances, combining chloroform liquid after washing by a small amount of chloroform, then washing twice by water, drying by anhydrous sodium sulfate, and concentrating to dryness. The residue was subjected to HPLC separation system to obtain compound F2.2g.
Example 7: preparation of (R) -3- (3-fluoro-4- ((4 AR, 7 AR) -octahydropyrrolo [3,4-b ] pyridin-6-yl) phenyl) -5- (hydroxymethyl) oxazolidin-2-one (Compound G)
Compound G
Taking 10g of (4 AR, 7 AR) -6- (4-bromo-2-fluorophenyl) -octahydro-1H-pyrrolo [3,4-b ] pyridine, adding 200ml of ethyl acetate to dissolve the pyridine, reducing the temperature of the solution to below 5 ℃, then adding 6.5g of (R) -5- (hydroxymethyl) oxazolidine-2-ketone in batches, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring the mixture to react for 8 hours, filtering out insoluble substances, washing a small amount of chloroform, then combining chloroform liquid, washing the chloroform liquid twice, drying the chloroform liquid by anhydrous sodium sulfate, and concentrating the dried chloroform liquid. The residue was subjected to HPLC separation system to obtain 3.0G of compound G.
Example 8: preparation of ((R) -3- (3-fluoro-4- (4- ((5-methyl-2-oxo-1, 3-dioxan-4-yl) methyl) piperazin-1-yl) phenyl) -5- (hydroxymethyl) oxazolidin-2-one (Compound H)
Compound H
Prepared by the method of example 7, except that the compound (4 AR, 7 AR) -6- (4-bromo-2-fluorophenyl) -octahydro-1H-pyrrolo [3,4-b ] pyridine is replaced with the compound 4- ((4- (4-bromo-2-fluorophenyl) piperidin-1-yl) methyl) -5-methyl-1, 3-dioxol-2-one.
Example 9: preparation of (R) -5- ((1H-1, 2, 3-triazol-1-yl) methyl) -3- (4- (3-aminopyrrolidin-1-yl) -3-fluorophenyl) oxazolidine-2-one (Compound I)
Compound I
Taking 10g of (1- (4-bromo-2-chlorophenyl) pyrrolidin-3-amine, adding 200ml of ethyl acetate to dissolve, then reducing the temperature of the solution to below 5 ℃, then adding 6.5g of (R) -5- ((1H-1, 2, 3-triazol-1-yl) methyl) oxazolidine-2-one in portions, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring and reacting for 8 hours, then filtering off insoluble substances, washing with a small amount of chloroform, then combining chloroform solutions, then washing with water twice, drying with anhydrous sodium sulfate, concentrating to dryness, and separating the residue by HPLC to obtain 3.3g of compound I.
Example 10: preparation of (R) -5- ((1H-1, 2, 3-triazol-1-yl) methyl) -3- (3-fluoro-4- (3- (methylamino) piperidin-1-yl) phenyl) oxazol-2-one (Compound J)
Compound J
Prepared by the method of example 9, except that the compound (1- (4-bromo-2-chlorophenyl) pyrrolidin-3-amine was replaced with the compound 1- (4-bromo-2-fluorophenyl) -N-methylpiperidin-3-amine.
Example 11: preparation of ((R) -3- (3-fluoro-4- ((4 AR, 7 AR) -octahydropyrrolo [3,4-b ] pyridin-6-yl) phenyl) -2-oxooxazolidin-5-yl) methyldihydrophosphate (Compound K)
Compound K
1G of compound G was dissolved in 10ml of a mixed solvent (tetrahydrofuran: dichloromethane ═ 1: 1). 0.6g of tetrazole and 2.3 g of bistetrabutyldiisopropylphosphoramide were added to the solution at room temperature and stirred at room temperature for 12 hours. The reaction mixture was cooled to-20 ℃ and 0.7g of m-chloroperbenzoic acid was added and stirred for 2 hours. After the reaction mixture was stirred for 2 hours, the reaction mixture was warmed to room temperature. Ethyl acetate was added to the reaction mixture. The separated organic layer was washed with sodium hydrogen sulfate, sodium hydrogen carbonate and brine, dehydrated, filtered and concentrated in vacuo, followed by purification by column chromatography, whereby compound K1.1 g was obtained.
Example 12: preparation of sodium ((R) -3- (3-fluoro-4- (4- ((5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl) piperazin-1-yl) phenyl) -2-oxooxazolidin-5-yl) methyl phosphate (Compound L)
Compound L
1g of compound H is dissolved in 10ml of a mixed solvent (tetrahydrofuran: dichloromethane: 1). 0.6g of tetrazole and 2.3 g of bistetrabutyldiisopropylphosphoramide were added to the solution at room temperature and stirred at room temperature for 12 hours. The reaction mixture was cooled to-20 ℃ and 0.7g of m-chloroperbenzoic acid was added and stirred for 2 hours. After the reaction mixture was stirred for 2 hours, the reaction mixture was warmed to room temperature. Ethyl acetate was added to the reaction mixture. The separated organic layer was washed with sodium hydrogen sulfate, sodium hydrogen carbonate and brine, dehydrated, filtered and concentrated in vacuo, followed by purification by column chromatography, whereby 1.0g of the compound was obtained
1.0g of the compound obtained by the above-mentioned method was dissolved in a mixture of methanol and chloroform, and then 3.4 ml of sodium methoxide (0.3 mol/l methanol solution) was added to the solution at room temperature, followed by stirring for 10 hours. Concentrating to dryness. The residue was subjected to HPLC separation system to obtain 0.6g of compound L.
EXAMPLE 13 preparation of (R) -5- (aminomethyl) -3- (3- (trifluoromethyl) -4- (3-hydroxyazetidin-1-yl) phenyl) oxazolidin-2-one hydrochloride (Compound M)
Compound M
Taking 10g of 1- (4-iodine-2- (trifluoromethyl) phenyl) azetidine-3-ol, adding 200ml of ethyl acetate to dissolve, reducing the temperature of the solution to be below 5 ℃, then adding 6.5g of (R) -5- (aminomethyl) oxazolidine-2-ketone in batches, controlling the internal temperature to be not more than 10 ℃, naturally raising the bath temperature to room temperature after the addition is finished, stirring for reaction for 8 hours, then filtering out insoluble substances, washing with a small amount of chloroform, combining chloroform solutions, washing with water twice, drying with anhydrous sodium sulfate, and concentrating to be dry. The residue was subjected to HPLC separation system to obtain 3.2g of the compound.
1.0g of the compound obtained by the above method was dissolved in a mixture of methanol and chloroform, and then 3.0 ml of concentrated hydrochloric acid was added to the solution at room temperature, followed by stirring for 10 hours. Concentrating to dryness. The residue was subjected to HPLC separation system to obtain 0.6g of Compound M
Comparative example 1: preparation of (R) -3- [4- (4-Aminomethylphenyl) -3-fluorophenyl ] -5-hydroxymethyloxazolidin-2-one (CN 103360379A)
Synthesis of (R) -3- [4- (4-aminomethylphenyl) -3-fluorophenyl ] -5-hydroxymethyl oxazolidin-2-one
Step A: synthesis of benzyl 3-fluoro- {4- [ (isoindoline-1, 3-diketo) methyl ] phenyl } phenyl carbamate
0.72g of benzyl 3-fluoro-4- (4-hydroxymethylphenyl) carbanilate was weighed out in a 100ml single-necked flask, 25ml of anhydrous tetrahydrofuran, 0.88g of phthalimide and 1.57g of triphenylphosphine were added thereto at 0 to 10 ℃, and a solution of diethyl azodicarboxylate (DEAD) in anhydrous THF (0.5ml in 5 ml) was slowly added dropwise under nitrogen protection, followed by reaction at 0 to 10 ℃ for 4 hours. The reaction mixture was concentrated, extracted with dichloromethane (3X 50ml), washed with 5% aqueous NaHCO3 solution (2X 30ml), and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The title compound was purified by filtration and column chromatography.
And B: synthesis of 3-fluoro- (4-aminomethyl phenyl) benzyl phenylcarbamate
Weighing 0.8g of the product obtained in the step A into a 250ml single-neck bottle, adding 80ml of ethanol and 0.64g of 80% hydrazine hydrate, carrying out reflux reaction until the reaction is completed, cooling to room temperature, filtering, concentrating the filtrate, extracting with dichloromethane (3X 30ml), combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain the title compound.
And C: synthesis of (R) -3- [4- (4-aminomethylphenyl) -3-fluorophenyl ] -5-hydroxymethyl oxazolidin-2-one
Weighing 0.7g of the product obtained in the step B, placing the product in a 100ml two-necked flask, adding anhydrous THF20ml, cooling to-78 ℃, sequentially adding 1ml of n-butyllithium (1.6M) and 0.32g of R-glycidylbutyrate under nitrogen protection, stirring at-78 ℃ for 4h, and stirring at normal temperature overnight. The reaction was stopped, 10ml of a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was concentrated and extracted with ethyl acetate (2X 10ml), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the title compound.
Comparative example 2: preparation of (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one (CN 1894242B)
Synthesis of (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one
37 g of (R) -3- (4-tributyltin-3-fluorophenyl) -2-oxo-5-oxazolidinylmethanol are dissolved in 150 ml of 2- (1-methyltetrazol-5-yl) -5-bromopyridine. 19.7 g of 2- (2-methyltetrazol-5-yl) -5-bromopyridine, 10.44 g of lithium chloride and 2.9 g of dichlorobis (triphenylphosphine) palladium (II) were added to the solution at room temperature, followed by stirring at 120 ℃ for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The resulting organic layer was separated, washed with brine, dehydrated, filtered, concentrated in vacuo and purified by column chromatography to give the title compound.
EXAMPLE 14 determination of the antibacterial Activity of part of the novel oxazolidinone Compounds of the invention
Inoculating pathogenic bacteria with sterilized nutrient broth culture medium, and culturing at room temperature for 7-8 hr to obtain pathogenic bacteria liquid. 1 mu L of pathogenic bacterium liquid is taken and inoculated into an agar culture medium containing the compound of the invention (the concentrations of the compound in the agar culture medium are respectively 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.062 mu g/mL of liquid medicine), the agar culture medium is cultured for 16 hours at 35 ℃, and the growth condition of pathogenic bacteria is observed. Simultaneously, linezolid (Zyvox), a negative control group and a solvent control group are set, and the test method is the same as the test method of the test drug. The results were recorded and the antibacterial activity was calculated. The results of the Staphylococcus aureus and Staphylococcus epidermidis tests are shown in Table 1
Table 1:
the results of the determination of some of the compounds pneumococcus, enterococcus faecalis ATCC29212 and enterococcus faecalis ATCC51299 are shown in Table 2:
table 2:
according to tables 1,2, the novel oxazolidinone compounds of the present invention have excellent antibacterial activity effect, and thus, the compounds of the present invention can be used as antibiotics.
Example 15: acute toxicity testing by oral administration of a portion of novel oxazolidinone compounds to mice
To test the acute toxicity of the compounds of the present invention, the following experiments were performed.
A mixture of 1% hydroxypropyl methylcellulose and 200mg of one selected from the group consisting of compounds 10, 12, 16, 17, 20, 22, 24 and 27 was administered to 5 ICR mice (5-week-old, male, 20 g ± 2g mouse). The lethality, body weight, symptoms, etc. were then observed after 2 weeks to determine the minimum lethal Dose (MLD, mg/Kg). Linezolid (Zyvox) from Pharmacia & Upjohn Inc was used as a control. The results are shown in Table 3.
Table 3;
compound (I) Minimum lethal dose (MLD, mg/Kg)
Zyvox >1000
Compound A >1000
Compound B >1000
Compound C >1000
Compound D >1000
Compound E >1000
Compound F >1000
Compound G >1000
Compound H >1000
Compound I >1000
Compound J >1000
Compound K >1000
Compound L >1000
Compound M >1000
Comparative example 1 >1000
Comparative example 2 >1000
The observation of survival rates, weight changes, blood tests and toxic syndromes demonstrate that there is no toxicity with the novel oxazolidinone compounds of the invention.
According to tables 1,2 and 3, the novel oxazolidinone compounds of the present invention have excellent antibacterial activity effect without any toxicity.

Claims (7)

1. Oxazolidinone compounds shown as a formula I, stereoisomers or pharmaceutically acceptable salts thereof,
wherein:
R1is selected from、、、、、
、、、、、、、、、；
R2Selected from hydrogen, hydroxy, methyl, halogen, hydroxymethyl, C1-C10Alkyl radical, C1-C10Alkenyl radical, C1-C10Alkoxy, aryl C1-C10Alkyl, hydroxy trifluoromethyl, difluoromethyl, fluoromethyl;
R3selected from OH, NH (C ═ O) CH3、-NR4R5、-OR6Hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, carboxyl or carboxylate, triazole, alkyl phosphate, phosphite, phosphate, or a metal salt of a phosphate;
wherein,
R4and R5The same or different, each represents hydrogen, alkyl of 1 to 4 carbon atoms or acetyl;
R6is hydrogen, alkyl of 1 to 3 carbon atoms or an acylated amino acid; when R is6In the case of an acylated amino acid, the amino acid is alanine, glycine, proline, isoleucine, leucine, phenylalanine, β -alanine, or valine.
2. An oxazolidinone compound, a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by general formula (II):
R1、R2and R3As defined in claim 1.
3. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is selected from one of the following structures:
。
4. an oxazolidinone compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to claims 1 to 3 wherein the pharmaceutically acceptable salt is the salt with: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or the like, or an alkali metal salt, alkaline earth metal salt and an alkali metal salt, alkaline earth metal salt of a phosphate of a compound of the general formula (I).
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 4, or an optical isomer, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
6. Use of a compound of any one of claims 1-4, and optical isomers, pharmaceutically acceptable salts thereof, or a pharmaceutical composition of claim 5, in the manufacture of a medicament for use in treating a microbial infection in a related manner.
7. A compound according to any one of claims 1 to 4 or an optical isomer, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5 for use in the prevention or treatment of a microbial infection.
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