CN115466253A - Oxazolidinone compound containing dithiocarbamate structure and preparation method thereof - Google Patents

Oxazolidinone compound containing dithiocarbamate structure and preparation method thereof Download PDF

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CN115466253A
CN115466253A CN202110664443.0A CN202110664443A CN115466253A CN 115466253 A CN115466253 A CN 115466253A CN 202110664443 A CN202110664443 A CN 202110664443A CN 115466253 A CN115466253 A CN 115466253A
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oxo
acetamide
fluoro
oxazolidinyl
methyl
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侯云雷
赵燕芳
刘思雨
刘玖玉
宫平
刘亚婧
秦铭泽
高占峰
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Shenyang Pharmaceutical University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/02—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
    • 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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Abstract

The invention relates to the field of medicinal chemistry, in particular to an oxazole compound containing a dithiocarbamate structure and a preparation method thereof. The compound is a compound shown as a general formula I and a stereoisomer or solvate thereof, and has a structural formula shown as the specification, wherein a substituent R 1 、R 2 、R 3 、R 4 X and n have the meanings given in the description. The invention also relates to the application of the compounds and the pharmaceutically acceptable salts, solvates or prodrugs thereof as antibacterial agents in treatment, in particular to the treatment of gram-positive bacteria infection and knotUse in the infection of a mycobacterium tuberculosis.

Description

Oxazolidinone compound containing dithiocarbamate structure and preparation method thereof
Technical Field
The invention relates to the field of medicinal chemistry, in particular to an oxazole compound containing a dithiocarbamate structure and a preparation method thereof.
Background
Due to the long-term use and even abuse of antibiotics, the drug resistance of bacteria rapidly develops, and clinically, the drug-resistant bacteria are increasing, such as methicillin-resistant staphylococcus aureus (MR (S) a), methicillin-resistant staphylococcus epidermidis (MR (S) E) and vancomycin-resistant enterococcus pneumoniae (VRE). Some nonpathogenic bacteria become opportunistic bacteria such as proteus, pseudomonas aeruginosa, etc. The emergence of drug-resistant bacteria causes bacteria to be no longer sensitive to antibacterial drugs, the therapeutic effect of the drugs is obviously reduced, and even a plurality of new antibacterial drugs have not come into clinic and a drug-resistant strain appears, so that the research and development of the new antibacterial drugs are once more challenged, and the development of novel drug-resistant antibacterial drugs, especially the antibacterial drugs with novel action mechanisms is particularly urgent.
The oxazolidinone antibacterial drug can be combined with bacterial ribosome 50S methylene, so that the synthesis of bacterial protein is inhibited, and due to the unique action mechanism, the oxazolidinone antibacterial drug basically does not have the phenomenon of cross drug resistance with other antibacterial drugs.
Dupont company, USA, discovered in 1987 that compound S-6132 has good antiproliferative activity on staphylococcus aureus and streptococcus pneumoniae. Subsequently, structural modification with S-6132 as the miao compound yielded DUP-105 and DUP-721 compounds, respectively, both having outstanding antibacterial activity and superior pharmacokinetic properties, but were terminated by the development of hepatotoxicity problems.
In 1996, pharmacia and Upjoin companies use DUP-721 as a lead compound to optimize the structure of a substituent on a benzene ring of the lead compound, and finally screen oxazolidinone compounds, namely linezolid and eperisolides, which both show good antibacterial activity. Because the pharmacokinetic properties of linezolid are more prominent than that of epezolid, linezolid was approved by the FDA for marketing in 2000, primarily for the treatment of gram-positive bacteria.
Figure BDA0003116731310000011
With the marketing of linezolid, the problem of drug-resistant bacterial infection is alleviated to some extent. However, due to the long-term widespread use of linezolid, drug-resistant strains aiming at linezolid gradually appear, and the drug resistance situation is increasingly serious.
The invention content is as follows:
the invention mainly aims to provide an oxazole compound containing a dithiocarbamate structure and a preparation method thereof, which can be used as an antibacterial agent.
In order to achieve the purpose, the invention adopts the technical scheme that:
an oxazolidinone compound containing a dithiocarbamate structure is a compound shown as a general formula I and a stereoisomer or a solvate thereof,
Figure BDA0003116731310000021
wherein, the first and the second end of the pipe are connected with each other,
R 1 is hydrogen, halogen or C 1 -C 4 A haloalkyl group of (a);
R 2 is selected from-NHCOCH 3 or-OH;
R 3 and R 4 Are identical or different and are each independently selected from hydrogen, unsubstituted or substituted by at least one identical or different R 5 Substituted C 1 -C 6 Alkyl radical, C 3 -C 6 A cycloalkyl group;
R 3 and R 4 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group formed also containsHaving 0 to 4 heteroatoms selected from N, O and/or S, said 4-to 10-membered heterocyclic ring formed may be unsubstituted or substituted with at least one R 5 O or S;
the aforementioned heterocycle optionally includes a 0-3 carbon-carbon double or triple bond, and substitution may occur at its (heterocyclic) carbon or heteroatom.
R 5 Is C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Hydroxyalkyl, hydroxy, halogen, C 1 -C 4 Halogenated alkyl group of (C) 1 -C 4 Halogenoalkoxy of (C) 1 -C 6 An alkylsulfonyl group or a nitro group;
x is C = O, CH 2 ；
n is an integer between 1 and 4.
Further, the compound is a compound shown in a general formula I and a stereoisomer thereof,
in the formula, R 1 Is halogen;
R 2 is-NHCOCH 3 ；
R 3 And R 4 Are identical or different and are each independently selected from hydrogen, unsubstituted or substituted by 1 to 3 identical or different R 5 Substituted C 1 -C 4 Alkyl radical, C 3 -C 5 A cycloalkyl group;
or R 3 And R 4 Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group formed further contains 0-4 heteroatoms selected from N, O and/or S, and the 4-7 membered heterocyclic group formed may be unsubstituted or substituted with at least one R 5 O or S;
R 5 is C 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Hydroxyalkyl radical, C 1 -C 4 Alkylsulfonyl, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro.
Still further, the compound is a compound shown in a general formula I and a stereoisomer thereof,
in the formula, R 1 Is fluorine;
R 2 is-NHCOCH 3 ；
R 3 And R 4 Are identical or different and are each independently selected from hydrogen, unsubstituted or substituted by 1 to 3 identical or different R 5 Substituted C 1 -C 4 Alkyl radical, C 3 -C 5 A cycloalkyl group;
or R 3 And R 4 Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group formed further contains 0-4 heteroatoms selected from N, O and/or S, and the 4-7 membered heterocyclic group formed may be unsubstituted or substituted with at least one R 5 O or S substitution;
R 5 is C 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Alkylsulfonyl, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro.
Most preferably the compound is
(S) -N- [ (3- { 3-fluoro-4- [4- (benzylsulfanylthiosulfonyl) piperazin-1-yl ] phenyl } -2-oxo-5-oxazolidinyl) methyl ] acetamide;
(S) -N- { [3- (3-fluoro-4- {4- [ (pyridin-4-ylmethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- {4- [ (pyridin-4-ylmethylsulfanyl) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (dimethylaminoethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [ -3- (3-fluoro-4- { [ (diethylamino) ethylthiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (pyrrolidin-1-yl) ethylthiocarbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (morpholinoethylthio) carbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (morpholinoethylthio) carbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ 2-oxo- (piperidin-1-yl) ethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-methylpiperidin-1-yl) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (morpholino-2-oxoethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (2-oxo-2-thiomorpholinoethylthio) carbosulfanyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (dimethylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (4-methylpiperazin-1-yl) -2-oxyethylthiocarbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-ethylpiperazin-1-yl) -2-oxoethylthio ] carbo-sulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopropylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclobutylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopentylamino) -2-oxyethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-acetylpiperazin-1-yl) -2-oxyethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
or (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (1,1-dioxothiomorpholinyl) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide.
Solvates of the compounds of formula I above, such as ethanol, water, and the like, may contain varying amounts of water, such as a monohydrate, a hemihydrate, a dihydrate, or a trihydrate.
The application of the compound and the application of the compound with the general formula in preparing medicines for treating microbial infection.
The microbial infection is a bacterial infection.
The bacterial infection is a gram-positive coccal infection or a tubercle bacillus infection.
A composition is prepared by mixing the compound with the general formula and a stereoisomer thereof as an active ingredient with pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein the active ingredient accounts for 0.01-99% of the mass of the composition.
The pharmaceutically acceptable salt is a salt with an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, or aspartic acid.
Use of a composition for the manufacture of a medicament for the treatment of a microbial infection.
The invention also includes prodrugs of the compounds of formula I. Prodrugs, according to the present invention, are derivatives of compounds of formula i which may themselves have poor or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The invention also includes racemates, optically active isomers, polymorphic forms or mixtures thereof of the compounds of formula I which possess the useful properties described herein. The compounds of general formula i according to the invention contain a chiral centre (C-5 position of the oxazolidinone ring) and thus exist as two enantiomers or as a racemic mixture of the two. The invention relates to two enantiomers of useful properties and to mixtures containing the two isomers.
The term "alkyl" as used herein, unless otherwise indicated, refers to straight or branched chain alkyl groups; "alkoxy" refers to straight or branched chain alkoxy groups; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; 5-10 membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, where the ring system of each heteroaryl group can be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5-10 atoms, and examples thereof include pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl, indolyl, naphthyl, and the like.
The invention also comprises a pharmaceutical composition which comprises the compound of the general formula I and pharmaceutically acceptable salts and/or solvates thereof as active ingredients and pharmaceutically acceptable carriers; the compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art and include: binders, lubricants, disintegrants, solubilizing agents, diluents, stabilizers, suspending agents, non-coloring agents, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The invention also includes the use thereof for the preparation of a medicament for the treatment of microbial, in particular bacterial, infections in mammals. The method of use provides an effective amount of a compound of formula I, which can be administered to a mammal orally, parenterally, transdermally or topically in a pharmaceutical composition.
The oxazolidinone compounds with the general formula I have antimicrobial infection and especially antibacterial activity. Further, the oxazolidinone compounds of the general formula I of the present invention can exhibit potent antibacterial activity against human and animal pathogenic bacteria including gram-positive bacteria such as Staphylococcus (Staphylococi), enterococcus (Enterococcci) and Streptococcus (Streptococcus), anaerobic bacteria such as Bacteroides fragilis (Bacteroides fragilis) and Mycobacterium tuberculosis (Mycobacterium tuberculosis). Thus, it may be used as a medicament for the treatment of bacterial infections in mammals, and the compounds according to the invention may be used as active ingredients in the preparation of a method for the treatment of bacterial infections in mammals, comprising administering to a patient suffering from, or susceptible to, such a condition a therapeutically effective amount of a compound according to the invention.
The precise amount of a compound of the invention required to treat a microbial, particularly a bacterial, infection will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the condition being treated, the particular compound used and the mode of administration, e.g., route and frequency of administration, and the like. An appropriate effective amount can be determined by one of ordinary skill in the art using no more than routine experimentation.
The amount of the compound to be administered may be from about 0.1 to 100mg/kg body weight per day, preferably 1 to 50mg/kg body weight per day. It will be appreciated that the dosage may vary with the needs of the patient, the severity of the bacterial infection being treated and the particular compound being used. Furthermore, it will be appreciated that the initial dose administered may be increased beyond the upper limit in order to reach the desired blood level rapidly, or the initial dose may be less than optimal and the daily dose may be increased gradually over the course of the treatment, depending on the particular situation. If desired, the daily dose may also be divided into multiple doses, for example 2-4 times per day.
Mammal means a human or an animal.
In combination therapy, the compound of the present invention and the other compound may be administered simultaneously or at intervals, and in the case of simultaneous administration, the compound of the present invention and the other compound may be combined in a single pharmaceutical composition or in separate compositions.
The following synthetic scheme A, B, C describes the preparation of the general formula I of this invention, all starting materials are prepared by the methods described in these synthetic schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final compounds of the invention are prepared by the methods described in these synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All of the variables used in these synthetic routes are as defined below or as defined above.
The compounds of the general formula I according to the invention in scheme A, scheme B and scheme C are exemplified by the following compounds: r 1 Hydrogen, fluorine, chlorine and trifluoromethyl. R 2 is-NHCOCH 3 or-OH. Substituent R 3 、R 4 Is as defined above
Figure BDA0003116731310000061
In the route A, 3,4-difluoronitrobenzene and N-Boc piperazine are subjected to substitution reaction to obtain an intermediate b2, the intermediate b3 is reduced by an iron/ammonium chloride reduction system, the intermediate b3 and ethyl chloroformate are subjected to acylation to obtain an intermediate b4, the intermediate b4 and (S) -N- (2-acetoxy-3-chloropropyl) acetamide are subjected to reaction in the presence of lithium tert-butoxide to obtain an intermediate b5, and the intermediate b5 and trifluoroacetic acid are subjected to de-Boc reaction to obtain an intermediate b6.
Figure BDA0003116731310000062
In the route B, a one-pot method is adopted, the intermediate B6 is not separated after reacting with carbon disulfide, and directly carries out substitution reaction with a micromolecular side chain to prepare the compound with the general formula I.
Figure BDA0003116731310000063
In the route V-C, the intermediate b4 in the route A is taken as a raw material, and the compound with the general formula I is prepared by cyclization, boc removal, carbon disulfide addition and substitution reaction with a micromolecule side chain.
The invention has the advantages that:
the compound with the general formula is a series of cyclization obtained by replacing a morpholine ring of linezolid with a piperazine ring through a biological electron isostere principle and introducing a dithiocarbamate fragment with an antibacterial effect into the end of the piperazine ring. The series of compounds have unpredictable synergistic antibacterial activity; the general formula of the compound of the general formula, the optical isomer, the pharmaceutically acceptable salt and/or the solvate thereof or the prodrug thereof is introduced with the dithiocarbamate fragment on the basis of oxazolidinone, so that the compound can unexpectedly cooperate with the main structure to improve the antibacterial activity and has a prominent effect on certain drug-resistant bacteria, and further can be used as an antibacterial agent for treatment and applied to treatment of infectious diseases.
The specific implementation mode is as follows:
in the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the compounds was measured using Bruker ARX-300 and Mass Spectroscopy was measured using Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
TABLE 1
Figure BDA0003116731310000071
Figure BDA0003116731310000081
Figure BDA0003116731310000091
Example 1 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (1,1-dioxothiomorpholinyl) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
1.1 Synthesis of (S) -N- { [3- (3 '-fluoro-4' -piperazinylphenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide (b 6)
1.1.1 Preparation of 4- (4-Boc-1-piperazinyl) -3-fluoronitrobenzene (b 2)
20.0g (126 mmol) 3,4-difluoronitrobenzene and 28.2g (151 mmol) potassium carbonate are dissolved in 200mL acetonitrile at room temperature. To the solution was slowly added 34.8g (252 mmol) of N-Boc piperazine at 0-5 ℃. After the addition, the reaction solution was heated to 80 ℃ and reacted for 6 hours. After the reaction, the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and 300mL of water was added to the residue, followed by stirring at room temperature for 30min. Solid was precipitated and filtered to obtain 39.2g of a yellow solid product in 96% yield.
1.1.2 Preparation of 4- (4-Boc-1-piperazinyl) -3-fluoroaniline (b 3)
8.6g (153 mmol) of iron powder and 16.4g (306 mmol) of ammonium chloride are introduced into 400mL of 50% methanol, activated at 60 ℃ for 10min and then 10.0g (31 mmol) of intermediate b2 are added in portions. After the addition, the reaction solution was heated to 70 ℃ to react for 5 hours. After the reaction was complete, the pad was filtered hot with suction and washed with preheated 200mL of methanol. The filtrate was concentrated under reduced pressure, 250mL of water was added to the residue to precipitate a solid, which was suction filtered to give 6.8g of a brown solid product in 75% yield.
1.1.3 Preparation of 1- { 2-fluoro-4 [ (ethoxycarbonyl) amino ] phenyl } -4-N-Boc-piperazine (b 4)
6.8g (23 mmol) of intermediate b3 and 1.8g (23 mmol) of pyridine are added to 100mL of dry dichloromethane at room temperature. A solution of 3.0g (28 mmol) of ethyl chloroformate in dry dichloromethane (100 mL) was added dropwise to the reaction mixture at 0 ℃ and the mixture was reacted at room temperature for 1 hour after completion of the addition. After the reaction, the reaction mixture was washed with 1M hydrochloric acid solution, water and saturated brine in this order, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 7.8g of a pink solid with a yield of 92%.
1.1.4 Preparation of (S) -N- { [3- (3 '-fluoro-4' - (N-Boc-1-piperazinyl) phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide (b 5)
7.5g (20 mmol) of intermediate b4 are dissolved in 80mL of dry THF and 5.04mL (37 mmol) of a 2.5mol/L solution of n-butyllithium are added under nitrogen. The temperature was reduced to-78 ℃ and the reaction was allowed to proceed for 1.5h, and then 4.7g (25 mmol) of a solution of (S) -N- (2-acetoxy-3-chloropropyl) acetamide in dry THF (50 mL) was slowly added dropwise to the reaction mixture. After dropping, the reaction was carried out at 25 ℃ for 18 hours. After the reaction, the reaction solution was cooled to-20 ℃ and 100mL of saturated aqueous ammonium chloride solution was added dropwise to the reaction solution, and the mixture was stirred at-20 ℃ for 0.5h. The reaction solution was extracted with dichloromethane (40 mL. Times.3), dried and evaporated to dryness to give a crude product as a brown-white solid. The crude product was purified by column chromatography [ silica gel, V (dichloromethane)/V (methanol) =70 ] to give 4.1g of a yellow-brown solid in a yield of 45%. ESI-MS m/z:459.0[ m + Na ] +.
1.1.5 Preparation of (S) -N- { [3- (3 '-fluoro-4' -piperazinylphenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide (b 6)
3g of intermediate b5 are dissolved in 30mL of dichloromethane, 6mL of trifluoroacetic acid are slowly added at 0 ℃ and, after the addition, reaction is carried out for 6h at 25 ℃. After the reaction, the reaction solution was concentrated, the pH was adjusted to 12 with 2M aqueous sodium hydroxide solution, and a solid precipitated, which was filtered under suction to give 1.25g of a yellow solid in 78% yield. ESI-MS m/z of 337.2[ deg. ] M + H] + .
Preparation of the Compound (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (1,1-dioxothiomorpholinyl) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
0.5g (1.5 mmol) of (S) -N- { [3- (3 '-fluoro-4' -piperazinylphenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide was dissolved in 5mL of DMF, 0.4mL (3.0 mmol) of triethylamine was added, the mixture was stirred at 25 ℃ for 15min, then 0.2mL (2.2 mmol) of CS2 was added, and the reaction was stirred at room temperature for 1.5h. The corresponding 2-chloro-1- (1,1-dioxo-4-thiomorpholinyl) ethanone (2.2 mmol) was added to the reaction mixture, and after the addition, the reaction was carried out at 35 ℃ for 12 hours. After the reaction, 50mL of water was added to the reaction solution, extraction was performed with ethyl acetate (20 mL. Times.4), the organic layers were combined, dried, evaporated to dryness under reduced pressure to obtain a crude product, and the crude product was purified by thin layer chromatography to obtain the target compound. The yield thereof was found to be 40%. ESI-MS m/z 609.9[ 2 ] M + Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,1H),7.55–7.48(m,1H),7.19(d,J＝8.7Hz,1H),7.12(t,1H),4.73–4.67(m,1H),4.43(d,4H),4.10(m,3H),3.99(s,2H),3.88(s,2H),3.74–3.66(m,1H),3.40(t,J＝5.3Hz,3H),3.10(s,6H),1.83(s,3H),0.85(t,J＝6.8Hz,1H).
Example 2 preparation of (S) -N- [ (3- { 3-fluoro-4- [ ({ [ (methylsulfonyl) piperazin-1-yl ] -2-oxyethylthio } carbonylthio) piperazin-1-yl ] phenyl } -2-oxo-5-oxazolidinyl) methyl ] acetamide
Using 2-chloro-1- (4-methylsulfonylpiperazin-1-yl) ethanone as a raw material, synthesizing a key intermediate according to the synthesis method of 1.1 in example 1, and then synthesizing (S) -N- [ (3- { 3-fluoro-4- [ ({ [ (methylsulfonyl) piperazin-1-yl) according to the synthesis method of 1.2 in example 1]-2-oxyethylthio } carbonylthio) piperazin-1-yl]Phenyl } -2-oxo-5-oxazolidinyl) methyl]An acetamide. The yield thereof was found to be 44%. ESI-MSm/z 639.0[ 2 ] M + Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.26(t,J＝5.8Hz,1H),7.50(d,J＝2.3Hz,1H),7.19(dd,J＝8.8,1.9Hz,1H),7.12(t,1H),4.74–4.68(m,1H),4.38(s,4H),4.19–4.04(m,3H),3.74–3.65(m,3H),3.57(s,2H),3.40(t,J＝5.5Hz,2H),3.21(s,2H),3.10(s,6H),2.90(s,3H),1.83(s,3H).
Example 3 preparation of (S) -N- { [3- (3-fluoro-4- { [ (piperidin-1-ylethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Starting from 1- (2-chloroethyl) piperidine hydrochloride, key intermediates were synthesized according to the synthesis method of 1.1 in example 1, and (S) -N- { [3- (3-fluoro-4- { [ (piperidin-1-ylethylthio) thiocarbonyl) was synthesized according to the synthesis method of 1.2 in example 1]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 58%. ESI-MS m/z 524.2[ 2 ] M + H] + ； 1 H NMR(600MHz,DMSO-d 6 )δ8.26(t,J＝5.8Hz,1H),7.51(dd,J＝14.7,2.5Hz,1H),7.18(dd,J＝8.9,2.5Hz,1H),7.10(t,J＝8.9Hz,1H),4.73–4.68(m,1H),4.40(s,2H),4.08(t,J＝9.1Hz,2H),3.71(t,J＝9.1,1H),3.51(s,1H),3.43(m,4H),3.08(s,4H),2.59(m,2H),2.44(s,3H),1.83(s,3H),1.50(m,4H),1.41–1.33(m,2H).
Example 4 preparation of (S) -N- { [3- (3-fluoro-4- { [ (dimethylaminoethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Synthesis of a Key intermediate Using 2-chloroethyldimethylamine hydrochloride as a starting Material according to the Synthesis method 1.1 in example 1, and Synthesis of (S) -N- { [3- (3-fluoro-4- { [ (dimethylaminoethylthio) thiocarbonyl group according to the Synthesis method 1.2 in example 1]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 55%. ESI-MS m/z:484.2[ 2 ], [ M ] +H] + ； 1 H NMR(600MHz,CDCl 3 )δ6.73(t,J＝9.0Hz,1H),6.36–6.27(m,2H),5.98(s,1H),4.42(s,1H),4.02(s,2H),3.90–3.84(m,1H),3.58(m,1H),3.47(t,J＝7.0Hz,2H),3.37(m,1H),3.34–3.29(m,1H),3.09(m,1H),3.02–2.92(m,5H),2.68(t,J＝6.7Hz,2H),2.32(s,6H),1.97(s,3H).
Example 5 preparation of (S) -N- { [ -3- (3-fluoro-4- { [ (diethylamino) ethylthiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Synthesis of (S) -N- { [ -3- (3-fluoro-4- { [ (diethylamino) ethylthio-carbyl thio-carbonyl ] using N, N-diethylchloroethylamine hydrochloride as a starting Material, the key intermediate according to the Synthesis method 1.1 in example 1, and then Synthesis of (S) -N- { [ -3- (3-fluoro-4- { [ (diethylamino) ethylthio-carbyl ] thio-carbonyl according to the Synthesis method 1.2 in example 1]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 50%. ESI-MS m/z:427.2[ 2 ], [ M ] +H] + ； 1 H NMR(600MHz,CDCl 3 )δ6.73(s,1H),6.32(m,2H),5.98(s,1H),4.42(s,2H),4.02(s,2H),3.87(m,1H),3.57(m,1H),3.40(d,2H),3.34–3.27(m,1H),3.12–3.05(m,1H),3.02–2.90(m,1H),2.83–2.76(m,5H),2.75(m,2H),2.64(m,4H),2.53(m,1H),1.97(s,3H),1.05(m,4H).
Example 6 preparation of (S) -N- { [3- (3-fluoro-4- { [ (pyrrolidin-1-yl) ethylthiocarbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Starting from N- (2-chloroethyl) pyrrole hydrochloride, key intermediates were synthesized according to the synthesis method of 1.1 in example 1, and (S) -N- { [3- (3-fluoro-4- { [ (pyrrolidin-1-yl) ethylthiocarbonylthio-ne was synthesized according to the synthesis method of 1.2 in example 1]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 52%. ESI-MS m/z:427.2[ 2 ] M + H] + ； 1 H NMR(600MHz,CDCl 3 )δ6.73(s,1H),6.37–6.25(m,2H),6.02(s,1H),4.42(s,2H),4.01(s,2H),3.90–3.83(m,1H),3.50(m,2H),3.38(m,1H),3.33–3.27(m,1H),3.09(m,1H),3.02–2.92(m,5H),2.82(m,2H),2.66(s,4H),1.97(s,3H),1.78(m,4H).
Example 7 preparation of (S) -N- { [3- (3-fluoro-4- { [ (morpholinoethylthio) carbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Starting from chloroethylmorpholine, a key intermediate was synthesized according to the synthesis method 1.1 in example 1, and (S) -N- { [3- (3-fluoro-4- { [ (morpholinoethylthio) carbonylthio ] carbonyl sulfide was synthesized according to the synthesis method 1.2 in example 1]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 51%. ESI-MS m/z:526.2[ 2 ] M + H] + .1H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝5.8Hz,1H),7.51(dd,J＝14.7,2.4Hz,1H),7.18(dd,J＝8.8,2.4Hz,1H),7.10(t,1H),4.71(m,1H),4.40(s,2H),4.08(m,3H),3.70(m,1H),3.58–3.53(m,4H),3.44–3.38(m,4H),3.11–3.03(m,4H),2.58(m,2H),2.42(s,4H),1.83(s,3H).
Example 8 preparation of (S) -N- { [3- (3-fluoro-4- { [ (diethylamino) -2-oxyethylthio ] carbosulfanyl } piperazin-1-yl) phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Synthesis of a Key intermediate Using N, N-diethyl-2-chloroacetamide as a starting Material and following the synthetic method of 1.1 in example 1, (S) -N- { [3- (3-fluoro-4- { [ (diethylamino) -2-oxyethylthio) -3-methyl ethyl ketone ] was synthesized according to the synthetic method of 1.2 in example 1]Carbosulfanyl } piperazin-1-yl) phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 48%. ESI-MS m/z:427.2[ 2 ] M + H] + .1H NMR(600MHz,DMSO-d 6 )δ8.23(t,J＝5.9Hz,1H),7.52(dd,J＝14.8,2.5Hz,1H),7.20–7.17(m,1H),7.11(t,J＝9.3Hz,1H),4.71(m,1H),4.39(s,2H),4.31(s,1H),4.09(t,J＝9.0Hz,3H),3.73–3.67(m,1H),3.51(s,1H),3.40(t,2H),3.09(s,4H),2.85(s,2H),2.63–2.59(m,1H),2.40–2.36(m,1H),1.99(m,2H),1.83(s,2H),1.24(s,3H),0.88–0.82(m,2H).
EXAMPLE 9 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ 2-oxo- (piperidin-1-yl) ethylthio ] carbo-thio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
Synthesis of a Key intermediate from 2-chloro-1-piperidin-1-yl-ethanone by the Synthesis method of 1.1 in example 1 and Synthesis of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ 2-oxo- (piperidin-1-yl) ethylsulfanyl) by the Synthesis method of 1.2 in example 1]Carbosulfanyl-piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 41%. ESI-MS m/z:427.2[ 2 ], [ M ] +H] + .1H NMR(600MHz,DMSO-d 6 )δ7.86(t,J＝5.8Hz,1H),6.88–6.84(m,1H),6.42(dd,J＝14.8,2.4Hz,1H),6.34(m,1H),5.59–5.49(m,1H),5.36–5.28(m,1H),4.97(s,1H),4.32(s,2H),4.08(s,3H),3.63(m,1H),3.50(m,J＝7.6Hz,1H),3.45–3.39(m,1H),3.19–3.11(m,1H),3.05–2.97(m,2H),2.96–2.91(m,1H),2.87(m,1H),2.64–2.57(m,1H),2.40–2.36(m,1H),2.30–2.23(m,1H),2.02–1.93(m,2H),1.82(s,2H),1.58(m,2H),1.43(m,2H).
EXAMPLE 10 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-methylpiperidin-1-yl) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
2-chloro-1- (4-methyl-1-piperidyl) ethanone is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1 in the example 1, and then (S) -N- ({ 3- [ 3-fluoro-4- ({ [ 2-oxo- (piperidin-1-yl) ethylthio) is synthesized according to the synthesis method of 1.2 in the example 1]Carbosulfanyl } piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 44%. ESI-MS m/z:574.1[ 2 ] M + Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24(s,1H),7.52(d,J＝14.2Hz,1H),7.19(d,J＝7.3Hz,1H),7.12(d,J＝8.6Hz,1H),4.71(s,1H),4.40–4.26(m,5H),4.09(m,3H),3.94(d,1H),3.71(s,1H),3.40(s,2H),3.10(s,5H),2.61–2.54(m,1H),1.83(s,3H),1.68(m,1H),1.64–1.56(m,2H),1.24(s,1H),1.18–1.11(s,1H),0.93–0.87(m,3H).
EXAMPLE 11 preparation of (S) -N- { [3- (3-fluoro-4- { [ (morpholino-2-oxoethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Synthesis of a Key intermediate from 4- (2-chloroacetyl) morpholine as a starting Material according to the Synthesis method of 1.1 in example 1, and Synthesis of (S) -N- { [3- (3-fluoro-4- { [ (morpholino-2-oxo) according to the Synthesis method of 1.2 in example 1Ethylthio) thiocarbonyl]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 51%. ESI-MS m/z 562.1[ 2 ] M + Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝5.8Hz,1H),7.52(dd,J＝14.7,2.5Hz,1H),7.19(dd,J＝9.1,2.5Hz,1H),7.11(t,J＝9.1Hz,1H),4.71(m,J＝8.7,6.1Hz,1H),4.38(s,1H),4.34(s,1H),4.09(m,1H),3.71(m,1H),3.63(d,3H),3.56(m,4H),3.46–3.43(m,2H),3.40(t,J＝5.5Hz,2H),3.09(m,4H),1.83(s,3H).
Example 12 preparation of (S) -N- { [3- (3-fluoro-4- { [ (2-oxo-2-thiomorpholinoethylthio) carbosulfanyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Synthesis of a Key intermediate from 4- (chloroacetyl) -thiomorpholine according to the Synthesis method of 1.1 in example 1 and Synthesis of (S) -N- { [3- (3-fluoro-4- { [ (2-oxo-2-thiomorpholinoethylthio) methylthio ] carbon based on the Synthesis method of 1.2 in example 1]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 42%. ESI-MS m/z:578.1[ 2 ] M + Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝5.0Hz,1H),7.52(d,J＝14.3Hz,1H),7.19(d,1H),7.11(t,J＝9.2Hz,1H),4.77–4.66(m,1H),4.36(s,1H),4.21–4.02(m,3H),3.82(s,2H),3.72(s,3H),3.40(s,2H),3.10(s,4H),2.72(s,2H),2.54(s,2H),1.83(s,3H).
EXAMPLE 13 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (dimethylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
2-chloro-N, N-dimethylacetamide was used as a raw material, a key intermediate was synthesized according to the synthesis method of 1.1 in example 1, and (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (dimethylamino) -2-oxyethylthio) -3-fluoro-4- ({ (dimethylamino) ethyl sulfide was synthesized according to the synthesis method of 1.2 in example 1]Carbonylthio } piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 54%. ESI-MS m/z 520.1[ 2 ] M + Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.23(t,J＝5.8Hz,1H),7.50(d,J＝2.3Hz,1H),7.18(d,J＝2.3Hz,1H),7.12(t,1H),4.74–4.65(m,1H),4.31(m,4H),4.07(m,3H),3.71(m,1H),3.40(s,2H),3.09(s,7H),2.85(s,3H),1.83(s,3H).
Example 14 preparation of (S) -N- { [3- (3-fluoro-4- { [ (4-methylpiperazin-1-yl) -2-oxoethylthiolcarbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide
Starting from 1- (2-chloro) -4-methyl-piperazine, key intermediates were synthesized according to the synthesis method of 1.1 in example 1, and (S) -N- { [3- (3-fluoro-4- { [ (4-methylpiperazin-1-yl) -2-oxyethylthiocarbonylthio-sulfanyl) -2-oxoethyl according to the synthesis method of 1.2 in example 1]Piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl]Methyl } acetamide. The yield thereof was found to be 41%. ESI-MS m/z of 553.1[ 2 ] M + H] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝5.7Hz,1H),7.54–7.48(dd,J＝14.7,2.5Hz,1H),7.18(d,1H),7.14–7.08(t,1H),4.74–4.66(m,1H),4.36(d,4H),4.17–4.05(m,3H),3.73–3.67(m,1H),3.56(s,2H),3.48(d,3H),3.42–3.38(t,2H),3.10(s,3H),2.39(s,2H),2.28(s,2H),2.20(s,2H),1.83(s,3H),0.88–0.82(m,2H).
EXAMPLE 15 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-ethylpiperazin-1-yl) -2-oxoethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
Starting from 1- (2-chloro) -4-ethyl-piperazine, the key intermediate was synthesized according to the synthesis method of 1.1 in example 1, and then (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-ethylpiperazin-1-yl) -2-oxoethylsulfanyl was synthesized according to the synthesis method of 1.2 in example 1]Carbosulfanyl } piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 42%. m.p. 171.2-172.5 deg.C; ESI-MS m/z 567.2[ 2 ], [ M + H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24(t,J＝5.7Hz,1H),7.52(d,J＝14.5Hz,1H),7.19(d,J＝7.9Hz,1H),7.11(t,J＝9.1Hz,1H),4.75–4.66(m,1H),4.50(s,1H),4.36(d,4H),4.10(m,3H),3.73–3.66(t,1H),3.56(s,3H),3.43–3.37(m,3H),3.10(s,3H),2.38(s,5H),1.83(s,3H),1.03(s,3H),0.87–0.79(m,1H).
EXAMPLE 16 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopropylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
2-chloro-N-cyclopropyl acetamide is used as a raw material, a key intermediate is synthesized according to the synthesis method 1.1 in the example 1, and then the key intermediate is synthesized according to the methodSynthesis of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopropylamino) -2-oxyethylthio) -2-oxoethylthio) in example 1]Carbonylthio } piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 56%. ESI-MS m/z:532.1[ 2 ] M + Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.23(t,2H),7.52(dd,J＝14.8,2.5Hz,1H),7.19(dd,J＝8.8,2.2Hz,1H),7.11(t,J＝9.3Hz,1H),4.71(m,1H),4.37(m,2H),4.14–4.05(m,3H),3.98(s,2H),3.71(t,1H),3.40(t,J＝5.5Hz,2H),3.12–3.07(m,4H),2.63–2.58(m,1H),1.83(s,3H),0.61(td,J＝6.8,3.5Hz,2H),0.41(dt,J＝6.8,3.5Hz,2H).
EXAMPLE 17 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclobutylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
2-chloro-N-cyclobutyl acetamide is used as a raw material, key intermediates are synthesized according to the synthesis method of 1.1 in example 1, and then (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclobutylamino) -2-oxyethylthio) -3 is synthesized according to the synthesis method of 1.2 in example 1]Carbonylthio } piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 48%. . ESI-MS m/z:546.1[ 2 ], [ M ] +Na ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.42(d,J＝7.6Hz,1H),8.23(t,J＝5.8Hz,1H),7.52(dd,J＝14.8,2.5Hz,1H),7.19(dd,J＝8.8,2.2Hz,1H),7.11(t,J＝9.3Hz,1H),4.71(m,1H),4.38(s,2H),4.21–4.04(m,4H),4.00(s,2H),3.73–3.67(m,1H),3.40(t,J＝5.5Hz,2H),3.12–3.06(m,3H),2.14(m,3H),1.88(m,2H),1.83(s,2H),1.69–1.54(m,3H).
EXAMPLE 18 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopentylamino) -2-oxyethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
2-chloro-N-cyclopentyl acetamide is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1 in example 1, and then (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopentylamino) -2-oxyethylthio) -3- (O-fluoro-4- ({ [ (meth) ylamino) -2-oxyethylthio) is synthesized according to the synthesis method of 1.2 in example 1]Carbosulfanyl } piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 44%. ESI-MS m/z:560.2[ 2 ], [ M ] +Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.23(t,J＝5.8Hz,1H),8.14(d,J＝7.2Hz,1H),7.52(dd,J＝14.7,2.5Hz,1H),7.19(dd,J＝8.8,2.3Hz,1H),7.11(t,J＝9.3Hz,1H),4.71(m,1H),4.38(s,2H),4.16–4.04(m,3H),3.99(m,3H),3.70(m,1H),3.40(t,J＝5.5Hz,2H),3.12–3.05(m,4H),1.83(s,3H),1.77(m,2H),1.65–1.60(m,2H),1.49(m,2H),1.38(m,2H).
EXAMPLE 19 preparation of (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-acetylpiperazin-1-yl) -2-oxyethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide
Starting from 1- (4-acetyl-1-piperazine) -2-chloroacetophenone, a key intermediate was synthesized according to the synthesis method of 1.1 in example 1, and then (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-acetylpiperazin-1-yl) -2-oxyethylthio) -2-oxoethylthio ] was synthesized according to the synthesis method of 1.2 in example 1]Carbosulfanyl } piperazin-1-yl) phenyl]-2-oxo-5-oxazolidinyl } methyl) acetamide. The yield thereof was found to be 41%. [ M + Na ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.25(s,1H),7.56–7.47(d,1H),7.19(d,J＝8.1Hz,1H),7.12(t,J＝9.3Hz,1H),5.32(s,1H),4.71(s,1H),4.37(s,4H),4.11(m,3H),3.74–3.67(t,1H),3.62(s,1H),3.52(d,4H),3.10(s,5H),2.00(m,6H),1.83(s,3H).
Meanwhile, other compounds represented by the general formula can be produced by substituting the raw materials according to the production method described above.
EXAMPLE 20 preparation of tablets (250 mg/tablet) containing the Compound of example 1 as an active ingredient
Taking 250g of the compound of example 1, 30g of starch, 80mL of HPMC aqueous solution 2%, 15g of sodium carboxymethyl starch and 2g of magnesium stearate, and carrying out the following steps:
a. preparing an appropriate amount of HPMC aqueous solution 2 percent for later use;
b. drying the above active ingredients and adjuvants, and sieving with 100 mesh sieve;
c. weighing the active ingredients and the auxiliary materials according to the formula amount. Mixing the compound of example 1, starch and sodium starch glycolate, adding 2% HPMC aqueous solution to make soft mass, and making wet granule with 20 mesh sieve;
d. drying wet granules at 55 deg.C for about 3 hr, cooling, adding magnesium stearate, and sieving with 20 mesh sieve; measuring the content and calculating the weight of the tablets;
e. pressing by using a 10mm shallow concave punch to obtain 1000 tablets;
f. and (5) inspecting the finished product, and packaging and warehousing after the finished product is qualified.
EXAMPLE 21 preparation of capsules (125 mg/capsule) containing the compound of example 3 as an active ingredient
Taking the following components: example 3 Compound 125g, starch 15g, lactose 15g, 2% HPMC in water about 40mL, sodium carboxymethyl starch 7.5g, magnesium stearate 1g. The method comprises the following steps:
a. an appropriate amount of HPMC solution was prepared for use by 2%.
b. Drying the raw materials and the auxiliary materials properly, and respectively sieving the dried raw materials and the auxiliary materials by a 100-mesh sieve for later use.
c. Weighing raw materials and auxiliary materials according to the prescription amount. The compound of example 2, starch, lactose, sodium carboxymethyl starch were mixed well, 2% HPMC solution was added to make a soft mass, and wet granulation was performed with a 20 mesh sieve.
d. The wet granules were dried at 55 ℃ for about 3 hours, slightly cooled after drying, added with magnesium stearate, and granulated with a 20-mesh sieve. Measuring the content and calculating the loading.
e. Filling the 2# capsule shell into granules to obtain 1000 capsules.
f. Polishing and removing dust from the capsule.
g. And (5) inspecting the finished product, and packaging and warehousing after the finished product is qualified.
EXAMPLE 22 preparation of dispersible tablets (250 mg/granule) with the Compound of example 7 as active ingredient
Taking the following components: example 7 Compound 250g, pregelatinized starch 50g, microcrystalline cellulose 50g, sodium carboxymethyl starch 20g, 2% HPMC in water solution approximately 90ml, gum Acacia 20g, stevioside 18g, magnesium stearate 2g, prepared according to the following procedure:
a. an appropriate amount of HPMC solution was prepared for use by 2%.
b. Drying the raw materials and the auxiliary materials properly, and respectively sieving the dried raw materials and the auxiliary materials by a 100-mesh sieve for later use.
c. Weighing raw materials and auxiliary materials according to the prescription amount. The compound of example 4, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, and rebaudioside were mixed well, then 2% HPMC solution was added to make a soft mass, and wet granulation was performed with a 20 mesh sieve.
d. Drying the wet granules at 55 deg.C for 3 hr, cooling, adding silica gel micropowder and magnesium stearate, and sieving with 20 mesh sieve. Measuring the content and calculating the weight of the tablet.
e. And (3) pressing by using a 11mm shallow concave punch to obtain 1000 tablets.
f. And (5) inspecting the finished product, and packaging and warehousing after the finished product is qualified.
EXAMPLE 23 preparation of sodium chloride injection (100 mL: 250 mg) with the Compound of example 8 as active ingredient
Taking the following components: example 4 compound 250g, sodium chloride 825g, citric acid 6.5g, water for injection to 100L, was carried out as follows:
a. the compound of example 4, sodium chloride and citric acid were weighed out in their prescribed amounts.
b. Dissolving the main and auxiliary materials in water for injection (about 80 deg.C) which accounts for about 90% of the total preparation amount, and stirring to completely dissolve.
c. Adding 0.05% of activated charcoal for injection activated at 120 deg.C for 2 hr, stirring, and standing for 15 min.
d. Filtering and decarburizing with 0.6 μm titanium rod filter, and adding water for injection to full dose.
The compound of the invention is studied for in vitro antibacterial activity, and the results are as follows:
test samples (compounds obtained from examples 1-19 above and controls) were sterilized and then double diluted in M-H broth to a range of concentrations, i.e., 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125mg/L. In each row of the 96-well dilution plate, 100. Mu.L of LM-H broth medium was added as a blank to the 12 th well, 50. Mu.L of LM-H broth was added to the 11 th well, and 50. Mu.L of the sample test solution was added sequentially from the 10 th well to the 1 st well in descending order.
Selecting a proper amount of test bacteria and standard strains to inoculate, namely staphylococcus aureus standard strains (S.aureus, ATCC-29213), wherein LREF is linezolid-resistant enterococcus faecalis, VREF is vancomycin-resistant enterococcus faecium, GBS is streptococcus agalactiae, and SPn is streptococcus pneumoniae. Culturing in Mueller-Hinton (M-H) nutrient broth culture medium suitable for growth at 37 deg.C for 16-18H to allow normal growth, adjusting concentration of the grown bacteria solution to 0.5 McLeod ratio standard with physiological saline, and diluting with M-H broth 1: 100 (v/v) to obtain test bacteria solution. Then 50 mul of test bacterial liquid is inoculated in the 1 st to 11 th holes, and the test bacterial liquid is placed in a square plate with a cover and covered by wet gauze after shaking and mixing, and cultured for 18 to 20 hours at the temperature of 37 ℃.
The observation result under the light source with black background shows that the bacteria-growing holes have diffuse turbidity or button-like sediment at the bottom of the holes, and the bacteria-free growing holes do not have the phenomenon. The lowest concentration of drug contained in the aseptically grown wells was the Minimum Inhibitory Concentration (MIC). The test results are shown in Table 2.
Table 2 activity MICs of some example compounds against gram-positive bacteria and tubercle bacillus: ug/mL
Examples of the invention S.aureus VREF LEFR GBS SPn
Example one 1 1 1 1 1
Example two 1 1 4 1 0.5
Example three 1 1 4 0.125 0.25
Example ten 2 1 1 0.25 1
Example eleven 1 1 1 1 1
Example thirteen 1 1 4 1 0.5
Example fourteen 1 0.5 1 1 1
Example fifteen 1 1 1 1 1
Example sixteen 1 1 1 0.25 0.125
Example seventeen 2 1 2 0.5 0.5
Example eighteen 1 1 2 0.5 0.5
Example nineteen 1 1 1 1 0.125
Linezolid 1 2 2 0.5 0.125
Note: staphylococcus aureus standard strain (s.aureus, ATCC-29213), LREF for linezolid-resistant enterococcus faecalis, VREF for vancomycin-resistant enterococcus faecium, GBS for streptococcus agalactiae, SPn for streptococcus pneumoniae.
The preliminary in vitro antibacterial activity test result shows that the compound has activity equivalent to or superior to that of linezolid, and has obvious inhibition effect on drug-resistant bacteria such as linezolid-resistant enterococcus faecalis (LREF) and vancomycin-resistant enterococcus faecium (VREF).

Claims (10)

1. An oxazolidinone compound containing a dithiocarbamate structure, which is characterized in that: the compound is a compound shown in a general formula I and a stereoisomer or a solvate thereof,
Figure FDA0003116731300000011
wherein, the first and the second end of the pipe are connected with each other,
R 1 is hydrogen, halogen or C 1 -C 4 A haloalkyl group of (a);
R 2 is selected from-NHCOCH 3 or-OH;
R 3 and R 4 Are identical or different and are each independently selected from hydrogen, unsubstituted or substituted by at least one identical or different R 5 Substituted C 1 -C 6 Alkyl radical, C 3 -C 6 A cycloalkyl group;
R 3 and R 4 Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group formedAnd further containing 0-4 heteroatoms selected from N, O and/or S, said 4-to 10-membered heterocyclic ring formed optionally substituted with at least one R 5 O or S;
R 5 is C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Hydroxyalkyl, hydroxy, halogen, C 1 -C 4 Halogenoalkyl of, C 1 -C 4 Halogenoalkoxy of (C) 1 -C 6 An alkylsulfonyl group or a nitro group;
x is C = O, CH 2 ；
n is an integer between 1 and 4.
2. A compound according to claim 1, characterized in that: the compound is a compound shown in a general formula I and a stereoisomer thereof,
in the formula, R 1 Is halogen;
R 2 is-NHCOCH 3 ；
R 3 And R 4 Are identical or different and are each independently selected from hydrogen, unsubstituted or substituted by 1 to 3 identical or different R 5 Substituted C 1 -C 4 Alkyl radical, C 3 -C 5 A cycloalkyl group;
or R 3 And R 4 Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group formed further contains 0-4 heteroatoms selected from N, O and/or S, and the 4-7 membered heterocyclic group formed may be unsubstituted or substituted with at least one R 5 O or S substitution;
R 5 is C 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Hydroxyalkyl radical, C 1 -C 4 Alkylsulfonyl, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro.
3. A compound according to claim 1, characterized in that: the compound is a compound shown in a general formula I and a stereoisomer thereof,
in the formula, R 1 Is fluorine;
R 2 is-NHCOCH 3 ；
R 3 And R 4 Are identical or different and are each independently selected from hydrogen, unsubstituted or substituted by 1 to 3 identical or different R 5 Substituted C 1 -C 4 Alkyl radical, C 3 -C 5 A cycloalkyl group;
or R 3 And R 4 Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group formed further contains 0-4 heteroatoms selected from N, O and/or S, and the 4-7 membered heterocyclic group formed may be unsubstituted or substituted with at least one R 5 O or S;
R 5 is C 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Alkylsulfonyl, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro.
4. A compound according to claim 1, characterized in that: the compound is
(S) -N- [ (3- { 3-fluoro-4- [4- (benzylsulfanylthiosulfonyl) piperazin-1-yl ] phenyl } -2-oxo-5-oxazolidinyl) methyl ] acetamide;
(S) -N- { [3- (3-fluoro-4- {4- [ (pyridin-4-ylmethylsulfanyl) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- {4- [ (pyridin-4-ylmethylsulfanyl) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (dimethylaminoethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [ -3- (3-fluoro-4- { [ (diethylamino) ethylthiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (pyrrolidin-1-yl) ethylthiocarbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (morpholinoethylthio) carbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (morpholinoethylthio) carbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ 2-oxo- (piperidin-1-yl) ethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-methylpiperidin-1-yl) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (morpholino-2-oxoethylthio) thiocarbonyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (2-oxo-2-thiomorpholinoethylthio) carbosulfanyl ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (dimethylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- { [3- (3-fluoro-4- { [ (4-methylpiperazin-1-yl) -2-oxyethylthiocarbonylthio ] piperazin-1-yl } phenyl) -2-oxo-5-oxazolidinyl ] methyl } acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-ethylpiperazin-1-yl) -2-oxoethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopropylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclobutylamino) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (cyclopentylamino) -2-oxyethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
(S) -N- ({ 3- [ 3-fluoro-4- ({ [ (4-acetylpiperazin-1-yl) -2-oxyethylthio ] carbosulfanyl } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide;
or (S) -N- ({ 3- [ 3-fluoro-4- ({ [ (1,1-dioxothiomorpholinyl) -2-oxyethylthio ] carbonylthio } piperazin-1-yl) phenyl ] -2-oxo-5-oxazolidinyl } methyl) acetamide.
5. Use of a compound according to any one of claims 1 to 4, wherein: the application of the compound with the general formula in preparing a medicament for treating microbial infection.
6. Use of a compound according to claim 5, wherein: the microbial infection is a bacterial infection.
7. The use of claim 6, wherein: the bacterial infection is a gram-positive coccal infection or a tubercle bacillus infection.
8. A composition characterized by: the composition is prepared by mixing the compound of the general formula shown in claim 1 and a stereoisomer thereof as an active ingredient with pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein the active ingredient accounts for 0.01-99% of the mass of the composition.
9. The composition of claim 8, wherein: the pharmaceutically acceptable salt is a salt with an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, or aspartic acid.
10. Use of a composition according to claim 8, wherein: the use of the composition in the manufacture of a medicament for the treatment of a microbial infection.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054161A1 (en) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl functionality
WO2000027830A1 (en) * 1998-11-11 2000-05-18 Hokuriku Seiyaku Co., Ltd. Thiocarbamic acid derivatives
WO2001058885A1 (en) * 2000-02-10 2001-08-16 Pharmacia & Upjohn Company Oxazolidinone thioamides with piperazine amide substituents
US20020137754A1 (en) * 2000-02-10 2002-09-26 Hester Jackson B. Oxazolidinone thioamides with piperazine amide substituents
WO2005005420A1 (en) * 2003-07-02 2005-01-20 Merck & Co., Inc. Cyclopropyl group substituted oyazolidinone antibiotics and derivatives thereof
CN101248067A (en) * 2005-06-27 2008-08-20 菲尔若国际公司 Oxazolidinone derivatives and use thereof as antibiotics
WO2009001192A2 (en) * 2007-06-22 2008-12-31 Orchid Research Laboratories Limited Novel compounds and their use

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054161A1 (en) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl functionality
WO2000027830A1 (en) * 1998-11-11 2000-05-18 Hokuriku Seiyaku Co., Ltd. Thiocarbamic acid derivatives
WO2001058885A1 (en) * 2000-02-10 2001-08-16 Pharmacia & Upjohn Company Oxazolidinone thioamides with piperazine amide substituents
US20020137754A1 (en) * 2000-02-10 2002-09-26 Hester Jackson B. Oxazolidinone thioamides with piperazine amide substituents
WO2005005420A1 (en) * 2003-07-02 2005-01-20 Merck & Co., Inc. Cyclopropyl group substituted oyazolidinone antibiotics and derivatives thereof
CN101248067A (en) * 2005-06-27 2008-08-20 菲尔若国际公司 Oxazolidinone derivatives and use thereof as antibiotics
WO2009001192A2 (en) * 2007-06-22 2008-12-31 Orchid Research Laboratories Limited Novel compounds and their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
冀希炜等: "恶唑烷酮类抗菌药物与革兰氏阳性菌治疗的研究现状", 中国临床药理学杂志, vol. 34, no. 7, 30 April 2018 (2018-04-30), pages 898 - 902 *

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