CN110372624A - A kind of Oxazolidinone derivative, preparation method and application - Google Patents

A kind of Oxazolidinone derivative, preparation method and application Download PDF

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Publication number
CN110372624A
CN110372624A CN201910745692.5A CN201910745692A CN110372624A CN 110372624 A CN110372624 A CN 110372624A CN 201910745692 A CN201910745692 A CN 201910745692A CN 110372624 A CN110372624 A CN 110372624A
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CN
China
Prior art keywords
oxazolidinone derivative
compound
formula
hydrogen
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201910745692.5A
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Chinese (zh)
Inventor
刘长茹
王英召
张旭
黄小根
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Beijing Haimeitong Pharmaceutical Technology Co Ltd
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Beijing Haimeitong Pharmaceutical Technology Co Ltd
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Priority to CN201910745692.5A priority Critical patent/CN110372624A/en
Publication of CN110372624A publication Critical patent/CN110372624A/en
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The embodiment of the invention discloses a kind of Oxazolidinone derivative, preparation method and applications, belong to medical compounds technical field.Shown in the structural formula of the compound such as formula (I).The present invention improves the structure of Linezolid, has obtained being expected to exploitation with the novel Oxazolidinone derivative for inhibiting gram-positive bacteria activity into one kind and having potential novel antibacterial drug.

Description

A kind of Oxazolidinone derivative, preparation method and application
Technical field
The present embodiments relate to medical compounds technical fields, and in particular to a kind of Oxazolidinone derivative, its system Preparation Method and application.
Background technique
Oxazolidinones antimicrobial is bacterio protein synthetic inhibitor, has the unique effect different from other antimicrobials Mechanism.By inhibit bacterio protein synthesize the initial stage in ribosomes and mRNA combination, cause in mRNA with ribosomes knot The end the sequence 3' fragment upstream of conjunction cannot be identified, and blocked the initial translation process of bacterio protein synthesis and played antibacterial work With.Oxazolidinone derivative prevents it from forming 70s functionality in conjunction with fMet-tRNA in conjunction with the site A of 50s subunit Initial composite object, and the formation of 70s initiation complex is the important step of bacterium translation process, to inhibit bacterio protein Synthesis generates antibacterial action.If 70s compound has been formed, in conjunction with oxazolidone after can inhibit peptide chain again and shifted to by the site A The site P, to hinder the synthesis of bacterioprotein.
Linezolid was approved by the FDA in the United States listing in 2000, was first oxazolidinones antimicrobial introduced to the market, Its structural formula are as follows:
Linezolid is very wide to the antimicrobial spectrum of gram-positive bacteria, but clinical discovery, and long-time service will lead to bacterial strain production It gives birth to drug resistance and influences therapeutic effect.Therefore, structure of modification is carried out to it, obtains novel antibacterial drug with wide and applies valence Value.
Summary of the invention
For this purpose, the embodiment of the present invention provides a kind of Oxazolidinone derivative, preparation method and application, the oxazolidone Class compound has good inhibiting effect to gram-positive bacteria, to solve bacterium caused by existing Linezolid is used for a long time Strain generates drug resistance, thus the problem of influencing therapeutic effect.
To achieve the goals above, the embodiment of the present invention provides the following technical solutions:
According to a first aspect of the embodiments of the present invention, the embodiment of the invention provides a kind of Oxazolidinone derivative, institutes Shown in the structural formula such as formula (I) for stating compound:
In formula, R1And R2It is identical or different and be each independently selected from hydrogen or halogen；R3For C1-C6Alkyl.Specifically, R1And R2It is identical or different and be each independently selected from hydrogen, fluorine, chlorine, bromine or iodine；R3It is the straight chain with 1-6 carbon atom Or the alkyl of branch, for example, methyl, ethyl, n-propyl and isopropyl, normal-butyl, isobutyl group and tert-butyl, amyl, neopentyl, Hexyl etc..
Preferably, R1For hydrogen, R2For halogen, R3For methyl or ethyl.
It is further preferred that R1For hydrogen, R2For fluorine, R3For ethyl.
According to a second aspect of the embodiments of the present invention, the embodiment of the invention provides above-mentioned Oxazolidinone derivatives Preparation method, specific synthetic route are as follows:
Wherein, R1、R2And R3It is as defined above.
The method are as follows: formula (II) compound and 3,3- difluoro propionic acid carry out condensation reaction and obtain formula (I) compound.
Specifically, the reaction is to dry DMF (n,N-Dimethylformamide) for reaction dissolvent, with DMAP (4- dimethylamino Pyridine) it is catalyst, 3,3- difluoro propionic acid are through 1- hydroxy benzo triazole and EDC-HCl (1- (3- dimethylaminopropyl) -3- Ethyl-carbodiimide hydrochloride) activation after, with formula (II) compound carry out condensation reaction obtain formula (I) compound.
According to a third aspect of the embodiments of the present invention, the embodiment of the invention provides a kind of pharmaceutical compositions, comprising above-mentioned Oxazolidinone derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: diluent, excipient are such as Water etc., filler such as starch, sucrose etc.；Adhesive such as cellulose derivative, alginates, gelatin and polyvinylpyrrolidone；It is wet Moisten agent such as glycerol；Disintegrating agent such as agar, calcium carbonate and sodium bicarbonate；Sorbefacient such as quaternary ammonium compound；Surfactant is such as Hexadecanol；Absorption carrier such as kaolin and soap clay；Lubricant such as talcum powder, calcium stearate and magnesium and polyethylene glycol etc..
The various dosage forms of pharmaceutical composition of the present invention can be prepared according to the conventional production process of pharmaceutical field.Such as make to live Property ingredient is mixed with one or more carriers, is then made into required dosage form.
According to a fourth aspect of the embodiments of the present invention, the embodiment of the invention provides above-mentioned Oxazolidinone derivative or Application of the pharmaceutical composition in preparation antibacterials.The antibacterials are the drug for inhibiting gram-positive bacteria, including gold Staphylococcus aureus, staphylococcus epidermis, enterococcus faecalis, enterococcus faecium.
The embodiment of the present invention has the advantages that
The present invention improves the structure of Linezolid, has obtained with the novel of inhibition gram-positive bacteria activity Oxazolidinone derivative, thus such compound or combinations thereof object are expected to exploitation into one kind and have potential novel antibacterial medicine Object.
Detailed description of the invention
Fig. 1 is a kind of Oxazolidinone derivative (R provided in an embodiment of the present invention1For hydrogen, R2For fluorine, R3For ethyl) Hydrogen nuclear magnetic resonance spectrogram.
Fig. 2 is a kind of Oxazolidinone derivative (R provided in an embodiment of the present invention1For hydrogen, R2For fluorine, R3For ethyl) Enantiomeric excess figure.
Specific embodiment
Embodiments of the present invention are illustrated by particular specific embodiment below, those skilled in the art can be by this explanation Content disclosed by book is understood other advantages and efficacy of the present invention easily, it is clear that described embodiment is the present invention one Section Example, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not doing Every other embodiment obtained under the premise of creative work out, shall fall within the protection scope of the present invention.
Embodiment
Oxazolidinone derivative C (i.e. R1For hydrogen, R2For fluorine, R3For ethyl) synthetic route it is as follows:
Compound A (100mg, 0.3mmol, No. CAS: 154590-66-6) is dissolved in the dry DMF of 2mL, and compound B is added, That is 3,3- difluoro propionic acid (24mg, 0.4mmol), 1- hydroxy benzo triazole (54mg, 0.4mmol), DMAP (44mg, 0.36mmol), it is stirred at room temperature 30 minutes, EDC-HCl (144mg, 0.75mmol) is then added and is stirred overnight at room temperature.Reaction terminates Concentration of reaction solution afterwards, silica gel column chromatography separation, eluant, eluent is ethyl acetate: methanol=50:1 obtains product (TLC detection, expansion Agent is ethyl acetate: methanol=40:1, Rf=0.3).Obtain product Compound C 73mg, yield 58%.
Product analysis result is as follows:
1H-NMR(CD3OD, 400MHz): 7.50 (m, 1H), 7.17 (m, 1H), 7.05 (m, 1H), 6.24 (m, 2H), 4.78 (m,1H),4.09(m,1H),3.68(m,4H),3.55(m,2H),3.20(m,6H),1.96(s,3H)；
19F-NMR(CDCl3, 376MHz): -117.8 (dt, J=56,15Hz), -122.5 (dd, J=11,7.5Hz)；
m/z M+1(429)。
Test example
(1) Oxazolidinone derivative C (i.e. R1For hydrogen, R2For fluorine, R3For ethyl) antibacterial activity in vitro detection method:
1, bacterium
Test strain is the reference culture and be clinically separated bacterium that 35 plants of laboratories save.
Quality Control bacterium selects staphylococcus aureus ATCC29213, enterococcus faecalis ATCC29212, escherichia coli ATCC25922 and pseudomonas aeruginosa ATCC27853.
2, minimum inhibitory concentration (MIC) measures
Referring to CLSI standard, drug sensitive experiment, test organisms MH meat soup or brain heart infusion are carried out using Double broth dilution method Increase bacterium.Medical fluid with the doubling dilution of MH meat soup at various required concentration, respectively plus in right amount into plate, after the fusing of MH agar medium Mixed in quantitative plate of the injection containing medical fluid, make the final concentration of sample HB090208 in plate be respectively 256,128 ... 0.06, 0.03μg/ml.After agar solidification, (inoculum concentration is about 10 to inoculation test bacterium4Cfu/ point) in drug containing plate, set 35 DEG C of constant temperature Observation is as a result, the smallest concentration of contained drug is minimum inhibitory concentration (Minimal in the plate of asepsis growth after cultivating 18h Inhibitory Concentration, MIC).
3, result:
Compound C and the detection of comparison medicine (lavo-ofloxacin) to vitro antibacterial activity, that is, MIC (μ g/ml) of 35 plants of bacteriums It the results are shown in Table 1.
Table 1
The MICs prescribed limit (CLSI) of lavo-ofloxacin: golden yellow Portugal bacterium coccus ATCC29213 (0.06-0.5 μ g/ Ml), enterococcus faecalis ATCC29212 (0.25-2 μ g/ml), escherichia coli ATCC25922 (0.008-0.06 μ g/ml), verdigris Aeruginosa atcc 27853 (0.5-4 μ g/ml), lavo-ofloxacin is to the MICs of Quality Control bacterium in CLSI prescribed limit.
The result shows that: compound C has preferable antibacterial action to tested gram-positive bacteria, wherein to golden yellow grape The MIC of coccus and staphylococcus epidermis is 0.5 μ g/ml, to the MIC of enterococcus faecalis and enterococcus faecium in 0.5~2 μ g/ml model In enclosing；Compound C is weaker without obvious antibacterial action or antibacterial action to tested Gram-negative bacteria, wherein to escherichia coli and The MIC of Shigella flexneri is within the scope of 256~> 256 μ g/ml, and the MIC to thunder pole Pu Lufeideng bacillus is 64 μ g/ml, to other The MIC of tested Gram-negative bacteria is all larger than 256 μ g/ml.
(2) compound C and novocillin the results are shown in Table 2 to the inhibiting effect of staphylococcus aureus ATCC29213.
Table 2
Sample Concentration (μ g/mL) Inhibiting rate (%)
Novocillin 1.25 95.855±0.672
Compound C 5 100.000±0.110
Compound C and vancomycin the results are shown in Table 3 to the inhibiting effect of staphylococcus aureus ATCC43300.
Table 3
Sample Concentration (μ g/mL) Inhibiting rate (%)
Vancomycin 1.25 99.952±0.084
Compound C 5 99.904±0
For compound C in 5 μ g/mL concentration, which has good suppression to two plants of staphylococcus aureuses as the result is shown System activity, inhibiting rate is respectively 100.000% and 99.952%.
The result shows that compound C has good inhibiting effect to gram-positive bacteria.
Although above having used general explanation and specific embodiment, the present invention is described in detail, at this On the basis of invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Therefore, These modifications or improvements without departing from theon the basis of the spirit of the present invention are fallen within the scope of the claimed invention.

Claims (9)

1. a kind of Oxazolidinone derivative, which is characterized in that shown in the structural formula of the compound such as formula (I):
In formula, R1And R2It is identical or different and be each independently selected from hydrogen or halogen；R3For C1-C6Alkyl.
2. Oxazolidinone derivative according to claim 1, which is characterized in that R1For hydrogen, R2For halogen, R3For methyl Or ethyl.
3. Oxazolidinone derivative according to claim 1, which is characterized in that R1For hydrogen, R2For fluorine, R3For ethyl.
4. the preparation method of Oxazolidinone derivative of any of claims 1-3, which is characterized in that the method Are as follows: formula (II) compound and 3,3- difluoro propionic acid carry out condensation reaction and obtain formula (I) compound；
Specific synthetic route is as follows:
Wherein, R1、R2And R3Definition such as claim 1.
5. the preparation method of Oxazolidinone derivative according to claim 4, which is characterized in that dry DMF be anti- Solvent is answered, using DMAP as catalyst, 3,3- difluoro propionic acid are after 1- hydroxy benzo triazole and EDC-HCl activation, with formula (II) Compound carries out condensation reaction and obtains formula (I) compound.
6. a kind of pharmaceutical composition includes Oxazolidinone derivative as claimed in any one of claims 1-3 or its pharmacy Upper acceptable salt and pharmaceutically acceptable carrier.
7. Oxazolidinone derivative described in claim 1 or pharmaceutical composition as claimed in claim 6 are preparing antimicrobial Application in object.
8. application according to claim 7, which is characterized in that the antibacterials are the medicine for inhibiting gram-positive bacteria Object.
9. application according to claim 8, which is characterized in that the gram-positive bacteria is staphylococcus aureus, table Skin staphylococcus, enterococcus faecalis, enterococcus faecium.
CN201910745692.5A 2019-08-13 2019-08-13 A kind of Oxazolidinone derivative, preparation method and application Pending CN110372624A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321523A (en) * 2020-05-13 2021-02-05 河南科技大学第一附属医院 Preparation method and application of oxazolone compound capable of inhibiting bacteria in patient care process

Citations (2)

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Publication number Priority date Publication date Assignee Title
CN1079964A (en) * 1992-05-08 1993-12-29 厄普约翰公司 The  (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antiseptic-germicide that contains the substituted diazine moieties base
CN101560193A (en) * 2008-04-17 2009-10-21 中山大学 Alpha-polyhalide acetyl piperazinyl oxazolidone compound and antibacterium application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
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CN1079964A (en) * 1992-05-08 1993-12-29 厄普约翰公司 The  (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antiseptic-germicide that contains the substituted diazine moieties base
CN101560193A (en) * 2008-04-17 2009-10-21 中山大学 Alpha-polyhalide acetyl piperazinyl oxazolidone compound and antibacterium application thereof

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Title
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曾戎 编著: "《多糖基高分子-药物轭合物的设计、合成、表征和评价》", 31 May 2011, 华南理工大学出版社 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321523A (en) * 2020-05-13 2021-02-05 河南科技大学第一附属医院 Preparation method and application of oxazolone compound capable of inhibiting bacteria in patient care process
CN112321523B (en) * 2020-05-13 2021-04-30 河南科技大学第一附属医院 Preparation method and application of oxazolone compound capable of inhibiting bacteria in patient care process

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Application publication date: 20191025