WO2008069619A1 - Novel oxazolidinone derivatives, process for preparing thereof and pharmaceutical composition containing the same - Google Patents

Novel oxazolidinone derivatives, process for preparing thereof and pharmaceutical composition containing the same Download PDF

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Publication number
WO2008069619A1
WO2008069619A1 PCT/KR2007/006364 KR2007006364W WO2008069619A1 WO 2008069619 A1 WO2008069619 A1 WO 2008069619A1 KR 2007006364 W KR2007006364 W KR 2007006364W WO 2008069619 A1 WO2008069619 A1 WO 2008069619A1
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alkyl group
hydrogen
methyl
fluorophenyl
oxooxazolidin
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PCT/KR2007/006364
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French (fr)
Inventor
Young Lag Cho
Sang Eun Chae
Bo Kyoung Song
Sung Yoon Baek
Hyang Sook Lee
Yong Zu Kim
Tae Kyo Park
Sung Ho Woo
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Legochem Bioscience Ltd.
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Priority claimed from KR1020070126433A external-priority patent/KR100948345B1/en
Application filed by Legochem Bioscience Ltd. filed Critical Legochem Bioscience Ltd.
Publication of WO2008069619A1 publication Critical patent/WO2008069619A1/en

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    • 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
    • C07D263/08—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
    • 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
    • C07D263/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel oxazolidinone derivative presented as Formula 1 below, its prodrugs, hydrates, solvates, isomers, pharmaceutically permitted salts, and its preparation methods and pharmaceutical compositions containing the same.
  • Formula 1 a novel oxazolidinone derivative presented as Formula 1 below, its prodrugs, hydrates, solvates, isomers, pharmaceutically permitted salts, and its preparation methods and pharmaceutical compositions containing the same.
  • bacterial pathogens are divided into gram-positive and gram-negative pathogens. It is considered that antibacterial compounds having effective activity against both gram-positive and gram- negative pathogens have a wide range of activity spectrum.
  • the compounds of the present invention are effective against both gram-positive and some specific gram-negative pathogens.
  • Gram-positive pathogens such as Staphylococcus, Enterococcus, Streptococcus, and mycobacteria are especially important, because once the resistant strains occur, it is hard to exterminate them from the clinic environment and difficult to treat.
  • the examples of such strains are methicillin resistant Staphylococcus (MRSA) , methicillin resistant coagulase negative staphylococcus (MRCNS) , penicillin resistant Streptococcus pneumoniae, and multi resistant Enterococcus faecium.
  • Vancomycin is a clinically effective antibiotic to treat these resistant gram-positive pathogens. Vancomycin is glycopeptide, being related to various toxicity including nephrotoxicity. Most importantly, there has been the occurrence of antibacterial resistance to vancomycin and other glycopeptides . This resistance increases at a steady rate, weakening the effect of the above agent that treat gram- positive pathogens. There is a tendency that the occurrence of resistance to agents such as ⁇ -lactam, quinolone, and macrolide, which are used to treat upper respiratory infections caused by specific gram-negative bacteria including H. influenzae and M. catarrhalis, is on the rise.
  • Pharmacia & Upjohn synthesized oxazolidinone derivatives of Formula B and C (PCT WO 93/23384, WO 95/14684, and WO 95/07271) .
  • the compound of Formula B is the first oxazolidinone type antibiotic and was approved by US Food and
  • WO 93/09103 discloses phenyl oxazolidinone derivatives having hetero cycles such as pyridine, thiazole, indole, oxazol, and quinol at 4-position of phenyl group, but substituents of hetero cycles are simply alkyl or amino groups, having no sufficient effects.
  • phenyl oxazolidinone derivatives with various pyridine or phenyl derivatives at 4-position of phenyl group were synthesized. These compounds have wide antibacterial spectrum and excellent antibacterial effect. Although phenyl oxazolidinone compounds having various pyridine derivatives at 4-position of oxazolidinone phenyl group have wider antibacterial spectrum and better antibacterial efficacy than Zyvox, most of them have less than 30 ug/mi of solubility in water, so they cannot be developed as injections.
  • the present inventors synthesized novel oxazolidinone derivatives to develop antibiotics with better antibacterial efficacy than existing ones and found that the novel oxazolidinone derivatives of the present invention had excellent antibacterial efficacy and much improved antibacterial spectrum and completed the present invention.
  • an object of the present invention is to provide a novel oxazolidinone derivative, its prodrugs, hydrates, solvates, isomers, and pharmaceutically permitted salts .
  • the present invention relates to a novel oxazolidinone derivative described as Formula 1 below, its prodrugs, hydrates, solvates, isomers, pharmaceutically permitted salts, and its preparation methods and pharmaceutical compositions containing the same.
  • Formula 1 a novel oxazolidinone derivative described as Formula 1 below, its prodrugs, hydrates, solvates, isomers, pharmaceutically permitted salts, and its preparation methods and pharmaceutical compositions containing the same.
  • R 1 is an acyclic substituent or hetero cyclic substituent of the structure below: O R 17 R14
  • R 13 and R 14 are respectively hydrogen, alkyl group of Ci-C 7 , - (CH 2 ) n NR 34 R 35 , -CONR 36 R 37 , -OR 38 , -OCOR 39 , -COR 40 , -OSO 2 R 41 , -SO 2 R 42 , or -CN;
  • R 15 is hydrogen, alkyl group of Ci-C 7 , or -OR 43 ;
  • R 16 and R 17 are respectively hydrogen, alkyl group of Ci-C 7 , or -OR 44 ;
  • A is alkylene of C 2 -C 3 and said alkylene can optionally contain one or more hetero moieties selected from the group consisting of N, 0, and S;
  • R 21 through R 33 are respectively hydrogen or alkyl group of Ci-C 7 ;
  • R 34 through R 42 are respectively hydrogen, alkyl group of C 1 -C 7 , phenyl, -COR 45 , -CO (CH 2 ) m NR 46 R 47 , -SO 2 R 48 , or -OCOR 49 ;
  • R 43 is hydrogen or alkyl group of Ci-C 7 ;
  • R 44 is hydrogen, alkyl group of C x -C 7 , or -CO (CH 2 ) m NR 50 R 51 ;
  • R 45 through R 49 are respectively hydrogen or alkyl group of Ci-C 7 ;
  • R 50 through R 51 are respectively hydrogen or alkyl group of Ci-C 7 ; n is an integer between 0 and 5; m is an integer between 1 and 5.]
  • R 1 is a hetero cyclic substituent of the structure selected from the group of:
  • R 14 is the same as in Formula 1 above; R through R 132 are respectively substituted to hydrogen, alkyl group of C 1 -C 7 , -COR 201 , or -SO 2 R 202 ; R 201 and R 202 are respectively hydrogen or alkyl group of Ci-C 7 .
  • the more desirable example of the oxazolidinone derivative as in Formula 1 of the present invention comprises compounds selected from Formula 2 through 5 of: [Formula 2]
  • R 11 is -NO 2 , -COOR 2I , or - (CH 2 ) n NR 24 R 25 ;
  • R 12 is -OR 26 , -OCOR 27 , -OSO 2 R 28 , -NR 29 R 30 , " C-NR 32 R 33 f or _ CN ;
  • R ,13 and R ,14 are respectively hydrogen, alkyl group of Ci-C 7 ,
  • R 15 is hydrogen, alkyl group of C x -C 7 , or -OR 43 ;
  • R 16 and R 17 are respectively hydrogen, alkyl group of Ci-C 7 , or -OR 44 ;
  • R 21 and R 24 through R 33 are respectively hydrogen or alkyl group of Ci-C 7 ;
  • R 34 , R 35 , and R 38 are respectively hydrogen, alkyl group of Ci-C 7 , -COR 45 , or -CO (CH 2 ) m NR 46 R 47 ;
  • R 43 is hydrogen or alkyl group of Ci-C 7 ;
  • R 44 is hydrogen, alkyl group of C x -C 7 , or -CO (CH 2 ) m NR 50 R 51 ;
  • R 45 through R 47 are respectively hydrogen or alkyl group of Ci-C 7 ;
  • hetero cyclic substituent for R 1 of the oxazolidinone derivative of the present invention is a hetero cyclic substituent of the structure selected from the group of:
  • R 12 is -OH, -NR 29 R 30 , " ⁇ C"* N H2 r O r -CN;
  • R 13 is hydrogen, alkyl
  • R 14 is hydrogen or alkyl group of Ci-C 7 ;
  • R 15 is hydrogen, alkyl group of C x -C 7 , or -OR 43 ;
  • R 16 and R 17 are respectively hydrogen, alkyl group of C x - C 7 , or -OR 44 ;
  • R 21 , R 29 , R 30 , R 34 , and R 35 are respectively hydrogen or alkyl group of Ci-C 7 ;
  • R 38 are hydrogen, alkyl group of Ci-C 7 , -COR 45 , or -CO (CH 2 ) m NH 2 ;
  • R 43 is hydrogen or alkyl group of C x -C 7 ;
  • R 44 is hydrogen, alkyl group of C x -C 7 , or -CO (CH 2 ) m NH 2 ;
  • R 45 is hydrogen or alkyl group of C 1 -C 7 ;
  • the oxazolidinone derivatives of Formula 2 can be synthesized from N- (( (S) -3- (4- (4-formylphenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) aceteamide (II) through the Suzuki coupling reaction using N- ( ( (S) -3- ( 4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) aceteamide (I) , 4-formylphenyl boronic acid, and palladium tetrakistriphenylphosphine (Pd (PPhs) 4 ) and then Horner-Emmons reaction and condensation in the presence of base.
  • Pd (PPhs) 4 palladium tetrakistriphenylphosphine
  • the oxazolidinone derivatives of Formula 3 can be synthesized from N- ( (S) -3- (4- (4-ethoxycarbonylphenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) aceteamide (III) through the Suzuki coupling reaction using N- ( ( (S) -3- (4-bromo- 3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) aceteamide (I ) , 4- ethoxycarbonylphenyl boronic acid, and palladium tetrakistriphenylphosphine (Pd (PPh 3 ) 4 ) , being followed by the reaction with hydroxyamine derivative, cyanamide, or guanidine, or ester hydrolysis and then condensation with hydrazine derivatives .
  • the oxazolidinone derivatives of Formula 4 or 5 can be synthesized through alkylation, acylation, sulfonylation, and reduction using palladium after making reaction with ketone derivatives, amino acid derivatives, hydroxylamine derivatives, or hydrazine derivatives.
  • the cyclic oxazolidinone derivatives of Formula 5 can be synthesized after making imidate through reaction between N- (( (S) -3- (4- (4-cyanophenyl) -3-fluorophenyl) - 2-oxooxazolidin-5-yl) methyl) aceteamide (IV) and hydrochloric acid, being followed by the reaction with diamine derivatives.
  • the oxazolidinone derivatives of Formula 1 according to the present invention can be used as a pharmaceutically permissible salt form.
  • the pharmaceutically permissible salts comprise acid addition salts formed by pharmaceutically permissible free acids.
  • free acids both inorganic acids and organic acids can be used.
  • Inorganic acids are hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc.; organic acids are citric acid, acetic acid, lactic acid, maleic acid, umaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc.
  • the oxazolidinone derivative of the present invention shows antibacterial efficacy against gram- positive pathogens such as staphylococcus aureus, Enterococcus faecalis, etc. and gram-negative pathogens such as haemophilus influenzae, moraxella catarrhalis, etc., which are resistant to existing antibiotics. It shows excellent antibacterial efficacy especially to Linezolid resistant Enterococcus faecalis . [Best Mode for Carrying Out the Invention]

Abstract

The present invention relates to a novel oxazolidinone derivative, its prodrugs, hydrates, solvates, isomers, pharmaceutically permitted salts, and its preparation methods and pharmaceutical compositions containing the same. The oxazolidinone derivative and its pharmaceutically permitted salts according to the present invention have wide antimicrobial spectrum against resistant bacteria and low toxicity, and they show strong antibacterial effect against gram-positive and gram-negative pathogens. So, they can be used as good antibiotics.

Description

NOVEL OXAZOLIDINONE DERIVATIVES, PROCESS FOR PREPARING THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
[Technical Field]
The present invention relates to a novel oxazolidinone derivative presented as Formula 1 below, its prodrugs, hydrates, solvates, isomers, pharmaceutically permitted salts, and its preparation methods and pharmaceutical compositions containing the same. [Formula 1]
Figure imgf000002_0001
[Background Art] Since penicillin was found, a number of pharmaceutical industries all over the world have seen strains that are resistant to lots of antibiotics such as β-Lactam type antibiotics as well as sulfonamide, tetracycline, aminoglucoside, macrolide, quinolone, glycopeptide, etc. that are fighting against bacteria infection.
In the international microbiology society, there are continuous concerns on the possible prevail of strains that could undermine currently used antibacterial agents due to the development of antibiotic resistance. In general, bacterial pathogens are divided into gram-positive and gram-negative pathogens. It is considered that antibacterial compounds having effective activity against both gram-positive and gram- negative pathogens have a wide range of activity spectrum. The compounds of the present invention are effective against both gram-positive and some specific gram-negative pathogens.
Gram-positive pathogens such as Staphylococcus, Enterococcus, Streptococcus, and mycobacteria are especially important, because once the resistant strains occur, it is hard to exterminate them from the clinic environment and difficult to treat. The examples of such strains are methicillin resistant Staphylococcus (MRSA) , methicillin resistant coagulase negative staphylococcus (MRCNS) , penicillin resistant Streptococcus pneumoniae, and multi resistant Enterococcus faecium.
Vancomycin is a clinically effective antibiotic to treat these resistant gram-positive pathogens. Vancomycin is glycopeptide, being related to various toxicity including nephrotoxicity. Most importantly, there has been the occurrence of antibacterial resistance to vancomycin and other glycopeptides . This resistance increases at a steady rate, weakening the effect of the above agent that treat gram- positive pathogens. There is a tendency that the occurrence of resistance to agents such as β-lactam, quinolone, and macrolide, which are used to treat upper respiratory infections caused by specific gram-negative bacteria including H. influenzae and M. catarrhalis, is on the rise.
The specific antibacterial agents containing oxazolidinone have been already published before. For instance, the oxazolidinone compound as a new antibacterial agent that can be taken by oral medications, which is not the result of fermentation, is known along with its derivatives with various structures. For example, 3-phenyl-2-oxazolidinone derivatives with one or two substituents are described in US Patent No. 4,948,801, No. 4,461,773, No. 4,340,606, No. 4,476,136, No. 4,250,318, and No. 4,128,654, and 3- [ (mono substituted) phenyl] -2-oxazolidinone derivative, presented as Formula A below, in EP 0312000, J. Med. Chem. 32, 1673(1989), J. Med. Chem. 33, 2569 (1990), Tetrahedron. 45, 123(1989), etc. [Formula A]
Also, Pharmacia & Upjohn synthesized oxazolidinone derivatives of Formula B and C (PCT WO 93/23384, WO 95/14684, and WO 95/07271) . The compound of Formula B is the first oxazolidinone type antibiotic and was approved by US Food and
Drug Administration (FDA) , being on the market as Zyvox as an oral medication and injection. Yet, existing oxazolidinone compounds have toxicity, with not a wide range of antibacterial spectrum, and its treatment effect decreases in vivo. In case of Zyvox, its solubility in water is about 3mg/ml, which is not enough for injections, so it is used with some limitation. [Formula B]
Figure imgf000005_0001
[Formula C]
Figure imgf000005_0002
Also, WO 93/09103 discloses phenyl oxazolidinone derivatives having hetero cycles such as pyridine, thiazole, indole, oxazol, and quinol at 4-position of phenyl group, but substituents of hetero cycles are simply alkyl or amino groups, having no sufficient effects.
To solve such problems, in WO 01/94342, phenyl oxazolidinone derivatives with various pyridine or phenyl derivatives at 4-position of phenyl group were synthesized. These compounds have wide antibacterial spectrum and excellent antibacterial effect. Although phenyl oxazolidinone compounds having various pyridine derivatives at 4-position of oxazolidinone phenyl group have wider antibacterial spectrum and better antibacterial efficacy than Zyvox, most of them have less than 30 ug/mi of solubility in water, so they cannot be developed as injections.
Recently, in WO 2006/038100, a compound was synthesized inducing hetero cyclic and acyclic compounds at 4-position of oxazolidinone phenyl group presented as Formula D. The compound similar to the present invention is the compound inducing tetrazole or oxadiazole derivatives such as Formula E and F. However, the compound that has great antibacterial efficacy and satisfying solubility has not been found yet. [Formula D]
Figure imgf000006_0001
[Formula E]
Figure imgf000006_0002
[Formula F]
Figure imgf000006_0003
[Disclosure of Invention] [Technical Subject]
Thus, the present inventors synthesized novel oxazolidinone derivatives to develop antibiotics with better antibacterial efficacy than existing ones and found that the novel oxazolidinone derivatives of the present invention had excellent antibacterial efficacy and much improved antibacterial spectrum and completed the present invention.
Therefore, an object of the present invention is to provide a novel oxazolidinone derivative, its prodrugs, hydrates, solvates, isomers, and pharmaceutically permitted salts .
[Technical Solution] The present invention relates to a novel oxazolidinone derivative described as Formula 1 below, its prodrugs, hydrates, solvates, isomers, pharmaceutically permitted salts, and its preparation methods and pharmaceutical compositions containing the same. [Formula 1]
Figure imgf000007_0001
[In Formula 1, R1 is an acyclic substituent or hetero cyclic substituent of the structure below: O R17 R14
H y— R16-N /-H
R11-^ , R15 , R13-N or ^N
R11 i s -NO2 , -COOR2 I , -CONR22R23 , or - ( CH2 ) nNR24R25 ;
NR31 R12 i s -OR26 , -OCOR27 , -OSO2R28 , -NR29R30 , "C-NR32R33 f o r _CN ;
R13 and R14 are respectively hydrogen, alkyl group of Ci-C7, - (CH2) nNR34R35, -CONR36R37, -OR38, -OCOR39, -COR40, -OSO2R41, -SO2R42, or -CN;
R15 is hydrogen, alkyl group of Ci-C7, or -OR43; R16 and R17 are respectively hydrogen, alkyl group of Ci-C7, or -OR44; A is alkylene of C2-C3 and said alkylene can optionally contain one or more hetero moieties selected from the group consisting of N, 0, and S;
R21 through R33 are respectively hydrogen or alkyl group of Ci-C7; R34 through R42 are respectively hydrogen, alkyl group of C1-C7, phenyl, -COR45, -CO (CH2) mNR46R47, -SO2R48, or -OCOR49; R43 is hydrogen or alkyl group of Ci-C7;
R44 is hydrogen, alkyl group of Cx-C7, or -CO (CH2) mNR50R51; R45 through R49 are respectively hydrogen or alkyl group of Ci-C7;
R50 through R51 are respectively hydrogen or alkyl group of Ci-C7; n is an integer between 0 and 5; m is an integer between 1 and 5.]
In the oxazolidinone derivative of the present invention, described as Formula 1, R1 is a hetero cyclic substituent of the structure selected from the group of:
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003
[wherein, R14 is the same as in Formula 1 above; R through R132 are respectively substituted to hydrogen, alkyl group of C1-C7, -COR201, or -SO2R202; R201 and R202 are respectively hydrogen or alkyl group of Ci-C7.] The more desirable example of the oxazolidinone derivative as in Formula 1 of the present invention comprises compounds selected from Formula 2 through 5 of: [Formula 2]
Figure imgf000010_0001
[Formula 3]
Figure imgf000010_0002
'Formula 4
Figure imgf000010_0003
[Formula 5]
Figure imgf000010_0004
[wherein, Formula 2 through 5, A is the same as in Formula 1; R11 is -NO2, -COOR2I, or - (CH2) nNR24R25;
NR31
Il
R12 is -OR26, -OCOR27, -OSO2R28, -NR29R30, "C-NR32R33 f or _CN;
R ,13 and R ,14 are respectively hydrogen, alkyl group of Ci-C7,
- (CH2) nNR ,3J4* πR35 , -0R 3J80, or -CN; R15 is hydrogen, alkyl group of Cx-C7, or -OR43; R16 and R17 are respectively hydrogen, alkyl group of Ci-C7, or -OR44;
R21 and R24 through R33 are respectively hydrogen or alkyl group of Ci-C7;
R34, R35, and R38 are respectively hydrogen, alkyl group of Ci-C7, -COR45, or -CO (CH2) mNR46R47;
R43 is hydrogen or alkyl group of Ci-C7;
R44 is hydrogen, alkyl group of Cx-C7, or -CO (CH2) mNR50R51; R45 through R47 are respectively hydrogen or alkyl group of Ci-C7;
R50 through R51 are respectively hydrogen or alkyl group of Ci-C7; n is an integer between 0 and 3; m is an integer between 1 and 5.]
It is desirable that the hetero cyclic substituent for R1 of the oxazolidinone derivative of the present invention, described as Formula 1, is a hetero cyclic substituent of the structure selected from the group of:
Figure imgf000011_0001
[wherein, R14 is the same as in Chemical Formula 5 above; R101 through R106 and R123 through R128 are respectively hydrogen or alkyl group of Ci-C7-]
The more desirable oxazolidinone derivative compound according to the present invention is as follows:
Figure imgf000012_0001
f o r
Figure imgf000012_0002
Figure imgf000012_0003
. R i i i s -NQ2 or -COOR21 ;
W
R12 is -OH, -NR29R30, "~C"*NH2 r Or -CN; R13 is hydrogen, alkyl
group of Ci-C7, - (CH2) nNR34R35, -OR38, or -CN; R14 is hydrogen or alkyl group of Ci-C7; R15 is hydrogen, alkyl group of Cx-C7, or -OR43; R16 and R17 are respectively hydrogen, alkyl group of Cx- C7, or -OR44; R21, R29, R30, R34, and R35 are respectively hydrogen or alkyl group of Ci-C7; R38 are hydrogen, alkyl group of Ci-C7, -COR45, or -CO (CH2) mNH2; R43 is hydrogen or alkyl group of Cx-C7; R44 is hydrogen, alkyl group of Cx-C7, or -CO (CH2) mNH2; R45 is hydrogen or alkyl group of C1-C7; R101 through R106 and R123 through R128 are respectively hydrogen or alkyl group of Ci-C7; m is an integer between 1 and 5; n is an integer between 0 and 3.
The oxazolidinone derivatives of Formula 1 according to the present invention can be presented as the compound below, which does not restrict the invention.
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000015_0001
The oxazolidinone derivatives of Formula 1 according to the present invention can exist as a tautomer as below.
Figure imgf000016_0001
For the preparation method of the oxazolidinone derivatives of Formula 1 according to the present invention, Scheme 1 is presented below as an example. It does not restrict the preparation methods for the compounds according to the present invention. It is obvious that a person skilled in the art can make changes in the preparation method below. The definition of substituents in the Scheme below, if not mentioned, is the same as in Formula 1.
As presented in Scheme 1 below, the oxazolidinone derivatives of Formula 2 can be synthesized from N- (( (S) -3- (4- (4-formylphenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) aceteamide (II) through the Suzuki coupling reaction using N- ( ( (S) -3- ( 4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) aceteamide (I) , 4-formylphenyl boronic acid, and palladium tetrakistriphenylphosphine (Pd (PPhs) 4) and then Horner-Emmons reaction and condensation in the presence of base.
Also, the oxazolidinone derivatives of Formula 3 can be synthesized from N- ( ( (S) -3- (4- (4-ethoxycarbonylphenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) aceteamide (III) through the Suzuki coupling reaction using N- ( ( (S) -3- (4-bromo- 3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) aceteamide (I ) , 4- ethoxycarbonylphenyl boronic acid, and palladium tetrakistriphenylphosphine (Pd (PPh3) 4) , being followed by the reaction with hydroxyamine derivative, cyanamide, or guanidine, or ester hydrolysis and then condensation with hydrazine derivatives .
Also, the oxazolidinone derivatives of formula 4 can be synthesized from N- (( (S) -3- (4- (4-cyanophenyl) -3-fluorophenyl) - 2-oxooxazolidin-5-yl) methyl) aceteamide (IV) through the Suzuki coupling reaction using N- (( (S) -3- (4-bromo-3-fluorophenyl) -2- oxooxazolidin-5-yl)methyl) aceteamide (I) , 4-cyanophenyl boronic acid, and palladium tetrakistriphenylphosphine (Pd (PPh3) 4) and then making reaction with hydroxyamine derivatives or hydrazine derivatives. Or the oxazolidinone derivatives of Formula 4 or 5 can be synthesized through alkylation, acylation, sulfonylation, and reduction using palladium after making reaction with ketone derivatives, amino acid derivatives, hydroxylamine derivatives, or hydrazine derivatives. Also, the cyclic oxazolidinone derivatives of Formula 5 can be synthesized after making imidate through reaction between N- (( (S) -3- (4- (4-cyanophenyl) -3-fluorophenyl) - 2-oxooxazolidin-5-yl) methyl) aceteamide (IV) and hydrochloric acid, being followed by the reaction with diamine derivatives.
On the other hand, the oxazolidinone derivative compound 5 can be synthesized by the cyclization reaction of the oxazolidinone derivative derivatives of Formula 4. [Scheme 1]
Figure imgf000018_0001
In Scheme 1 on the above, N- ( ( (S) -3- (4-bromo-3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) aceteamide ( I ) , which is used as a starting material, can be synthesized from Scheme 2 below.
[Scheme 2]
Figure imgf000019_0001
Figure imgf000019_0002
From 2- ( ( (S) -oxiran-2-yl) methyl) isoindolin-1, 3-dione (V) and 4-bromo-3-fluoroaniline, whose synthesizing methods are known, 2- ( (R) -3- (4-bromo-3-fluorophenyl) -2- hydroxypropyl) isoindolin-1, 3-dione (VI) is synthesized. Then, using 1, 1-carbonyldiimidazole and DMAP, oxazolidinine cycle of 2- ( (S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) isoindolin-1, 3-dione (VII) is formed. Using hydrazine, the amine derivative of (S) -5- (aminomethyl) -3- (4-bromo-3- fluorophenyl) oxazolidin-2-one (VIII) is synthesized. In the presence of pyridine as a solvent, N- ( ( (S) -3- (4-bromo-3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) aceteamide (I) is synthesized through acetylation.
The oxazolidinone derivatives of Formula 1 according to the present invention can be used as a pharmaceutically permissible salt form. The pharmaceutically permissible salts comprise acid addition salts formed by pharmaceutically permissible free acids. For free acids, both inorganic acids and organic acids can be used. Inorganic acids are hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc.; organic acids are citric acid, acetic acid, lactic acid, maleic acid, umaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc.
The amount of the oxazolidinone derivatives of Formula 1, its prodrugs, hydrates, solvates, isomers, its pharmaceutically permissible salts, which are used to accomplish the therapeutic or preventive effect, are obviously different depending on specific compounds, medication method, patients and diseases to treat but they usually depend on usual dosage of medicine. More desirably, the effective dosage of the oxazolidinone derivative of the present invention is within the range of 1-100 mg/kg (weight) /1 day. It is taken one time or several times a day within the range of the dosage. Also, the pharmaceutical compositions for antibiotics of the present invention can be formulated in various forms for oral medications (e.g. tablets, powders, dried syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, drinks, sublingual tablets, etc.), injections (e.g. vein, eye, coeliac, and muscle), or topical medications (e.g. tincture, cream, lotion, gel, spray, liquid medicine, and 64
20
bandage) . The compositions of the present invention can be formulated into implants, transdermal patches, or capsules for controlled release. The tablets of the present invention can be taken through a certain form or way that has bioavailability with effective amounts, which is oral medication. Depending on the characteristics of the disease to treat or prevent, stage of the disease, and other circumstances, a proper medication form or way can be selected. In case the compositions of the present invention is a tablet, it can comprise more than one pharmaceutically permitted excipient, whose rate and property are decided by solubility and chemical property of the selected tablets, selected medicating process, and standard medication practices.
Even in much lower concentration than Linezolid that is currently on the market, the oxazolidinone derivative of the present invention shows antibacterial efficacy against gram- positive pathogens such as staphylococcus aureus, Enterococcus faecalis, etc. and gram-negative pathogens such as haemophilus influenzae, moraxella catarrhalis, etc., which are resistant to existing antibiotics. It shows excellent antibacterial efficacy especially to Linezolid resistant Enterococcus faecalis . [Best Mode for Carrying Out the Invention]
Hereinafter, the present invention is described in more detail based on the following examples. But, these examples are not intended to limit the scope of the present invention.
[Preparation example 1] Preparation of N- ( ( (S) -3- (4-bromo-3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound D
Figure imgf000022_0001
Figure imgf000022_0002
Preparation of 2- ( (R) -3- (4-bromo-3-fluorophenylamino) -2- hydroxypropyl) isoindolin-1, 3-dione (Compound VI)
4-Bromo-3-fluoroaniline (5g, 25.53mmol) and 2-(((S)- oxiran-2-yl) methyl) isoindolin-1, 3-dione (37.95mmol) were added to 2-propylalcohol (75ml) . After refluxing the mixture with stirring for 12 hrs, the resulting solid was filtered under reduced pressure, and then washed with diethyl ether (30ml) to give 2- ( (R) -3- (4-bromo-3-fluorophenylamino) -2- hydroxypropyl) isoindolin-1, 3-dione (6g, 15.2βmmol, 59.76%). 1H NMR (400 MHz, chloroform-di) δ 7.86-7.84 (m, 2H), 7.78- 7.76 (m, 2H), 7.21-7.17 (m, IH), 6.43 (dd, IH, J1 = 11.6 Hz, J2 = 2.8 Hz), 6.35 (dd, IH, Jx = 8.6 Hz, J2 = 2.6 Hz), 5.19 (t, IH, J = 5.4 Hz), 5.03 (d, IH, J = 5.2 Hz), 4.16-4.08 (m, IH), 3.87-3.71 (m, 2H), 3.23-3.06 (m, 2H)
Preparation of 2- (( (S) -3- (4-bromo-3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) isoindolin-1, 3-dione (Compound VII)
2- ( (R) -3- (4-bromo-3-fluorophenylamino) -2- hydroxypropyl) isoindolin-1, 3-dione (6g, 15.26mmol) obtained above, 1, 1-carbonyldiimidazole (3.7g, 22.9mmol), and dimethylamino pyridine (0.93g, 7.63mmol) were added sequentially to tetrahydrofuran (60ml) and the mixture was refluxed with stirring for 20 hrs . The resulting mixture was concentrated under reduced pressure, dissolved in ethyl acetate (100ml) , then washed sequentially with lN-aqueous hydrochloride solution (50ml) and an aqueous solution of sodium bicarbonate (50ml) . After the dehydration over sodium sulfate and concentration under reduced pressure, the resultant was washed with diethyl ether (80ml) to give 2- ( ( (S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) isoindolin-1, 3-dione (4.9g, 11.69mmol, 76.61%).
1H NMR (400 MHz, chloroform-di) δ 7.86-7.84 (m, 2H), 7.75- 7.73 (m, 2H), 7.49-7.45 (m, 2H), 7.12-7.09 (m, IH), 5.00-4.93 7006364
23
(m, IH) , 4.14-4.05 (m, 2H) , 3.98-3.93 (m, IH) , 3.88-3.85 (m, IH)
Preparation of (S) -5- (aminomethyl) -3- (4-bromo-3- fluorophenyl) oxazolidin-2-one (Compound VIII)
2- ( ( (S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) isoindolin-1, 3-dione (4.9g, 11.69mmol) obtained above and hydrazine (1.17g , 23.38mmol) were dissolved sequentially in ethyl alcohol (70ml) . After refluxing the mixture with stirring for 1 hr, the resultant was cooled to room temperature, filtered, and washed with diethyl ether (30ml) to give (S) -5- (aminomethyl) -3- (4-bromo-3- fluorophenyl) oxazolidin-2-one (3.14g, 10.18mmol, 87.08%). 1H NMR (400 MHz, chloroform-di) δ 7.55-7.34 (m, 2H), 7.05 (dd, IH, Ji = 8.8 Hz, J 2 = 2.4 Hz), 6.18 (t, IH, J = 5.2 Hz), 4.32-4.12 (m, IH), 4.00 (t, IH, J = 9.2 Hz), 3.74 (dd, IH, J x = 9.2 Hz, J 2 = 6.8 Hz), 3.67-3.49 (m, 2H), 1.99 (s, 3H)
Preparation of N- (( (S) -3- (4-bromo-3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound I)
(S) -5- (aminomethyl) -3- (4-bromo-3-fluorophenyl) oxazolidin- 2-one (3.14g, lO.lδmmol) obtained above was dissolved in pyridine (30ml) and cooled to 0°C. Acetyl chloride (1.45ml, 20.3βmmol) was slowly added dropwise thereto and the mixture was stirred for 2 hrs at room temperature. After the concentration under reduced pressure, the reaction mixture was dissolved in ethyl acetate (80ml) and then washed sequentially with lN-aqueous hydrochloride solution (50ml), an aqueous solution of sodium bicarbonate (50ml) and brine (20ml) . After the dehydration over sodium sulfate and the concentration under reduced pressure, the title compound of N- (( (S) -3- (4- bromo-3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (3.3g, 9.97mmol, 97.93%) was obtained.
1H NMR (400 MHz, DMSOd6) δ 7.77 (dd, IH, J1 = J2 = 8.68 Hz), 7.62 (dd, IH, J1 = 11.6 Hz, J2 = 2.4 Hz), 7.32-7.29 (m, IH), 4.62-4.55 (m, IH), 4.03-3.99 (m, IH,), 3.83-3.79 (m, IH), 2.83-2.71 (m, 2H),
[Preparation example 2] Preparation of N- (( (S) -3- (4- (4- formylphenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound II)
Figure imgf000025_0001
N- ( ( (S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (0.2g, 0.604mmol) obtained in the above Preparation example 1 and 4-formylphenyl boronic acid (O.lg, 0.604mmol) were added to a flask. After purging the flask with nitrogen gas, tetrahydrofuran (8ml) was added to dissolve them and then palladium tetrakistriphenylphosphine (0.21g, O.lδmmol) and an aqueous solution of 2M potassium carbonate (O.βml) were added thereto. The mixture was refluxed with stirring for 20 hrs . Then, solvent was removed by concentration under reduced pressure. A column chromatography was carried out by using ethyl acetate to give the title compound of N- ( ( (S) -3- (4- (4-formylphenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (0.07g, 0.197mmol, 33%).
1H NMR (400 MHz, DMSOd6) δ 10.01 (s, IH), 8.23 (t, IH, J = 5.8 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.67-7.54 (m, 2H), 7.42 (dd, IH, J1 = 8.8 Hz, J 2 = 2.4 Hz), 4.78-4.64 (m, IH), 4.13 (t, IH, J = 9.2 Hz), 3.75 (dd, IH, J 1 = 9.2 Hz, J2 = 6-4 Hz), 3.39 (t, 2H, J= 5.4 Hz), 1.79 (s, 3H)
[Preparation example 3] Preparation of N- (( (S) -3- (4- (4- ethoxycarbonylphenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound III)
Figure imgf000026_0001
N- ( ( (S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (0.5g, 1.51mmol) obtained in the above Preparation example 1 and 4-ethoxycarbonyl boronic acid (0.32g , l.δδmmol) were added to a flask. After purging the flask with nitrogen gas, tetrahydrofuran (15ml) was added to dissolve them and then palladium tetrakistriphenylphosphine (0.052g, 0.045mmol) and 2M potassium carbonate (1.5ml) were added thereto. The mixture was refluxed with stirring for 5 hrs . Solvent was removed by concentration under reduced pressure. Water was added to the resulting mixture and filtered off. The resultant was washed with hexane to give the title compound of N- ( ( (S) -3- (4- (4-ethoxycarbonylphenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (0.42g, 0.168mmol, 69%) as a brown solid.
1H NMR (400 MHz, chloroform- di) δ 8.11 (dd, 2H, J1 = 8.4 Hz, J2 = 1.6 Hz), 7.60 (dd, 2H, J1 = 8.4 Hz, J2 = 1.6 Hz), 7.56 (dd, IH, J1= 12.8 Hz, J2= 2.0 Hz), 7.49-7.45 (m, IH), 7.31 (dd, IH, J1 = 8.8 Hz, J2 = 2.4 Hz), β.00 (t, IH, J = 6.0 Hz), 4.86- 4.80 (m, IH), 4.41 (q, 2H, J = 7.2 Hz), 4.13-4.01 (m, IH), 3.85-3.60 (m, 3H), 1.57 (s, 3H), 1.42 (t, 3H, J= 7.2 Hz)
[Preparation example 4] Preparation of N- (( (S) -3- (4- (4- cyanophenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl ) methyl ) acetamide (Compound IV)
NC
BfHf V-N Y 7 -TW«- MC-f V-f V-N I i
F' T F' X N- ( ( (S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Ig, 3.02mmol) obtained in the above Preparation example 1 and 4-cyanophenyl boronic acid (0.44g, 3.02mmol) were added to a flask. After purging the flask with nitrogen gas, tetrahydrofuran (30ml) was added to dissolve them and then palladium tetrakistriphenylphosphine (Ig, 0.906mmol) and an aqueous solution of 2M potassium carbonate (3ml) were added thereto. The mixture was refluxed with stirring for 5 hrs . Solvent was removed by concentration under reduced pressure. The resultant was washed with brine and an extraction was carried out with ethyl acetate. Anhydrous sodium sulfate was used for dehydration and the resulting mixture was filtered and concentrated under reduced pressure. A column chromatography was carried out by using ethyl acetate to give the title compound of N- (( (S) -3- (4- (4-cyanophenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl)methyl) acetamide (Ig/ 2.83mmol, 94%) .
1H NMR (400 MHz, chloroform-di) δ 7.70 (d, 2H, J = 8.8 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.54 (dd, IH, J i = 13 Hz, J 2 = 2.2 Hz), 7.41 (dd, IH, J 1 = J 2 = 8.6 Hz), 7.29 (dd, IH, J 1 = 8.4 Hz, J 2 = 2.4 Hz), 6.01-5.98 (m, IH), 4.82-4.76 (m, IH), 4.09- 4.04 (m, IH), 3.82-3.78 (m, IH), 3.69-3.59 (m, 2H), 2.00 (s, 3H) [Example 1] Preparation of ( S,E) -N- ( (3- (4- (4- (2- nitrovinyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl ) methyl ) acetamide (Compound 101)
Figure imgf000029_0001
N- ( ( (S) -3- (4- (4-formylphenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (lOOmg, 0.28mmol) obtained in the above Preparation example 2, ammonium acetate (300mg) and nitromethane (ImI) were added sequentially to acetic acid (5ml) and the mixture was refluxed with stirring for 2 hrs . After the completion of the reaction, the resulting mixture was cooled to room temperature, concentrated under reduced pressure, dissolved in ethyl acetate (10ml) and then washed with water (10ml) . The organic layer was dehydrated over magnesium sulfate, filtered, and then concentrated under reduced pressure to give the title compound of (S,E) -N- ( (3- (4- (4- (2-nitrovinyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide as a yellow solid (lOOmg, 89%).
1H NMR (400 MHz, chloroform-di) δ 8.01 (d, IH, J = 13.6 Hz), 7.70-7.04 (m, 8H), 6.09-5.91 (m, IH), 4.87-4.70 (m, IH), 3.82-3.59 (m, 3H), 2.01 (s, 3H)
LCMS : 400 (M+H+) for C20Hi8FN3O5 [Example 2] Preparation of (S,E) -methyl 3- (4- (2-fluoro-4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl) phenyl) phenyl) acrylate (Compound 102)
Figure imgf000030_0001
To nitromethane (5ml) , trimethyl phosphono acetate (0.05ml, 0.34mmol) was added, and lithium chloride (14mg, 0.34mmol) and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene (0.04ml, 0.28mmol) were further added thereto, followed by stirring at room temperature. To the resulting mixture, N- (( (S) -3- (4- (4- formylphenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (lOOmg, 0.28mmol) obtained in the above Preparation example 2 was added and the mixture was stirred for additional 2 hrs at room temperature. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in ethyl acetate (30ml) and washed with an aqueous solution of ammonium chloride (15ml) . The organic layer was dehydrated over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound of (S,E)- methyl 3- (4- (2-fluoro-4- (5- (acetamidomethyl) -2-oxooxazolidin- 3-yl) phenyl) phenyl) acrylate as a yellow solid (lOOmg, 86%).
1H NMR (400 MHz, chloroform-di) δ 7.57 (d, IH, J = 16 Hz), 7.51-6.94 (m, 7H), 6.34 (d, IH, J = 16 Hz), 4.80-4.57 (m, IH), 4.07-3.80 (m, IH) , 3.75-3.64 (m, 4H) , 3.56-3.42 (m, 2H) , 1.90 (s, 3H)
LCMS : 413 (M+H+) for C22H2IFN2O5
[Example 3] Preparation of (S) -N- ( (3- (4- (4- (N- hydroxycarbamoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 103)
Figure imgf000031_0001
Hydroxyamine (2.4g, 34.55mmol) and potassium hydroxide (2.4g, 42.77mmol) were dissolved separately in methanol (3OmL), and then the potassium hydroxide solution was added to the hydroxylamine solution. The mixture was stirred until potassium chloride is formed, and then filtered. The resulting filtrate was added to N- ( ( (S) -3- (4- (4-ethoxycarbonylphenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide ( lOOmg, 0.25mmol) obtained in the above Preparation example 3 and stirred at room temperature for 1 hr. Acetic acid (2ml) was added and a distillation was carried out under reduced pressure. Solid formed after the addition of distilled water (30ml) was filtered and washed with ethyl ether and dichloromethane to give the title compound of (S) -N- ( (3- (4- (4- (N-hydroxycarbamoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl ) methyl ) acetamide (20 mg, 21%).
1H NMR (400 MHz, DMSO-d5) d 8.28 (s, IH), 7.85 (d, J = 8.4 Hz), 7.69-7.57 (m, 4H), 7.44 9d, IH, J = 8.4 Hz), 4.85-4.71 (m IH), 4.18 (t, IH, J = 9.2 Hz), 3.80 (t, IH, J = 7.8 Hz), 3.50- 3.40 (m, 2H), 1.84 (s, 3H)
LCMS calc. for Ci9H18FN3O5 (M+H+) : 387, found 388.
[Example 4] Preparation of (S, Z) -N- ( (3- (4- (4- (N1 - hydroxycarbamimidoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin- 5-yl) methyl) acetamide (Compound 104)
Figure imgf000032_0001
N- ( ( (S) -3- (4- (4-cyanophenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (500mg, 1.415mmol) obtained in the above Preparation example 4 was dissolved in ethanol (20ml), and hydroxy amine (295mg, 4.245mmol) was added thereto, followed by the addition of sodium carbonate ( 225mg , 2.122mmol) and water (5ml). The resulting mixture was refluxed with stirring for 4 hrs . After removing the solvent by concentration under reduced pressure, 60ml of a mixture solution containing ethyl acetate and water (v/v=l/l) was added, stirred, and filtered to give the title compound of (S, Z) -N- ( (3- (4- (4- (N '-hydroxycarbamimidoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide as a white solid (0.34g, 63%) .
1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, IH), 8.21 (t, IH, J= 5.8 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.61-7.49 (m, 4H), 7.37 (dd, IH, J i = 8.8 Hz, J 2 = 2.4 Hz), 5.81 (br-s, 2H), 4.74-4.68 (m, IH), 4.14-4.10 (m, IH), 3.76-3.72 (m, IH), 3.40-3.37 (m, 2H), 1.79 (s, 3H)
LCMS : 387 (M+H+) for Ci9Hi9FN4O4
[Example 5] Preparation of (S) -N- ( (3- (4- (4- (carbamimidoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 105)
Figure imgf000033_0001
(S, Z) -N- ( (3-(4-(4-(N'- hydroxycarbamimidoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (0.24g, 0.621mmol) obtained in the above Example 4 was dissolved in methanol (20ml) . Palladium charcoal (Pd/C) catalyst (50mg) and acetic anhydride (0.1ml) were added thereto, and hydrogen gas was introduced to reduce the starting compound of (S, Z) -N- ((3- (4- (4- (N' - hydroxycarbamimidoyl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl)methyl) acetamide, with stirring overnight. Palladium was removed through Celite filter and the solvent was removed by concentration under reduced pressure to give the title compound of (S) -N- ( (3- (4- (4- (carbamimidoyl) phenyl) - 3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (0.14g, 64%) . 1H NMR (400 MHz, DMSOd6) δ 8.35 (t, IH, J = 5.6 Hz), 7.90 (d, 2H, J = 8.0 Hz), 7.75 (d, 2H, J = 7.6 Hz), 7.68-7.62 (m. 2H), 7.47 (dd, IH, J x = 8.6 Hz, J 2 = 1.8 Hz), 4.80-4.76 (m, IH), 4.21-4.16 (m, IH), 3.83-3.79 (m, IH), 3.46-3.43 (m, 2H), 1.85 (s, 3H) LCMS : 371 (M+H+) for Ci9Hi9FN4O3
[Example 6] Preparation of (S, Z) -N- ( (3- (4- (4- (N' - methoxycarbamimidoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin- 5-yl) methyl) acetamide (Compound 106)
Figure imgf000034_0001
(S, Z) -N- ( (3- (4- (4- (N'- hydroxycarbamimidoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (23mg, 0.0595mmol) obtained in the above Example 4 was dissolved in tetrahydrofuran (ImI) . Potassium tert-butoxide (IM solution in THF, 0.06ml, 0.0595mmol) and methyl iodide (CH3I, 0.01ml, 0.1785mmol) were added thereto and the mixture was stirred at room temperature for 3 hrs. Solvent was removed by concentration under reduced pressure and the residue was washed with water, extracted with ethyl acetate, dehydrated over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound of (S, Z) -N- ( (3- (4- (4- (N '- methoxycarbamimidoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin- 5-yl) methyl) acetamide (15.7mg, 66%).
1H NMR (400 MHz, DMSO-d6) δ 8.24 (t, IH, J = 5.8 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.61-7.51 (m, 4H), 7.38 (dd, IH, J1 = 8.6Hz, J2 = 2.2 Hz), 6.08 (s, IH), 4.75-4.69 (m, IH), 4.15-4.10 (m, 2H), 3.76-3.72 (m, 2H), 3.71 (s, 3H), 1.79 (s, 3H)
LCMS : 401 (M+H+) for C20H2IFN4O4
[Example 7] Preparation of (S) -N- ( (3- (4- (4- (4 , 5-dihydro-5, 5- dimethyl-1, 2, 4-oxadiazol -3-yl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 107)
Figure imgf000035_0001
(S, Z) -N- ( (3- (4- (4- (N' - hydroxycarbamimidoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl)methyl) acetamide (23.8mg, 0.0616mmol) obtained in the above Example 4 was dissolved in acetone (3ml). Acetic acid (0.75ml) was added thereto and the mixture was stirred for 48 hrs. Solvent was removed by concentration under reduced pressure and a column chromatography was carried out by using an eluent comprising methanol : dichloromethane (1:9) to give the title compound of (S)-N- ( (3- (4- (4- (4, 5-dihydro-5, 5-dimethyl-l, 2, 4-oxadiazol -3- yl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl ) methyl ) acetamide (12.9mg, 49%).
1H NMR (400 MHz, DMSOd6) δ 8.22 (t, IH, J = 5.8 Hz), 7.69 (d, 2H, J = 8.4 Hz), 7.60-7.55 (m, 4H), 7.46 (s, IH), 7.39 (dd, IH, J1 = 8.8 Hz, J2 = 2.0 Hz), 4.75-4.69 (m, IH), 4.15-4.10 (m, IH), 3.76-3.72 (m, IH), 3.40-3.37 (m, IH), 1.79 (s, 3H), 1.40 (s, 6H)
LCMS : 427 (M+H+) for C22H23FN4O4
[Example 8] Preparation of (S) -N- ( (3- (4- (4- (5-oxo-l, 2, 4- oxadiazol -3-yl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 108)
Figure imgf000036_0001
(S, Z) -N- ( (3- (4- (4- (N' - hydroxycarbamimidoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (23.3mg, 0.0603mmol) obtained in the above Example 4 was dissolved in pyridine (2ml). Methyl chloroformate (0.01ml, 0.12mmol) was added thereto and the mixture was refluxed with stirring for 3 hrs. Solvent was removed by concentration under reduced pressure and a column chromatography was carried out by using an eluent comprising methanol : dichloromethane (1:9) to give the title compound of (S) -N- ( (3- (4- (4- (5-oxo-l, 2, 4-oxadiazol- 3-yl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (8.1mg, 33%).
1H NMR (400 MHz, DMSO-d6) δ 8.22 (t, IH, J= 5.8 Hz), 7.85
(d, 2H, J = 8.0 Hz), 7.70 (d. 2H, J = 8.0 Hz), 7.63-7.57 (m,
2H), 7.40 (d. IH, J = 8.0 Hz), 5.71 (s, IH), 4.72 (m, IH),
4.15-4.11 (m, IH), 3.76-3.73 (m, IH), 3.39 (m, 2H), 1.79 (s, 3H)
LCMS : 413 (M+H+) for C20Hi7FN4O5
[Example 9] Preparation of (S) -N- ( (3- (4- (4- (N- aminocarbamoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 109)
Figure imgf000037_0001
(S) -N- ( (3- (4- (4- (N-aminocarbamoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 109) was obtained according to the procedure the same as that described in the above Example 3, except that hydrazine was used instead of hydroxyamine .
1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, IH), 8.30 (t, IH, J = 5.6 Hz) , 8.05-8.03 (m, 2H) , 1.16-1.62 (m, 4H) , 7.46 (dd, IH, J i = 8.8 Hz, J 2 = 2.4 Hz) , 4.80-4.74 (m, IH) , 4.20-4.16 (m, IH) , 3.81-3.77 (m, IH) , 3.47-3.41 (m, 2H) , 1.84 (s, 3H)
LCMS : 387 (M+H+) for C19Hi9FiN4O4
[Example 10] Preparation of (S, Z) -N- ( (3- (4- (4- (N '- aminocarbamimidoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 110)
HHggNN--NNHH22
Figure imgf000038_0002
Figure imgf000038_0001
(S, Z) -N- ( (3- (4- (4- (N' -aminocarbamimidoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 110) was obtained according to the procedure the same as that described in the above Example 4, except that hydrazine was used instead of hydroxyamine .
1H NMR (400 MHz, DMSO-d6) δ 8.29 (t, IH, J= 5.6 Hz), 8.05 (br s, IH), 7.98-7.96 (m, 2H), 7.65-7.59 (m, 4H), 7.44 (dd, IH, J i = 8.8 Hz, J 2 = 2.4 Hz), 4.80-4.74 (m, IH), 4.20-4.16 (m, IH), 3.81-3.77 (m, IH), 3.45-3.42 (m, 2H), 1.84 (s, 3H) LCMS : 386 (M+H+) for Ci9H20FxN5O3
[Example 11] Preparation of (S, Z) -N- ( (3- (4- (4- (4, 5-dihydro-l- methyl-lH-imidazol-2-yl) phenyl) -3-f luorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 111)
Figure imgf000039_0001
N- ( ( (S) -3- (4- (4-cyanophenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide obtained in the above Preparation example 4 was reacted in ethanol with gaseous HCl, concentrated under reduced pressure and then reacted in ethanol with N-methylethylenediamine to give (S, Z) -N- ( (3- (4- (4- (4, 5-dihydro-l-methyl-lH-imidazol-2-yl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 111) .
1H NMR (400 MHz, DMSO-d6) δ 8.27 (t, IH, J = 6.0 Hz), 7.67-7.60 (m, 6H), 7.45 (dd, IH, J 1 = 8.8 Hz, J 2 = 2.4 Hz), 4.80-4.76 (m, IH), 4.21-4.16 (m, IH), 3.82-3.75 (m, 3H), 3.58- 3.53 (m, 2H), 3.45-3.42 (m, 2H), 2.84 (s, 3H), 1.84 (s, 3H) LCMS : 411 (M+H+) for C22H23F1N4O3
[Example 12] Preparation of (S, Z) -N- ( (3- (4- (4- (N' - (methylcarbonyloxy) carbamimidoyl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 112)
Figure imgf000039_0002
(S,Z)-N-( (3-(4-(4-(N'-
(methylcarbonyloxy) carbamimidoyl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl)methyl) acetamide (Compound 112) was obtained according to the procedure the same as that described in the above Example 6, except that acetyl chloride was used instead of methyl iodide (CH3I) .
1H NMR (400 MHz, DMSOd6) δ 8.28 (t, IH, J = 5.6 Hz),
7.83-7.81 (m, 2H), 7.66-7.60 (m, 4H), 7.44 (dd, IH, J 1 = 8.8 Hz, J 2 = 2.4 Hz), 6.88 (br s, 2H), 4.80-4.74 (m, IH), 4.20-
4.16 (m, IH), 3.81-3.77 (m, IH), 3.45-3.43 (m, 2H), 2.14 (s,
3H), 1.84 (s, 3H)
LCMS : 429 (M+H+) for C2IH2IF1N4O5
[Example 13] Preparation of (S, Z) -N- ( (3- (4- (4- (4 , 5-dihydro-lH- imidazol-2-yl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 113)
Figure imgf000040_0001
N- (( (S) -3- (4- (4-cyanophenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide obtained in the above Preparation example 4 was reacted in ethanol with gaseous HCl, concentrated under reduced pressure and then reacted in ethanol with ethylenediamine to give (S, Z) -N- ( (3- (4- (4- (4 , 5- dihydro-lH-imidazol-2-yl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 113).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (t, IH, J = 6.0 Hz), 7.95 (d, 2H, J = 8.4 Hz), 7.67-7.60 (m, 4H), 7.44 (dd, IH, J 1 = 8.8 Hz, J 2 = 2.4 Hz), 4.79-4.76 (m, IH), 4.21-4.16 (m, IH), 3.83- 3.79 (m, IH), 3.69 (s, 4H), 3.45-3.42 (m, 2H), 1.84 (s, 3H)
LCMS : 397 (M+H+) for C21H21F1N4O3
[Example 14] Preparation of (S, Z) -N- ( (3- (4- (4- (1, 4 , 5, 6- tetrahydro-pyrimidin-2-yl) phenyl) -3-f luorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 114)
Figure imgf000041_0001
N- (( (S) -3- (4- (4-cyanophenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide obtained in the above Preparation example 4 was reacted in ethanol with gaseous HCl, concentrated under reduced pressure and then reacted in ethanol with 1, 3-propylenediamine to give (S, Z) -N- ( (3- (4- (4- (1,4,5, 6-tetrahydro-pyrimidin-2-yl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 114).
1H NMR (400 MHz, DMSO-d6) δ 8.34 (t, IH, J = 5.8 Hz), 7.88-7.86 (m, 2H), 7.80-7.77 (m, 2H), 7.70-7.62 (m, 2H), 7.47 (dd, IH, J i = 8.8 Hz, J 2 = 2.4 Hz) , 4.80-4.76 (m, IH) , 4.21- 4.16 (m, IH) , 3.84-3.80 (m, IH) , 3.52-3.42 (m, 6H) , 1.99-1.97 (m, 2H) , 1.84 (s, 3H)
LCMS : 411 (M+H+) for C22H23F1N4O3
[Example 15] Preparation of (S) -N- ( (3- (4- (4- (N- (dimethylamino) carbamoyl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 115)
Figure imgf000042_0001
(S) -N- ( (3- (4- (4- (N- (dimethylamino) carbamoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 115) was obtained according to the procedure the same as that described in the above Example 3, except that N,N-dimethyl hydrazine was used instead of hydroxyamine.
1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, IH), 8.28 (t, IH, J = 5.6 Hz), 7.87-7.85 (m, 2H), 7.69-7.60 (m, 4H), 7.44 (dd, IH, J 1 = 8.8 Hz, J 2 = 2.4 Hz), 4.80-4.74 (m, IH), 4.20-4.16 (m, IH), 3.81-3.77 (m, IH), 3.45-3.43 (m, 2H), 2.60 (s, 6H), 1.84 (s, 3H)
LCMS : 415 (M+H+) for C2IH23FiN4O4
[Example 16] Preparation of (S) -N- ( (3- (4- (4- (N- cyanocarbamoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 116)
Figure imgf000043_0001
(S) -N- ( (3- (4- (4- (N-cyanocarbamoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 116) was obtained according to the procedure the same as that described in the above Example 3, except that cyanamide was used instead of hydroxyamine.
1H NMR (400 MHz, DMSOd6) δ 8.23 (t, IH, J = 5.8 Hz), 7.96-7.93 (m, 2H), 7.59-7.48 (m, 4H), 7.38 (dd, IH, J i = 8.8 Hz, J 2 = 2.4 Hz), 4.74-4.68 (m, IH), 4.14-4.10 (m, IH), 3.76- 3.71 (m, IH), 3.39-3.36 (m, 2H), 1.79 (s, 3H)
LCMS : 397 (M+H+) for C20Hi7F1N4O4
[Example 17] Preparation of (S, Z) -N- ( (3- (4- (4- (2, 3-dihydro- 3, 3-dimethyl-lH-l, 2, 4-triazol-5-yl) phenyl) -3-fluorophenyl) -2- oxooxazolidin-5-yl) methyl) acetamide (Compound 117)
Figure imgf000043_0002
Compound 110 was reacted with acetone to give (S, Z) -N- ( (3- (4- (4-(2,3-dihydro-3,3-dimethyl-lH-l,2,4-triazol-5- yl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 117).
1H NMR (400 MHz, CDCl3) δ 7.91-7.87 (m, 2H), 7.56-7.42 (m, 4H), 7.28-7.25 (m, 2H), 6.20 (t, IH, J = 6.0 Hz), 5.40 (br s, 2H), 4.85-4.78 (m, IH), 4.10-4.06 (m, IH), 3.84-3.79 (m, IH), 3.71-3.62 (m, 2H), 2.13 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H)
LCMS : 426 (M+H+) for C22H24FiN5O3
[Example 18] Preparation of (S) -N- ( (3- (4- (4- (N-hydroxy-N- methylcarbamoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 118)
Figure imgf000044_0001
(S) -N- ( (3- (4- (4- (N-hydroxy-N-methylcarbamoyl) phenyl) -3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 118) was obtained according to the procedure the same as that described in the above Example 3, except that N-methyl hydroxyamine was used instead of hydroxyamine . 1H NMR (400 MHz, DMSO-d6) δ 10.0 (s, IH), 8.21 (t, IH, J = 5.8 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.59-7.53 (m, 4H), 7.38 (dd, IH, J i = 8.8 Hz, J 2 = 2.4 Hz), 4.74-4.68 (m, IH), 4.14-4.10 (m, IH), 3.76-3.71 (m, IH), 3.39-3.36 (in, 2H), 3.21 (s, 3H), 1 . 7 9 ( s f 3H )
LCMS : 402 (M+H+) for C20H20FiN3O5
[Example 19] Preparation of (S) -N- ( (3- (4- (4- (N-hydroxy-N- methyl-carbamimidoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin- 5-yl) methyl) acetamide (Compound 119)
Figure imgf000045_0001
(S)-N- ( (3- (4- (4- (N-hydroxy-N-methyl- carbamimidoyl) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 119) was obtained according to the procedure the same as that described in the above Example 4, except that N-methyl hydroxyamine was used instead of hydroxyamine . 1H NMR (400 MHz, DMSO-d6) δ 8.26 (t, IH, J = 5.6 Hz), 7.63-7.51 (m, 6H), 7.39 (dd, IH, J 1 = 8.8 Hz, J 2 = 2.4 Hz), 6.83 (br s, 2H), 4.74-4.68 (m, IH), 4.15-4.11 (m, IH), 3.77- 3.72 (m, IH), 3.39-3.36 (m, 2H), 3.27 (s, 3H), 1.79 (s, 3H)
LCMS : 401 (M+H+) for C20H2iFiN4O4
[Example 20] Preparation of (S) -N- ( (3- (4- (4- (guanidinylcarbony) phenyl) -3-fluorophenyl) -2-oxooxazolidin-5- yl) methyl) acetamide (Compound 120)
Figure imgf000046_0001
(S) -N- ( (3-(4-(4-(guanidinylcarbonyl)phenyl)-3- fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 120) was obtained according to the procedure the same as that described in the above Example 3, except that N-boc-guanidine was used instead of hydroxylamine, followed by the treatment with HCl.
1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, IH), 8.51 (br s, 2H), 8.37 (br s, 2H), 8.28 (t, IH, J = 5.6 Hz), 8.07-8.04 (m, 2H),
7.83-7.81 (m, 2H), 7.71-7.63 (m, 2H), 7.47 (dd, IH, J 1 = 8.8
Hz, J 2 = 2.4 Hz), 4.80-4.75 (m, IH), 4.21-4.16 (m, IH), 3.82-
3.78 (m, IH), 3.67-3.41 (m, 2H), 1.84 (s, 3H)
LCMS : 414 (M+H+) for C20H20FiN5O4
[Example 21] Preparation of (S, Z) -N- ( (3- (4- (4- (N- (aminomethylcarbonyloxy) carbamimidoyl) phenyl) -3-fluorophenyl) -
2-oxooxazolidin-5-yl) methyl) acetamide (Compound 121)
(S,Z)-N-( (3-(4-(4-(N- (aminomethylcarbonyloxy) carbamimidoyl) phenyl) -3-fluorophenyl) - 2-oxooxazolidin-5-yl) methyl) acetamide (Compound 121) was obtained according to the procedure the same as that described in the above Example 6, except that N-boc-Glycine hydroxysuccinimide ester (boc-Gly-OSU) was used instead of methyl iodide (CH3I) , followed by the treatment with HCl.
1H NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 2H), 8.31 (t, IH, J = 5.6 Hz), 8.18 (br s, IH), 7.84-7.78 (m, 3H), 7.67-7.61 (m, 3H), 7.46 (dd, IH, J 1 = 8.8 Hz, J 2 = 2.4 Hz), 7.20 (br s, IH), 4.81-4.77 (m, IH), 4.21-4.16 (m, IH), 4.11-3.98 (m, IH), 3.82- 3.79 (m, IH), 3.67-3.41 (m, 3H), 1.85 (s, 3H)
LCMS : 444 (M+H+) for C2IH22FiN5O5
[Example 22] Preparation of (S, Z) -N- ( (3- (4- (4- (N- (aminopropylcarbonyloxy) carbamimidoyl) phenyl) -3-fluorophenyl) - 2-oxooxazolidin-5-yl) methyl) acetamide (Compound 122)
Figure imgf000047_0001
( S , Z ) -N- ( ( 3 - ( 4 - ( 4 - ( N- (aminopropylcarbonyloxy) carbamimidoyl) phenyl) -3-fluorophenyl) - 2-oxooxazolidin-5-yl)methyl) acetamide (Compound 122) was obtained according to the procedure the same as that described in the above Example 6, except that boc-gamma-aminobutyric hydroxysuccinimide ester (boc-GABA-OSU) was used instead of methyl iodide (CH3I) , followed by the treatment with HCl.
1H NMR (400 MHz, DMSO-d6) δ 8.30 (t, IH, J= 5.6 Hz), 7.88 (br s, 2H), 7.83-7.80 (m, 2H), 7.65-7.61 (m, 4H), 7.44 (dd, IH, J i = 8.8 Hz, J 2 = 2.4 Hz), 6.93 (br s, IH), 4.81-4.77 (m, IH), 4.21-4.16 (m, IH), 3.82-3.79 (m, 2H), 3.45-3.42 (m, 2H), 2.89- 2.83 (m, 2H), 2.62 (t, 2H, J = 7.2 Hz), 1.88 (t, 2H, J = 7.2 Hz) 1.84 (s, 3H)
LCMS : 472 (M+H+) for C23H26FiN5O5
[Experimental example 1] Measurement of antibiotic activity in vitro
In order to find out the antibacterial power of the oxazolidinone derivatives of the present invention, which were synthesized in Example 1 through 22, the activity test in vitro was conducted as follows.
The antibiotic activity of the oxazolidinone derivatives in Example 1 through 22 in vitro was evaluated by measuring 90% inhibitory concentration (MICg0, ug/mL) , which is a minimum concentration of antibiotics inhibiting up to 90% of bacteria growth, being compared to the growth in the control group that was drug-untreated by spectroscopy measurement. MIC90 was measured by the broth microdilution method based on NCCLS Standard [See: National Committee for Clinical Laboratory Standards (2000) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fifth Edition: M7-A5. NCCLS, Villanova, PA].
1) Tested strains Total 12 strains were used comprising methicillin susceptible Staphylococcus aureus (MSSA) , methicillin resistant Staphylococcus aureus (MRSA) , Vancomycin resistant Enterococci (VRE), Haemophilus Influenzae, moraxella, etc. Some part of the result was shown in Table 1 through 3.
2) Preparation methods of test materials
The test materials (the oxazolidinone derivative compound 101 through 122 that were synthesized in Example 1 through 22) were dissolved in DMSO in concentration of 10240ug/mL and serially diluted two-fold and twenty-fold in sterilized third distilled water. The final concentration during antibiotic experiment was maximum 128ug/mL to minimum 0.0625ug/mL. The concentration of DMSO as an excipient was 2.5% (V/V) at the end. For a reference material, the Linezolid (Formula B) was used to compare antibiotic activity. The results were shown in Table 1 through 3 below. [Formula B]
Figure imgf000049_0001
[Table 1]
Figure imgf000050_0001
[ Table 3 ]
Figure imgf000051_0001
1. Staphylococcus aureus
2. Methicillin resistant Staphylococcus aureus
3. Staphylococcus epidermidis
4. Methicillin resistant Staphylococcus epidermidis
5. Enterococcus faecalis
6. Vancomycin resistant Enterococcus faecalis
7. Linezolid resistant Enterococcus faecalis
8. Vancomycin resistant Enterococcus faecalis
9. Enterococcus faecium
10. Eschrichia coli
11. Haemophilus influenzae
12. Moraxella catarrhalis As shown in Table 1 through 3, even in much lower concentration than Linezolid, which is a reference material, the oxazolidinone derivative of the present invention shows strong antibacterial efficacy against gram-positive pathogens such as Staphylococcus aureus, Enterococcus faecalis, etc. and gram-negative pathogens such as haemophilus influenzae, moraxella catarrhalis, etc., which are resistant to existing antibiotics. It shows excellent antibacterial efficacy especially to Linezolid resistant Enterococcus faecalis.
Therefore, it was found that the oxazolidinone derivative of the present invention can be used as a good antibiotic.
[industrial Applicability] The novel oxazolidinone derivative of the present invention has wide antimicrobial spectrum against resistant bacteria and low toxicity. Also, even in much lower concentration than Linezolid, which is a reference material, it shows strong antibacterial efficacy against gram-positive pathogens such as Staphylococcus aureus, Enterococcus faecalis, etc. and gram-negative pathogens such as haemophilus influenzae, moraxella catarrhalis, etc., which are resistant to existing antibiotics. It shows excellent antibacterial efficacy especially to Linezolid resistant Enterococcus faecalis, so it can be used as a good antibiotic.

Claims

[CLAIMS]
[Claim l]
An oxazolidinone derivative of formula 1: [Formula 1]
Figure imgf000053_0001
or prodrug, hydrate, solvate, isomer or pharmaceutically permitted salt thereof.
[wherein, R1 is an acyclic substituent or hetero cyclic substituent of the structure below:
Figure imgf000053_0002
R11 i s -NO2 , -COOR2 I , -CONR22R23 , or - ( CH2 ) nNR24R25 ;
NR31 R12 i s -OR26 , -OCOR27 , -OSO2R28 , -NR29R30 , -C-NR32R33 f o r _CN ;
R13 and R14 are respectively hydrogen, alkyl group of Ci-C7, - (CH2) nNR34R35, -CONR36R37, -OR38, -OCOR39, -COR40, -OSO2R41, -SO2R42, or -CN;
R15 is hydrogen, alkyl group of Ci-C7, or -OR43; R16 and R17 are respectively hydrogen, alkyl group of Ci-C7, or -OR44;
A is alkylene of C2-C3 and said alkylene can optionally contain one or more hetero moieties selected from the group consisting of N, 0, and S; R21 through R33 are respectively hydrogen or alkyl group of Ci-C7;
R34 through R42 are respectively hydrogen, alkyl group of Ci-C7, phenyl, -COR45, -CO (CH2) mNR46R47, -SO2R48, or -OCOR49; R43 is hydrogen or alkyl group of C1-C7;
R44 is hydrogen, alkyl group of Cx-C7, or -CO (CH2) mNR50R51;
R45 through R49 are respectively hydrogen or alkyl group of Ci-C7;
R50 through R51 are respectively hydrogen or alkyl group of Ci-C7; n is an integer between 0 and 5; m is an integer between 1 and 5.]
[Claim 2]
Rt4
An oxazolidinone derivative of claim 1, wherein said " is
a hetero cyclic substituent of the structure selected from the group of:
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000055_0002
[wherein, R14 is the same as in formula 1 of claim 1; R through R132 are respectively hydrogen, alkyl group of Ci-C7, - COR201, or -SO2R202; R201 and R202 are respectively hydrogen or alkyl group of Ci-C7.]
[Claim 3]
An oxazolidinone derivative of claim 1, wherein said oxazolidinone derivative is selected from the Formula 2 through 5 of: [Formula 2]
Figure imgf000055_0003
[Formula 3]
[Formula 4]
Figure imgf000056_0002
[Formula 5]
Figure imgf000056_0003
[wherein, Formula 2 through 5, A is the same as in Formula 1 of claim 1;
R11 is -NO2 , -COOR2I , or - ( CH2 ) nNR24R25 ;
NR3t R12 is -OR26, -OCOR27 , -OSO2R28 , -NR29R30 , -C-NR32R33 , or _CN ;
R13 and R14 are respectively hydrogen, alkyl group of Ci-C7, - (CH2) nNR34R35, -OR38, or -CN;
R15 is hydrogen, alkyl group of Ci-C7, or -OR43; R16 and R17 are respectively hydrogen, alkyl group of Ci-C7, or -OR44;
R21 and R24 through R33 are respectively hydrogen or alkyl group of Ci-C7;
R34, R35, and R38 are respectively hydrogen, alkyl group of Ci-C7 , -COR45 , or -CO ( CH2 ) mNR46R47 ;
R43 is hydrogen or alkyl group of C1-C7;
R44 is hydrogen, alkyl group of Ci-C7, or -CO (CH2) mNR50R51; R45 through R47 are respectively hydrogen or alkyl group of Cx-C7;
R50 through R51 are respectively hydrogen or alkyl group of Ci-C7; n is an integer between 0 and 3; m is an integer between 1 and 5.]
[Claim 4]
An oxazolidinone derivative of claim 3, wherein said
Figure imgf000057_0001
is
a hetero cyclic substituent of the structure selected from the group of:
Figure imgf000057_0002
[wherein, R14 is the same as in claim 3 ; R101 through R106 and R123 through R128 are respectively hydrogen or alkyl group of C1- C7 . ] [Claim 5 ]
An oxazolidinone derivative of claim 1, wherein R1 is
Figure imgf000058_0001
Figure imgf000058_0002
or -CN; R13 is hydrogen, alkyl group of Ci-C7, - (CH2) nNR R , - OR38, or -CN; R14 is hydrogen or alkyl group of Ci-C7; R15 is hydrogen, alkyl group of Cx-C7, or -OR43; R16 and R17 are respectively hydrogen, alkyl group of Ci-C7, or -OR44; R21, R29, R30, R34, and R35 are respectively hydrogen or alkyl group of Ci- C7; R38 are hydrogen, alkyl group of Cx-C7, -COR45, or - CO (CH2) mNH2; R43 is hydrogen or alkyl group of Cx-C7; R44 is hydrogen, alkyl group of Cx-C7, or -CO (CH2)mNH2; R45 is hydrogen or alkyl group of C1-C7; R101 through R106 and R123 through R128 are respectively hydrogen or alkyl group of Cx-C7; m is an integer between 1 and 5; n is an integer between 0 and 3.
[Claim 6]
An oxazolidinone derivative of claim 5, wherein said oxazolidinone derivative is selected from the compounds of:
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000061_0002
[Claim 7 ]
Pharmaceutical compositions for antibiotics containing the oxazolidinone derivative of any one of claims 1 to 6 as an effective component.
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CN105348212A (en) * 2015-03-31 2016-02-24 安徽悦康凯悦制药有限公司 Preparation method for Linezolid
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CN108135887A (en) * 2015-10-22 2018-06-08 默沙东公司 Oxazolidinone compounds and its application method as antiseptic
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