WO2007040326A1 - A novel oxazolidinone formamide derivative and preparation method therof - Google Patents
A novel oxazolidinone formamide derivative and preparation method therof Download PDFInfo
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- WO2007040326A1 WO2007040326A1 PCT/KR2006/003960 KR2006003960W WO2007040326A1 WO 2007040326 A1 WO2007040326 A1 WO 2007040326A1 KR 2006003960 W KR2006003960 W KR 2006003960W WO 2007040326 A1 WO2007040326 A1 WO 2007040326A1
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- WIPO (PCT)
- Prior art keywords
- formula
- formamide
- fluoro
- independently
- phenyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title abstract description 9
- VAWBZFMRWXIHHA-UHFFFAOYSA-N formamide;1,3-oxazolidin-2-one Chemical class NC=O.O=C1NCCO1 VAWBZFMRWXIHHA-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- -1 oxazolidinone formamide compound Chemical class 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 150000002825 nitriles Chemical class 0.000 claims description 12
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 150000001299 aldehydes Chemical class 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 235000013877 carbamide Nutrition 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 claims description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- QMIGEDXMDGEZSR-UHFFFAOYSA-N 2,5-dimethoxyoxolane-3-carbaldehyde Chemical compound COC1CC(C=O)C(OC)O1 QMIGEDXMDGEZSR-UHFFFAOYSA-N 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
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- 230000000845 anti-microbial effect Effects 0.000 abstract description 3
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- 238000001228 spectrum Methods 0.000 abstract description 3
- 229960003165 vancomycin Drugs 0.000 abstract description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 abstract description 3
- 241000194033 Enterococcus Species 0.000 abstract description 2
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 41
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 39
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- 239000007787 solid Substances 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 238000009835 boiling Methods 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
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- 239000002253 acid Substances 0.000 description 5
- 150000001540 azides Chemical class 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 4
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 4
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- 239000002904 solvent Substances 0.000 description 4
- 229940086542 triethylamine Drugs 0.000 description 4
- 0 *=Cc1c[n](-c(c(F)c2)ccc2N(C[C@](CNC=O)O2)C2=O)nn1 Chemical compound *=Cc1c[n](-c(c(F)c2)ccc2N(C[C@](CNC=O)O2)C2=O)nn1 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
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- 238000001727 in vivo Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- VHWBWHBJEXGPNM-UHFFFAOYSA-N N(2)-(2,4-dichlorophenyl)-N-(7-{[(2,4-dichlorophenyl)amino]sulfonyl}-1-oxo-1,2-dihydronaphthalen-2-yl)glycinamide Chemical compound ClC1=CC(Cl)=CC=C1NCC(=O)NC1C(=O)C2=CC(S(=O)(=O)NC=3C(=CC(Cl)=CC=3)Cl)=CC=C2C=C1 VHWBWHBJEXGPNM-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- NHYZIZJWRDWCQL-NSHDSACASA-N OC(c1c[n](-c(c(F)c2)ccc2N(C[C@H](CNC=O)O2)C2=O)nc1)=O Chemical compound OC(c1c[n](-c(c(F)c2)ccc2N(C[C@H](CNC=O)O2)C2=O)nc1)=O NHYZIZJWRDWCQL-NSHDSACASA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229950008631 eperezolid Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- KACZQOKEFKFNDB-UHFFFAOYSA-N ethyl 1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1 KACZQOKEFKFNDB-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 244000000059 gram-positive pathogen Species 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940118019 malondialdehyde Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- AEULHJVQSRALLI-MERQFXBCSA-N n-[[(5s)-3-(3-fluoro-4-pyrazol-1-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]formamide;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.FC1=CC(N2C(O[C@@H](CNC=O)C2)=O)=CC=C1N1C=CC=N1 AEULHJVQSRALLI-MERQFXBCSA-N 0.000 description 1
- PQGCCEFOVJJXLH-MERQFXBCSA-N n-[[(5s)-3-(3-fluoro-4-pyrazol-1-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]formamide;hydrochloride Chemical compound Cl.FC1=CC(N2C(O[C@@H](CNC=O)C2)=O)=CC=C1N1C=CC=N1 PQGCCEFOVJJXLH-MERQFXBCSA-N 0.000 description 1
- PIVUJTOSIYVWBD-YDALLXLXSA-N n-[[(5s)-3-(3-fluoro-4-pyrrol-1-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]formamide;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.FC1=CC(N2C(O[C@@H](CNC=O)C2)=O)=CC=C1N1C=CC=C1 PIVUJTOSIYVWBD-YDALLXLXSA-N 0.000 description 1
- SJYSRPBDRHDWHQ-YDALLXLXSA-N n-[[(5s)-3-(3-fluoro-4-pyrrol-1-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]formamide;sulfuric acid Chemical compound OS(O)(=O)=O.FC1=CC(N2C(O[C@@H](CNC=O)C2)=O)=CC=C1N1C=CC=C1 SJYSRPBDRHDWHQ-YDALLXLXSA-N 0.000 description 1
- POXUJOYUVLWPQN-ZDUSSCGKSA-N n-[[(5s)-3-(4-acetylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C(C)=O)C=C1 POXUJOYUVLWPQN-ZDUSSCGKSA-N 0.000 description 1
- LYUFCOLVBWJZRI-QMMMGPOBSA-N n-[[(5s)-3-(4-azido-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]formamide Chemical compound C1=C(N=[N+]=[N-])C(F)=CC(N2C(O[C@@H](CNC=O)C2)=O)=C1 LYUFCOLVBWJZRI-QMMMGPOBSA-N 0.000 description 1
- SIMWTRCFFSTNMG-AWEZNQCLSA-N n-[[(5s)-3-[3-fluoro-4-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCN(C(=O)CO)CC1 SIMWTRCFFSTNMG-AWEZNQCLSA-N 0.000 description 1
- QMRPHGBMRSQMHY-UHFFFAOYSA-N n-[[3-(3-fluoro-4-pyrazol-1-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]formamide Chemical compound FC1=CC(N2C(OC(CNC=O)C2)=O)=CC=C1N1C=CC=N1 QMRPHGBMRSQMHY-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940071117 starch glycolate Drugs 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
Definitions
- the present invention relates to novel oxazolidinone formamide compound represented by formula I or a their pharmaceutically acceptable salts and a process for the preparation thereof, showing superior antimicrobial activities against gram-positive germs including resistant strains such as methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococcus.
- Y is each and independently
- the oxazolidinones represent a new class of antibacterial agents which showed activity against a wide spectrum of gram-positive bacterial infections, including those infections caused by strains resistant to other antibiotics.
- the oxazolidinones is a relatively new class of orally active, totally synthetic antibacterial agent.
- Dupont Co. reported first that Dup-721 (Formula A), a compound of oxa- zolidinone derivative, showed good activities against gram-positive pathogens (including MRSA, MRSE), gram-negative anaerobes, and Mycobacterium tuberculosis . (EP 0312000, J. Med. Chem. 1989, 32, 1673)
- oxazolidinones generally do not demonstrate an activity at a useful level against aerobic gram-negative organism.
- oxazolidinone formamide compound represented by the following formula I.
- hy- droxymethyl side chain was then elaborated to the azide analogue 4 via standard transformations. Reduction of the azide by hydrogenation over Pd/C or triphenylphosphine gives an amine 5 which can be formylate in situ with acetic anhydride and formic acid to afforded oxazolidinone formamide (1-1).
- the compounds of formula I-1 ⁇ I-16 may be used in its native form or as a salt. In cases where forming a stable nontoxic acid or base salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate.
- Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, alkali metal (for example, sodium or potassium) or alkaline earth metal (for example, calcium or magnesium) salts of carboxylic acids can be made. And reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion (for example, ammonium, triethylamine, pyridine and N,N - dimethylethanolamine salt).
- Suitable inorganic salts are formed, including hydrochloride, hydrobromide, sulfate and nitrate salts.
- Organic acid addition salts may also be formed with acids which form a physiological acceptable anion, for example, formic acid, acetic acid, tartaric acid, citric acid, methylsulfonic acid, lactic acid, succinic acid and benzenesulfonic acid.
- the compounds of formula 1-1' 1-16 show inhibitory activity against a broad spectrum of bacteria, but its antibacterial activity is excellent in vivo.
- the compound of the present invention can exert potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, as well as gram-negative bacteria, such as Escherichia coli and Klebsiella oxytoca.
- the oxazolidinone antibacterial agents of this invention have good activity against gram-positive bacterial infection, including MRSA and VRE strains.
- the compounds of the present invention can be used in the therapeutic treatment of human beings or animals infected with variety of gram-positive bacteria.
- compositions comprising one or more of the compound I and their derivatives as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary.
- the compositions may be formulated into various forms such as tablets, capsules, troche, suspension, solution, suppositories, ointment, cream, injection, which may contain conventional additives such as a dispersant, suspending agent, stabilizer and the like.
- the compounds of formula I according to this invention are administered orally and parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration.
- compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water- for-injection and a buffer to provide a suitably buffered isotonic solution.
- a pharmaceutically acceptable liquid carrier such as, for example, water- for-injection
- a buffer to provide a suitably buffered isotonic solution.
- Suitable buffering agents include, for example, Z ⁇ (+)-lysine, L-(+)-arginine, N - methylglucamine, sodium citrate, sodium bicarbonate and trisodium orthophosphate to name but a few representative buffering agents.
- Citric acid (leq) was added to a solution of 1-1 (42mg, 0.14mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 53.5mg (78%).
- Citric acid (leq) was added to a solution of 1-2 (40mg, 0.13mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 41.1mg (63%).
- Citric acid (leq) was added to a solution of 1-3 (41mg, 0.13mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 32.1mg (48%).
- Citric acid (leq) was added to a solution of 1-4 (35mg, 0.1 lmmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 34.8mg (61%).
- Citric acid (leq) was added to a solution of 1-8 (32mg, 0.14mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 41.3mg (58%).
- Citric acid (leq) was added to a solution of 1-12 (41mg, 0.12mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 37.6mg (58%).
- Citric acid (leq) was added to a solution of 1-16 (36mg, 0.1 lmmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 35.8mg (63%).
- the oxazolidinonoe compounds of formula I have potent antibacterial activity against a broad spectrum of bacteria and their antibacterial activity is maintained high in vivo. Exerting potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci andgram-negative bacteria, such as Escherichia coli and Klebsiella oxytoca., the compounds of the present invention are therefore useful as antibiotics
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to novel oxazolidinone formamide compound represented by formula I or a their pharmaceutically acceptable salts and a process for the preparation thereof, showing superior antimicrobial activities against gram-positive germs including resistant strains such as methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococcus, as well as gram-negative bacteria, such as Escherichia coli and Klebsiella oxytoca. The compounds of the present invention have wide antibacterial spectrum, superior an¬ tibacterial activity, such that the compound of this invention can be used as an antibacterial agent.
Description
Description
A NOVEL OXAZOLIDINONE FORMAMIDE DERIVATIVE AND PREPARATION METHOD THEROF
Technical Field
[1] The present invention relates to novel oxazolidinone formamide compound represented by formula I or a their pharmaceutically acceptable salts and a process for the preparation thereof, showing superior antimicrobial activities against gram-positive germs including resistant strains such as methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococcus.
[2]
[3] Formula I
[4]
Formula I
[5]
[6] wherein,
[7] X is each and independently
[8] (a) carbon or
[9] (b) nitrogen atom
[10] Y is each and independently
[H] (a) carbon or
[12] (b) nitrogen atom
[13] Z is each and independently
[14] (a) CRl or
[15] (b) nitrogen atom
[16] Rl is
[17] (a) hydrogen atom
[18] (b) hydroxymethyl
[19] (c) ethylcarboxylate
[20] (d) carboxylic acid
[21] (e) carbamide
[22] (f) diethoxymethyl
[23] (g) aldehyde
[24] (h) hydroxyoxime or
[25] (i) nitrile
[26] R2 is
[27] (a) hydrogen atom or
[28] (b) nitrile
[29]
Background Art
[30] In 1980s, the oxazolidinones represent a new class of antibacterial agents which showed activity against a wide spectrum of gram-positive bacterial infections, including those infections caused by strains resistant to other antibiotics. The oxazolidinones is a relatively new class of orally active, totally synthetic antibacterial agent.
[31]
[32] In 1987, Dupont Co. reported first that Dup-721 (Formula A), a compound of oxa- zolidinone derivative, showed good activities against gram-positive pathogens (including MRSA, MRSE), gram-negative anaerobes, and Mycobacterium tuberculosis . (EP 0312000, J. Med. Chem. 1989, 32, 1673)
[33]
[34] Formula A
[35]
[36]
[37] Subsequem t studies at Pharmacia a zolidinone antibacterial agents, linezolid (Formula B) and eperezolid (Formula C). These compound showed good activity against gram-positive bacterial infections, including the resistant strain of methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant en- teroccocci (VRE)
[38] However, oxazolidinones generally do not demonstrate an activity at a useful level against aerobic gram-negative organism.
[39]
[40] Formula B
[41]
[42] [43] Formula C [44]
[45] [46] Thus, the use of these oxazolidinone antibacterial agents is limited to infectious states due to gram-positive bacterial. Accordingly, it is among the objects of the present invention to provide pharmaceutical compounds which have broader antibacterial activity including the activity against aerobic gram-negative organisms. We have now discovered that the new oxazolidinone formamide (formula I) of the present invention increase the spectrum of activity to include gram-negative organism such as Escherichia coli DC2 and Klebsiella oxytoca 1082E as well as showed good in vivo efficacy.
[47]
Disclosure of Invention [48]
Mode for the Invention [49] Therefore, it is an object of the present invention to provide oxazolidinone formamide derivatives of formula I, which can be used as an antibiotic exhibiting higher activities against multi-drug resistant strains (MRSA), and pharmaceutically acceptable salts thereof.
[50] It is another object of the present invention to provide a process for preparing such an oxazolidinone derivative of formula I, or its pharmaceutically acceptable salt. [51] There are provided oxazolidinone formamide compound represented by the following formula I.
[52] Formula I- 1
[54] Formula 1-2
[55]
[56] Formula 1-3
[57]
[58] Formula 1-4
[59]
[60] Formula 1-5
[61]
[62] Formula 1-6
[63]
[64] Formula 1-7 [65]
[66] Formula 1-8 [67]
[68] Formula 1-9 [69]
[70] Formula I- 10 [71]
[72] Formula I- 11 [73]
[74] Formula 1-12
[75]
[76] Formula 1-13
[77]
[78] Formula 1-14 [79]
[80] Formula 1-15 [81]
[82] Formula 1-16 [83]
[84]
[85] Hereinafter, a preparation method of the compound represented by the formula I will be described by the following scheme 1~4.
[86] [87] Scheme 1 [88]
[89] wherein, X, Z, Rl and R2 are each as defined above. [90] The general preparation involved nucleophilic aromatic substitution reaction between the pyrrole and 3,4-difluoronitrobenzene 1 to give the 3-fluoro-4-azolylnitrobenzene intermediates. Reduction of the nitro group by hy- drogenation in the presence of 10% palladium on carbon catalyst and Cbz protection of the resulting aniline gave intermediates 2. Deprotonation with base (n-BuLi) followed by treatment with (/?)-(-)-glycidyl butyrate afforded oxazoldinones 3. The hy- droxymethyl side chain was then elaborated to the azide analogue 4 via standard transformations. Reduction of the azide by hydrogenation over Pd/C or triphenylphosphine gives an amine 5 which can be formylate in situ with acetic anhydride and formic acid to afforded oxazolidinone formamide (1-1).
[91] [92] Pyrazole was synthesized in using similar method. (1-2) [93] [94] 1,2,4-triazole was synthesized in using similar method. (1-3) [95]
[96] 2-cyanopyrrole was synthesized in using similar method. (1-5)
[97] [98] Scheme 2 [99]
[100] wherein, Rl are each as defined above. [101] [102] And also, treatment of an acetonitrile solution of 3,4-difluoronitrobenzene 1 with benzylamine in the presence of triethylamine afforded in high yield. The nitro group of structure is then reduced by hydrogenation in the presence of platinum catalyst in a suitable solvent such as THF or Methanol. The aniline 6 is then converted to its Cbz intermediate and then deprotonated by n-BuLi in THF to give a lithiated intermediate which is then treated with commercially available (/?)-(-)-glycidyl butyrate. Warming to ambient temperature affords the compound 7. This alcohol is then converted to the corresponding mesylate. The resultant sulfonate derivative is then reacted with sodium azide in DMF to provide the azide analogue 8, which is then reduced and formylated by Pd/C and formic acid. And then formamide analogue 9 was deprotected by hydrogenation to afford key intermediate aniline 10. The aniline was condensed with 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde to yield the formylpyrrole (formula I- 6) which was exploited for the preparation of oximepyrrole (formula 1-7) via standard transformations. Dehydration of the oxime with trichloroacetyl chloride in dichloromethane yielded the 3-cyano analogue (formula 1-8)
[103] [104] Scheme 3 [105]
13 15
Formula I-9
[106] wherein, Rl are each as defined above. [107] [108] And also, the arylhydrazine 11 was synthesized and condensed with the known (ethoxycarbonyl)malondialdehyde (J. Org. Chem, 1982, 47, 2116-2217) to give the ethyl 4-pyrazolecarboxylate 12. This material was then converted to (formula 1-9) employing the azide intermediate 15 for the introduction of the acetylaminomethyl side chain. Ester (formula 1-9) was further converted to (formula I-10~I-12)
[109] [HO] Scheme 4 [111]
[112] wherein, Rl are each as defined above. [113] The amine 10 is then reacted with sodium nitrite, sodium azide and sodium acetate in hydrochloride to provide the azide analogue 16 which is then cyclized by refluxing vinyl acetate or propiolaldehyde diethylacetal to afforded triazole oxazoldinone formamide (formula 1-4 or formula 1-13). Deprotection of the diethylacetal (formula I- 13) with trifluoroacetic acid afforded the 4-carbaldehydetriazole (formula 1-14), which was exploited for the preparation of 4-oximepyrrole (formula 1-15) via standard transformations. Dehydration of the oxime (formula 1-15) with trichloroacetyl chloride in dichloromethane yielded the 4-cyano analogue (formula 1-16).
[114] [115] The compounds of formula I-1~I-16 may be used in its native form or as a salt. In cases where forming a stable nontoxic acid or base salt is desired, administration of the
compound as a pharmaceutically acceptable salt may be appropriate. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, alkali metal (for example, sodium or potassium) or alkaline earth metal (for example, calcium or magnesium) salts of carboxylic acids can be made. And reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion (for example, ammonium, triethylamine, pyridine and N,N - dimethylethanolamine salt). Suitable inorganic salts are formed, including hydrochloride, hydrobromide, sulfate and nitrate salts. Organic acid addition salts may also be formed with acids which form a physiological acceptable anion, for example, formic acid, acetic acid, tartaric acid, citric acid, methylsulfonic acid, lactic acid, succinic acid and benzenesulfonic acid.
[116]
[117] It is found that not only does the compounds of formula 1-1' 1-16 show inhibitory activity against a broad spectrum of bacteria, but its antibacterial activity is excellent in vivo. For example, the compound of the present invention can exert potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, as well as gram-negative bacteria, such as Escherichia coli and Klebsiella oxytoca.
[118]
[119] EXPERIMENT 1>
[120] MIC Test Method
[121] The in vitro Minimum Inhibitory Concentration (MIC: D/D) of test compounds were determined by a standard agar dilution method. (Chemotheraphy, 1981, 29 (Y), 76). Linezolid is included in the assay and serves as a comparator and quality control compound of test compounds. The activity of compounds of this invention is shown in Table 1.
[122]
[123] Table 1
■ — compound MIC (mg/L) organism ■ — — ____ Linβzolid HI 1-2 1-5 1-8 1-12
S. aureus Met R 1.6 1.6 6.3 3.1 0.2 0.4
S. aureus Met S 1.6 1.6 6.3 3.1 0.4 0.4
Coagulase negative S. Met R 1.6 0.8 6.3 3.1 0.4 0.4
Coagulase negative S. Met S 1.6 0.8 3.1 3.1 0.4 • 0.8
Enterococcus faecalis Van R 1.6 1.6 6.3 3.1 0.4 0.8
Enterococcus faecalis Van S 1.6 1.6 6.3 3.1 0.2 0.8
Enterococcus faecium Van R 0.8 0.8 1.6 1.6 0.2 0.4
Enterococcus faecium Van S 0.8 1.6 6.3 3.1 0.2 0.4
Str. pneumoniae Pen NS 0.8 0.4 1.6 1.6 0.2 0.4
Str. pneumoniae Pen S 0.8 0.4 1.6 0.8 0.1 0.4
Str. Pyogenes 0.8 0.8 0.8 3.1 0.2 0.4
Str. Agalactiae 1.6 1.6 6.3 3.1 0.2 0.8
Str. Faecium MD 8b 1.6 1.6 1.6 3.1 0.2 0.8
S. aureus SG 511 0.8 0.4 1.6 3.1 0.1 0.8
S. aureus 285 1.6 0.8 3.1 3.1 0.2 0.8
S. aureus 503 0.8 0.2 0.8 1.6 0.1 0.4
[124] As can be seen from Table 1, the oxazolidinone antibacterial agents of this invention have good activity against gram-positive bacterial infection, including MRSA and VRE strains.
[125] [126] EXPERIMENT 2> [127] Acute Toxicity Studies [128] In order to illustrate usefulness of the compounds of the present invention, acute toxicity test of the compounds synthesized in the Examples were carried out. Each dose of the compounds dissolved in 50% PEG (Polyethylene glycol), was determined in mice using oral route of administration. Mortalities of the animals was recorded 2 weeks later, the results of the acute toxicity studies are shown in Table 2.
[129] [130] Table 2
[131] * Mouse: Male ICR strain, 4 weeks [132] [133] The compounds are shown high stability as an antimicrobial medicament from LD
50
>4000mg/kg in oral routes. Accordingly, the compounds of the present invention can be used in the therapeutic treatment of human beings or animals infected with variety of gram-positive bacteria.
[134]
[135] The present invention includes within its scope pharmaceutical compositions comprising one or more of the compound I and their derivatives as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary. The compositions may be formulated into various forms such as tablets, capsules, troche, suspension, solution, suppositories, ointment, cream, injection, which may contain conventional additives such as a dispersant, suspending agent, stabilizer and the like. The compounds of formula I according to this invention are administered orally and parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water- for-injection and a buffer to provide a suitably buffered isotonic solution. Suitable buffering agents include, for example, Z^(+)-lysine, L-(+)-arginine, N - methylglucamine, sodium citrate, sodium bicarbonate and trisodium orthophosphate to name but a few representative buffering agents.
[136]
[137] Formulation examples are described below.
[138]
[139] Formulation example 1
[140]
[141] Excipient Amount
[142] The compound of prepared Example 1 400.0mg
[143] Lactose NF 80.0mg
[144] Povidone NF 4.00mg
[145] Microcrystalline cellulose NF 40.0mg
[146] Sod. starch Glycolate NF 20.0mg
[147] Mg. stearate NF 5.6mg
[148] Water purified
[149]
[150] Film coating phase
[151] Opadry white YS-1-18202-A 16.8mg
[152] Water purified 129.2mg
[153]
[154] Polisher
[155] Carnauba wax 0.0224mg
[156]
[157] Description of the Preferred Embodiments
[158]
[159] The following examples are provided to further illustrate this invention but they should not be taken as limiting. [160]
[161] <Example 1>
[162] N-((GS)-3-(3-fluoro-4-(lH - pyrrol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide (I- 1 ) : [163]
[164] To 4.8ml of CH2Cl2 were added 122mg (0.443mmol) of (S
)-5-(aminomethyl)-3-(3-fluoro-4-( lH-pyrrol- 1 -yl)phenyl)oxazolidin-2-one, 2.173ml of formic acid, and 2.173ml of acetic anhydride. The reaction mixture was stirred for 3h at 0°C. The mixture was extracted with methylene chloride, water and 2N-ΗC1. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (107mg, 0.35mmol) in a yield of 80%.
[165]
[166] 1K NMR (DMSO-dp δ 8.43 (IH, s), 8.09 (IH, dd), 7.66 (IH, dd), 7.41 (IH, dd),
7.10 (2H, dd), 6.26 (2H, dd), 4.80 (IH, m), 4.17 (IH, t), 3.78 (IH, dd), 3.48 (2H, dd)
[167]
[168] <Example 2>
[169] N-(((S)-3-(3-fluoro-4-(lH - pyrazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide (1-2) :
[170]
)-5-(aminomethyl)-3-(3-fluoro-4-( lH-pyrazol- 1 -yl)phenyl)oxazolidin-2-one, 1.574ml of formic acid, and 0.32ml of acetic anhydride. The reaction mixture was stirred for 3h at 0°C. The mixture was extracted with methylene chloride, water and 2N-ΗC1. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (40mg, 0.13mmol) in a yield of 41%.
[172]
[173] 1H NMR (DMSO-d6) δ 8.43 (IH, s), 8.15 (2H, dd), 7.76 (3H, m), 7.46 (IH, dd),
6.53 (IH, dd), 4.83 (IH, m), 4.17 (IH, t), 3.87 (IH, dd), 3.48 (2H, dd)
[174]
[175] <Example 3>
[176] N-((GS)-3-(3-fluoro-4-(lH -
1 ,2,4-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide (1-3) :
[177]
[178] To 2.1ml of CH 2 Cl 2 were added 52mg (0.19mmol) of (S
)-5-(aminomethyl)-3-(3-fluoro-4-( IH- 1 ,2,4-triazol- 1 -yl)phenyl)oxazolidin-2-one, 0.92ml of formic acid, and 0.19ml of acetic anhydride. The reaction mixture was stirred for 3h at 0°C. The mixture was extracted with methylene chloride, water and 2N-ΗC1. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (48.8mg, 0.16mmol) in a yield of 84%.
[179]
[180] 1H NMR (DMSO-dp δ 8.45 (IH, s) 8.40 (IH, s), 8.07 (IH, s), 7.52 (IH, dd),
6.50-6.55 (2H, m), 4.81 (IH, m), 4.15 (IH, t), 3.85 (IH, dd), 3.46 (2H, dd)
[181]
[182] < Example 4>
[183] N-(((S)-3-(3-fluoro-4-(2-cyaono-lH - pyrrol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide (1-5) :
[184]
[185] To 2.1ml of CH^ were added 52mg (0.19mmol) of 1-(4-((S
)-5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)-lH-pyrrole-2-carbonitrile, 0.95ml of formic acid, and 0.19ml of acetic anhydride. The reaction mixture was stirred for 3h at 0°C. The mixture was extracted with methylene chloride, water and 2N-ΗC1. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (48.3mg, 0.15mmol) in a yield of 76%.
[186]
[187] 1K NMR (DMSO-d6) δ 8.29 (IH, s), 7.73 (IH, dd), 7.47 (IH, dd), 7.28 (lH,dd),
6.99 (2H, dd), 6.37 (IH, dd), 4.86 (IH, m), 4.13 (IH, t), 3.88 (IH, dd), 3.69 (2H, dd)
[188]
[189] <Example 5>
[190] Benzyl-[2-fluoro-4-(5-fomylaminomethyl-2-oxo-oxazolidin-3-yl-phenyl]-carbamic acid benzylester:
[191]
[192] To 2.8ml of CH2Cl2 were added 120mg (0.252mmol) of benzyl 4-((S
)-5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenylbenzylcarbamate, 1.24ml of formic acid, and 0.25ml of acetic anhydride. The reaction mixture was stirred for 3h at 0°C. The mixture was extracted with methylene chloride, water and 2N-HC1. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (87mg, O.lδmmol) in a yield of 72%.
[193]
[194] 1K NMR (CDCl3) δ 8.41 (IH, s), 7.45-6.50 (13H, m), 5.34 (2H, s), 4.97 (2H, s),
4.85 (IH, m), 4.30 (IH, t), 3.89 (IH, dd), 3.70 (2H, dd)
[195]
[196] <Example 6>
[ 197] N-(((S)-3-(4-amino-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide:
[198]
[199] A solution of benzyl-
[2-fluoro-4-(5-fomylaminomethyl-2-oxo-oxazolidin-3-yl-phenyl]-carbamic acid benzylester (87mg, O.lδmmol) in ethanol (5.6ml) was added 37mg of 10% Pd/C catalyst. The mixture was placed on a Parr hydrogenator for 7.5h. There was then added an additional 3.7mg of 10% Pd/C catalyst and the reaction was allowed to continue. After an additional 15.5h the catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo to afford the title compound (38mg, 0.15mmol) in a yield of 83%.
[200]
[201] 1K NMR (CDCl3) δ 8.22 (IH, s), 7.73 (IH, dd), 7.15 (IH, dd), 6.98 (IH, dd), 5.09
(2H, bs), 4.82 (IH, m), 4.32 (IH, t), 3.80 (IH, dd), 3.61 (2H, dd)
[202]
[203] <£xample 7>
[204] N-{3-[3-fluoro-4-(3-formyl-pyrrole-l-yl)-phenyl] -
2-oxo-oxazoldin-5-ylmethyl } -formamide (1-6) :
[205]
[206] A solution of N-(((S
)-3-(4-amino-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide (230mg, 0.91mmol) and 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (182D, 1.29mmol) in acetic acid (6.4ml) was refluxed for 24h. The solution was cooled and the solvent removed under high vacuum, azeothroping the residue with toluene to remove the last traces of acetic acid. The residue was chromatographed (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (225mg, 0.68mmol) in a yield of 75%.
[207]
[208] 1K NMR (CDCl3) δ 9.85 (IH, s), 8.75 (IH, s), 7.71 (IH, dd), 7.27-7.66 (3H, m),
6.58-6.62 (2H, m), 4.91 (IH, m), 4.42 (IH, t), 3.90 (IH, dd), 3.60 (2H, dd)
[209]
[210] < Example 8>
[211] N-(3-{3-fluoro-4-[3-(hydroxyimino-methyl)-pyrrole-l-yl] - phenyl } -2-oxo-oxazoldin-5-ylmethyl } -formamide(I-7) : [212]
[213] N-{3-[3-fluoro-4-(3-formyl-pyrrole-l-yl)-phenyl] -
2-oxo-oxazoldin-5-ylmethyl}-formamide (225mg, 0.68mmol), hydroxylamine hydrochloride (32.3mg, 0.46mmol) and potassium carbonate (48.5mg, 0.36mmol) were stirred in methanol/dichloromethane (1:1) (1.6ml/1.6ml) for overnight. And then the resulting precipitate was collected, washed with water and dried under vacuum to yield 166mg, 0.48mmol (70%) of title compound.
[214]
[215] 1K NMR (DMSO-d6) δ 8.78 (IH, s), 7.71 (IH, dd), 7.21-7.46 (2H, m), 6.81 (IH,
S), 6.78-6.89 (2H, m), 4.83 (IH, m), 4.12 (IH, t), 3.89 (IH, dd), 3.71 (2H, dd)
[216]
[217] < Example 9>
[218] N-{3-[4-(3-cyano-pyrrole-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazoldin-5-ylmethyl } -formamide (1-8) :
[219]
[220] To a stirred solution of the N-(3-{ 3-fluoro-4-[3-(hydroxyimino-methyl)-pyrrole-l-yl
]-phenyl}-2-oxo-oxazoldin-5-ylmethyl}-formamide (166mg, 0.48mmol) and tri- ethylamine (13 ID, 0.94mmol) in dichloromethane (2ml), a solution of trichloroacetyl chloride (53.9D, 0.48mmol) in dichloromethane (2ml) is added dropwise at 0°C. The mixture is allowed to reach room temperature and is stirred for 24h. The mixture was diluted with dichloromethane and washed with water. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (dichloromethane/methanol = 9/1) to afford the title compound (91.3mg, 0.28mmol) in a yield of 58%.
[221]
[222] 1K NMR (DMSO-dJ δ 8.42 (IH, s), 8.08 (IH, s), 7.99 (IH, s), 7.67 (2H, m), 7.43
(IH, dd), 6.72 (IH, s), 4.83 (IH, m), 4.21 (IH, t), 3.78 (IH, dd), 3.49 (2H, dd) [223]
[224] <£xample 10>
[225] N-(((S)-3-(4-azido-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide:
[226]
[227] N-(((S)-3-(4-amino-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide
(243mg, 0.95mmol) was dissolved in concentrated hydrochloride 2.1ml and water 2.1ml and cooled to 0°C. Sodium nitrite (72mg, 1.04mmol) was added and the yellow solution was stirred at 0°C for 2h. A solution of sodium azide (123mg, 1.9mmol) and sodium acetate (1.56g, 19mmol) was added dropwise. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (magnesium sulfate). Removal of solvent gave product as a tan solid. This was crystallized from ethyl acetate/hexane to give 223mg, 0.80mmol in a yield of 84%.
[228]
[229] 1K NMR (CDCl3) δ 8.34 (IH, s), 7.75 (IH, dd), 7.54 (IH, dd), 7.30 (IH, dd), 4.88
(IH, m), 4.26 (IH, t), 4.12 (IH, dd), 3.78 (2H, dd)
[230]
[231] <Example ll>
[232] N-((GS)-3-(3-fluoro-4-(lH -
1 ,2,3-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide (1-4) :
[233]
[234] Vinylacetate 2.0ml and N -
(((S)-3-(4-azido-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide (223mg, 0.80mmol) were heated to 90°C for 48h, followed by cooling and concentration in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol = 4/4/1) to afford the title compound (212mg, 0.696mmol) in a yield of 87%.
[235]
[236] 1H NMR (CDCy δ 8.45 (IH, s) 8.15 (IH, s), 7.75 (IH, s), 7.49 (IH, dd), 7.26-7.34
(2H, m), 5.12 (IH, m), 4.12 (IH, t), 3.86 (IH, dd), 3.47 (2H, dd) [237]
[238] <£xample 12>
[239] N-(((S)-3-(4-(4-(diethoxymethyl)- IH -
1 ,2,3-triazol- 1 -yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide (1-13): [240]
[241] A solution of propiolaldehyde diethylacetal (206D, 1.42mmol) andV-(((S
)-3-(4-azido-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide (320mg, 1.15mmol) in beznene (1.85ml) were refluxed for 30h. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (183.3mg, 0.45mmol) in a yield of 63%.
[242]
[243] 1K NMR (DMSO-d6) δ 8.76 (IH, s), 7.78 (IH, s), 7.50 (IH, dd), 7.28 (IH, dd),
7.17 (IH, dd), 4.89 (IH, m), 4.11 (IH, t), 3.98 (4H, q), 3.82 (IH, dd), 3.45 (2H, dd), 1.24 (6H, t)
[244]
[245] <£xample 13>
[246] N-{3-[3-fluoro-4-(4-formyl-[l,2,3]triazol-l-yl)-phenyl] -
2-oxo-oxazolidin-5-yl-methyl)formamide (1-14):
[247]
[248] N-(((S)-3-(4-(4-(diethoxymethyl)- IH -
1 ,2,3-triazol- 1 -yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)formamide ( 105mg, 0.25mmol) was dissolved in chloroform 1.5ml and cooled to 0°C. 50% aqueous triflu- oroacetic acid (530D, 6.82mmol) was added and the solution was stirred at 0°C for 1.5h. The mixture was extracted with methylene chloride, water and aq.NaΗCO . Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel
column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (52mg, O.lόmmol) in a yield of 63%. [249] [250] 1K NMR (CDCl3) δ 9.05 (IH, s), 8.79 (IH, s), 7.67 (IH, s), 7.48 (IH, dd), 7.28
(IH, dd), 7.10 (IH, dd), 4.87 (IH, m), 4.12 (IH, t), 3.81 (IH, dd), 3.46 (2H, dd) [251]
[252] <Example 14>
[253] N-(3-{3-fluoro-4-[4-(hydroxyimino-methyl)-[l,2,3] triazol-
1 -yl)-phenyl } -2-oxo-oxazolidin-5-ylmethyl)-formamide (1-15): [254]
[255] N-{3-[3-fluoro-4-(4-formyl-[l,2,3]triazol-l-yl)-phenyl] -
2-oxo-oxazolidin-5-yl-methyl)formamide (52mg, O.lόmmol), hydroxylamine hydrochloride (16mg, 0.25mmol) and potassium carbonate (34mg, 0.25mmol) were stirred in methanol/dichloromethane (1:1) (2.15ml/2.15ml) for overnight. And then the resulting precipitate was collected, washed with water and dried under vacuum to yield 42mg, 0.12mmol (75%) of title compound.
[256]
[257] 1K NMR (DMSO-d6) δ 9.34 (IH, s), 8.88 (IH, s), 7.79 (IH, s), 7.75 (IH, dd), 7.51
(IH, dd), 7. 46 (IH, dd), 4.80 (IH, m), 4.34 (IH, t), 3.92 (IH, dd), 3.47 (2H, dd)
[258]
[259] <Example 15>
[260] N-{3-[4-(4-cyano-[l,2,3]triazol-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazolidin-5-ylmethyl)-formamide (1-16):
[261]
[262] To a solution of the N-(3-{3-fluoro-4-[4-(hydroxyimino-methyl)-[l,2,3] triazol- l-yl)-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-formamide (42mg, 0.12mmol) and tri- ethylamine (34D, 0.24mmol) in dichloromethane (ImI), a solution of trichloroacetyl chloride (14D, 0.13mmol) in dichloromethane (ImI) is added dropwise at 0°C. The
mixture is allowed to reach room temperature and is stirred for 24h. The mixture was diluted with dichloromethane and washed with water. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (18mg, 0.054mmol) in a yield of 45%.
[263]
[264] 1K NMR (DMSO-d6) δ 8.65 (IH, s), 7.69 (IH, s), 7.79 (IH, dd), 7.53-7.62 (2H, m),
4.86 (IH, m), 4.31 (IH, t), 3.93 (IH, dd), 3.41 (2H, dd)
[265]
[266] <£xample 16>
[267] l-[2-fluoro-4-(5-formylaminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-lH-pyrazole-
4-carboxylic acid ethylester (1-9):
[268]
[269] To 5.8ml of CH2Cl2 were added 200mg (0.53mol) of l-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-lH-pyrazole-4-carboxyl ic acid ethylester, 2.65ml of formic acid, and 0.53ml of acetic anhydride. The reaction mixture was stirred for 3h at 0°C. The mixture was extracted with methylene chloride, water and 2N-ΗC1. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate/ hexane/methanol = 4/4/1) to afford the title compound (125.6mg, 0.33mmol) in a yield of 63%.
[270]
[271] 1K NMR (CDCl3) δ 8.56 (IH, s), 8.40 (IH, s), 8.10 (IH, s), 7.59-7.81 (2H, m), 7.20
(IH, dd), 4.77 (IH, m), 4.34 (2H, q), 4.14 (IH, t), 3.91 (IH, dd), 3.40 (2H, dd), 1.37 (3H, t)
[272]
[273] <£xample 17>
[274] 1 - [2-fluoro-4-(5-formylaminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]- lH-pyrazole-
4-carboxylic acid (I- 10):
[275]
[276] l-[2-fluoro-4-(5-formylaminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-lH-pyrazole-
4-carboxylic acid ethylester (125.6mg, 0.33mmol) was placed in THF : H O (2.4ml/2.4ml) and cooled to 0°C. LiOH-H O (113mg, 2.8mmol) was added and the reaction was stirred at room temperature for 15h. The mixture was extracted with ethyl acetate, water and IN-HCl. And the water layer was controlled pH 2.5. And then the resulting precipitate was collected, washed with water and dried under vacuum to yield 91.9mg, 0.264mmol (80%) of title compound.
[277]
[278] 1K NMR (DMSO-d6) δ 10.56 (IH, bs), 8.71 (IH, s), 8.40 (IH, s), 8.12 (IH, s),
7.61-7.79 (2H, m), 7.17 (IH, dd), 4.76 (IH, m), 4.12 (IH, t), 3.86 (IH, dd), 3.39 (2H, dd),
[279]
[280] <£xample 18>
[281] N-{3-[4-(4-cyano-pyrazole-l-yl)-3-fluoro-pheynl] -
2-oxo-oxazolidin-5-ylmethyl } -formamide (I- 12) :
[282]
[283] A solution of l-[2-fluoro-4-(5-formylaminomethyl-2-oxo-oxazolidin-3-yl)-phenyl] - lH-pyrazole-4-carboxylic acid (91.9mg, 0.264mmol) and DMF 2D in benzene ImI at 0°C. And thionyl chloride (36D, 0.5mmol) was added dropwise. The solution was refluxed for 2.5h. The solution was cooled and the solvent removed under high vacuum, azeotroping the residue with toluene to remove. To a solution of this residue in 1,4-dioxane 10ml was added 28% ammonium solution. And then the resulting precipitate was collected, washed with water and dried under vacuum. A solution of this amide 45mg in DMF 20ml at 0°C. And oxayl chloride 2.3ml was added dropwise. The solution was stirred for Ih at 0°C. The mixture was added 250ml of 5N-NaOH dropwse. And then the resulting precipitate was collected, washed with water and dried under vacuum to yield 53mg, 0.153mmol (58%) of title compound.
[284]
[285] 1K NMR (DMSO-dJ δ 9.04 (IH, s), 8.38 (IH, s), 8.09 (IH, s), 7.74-7.83 (2H, m),
7.48 (IH, dd), 4.80 (IH, m), 4.18 (IH, t), 3.86 (IH, dd), 3.44 (2H, dd) [286]
[287] <£xample 19>
[288] N-((GS)-3-(3-fluoro-4-(lH - pyrrol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide hydrochloride: : [289] [290] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-1 (32mg,
O.lOmmol) in chloroform (ImI) and was concentrated in vacuo. This solid was removed by filtration and washed with ethyl acetate/hexane and dried under vacuum to yield 28mg (88%). [291]
[292] <£xample 20>
[293] N-(((S)-3-(3-fluoro-4-(lH - pyrazol-l-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide hydrochloride: [294] [295] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-2 (30mg,
O.lOmmol) in chloroform (ImI) and was concentrated in vacuo. This solid was removed by filtration and washed with ethyl acetate/hexane and dried under vacuum to yield 27.5mg (82%). [296]
[297] <£xample 21>
[298] N-(((S)-3-(3-fluoro-4-(lH -
1 ,2,4-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide hydrochloride: [299] [300] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-3 (32mg,
0.104mmol) in chloroform (ImI) and was concentrated in vacuo. This solid was removed by filtration and washed with ethyl acetate/hexane and dried under vacuum to yield 25.8mg (72%). [301]
[302] <£xample 22>
[303] N-(((S)-3-(3-fluoro-4-(lH -
1 ,2,3-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide hydrochloride: [304] [305] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-4 (45mg,
0.15mmol) in chloroform (ImI) and was concentrated in vacuo. This solid was removed by filtration and washed with ethyl acetate/hexane and dried under vacuum to yield 33.7mg (67%).
[306]
[307] <£xample 23>
[308] N-{3-[4-(3-cyano-pyrrole-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazoldin-5-ylmethyl } -formamide hydrochloride:
[309]
[310] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-8 (52mg,
O.lόmmol) in chloroform (ImI) and was concentrated in vacuo. This solid was removed by filtration and washed with ethyl acetate/hexane and dried under vacuum to yield 42.1mg (73%).
[311]
[312] < Example 24>
[313] N-{3-[4-(4-cyano-pyrazole-l-yl)-3-fluoro-pheynl] -
2-oxo-oxazolidin-5-ylmethyl} -formamide hydrochloride:
[314]
[315] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-12 (40mg,
0.12mmol) in chloroform (ImI) and was concentrated in vacuo. This solid was removed by filtration and washed with ethyl acetate/hexane and dried under vacuum to yield 30.2mg (68%).
[316]
[317] <Example 25>
[318] N-{3-[4-(4-cyano-[l,2,3]triazol-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazolidin-5-ylmethyl)-formamide hydrochloride:
[319]
[320] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-16 (47mg,
0.146mmol) in chloroform (ImI) and was concentrated in vacuo. This solid was removed by filtration and washed with ethyl acetate/hexane and dried under vacuum to yield 33.4mg (73%).
[321]
[322] <£xample 26>
[323] N-(((S)-3-(3-fluoro-4-(lH - pyrrol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide sulfuric acid
[324]
[325] Sulfuric acid (ImI) was added to a solution of 1-1 (30mg, 0.099mmol) in iso- propylalcohol (ImI) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 33mg (82%)
[326]
[327] <£xample 27>
[328] N-(((S)-3-(3-fluoro-4-(lH -
pyrazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide sulfuric acid
[329]
[330] Sulfuric acid (ImI) was added to a solution of 1-2 (32mg, 0.1 lmmol) in iso- propylalcohol (ImI) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 33mg (78%)
[331]
[332] <£xample 28>
[333] N-(((S)-3-(3-fluoro-4-(lH -
1 ,2,4-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide sulfuric acid
[334]
[335] Sulfuric acid (ImI) was added to a solution of 1-3 (31mg, O.lOmmol) in isopropylalcohol (ImI) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 29.9mg (73%)
[336]
[337] <£xample 29>
[338] N-(((S)-3-(3-fluoro-4-(lH -
1 ,2,3-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide sulfuric acid
[339]
[340] Sulfuric acid (ImI) was added to a solution of 1-4 (42mg, 0.14mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 36.7mg (65%)
[341]
[342] <£xample 30>
[343] N-{3-[4-(3-cyano-pyrrole-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazoldin-5-ylmethyl}-formamide sulfuric acid
[344]
[345] Sulfuric acid (ImI) was added to a solution of 1-8 (48mg, 0.15mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 38.6mg (62%)
[346]
[347] <£xample 31>
[348] N-{3-[4-(4-cyano-pyrazole-l-yl)-3-fluoro-pheynl] -
2-oxo-oxazolidin-5-ylmethyl}-formamide sulfuric acid
[349]
[350] Sulfuric acid (ImI) was added to a solution of 1-12 (40mg, 0.12mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afforded a solid which was recrystallized from boiling isopropylalcohol to afford title compound 34.8mg (67%)
[351]
[352] <Example 32>
[353] N-{3-[4-(4-cyano-[l,2,3]triazol-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazolidin-5-ylmethyl)-formamide sulfuric acid
[354]
[355] Sulfuric acid (ImI) was added to a solution of 1-16 (53mg, O.lόmmol) in iso- propylalcohol (ImI) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 56.3mg (82%)
[356]
[357] <Example 33>
[358] N-(((S)-3-(3-fluoro-4-(lH - pyrrol-l-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide citric acid
[359]
[360] Citric acid (leq) was added to a solution of 1-1 (42mg, 0.14mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 53.5mg (78%).
[361]
[362] <Example 34>
[363] N-(((S)-3-(3-fluoro-4-(lH - pyrazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide citric acid
[364]
[365] Citric acid (leq) was added to a solution of 1-2 (40mg, 0.13mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 41.1mg (63%).
[366]
[367] <£xample 35>
[368] N-(((S)-3-(3-fluoro-4-(lH -
1 ,2,4-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide citric acid
[369]
[370] Citric acid (leq) was added to a solution of 1-3 (41mg, 0.13mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 32.1mg (48%).
[371]
[372] <£xample 36>
[373] N-(((S)-3-(3-fluoro-4-(lH -
1 ,2,3-triazol- 1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)formamide citric acid
[374]
[375] Citric acid (leq) was added to a solution of 1-4 (35mg, 0.1 lmmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re-
crystallized from boiling isopropylalcohol to afford title compound 34.8mg (61%).
[376]
[377] <£xample 37>
[378] N-{3-[4-(3-cyano-pyrrole-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazoldin-5-ylmethyl}-formamide citric acid
[379]
[380] Citric acid (leq) was added to a solution of 1-8 (32mg, 0.14mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 41.3mg (58%).
[381]
[382] <£xample 38>
[383] N-{3-[4-(4-cyano-pyrazole-l-yl)-3-fluoro-pheynl] -
2-oxo-oxazolidin-5-ylmethyl}-formamide citric acid
[384]
[385] Citric acid (leq) was added to a solution of 1-12 (41mg, 0.12mmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 37.6mg (58%).
[386]
[387] <£xample 39>
[388] N-{3-[4-(4-cyano-[l,2,3]triazol-l-yl)-3-fluoro-phenyl] -
2-oxo-oxazolidin-5-ylmethyl)-formamide citric acid
[389]
[390] Citric acid (leq) was added to a solution of 1-16 (36mg, 0.1 lmmol) in isopropylalcohol (ImI) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 35.8mg (63%).
[391]
Industrial Applicability
[392] As described hereinbefore, the oxazolidinonoe compounds of formula I have potent antibacterial activity against a broad spectrum of bacteria and their antibacterial activity is maintained high in vivo. Exerting potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci andgram-negative bacteria, such as Escherichia coli and Klebsiella oxytoca., the compounds of the present invention are therefore useful as antibiotics
[393]
[394] According to the present invention an oxazoldinone compound or a salt thereof, and a preparation method thereof was provided as described above. As shown in tables 1, it was discovered in vitro experiments that the compound of the present invention shows
superior biological activities against the strains exhibiting resistance to the conventional antibiotics. Therefore, the compound according to the present invention is expected to be used to treat infectious diseases caused by viruses exhibiting resistance to the conventional antibiotics.
Claims
[1] Derivatives of oxazolidinone of formula I, and pharmaceutically acceptable salt thereof: Formula I
Formula I wherein,
X is each and independently
(a) carbon or
(b) nitrogen atom
Y is each and independently
(a) carbon or
(b) nitrogen atom
Z is each and independently
(a) CRl or
(b) nitrogen atom Rl is
(a) hydrogen atom
(b) hydroxymethyl
(c) ethylcarboxylate
(d) carboxylic acid
(e) carbamide
(f) diethoxymethyl
(g) aldehyde
(h) hydroxyoxime or
(i) nitrile
R2 is
(a) hydrogen atom or
(b) nitrile
[2] A method for preparing a compound of formula I which comprises reducing azide compounds of formula 1-4, 2-8, 3-15 with triphenylphosphine, Pd/C or Pt/ C and formylating with acetic anhydride and formic acid. Formula 1-4, Formula 2-8, Formula 3-15
Formula 1-4 Formula 2-8 formula 3- 15 wherein,
X is each and independently
(a) carbon or
(b) nitrogen atom
Z is each and independently
(a) CRl or
(b) nitrogen atom Rl is
(a) hydrogen atom
(b) hydroxymethyl
(c) ethylcarboxylate
(d) carboxylic acid
(e) carbamide
(f) diethoxymethyl
(g) aldehyde
(h) hydroxyoxime or
(i) nitrile
R2 is
(a) hydrogen atom or
(b) nitrile Formula I
X is each and independently
(a) carbon or
(b) nitrogen atom
Y is each and independently
(a) carbon or
(b) nitrogen atom
Z is each and independently
(a) CRl or
(b) nitrogen atom Rl is
(a) hydrogen atom
(b) hydroxymethyl
(c) ethylcarboxylate
(d) carboxylic acid
(e) carbamide
(f) diethoxymethyl
(g) aldehyde
(h) hydroxyoxime or
(i) nitrile
R2 is
(a) hydrogen atom or
(b) nitrile
[3] A method for preparing a compound of formula I which comprises reacting a compound of formula 2-10 with
2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde, and hydroxylamine hydrochloride and trichloroacetyl chloride by turns. Formula 2-10
Formula 2-10
Formula I
Formula wherein,
X is each and independently
(a) carbon or
(b) nitrogen atom
Y is each and independently
(a) carbon or
(b) nitrogen atom
Z is each and independently
(a) CRl or
(b) nitrogen atom Rl is
(a) hydrogen atom
(b) hydroxymethyl
(c) ethylcarboxylate
(d) carboxylic acid
(e) carbamide
(f) diethoxymethyl
(g) aldehyde
(h) hydroxyoxime or
(i) nitrile
R2 is
(a) hydrogen atom or
(b) nitrile
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020050093322A KR20070038236A (en) | 2005-10-05 | 2005-10-05 | A novel oxazolidinone formamide derivative and manufacturing process thereof |
| KR10-2005-0093322 | 2005-10-05 |
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| Publication Number | Publication Date |
|---|---|
| WO2007040326A1 true WO2007040326A1 (en) | 2007-04-12 |
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ID=37906357
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| KR (1) | KR20070038236A (en) |
| WO (1) | WO2007040326A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8841306B2 (en) | 2008-11-20 | 2014-09-23 | Panacea Biotec Ltd. | Antimicrobials |
| US8906913B2 (en) | 2009-06-26 | 2014-12-09 | Panacea Biotec Limited | Azabicyclohexanes |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100848232B1 (en) * | 2007-04-12 | 2008-07-24 | 일동제약주식회사 | A novel heterocycle or alkoxyaminomethyl oxazolidinone derivative and manufacturing process thereof |
| CN113754646B (en) * | 2021-07-19 | 2023-07-25 | 安徽医科大学 | (4- (1, 2, 4-oxadiazol-5-yl) phenyl) carboxamide derivatives and application thereof in anti-arthritis drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999010343A1 (en) * | 1997-08-22 | 1999-03-04 | Zeneca Limited | Oxazolidinone derivatives and their use as antibacterial agents |
| WO2000032599A1 (en) * | 1998-11-27 | 2000-06-08 | Pharmacia & Upjohn Company | Oxazolidinone antibacterial agents having a thiocarbonyl functionality |
| WO2004026848A1 (en) * | 2002-09-20 | 2004-04-01 | Lupin Limited | Oxazolidinone derivatives, process for their preperation and their use as antimycobacterial agents |
-
2005
- 2005-10-05 KR KR1020050093322A patent/KR20070038236A/en not_active Application Discontinuation
-
2006
- 2006-10-02 WO PCT/KR2006/003960 patent/WO2007040326A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999010343A1 (en) * | 1997-08-22 | 1999-03-04 | Zeneca Limited | Oxazolidinone derivatives and their use as antibacterial agents |
| WO2000032599A1 (en) * | 1998-11-27 | 2000-06-08 | Pharmacia & Upjohn Company | Oxazolidinone antibacterial agents having a thiocarbonyl functionality |
| WO2004026848A1 (en) * | 2002-09-20 | 2004-04-01 | Lupin Limited | Oxazolidinone derivatives, process for their preperation and their use as antimycobacterial agents |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8841306B2 (en) | 2008-11-20 | 2014-09-23 | Panacea Biotec Ltd. | Antimicrobials |
| US8906913B2 (en) | 2009-06-26 | 2014-12-09 | Panacea Biotec Limited | Azabicyclohexanes |
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| KR20070038236A (en) | 2007-04-10 |
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