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 PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl group
- hydrogen
- methyl
- fluorophenyl
- oxooxazolidin
- Prior art date
Links
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 13
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 229940002612 prodrug Drugs 0.000 claims abstract description 6
- 239000000651 prodrug Substances 0.000 claims abstract description 6
- 239000012453 solvate Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 239000001257 hydrogen Substances 0.000 claims description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 150000001875 compounds Chemical class 0.000 claims description 54
- 150000002431 hydrogen Chemical class 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- -1 hydrate Substances 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 51
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 19
- 244000000059 gram-positive pathogen Species 0.000 abstract description 9
- 244000000058 gram-negative pathogen Species 0.000 abstract description 7
- 238000001228 spectrum Methods 0.000 abstract description 7
- 241000894006 Bacteria Species 0.000 abstract description 6
- 150000004677 hydrates Chemical class 0.000 abstract description 5
- 230000000845 anti-microbial effect Effects 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 238000000034 method Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 0 CC(NC=C(CN1c2ccc(-c3ccc(*)cc3)c(F)c2)OC1=O)=O Chemical compound CC(NC=C(CN1c2ccc(-c3ccc(*)cc3)c(F)c2)OC1=O)=O 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 241000194032 Enterococcus faecalis Species 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 229940032049 enterococcus faecalis Drugs 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000003115 biocidal effect Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 8
- 229960003907 linezolid Drugs 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 241000191967 Staphylococcus aureus Species 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000606768 Haemophilus influenzae Species 0.000 description 6
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 6
- 108010059993 Vancomycin Proteins 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229960003085 meticillin Drugs 0.000 description 6
- SYSAYGFWQXJHBE-VIFPVBQESA-N n-[[(5s)-3-(4-bromo-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(Br)C(F)=C1 SYSAYGFWQXJHBE-VIFPVBQESA-N 0.000 description 6
- UAIPMAZMWKHUQZ-HNNXBMFYSA-N n-[[(5s)-3-[3-fluoro-4-[4-(n'-hydroxycarbamimidoyl)phenyl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(\N)=N\O)C(F)=C1 UAIPMAZMWKHUQZ-HNNXBMFYSA-N 0.000 description 6
- ZLAUYJFLLPXEKV-INIZCTEOSA-N n-[[(5s)-3-[4-(4-cyanophenyl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C#N)C(F)=C1 ZLAUYJFLLPXEKV-INIZCTEOSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 6
- 229960003165 vancomycin Drugs 0.000 description 6
- 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 description 6
- AFLKSCUXTJDCNS-ZETCQYMHSA-N (5s)-5-(aminomethyl)-3-(4-bromo-3-fluorophenyl)-1,3-oxazolidin-2-one Chemical compound O=C1O[C@@H](CN)CN1C1=CC=C(Br)C(F)=C1 AFLKSCUXTJDCNS-ZETCQYMHSA-N 0.000 description 5
- WMMGIYRILUMQAS-LLVKDONJSA-N 2-[(2r)-3-(4-bromo-3-fluoroanilino)-2-hydroxypropyl]isoindole-1,3-dione Chemical compound C([C@@H](O)CN1C(C2=CC=CC=C2C1=O)=O)NC1=CC=C(Br)C(F)=C1 WMMGIYRILUMQAS-LLVKDONJSA-N 0.000 description 5
- 241000588655 Moraxella catarrhalis Species 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940047650 haemophilus influenzae Drugs 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- NCTCGHLIHJJIBK-UHFFFAOYSA-N 3-phenyl-1,3-oxazolidin-2-one Chemical class O=C1OCCN1C1=CC=CC=C1 NCTCGHLIHJJIBK-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- ZXGXWNJMLQAXRY-INIZCTEOSA-N n-[[(5s)-3-[3-fluoro-4-(4-formylphenyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(C=O)=CC=2)C(F)=C1 ZXGXWNJMLQAXRY-INIZCTEOSA-N 0.000 description 4
- DXKIOWFNCRZIBL-HNNXBMFYSA-N n-[[(5s)-3-[3-fluoro-4-[4-(hydrazinecarbonyl)phenyl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(=O)NN)C(F)=C1 DXKIOWFNCRZIBL-HNNXBMFYSA-N 0.000 description 4
- BJDMCCATRJGDFS-INIZCTEOSA-N n-[[(5s)-3-[3-fluoro-4-[4-(n-hydroxy-n-methylcarbamimidoyl)phenyl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1=CC(C(=N)N(O)C)=CC=C1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F BJDMCCATRJGDFS-INIZCTEOSA-N 0.000 description 4
- BHVTZIWKPAXOSB-HNNXBMFYSA-N n-[[(5s)-3-[4-[4-[(z)-c-aminocarbonohydrazonoyl]phenyl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(\N)=N\N)C(F)=C1 BHVTZIWKPAXOSB-HNNXBMFYSA-N 0.000 description 4
- 229940126701 oral medication Drugs 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- AISAWPUTZLBPJA-LLVKDONJSA-N 2-[[(5s)-3-(4-bromo-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]isoindole-1,3-dione Chemical compound C1=C(Br)C(F)=CC(N2C(O[C@@H](CN3C(C4=CC=CC=C4C3=O)=O)C2)=O)=C1 AISAWPUTZLBPJA-LLVKDONJSA-N 0.000 description 3
- KKUOCHZLXDIWBM-HNNXBMFYSA-N 4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-n-(diaminomethylidene)benzamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(=O)N=C(N)N)C(F)=C1 KKUOCHZLXDIWBM-HNNXBMFYSA-N 0.000 description 3
- OPSUDVOFHFVRHQ-HNNXBMFYSA-N 4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-n-hydroxybenzamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(=O)NO)C(F)=C1 OPSUDVOFHFVRHQ-HNNXBMFYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 3
- 108010015899 Glycopeptides Proteins 0.000 description 3
- 102000002068 Glycopeptides Human genes 0.000 description 3
- 241000191940 Staphylococcus Species 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- FHDWQORTNAJTGR-INIZCTEOSA-N [[[4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]phenyl]-aminomethylidene]amino] 2-aminoacetate Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(N)=NOC(=O)CN)C(F)=C1 FHDWQORTNAJTGR-INIZCTEOSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- NVAGCCUDHCAOCD-KRWDZBQOSA-N ethyl 4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F NVAGCCUDHCAOCD-KRWDZBQOSA-N 0.000 description 3
- 150000002429 hydrazines Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- PMBUTYZPLSRVBO-INIZCTEOSA-N n-[[(5s)-3-[3-fluoro-4-[4-[(e)-n'-methoxycarbamimidoyl]phenyl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1=CC(C(\N)=N/OC)=CC=C1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F PMBUTYZPLSRVBO-INIZCTEOSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 239000012925 reference material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940061740 zyvox Drugs 0.000 description 3
- LJCWRJYVPJJTMB-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate Chemical compound CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O LJCWRJYVPJJTMB-UHFFFAOYSA-N 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 2
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 2
- VXWBQOJISHAKKM-UHFFFAOYSA-N (4-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=O)C=C1 VXWBQOJISHAKKM-UHFFFAOYSA-N 0.000 description 2
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 2
- DUILGEYLVHGSEE-ZETCQYMHSA-N 2-[[(2s)-oxiran-2-yl]methyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C[C@H]1CO1 DUILGEYLVHGSEE-ZETCQYMHSA-N 0.000 description 2
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- TZVXQPMDOHOXIP-INIZCTEOSA-N 4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-n-cyanobenzamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(=O)NC#N)C(F)=C1 TZVXQPMDOHOXIP-INIZCTEOSA-N 0.000 description 2
- GACVIELECXZZEV-INIZCTEOSA-N 4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-n-hydroxy-n-methylbenzamide Chemical compound C1=CC(C(=O)N(O)C)=CC=C1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F GACVIELECXZZEV-INIZCTEOSA-N 0.000 description 2
- YTMVYYAKOPIJCZ-UHFFFAOYSA-N 4-bromo-3-fluoroaniline Chemical compound NC1=CC=C(Br)C(F)=C1 YTMVYYAKOPIJCZ-UHFFFAOYSA-N 0.000 description 2
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 2
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- 241000194031 Enterococcus faecium Species 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- KYHXQMYWJMOIKC-SFHVURJKSA-N [[[4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]phenyl]-aminomethylidene]amino] 4-aminobutanoate Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(N)=NOC(=O)CCCN)C(F)=C1 KYHXQMYWJMOIKC-SFHVURJKSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229950006191 gluconic acid Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- GMEQFQZXWSOUDU-IJDCCNJMSA-N n-[[(5s)-3-[3-fluoro-4-[4-[(e)-2-nitroethenyl]phenyl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(\C=C\[N+]([O-])=O)=CC=2)C(F)=C1 GMEQFQZXWSOUDU-IJDCCNJMSA-N 0.000 description 2
- FPAFSSKRFFRDRW-HNNXBMFYSA-N n-[[(5s)-3-[4-(4-carbamimidoylphenyl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(N)=N)C(F)=C1 FPAFSSKRFFRDRW-HNNXBMFYSA-N 0.000 description 2
- KGLFSLRPNJKYFI-KRWDZBQOSA-N n-[[(5s)-3-[4-[4-(5,5-dimethyl-2h-1,2,4-oxadiazol-3-yl)phenyl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C=2NOC(C)(C)N=2)C(F)=C1 KGLFSLRPNJKYFI-KRWDZBQOSA-N 0.000 description 2
- GMWPHBWFTRWZRK-KRWDZBQOSA-N n-[[(5s)-3-[4-[4-(dimethylaminocarbamoyl)phenyl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1=CC(C(=O)NN(C)C)=CC=C1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F GMWPHBWFTRWZRK-KRWDZBQOSA-N 0.000 description 2
- CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical compound CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- ZLNFACCFYUFTLD-UHFFFAOYSA-N (4-ethoxycarbonylphenyl)boronic acid Chemical compound CCOC(=O)C1=CC=C(B(O)O)C=C1 ZLNFACCFYUFTLD-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 108010065152 Coagulase Proteins 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- FDBACDICLRQCHX-LLVKDONJSA-N O[C@@H](CN1C(=O)c2ccccc2C1=O)Cc1ccc(Br)c(F)c1 Chemical compound O[C@@H](CN1C(=O)c2ccccc2C1=O)Cc1ccc(Br)c(F)c1 FDBACDICLRQCHX-LLVKDONJSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- LUFJLIDJYJCTPW-KRWDZBQOSA-N [(z)-[[4-[4-[(5s)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]phenyl]-aminomethylidene]amino] acetate Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(=CC=2)C(\N)=N\OC(C)=O)C(F)=C1 LUFJLIDJYJCTPW-KRWDZBQOSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000001260 acyclic compounds Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000002576 ketones Chemical class 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
- 239000006210 lotion Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- UMOZLQVSOVNSCA-UHFFFAOYSA-N tert-butyl n-(diaminomethylidene)carbamate Chemical compound CC(C)(C)OC(=O)NC(N)=N UMOZLQVSOVNSCA-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940126702 topical medication Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- 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]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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]
[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]
[Formula C]
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]
[Formula F]
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]
[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:
[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]
[Formula 3]
'Formula 4
[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:
[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:
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.
The oxazolidinone derivatives of Formula 1 according to the present invention can exist as a tautomer as below.
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]
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.
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
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)
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)
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)
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)
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)
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)
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)
(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)
(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)
(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)
(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)
(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)
(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)
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)
(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)
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)
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)
(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)
(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)
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)
(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)
(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)
(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)
( 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]
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]
[wherein, R1 is an acyclic substituent or hetero cyclic substituent of the structure below:
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:
[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]
[Formula 4]
[Formula 5]
[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]
a hetero cyclic substituent of the structure selected from the group of:
[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
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:
[Claim 7 ]
Pharmaceutical compositions for antibiotics containing the oxazolidinone derivative of any one of claims 1 to 6 as an effective component.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2006-0124412 | 2006-12-08 | ||
KR20060124412 | 2006-12-08 | ||
KR1020070126433A KR100948345B1 (en) | 2006-12-08 | 2007-12-06 | Novel Oxazolidinone derivatives, Process For Preparing Thereof and Pharmaceutical Composition Containing the same |
KR10-2007-0126433 | 2007-12-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008069619A1 true WO2008069619A1 (en) | 2008-06-12 |
Family
ID=39492412
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2007/006364 WO2008069619A1 (en) | 2006-12-08 | 2007-12-07 | Novel oxazolidinone derivatives, process for preparing thereof and pharmaceutical composition containing the same |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2008069619A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105348212A (en) * | 2015-03-31 | 2016-02-24 | 安徽悦康凯悦制药有限公司 | Preparation method for Linezolid |
US9944654B2 (en) | 2014-10-22 | 2018-04-17 | Merck Sharp & Dohme Corp. | Nargenicin compounds and uses thereof as antibacterial agents |
CN108135887A (en) * | 2015-10-22 | 2018-06-08 | 默沙东公司 | Oxazolidinone compounds and its application method as antiseptic |
CN111566086A (en) * | 2018-01-04 | 2020-08-21 | 北京大学深圳研究生院 | Compound for simultaneously inhibiting LSD1 and HDAC target and application thereof |
US10807944B2 (en) * | 2014-04-04 | 2020-10-20 | University Of Florida Research Foundation, Inc. | HDAC inhibitor compounds and methods of treatment |
RU2794494C2 (en) * | 2016-10-17 | 2023-04-19 | МЕРК ШАРП И ДОУМ ЭлЭлСи | Oxazolidinone compounds and methods of their application as antibacterial agents |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003063862A1 (en) * | 2002-01-25 | 2003-08-07 | Pharmacia & Upjohn Company | Cotherapy with an oxazolidinone and a vitamin b |
WO2004048350A2 (en) * | 2002-11-28 | 2004-06-10 | Astrazeneca Ab | Oxazolidinones as antibacterial agents |
WO2005005420A1 (en) * | 2003-07-02 | 2005-01-20 | Merck & Co., Inc. | Cyclopropyl group substituted oyazolidinone antibiotics and derivatives thereof |
US6927229B2 (en) * | 2002-06-28 | 2005-08-09 | Pharmacia & Upjohn Company | Difluorothioacetamides of oxazolidinones as antibacterial agents |
-
2007
- 2007-12-07 WO PCT/KR2007/006364 patent/WO2008069619A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003063862A1 (en) * | 2002-01-25 | 2003-08-07 | Pharmacia & Upjohn Company | Cotherapy with an oxazolidinone and a vitamin b |
US6927229B2 (en) * | 2002-06-28 | 2005-08-09 | Pharmacia & Upjohn Company | Difluorothioacetamides of oxazolidinones as antibacterial agents |
WO2004048350A2 (en) * | 2002-11-28 | 2004-06-10 | Astrazeneca Ab | Oxazolidinones as antibacterial agents |
WO2005005420A1 (en) * | 2003-07-02 | 2005-01-20 | Merck & Co., Inc. | Cyclopropyl group substituted oyazolidinone antibiotics and derivatives thereof |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10807944B2 (en) * | 2014-04-04 | 2020-10-20 | University Of Florida Research Foundation, Inc. | HDAC inhibitor compounds and methods of treatment |
US11731934B2 (en) * | 2014-04-04 | 2023-08-22 | University Of Florida Research Foundation, Inc. | HDAC inhibitor compounds and methods of treatment |
US20210009509A1 (en) * | 2014-04-04 | 2021-01-14 | University Of Florida Research Foundation, Inc. | Hdac inhibitor compounds and methods of treatment |
US9944654B2 (en) | 2014-10-22 | 2018-04-17 | Merck Sharp & Dohme Corp. | Nargenicin compounds and uses thereof as antibacterial agents |
US10144741B2 (en) | 2014-10-22 | 2018-12-04 | Merck Sharp & Dohme Corp. | Nargenicin compounds and uses thereof as antibacterial agents |
CN105348212B (en) * | 2015-03-31 | 2019-01-15 | 安徽悦康凯悦制药有限公司 | The preparation method of Linezolid |
CN105348212A (en) * | 2015-03-31 | 2016-02-24 | 安徽悦康凯悦制药有限公司 | Preparation method for Linezolid |
US10947205B2 (en) | 2015-10-22 | 2021-03-16 | Merck Sharp & Dohme Corp. | Oxazolidinone compounds and methods of use thereof as antibacterial agents |
EP3364968A4 (en) * | 2015-10-22 | 2019-05-01 | Merck Sharp & Dohme Corp. | Oxazolidinone compounds and methods of use thereof as antibacterial agents |
CN108135887B (en) * | 2015-10-22 | 2021-07-30 | 默沙东公司 | Oxazolidinone compounds and methods of use as antibacterial agents |
CN108135887A (en) * | 2015-10-22 | 2018-06-08 | 默沙东公司 | Oxazolidinone compounds and its application method as antiseptic |
RU2794494C2 (en) * | 2016-10-17 | 2023-04-19 | МЕРК ШАРП И ДОУМ ЭлЭлСи | Oxazolidinone compounds and methods of their application as antibacterial agents |
CN111566086A (en) * | 2018-01-04 | 2020-08-21 | 北京大学深圳研究生院 | Compound for simultaneously inhibiting LSD1 and HDAC target and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2414469C2 (en) | Novel oxazolidinone derivatives | |
US6689779B2 (en) | Oxazolidinone derivatives and a process for the preparation thereof | |
JP2004504321A (en) | Oxazolidinone derivatives as antimicrobial agents | |
JP2005502634A (en) | Substituted isoxazoles and their use as antibiotics | |
WO2008069619A1 (en) | Novel oxazolidinone derivatives, process for preparing thereof and pharmaceutical composition containing the same | |
RU2522582C2 (en) | New antimicrobial agents | |
KR100872059B1 (en) | Novel Oxazolidinones with amidoxime or hydroxamide and Pharmaceutical Compositions and derivatives thereof | |
JP2012503599A (en) | Novel oxazolidinone derivative having cyclic amidoxime or cyclic amidrazon group and pharmaceutical composition containing the same | |
KR100948345B1 (en) | Novel Oxazolidinone derivatives, Process For Preparing Thereof and Pharmaceutical Composition Containing the same | |
KR101169359B1 (en) | Novel Oxazolidinone derivatives with cyclic amidrazone and Pharmaceutical Compositions thereof | |
KR100731469B1 (en) | Oxazolidinone derivatives containing pyridine moiety and process for the preparation thereof | |
KR100713170B1 (en) | Oxazolidinone derivatives containing pyridine substituted with heterocycle or heteroaromatic cycle and process for the preparation thereof | |
KR100674096B1 (en) | Novel oxazolidinone derivatives containing pyrimidine moiety and method for preparation thereof | |
KR100856745B1 (en) | Oxazolidinone derivatives containing pyridine substituted with or fused with heterocycle or heteroaromatic cycle and process for the preparation thereof | |
KR100629327B1 (en) | Novel Triazolylmethyloxazolidinone Derivatives | |
KR20120081579A (en) | Novel oxazolidinone derivatives with cyclic amidrazone and pharmaceutical compositions thereof | |
AU2001258897A2 (en) | Novel oxazolidinone derivatives and a process for the preparation thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07851335 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 07851335 Country of ref document: EP Kind code of ref document: A1 |