JP2006515012A - 抗バクテリア・インドロン・オキサゾリジノン、その製造用中間体、及びそれを含有する医薬組成物 - Google Patents
抗バクテリア・インドロン・オキサゾリジノン、その製造用中間体、及びそれを含有する医薬組成物 Download PDFInfo
- Publication number
- JP2006515012A JP2006515012A JP2005518544A JP2005518544A JP2006515012A JP 2006515012 A JP2006515012 A JP 2006515012A JP 2005518544 A JP2005518544 A JP 2005518544A JP 2005518544 A JP2005518544 A JP 2005518544A JP 2006515012 A JP2006515012 A JP 2006515012A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- oxo
- difluoro
- dihydro
- indol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title description 10
- 230000000844 anti-bacterial effect Effects 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- -1 C (= O) N (H) OH Proteins 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- NZKREZAIZZAEIG-UHFFFAOYSA-N 5-amino-3,3-difluoro-1-methylindol-2-one Chemical compound NC1=CC=C2N(C)C(=O)C(F)(F)C2=C1 NZKREZAIZZAEIG-UHFFFAOYSA-N 0.000 claims description 8
- ZFGNSEPCIYIKCL-CYBMUJFWSA-N butyl (5r)-3-(3,3-difluoro-1-methyl-2-oxoindol-5-yl)-2-oxo-1,3-oxazolidine-5-carboxylate Chemical compound O=C1O[C@@H](C(=O)OCCCC)CN1C1=CC=C(N(C)C(=O)C2(F)F)C2=C1 ZFGNSEPCIYIKCL-CYBMUJFWSA-N 0.000 claims description 8
- AROWSJMUCOGVDJ-UHFFFAOYSA-N 3,3-difluoro-1-methyl-5-nitroindol-2-one Chemical compound [O-][N+](=O)C1=CC=C2N(C)C(=O)C(F)(F)C2=C1 AROWSJMUCOGVDJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- UAQSLJSHPUOVTP-UHFFFAOYSA-N benzyl n-(3,3-difluoro-1-methyl-2-oxoindol-5-yl)carbamate Chemical compound C=1C=C2N(C)C(=O)C(F)(F)C2=CC=1NC(=O)OCC1=CC=CC=C1 UAQSLJSHPUOVTP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- IBPFGRAVEHEICP-SNVBAGLBSA-N (5r)-3-(1-ethyl-3,3-difluoro-2-oxoindol-5-yl)-2-oxo-1,3-oxazolidine-5-carboxamide Chemical compound C=1C=C2N(CC)C(=O)C(F)(F)C2=CC=1N1C[C@H](C(N)=O)OC1=O IBPFGRAVEHEICP-SNVBAGLBSA-N 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- GUSGRNCCRWWBFS-UHFFFAOYSA-N 5-amino-1-ethyl-3,3-difluoroindol-2-one Chemical compound NC1=CC=C2N(CC)C(=O)C(F)(F)C2=C1 GUSGRNCCRWWBFS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- XTEAGIYUAUQYSW-LLVKDONJSA-N (5r)-3-(1-ethyl-3,3-difluoro-2-oxoindol-5-yl)-n-methyl-2-oxo-1,3-oxazolidine-5-carboxamide Chemical compound C=1C=C2N(CC)C(=O)C(F)(F)C2=CC=1N1C[C@H](C(=O)NC)OC1=O XTEAGIYUAUQYSW-LLVKDONJSA-N 0.000 claims description 3
- JXEUPGNOPULURR-SECBINFHSA-N (5r)-3-(3,3-difluoro-1-methyl-2-oxoindol-5-yl)-2-oxo-1,3-oxazolidine-5-carboxamide Chemical compound C=1C=C2N(C)C(=O)C(F)(F)C2=CC=1N1C[C@H](C(N)=O)OC1=O JXEUPGNOPULURR-SECBINFHSA-N 0.000 claims description 3
- JLVDPBJXTAQMQJ-SNVBAGLBSA-N (5r)-3-(3,3-difluoro-1-methyl-2-oxoindol-5-yl)-n-methyl-2-oxo-1,3-oxazolidine-5-carboxamide Chemical compound O=C1O[C@@H](C(=O)NC)CN1C1=CC=C(N(C)C(=O)C2(F)F)C2=C1 JLVDPBJXTAQMQJ-SNVBAGLBSA-N 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000000813 microbial effect Effects 0.000 claims description 3
- ALQAPOXOTXAZHC-NSHDSACASA-N n-[[(5s)-3-(1-ethyl-3,3-difluoro-2-oxoindol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C=1C=C2N(CC)C(=O)C(F)(F)C2=CC=1N1C[C@H](CNC(C)=O)OC1=O ALQAPOXOTXAZHC-NSHDSACASA-N 0.000 claims description 3
- AYBWRAOVCPMJDG-JTQLQIEISA-N n-[[(5s)-3-(3,3-difluoro-1-methyl-2-oxoindol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C=1C=C2N(C)C(=O)C(F)(F)C2=CC=1N1C[C@H](CNC(C)=O)OC1=O AYBWRAOVCPMJDG-JTQLQIEISA-N 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- ARRNIHYZUQTUGN-UHFFFAOYSA-N 1-ethyl-3,3-difluoro-5-nitroindol-2-one Chemical compound [O-][N+](=O)C1=CC=C2N(CC)C(=O)C(F)(F)C2=C1 ARRNIHYZUQTUGN-UHFFFAOYSA-N 0.000 claims description 2
- NTSDOTAMHHORSQ-UHFFFAOYSA-N benzyl n-(1-ethyl-3,3-difluoro-2-oxoindol-5-yl)carbamate Chemical compound C=1C=C2N(CC)C(=O)C(F)(F)C2=CC=1NC(=O)OCC1=CC=CC=C1 NTSDOTAMHHORSQ-UHFFFAOYSA-N 0.000 claims description 2
- HNFIOOHFXPNAQX-CQSZACIVSA-N butyl (5r)-3-(1-ethyl-3,3-difluoro-2-oxoindol-5-yl)-2-oxo-1,3-oxazolidine-5-carboxylate Chemical compound O=C1O[C@@H](C(=O)OCCCC)CN1C1=CC=C(N(CC)C(=O)C2(F)F)C2=C1 HNFIOOHFXPNAQX-CQSZACIVSA-N 0.000 claims description 2
- 101150009274 nhr-1 gene Proteins 0.000 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 abstract description 4
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 125000000392 cycloalkenyl group Chemical group 0.000 description 24
- 238000000034 method Methods 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 125000001424 substituent group Chemical group 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 15
- 125000004093 cyano group Chemical group *C#N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Chemical class 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 0 CC1(C)c2c(*)c(N)c(*)c(C3CC3)c2N(*)C1=* Chemical compound CC1(C)c2c(*)c(N)c(*)c(C3CC3)c2N(*)C1=* 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- MHNAXLAGKSOPBH-UHFFFAOYSA-N 1-amino-3h-indol-2-one Chemical compound C1=CC=C2N(N)C(=O)CC2=C1 MHNAXLAGKSOPBH-UHFFFAOYSA-N 0.000 description 3
- ITQZGBLSWNNLFL-UHFFFAOYSA-N 2-oxo-1,3-oxazolidine-5-carboxylic acid Chemical compound OC(=O)C1CNC(=O)O1 ITQZGBLSWNNLFL-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 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
- 238000007796 conventional method Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- MCVFFRWZNYZUIJ-UHFFFAOYSA-M lithium;trifluoromethanesulfonate Chemical compound [Li+].[O-]S(=O)(=O)C(F)(F)F MCVFFRWZNYZUIJ-UHFFFAOYSA-M 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 238000011176 pooling Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CUYUBEFFEABTMX-UHFFFAOYSA-N (1-ethyl-3,3-difluoro-2-oxoindol-5-yl)carbamic acid Chemical compound OC(=O)NC1=CC=C2N(CC)C(=O)C(F)(F)C2=C1 CUYUBEFFEABTMX-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 241000186367 Mycobacterium avium Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000002814 agar dilution Methods 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000001974 tryptic soy broth Substances 0.000 description 2
- 108010050327 trypticase-soy broth Proteins 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 1
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
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- 239000004332 silver Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical compound C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
Description
オキサゾリジノン抗バクテリア剤は、グラム陽性好気性バクテリア、例えば、多剤耐性スタフィロコッカス(staphylococci)及びストレプトコッカス(streptococci)、嫌気性生物、例えば、バクテロイド(bacteroides)及びクロストリジウム(clostridia)種、並びに抗酸性生物、例えば、マイコバクテリウム・チューバーキュローシス(Mycobacterium tuberculosis)及びマイクゴハクテリウム・アビウム(Mycobacterium avium)を含む、多数のヒト及び獣医学的病原体に対する有効な活性を有する新規合成クラスの抗バクテリア剤である。
1の局面においては、本発明は、
以下の式(I):
nは、0又は1であり;
Xは、O、S、NH、Nアルキル、NOH、又はNOアルキルであり;
Zは、NHC(=O)R1、NHC(=S)R1、C(=O)NHR1、C(=O)N(H)OH、NHC(=NCN)R1、NH−het1、O−het1、S−het1、又はhet2であり;
R1は、H、NH2、NHC1-4アルキル、C1-4アルキル、C2-4アルケニル、−(CH2)mC(=O)C1−C4アルキル、OC1-4アルキル、SC1-4アルキル、(CH2)mC3-6シクロアルキル、CH=CH−アリール、CH=CH−het1、CH2C(=O)−アリール、又はCH2C(=O)−het1であり、上記アルキル、アリール又はhetは、それぞれ、場合により、置換アルキル、置換アリール又は置換hetであり;
R2とR3は、独立に、H又はFであり;
R4は、H、Cl、F、CH3、CF3、NH2、NO2又はCNであり;
R5とR6は、独立に、H、アルキル、置換アルキル、−Sアルキル、−Oアルキル、アルケニル、置換アルケニル、ヒドロキシ、アリール、又はハロであり;
R7は、H、アルキル、置換アルキル、シクロアルキル、C(=O)アルキル、C(=O)置換アルキル、アリール、アルケニル、置換アルケニル、het、置換het、又は置換アリールであり;
het1は、酸素、硫黄、及び窒素から選ばれる1〜4個の複素原子を含むC結合5又は6員複素環であり;
het2は、酸素、硫黄、及び窒素から選ばれる1〜4個の複素原子を含むN又はC結合5又は6員複素環であり;
各mは、独立に、0、1又は2である。}で表される化合物である。
Mは、NO2、NH2、NHC(O)OR8、又は以下の構造式(i):
有利には、本発明の化合物は、強力な抗バクテリア活性を示す。
以下の定義を、別段の定めなき限り、使用する。
各種炭化水素含有成分の炭素原子含有量は、当該成分中の炭素原子の最小及び最大数を示すプレフィックスにより示される、すなわち、プレフィックスCi-jは、整数「i」〜整数「j」個(含む)の炭素原子を有する成分を示す。したがって例えば、C1-7アルキルは、1〜7個(含む)の炭素原子を有するアルキルを指す。
用語「アルキル」は、直鎖成分と分枝成分の両者を指す。別段の定めなき限り、アルキル成分は、1〜6個の炭素原子を含む。
用語「アルキニル」とは、少なくとも1個の−C≡C−を含む直鎖成分と分枝成分の両者をいう。別段の定めなき限り、アルキニル成分は、1〜6個の炭素原子を含む。
用語「シクロアルキル」とは、環状アルキル成分をいう。特段の定めなき限り、シクロアルキル成分は、3〜7個の炭素原子を含むであろう。
用語「シクロアルケニル」とは、環状アルケニル成分をいう。別段の定めなき限り、シクロアルケニル成分は、3〜7個の炭素原子を、そして当該環内に少なくとも1個の−C=C−基を含むであろう。
用語「アリール」とは、フェニル及びナフチルをいう。
用語「het」とは、0、S、及びNから選ばれる少なくとも1個の複素原子を含む単又は2環系をいう。各単環は、芳香族、飽和、又は部分飽和でありうる。2環系は、シクロアルキル又はアリール基と縮合した少なくとも1個の複素原子を含む単環を含みうる。2環系は、他のhet単環系と縮合した少なくとも1個の複素原子を含む単環を含んでもよい。用語「het」は、het1、het2、及び本明細書中に記載する複素シクロアルキルを包含する。
用語「置換アルキル」とは、ハロ、het、シクロアルキル、シクロアルケニル、アリール、−OQ10、−SQ10、−S(O)Q10、−S(O)Q10、−OS(O)2Q10、−C(=NQ10)Q10、−C(=NOQ10)Q10、−SC(O)Q10、−NQ10Q10、−C(O)Q10、−C(S)Q10、−C(O)OQ10、−OC(O)Q10、−C(O)NQ10Q10、−C(O)C(Q16)2OC(O)Q10、−CN、=O、=S、−NQ10C(O)Q10、−NQ10C(O)NQ10Q10、−S(O)2NQ10Q10、−NQ10S(O)2Q10、−NQ10S(O)Q10、−NQ10SQ10、−NO2、及び−SNQ10Q10から選ばれる1〜4個の置換基を含むアルキル成分をいう。
本発明の化合物は、一般に、約1mg/mL〜約400mg/mL溶液の範囲内の医薬として許容される注射濃度を提供するために十分な量で上記担体中に溶解されるであろう。得られた液体医薬組成物は、上述の抗バクテリア有効投与量を獲得するように投与されるであろう。本発明の化合物は、有利には、固体及び液体投与形態で投与される。
米国特許第5,164,510号;PCT出願及び公開WO95/07271、WO00/21960、WO99/40094、WO99/64417、WO99/64416、WO00/21960、及びWO01/81350;ヨーロッパ特許第EP738726号、及びドイツ特許第DE19802239号。
(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−メチル−2−オキソ−1H−インドール−5−イル)−N−メチル−2−オキソ−5−オキサゾリジンカルボキサミド;
(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−メチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジンカルボキサミド;
(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−エチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジンカルボキサミド;
(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−エチル−2−オキソ−1H−インドール−5−イル)−N−メチル−2−オキソ−5−オキサゾリジンカルボキサミド;
N−[[(5S)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−メチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジニル]メチル]アセトアミド;及び
N−[[(5S)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−エチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジニル]メチル]アセトアミド。
さらに詳細に説明せずとも、共の説明を用いて、当業者は本発明を最大限に実施することができると思われる。以下の詳細な実施例は、本発明の様々な化合物をどのように製造し、及び/又は様々な方法をどのように実施するかを説明するものであり、単なる説明であって、いかなる方法によっても先の開示を何ら限定するものではないと解釈すべきである。当業者は、反応体と反応条件及び技術の両者に関して、上記手順からの適当な変形を直ちに理解するであろう。
MIC試験法
試験化合物のインビトロMICを、標準寒天希釈法により測定した。各アナログのストック医薬溶液を、好ましい溶媒、通常DMSO:H2O(1:3)中に調製した。各サンプルの逐次2倍希釈を、滅菌蒸留水の1.0mlアリコートを用いて行う。医薬の各1.0mlアリコートに、溶融Mueller Hinton寒天培地9mlを添加した。上記医薬補給寒天を混合し、15×100mmペトリ皿に注ぎ、そして接種に先立って固化・乾燥させた。
Claims (14)
- 以下の式(I):
nは、0又は1であり;
Xは、O、S、NH、Nアルキル、NOH、又はNOアルキルであり;
Zは、NHC(=O)R1、NHC(=S)R1、C(=O)NHR1、C(=O)N(H)OH、NHC(=NCN)R1、NH−het1、O−het1、S−het1、又はhet2であり;
R1は、H、NH2、NHC1-4アルキル、C1-4アルキル、C2-4アルケニル、−(CH2)mC(=O)C1−C4アルキル、OC1-4アルキル、SC1-4アルキル、(CH2)mC3-6シクロアルキル、CH=CH−アリール、CH=CH−het1、CH2C(=O)−アリール、又はCH2C(=O)−het1であり、上記アルキル、アリール又はhetは、それぞれ、場合により、置換アルキル、置換アリール又は置換hetであり;
R2とR3は、独立に、H又はFであり;
R4は、H、Cl、F、CH3、CF3、NH2、NO2又はCNであり;
R5とR6は、独立に、H、アルキル、置換アルキル、−Sアルキル、−Oアルキル、アルケニル、置換アルケニル、ヒドロキシ、アリール、又はハロであり;
R7は、H、アルキル、置換アルキル、シクロアルキル、C(=O)アルキル、C(=O)置換アルキル、アリール、アルケニル、置換アルケニル、het、置換het、又は置換アリールであり;
het1は、酸素、硫黄、及び窒素から選ばれる1〜4個の複素原子を含むC結合5又は6員複素環であり;
het2は、酸素、硫黄、及び窒素から選ばれる1〜4個の複素原子を含むN又はC結合5又は6員複素環であり;
各mは、独立に、0、1又は2である。}で表される化合物。 - R7が、アルキル又は置換アルキルである、請求項1に記載の化合物。
- R5がハロである、請求項1に記載の化合物。
- R6がハロである、請求項4に記載の化合物。
- 以下の群:
a)(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−メチル−2−オキソ−1H−インドール−5−イル)−N−メチル−2−オキソ−5−オキサゾリジンカルボキサミド;
b)(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−メチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジンカルボキサミド;
c)(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−エチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジンカルボキサミド;
d)(5R)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−エチル−2−オキソ−1H−インドール−5−イル)−N−メチル−2−オキソ−5−オキサゾリジンカルボキサミド;
e)N−[[(5S)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−メチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジニル]メチル]アセトアミド;及び
f)N−[[(5S)−(−)−3−(3,3−ジフルオロ−2,3−ジヒドロ−1−エチル−2−オキソ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジニル]メチル]アセトアミド、
から選ばれる、請求項1に記載の化合物。 - R7がアルキル又は置換アルキルである、請求項7に記載の化合物。
- 以下の群:
a)ブチル(5R)−3−(3,3−ジフルオロ−1−メチル−2−オキソ−2,3−ジヒドロ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジンカルボキシレート;
b)ベンジル1−エチル−3,3−ジフルオロ−2−オキソ−2,3−ジヒドロ−1H−インドール−5−イルカルバメート;
c)5−アミノ−1−エチル−3,3−ジフルオロ−1,3−ジヒドロ−2H−インドール−2−オン;
d)1−エチル−3,3−ジフルオロ−5−ニトロ−1,3−ジヒドロ−2H−インドール−2−オン;
e)ベンジル3,3−ジフルオロ−1−メチル−2−オキソ−2,3−ジヒドロ−1H−インドール−5−イルカルバメート;
f)5−アミノ−3,3−ジフルオロ−1−メチル−1,3−ジヒドロ−2H−インドール−2−オン;
g)3,3−ジフルオロ−1−メチル−5−ニトロ−1,3−ジヒドロ−2H−インドール−2−オン;及び
h)ブチル(5R)−3−(3,3−ジフルオロ−1−エチル−2−オキソ−2,3−ジヒドロ−1H−インドール−5−イル)−2−オキソ−5−オキサゾリジンカルボキシレート、
から選ばれる、請求項7に記載の化合物。 - 哺乳動物における微生物感染を治療するための医薬の製造のための請求項1又は7に記載の化合物の使用。
- 前記医薬が、経口、非経口、経皮、又は表在局所的投与のために製造される、請求項10に記載の使用。
- 前記医薬が、請求項1又は7に記載の化合物約0.1〜約1,000mgを含む、請求項10に記載の使用。
- 前記医薬が、請求項1又は7に記載の化合物約0.1〜約500mgを含む、請求項10に記載の化合物の使用。
- 請求項1又は7に記載の化合物、及び医薬として許容される担体を含む医薬組成物。
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Cited By (4)
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JP2011207774A (ja) * | 2010-03-29 | 2011-10-20 | Sagami Chemical Research Institute | 3,3−ジフルオロ−2,3−ジヒドロインドール−2−オン誘導体およびその製造方法 |
WO2014061752A1 (ja) * | 2012-10-17 | 2014-04-24 | 国立大学法人岡山大学 | 化合物、その互変異性体、幾何異性体、乃至それらの塩、及びそれらの製造方法、抗菌剤、並びに感染症治療薬 |
JPWO2014061752A1 (ja) * | 2012-10-17 | 2016-09-05 | 国立大学法人 岡山大学 | 化合物、その互変異性体、幾何異性体、乃至それらの塩、及びそれらの製造方法、抗菌剤、並びに感染症治療薬 |
US9512075B2 (en) | 2012-10-17 | 2016-12-06 | Okayama University | Compound; tautomer and geometric isomer thereof; salt of said compound, tautomer, or geometric isomer; method for manufacturing said compound, tautomer, isomer, or salt; antimicrobial agent; and anti-infective drug |
Also Published As
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CO5601039A2 (es) | 2006-01-31 |
ZA200505225B (en) | 2006-11-29 |
MA27661A1 (fr) | 2005-12-01 |
KR100701226B1 (ko) | 2007-03-29 |
KR20050102135A (ko) | 2005-10-25 |
EA009725B1 (ru) | 2008-02-28 |
CN1742008A (zh) | 2006-03-01 |
OA13032A (en) | 2006-11-10 |
CA2515984A1 (en) | 2004-09-02 |
WO2004074282A1 (en) | 2004-09-02 |
PL377428A1 (pl) | 2006-02-06 |
EP1599470A1 (en) | 2005-11-30 |
CN100349892C (zh) | 2007-11-21 |
MXPA05008960A (es) | 2005-11-04 |
RS20050649A (en) | 2007-11-15 |
NO20052794D0 (no) | 2005-06-09 |
EA200501341A1 (ru) | 2006-02-24 |
US20040176610A1 (en) | 2004-09-09 |
US7012088B2 (en) | 2006-03-14 |
UA80326C2 (en) | 2007-09-10 |
CR7956A (es) | 2005-12-01 |
IS7883A (is) | 2005-06-09 |
AP2005003375A0 (en) | 2005-09-30 |
HRP20050658A2 (en) | 2005-12-31 |
AU2004213246A1 (en) | 2004-09-02 |
TNSN05202A1 (fr) | 2007-06-11 |
JP3887396B2 (ja) | 2007-02-28 |
ECSP055980A (es) | 2006-01-16 |
NO20052794L (no) | 2005-11-01 |
GEP20084306B (en) | 2008-02-11 |
HK1082253A1 (en) | 2006-06-02 |
BRPI0406824A (pt) | 2005-12-27 |
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