JP5579432B2 - 新規ヒドロキシフェニル誘導体およびその生物学的適用 - Google Patents
新規ヒドロキシフェニル誘導体およびその生物学的適用 Download PDFInfo
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- JP5579432B2 JP5579432B2 JP2009504857A JP2009504857A JP5579432B2 JP 5579432 B2 JP5579432 B2 JP 5579432B2 JP 2009504857 A JP2009504857 A JP 2009504857A JP 2009504857 A JP2009504857 A JP 2009504857A JP 5579432 B2 JP5579432 B2 JP 5579432B2
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- fluoro
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- 125000004464 hydroxyphenyl group Chemical group 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 252
- 238000000034 method Methods 0.000 claims description 159
- 238000006243 chemical reaction Methods 0.000 claims description 87
- 239000000203 mixture Substances 0.000 claims description 78
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 63
- -1 ethyl compound Chemical class 0.000 claims description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 150000002989 phenols Chemical class 0.000 claims description 13
- 241000588724 Escherichia coli Species 0.000 claims description 12
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 150000001721 carbon Chemical class 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 244000045947 parasite Species 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 201000004792 malaria Diseases 0.000 claims description 4
- 244000000010 microbial pathogen Species 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 241000590002 Helicobacter pylori Species 0.000 claims description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 3
- 125000000815 N-oxide group Chemical group 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229940037467 helicobacter pylori Drugs 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 241000191967 Staphylococcus aureus Species 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 201000008827 tuberculosis Diseases 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 2
- 239000012445 acidic reagent Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 150000002148 esters Chemical group 0.000 claims 1
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 472
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 406
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 175
- 235000019439 ethyl acetate Nutrition 0.000 description 157
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 130
- 238000012746 preparative thin layer chromatography Methods 0.000 description 110
- 239000000243 solution Substances 0.000 description 109
- 238000000746 purification Methods 0.000 description 108
- 239000003921 oil Substances 0.000 description 101
- 235000019198 oils Nutrition 0.000 description 101
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 89
- 238000005481 NMR spectroscopy Methods 0.000 description 87
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 77
- 239000007787 solid Substances 0.000 description 77
- 239000011541 reaction mixture Substances 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 65
- 229910052786 argon Inorganic materials 0.000 description 65
- 239000011734 sodium Substances 0.000 description 61
- 239000012074 organic phase Substances 0.000 description 59
- 239000000741 silica gel Substances 0.000 description 59
- 229910002027 silica gel Inorganic materials 0.000 description 59
- 230000002829 reductive effect Effects 0.000 description 55
- PPXNHYNGMQBJPX-UHFFFAOYSA-N 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine Chemical compound COC1=CC(CCC)=CC=C1OC1=NC(Cl)=CC=C1N PPXNHYNGMQBJPX-UHFFFAOYSA-N 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- 229920006395 saturated elastomer Polymers 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- CHWNEIVBYREQRF-UHFFFAOYSA-N 4-Ethyl-2-methoxyphenol Chemical compound CCC1=CC=C(O)C(OC)=C1 CHWNEIVBYREQRF-UHFFFAOYSA-N 0.000 description 29
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 26
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 23
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical class OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 23
- NJIAKRXOOKQTSD-UHFFFAOYSA-N 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene Chemical compound COC1=CC(CC)=CC=C1OC1=CC=C([N+]([O-])=O)C=C1C(F)(F)F NJIAKRXOOKQTSD-UHFFFAOYSA-N 0.000 description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- 229960003500 triclosan Drugs 0.000 description 19
- ODVLIMANKCZDOT-UHFFFAOYSA-N 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine Chemical compound COC1=CC(CCC)=CC=C1OC1=CC=CC(F)=N1 ODVLIMANKCZDOT-UHFFFAOYSA-N 0.000 description 18
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- MHVSUDUCUYPKHY-UHFFFAOYSA-N 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline Chemical compound COC1=CC(CC)=CC=C1OC1=CC=C(N)C=C1F MHVSUDUCUYPKHY-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 230000001580 bacterial effect Effects 0.000 description 10
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- DNTHMWUMRGOJRY-UHFFFAOYSA-N 1-fluoro-4-nitro-2-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(C(F)(F)F)=C1 DNTHMWUMRGOJRY-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- IJVFHCSUEBAAOZ-UHFFFAOYSA-N 3-fluoro-2-nitropyridine Chemical compound [O-][N+](=O)C1=NC=CC=C1F IJVFHCSUEBAAOZ-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 8
- PXIKRTCSSLJURC-UHFFFAOYSA-N Dihydroeugenol Chemical compound CCCC1=CC=C(O)C(OC)=C1 PXIKRTCSSLJURC-UHFFFAOYSA-N 0.000 description 8
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 235000009518 sodium iodide Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XHUBSJRBOQIZNI-UHFFFAOYSA-N (4-Hydroxy-3-methoxyphenyl)ethanol Chemical compound COC1=CC(CCO)=CC=C1O XHUBSJRBOQIZNI-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 0 *c(c(*)c1O*)c(*)c(*)c1O* Chemical compound *c(c(*)c1O*)c(*)c(*)c1O* 0.000 description 6
- DYAGYHAGWHVKBO-UHFFFAOYSA-N 4-(4-ethyl-2-phenylmethoxyphenoxy)-3-fluoroaniline Chemical compound C=1C=CC=CC=1COC1=CC(CC)=CC=C1OC1=CC=C(N)C=C1F DYAGYHAGWHVKBO-UHFFFAOYSA-N 0.000 description 6
- ZUNDLPMNAZXQES-UHFFFAOYSA-N 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine Chemical compound COC1=CC(CCC)=CC=C1OC1=CC=C(Br)C=N1 ZUNDLPMNAZXQES-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ISSIKGQWMOOEBT-UHFFFAOYSA-N N(NO)[N+](=O)[O-] Chemical group N(NO)[N+](=O)[O-] ISSIKGQWMOOEBT-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-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
- 238000005406 washing Methods 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- MBTGBRYMJKYYOE-UHFFFAOYSA-N 2,6-difluoropyridine Chemical compound FC1=CC=CC(F)=N1 MBTGBRYMJKYYOE-UHFFFAOYSA-N 0.000 description 5
- WZNVXMTUSPSPNC-UHFFFAOYSA-N 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine Chemical compound COC1=CC(CC)=CC=C1OC1=CC=CC(F)=N1 WZNVXMTUSPSPNC-UHFFFAOYSA-N 0.000 description 5
- RNSVHYKUWXBUHV-UHFFFAOYSA-N 3-(4-ethyl-5-fluoro-2-methoxyphenoxy)-2-fluoropyridine Chemical compound C1=C(F)C(CC)=CC(OC)=C1OC1=CC=CN=C1F RNSVHYKUWXBUHV-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
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- 238000001727 in vivo Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IWCDWGBUIGLXBG-UHFFFAOYSA-N 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone Chemical compound OC1=CC(CC)=CC=C1OC1=CC=C(C(C)=O)C=C1F IWCDWGBUIGLXBG-UHFFFAOYSA-N 0.000 description 4
- TWNRQWPXZZBWJA-UHFFFAOYSA-N 2-(2,6-difluoropyridin-4-yl)oxy-5-propylphenol Chemical compound OC1=CC(CCC)=CC=C1OC1=CC(F)=NC(F)=C1 TWNRQWPXZZBWJA-UHFFFAOYSA-N 0.000 description 4
- FQBXPJKQAGLNJO-UHFFFAOYSA-N 2-(4,6-difluoropyridin-2-yl)oxy-5-propylphenol Chemical compound OC1=CC(CCC)=CC=C1OC1=CC(F)=CC(F)=N1 FQBXPJKQAGLNJO-UHFFFAOYSA-N 0.000 description 4
- VBJXTQISHZIZAA-UHFFFAOYSA-N 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine Chemical compound COC1=CC(Br)=C(F)C=C1OC1=CC=CC(F)=N1 VBJXTQISHZIZAA-UHFFFAOYSA-N 0.000 description 4
- KPIHDZYPSJKPBJ-UHFFFAOYSA-N 2-[3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenoxy]propyl]isoindole-1,3-dione Chemical compound OC1=CC(CC)=CC=C1OC(C(=C1)F)=CC=C1OCCCN1C(=O)C2=CC=CC=C2C1=O KPIHDZYPSJKPBJ-UHFFFAOYSA-N 0.000 description 4
- USONFEVIKSYSEM-UHFFFAOYSA-N 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine Chemical compound COC1=CC(CC)=CC=C1OC1=CC=CN=C1[N+]([O-])=O USONFEVIKSYSEM-UHFFFAOYSA-N 0.000 description 4
- ZFLMBQSKMXMSCC-UHFFFAOYSA-N 3-(4-ethyl-5-fluoro-2-methoxyphenoxy)-1h-pyridin-2-one Chemical compound C1=C(F)C(CC)=CC(OC)=C1OC1=CC=CN=C1O ZFLMBQSKMXMSCC-UHFFFAOYSA-N 0.000 description 4
- VAFFBCPXJUYWID-UHFFFAOYSA-N 3-(4-ethyl-5-fluoro-2-methoxyphenoxy)pyridin-2-amine Chemical compound C1=C(F)C(CC)=CC(OC)=C1OC1=CC=CN=C1N VAFFBCPXJUYWID-UHFFFAOYSA-N 0.000 description 4
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
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- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
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- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
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- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) 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)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
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- DSDCDMKASWVZHI-UHFFFAOYSA-M zinc;2-methanidylpropane;bromide Chemical compound Br[Zn+].CC(C)[CH2-] DSDCDMKASWVZHI-UHFFFAOYSA-M 0.000 description 1
Images
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- C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
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- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/90—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
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- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (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)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP20060290611 EP1845087A1 (en) | 2006-04-14 | 2006-04-14 | Hydroxyphenyl derivatives and biological applications thereof |
| EP06290611.0 | 2006-04-14 | ||
| PCT/IB2007/002127 WO2007135562A2 (en) | 2006-04-14 | 2007-04-16 | Hydroxyphenyl derivatives and biological applications thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2009533417A JP2009533417A (ja) | 2009-09-17 |
| JP2009533417A5 JP2009533417A5 (https=) | 2010-05-27 |
| JP5579432B2 true JP5579432B2 (ja) | 2014-08-27 |
Family
ID=37007447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009504857A Expired - Fee Related JP5579432B2 (ja) | 2006-04-14 | 2007-04-16 | 新規ヒドロキシフェニル誘導体およびその生物学的適用 |
Country Status (8)
| Country | Link |
|---|---|
| US (3) | US8722746B2 (https=) |
| EP (2) | EP1845087A1 (https=) |
| JP (1) | JP5579432B2 (https=) |
| CN (1) | CN101500999B (https=) |
| AU (1) | AU2007252917C1 (https=) |
| CA (1) | CA2649196C (https=) |
| IL (1) | IL194781A (https=) |
| WO (1) | WO2007135562A2 (https=) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1845087A1 (en) | 2006-04-14 | 2007-10-17 | Mutabilis SA | Hydroxyphenyl derivatives and biological applications thereof |
| DE102008053242A1 (de) * | 2008-10-25 | 2010-05-06 | Saltigo Gmbh | Heteroaryl-Arylether |
| JP5626737B2 (ja) * | 2009-09-01 | 2014-11-19 | ファブ ファーマ エスエーエス | 新規抗菌性ヒドロキシフェニル化合物 |
| JP5752138B2 (ja) * | 2009-10-20 | 2015-07-22 | ファブ ファーマ エスエーエス | 新規なアシルピペラジノン、及び医薬としてのそれらの使用 |
| MX2012005759A (es) | 2009-11-18 | 2012-10-03 | Fab Pharma S A S | Acrilamidas heterociclicas novedosas y su uso como farmacos. |
| WO2011106630A2 (en) | 2010-02-27 | 2011-09-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chrysophaentin antimicrobial compounds that inhibit ftsz protein |
| EP2474313A1 (en) * | 2011-01-11 | 2012-07-11 | ABRA Pharmaceuticals sàrl | Novel self-assembling polyphenol-quinonoid polymer derivatives and use thereof |
| GB201522179D0 (en) * | 2015-12-16 | 2016-01-27 | Autifony Therapeutics Ltd | Novel compounds |
| US11905286B2 (en) | 2018-08-09 | 2024-02-20 | Antabio Sas | Diazabicyclooctanones as inhibitors of serine beta-lactamases |
| EP3833665B1 (en) | 2018-08-09 | 2023-07-19 | Antabio SAS | Diazabicyclooctanones as inhibitors of serine beta-lactamases |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3391195A (en) * | 1963-12-04 | 1968-07-02 | Monsanto Res Corp | Fluorinated polyphenyl ethers |
| CH1085567A4 (de) * | 1967-08-01 | 1969-03-14 | Ciba Geigy Ag | Verfahren zum antimikrobiellen Ausrüsten bzw. zum Schützen von Textilien gegen den Befall durch Mikroorganismen und eine Flotte bzw. ein Bad zur Durchführung dieses Verfahrens |
| GB1390616A (en) * | 1971-07-27 | 1975-04-16 | Ciba Geigy Ag | Antibacterial compositions |
| US5578295A (en) * | 1995-04-28 | 1996-11-26 | The Procter & Gamble Company | Oral care compositions comprising certain substituted diphenyl ethers |
| EP1042265A2 (en) * | 1997-12-12 | 2000-10-11 | Ciba SC Holding AG | O-derivatives of halogenated diphenyl ether compounds |
| GB9827391D0 (en) | 1998-12-11 | 1999-02-03 | Fundation O N C F | Aldose reductase inhibitors and pharmaceutical compositions |
| DE10015525A1 (de) | 2000-03-30 | 2001-10-11 | Deutsches Krebsforsch | Synthetische Derivate von Lunularsäure, Arzneimittel enthaltend diese Verbindung, Verfahren zur Herstellung der Lunularsäurederivate sowie deren Verwendung |
| CN1662238A (zh) * | 2002-04-18 | 2005-08-31 | 塞米得肿瘤学美国公司 | 肽去甲酰酶活化的前体药物 |
| FR2839448A1 (fr) * | 2002-05-07 | 2003-11-14 | Oreal | Utilisation d'esters de triclosan, de piroctone et de tropolone dans une composition a liberation controlee |
| WO2004043400A2 (en) * | 2002-11-14 | 2004-05-27 | Celmed Oncology (Usa), Inc. | Peptide deformylase activated prodrugs |
| EP1781280A2 (en) * | 2004-08-18 | 2007-05-09 | Warner-Lambert Company LLC | Androgen modulators |
| US7687547B2 (en) | 2004-08-23 | 2010-03-30 | Research Foundation Of State University Of New York | Diphenyl ether antimicrobial compounds |
| US20060211697A1 (en) * | 2004-12-08 | 2006-09-21 | Liren Huang | 2-(2 Or 4-substituted aryloxy)-phenol derivatives as antibacterial agents |
| WO2007027878A2 (en) | 2005-08-31 | 2007-03-08 | Emergent Product Development Gaithersburg Inc. | 4-substituted 2-aryloxyphenol derivatives as antibacterial agents |
| EP1845087A1 (en) | 2006-04-14 | 2007-10-17 | Mutabilis SA | Hydroxyphenyl derivatives and biological applications thereof |
| JP5626737B2 (ja) | 2009-09-01 | 2014-11-19 | ファブ ファーマ エスエーエス | 新規抗菌性ヒドロキシフェニル化合物 |
-
2006
- 2006-04-14 EP EP20060290611 patent/EP1845087A1/en not_active Withdrawn
-
2007
- 2007-04-16 US US12/226,281 patent/US8722746B2/en not_active Expired - Fee Related
- 2007-04-16 AU AU2007252917A patent/AU2007252917C1/en not_active Ceased
- 2007-04-16 EP EP07789559A patent/EP2010495A2/en not_active Withdrawn
- 2007-04-16 CA CA2649196A patent/CA2649196C/en not_active Expired - Fee Related
- 2007-04-16 JP JP2009504857A patent/JP5579432B2/ja not_active Expired - Fee Related
- 2007-04-16 CN CN200780022244.8A patent/CN101500999B/zh not_active Expired - Fee Related
- 2007-04-16 WO PCT/IB2007/002127 patent/WO2007135562A2/en not_active Ceased
-
2008
- 2008-10-22 IL IL194781A patent/IL194781A/en not_active IP Right Cessation
-
2014
- 2014-03-28 US US14/228,893 patent/US9309179B2/en not_active Expired - Fee Related
-
2016
- 2016-03-08 US US15/063,891 patent/US20160185724A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US9309179B2 (en) | 2016-04-12 |
| US20140213589A1 (en) | 2014-07-31 |
| AU2007252917B2 (en) | 2012-05-10 |
| CA2649196A1 (en) | 2007-11-29 |
| CA2649196C (en) | 2016-06-07 |
| JP2009533417A (ja) | 2009-09-17 |
| US20100041658A1 (en) | 2010-02-18 |
| WO2007135562A3 (en) | 2008-01-24 |
| IL194781A (en) | 2013-08-29 |
| CN101500999A (zh) | 2009-08-05 |
| EP2010495A2 (en) | 2009-01-07 |
| CN101500999B (zh) | 2014-01-15 |
| AU2007252917A1 (en) | 2007-11-29 |
| US8722746B2 (en) | 2014-05-13 |
| EP1845087A1 (en) | 2007-10-17 |
| US20160185724A1 (en) | 2016-06-30 |
| IL194781A0 (en) | 2009-08-03 |
| AU2007252917C1 (en) | 2014-05-29 |
| WO2007135562A2 (en) | 2007-11-29 |
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