MXPA05011352A - Derivados de piperazina y su uso para el tratamiento de enfermedades neurologicas y psiquiatricas. - Google Patents
Derivados de piperazina y su uso para el tratamiento de enfermedades neurologicas y psiquiatricas.Info
- Publication number
- MXPA05011352A MXPA05011352A MXPA05011352A MXPA05011352A MXPA05011352A MX PA05011352 A MXPA05011352 A MX PA05011352A MX PA05011352 A MXPA05011352 A MX PA05011352A MX PA05011352 A MXPA05011352 A MX PA05011352A MX PA05011352 A MXPA05011352 A MX PA05011352A
- Authority
- MX
- Mexico
- Prior art keywords
- carbonyl
- piperidine
- diazepan
- cyano
- piperazine
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 18
- 208000012902 Nervous system disease Diseases 0.000 title claims abstract description 8
- 208000025966 Neurological disease Diseases 0.000 title claims abstract description 8
- 208000020016 psychiatric disease Diseases 0.000 title abstract description 5
- 230000000926 neurological effect Effects 0.000 title abstract description 4
- 150000004885 piperazines Chemical class 0.000 title description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 80
- 230000008569 process Effects 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 242
- -1 Ci_6 alkylamidoalkyl Chemical group 0.000 claims description 144
- 229910052739 hydrogen Inorganic materials 0.000 claims description 68
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 229960003529 diazepam Drugs 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000006684 polyhaloalkyl group Polymers 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- 125000005533 aryl carboxamido group Chemical group 0.000 claims description 5
- 125000005421 aryl sulfonamido group Chemical group 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- CGZUTBPQKHYXHB-UHFFFAOYSA-N (4-cyclobutylpiperazin-1-yl)-[1-[6-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl]methanone Chemical compound C1=NC(C(F)(F)F)=CC=C1N1CCC(C(=O)N2CCN(CC2)C2CCC2)CC1 CGZUTBPQKHYXHB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- LWMXYGRIPRADKA-UHFFFAOYSA-N 4-[4-(4-cyclobutyl-1,4-diazepane-1-carbonyl)piperidin-1-yl]benzonitrile Chemical compound C1CCN(C2CCC2)CCN1C(=O)C(CC1)CCN1C1=CC=C(C#N)C=C1 LWMXYGRIPRADKA-UHFFFAOYSA-N 0.000 claims description 4
- NIEDPANBEFZRHH-UHFFFAOYSA-N 4-[4-(4-cyclopentylpiperazine-1-carbonyl)piperidin-1-yl]benzonitrile Chemical compound C1CN(C2CCCC2)CCN1C(=O)C(CC1)CCN1C1=CC=C(C#N)C=C1 NIEDPANBEFZRHH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical group C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- BTRCWAYXXBYDCQ-UHFFFAOYSA-N 3-chloro-4-[4-(4-cyclobutyl-1,4-diazepane-1-carbonyl)piperidin-1-yl]benzonitrile Chemical compound ClC1=CC(C#N)=CC=C1N1CCC(C(=O)N2CCN(CCC2)C2CCC2)CC1 BTRCWAYXXBYDCQ-UHFFFAOYSA-N 0.000 claims description 3
- XOZZNXMLZSVHRO-UHFFFAOYSA-N 4-[4-(4-cyclobutylpiperazine-1-carbonyl)piperidin-1-yl]-2-fluorobenzonitrile Chemical compound C1=C(C#N)C(F)=CC(N2CCC(CC2)C(=O)N2CCN(CC2)C2CCC2)=C1 XOZZNXMLZSVHRO-UHFFFAOYSA-N 0.000 claims description 3
- MHRVMXWAOUZACF-UHFFFAOYSA-N 4-[4-(4-cyclobutylpiperazine-1-carbonyl)piperidin-1-yl]benzonitrile Chemical compound C1CN(C2CCC2)CCN1C(=O)C(CC1)CCN1C1=CC=C(C#N)C=C1 MHRVMXWAOUZACF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- FHDDKNRLIJOKNI-UHFFFAOYSA-N 5-[4-(4-propan-2-ylpiperazine-1-carbonyl)piperidin-1-yl]pyridine-2-carbonitrile Chemical compound C1CN(C(C)C)CCN1C(=O)C1CCN(C=2C=NC(=CC=2)C#N)CC1 FHDDKNRLIJOKNI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- KWDBHXUIVWIYBV-UHFFFAOYSA-N (4-cyclobutyl-1,4-diazepan-1-yl)-[1-[6-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl]methanone Chemical compound C1=NC(C(F)(F)F)=CC=C1N1CCC(C(=O)N2CCN(CCC2)C2CCC2)CC1 KWDBHXUIVWIYBV-UHFFFAOYSA-N 0.000 claims 1
- FOCIOGAYZXDVNE-UHFFFAOYSA-N (4-cyclobutylpiperazin-1-yl)-[1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl]methanone Chemical compound N1=CC(C(F)(F)F)=CC=C1N1CCC(C(=O)N2CCN(CC2)C2CCC2)CC1 FOCIOGAYZXDVNE-UHFFFAOYSA-N 0.000 claims 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- MEZQPJQVIZGCIB-UHFFFAOYSA-N 2-chloro-4-[4-(4-cyclobutyl-1,4-diazepane-1-carbonyl)piperidin-1-yl]benzonitrile Chemical compound C1=C(C#N)C(Cl)=CC(N2CCC(CC2)C(=O)N2CCN(CCC2)C2CCC2)=C1 MEZQPJQVIZGCIB-UHFFFAOYSA-N 0.000 claims 1
- BDDVAWDNVWLHDQ-UHFFFAOYSA-N 2-chloro-4-hydroxybenzonitrile Chemical compound OC1=CC=C(C#N)C(Cl)=C1 BDDVAWDNVWLHDQ-UHFFFAOYSA-N 0.000 claims 1
- JKDIFUZVTSXGST-UHFFFAOYSA-N 4-[4-(4-cyclobutyl-1,4-diazepane-1-carbonyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile Chemical compound C1=C(C#N)C(C(F)(F)F)=CC(N2CCC(CC2)C(=O)N2CCN(CCC2)C2CCC2)=C1 JKDIFUZVTSXGST-UHFFFAOYSA-N 0.000 claims 1
- AGLOUAIOTHNXJX-UHFFFAOYSA-N 4-[4-(4-cyclobutylpiperazine-1-carbonyl)piperidin-1-yl]-2-(trifluoromethyl)benzonitrile Chemical compound C1=C(C#N)C(C(F)(F)F)=CC(N2CCC(CC2)C(=O)N2CCN(CC2)C2CCC2)=C1 AGLOUAIOTHNXJX-UHFFFAOYSA-N 0.000 claims 1
- CFUNZNFORJABNT-UHFFFAOYSA-N 4-[4-(4-cyclobutylpiperazine-1-carbonyl)piperidin-1-yl]-3,5-difluorobenzonitrile Chemical compound FC1=CC(C#N)=CC(F)=C1N1CCC(C(=O)N2CCN(CC2)C2CCC2)CC1 CFUNZNFORJABNT-UHFFFAOYSA-N 0.000 claims 1
- PBMGIRHMQNGTDP-UHFFFAOYSA-N 4-[4-(4-propan-2-ylpiperazine-1-carbonyl)piperidin-1-yl]benzonitrile Chemical group C1CN(C(C)C)CCN1C(=O)C1CCN(C=2C=CC(=CC=2)C#N)CC1 PBMGIRHMQNGTDP-UHFFFAOYSA-N 0.000 claims 1
- FZPZUNGFQLGPKM-KRWDZBQOSA-N 4-[4-[(3s)-3-methyl-4-propan-2-ylpiperazine-1-carbonyl]piperidin-1-yl]benzonitrile Chemical compound C1[C@H](C)N(C(C)C)CCN1C(=O)C1CCN(C=2C=CC(=CC=2)C#N)CC1 FZPZUNGFQLGPKM-KRWDZBQOSA-N 0.000 claims 1
- SNJNSMATZNKRMC-INIZCTEOSA-N 5-[4-[(3s)-3-methyl-4-propan-2-ylpiperazine-1-carbonyl]piperidin-1-yl]pyridine-2-carbonitrile Chemical compound C1[C@H](C)N(C(C)C)CCN1C(=O)C1CCN(C=2C=NC(=CC=2)C#N)CC1 SNJNSMATZNKRMC-INIZCTEOSA-N 0.000 claims 1
- GICALJMBTQYCBH-INIZCTEOSA-N 6-[4-[(3s)-3-methyl-4-propan-2-ylpiperazine-1-carbonyl]piperidin-1-yl]pyridine-3-carbonitrile Chemical compound C1[C@H](C)N(C(C)C)CCN1C(=O)C1CCN(C=2N=CC(=CC=2)C#N)CC1 GICALJMBTQYCBH-INIZCTEOSA-N 0.000 claims 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 1
- FMXNDUUAVIXCII-AWEZNQCLSA-N [(3s)-3-methyl-4-propan-2-ylpiperazin-1-yl]-[1-[6-(trifluoromethyl)pyridazin-3-yl]piperidin-4-yl]methanone Chemical compound C1[C@H](C)N(C(C)C)CCN1C(=O)C1CCN(C=2N=NC(=CC=2)C(F)(F)F)CC1 FMXNDUUAVIXCII-AWEZNQCLSA-N 0.000 claims 1
- ZWRZXTARQLPFSM-UHFFFAOYSA-N [1-(2-methylquinolin-6-yl)piperidin-4-yl]-(4-propan-2-ylpiperazin-1-yl)methanone Chemical compound C1CN(C(C)C)CCN1C(=O)C1CCN(C=2C=C3C=CC(C)=NC3=CC=2)CC1 ZWRZXTARQLPFSM-UHFFFAOYSA-N 0.000 claims 1
- PNRPFNJBDCWWQV-UHFFFAOYSA-N [1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl]-(4-cyclobutylpiperazin-1-yl)methanone Chemical compound ClC1=CC(C(F)(F)F)=CN=C1N1CCC(C(=O)N2CCN(CC2)C2CCC2)CC1 PNRPFNJBDCWWQV-UHFFFAOYSA-N 0.000 claims 1
- 235000019256 formaldehyde Nutrition 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 46
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- DQQXRIVSTFNSSR-UHFFFAOYSA-N piperazin-2-ylidenemethanone;piperidine Chemical class C1CCNCC1.O=C=C1CNCCN1 DQQXRIVSTFNSSR-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 258
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 206
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 100
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 98
- 238000005481 NMR spectroscopy Methods 0.000 description 85
- 239000000047 product Substances 0.000 description 73
- 239000007787 solid Substances 0.000 description 73
- 239000000243 solution Substances 0.000 description 68
- 238000006243 chemical reaction Methods 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- 235000019439 ethyl acetate Nutrition 0.000 description 59
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 58
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 58
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 55
- 239000011541 reaction mixture Substances 0.000 description 53
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 52
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 52
- 239000012458 free base Substances 0.000 description 48
- 239000000741 silica gel Substances 0.000 description 47
- 229910002027 silica gel Inorganic materials 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- NIBDMEFIKCXNPN-UHFFFAOYSA-N piperidin-4-yl-(4-propan-2-ylpiperazin-1-yl)methanone Chemical compound C1CN(C(C)C)CCN1C(=O)C1CCNCC1 NIBDMEFIKCXNPN-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 32
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- 229910001868 water Inorganic materials 0.000 description 30
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 29
- 235000011114 ammonium hydroxide Nutrition 0.000 description 29
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 28
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 28
- 229910000027 potassium carbonate Inorganic materials 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- VXNAHXQHJCMCIO-UHFFFAOYSA-N piperidin-4-yl-(4-propan-2-yl-1,4-diazepan-1-yl)methanone Chemical compound C1CN(C(C)C)CCCN1C(=O)C1CCNCC1 VXNAHXQHJCMCIO-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 229910052786 argon Inorganic materials 0.000 description 26
- 239000012267 brine Substances 0.000 description 26
- 238000001704 evaporation Methods 0.000 description 26
- 238000001819 mass spectrum Methods 0.000 description 25
- 235000011181 potassium carbonates Nutrition 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 23
- 230000008020 evaporation Effects 0.000 description 22
- 150000002500 ions Chemical class 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- JEDKFRUWDJYLCQ-UHFFFAOYSA-N (4-cyclobutyl-1,4-diazepan-1-yl)-piperidin-4-ylmethanone Chemical compound C1CCN(C2CCC2)CCN1C(=O)C1CCNCC1 JEDKFRUWDJYLCQ-UHFFFAOYSA-N 0.000 description 17
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 15
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 14
- 229910021529 ammonia Inorganic materials 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- KWCXEOVSAJSXRS-UHFFFAOYSA-N 1-(4-cyanophenyl)piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C1=CC=C(C#N)C=C1 KWCXEOVSAJSXRS-UHFFFAOYSA-N 0.000 description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 229910052801 chlorine Inorganic materials 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- AIEGIFIEQXZBCP-UHFFFAOYSA-N 2-chloro-5-(trifluoromethyl)pyrazine Chemical compound FC(F)(F)C1=CN=C(Cl)C=N1 AIEGIFIEQXZBCP-UHFFFAOYSA-N 0.000 description 10
- GIFDWXWNFKZVEI-UHFFFAOYSA-N 5-bromo-2-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=NC=C(Br)C=N1 GIFDWXWNFKZVEI-UHFFFAOYSA-N 0.000 description 10
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 10
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Classifications
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- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- 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
- C07D401/10—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 carbon chain containing aromatic rings
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- C07D401/14—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 three or more hetero rings
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Organic Chemistry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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| GB0323109A GB0323109D0 (en) | 2003-10-02 | 2003-10-02 | Novel compounds |
| PCT/EP2004/004245 WO2004101546A1 (en) | 2003-04-23 | 2004-04-21 | Piperazine derivatives and their use for the treatment of neurological and psychiatric diseases |
Publications (1)
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| MXPA05011352A true MXPA05011352A (es) | 2005-11-28 |
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| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| GB0324159D0 (en) | 2003-10-15 | 2003-11-19 | Glaxo Group Ltd | Novel compounds |
| EP1768959A2 (en) * | 2004-06-28 | 2007-04-04 | Janssen Pharmaceutica N.V. | Hetero isonipecotic modulators of vanilloid vr1 receptor |
| PL1802307T3 (pl) * | 2004-10-15 | 2008-07-31 | Glaxo Group Ltd | Pochodne pirolidyny jako ligandy receptorów histaminowych |
| EP1902046B1 (en) | 2005-06-20 | 2009-12-02 | Schering Corporation | Piperidine derivatives useful as histamine h3 antagonists |
| US7408066B2 (en) | 2005-06-20 | 2008-08-05 | Schering Corproation | Carbon-linked substituted piperidines and derivatives thereof useful as histamine H3 antagonists |
| ES2354569T3 (es) | 2005-06-22 | 2011-03-16 | Pfizer Products Inc. | Antagonistas del receptor de histamina-3. |
| JP2009506987A (ja) * | 2005-08-02 | 2009-02-19 | ニューロゲン コーポレイション | ジピペラジニルケトンおよび関連する類似体 |
| CA2623025A1 (en) | 2005-09-20 | 2007-03-29 | Schering Corporation | 1- [ [1- [ (2-amin0-6-methyl-4-pyridinyl) methyl] -4-flu0r0-4-piperidinyl,] carbonyl] -4- [2- (2-pyridinyl) -3h-imidaz0 [4 , 5-b] pyridin-3-yl] piperidine useful as histamine h3 antagonist |
| WO2007075688A2 (en) | 2005-12-21 | 2007-07-05 | Schering Corporation | Substituted aniline derivatives useful as histamine h3 antagonists |
| JP2009521448A (ja) | 2005-12-21 | 2009-06-04 | シェーリング コーポレイション | ヒスタミンh3アンタゴニストとして有用なフェノキシピペリジンおよびそのアナログ |
| US9108948B2 (en) | 2006-06-23 | 2015-08-18 | Abbvie Inc. | Cyclopropyl amine derivatives |
| CN101472887A (zh) | 2006-06-23 | 2009-07-01 | 艾博特公司 | 作为组胺h3受体调节物的环丙胺衍生物 |
| EP2136805A2 (en) * | 2007-03-02 | 2009-12-30 | Schering Corporation | Piperidinyl-piperidine and piperazinyl-piperidine for use in the treatment of diabetes or pain |
| TW200902007A (en) * | 2007-05-25 | 2009-01-16 | Astrazeneca Ab | Spirocyclopropyl piperidine derivatives |
| CA2687931C (en) | 2007-05-31 | 2016-05-24 | Boehringer Ingelheim International Gmbh | Ccr2 receptor antagonists and uses thereof |
| CA2688585A1 (en) | 2007-06-11 | 2008-12-18 | F. Hoffmann-La Roche Ag | Cyclohexyl derivatives |
| BRPI0815591B8 (pt) | 2007-08-22 | 2021-05-25 | Astrazeneca Ab | composto, composição farmacêutica, e, uso de um composto. |
| WO2009030716A1 (en) | 2007-09-06 | 2009-03-12 | Glaxo Group Limited | Piperazine derivative having affinity for the histamine h3 receptor |
| US20100130477A1 (en) * | 2008-11-25 | 2010-05-27 | Astrazeneca Ab | Spirocyclobutyl Piperidine Derivatives |
| CN103724328B (zh) | 2008-12-19 | 2015-10-14 | 贝林格尔.英格海姆国际有限公司 | 作为ccr2受体拮抗剂用于治疗炎症、哮喘和copd的环状嘧啶-4-甲酰胺 |
| TW201039825A (en) | 2009-02-20 | 2010-11-16 | Astrazeneca Ab | Cyclopropyl amide derivatives 983 |
| US9186353B2 (en) * | 2009-04-27 | 2015-11-17 | Abbvie Inc. | Treatment of osteoarthritis pain |
| PL2513093T3 (pl) | 2009-12-17 | 2015-03-31 | Centrexion Therapeutics Corp | Nowi antagoniści receptora CCR2 i ich zastosowanie |
| WO2011102793A1 (en) * | 2010-02-18 | 2011-08-25 | Astrazeneca Ab | Solid forms comprising a cyclopropyl amide derivative |
| AU2011218492B2 (en) * | 2010-02-18 | 2014-11-13 | Astrazeneca Ab | New crystalline form of a cyclopropyl benzamide derivative |
| EP2569295B1 (en) | 2010-05-12 | 2014-11-19 | Boehringer Ingelheim International GmbH | New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
| JP2013526507A (ja) | 2010-05-12 | 2013-06-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規ccr2受容体アンタゴニスト、その製造方法及び薬物としてのその使用 |
| US8841313B2 (en) | 2010-05-17 | 2014-09-23 | Boehringer Ingelheim International Gmbh | CCR2 antagonists and uses thereof |
| JP5636094B2 (ja) | 2010-05-25 | 2014-12-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ccr2受容体アンタゴニスト |
| EP2576538B1 (en) | 2010-06-01 | 2015-10-28 | Boehringer Ingelheim International GmbH | New CCR2 antagonists |
| WO2012037258A1 (en) | 2010-09-16 | 2012-03-22 | Abbott Laboratories | Processes for preparing 1,2-substituted cyclopropyl derivatives |
| WO2013010839A1 (en) | 2011-07-15 | 2013-01-24 | Boehringer Ingelheim International Gmbh | Novel and selective ccr2 antagonists |
| AR088256A1 (es) | 2011-10-08 | 2014-05-21 | Novartis Ag | Derivados de carbamato / urea como antagonistas del receptor h3 |
| WO2013151982A1 (en) | 2012-04-03 | 2013-10-10 | Arena Pharmaceuticals, Inc. | Methods and compounds useful in treating pruritus, and methods for identifying such compounds |
| EP2647377A1 (en) | 2012-04-06 | 2013-10-09 | Sanofi | Use of an h3 receptor antagonist for the treatment of alzheimer's disease |
| US9034874B2 (en) | 2012-07-20 | 2015-05-19 | Novartis Ag | Carbamate/urea derivatives |
| AU2016287584B2 (en) | 2015-07-02 | 2020-03-26 | Centrexion Therapeutics Corporation | (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4yl)methanone citrate |
| AU2023247609A1 (en) * | 2022-03-31 | 2024-10-17 | Bebetter Med Inc. | 1,4-diheterocyclic substituted aromatic ring or aromatic heterocyclic compound and use thereof |
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| ATE365209T1 (de) | 1992-05-14 | 2007-07-15 | Baylor College Medicine | Mutierte steroidhormonrezeptoren, methoden für ihre benutzung und molekularer schalter für gentherapie |
| US5364791A (en) | 1992-05-14 | 1994-11-15 | Elisabetta Vegeto | Progesterone receptor having C. terminal hormone binding domain truncations |
| IL115420A0 (en) | 1994-09-26 | 1995-12-31 | Zeneca Ltd | Aminoheterocyclic derivatives |
| GB9516709D0 (en) | 1995-08-15 | 1995-10-18 | Zeneca Ltd | Medicament |
| GB9526546D0 (en) | 1995-12-23 | 1996-02-28 | Pfizer Ltd | Compounds useful in therapy |
| IL128428A0 (en) * | 1996-08-14 | 2000-01-31 | Zeneca Ltd | Substituted pyrimidine derivatives and their pharmaceutical use |
| EP1058549A4 (en) | 1998-12-23 | 2003-11-12 | Bristol Myers Squibb Pharma Co | FACTOR Xa OR THROMBIN INHIBITORS |
| US6683093B2 (en) | 2000-05-12 | 2004-01-27 | Pharmacia Corporation | Aromatic sulfone hydroxamic acids and their use as protease inhibitors |
| PE20020507A1 (es) | 2000-10-17 | 2002-06-25 | Schering Corp | Compuestos no-imidazoles como antagonistas del receptor histamina h3 |
| CA2432825A1 (en) * | 2000-12-15 | 2002-06-20 | Emory University | Nonpeptide agonists and antagonists of vasopressin receptors |
| AU2002244271A1 (en) | 2001-03-13 | 2002-09-24 | Pharmacopeia, Inc. | Non-imidazole compounds as histamine h3 antagonists |
| AU2002254114A1 (en) | 2001-03-23 | 2002-10-08 | Eli Lilly And Company | Non-imidazole aryl alkylamines compounds as histamine h3 receptor antagonists, preparation and therapeutic uses |
| ATE449090T1 (de) | 2001-07-02 | 2009-12-15 | High Point Pharmaceuticals Llc | Substituierte piperazin- und diazepanderivate zur verwendung als histamin h3 rezeptormodulatoren |
| ES2349118T3 (es) | 2001-09-14 | 2010-12-28 | High Point Pharmaceuticals, Llc | Nuevos derivados de aminoazetidina, pirrolidina y piperidina. |
| WO2003024928A2 (en) | 2001-09-14 | 2003-03-27 | Novo Nordisk A/S | Novel aminoazetidine, -pyrrolidine and -piperidine derivatives |
| JPWO2003062234A1 (ja) | 2002-01-23 | 2005-05-19 | 山之内製薬株式会社 | キノキサリン化合物 |
| WO2003088967A1 (en) | 2002-04-18 | 2003-10-30 | Schering Corporation | (1-4-piperidinyl) benzimidazole derivatives useful as histamine h3 antagonists |
| NZ535764A (en) | 2002-04-18 | 2007-10-26 | Schering Corp | 1-(4-piperidinyl) benzimidazolones as histamine H3 antagonists |
| WO2004037800A1 (en) | 2002-10-22 | 2004-05-06 | Glaxo Group Limited | Aryloxyalkylamine derivates as h3 receptor ligands |
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2004
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- 2004-04-21 HR HR20080541T patent/HRP20080541T3/xx unknown
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- 2004-04-21 DE DE602004015269T patent/DE602004015269D1/de not_active Expired - Lifetime
- 2004-04-21 KR KR1020057019965A patent/KR20050121268A/ko not_active Withdrawn
- 2004-04-21 WO PCT/EP2004/004245 patent/WO2004101546A1/en not_active Ceased
- 2004-04-21 CA CA002523431A patent/CA2523431A1/en not_active Abandoned
- 2004-04-21 BR BRPI0409611-8A patent/BRPI0409611A/pt not_active IP Right Cessation
- 2004-04-21 EP EP04728561A patent/EP1615909B1/en not_active Expired - Lifetime
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- 2004-04-21 TW TW093111027A patent/TW200503713A/zh unknown
- 2004-04-21 AR ARP040101348A patent/AR044045A1/es not_active Application Discontinuation
- 2004-04-21 JP JP2006529693A patent/JP2006528939A/ja active Pending
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2005
- 2005-10-19 MA MA28564A patent/MA27675A1/fr unknown
- 2005-10-21 CO CO05106973A patent/CO5700754A2/es not_active Application Discontinuation
- 2005-11-21 IS IS8134A patent/IS8134A/is unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HK1090634A1 (en) | 2006-12-29 |
| ATE402165T1 (de) | 2008-08-15 |
| AR044045A1 (es) | 2005-08-24 |
| CA2523431A1 (en) | 2004-11-25 |
| HRP20080541T3 (en) | 2008-12-31 |
| RU2005136368A (ru) | 2006-06-10 |
| KR20050121268A (ko) | 2005-12-26 |
| AU2004238447B2 (en) | 2008-10-30 |
| MA27675A1 (fr) | 2005-12-01 |
| US7592347B2 (en) | 2009-09-22 |
| WO2004101546A1 (en) | 2004-11-25 |
| CO5700754A2 (es) | 2006-11-30 |
| PT1615909E (pt) | 2008-10-30 |
| EP1615909B1 (en) | 2008-07-23 |
| EP1615909A1 (en) | 2006-01-18 |
| IS8134A (is) | 2005-11-21 |
| DK1615909T3 (da) | 2008-11-17 |
| PL1615909T3 (pl) | 2009-01-30 |
| US20070054917A1 (en) | 2007-03-08 |
| TW200503713A (en) | 2005-02-01 |
| JP2006528939A (ja) | 2006-12-28 |
| AU2004238447C1 (en) | 2009-06-11 |
| AU2004238447A1 (en) | 2004-11-25 |
| BRPI0409611A (pt) | 2006-04-18 |
| SI1615909T1 (sl) | 2008-12-31 |
| ES2311152T3 (es) | 2009-02-01 |
| DE602004015269D1 (de) | 2008-09-04 |
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