ES2291694T3 - Benzotiofeno-, benzofurano- e indol-ureas y su uso como agonistas de alfa 7-achr. - Google Patents
Benzotiofeno-, benzofurano- e indol-ureas y su uso como agonistas de alfa 7-achr. Download PDFInfo
- Publication number
- ES2291694T3 ES2291694T3 ES03766162T ES03766162T ES2291694T3 ES 2291694 T3 ES2291694 T3 ES 2291694T3 ES 03766162 T ES03766162 T ES 03766162T ES 03766162 T ES03766162 T ES 03766162T ES 2291694 T3 ES2291694 T3 ES 2291694T3
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- Spain
- Prior art keywords
- alkyl
- amino
- substituted
- necessary
- compounds
- 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.)
- Expired - Lifetime
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- 239000000556 agonist Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- -1 1-aza-bicyclo [2.2.2] oct-3-yl Chemical group 0.000 claims abstract description 109
- 239000012453 solvate Substances 0.000 claims abstract description 70
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 66
- 239000001257 hydrogen Substances 0.000 claims abstract description 66
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 43
- 125000002252 acyl group Chemical group 0.000 claims abstract description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 36
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 29
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 27
- 150000002367 halogens Chemical class 0.000 claims abstract description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
- 239000001301 oxygen Substances 0.000 claims abstract description 27
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000011593 sulfur Substances 0.000 claims abstract description 18
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 15
- 125000005605 benzo group Chemical group 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims abstract description 13
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract 2
- 239000002253 acid Substances 0.000 claims description 43
- 239000000460 chlorine Substances 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 239000012141 concentrate Substances 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 230000015654 memory Effects 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 230000013016 learning Effects 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 230000008447 perception Effects 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 150000002221 fluorine Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 abstract description 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 abstract description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 2
- 125000006823 (C1-C6) acyl group Chemical group 0.000 abstract 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 abstract 1
- 125000004043 oxo group Chemical group O=* 0.000 abstract 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 abstract 1
- 125000000464 thioxo group Chemical group S=* 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 63
- 238000004128 high performance liquid chromatography Methods 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 239000000203 mixture Substances 0.000 description 44
- 239000000047 product Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
- 238000012360 testing method Methods 0.000 description 30
- 239000002585 base Substances 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 22
- NLMFPPVQAZLCMR-GXKRWWSZSA-N 6-amino-n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-1-benzothiophene-2-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1N(CC2)CCC2[C@H]1NC(=O)C1=CC2=CC=C(N)C=C2S1 NLMFPPVQAZLCMR-GXKRWWSZSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 238000002953 preparative HPLC Methods 0.000 description 18
- 239000000126 substance Substances 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 241000700159 Rattus Species 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 235000008504 concentrate Nutrition 0.000 description 12
- 150000004702 methyl esters Chemical class 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 208000002193 Pain Diseases 0.000 description 10
- 206010012289 Dementia Diseases 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000007821 HATU Substances 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012948 isocyanate Substances 0.000 description 6
- IGNPOXGBNFMJHE-SSDOTTSWSA-N (2r)-1-azabicyclo[2.2.2]octan-2-amine Chemical compound C1CN2[C@@H](N)CC1CC2 IGNPOXGBNFMJHE-SSDOTTSWSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 230000036407 pain Effects 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical class C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 description 4
- 102000035037 5-HT3 receptors Human genes 0.000 description 4
- 108091005477 5-HT3 receptors Proteins 0.000 description 4
- OQHZMCSQBFHZNU-UHFFFAOYSA-N 6-nitro-1-benzothiophene-2-carboxylic acid Chemical compound C1=C([N+]([O-])=O)C=C2SC(C(=O)O)=CC2=C1 OQHZMCSQBFHZNU-UHFFFAOYSA-N 0.000 description 4
- YYKIKWNYRWUIKB-UHFFFAOYSA-N 7-bromo-1-benzothiophene-2-carboxylic acid Chemical compound C1=CC(Br)=C2SC(C(=O)O)=CC2=C1 YYKIKWNYRWUIKB-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 208000000094 Chronic Pain Diseases 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 229920002873 Polyethylenimine Polymers 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 3
- CKBBSFOOIOHLPC-UHFFFAOYSA-N 6-bromo-1-benzothiophene-2-carboxylic acid Chemical compound C1=C(Br)C=C2SC(C(=O)O)=CC2=C1 CKBBSFOOIOHLPC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
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- 208000026139 Memory disease Diseases 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 3
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 3
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- 235000013877 carbamide Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 208000010877 cognitive disease Diseases 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
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- 239000013049 sediment Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- REUAXQZIRFXQML-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-amine Chemical compound C1CC2C(N)CN1CC2 REUAXQZIRFXQML-UHFFFAOYSA-N 0.000 description 2
- XFOREGNWACQXLW-UHFFFAOYSA-N 2-(hydroxymethyl)-5-nitrophenol Chemical compound OCC1=CC=C([N+]([O-])=O)C=C1O XFOREGNWACQXLW-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
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- VQLOWUHNXYIAKY-FYZYNONXSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-7-(phenylcarbamoylamino)-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.C=1C=CC=2C=C(C(=O)N[C@@H]3C4CCN(CC4)C3)SC=2C=1NC(=O)NC1=CC=CC=C1 VQLOWUHNXYIAKY-FYZYNONXSA-N 0.000 description 1
- CSDWOMRGGUXKTK-ZOWNYOTGSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-7-bromo-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@H]1NC(=O)C1=CC(C=CC=C2Br)=C2S1 CSDWOMRGGUXKTK-ZOWNYOTGSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005185 naphthylcarbonyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 230000007996 neuronal plasticity Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000004675 pentylcarbonyl group Chemical group C(CCCC)C(=O)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000024587 synaptic transmission, glutamatergic Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000000542 thalamic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- LYTCVQQGCSNFJU-LKGYBJPKSA-N α-bungarotoxin Chemical compound C(/[C@H]1O[C@H]2C[C@H]3O[C@@H](CC(=C)C=O)C[C@H](O)[C@]3(C)O[C@@H]2C[C@@H]1O[C@@H]1C2)=C/C[C@]1(C)O[C@H]1[C@@]2(C)O[C@]2(C)CC[C@@H]3O[C@@H]4C[C@]5(C)O[C@@H]6C(C)=CC(=O)O[C@H]6C[C@H]5O[C@H]4C[C@@H](C)[C@H]3O[C@H]2C1 LYTCVQQGCSNFJU-LKGYBJPKSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10234424 | 2002-07-29 | ||
| DE10234424A DE10234424A1 (de) | 2002-07-29 | 2002-07-29 | Benzothiophen-, Benzofuran- und Indolharnstoffe |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2291694T3 true ES2291694T3 (es) | 2008-03-01 |
Family
ID=30128473
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES03766162T Expired - Lifetime ES2291694T3 (es) | 2002-07-29 | 2003-07-14 | Benzotiofeno-, benzofurano- e indol-ureas y su uso como agonistas de alfa 7-achr. |
Country Status (8)
| Country | Link |
|---|---|
| US (6) | US7795453B2 (https=) |
| EP (1) | EP1527073B1 (https=) |
| JP (1) | JP4601424B2 (https=) |
| AU (1) | AU2003254343A1 (https=) |
| CA (1) | CA2494352C (https=) |
| DE (2) | DE10234424A1 (https=) |
| ES (1) | ES2291694T3 (https=) |
| WO (1) | WO2004013136A1 (https=) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| CN1675204A (zh) | 2002-06-10 | 2005-09-28 | 拜耳医药保健股份公司 | 2－杂芳基甲酰胺 |
| DE10234424A1 (de) * | 2002-07-29 | 2004-02-12 | Bayer Ag | Benzothiophen-, Benzofuran- und Indolharnstoffe |
| GB0220581D0 (en) * | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
| PE20060437A1 (es) * | 2004-06-18 | 2006-06-08 | Novartis Ag | COMPUESTOS AZA-BICICLONONANOS COMO LIGANDOS COLINERGICOS DE nAChR |
| GB0415746D0 (en) | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
| GB0521508D0 (en) * | 2005-10-21 | 2005-11-30 | Novartis Ag | Organic compounds |
| GB0525673D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
| GB0525672D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
| KR20180011888A (ko) | 2008-11-19 | 2018-02-02 | 포럼 파마슈티칼즈 인크. | (ｒ)-７-클로로-ｎ-(퀴누클리딘-３-일)벤조［ｂ］티오펜-２-카르복사미드 및 그 약학적으로 허용가능한 염을 이용한 인지 장애의 치료 |
| PE20120324A1 (es) * | 2009-05-11 | 2012-04-17 | Envivo Pharmaceuticals Inc | Combinacion que comprende (r)-7-cloro-n-(quinuclidin-3-il)benzo[b]tiofeno-2-carboxamida y donezepilo como moduladora de trastornos cognitivos |
| JO3250B1 (ar) | 2009-09-22 | 2018-09-16 | Novartis Ag | إستعمال منشطات مستقبل نيكوتينيك أسيتيل كولين ألفا 7 |
| AR081402A1 (es) | 2010-05-17 | 2012-08-29 | Envivo Pharmaceuticals Inc | Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin-3-il) benzo(b)tiofeno-2-carboxamida monohidrato |
| KR20140003580A (ko) | 2011-01-27 | 2014-01-09 | 노파르티스 아게 | 니코틴성 아세틸콜린 수용체 알파 7 활성화제의 용도 |
| WO2012127393A1 (en) | 2011-03-18 | 2012-09-27 | Novartis Ag | COMBINATIONS OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR ACTIVATORS AND mGluR5 ANTAGONISTS FOR USE IN DOPAMINE INDUCED DYSKINESIA IN PARKINSON'S DISEASE |
| JP6162705B2 (ja) | 2011-10-20 | 2017-07-12 | ノバルティス アーゲー | アルファ７ニコチン性アセチルコリン受容体活性化剤による処置に対する応答性を予測するバイオマーカー |
| CA2872005A1 (en) | 2012-05-08 | 2013-11-14 | Forum Pharmaceuticals, Inc. | Methods of maintaining, treating or improving cognitive function |
| KR102043309B1 (ko) | 2012-12-11 | 2019-11-11 | 노파르티스 아게 | 알파 7 니코틴성 아세틸콜린 수용체 활성화제 치료에 대한 반응성의 예측 바이오마커 |
| WO2016100184A1 (en) | 2014-12-16 | 2016-06-23 | Forum Pharmaceuticals, Inc. | Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors |
| MX2017016231A (es) | 2015-06-10 | 2018-11-29 | Axovant Sciences Gmbh | Compuestos de aminobencisoxazol como agonistas de receptores a7-nicotínicos de acetilcolina. |
| WO2017027600A1 (en) | 2015-08-12 | 2017-02-16 | Forum Pharmaceuticals, Inc. | GEMINAL SUBSTITUTED AMINOBENZISOXAZOLE COMPOUNDS AS AGONISTS OF α7-NICOTINIC ACETYLCHOLINE RECEPTORS |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4605652A (en) * | 1985-02-04 | 1986-08-12 | A. H. Robins Company, Inc. | Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes |
| HU895334D0 (en) | 1986-07-30 | 1990-01-28 | Sandoz Ag | Process for the preparation of nasal pharmaceutical compositions |
| DE3841313A1 (de) * | 1988-12-08 | 1990-06-13 | Bayer Ag | Schwarzes pigment, verfahren zu seiner herstellung sowie dessen verwendung |
| US5189041A (en) * | 1990-11-16 | 1993-02-23 | Syntex (U.S.A.) Inc. | Tricyclic 5-ht3 receptor antagonists |
| GB9201749D0 (en) | 1992-01-28 | 1992-03-11 | Smithkline Beecham Plc | Medicaments |
| US6169759B1 (en) * | 1999-03-22 | 2001-01-02 | Golden Bridge Technology | Common packet channel |
| SE9903997D0 (sv) * | 1999-11-03 | 1999-11-03 | Astra Ab | New compounds |
| GB0010955D0 (en) * | 2000-05-05 | 2000-06-28 | Novartis Ag | Organic compounds |
| JP4616971B2 (ja) | 2000-07-18 | 2011-01-19 | 田辺三菱製薬株式会社 | １−アザビシクロアルカン化合物およびその医薬用途 |
| US6492385B2 (en) * | 2000-08-18 | 2002-12-10 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| US6599916B2 (en) * | 2000-08-21 | 2003-07-29 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| EP1311505A2 (en) * | 2000-08-21 | 2003-05-21 | PHARMACIA & UPJOHN COMPANY | Quinuclidine-substituted heteroaryl moieties for treatment of disease ( nicotinic acetylcholine receptor ligands ) |
| DE10164139A1 (de) * | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| DE10234424A1 (de) * | 2002-07-29 | 2004-02-12 | Bayer Ag | Benzothiophen-, Benzofuran- und Indolharnstoffe |
| AR081402A1 (es) * | 2010-05-17 | 2012-08-29 | Envivo Pharmaceuticals Inc | Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin-3-il) benzo(b)tiofeno-2-carboxamida monohidrato |
-
2002
- 2002-07-29 DE DE10234424A patent/DE10234424A1/de not_active Withdrawn
-
2003
- 2003-07-14 EP EP03766162A patent/EP1527073B1/de not_active Expired - Lifetime
- 2003-07-14 DE DE50308015T patent/DE50308015D1/de not_active Expired - Lifetime
- 2003-07-14 WO PCT/EP2003/007588 patent/WO2004013136A1/de not_active Ceased
- 2003-07-14 US US10/522,611 patent/US7795453B2/en not_active Expired - Fee Related
- 2003-07-14 CA CA2494352A patent/CA2494352C/en not_active Expired - Fee Related
- 2003-07-14 JP JP2004525191A patent/JP4601424B2/ja not_active Expired - Fee Related
- 2003-07-14 AU AU2003254343A patent/AU2003254343A1/en not_active Abandoned
- 2003-07-14 ES ES03766162T patent/ES2291694T3/es not_active Expired - Lifetime
-
2010
- 2010-08-30 US US12/871,495 patent/US8153799B2/en not_active Expired - Fee Related
-
2012
- 2012-04-06 US US13/441,407 patent/US8772511B2/en not_active Expired - Fee Related
-
2014
- 2014-06-09 US US14/299,750 patent/US9714242B2/en not_active Expired - Fee Related
-
2017
- 2017-06-15 US US15/624,227 patent/US10196388B2/en not_active Expired - Fee Related
-
2018
- 2018-12-20 US US16/228,182 patent/US20190367504A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20100324085A1 (en) | 2010-12-23 |
| US20060106096A1 (en) | 2006-05-18 |
| US20190367504A1 (en) | 2019-12-05 |
| EP1527073B1 (de) | 2007-08-22 |
| AU2003254343A1 (en) | 2004-02-23 |
| US8153799B2 (en) | 2012-04-10 |
| CA2494352A1 (en) | 2004-02-12 |
| US20130060039A1 (en) | 2013-03-07 |
| WO2004013136A1 (de) | 2004-02-12 |
| US7795453B2 (en) | 2010-09-14 |
| JP4601424B2 (ja) | 2010-12-22 |
| JP2005538111A (ja) | 2005-12-15 |
| EP1527073A1 (de) | 2005-05-04 |
| US10196388B2 (en) | 2019-02-05 |
| US20150065537A1 (en) | 2015-03-05 |
| US20180127409A1 (en) | 2018-05-10 |
| CA2494352C (en) | 2011-11-08 |
| US8772511B2 (en) | 2014-07-08 |
| DE10234424A1 (de) | 2004-02-12 |
| US9714242B2 (en) | 2017-07-25 |
| DE50308015D1 (de) | 2007-10-04 |
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