AU2003238450A1 - 2-heteroaryl carboxamides - Google Patents
2-heteroaryl carboxamides Download PDFInfo
- Publication number
- AU2003238450A1 AU2003238450A1 AU2003238450A AU2003238450A AU2003238450A1 AU 2003238450 A1 AU2003238450 A1 AU 2003238450A1 AU 2003238450 A AU2003238450 A AU 2003238450A AU 2003238450 A AU2003238450 A AU 2003238450A AU 2003238450 A1 AU2003238450 A1 AU 2003238450A1
- Authority
- AU
- Australia
- Prior art keywords
- mmol
- oct
- azabicyclo
- alkyl
- salts
- 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.)
- Abandoned
Links
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 230000013016 learning Effects 0.000 claims abstract description 11
- 230000015654 memory Effects 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 238000011321 prophylaxis Methods 0.000 claims abstract description 7
- 230000008447 perception Effects 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 331
- 238000000034 method Methods 0.000 claims description 231
- -1 1-azabicyclo[2.2.2]oct-3-yl Chemical group 0.000 claims description 212
- 239000000203 mixture Substances 0.000 claims description 162
- 239000002904 solvent Substances 0.000 claims description 147
- 150000003839 salts Chemical class 0.000 claims description 82
- 239000012453 solvate Substances 0.000 claims description 75
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 58
- 229910052736 halogen Inorganic materials 0.000 claims description 56
- 150000002367 halogens Chemical class 0.000 claims description 56
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 12
- 125000005605 benzo group Chemical group 0.000 claims description 12
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- 125000000732 arylene group Chemical group 0.000 claims description 7
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 7
- 125000005549 heteroarylene group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- WXLPFZKLJWNZSL-UHFFFAOYSA-N [N].C1CC2CCN1CC2 Chemical group [N].C1CC2CCN1CC2 WXLPFZKLJWNZSL-UHFFFAOYSA-N 0.000 claims description 4
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 3
- 230000002152 alkylating effect Effects 0.000 claims description 3
- 230000006735 deficit Effects 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 3
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 519
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 305
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 216
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 195
- 238000004128 high performance liquid chromatography Methods 0.000 description 178
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 176
- 239000000243 solution Substances 0.000 description 169
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 156
- 239000012458 free base Substances 0.000 description 128
- 238000005160 1H NMR spectroscopy Methods 0.000 description 127
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 119
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 109
- 238000001035 drying Methods 0.000 description 101
- 239000000047 product Substances 0.000 description 101
- 101150003085 Pdcl gene Proteins 0.000 description 97
- 238000002953 preparative HPLC Methods 0.000 description 95
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- 239000011541 reaction mixture Substances 0.000 description 83
- 238000007429 general method Methods 0.000 description 79
- 238000000746 purification Methods 0.000 description 67
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 66
- 239000012043 crude product Substances 0.000 description 66
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 65
- 229910000029 sodium carbonate Inorganic materials 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- 235000017550 sodium carbonate Nutrition 0.000 description 58
- 235000011121 sodium hydroxide Nutrition 0.000 description 58
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 48
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 29
- 238000001816 cooling Methods 0.000 description 29
- 239000003480 eluent Substances 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- JWCRXRGSXCXKPX-ZOWNYOTGSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-7-bromo-1-benzofuran-2-carboxamide;hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@H]1NC(=O)C1=CC(C=CC=C2Br)=C2O1 JWCRXRGSXCXKPX-ZOWNYOTGSA-N 0.000 description 27
- 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 27
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- 235000011056 potassium acetate Nutrition 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 23
- 238000012360 testing method Methods 0.000 description 22
- 238000010438 heat treatment Methods 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 21
- 150000003254 radicals Chemical class 0.000 description 21
- BVYUKLDJKTVDRA-FYZYNONXSA-N 3-[2-[[(3r)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl]-1-benzofuran-7-yl]benzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CC(C=2C=3OC(=CC=3C=CC=2)C(=O)N[C@@H]2C3CCN(CC3)C2)=C1 BVYUKLDJKTVDRA-FYZYNONXSA-N 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 239000007821 HATU Substances 0.000 description 18
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 17
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 17
- 238000004611 spectroscopical analysis Methods 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 150000002500 ions Chemical class 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- VZGVVSVVVHCQOR-FYZYNONXSA-N 3-[2-[[(3r)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl]-1-benzothiophen-7-yl]benzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CC(C=2C=3SC(=CC=3C=CC=2)C(=O)N[C@@H]2C3CCN(CC3)C2)=C1 VZGVVSVVVHCQOR-FYZYNONXSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 15
- 229910052796 boron Inorganic materials 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 229910021529 ammonia Inorganic materials 0.000 description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 14
- 229940087646 methanolamine Drugs 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- YYSWMYSFKQPZMS-FYZYNONXSA-N 7-(3-aminophenyl)-n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.NC1=CC=CC(C=2C=3SC(=CC=3C=CC=2)C(=O)N[C@@H]2C3CCN(CC3)C2)=C1 YYSWMYSFKQPZMS-FYZYNONXSA-N 0.000 description 13
- 101100028920 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cfp gene Proteins 0.000 description 13
- 241000700159 Rattus Species 0.000 description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
- OMJHFZCWUQSYEQ-CYBMUJFWSA-N n-[(3s)-1-azabicyclo[2.2.2]octan-3-yl]-7-bromo-1-benzofuran-2-carboxamide Chemical compound C1N(CC2)CCC2[C@@H]1NC(=O)C1=CC(C=CC=C2Br)=C2O1 OMJHFZCWUQSYEQ-CYBMUJFWSA-N 0.000 description 13
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- 239000012312 sodium hydride Substances 0.000 description 13
- UVKVGWAZQWEEQA-IBGZPJMESA-N 7-(3-aminophenyl)-n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-1-benzofuran-2-carboxamide Chemical compound NC1=CC=CC(C=2C=3OC(=CC=3C=CC=2)C(=O)N[C@@H]2C3CCN(CC3)C2)=C1 UVKVGWAZQWEEQA-IBGZPJMESA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 12
- 235000019253 formic acid Nutrition 0.000 description 12
- GRHBNDHCXARNLO-ZDUSSCGKSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-5-bromo-1-benzofuran-2-carboxamide Chemical compound C1N(CC2)CCC2[C@H]1NC(=O)C1=CC2=CC(Br)=CC=C2O1 GRHBNDHCXARNLO-ZDUSSCGKSA-N 0.000 description 12
- KXMRMWGSFCMYEJ-ZOWNYOTGSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-6-bromo-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@H]1NC(=O)C1=CC2=CC=C(Br)C=C2S1 KXMRMWGSFCMYEJ-ZOWNYOTGSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 229960001866 silicon dioxide Drugs 0.000 description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 11
- 208000002193 Pain Diseases 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- STZHBULOYDCZET-KLXURFKVSA-N (3r)-1-azabicyclo[2.2.2]octan-3-amine;dihydrochloride Chemical compound Cl.Cl.C1CC2[C@@H](N)CN1CC2 STZHBULOYDCZET-KLXURFKVSA-N 0.000 description 10
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 10
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 235000011054 acetic acid Nutrition 0.000 description 10
- 150000003857 carboxamides Chemical class 0.000 description 10
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- JXHYCCGOZUGBFD-UHFFFAOYSA-N benzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CC=C1 JXHYCCGOZUGBFD-UHFFFAOYSA-N 0.000 description 9
- 230000003197 catalytic effect Effects 0.000 description 9
- NTMXUUXGPAUABI-ZDUSSCGKSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-6-bromo-1-benzofuran-2-carboxamide Chemical compound C1N(CC2)CCC2[C@H]1NC(=O)C1=CC2=CC=C(Br)C=C2O1 NTMXUUXGPAUABI-ZDUSSCGKSA-N 0.000 description 9
- OMJHFZCWUQSYEQ-ZDUSSCGKSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-7-bromo-1-benzofuran-2-carboxamide Chemical compound C1N(CC2)CCC2[C@H]1NC(=O)C1=CC(C=CC=C2Br)=C2O1 OMJHFZCWUQSYEQ-ZDUSSCGKSA-N 0.000 description 9
- CSDWOMRGGUXKTK-BTQNPOSSSA-N n-[(3s)-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-BTQNPOSSSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- WHDIUBHAKZDSJL-UHFFFAOYSA-N (4-morpholin-4-ylphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1N1CCOCC1 WHDIUBHAKZDSJL-UHFFFAOYSA-N 0.000 description 8
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- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- DVCFNCQPOANJGU-UHFFFAOYSA-N oxolane-2-carbonyl chloride Chemical compound ClC(=O)C1CCCO1 DVCFNCQPOANJGU-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical class [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- 125000004675 pentylcarbonyl group Chemical group C(CCCC)C(=O)* 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 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
- 238000000159 protein binding assay Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl 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
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 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
- 239000011593 sulfur Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 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
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- QKIPWYSRBGTXRG-UHFFFAOYSA-N tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(Br)C=C1 QKIPWYSRBGTXRG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 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
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10225536 | 2002-06-10 | ||
| DE10225536.9 | 2002-06-10 | ||
| DE10257078A DE10257078A1 (de) | 2002-12-06 | 2002-12-06 | 2-Heteroarylcarbonsäureamide |
| DE10257078.7 | 2002-12-06 | ||
| DE10257537.1 | 2002-12-10 | ||
| DE2002157537 DE10257537A1 (de) | 2002-12-10 | 2002-12-10 | 2-Heteroarylcarbonsäureamide |
| DE10305922.9 | 2003-02-13 | ||
| DE10305922A DE10305922A1 (de) | 2002-06-10 | 2003-02-13 | 2-Heteroarylcarbonsäureamide |
| PCT/EP2003/005735 WO2003104227A1 (de) | 2002-01-20 | 2003-06-02 | 2-heteroarylcarbonsäureamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2003238450A1 true AU2003238450A1 (en) | 2003-12-22 |
Family
ID=29740887
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2003238450A Abandoned AU2003238450A1 (en) | 2002-06-10 | 2003-06-02 | 2-heteroaryl carboxamides |
Country Status (16)
| Country | Link |
|---|---|
| US (5) | US7977485B2 (enExample) |
| EP (1) | EP1515967B1 (enExample) |
| JP (1) | JP4542891B2 (enExample) |
| CN (1) | CN1675204A (enExample) |
| AT (1) | ATE344262T1 (enExample) |
| AU (1) | AU2003238450A1 (enExample) |
| BR (1) | BR0312446A (enExample) |
| CA (1) | CA2488761C (enExample) |
| DE (1) | DE50305587D1 (enExample) |
| ES (1) | ES2276072T3 (enExample) |
| IL (1) | IL165505A0 (enExample) |
| MX (1) | MXPA04012439A (enExample) |
| NO (1) | NO20050063L (enExample) |
| PL (1) | PL374551A1 (enExample) |
| UY (1) | UY27841A1 (enExample) |
| WO (1) | WO2003104227A1 (enExample) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| US7977485B2 (en) * | 2002-06-10 | 2011-07-12 | Bayer Schering Pharma Aktiengesellshaft | 2-heteroaryl carboxamides |
| CA2499128C (en) * | 2002-09-25 | 2012-07-31 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof |
| DE602004031124D1 (de) | 2003-08-13 | 2011-03-03 | Neurosearch As | Neue chinuklidinderivative und deren pharmazeutische verwendung |
| US7396833B2 (en) | 2003-12-22 | 2008-07-08 | Memory Pharmaceuticals Corporation | Indoles, 1H-indazoles, 1,2-benzisoxazoles, and 1,2-benzisothiazoles, and preparation and uses thereof |
| CN103724343A (zh) | 2004-03-25 | 2014-04-16 | 记忆药物公司 | 吲唑、苯并噻唑、苯并异噻唑、苯并异噁唑及其制备和用途 |
| JP2007538046A (ja) | 2004-05-19 | 2007-12-27 | ノイロサーチ アクティーゼルスカブ | 新規なアザビシクロアリール誘導体 |
| CN100588657C (zh) * | 2004-10-15 | 2010-02-10 | 神经研究公司 | 新的氮杂双环芳基衍生物及其医药用途 |
| US8106066B2 (en) * | 2005-09-23 | 2012-01-31 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof |
| RU2474581C2 (ru) * | 2007-12-26 | 2013-02-10 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Способ получения замещенных гетероциклом производных пиридина |
| US8367676B2 (en) * | 2009-06-30 | 2013-02-05 | Astrazeneca Ab | 2-carboxamide-7-piperazinyl-benzofuran derivatives 774 |
| CN103221411B (zh) | 2010-05-17 | 2016-05-11 | 富瑞姆制药公司 | (R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺盐酸盐单水合物的晶型 |
| WO2012087229A1 (en) | 2010-12-20 | 2012-06-28 | Astrazeneca Ab | 2-carboxamide-4-piperazinyl-benzofuran derivative |
| KR101928505B1 (ko) * | 2011-01-28 | 2018-12-12 | 에스케이바이오팜 주식회사 | 피리돈 유도체 및 이를 포함하는 약학적 조성물 |
| AU2013259871A1 (en) | 2012-05-08 | 2014-11-20 | Forum Pharmaceuticals Inc. | Methods of maintaining, treating or improving cognitive function |
| CN111205283A (zh) * | 2020-01-20 | 2020-05-29 | 广州九植医药科技有限公司 | 一种盐酸帕洛诺司琼有关物质b的合成方法 |
| CN111205284A (zh) * | 2020-01-20 | 2020-05-29 | 广州九植医药科技有限公司 | 一种盐酸帕洛诺司琼有关物质a的合成方法 |
| US20230391758A1 (en) * | 2020-09-18 | 2023-12-07 | Merck Sharp & Dohme Llc | Modified benzofuran-carboxamides as glucosylceramide synthase inhibitors |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0000540D0 (sv) * | 2000-02-18 | 2000-02-18 | Astrazeneca Ab | New 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 |
| AR036040A1 (es) | 2001-06-12 | 2004-08-04 | Upjohn Co | Compuestos de heteroarilo multiciclicos sustituidos con quinuclidinas y composiciones farmaceuticas que los contienen |
| US6911543B2 (en) | 2001-10-02 | 2005-06-28 | Pfizer Inc. | Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease |
| DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| US7977485B2 (en) * | 2002-06-10 | 2011-07-12 | Bayer Schering Pharma Aktiengesellshaft | 2-heteroaryl carboxamides |
| DE10234424A1 (de) | 2002-07-29 | 2004-02-12 | Bayer Ag | Benzothiophen-, Benzofuran- und Indolharnstoffe |
-
2003
- 2003-06-02 US US10/516,777 patent/US7977485B2/en not_active Expired - Fee Related
- 2003-06-02 AT AT03732517T patent/ATE344262T1/de not_active IP Right Cessation
- 2003-06-02 AU AU2003238450A patent/AU2003238450A1/en not_active Abandoned
- 2003-06-02 JP JP2004511297A patent/JP4542891B2/ja not_active Expired - Fee Related
- 2003-06-02 DE DE50305587T patent/DE50305587D1/de not_active Expired - Lifetime
- 2003-06-02 EP EP03732517A patent/EP1515967B1/de not_active Expired - Lifetime
- 2003-06-02 CA CA2488761A patent/CA2488761C/en not_active Expired - Fee Related
- 2003-06-02 ES ES03732517T patent/ES2276072T3/es not_active Expired - Lifetime
- 2003-06-02 WO PCT/EP2003/005735 patent/WO2003104227A1/de not_active Ceased
- 2003-06-02 MX MXPA04012439A patent/MXPA04012439A/es unknown
- 2003-06-02 BR BR0312446-0A patent/BR0312446A/pt not_active Application Discontinuation
- 2003-06-02 PL PL03374551A patent/PL374551A1/xx not_active Application Discontinuation
- 2003-06-02 CN CNA038188511A patent/CN1675204A/zh active Pending
- 2003-06-10 UY UY27841A patent/UY27841A1/es not_active Application Discontinuation
-
2004
- 2004-12-02 IL IL16550504A patent/IL165505A0/xx unknown
-
2005
- 2005-01-06 NO NO20050063A patent/NO20050063L/no not_active Application Discontinuation
-
2011
- 2011-07-11 US US13/179,957 patent/US20110263591A1/en not_active Abandoned
-
2012
- 2012-03-06 US US13/412,946 patent/US20120258964A1/en not_active Abandoned
-
2014
- 2014-04-25 US US14/261,616 patent/US9067931B2/en not_active Expired - Fee Related
-
2015
- 2015-06-08 US US14/733,804 patent/US10214524B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US9067931B2 (en) | 2015-06-30 |
| US20160122337A1 (en) | 2016-05-05 |
| CA2488761C (en) | 2011-05-31 |
| JP2005533052A (ja) | 2005-11-04 |
| CA2488761A1 (en) | 2003-12-18 |
| JP4542891B2 (ja) | 2010-09-15 |
| ATE344262T1 (de) | 2006-11-15 |
| MXPA04012439A (es) | 2005-04-19 |
| US20060160877A1 (en) | 2006-07-20 |
| BR0312446A (pt) | 2005-04-19 |
| NO20050063L (no) | 2005-01-06 |
| DE50305587D1 (en) | 2006-12-14 |
| US10214524B2 (en) | 2019-02-26 |
| EP1515967A1 (de) | 2005-03-23 |
| US7977485B2 (en) | 2011-07-12 |
| US20110263591A1 (en) | 2011-10-27 |
| UY27841A1 (es) | 2003-12-31 |
| WO2003104227A1 (de) | 2003-12-18 |
| ES2276072T3 (es) | 2007-06-16 |
| US20120258964A1 (en) | 2012-10-11 |
| PL374551A1 (en) | 2005-10-31 |
| US20140350008A1 (en) | 2014-11-27 |
| CN1675204A (zh) | 2005-09-28 |
| IL165505A0 (en) | 2006-01-15 |
| EP1515967B1 (de) | 2006-11-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1 | Application lapsed section 142(2)(a) - no request for examination in relevant period |