JP2007505877A - 疼痛治療用バニロイド−１受容体（ｖｒ１）モジュレーターとしてのｎ−（１ｈ−インダゾリル）−尿素誘導体及びｎ−（１ｈ−インドリル）−尿素誘導体並びに関連化合物 - Google Patents
疼痛治療用バニロイド−１受容体（ｖｒ１）モジュレーターとしてのｎ−（１ｈ−インダゾリル）−尿素誘導体及びｎ−（１ｈ−インドリル）−尿素誘導体並びに関連化合物 Download PDFInfo
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- JP2007505877A JP2007505877A JP2006526691A JP2006526691A JP2007505877A JP 2007505877 A JP2007505877 A JP 2007505877A JP 2006526691 A JP2006526691 A JP 2006526691A JP 2006526691 A JP2006526691 A JP 2006526691A JP 2007505877 A JP2007505877 A JP 2007505877A
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- Prior art keywords
- trifluoromethyl
- benzyl
- urea
- alkyl
- formula
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 156
- 208000002193 Pain Diseases 0.000 title abstract description 26
- 108010025083 TRPV1 receptor Proteins 0.000 title abstract description 25
- -1 N- (1H-indazolyl) -urea derivatives Chemical class 0.000 title description 80
- KYHGSAOIGRIGQV-UHFFFAOYSA-N indol-1-ylurea Chemical class C1=CC=C2N(NC(=O)N)C=CC2=C1 KYHGSAOIGRIGQV-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 113
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 66
- 125000005843 halogen group Chemical group 0.000 claims abstract description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 50
- 239000001257 hydrogen Substances 0.000 claims abstract description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 42
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 30
- 150000002367 halogens Chemical class 0.000 claims abstract description 26
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 19
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 11
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 11
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 11
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 10
- 125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 7
- 125000005059 halophenyl group Chemical group 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 27
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 26
- 229940002612 prodrug Drugs 0.000 claims description 18
- 239000000651 prodrug Substances 0.000 claims description 18
- 150000001204 N-oxides Chemical class 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- UYFJNTVXZQWDTQ-UHFFFAOYSA-N 1-(1-methyl-2-oxo-3h-indol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound CN1C(=O)CC2=C1C=CC=C2NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 UYFJNTVXZQWDTQ-UHFFFAOYSA-N 0.000 claims description 3
- DJTQGUFXNJDXRL-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-[[4-(trifluoromethoxy)phenyl]methyl]urea Chemical compound C1=CC(OC(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1C=NN2 DJTQGUFXNJDXRL-UHFFFAOYSA-N 0.000 claims description 3
- MMDHAGYNJNCDAF-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1C=NN2 MMDHAGYNJNCDAF-UHFFFAOYSA-N 0.000 claims description 3
- GZNMGIKMOUGAQS-UHFFFAOYSA-N 1-(1h-indazol-6-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=C(C=NN2)C2=C1 GZNMGIKMOUGAQS-UHFFFAOYSA-N 0.000 claims description 3
- DIZORDSNHUYNCI-UHFFFAOYSA-N 1-(1h-indol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1C=CN2 DIZORDSNHUYNCI-UHFFFAOYSA-N 0.000 claims description 3
- IOSPLGKBWAXALM-UHFFFAOYSA-N 1-(1h-indol-5-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=C(NC=C2)C2=C1 IOSPLGKBWAXALM-UHFFFAOYSA-N 0.000 claims description 3
- WFBXIGJUMYSJIG-UHFFFAOYSA-N 1-(7-amino-1,2-benzothiazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=2C=NSC=2C(N)=CC=C1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 WFBXIGJUMYSJIG-UHFFFAOYSA-N 0.000 claims description 3
- OYSDRSMNMVUQNK-UHFFFAOYSA-N 1-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-3-(1h-indazol-4-yl)urea Chemical compound FC1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1C=NN2 OYSDRSMNMVUQNK-UHFFFAOYSA-N 0.000 claims description 3
- TYTGHPXWAYOTEG-UHFFFAOYSA-N 1-[[3-fluoro-4-(trifluoromethyl)phenyl]methyl]-3-(1h-indazol-4-yl)urea Chemical compound C1=C(C(F)(F)F)C(F)=CC(CNC(=O)NC=2C=3C=NNC=3C=CC=2)=C1 TYTGHPXWAYOTEG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- ZKHZJGDJWVTEDF-UHFFFAOYSA-N 1-(1,2-benzothiazol-5-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=C(SN=C2)C2=C1 ZKHZJGDJWVTEDF-UHFFFAOYSA-N 0.000 claims description 2
- MIWVXXPEKGDYBA-UHFFFAOYSA-N 1-(1,2-benzothiazol-7-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1SN=C2 MIWVXXPEKGDYBA-UHFFFAOYSA-N 0.000 claims description 2
- FXFDPRICOKENNR-UHFFFAOYSA-N 1-(1,3-benzothiazol-5-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=C(SC=N2)C2=C1 FXFDPRICOKENNR-UHFFFAOYSA-N 0.000 claims description 2
- GWZIRRZEGZMKCL-UHFFFAOYSA-N 1-(1,3-benzothiazol-6-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=C(N=CS2)C2=C1 GWZIRRZEGZMKCL-UHFFFAOYSA-N 0.000 claims description 2
- VWTCLFQQYGVGNJ-UHFFFAOYSA-N 1-(1,3-benzothiazol-7-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1SC=N2 VWTCLFQQYGVGNJ-UHFFFAOYSA-N 0.000 claims description 2
- RJWWWCFBFUBOEB-UHFFFAOYSA-N 1-(1-methylindazol-4-yl)-3-[[4-(trifluoromethoxy)phenyl]methyl]urea Chemical compound C1=CC=C2N(C)N=CC2=C1NC(=O)NCC1=CC=C(OC(F)(F)F)C=C1 RJWWWCFBFUBOEB-UHFFFAOYSA-N 0.000 claims description 2
- CFGGYUAMWOASFU-UHFFFAOYSA-N 1-(1-methylindazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC=C2N(C)N=CC2=C1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 CFGGYUAMWOASFU-UHFFFAOYSA-N 0.000 claims description 2
- DTVUVWWLSNDWLJ-UHFFFAOYSA-N 1-(1h-benzimidazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1N=CN2 DTVUVWWLSNDWLJ-UHFFFAOYSA-N 0.000 claims description 2
- BCJWPBONPCHUCK-UHFFFAOYSA-N 1-(1h-indazol-5-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=C(NN=C2)C2=C1 BCJWPBONPCHUCK-UHFFFAOYSA-N 0.000 claims description 2
- WINLWNYSQIMVGM-UHFFFAOYSA-N 1-(2,3-dihydro-1-benzofuran-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1CCO2 WINLWNYSQIMVGM-UHFFFAOYSA-N 0.000 claims description 2
- BGBCEEDDPITDGW-UHFFFAOYSA-N 1-(2-methyl-1,3-benzothiazol-5-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C=1C=C2SC(C)=NC2=CC=1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 BGBCEEDDPITDGW-UHFFFAOYSA-N 0.000 claims description 2
- SKHLZELKYZFSHO-UHFFFAOYSA-N 1-(2-methyl-1,3-benzoxazol-5-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C=1C=C2OC(C)=NC2=CC=1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 SKHLZELKYZFSHO-UHFFFAOYSA-N 0.000 claims description 2
- GJPALMHDYAOBRM-UHFFFAOYSA-N 1-(2-methyl-1,3-benzoxazol-7-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C=12OC(C)=NC2=CC=CC=1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 GJPALMHDYAOBRM-UHFFFAOYSA-N 0.000 claims description 2
- YTLIVSBWOLDSTF-UHFFFAOYSA-N 1-(2-methylindazol-4-yl)-3-[[4-(trifluoromethoxy)phenyl]methyl]urea Chemical compound C=1C=CC2=NN(C)C=C2C=1NC(=O)NCC1=CC=C(OC(F)(F)F)C=C1 YTLIVSBWOLDSTF-UHFFFAOYSA-N 0.000 claims description 2
- MMLOGZYVHBSNCW-UHFFFAOYSA-N 1-(2-oxo-1,3-dihydroindol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1CC(=O)N2 MMLOGZYVHBSNCW-UHFFFAOYSA-N 0.000 claims description 2
- AMXZKXUOBCCOFN-UHFFFAOYSA-N 1-(3-methyl-2h-indazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C=12C(C)=NNC2=CC=CC=1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 AMXZKXUOBCCOFN-UHFFFAOYSA-N 0.000 claims description 2
- AIPSQHDGMAAIJT-UHFFFAOYSA-N 1-(4-chloro-1,2-benzothiazol-7-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=C(Cl)C2=C1SN=C2 AIPSQHDGMAAIJT-UHFFFAOYSA-N 0.000 claims description 2
- XCGMGBBVHOJQRA-UHFFFAOYSA-N 1-(4h-imidazo[1,2-a]indol-5-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=C1CC1=NC=CN21 XCGMGBBVHOJQRA-UHFFFAOYSA-N 0.000 claims description 2
- RJIBXKJKRRRUGA-UHFFFAOYSA-N 1-(5-fluoro-1h-indazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound FC1=CC=C2NN=CC2=C1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 RJIBXKJKRRRUGA-UHFFFAOYSA-N 0.000 claims description 2
- VSLKBALQNGPKGC-UHFFFAOYSA-N 1-(6-fluoro-1-methylindazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=C(F)C=C2N(C)N=CC2=C1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 VSLKBALQNGPKGC-UHFFFAOYSA-N 0.000 claims description 2
- SMIDUPZPRWZJRE-UHFFFAOYSA-N 1-(6-fluoro-1h-indazol-4-yl)-3-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C=12C=NNC2=CC(F)=CC=1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1F SMIDUPZPRWZJRE-UHFFFAOYSA-N 0.000 claims description 2
- PDTNMCHJOHAQKV-UHFFFAOYSA-N 1-(6-fluoro-1h-indazol-4-yl)-3-[[4-(trifluoromethoxy)phenyl]methyl]urea Chemical compound C=12C=NNC2=CC(F)=CC=1NC(=O)NCC1=CC=C(OC(F)(F)F)C=C1 PDTNMCHJOHAQKV-UHFFFAOYSA-N 0.000 claims description 2
- IHTTZJGIEQLKSD-UHFFFAOYSA-N 1-(6-fluoro-1h-indazol-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C=12C=NNC2=CC(F)=CC=1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 IHTTZJGIEQLKSD-UHFFFAOYSA-N 0.000 claims description 2
- MKVVWGHDVFQXJI-UHFFFAOYSA-N 1-(triazolo[1,5-a]pyridin-4-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CN2C1=CN=N2 MKVVWGHDVFQXJI-UHFFFAOYSA-N 0.000 claims description 2
- RUDQTOXUQFTRGA-UHFFFAOYSA-N 1-(triazolo[1,5-a]pyridin-7-yl)-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=CN=NN12 RUDQTOXUQFTRGA-UHFFFAOYSA-N 0.000 claims description 2
- LETSCFBFLUPBOV-UHFFFAOYSA-N 1-[1-methyl-6-(trifluoromethyl)indazol-4-yl]-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=C(C(F)(F)F)C=C2N(C)N=CC2=C1NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 LETSCFBFLUPBOV-UHFFFAOYSA-N 0.000 claims description 2
- WHSRYKAYDMTIFW-UHFFFAOYSA-N 1-[6-(trifluoromethyl)-1h-indazol-4-yl]-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC(C(F)(F)F)=CC2=C1C=NN2 WHSRYKAYDMTIFW-UHFFFAOYSA-N 0.000 claims description 2
- NZFJCKJVSPFQBS-UHFFFAOYSA-N 1-imidazo[1,2-a]pyridin-5-yl-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=NC=CN12 NZFJCKJVSPFQBS-UHFFFAOYSA-N 0.000 claims description 2
- FNPGUYUTCVNRGL-UHFFFAOYSA-N 1-imidazo[1,5-a]pyridin-5-yl-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CC2=CN=CN12 FNPGUYUTCVNRGL-UHFFFAOYSA-N 0.000 claims description 2
- QCUZNAKLEPBLHQ-UHFFFAOYSA-N 1-imidazo[1,5-a]pyridin-8-yl-3-[[4-(trifluoromethyl)phenyl]methyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC(=O)NC1=CC=CN2C1=CN=C2 QCUZNAKLEPBLHQ-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 230000001668 ameliorated effect Effects 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 8
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 34
- 125000001424 substituent group Chemical group 0.000 abstract description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 19
- 150000002431 hydrogen Chemical class 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 88
- 238000005481 NMR spectroscopy Methods 0.000 description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000007787 solid Substances 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 26
- 238000010992 reflux Methods 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 229910052731 fluorine Inorganic materials 0.000 description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 15
- 229960002504 capsaicin Drugs 0.000 description 14
- 235000017663 capsaicin Nutrition 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000011737 fluorine Substances 0.000 description 13
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000005557 antagonist Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000012948 isocyanate Substances 0.000 description 8
- 150000002513 isocyanates Chemical class 0.000 description 8
- 239000000463 material Substances 0.000 description 8
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- QAOWRAOTWHLVRO-UHFFFAOYSA-N tert-butyl n-(triazolo[1,5-a]pyridin-4-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN2N=NC=C12 QAOWRAOTWHLVRO-UHFFFAOYSA-N 0.000 description 1
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- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
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- LZISVZBSKHHYQG-UHFFFAOYSA-N triazolo[1,5-a]pyridin-7-amine Chemical compound NC1=CC=CC2=CN=NN12 LZISVZBSKHHYQG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0322016.7A GB0322016D0 (en) | 2003-09-19 | 2003-09-19 | New compounds |
| PCT/GB2004/003968 WO2005028445A2 (en) | 2003-09-19 | 2004-09-16 | Derivatives of n-(1h-indazolyl)- and n-(1h-indolyl)-urea as well as related compounds as modulators of the vanilloid-1 receptor (vr1) for the treatment of pain |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2007505877A true JP2007505877A (ja) | 2007-03-15 |
| JP2007505877A5 JP2007505877A5 (enExample) | 2007-11-08 |
Family
ID=29266326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006526691A Withdrawn JP2007505877A (ja) | 2003-09-19 | 2004-09-16 | 疼痛治療用バニロイド−１受容体（ｖｒ１）モジュレーターとしてのｎ−（１ｈ−インダゾリル）−尿素誘導体及びｎ−（１ｈ−インドリル）−尿素誘導体並びに関連化合物 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20070078156A1 (enExample) |
| EP (1) | EP1675587A2 (enExample) |
| JP (1) | JP2007505877A (enExample) |
| CN (1) | CN1856304A (enExample) |
| AU (1) | AU2004274230A1 (enExample) |
| CA (1) | CA2538454A1 (enExample) |
| GB (1) | GB0322016D0 (enExample) |
| WO (1) | WO2005028445A2 (enExample) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010523727A (ja) * | 2007-04-16 | 2010-07-15 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | バニロイド受容体リガンドおよび医薬の製造へのその使用 |
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| JP2019142838A (ja) * | 2017-12-26 | 2019-08-29 | 財團法人工業技術研究院Ｉｎｄｕｓｔｒｉａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ | Ａｇｃキナーゼを阻害する化合物およびそれを含む医薬組成物 |
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| US6933311B2 (en) * | 2003-02-11 | 2005-08-23 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
-
2003
- 2003-09-19 GB GBGB0322016.7A patent/GB0322016D0/en not_active Ceased
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- 2004-09-16 US US10/571,544 patent/US20070078156A1/en not_active Abandoned
- 2004-09-16 EP EP04768514A patent/EP1675587A2/en not_active Withdrawn
- 2004-09-16 AU AU2004274230A patent/AU2004274230A1/en not_active Abandoned
- 2004-09-16 WO PCT/GB2004/003968 patent/WO2005028445A2/en not_active Ceased
- 2004-09-16 CN CNA2004800271826A patent/CN1856304A/zh active Pending
- 2004-09-16 CA CA002538454A patent/CA2538454A1/en not_active Abandoned
- 2004-09-16 JP JP2006526691A patent/JP2007505877A/ja not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010523727A (ja) * | 2007-04-16 | 2010-07-15 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | バニロイド受容体リガンドおよび医薬の製造へのその使用 |
| US8785474B2 (en) | 2007-04-16 | 2014-07-22 | Gruenenthal Gmbh | Vanilloid receptor ligands, pharmaceutical compositions containing them, process for making them, and use thereof to treat pain and other conditions |
| JP2013523663A (ja) * | 2010-03-30 | 2013-06-17 | ファルメステ ソシエタ ア レスポンサビリタ リミタータ | 二環式部分を持つｔｒｐｖ１バニロイド受容体拮抗薬 |
| JP2019142838A (ja) * | 2017-12-26 | 2019-08-29 | 財團法人工業技術研究院Ｉｎｄｕｓｔｒｉａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ | Ａｇｃキナーゼを阻害する化合物およびそれを含む医薬組成物 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004274230A1 (en) | 2005-03-31 |
| CA2538454A1 (en) | 2005-03-31 |
| CN1856304A (zh) | 2006-11-01 |
| GB0322016D0 (en) | 2003-10-22 |
| WO2005028445A3 (en) | 2005-06-02 |
| US20070078156A1 (en) | 2007-04-05 |
| EP1675587A2 (en) | 2006-07-05 |
| WO2005028445A2 (en) | 2005-03-31 |
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