JP2005504120A - 新規な化合物 - Google Patents
新規な化合物 Download PDFInfo
- Publication number
- JP2005504120A JP2005504120A JP2003532440A JP2003532440A JP2005504120A JP 2005504120 A JP2005504120 A JP 2005504120A JP 2003532440 A JP2003532440 A JP 2003532440A JP 2003532440 A JP2003532440 A JP 2003532440A JP 2005504120 A JP2005504120 A JP 2005504120A
- Authority
- JP
- Japan
- Prior art keywords
- benzonitrile
- chloro
- phenoxy
- methylaminomethyl
- mmol
- 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.)
- Pending
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 112
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 36
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims abstract description 27
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims abstract description 27
- 230000002265 prevention Effects 0.000 claims abstract description 11
- 229910052720 vanadium Inorganic materials 0.000 claims abstract description 11
- 208000002193 Pain Diseases 0.000 claims abstract description 9
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 9
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 7
- -1 hydroxy, cyano, trifluoromethyl Methyl Chemical group 0.000 claims description 96
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 229910052770 Uranium Inorganic materials 0.000 claims description 10
- 229910052721 tungsten Inorganic materials 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- MXPOMMFUMQYDFU-UHFFFAOYSA-N 2-[3-(aminomethyl)-2-ethylphenoxy]-4-chlorobenzonitrile Chemical compound CCC1=C(CN)C=CC=C1OC1=CC(Cl)=CC=C1C#N MXPOMMFUMQYDFU-UHFFFAOYSA-N 0.000 claims description 5
- DICMZASQPOFJSB-UHFFFAOYSA-N 2-[3-(aminomethyl)-2-propylphenoxy]-4-chlorobenzonitrile Chemical compound CCCC1=C(CN)C=CC=C1OC1=CC(Cl)=CC=C1C#N DICMZASQPOFJSB-UHFFFAOYSA-N 0.000 claims description 5
- SRSLGWQXJPTULO-UHFFFAOYSA-N 4-chloro-2-[3-[(dimethylamino)methyl]-2-ethylsulfanylphenoxy]benzonitrile Chemical compound CCSC1=C(CN(C)C)C=CC=C1OC1=CC(Cl)=CC=C1C#N SRSLGWQXJPTULO-UHFFFAOYSA-N 0.000 claims description 5
- 241000282412 Homo Species 0.000 claims description 5
- 208000019695 Migraine disease Diseases 0.000 claims description 5
- 230000009286 beneficial effect Effects 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- CIIRUVUPBSZAAJ-UHFFFAOYSA-N 4-chloro-2-[3-[(dimethylamino)methyl]-4-fluorophenoxy]benzonitrile Chemical compound C1=C(F)C(CN(C)C)=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 CIIRUVUPBSZAAJ-UHFFFAOYSA-N 0.000 claims description 4
- PJHUTZQNRFUQNA-UHFFFAOYSA-N 4-chloro-2-[3-hydroxy-5-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC(O)=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 PJHUTZQNRFUQNA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 206010027599 migraine Diseases 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- NPXPMIKNHHWSEM-UHFFFAOYSA-N 4-chloro-2-[3-(methylaminomethyl)-2-propoxyphenoxy]benzonitrile Chemical compound CCCOC1=C(CNC)C=CC=C1OC1=CC(Cl)=CC=C1C#N NPXPMIKNHHWSEM-UHFFFAOYSA-N 0.000 claims description 3
- ZILFAHDRVZPEEE-UHFFFAOYSA-N 4-chloro-2-[3-[(dimethylamino)methyl]-2-ethylphenoxy]benzonitrile Chemical compound CCC1=C(CN(C)C)C=CC=C1OC1=CC(Cl)=CC=C1C#N ZILFAHDRVZPEEE-UHFFFAOYSA-N 0.000 claims description 3
- CFJUJNWKXLXPNQ-UHFFFAOYSA-N 4-chloro-2-[3-[(dimethylamino)methyl]-2-methylsulfanylphenoxy]benzonitrile Chemical compound CSC1=C(CN(C)C)C=CC=C1OC1=CC(Cl)=CC=C1C#N CFJUJNWKXLXPNQ-UHFFFAOYSA-N 0.000 claims description 3
- CWFDFILBFBJLTA-UHFFFAOYSA-N 4-chloro-2-[3-[(dimethylamino)methyl]-2-propylphenoxy]benzonitrile Chemical compound CCCC1=C(CN(C)C)C=CC=C1OC1=CC(Cl)=CC=C1C#N CWFDFILBFBJLTA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- MTROOCWXDNNTLA-UHFFFAOYSA-N 2-[2-methoxy-3-(methylaminomethyl)phenoxy]-4-(trifluoromethyl)benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(C=2)C(F)(F)F)C#N)=C1OC MTROOCWXDNNTLA-UHFFFAOYSA-N 0.000 claims description 2
- REUYXENIPROLPB-UHFFFAOYSA-N 2-[2-methoxy-3-(methylaminomethyl)phenoxy]-6-(trifluoromethyl)pyridine-3-carbonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(N=2)C(F)(F)F)C#N)=C1OC REUYXENIPROLPB-UHFFFAOYSA-N 0.000 claims description 2
- OUAYJZWHAONSJV-UHFFFAOYSA-N 2-[2-methoxy-3-(methylaminomethyl)phenoxy]-6-methylpyridine-3-carbonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(C)N=2)C#N)=C1OC OUAYJZWHAONSJV-UHFFFAOYSA-N 0.000 claims description 2
- NJFMMWJMZLCKRV-UHFFFAOYSA-N 2-[3-(aminomethyl)-2-ethylsulfanylphenoxy]-4-chlorobenzonitrile Chemical compound CCSC1=C(CN)C=CC=C1OC1=CC(Cl)=CC=C1C#N NJFMMWJMZLCKRV-UHFFFAOYSA-N 0.000 claims description 2
- YHUOCXTVQLWTFY-UHFFFAOYSA-N 2-[3-(aminomethyl)-2-methylsulfanylphenoxy]-4-chlorobenzonitrile Chemical compound CSC1=C(CN)C=CC=C1OC1=CC(Cl)=CC=C1C#N YHUOCXTVQLWTFY-UHFFFAOYSA-N 0.000 claims description 2
- OFMJHTOBSHQBLC-UHFFFAOYSA-N 2-[3-(aminomethyl)phenoxy]-4-chlorobenzonitrile Chemical compound NCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 OFMJHTOBSHQBLC-UHFFFAOYSA-N 0.000 claims description 2
- QFDCWXKPHFWANB-UHFFFAOYSA-N 2-[3-(methylaminomethyl)-4-phenylphenoxy]-4-(trifluoromethyl)benzonitrile Chemical compound C=1C=C(C=2C=CC=CC=2)C(CNC)=CC=1OC1=CC(C(F)(F)F)=CC=C1C#N QFDCWXKPHFWANB-UHFFFAOYSA-N 0.000 claims description 2
- ONVQAQZCYYHCGI-UHFFFAOYSA-N 2-[4-(methylaminomethyl)-3-phenylphenoxy]-4-(trifluoromethyl)benzonitrile Chemical compound C1=C(C=2C=CC=CC=2)C(CNC)=CC=C1OC1=CC(C(F)(F)F)=CC=C1C#N ONVQAQZCYYHCGI-UHFFFAOYSA-N 0.000 claims description 2
- ZIBPTPRWBBFXAQ-UHFFFAOYSA-N 2-[4-bromo-3-(methylaminomethyl)phenoxy]-4-(trifluoromethyl)benzonitrile Chemical compound C1=C(Br)C(CNC)=CC(OC=2C(=CC=C(C=2)C(F)(F)F)C#N)=C1 ZIBPTPRWBBFXAQ-UHFFFAOYSA-N 0.000 claims description 2
- TWRYTDBQLLEZJZ-UHFFFAOYSA-N 3-[3-(aminomethyl)phenoxy]-n-methyl-4-nitroaniline Chemical compound CNC1=CC=C([N+]([O-])=O)C(OC=2C=C(CN)C=CC=2)=C1 TWRYTDBQLLEZJZ-UHFFFAOYSA-N 0.000 claims description 2
- LVZDYMBITAXXGP-UHFFFAOYSA-N 3-fluoro-2-[2-methoxy-3-(methylaminomethyl)phenoxy]-4-methylbenzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(C)C=2F)C#N)=C1OC LVZDYMBITAXXGP-UHFFFAOYSA-N 0.000 claims description 2
- ZBVDVTCHEYXMKB-UHFFFAOYSA-N 4-bromo-2-[2-methoxy-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Br)C=2)C#N)=C1OC ZBVDVTCHEYXMKB-UHFFFAOYSA-N 0.000 claims description 2
- AIGSJAWHLXXXOU-UHFFFAOYSA-N 4-chloro-2-[2-(2-fluoroethoxy)-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1OCCF AIGSJAWHLXXXOU-UHFFFAOYSA-N 0.000 claims description 2
- WUEXCPKXDNHFFP-UHFFFAOYSA-N 4-chloro-2-[2-(2-hydroxyethoxy)-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1OCCO WUEXCPKXDNHFFP-UHFFFAOYSA-N 0.000 claims description 2
- CQPQILXCZVQVGQ-UHFFFAOYSA-N 4-chloro-2-[2-ethoxy-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CCOC1=C(CNC)C=CC=C1OC1=CC(Cl)=CC=C1C#N CQPQILXCZVQVGQ-UHFFFAOYSA-N 0.000 claims description 2
- UNZZVEFWPFGIOP-UHFFFAOYSA-N 4-chloro-2-[2-ethoxy-4-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CCOC1=CC(CNC)=CC=C1OC1=CC(Cl)=CC=C1C#N UNZZVEFWPFGIOP-UHFFFAOYSA-N 0.000 claims description 2
- NMKOVIVDBCMBRM-UHFFFAOYSA-N 4-chloro-2-[2-ethyl-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CCC1=C(CNC)C=CC=C1OC1=CC(Cl)=CC=C1C#N NMKOVIVDBCMBRM-UHFFFAOYSA-N 0.000 claims description 2
- CUQFOACQEGOZKT-UHFFFAOYSA-N 4-chloro-2-[2-ethylsulfanyl-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CCSC1=C(CNC)C=CC=C1OC1=CC(Cl)=CC=C1C#N CUQFOACQEGOZKT-UHFFFAOYSA-N 0.000 claims description 2
- QNRGSHREYDARKN-UHFFFAOYSA-N 4-chloro-2-[2-hydroxy-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1O QNRGSHREYDARKN-UHFFFAOYSA-N 0.000 claims description 2
- NALRDGJPJMOQHT-UHFFFAOYSA-N 4-chloro-2-[2-methoxy-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1OC NALRDGJPJMOQHT-UHFFFAOYSA-N 0.000 claims description 2
- OITXEMVVMHRYML-UHFFFAOYSA-N 4-chloro-2-[2-methoxy-4-(methylaminomethyl)phenoxy]benzonitrile Chemical compound COC1=CC(CNC)=CC=C1OC1=CC(Cl)=CC=C1C#N OITXEMVVMHRYML-UHFFFAOYSA-N 0.000 claims description 2
- RNXUWTOEXCIWOY-UHFFFAOYSA-N 4-chloro-2-[3-(methylaminomethyl)-2-(2,2,2-trifluoroethoxy)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1OCC(F)(F)F RNXUWTOEXCIWOY-UHFFFAOYSA-N 0.000 claims description 2
- UXLZTEDWYGQYDW-UHFFFAOYSA-N 4-chloro-2-[3-(methylaminomethyl)-2-propylphenoxy]benzonitrile Chemical compound CCCC1=C(CNC)C=CC=C1OC1=CC(Cl)=CC=C1C#N UXLZTEDWYGQYDW-UHFFFAOYSA-N 0.000 claims description 2
- PWQVPDQRVMKOMX-UHFFFAOYSA-N 4-chloro-2-[3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 PWQVPDQRVMKOMX-UHFFFAOYSA-N 0.000 claims description 2
- UPWSSYKLFNIPFA-UHFFFAOYSA-N 4-chloro-2-[3-(propylaminomethyl)phenoxy]benzonitrile Chemical compound CCCNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 UPWSSYKLFNIPFA-UHFFFAOYSA-N 0.000 claims description 2
- ZMBUZBVWDSLQSW-UHFFFAOYSA-N 4-chloro-2-[3-(pyrrolidin-1-ylmethyl)phenoxy]benzonitrile Chemical compound ClC1=CC=C(C#N)C(OC=2C=C(CN3CCCC3)C=CC=2)=C1 ZMBUZBVWDSLQSW-UHFFFAOYSA-N 0.000 claims description 2
- MPPLOAVJFUJHBV-UHFFFAOYSA-N 4-chloro-2-[3-[(2-methoxyethylamino)methyl]phenoxy]benzonitrile Chemical compound COCCNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 MPPLOAVJFUJHBV-UHFFFAOYSA-N 0.000 claims description 2
- ABOUSTARNFHCMZ-UHFFFAOYSA-N 4-chloro-2-[3-[(3-hydroxypropylamino)methyl]phenoxy]benzonitrile Chemical compound OCCCNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 ABOUSTARNFHCMZ-UHFFFAOYSA-N 0.000 claims description 2
- GQZGACPGGNYGAX-UHFFFAOYSA-N 4-chloro-2-[3-[(dimethylamino)methyl]phenoxy]benzonitrile Chemical compound CN(C)CC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 GQZGACPGGNYGAX-UHFFFAOYSA-N 0.000 claims description 2
- BTBZKFAJGIIPKQ-UHFFFAOYSA-N 4-chloro-2-[3-[[2-(dimethylamino)ethylamino]methyl]phenoxy]benzonitrile Chemical compound CN(C)CCNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 BTBZKFAJGIIPKQ-UHFFFAOYSA-N 0.000 claims description 2
- DUWKDMXYMMMFRN-UHFFFAOYSA-N 4-chloro-2-[3-methoxy-4-(methylaminomethyl)phenoxy]benzonitrile Chemical compound C1=C(OC)C(CNC)=CC=C1OC1=CC(Cl)=CC=C1C#N DUWKDMXYMMMFRN-UHFFFAOYSA-N 0.000 claims description 2
- RBARWUPGFBXQNC-UHFFFAOYSA-N 4-chloro-2-[3-methoxy-5-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC(OC)=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 RBARWUPGFBXQNC-UHFFFAOYSA-N 0.000 claims description 2
- FFDIYKZGKCUKOI-UHFFFAOYSA-N 4-chloro-2-[4-(methylaminomethyl)naphthalen-1-yl]oxybenzonitrile Chemical compound C12=CC=CC=C2C(CNC)=CC=C1OC1=CC(Cl)=CC=C1C#N FFDIYKZGKCUKOI-UHFFFAOYSA-N 0.000 claims description 2
- AYHZEOMMVITVJY-UHFFFAOYSA-N 4-chloro-2-[4-methoxy-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound C1=C(OC)C(CNC)=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1 AYHZEOMMVITVJY-UHFFFAOYSA-N 0.000 claims description 2
- XBWFTNJJCHLOSE-UHFFFAOYSA-N 4-chloro-2-[[1-(methylamino)-2,3-dihydro-1h-inden-4-yl]oxy]benzonitrile Chemical compound CNC1CCC2=C1C=CC=C2OC1=CC(Cl)=CC=C1C#N XBWFTNJJCHLOSE-UHFFFAOYSA-N 0.000 claims description 2
- HCAQDJCLTOWYCI-UHFFFAOYSA-N 4-chloro-2-[[5-(methylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]oxy]benzonitrile Chemical compound C1=CC=C2C(NC)CCCC2=C1OC1=CC(Cl)=CC=C1C#N HCAQDJCLTOWYCI-UHFFFAOYSA-N 0.000 claims description 2
- WUIFPYXHWKPZKG-UHFFFAOYSA-N 4-chloro-5-fluoro-2-[2-methoxy-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC(F)=C(Cl)C=2)C#N)=C1OC WUIFPYXHWKPZKG-UHFFFAOYSA-N 0.000 claims description 2
- CEUQSDBQNBWEEG-UHFFFAOYSA-N 4-methoxy-2-[2-methoxy-3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(OC)C=2)C#N)=C1OC CEUQSDBQNBWEEG-UHFFFAOYSA-N 0.000 claims description 2
- XRTSTCDLAMIACS-UHFFFAOYSA-N 4-methyl-2-[3-(methylaminomethyl)phenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(C)C=2)C#N)=C1 XRTSTCDLAMIACS-UHFFFAOYSA-N 0.000 claims description 2
- CTAKYLWSOIXNPN-UHFFFAOYSA-N 6-ethyl-2-[2-methoxy-3-(methylaminomethyl)phenoxy]pyridine-3-carbonitrile Chemical compound CCC1=CC=C(C#N)C(OC=2C(=C(CNC)C=CC=2)OC)=N1 CTAKYLWSOIXNPN-UHFFFAOYSA-N 0.000 claims description 2
- ZBQGXKASHIFWIV-UHFFFAOYSA-N 6-methyl-2-[3-(methylaminomethyl)phenoxy]pyridine-3-carbonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(C)N=2)C#N)=C1 ZBQGXKASHIFWIV-UHFFFAOYSA-N 0.000 claims description 2
- KXSVIUQKPYUOGG-UHFFFAOYSA-N [3-(5-chloro-2-nitrophenoxy)phenyl]methanamine Chemical compound NCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)[N+]([O-])=O)=C1 KXSVIUQKPYUOGG-UHFFFAOYSA-N 0.000 claims description 2
- XPDZIHOVUCQSSR-UHFFFAOYSA-N [3-(5-fluoro-2-nitrophenoxy)phenyl]methanamine Chemical compound NCC1=CC=CC(OC=2C(=CC=C(F)C=2)[N+]([O-])=O)=C1 XPDZIHOVUCQSSR-UHFFFAOYSA-N 0.000 claims description 2
- CSHMOEMMQGLRCV-UHFFFAOYSA-N [3-(5-methoxy-2-nitrophenoxy)phenyl]methanamine Chemical compound COC1=CC=C([N+]([O-])=O)C(OC=2C=C(CN)C=CC=2)=C1 CSHMOEMMQGLRCV-UHFFFAOYSA-N 0.000 claims description 2
- SSKADNBBIMXCBJ-UHFFFAOYSA-N [3-(5-methyl-2-nitrophenoxy)phenyl]methanamine Chemical compound CC1=CC=C([N+]([O-])=O)C(OC=2C=C(CN)C=CC=2)=C1 SSKADNBBIMXCBJ-UHFFFAOYSA-N 0.000 claims description 2
- DPYBZQWAHQVKPH-UHFFFAOYSA-N [3-(5-methyl-2-nitrophenyl)sulfanylphenyl]methanamine Chemical compound CC1=CC=C([N+]([O-])=O)C(SC=2C=C(CN)C=CC=2)=C1 DPYBZQWAHQVKPH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- WHRXUUZIXUEFOA-UHFFFAOYSA-N 4-chloro-2-[3-(methylaminomethyl)-2-methylsulfanylphenoxy]benzonitrile Chemical compound CNCC1=CC=CC(OC=2C(=CC=C(Cl)C=2)C#N)=C1SC WHRXUUZIXUEFOA-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 28
- 239000003112 inhibitor Substances 0.000 abstract description 12
- 239000000126 substance Substances 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 612
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 264
- 239000000243 solution Substances 0.000 description 193
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 190
- 239000002904 solvent Substances 0.000 description 154
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 130
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 129
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 125
- 238000005160 1H NMR spectroscopy Methods 0.000 description 116
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 114
- 239000007787 solid Substances 0.000 description 113
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 106
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 106
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 97
- 238000001914 filtration Methods 0.000 description 94
- 239000010410 layer Substances 0.000 description 91
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 87
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 75
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 67
- 238000003756 stirring Methods 0.000 description 67
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 65
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/90—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
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- 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)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
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- Rheumatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
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| SE0103325A SE0103325D0 (sv) | 2001-10-04 | 2001-10-04 | Novel compounds |
| PCT/SE2002/001803 WO2003029185A1 (en) | 2001-10-04 | 2002-10-02 | Novel compounds |
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| JP2005504120A true JP2005504120A (ja) | 2005-02-10 |
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| US20090186854A1 (en) * | 2006-03-23 | 2009-07-23 | Meditor Pharmaceuticals Ltd. | S-alkylisothiouronium derivatives for the treatment of inflammatory diseases |
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|---|---|---|---|---|
| SE363818B (enExample) * | 1968-08-15 | 1974-02-04 | Lilly Co Eli | |
| FI874121A7 (fi) * | 1986-09-24 | 1988-03-25 | Sumitomo Chemical Co | Heterocykliska foereningar, och deras framstaellning och anvaendning. |
| GB9215921D0 (en) * | 1992-07-27 | 1992-09-09 | Wellcome Found | Anti-inflammatory compounds |
| CZ293595A3 (cs) * | 1995-11-09 | 1999-12-15 | Farmak A. S. | Deriváty N,N-dimethyl-2-(arylthio)benzylaminu, jejich soli, způsoby jejich přípravy a jejich použití v léčivých přípravcích |
| CA2348159A1 (en) * | 1998-10-20 | 2000-04-27 | Satoru Oi | Aromatic amine derivatives, their production and use |
| KR20020059730A (ko) | 1999-11-15 | 2002-07-13 | 피터 지. 스트링거 | 가축 생산성 개선을 위한 아릴옥시 프로판올아민 |
| WO2002006276A1 (en) | 2000-07-13 | 2002-01-24 | Eli Lilly And Company | Beta3 adrenergic agonists |
-
2001
- 2001-10-04 SE SE0103325A patent/SE0103325D0/xx unknown
-
2002
- 2002-10-02 US US10/491,264 patent/US7119122B2/en not_active Expired - Fee Related
- 2002-10-02 EP EP02775639A patent/EP1434756A1/en not_active Withdrawn
- 2002-10-02 JP JP2003532440A patent/JP2005504120A/ja active Pending
- 2002-10-02 WO PCT/SE2002/001803 patent/WO2003029185A1/en not_active Ceased
-
2006
- 2006-05-25 US US11/440,994 patent/US7276528B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US20040260088A1 (en) | 2004-12-23 |
| WO2003029185A1 (en) | 2003-04-10 |
| US20060217424A1 (en) | 2006-09-28 |
| US7276528B2 (en) | 2007-10-02 |
| EP1434756A1 (en) | 2004-07-07 |
| US7119122B2 (en) | 2006-10-10 |
| SE0103325D0 (sv) | 2001-10-04 |
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