CA2580852A1 - Compounds for inflammation and immune-related uses - Google Patents
Compounds for inflammation and immune-related uses Download PDFInfo
- Publication number
- CA2580852A1 CA2580852A1 CA002580852A CA2580852A CA2580852A1 CA 2580852 A1 CA2580852 A1 CA 2580852A1 CA 002580852 A CA002580852 A CA 002580852A CA 2580852 A CA2580852 A CA 2580852A CA 2580852 A1 CA2580852 A1 CA 2580852A1
- Authority
- CA
- Canada
- Prior art keywords
- optionally substituted
- phenyl
- benzoimidazol
- trifluoromethyl
- benzamide
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 345
- 206010061218 Inflammation Diseases 0.000 title description 12
- 230000004054 inflammatory process Effects 0.000 title description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 93
- 229940002612 prodrug Drugs 0.000 claims abstract description 87
- 239000000651 prodrug Substances 0.000 claims abstract description 87
- 239000012453 solvate Substances 0.000 claims abstract description 86
- 208000026278 immune system disease Diseases 0.000 claims abstract description 28
- 230000004968 inflammatory condition Effects 0.000 claims abstract description 18
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 5
- 229940125721 immunosuppressive agent Drugs 0.000 claims abstract description 4
- -1 benzoimidazolyl Chemical group 0.000 claims description 340
- 125000000217 alkyl group Chemical group 0.000 claims description 113
- 125000001072 heteroaryl group Chemical group 0.000 claims description 99
- 125000000623 heterocyclic group Chemical group 0.000 claims description 93
- 239000000203 mixture Substances 0.000 claims description 87
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 78
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 73
- 125000003107 substituted aryl group Chemical group 0.000 claims description 72
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 71
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 69
- 238000000034 method Methods 0.000 claims description 66
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 59
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 57
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 56
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 53
- 239000008194 pharmaceutical composition Substances 0.000 claims description 52
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- 125000001188 haloalkyl group Chemical group 0.000 claims description 48
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 46
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
- 210000004027 cell Anatomy 0.000 claims description 42
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 42
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 208000023275 Autoimmune disease Diseases 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 108090000862 Ion Channels Proteins 0.000 claims description 22
- 102000004310 Ion Channels Human genes 0.000 claims description 22
- 241000282414 Homo sapiens Species 0.000 claims description 21
- 230000002401 inhibitory effect Effects 0.000 claims description 20
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- 238000006243 chemical reaction Methods 0.000 claims description 19
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 19
- 101000844504 Homo sapiens Transient receptor potential cation channel subfamily M member 4 Proteins 0.000 claims description 18
- 101000994669 Homo sapiens Potassium voltage-gated channel subfamily A member 3 Proteins 0.000 claims description 17
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 17
- 230000000172 allergic effect Effects 0.000 claims description 17
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- 102000004127 Cytokines Human genes 0.000 claims description 15
- 108090000695 Cytokines Proteins 0.000 claims description 15
- 108010002616 Interleukin-5 Proteins 0.000 claims description 14
- 150000001204 N-oxides Chemical class 0.000 claims description 14
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 13
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 12
- 102000003816 Interleukin-13 Human genes 0.000 claims description 12
- 108090000176 Interleukin-13 Proteins 0.000 claims description 12
- 102000004388 Interleukin-4 Human genes 0.000 claims description 12
- 108090000978 Interleukin-4 Proteins 0.000 claims description 12
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 10
- 208000006673 asthma Diseases 0.000 claims description 10
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 10
- 210000002865 immune cell Anatomy 0.000 claims description 10
- 230000005931 immune cell recruitment Effects 0.000 claims description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 10
- 230000016396 cytokine production Effects 0.000 claims description 9
- 210000003630 histaminocyte Anatomy 0.000 claims description 9
- 210000000987 immune system Anatomy 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- JXQTVHIQYHIKJV-UHFFFAOYSA-N 2,3-difluoro-n-[4-[2-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl]phenyl]benzamide Chemical compound FC1=CC=CC(C(=O)NC=2C=CC(=CC=2)C=2N3CCCCC3=CC=2C(F)(F)F)=C1F JXQTVHIQYHIKJV-UHFFFAOYSA-N 0.000 claims description 8
- RDLXPCACGCVSPE-UHFFFAOYSA-N 3,5-dichloro-n-[4-[5-methoxy-2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound FC(F)(F)C1=NC2=CC(OC)=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC(Cl)=CC(Cl)=C1 RDLXPCACGCVSPE-UHFFFAOYSA-N 0.000 claims description 8
- 239000000427 antigen Substances 0.000 claims description 8
- 102000036639 antigens Human genes 0.000 claims description 8
- 108091007433 antigens Proteins 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 201000006417 multiple sclerosis Diseases 0.000 claims description 8
- 230000004044 response Effects 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 7
- 239000004202 carbamide Substances 0.000 claims description 6
- UUQRYBZFXIXZPR-UHFFFAOYSA-N 2,3-difluoro-n-[4-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]phenyl]benzamide Chemical compound FC1=CC=CC(C(=O)NC=2C=CC(=CC=2)C=2N3C=CC=CC3=NC=2C(F)(F)F)=C1F UUQRYBZFXIXZPR-UHFFFAOYSA-N 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 5
- 208000003455 anaphylaxis Diseases 0.000 claims description 5
- 239000000739 antihistaminic agent Substances 0.000 claims description 5
- 230000004663 cell proliferation Effects 0.000 claims description 5
- GVBBXQKANCRVLH-UHFFFAOYSA-N 1-(2,5-difluorophenyl)-3-[6-[2-(trifluoromethyl)benzimidazol-1-yl]pyridin-3-yl]thiourea Chemical compound FC1=CC=C(F)C(NC(=S)NC=2C=NC(=CC=2)N2C3=CC=CC=C3N=C2C(F)(F)F)=C1 GVBBXQKANCRVLH-UHFFFAOYSA-N 0.000 claims description 4
- PLEKOTCSQOTABV-UHFFFAOYSA-N 1-[4-[(2,3-difluorobenzoyl)amino]phenyl]-2-(trifluoromethyl)benzimidazole-5-carboxamide Chemical compound FC(F)(F)C1=NC2=CC(C(=O)N)=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC=CC(F)=C1F PLEKOTCSQOTABV-UHFFFAOYSA-N 0.000 claims description 4
- GICUSOPCJYWPHT-UHFFFAOYSA-N 2,3,4-trifluoro-n-[4-[5-methoxy-2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound FC(F)(F)C1=NC2=CC(OC)=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC=C(F)C(F)=C1F GICUSOPCJYWPHT-UHFFFAOYSA-N 0.000 claims description 4
- QVFINXWCWBWOIK-UHFFFAOYSA-N 2,3,5-trifluoro-n-[4-[5-methoxy-2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound FC(F)(F)C1=NC2=CC(OC)=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC(F)=CC(F)=C1F QVFINXWCWBWOIK-UHFFFAOYSA-N 0.000 claims description 4
- YQNHUFQCSKLAQP-UHFFFAOYSA-N 2,3,6-trifluoro-n-[4-[5-methoxy-2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound FC(F)(F)C1=NC2=CC(OC)=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=C(F)C=CC(F)=C1F YQNHUFQCSKLAQP-UHFFFAOYSA-N 0.000 claims description 4
- YAORPEGMKMDMRA-UHFFFAOYSA-N 2,3-dichloro-n-[4-[2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound FC(F)(F)C1=NC2=CC=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC=CC(Cl)=C1Cl YAORPEGMKMDMRA-UHFFFAOYSA-N 0.000 claims description 4
- DZMKYTWSNMTCKO-UHFFFAOYSA-N 2,3-difluoro-n-[2-[2-(trifluoromethyl)benzimidazol-1-yl]pyridin-3-yl]benzamide Chemical compound FC1=CC=CC(C(=O)NC=2C(=NC=CC=2)N2C3=CC=CC=C3N=C2C(F)(F)F)=C1F DZMKYTWSNMTCKO-UHFFFAOYSA-N 0.000 claims description 4
- SJYDPDQXLCEMTM-UHFFFAOYSA-N 2,3-difluoro-n-[2-methyl-4-[2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound CC1=CC(N2C3=CC=CC=C3N=C2C(F)(F)F)=CC=C1NC(=O)C1=CC=CC(F)=C1F SJYDPDQXLCEMTM-UHFFFAOYSA-N 0.000 claims description 4
- USHXWCFLWKHXCT-UHFFFAOYSA-N 2,3-difluoro-n-[3-methyl-4-[2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound C=1C=C(N2C3=CC=CC=C3N=C2C(F)(F)F)C(C)=CC=1NC(=O)C1=CC=CC(F)=C1F USHXWCFLWKHXCT-UHFFFAOYSA-N 0.000 claims description 4
- WLTVMYFIMILLEK-UHFFFAOYSA-N 2,3-difluoro-n-[4-(2-iodobenzimidazol-1-yl)phenyl]benzamide Chemical compound FC1=CC=CC(C(=O)NC=2C=CC(=CC=2)N2C3=CC=CC=C3N=C2I)=C1F WLTVMYFIMILLEK-UHFFFAOYSA-N 0.000 claims description 4
- ZLXZGMSSHOAYQU-UHFFFAOYSA-N 2,3-difluoro-n-[4-(2-methylsulfanylbenzimidazol-1-yl)phenyl]benzamide Chemical compound CSC1=NC2=CC=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC=CC(F)=C1F ZLXZGMSSHOAYQU-UHFFFAOYSA-N 0.000 claims description 4
- CABLTRGIQPFHIH-UHFFFAOYSA-N 2,3-difluoro-n-[4-(2-methylsulfinylbenzimidazol-1-yl)phenyl]benzamide Chemical compound CS(=O)C1=NC2=CC=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC=CC(F)=C1F CABLTRGIQPFHIH-UHFFFAOYSA-N 0.000 claims description 4
- OHCMLEBTCDKRNK-UHFFFAOYSA-N 2,3-difluoro-n-[4-(2-propan-2-ylbenzimidazol-1-yl)phenyl]benzamide Chemical compound CC(C)C1=NC2=CC=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC=CC(F)=C1F OHCMLEBTCDKRNK-UHFFFAOYSA-N 0.000 claims description 4
- BIQYZPDBEJUQGM-UHFFFAOYSA-N 2,3-difluoro-n-[4-[2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzenecarbothioamide Chemical compound FC1=CC=CC(C(=S)NC=2C=CC(=CC=2)N2C3=CC=CC=C3N=C2C(F)(F)F)=C1F BIQYZPDBEJUQGM-UHFFFAOYSA-N 0.000 claims description 4
- AQUYHDDKQMGPMS-UHFFFAOYSA-N 2,3-difluoro-n-[4-[2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzenesulfonamide Chemical compound FC1=CC=CC(S(=O)(=O)NC=2C=CC(=CC=2)N2C3=CC=CC=C3N=C2C(F)(F)F)=C1F AQUYHDDKQMGPMS-UHFFFAOYSA-N 0.000 claims description 4
- YDVJLKAAQWIUBE-UHFFFAOYSA-N 2,3-difluoro-n-[4-[2-(trifluoromethyl)imidazo[4,5-b]pyridin-3-yl]phenyl]benzamide Chemical compound FC1=CC=CC(C(=O)NC=2C=CC(=CC=2)N2C3=NC=CC=C3N=C2C(F)(F)F)=C1F YDVJLKAAQWIUBE-UHFFFAOYSA-N 0.000 claims description 4
- KXEPQFRTQMIREX-UHFFFAOYSA-N 2,3-difluoro-n-[4-[2-(trifluoromethyl)imidazo[4,5-c]pyridin-1-yl]phenyl]benzamide Chemical compound FC1=CC=CC(C(=O)NC=2C=CC(=CC=2)N2C3=CC=NC=C3N=C2C(F)(F)F)=C1F KXEPQFRTQMIREX-UHFFFAOYSA-N 0.000 claims description 4
- ADJJXDPCIXFJKO-UHFFFAOYSA-N 2,3-difluoro-n-[4-[5-hydroxy-2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound FC(F)(F)C1=NC2=CC(O)=CC=C2N1C(C=C1)=CC=C1NC(=O)C1=CC=CC(F)=C1F ADJJXDPCIXFJKO-UHFFFAOYSA-N 0.000 claims description 4
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- WJONHQVDSQWGHO-UHFFFAOYSA-N 2,5-dimethoxy-n-[4-[5-methoxy-2-(trifluoromethyl)benzimidazol-1-yl]phenyl]benzamide Chemical compound COC1=CC=C(OC)C(C(=O)NC=2C=CC(=CC=2)N2C3=CC=C(OC)C=C3N=C2C(F)(F)F)=C1 WJONHQVDSQWGHO-UHFFFAOYSA-N 0.000 claims description 4
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- NOCCHZQVBIVCQW-UHFFFAOYSA-N 2-ethyl-n-[4-[5-methoxy-2-(trifluoromethyl)benzimidazol-1-yl]phenyl]hexanamide Chemical compound C1=CC(NC(=O)C(CC)CCCC)=CC=C1N1C2=CC=C(OC)C=C2N=C1C(F)(F)F NOCCHZQVBIVCQW-UHFFFAOYSA-N 0.000 claims description 4
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- NVVCPKOGHZWTJA-UHFFFAOYSA-N 2-methyl-n-[4-[2-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl]phenyl]benzamide Chemical compound CC1=CC=CC=C1C(=O)NC1=CC=C(C=2N3CCCCC3=CC=2C(F)(F)F)C=C1 NVVCPKOGHZWTJA-UHFFFAOYSA-N 0.000 claims description 4
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-
2005
- 2005-09-21 MX MX2007003342A patent/MX2007003342A/es not_active Application Discontinuation
- 2005-09-21 JP JP2007532665A patent/JP2008513508A/ja active Pending
- 2005-09-21 BR BRPI0515546-0A patent/BRPI0515546A/pt not_active IP Right Cessation
- 2005-09-21 US US11/233,224 patent/US7709518B2/en not_active Expired - Fee Related
- 2005-09-21 CA CA002580852A patent/CA2580852A1/en not_active Abandoned
- 2005-09-21 AU AU2005286701A patent/AU2005286701A1/en not_active Abandoned
- 2005-09-21 CN CNA200580038882XA patent/CN101083985A/zh active Pending
- 2005-09-21 EP EP05814906A patent/EP1809294A4/en not_active Withdrawn
- 2005-09-21 TW TW094132617A patent/TW200621232A/zh unknown
- 2005-09-21 WO PCT/US2005/033980 patent/WO2006034402A2/en not_active Ceased
- 2005-09-21 KR KR1020077008930A patent/KR20070057965A/ko not_active Withdrawn
-
2007
- 2007-03-19 IL IL182025A patent/IL182025A0/en unknown
- 2007-03-20 ZA ZA200702350A patent/ZA200702350B/xx unknown
-
2010
- 2010-03-05 US US12/718,366 patent/US8314134B2/en not_active Expired - Fee Related
-
2012
- 2012-10-16 US US13/652,878 patent/US8524756B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| KR20070057965A (ko) | 2007-06-07 |
| ZA200702350B (en) | 2008-12-31 |
| US7709518B2 (en) | 2010-05-04 |
| WO2006034402A3 (en) | 2007-08-09 |
| US20070249661A1 (en) | 2007-10-25 |
| BRPI0515546A (pt) | 2008-07-29 |
| EP1809294A4 (en) | 2008-08-06 |
| US8524756B2 (en) | 2013-09-03 |
| AU2005286701A1 (en) | 2006-03-30 |
| IL182025A0 (en) | 2007-07-24 |
| CN101083985A (zh) | 2007-12-05 |
| EP1809294A2 (en) | 2007-07-25 |
| WO2006034402A2 (en) | 2006-03-30 |
| US20130142831A1 (en) | 2013-06-06 |
| TW200621232A (en) | 2006-07-01 |
| US8314134B2 (en) | 2012-11-20 |
| JP2008513508A (ja) | 2008-05-01 |
| MX2007003342A (es) | 2007-06-05 |
| US20100311787A1 (en) | 2010-12-09 |
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