AU5785900A - Method for treating chronic pain using mek inhibitors - Google Patents
Method for treating chronic pain using mek inhibitors Download PDFInfo
- Publication number
- AU5785900A AU5785900A AU57859/00A AU5785900A AU5785900A AU 5785900 A AU5785900 A AU 5785900A AU 57859/00 A AU57859/00 A AU 57859/00A AU 5785900 A AU5785900 A AU 5785900A AU 5785900 A AU5785900 A AU 5785900A
- Authority
- AU
- Australia
- Prior art keywords
- methyl
- phenyl
- iodo
- phenylamino
- fluoro
- 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
- 238000000034 method Methods 0.000 title claims description 51
- 208000002193 Pain Diseases 0.000 title claims description 40
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title claims description 25
- 208000000094 Chronic Pain Diseases 0.000 title claims description 21
- -1 hydrocarbon radical Chemical class 0.000 claims description 247
- 150000001875 compounds Chemical class 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 23
- 150000002148 esters Chemical class 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 230000036407 pain Effects 0.000 claims description 18
- 208000004296 neuralgia Diseases 0.000 claims description 16
- 208000021722 neuropathic pain Diseases 0.000 claims description 16
- 229940124647 MEK inhibitor Drugs 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 208000027418 Wounds and injury Diseases 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 230000006378 damage Effects 0.000 claims description 8
- 208000014674 injury Diseases 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 208000004550 Postoperative Pain Diseases 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- FLWVAHBGRKYNEE-UHFFFAOYSA-N 2-sulfanyl-3h-oxadiazole Chemical compound SN1NC=CO1 FLWVAHBGRKYNEE-UHFFFAOYSA-N 0.000 claims description 5
- URUXUUSWKYMMRR-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-oxadiazole-2-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(S)O1 URUXUUSWKYMMRR-UHFFFAOYSA-N 0.000 claims description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
- 206010003246 arthritis Diseases 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- QYIPXKFVULIACW-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydro-1,2,4-triazole-3-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(S)N1 QYIPXKFVULIACW-UHFFFAOYSA-N 0.000 claims description 4
- 208000007848 Alcoholism Diseases 0.000 claims description 4
- 208000000412 Avitaminosis Diseases 0.000 claims description 4
- 208000037157 Azotemia Diseases 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 208000001387 Causalgia Diseases 0.000 claims description 4
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 208000014439 complex regional pain syndrome type 2 Diseases 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 208000009852 uremia Diseases 0.000 claims description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 3
- RULVVSJRJXIGND-UHFFFAOYSA-N 2,4-bis(2-chloro-4-iodoanilino)-3-fluoro-5-nitrobenzoic acid Chemical compound FC1=C(NC=2C(=CC(I)=CC=2)Cl)C(C(=O)O)=CC([N+]([O-])=O)=C1NC1=CC=C(I)C=C1Cl RULVVSJRJXIGND-UHFFFAOYSA-N 0.000 claims description 3
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 3
- 208000025962 Crush injury Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000005890 Neuroma Diseases 0.000 claims description 3
- 206010047115 Vasculitis Diseases 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
- 208000003532 hypothyroidism Diseases 0.000 claims description 3
- 230000002989 hypothyroidism Effects 0.000 claims description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 238000011542 limb amputation Methods 0.000 claims description 3
- 150000003573 thiols Chemical class 0.000 claims description 3
- 208000037816 tissue injury Diseases 0.000 claims description 3
- 206010044652 trigeminal neuralgia Diseases 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- APKZPKINPXTSNL-UHFFFAOYSA-N 1,3,4-oxadiazol-2-amine Chemical compound NC1=NN=CO1 APKZPKINPXTSNL-UHFFFAOYSA-N 0.000 claims description 2
- JCPNJTWIJHNAIN-UHFFFAOYSA-N 1-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]triazol-4-ol Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1N1N=NC(O)=C1 JCPNJTWIJHNAIN-UHFFFAOYSA-N 0.000 claims description 2
- RGJVRVILAKALFK-UHFFFAOYSA-N 1-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-4-methyltetrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1N1C(=O)N(C)N=N1 RGJVRVILAKALFK-UHFFFAOYSA-N 0.000 claims description 2
- UBJAZLPIPCIXCH-UHFFFAOYSA-N 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]tetrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1N1C(=O)N(C)N=N1 UBJAZLPIPCIXCH-UHFFFAOYSA-N 0.000 claims description 2
- VYSBJZZJRDWJGA-UHFFFAOYSA-N 2-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-5-fluoro-n-(4-iodo-2-methylphenyl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NC(C)(C)CO1 VYSBJZZJRDWJGA-UHFFFAOYSA-N 0.000 claims description 2
- SOUZEYPLRWUWLG-UHFFFAOYSA-N 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1h-pyrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=CN(C)N=C1O SOUZEYPLRWUWLG-UHFFFAOYSA-N 0.000 claims description 2
- WQRGDLXRCFRGOQ-UHFFFAOYSA-N 3-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-2h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=CC(=O)ON1 WQRGDLXRCFRGOQ-UHFFFAOYSA-N 0.000 claims description 2
- VIDTXRFNAHTNJK-UHFFFAOYSA-N 3-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-2h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=CC(=O)ON1 VIDTXRFNAHTNJK-UHFFFAOYSA-N 0.000 claims description 2
- YGTAZAAYPMKQMA-UHFFFAOYSA-N 3-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-2h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=CC(=O)ON1 YGTAZAAYPMKQMA-UHFFFAOYSA-N 0.000 claims description 2
- WTSXVIMLKCKWIW-UHFFFAOYSA-N 3h-1,3,4-oxadiazol-2-one Chemical compound O=C1NN=CO1 WTSXVIMLKCKWIW-UHFFFAOYSA-N 0.000 claims description 2
- UPGDPKNDUGBHJO-UHFFFAOYSA-N 4-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=CON=C1O UPGDPKNDUGBHJO-UHFFFAOYSA-N 0.000 claims description 2
- DDOSQEBJCJFTSI-UHFFFAOYSA-N 4-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=CSN=C1O DDOSQEBJCJFTSI-UHFFFAOYSA-N 0.000 claims description 2
- JROAVHUBFWGXMF-UHFFFAOYSA-N 4-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-4h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1C(=O)ON=C1 JROAVHUBFWGXMF-UHFFFAOYSA-N 0.000 claims description 2
- JSPJSYCERHKJBF-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-4h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1C(=O)ON=C1 JSPJSYCERHKJBF-UHFFFAOYSA-N 0.000 claims description 2
- ATIIDUMSUKPVSW-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-2-methyl-1h-pyrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=CN(C)N=C1O ATIIDUMSUKPVSW-UHFFFAOYSA-N 0.000 claims description 2
- LKQJQXKFAZEKEK-UHFFFAOYSA-N 4-bromo-6-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-2,3-difluoro-n-(4-iodo-2-methylphenyl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NC(C)(C)CO1 LKQJQXKFAZEKEK-UHFFFAOYSA-N 0.000 claims description 2
- UXNDHURSMOJOAZ-UHFFFAOYSA-N 5-[2-(2-amino-4-iodoanilino)-4-fluoro-5-nitrophenyl]-1-methyltriazol-4-ol Chemical compound CN1N=NC(O)=C1C1=CC([N+]([O-])=O)=C(F)C=C1NC1=CC=C(I)C=C1N UXNDHURSMOJOAZ-UHFFFAOYSA-N 0.000 claims description 2
- ODICWDLFZBBTMP-UHFFFAOYSA-N 5-[2-(2-amino-4-iodoanilino)-5-bromo-3,4-difluorophenyl]-1-methyltriazol-4-ol Chemical compound CN1N=NC(O)=C1C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1N ODICWDLFZBBTMP-UHFFFAOYSA-N 0.000 claims description 2
- KJOHWOXRXVNBIO-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,3,4-oxadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(N)O1 KJOHWOXRXVNBIO-UHFFFAOYSA-N 0.000 claims description 2
- GORCZIPKZLSMHH-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-oxadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(O)O1 GORCZIPKZLSMHH-UHFFFAOYSA-N 0.000 claims description 2
- JFWLPLIRIUYILG-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-oxadiazole-2-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(S)O1 JFWLPLIRIUYILG-UHFFFAOYSA-N 0.000 claims description 2
- PAFBJOBUVMWSRW-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(O)S1 PAFBJOBUVMWSRW-UHFFFAOYSA-N 0.000 claims description 2
- JVDGOPGIZANNNS-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(S)S1 JVDGOPGIZANNNS-UHFFFAOYSA-N 0.000 claims description 2
- PWZDHDLDKBQMSH-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(O)N1 PWZDHDLDKBQMSH-UHFFFAOYSA-N 0.000 claims description 2
- PWOCQFXWCJLJQA-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=CC(O)=NO1 PWOCQFXWCJLJQA-UHFFFAOYSA-N 0.000 claims description 2
- VTMWBHRBNZTMSE-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=CC(O)=NS1 VTMWBHRBNZTMSE-UHFFFAOYSA-N 0.000 claims description 2
- CFBVQEZLISVQOX-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,3,4-oxadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(N)O1 CFBVQEZLISVQOX-UHFFFAOYSA-N 0.000 claims description 2
- XECMFJLNUYXNMZ-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1h-1,2,4-triazol-3-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(N)N1 XECMFJLNUYXNMZ-UHFFFAOYSA-N 0.000 claims description 2
- LYXHUBJGUCHEQL-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-oxadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(O)O1 LYXHUBJGUCHEQL-UHFFFAOYSA-N 0.000 claims description 2
- XTZXRXGVCIMKOH-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,2-dihydro-1,2,4-triazole-3-thione Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(S)N1 XTZXRXGVCIMKOH-UHFFFAOYSA-N 0.000 claims description 2
- QVDLZEGBOGIZDG-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,2-dihydropyrazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=CC(O)=NN1 QVDLZEGBOGIZDG-UHFFFAOYSA-N 0.000 claims description 2
- NGKZPTSKUSNITC-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=CC(O)=NO1 NGKZPTSKUSNITC-UHFFFAOYSA-N 0.000 claims description 2
- IOYHXSMGIUHSDX-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,3,4-oxadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(N)O1 IOYHXSMGIUHSDX-UHFFFAOYSA-N 0.000 claims description 2
- KFEZKBOFUMYUOU-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,3,4-thiadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(N)S1 KFEZKBOFUMYUOU-UHFFFAOYSA-N 0.000 claims description 2
- FNEGQYQGDVYILD-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=C(O)N1 FNEGQYQGDVYILD-UHFFFAOYSA-N 0.000 claims description 2
- YEFHFAQQWRVWEO-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydro-1,2,4-triazole-3-thione Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=C(S)N1 YEFHFAQQWRVWEO-UHFFFAOYSA-N 0.000 claims description 2
- DKGBUVAKILBEQF-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydropyrazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=CC(O)=NN1 DKGBUVAKILBEQF-UHFFFAOYSA-N 0.000 claims description 2
- KYJDAVBVYZEVOJ-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=CC(O)=NO1 KYJDAVBVYZEVOJ-UHFFFAOYSA-N 0.000 claims description 2
- YEPPKVMEYRBWMU-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=CC(O)=NS1 YEPPKVMEYRBWMU-UHFFFAOYSA-N 0.000 claims description 2
- TZQHVGWTHYZJOI-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,3,4-thiadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=C(N)S1 TZQHVGWTHYZJOI-UHFFFAOYSA-N 0.000 claims description 2
- FERIYZBMZAKVTM-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-oxadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=C(O)O1 FERIYZBMZAKVTM-UHFFFAOYSA-N 0.000 claims description 2
- JOBJXXCFSXRKRF-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(O)N1 JOBJXXCFSXRKRF-UHFFFAOYSA-N 0.000 claims description 2
- KBNSOAVKWSDKLE-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,3,4-thiadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(N)S1 KBNSOAVKWSDKLE-UHFFFAOYSA-N 0.000 claims description 2
- YJHSCIHOYYWCQW-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1h-1,2,4-triazol-3-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(N)N1 YJHSCIHOYYWCQW-UHFFFAOYSA-N 0.000 claims description 2
- HDNIRQUOIOKKRS-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(O)S1 HDNIRQUOIOKKRS-UHFFFAOYSA-N 0.000 claims description 2
- WCOVGMYPWHYONR-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(S)S1 WCOVGMYPWHYONR-UHFFFAOYSA-N 0.000 claims description 2
- IKCKSPFZYKIPEC-UHFFFAOYSA-N 5-fluoro-n-(4-iodo-2-methylphenyl)-4-nitro-2-(2h-tetrazol-5-yl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=NN1 IKCKSPFZYKIPEC-UHFFFAOYSA-N 0.000 claims description 2
- NHOACUWHLVOOFZ-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=C(O)N(C)N=N1 Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=C(O)N(C)N=N1 NHOACUWHLVOOFZ-UHFFFAOYSA-N 0.000 claims description 2
- BKIZNXZPDHMPNB-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=C(O)N(C)N=C1 Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=C(O)N(C)N=C1 BKIZNXZPDHMPNB-UHFFFAOYSA-N 0.000 claims description 2
- 201000005569 Gout Diseases 0.000 claims description 2
- 208000028389 Nerve injury Diseases 0.000 claims description 2
- 208000004983 Phantom Limb Diseases 0.000 claims description 2
- 206010056238 Phantom pain Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- 230000008764 nerve damage Effects 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- QEASJVYPHMYPJM-UHFFFAOYSA-N 1,2-dihydrotriazol-5-one Chemical compound OC1=CNN=N1 QEASJVYPHMYPJM-UHFFFAOYSA-N 0.000 claims 3
- HHDMWXPOIBGYHM-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=CSN=C1O HHDMWXPOIBGYHM-UHFFFAOYSA-N 0.000 claims 2
- 206010021135 Hypovitaminosis Diseases 0.000 claims 2
- 208000030401 vitamin deficiency disease Diseases 0.000 claims 2
- LZTSCEYDCZBRCJ-UHFFFAOYSA-N 1,2-dihydro-1,2,4-triazol-3-one Chemical compound OC=1N=CNN=1 LZTSCEYDCZBRCJ-UHFFFAOYSA-N 0.000 claims 1
- WFDALXPULMQOGY-UHFFFAOYSA-N 1-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-4-methyltetrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1N1C(=O)N(C)N=N1 WFDALXPULMQOGY-UHFFFAOYSA-N 0.000 claims 1
- FVTJNFQCZSPAPJ-UHFFFAOYSA-N 1-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-4-methyltetrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1N1C(=O)N(C)N=N1 FVTJNFQCZSPAPJ-UHFFFAOYSA-N 0.000 claims 1
- NNQKOSQYWYUCNE-UHFFFAOYSA-N 1-methyltriazol-4-ol Chemical compound CN1C=C(O)N=N1 NNQKOSQYWYUCNE-UHFFFAOYSA-N 0.000 claims 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims 1
- WIISOYLZJJYTHT-UHFFFAOYSA-N 2-methyl-1h-pyrazol-5-one Chemical compound CN1C=CC(O)=N1 WIISOYLZJJYTHT-UHFFFAOYSA-N 0.000 claims 1
- ZBHZDNXGSWNMOI-UHFFFAOYSA-N 3-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-2h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=CC(=O)ON1 ZBHZDNXGSWNMOI-UHFFFAOYSA-N 0.000 claims 1
- WOLJKRQMWVGOCZ-UHFFFAOYSA-N 4-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-4h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1C(=O)ON=C1 WOLJKRQMWVGOCZ-UHFFFAOYSA-N 0.000 claims 1
- BZHFBSLDGULCTM-UHFFFAOYSA-N 4-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=CON=C1O BZHFBSLDGULCTM-UHFFFAOYSA-N 0.000 claims 1
- VVPPJZLDNIBPQW-UHFFFAOYSA-N 4-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=CSN=C1O VVPPJZLDNIBPQW-UHFFFAOYSA-N 0.000 claims 1
- GIGIQHHCOYTASR-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=CON=C1O GIGIQHHCOYTASR-UHFFFAOYSA-N 0.000 claims 1
- GKBNTEJRQLGWFH-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=CON=C1O GKBNTEJRQLGWFH-UHFFFAOYSA-N 0.000 claims 1
- XCEAAXNFYQTNRX-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=CSN=C1O XCEAAXNFYQTNRX-UHFFFAOYSA-N 0.000 claims 1
- FDKCGBRXTKECRT-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-4h-1,2-oxazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1C(=O)ON=C1 FDKCGBRXTKECRT-UHFFFAOYSA-N 0.000 claims 1
- ODMPNWXCSIYDGM-UHFFFAOYSA-N 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-2-methyl-1h-pyrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=CN(C)N=C1O ODMPNWXCSIYDGM-UHFFFAOYSA-N 0.000 claims 1
- GVZOBHGQDYMLOM-UHFFFAOYSA-N 4-bromo-2,3-difluoro-n-(4-iodo-2-methylphenyl)-6-(2h-tetrazol-5-yl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=NN1 GVZOBHGQDYMLOM-UHFFFAOYSA-N 0.000 claims 1
- NFRNXQCUJHGTOD-UHFFFAOYSA-N 5-[2-(2-amino-4-iodoanilino)-3,4,5-trifluorophenyl]-1-methyltriazol-4-ol Chemical compound CN1N=NC(O)=C1C1=CC(F)=C(F)C(F)=C1NC1=CC=C(I)C=C1N NFRNXQCUJHGTOD-UHFFFAOYSA-N 0.000 claims 1
- MTZZXFIKCUBSPB-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydropyrazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=CC(O)=NN1 MTZZXFIKCUBSPB-UHFFFAOYSA-N 0.000 claims 1
- NWYZNCYPLDVQAW-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=CC(O)=NO1 NWYZNCYPLDVQAW-UHFFFAOYSA-N 0.000 claims 1
- ZRJQUKGUSJAEQR-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=CC(O)=NS1 ZRJQUKGUSJAEQR-UHFFFAOYSA-N 0.000 claims 1
- BJRPARRNOUWNFK-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydropyrazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=CC(O)=NN1 BJRPARRNOUWNFK-UHFFFAOYSA-N 0.000 claims 1
- KPGXOIWUBAUIQJ-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,3,4-thiadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(N)S1 KPGXOIWUBAUIQJ-UHFFFAOYSA-N 0.000 claims 1
- ICFOZMCFRHMZKD-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(O)S1 ICFOZMCFRHMZKD-UHFFFAOYSA-N 0.000 claims 1
- KNMDLUPXTQDNHJ-UHFFFAOYSA-N 5-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=C(S)S1 KNMDLUPXTQDNHJ-UHFFFAOYSA-N 0.000 claims 1
- RXVJKZPEWXGYQH-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1h-1,2,4-triazol-3-amine Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(N)N1 RXVJKZPEWXGYQH-UHFFFAOYSA-N 0.000 claims 1
- PLHIYIVMGXBALK-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-3h-1,3,4-thiadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(O)S1 PLHIYIVMGXBALK-UHFFFAOYSA-N 0.000 claims 1
- KKNARJPQRJIQKC-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-1h-1,2,4-triazol-3-amine Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=C(N)N1 KKNARJPQRJIQKC-UHFFFAOYSA-N 0.000 claims 1
- GHAWIWSZYAEARU-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,3,4-oxadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(N)O1 GHAWIWSZYAEARU-UHFFFAOYSA-N 0.000 claims 1
- BFHWUKOHFWNRDR-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-oxadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(O)O1 BFHWUKOHFWNRDR-UHFFFAOYSA-N 0.000 claims 1
- LQXJTBZNAMNDLE-UHFFFAOYSA-N 6-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-2,3,4-trifluoro-n-(4-iodo-2-methylphenyl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NC(C)(C)CO1 LQXJTBZNAMNDLE-UHFFFAOYSA-N 0.000 claims 1
- IVEQTMOSBYJXPN-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=C(O)N(C)N=C1 Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=C(O)N(C)N=C1 IVEQTMOSBYJXPN-UHFFFAOYSA-N 0.000 claims 1
- ZROOXJUDUNBDMY-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=C(O)N(C)N=N1 Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=C(O)N(C)N=N1 ZROOXJUDUNBDMY-UHFFFAOYSA-N 0.000 claims 1
- JIPMATZRMPAVCO-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=C(O)N(C)N=N1 Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=C(O)N(C)N=N1 JIPMATZRMPAVCO-UHFFFAOYSA-N 0.000 claims 1
- SZGAZIXGPNGOJI-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=C(O)N(C)N=C1 Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=C(O)N(C)N=C1 SZGAZIXGPNGOJI-UHFFFAOYSA-N 0.000 claims 1
- TVCLKQLFVRTJTA-UHFFFAOYSA-N CN1N=NC=C1O Chemical compound CN1N=NC=C1O TVCLKQLFVRTJTA-UHFFFAOYSA-N 0.000 claims 1
- 125000004212 difluorophenyl group Chemical group 0.000 claims 1
- HZVPJXOQDCOJRJ-UHFFFAOYSA-N isoxazolin-5-one Chemical compound O=C1C=CNO1 HZVPJXOQDCOJRJ-UHFFFAOYSA-N 0.000 claims 1
- 210000001428 peripheral nervous system Anatomy 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 208000004454 Hyperalgesia Diseases 0.000 description 38
- 241001465754 Metazoa Species 0.000 description 36
- 206010053552 allodynia Diseases 0.000 description 36
- UHAXDAKQGVISBZ-UHFFFAOYSA-N N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C(=O)NOCC1CC1 UHAXDAKQGVISBZ-UHFFFAOYSA-N 0.000 description 35
- 230000003068 static effect Effects 0.000 description 35
- RNLSQSUHSKNIPT-UHFFFAOYSA-N 2-fluoro-5-(5-hydroxy-3-methyltriazol-4-yl)-4-(4-iodo-2-methylanilino)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=C(O)N=NN1C RNLSQSUHSKNIPT-UHFFFAOYSA-N 0.000 description 30
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 29
- 229960001233 pregabalin Drugs 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 24
- FDGXOEXYVKIQTN-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2,3-difluoro-5-(2-oxo-5h-1,2,3,5-oxathiadiazol-4-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C(F)=C(F)C(S(=O)(=O)N)=CC=1C1=NOS(=O)N1 FDGXOEXYVKIQTN-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 20
- 210000004209 hair Anatomy 0.000 description 19
- 239000003981 vehicle Substances 0.000 description 19
- LCEWEDYKXIKOKI-UHFFFAOYSA-N 2,6-difluoro-3-(4-iodoanilino)-4-(3-methyl-2-oxo-1,2,3,5-oxathiadiazol-4-yl)benzenesulfonamide Chemical compound O1S(=O)N(C)C(C=2C(=C(F)C(=C(F)C=2)S(N)(=O)=O)NC=2C=CC(I)=CC=2)=N1 LCEWEDYKXIKOKI-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 18
- 229960001052 streptozocin Drugs 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 16
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 16
- 210000002683 foot Anatomy 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- ADKYFLJOHGFGLH-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2,3-difluoro-5-(3-methyl-2-oxo-1,2,3,5-oxathiadiazol-4-yl)benzenesulfonamide Chemical compound O1S(=O)N(C)C(C=2C(=C(F)C(F)=C(C=2)S(N)(=O)=O)NC=2C(=CC(I)=CC=2)Cl)=N1 ADKYFLJOHGFGLH-UHFFFAOYSA-N 0.000 description 14
- MJFYUSFICSBZGY-UHFFFAOYSA-N 2,3-difluoro-4-(4-iodo-2-methylanilino)-5-(5-oxo-2h-tetrazol-1-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(S(N)(=O)=O)C=C1N1C(=O)NN=N1 MJFYUSFICSBZGY-UHFFFAOYSA-N 0.000 description 13
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 13
- 241000700159 Rattus Species 0.000 description 13
- 238000007913 intrathecal administration Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000003776 cleavage reaction Methods 0.000 description 11
- 230000007017 scission Effects 0.000 description 11
- 102000043136 MAP kinase family Human genes 0.000 description 10
- 108091054455 MAP kinase family Proteins 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000012353 t test Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- 230000003574 anti-allodynic effect Effects 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 230000026731 phosphorylation Effects 0.000 description 7
- 238000006366 phosphorylation reaction Methods 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000016914 ras Proteins Human genes 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 6
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 208000026935 allergic disease Diseases 0.000 description 6
- KHBQMWCZKVMBLN-IDEBNGHGSA-N benzenesulfonamide Chemical group NS(=O)(=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 KHBQMWCZKVMBLN-IDEBNGHGSA-N 0.000 description 6
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000008389 polyethoxylated castor oil Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 description 5
- 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000009610 hypersensitivity Effects 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000002981 neuropathic effect Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 4
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 210000003497 sciatic nerve Anatomy 0.000 description 4
- 150000000185 1,3-diols Chemical class 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 3
- ZZLTXWMPUKJTFS-UHFFFAOYSA-N 2-hydroxy-3h-oxadiazole Chemical compound ON1NC=CO1 ZZLTXWMPUKJTFS-UHFFFAOYSA-N 0.000 description 3
- GSVLNNGNWIIQNS-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)benzohydrazide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NN GSVLNNGNWIIQNS-UHFFFAOYSA-N 0.000 description 3
- XRNCNLRJMNWXRG-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(O)=O XRNCNLRJMNWXRG-UHFFFAOYSA-N 0.000 description 3
- 208000008035 Back Pain Diseases 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 101710178035 Chorismate synthase 2 Proteins 0.000 description 3
- 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 description 3
- 101710152694 Cysteine synthase 2 Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000004103 aminoalkyl group Chemical group 0.000 description 3
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 3
- 150000002081 enamines Chemical class 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 3
- 125000005027 hydroxyaryl group Chemical group 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- 150000005217 methyl ethers Chemical class 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 238000007910 systemic administration Methods 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- NOYJVIQFEOIOPH-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2,3-difluoro-5-(5-oxo-1,2-dihydrotriazol-4-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C(F)=C(F)C(S(=O)(=O)N)=CC=1C=1NN=NC=1O NOYJVIQFEOIOPH-UHFFFAOYSA-N 0.000 description 2
- BAKYASSDAXQKKY-UHFFFAOYSA-N 4-Hydroxy-3-methylbenzaldehyde Chemical compound CC1=CC(C=O)=CC=C1O BAKYASSDAXQKKY-UHFFFAOYSA-N 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 description 2
- XFEZJJWXJXULKK-UHFFFAOYSA-N 5-(5-amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methylanilino)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=NN=C(N)O1 XFEZJJWXJXULKK-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 208000007514 Herpes zoster Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000035154 Hyperesthesia Diseases 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 2
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 206010047627 Vitamin deficiencies Diseases 0.000 description 2
- 229940022663 acetate Drugs 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000005001 aminoaryl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000001174 ascending effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000000351 effect on allodynia Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 2
- 125000005020 hydroxyalkenyl group Chemical group 0.000 description 2
- 125000005016 hydroxyalkynyl group Chemical group 0.000 description 2
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 230000002297 mitogenic effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 230000001473 noxious effect Effects 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003871 sulfonates Chemical class 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000035900 sweating Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 description 1
- YLKHAMLPZAGCGO-UHFFFAOYSA-N 1,1,1-trichloro-3-(4-methoxyphenyl)hepta-2,5-dien-4-one Chemical compound COC1=CC=C(C(=CC(Cl)(Cl)Cl)C(=O)[C-]=CC)C=C1 YLKHAMLPZAGCGO-UHFFFAOYSA-N 0.000 description 1
- XBYRMPXUBGMOJC-UHFFFAOYSA-N 1,2-dihydropyrazol-3-one Chemical compound OC=1C=CNN=1 XBYRMPXUBGMOJC-UHFFFAOYSA-N 0.000 description 1
- GZMPNWZNKXKPGC-UHFFFAOYSA-N 1,3,5-triazinan-2-one Chemical compound O=C1NCNCN1 GZMPNWZNKXKPGC-UHFFFAOYSA-N 0.000 description 1
- VJRIPOXOZAXBJJ-UHFFFAOYSA-N 1-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]triazol-4-ol Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1N1N=NC(O)=C1 VJRIPOXOZAXBJJ-UHFFFAOYSA-N 0.000 description 1
- COSUQWQBWJNFAU-UHFFFAOYSA-N 1-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]triazol-4-ol Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1N1N=NC(O)=C1 COSUQWQBWJNFAU-UHFFFAOYSA-N 0.000 description 1
- FATBYIUGJJGIOP-UHFFFAOYSA-N 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-4-methyltetrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1N1C(=O)N(C)N=N1 FATBYIUGJJGIOP-UHFFFAOYSA-N 0.000 description 1
- SBARIDAAXOQZEA-UHFFFAOYSA-N 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]triazol-4-ol Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1N1N=NC(O)=C1 SBARIDAAXOQZEA-UHFFFAOYSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- ATPQHBQUXWELOE-UHFFFAOYSA-N 1-hydroxysulfanyl-2,4-dinitrobenzene Chemical compound OSC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O ATPQHBQUXWELOE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- QGDAAPPGTYAIIW-UHFFFAOYSA-N 2,3,4-trifluoro-n-(4-iodo-2-methylphenyl)-6-(2h-tetrazol-5-yl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=NN1 QGDAAPPGTYAIIW-UHFFFAOYSA-N 0.000 description 1
- HTQBPMWYFUJBMZ-UHFFFAOYSA-N 2,3-difluoro-4-(4-iodo-2-methylanilino)-5-(3-methyl-2-oxo-1,2,3,5-oxathiadiazol-4-yl)benzenesulfonamide Chemical compound O1S(=O)N(C)C(C=2C(=C(F)C(F)=C(C=2)S(N)(=O)=O)NC=2C(=CC(I)=CC=2)C)=N1 HTQBPMWYFUJBMZ-UHFFFAOYSA-N 0.000 description 1
- COSIAPCCAMTTOC-UHFFFAOYSA-N 2,3-difluoro-4-(4-iodo-2-methylanilino)-5-(3-oxo-1,2-dihydropyrazol-4-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(S(N)(=O)=O)C=C1C1=C(O)NN=C1 COSIAPCCAMTTOC-UHFFFAOYSA-N 0.000 description 1
- PDWDLESRZKZNTF-UHFFFAOYSA-N 2,3-difluoro-4-(4-iodo-2-methylanilino)-5-(5-oxo-1,2-dihydro-1,2,4-triazol-3-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(S(N)(=O)=O)C=C1C1=NN=C(O)N1 PDWDLESRZKZNTF-UHFFFAOYSA-N 0.000 description 1
- HSLAOXLKYNIDNR-UHFFFAOYSA-N 2,3-difluoro-4-(4-iodo-2-methylanilino)-5-(5-oxo-1,2-dihydrotriazol-4-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(S(N)(=O)=O)C=C1C1=C(O)N=NN1 HSLAOXLKYNIDNR-UHFFFAOYSA-N 0.000 description 1
- UWHMFZJDNMMEGF-UHFFFAOYSA-N 2,3-difluoro-4-(4-iodo-2-methylanilino)-5-(5-oxo-2h-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(S(N)(=O)=O)C=C1C1=CC(=O)ON1 UWHMFZJDNMMEGF-UHFFFAOYSA-N 0.000 description 1
- ZQCOIPTWLZLEKL-UHFFFAOYSA-N 2,3-difluoro-n-(4-iodo-2-methylphenyl)-6-(1,3,4-oxadiazol-2-yl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=CO1 ZQCOIPTWLZLEKL-UHFFFAOYSA-N 0.000 description 1
- JVQDJRVZPPUWHQ-UHFFFAOYSA-N 2,3-difluoro-n-(4-iodo-2-methylphenyl)-6-(2h-tetrazol-5-yl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=NN=NN1 JVQDJRVZPPUWHQ-UHFFFAOYSA-N 0.000 description 1
- DWBWMAAYLWUXQK-UHFFFAOYSA-N 2,3-difluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(F)=C1F DWBWMAAYLWUXQK-UHFFFAOYSA-N 0.000 description 1
- FFFIRKXTFQCCKJ-UHFFFAOYSA-M 2,4,6-trimethylbenzoate Chemical compound CC1=CC(C)=C(C([O-])=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-M 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- YURLCYGZYWDCHL-UHFFFAOYSA-N 2-(2,6-dichloro-4-methylphenoxy)acetic acid Chemical compound CC1=CC(Cl)=C(OCC(O)=O)C(Cl)=C1 YURLCYGZYWDCHL-UHFFFAOYSA-N 0.000 description 1
- XWZXFBYXIPRUSM-UHFFFAOYSA-N 2-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-5-fluoro-n-(4-iodo-2-methylphenyl)-4-nitroaniline Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NC(C)(C)CO1 XWZXFBYXIPRUSM-UHFFFAOYSA-N 0.000 description 1
- RHTRAVVGRYHJES-UHFFFAOYSA-N 2-(4-iodoanilino)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1NC1=CC=C(I)C=C1 RHTRAVVGRYHJES-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- RQDKNFDEXBVLPV-UHFFFAOYSA-N 2-azidobutanoic acid Chemical compound CCC(C(O)=O)N=[N+]=[N-] RQDKNFDEXBVLPV-UHFFFAOYSA-N 0.000 description 1
- UJRMHFPTLFNSTA-UHFFFAOYSA-N 2-chloro-2,2-diphenylacetic acid Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)O)C1=CC=CC=C1 UJRMHFPTLFNSTA-UHFFFAOYSA-N 0.000 description 1
- QEQLOHQUVFMNFY-UHFFFAOYSA-N 2-fluoro-4-(4-iodo-2-methylanilino)-5-(2-oxo-3h-1,3,4-oxadiazol-5-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=NN=C(O)O1 QEQLOHQUVFMNFY-UHFFFAOYSA-N 0.000 description 1
- UHBZLMBRIQCCCE-UHFFFAOYSA-N 2-fluoro-4-(4-iodo-2-methylanilino)-5-(4-methyl-5-oxotetrazol-1-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1N1C(=O)N(C)N=N1 UHBZLMBRIQCCCE-UHFFFAOYSA-N 0.000 description 1
- JDXUTFIBCRZSPW-UHFFFAOYSA-N 2-fluoro-4-(4-iodo-2-methylanilino)-5-(5-oxo-1,2-dihydro-1,2,4-triazol-3-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=NN=C(O)N1 JDXUTFIBCRZSPW-UHFFFAOYSA-N 0.000 description 1
- HAGZBZRGHCVPNV-UHFFFAOYSA-N 2-fluoro-4-(4-iodo-2-methylanilino)-5-(5-oxo-2h-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=CC(=O)ON1 HAGZBZRGHCVPNV-UHFFFAOYSA-N 0.000 description 1
- SHHKMWMIKILKQW-UHFFFAOYSA-M 2-formylbenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1C=O SHHKMWMIKILKQW-UHFFFAOYSA-M 0.000 description 1
- CJNZAXGUTKBIHP-UHFFFAOYSA-M 2-iodobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-M 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 description 1
- MSQFTSHTPYBFNS-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)benzonitrile Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C#N MSQFTSHTPYBFNS-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 150000000499 3-oxazolines Chemical class 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- RUBRCWOFANAOTP-UHFFFAOYSA-N 3h-1,3,4-oxadiazole-2-thione Chemical compound S=C1NN=CO1 RUBRCWOFANAOTP-UHFFFAOYSA-N 0.000 description 1
- OVZHELCFKSFINS-UHFFFAOYSA-N 3h-1,3,4-thiadiazol-2-one Chemical compound O=C1NN=CS1 OVZHELCFKSFINS-UHFFFAOYSA-N 0.000 description 1
- UBARRNXCKBFUEN-UHFFFAOYSA-N 4,5-diphenyl-5h-1,3-oxazol-2-one Chemical compound N=1C(=O)OC(C=2C=CC=CC=2)C=1C1=CC=CC=C1 UBARRNXCKBFUEN-UHFFFAOYSA-N 0.000 description 1
- XRHSJCRCPCSWRI-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2,3-difluoro-5-(2-oxo-3h-1,3,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C(F)=C(F)C(S(=O)(=O)N)=CC=1C1=NN=C(O)S1 XRHSJCRCPCSWRI-UHFFFAOYSA-N 0.000 description 1
- KJJKLXDHHBMCLY-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2,3-difluoro-5-(5-oxo-1,2-dihydro-1,2,4-triazol-3-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C(F)=C(F)C(S(=O)(=O)N)=CC=1C1=NN=C(O)N1 KJJKLXDHHBMCLY-UHFFFAOYSA-N 0.000 description 1
- QHMKHKRRYKNCKR-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2,3-difluoro-5-(5-oxo-2h-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C(F)=C(F)C(S(=O)(=O)N)=CC=1C1=CC(=O)ON1 QHMKHKRRYKNCKR-UHFFFAOYSA-N 0.000 description 1
- FSGIWPATYUPZDY-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2-fluoro-5-(2-sulfanylidene-3h-1,3,4-oxadiazol-5-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C=C(F)C(S(=O)(=O)N)=CC=1C1=NN=C(S)O1 FSGIWPATYUPZDY-UHFFFAOYSA-N 0.000 description 1
- RIRIGKGEPQZBFV-UHFFFAOYSA-N 4-(2-chloro-4-iodoanilino)-2-fluoro-n-methyl-5-(3-methyl-2-oxo-1,2,3,5-oxathiadiazol-4-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC=1C=C(F)C(S(=O)(=O)NC)=CC=1C1=NOS(=O)N1C RIRIGKGEPQZBFV-UHFFFAOYSA-N 0.000 description 1
- ZICMEXBGXFWOAD-UHFFFAOYSA-N 4-[3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-2-methyl-1h-pyrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C1=CN(C)N=C1O ZICMEXBGXFWOAD-UHFFFAOYSA-N 0.000 description 1
- YZEHYLDQCQSQOE-UHFFFAOYSA-N 4-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-2-methyl-1h-pyrazol-5-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=CN(C)N=C1O YZEHYLDQCQSQOE-UHFFFAOYSA-N 0.000 description 1
- BYRWCWFJIUSCAW-UHFFFAOYSA-N 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=CON=C1O BYRWCWFJIUSCAW-UHFFFAOYSA-N 0.000 description 1
- HTSYSXSLJHYHEG-UHFFFAOYSA-N 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=CSN=C1O HTSYSXSLJHYHEG-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 1
- KHKJLJHJTQRHSA-UHFFFAOYSA-N 4-methyl-4-nitropentanoic acid Chemical compound [O-][N+](=O)C(C)(C)CCC(O)=O KHKJLJHJTQRHSA-UHFFFAOYSA-N 0.000 description 1
- NNJMFJSKMRYHSR-UHFFFAOYSA-M 4-phenylbenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-M 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- GBXDPDKKAKBOGP-UHFFFAOYSA-N 5-(3-amino-1h-1,2,4-triazol-5-yl)-2-fluoro-4-(4-iodo-2-methylanilino)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=NN=C(N)N1 GBXDPDKKAKBOGP-UHFFFAOYSA-N 0.000 description 1
- YHJSMPYGHGLHSU-UHFFFAOYSA-N 5-(5-amino-1,3,4-oxadiazol-2-yl)-2,3-difluoro-4-(4-iodo-2-methylanilino)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(S(N)(=O)=O)C=C1C1=NN=C(N)O1 YHJSMPYGHGLHSU-UHFFFAOYSA-N 0.000 description 1
- APXYYAOIFFKDBI-UHFFFAOYSA-N 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodoanilino)-2,3-difluoro-n-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide Chemical compound C1CN(C)CCN1CCCNS(=O)(=O)C(C(=C1F)F)=CC(C=2OC(N)=NN=2)=C1NC1=CC=C(I)C=C1Cl APXYYAOIFFKDBI-UHFFFAOYSA-N 0.000 description 1
- YALWEHBJSHKOGV-UHFFFAOYSA-N 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodoanilino)-2-fluorobenzenesulfonamide Chemical compound O1C(N)=NN=C1C1=CC(S(N)(=O)=O)=C(F)C=C1NC1=CC=C(I)C=C1Cl YALWEHBJSHKOGV-UHFFFAOYSA-N 0.000 description 1
- VXVCRVJROPWWFM-UHFFFAOYSA-N 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methylanilino)benzenesulfonamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=NN=C(N)S1 VXVCRVJROPWWFM-UHFFFAOYSA-N 0.000 description 1
- MUHVNNHGNKACDV-UHFFFAOYSA-N 5-(5-amino-1,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodoanilino)-2-fluorobenzenesulfonamide Chemical compound S1C(N)=NN=C1C1=CC(S(N)(=O)=O)=C(F)C=C1NC1=CC=C(I)C=C1Cl MUHVNNHGNKACDV-UHFFFAOYSA-N 0.000 description 1
- POZBLOICDUEJOH-UHFFFAOYSA-N 5-[2-(2-amino-4-iodoanilino)-3,4-difluorophenyl]-1-methyltriazol-4-ol Chemical compound CN1N=NC(O)=C1C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1N POZBLOICDUEJOH-UHFFFAOYSA-N 0.000 description 1
- RHGLMCDRXHZKPZ-UHFFFAOYSA-N 5-[2-(2-amino-4-iodoanilino)-4-fluorophenyl]-1-methyltriazol-4-ol Chemical compound CN1N=NC(O)=C1C1=CC=C(F)C=C1NC1=CC=C(I)C=C1N RHGLMCDRXHZKPZ-UHFFFAOYSA-N 0.000 description 1
- ZKAUXPXXFYNVAF-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydro-1,2,4-triazole-3-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(S)N1 ZKAUXPXXFYNVAF-UHFFFAOYSA-N 0.000 description 1
- VUEDPIOQVJPKKV-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1,3,4-thiadiazol-2-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(N)S1 VUEDPIOQVJPKKV-UHFFFAOYSA-N 0.000 description 1
- IUPRGMLHKTURBG-UHFFFAOYSA-N 5-[3,4,5-trifluoro-2-(4-iodo-2-methylanilino)phenyl]-1h-1,2,4-triazol-3-amine Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=NN=C(N)N1 IUPRGMLHKTURBG-UHFFFAOYSA-N 0.000 description 1
- SXMWYAMUARNTMT-UHFFFAOYSA-N 5-[4-[2-(dimethylamino)ethyl]-5-oxotetrazol-1-yl]-2-fluoro-4-(4-iodoanilino)benzenesulfonamide Chemical compound O=C1N(CCN(C)C)N=NN1C1=CC(S(N)(=O)=O)=C(F)C=C1NC1=CC=C(I)C=C1 SXMWYAMUARNTMT-UHFFFAOYSA-N 0.000 description 1
- MJTBYZMYYIMRQJ-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(O)N1 MJTBYZMYYIMRQJ-UHFFFAOYSA-N 0.000 description 1
- FLTOBUAOCWCIMO-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=CC(O)=NS1 FLTOBUAOCWCIMO-UHFFFAOYSA-N 0.000 description 1
- QGIZNDBTLCVKRW-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-3h-1,3,4-oxadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(O)O1 QGIZNDBTLCVKRW-UHFFFAOYSA-N 0.000 description 1
- SBJZMEOHIODPCZ-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)-5-nitrophenyl]-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=NN=C(S)S1 SBJZMEOHIODPCZ-UHFFFAOYSA-N 0.000 description 1
- TWCKPKFJGMRVNZ-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazol-2-one Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=C(O)S1 TWCKPKFJGMRVNZ-UHFFFAOYSA-N 0.000 description 1
- HXERUZYXWJSQFS-UHFFFAOYSA-N 5-[4-fluoro-2-(4-iodo-2-methylanilino)phenyl]-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=C(S)S1 HXERUZYXWJSQFS-UHFFFAOYSA-N 0.000 description 1
- FWFXUHOEUIXYMP-UHFFFAOYSA-N 5-[5-amino-4-[3-(dimethylamino)propyl]-1,2,4-triazol-3-yl]-2-fluoro-4-(4-iodoanilino)benzenesulfonamide Chemical compound CN(C)CCCN1C(N)=NN=C1C1=CC(S(N)(=O)=O)=C(F)C=C1NC1=CC=C(I)C=C1 FWFXUHOEUIXYMP-UHFFFAOYSA-N 0.000 description 1
- HCFIYGRTRUMJJH-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydro-1,2,4-triazole-3-thione Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=NN=C(S)N1 HCFIYGRTRUMJJH-UHFFFAOYSA-N 0.000 description 1
- QMZIHEDWFZAVQG-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-dihydropyrazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=CC(O)=NN1 QMZIHEDWFZAVQG-UHFFFAOYSA-N 0.000 description 1
- UZQAKKCETQXWTR-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-oxazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=CC(O)=NO1 UZQAKKCETQXWTR-UHFFFAOYSA-N 0.000 description 1
- DMJSTYIZGPMWRM-UHFFFAOYSA-N 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methylanilino)phenyl]-1,2-thiazol-3-one Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(Br)C=C1C1=CC(O)=NS1 DMJSTYIZGPMWRM-UHFFFAOYSA-N 0.000 description 1
- YOFUTLXOCSCHBA-UHFFFAOYSA-N 5-[6-(2-chloro-4-iodoanilino)-7-fluoro-2,3-dihydro-1h-isoindol-5-yl]-3h-1,3,4-oxadiazol-2-one Chemical compound O1C(O)=NN=C1C(C(=C1F)NC=2C(=CC(I)=CC=2)Cl)=CC2=C1CNC2 YOFUTLXOCSCHBA-UHFFFAOYSA-N 0.000 description 1
- HULDRQRKKXRXBI-UHFFFAOYSA-N 5-chloro-2-methoxybenzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(O)=O HULDRQRKKXRXBI-UHFFFAOYSA-N 0.000 description 1
- UAHQCZNAVYTCSC-UHFFFAOYSA-N 5-fluoro-n-(4-iodo-2-methylphenyl)-2-(2h-tetrazol-5-yl)aniline Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=NN=NN1 UAHQCZNAVYTCSC-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- PYGOPEBHZKRETO-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=C(O)N(C)N=C1 Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C1=C(O)N(C)N=C1 PYGOPEBHZKRETO-UHFFFAOYSA-N 0.000 description 1
- JAWDABZODJMKEM-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=C(O)N(C)N=C1 Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C(S(N)(=O)=O)C=C1C1=C(O)N(C)N=C1 JAWDABZODJMKEM-UHFFFAOYSA-N 0.000 description 1
- UFBFRYDHHVTGJS-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=C(O)N(C)N=C1 Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=C(O)N(C)N=C1 UFBFRYDHHVTGJS-UHFFFAOYSA-N 0.000 description 1
- QAXGSZGBWAPUIG-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=C(O)N(C)N=N1 Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C1=C(O)N(C)N=N1 QAXGSZGBWAPUIG-UHFFFAOYSA-N 0.000 description 1
- MGUKQXQTYXXBTF-UHFFFAOYSA-N CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=C(O)N(C)N=N1 Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C1=C(O)N(C)N=N1 MGUKQXQTYXXBTF-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 102100023275 Dual specificity mitogen-activated protein kinase kinase 3 Human genes 0.000 description 1
- 108030004793 Dual-specificity kinases Proteins 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 241000506654 Haemulon album Species 0.000 description 1
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 1
- 101001115394 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 3 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000939500 Homo sapiens UBX domain-containing protein 11 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 102000001702 Intracellular Signaling Peptides and Proteins Human genes 0.000 description 1
- 108010068964 Intracellular Signaling Peptides and Proteins Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 description 1
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FNJSWIPFHMKRAT-UHFFFAOYSA-N Monomethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(O)=O FNJSWIPFHMKRAT-UHFFFAOYSA-N 0.000 description 1
- 229910014296 N-S Inorganic materials 0.000 description 1
- 229910014299 N-Si Inorganic materials 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical class CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 102000014750 Phosphorylase Kinase Human genes 0.000 description 1
- 108010064071 Phosphorylase Kinase Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010065306 Post procedural hypothyroidism Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 102100029645 UBX domain-containing protein 11 Human genes 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- UPSCZEULKGNPSV-UHFFFAOYSA-N [[3,4-difluoro-2-(4-iodo-2-methylanilino)benzoyl]amino]thiourea Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NNC(N)=S UPSCZEULKGNPSV-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005585 adamantoate group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005741 alkyl alkenyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000005021 aminoalkenyl group Chemical group 0.000 description 1
- 125000005014 aminoalkynyl group Chemical group 0.000 description 1
- 125000005124 aminocycloalkyl group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KVPFKMBYCSISTN-UHFFFAOYSA-N benzylsulfanylformic acid Chemical compound OC(=O)SCC1=CC=CC=C1 KVPFKMBYCSISTN-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- JFIOVJDNOJYLKP-UHFFFAOYSA-N bithionol Chemical compound OC1=C(Cl)C=C(Cl)C=C1SC1=CC(Cl)=CC(Cl)=C1O JFIOVJDNOJYLKP-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 125000004965 chloroalkyl group Chemical group 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 125000006011 chloroethoxy group Chemical group 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940058352 levulinate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008338 local blood flow Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 1
- QZHVJQPDGJBDOK-UHFFFAOYSA-N methyl 3,4-difluoro-2-(4-iodo-2-methylanilino)benzoate Chemical compound COC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C QZHVJQPDGJBDOK-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- NYEBKUUITGFJAK-UHFFFAOYSA-N methylsulfanylmethanethioic s-acid Chemical compound CSC(O)=S NYEBKUUITGFJAK-UHFFFAOYSA-N 0.000 description 1
- QXJSNJMLOMKMMR-UHFFFAOYSA-N methylsulfanylmethoxymethyl benzoate Chemical compound CSCOCOC(=O)C1=CC=CC=C1 QXJSNJMLOMKMMR-UHFFFAOYSA-N 0.000 description 1
- GRFNBEZIAWKNCO-UHFFFAOYSA-N mhp Natural products OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 201000005518 mononeuropathy Diseases 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- DIIYXHXJBCRRKT-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-2-fluoro-4-(4-iodoanilino)-n-methyl-5-(2-oxo-3h-1,3,4-oxadiazol-5-yl)benzenesulfonamide Chemical compound C=1C=C(I)C=CC=1NC=1C=C(F)C(S(=O)(=O)N(C)CCN(C)C)=CC=1C1=NN=C(O)O1 DIIYXHXJBCRRKT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000007433 nerve pathway Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical class NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- LOFZYSZWOLKUGE-UHFFFAOYSA-N s-benzyl carbamothioate Chemical compound NC(=O)SCC1=CC=CC=C1 LOFZYSZWOLKUGE-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 101150114085 soc-2 gene Proteins 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- CPRPKIMXLHBUGA-UHFFFAOYSA-N triethyltin Chemical group CC[Sn](CC)CC CPRPKIMXLHBUGA-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
WO 01/05391 PCT/USOO/18346 METHOD FOR TREATING CHRONIC PAIN USING MEK INHIBITORS 5 BACKGROUND The invention features a method for treating chronic pain using MEK inhibitors. Chronic pain includes neuropathic pain, and chronic inflammatory pain. 10 Abnormality anywhere in a nerve pathway disrupts nerve signals, which in turn are abnormally interpreted in the brain, causing neuropathic pain. Neuropathic pain may be, for example, a deep ache, a burning sensation, or hypersensitivity to touch. Diseases or conditions associated with neuropathic 15 pain include, without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crush injury, viral infections (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the periphery to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and 20 vitamin deficiencies. Infections such as herpes zoster (shingles) can cause nerve inflammation and produce postherpetic neuralgia, a chronic burning localized to the area of viral infection. Hyperalgesia is when an already noxious stimulus becomes more painful, and allodynia, when a previously non-noxious 25 stimulus becomes painful (such as contact of clothing or a breeze). Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy, or osteoporosis. Causalgia, including severe burning pain and swelling, sweating, and changes in blood flow, may follow an injury or disease of a major nerve such as the sciatic nerve. Some 30' types of chronic low back pain can have a neuropathic component (e.g., sciatica, postpoliomyelitis and CPRM). Neuropathic pain may also be induced by cancer or chemotherapy. 1 WO 01/05391 PCT/USOO/18346 Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitryptaline. NSAIDS and opioids generally have little effect (Fields et al 1994 Textbook of Pain p 991 996 (pub: Churchill Livingstone), James & Page 1994 5 J.Am.Pediatr.Med.Assoc, 8: 439-44 7, Galer, 1995 Neurology 45 SI 7-S25. Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD). The generally weak efficacy of antiinflammatory agents suggests that the 10 mechanism for chronic pain is separate from hyperalgesia. SUMMARY OF THE INVENTION The invention features a method for treating chronic pain, which 15 method includes the step of administering a composition including a MEK inhibitor to a patient in need of such treatment. Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiencies, uremia, hypothyroidism post-operative pain, arthritis, back pain, and chronic alcoholism. The invention also features compositions as 20 disclosed, formulated for the treatment of chronic pain. Such a composition may include one or more MEK inhibitor compounds having a structure disclosed in patent application PCT/US99/30416, international filing date December 21, 1999. Examples of MEK inhibitors include a compound having the formula (1) 25 below: W R4 R1 3 R2 2 WO 01/05391 PCT/USOO/18346 W is one of the following formulae (i) - (xiii): X2 H 0, N X 2
R
5
N-NR
5 O-N O O-S, N X
N
Y X 2 N\X 0 N- H N NR 5 (i) (ii) (iii) (iV) (v) (vi) (vii)
X
2
X
2
N-NR
5 N-\/X Nr=N
N-NR
5 Xj- -N N, R I N 0 N 5 2 X2 I IX7 (viii) (ix) (x) (xi) (xii) (xiii) 5 HO 0 0 0-0 N-N X2 X X 1 N X N NN 'xx N (xiv) (xv) (xvi) (xvii) 10 X1 is 0, S, or NRF. X 2 is OH, SH, or NHRE. Each of RE and RF is H or C 1-4 alkyl; each of R 1 and R 2 is independently selected from H, F, NO 2 , Br and Cl; R 1 can also be SO2NRGRH, or R 1 and R 2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, 15 benzothiophene, indazole, benzimidazole, or benzthioazole. R 3 is selected from H and F; each of RG, RH, and R 4 is independently selected from H, Cl and CH 3 . R 5 is H or C 1-4 alkyl. Each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO 2 . Each heterocyclic radical 3 WO 01/05391 PCT/USOO/18346 above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-4 alkenyl, C 3 4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO 2 , wherein each substituent alky1, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally 5 substituted with between 1 and 2 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 . The invention also features a pharmaceutically acceptable salt or C 1-8 ester of a disclosed compound. For example, the disclosed alcohol compounds may form esters having the structure obtained by replacing the H of a hydroxyl group with a -C(=O)C 1-7 10 acyl group. Preferred embodiments of the invention include methods of using one or more of the following compounds: (a) said MEK inhibitor has a structure selected from: 2,4-bis-(2-chloro-4-iodo phenylamino)-3-fluoro-5-nitro-benzoic acid; 5-[3,4difluoro-2-(4-iodo-2-methyl 15 phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; (2,3-difluoro-6 [1,3,4]oxadiazol-2-yl-phenyl)(-(4-iodo-2-methyl-phenyl)-amine; 5-[3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5 [3,4difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3 20 ylamine; and 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazole-3-thiol; and (b) said MEK inhibitor has the structure selected from: 2,4-bis-(2-chloro-4 iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid. Other aspects of the invention are provided in the description, 25 examples and claims below. BRIEF DESCRIPTION OF THE FIGURES 30 FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) in grams as a function of time in days. The empty, cross-hatched, and single 4 WO 01/05391 PCT/USOO/18346 hatched bars are vehicle, PD 198306, and pregabalin, respectively. The arrows indicate time of drug administration (30 mg/kg, p.o.). FIG 2. is a bar graph representing the force required in grams to elicit 5 paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin (30mg/kg) and withdrawal thresholds were re-assessed 1 h after treatment. Treatments were repeated twice a day for two days. Results are expressed 10 median ± 1 st and 3 rd quartiles. *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8). FIG. 3. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. 15 Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin (30mg/kg) and withdrawal thresholds were re-assessed 1 h after treatment. Treatments were repeated twice a day for two days. Results are expressed median ± 1 st and 3 rd quartiles. **P<0.01 significantly different from vehicle 20 treated animals (Mann-Whitney t test; n=6). FIG. 4. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received 25 a single i.t. administration of PD 198306 (1-30ptg/10Ipl), or pregabalin (1 00ptg/I O1l) and withdrawal thresholds were re-assessed at 30min, 1 h and 2h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. *P<0.05, ***P<0.001 significantly different from vehicle treated animals (Mann Whitney t test; n=7-9). 30 FIG. 5. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. 5 WO 01/05391 PCT/USOO/18346 Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD 198306 (1-30tg/10pl), or pregabalin (100ig/lOptl) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. 5 *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-8). FIG. 6 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days . 10 Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/1 00pl), or an intrathecal injection of PD 198306 (30pg/l Op) and withdrawal thresholds were re-assessed 1 h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-9). 15 FIG. 7. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/1 00ptl), or an intrathecal injection of PD 198306 (30pg/10pld) and 20 withdrawal thresholds were re-assessed 1 h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6). FIG. 8 is a bar graph representing the force required in grams to elicit 25 paw withdrawal using von Frey hair filaments. Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD219622, PD297447, PD 184352, or PD 254552 (30ptg/10pl), or pregabalin (100pg/10ld) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. 30 *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8). 6 WO 01/05391 PCT/USOO/18346 DETAILED DESCRIPTION The compounds disclosed herein are pharmaceutically active, for example, they inhibit MEK. MEK enzymes are dual specificity kinases 5 involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis. Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular 10 concentration of one or more signaling proteins in the signaling cascade .The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur 15 in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP bound state. This signal is an absolute prerequisite for proliferation in most 20 cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated. Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an 25 active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK 1 and MEK 2 ) which then activates MAP kinase, ERK (ERK, and ERK 2 ). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of 30 a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of 7 WO 01/05391 PCT/USOO/18346 Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S 2 18 and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates 5 MAP kinase on both a tyrosine, Y 18 5 , and a threonine residue, T 18 3 , separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. 10 Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, 15 no substrate for MEK other than the MAP kinase , ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK 20 may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, 25 may be found. The effect of the MEK inhibitor PD 198306 has been investigated in two animal models of neuropathic pain by assessing static allodynia with von Frey hairs. Oral administration of PD 198306 (3-30mg/kg) had no effect in the model 30 of chronic constriction injury of the sciatic nerve (CCI). However, after repeated administration (3 doses over two days) it had a transient effect in the diabetic neuropathy model (streptozocin). This may be due to disorders of the blood 8 WO 01/05391 PCT/USOO/18346 brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound. Intrathecal administration of PD 198306 (1 30ptg) dose-dependently blocked static allodynia in both the streptozocin and the CCI models of neuropathic pain, with minimum effective doses (MED) of 3 and 5 10ptg respectively. The highest dose used (30ptg) totally blocked the maintenance of static allodynia, for up to 1h. Intraplantar administration of PD 198306 (3mg/100pl) at a dose 100-fold higher than the dose shown to be effective intrathecally (30pg/1 0Il) had no effect on static allodynia in either of the neuropathic pain models. This finding confirms the lack of effect seen after 10 systemic administration and suggests a central site of action for the compound. From this study we can suggest the use of MEK inhibitors as potential new therapeutic tools for chronic pain. The study of potential side-effects, especially related to memory, of future brain-penetrant MEK inhibitors will indicate the therapeutic window for this novel class of compounds in the 15 treatment of pain. 9 WO 01/05391 PCT/USOO/18346 A. Terms Certain terms are defined below and by their usage throughout this disclosure. Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical 5 structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1 dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, 10 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Alkyl groups can be substituted with 1, 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Specific examples include 15 fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl. Alkenyl groups are analogous to alkyl groups, but have at least one 20 double bond (two adjacent sp 2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple 25 bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example. Examples of alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 30 3-methyl(5-phenyl)-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2 propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2 10 WO 01/05391 PCT/USOO/18346 propenyl. In formula (1), alkenyls and alkynyls can be C 2-4 or C 2-8, for example, and are preferably C 3-4 or C 3-8. More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, 5 and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents. According to formula (1), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, 10 dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl. R 1 thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth. 15 Similarly, RA includes hydroxyalkyl and aminoaryl, and RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl. Heterocyclic radicals, which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their 20 nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahyd ropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl. Selective MEK 1 or MEK 2 inhibitors are those compounds which 25 inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC 50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 50 for one of the above-named other enzymes. Preferably, 30 a selective inhibitor has an IC 50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC 50 or one or more of the above-named enzymes. 11 WO 01/05391 PCT/USOO/18346 B. Compounds One aspect of the invention features the disclosed compounds shown in formula (1) in the Summary section. Embodiments of the invention include compounds wherein: (a) R, is 5 bromo or chloro; (b) R 2 is fluoro; (c) R 3 is H; (d) each of R 2 and R 3 is H; (e) each of R 2 and R 3 is fluoro; (f) R 1 is bromo; (g) each of R 1 , R 2 and R 3 is fluoro; (h) R 2 is nitro; (i) R 3 is H; (j) R 4 is chloro; (k) R 4 is methyl; (1) R 5 is H; (m) R 5 is CH 3 ; (n) X 1 is 0 or S; (o) X 1 is NH or NCH 3 ; (p) X 2 is OH, SH, or
NH
2 ; (q) X 2 is OH; (r) X 2 is NHRE; (s) R 4 is H; (t) R 4 is chloro or methyl; or 10 combinations thereof. Preferably, where one of the substituents on a heterocyclic radical is an alkenyl or alkynyl group, the double or triple bond, respectively, is not adjacent the point of attachment when it is a heteroatom. For example, in such a situation, the substituent is preferably prop-2-ynyl, or but-2 or 3-enyl, and less 15 preferably prop-1-ynyl or but-1-enyl. Examples of compounds include: [5-fluoro-2-(1 H-tetrazol-5-yl) phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2,3-difluoro-6-(1H-tetrazol-5-yl) phenyl]-(4-iodo-2-methyl-phenyl)- amine; (4-iodo-2-methyl-phenyl)-[2,3,4 trifluoro-6-(1H-tetrazol-5-yl)-phenyl]-amine; [4-bromo-2,3-difluoro-6-(1H 20 tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(1H tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2-(4,4-dimethyl-4,5 dihydro-oxazol-2-yl)-5-fluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4 d imethyl-4,5-d ihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3,4-trifluoro 25 phenyl]-(4-iodo-2-methyl-phenyl)-amine; [4-bromo-6-(4,4-dimethyl-4,5 dihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2 (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-4-nitro-phenyl]-(4-iodo-2 methyl-phenyl)-amine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]thiadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-pheny] 30 [1,3,4]thiadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]thiadiazol-2-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl 12 WO 01/05391 PCT/USOO/18346 phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl-[1,3,4]oxadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo 2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[5-bromo-3,4-difluoro 5 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[4-fluoro-2 (4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 5-[3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 5 [3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 10 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ol; and 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-4H-[1,2,4]triazol-3-ol. Further examples include: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4-Difluoro-2-(4-iodo-2-methyl 15 phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo 2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol 2-ylamine; 5-[4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 20 [1,3,4]oxadiazol-2-ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-yIamine; 5-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2-ylamine; 25 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3 ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4 30 iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5 [3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2 13 WO 01/05391 PCT/USOO/18346 thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2 5 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5 [5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-pheny] [1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro 10 phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[5-bromo-3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 15 and 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H [1,2,4]triazole-3-thiol. Additional examples are: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-isothiazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-isothiazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) 20 phenyl]-isothiazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl 25 phenylamino)-phenyl]-isoxazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl 30 phenylamino)-phenyl]-1 H-pyrazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-1 H-pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 14 WO 01/05391 PCT/USOO/18346 phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isothiazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylam ino)-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 5 phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl-isoxazol-3-ol; 4-[3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 10 phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 1-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H 15 pyrazol-3-ol; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl] 1-methyl-1 H-pyrazol-3-ol. The invention also features compounds such as: 5-[2-(2-amino-4-iodo phenylamino)-4-fluoro-phenyl]-i -methyl-1 H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4 iodo-phenylamino)-3,4-difluoro-phenyl]-1 -methyl-1 H-[1,2,3]triazol-4-ol; 5-[2-(2 20 amino-4-iodo-phenylamino)-3,4,5-trifluoro-phenyl]-1 -methyl-1 H-[1,2,3]triazol 4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl]-1 methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-5 nitro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 5-[3,4-difluoro-2-(4-iodo 25 2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 3-methyl-5 [3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl 3H-[1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 30 phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 2-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-pyrazol-3-ol; 4-[5 15 WO 01/05391 PCT/USOO/18346 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2 methyl-2H-pyrazol-3-ol; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 4-methyl-1,4-dihydro-tetrazol-5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl 5 phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl 1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5 n itro-phenyl]-4-methyl- 1,4-d ihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2 10 methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4,5-trifluoro-2-(4-iodo 2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[5-bromo-3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; and 1-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1 H-[1,2,3]triazol-4-ol. 15 Further examples of the invention include 3-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4 20 iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2 oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl phenyl)-amine; [2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol 4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2,3,4 trifluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-amine; 25 [4-bromo-2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl) phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro 21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; 4 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4,5 30 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5 16 WO 01/05391 PCT/USOO/18346 one; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H isoxazol-5-one. Further compounds, where R 1 can also be SO 2 NRGRH, or R 1 and R 2 together with the benzene ring to which they are attached constitute an indole, 5 isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole, include the following groups: Group 1 10 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2 yl)-N-methyl-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-2-methyl 15 phenylamino)-N,N-dimethyl-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4 oxad iazol-2-yl)-N-methyl-N-(3-morpholin-4-yl-propyl) benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-phenylamino)-N-[2 20 (2-methoxy-ethoxy)-ethyl]-benzenesulfonamide (6) N-(2-Dimethylamino-ethyl)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4 (4-iodo-phenylamino)-N-methyl-benzenesulfonamide 25 Group 2 (1) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2 fluoro- benzenesulfonamide 30 (3) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,3-difluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 17 WO 01/05391 PCT/USOO/18346 (4) 5-(5-Amino-1,3,4-oxadiazol-2-yI)-4-(2-chloro-4-iodo-phenylamino)-2,3 difluoro-benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yI)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide 5 (6) 4-(5-Amino-1,3,4-oxadiazol-2-yI)-2-fluoro-5-(4-iodo-phenylamino) benzenesulfonamide Group 2b 10 (1) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 5-(5-Amino-1,3,4-oxadiazol-2-yI)-2-fluoro-4-(4-iodo-phenylamino)-N methyl-N-(3-morpholin-4-yl-propyl)-benzenesulfonamide (3) 5-(5-Am ino- 1,3,4-oxadiazol-2-yl)-2,3-d ifluoro-4-(4-iodo-2-methyl 15 phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3 difluoro-N-[3-(4-methyl-piperazin-1 -yl)-propyl]-benzenesulfonamide 20 (6) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2 fluoro-N-(3-piperidin-1 -yi-propyl)-benzenesulfonamide Group 3 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol 25 2-yl)-benzenesulfonamide (2) 2-Fluoro-5-(4-iodo-phenylamino)-4-(5-mercapto-1,3,4-oxadiazol-2-yl) benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4 oxadiazol-2-yl)-benzenesulfonamide 30 (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl) benzenesulfonamide 18 WO 01/05391 PCT/USOO/18346 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-mercapto-1,3,4 oxadiazol-2-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-mercapto-1,3,4-oxadiazol 2-yl)-benzenesulfonamide 5 Group 4 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yI)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-(5-hydroxy-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenylamino) 10 benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yI)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yI)-4-(4-iodo-phenylamino) benzenesulfonamide 15 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4 thiadiazol-2-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2 yl)-benzenesulfonamide 20 Group 5 (1) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(5-Amino-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenylamino)-2-mercapto benzenesulfonamide 25 (3) 5-(5-Amino-1,3,4-thiad iazol-2-yl)-2,3-d ifluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide (5) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3 30 difluoro-benzenesulfonamide (6) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2 fluoro-benzenesulfonamide 19 WO 01/05391 PCT/USOO/18346 Group 6 (1) 2-Fluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 5 (2) 2-Fluoro-4-(5-hydroxy-4H-1,2,4-triazol-3-yl)-5-(4-iodo-phenylamino) benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 5-[4-(2-Dimethylamino-ethyl)-5-hydroxy-4H-1,2,4-triazol-3-yl]-2-fluoro-4 10 (4-iodo-phenylamino)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-4H-1,2,4 triazol-3-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-4-methyl-4H-1,2,4 triazol-3-yI)-benzenesulfonamide 15 Group 7 (1) 5-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-5-(4-iodo-phenylamino) 20 benzenesulfonamide (3) 5-(5-Amino-4-methyl-4H-1 ,2 ,4-triazol-3-yl)-2,3-d ifluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 5-[5-Amino-4-(3-dimethylamino-propyl)-4H-1,2,4-triazol-3-yl]-2-fluoro-4-(4 iodo-phenylamino)-benzenesulfonamide 25 (5) 5-(5-Amino-4H-1,2,4-triazol-3-yI)-4-(2-chloro-4-iodo-phenylamino)-2,3 difluoro-benzenesulfonamide (6) 5-(5-Amino-4-methyl-4H-1,2,4-triazol-3-yI)-4-(2-chloro-4-iodo phenylamino)-2-fluoro-benzenesulfonamide 30 Group 8 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-5-yI)-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 20 WO 01/05391 PCT/USOO/18346 (2) 2-Fluoro-4-(3-hyd roxy-isoxazol-5-yI)-5-(4-iodo-phenylamino) benzenesulfonamide (3) 2 ,3-Difluoro-5-(3-hydroxy-isoxazol-5-yI)-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 5 (4) 2-Fluoro-5-(3-hydroxy-isoxazol-5-yI)-4-(4-iodo-phenylamino) benzenesu Ifonam ide (5) 4-(2-Chloro-4-iodo-phenylamino)-2, 3-d ifluoro-5-(3-hyd roxy-isoxazol-5-yI) benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylam ino)-2-fluoro-5-(3-hydroxy-isoxazol-5-yI) 10 benzenesulfonamide Group 9 (1) 5-(3-Am ino-isoxazol-5-yI)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 15 (2) 4-(3-Am ino-isoxazol-5-yI)-2-bromo-5-(4-iodo-phenylamino) benzenesulfonamide (3) 5-(3-Am ino-isoxazol-5-yi)-2,3-d ifluoro-4-(4-iodo-2-methyl-phenylamino) benzenesu Ifonam ide (4) 5-(3-Am ino-isoxazol-5-yI)-2-fluoro-4-(4-iodo-phenylamino) 20 benzenesulfonamide (5) 5-(3-Amino-isoxazol-5-yI)-4-(2-chloro-4-iodo-phenylamino)-2, 3-difluoro benzenesulfonamide (6) 5-(3-Amino-isoxazol-5-yI)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide 25 Group 10 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-mercapto-isoxazol-5-yI) benzenesulfonamide (2) 4-(2-Ch Ioro-4-iodo-phenylamino)-2-fluoro-5-(3-mercapto-isoxazo-5-yi) 30 benzenesulfonamide (3) 2, 3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-mercapto-isoxazoI-5 yI)-benzenesulfonam ide 21 WO 01/05391 PCT/USOO/18346 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-mercapto-isoxazol-5 yi)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-mercapto-isoxazol-5-yl) benzenesulfonamide 5 (6) 2-Bromo-5-(4-iodo-phenylamino)-4-(3-mercapto-isoxazol-5-y) benzenesulfonamide Group 11 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino) 10 benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(3-hydroxy-isoxazol-4-yl) benzenesulfonamide (3) 2,3-Difluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 15 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-hydroxy-isoxazol-4-yl) benzenesulfonamide (5) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yI)-4-(4-iodo-phenylamino) benzenesulfonamide (6) 2-Bromo-4-(3-hydroxy-isoxazol-4-yl)-5-(4-iodo-phenylamino) 20 benzenesulfonamide Group 12 (1) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 25 (2) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro 30 benzenesulfonamide (5) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide 22 WO 01/05391 PCT/USOO/18346 (6) 4-(3-Amino-isoxazol-4-yl)-2-chloro-5-(4-iodo-phenylamino) benzenesulfonamide Group 13 5 (1) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide (2) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino) 10 benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro benzenesulfonamide" (5) 5-(3-Amino-isoxazol-4-yI)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide 15 (6) 4-(3-Amino-isoxazol-4-yI)-2-chloro-5-(4-iodo-phenylamino) benzenesulfonamide Group 14 (1) 5-(2-Amino-5H-pyrrol-3-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) 20 benzenesulfonamide (2) 5-(2-Amino-5H-pyrrol-3-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide (3) 5-(2-Amino-5H-pyrrol-3-yI)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 25 (4) 5-(2-Amino-5H-pyrrol-3-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro benzenesulfonamide (5) 5-(2-Amino-5H-pyrrol-3-yI)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide (6) 4-(2-Amino-5H-pyrrol-3-yl)-2-chloro-5-(4-iodo-phenylamino) 30 benzenesulfonamide 23 WO 01/05391 PCT/USOO/18346 Group 15 (1) 2-Fluoro-5-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1 H-pyrazol-4-yl) 5 benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1H-pyrazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1 H-pyrazol-4 yl)-benzenesulfonamide 10 (5) 2-Fluoro-5-{5-hydroxy-1-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrazol-4 yl}-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-4-(5-hydroxy-1H-pyrazol-4-yl)-5-(4-iodo-phenylamino) benzenesulfonamide 15 Group 16 (1) 2-Fluoro-5-(5-hyd roxy-3-methyl-3H- 1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4 yi)-benzenesulfonamide 20 (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yI)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-3H-1,2,3 triazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino) 25 benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4 yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 17 30 (1) 2-Fluoro-5-(5-hydroxy-3-methyl-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 24 WO 01/05391 PCT/USOO/18346 (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4 yl)- benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 5 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-3H-1,2,3 triazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino) benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4 10 yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 18 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1 yl)-benzenesulfonamide e15 (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-4,5-dihydro-tetrazol-1 yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro tetrazol-1 -yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-4,5-dihydro 20 tetrazol-1 -yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1-yI) benzenesulfonamide (6) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-4,5-dihydro-tetrazol-1-yI) benzenesulfonamide 25 Group 19 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(4-methyl-5-oxo-4,5-dihydro tetrazol-1 -yl)- benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro 30 tetrazol-1 -yl)- benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro tetrazol-1 -yl)-benzenesulfonamide 25 WO 01/05391 PCT/USOO/18346 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-4,5-dihydro tetrazol-1 -yi)-benzenesulfonamide (5) 5-[4-(2-Dimethylamino-ethyl)-5-oxo-4,5-dihydro-tetrazol-1-yl]-2-fluoro-4-(4 iodo-phenylamino)-benzenesulfonamide 5 (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1 yi)-benzenesulfonamide Group 20 10 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro 15 1,2,3,5-oxathiadiazol-4-yI)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(2-oxo-2,3-dihydro 1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide 20 (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide Group 21 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro 25 1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(3-methyl-2-oxo-2,3-dihydro 1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3 dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide 30 (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide 26 WO 01/05391 PCT/USOO/18346 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-methyl-2-oxo-2,3 dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-N-methyl-5-(3-methyl-2-oxo-2,3 dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide 5 Group 22 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol 3-yl)-benzenesulfonamide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-2,5-dihydro-isoxazol-3-yl) 10 benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro isoxazol-3-yl)-benzenesulfonamide (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yI) benzenesulfonamide 15 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-2,5-dihydro isoxazol-3-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-2,5-dihydro-isoxazol-3 yl)-benzenesulfonamide 20 Group 23 (1) 5-[6-(4-lodo-2-methyl-phenylamino)-1H-benzimidazol-5-yl]-1,3,4 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-benzofuran-5-yl]-1,3,4-oxadiazol-2-oI (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-y]-1,3,4 25 oxadiazol-2-ol (4) 5-[5-(4-lodo-phenylamino)-benzofuran-6-yl]-1,3,4-oxadiazol-2-oI (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro-isobenzofuran-5 yl]-1,3,4-oxadiazol-2-ol (6) 5-[6-(2-Chloro-4-iodo-phenylamino)-1-methyl-1H-benzimidazol-5-yl]-1,3,4 30 oxadiazol-2-ol 27 WO 01/05391 PCT/USOO/18346 Group 24 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-1H-benzimidazol-5-yl]-1,3,4 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-benzo[b]thiophen-5-yl]-1,3,4-oxadiazol-2-oI 5 (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4 oxadiazol-2-ol (4) 5-[5-(4-lodo-phenylamino)-benzo[b]thiophen-6-yl]-1,3,4-oxadiazol-2-oI (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro benzo[c]thiophen-5-yl]- 1, 3,4-oxad iazol-2-ol 10 (6) 5-[6-(2-Chloro-4-iodo-phenylamino)-2-oxo-2,3-dihydro-1H-2$1>4_-2,1,3 benzothiadiazol-5-yl]-1,3,4-oxadiazol-2-oI Group 25 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4 15 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yl]-1,3,4-oxadiazol-2-oI (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4 oxadiazol-2-ol (4) 5-[5-(4-lodo-phenylamino)-1H-indol-6-yl]-1,3,4-oxadiazol-2-oI 20 (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1H-isoindol-5-yl] 1,3,4-oxadiazol-2-ol (6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1H-indazol-6-y]-1,3,4-oxadiazol-2-oI Group 26 25 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yI]-1,3,4 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yI]-1,3,4-oxadiazol-2-oI (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-yl]-1,3,4 oxadiazol-2-ol 30 (4) 5-[5-(4-lodo-phenylamino)-benzoxazol-6-yl]-1,3,4-oxadiazol-2-oI (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1H-isoindol-5-yI] 1,3,4-oxadiazol-2-ol 28 WO 01/05391 PCT/USOO/18346 (6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1H-indazol-6-yl]-1,3,4-oxadiazol-2-oI 29 WO 01/05391 PCT/USOO/18346 C. Synthesis The disclosed compounds can be synthesized according to Schemes 1-25 or analogous variants thereof. These synthetic strategies are further 5 exemplified in Examples 1-8 below. The solvent between compounds 4 and 5 in Scheme 1 is toluene (PhMe). 30 WO 01/05391 PCT/USOO/18346 Scheme 1 OH O
H
2 NN,, HHkj H H H N N NCI Cki N N DMF N RR I RRR, R2 , R2 5 R R 3 I hCI3
R
2
R
2 7 N CH 3 9HO Nx 0 N\ 0 OHOH N N Ph H & H RR 2 R2R 2 H -NNH 2 Ph/A N N NH 2 N\ 0 H N _H N N N N 31 R 7 4 Ph? 0 OH aNA( H H H H' N N conc.HCIN I I EtOH ,R R2 R 2 8 9 5 31 WO 01/05391 PCT/USOO/18346 Scheme 2 OH Ph-O NH H N\ NH H )l NH 2 H
H
2 N N N R, R I Pyridine R, R R2 R2 10 11 OH N - OH C I N R4 N NH R4 N K-N=S=0 N R R3 I Et3N/Ph RI R3 R2 R2 12 13 Ph O HO N -- N H R4 NH R4 N H 2 NNH2 N I I I EtOH R, R3 i tHRi R3 R2 R2 14 15 HO 0 N O NN 0 H R 4
OCH
3 SOC12 OCH 3 LDA N R, R 3
H
2 N OH R 1
R
3 H2 R 4
R
1 R3 R2 R2R2 16 17 I 18 32 WO 01/05391 PCT/USOO/18346 Scheme 3 OEt 0H'flNN N\N NH 0 OH O, ,N' H 1. AcONa/Br 2 F FI /AcOH - 1 2. KSCN F R R3 R R 3 2. KOH, EtOH R, R 3 3. EtOH R, R 3 R2 R 2
R
2 4. NH 2
NH
2
R
2 19 20 / 21 , 22 0 HCl
H
2 N N NH2 H 0 OH ' OH O I''R4'N HO o A ,N 0 N\ NH H2N N\ NH HN H 2 NH R F F NaOH F N R R 3 R, RH R, R3 LDA R R3
R
2
R
2 R2 2 22 23 24 25 1. HCI/ H 2 0
NH
2
NH
2 2. NaOH/H 2 0 PyBOP H
H
2 N F HOCN Ri R,+
NH
3 R2 26 33 WO 01/05391 PCT/USOO/18346 Scheme 4 OH OH HR HN-N O N HNk4N F N F N - I R, R, R R3 LDA R R 3 R2 R2 R2 26 24 25 S Cl iJCl pC1 5 /POCl 3 1. PCl 5 /POCl 3 SH Cl N 0N 2. HO NH 2 F F R, R3 Rl R3 R2 R2 27 28 1. CH3 2. KMnO 4 0 N " N O0H N O HO -. NH 2 NN H R F A N R, R3 R, R3I R2 R2 29 30 34 WO 01/05391 PCT/USOO/18346 Scheme 5 OH N=(OH
CH
3 N S H 2 N\ S F Ph N OEt F N R R3 Lawesson's reagent , R LDA R, R3I R2 R2 R2 31 32 33 0 0 HS S O O S S 0 Ph, N N'N S F HO Br F Ph, NH2 H H N), BO , F NN'N F H H H R, R2 R 3 piperidine/acetone R, R3 R R3 34 35 36 OH OH R4 N S H 2 N N N\ S H conc. HCI FN EtOH R R3 LDA R R3 1
R
2 R2 37 9 35 WO 01/05391 PCT/USOO/18346 Scheme 6 R4 COOH H2N COOH R4 RI R3 LHMDS RI R3 I R2 R2 N O R4 (1)(COCR) 2 (2) H OH 2 RI R3 1 (3) SOCI 2 R2 36 WO 01/05391 PCT/USOO/18346 Scheme 7 R4 COOH H 2 N COOH R4 RI R3 LHMDS RI R3 I R2 R2 0 H2N O R4 2H AO R4
NH
2
NH
2 ,PY-BOPH 2 N R4 CICO 2
C
2 H, 5 RI R3 i RI R3 R2 R2 OH N POcla N 0 R4 RI R3 I R2 37 WO 01/05391 PCT/USOO/18346 Scheme 8 R4 COOH H2N COOH R4 F RI R3 LHMDS RI R3 I R2 R2 0 O
C
2
H
6 0 R4
NH
2
NH
2 ,PY-BOP H2N
CCO
2
C
2 H RI R3 I RI R3 R2 R2 Lawesson s Reagent Lawesson's Reagent Xylene ~Tol uene SH OH N N N S R4 N S R1 R3 I RI R3 R2 R2 38 WO 01/05391 PCT/USOO/18346 Scheme 9 R4 COOH 2 COOH R4 F I I RI R3 LHMDS RI R361 R2 R2
NH
2 S N H2N - O4 [H+] N 111S R4 (1)(COCI) 2 R4 (2) NH 2
NHC(S)NH
2 RI R3 RI R3 R2 R2 NaOCH 3
/CH
3 OH Reflux SH N NN NH R4 RI R3 I R2 39 WO 01/05391 PCT/USOO/18346 Scheme 10 R4 COOH FHN6COOH M R4 RI R3 LHMDS RI R3I R2 R2
NH
2
NH
2
NH
2 H2 4BrCNINaHCO 3 (aq.) N 110R4 PY-BO ' Dioxane, r.t. RIR3 I RI R3 R2 R2 S1)CS 2 , KOH 2)HCI SH N N~O R4 RI R3 I R2 40 WO 01/05391 PCT/USOO/18346 Scheme 11 R4 COOH COOH R4 HF H 2 NN RI R3 LHMDS R1 R3 I R2 R2
NH
2 I
COOCH
3 R4 N NH H aminoguanidine nitrate R4
CH
3 0HIH 2
SO
4 N ________H NaOCH 3
/CH
3 0H N RI R3 I RI R3 R2 S MeNH
NH
2 N MeNCS N N R4 RI R3 I R2 41 WO 01/05391 PCT/USOO/18346 Scheme 12 0 C0 2 C 2 HS F (1)PPh 3 ,CBr 4 F (2)n-BuLi, I RI R3 then CICO 2
C
2 HsRI R3 R2 R2 COACH5 HO R4 LHMDS
NH
2
NHCH
3
NHCH
3 R4
H
2 N R4 RI R3 IN' R2 RI ""R3 R2 42 WO 01/05391 PCT/USOO/18346 Scheme 13 R4 COOH
H
2 N R COOH R4 1 -RI R3 : RI R3 LHMDS R3 R2 CH OH R4
CH
2 Br R4
CH
2 CN R4 N R3 Bromination Rl R3 . RIj R3 RI R3)~ 1 RI j R3 N-S NC CS 2 Na R4 HO SO 3 Na M ' 'N excess H 2 0 2 HCONMe 2 RI R3 I RI R3 R2 R2 N-S [H+] HO R4 RI R3 I R2 43 WO 01/05391 PCT/USOO/18346 Scheme 14 COOH R4 COOH 0 CO F HM1 jR4 R R2 RI4 R3 I R2 R2 COWS2 H 5. 00 R4 BF, H SC HR4 -~ ~ etherate M25 R3 RI 4 R3 R ~JIJ N-N NHN2R4 Alkalation " OH R4 RI R31tI RI R3 R2 R2 44 WO 01/05391 PCT/USOO/18346 Scheme 15 R4 COOH F 2, COOH M R4 RI R3 LHMDS RI R3 R2 R2 OH
N
C
2 H0 0 R4 N
NH
2
NH
2 ,EtOH R4 RI R3 I RI R3 R2 I R2
NH
2
NHCH
3 ,EtOH OH N N R4 RI R3 I R2 45 WO 01/05391 PCT/USOO/18346 Scheme 16 R4 COOH H 2 N COOH H R4 F N R1 R3 LHMDS R R3 I R2 R2 EtOOC Br CH2COOEt R4 R4 N I)LDA I 2)Br2 -~ ii R3 RI R3 1 R2 R2 INH 2 EtOOC N 3 EtOOC N=N R4 NaN 3 /DMF H 2 RI R3 RI R3 R2 R2 R --N N-N 0 N alkylation HO N O___R4 aMH R4 RI R3 I RI R3 R2 R2 alkylation N N HO N-R R4 RI R3 I R2 46 WO 01/05391 PCT/USOO/18346 Scheme 17 R4 CN H 2 N CN R4 F 1 R1 R3 LHMDS R1 R3 I R2 R2 0 OH S-O
NH
2 OH.HCI H 2 N N HN N aCCaCaHH R4 sc/tNR4 NaOCH 3
/CH
3 OH H SOCIJEt 3 N RI R3 I RI R3 R2 R2 0 S-O / \
R
5 'N 7 N alkylation R4 RI R3 I R2 47 WO 01/05391 PCT/USOO/18346 Scheme 18 R4 COOH H2N COOH R4 F II RI R3 LHMDS R1 R3 R2 R2 OH N O Ns NH
NH
2
NH
2 ,PY-BOP
H
2 N R4 Urea/KOH/EtOH R4 RI R3 RI R3 I R2 R2 RsNCO/NaOHIH 2 0 OH N NK N'RS R4 H N RI R3 I R2 48 WO 01/05391 PCT/USOO/18346 Scheme 19 R4 CN H 2 N CN R4 F RI R3 LHMDS RI R3 R2 R2 0 OH H2N ZNNN
NH
2 OH.HCI 2 R4 CICOOC 2 H6 N , N R4 NaOCH 3
/CH
3 OH pyridine RI R3 RI R3 R2 R2 49 WO 01/05391 PCT/USOO/18346 Scheme 20 O C0 2 CHS C0 2
CH
5 F (I)PPh 3 ,CBr, F LHMDS R RI R3 (2)n-BuLi, il-HN R then CICO 2
C
2
H
5 RI R3 2 R~ RI- R3 R2 R2 R2 HO MeO
NH
2 OH.HCI ""~ R4 CH 2
N
2
ICH
3 OH ""0 R4 RI R31t I RI R31t R2 R2 MeO MeO I)n-BuLiITHF -NI)DPPAIEt 3 N 2)C0 2 2)TMS(CH 2
)
2 0H 2)H 3 C HOC2 0 3)n-Bu4NFITHF 0 N ~ R 3)HO- OOCR4 ______R4_ RI R3 1 RI R31: R2 R2 HO NN RI R3I R2 50 WO 01/05391 PCT/USOO/18346 Scheme 21 R4 COOH F 2,CCOOH M R4 RI R3 LHMDS RI R3 EtO C 0~ R4 N2HEtH HNHNOC 0O R4 (I )(COCI) 2 NN ,EONN (2)CNCH 2
CO
2
C
2
H
5 Et 3 NITHF RI R3 RI R3 R2 R2 HO N RI R3 I R2 51 WO 01/05391 PCT/USOO/18346 Scheme 22 R4
NO
2
H
2 N NO 2 R4 NH 2 R4 RI R3 LHMDS R1 R3 I RI R3 R2 R2 R2 0 H N R4 -N N R3 IICH 2 =CHO R N R4 RRI R3 R2 R2 N, N OH R4 N OH R4 IMil RR3RI R3 R2 R2 Alternate synthesis: OH(TMS) N /N N R4 OH(TMS) N OH(TMS) N R 3H C O(MS R4 N R4 RI R3 I RI R3 IR1 R3 2 R2 R2 52 WO 01/05391 PCT/USOO/18346 Scheme 23 R4
NO
2 FH 2 N,6 1 NO 2 R4 NH 2 R4 'N.'~ [H] 30 R1 R3 LHMDS RI R3 I I R3 R2 R2 R2 N-N N R4 N R4 HC(OEt) 3 , NaN 3 N RI R3 I RI R3 i R2 R2 N-N 12, H NR ArOHK 2
CO
3 N N OAr R4 2KMnO 4
,H
2 S0 4 'N R4 W R1 R3 I R1 R3 R2 R2 R5 N-N NaH 2 PO2Pd-C NN>,O R4 Alkylation N O R4 R1 R3 RI R3 R2 R2 53 WO 01/05391 PCT/USOO/18346 Scheme 24 R4 CHO H 2 N CHO R4 F R1 R3 LHMDS R1 R3 I R2 NH R2 ON HO N R4
KCN/(NH
4
)
2
CO
3
/NH
4 CI EtOH/H 2 0 RI R3 I R2 Alternate Sythesis:
NH
2 CHO HO N F KCN/(NH 4
)
2
CO
3
/NH
4 CI EtOH/H 2 O F RI R3 R2 RI R3 R2
NH
2 H2N HO N R4 LHMDS R1 R3 R2 54 WO 01/05391 PCT/USOO/18346 Scheme 25 R4 COOH H 2 N COOH R4 F N RI R3 LHMDS RI R3 I R2 R2 COOH 0 NH N O R4
H
2 N COOH R4 DMF/SOCl 2 RI R3 I R1 R3 R2 R2 55 WO 01/05391 PCT/USOO/18346 D. Uses The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions relating to chronic pain, 5 including neuropathic pain, as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade. For example, in one embodiment, the disclosed method relates to postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, 10 vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain, or limb amputation For example, local injuries can be treated with local or topical administration. Chronic pain affecting the entire body, such as diabetic neuropathy can be treated with systemic administration (injection or orally) of 15 a disclosed composition. Treatment for chronic pain (e.g., post-operative pain) confined to the lower body can be administered centrally, e.g., epidurally. Formulations and methods of administration can include the use of more than one MEK inhibitor, or a combination of a MEK inhibitor and another pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle 20 relaxing, or anti-infective agent. Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and, for non-human mammals, intraplantar, and are preferably epidural. 1. Dosages 25 Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of pain requiring treatment, and the presence of other medications. In general, an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg 30 body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other 56 WO 01/05391 PCT/USOO/18346 formulations (such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods. 2. Formulations 5 Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. 10 Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray). Parenteral formulations include pharmaceutically acceptable aqueous 15 or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate 20 particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants. Compositions may also contain adjuvants such as preserving, wetting, 25 emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents. 57 WO 01/05391 PCT/USOO/18346 3. Related compounds The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected 5 forms; and racemic mixtures, or enantiomerically or optically pure forms. Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C 1-8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for 10 contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, 15 lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 20 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C 1-6 alkyl amines and secondary di (C 1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and 25 optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C 1-3 alkyl primary amines, and di (C 1-2 alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C 1-7 alkyl, C 5.7 cycloalkyl, phenyl, and phenyl(C 1 .)alkyl esters. Preferred esters include methyl esters. 30 The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically 58 WO 01/05391 PCT/USOO/18346 acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention. 5 HYDROXYL PROTECTING GROUPS Hydroxyl protecting groups include: ethers, esters, and protection for 1,2- and 1,3-diols. The ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups. 10 Substituted Methyl Ethers Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 15 2,2,2-trich loroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2 (trimethylsilyl)ethoxymethyl, tetrahyd ropyranyl, 3-bromotetrahydro-pyranyl, tetrahyd rothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4 methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxido, 1 -[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, 20 tetrahydrofuranyl, tetrahydrothiofuranyl, and 2,3,3a,4,5,6,7,7a-octahydro 7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl. Substituted Ethyl Ethers Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1 -benzyloxy-2 25 fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl. Substituted Benzyl Ethers Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 30 p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenyl methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, 59 WO 01/05391 PCT/USOO/18346 tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4" tris(levulinoyloxyphenyl) methyl, 4,4',4"tris(benzoyloxyphenyl)methyl, 3 (imidazol-1 -ylmethyl)bis(4',4"-dimethoxyphenyl)-methyl, 1,1-bis(4 5 methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9 phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl SS dioxido. Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, 10 dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenysilyl. ESTERS 15 Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates. Esters Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, 20 methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4 oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate, crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate). 25 Carbonates Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4 dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4 30 ethoxy-1-naphthyl, and methyl dithiocarbonate. 60 WO 01/05391 PCT/USOO/18346 Assisted Cleavage Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4 azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2 formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4 5 (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate. Miscellaneous Esters In addition to the above classes, miscellaneous esters include: 2,6-dichloro-4 methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl) 10 phenoxyacetate, 2,4-bis(1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate (tigloate), o (methoxycarbonyl) benzoate, p-P-benzoate, c-naphthoate, nitrate, alkyl NN,N SN '-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, 15 dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate. Sulfonates Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate. 20 PROTECTION FOR 1,2- AND 1,3-DIOLS The protection for 1,2 and 1,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives. Cyclic Acetals and Ketals Cyclic acetals and ketals include: methylene, ethylidene, 1-t-butylethylidene, 25 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4 dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene. Cyclic Ortho Esters 30 Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2 dimethoxyethylidene, 61 WO 01/05391 PCT/USOO/18346 a-methoxybenzylidene, 1-(NN-dimethylamino)ethylidene derivative, a-(NN dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene. 5 PROTECTION FOR THE CARBOXYL GROUP ESTERS Ester protecting groups include: esters, substituted methyl esters, 2 substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters. 10 Substituted Methyl Esters Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahyd ropyranyl, tetrahyd rofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N 15 phthalimidomethyl. 2-Substituted Ethyl Esters 2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-haloethyl, | chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyridyl)ethyl, 2 20 (diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, a methylcinnamyl, phenyl, p-(methylmercapto)-phenyl, and benzyl. Substituted Benzyl Esters Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, 25 bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5 d ibenzo-suberyl, 1 -pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6 trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl. 30 Silyl Esters Silyl esters include: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i propyldimethylsilyl, phenyldimethylsilyl, and di- t-butylmethylsilyl. 62 WO 01/05391 PCT/USOO/18346 Miscellaneous Derivatives Miscellaneous derivatives includes: oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl 5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(Ill) complex. 5 Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl. AMIDES AND HYDRAZIDES Amides include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6 10 dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-1,2,3,4 tetrahydroquinolyl, and p-P-benzenesulfonamides. Hydrazides include: N phenyl, N,N'-diisopropyl and other dialkyl hydrazides. PROTECTION FOR THE AMINO GROUP 15 CARBAMATES Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates. Carbamates 20 Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2 sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10 dioxo-1 0,10,10,1 0-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl. Substituted Ethyl Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2 25 trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl 2-haloethyl, 1,1dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1 methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-(N,N-icyclohexylcarboxamido)- ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N 30 hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p bromobenzyl, p-chlorobenzyl, 2,4dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl. 63 WO 01/05391 PCT/USOO/18346 Assisted Cleavage Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 5 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2cyanoethyl, m-chloro-p acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl. Photolytic Cleavage 10 Photolytic cleavage methods use groups such as: m-nitrophenyl, 3,5 dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o nitrophenyl)methyl. Urea-Type Derivatives Examples of of urea-type derivatives include: phenothiazinyl-(1 0)-carbonyl 15 derivative, N'-p-toluenesulfonylaminocarbonyl, and N' phenylaminothiocarbonyl. Miscellaneous Carbamates In addition to the above, miscellaneous carbamates include: t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, 20 cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2 dimethoxycarbonylvinyl, o-(NN-dimethyl-carboxamido)-benzyl, 1,1-dimethyl 3(N,N-dimethylcarboxamido)propyl, 1,1-dimethyl-propynyl, d i(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p' methoxyphenyl- azo)benzyl, 1 -methylcyclobutyl, 1 -methylcyclohexyl, 1 25 methyl-1 -cyclopropyl- methyl, 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl 1 (p-henylazophenyl)- ethyl, 1-methyl-1 -phenylethyl, 1-methyl-1 -(4 pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4 (trimethylammonium) benzyl, and 2,4,6-trimethylbenzyl. 30 64 WO 01/05391 PCT/USOO/18346 AIDES Amides Amides includes: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3 5 pyridyl-carboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, and N-p phenylbenzoyl. Assisted Cleavage Assisted cleavage groups include: N-o-nitrophenylacetyl, N-o nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl, 10 N-3-(p-hydroxphenyl) propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2 (o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4 chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N acetylmethionine derivative, N-o-nitrobenzoyl, N-o (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one. 15 Cyclic Imide Derivatives Cyclic imide derivatives include: N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenyl-maleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1, 3-d imethyl- 1, 3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl 20 1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl. SPECIAL -NH PROTECTIVE GROUPS Protective groups for - NH include: N-alkyl and N-aryl amines, imine 25 derivatives, enamine derivatives, and N-hetero atom derivatives (such as N metal, N-N, N-P, N-Si, and N-S), N-sulfenyl, and N-sulfonyl. N-Alkyl and N-Aryl Amines N-alkyl and N-aryl amines include: N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxyl]-methyl, N-3-acetoxypropyl, 30 N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, 65 WO 01/05391 PCT/USOO/18346 N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine N'-oxide. Imine Derivatives Imine derivatives include: N-1, 1 -dimethylthiomethylene, N-benzylidene, 5 N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, N-(N',N'-dimethylaminomethylene), N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and N-cyclohexylidene. 10 Enamine Derivative An example of an enamine derivative is N-(5,5-dimethyl-3-oxo-1 -cyclohexenyl). N-Hetero Atom Derivatives N-metal derivatives include: N-borane derivatives, N-diphenylborinic acid 15 derivative, N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and N-copper or N-zinc chelate. Examples of N-N derivatives include: N-nitro, N-nitroso, and N-oxide. Examples of N-P derivatives include: N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, and N-diphenyl phosphoryl. 20 Examples of N-sulfenyl derivatives include: N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesufenyl, N-2-nitro-4-methoxy-benzenesulfenyl, N triphenylmethylsulfenyl, and N-3-nitropyridinesulfenyl. N-sulfonyl derivatives include: N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl 25 4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N 2,6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N 2,3,5,6-tetramethyl-4-methoxybenzene- sulfonyl, N 4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N 2,6-dimethoxy- 4-methylbenzenesulfonyl, N 30 2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, 66 WO 01/05391 PCT/USOO/18346 N-p6-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N 4-(4',8'-dimethoxynaphthylmethyl)-benzenesulfonyl, N-benzylsulfonyl, N trifluoromethylsulfonyl, and N-phenacylsulfonyl. 5 Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism. This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes. 10 Features of the invention are further described in the examples below. 67 WO 01/05391 PCT/USOO/18346 E. Examples BIOLOGICAL EXAMPLES 5 Example 1 Effect of PD 198306 on streptozocin-induced static allodynia Animals Male Sprague Dawley rats (250-300g), obtained from Bantin and 10 Kingman, (Hull, U.K.) were housed in groups of 3. All animals were kept under a 12h light/dark cycle (lights on at 07h 00min) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments. Development of diabetes in the rat 15 Diabetes was induced in rats by a single i.p. injection of streptozocin (50 mg/kg) as described previously (Courteix et al., 1993). Evaluation of static allodynia Mechanical hypersensitivity was measured using Semmes-Weinstein 20 von Frey hairs (Stoelting, Illinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical hypersensitivity was tested by touching the plantar surface of the animals right hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 25 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6 sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von Frey hair until no response occurred. The highest force of 29 g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest amount of force required to elicit a response was recorded as the paw 30 withdrawal threshold (PWT) in grams. 68 WO 01/05391 PCT/USOO/18346 Drugs PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-benzamide] and CI-1008 (pregabalin) were synthesized at Parke-Davis (Ann Arbor, MI, USA). PD 198306 was suspended in 5 cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally. Drug administrations were made in a volume of 1 mi/kg. 10 Statistics The static allodynia data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test. Experimental protocol 15 Static allodynia was assessed with von Frey hairs, before (baseline, BL) and Ih after oral administration of PD 198306 (30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (30mg/kg, p.o.) (test). Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static allodynia was assessed only 20 before and 1 h after the afternoon administration, in order to minimise the habituation of the animals to the testing conditions. Animals treated with pregabalin received water in the morning administration, in order to avoid the potential development of tolerance to the compound with repeated administration. 25 Day 1: Day2: a.m.: PD 198306 Water 30 Vehicle p.m.: BL p.m.: BL 69 WO 01/05391 PCT/USOO/18346 PD 198306 PD 198306 Pregabalin Pregabalin Vehicle Vehicle Test Test 5 RESULTS A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (30mg/kg, p.o) had no effect on 10 streptozocin-induced static allodynia 1h after administration (see below). However, after the compound had been administered twice more on the following day, it significantly blocked streptozocin-induced static allodynia 1h after the third administration. The effects had disappeared by the following day (see FIG. 1). 15 Example 2 MATERIALS AND METHODS Animals 20 Male Sprague Dawley rats (250-300g), obtained from Charles River, Margate, U.K.) were housed in groups of 3-6. All animals were kept under a 12h light/dark cycle (lights on at 07h 00min) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments. Diabetes was induced in rats by a single i.p. injection of streptozocin 25 (50mg/kg) as described previously (Courteix et al., 1993). Development of Chronic Constriction Injury in the rat Animals were anaesthetised with 2% isoflurane 1:4 0 2
/N
2 0 mixture maintained during surgery via a nose cone. The sciatic nerve was ligated as 30 previously described by Bennett and Xie, 1988. Animals were placed on a homeothermic blanket for the duration of the procedure. After surgical preparation the common sciatic nerve was exposed at the middle of the thigh 70 WO 01/05391 PCT/USOO/18346 by blunt dissection through biceps femoris. Proximal to the sciatic trifurcation, about 7mm of nerve was freed of adhering tissue and 4 ligatures (4-0 silk) were tied loosely around it with about 1mm spacing. The incision was closed in layers and the wound treated with topical antibiotics. 5 Intrathecal injections PD 198306 and pregabalin were administered intrathecally in a volume of 10 pl using a 100 pl Hamilton syringe by exposing the spine of the rats under brief isoflurane anaesthesia. Injections were made into the intrathecal space 10 between lumbar region 5-6 with a 10 mm long 27 gauge needle. Penetrations were judged successful if there was a tail flick response. The wound was sealed with an autoclip and rats appeared fully awake within 2-3 min following injection. Evaluation of static allodynia 15 Mechanical hypersensitivity was measured using Semmes-Weinstein von Frey hairs (Stoelting, Illinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical hypersensitivity was tested by touching the plantar surface of the animals right 20 hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von Frey hair until no response occurred. The highest force of 29g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest 25 amount of force required to elicit a response was recorded as the paw withdrawal threshold (PWT) in grams. Experimental protocol Static allodynia was assessed with von Frey hairs, before (baseline, 30 BL) and 0.5h, 1 h and 2h after intrathecal or intraplantar administration of PD 198306 (1-30pg, i.t.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (10pg, i.t). For oral administration experiments, static allodynia was assessed 71 WO 01/05391 PCT/USOO/18346 with von Frey hairs, before (baseline, BL) and 1 h after oral administration of PD 198306 (3-30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (30mg/kg, p.o.). Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static 5 allodynia was assessed before and 1 h after the morning administration. In the afternoon static allodynia was assessed before, 1h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1 h and 2h after administration 10 Drugs used PD 198306 and pregabalin were synthesised at Parke-Davis (Ann Arbor, MI, USA). PD 198306 was suspended in cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally, intrathecally or intraplantar in volumes of 1ml/kg, 10ljI and 15 100pl respectively. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally in a volume of lml/kg. Statistics Data were analysed using a Kruskall-Wallis ANOVA for non-parametric 20 results, followed when significant by Mann-Whitney's t test vs vehicle group. RESULTS 1. Effects of PD 198306 on static allodynia, following systemic administration 25 1.1. Effect of PD198306 on streptozocin-induced static allodynia A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (3-30mg/kg, p.o) had no effect on streptozocin-induced static allodynia 1 h after administration (FIG. 2). 30 However, after the compound had been administered twice more on the following day, PD 198306 (30mg/kg) significantly blocked streptozocin induced static allodynia for 2h after the third administration (FIG. 2). 72 WO 01/05391 PCT/USOO/18346 1.2. Effect of PD198306 on CCI-induced static allodynia A single administration of pregabalin (30mg/kg, p.o.) significantly blocked CCI induced static allodynia 1 h after administration. In contrast, neither a single or 5 multiple administration of PD 198306 (3-30mg/kg, p.o) had any effect on CCI induced static allodynia (FIG. 3). 2. Effects of PD 198306 on static allodynia, following intrathecal administration 10 Intrathecally administered PD198306 (1-30ptg) dose-dependently blocked the maintenance of static allodynia in both streptozocin (FIG. 4) and CCI animals (FIG. 5) with respective MEDs of 3 and 10 pig. This antiallodynic effect lasted for 1h. 15 3. Effects of PD 198306 on static allodynia, following intraplantar administration An intrathecal administration of PD 198306 (30pjg) significantly blocked static allodynia in both neuropathic pain models (FIGS. 6,7). In contrast, a single administration of PD 198306 at a dose 100-fold higher (3mg/1 00pl) directly 20 into the paw had no effect on streptozocin (FIG. 6) or CCI-induced static allodynia (FIG. 7). REFERENCES Bennett GJ, Xie Y-K. A peripheral mononeuropathy in rat that produces 25 disorders of pain sensation like those seen in man. Pain 1988;33:87-107. Courteix C, Eschalier A and Lavarenne J. Streptozocin -induced rats: behavioural evidence for a model of chronic pain. Pain 1993;53:81-8 73 WO 01/05391 PCT/USOO/18346 Example 3 Effect of other MEK inhibitors in a neuropathic pain model in the rat 5 SUMMARY The effect of several MEK inhibitors, with different binding affinities, has been investigated in the CCI model of neuropathic pain in the rat, by assessing static allodynia with von Frey hairs. Intrathecal administration of PD219622 or PD297447 (30ptg) had no significant effect on allodynia. This lack of effect 10 may reflect the low affinity or solubility of the compounds. However, intrathecal administration of PD 254552 or PD 184352 (30pg), which posses higher binding affinities, blocked the maintenance of static allodynia in CCI animals. The antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100pg). The magnitude of 15 the effect was similar for 30ptg of PD 184352 and 100ptg of pregabalin. From this study it is concluded that MEK inhibitors exert an antiallodynic effect in CCI-induced neuropathic rats when administered intrathecally, and that the antiallodynic effect correlates with the affinity of the compounds. 20 The animals and methods for developing chronic constriction injury in the rat, injecting test compounds, and evaluation of static allodynia were according to Example 2 above. PD219622, PD297447, PD 184352, PD 254552 and pregabalin were administered intrathecally at doses of 30ptg for all PD compounds and 100ptg for pregabalin. Static allodynia was assessed with 25 von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal administration of the compounds Drugs used PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin 30 were synthesised at Parke-Davis (Ann Arbor, MI, USA). PD297447, PD219622, PD 254552 and PD 184352 were suspended in 74 WO 01/05391 PCT/USOO/18346 cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10ptl volume. Statistics 5 Data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test vs vehicle group. RESULTS Intrathecally administered PD297447 or PD219622 (30pg) had no 10 significant effect on allodynia. This lack of effect may reflect the low affinity of the compounds (965nM and 100nM respectively). However, intrathecal administration of PD 184352 or PD 254552 (30tg) blocked the maintenance of static allodynia in CCI animals (see FIG. 8). These compounds possess higher affinity (2 and 5 nM respectively). The antiallodynic effect was only 15 evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100pg). The magnitude of the effect was similar for 30pg of PD 184352 and 100ptg of pregabalin. The results indicate that MEK inhibitors exert an antiallodynic effect in CCI-induced neuropathic rats when administered intrathecally, and that the 20 antiallodynic effect correlates with the affinity of the compounds. 75 WO 01/05391 PCT/USOO/18346 CHEMICAL EXAMPLES EXAMPLE 1 5 [4-Chloro-2-(4,4-Dimethyl-4,5-dihvdro-oxazol-2-yl)-phenvll-(4-iodo-2-methyl phenyl)-amine (18). (Scheme 2, R 1 =CI, R 2
=R
3 =H, R 4
=CH
3 ) a). A mixture of 5-chloro-2-methoxybenzoic acid 16 (14.8 g, 0.0793 mole) and SOC1 2 (28.31 g, 14.97 ml, 0.1584 mole) was refluxed for 2 hours and 10 excess SOC1 2 removed leaving a white residue. The solid was dissolved in
CH
2
CI
2 and added to a solution of 2-amino-2-methyl-1-propanol (13.98 g, 14.97 ml, 0.1584 mole) in CH 2
CI
2 cooled with ice-bath. The ice-bath was removed, and after stirring at room temperature for 3 hours a white solid precipitated. The precipitate was separated by filtration and discarded. The 15 filtrate was concentrated leaving a thick colorless oil. SOC 2 (17.4 ml) was added to the oil dropwise. An exothermic reaction took place resulting in to a freely flowing solution. After stirring for 30 minutes, the reaction mixture was poured in to Et 2 0 (200 ml). An oil separated out. The Et 2 0 layer was removed by decanting and discarded. The oily residue was dissolved in a 20 minimum amount of water, basified with aqueous 20% NaOH, and extracted with Et 2 0. The Et 2 0 layer was dried (K 2
CO
3 ) and concentrated to give 17 as tan oil. Yield 14.63 g (77%). b). LDA (5 ml of 2.0 M solution in THF) was added to a solution of 4-iodo 25 2-methylaniline (2.33 g, 0.010 mole) in THF (15 ml) at-78 *C. The mixture was stirred at -78 *C for 30 minutes. To this, a solution of 17 (1.199 g, 0.005 mole) in THF (15 ml) was added. The mixture stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous NH 4 CI and extracted with Et 2 O. The Et 2 0 layer was dried (MgSO 4 ) 30 and concentrated to give crude 18 as brown oil. The oil was purified on silica column chromatography. Eluting with CH 2
CI
2 gave pure 1.7 g (77%) of 18 as brown oil. Four hundred and nine milligrams of the oil were dissolved in Et 2 0 and treated with Et 2 0-HCI giving the HCI salt as a light yellow solid 76 WO 01/05391 PCT/USOO/18346 precipitate. Yield 356.4 mg (81%); mp 324-330 0C; Anal. Calcd/found for
C
18
H
18
N
2 0Cll.HCI.0.5H 2 0: C, 44.47/44.32; H, 4.15/3.94; N, 5.76/5.66. EXAMPLE 2 5 [2,3-Difluoro-6-( H-tetrazol-5-yI)-phenvll-(4-iodo-2-methyl-phenyl)-amine N=N / \ CN N, NH H N NaN 3 , (C 2
H,)
3 N.HCI N toluene/reflux F F F F F 10 [2,3-Difluoro-6-cyano-phenyl]-(4-iodo-2-methyl-phenyl)-amine (1.11 g, 3mmol) and Sodium azide(0.255g, 3.9mmol) and triethylamine hydrochloride (0.537g, 3.9mmol) were all suspended in 1Oml toluene and stirred at 100*C for 12 hours. The mixture was concentrated and the residue purified by column chromatography with ethyl acetate/methanol (10/1) to give the product 15 as a foam-like solid. The yield: -50% m.p: 83.4-88.7*C 1 H NMR(CDC1 3 , 400Hz): 8/ppm 7.69(1 H, m, Phenyl-H); 7.42(1 H, s, Phenyl-H); 7.27(1H, m, Phenyl-H); 6.91(1H, dd, J=16.2Hz, 8.3Hz, Phenyl-H); 6.40(1H, dd, Phenyl-H); 2.28(3H, s, CH 3 ) 20 77 WO 01/05391 PCT/USOO/18346 EXAMPLE 3 [6-(4,4-Dimethyl-4,5-d ihyd ro-oxazol-2-yl)-2,3-d ifluoro-phenyll-(4-iodo-2 methyl-phenyl)-amine COOH H N 0 N (1) (COCi) 2 H N (2)2-amino-2-methyl-1-propanol F I F F 1 5 F A solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (1.17g, 3mmol), oxalyl chloride (0.457g, 3.6mmol) in 30ml dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours then concentrated. The residue was dissolved in 25 ml 10 dichloromethane then the solution was added dropwise to a solution of 2 amino-2-methyl-1-propanol (0.623g, 7mmol) in 25 ml dichloromethane at 0*C, then stirred at room temperature for 12 hours, filtered off the precipitate, the filtration was washed with water, 5% aqueous sodium bicarbonate, 1 N HCI, brine, dried with sodium sulfate. Concentration gave the crude product, then 15 resuspended in 25 ml chloroform, then thionyl chloride was added at 0*C and stirred at room temperature for 15 hours, then concentrated and the residue was dissolved in 30 ml dichloromethane , 1 N HCI was added to adjusted the pH value to 11, the separated and extracted with chloroform, dried with sodium sulfate. Concentrated and then run column with 20 hexanes/dichloromethane (20/1) to give the compound as a white crystal. The yield: 65% m.p.: 103.7-104.4 0 C 1 H NMR(CDCl 3 , 400Hz): S/ppm 10.2(1H, s, NH), 7.48-7.58(1H, m, Phenyl-H); 7.48(1H, s, Phenyl-H); 7.38(1H, d, J=8.5Hz, Phenyl-H), 6.66-6.72(1H, m, 25 Phenyl-H); 6.58(1H, t, J=8.OHz, Phenyl-H); 4.01(2H, s, -CH 2 -); 2.31(3H, s, Phenyl-CH 3 ); 1.32(6H, s, -C(CH 3
)
2 -) 78 WO 01/05391 PCT/USOO/18346 EXAMPLE 4 5 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid methyl ester COOH O O H H N
H
2
SO
4
/CH
3 0H N reflux F I F I F F 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (5g) was dissolved 10 in 100ml methanol and 5 drops of concentrated sulfuric acid was added, reflux for 4 days. Run column with hexanes/dichloromethane to give the product as a white solid, yield: 50%. m.p.:90.1-90.4 0 C 1 H NMR(CDCl 3 , 400Hz): S/ppm 8.92(1H, s, NH), 7.75-7.78(1H, m, Phenyl-H); 15 7.49(1 H, s, Phenyl-H); 7.38(1H, dd, J=8.5Hz, 2.0Hz, Phenyl-H), 6.66-6.73(1 H, m, Phenyl-H); 6.56-6.60(1H, m, Phenyl-H); 3.88(3H, s, -OCH 3 ); 2.30(3H, s, Phenyl-CH 3 ) 79 WO 01/05391 PCT/USOO/18346 EXAMPLE 5 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-4H-[1,2.41triazol-3 Vlamine 5
H
2 N \N 0 0 N NH H N aminohuanidine nitrate H NaOCH 3
/CH
3 0H 4 F F F I F F Aminoguanidine nitrate (1.65g, 12mmol) was added to a solution of sodium methoxide (0.648g, 12mmol) in methanol (12ml) at 0 0 C, then 3,4-Difluoro-2 (4-iodo-2-methyl-phenylamino)-benzoic acid methyl ester was added as a 10 solution of methanol and refulx for 20 hours, concentration and run column with hexanes/ethyl acetate to give the product as a white crystal. The yield: 60% m.p.: 191.7-192.0OC 1 H NMR(DMSO, 400Hz): 6/ppm 9.45(1H, s, -NH-); 7.79(1H, t, J=7.3Hz, 15 Phenyl-H); 7.51(1H, s, Phenyl-H); 7.35(1H, d, J=10.lHz, Phenyl-H); 7.05 7.11(1H, m, Phenyl-H); 6.44-6.48(1H, m, Phenyl-H); 6.32(2H, s, -NH 2 ), 2.32(3H, s, CH 3 ) 80 WO 01/05391 PCT/USOO/18346 EXAMPLE 6 5-f3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-[1,3,4loxadiazol-2 ylamine 5
H
2 N N 0 NHNH 2 O N H N BrCN/NaHCO 3 (aq) H dioxane, r.t. F I F I F F To a solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (0.806g, 2mmol) in 5ml of dioxane was added cyanogen bromide (0.212g, 2mmol) followed by a solution of sodium bicarbonate (0.17g, 2mmol) 10 in 5ml of water. The resulting mixture was stirred 18 hours at room temperature the solution was concentrated and the residure was run column with hexanes/ethyl acetate (3/1) to give the product which was recrystallized from ethyl acetate / hexanes to provide a pale-yellow crystal. The yield: 58% m.p.: 183.7-184.0*C 15 1 H NMR(CDCl 3 , 400Hz): s/ppm 8.87(1H, s, -NH-); 7.52(1H, s, Phenyl-H); 7.45-7.49(1H, m, Phenyl-H); 7.40(1H, d, J=8.3Hz, Phenyl-H); 6.77-6.83(1H, m, Phenyl-H); 6.60-6.63(1H, m, Phenyl-H); 5.02(2H, s, -NH 2 ), 2.36(3H, s,
CH
3 ) 81 WO 01/05391 PCT/USOO/18346 EXAMPLE 7 2-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino) benzovllhvdrazinecarbothioamide 5 S COOH .O H H2N N N (1) (CO1) 2 H H N (2) thiosemicarbazide F I F I F F A solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (3.9g, 0.01mol), oxalyl chloride (1.90g, 0.015mol) in 40ml dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 10 hours before concentration. The residue was dissolved in 10 ml tetrahydrofuran and added to a solution of thiosemicarbazide (2.0g, 0.022mol) in 50ml tetrahydrofuran at 0*C, stirred at room temperature for 14 hours. Concentrated and run column chromatography with hexanes/ethyl acetate (1/1) to give the product as a yellow solid. 2.91g. The yield: 63% 15 m.p.: 159.5-160.0 0 C 1 H NMR(DMSO, 400Hz): 6/ppm 10.58(1H, s, -NH-); 9.28(1H, s, -NH-); 8.83(1H, s, -NH-); 7.95(1H, s, Phenyl-H); 7.12-7.75(2H, m, NH 2 ); 7.51(1H, s, Phenyl-H); 7.37(1H, dd, J=8.6Hz, 1.7Hz, Phenyl-H); 7.16(1H,dd, J=17Hz, 9.0Hz, Phenyl-H); 6.40-6.50(1 H, m, Phenyl-H); 5.02(2H, s, -NH 2 ), 2.00(3H, s, 20 CH 3 ) 82 WO 01/05391 PCT/USOO/18346 EXAMPLE 8 5-[3,4-Difuoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-4H-[1,2,4]triazole-3 thiol 5 H S S N HN N 0N~ NH H2N N 2 H H H N NaOCH 3
/CH
3 0H N reflux 1 F I F I F F 2-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino) benzoyl]hydrazinecarbothioamide (1.386g, 3mmol) was dissolved in 15 ml 10 anhydrous methanol, sodium methoxide (25% wt% in methanol) 2.5ml was added at 00C in one portion. The resulting mixture was heated at reflux for 17 hours before concentration. Run column with hexanes/ethyl acetate to give the product as a needle white crystal. The yield: 40% m.p.: 196.5(dec.) 15 'H NMR(DMSO, 400Hz): 6/ppm 13.87(1H, s, -NH-); 13.80(1H, s, -NH-); 8.16(1H, s, -NH-); 7.61-7.65(1H, m, Phenyl-H); 7.48(1H, s, Phenyl-H); 7.32(1H, dd, J=8.6Hz, 2.2Hz, Phenyl-H); 7.24(1H,dd, J=16.4Hz, 9.5Hz, Phenyl-H); 6.42-6.46(1H, m, Phenyl-H); 5.02(2H, s, -NH 2 ), 2.20(3H, s, CH 3 ). 83 WO 01/05391 PCT/USOO/18346 EXAMPLE 9 (2,3-Difluoro-6-[1,3,4loxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine NN N O N O N HC(OEt) 3 N pTsOH, EtOH F I F I 5 F F 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (146 mg, 0.36 mmol) was suspended in 7 mL of absolute EtOH and 2 mL of HC(OEt) 3 was added along with approximately 3 mg of pTsOH> The reaction 10 was heated to reflux for 3h, cooled and concentration on a rotary evaporator. The reaction was purified (SiO2, 4:1 Hexane/EtOAc) to afford 117 mg (79%) of (2,3-difluoro-6-[1,3,4]oxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine as a yellow powder. M.p. = 144.4 - 145.5 0C. 1 H NMR (400MHz, CDCl 3 ) 8 8.89 (s, 1H), 8.44 (s, 1H), 7.66 (m, 1H), 7.52 (d, J = 1.7 Hz, 1 H), 7.38 (dd, J = 15 8.5, 1.9 Hz, 1 H), 6.83 (m, 1H), 6.14 (dd, J = 8.5, 5.9 Hz, 1 H), 2.37 (s, 3 H). EXAMPLE 10 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-[1,3,4loxadiazole-2 thiol S N O N - IN N 0 N CS 2 , KOH N F i EtOHFI F IF 20 F F 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (170 mg, 0.42 mmol) was suspended in 7 mL of absolute EtOH and cooled to 84 WO 01/05391 PCT/USOO/18346 0 'C. Carbon disulfide (74 mg, 0.97 mmol) was added followed by 24 mg (0.42 mmol) of powdered KOH. The reaction was stirred for 1 h at 0 *C, 1 h at rt, and refluxed for 3 h to afford a homogeneous reaction. The reaction was cooled to rt, at which point a ppt formed. Water was added and the reaction 5 diluted with 5 mL of EtOAc. 1N HCI was added to acidify the aqueous layer (pH = 2). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na 2
SO
4 and concentrated to obtain 96 mg (51%) of 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]oxadiazole-2-thiol as a yellow powder. M.p. = 231.8 - 232.8 *C. 'H 10 NMR (400MHz, CDCl 3 ) 5 7.62 (m, 2H), 7.47 (s, 1H), 7.30 (complex m, 2H), 6.44 (dd, J = 8.0, 4.5 Hz, 1H), 2.19 (s, 3H). F. OTHER EMBODIMENTS From the above disclosure and examples, and from the claims below, the essential features of the invention are readily apparent. The scope of the 15 invention also encompasses various modifications and adaptations within the knowledge of a person of ordinary skill. Examples include a disclosed compound modified by addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid, or amide of a disclosed compound. Publications cited herein are hereby incorporated by reference in their 20 entirety. What is claimed is: 85
Claims (33)
1. A method for treating chronic pain, said method comprising administering to a subject in need of such treatment a composition comprising 5 a MEK inhibitor selected from: a compound of formula (1): W R4 R1 3 R, R3 R2 10 W is one of the following formulae (i) - (xiii): NX2 RN X 2 NX 1 0 y X NH N N 5 X 2 X 2 N--( 5 5>INR -NN N 0 N R5N X2 X2 X2 I IX (viii) (ix) (x) (xi) (xii) (xiii) HO 0 0 0 0 \N /N-N X2 X X N X, N N N (xiv) (xv) (xvi) (xvii) 15 X 1 is 0, S, or NRF; 86 WO 01/05391 PCT/USOO/18346 X 2 is OH, SH, or NHRE; each of RE and RF is H or C 1-4 alkyl; 5 each of R 1 and R 2 is independently selected from H, F, NO 2 , Br and Cl; R 1 can also be SO2NRGRH, or R 1 and R 2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole; 10 R 3 is H or F; each of RG, RH, and R 4 is independently selected from H, Cl and CH 3 ; 15 R 5 is H or C 34 alkyl; and wherein each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO 2 ; and 20 wherein each heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 3-4 alkyl, C 3-6 cycloalkyl, C 34 alkenyl, C 34 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO 2 , wherein each substituent alkyl, cycloalkyl, alkenyl, 25 alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 ; or a pharmaceutically acceptable salt or C 1-8 ester thereof. 30 87 WO 01/05391 PCT/USOO/18346
2. The method of claim 1, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.
3. The method of claim 2, wherein said chronic pain is a type of 5 neuropathic pain.
4. The method of claim 3, wherein said neuropathic pain is associated with one of the following: inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, 10 viral infection, crush injury, constriction injury, tissue injury, limb amputation, post-operative pain, arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.
5. The method of claim 2, wherein said chronic pain is associated with 15 chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.
6. The method of claim 2, wherein said chronic pain is associated with idiopathic pain. 20
7. The method of claim 1, wherein said chronic pain is associated with inflammation.
8. The method of claim 1, wherein said chronic pain is associated with arthritis. 25
9. The method of claim 1, wherein said chronic pain is associated with post-operative pain. 30
10. The method of claim 1, wherein R 1 is bromo or chloro. 88 WO 01/05391 PCT/USOO/18346
11. A method of claim 1, wherein R 2 is fluoro.
12. A method of claim 1, wherein R 3 is H. 5
13. A method of claim 12, wherein each of R 2 and R 3 is H.
14. A method of claim 1, wherein each of R 2 and R 3 is fluoro. 10
15. A method of claim 14, wherein R 1 is bromo.
16. A method of claim 14, wherein R 1 is fluoro.
17. A method of claim 1, wherein R 2 is nitro. 15
18. A method of claim 16, wherein R 3 is H.
19. A method of claim 1, wherein R 4 is chloro.
20 20. A method of claim 1, wherein R 4 is methyl.
21. A method of claim 1, wherein R 5 is H.
22. A method of claim 1, wherein R 5 is CH 3 . 25
23. A method of claim 1, wherein X 1 is 0 or S.
24. A method of claim 1, wherein X 1 is NH or NCH 3 . 30
25. A method of claim 1, wherein X 2 is OH, SH, or NH 2 .
26. A method of claim 1, wherein X 2 is NHCH 3 or OH. 89 WO 01/05391 PCT/USOO/18346
27. A method of claim 1, wherein said MEK inhibitor has a structure selected from: [5-fluoro-2-(1H-tetrazol-5-yI)-phenyl]-(4-iodo-2-methyl-phenyl) amine; [2,3-difluoro-6-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl) 5 amine; (4-iodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(1 H-tetrazol-5-yl)-phenyl] amine; [4-bromo-2,3-difluoro-6-(1H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl phenyl)-amine; [5-fluoro-4-nitro-2-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl phenyl)-amine; [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-phenyl]-(4 iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yI)-2,3 10 difluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro oxazol-2-yl)-2,3,4-trifluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [4-bromo 6-(4,4-dimethyl-4,5-d ihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl phenyl)-amine; [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yI)-5-fluoro-4-nitro phenyl]-(4-iodo-2-methyl-phenyl)-amine; 5-[4-fluoro-2-(4-iodo-2-methyl 15 phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4 iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro 20 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol 2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl] 25 [1,3,4]oxadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 4H-[1,2,4]triazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; and 5-[4-fluoro-2-(4-iodo-2 30 methyl-phenylamino)-5-nitro-phenyl]-4H-[1,2,4]triazol-3-ol. 90 WO 01/05391 PCT/USOO/18346
28. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]thiadiazol-2-ylamine; 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo-2-methyl 5 phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2 ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 10 [1,3,4]oxadiazol-2-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo 2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[3,4 15 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3 ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl 20 phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazole-2 25 thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2 thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]oxadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[5-bromo-3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl 30 phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4,5 91 WO 01/05391 PCT/USOO/18346 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5 [5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazole-3-thiol; and 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-4H-[1,2,4]triazole-3-thiol. 5
29. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol 3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 5-[5 10 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 5 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4,5-trifluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[5-bromo-3,4-difluoro-2 15 (4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4 20 iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-5-nitro-phenyl]-1 H-pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4 25 iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2 30 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1 -methyl-1 H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 92 WO 01/05391 PCT/USOO/18346 methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 1-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H pyrazol-3-ol; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl] 5 1-methyl-1 H-pyrazol-3-ol.
30. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-phenyl]-l-methyl 1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-3,4-difluoro-phenyl] 10 1-methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-3,4,5 trifluoro-phenyl]-1 -methyl-1 H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo phenylamino)-5-bromo-3,4-difluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5 [2-(2-amino-4-iodo-phenylamino)-4-fluoro-5-nitro-phenyl]-1 -methyl-1 H [1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3 15 methyl-3H-[1,2,3]triazol-4-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 3-methyl-5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-ol; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-3-methyl-3H 20 [1,2,3]triazol-4-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2 methyl-2H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-2-methyl-2H-pyrazol-3-ol; 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-pyrazo-3-ol; 4-[5-bromo-3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[4-fluoro-2 25 (4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2-methyl-2H-pyrazol-3-ol; 1-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl- 1,4-dihyd ro-tetrazol 5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl- 1,4 dihydro-tetrazol-5-one; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2 30 (4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4-methyl-1,4 dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 93 WO 01/05391 PCT/USOO/18346 1H-[1,2,3]triazol-4-ol; 1 -[3,4-d ifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 1H-[1,2,3]triazol-4-ol; 1-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-1H-[1,2,3]triazol-4-ol; 1 -[5-bromo-3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1 H-[1,2,3]triazol-4-ol; and 1-[4-fluoro-2-(4-iodo-2 5 methyl-phenylamino)-5-nitro-phenyl]-1 H-[1,2,3]triazol-4-ol.
31. The method of claim 1, wherein said MEK inhibitor has a structure selected from: 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H 10 isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5 nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2-oxo-2,3-dihydro-21>4_ [1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2,3 15 difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yI)-phenyl]-(4 iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(2 oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yI)-phenyl]-amine; [4-bromo 2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4 iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro-21>4 20 [1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; 4-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5 25 one; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H isoxazol-5-one.
32. The method of claim 1, wherein said MEK inhibitor has a structure selected from: 2,4-bis-(2-chloro-4-iodo-phenylamino)-3fluoro5-nitro-benzoic 30 acid; 5-[3,4difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol 2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]oxadiazol-2-ol; (2,3-difluoro-6-[1,3,4]oxadiazol-2-yI-phenyl)(-(4-iodo-2 94 WO 01/05391 PCT/USOO/18346 methyl-phenyl)-amine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-4H-[1,2,4]triazole-3-ylamine; and 5-[3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol. 5
33. The method of claim 1, wherein said MEK inhibitor has the structure: 2,4 bis-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid. 95
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14440399P | 1999-07-16 | 1999-07-16 | |
US60144403 | 1999-07-16 | ||
PCT/US2000/018346 WO2001005391A2 (en) | 1999-07-16 | 2000-07-05 | Method for treating chronic pain using mek inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
AU5785900A true AU5785900A (en) | 2001-02-05 |
Family
ID=22508429
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU57859/00A Abandoned AU5785900A (en) | 1999-07-16 | 2000-07-05 | Method for treating chronic pain using mek inhibitors |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP1202732A2 (en) |
JP (1) | JP2003504399A (en) |
KR (1) | KR20020015379A (en) |
CN (1) | CN1358095A (en) |
AU (1) | AU5785900A (en) |
CA (1) | CA2377100A1 (en) |
CO (1) | CO5190702A1 (en) |
HK (1) | HK1047039A1 (en) |
HU (1) | HUP0202381A3 (en) |
IL (1) | IL147617A0 (en) |
PE (1) | PE20010547A1 (en) |
PL (1) | PL352705A1 (en) |
TR (1) | TR200200204T2 (en) |
UY (1) | UY26248A1 (en) |
WO (1) | WO2001005391A2 (en) |
ZA (1) | ZA200109903B (en) |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100984573B1 (en) | 2002-03-13 | 2010-09-30 | 어레이 바이오파마 인크. | N3 Alkylated Benzimidazole Derivatives as MEK Inhibitors |
US7235537B2 (en) | 2002-03-13 | 2007-06-26 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US20050004186A1 (en) * | 2002-12-20 | 2005-01-06 | Pfizer Inc | MEK inhibiting compounds |
US7144907B2 (en) | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
US7538120B2 (en) | 2003-09-03 | 2009-05-26 | Array Biopharma Inc. | Method of treating inflammatory diseases |
KR101013932B1 (en) | 2003-10-21 | 2011-02-14 | 워너-램버트 캄파니 엘엘씨 | Polymorphic form of n-[r-2,3-dihydroxy-propoxy]-3,4-difluoro-2-2-fluoro-4-iodophenylamino-benzamide |
US7517994B2 (en) | 2003-11-19 | 2009-04-14 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
AU2004293017B2 (en) | 2003-11-19 | 2010-08-19 | Array Biopharma Inc. | Bicyclic inhibitors of MEK and methods of use thereof |
US7732616B2 (en) | 2003-11-19 | 2010-06-08 | Array Biopharma Inc. | Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof |
KR101223914B1 (en) | 2003-11-21 | 2013-01-18 | 어레이 바이오파마 인크. | Akt protein kinase inhibitors |
US7956191B2 (en) | 2004-10-20 | 2011-06-07 | Merck Serono Sa | 3-arylamino pyridine derivatives |
ES2378760T3 (en) | 2005-05-18 | 2012-04-17 | Array Biopharma, Inc. | MEK heterocyclic inhibitors and methods of use thereof |
CN110668988A (en) | 2005-10-07 | 2020-01-10 | 埃克塞利希斯股份有限公司 | Azetidines as MEK inhibitors for the treatment of proliferative diseases |
EP2054418B1 (en) | 2006-07-06 | 2011-11-09 | Array Biopharma Inc. | Dihydrothieno pyrimidines as akt protein kinase inhibitors |
RU2481336C2 (en) | 2006-07-06 | 2013-05-10 | Эррэй Биофарма Инк. | Cyclopenta(d)pyrimidines as protein kinase akt inhibitors |
US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
CA2656566C (en) | 2006-07-06 | 2014-06-17 | Array Biopharma Inc. | Dihydrofuro pyrimidines as akt protein kinase inhibitors |
WO2008066131A1 (en) * | 2006-12-01 | 2008-06-05 | Banyu Pharmaceutical Co., Ltd. | Novel phenyl-isoxazol-3-ol derivative |
AU2007334402B2 (en) | 2006-12-14 | 2014-02-13 | Exelixis, Inc. | Methods of using MEK inhibitors |
EP2121620B1 (en) * | 2007-01-19 | 2015-06-17 | Ardea Biosciences, Inc. | Inhibitors of mek |
US9409886B2 (en) | 2007-07-05 | 2016-08-09 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
KR101624361B1 (en) | 2007-07-05 | 2016-05-25 | 어레이 바이오파마 인크. | Pyrimidyl cyclopentanes as akt protein kinase inhibitors |
US8846683B2 (en) | 2007-07-05 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
NZ582692A (en) | 2007-07-05 | 2012-05-25 | Array Biopharma Inc | Pyrimidyl cyclopentanes as akt protein kinase inhibitors |
ES2422733T3 (en) | 2008-01-09 | 2013-09-13 | Array Biopharma Inc | Hydroxylated pyrimidylcyclopentanes as AKT protein kinase inhibitors |
NZ586720A (en) | 2008-01-09 | 2012-11-30 | Array Biopharma Inc | Hydroxylated pyrimidyl cyclopentane as akt protein kinase inhibitor |
US8993630B2 (en) | 2008-11-10 | 2015-03-31 | Bayer Intellectual Property Gmbh | Substituted sulphonamido phenoxybenzamides |
EP2491016A1 (en) | 2009-10-21 | 2012-08-29 | Bayer Pharma Aktiengesellschaft | Substituted benzosulphonamides |
JP2013508320A (en) | 2009-10-21 | 2013-03-07 | バイエル・ファルマ・アクチェンゲゼルシャフト | Substituted halophenoxybenzamide derivatives |
JP2013508318A (en) | 2009-10-21 | 2013-03-07 | バイエル・ファルマ・アクチェンゲゼルシャフト | Substituted benzosulfonamide derivatives |
JP2013542214A (en) | 2010-10-29 | 2013-11-21 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Substituted phenoxypyridines |
CN110433165A (en) | 2011-04-01 | 2019-11-12 | 基因泰克公司 | The combination and its application method of AKT and mek inhibitor compound |
BR112013025353A8 (en) | 2011-04-01 | 2018-01-02 | Genentech Inc | combination of a) a compound of formula ia, compound of formula ia or a pharmaceutically acceptable salt thereof, method for treating a hyperproliferative disorder in a mammal, use of a compound of formula ia or a pharmaceutically acceptable salt thereof, kit and product |
NZ706723A (en) | 2012-10-12 | 2018-07-27 | Exelixis Inc | Novel process for making compounds for use in the treatment of cancer |
JP2020518669A (en) | 2017-05-03 | 2020-06-25 | ビバーチェ セラピューティクス,インク. | Non-fused tricyclic compound |
CN111542315B (en) | 2017-08-21 | 2023-05-12 | 维瓦斯治疗公司 | Benzosulfonyl compounds |
WO2019113236A1 (en) | 2017-12-06 | 2019-06-13 | Vivace Therapeutics, Inc. | Benzocarbonyl compounds |
CA3100503A1 (en) | 2018-05-16 | 2019-11-21 | Vivace Therapeutics, Inc. | Oxadiazole compounds |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU5610398A (en) * | 1997-02-28 | 1998-09-18 | Warner-Lambert Company | Method of treating or preventing septic shock by administering a mek inhibitor |
ATE344791T1 (en) * | 1997-07-01 | 2006-11-15 | Warner Lambert Co | 2-(4-BROMINE OR 4-IODINE PHENYLAMINO)BENZOIC ACID DERIVATIVES AND THEIR USE AS MEK INHIBITORS |
AU776788C (en) * | 1998-12-16 | 2005-10-27 | Warner-Lambert Company | Treatment of arthritis with MEK inhibitors |
WO2000042029A1 (en) * | 1999-01-13 | 2000-07-20 | Warner-Lambert Company | 1-heterocycle substituted diarylamines |
-
2000
- 2000-07-05 WO PCT/US2000/018346 patent/WO2001005391A2/en not_active Application Discontinuation
- 2000-07-05 PL PL00352705A patent/PL352705A1/en unknown
- 2000-07-05 AU AU57859/00A patent/AU5785900A/en not_active Abandoned
- 2000-07-05 EP EP00943382A patent/EP1202732A2/en not_active Withdrawn
- 2000-07-05 JP JP2001510448A patent/JP2003504399A/en active Pending
- 2000-07-05 HU HU0202381A patent/HUP0202381A3/en unknown
- 2000-07-05 CA CA002377100A patent/CA2377100A1/en not_active Abandoned
- 2000-07-05 TR TR2002/00204T patent/TR200200204T2/en unknown
- 2000-07-05 CN CN00809525A patent/CN1358095A/en active Pending
- 2000-07-05 IL IL14761700A patent/IL147617A0/en unknown
- 2000-07-05 KR KR1020027000665A patent/KR20020015379A/en not_active Application Discontinuation
- 2000-07-14 CO CO00053308A patent/CO5190702A1/en not_active Application Discontinuation
- 2000-07-14 PE PE2000000703A patent/PE20010547A1/en not_active Application Discontinuation
- 2000-07-14 UY UY26248A patent/UY26248A1/en not_active Application Discontinuation
-
2001
- 2001-11-30 ZA ZA200109903A patent/ZA200109903B/en unknown
-
2002
- 2002-11-29 HK HK02108607.6A patent/HK1047039A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2001005391A3 (en) | 2001-07-19 |
TR200200204T2 (en) | 2002-11-21 |
HUP0202381A2 (en) | 2002-11-28 |
EP1202732A2 (en) | 2002-05-08 |
JP2003504399A (en) | 2003-02-04 |
UY26248A1 (en) | 2000-10-31 |
HUP0202381A3 (en) | 2004-12-28 |
CN1358095A (en) | 2002-07-10 |
CO5190702A1 (en) | 2002-08-29 |
ZA200109903B (en) | 2003-05-28 |
HK1047039A1 (en) | 2003-02-07 |
PL352705A1 (en) | 2003-09-08 |
WO2001005391A2 (en) | 2001-01-25 |
KR20020015379A (en) | 2002-02-27 |
CA2377100A1 (en) | 2001-01-25 |
PE20010547A1 (en) | 2001-06-04 |
IL147617A0 (en) | 2002-08-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU5785900A (en) | Method for treating chronic pain using mek inhibitors | |
US6545030B1 (en) | 1-heterocycle substituted diarylamines | |
CA2377092A1 (en) | Method for treating chronic pain using mek inhibitors | |
DE60005688T2 (en) | METHOD FOR TREATING CHRONIC PAIN BY ADMINISTRATING A MEK INHIBITOR | |
JP2003504400A (en) | Method for treating chronic pain using MEK inhibitor | |
JP2003527379A (en) | 5-Amido-substituted diarylamines as MEX inhibitors | |
US7030119B1 (en) | Method for treating chronic pain using MEK inhibitors | |
UA72239C2 (en) | Substituted 1-heterocyclic diarylamines | |
JP2004503535A (en) | Indole and benzimidazole 15-lipoxygenase inhibitors | |
JP2001055376A (en) | Diaryl amine | |
JP2000212157A (en) | Diarylamine | |
MXPA01006659A (en) | 1-heterocycle substituted diarylamines |