WO2005009975A2 - Benzimidazole derivatives as mek inhibitors - Google Patents
Benzimidazole derivatives as mek inhibitors Download PDFInfo
- Publication number
- WO2005009975A2 WO2005009975A2 PCT/IB2004/002355 IB2004002355W WO2005009975A2 WO 2005009975 A2 WO2005009975 A2 WO 2005009975A2 IB 2004002355 W IB2004002355 W IB 2004002355W WO 2005009975 A2 WO2005009975 A2 WO 2005009975A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- optionally substituted
- methyl
- nhch
- Prior art date
Links
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title description 4
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 2
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 184
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 56
- -1 C 6 amides Chemical class 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 125000001424 substituent group Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 239000011737 fluorine Chemical group 0.000 claims description 26
- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 208000002193 Pain Diseases 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 239000000460 chlorine Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000005675 difluoroethenyl group Chemical group [H]C(*)=C(F)F 0.000 claims description 6
- 230000002062 proliferating effect Effects 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 208000000094 Chronic Pain Diseases 0.000 claims description 5
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 208000004296 neuralgia Diseases 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 21
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 102000043136 MAP kinase family Human genes 0.000 description 13
- 108091054455 MAP kinase family Proteins 0.000 description 13
- 241000700159 Rattus Species 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 0 CCC(c1nnc(*)[o]1)NC Chemical compound CCC(c1nnc(*)[o]1)NC 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 150000005440 nitrobenzoic acid derivatives Chemical class 0.000 description 11
- 230000026731 phosphorylation Effects 0.000 description 11
- 238000006366 phosphorylation reaction Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000000679 carrageenan Substances 0.000 description 10
- 235000010418 carrageenan Nutrition 0.000 description 10
- 229920001525 carrageenan Polymers 0.000 description 10
- 229940113118 carrageenan Drugs 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 230000036407 pain Effects 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 8
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102000016914 ras Proteins Human genes 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 208000004454 Hyperalgesia Diseases 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 7
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 206010003246 arthritis Diseases 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000009466 transformation Effects 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 5
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 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
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 210000002683 foot Anatomy 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- 208000035154 Hyperesthesia Diseases 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 150000001345 alkine derivatives Chemical class 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 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 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 239000003880 polar aprotic solvent Substances 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- XAUKOYDFWGJRNP-UHFFFAOYSA-N 6-(4-ethyl-2-fluoroanilino)-5-fluoro-3-methyl-2h-benzimidazole-5-carboxamide Chemical compound FC1=CC(CC)=CC=C1NC1=CC2=NCN(C)C2=CC1(F)C(N)=O XAUKOYDFWGJRNP-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000000503 Collagen Type II Human genes 0.000 description 3
- 108010041390 Collagen Type II Proteins 0.000 description 3
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 3
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 3
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 3
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 238000003556 assay 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
- 230000037396 body weight Effects 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000000183 esterificating effect Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- BRIMESWRFXRALB-UHFFFAOYSA-N methyl 6-(4-ethenyl-2-fluoroanilino)-5-fluoro-3-methyl-2h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(C=C)C=C1F BRIMESWRFXRALB-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 2
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 2
- WDPHYSBBAAXFID-UHFFFAOYSA-N 5-fluoro-6-(2-fluoro-4-iodoanilino)-3-methyl-2h-benzimidazole-5-carboxylic acid Chemical compound OC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1F WDPHYSBBAAXFID-UHFFFAOYSA-N 0.000 description 2
- BKVXNLMOHUTOCU-UHFFFAOYSA-N 5-fluoro-6-(4-iodo-2-methylanilino)-3-methyl-2h-benzimidazole-5-carbohydrazide Chemical compound NNC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1C BKVXNLMOHUTOCU-UHFFFAOYSA-N 0.000 description 2
- IADGQTUKMBXVLN-UHFFFAOYSA-N 5-fluoro-6-(4-iodo-2-methylanilino)-3-methyl-2h-benzimidazole-5-carboxylic acid Chemical compound OC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1C IADGQTUKMBXVLN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- 230000005723 MEK inhibition Effects 0.000 description 2
- 229940124647 MEK inhibitor Drugs 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- 206010040070 Septic Shock Diseases 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
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 150000001344 alkene derivatives Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 230000002862 amidating effect Effects 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000006210 cyclodehydration reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 210000000624 ear auricle Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XGTQMCCNKNIPMH-UHFFFAOYSA-N methyl 5-fluoro-6-(2-fluoro-4-iodoanilino)-3-methyl-2h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1F XGTQMCCNKNIPMH-UHFFFAOYSA-N 0.000 description 2
- JVLSCPRZSHXFAZ-UHFFFAOYSA-N methyl 6-(4-ethyl-2-fluoroanilino)-5-fluoro-3-methyl-2h-benzimidazole-5-carboxylate Chemical compound FC1=CC(CC)=CC=C1NC1=CC2=NCN(C)C2=CC1(F)C(=O)OC JVLSCPRZSHXFAZ-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 230000002297 mitogenic effect Effects 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical compound O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 230000007420 reactivation Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001544 thienyl group Chemical group 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
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- VCQURUZYYSOUHP-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 2,2,2-trifluoroacetate Chemical compound FC1=C(F)C(F)=C(OC(=O)C(F)(F)F)C(F)=C1F VCQURUZYYSOUHP-UHFFFAOYSA-N 0.000 description 1
- PCYNYKRHMXDBOU-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 5-fluoro-6-(2-fluoro-4-iodoanilino)-3-methyl-2h-benzimidazole-5-carboxylate Chemical compound FC=1C(F)=C(F)C(F)=C(F)C=1OC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1F PCYNYKRHMXDBOU-UHFFFAOYSA-N 0.000 description 1
- FPDYICZFJZWGJK-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 5-fluoro-6-(4-iodo-2-methylanilino)-3-methyl-2h-benzimidazole-5-carboxylate Chemical compound FC=1C(F)=C(F)C(F)=C(F)C=1OC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1C FPDYICZFJZWGJK-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-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
- BCMIOBTWFPSPJJ-UHFFFAOYSA-N 197520-71-1 Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(F)C(F)=C1F BCMIOBTWFPSPJJ-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- WWWTWPXKLJTKPM-UHFFFAOYSA-N 2-aminooxyethanol Chemical compound NOCCO WWWTWPXKLJTKPM-UHFFFAOYSA-N 0.000 description 1
- CUMTUBVTKOYYOU-UHFFFAOYSA-N 2-fluoro-4-iodoaniline Chemical compound NC1=CC=C(I)C=C1F CUMTUBVTKOYYOU-UHFFFAOYSA-N 0.000 description 1
- AFENDNXGAFYKQO-UHFFFAOYSA-N 2-hydroxybutyric acid Chemical compound CCC(O)C(O)=O AFENDNXGAFYKQO-UHFFFAOYSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- HMGCGUWFPZVPEK-UHFFFAOYSA-N 2-naphthalen-2-ylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=C1 HMGCGUWFPZVPEK-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- GKAKRBVVSDYLFJ-UHFFFAOYSA-N 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(F)C(F)=C1NC1=CC=C(I)C=C1F GKAKRBVVSDYLFJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CSSGKHVRDGATJL-UHFFFAOYSA-N 3-fluoro-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C(F)=C1 CSSGKHVRDGATJL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- BGKLFAQCHHCZRZ-UHFFFAOYSA-N 4-iodo-2-methylaniline Chemical compound CC1=CC(I)=CC=C1N BGKLFAQCHHCZRZ-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- GEHRSERUQRFUFW-UHFFFAOYSA-N 5-ethylhex-2-ynedioic acid Chemical compound CCC(C(O)=O)CC#CC(O)=O GEHRSERUQRFUFW-UHFFFAOYSA-N 0.000 description 1
- HEHWFPZXAMTAJD-UHFFFAOYSA-N 5-fluoro-6-(2-fluoro-4-iodoanilino)-3-methyl-2h-benzimidazole-5-carboxamide Chemical compound NC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1F HEHWFPZXAMTAJD-UHFFFAOYSA-N 0.000 description 1
- DRAJPDWTOVALMA-UHFFFAOYSA-N 7-fluoro-6-(2-fluoro-4-iodoanilino)-3-methyl-2-(2,3,4,5,6-pentafluorophenyl)benzimidazole-5-carboxylic acid Chemical compound OC(=O)C=1C=C2N(C)C(C=3C(=C(F)C(F)=C(F)C=3F)F)=NC2=C(F)C=1NC1=CC=C(I)C=C1F DRAJPDWTOVALMA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 125000006847 BOC protecting group Chemical group 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241001474374 Blennius Species 0.000 description 1
- 206010051728 Bone erosion Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YUJVMSLMIGONMN-UHFFFAOYSA-N CC(C)C(O1)=NNC1=O Chemical compound CC(C)C(O1)=NNC1=O YUJVMSLMIGONMN-UHFFFAOYSA-N 0.000 description 1
- DOVVDNVEFWBPIQ-UHFFFAOYSA-N CCC(C=C1C)=CCC1Nc(c(C(NOCC(CO)O)=O)cc1c2nc[n]1C)c2F Chemical compound CCC(C=C1C)=CCC1Nc(c(C(NOCC(CO)O)=O)cc1c2nc[n]1C)c2F DOVVDNVEFWBPIQ-UHFFFAOYSA-N 0.000 description 1
- CAMYJMVUXIQFSG-UHFFFAOYSA-N CCc(cc1F)ccc1Nc(c(C(N)=O)cc1c2nc[n]1C)c2F Chemical compound CCc(cc1F)ccc1Nc(c(C(N)=O)cc1c2nc[n]1C)c2F CAMYJMVUXIQFSG-UHFFFAOYSA-N 0.000 description 1
- BIYFKQMREAXRCZ-UHFFFAOYSA-N C[n]1c(cc(C(NC(C(N)=O)C(N)=O)=O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 Chemical compound C[n]1c(cc(C(NC(C(N)=O)C(N)=O)=O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 BIYFKQMREAXRCZ-UHFFFAOYSA-N 0.000 description 1
- CPEDDCCBJDGQPE-UHFFFAOYSA-N C[n]1c(cc(C(NC(OCc2ccccc2)=O)O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 Chemical compound C[n]1c(cc(C(NC(OCc2ccccc2)=O)O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 CPEDDCCBJDGQPE-UHFFFAOYSA-N 0.000 description 1
- RJMIRFZHUXPGIP-UHFFFAOYSA-N C[n]1c(cc(C(NCc2ccccc2O)=O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 Chemical compound C[n]1c(cc(C(NCc2ccccc2O)=O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 RJMIRFZHUXPGIP-UHFFFAOYSA-N 0.000 description 1
- PIOZTCWHTFWQCF-UHFFFAOYSA-N C[n]1c(cc(C(O)=O)c(Nc(ccc(I)c2)c2F)c2F)c2nc1 Chemical compound C[n]1c(cc(C(O)=O)c(Nc(ccc(I)c2)c2F)c2F)c2nc1 PIOZTCWHTFWQCF-UHFFFAOYSA-N 0.000 description 1
- UTOCIQRDRMRYQH-UHFFFAOYSA-N C[n]1c(cc(C(Oc(c(F)c(c(F)c2F)F)c2F)=O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 Chemical compound C[n]1c(cc(C(Oc(c(F)c(c(F)c2F)F)c2F)=O)c(Nc(c(F)c2)ccc2I)c2F)c2nc1 UTOCIQRDRMRYQH-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000001387 Causalgia Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- DUWMZTNXLKZWBD-UHFFFAOYSA-N Cc(cc(cc1)I)c1Nc(c(C(O)=O)cc([N+]([O-])=O)c1F)c1F Chemical compound Cc(cc(cc1)I)c1Nc(c(C(O)=O)cc([N+]([O-])=O)c1F)c1F DUWMZTNXLKZWBD-UHFFFAOYSA-N 0.000 description 1
- AUOWWGXJJAEWSJ-UHFFFAOYSA-N Cc(cc(cc1)I)c1Nc(c(C(O)=O)cc([N+]([O-])=O)c1NCCO)c1F Chemical compound Cc(cc(cc1)I)c1Nc(c(C(O)=O)cc([N+]([O-])=O)c1NCCO)c1F AUOWWGXJJAEWSJ-UHFFFAOYSA-N 0.000 description 1
- BGGWCIPVGKWLMH-UHFFFAOYSA-N Cc1cc(I)ccc1Nc(c(C(N)=O)cc1c2nc[n]1C)c2F Chemical compound Cc1cc(I)ccc1Nc(c(C(N)=O)cc1c2nc[n]1C)c2F BGGWCIPVGKWLMH-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
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 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
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression 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
- 238000001061 Dunnett's test Methods 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- XYZZKVRWGOWVGO-UHFFFAOYSA-N Glycerol-phosphate Chemical compound OP(O)(O)=O.OCC(O)CO XYZZKVRWGOWVGO-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 108010046732 HLA-DR4 Antigen Proteins 0.000 description 1
- 206010019842 Hepatomegaly 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021135 Hypovitaminosis 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
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 206010023198 Joint ankylosis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 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
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 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
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 101150076359 Mhc gene Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- FLELZESNRRRJTG-UHFFFAOYSA-N OCCCc(cc1F)ccc1Nc(c(CO)cc1c2N=CC1)c2F Chemical compound OCCCc(cc1F)ccc1Nc(c(CO)cc1c2N=CC1)c2F FLELZESNRRRJTG-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 206010056238 Phantom pain Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 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
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102100029645 UBX domain-containing protein 11 Human genes 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- FXLDDUNGZVEVFJ-UHFFFAOYSA-N acetic acid;methanimidamide;2-methoxyethanol Chemical compound NC=N.CC(O)=O.COCCO FXLDDUNGZVEVFJ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-L acetylenedicarboxylate(2-) Chemical compound [O-]C(=O)C#CC([O-])=O YTIVTFGABIZHHX-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000000730 antalgic agent Substances 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
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 201000004983 autoimmune atherosclerosis Diseases 0.000 description 1
- 238000001266 bandaging Methods 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- ICPVRQLUILMVAP-UHFFFAOYSA-K bis(fluoromethylsulfonyloxy)indiganyl fluoromethanesulfonate Chemical compound [In+3].FCS(=O)(=O)[O-].FCS(=O)(=O)[O-].FCS(=O)(=O)[O-] ICPVRQLUILMVAP-UHFFFAOYSA-K 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 1
- AQNQQHJNRPDOQV-UHFFFAOYSA-N bromocyclohexane Chemical compound BrC1CCCCC1 AQNQQHJNRPDOQV-UHFFFAOYSA-N 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001723 carbon free-radicals Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 208000014439 complex regional pain syndrome type 2 Diseases 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
- 239000012043 crude product Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([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
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- DKWOHBPRFZIUQL-UHFFFAOYSA-N dimethyl-methylidene-oxo-$l^{6}-sulfane Chemical compound C[S+](C)([CH2-])=O DKWOHBPRFZIUQL-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000022602 disease susceptibility Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 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
- 210000003414 extremity Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 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
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical compound OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-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
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 238000013198 immunometric assay Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 210000001503 joint Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 238000011542 limb amputation Methods 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- WJHHIVYNOVTVGY-UHFFFAOYSA-N methyl 3h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1=CC=C2N=CNC2=C1 WJHHIVYNOVTVGY-UHFFFAOYSA-N 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- PRBQFNMIHZUNRQ-UHFFFAOYSA-N methyl 5-amino-3-fluoro-2-(2-fluoro-4-iodoanilino)-4-(prop-2-enylamino)benzoate Chemical compound COC(=O)C1=CC(N)=C(NCC=C)C(F)=C1NC1=CC=C(I)C=C1F PRBQFNMIHZUNRQ-UHFFFAOYSA-N 0.000 description 1
- AOYFCRGTMOHTJJ-UHFFFAOYSA-N methyl 5-fluoro-6-(4-iodo-2-methylanilino)-3-methyl-2h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1(F)C=C2N(C)CN=C2C=C1NC1=CC=C(I)C=C1C AOYFCRGTMOHTJJ-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000003040 nociceptive effect Effects 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
- 230000000269 nucleophilic 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
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- CQDAMYNQINDRQC-UHFFFAOYSA-N oxatriazole Chemical class C1=NN=NO1 CQDAMYNQINDRQC-UHFFFAOYSA-N 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
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 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
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- LBKJNHPKYFYCLL-UHFFFAOYSA-N potassium;trimethyl(oxido)silane Chemical compound [K+].C[Si](C)(C)[O-] LBKJNHPKYFYCLL-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 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
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical class CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- MZIYQMVHASXABC-UHFFFAOYSA-N tetrakis(ethenyl)stannane Chemical compound C=C[Sn](C=C)(C=C)C=C MZIYQMVHASXABC-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl 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
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 230000005641 tunneling Effects 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
- 208000009852 uremia Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- HOFQVRTUGATRFI-XQKSVPLYSA-N vinblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 HOFQVRTUGATRFI-XQKSVPLYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- FKBHRUQOROFRGD-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2[C]3C=CC=CC3=NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC FKBHRUQOROFRGD-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- N-METHYL-SUBSTITUTED BENZAMIDAZOLES Field of the Invention relates to N-methyl-substituted benzamidazole derivatives, pharmaceutical compositions and methods of use thereof.
- MAPK/ERK Kinase (“MEK”) enzymes are dual specificity kinases 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 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 in genes encoding the protein known as
- Ras a G-protein that is activated when bound to GTP, and inactivated when bound to GDP.
- This signal is an absolute prerequisite for proliferation in most 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 active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., ME ⁇ and MEK.) which then activates the MAP kinase, ERK (ERK 1 and ERK.).
- MAP kinase 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 a dominant negative Raf-i protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.
- Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism.
- Raf and other kinases phosphorylate MEK on two closely 218 222 adjacent serine residues, S and S in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase.
- MEK in turn phosphorylates MAP kinase on both a tyrosine, 185 183
- MAP kinase a threonine residue
- Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein.
- target protein such as a kinase, a transcription factor, or another cellular protein.
- other kinases activate MEK, and MEK itself appears to be a signal integrating kinase.
- MEK is highly specific for the phosphorylation of MAP kinase.
- 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 may require a prior strong interaction between the two proteins.
- the present invention provides a compound of Formula
- Q is -0-R 3 , -NH 2 , -NH[(CH 2 ) k CH 3 ], or -NH[0(CH.) k CH_], wherein the -NH. is optionally substituted with 1 and 2 substituents independently selected from methyl and -NR 9 R 9a , and the -(CH.) k CH 3 moieties of the -NH[(CH_) k CH_], and -NH[0(CH 2 ) k CH 3 ] groups are optionally substituted with 1 and 3 substituents independently selected from -OH, -NR 9 R 9a , C 1 _.
- Z is -NH., -NH[(CH.) k CH 3 ], or -NH[0(CH 2 ) k CH 3 ], wherein the -NH.
- Ri is hydrogen, C r6 alkyl, C alkenyl, C alkynyl, C _C 12 cycloalkyl, -(CR ⁇ oR ⁇ )q(C 6 -C ⁇ o aryl), or -(CR ⁇ 0 Rn) q (4-10 membered heterocyclic); wherein said Ri is optionally substituted with 1 to 3 substituents selected from the group consisting of -COOH, -COOR ⁇ , -COR 9 , -(CR ⁇ 0 R ⁇ )q(C 6 -C 10 aryl), -(CR
- R 4 is bromine, chlorine, fluorine, iodine, C r6 alkyl, C 2 . 4 alkenyl, C 2 __ alkynyl, C ⁇ _ cycloalkyl, -(CH_)-C__.
- alkyl R. is hydrogen or fluorine; R- and R. are each independently hydrogen, methyl, or ethyl; Rg and R 9a are each independently hydrogen or C . alkyl; k is 0 to 3; m is 1 to 4; n is 1 to 2; p is 0 to 2; t is 0 to 1 ; v is 1 to 5; and pharmaceutically acceptable salts, C 1 _. amides and C ⁇ . esters thereof.
- An embodiment of the present invention provide a compound of formula I, as defined above, and pharmaceutically acceptable salts thereof. Additionally, the present invention also provides compounds of formula (I); wherein W is -COOH.
- the present invention also provides compounds of formula (I); wherein W is -CO-Q; wherein Q is -0-R 3 , -NH 2 , -NHR 1Q , -NR ⁇ R ⁇ , wherein the -NH 2 is optionally substituted with 1 and 2 substituents independently selected from methyl and amino, and the -0-R 3
- R moieties are optionally substituted with 1 and 3 substituents independently selected from -OH, C _ alkyl, and C ⁇ _ cycloalkyl.
- the present invention also provides compounds of Formula I wherein R 1 is methyl; R 1 is methyl substituted with -COOH; R, is fluorine; R. is iodine, C , alkyl, C-_. alkenyl, C-_, alkynyl, or -S-CH 3 ; R 4 is iodine; R 4 is ethyl, ethenyl, acetylene or -S-CH 3 ; R 4 is iodine, ethyl, or acetylene; or R. is fluorine.
- the present invention provides a method of preparing a compound or a salt of formula (I):
- the present invention provides a method of preparing a compound or a salt of formula (I), wherein W is -CO-Q; and Q is -0-R 3 , -NH 2 , -NHR 10 , -NR R , wherein the -NH 2 is optionally substituted with 1 and 2 substituents independently selected from methyl and amino, and the -0-R 3j R 1Q and R ⁇ moieties are optionally substituted with 1 and 3 substituents independently selected from -OH, C alkyl, and C ⁇ .
- the present invention provides a method of preparing a compound or a salt of formula (I), wherein W is -CO-Q; and Q is -NR.-R ⁇ (j e _ compounds of formula la):
- the present invention provides a method of preparing said compound or a salt of formula (I) further comprising the step of preparing said compound of formula (II); comprising: (b) treating a compound of formula (IV): wherein R 1 f R 2 , R 4 , and R 5 are as described above; with a compound of formula C ⁇ F 5 OH in the presence of a coupling agent in a solvent.
- the coupling agent is DCC.
- the present invention provides a method of preparing said compound or a salt of formula (II) further comprising the step of preparing said compound of formula (IV); comprising: (c) treating a compound of formula (V):
- R R 2 , R 4 , and R 5 are as described above; and R 15 is -0-R 3 , -NH 2 , -NH[(CH 2 ) k CH 3 ], or -NH[0(CH.) k CH_], wherein the -NH 2 is optionally substituted with 1 and 2 substituents independently selected from methyl and -NR 9 R 9a , and the -(CH 2 ) k CH 3 moieties of the -NH[(CH 2 ) k CH 3 ], and -NH[0(CH.) CH 3 ] groups are optionally substituted with 1 and 3 substituents independently selected from -OH, -NRgRg a , C alkyl, and C 3 _C 12 cycloalkyl; wherein Rg, Rg a , and k are as described above; with a hydrolyzing agent in a solvent.
- the hydrolizing agent is potassium t methyl silanote.
- R 15 is -O-R 3 , wherein R 3 is C - alkyl; such as methyl.
- the present invention provides a method of preparing said compound or a salt of formula (IV) further comprising the step of preparing said compound of formula (V); comprising: (d) treating a compound of formula (VI): wherein R ⁇ R 2 , R , R5, and R 15 are as described above; R 8 is selected from the group consisting of C g alkyl, C._. alkenyl, C 2 - 6 alkynyl,
- Lg is a leaving group selected from the group consisting of halo, sulfate esters, sulfonate esters, tetrafluoroborate and hexafluorophosphate; each q is 0 to 5
- R 15 is - O-R 3 , wherein R 3 is C alkyl; such as methyl.
- the present invention provides a method of preparing said compound or a salt of formula (IV) further comprising the step of preparing said compound of formula (VI); comprising: (e) treating a compound of formula (VII):
- R , R , R5, Re, and R 15 are as described in compound of formula (VI); with a suitable alkylating agent; in a solvent.
- said suitable alkylating agent is C h alky! tosylate, such as methyl tosylate; or d. 6 alkyl triflate, such as methyl triflate.
- said suitable alkylating agent is C h alky! halide; such as methyl iodide.
- said suitable alkylating agent is trimethyloxonium tetrafluoroborate.
- R 15 is -0-R 3 , wherein R 3 is C r6 alkyl; such as methyl.
- the present invention provides a method of preparing said compound or a salt of formula (VI), further comprising the step of preparing said compound of formula (VII); comprising: (f) treating a compound of formula (VIM):
- R 15 is -O-R 3 , wherein R 3 is C alkyl; such as methyl.
- the present invention provides a method of preparing said compound or a salt of formula (VII), further comprising the step of preparing said compound of formula (VIII); comprising: (g) treating a compound of formula (IX):
- R 15 is -0-R 3 , wherein R 3 is C r . alkyl; such as methyl.
- the present invention provides a method of preparing said compound or a salt of formula (VIII), further comprising the step of preparing said compound of formula (IX); comprising: (h) treating a compound of formula (X):
- R 2 , R , Rs, and R15 are as described above; with a compound of formula R 8 -NH 2 , wherein R 8 is as described above; in a solvent.
- said compound of formula R 8 -NH 2 is 2-hydroxyethylamine or 4- methoxybenzylamine.
- R 15 is -O- R 3 , wherein R 3 is C 6 alkyl; such as methyl.
- the present invention provides a method of preparing said compound or a salt of formula (IX), further comprising the step of preparing said compound of formula (X); comprising: (i) treating a compound of formula (XI):
- a suitable esterificating agent includes a combination of a halogenating agent, such as SOCI 2 , and a suitable alcohol, such as H-0-R 3 .
- a suitable esterificating agent includes a combination of a catalytic acid, such as catalytic HCl, and a suitable alcohol, such as H-O-R 3 .
- a suitable amidating agent includes includes a combination of a halogenating agent, such as SOCI , and a suitable amine, such as -NH 2 , -NH[(CH 2 ) k CH 3 ], or -NH[0(CH.) k CH.].
- a method of preparing said compound or a salt of formula (X) comprising: (j) treating a compound of formula (XII):
- the present invention provides a method of preparing said compound or a salt of formula (XI), further comprising the step of preparing said compound of formula (XII); comprising: (k) treating a compound of formula (XIV):
- R 5 is as described above; with a nitro-producing agent in a solvent.
- said nitro-producing agent is HCI/H 2 S0 4 .
- the present invention provides a compound of formula (VI):
- the invention also provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. Additionally, the invention provides a method of treating a proliferative disease in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I.
- the invention provides methods of treating cancer, restenosis, psoriasis, autoimmune disease, atherosclerosis, osteoarthritis, rheumatoid arthritis, heart failure, chronic pain, and neuropathic pain in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I.
- the invention provides a method for treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I in combination with radiation therapy or at least one chemotherapeutic agent.
- the invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of the disease states or diseases provided above. Detailed Description of the Invention Certain terms are defined below and by their usage throughout this disclosure.
- halogen or “halo” in the present invention refer to a fluorine, bromine, chlorine, and iodine atom or fluoro, bromo, chloro, and iodo.
- fluorine and fluoro for example, are understood to be equivalent herein.
- Alkyl groups such as “C r _ alkyl”, include aliphatic chains (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures.
- C r6 alkyl includes within its definition the terms
- C r4 alkyl and “C r2 alkyl”.
- alkoxy refers to a straight or branched alkyl chain attached to an oxygen atom.
- C ⁇ alkoxy refers to a straight or branched alkyl chain having from one to eight carbon atoms attached to an oxygen atom. Typical alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
- C ⁇ _ 8 alkoxy includes within its definition the terms “C alkoxy” and "C r4 alkoxy”.
- Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be e ⁇ tadel (E), or sixteen (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 bonds, respectively, or a mixture thereof. Like alkyl groups, unsaturated groups may be straight chain or branched.
- alkenyls and alkynyls examples include vinyl, allyl, 2 -methyl-2-propenyl, cis-2- butenyl, trans-2-butenyl, and acetyl.
- Cycloalkyl groups such as C ⁇ . cycloalkyl, refer to a saturated hydrocarbon ring structure containing from 3 to 6 atoms. Typical C ⁇ . cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- aryl means an unsubstituted aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic (e.g., 1 ,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
- Heterocyclic radicals which include but are not limited to heteroaryls, include: furyl,
- heterocyclic radicals include thienyl, piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, octahydrobenzofuranyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.
- heteroaryl includes monocyclic aromatic heterocycles containing five or six ring members, of which from 1 to 4 can be heteroatoms selected, independently, from N, S and O, and bicyclic aromatic heterocycles containing from eight to twelve ring members, of which from 1 to 4 can be heteroatoms selected, independently, from N, S and O.
- the present invention includes the hydrates and the pharmaceutically acceptable salts and solvates of the compounds defined by Formula I.
- the compounds of this invention can possess a sufficiently basic functional group, and accordingly react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
- pharmaceutically acceptable salt refers to salts of the compounds of Formula I which are substantially non-toxic to living organisms.
- Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
- Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 1955;66:2-19, which are known to the skilled artisan.
- Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
- organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and
- Example of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, hydrobromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, glucuronate, glutamate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymateate, mandelate, mesylate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, stearate, phthalate,
- a preferred pharmaceutically acceptable salt is hydrochloride. It should be recognized that the particular counterion forming a part of any salt of this inventions is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
- the enantiomers of compounds of the present invention can be resolved by one of ordinary skill in the art using standard techniques well-known in the art, such as those described by J. Jacques, et al., “Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc 1981. Examples of resolutions include recrystallization techniques or chiral chromatography.
- the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
- the compounds of Formula I can be prepared by techniques and procedures readily available to one of ordinary skill in the art, for example by following the procedures as set forth in the following Schemes, or analogous variants thereof. These synthetic strategies are further exemplified in examples below. These schemes are not intended to limit the scope of the invention in any way.
- Scheme 1 provides syntheses of the compounds of Formula I.
- R 10 and Rn are indepentely hydrogen, amino, alkyl, substituted alkyl, alkoxy or substituted alkoxy.
- Step A a suitable benzoic acid derivative (1) is converted to the nitrobenzoic acid derivative (3) by a procedure known to one of skill in the art.
- Step B the 2-(arylamino)-5- ⁇ itrobenzoic acid derivative (4) is prepared from the coupling of the nitrobenzoic acid derivative (3) and a suitable aniline (2) in the presence of a strong base, for example, lithium bis(thmethylsilyl)amide (LiHMDS) or lithium diisopropylamide, in a polar aprotic solvent such as tetrahydrofuran, acetonitrile or dimethylformamide.
- a strong base for example, lithium bis(thmethylsilyl)amide (LiHMDS) or lithium diisopropylamide
- a polar aprotic solvent such as tetrahydrofuran, acetonitrile or dimethylformamide.
- the aniline (2) and the nitrobenzoic acid (3) are dissolved in a suitable organic solvent and cooled to about -58°C under nitrogen.
- the suspension is treated with an excess of a suitable base, such as the lithium base, LiHMDS, and allowed to warm to room temperature.
- the reaction is typically complete within about 2 hours to about 5 days.
- the resulting nitrobenzoic acid derivative (4) can be isolated by removing the solvent, for example by evaporation under reduced pressure or by filtering the precipitated solid through Celite® and washing with a suitable solvent.
- the nitrobenzoic acid derivative (4) can be further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
- Step C the nitrobenzoic acid derivative (4) is converted to the methyl ester derivative (5) by a procedure generally known in the art.
- the nitrobenzoic acid derivative (4) in a suitable solvent is treated with sodium bicarbonate followed by a dimethylsulfate.
- Step D a suitable amine, such as allylamine was added to the methyl ester derivative (5) in a suitable solvent system such as, methanol, THF and water, to provide the alkynyl-amino methyl ester derivative (6).
- Step E the nitro substituent of the alkenyl-amino methyl ester derivative (6) was converted to the corresponding amine (5) according to a procedure known in the art.
- the nitro methyl ester derivative (6) is treated with ammonium chloride in a mixture of a suitable solvent, such as methanol, and dioxane. Iron powder is added under nitrogen and the entire mixture is refluxed to provide the amine (5).
- Step F the benzamidazole (8) is formed from the amine (5).
- the amine (5) in a suitable solvent, such as methanol is treated with formamidine acetate and refluxed under nitrogen to provide the benzamidazole (8).
- Step G benzamidazole (8) is converted to a substituted benzamidazole (9) by treating the benzamidazole (8) with iodomethane in a suitable solvent, such as acetonitrile.
- Step H substituted benzamidazole (9) is deprotected to provide the compound (10).
- Step I compound (10) is treated with potassium trimethyl silanolate in a solvent, such as THF/water.
- a compound (11) is reacted with an active ester, in the presence of a base, if necessary, to produce an activated compound (12).
- Preferred active esters include pentafluorophenyl trifluoroacetate and preferred bases include diisopropylethylamine, triethylamine, 4-methylmorpholine, pyridine or a substituted pyridine, for example, 4-dimethylaminopyridine or 2,6-dimethylpyridine.
- Preferred solvents are polar aprotic solvents such as dichloromethane, tetrahydrofuran, dimethylformamide, or N,N- dimethylacetamide.
- the compounds of formula I are generally obtained by the union of a compound (12) with amine or alkoxylamine in the presence of a base, if necessary.
- Preferred bases include diisopropylethylamine, triethylamine, 4-methylmorpholine, pyridine or a substituted pyridine, for example, 4-dimethylaminopyridine or 2,6-dimethylpyridine.
- Preferred solvents are polar aprotic solvents such as dichloromethane, tetrahydrofuran, dimethylformamide, or ⁇ /, ⁇ /-dimethylacetamide.
- the reactions are generally carried out at a temperature between about -58 °C to about 25 °C, and are normally complete within about 1 hour to about 5 days.
- the product amide can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
- Step A an acyl hydrazide of formula Ie is converted to an oxadiazolinone of formula Id.
- a preferred reagent is carbonyldiimidazole in polar aprotic solvents such as dimethylformamide.
- Step B compound (15) is obtained by the union of oxadiazolinone (Id) with an alkyl amine or substituted alkylamine.
- Preferred solvents for this transformation include pyridine, isopropanol and ethanol at temperatures between 80 °C and 120°C. Reactions are generally complete between 1 h and 5 days.
- step C the urea (15) is subjected to conditions of cyclodehydration to afford oxazdiazoles for formula If.
- Preferred conditions for this transformation are the combination of carbon tetrachloride and triphenyphosphine (or polymer-supported triphenylphoshine) and a base such as triethylamine.
- Preferred solvents for this transformation include dichloromethane or 1 ,2-dichloroethane at temperatures between 35 °C and 100 °C.
- hydroxyl or amino substituents on the R 10 alkyl chain may be chemically protected, if necessary, using protecting groups familiar to those skilled in the art. Accordingly, a protection/deprotection sequence, if necessary, is implicit in Step C.
- preferred protecting groups include silyl ethers, for example tert- butyldimethylsilyl ethers, tiethylsilyl ethers, or triisopropylsilyl ethers.
- silyl ethers are chemically removed using fluoride.
- Preferred reagents for this deprotection include tetrabutylamonium floride or cesium fluoride.
- R 4 is halogen
- R 4 is not halogen
- the compounds of formula I, wherein R4 is not halogen are prepared from the compounds of formula I wherein R 4 is halogen, by transition metal-promoted coupling with reagent M-R 4 wherein R 4 is non-halogen (12) in a suitable solvent or solvents such as triethylamine, tetrahydrofuran or dimethylformamide.
- the transition metal-promoted coupling may be carried out with a palladium(O) or palladium (II) coupling agent, such as
- M is defined as a functional group known to transfer a carbon radical fragment in transition metal-promoted coupling processes.
- a suitable M group include trialkylstannyl, trialkylsilyl, trimethylsilyl, zinc, tin, copper, boron, magnesium and lithium.
- Preferred halogens when R 4 is halogen, are bromine and iodine.
- the resulting compound of formula I, as well as the protected Formula I compound can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation. It would be understood by * one of skill in the art that the substituent R 4 token, when R 4 relieve is non-halogen, may be further transformed, such as by oxidation, reduction, deprotection, or hydrogenation.
- a compound wherein R 4 is C 2 _ 4 alkenyl may be transformed to a compound wherein
- R 4 is -OH-substituted alkyl by treating the double bond of the alkene with ozone and NaBH 4 .
- a compound wherein R 4 is C 2 _ 4 alkenyl may be transformed to a compound wherein R 4 is alkyl substituted with 2 -OH substituents by treating the double bond of the alkene with OsOont.
- a compound wherein R 4 is an alkene or alkyne derivative may be reduced under conditions known in the art, such as through hydrogenation, such as with Pd/C under an atmosphere of hydrogen.
- the alkyne derivative is dissolved in a suitable solvent, such as absolute ethanol, in the presence of a metal catalyst, such as palladium on carbon. This mixture is stirred under an atmosphere of hydrogen from about 1 to 24 hours at room temperature to provide the fully saturated derivative.
- the alkyne derivative is partially reduced via hydrogenation to provide the alkene derivative.
- the alkyne derivative is dissolved in a suitable solvent, such as tetrahydrofuran, in the presence of a catalyst, such as Lindlar catalyst or palladium on carbon and, if desired, a suitable compound which disrupts the actions of the catalyst, such as quinoline or pyridine.
- a catalyst such as Lindlar catalyst or palladium on carbon
- a suitable compound which disrupts the actions of the catalyst such as quinoline or pyridine.
- This mixture is stirred under an atmosphere of hydrogen from about 1 to 24 hours at room temperature to provide the alkene derivative.
- the substituent R 4 may also be transformed into a different R 4 through standard synthetic procedures known to one of skill in the art.
- R 4 may be transformed before the coupling of the ester (1) and aniline (2) as shown in Scheme 1 , Step A. Further transformations of R 4 ho are shown in Scheme 5 below.
- step A the compound of formula lg is dissolved in a suitable solvent such as tetrahydrofuran and reacted with methanesulfonyl chloride to give the intermediate mesylate, then Nal in EtOAc to give the iodide compound (13).
- step B the iodide compound (13) is reacted with a suitable amine, such as methylamine or dimethylamine, or a suitable alkoxide to give compounds of formula Ih.
- a suitable amine such as methylamine or dimethylamine
- an aniline (2) may be prepared to include the desired R4.
- aniline (2) can be prepared by techniques and procedures readily available to one of ordinary skill in the art and by following the procedures as set forth in the following Schemes, or analogous variants thereof. Additionally, anilines (2) are taught in USSN 10/349,801 filed January 23, 2003 and USSN 10/349,826 filed January 23, 2003, the disclosure of which is hereby incorporated by reference. These Schemes are not intended to limit the scope of the invention in any way.
- Step A a suitable amine or alkoxide (14) is reacted with a 4-terf- butoxycarbonylamino-3-substituted-benzyl bromide (13), such as 4-fert-butoxycarbonylamino- 3-fluorobenzyl bromide (J. Med. Chem., 2000/43:5015).
- Step B the BOC protecting group of compound of structure (15) is hydrolized with, for example, TFA, to provide the desired aniline (2a).
- Step A a suitable 3-substituted-4-nitrophenol (16), such as 3-fluoro-4- nitrophenol, is alkylated with a compound of structure (15) in the presence of a suitable base to provide a compound of structure (18).
- Step B compound (18) is reduced via hydrogenation in the presence of a metal catalyst, such as palladium on carbon, in an atmosphere of hydrogen to provide the desired aniline (2b).
- a metal catalyst such as palladium on carbon
- a suitable 4-(aminophenyl)thiocyanate (19) is alkylated with a compound of structure (15') in the presence of a suitable nucleophilic base to provide an alkylthio compound of structure (2c).
- this compound is then oxidized to the corresponding sulfonyl compound, also generally, the diphenylamine (3), wherein R 4 is -SO.-(alkyl) .
- the desired aniline (2e) wherein R2 is methyl, fluorine or chlorine, using compound (21) as the starting material can be prepared.
- R2 is fluorine
- the sulfonyl chloride derivative (21) is a compound known in the literature (German Patent DE 2630060, 1958).
- the sulfonyl chloride derivative (21) is also known in the literature (German Patent. DE 2550150, 1958).
- the sulfonyl chloride derivative (21) where R2 is chlorine is commercially available.
- acetylating anilines For example, heating the aniline and acetic anhydride together in a suitable solvent, such as acetic acid, would achieve the same result.
- Compounds of the present invention also include, but are not limited to the following compounds: Compound Structure Number
- Compounds of the present invention also include, but are not limited to the following compounds:
- compounds of the present invention also include
- compounds of the present invention also include and a pharmaceutically acceptable salt thereof. In another embodiment, compounds of the present invention also include
- compounds of the present invention also include
- compounds of the present invention also include
- compounds of the present invention also include
- compounds of the present invention also include;
- compounds of the present invention also include
- compounds of the present invention also include;
- compounds of the present invention also include;
- the term "patient” refers to any warm-blooded animal such as, but not limited to, a human, horse, dog, guinea pig, or mouse. Preferably, the patient is human.
- treating for purposes of the present invention refers to treatment, prophylaxis or prevention, amelioration or elimination of a named condition once the condition has been established.
- Selective MEK 1 or MEK 2 inhibitors are those compounds which 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.
- a selective MEK 1 or MEK 2 inhibitor has an IC50 for MEK 1 or MEK 2 that is at least one- fiftieth (1/50) that of its ICsg for one of the above-named other enzymes.
- a selective inhibitor has an IC50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC50 or one or more of the above-named enzymes.
- the disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the MEK cascade.
- the invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis.
- Other aspects of the invention include methods for treating MEK-related (including ras-related) cancers, whether solid or hematopoietic.
- cancers include brain, breast, lung, such as non-small cell lung, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer.
- Further aspects of the invention include methods for treating or reducing the symptoms of xenograft (cell(s), skin, limb, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy), hepatomegaly, cardiomegaly, stroke (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma, Alzheimer's disease, and chronic or neuropathic pain.
- xenograft cell(s), skin, limb, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy),
- Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV).
- B hepatitis virus
- HPV human papilloma virus
- CMV cytomegalovirus
- EBV Epstein-Barr virus
- chronic pain for purposes of the present invention includes, but is not limited to, neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.
- Chronic pain is associated with numerous conditions including, but not limited to, inflammation, arthritis, and post-operative pain.
- the term "neuropathic pain” is associated with numerous conditions which include, but are not limited to, inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, arthritis pain, and nerve injury between the peripheral nervous system and the central nervous system.
- the invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid.
- mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine.
- Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1 H,3H)- pyrimidinedione (5FU), flutamide, and gemcitabine.
- the chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.
- an effective amount or a therapeutically-effective amount will be between about 0.1 and about 1000 mg/kg per day, preferably between about 1 and about 300 mg/kg body weight, and daily dosages will be between about 10 and about 5000 mg for an adult subject of normal weight.
- Commercially available capsules or other formulations such as liquids and film-coated tablets) of 100, 200, 300, or 400 mg can be administered according to the disclosed methods.
- compositions of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
- the active ingredient such as a compound of Formula I
- the carrier or diluted by a carrier or enclosed within a carrier.
- Dosage unit forms or pharmaceutical compositions 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 be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.
- Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracistemal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
- Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof.
- carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate.
- 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, 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.
- adjuvants such as preserving, wetting, 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
- absorption-enhancing agents such as aluminum monostearate and gelatin.
- HN0 3 Fuming HN0 3 was added dropwise to the cold (5 to -10° C) cone.
- H 2 S0 (5L) and stirred in a three-necked round bottom flask (20L), maintaining the temperature between 5 to - 10° C.
- 2 , 3 e-trifluorobenzoic acid (1 kg, 5.6 mol) in portions, maintaining the temperature at 5o C and after completion of the addition the reaction mixture was allowed to warm to room temperature, stirred for 2h and (the suspension becomes light yellow solution) then poured into 30 kg of crushed ice.
- Step B Preparation of the 3.4-difluoro-2-(2-fluoro-4-iodo-phenylaminoV5-nitro-benzoic acid
- reaction mixture A A stirred solution of 2,3,4-trifluoro-5-nitrobenzoic acid (400 g, 1.9 mol) in dry THF (6L) under nitrogen was cooled to -58° C and a solution of 2.0 L 1.0 M LiHMDS (1.0M, 2L, 2.0 mol) was added dropwise at -58° C.
- This reaction mixture (yellow solution turned into yellow orange suspension) was designated as reaction mixture A.
- 2-fluoro-4-iodoaniline (400g, 1.0 mol) in THF (4L) was cooled to -58° C under nitrogen and a solution LiHMDS (1.0M, 3.65L, 3.6 mol) was added dropwise at -58° C (the yellow solution turned into a white suspension).
- reaction mixture B This reaction mixture was designated as mixture B. Both the reaction mixtures A and B were stirred for 45 min., maintaining the temperature at -58° C and mixture A was transferred into reaction mixture B by a ca ⁇ nula. The resulting orange suspension was stirred for 1 h at -58° C, then allowed to warm-up to room temperature and stirred overnight under nitrogen. The reaction mixture was cooled to -10° C and adjusted to pH 1 by bubbling HCl gas. The white solid separated was filtered through a short bed of Celite®, washed with THF (3L) and the filtrate (brown) was evaporated under vacuum. The residue (yellow orange solid) obtained was triturated with 10% aq.
- Step C Preparation of 3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid methyl ester
- Step D Preparation of 4-allylamino-3-fluoro-2-(2-fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid methyl ester
- Step E Preparation of 4-allylamino-5-amino-3-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzoic acid methyl ester
- reaction mixture was refluxed for 16 h (completion of reaction is confirmed by TLC - EtOA ⁇ Hexane/ 3:5) and poured onto a mixture of 10 kg of crushed ice and 6.5L of saturated sodium bicarbonate. To the mixture was added 1 kg of Celite®, stirred and the thick suspension was filtered through a Celite®bed. The Celite® bed was rinsed with water, then with ethyl acetate and ethyl acetate layer was separated.
- Step F Preparation of 1-allyl-5-fluoro-6-.2-fluoro-4-iodo-phenylamino 1 H-benzoimidazole-5- carboxylic acid methyl ester
- Step G Preparation of 3-Allyl-4-fluoro-5-(2-fluoro-4-iodo-phenylamino 6-methoxycarbonyl-1- methyl-3H-benzoimidazol-1-ium iodide
- Step H Preparation of 5-fluoro-6- ( 2-fluoro-4-iodo-phenylamino)-3-methyl-3H- benzoimidazole-5-carboxylic acid methyl ester
- reaction mixture was stirred for 2 h at room temperature (completion of reaction is confirmed by TLC -DCM:MeOH 9:1) and evaporated under vacuum. The residue was partitioned between DCM (1.5L) and 1N HCl (1.5L) and the organic layer was separated.
- Step I Preparation of 5-fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole- 5-carboxylic acid
- Step J Preparation of 5-fluoro-6-(2-fluoro-4-iodo-phenylamino 3-methyl-3H-benzoimidazole- 5-carboxylic acid pentafluorophenyl ester
- Step K Preparation of 5-fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H- benzoimidazole-5-carboxylic acid .2--OH-ethoxy)-amide
- 2-(aminooxy)ethan-1-ol 25.31 g, 0.354 mol
- Step A Preparation of 5-Fluoro-6-(2-fluoro-4-vinyl-phenylamino)-3-methyl-3H- benzoimidazole-5-carboxylic acid methyl ester
- reaction mixture was allowed to cool to ambient temperature and was filtered through a pad of Celite and washed with ethyl acetate (255 mL).
- Aqueous potassium fluoride (1M, 50 mL) was added to the filtrate and the biphasic mixture was shaken.
- the resultant precipitate was removed by filtration and the organics were further washed with aqueous potassium fluoride (1 M, 50 mL), water (2 x 100 mL), and saturated brine (100 mL).
- the solution was dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel.
- Step B Preparation of 6- ⁇ 4-Ethyl-2-fluoro-phenylamino)-5-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid methyl ester
- Step C Preparation of 6-(4-Ethyl-2-fluoro-phenylamino)-5-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid amide
- Step A Preparation of 1-Allyl-5-fluoro-6-(4-iodo-2-methyl-phenylamino) 1 /-/-benzoitnidazole- 5-carboxylic acid methyl ester
- step A can be prepared by the sequence of example 1 , steps A-F using 4- iodo-2-methylaniline. Alternately, the compound can be prepared by the modified sequence shown below.
- B-1 TMSCHN TMSCHN
- Step B Preparation of 3-Allyl-4-fluoro-5-(4-iodo-2-methyl-phenylamino)-6-methoxycarbonyl- 1-methyl-3H-benzoimidazol-1-ium iodide
- Step C Preparation of 5-Fluoro-6-(4-iodo-2-methyl-phenylamino 3-methyl-3H- benzoimidazole-5-carboxylic acid methyl ester Deprotection of 3-allyl-4-fluoro-5-(4-iodo-2-methylanilino)-6-(methoxycarbonyl)-1 -methyl-3/-/- benzimidazol-1-ium iodide was performed in a fashion analogous with example 1 step H to give the title compound in 88% yield, mp. 235-235°C.
- Step A Preparation of 5-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1-(4-methoxy-benzyl)-1H- benzoimidazole-5-carboxylic acid methyl ester
- step A can be prepared by the sequence of example 1, steps A-F using 4- methoxybenzylamine in place of allylamine
- the compound can be prepared by the modified sequence shown below
- Step B Preparation of 4-Fluoro-5-(4- ⁇ odo-2-methyl-phenylam ⁇ no)-3-(4-methoxy-benzyl)-6- methoxycarbonyl-1-methyl-3 --benzo ⁇ m ⁇ dazol-1- ⁇ um iodide
- Step C Preparation of 5-Fluoro-6-.4-iodo-2-methyl-phenylamino)-3-methyl-3H- benzoimidazole-5-carboxylic acid methyl ester
- Procedure C Via intermediates containing CH 2 CH 2 CN.
- MEK inhibitors were evaluated by determining their ability to inhibit phosphorylation of MAP kinase (ERK) in murine colon 26 (C26) carcinoma cells. Since ERK1 and ERK2 represent the only known substrates for MEKIand MEK2, the measurement of inhibition of ERK phosphorylation in cells provides direct read out of cellular MEK inhibition by the compounds of the invention. Detection of phosphorylation of ERK was carried out either by Western blot or ELISA format.
- the assays involve treatment of exponentially growing C26 cells with varying concentrations of the test compound (or vehicle control) for one hour at 35° C.
- test compound or vehicle control
- Western blot assay cells were rinsed free of compound/vehicle and lysed in a solution containing 50 mM NaCI, 50 mM glycerol phosphate, 10 mM HEPES, pH 5.4, 1% Triton X-100, 1 mM Na3V04, 100 ⁇ M PMSF, 10 ⁇ M leupeptin and 10 ⁇ M pepstatin.
- Supernatants were then subjected to gel electrophoresis and hybridized to a primary antibody recognizing dually phosphorylated ERK1 and ERK2.
- blots were subsequently 'stripped' and re-probed with a 1 :1 mixture of polyclonal antibodies recognizing unphosphorylated ERK1 and ERK2.
- pERK TiterZyme Enzyme immunometric Assay kits were acquired from Assay Designs, Inc (Ann Arbor, Ml). Briefly, cells were harvested in lysis solution containing 50mM ⁇ -glycerophosphate, 10mM HEPES, pH5.4, 50mM NaCI, 2mM EDTA and 1%SDS and protein lysates were diluted 1:15 with supplied Assay buffer prior to the execution of the assay. The subsequent steps were carried out essentially as recommended by the manufacturer.
- COMPOUND ID C26CPA1 C26ELSA 1 0.55 6 0.569 9 0.012 11 1 12 0.022 13 0.0034
- COMPOUND ID C26CPA1 C26ELSA 14 0.028 15 0.086 16 0.11 15 0.11 20 0.19 21 0.268 22 0.041 23 0.002 0.00842 24 0.556 25 0.122 26 0.15 28 0.566 30 0.0004 31 1 32 0.0019 34 0.022 35 0.00885 38 0.23 40 0.08 42 0.28
- Example 9 Carraqeenan-induced Footpad Edema (CFE) Rat Model Male outbred Wistar rats (135-150 g, Charles River Labs) are dosed orally with 10 mL kg vehicle or test compound 1 hour prior to administration of a sonicated suspension of carrageenan (1 mg/0.1 mL saline). Carrageenan is injected into the subplantar region of the right hind paw. Paw volume is determined by mercury plethysmography immediately after injection and again five hours after carrageenan injection. Percent inhibition of edema is determined, and the ID40 calculated by linear regression. Differences in swelling compared to control animals are assessed by a 1-way ANOVA, followed by Dunnett's test.
- CFE Carraqeenan-induced Footpad Edema
- Example 10 Collagen-Induced Arthritis in Mice
- Type II collagen-induced arthritis (CIA) in mice is an experimental model of arthritis that has a number of pathologic, immunologic, and genetic features in common with rheumatoid arthritis.
- the disease is induced by immunization of DBA/1 mice with 100 ⁇ g type II collagen, which is a major component of joint cartilage, delivered intradermally in Freund's complete adjuvant.
- the disease susceptibility is regulated by the class II MHC gene locus, which is analogous to the association of rheumatoid arthritis with HLA-DR4.
- a progressive and inflammatory arthritis develops in the majority of mice immunized, characterized by paw width increases of up to 100%.
- a test compound is administered to mice in a range of amounts, such as 20, 60, 100, and 200 mg/kg body weight/day. The duration of the test can be several weeks to a few months, such as 40, 60, or 80 days.
- a clinical scoring index is used to assess disease progression from erythema and edema (stage 1), joint distortion (stage 2), to joint ankylosis (stage 3). The disease is variable in that it can affect one or all paws in an animal, resulting in a total possible score of 12 for each mouse. Histopathology of an arthritic joint reveals synovitis, pannus formation, and cartilage and bone erosions. All mouse strains that are susceptible to CIA are high antibody responders to type II collagen, and there is a marked cellular response to CM.
- Example 11 SCW-induced monoarticular arthritis Arthritis is induced as described by Schwab et al., Infection and Immunity, 1991 ;59:4436-4442 with minor modifications. Rats receive 6 ⁇ g sonicated SCW [in 10 ⁇ L Dulbecco's PBS (DPBS)] by an intraarticular injection into the right tibiotalar joint on Day 0. On Day 21 , the DTH is initiated with 100 ⁇ g of SCW (250 ⁇ L) administered IV. For oral compound studies, compounds are suspended in vehicle (0.5% hydroxypropyl- methylcellulose/0.2% Tween 80), sonicated, and administered twice daily (10 mlJkg volume) beginning 1 hour prior to reactivation with SCW. Compounds are administered in amounts between 10 and 500 mg/kg body weight/day, such as 20, 30, 60, 100, 200, and
- Edema measurements are obtained by determining the baseline volumes of the sensitized hindpaw before reactivation on Day 21, and comparing them with volumes at subsequent time points such as Day 22, 23, 24, and 25. Paw volume is determined by mercury plethysmography.
- Mouse ear-heart transplant model Fey T.A. et al. describe methods for transplanting split-heart neonatal cardiac grafts into the ear pinna of mice and rats (J. Pharm. and Toxic. Meth., 1998;39:9-15).
- Compounds are dissolved in solutions containing combinations of absolute ethanol, 0.2% hydroxypropyl methylcellulose in water, propylene glycol, cremophor, and dextrose, or other solvent or suspending vehicle.
- Mice are dosed orally or intraperitoneally once, twice or three times daily from the day of transplant (Day 0) through Day 13 or until grafts have been rejected.
- Rats are dosed once, twice, or three times daily from Day O through Day 13.
- Each animal is anesthetized and an incision is made at the base of the recipient ear, cutting only the dorsal epidermis and dermis.
- the incision is spread open and down to the cartilage parallel to the head, and sufficiently wide to accommodate the appropriate tunneling for a rat or insertion tool for a mouse.
- a neonatal mouse or rat pup less than 60 hours old is anesthetized and cervically dislocated.
- the heart is removed from the chest, rinsed with saline, bisected longitudinally with a scalpel, and rinsed with sterile saline.
- the donor heart fragment is placed into the preformed tunnel with the insertion tool and air or residual fluid is gently expressed from the tunnel with light pressure.
- Implants are examined at 10- to 20-fold magnification with a stereoscopic dissecting microscope without anesthesia. Recipients whose grafts are not visibly beating may be anesthetized and evaluated for the presence of electrical activity using Grass E-2 platinum subdermal pin microelectodes placed either in the pinna or directly into the graft and a tachograph. Implants can be examined 1 to 4 times a day for 10, 20, 30 or more days. The ability of a test compound to ameliorate symptoms of transplant rejection can be compared with a control compound such as cyclosporine, tacrolimus, or orally-administered lefluonomide.
- a control compound such as cyclosporine, tacrolimus, or orally-administered lefluonomide.
- Example 13 The analgesic activity of the compounds of the present invention is assessed by a test with rats. Rats weighing from 155 to 200 g are injected with carrageenan (2% in 0.9% sodium chloride aqueous solution, 100 ⁇ L injection volume) into the footpad of one hind limb. The rats are placed on a glass plate with illumination from a halogen lamp placed directly under the injected paw. The time (in seconds) from beginning illumination until the hindlimb was withdrawn from the glass was measured and scored as Paw Withdrawal Latency (PWL). Drug substances were given by oral gavage injection 2A hours after carrageenan injection to the footpad.
- PWL Paw Withdrawal Latency
- PWL was measured prior to carrageenan injection, just prior to drug injection, and 1 , 2 (and sometimes 3) hours after drug injection.
- Carrageenan a polysaccharide extracted from seaweed
- hyperalgesia Pain-related behavioral responses of greater intensity than expected
- This hyperalgesia is maximal 2 to 3 hours after injection.
- Treatment of rats with various analgesic drugs reduces hyperalgesia measured in this way and is a conventional test for detection of analgesic activity in rats.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA06000921A MXPA06000921A (en) | 2003-07-24 | 2004-07-12 | N-methyl-substituted benzamidzoles. |
EP04744015A EP1651214B1 (en) | 2003-07-24 | 2004-07-12 | Benzimidazole derivatives as mek inhibitors |
AT04744015T ATE442847T1 (en) | 2003-07-24 | 2004-07-12 | BENZIMIDAZOLE DERIVATIVES AS MEK INHIBITORS |
BRPI0412851-6A BRPI0412851A (en) | 2003-07-24 | 2004-07-12 | n-methyl-substituted benzamidazoles |
DE602004023207T DE602004023207D1 (en) | 2003-07-24 | 2004-07-12 | BENZIMIDAZOLE DERIVATIVES AS MEK INHIBITORS |
JP2006520928A JP4896717B2 (en) | 2003-07-24 | 2004-07-12 | N-methyl-substituted benzamidazole |
CA2532067A CA2532067C (en) | 2003-07-24 | 2004-07-12 | N-methyle-substituted benzamidazoles |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US49001203P | 2003-07-24 | 2003-07-24 | |
US60/490,012 | 2003-07-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005009975A2 true WO2005009975A2 (en) | 2005-02-03 |
WO2005009975A3 WO2005009975A3 (en) | 2005-04-07 |
Family
ID=34102957
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/002355 WO2005009975A2 (en) | 2003-07-24 | 2004-07-12 | Benzimidazole derivatives as mek inhibitors |
Country Status (10)
Country | Link |
---|---|
US (1) | US7160915B2 (en) |
EP (1) | EP1651214B1 (en) |
JP (1) | JP4896717B2 (en) |
AT (1) | ATE442847T1 (en) |
BR (1) | BRPI0412851A (en) |
CA (1) | CA2532067C (en) |
DE (1) | DE602004023207D1 (en) |
ES (1) | ES2331246T3 (en) |
MX (1) | MXPA06000921A (en) |
WO (1) | WO2005009975A2 (en) |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1663210A1 (en) * | 2003-08-29 | 2006-06-07 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as mek inhibitors |
WO2007025090A2 (en) * | 2005-08-25 | 2007-03-01 | Kalypsys, Inc. | Heterobicyclic and - tricyclic inhibitors of mapk/erk kinase |
EP1904481A2 (en) * | 2005-06-23 | 2008-04-02 | Array Biopharma, Inc. | Process for preparing benzimidazole compounds |
EP1904061A1 (en) * | 2005-06-23 | 2008-04-02 | Array Biopharma, Inc. | SNAr PROCESS FOR PREPARING BENZIMIDAZOLE COMPOUNDS |
WO2009021887A1 (en) * | 2007-08-16 | 2009-02-19 | F. Hoffmann-La Roche Ag | Substituted hydantoins |
WO2009037705A2 (en) * | 2007-09-20 | 2009-03-26 | Ramot At Tel Aviv University Ltd. | Esters of n-phenylanthranilic acid for use in the treatment of cancer and inflammation |
WO2010051933A2 (en) | 2008-11-10 | 2010-05-14 | Bayer Schering Pharma Aktiengesellschaft | Substituted sulphonamido phenoxybenzamides |
WO2010068738A1 (en) | 2008-12-10 | 2010-06-17 | Dana-Farber Cancer Institute, Inc. | Mek mutations conferring resistance to mek inhibitors |
US7803839B2 (en) | 2005-10-07 | 2010-09-28 | Exelixis, Inc. | Azetidines as MEK inhibitors for the treatment of proliferative diseases |
WO2010143733A1 (en) | 2009-06-09 | 2010-12-16 | Takeda Pharmaceutical Company Limited | Novel fused cyclic compound and use thereof |
WO2011047796A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Schering Pharma Aktiengesellschaft | Substituted halophenoxybenzamide derivatives |
WO2011047795A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Schering Pharma Aktiengesellschaft | Substituted benzosulphonamides |
WO2011047788A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Schering Pharma Aktiengesellschaft | Substituted benzosulphonamides |
US7973170B2 (en) | 2002-03-13 | 2011-07-05 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US7999006B2 (en) | 2006-12-14 | 2011-08-16 | Exelixis, Inc. | Methods of using MEK inhibitors |
WO2011106298A1 (en) | 2010-02-25 | 2011-09-01 | Dana-Farber Cancer Institute, Inc. | Braf mutations conferring resistance to braf inhibitors |
US8022057B2 (en) | 2007-11-12 | 2011-09-20 | Takeda Pharmaceutical Company Limited | MAPK/ERK kinase inhibitors |
US8030317B2 (en) | 2006-12-20 | 2011-10-04 | Takeda Pharmaceutical Company Limited | MAPK/ERK kinase inhibitors |
US8063085B2 (en) | 2007-12-20 | 2011-11-22 | Hoffmann-La Roche Inc. | Substituted hydantoins |
WO2012055953A1 (en) | 2010-10-29 | 2012-05-03 | Bayer Pharma Aktiengesellschaft | Substituted phenoxypyridines |
US8278357B2 (en) | 2002-10-21 | 2012-10-02 | Ramot At Tel-Aviv University Ltd. | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
US8283359B2 (en) | 2006-01-31 | 2012-10-09 | Ucb Pharma S.A. | Thieno-pyridine derivatives as MEK inhibitors |
US8350037B2 (en) | 2007-07-23 | 2013-01-08 | Ucb Pharma, S.A. | Thieno-pyridine derivatives as MEK inhibitors |
US8487101B2 (en) | 2008-01-21 | 2013-07-16 | Ucb Pharma S.A. | Thieno-pyridine derivatives as MEK inhibitors |
WO2013107283A1 (en) | 2012-01-17 | 2013-07-25 | Tianjin Binjiang Pharma, Inc. | Benzoheterocyclic compounds and use thereof |
WO2013169858A1 (en) | 2012-05-08 | 2013-11-14 | The Broad Institute, Inc. | Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy |
US8637491B2 (en) | 2008-06-19 | 2014-01-28 | Ucb Pharma S.A. | Thieno-pyridine derivatives as MEK inhibitors |
US8765815B2 (en) | 2007-09-20 | 2014-07-01 | Ramot At Tel-Aviv University Ltd. | N-phenyl anthranilic acid derivatives and uses thereof |
US11078540B2 (en) | 2010-03-09 | 2021-08-03 | Dana-Farber Cancer Institute, Inc. | Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy |
US11414396B2 (en) | 2012-10-12 | 2022-08-16 | Exelixis, Inc. | Process for making compounds for use in the treatment of cancer |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8101799B2 (en) * | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
RU2495028C2 (en) * | 2008-07-01 | 2013-10-10 | Дженентек, Инк. | Isoindolones and methods for using them |
AU2013269809B2 (en) | 2012-05-31 | 2017-12-21 | Bayer Pharma Aktiengesellschaft | Biomarkers for determining effective response of treatments of Hepatocellular carcinoma (HCC) patients |
PL2909182T3 (en) * | 2012-10-19 | 2020-06-01 | Array Biopharma Inc. | Preparation of and formulation comprising a mek inhibitor |
CN111518031B (en) * | 2020-05-29 | 2023-01-17 | 中国药科大学 | Hydroxamic acid-containing compound and preparation method and application thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000005390A2 (en) | 1998-07-20 | 2000-02-03 | State Of Israel-Ministry Of Agriculture | Controlling starch synthesis |
WO2000042022A1 (en) | 1999-01-13 | 2000-07-20 | Warner-Lambert Company | Benzoheterocycles and their use as mek inhibitors |
WO2001005392A2 (en) | 1999-07-16 | 2001-01-25 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
WO2003077855A2 (en) | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
WO2003077914A1 (en) | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
US20040043388A1 (en) | 2001-03-02 | 2004-03-04 | Come Jon H. | Three hybrid assay system |
US20040116710A1 (en) | 2002-03-13 | 2004-06-17 | Wallace Eli M. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5155110A (en) * | 1987-10-27 | 1992-10-13 | Warner-Lambert Company | Fenamic acid hydroxamate derivatives having cyclooxygenase and 5-lipoxygenase inhibition |
US5525625A (en) * | 1995-01-24 | 1996-06-11 | Warner-Lambert Company | 2-(2-Amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran for treating proliferative disorders |
AU5610398A (en) | 1997-02-28 | 1998-09-18 | Warner-Lambert Company | Method of treating or preventing septic shock by administering a mek inhibitor |
US6310060B1 (en) * | 1998-06-24 | 2001-10-30 | Warner-Lambert Company | 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors |
ATE277895T1 (en) | 1997-07-01 | 2004-10-15 | Warner Lambert Co | 4-BROMINE OR 4-IODINE-PHENYLAMINO-BENZHYDROXAMIC ACID DERIVATIVES AND THEIR USE AS MEK INHIBITORS |
CA2346448A1 (en) | 1998-12-16 | 2000-06-22 | Warner-Lambert Company | Treatment of arthritis with mek inhibitors |
JP2000204079A (en) * | 1999-01-13 | 2000-07-25 | Warner Lambert Co | Diarylamine |
WO2001005390A2 (en) * | 1999-07-16 | 2001-01-25 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
-
2004
- 2004-07-12 WO PCT/IB2004/002355 patent/WO2005009975A2/en active Application Filing
- 2004-07-12 MX MXPA06000921A patent/MXPA06000921A/en unknown
- 2004-07-12 DE DE602004023207T patent/DE602004023207D1/en not_active Expired - Lifetime
- 2004-07-12 CA CA2532067A patent/CA2532067C/en not_active Expired - Fee Related
- 2004-07-12 JP JP2006520928A patent/JP4896717B2/en not_active Expired - Fee Related
- 2004-07-12 EP EP04744015A patent/EP1651214B1/en not_active Expired - Lifetime
- 2004-07-12 BR BRPI0412851-6A patent/BRPI0412851A/en not_active IP Right Cessation
- 2004-07-12 AT AT04744015T patent/ATE442847T1/en not_active IP Right Cessation
- 2004-07-12 ES ES04744015T patent/ES2331246T3/en not_active Expired - Lifetime
- 2004-07-22 US US10/897,464 patent/US7160915B2/en not_active Expired - Fee Related
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000005390A2 (en) | 1998-07-20 | 2000-02-03 | State Of Israel-Ministry Of Agriculture | Controlling starch synthesis |
WO2000042022A1 (en) | 1999-01-13 | 2000-07-20 | Warner-Lambert Company | Benzoheterocycles and their use as mek inhibitors |
WO2001005392A2 (en) | 1999-07-16 | 2001-01-25 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
US20040043388A1 (en) | 2001-03-02 | 2004-03-04 | Come Jon H. | Three hybrid assay system |
WO2003077855A2 (en) | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
WO2003077914A1 (en) | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
US20040116710A1 (en) | 2002-03-13 | 2004-06-17 | Wallace Eli M. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
Non-Patent Citations (3)
Title |
---|
HARGREAVES K ET AL.: "A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia", PAIN, 1988, pages 56 - 88 |
JOUMAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1955, pages 2 - 19 |
KAYSER V; GUILBAUD G: "Local and remote modifications of nociceptive sensitivity during carrageenan-induced inflammation in the rat", PAIN, vol. 28, 1985, pages 99 - 108 |
Cited By (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8178693B2 (en) | 2002-03-13 | 2012-05-15 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US8193230B2 (en) | 2002-03-13 | 2012-06-05 | Array Biopharma Inc. | Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof |
US8193231B2 (en) | 2002-03-13 | 2012-06-05 | Array Biopharma Inc. | Compositions comprising N3 alkylated benzimidazole derivatives as MEK inhibitors and methods of use thereof |
US8193229B2 (en) | 2002-03-13 | 2012-06-05 | Array Biopharma Inc. | Method of treatment using N3 alkylated benzimidazole derivatives as MEK inhibitors |
US8003805B2 (en) | 2002-03-13 | 2011-08-23 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US7973170B2 (en) | 2002-03-13 | 2011-07-05 | Array Biopharma Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
US8513293B2 (en) | 2002-03-13 | 2013-08-20 | Array Biopharma Inc. | Methods of treating a hyperproliferative disorder or inhibiting cell growth in a mammal |
US8618169B2 (en) | 2002-10-21 | 2013-12-31 | Ramot At Tel-Aviv University Ltd. | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
US8278357B2 (en) | 2002-10-21 | 2012-10-02 | Ramot At Tel-Aviv University Ltd. | Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators |
EP1663210A4 (en) * | 2003-08-29 | 2009-04-22 | Array Biopharma Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
EP1663210A1 (en) * | 2003-08-29 | 2006-06-07 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as mek inhibitors |
US8383832B2 (en) | 2005-06-23 | 2013-02-26 | Array Biopharma Inc. | Process for preparing benzimidazole compounds |
AU2006262259B2 (en) * | 2005-06-23 | 2013-03-14 | Array Biopharma Inc. | Process for preparing benzimidazole compounds |
KR101357361B1 (en) | 2005-06-23 | 2014-02-03 | 아스트라제네카 아베 | SnAr PROCESS FOR PREPARING BENZIMIDAZOLE COMPOUNDS |
EP1904481A2 (en) * | 2005-06-23 | 2008-04-02 | Array Biopharma, Inc. | Process for preparing benzimidazole compounds |
EP1904481A4 (en) * | 2005-06-23 | 2010-11-10 | Array Biopharma Inc | Process for preparing benzimidazole compounds |
EP1904061A4 (en) * | 2005-06-23 | 2010-11-17 | Array Biopharma Inc | SNAr PROCESS FOR PREPARING BENZIMIDAZOLE COMPOUNDS |
US9024040B2 (en) | 2005-06-23 | 2015-05-05 | Array Biopharma Inc. | Processes for preparing benzimidazole compounds |
US8039637B2 (en) | 2005-06-23 | 2011-10-18 | Array Biopharma Inc. | Process for preparing benzimidazole compounds |
EP1904061A1 (en) * | 2005-06-23 | 2008-04-02 | Array Biopharma, Inc. | SNAr PROCESS FOR PREPARING BENZIMIDAZOLE COMPOUNDS |
US8501956B2 (en) | 2005-06-23 | 2013-08-06 | Array Biopharma Inc. | Benzimidazole compounds |
TWI391380B (en) * | 2005-06-23 | 2013-04-01 | Array Biopharma Inc | Process for preparing benzimidazole compounds |
KR101351190B1 (en) * | 2005-06-23 | 2014-01-14 | 아스트라제네카 아베 | Process for preparing benzimidazole compounds |
JP2009501146A (en) * | 2005-06-23 | 2009-01-15 | アレイ バイオファーマ、インコーポレイテッド | Method for preparing benzimidazole compound |
US8183385B2 (en) | 2005-06-23 | 2012-05-22 | Array Biopharma Inc. | SNAR process for preparing benzimidazole compounds |
JP2009501145A (en) * | 2005-06-23 | 2009-01-15 | アレイ バイオファーマ、インコーポレイテッド | SNAr method for preparing benzimidazole compounds |
WO2007025090A3 (en) * | 2005-08-25 | 2007-06-07 | Kalypsys Inc | Heterobicyclic and - tricyclic inhibitors of mapk/erk kinase |
WO2007025090A2 (en) * | 2005-08-25 | 2007-03-01 | Kalypsys, Inc. | Heterobicyclic and - tricyclic inhibitors of mapk/erk kinase |
US8362002B2 (en) | 2005-10-07 | 2013-01-29 | Exelixis, Inc. | Azetidines as MEK inhibitors for the treatment of proliferative diseases |
US11597699B2 (en) | 2005-10-07 | 2023-03-07 | Exelixis, Inc. | MEK inhibitors and methods of their use |
US7915250B2 (en) | 2005-10-07 | 2011-03-29 | Exelixis, Inc. | Azetidines as MEK inhibitors for the treatment of proliferative diseases |
CN109053523A (en) * | 2005-10-07 | 2018-12-21 | 埃克塞利希斯股份有限公司 | Azetidine as the mek inhibitor for treating proliferative disease |
US7803839B2 (en) | 2005-10-07 | 2010-09-28 | Exelixis, Inc. | Azetidines as MEK inhibitors for the treatment of proliferative diseases |
US8604051B2 (en) | 2006-01-31 | 2013-12-10 | Ucb Pharma S.A. | Thieno-pyridine derivatives as MEK inhibitors |
US8394822B2 (en) | 2006-01-31 | 2013-03-12 | Ucb Pharma, S.A. | Thieno-pyridine derivatives as MEK inhibitors |
US8283359B2 (en) | 2006-01-31 | 2012-10-09 | Ucb Pharma S.A. | Thieno-pyridine derivatives as MEK inhibitors |
US7999006B2 (en) | 2006-12-14 | 2011-08-16 | Exelixis, Inc. | Methods of using MEK inhibitors |
US8030317B2 (en) | 2006-12-20 | 2011-10-04 | Takeda Pharmaceutical Company Limited | MAPK/ERK kinase inhibitors |
US8470837B2 (en) | 2006-12-20 | 2013-06-25 | Takeda Pharmaceutical Company Limted | MAPK/ERK kinase inhibitors |
US8350037B2 (en) | 2007-07-23 | 2013-01-08 | Ucb Pharma, S.A. | Thieno-pyridine derivatives as MEK inhibitors |
JP2010536723A (en) * | 2007-08-16 | 2010-12-02 | エフ.ホフマン−ラ ロシュ アーゲー | Substituted hydantoin |
US7557221B2 (en) | 2007-08-16 | 2009-07-07 | Hoffman-La Roche Inc. | Substituted hydantoins |
WO2009021887A1 (en) * | 2007-08-16 | 2009-02-19 | F. Hoffmann-La Roche Ag | Substituted hydantoins |
US9403756B2 (en) | 2007-09-20 | 2016-08-02 | Ramot At Tel-Aviv University Ltd. | N-phenyl anthranilic acid derivatives and uses thereof |
WO2009037705A2 (en) * | 2007-09-20 | 2009-03-26 | Ramot At Tel Aviv University Ltd. | Esters of n-phenylanthranilic acid for use in the treatment of cancer and inflammation |
US8765815B2 (en) | 2007-09-20 | 2014-07-01 | Ramot At Tel-Aviv University Ltd. | N-phenyl anthranilic acid derivatives and uses thereof |
WO2009037705A3 (en) * | 2007-09-20 | 2009-07-09 | Univ Ramot | Esters of n-phenylanthranilic acid for use in the treatment of cancer and inflammation |
US8022057B2 (en) | 2007-11-12 | 2011-09-20 | Takeda Pharmaceutical Company Limited | MAPK/ERK kinase inhibitors |
US8063085B2 (en) | 2007-12-20 | 2011-11-22 | Hoffmann-La Roche Inc. | Substituted hydantoins |
US8487101B2 (en) | 2008-01-21 | 2013-07-16 | Ucb Pharma S.A. | Thieno-pyridine derivatives as MEK inhibitors |
US8637491B2 (en) | 2008-06-19 | 2014-01-28 | Ucb Pharma S.A. | Thieno-pyridine derivatives as MEK inhibitors |
WO2010051933A2 (en) | 2008-11-10 | 2010-05-14 | Bayer Schering Pharma Aktiengesellschaft | Substituted sulphonamido phenoxybenzamides |
US9084781B2 (en) | 2008-12-10 | 2015-07-21 | Novartis Ag | MEK mutations conferring resistance to MEK inhibitors |
WO2010068738A1 (en) | 2008-12-10 | 2010-06-17 | Dana-Farber Cancer Institute, Inc. | Mek mutations conferring resistance to mek inhibitors |
WO2010143733A1 (en) | 2009-06-09 | 2010-12-16 | Takeda Pharmaceutical Company Limited | Novel fused cyclic compound and use thereof |
WO2011047795A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Schering Pharma Aktiengesellschaft | Substituted benzosulphonamides |
WO2011047796A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Schering Pharma Aktiengesellschaft | Substituted halophenoxybenzamide derivatives |
WO2011047788A1 (en) | 2009-10-21 | 2011-04-28 | Bayer Schering Pharma Aktiengesellschaft | Substituted benzosulphonamides |
US9279144B2 (en) | 2010-02-25 | 2016-03-08 | Dana-Farber Cancer Institute, Inc. | Screening method for BRAF inhibitors |
EP3028699A1 (en) | 2010-02-25 | 2016-06-08 | Dana-Farber Cancer Institute, Inc. | Braf mutations conferring resistance to braf inhibitors |
WO2011106298A1 (en) | 2010-02-25 | 2011-09-01 | Dana-Farber Cancer Institute, Inc. | Braf mutations conferring resistance to braf inhibitors |
US11078540B2 (en) | 2010-03-09 | 2021-08-03 | Dana-Farber Cancer Institute, Inc. | Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy |
WO2012055953A1 (en) | 2010-10-29 | 2012-05-03 | Bayer Pharma Aktiengesellschaft | Substituted phenoxypyridines |
WO2013107283A1 (en) | 2012-01-17 | 2013-07-25 | Tianjin Binjiang Pharma, Inc. | Benzoheterocyclic compounds and use thereof |
US9290468B2 (en) | 2012-01-17 | 2016-03-22 | Shanghai Kechow Pharma, Inc. | Benzoheterocyclic compounds and use thereof |
US9937158B2 (en) | 2012-01-17 | 2018-04-10 | Shanghai Kechow Pharma, Inc. | Benzoheterocyclic compounds and use thereof |
WO2013169858A1 (en) | 2012-05-08 | 2013-11-14 | The Broad Institute, Inc. | Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy |
US11414396B2 (en) | 2012-10-12 | 2022-08-16 | Exelixis, Inc. | Process for making compounds for use in the treatment of cancer |
Also Published As
Publication number | Publication date |
---|---|
BRPI0412851A (en) | 2006-10-03 |
US7160915B2 (en) | 2007-01-09 |
CA2532067C (en) | 2010-12-21 |
ES2331246T3 (en) | 2009-12-28 |
WO2005009975A3 (en) | 2005-04-07 |
JP4896717B2 (en) | 2012-03-14 |
DE602004023207D1 (en) | 2009-10-29 |
EP1651214B1 (en) | 2009-09-16 |
US20050026970A1 (en) | 2005-02-03 |
CA2532067A1 (en) | 2005-02-03 |
MXPA06000921A (en) | 2006-03-30 |
EP1651214A2 (en) | 2006-05-03 |
JP2006528621A (en) | 2006-12-21 |
ATE442847T1 (en) | 2009-10-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2532067C (en) | N-methyle-substituted benzamidazoles | |
US7273877B2 (en) | 5-substituted-4-[(substituted phenyl) amino]-2-pyridone derivatives | |
US20050049276A1 (en) | Imidazopyridines and triazolopyridines | |
AU681075B2 (en) | Antiproliferative quinazolines | |
EP0260817B1 (en) | Quinazolinediones and pyridopyrimidinediones | |
AU2008203305A1 (en) | New benzimidazole derivatives | |
PL233177B1 (en) | N3 alkylated benzimidazole derivatives as MEK inhibitors | |
SK285703B6 (en) | 2-Aryl-8-oxodihydropurine derivatives, process for producing the same, medicinal compositions containing the same, and intermediates thereof | |
KR20080016671A (en) | Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof | |
WO1995028387A1 (en) | Benzamide compound and medicinal use thereof | |
KR20080046219A (en) | Heterocyclic compounds | |
WO2019026014A1 (en) | Processes for preparation of lifitegrast and intermediates thereof | |
US20050059710A1 (en) | Diphenylamino ketone derivatives as MEK inhibitors | |
JP2009516658A (en) | 3,6-dihydro-2-oxo-6H-1,3,4-thiadiazine derivative | |
KR20150015488A (en) | Amides of 2-amino-4-arylthiazole compounds and their salts | |
EP0874849B1 (en) | 2,7-substituted octahydro-pyrrolo 1,2-a]pyrazine derivatives | |
US4018790A (en) | Substituted 1-sulfonylbenzimidazoles | |
ZA200402467B (en) | Mechanical reinforcement to improve high current, short duration withstand of a monolithic disk or bonded disk stack | |
CA2569088C (en) | Pyrrolobenzimidazolones and their use as antiproliferative agents | |
JPH05117243A (en) | 2-aminopyrimidine-4-carboxamide derivative, process for manufacturing same and application of same in treatment | |
EP2170822A2 (en) | Proton acceptor iminium/carbocation-type coupling agents | |
CS268189B2 (en) | Method of quinazolinediones and pyridopyrimidinodiones production | |
WO2006059165A1 (en) | Pyrrolopyridine-2-carboxylic acid amide derivative useful as inhibitor of glycogen phosphorylase | |
US4316021A (en) | Substituted 1-sulfonylbenzimidazoles | |
KR20000069132A (en) | Process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2532067 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2006/000921 Country of ref document: MX Ref document number: 2006520928 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004744015 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2004744015 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0412851 Country of ref document: BR |