ES2355797T7 - Inhibidores heterocíclicos de MEK - Google Patents
Inhibidores heterocíclicos de MEK Download PDFInfo
- Publication number
- ES2355797T7 ES2355797T7 ES04811727T ES04811727T ES2355797T7 ES 2355797 T7 ES2355797 T7 ES 2355797T7 ES 04811727 T ES04811727 T ES 04811727T ES 04811727 T ES04811727 T ES 04811727T ES 2355797 T7 ES2355797 T7 ES 2355797T7
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- heteroaryl
- aryl
- halogen
- heterocyclyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
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- 239000003112 inhibitor Substances 0.000 title description 21
- -1 nitro, azido, fluoromethyl Chemical group 0.000 claims abstract description 201
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 124
- 125000003118 aryl group Chemical group 0.000 claims abstract description 111
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 110
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 80
- 150000002367 halogens Chemical class 0.000 claims abstract description 80
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 70
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 67
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 64
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 46
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 43
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 33
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 31
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 30
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims abstract description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 26
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 25
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims abstract description 23
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 22
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 21
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 21
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 20
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims abstract description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 14
- 125000004429 atom Chemical group 0.000 claims abstract description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 10
- 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 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 5
- 239000010452 phosphate Substances 0.000 claims abstract description 4
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims abstract description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract 19
- 125000006725 C1-C10 alkenyl group Chemical group 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 56
- 239000002253 acid Substances 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 230000003463 hyperproliferative effect Effects 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 12
- YHNRUSMOYCDMJS-UHFFFAOYSA-N o-(cyclopropylmethyl)hydroxylamine Chemical compound NOCC1CC1 YHNRUSMOYCDMJS-UHFFFAOYSA-N 0.000 claims description 9
- 150000001448 anilines Chemical class 0.000 claims description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000004968 inflammatory condition Effects 0.000 claims description 5
- 239000007822 coupling agent Substances 0.000 claims description 4
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000539 amino acid group Chemical group 0.000 claims description 3
- GGTGURVRZLLVEB-UHFFFAOYSA-N 2-(2-fluoro-4-methylanilino)-n-(2-hydroxyethoxy)-1-methyl-6-oxopyridine-3-carboxamide Chemical compound FC1=CC(C)=CC=C1NC1=C(C(=O)NOCCO)C=CC(=O)N1C GGTGURVRZLLVEB-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 25
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 4
- BGFHMYJZJZLMHW-UHFFFAOYSA-N 4-[2-[[2-(1-benzothiophen-3-yl)-9-propan-2-ylpurin-6-yl]amino]ethyl]phenol Chemical group N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 BGFHMYJZJZLMHW-UHFFFAOYSA-N 0.000 claims 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 3
- OEUDFZQKJRTOKB-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-1-methyl-6-oxopyridine-3-carboxylic acid Chemical compound C1=CC(=O)N(C)C(NC=2C(=CC(Br)=CC=2)F)=C1C(O)=O OEUDFZQKJRTOKB-UHFFFAOYSA-N 0.000 claims 2
- 150000004820 halides Chemical class 0.000 claims 2
- GESYOIMNOCSPHL-UHFFFAOYSA-N 2-(2-fluoro-4-iodoanilino)-n-methoxy-1-methyl-6-oxopyridine-3-carboxamide Chemical compound C1=CC(=O)N(C)C(NC=2C(=CC(I)=CC=2)F)=C1C(=O)NOC GESYOIMNOCSPHL-UHFFFAOYSA-N 0.000 claims 1
- FDXXPGVUUMVTHN-UHFFFAOYSA-N 2-(4-bromo-2-fluoroanilino)-1-ethyl-n-(2-hydroxyethoxy)-6-oxopyridine-3-carboxamide Chemical compound C1=CC(=O)N(CC)C(NC=2C(=CC(Br)=CC=2)F)=C1C(=O)NOCCO FDXXPGVUUMVTHN-UHFFFAOYSA-N 0.000 claims 1
- ZSSYVFZMPJTGPE-UHFFFAOYSA-N 2-aminooxyethanol Chemical compound NOCCO.NOCCO ZSSYVFZMPJTGPE-UHFFFAOYSA-N 0.000 claims 1
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 abstract description 30
- 150000002431 hydrogen Chemical class 0.000 abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 abstract 12
- 125000003282 alkyl amino group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 142
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 130
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 121
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
- 238000005481 NMR spectroscopy Methods 0.000 description 81
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 80
- 238000006243 chemical reaction Methods 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 69
- 239000000243 solution Substances 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
- 230000015572 biosynthetic process Effects 0.000 description 57
- 238000003786 synthesis reaction Methods 0.000 description 55
- 239000000047 product Substances 0.000 description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 48
- 230000002829 reductive effect Effects 0.000 description 43
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 42
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 40
- 235000019341 magnesium sulphate Nutrition 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 241000124008 Mammalia Species 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- 239000000460 chlorine Chemical group 0.000 description 30
- 201000010099 disease Diseases 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- 239000003960 organic solvent Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 150000001350 alkyl halides Chemical class 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 22
- 239000000284 extract Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 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 22
- 238000003818 flash chromatography Methods 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 239000008194 pharmaceutical composition Substances 0.000 description 21
- 208000035475 disorder Diseases 0.000 description 20
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- 206010028980 Neoplasm Diseases 0.000 description 19
- 239000002585 base Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 230000002159 abnormal effect Effects 0.000 description 18
- 239000008346 aqueous phase Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 150000001408 amides Chemical class 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- 230000029936 alkylation Effects 0.000 description 16
- 238000005804 alkylation reaction Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 13
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 13
- 150000001299 aldehydes Chemical class 0.000 description 13
- 230000010261 cell growth Effects 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 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 13
- 239000000725 suspension Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- 229910052794 bromium Inorganic materials 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- 150000004702 methyl esters Chemical class 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000001665 trituration Methods 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 11
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 11
- 238000010511 deprotection reaction Methods 0.000 description 11
- 230000001404 mediated effect Effects 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- 230000004913 activation Effects 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- 102000043136 MAP kinase family Human genes 0.000 description 9
- 108091054455 MAP kinase family Proteins 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000003102 growth factor Substances 0.000 description 9
- 230000037361 pathway Effects 0.000 description 9
- KQLHRXQKORXSTC-UHFFFAOYSA-N 3-amino-1h-pyrazin-2-one Chemical compound NC1=NC=CNC1=O KQLHRXQKORXSTC-UHFFFAOYSA-N 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 7
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000032050 esterification Effects 0.000 description 7
- 238000005886 esterification reaction Methods 0.000 description 7
- 125000004494 ethyl ester group Chemical group 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000003765 sweetening agent Substances 0.000 description 7
- AJPKQSSFYHPYMH-UHFFFAOYSA-N 2,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1Cl AJPKQSSFYHPYMH-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 6
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 6
- 201000004681 Psoriasis Diseases 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004103 aminoalkyl group Chemical group 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 210000002307 prostate Anatomy 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- IGWCCXVJTCRXRH-UHFFFAOYSA-N 4-(4-bromo-2-fluoroanilino)-1,5-dimethyl-6-oxopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN(C)C(=O)C(C)=C1NC1=CC=C(Br)C=C1F IGWCCXVJTCRXRH-UHFFFAOYSA-N 0.000 description 5
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 5
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 238000006880 cross-coupling reaction Methods 0.000 description 5
- 230000017858 demethylation Effects 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52327003P | 2003-11-19 | 2003-11-19 | |
| US523270P | 2003-11-19 | ||
| PCT/US2004/039060 WO2005051301A2 (en) | 2003-11-19 | 2004-11-18 | Heterocyclic inhibitors of mek and methods of use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2355797T3 ES2355797T3 (es) | 2011-03-31 |
| ES2355797T7 true ES2355797T7 (es) | 2013-04-01 |
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Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04811726T Expired - Lifetime ES2369835T3 (es) | 2003-11-19 | 2004-11-18 | Inhibidores bicíclicos de mek y métodos de síntesis de los mismos. |
| ES10008429.2T Expired - Lifetime ES2453367T3 (es) | 2003-11-19 | 2004-11-18 | Inhibidores heterocíclicos de MEK |
| ES04811727T Active ES2355797T7 (es) | 2003-11-19 | 2004-11-18 | Inhibidores heterocíclicos de MEK |
| ES04811728T Expired - Lifetime ES2389628T3 (es) | 2003-11-19 | 2004-11-18 | Inhibidores bicíclicos de MEK |
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| ES10008429.2T Expired - Lifetime ES2453367T3 (es) | 2003-11-19 | 2004-11-18 | Inhibidores heterocíclicos de MEK |
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| ZA (2) | ZA200604580B (OSRAM) |
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