JP2002511092A - 4−ブロモまたは4−ヨードフェニルアミノベンズヒドロキサム酸誘導体およびそのmek阻害剤としての使用 - Google Patents
4−ブロモまたは4−ヨードフェニルアミノベンズヒドロキサム酸誘導体およびそのmek阻害剤としての使用Info
- Publication number
- JP2002511092A JP2002511092A JP50722899A JP50722899A JP2002511092A JP 2002511092 A JP2002511092 A JP 2002511092A JP 50722899 A JP50722899 A JP 50722899A JP 50722899 A JP50722899 A JP 50722899A JP 2002511092 A JP2002511092 A JP 2002511092A
- Authority
- JP
- Japan
- Prior art keywords
- benzamide
- iodo
- phenylamino
- methyl
- difluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 title description 4
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title description 3
- QAMBBWKIAJFFRF-UHFFFAOYSA-N n-hydroxy-2-(4-iodoanilino)benzamide Chemical class ONC(=O)C1=CC=CC=C1NC1=CC=C(I)C=C1 QAMBBWKIAJFFRF-UHFFFAOYSA-N 0.000 title description 3
- -1 alkyl Chemical compound 0.000 claims abstract description 117
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 230000002062 proliferating effect Effects 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 208000037803 restenosis Diseases 0.000 claims abstract description 10
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 102
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 27
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 238000007792 addition Methods 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- AAVSAALNWBQXSB-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-n-[2-(dimethylamino)ethoxy]-3,4-difluorobenzamide;hydrochloride Chemical compound Cl.CN(C)CCONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl AAVSAALNWBQXSB-UHFFFAOYSA-N 0.000 claims description 3
- UHAXDAKQGVISBZ-UHFFFAOYSA-N N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=C(F)C=C1C(=O)NOCC1CC1 UHAXDAKQGVISBZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- ZHMSIFGQMCBYIY-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-3,4,5-trifluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(F)=C(F)C(F)=C1NC1=CC=C(I)C=C1Br ZHMSIFGQMCBYIY-UHFFFAOYSA-N 0.000 claims description 2
- BZJWSLFAFFNFIW-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1Br BZJWSLFAFFNFIW-UHFFFAOYSA-N 0.000 claims description 2
- JHBIWAOIBNORTA-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-3,4,5-trifluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(F)=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl JHBIWAOIBNORTA-UHFFFAOYSA-N 0.000 claims description 2
- NXUSIIDZHWMSCV-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl NXUSIIDZHWMSCV-UHFFFAOYSA-N 0.000 claims description 2
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 claims description 2
- ROCRLSIAQQGIPN-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-(cyclobutylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CCC1 ROCRLSIAQQGIPN-UHFFFAOYSA-N 0.000 claims description 2
- UOPHVVWHOCFXFI-UHFFFAOYSA-N 2-(2-fluoro-4-iodoanilino)-n-hydroxy-4-nitrobenzamide Chemical compound ONC(=O)C1=CC=C([N+]([O-])=O)C=C1NC1=CC=C(I)C=C1F UOPHVVWHOCFXFI-UHFFFAOYSA-N 0.000 claims description 2
- IPVITVKNQFEBEA-UHFFFAOYSA-N 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F IPVITVKNQFEBEA-UHFFFAOYSA-N 0.000 claims description 2
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 2
- 208000006029 Cardiomegaly Diseases 0.000 claims description 2
- 206010010904 Convulsion Diseases 0.000 claims description 2
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 2
- 230000001028 anti-proliverative effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- PNTKSRDALUNXIE-UHFFFAOYSA-N n-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound C=1C=C(I)C=C(F)C=1NC=1C(F)=C(F)C(F)=CC=1C(=O)NOCC1CC1 PNTKSRDALUNXIE-UHFFFAOYSA-N 0.000 claims description 2
- DQHARHQBVRLSQS-UHFFFAOYSA-N n-(cyclopropylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound C=1C=C(I)C=C(F)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 DQHARHQBVRLSQS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- SRMDAFUJVQJZFI-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1Cl SRMDAFUJVQJZFI-UHFFFAOYSA-N 0.000 claims 3
- ZSOPSNFTRFGERY-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-3,4-difluoro-n-(oxan-2-yloxy)benzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOC1CCCCO1 ZSOPSNFTRFGERY-UHFFFAOYSA-N 0.000 claims 2
- UUQXUOKQBSWOHD-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-hydroxy-4-nitrobenzamide Chemical compound ONC(=O)C1=CC=C([N+]([O-])=O)C=C1NC1=CC=C(I)C=C1Cl UUQXUOKQBSWOHD-UHFFFAOYSA-N 0.000 claims 2
- AYEUPCJRNJQNQD-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(oxan-2-yloxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOC1OCCCC1 AYEUPCJRNJQNQD-UHFFFAOYSA-N 0.000 claims 2
- TYSFIFCGLKBEJN-UHFFFAOYSA-N 4-fluoro-n-hydroxy-2-(4-iodo-2-methylanilino)-5-nitrobenzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=C([N+]([O-])=O)C=C1C(=O)NO TYSFIFCGLKBEJN-UHFFFAOYSA-N 0.000 claims 2
- IBZPDAZZGTZKNJ-UHFFFAOYSA-N 5-bromo-n-[2-(dimethylamino)propoxy]-3,4-difluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CN(C)C(C)CONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1C IBZPDAZZGTZKNJ-UHFFFAOYSA-N 0.000 claims 2
- HPFQWCKXOZLYJQ-UHFFFAOYSA-N n-but-2-enoxy-3,4-difluoro-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC=CCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C HPFQWCKXOZLYJQ-UHFFFAOYSA-N 0.000 claims 2
- AVIWCXSGNKPKKK-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-5-chloro-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Cl)=C(F)C(F)=C1NC1=CC=C(I)C=C1Br AVIWCXSGNKPKKK-UHFFFAOYSA-N 0.000 claims 1
- NMGPTKSLPIARAK-UHFFFAOYSA-N 2-(2-bromo-4-iodoanilino)-n-hydroxy-4-nitrobenzamide Chemical compound ONC(=O)C1=CC=C([N+]([O-])=O)C=C1NC1=CC=C(I)C=C1Br NMGPTKSLPIARAK-UHFFFAOYSA-N 0.000 claims 1
- IJCHFSDTDHLRIQ-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-4-fluoro-n-(oxan-2-yloxy)benzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=CC(F)=CC=C1C(=O)NOC1CCCCO1 IJCHFSDTDHLRIQ-UHFFFAOYSA-N 0.000 claims 1
- SHNRDYXLGNJCOC-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-n-hydroxy-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NO)C(NC=2C(=CC(I)=CC=2)Cl)=C1 SHNRDYXLGNJCOC-UHFFFAOYSA-N 0.000 claims 1
- BYNKDEUDKDVPPJ-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-3,4-difluoro-n-(2-methylprop-2-enoxy)benzamide Chemical compound CC(=C)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(Br)C=C1C BYNKDEUDKDVPPJ-UHFFFAOYSA-N 0.000 claims 1
- NITWKACUMSHLOB-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-3,4-difluoro-n-(2-phenoxyethoxy)benzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCCOC1=CC=CC=C1 NITWKACUMSHLOB-UHFFFAOYSA-N 0.000 claims 1
- YDOWUWRHGYWZHT-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-3,4-difluoro-n-(furan-3-ylmethoxy)benzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC1=COC=C1 YDOWUWRHGYWZHT-UHFFFAOYSA-N 0.000 claims 1
- ULZOCHGQJGYENN-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-3,4-difluoro-n-(thiophen-2-ylmethoxy)benzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC1=CC=CS1 ULZOCHGQJGYENN-UHFFFAOYSA-N 0.000 claims 1
- WGIDTTDBLPTUHP-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-3,4-difluoro-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(Br)C=C1C WGIDTTDBLPTUHP-UHFFFAOYSA-N 0.000 claims 1
- LUDUVSBHPMEVQH-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-3,4-difluoro-n-propan-2-yloxybenzamide Chemical compound CC(C)ONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(Br)C=C1C LUDUVSBHPMEVQH-UHFFFAOYSA-N 0.000 claims 1
- QTCFRZPPKGEZKF-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-(4,4-dimethylpent-2-ynoxy)-3,4-difluorobenzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC#CC(C)(C)C QTCFRZPPKGEZKF-UHFFFAOYSA-N 0.000 claims 1
- BHEYIPCYQCTTAR-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 BHEYIPCYQCTTAR-UHFFFAOYSA-N 0.000 claims 1
- SLODYXNZAINLFD-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-but-2-enoxy-3,4-difluorobenzamide Chemical compound CC=CCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(Br)C=C1C SLODYXNZAINLFD-UHFFFAOYSA-N 0.000 claims 1
- LNTZEUIWPWPUGC-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-but-3-yn-2-yloxy-3,4-difluorobenzamide Chemical compound C#CC(C)ONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(Br)C=C1C LNTZEUIWPWPUGC-UHFFFAOYSA-N 0.000 claims 1
- LWZBCTIJTITZBA-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-but-3-ynoxy-3,4-difluorobenzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCCC#C LWZBCTIJTITZBA-UHFFFAOYSA-N 0.000 claims 1
- LUVODTHAYCCRJL-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-cyclobutyloxy-3,4-difluorobenzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOC1CCC1 LUVODTHAYCCRJL-UHFFFAOYSA-N 0.000 claims 1
- BZEJFQCJTPHNOF-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-cyclopentyloxy-3,4-difluorobenzamide Chemical compound CC1=CC(Br)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOC1CCCC1 BZEJFQCJTPHNOF-UHFFFAOYSA-N 0.000 claims 1
- YDBKFXZLWHEYBN-UHFFFAOYSA-N 2-(4-bromo-2-methylanilino)-n-ethoxy-3,4-difluorobenzamide Chemical compound CCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(Br)C=C1C YDBKFXZLWHEYBN-UHFFFAOYSA-N 0.000 claims 1
- HDLXUSUTCIBXQZ-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(2-methylprop-2-enoxy)benzamide Chemical compound CC(=C)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C HDLXUSUTCIBXQZ-UHFFFAOYSA-N 0.000 claims 1
- HYIXUGDJHLKVGF-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(2-phenoxyethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCCOC1=CC=CC=C1 HYIXUGDJHLKVGF-UHFFFAOYSA-N 0.000 claims 1
- ILKRGOONQZFQPI-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(3-methyl-5-phenylpent-2-en-4-ynoxy)benzamide Chemical compound C=1C=CC=CC=1C#CC(C)=CCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C ILKRGOONQZFQPI-UHFFFAOYSA-N 0.000 claims 1
- RLUBNNSZZPDBIV-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(3-phenylprop-2-ynoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC#CC1=CC=CC=C1 RLUBNNSZZPDBIV-UHFFFAOYSA-N 0.000 claims 1
- HAONTWSXIVMMHV-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-(thiophen-2-ylmethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC1=CC=CS1 HAONTWSXIVMMHV-UHFFFAOYSA-N 0.000 claims 1
- ZWXXSMYLKXWUIM-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-prop-2-ynoxybenzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC#C ZWXXSMYLKXWUIM-UHFFFAOYSA-N 0.000 claims 1
- FUDMVYZZNQDLOV-UHFFFAOYSA-N 3,4-difluoro-2-(4-iodo-2-methylanilino)-n-propoxybenzamide Chemical compound CCCONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1C FUDMVYZZNQDLOV-UHFFFAOYSA-N 0.000 claims 1
- YPKLFSUXFMFTNP-UHFFFAOYSA-N 3,4-difluoro-n-(furan-3-ylmethoxy)-2-(4-iodo-2-methylanilino)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=C(F)C(F)=CC=C1C(=O)NOCC1=COC=C1 YPKLFSUXFMFTNP-UHFFFAOYSA-N 0.000 claims 1
- OEDQBUOUDGINPB-UHFFFAOYSA-N 4-fluoro-2-(2-fluoro-4-iodoanilino)-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1F OEDQBUOUDGINPB-UHFFFAOYSA-N 0.000 claims 1
- XYPDOWBXGOOEOA-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-(2-phenoxyethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCCOC1=CC=CC=C1 XYPDOWBXGOOEOA-UHFFFAOYSA-N 0.000 claims 1
- PBAMOEUDSFIDGM-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-(thiophen-2-ylmethoxy)benzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC1=CC=CS1 PBAMOEUDSFIDGM-UHFFFAOYSA-N 0.000 claims 1
- PEZQORQECWUYJA-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-methoxybenzamide Chemical compound CONC(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C PEZQORQECWUYJA-UHFFFAOYSA-N 0.000 claims 1
- PFWAYQMMRCDJJX-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-prop-2-enoxybenzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC=C PFWAYQMMRCDJJX-UHFFFAOYSA-N 0.000 claims 1
- VFLRZRPXLGMONP-UHFFFAOYSA-N 4-fluoro-2-(4-iodo-2-methylanilino)-n-prop-2-ynoxybenzamide Chemical compound CC1=CC(I)=CC=C1NC1=CC(F)=CC=C1C(=O)NOCC#C VFLRZRPXLGMONP-UHFFFAOYSA-N 0.000 claims 1
- DPWYBHGUHGHXDP-UHFFFAOYSA-N 4-fluoro-n-hydroxy-2-(4-iodo-2-methylanilino)-n-methylbenzamide Chemical compound CN(O)C(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C DPWYBHGUHGHXDP-UHFFFAOYSA-N 0.000 claims 1
- GRGWLBCAWYUDDI-UHFFFAOYSA-N 4-fluoro-n-hydroxy-2-(4-iodo-2-methylanilino)-n-propan-2-ylbenzamide Chemical compound CC(C)N(O)C(=O)C1=CC=C(F)C=C1NC1=CC=C(I)C=C1C GRGWLBCAWYUDDI-UHFFFAOYSA-N 0.000 claims 1
- RPWNJSYAWBWAFW-UHFFFAOYSA-N 5-bromo-2-(2-bromo-4-iodoanilino)-3,4-difluoro-n-hydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1Br RPWNJSYAWBWAFW-UHFFFAOYSA-N 0.000 claims 1
- FVMCFMHLFMOYCO-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-3,4-difluoro-n-(oxan-2-yloxy)benzamide Chemical compound C1CCCOC1ONC(=O)C=1C=C(Br)C(F)=C(F)C=1NC1=CC=C(I)C=C1Cl FVMCFMHLFMOYCO-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/42—Singly bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
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- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Psychiatry (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Furan Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5144097P | 1997-07-01 | 1997-07-01 | |
| US60/051,440 | 1997-07-01 | ||
| PCT/US1998/013106 WO1999001426A1 (en) | 1997-07-01 | 1998-06-24 | 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as mek inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002511092A true JP2002511092A (ja) | 2002-04-09 |
| JP2002511092A5 JP2002511092A5 (enExample) | 2005-12-22 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50722899A Abandoned JP2002511092A (ja) | 1997-07-01 | 1998-06-24 | 4−ブロモまたは4−ヨードフェニルアミノベンズヒドロキサム酸誘導体およびそのmek阻害剤としての使用 |
Country Status (26)
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|---|---|
| EP (1) | EP0993439B1 (enExample) |
| JP (1) | JP2002511092A (enExample) |
| KR (1) | KR20010014362A (enExample) |
| CN (1) | CN1163475C (enExample) |
| AR (1) | AR016762A1 (enExample) |
| AT (1) | ATE277895T1 (enExample) |
| AU (1) | AU757046B2 (enExample) |
| BR (1) | BR9810366A (enExample) |
| CA (1) | CA2290506C (enExample) |
| CO (1) | CO4940442A1 (enExample) |
| DE (1) | DE69826662T2 (enExample) |
| ES (1) | ES2229515T3 (enExample) |
| HR (1) | HRP980368A2 (enExample) |
| HU (1) | HUP0003731A3 (enExample) |
| IL (1) | IL132840A (enExample) |
| IS (1) | IS5256A (enExample) |
| MY (1) | MY120994A (enExample) |
| NO (1) | NO315271B1 (enExample) |
| NZ (1) | NZ501276A (enExample) |
| PE (1) | PE97999A1 (enExample) |
| PL (1) | PL337698A1 (enExample) |
| PT (1) | PT993439E (enExample) |
| TW (1) | TW396149B (enExample) |
| UY (1) | UY25076A1 (enExample) |
| WO (1) | WO1999001426A1 (enExample) |
| ZA (1) | ZA985728B (enExample) |
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| WO2010068738A1 (en) | 2008-12-10 | 2010-06-17 | Dana-Farber Cancer Institute, Inc. | Mek mutations conferring resistance to mek inhibitors |
| WO2011106298A1 (en) | 2010-02-25 | 2011-09-01 | Dana-Farber Cancer Institute, Inc. | Braf mutations conferring resistance to braf inhibitors |
| 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 |
| JP2019528256A (ja) * | 2016-07-28 | 2019-10-10 | ザ ジョンズ ホプキンス ユニバーシティ | O−置換ヒドロキサム酸 |
| 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 |
| JP2022510586A (ja) * | 2018-11-20 | 2022-01-27 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚障害の処置のためのチエニル-アニリン化合物 |
| JP2022513089A (ja) * | 2018-11-20 | 2022-02-07 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚癌の処置のためのアリールアニリンおよびヘテロアリールアニリン化合物 |
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| ATE311363T1 (de) | 1999-01-13 | 2005-12-15 | Warner Lambert Co | Sulfohydroxamsäure and sulfohydroxamate und ihre verwendung als mek-inhibitoren |
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| PL351085A1 (en) * | 1999-04-21 | 2003-03-24 | Warner Lambert Co | Method for making 2-(n-phenylamino)benzoic acids |
| GB9910577D0 (en) * | 1999-05-08 | 1999-07-07 | Zeneca Ltd | Chemical compounds |
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- 1998-06-24 JP JP50722899A patent/JP2002511092A/ja not_active Abandoned
- 1998-06-24 CA CA002290506A patent/CA2290506C/en not_active Expired - Fee Related
- 1998-06-24 AU AU82627/98A patent/AU757046B2/en not_active Ceased
- 1998-06-24 PT PT98932830T patent/PT993439E/pt unknown
- 1998-06-24 KR KR1019997012519A patent/KR20010014362A/ko not_active Ceased
- 1998-06-24 AT AT98932830T patent/ATE277895T1/de not_active IP Right Cessation
- 1998-06-24 WO PCT/US1998/013106 patent/WO1999001426A1/en not_active Ceased
- 1998-06-24 BR BR9810366-0A patent/BR9810366A/pt not_active Application Discontinuation
- 1998-06-24 HU HU0003731A patent/HUP0003731A3/hu unknown
- 1998-06-24 NZ NZ501276A patent/NZ501276A/xx unknown
- 1998-06-24 ES ES98932830T patent/ES2229515T3/es not_active Expired - Lifetime
- 1998-06-24 PL PL98337698A patent/PL337698A1/xx unknown
- 1998-06-24 DE DE69826662T patent/DE69826662T2/de not_active Expired - Lifetime
- 1998-06-24 IL IL13284098A patent/IL132840A/en not_active IP Right Cessation
- 1998-06-24 EP EP98932830A patent/EP0993439B1/en not_active Expired - Lifetime
- 1998-06-24 CN CNB988067501A patent/CN1163475C/zh not_active Expired - Fee Related
- 1998-06-25 TW TW087110252A patent/TW396149B/zh not_active IP Right Cessation
- 1998-06-29 MY MYPI98002946A patent/MY120994A/en unknown
- 1998-06-30 ZA ZA985728A patent/ZA985728B/xx unknown
- 1998-06-30 HR HR60/051,440A patent/HRP980368A2/hr not_active Application Discontinuation
- 1998-06-30 PE PE1998000579A patent/PE97999A1/es not_active Application Discontinuation
- 1998-06-30 CO CO98036883A patent/CO4940442A1/es unknown
- 1998-06-30 UY UY25076A patent/UY25076A1/es not_active Application Discontinuation
- 1998-06-30 AR ARP980103165A patent/AR016762A1/es unknown
-
1999
- 1999-11-19 IS IS5256A patent/IS5256A/is unknown
- 1999-12-27 NO NO19996491A patent/NO315271B1/no not_active IP Right Cessation
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008075741A1 (ja) * | 2006-12-20 | 2008-06-26 | Keio University | 糖尿病治療剤及び予防剤 |
| WO2010068738A1 (en) | 2008-12-10 | 2010-06-17 | Dana-Farber Cancer Institute, Inc. | Mek mutations conferring resistance to mek inhibitors |
| US9084781B2 (en) | 2008-12-10 | 2015-07-21 | Novartis Ag | MEK mutations conferring resistance to MEK 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 |
| US8637246B2 (en) | 2010-02-25 | 2014-01-28 | Dana-Farber Cancer Institute, Inc. | BRAF mutations conferring resistance to BRAF inhibitors |
| US9279144B2 (en) | 2010-02-25 | 2016-03-08 | Dana-Farber Cancer Institute, Inc. | Screening method for 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 |
| 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 |
| JP2019528256A (ja) * | 2016-07-28 | 2019-10-10 | ザ ジョンズ ホプキンス ユニバーシティ | O−置換ヒドロキサム酸 |
| JP7194436B2 (ja) | 2016-07-28 | 2022-12-22 | ザ ジョンズ ホプキンス ユニバーシティ | O-置換ヒドロキサム酸 |
| JP2022510586A (ja) * | 2018-11-20 | 2022-01-27 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚障害の処置のためのチエニル-アニリン化合物 |
| JP2022513089A (ja) * | 2018-11-20 | 2022-02-07 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚癌の処置のためのアリールアニリンおよびヘテロアリールアニリン化合物 |
| JP7546297B2 (ja) | 2018-11-20 | 2024-09-06 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚障害の処置のためのチエニル-アニリン化合物 |
| JP7576799B2 (ja) | 2018-11-20 | 2024-11-01 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚癌の処置のためのアリールアニリンおよびヘテロアリールアニリン化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU757046B2 (en) | 2003-01-30 |
| CA2290506A1 (en) | 1999-01-14 |
| HUP0003731A3 (en) | 2002-11-28 |
| PT993439E (pt) | 2004-12-31 |
| WO1999001426A1 (en) | 1999-01-14 |
| DE69826662D1 (de) | 2004-11-04 |
| IL132840A (en) | 2004-12-15 |
| ATE277895T1 (de) | 2004-10-15 |
| PL337698A1 (en) | 2000-08-28 |
| BR9810366A (pt) | 2000-08-29 |
| NZ501276A (en) | 2000-10-27 |
| HUP0003731A2 (hu) | 2001-04-28 |
| CA2290506C (en) | 2005-12-27 |
| ES2229515T3 (es) | 2005-04-16 |
| KR20010014362A (ko) | 2001-02-26 |
| NO996491D0 (no) | 1999-12-27 |
| NO996491L (no) | 1999-12-29 |
| CN1261877A (zh) | 2000-08-02 |
| HRP980368A2 (en) | 1999-04-30 |
| UY25076A1 (es) | 1998-12-01 |
| IL132840A0 (en) | 2001-03-19 |
| EP0993439B1 (en) | 2004-09-29 |
| IS5256A (is) | 1999-11-19 |
| DE69826662T2 (de) | 2005-02-17 |
| MY120994A (en) | 2005-12-30 |
| EP0993439A1 (en) | 2000-04-19 |
| ZA985728B (en) | 1999-01-27 |
| NO315271B1 (no) | 2003-08-11 |
| AR016762A1 (es) | 2001-08-01 |
| CO4940442A1 (es) | 2000-07-24 |
| TW396149B (en) | 2000-07-01 |
| CN1163475C (zh) | 2004-08-25 |
| PE97999A1 (es) | 1999-11-05 |
| AU8262798A (en) | 1999-01-25 |
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