KR20070092305A - 섬유성 질환의 치료 또는 예방용 약제 - Google Patents
섬유성 질환의 치료 또는 예방용 약제 Download PDFInfo
- Publication number
- KR20070092305A KR20070092305A KR1020077017059A KR20077017059A KR20070092305A KR 20070092305 A KR20070092305 A KR 20070092305A KR 1020077017059 A KR1020077017059 A KR 1020077017059A KR 20077017059 A KR20077017059 A KR 20077017059A KR 20070092305 A KR20070092305 A KR 20070092305A
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- phenyl
- methylene
- indolinone
- amino
- Prior art date
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 17
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- 150000003839 salts Chemical class 0.000 claims abstract description 23
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- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims abstract description 5
- -1 furan-2-yl-carbonyl Chemical group 0.000 claims description 259
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 67
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- HFMPQHGPYCRGSU-DQSJHHFOSA-N 3-[4-[(z)-[4-(diethylaminomethyl)anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoic acid Chemical compound C1=CC(CN(CC)CC)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O HFMPQHGPYCRGSU-DQSJHHFOSA-N 0.000 claims description 4
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- 238000010841 mRNA extraction Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- QIHNQXPWGLBQSD-VHXPQNKSSA-N methyl 2-[3-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-(4-methylsulfonylanilino)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)S(C)(=O)=O)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 QIHNQXPWGLBQSD-VHXPQNKSSA-N 0.000 description 1
- GOQURTOZVWSYGV-QPLCGJKRSA-N methyl 2-[3-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(1-methylimidazol-2-yl)anilino]methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)C=2N(C=CN=2)C)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 GOQURTOZVWSYGV-QPLCGJKRSA-N 0.000 description 1
- IZQALCRDSLSONT-DQSJHHFOSA-N methyl 2-[3-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(4-methylpiperazine-1-carbonyl)anilino]methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)C(=O)N2CCN(C)CC2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 IZQALCRDSLSONT-DQSJHHFOSA-N 0.000 description 1
- HFRNBBCBKYPZBB-QPLCGJKRSA-N methyl 2-[3-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(C(\NC=2C=CC(CN(C)C)=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 HFRNBBCBKYPZBB-QPLCGJKRSA-N 0.000 description 1
- AFAMETNODVDPTQ-QPLCGJKRSA-N methyl 2-[3-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(CN(C)C)=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 AFAMETNODVDPTQ-QPLCGJKRSA-N 0.000 description 1
- SZHJCHJQRUOWLY-DQSJHHFOSA-N methyl 2-[3-[(z)-[4-[2-(dimethylamino)ethyl-methylsulfonylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)N(CCN(C)C)S(C)(=O)=O)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 SZHJCHJQRUOWLY-DQSJHHFOSA-N 0.000 description 1
- HTRJJHQZAWZQBH-RQZHXJHFSA-N methyl 2-[3-[(z)-[4-[2-(dimethylamino)ethyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(CCN(C)C)=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 HTRJJHQZAWZQBH-RQZHXJHFSA-N 0.000 description 1
- GOSLUXVTIMFOKC-ZIADKAODSA-N methyl 2-[3-[(z)-[4-[3-(dimethylamino)propanoyl-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)N(C)C(=O)CCN(C)C)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 GOSLUXVTIMFOKC-ZIADKAODSA-N 0.000 description 1
- AUYNHACROASTOJ-FLWNBWAVSA-N methyl 2-[3-[(z)-[4-[4-(dimethylamino)butanoyl-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)N(C)C(=O)CCCN(C)C)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 AUYNHACROASTOJ-FLWNBWAVSA-N 0.000 description 1
- JODRENDAASRETI-KTMFPKCZSA-N methyl 2-[3-[(z)-[4-[5-(dimethylamino)pentanoyl-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)N(C)C(=O)CCCCN(C)C)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 JODRENDAASRETI-KTMFPKCZSA-N 0.000 description 1
- JMBLLSPTWOCMQN-DQSJHHFOSA-N methyl 2-[3-[(z)-[4-[[2-(dimethylamino)-2-oxoethyl]-methylsulfonylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC(=CC=2)N(CC(=O)N(C)C)S(C)(=O)=O)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 JMBLLSPTWOCMQN-DQSJHHFOSA-N 0.000 description 1
- USKVKVCGRMRUHN-FCQUAONHSA-N methyl 2-[3-[(z)-anilino-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound COC(=O)CC1=CC=CC(C(\NC=2C=CC=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 USKVKVCGRMRUHN-FCQUAONHSA-N 0.000 description 1
- FABFYDNXKUBLFH-VHXPQNKSSA-N methyl 2-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-(4-methylsulfonylanilino)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)S(C)(=O)=O)=C\1C2=CC=C(F)C=C2NC/1=O FABFYDNXKUBLFH-VHXPQNKSSA-N 0.000 description 1
- JIQYQIBWEIILEC-QPLCGJKRSA-N methyl 2-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(1-methylimidazol-2-yl)anilino]methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)C=1N(C=CN=1)C)=C\1C2=CC=C(F)C=C2NC/1=O JIQYQIBWEIILEC-QPLCGJKRSA-N 0.000 description 1
- IOOGCGMOCOGTDQ-DQSJHHFOSA-N methyl 2-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(4-methylpiperazine-1-carbonyl)anilino]methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)C(=O)N1CCN(C)CC1)=C\1C2=CC=C(F)C=C2NC/1=O IOOGCGMOCOGTDQ-DQSJHHFOSA-N 0.000 description 1
- UIZZMPJBPGNSGI-QPLCGJKRSA-N methyl 2-[4-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OC)=CC=C1C(\NC=1C=CC(CN(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O UIZZMPJBPGNSGI-QPLCGJKRSA-N 0.000 description 1
- QMFZCFUJLGGNCP-QPLCGJKRSA-N methyl 2-[4-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(CN(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O QMFZCFUJLGGNCP-QPLCGJKRSA-N 0.000 description 1
- YWXJNCLKPHVGPQ-RQZHXJHFSA-N methyl 2-[4-[(z)-[4-[2-(dimethylamino)ethyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(CCN(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O YWXJNCLKPHVGPQ-RQZHXJHFSA-N 0.000 description 1
- KQRWJSXMOVIJKV-ZIADKAODSA-N methyl 2-[4-[(z)-[4-[3-(dimethylamino)propanoyl-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(C)C(=O)CCN(C)C)=C\1C2=CC=C(F)C=C2NC/1=O KQRWJSXMOVIJKV-ZIADKAODSA-N 0.000 description 1
- UIRDUSMACINBJL-FLWNBWAVSA-N methyl 2-[4-[(z)-[4-[4-(dimethylamino)butanoyl-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(C)C(=O)CCCN(C)C)=C\1C2=CC=C(F)C=C2NC/1=O UIRDUSMACINBJL-FLWNBWAVSA-N 0.000 description 1
- REZPPMFUSUOFJJ-DQSJHHFOSA-N methyl 2-[4-[(z)-[4-[[2-(dimethylamino)-2-oxoethyl]-methylsulfonylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(CC(=O)N(C)C)S(C)(=O)=O)=C\1C2=CC=C(F)C=C2NC/1=O REZPPMFUSUOFJJ-DQSJHHFOSA-N 0.000 description 1
- BZNJSXAKWABNQC-QPLCGJKRSA-N methyl 2-[4-[(z)-[4-[acetyl(methyl)amino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(C)C(C)=O)=C\1C2=CC=C(F)C=C2NC/1=O BZNJSXAKWABNQC-QPLCGJKRSA-N 0.000 description 1
- MQXAFJHFVMELDE-FCQUAONHSA-N methyl 2-[4-[(z)-anilino-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(\NC=1C=CC=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O MQXAFJHFVMELDE-FCQUAONHSA-N 0.000 description 1
- CRBILHZMYDIQRQ-UHFFFAOYSA-N methyl 2-cyclopropylacetate Chemical compound COC(=O)CC1CC1 CRBILHZMYDIQRQ-UHFFFAOYSA-N 0.000 description 1
- NRZDFSARADRFDO-RQZHXJHFSA-N methyl 3-[3-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-[(dimethylamino)methyl]anilino]methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(CN(C)C)=CC=2)=C\2C3=CC=C(Cl)C=C3NC/2=O)=C1 NRZDFSARADRFDO-RQZHXJHFSA-N 0.000 description 1
- ODLANNNJAZLBDO-QPLCGJKRSA-N methyl 3-[3-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-[methyl(methylsulfonyl)amino]anilino]methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(=CC=2)N(C)S(C)(=O)=O)=C\2C3=CC=C(Cl)C=C3NC/2=O)=C1 ODLANNNJAZLBDO-QPLCGJKRSA-N 0.000 description 1
- BRFZJMHHONNLJL-DQSJHHFOSA-N methyl 3-[3-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(imidazol-1-ylmethyl)anilino]methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(CN3C=NC=C3)=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 BRFZJMHHONNLJL-DQSJHHFOSA-N 0.000 description 1
- DKIQYCMJVKQMPB-FLWNBWAVSA-N methyl 3-[3-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-[(4-methylpiperazin-1-yl)methyl]anilino]methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(CN3CCN(C)CC3)=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 DKIQYCMJVKQMPB-FLWNBWAVSA-N 0.000 description 1
- HGROPEURVANFTI-MVJHLKBCSA-N methyl 3-[3-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(=CC=2)N(C)C(=O)CN2CCN(C)CC2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 HGROPEURVANFTI-MVJHLKBCSA-N 0.000 description 1
- ROGDAMZEESOPEH-RQZHXJHFSA-N methyl 3-[3-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(CN(C)C)=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 ROGDAMZEESOPEH-RQZHXJHFSA-N 0.000 description 1
- MZIAQQSLVWASGK-ZIADKAODSA-N methyl 3-[3-[(z)-[4-[[2-(dimethylamino)acetyl]-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(=CC=2)N(C)C(=O)CN(C)C)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 MZIAQQSLVWASGK-ZIADKAODSA-N 0.000 description 1
- MWVKQSDEQORFBU-KTMFPKCZSA-N methyl 3-[3-[(z)-[4-[acetyl-[3-(dimethylamino)propyl]amino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound COC(=O)CCC1=CC=CC(C(\NC=2C=CC(=CC=2)N(CCCN(C)C)C(C)=O)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 MWVKQSDEQORFBU-KTMFPKCZSA-N 0.000 description 1
- TYRBZSTYNFZZJG-ZIADKAODSA-N methyl 3-[4-[(z)-(6-bromo-2-oxo-1h-indol-3-ylidene)-[4-(pyrrolidin-1-ylmethyl)anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN2CCCC2)=CC=1)=C\1C2=CC=C(Br)C=C2NC/1=O TYRBZSTYNFZZJG-ZIADKAODSA-N 0.000 description 1
- DBSGWGZUQPGWDT-RQZHXJHFSA-N methyl 3-[4-[(z)-(6-bromo-2-oxo-1h-indol-3-ylidene)-[4-[(dimethylamino)methyl]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN(C)C)=CC=1)=C\1C2=CC=C(Br)C=C2NC/1=O DBSGWGZUQPGWDT-RQZHXJHFSA-N 0.000 description 1
- WZZPXLMFERAYDE-RQZHXJHFSA-N methyl 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[3-[(dimethylamino)methyl]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=C(CN(C)C)C=CC=1)=C\1C2=CC=C(Cl)C=C2NC/1=O WZZPXLMFERAYDE-RQZHXJHFSA-N 0.000 description 1
- BZBSGUNODMYWNA-ZIADKAODSA-N methyl 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-(pyrrolidin-1-ylmethyl)anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN2CCCC2)=CC=1)=C\1C2=CC=C(Cl)C=C2NC/1=O BZBSGUNODMYWNA-ZIADKAODSA-N 0.000 description 1
- HRBSFUACTNRHGX-ASDRPUQFSA-N methyl 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-[(dimethylamino)methyl]anilino]methyl]phenyl]prop-2-enoate Chemical compound C1=CC(C=CC(=O)OC)=CC=C1C(\NC=1C=CC(CN(C)C)=CC=1)=C\1C2=CC=C(Cl)C=C2NC/1=O HRBSFUACTNRHGX-ASDRPUQFSA-N 0.000 description 1
- RJITXNDFZFDIOH-RQZHXJHFSA-N methyl 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-[(dimethylamino)methyl]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN(C)C)=CC=1)=C\1C2=CC=C(Cl)C=C2NC/1=O RJITXNDFZFDIOH-RQZHXJHFSA-N 0.000 description 1
- OTSLAUSJSMDVSR-IZHYLOQSSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-(4-methylsulfonylanilino)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)S(C)(=O)=O)=C\1C2=CC=C(F)C=C2NC/1=O OTSLAUSJSMDVSR-IZHYLOQSSA-N 0.000 description 1
- NOXGXFPKKVATAO-RQZHXJHFSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(1-methylimidazol-2-yl)anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)C=1N(C=CN=1)C)=C\1C2=CC=C(F)C=C2NC/1=O NOXGXFPKKVATAO-RQZHXJHFSA-N 0.000 description 1
- CNHQQWXLMJVNMM-ZIADKAODSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(4-methylpiperazine-1-carbonyl)anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)C(=O)N1CCN(C)CC1)=C\1C2=CC=C(F)C=C2NC/1=O CNHQQWXLMJVNMM-ZIADKAODSA-N 0.000 description 1
- XNVRUHBZRJGWFA-DQSJHHFOSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(imidazol-1-ylmethyl)anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN2C=NC=C2)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O XNVRUHBZRJGWFA-DQSJHHFOSA-N 0.000 description 1
- ZJSDONWEPXLFAZ-ZIADKAODSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(pyrrolidin-1-ylmethyl)anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN2CCCC2)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O ZJSDONWEPXLFAZ-ZIADKAODSA-N 0.000 description 1
- PEFALYLKOKEIPN-FLWNBWAVSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-[(4-methylpiperazin-1-yl)methyl]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN2CCN(C)CC2)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O PEFALYLKOKEIPN-FLWNBWAVSA-N 0.000 description 1
- KSIHKYHXNNWPJN-DQSJHHFOSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CNC(=O)OC(C)(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O KSIHKYHXNNWPJN-DQSJHHFOSA-N 0.000 description 1
- PKNBMXHSAIHWJO-FLWNBWAVSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-[[[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]methyl]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CNCC(=O)OC(C)(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O PKNBMXHSAIHWJO-FLWNBWAVSA-N 0.000 description 1
- RXAWPWGNDQQWGB-MVJHLKBCSA-N methyl 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(C)C(=O)CN1CCN(C)CC1)=C\1C2=CC=C(F)C=C2NC/1=O RXAWPWGNDQQWGB-MVJHLKBCSA-N 0.000 description 1
- SEWXYEQONCNYPH-RQZHXJHFSA-N methyl 3-[4-[(z)-[3-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=C(CN(C)C)C=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O SEWXYEQONCNYPH-RQZHXJHFSA-N 0.000 description 1
- VKYIHAVAGNKJLW-IZHYLOQSSA-N methyl 3-[4-[(z)-[4-(aminomethyl)anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O VKYIHAVAGNKJLW-IZHYLOQSSA-N 0.000 description 1
- KBIWOFWIICHQDX-RQZHXJHFSA-N methyl 3-[4-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O KBIWOFWIICHQDX-RQZHXJHFSA-N 0.000 description 1
- GFSDVYJIQYQFKU-DQSJHHFOSA-N methyl 3-[4-[(z)-[4-[2-(dimethylamino)ethyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CCN(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O GFSDVYJIQYQFKU-DQSJHHFOSA-N 0.000 description 1
- KSPWZKKUEKYADS-ZIADKAODSA-N methyl 3-[4-[(z)-[4-[[2-(dimethylamino)acetyl]-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(C)C(=O)CN(C)C)=C\1C2=CC=C(F)C=C2NC/1=O KSPWZKKUEKYADS-ZIADKAODSA-N 0.000 description 1
- YWTKPHJODUFQBP-FLWNBWAVSA-N methyl 3-[4-[(z)-[4-[[2-(dimethylamino)ethyl-methylamino]methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CN(C)CCN(C)C)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O YWTKPHJODUFQBP-FLWNBWAVSA-N 0.000 description 1
- IKOWJFNGKOQLFU-RQZHXJHFSA-N methyl 3-[4-[(z)-[4-[acetyl(methyl)amino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(C)C(C)=O)=C\1C2=CC=C(F)C=C2NC/1=O IKOWJFNGKOQLFU-RQZHXJHFSA-N 0.000 description 1
- ZNYCFFBGJRZTHM-FLWNBWAVSA-N methyl 3-[4-[(z)-[4-[acetyl-[2-(dimethylamino)ethyl]amino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(CCN(C)C)C(C)=O)=C\1C2=CC=C(F)C=C2NC/1=O ZNYCFFBGJRZTHM-FLWNBWAVSA-N 0.000 description 1
- IATPSFJQKLCUBK-KTMFPKCZSA-N methyl 3-[4-[(z)-[4-[acetyl-[3-(dimethylamino)propyl]amino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(=CC=1)N(CCCN(C)C)C(C)=O)=C\1C2=CC=C(F)C=C2NC/1=O IATPSFJQKLCUBK-KTMFPKCZSA-N 0.000 description 1
- ZTFXASAPRUYRIU-VHXPQNKSSA-N methyl 3-[4-[(z)-anilino-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O ZTFXASAPRUYRIU-VHXPQNKSSA-N 0.000 description 1
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Abstract
Description
본 발명은 6 위치에 치환된 화학식 I의 인돌리논, 이의 호변체, 입체 이성질체, 거울상 이성질체, 혼합물 및 이의 염, 특히 생리학적으로 허용되는 이의 염의 신규의 용도에 관한 것이다.
상기 화학식 I의 화합물, 이의 호변체, 입체 이성질체, 거울상 이성질체, 혼합물 및 이의 염, 특히 생리학적으로 허용되는 이의 염은 WO 04/009547에 중요한 약학적 특성, 특히 다양한 키나제, 특히 VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R 및 HGFR, Flt-3과 같은 수용체 타이로신 키나제에 대해서, 및 배양된 사람 세포, 예를 들어 혈관 생성에서, 특히 내피 세포의 증식에 대해, 또한 다른 세포, 특히 종양 세포의 증식에 대해 억제 효과를 갖는 것으로 기재되어 있다.
그러나, 본 발명에 나타난 이들 화합물의 섬유성 질환의 치료 또는 예방에의 용도는 기재되어 있지 않다.
리모델링은 몸 전체의 많은 조직에서 관찰되는 조직 손상 및 염증에 대한 통상의 반응이다. 염증의 소실 및 조직 손상의 회복 이후, 조직은 통상적으로 이의 원래의 상태로 돌아간다. 조절되지 않은 과다한 조직 회복 또는 더 이상 요구되지 않는 경우의 리모델링 중단의 실패는 섬유증이라고 알려진 상태를 일으킨다. 섬유증은 세포외 기질 성분의 과다한 침착 및 섬유모세포의 과다 성장으로 특징지어진다. 섬유증은 모든 조직에서 일어날 수 있지만 폐, 피부, 소화관, 신장 및 간을 포함하는 화학적 및 생물학적 손상에 자주 노출되는 장기에 특히 널리 존재한다[참조: Eddy, 1996, J Am Soc Nephrol, 7(12):2495-503; Dacic et al., 2003, Am J Respir Cell Mol Biol, 29S: S5-9; Wynn, 2004, Nat Rev Immunol, 4(8):583-94]. 섬유증은 종종 장기의 통상적인 기능(들)을 심각하게 손상시키고, 많은 섬유성 질환은 사실상 생명을 위협하거나 심각하게 변형시키는, 특발성폐섬유증(IPF: idiopathic pulmonary fibrosis), 간경화증, 피부 경화증(scleroderma), 또는 신장 섬유증(renal fibrosis)과 같은 것들이다. 이러한 질환의 치료 선택은 종종 위험하고 비싼 과정인, 장기 이식에 한정된다.
문헌의 많은 부분은 섬유증의 유도 및 지속에서의 성장 인자 계열인 혈소판-유래 성장인자(PDGF: platelet-derived growth factor), 섬유모세포 성장 인자(FGF: fibroblast growth factor), 혈관 내피 세포 성장 인자(VEGF: vascular endothelial growth factor), 표피 성장 인자(EGF: epidermal growth factor) 및 전환 성장 인자 베타(TGFb: transforming growth factor beta)를 포함한다[참조: Levitzki, Cytokine Growth Factor Rev, 2004, 15(4):229-35; Strutz et al., Kidney Intl, 2000, 57:1521-38; Strutz et al., 2003, Springer Semin Immunopathol, 24:459-76; Rice et al., 1999, Amer J Pathol, 155(1):213-221; Broekelmann et al., 1991, Proc Nat Acad Sci, 88:6642-6; Wynn, 2004, Nat Rev Immunol, 4(8):583-94].
PDGF, EGF 및 FGF 계열 성분은 평활근세포, 근육모세포 및 섬유모세포와 같은 중간엽세포(mesenchymal cells)에 대한 효능있는 미토겐이고[참조: Benito et al., 1993, Growth Regul 3(3):172-9; Simm et al, 1998, Basic Res Cardiol, 93(S3):40-3; Klagsburn, Prog Growth Factor Res, 1989, 1(4):207-35; Kirkland et al., 1998, J Am Soc Nephrol, 9(8):1464-73], 섬유증에서 통상의 조직을 대신하는 해당 세포는 조직 리모델링에서 역할을 하는 것으로 여겨진다[참조: Abboud, 1995, Annu Rev Physiol., 57:297-309; Jinnin et al., 2004, J Cell Physiol, online; Martinet et al., 1996, Arch Toxicol 18:127-39; Desmouliere, Cell Biology International, 1995, 19:471-6; Jelaska et al., Springer Semin Immunopathol, 2000, 21:385-95].
PDGF 억제는 실험 모델에서의 간 섬유증 및 폐 섬유증 모두를 약화시키고, 이는 서로 다른 장기에서의 섬유증이 공통된 기원을 갖는다는 것을 암시한다[참조: Borkham-Kamphorst et al., 2004, Biochem Biophys Res Commun; Rice et al., 1999, Amer J Pathol, 155(1):213-221]. EGF 수용체 키나제 억제제는 또한 이러한 폐 섬유증 모델에서 활성이다. 마우스의 이자섬(pancreas islets)에서의, TEGF 부류 성분인 HB-EGF의 3중 과발현은 외분비 및 내분비 구획 모두에서 섬유증을 일으키기에 충분하다[참조: Means et al., 2003, Gastroenterology, 124(4):1020-36].
유사하게, FGF1/FGF2-결핍 마우스는 만성 사염화탄소(CCl4) 노출 이후 급격하게 감소된 간 섬유증을 보인다[참조: Yu et al., 2003, Am J Pathol, 163(4):1653-62]. FGF 발현은 사이질 상처 형성(scarring)과 밀접하게 관련된 사람 신장 사이질 섬유증 뿐 아니라[참조: Strutz et al., 2000, Kidney Intl, 57:1521-38], 실험적 폐 섬유증 모델에서[참조: Barrios et al., 1997, Am J Physiol, 273 (2 Pt 1):L451-8] 증가되고, 이는 다시 다양한 조직에서의 섬유증이 공통된 기원을 갖는다는 생각에 확신을 준다.
추가로, VEGF의 증가된 수준이 천식이 있는 사람에서의 몇몇 연구에서 관찰되었다[참조: Hoshino et al., 2001, J Allergy Clin Immunol 107:1034-39; Hoshino et al. , 2001, J Allergy Clin Immunol 107:295-301; Kanazawa et al. , 2002, Thorax 57:885-8; Asai et al., J Allergy Clin Immunol 110:571-5, 2002; Kanazawa et al., 2004, Am J Respir Crit Care Med, 169:1125-30]. 유전자 도입 마우스 모델에서의 VEGF의 유도성 발현은 천식과 유사한 표현형, 부종, 혈관 형성 및 평활근 과다 형성을 유발한다[참조: Lee et al., 2004, Nature Med 10:1095-1103].
마지막으로, TGFb는 피브로넥틴 및 콜라겐을 포함하는 세포외 기질 단백질의 생산을 자극하고 많은 조직의 섬유증에서 중요한 역할을 하는 것으로 여겨진다[참조: Leask et al., 2004, FASEB J 18(7):816-27; Bartram et al., 2004, Chest 125(2):754-65; Strutz et al., 2003, Springer Semin Immunopathol, 24:459-76; Wynn, 2004, Nat Rev Immunol, 4(8):583-94]. TGFb 생산 및 신호 전달 경로의 억제제는 많은 동물 모델의 섬유증에서 활성이다[참조: Wang et al., 2002, Exp Lung Res, 28:405-17; Laping, 2003, Curr Opin Pharmacol, 3(2):204-8].
상기 요약한 바와 같이, 몇몇 성장 인자는 섬유증에서 조절되지 않고 단일 인자의 억제는 섬유증 모델에서 섬유증의 심각성을 감소시키는 것으로 보인다.
발명의 요약
놀랍게도, 본 발명에 이르러 상기 화학식 I의 화합물이 특정 섬유성 질환의 치료 또는 예방에 효과적이라는 것이 밝혀졌다.
따라서 본 발명은 특정 섬유성 질환의 치료 또는 예방용 약제의 제조를 위한 상기 화학식 I의 화합물의 용도에 관한 것이다.
본 발명은 또한 상기 화학식 I의 화합물과 약제학적으로 적합한 담체를 함께 포함하는 약제학적 조성물을 필요로 하는 환자에게 투여하여, 특정 섬유성 질환을 치료하는 방법에 관한 것이다. 용어 "환자"는 포유류 동물의 몸, 특히 사람의 몸을 포함하는 것을 나타낸다.
본 발명은 추가로 상기 화학식 I의 화합물을 단독으로 또는 하나 이상의 추 가적인 치료 약제와 함께 포함하는 특정 섬유성 질환의 치료 또는 예방용 약제학적 조성물에 관한 것이다.
본 발명에 따라, 화학식 I의 화합물은 하기 화학식의 화합물, 이의 호변체, 거울상 이성질체, 부분입체 이성질체, 이의 혼합물 및 이의 염이다.
화학식 I
I. 상기 화학식 I에서,
X는 산소 원자이고,
R1은 수소 원자이고,
R2는 불소, 염소 또는 브롬 원자 또는 시아노 그룹이고,
R3는 페닐 그룹, 또는 불소, 염소, 브롬 또는 요오드 원자에 의하거나 C1 -3-알콕시 그룹에 의해 일치환된 페닐 그룹이고, 여기서 상술한 비치환되고 일치환된 페닐 그룹은 3- 또는 4-위치에서
불소, 염소 또는 브롬 원자에 의해,
시아노 그룹에 의해,
C1 -3-알콕시 또는 C1 -2-알킬-카보닐-아미노 그룹에 의해,
시아노-C1 -3-알킬, 카복시-C1 -3-알킬, 카복시-C1 -4-알콕시, 카복시-C1 -3-알킬아미노, 카복시-C1 -3-알킬-N-(C1 -3-알킬)-아미노, C1 -4-알콕시-카보닐-C1 -3-알킬, C1 -4-알콕시-카보닐-C1 -3-알콕시, C1 -4-알콕시-카보닐-C1 -3-알킬아미노, C1 -4-알콕시-카보닐-C1 -3-알킬-N-(C1 -3-알킬)-아미노, 아미노-C1 -3-알킬, 아미노-카보닐-C1 -3-알킬, (C1-2-알킬-아미노)-카보닐-C1 -3-알킬, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬, (C1 -2-알킬-카보닐)-아미노-C1 -3-알킬, (C1 -4-알콕시-카보닐)-아미노-C1 -3-알킬, (C3 -6-알킬-카보닐)-아미노-C1 -3-알킬, (페닐-카보닐)-아미노-C1 -3-알킬, (C3 -6-사이클로알킬-카보닐)-아미노-C1 -3-알킬, (C3 -6-사이클로알킬-C1 -3-알킬-카보닐)-아미노-C1 -3-알킬, (티오핀-2-일-카보닐)-아미노-C1 -3-알킬, (퓨란-2-일-카보닐)-아미노-C1 -3-알킬, (페닐-C1 -3-알킬-카보닐)-아미노-C1 -3-알킬, (2-(C1 -4-알콕시)-벤조일-카보닐)-아미노-C1 -3-알킬, (피리딘-2-일-카보닐)-아미노-C1 -3-알킬, (피리딘-3-일-카보닐)-아미노-C1 -3-알킬-, (피리딘-4-일-카보닐)-아미노-C1 -3-알킬- 또는 C1 -3-알킬-피페라진-1-일-카보닐-C1 -3-알킬 그룹에 의해,
카복시-C2 -3-알케닐, 아미노-카보닐-C2 -3-알케닐, (C1 -3-알킬-아미노)-카보닐-C2 -3-알케닐, 디-(C1 -3-알킬)-아미노-카보닐-C2 -3-알케닐 또는 C1 -4-알콕시-카보닐-C2 -3-알케닐 그룹에 의해 추가로 치환될 수 있고,
여기서 상기 치환체는 동일하거나 상이할 수 있고,
R4는 페닐 그룹 또는
아미노, 구아니디노, 모노- 또는 디-(C1 -2-알킬)-아미노-, N-[ω-디-(C1 -3-알킬)-아미노-C2 -3-알킬]-N-(C1 -3-알킬)-아미노, N-메틸-(C3 -4-알킬)-아미노, N-(C1 -3-알킬)-N-벤질아미노, N-(C1 -4-알콕시카보닐)-아미노, N-(C1 -4-알콕시카보닐)-C1 -4-알킬아미노, 4-(C1 -3-알킬)-피페라진-1-일, 이미다졸-1-일, 피롤리딘-1-일, 아제티딘-1-일, 모르폴린-4-일, 피페라진-1-일, 티오모르폴린-4-일 그룹에 의해 말단이 치환된 C1 -3-알킬 그룹에 의해,
디-(C1 -3-알킬)-아미노-(C1 -3-알킬)-술포닐, 2-[디-(C1 -3-알킬)-아미노]-에톡시, 4-(C1 -3-알킬)-피페라진-1-일-카보닐, {ω-[디-(C1 -3-알킬)-아미노]-(C2 -3-알킬)}-N-(C1 -3-알킬)-아미노-카보닐, 1-(C1 -3-알킬)이미다졸-2-일, (C1 -3-알킬)-술포닐 그룹에 의해 또는
화학식
의 그룹에 의해 일치환된 페닐 그룹이고,
여기서
R7은 C1 -2-알킬, C1 -2-알킬-카보닐, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬 또는 C1 -3-알킬술포닐 그룹이고,
R8은 C1 -3-알킬, ω-[디-(C1 -2-알킬)-아미노]-C2 -3-알킬, ω-[모노-(C1 -2-알킬)-아미노]-C2 -3-알킬 그룹, 또는
디-(C1 -2-알킬)-아미노, 피페라진-1-일 또는 4-(C1 -3-알킬)-피페라진-1-일 그룹에 의해 말단이 치환된 (C1 -3-알킬)-카보닐, (C4 -6-알킬)-카보닐 또는 카보닐-(C1 -3-알킬) 그룹이고,
여기서 라디칼 R4에 존재하는 모든 디알킬아미노 그룹은 또한 4급 형태(quaternized form)로, 예를 들어 N-메틸-(N,N-디알킬)-암모늄 그룹으로 존재할 수 있고, 여기서 반대 이온은 바람직하게는 아이오다이드, 클로라이드, 브로마이드, 메틸술포네이트, 파라-톨루엔술포네이트 및 트리플루오로아세테이트로 이루어진 그룹으로부터 선택되고,
R5는 수소 원자이고,
R6는 수소 원자이고,
여기서 상술한 알킬 그룹은, 추가로 1 내지 3개의 수소 원자가 불소 원자에 의해 대체될 수 있는 직쇄 또는 측쇄 알킬 그룹을 포함하고,
여기서 추가로, 존재하는 카복실, 아미노 또는 이미노 그룹은 생체내에서 제거가능한 라디칼에 의해 치환될 수 있거나, 프로드럭 라디칼의 형태, 예를 들어 생체내에서 카복실 그룹으로 전환될 수 있는 그룹의 형태 또는 생체내에서 이미노 또는 아미노 그룹으로 전환될 수 있는 그룹의 형태로 존재할 수 있다.
II. 특히 바람직한 상기 화학식 I의 화합물에서
X, R1, R5 및 R6는 I에서 정의된 바와 같고,
II.i. R2 및 R4는 I에서 정의된 바와 같고
R3는 페닐 그룹, 또는 불소, 염소, 브롬 또는 요오드 원자에 의하거나 C1 -3-알콕시 그룹에 의해 일치환된 페닐 그룹이고, 여기서 상술한 비치환되고 일치환된 페닐 그룹은 3- 또는 4-위치에서
불소, 염소 또는 브롬 원자에 의해,
시아노 그룹에 의해,
C1 -3-알콕시 또는 C1 -2-알킬-카보닐-아미노 그룹에 의해,
시아노-C1 -3-알킬, 카복시-C1 -3-알킬, 카복시-C1 -4-알콕시, 카복시-C1 -3-알킬아미노, 카복시-C1 -3-알킬-N-(C1 -3-알킬)-아미노, C1 -4-알콕시-카보닐-C1 -3-알킬, C1 -4-알콕시-카보닐-C1-3-알콕시, C1-4-알콕시-카보닐-C1-3-알킬아미노, C1-4-알콕시-카보닐-C1 -3-알킬-N-(C1 -3-알킬)-아미노, 아미노-C1 -3-알킬, 아미노카보닐-C1 -3-알킬, (C1-2-알킬-아미노)-카보닐-C1 -3-알킬, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬, (C1 -2-알킬-카보닐)-아미노-C1 -3-알킬, (C1 -4-알콕시-카보닐)-아미노-C1 -3-알킬, (C3 -6-알킬-카보닐)-아미노-C1 -3-알킬, (페닐-카보닐)-아미노-C1 -3-알킬, (C3 -6-사이클로알킬-카보닐)-아미노-C1-3-알킬, (C3-6-사이클로알킬-C1-3-알킬-카보닐)-아미노-C1-3-알킬, (티오핀-2-일-카보닐)-아미노-C1-3-알킬, (퓨란-2-일-카보닐)-아미노-C1-3-알킬, (페닐-C1-3-알킬-카보닐)-아미노-C1-3-알킬, (2-(C1-4-알콕시)-벤조일-카보닐)-아미노-C1-3-알킬, (피리딘-2-일-카보닐)-아미노-C1-3-알킬, (피리딘-3-일-카보닐)-아미노-C1-3-알킬, (피리딘-4-일-카보닐)-아미노-C1-3-알킬 또는 C1-3-알킬-피페라진-1-일-카보닐-C1 -3-알킬 그룹에 의해,
카복시-C2 -3-알케닐, 아미노-카보닐-C2 -3-알케닐-, (C1 -3-알킬-아미노)-카보닐-C2 -3-알케닐-, 디-(C1 -3-알킬)-아미노-카보닐-C2 -3-알케닐 또는 C1 -4-알콕시-카보닐-C2 -3-알케닐 그룹에 의해 추가로 치환될 수 있고,
여기서 상기 치환체는 동일하거나 상이할 수 있고;
II.ii. R2 및 R4는 I에서 정의된 바와 같고
R3는
C1 -2-알킬-카보닐-아미노 그룹에 의해,
카복시-C1 -3-알킬, 카복시-C1 -4-알콕시, C1 -4-알콕시-카보닐-C1 -3-알킬, C1 -4-알콕시-카보닐-C1 -3-알콕시, 아미노카보닐-C1 -3-알킬, (C1 -2-알킬-아미노)-카보닐-C1 -3-알킬, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬, (C1 -2-알킬-카보닐)-아미노-C1 -3-알킬, (C1-4-알콕시-카보닐)-아미노-C1 -3-알킬, (페닐-카보닐)-아미노-C1 -3-알킬, (C3 -6-사이클로알킬-카보닐)-아미노-C1 -3-알킬, (C3 -6-사이클로알킬-C1 -3-알킬-카보닐)-아미노-C1-3-알킬, (티오핀-2-일-카보닐)-아미노-C1-3-알킬, (퓨란-2-일-카보닐)-아미노-C1-3-알킬, (페닐-C1-3-알킬-카보닐)-아미노-C1-3-알킬, (2-(C1-4-알콕시)-벤조일-카보닐)-아미노-C1-3-알킬, (피리딘-2-일-카보닐)-아미노-C1-3-알킬, (피리딘-3-일-카보닐)-아미노-C1-3-알킬, (피리딘-4-일-카보닐)-아미노-C1-3-알킬 또는 C1-3-알킬-피페라진-1-일-카보닐-C1 -3-알킬 그룹에 의해,
아미노카보닐-C2 -3-알케닐, (C1 -3-알킬-아미노)-카보닐-C2 -3-알케닐, 디-(C1 -3-알킬-)-아미노-카보닐-C2 -3-알케닐 또는 C1 -4-알콕시-카보닐-C2 -3-알케닐 그룹에 의해 치환된 페닐 그룹이고;
II.iii. R2 및 R4는 I에 정의된 바와 같고
R3는 카복시-C1 -3-알킬 또는 C1 -4-알콕시-카보닐-C1 -3-알킬 그룹에 의해 치환된 페닐그룹이고;
II.iv. R3 및 R4는 I에 정의된 바와 같고
R2는 불소 또는 염소 원자이고;
II.v. R2 및 R3는 I에 정의된 바와 같고
R4는 페닐 그룹, 또는 아미노, 구아니디노, 모노- 또는 디-(C1 -2-알킬)-아미노-, N-[ω-디-(C1 -3-알킬)-아미노-C2 -3-알킬]-N-(C1 -3-알킬)-아미노, N-메틸-(C3 -4-알킬)-아미노, N-(C1 -3-알킬)-N-벤질아미노, N-(C1 -4-알콕시카보닐)-아미노, N-(C1 -4-알콕시카보닐)-C1 -4-알킬아미노, 4-(C1 -3-알킬)-피페라진-1-일, 이미다졸-1-일, 피롤리딘-1-일, 아제티딘-1-일, 모르폴린-4-일, 피페라진-1-일, 티오모르폴린-4-일 그룹에 의해 말단이 치환된 C1 -3-알킬 그룹에 의해,
디-(C1 -3-알킬)-아미노-(C1 -3-알킬)-술포닐, 2-[디-(C1 -3-알킬)-아미노]-에톡시, 4-(C1 -3-알킬)-피페라진-1-일-카보닐, {ω-[디-(C1 -3-알킬)-아미노]-(C2 -3-알킬)}-N-(C1 -3-알킬)-아미노-카보닐, 1-(C1 -3-알킬)이미다졸-2-일, (C1 -3-알킬)-술포닐 그룹에 의해, 또는
화학식
의 그룹에 의해 일치환된 페닐 그룹이고
여기서
R7는 C1 -2-알킬, C1 -2-알킬-카보닐, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬 또는 C1 -3-알킬술포닐 그룹이고
R8는 C1 -3-알킬, ω-[디-(C1 -2-알킬)-아미노]-C2 -3-알킬, ω-[모노-(C1 -2-알킬)-아미노]-C2 -3-알킬 그룹, 또는
디-(C1 -2-알킬)-아미노, 피페라진-1-일 또는 4-(C1 -3-알킬)-피페라진-1-일 그룹에 의해 말단이 치환된 (C1 -3-알킬)-카보닐, (C4 -6-알킬)-카보닐 또는 카보닐-(C1 -3-알킬) 그룹이고,
여기서 R4에 존재하는 모든 디알킬아미노 그룹은 또한 4급 형태로, 예를 들어 N-메틸-(N,N-디알킬)-암모늄 그룹으로 존재할 수 있고, 여기서 반대 이온은 바람직하게는 아이오다이드, 클로라이드, 브로마이드, 메틸술포네이트, 파라-톨루엔술포네이트 및 트리플루오로아세테이트로 이루어진 그룹으로부터 선택된다.
III. 특히 언급되는 상기 화학식 I의 특히 바람직한 화합물의 하위 그룹은 다음과 같다:
III.i. X, R1, R2, R5 및 R6는 I에 정의된 바와 같고, R3는 II.i.에 정의된 바와 같고 R4는 II.v.에 정의된 바와 같다;
III.ii. X, R1, R2, R5 및 R6는 I에 정의된 바와 같고, R3는 II.ii.에 정의된 바와 같고 R4는 II.v.에 정의된 바와 같다;
III.iii. X, R1, R2, R5 및 R6는 I에 정의된 바와 같고, R3는 II.iii.에 정의된 바와 같고 R4는 II.v.에 정의된 바와 같다;
III.iv. X, R1, R5 및 R6는 I에 정의된 바와 같고, R2는 II.iv.에 정의된 바와 같고, R3는 II.i., II.ii. 또는 II.iii.에 정의된 바와 같고 R4는 II.v.에 정의된 바와 같다.
상기 화학식 I의 추가의 바람직한 그룹은
X는 산소 원자이고,
R1은 수소 원자이고,
R2는 불소, 염소 또는 브롬 원자 또는 시아노 그룹이고,
R3는 페닐 그룹 또는 불소, 염소, 브롬 또는 요오드 원자 또는 C1 -3-알콕시 그룹에 의해 일치환된 페닐 그룹이고, 여기서 상술한 비치환되거나 일치환된 페닐 그룹은 추가로
불소, 염소 또는 브롬 원자에 의해,
C1 -3-알콕시 또는 C1 -2-알킬-카보닐-아미노 그룹에 의해,
카복시-C1 -3-알킬, 아미노-카보닐-C1 -3-알킬, (C1 -2-알킬-아미노)-카보닐-C1 -3-알킬, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬, (C1 -2-알킬-카보닐)-아미노-C1 -3-알킬 또는 (페닐-카보닐)-아미노-C1 -3-알킬 그룹에 의해 3- 또는 4- 위치에 치환될 수 있고,
여기서 상기 치환체는 동일하거나 상이할 수 있고,
R4는
디-(C1 -2-알킬)-아미노 그룹에 의해 말단이 치환된 C1 -3-알킬 그룹에 의해, 또는
화학식
의 그룹에 의해 치환된 페닐 그룹이고,
여기서
R7는 C1 -2-알킬, C1 -2-알킬-카보닐, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬 또는 C1 -3-알킬술포닐 그룹이고,
R8는 C1 -3-알킬 또는 w-[디-(C1 -2-알킬)-아미노]-C2 -3-알킬 그룹, 또는
디-(C1 -2-알킬)-아미노, 피페라지노 또는 4-(C1 -3-알킬)-피페라진-1-일 그룹에 의해 말단이 치환된 C1 -3-알킬-카보닐 그룹이고,
R5는 수소 원자이고,
R6는 수소 원자이고,
여기서 상술한 알킬 그룹은, 추가로 1 내지 3개의 수소 원자가 불소 원자에 의해 대체될 수 있는 직쇄 또는 측쇄 알킬 그룹을 포함하고,
여기서 추가로, 존재하는 카복실, 아미노 또는 이미노 그룹은 생체내에서 제거가능한 라디칼에 의해 치환될 수 있는, 화학식 I의 화합물, 이의 호변체, 거울상 이성질체, 부분입체이성질체, 이의 혼합물 및 이의 염이다.
다음의 화학식 I의 화합물, 이의 호변체, 거울상 이성질체, 부분입체이성질체, 이의 혼합물 및 이의 염이 특히 바람직하며,
(a) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(b) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(c) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(d) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(e) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(f) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(g) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(h) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(i) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(j) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(k) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(l) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(m) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(n) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(o) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(p) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(q) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)-메틸렌]-6-브로모-2-인돌리논
여기서 추가로, 존재하는 카복실, 아미노 또는 이미노 그룹은 생체내에서 제거가능한 라디칼에 의해 치환될 수 있거나 프로드럭 라디칼의 형태, 예를 들어 생체내에서 카복실 그룹으로 전환될 수 있는 그룹의 형태 또는 생체내에서 이미노 또는 아미노 그룹으로 전환될 수 있는 그룹의 형태로 존재할 수 있다.
생체 내에서 카복실 그룹으로 전환될 수 있는 그룹은, 예를 들어,
하이드록시메틸 그룹, 카복실 그룹이고, 이는 알코올로 에스테르화되고 여기서 알코올 잔기가 바람직하게는 C1 -6-알카놀, 페닐-C1 -3-알카놀, C3 -9-사이클로알카놀(여기서 C5 -8-사이클로알카놀이 추가로 1 또는 2개의 C1 -3-알킬 그룹에 의해 치환될 수 있다), C5 -8-사이클로알카놀(3- 또는 4- 위치의 하나의 메틸렌 그룹이 산소 원자 또는 C1 -3-알킬, 페닐-C1 -3-알킬, 페닐-C1 -3-알콕시-카보닐 또는 C1 -6-알킬-카보닐 그룹에 의해 임의로 치환된 이미노 그룹에 의해 대체되고 사이클로알카놀 잔기가 추가로 1 또는 2개의 C1 -3-알킬 그룹에 의해 치환될 수 있다), C4 -7-사이클로알케놀, C3 -5-알케놀, 페닐-C3 -5-알케놀, C3 -5-알키놀 또는 페닐-C3 -5-알키놀이고(이 때 이중 또는 삼중 결합을 하는 탄소 원자에 연결된 산소 원자에는 결합이 존재하지 않는다), C3 -8-사이클로알킬-C1 -3-알카놀, 바이사이클로알카놀(1 또는 2개의 C1 -3-알킬 그룹에 의해 바이사이클로알킬 잔기가 추가로 치환될 수 있는 총 8 내지 10개의 탄소 원자를 갖는다), 1,3-디하이드로-3-옥소-1-이소벤조퓨라놀 또는 화학식
Ra-CO-O-(RbCRc)-OH의 알콜
(여기서
Ra는 C1 -8-알킬, C5 -7-사이클로알킬, 페닐 또는 페닐-C1 -3-알킬 그룹이고,
Rb는 수소 원자, C1 -3-알킬, C5 -7-사이클로알킬 또는 페닐 그룹이고,
Rc는 수소 원자 또는 C1 -3-알킬 그룹이다),
을 나타내는 것으로 이해되고,
이미노 또는 아미노 그룹으로부터 생체내에서 제거가능한 라디칼은 예를 들어, 하이드록실 그룹, 아실 그룹(예를 들어, 벤조일 또는 피리디노일 그룹), 또는 C1-16-알킬카보닐 그룹(예를 들어, 포르밀, 아세틸, 프로피오닐, 부타노일, 펜타노일 또는 헥사노일 그룹), 알릴옥시카보닐 그룹, C1 -16-알콕시-카보닐 그룹(예를 들어, 메톡시카보닐, 에톡시카보닐, 프로폭시카보닐, 이소프로폭시카보닐, 부톡시카보닐, 3급-부톡시카보닐, 펜톡시카보닐, 헥실옥시카보닐, 옥틸옥시카보닐, 노닐옥시카보닐, 데실옥시카보닐, 운데실옥시카보닐, 도데실옥시카보닐 또는 헥사데실옥시카보닐 그룹), 페닐-C1 -6-알콕시-카보닐 그룹(예를 들어, 벤질옥시카보닐, 페닐에톡시카보닐 또는 페닐프로폭시카보닐 그룹), C1 -3-알킬술포닐-C1 -4-알콕시-카보닐, C1 -3-알콕시-C2 -4-알콕시-C2 -4-알콕시-카보닐 또는 RaCO-O-(RbCRc)-O-CO- 그룹이고,
여기서 Ra는 C1 -8-알킬, C5 -7-사이클로알킬, 페닐 또는 페닐-C1 -3-알킬 그룹이고,
Rb는 수소 원자, C1 -3-알킬, C5 -7-사이클로알킬 또는 페닐 그룹이고,
Rc는 수소 원자, C1 -3-알킬 또는 RaCO-O-(RbCRc)-O- 그룹이고, 여기서 Ra 내지 Rc 는 상기 정의된 바와 같고,
추가로, 아미노 그룹에 대해, 프탈이미도 그룹을 나타내는 것으로 이해되고, 여기서 상술한 에스테르 라디칼은 또한 생체내에서 카복실 그룹으로 전환될 수 있는 그룹으로 사용될 수 있다.
바람직한 프로드럭 라디칼은 카복실 그룹에 대해 C1 -6-알콕시-카보닐 그룹(예를 들어 메톡시카보닐, 에톡시카보닐, n-프로필옥시카보닐, 이소프로필옥시카보닐, n-부틸옥시-카보닐, n-펜틸옥시카보닐, n-헥실옥시-카보닐 또는 사이클로헥실옥시카보닐 그룹), 또는 페닐-C1 -3-알콕시-카보닐 그룹(예를 들어 벤질옥시카보닐 그룹)이고,
이미노 또는 아미노 그룹에 대해, C1 -9-알콕시-카보닐 그룹(예를 들어 메톡시-카보닐, 에톡시카보닐, n-프로필옥시카보닐, 이소프로필옥시카보닐, n-부틸옥시-카보닐, n-펜틸옥시-카보닐, n-헥실옥시카보닐, 사이클로헥실옥시카보닐, n-헵틸옥시카보닐, n-옥틸옥시카보닐 또는 n-노닐옥시카보닐 그룹), 페닐-C1 -3-알콕시-카보닐 그룹(예를 들어 벤질-옥시카보닐 그룹), C1 -3-알킬 그룹에 의해 임의로 치환된 페닐카보닐 그룹(예를 들어 벤조일 또는 4-에틸-벤조일 그룹), 피리디노일 그룹(예를 들어 니코티노일 그룹), C1 -3-알킬술포닐-n-C2 -3-알콕시-카보닐 또는 C1 -3-알콕시-C2 -3-알콕시-C1 -4-알콕시-카보닐 그룹(예를 들어 2-메틸술포닐에톡시카보닐 또는 2-(2-에톡시)-에톡시카보닐 그룹)이다.
상기 예시된 화합물, 이의 호변체, 이의 부분입체 이성질체 또는 이의 생리학적으로 허용되는 염 뿐만 아니라, 이의 제조 방법이 WO 04/009547에 기재되어 있고, 이의 내용을 본원에서 참조로 인용하고 있다.
다음의 특정 화합물 목록은 본 발명을 설명하지만, 이의 범주에 어떠한 제한을 두지는 않는다:
(1) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(3-아이오도페닐)-메틸렌]-6-클로로-2-인돌리논
(2) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-아이오도페닐)메틸렌]-6-클로로-2-인돌리논
(3) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-클로로페닐)메틸렌]-6-클로로-2-인돌리논
(4) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-클로로페닐)메틸렌]-6-클로로-2-인돌리논
(5) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-클로로페닐)메틸렌]-6-클로로-2-인돌리논
(6) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-클로로페닐)메틸렌]-6-클로로-2-인돌리논
(7) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-클로로페닐)메틸렌]-6-클로로-2-인돌리논
(8) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3,4-디메톡시페닐)메틸렌]-6-클로로-2-인돌리논
(9) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3,4-디메톡시페닐)메틸렌]-6-클로로-2-인돌리논
(10) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3,4-디메톡시페닐)메틸렌]-6-클로로-2-인돌리논
(11) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3,4-디메톡시페닐)-메틸렌]-6-클로로-2-인돌리논
(12) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸카바모일)아닐리노)-1-(3,4-디메톡시페닐)메틸렌]-6-클로로-2-인돌리논
(13) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-시아노페닐)-메틸렌]-6-클로로-2-인돌리논
(14) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-아이오도페닐)메틸렌]-6-플루오로-2-인돌리논
(15) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-플루오로페닐)메틸렌]-6-플루오로-2-인돌리논
(16) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-플루오로페닐)메틸렌]-6-플루오로-2-인돌리논
(17) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-플루오로페닐)메틸렌]-6-플루오로-2-인돌리논
(18) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-아세틸아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(19) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-아세틸아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(20) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-아세틸아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(21) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(22) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-아이오도페닐)메틸렌]-6-플루오로-2-인돌리논
(23) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(24) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-(N-3급-부톡시카보닐-아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(25) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(26) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(27) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-시아노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(28) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(N-3급-부톡시카보닐-아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(29) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(N-3급-부톡시카보닐-아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(30) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-(N-3급-부톡시카보닐-2-아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(31) 3-Z-[1-(4-(N-아세틸-N-메틸아미노)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(32) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(33) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(34) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(35) 3-Z-[1-(4-(N-3급-부톡시카보닐메틸아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(36) 3-Z-[1-(4-(4-메틸피페라진-1-일-카보닐)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(37) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(38) 3-Z-[1-(4-메틸술포닐아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(39) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(40) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(41) 3-Z-[1-(4-(4-메틸피페라진-1-일-카보닐)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(42) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(43) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(44) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(45) 3-Z-[1-(4-(N-(4-디메틸아미노-부틸카보닐)-N-메틸아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(46) 3-Z-[1-아닐리노-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(47) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(48) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(49) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(50) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(51) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(52) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(53) 3-Z-[1-(4-메틸술포닐아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(54) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(55) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(56) 3-Z-[1-아닐리노-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(57) 3-Z-[1-(4-메틸술포닐아닐리노)-1-(3-메톡시카보닐메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(58) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(59) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(60) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(61) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(62) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(63) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(64) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(65) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(66) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(N-3급-부톡시카보닐-아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(67) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(3-아세틸아미노메틸페닐)메틸렌]-6-클로로-2-인돌리논
(68) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-아세틸아미노메틸페닐)메틸렌]-6-클로로-2-인돌리논
(69) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3-아세틸아미노메틸페닐)메틸렌]-6-클로로-2-인돌리논
(70) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-아세틸아미노메틸페닐)메틸렌]-6-클로로-2-인돌리논
(71) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(72) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(73) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(74) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(75) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(76) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(77) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(78) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(79) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(80) 3-Z-[1아닐리노-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(81) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(82) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(83) 3-Z-[1-(4-(N-3급-부톡시카보닐아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(84) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(3-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(85) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-메톡시카보닐메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(86) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(87) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(88) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-에톡시카보닐에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(89) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(90) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(91) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(92) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(93) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(94) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(95) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(96) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(97) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(98) 3-Z-[1아닐리노-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(99) 3-Z-[1-(4-(N-3급-부톡시카보닐아미노메틸)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(100) 3-Z-[1-(4-(N-3급-부톡시카보닐메틸아미노메틸)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(101) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-메톡시카보닐메톡시-페닐)메틸렌]-6-플루오로-2-인돌리논
(102) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-메톡시카보닐메톡시-페닐)메틸렌]-6-플루오로-2-인돌리논
(103) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-에톡시카보닐-에톡시)페닐)메틸렌]-6-플루오로-2-인돌리논
(104) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(105) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(106) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(107) 3-Z-[1-(3-디메틸아미노메틸아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(108) 3-Z-[1-(3-디메틸아미노메틸아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(109) 3-Z-[1-(3-디메틸아미노메틸아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(110) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3,4-디메톡시페닐)-메틸렌]-6-시아노-2-인돌리논
(111) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(3-(2-메톡시카보닐비닐)페닐)메틸렌]-6-클로로-2-인돌리논
(112) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐-비닐)페닐)메틸렌]-6-클로로-2-인돌리논
(113) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-카바모일-비닐)페닐)메틸렌]-6-플루오로-2-인돌리논
(114) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐-비닐)페닐)메틸렌]-6-플루오로-2-인돌리논
(115) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-(2-메톡시카보닐-비닐)페닐)메틸렌]-6-플루오로-2-인돌리논
(116) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(117) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(118) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(119) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(120) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(121) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-아미노메틸페닐)-메틸렌]-6-클로로-2-인돌리논
(122) 3-Z-[1-(4-(N-((4-메틸피페라진-1-일)메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-아미노메틸페닐)메틸렌]-6-클로로-2-인돌리논
(123) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(124) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(3-(2-아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(125) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(126) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(127) 3-Z-[1-(4-(메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(128) 3-Z-[1-(4-(메틸아미노메틸)아닐리노)-1-(4-(2-메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(129) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(130) 3-Z-[1-(4-(아미노메틸)아닐리노)-1-(4-(2-메톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(131) 3-Z-[1-(4-(아미노메틸)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(132) 3-Z-[1-(4-(메틸아미노메틸)아닐리노)-1-(3-(2-에톡시카보닐에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(133) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(134) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(135) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(136) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(137) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(138) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(139) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(140) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(141) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(142) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(143) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(144) 3-Z-[1-(4-(N-3급-부톡시카보닐메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(145) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(146) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(147) 3-Z-[1-(4-메틸술포닐아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(148) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(3-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(149) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(150) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(151) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(3-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(152) 3-Z-[1-아닐리노-1-(3-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(153) 3-Z-[1-(4-메틸술포닐아닐리노)-1-(3-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(154) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(3-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(155) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(3-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(156) 3-Z-[1아닐리노-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(157) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-카복시메틸페닐)-메틸렌]-6-
(158) 플루오로-2-인돌리논
(159) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(160) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(161) 3-Z-[1-(4-(4-메틸피페라진-1-일-카보닐)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(162) 3-Z-[1-(4-메틸술포닐아닐리노)-1-(4-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(163) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(4-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(164) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(165) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(166) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(4-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(167) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(168) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3-카복시메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(169) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(170) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(171) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(172) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(173) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(174) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(175) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(176) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(177) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(178) 3-Z-[1-(4-(N-(4-디메틸아미노-부틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(179) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(180) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(181) 3-Z-[1아닐리노-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(182) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(183) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(184) 3-Z-[1-(4-아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(185) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(3-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(186) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-카복시메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(187) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(188) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(189) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(190) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(191) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(192) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(193) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(194) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(195) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(196) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(197) 3-Z-[1아닐리노-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(198) 3-Z-[1-(4-아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(199) 3-Z-[1-(4-메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(200) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카복시메톡시-페닐)-메틸렌]-6-플루오로-2-인돌리논
(201) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카복시메톡시-페닐)페닐)메틸렌]-6-플루오로-2-인돌리논
(202) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(203) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(204) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)-메틸렌]-6-브로모-2-인돌리논
(205) 3-Z-[1-(3-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(206) 3-Z-[1-(3-디메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리
(207) 3-Z-[1-(3-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(208) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카바모일-에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(209) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-메틸카바모일-에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(210) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(211) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-디메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(212) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(213) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(214) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-디메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(215) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카바모일메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(216) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(217) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카바모일메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(218) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-디메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(219) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-(4-메틸피페라진-1-일-카보닐)에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(220) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(221) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(222) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-디메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(223) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(224) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(225) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-디메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(226) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(227) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(4-(2-메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(228) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(229) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-메틸카바모일에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(230) 3-Z-[1-(4-(N-3급-부톡시카보닐메틸아미노메틸)아닐리노)-1-(4-(2-메틸카바모일에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(231) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(232) 3-Z-[1-(4-메틸술포닐아닐리노)-1-(4-(2-메틸카바모일-에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(233) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(4-(2-메틸카바모일에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(234) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(3-메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(235) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-메틸카바모일메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(236) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-아세틸아미노메틸페닐)-메틸렌]-6-클로로-2-인돌리논
(237) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-아세틸아미노메틸페닐)메틸렌]-6-클로로-2-인돌리논
(238) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-벤조일아미노페닐)-메틸렌]-6-클로로-2-인돌리논
(239) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-벤조일아미노메틸페닐)메틸렌]-6-클로로-2-인돌리논
(240) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-아세틸아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(241) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-프로피오닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(242) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-벤조일아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(243) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-페닐아세틸아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(244) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-아세틸아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(245) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-벤조일아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(246) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-프로피오닐아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(247) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-페닐아세틸아미노에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(248) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-아세틸아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(249) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-프로피오닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(250) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-페닐아세틸아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(251) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-아세틸아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(252) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-프로피오닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(253) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-페닐아세틸아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(254) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-사이클로프로필카보닐아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(255) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-사이클로부틸카보닐아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(256) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(피리딘-2-일-카보닐아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(257) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-사이클로헥실카보닐아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(258) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(피리딘-3-일-카보닐아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(259) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-이소부티릴아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(260) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(3-메틸부티릴아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(261) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-사이클로헥실메틸카보닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(262) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-메톡시아세틸아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(263) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-메톡시벤조일-아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(264) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-3급-부틸아세틸아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(265) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-티오핀-카보닐아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(266) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-피발로일아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(267) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-퓨로일아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(268) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-아세틸아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(269) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-프로피오닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(270) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-벤조일아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(271) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-페닐아세틸아미노메틸페닐)-메틸렌]-6-플루오로-2-인돌리논
(272) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-사이클로프로필카보닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(273) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-사이클로부틸카보닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(274) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(피리딘-2-일-카보닐아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(275) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-사이클로헥실카보닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(276) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(피리딘-3-일-카보닐아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(277) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-이소부티릴아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(278) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(3-메틸부티릴-아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(279) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-사이클로헥실메틸카보닐아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(280) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-메톡시아세틸아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(281) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-메톡시벤조일-아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(282) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-3급-부틸아세틸아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(283) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-티오핀카보닐아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(284) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-피발로일아미노메틸페닐)메틸렌]-6-플루오로-2-인돌리논
(285) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-퓨로일아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(286) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(피리딘-4-일-카보닐아미노메틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(287) 3-Z-[1-(4-트리메틸암모늄메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논 아이오다이드
(288) 3-Z-[1-(4-tri메틸암모늄메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논 아이오다이드
(289) 3-Z-[1-(4-구아니디노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(290) 3-Z-[1-(4-구아니디노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(291) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(292) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(293) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(294) 3-Z-[1-(4-(N-(2-메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(295) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(296) 3-Z-[1-(4-(N-(3-메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(297) 3-Z-[1-(4-(3-디메틸아미노프로필)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(298) 3-Z-[1-(4-에틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(299) 3-Z-[1-(4-메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(300) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(301) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(302) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(303) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-프로필술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(304) 3-Z-[1-(4-아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(305) 3-Z-[1-(3-(메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(306) 3-Z-[1-(3-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(307) 3-Z-[1-(3-(3-디메틸아미노프로필)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(308) 3-Z-[1-(4-(N-(디메틸아미노-카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(309) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(310) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(311) 3-Z-[1-(4-(N-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(312) 3-Z-[1-(4-(2-디에틸아미노에틸술포닐)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(313) 3-Z-[1-(4-(N-(2-디메틸아미노에틸-카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(314) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(315) 3-Z-[1-(4-(2-디메틸아미노에톡시)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(316) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(317) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(318) 3-Z-[1-(4-(메틸에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(319) 3-Z-[1-(4-(메틸프로필아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(320) 3-Z-[1-(4-(메틸벤질아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(321) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐메틸렌]-6-클로로-2-인돌리논
(322) 3-Z-[1-(4-(아제티딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(323) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(324) 3-Z-[1-(4-(피페라진-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(325) 3-Z-[1-(4-(모르폴린-4-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(326) 3-Z-[1-(4-(티오모르폴린-4-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(327) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(328) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(329) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(330) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(331) 3-Z-[1-(4-(N-(2-메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(332) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(333) 3-Z-[1-(4-(N-(3-메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(334) 3-Z-[1-(4-(3-디메틸아미노프로필)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(335) 3-Z-[1-(4-에틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(336) 3-Z-[1-(4-메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(337) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(338) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(339) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(340) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-프로필술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(341) 3-Z-[1-(4-아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(342) 3-Z-[1-(3-(디메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(343) 3-Z-[1-(3-(메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(344) 3-Z-[1-(3-(2-디메틸아미노에틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(345) 3-Z-[1-(3-(3-디메틸아미노프로필)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(346) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(347) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(348) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(349) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(350) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(351) 3-Z-[1-(4-(N-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(352) 3-Z-[1-(4-(2-디에틸아미노에틸술포닐)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(353) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(354) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(355) 3-Z-[1-(4-(2-디메틸아미노에톡시)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(356) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(357) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(358) 3-Z-[1-(4-(메틸에틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(359) 3-Z-[1-(4-(메틸프로필아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(360) 3-Z-[1-(4-(메틸벤질아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(361) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(362) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐메틸렌]-6-클로로-2-인돌리논
(363) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(364) 3-Z-[1-(4-(아제티딘-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(365) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(366) 3-Z-[1-(4-(피페라진-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(367) 3-Z-[1-(4-(모르폴린-4-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(368) 3-Z-[1-(4-(티오모르폴린-4-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(369) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논
(370) 3-Z-[1-(4-(N-(2-메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(371) 3-Z-[1-(4-(N-(3-메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(372) 3-Z-[1-(4-(3-디메틸아미노프로필)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(373) 3-Z-[1-(4-에틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(374) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(375) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-프로필술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(376) 3-Z-[1-(3-(메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(377) 3-Z-[1-(3-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(378) 3-Z-[1-(3-(3-디메틸아미노프로필)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(379) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(380) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(381) 3-Z-[1-(4-(N-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(382) 3-Z-[1-(4-(2-디에틸아미노에틸술포닐)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(383) 3-Z-[1-(4-(2-디메틸아미노에톡시)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(384) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(385) 3-Z-[1-(4-(메틸에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(386) 3-Z-[1-(4-(메틸프로필아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(387) 3-Z-[1-(4-(메틸벤질아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(388) 3-Z-[1-(4-(아제티딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(389) 3-Z-[1-(4-(피페라진-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(390) 3-Z-[1-(4-(모르폴린-4-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(391) 3-Z-[1-(4-(티오모르폴린-4-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(392) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(393) 3-Z-[1-(4-(N-(2-메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(394) 3-Z-[1-(4-(N-(3-메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(395) 3-Z-[1-(4-(3-디메틸아미노프로필)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(396) 3-Z-[1-(4-에틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(397) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(398) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(399) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-프로필술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(400) 3-Z-[1-(3-(메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(401) 3-Z-[1-(3-(2-디메틸아미노에틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(402) 3-Z-[1-(3-(3-디메틸아미노프로필)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(403) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(404) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(405) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(406) 3-Z-[1-(4-(N-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(407) 3-Z-[1-(4-(2-디에틸아미노에틸술포닐)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(408) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(409) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(410) 3-Z-[1-(4-(2-디메틸아미노에톡시)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(411) 3-Z-[1-(4-(메틸에틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(412) 3-Z-[1-(4-(메틸프로필아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(413) 3-Z-[1-(4-(메틸벤질아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(414) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(415) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(416) 3-Z-[1-(4-(아제티딘-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(417) 3-Z-[1-(4-(피페라진-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(418) 3-Z-[1-(4-(모르폴린-4-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(419) 3-Z-[1-(4-(티오모르폴린-4-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논
(420) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(421) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(422) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(423) 3-Z-[1-(4-(N-(2-메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(424) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(425) 3-Z-[1-(4-(N-(3-메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(426) 3-Z-[1-(4-(3-디메틸아미노프로필)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(427) 3-Z-[1-(4-에틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(428) 3-Z-[1-(4-메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(429) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(430) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(431) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(432) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-프로필술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(433) 3-Z-[1-(4-아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(434) 3-Z-[1-(3-(디메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(435) 3-Z-[1-(3-(메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(436) 3-Z-[1-(3-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(437) 3-Z-[1-(3-(3-디메틸아미노프로필)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(438) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(439) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(440) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(441) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(442) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(443) 3-Z-[1-(4-(N-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(444) 3-Z-[1-(4-(2-디에틸아미노에틸술포닐)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(445) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(446) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(447) 3-Z-[1-(4-(2-디메틸아미노에톡시)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(448) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(449) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(450) 3-Z-[1-(4-(메틸에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(451) 3-Z-[1-(4-(메틸프로필아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(452) 3-Z-[1-(4-(메틸벤질아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(453) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(454) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)-페닐메틸렌]-6-브로모-2-인돌리논
(455) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(456) 3-Z-[1-(4-(아제티딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(457) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(458) 3-Z-[1-(4-(피페라진-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(459) 3-Z-[1-(4-(모르폴린-4-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(460) 3-Z-[1-(4-(티오모르폴린-4-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(461) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(462) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(463) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(464) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(465) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(466) 3-Z-[1-(4-(N-(2-메틸아미노에틸)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(467) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(468) 3-Z-[1-(4-(N-(3-메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(469) 3-Z-[1-(4-(3-디메틸아미노프로필)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(470) 3-Z-[1-(4-에틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(471) 3-Z-[1-(4-메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(472) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(473) 3-Z-[1-(4-(4-메틸피페라진-1-일카보닐)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(474) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(475) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-프로필술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(476) 3-Z-[1-(4-아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(477) 3-Z-[1-(3-(디메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(478) 3-Z-[1-(3-(메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(479) 3-Z-[1-(3-(2-디메틸아미노에틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(480) 3-Z-[1-(3-(3-디메틸아미노프로필)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(481) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(482) 3-Z-[1-(4-(N-(디메틸아미노카보닐메틸)-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(483) 3-Z-[1-(4-(N-메틸-N-메틸술포닐아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(484) 3-Z-[1-(4-(N-메틸-N-아세틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(485) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(486) 3-Z-[1-(4-(N-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(487) 3-Z-[1-(4-(2-디에틸아미노에틸술포닐)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(488) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(489) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(490) 3-Z-[1-(4-(2-디메틸아미노에톡시)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(491) 3-Z-[1-(4-(N-(4-디메틸아미노부틸카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(492) 3-Z-[1-(4-(N-(3-디메틸아미노프로필카보닐)-N-메틸아미노)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(493) 3-Z-[1-(4-(메틸에틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(494) 3-Z-[1-(4-(메틸프로필아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(495) 3-Z-[1-(4-(메틸벤질아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(496) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(497) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸아미노메틸)아닐리노)-1-(3-(2-카복시에틸)페닐메틸렌]-6-브로모-2-인돌리논
(498) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(499) 3-Z-[1-(4-(아제티딘-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(500) 3-Z-[1-(4-((4-메틸피페라진-1-일)메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(501) 3-Z-[1-(4-(피페라진-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(502) 3-Z-[1-(4-(모르폴린-4-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(503) 3-Z-[1-(4-(티오모르폴린-4-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(504) 3-Z-[1-(4-(이미다졸-1-일메틸)아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논
(505) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카복시메틸아미노페닐)-메틸렌]-6-플루오로-2-인돌리논
(506) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카복시메틸아미노-페닐)-메틸렌]-6-플루오로-2-인돌리논
(507) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(N-메틸-카복시메틸아미노)페닐)메틸렌]-6-플루오로-2-인돌리논
(508) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(N-메틸-카복시메틸아미노)페닐)메틸렌]-6-플루오로-2-인돌리논
(509) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카복시메톡시페닐)-메틸렌]-6-클로로-2-인돌리논
(510) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카복시메톡시페닐)-메틸렌]-6-클로로-2-인돌리논
(511) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카복시메틸아미노페닐)-메틸렌]-6-클로로-2-인돌리논
(512) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카복시메틸아미노페닐)-메틸렌]-6-클로로-2-인돌리논
(513) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(N-메틸-카복시메틸아미노)페닐)메틸렌]-6-클로로-2-인돌리논
(514) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(N-메틸-카복시메틸아미노)페닐)메틸렌]-6-클로로-2-인돌리논
(515) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카복시메톡시페닐)-메틸렌]-6-브로모-2-인돌리논
(516) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카복시메톡시페닐)-메틸렌]-6-브로모-2-인돌리논
(517) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-카복시메틸아미노페닐)-메틸렌]-6-브로모-2-인돌리논
(518) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-카복시메틸아미노페닐)-메틸렌]-6-브로모-2-인돌리논
(519) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(N-메틸-카복시메틸아미노)페닐)메틸렌]-6-브로모-2-인돌리논
(520) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(N-메틸-카복시메틸아미노)페닐)메틸렌]-6-브로모-2-인돌리논 뿐 아니라, 이의 호변체, 이의 입체 이성질체 또는 이의 생리학적으로 허용되는 염.
따라서, 화학식 I의 화합물, 이의 호변체, 이의 입체 이성질체 또는 이의 생리학적으로 허용되는 염은 다음으로 이루어진 그룹으로부터 선택된 특정 섬유성 질환의 예방 또는 치료에 적합하다:
만성 폐쇄성 폐질환(COPD), 만성 기관지염 및 폐기종에서의 섬유증 및 폐 조직의 리모델링;
이에 제한되지는 않지만, 특발성 폐 섬유증(IPF), 거대 세포 사이질 폐렴(GIP: giant cell interstitial pneumonia), 사르코이드증(sarcodosis), 낭성 섬유증, 호흡 곤란 증후군(ARDS), 육아종증, 규폐증(silicosis), 약물-유발 폐 섬유증(예를 들어, 블레오마이신, 비스-클로로니트로소우레아, 사이클로포스파미드, 아미오다론(amiodarone), 프로카인아미드, 페니실라민, 금 또는 니트로퓨란토인과 같은 약물에 의해 유발된다), 규폐증, 석면증, 전신 경피증을 포함하는, 폐 섬유증 및 섬유성 성분을 갖는 폐 질환;
천식에서의 섬유증 및 리모델링;
류마티스 관절염에서의 섬유증;
바이러스 유발 간경변증, 예를 들어 C형 간염;
방사선-유발 섬유증;
재협착(Restenosis), 후 혈관성형(post angioplasty);
만성 사구체신염, 사이클로스포린을 수용하는 환자의 신장 섬유증 및 고혈압에 기인한 신장 섬유증을 포함하는 신장 질환;
섬유성 성분을 갖는 피부 질환은 이에 제한되지는 않지만, 경피증, 사르코이드증, 전신 홍반 루푸스;
과다 흉터 형성을 포함한다.
본 발명에 따른 바람직한 양태에서, 화학식 I의 화합물, 이의 호변체, 이의 부분입체 이성질체 또는 이의 생리학적으로 허용되는 염은 특히 특발성 폐섬유증의 예방 또는 치료에 적합하다.
생물학적 활성
하기의 실험 결과는 본 발명의 범주를 제한하지 않으면서 본 발명을 설명한다.
약어
DEPC (디에틸파이로카보네이트)
dNTP (디옥시리보누클레오타이드 트리포스페이트)
CT (증폭이 일련의 역치에 도달하는 순환)
DNA (디옥시리보핵산)
cDNA (상보성 DNA)
RNA (리보핵산)
mRNA (메신저 RNA)
PCR (폴리머라제 연쇄 반응)
실시예 B1:
실시예 B1의 다음의 실험에서, 실시예 A는 화합물 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논을 나타내고, 이는 화합물 목록의 화합물 (134)이고 바람직한 화합물 목록의 화합물 (b)이다.
(A) 블레오마이신-유발 폐 섬유증에 따른 폐 손상에 대한 대표적인 화합물의 영향
물질 및 방법
블레오마이신 술페이트(Bleomycin HEXAL™)를 지역의 약국에서 구매하였다.
블레오마이신 투여 및 치료 프로토콜
모든 실험을 동물 복지에 대한 독일 가이드라인(German guidelines for animal welfare)에 따라, 동물을 연구하도록 보증되고 신뢰할 수 있는 권위자에 의해 승인된 자에 의해 수행하였다. 수컷 위스타 래트(Male Wistar rats)를 마취제 이소플루오란에 5분 동안 노출시킨 다음, 블레오마이신 술페이트(300 ㎕ 식염수 내의 체중 1 kg 당 10 U) 또는 식염수만을(식염수 대조군) 카테터(catheter)(0.5 mm 내부 직경, 1.0 mm 외부 직경)를 사용하여 비강 통로를 통해 기관내 주입하였다. 다음날, 래트에 실시예 A(화합물 (134)) 또는 1 ml 0.1 % 나트로졸(Natrosol)에 현탁된 식염수를 경구적으로 처리하였다. 대조군 래트에 1 ml 0.1 % 나트로졸(비이클 대조군)을 투여하였다.
총 30마리의 래트를 연구하고 분류하고 표 1에 나타난 바와 같이 처리하였다.
기관내 점적 주입 | 동물의 수 | 화합물 | 처리 일정 |
블레오마이신 10 U /kg | 10 | 실시예 A (화합물 (134)) | 1-21일 |
블레오마이신 10 U /kg | 10 | 비이클 단독 | 1-21일 |
Saline (300 ㎕) | 10 | 비이클 단독 | 1-21일 |
블레오마이신 점적 주입(instillation)으로부터 21일 이후, 래트를 치사량의 Narcoren™(Pentobarbital Sodium, Rhone Merieux)의 복막내 주입으로 죽였다. 이후 폐를 제거하고, 건조시키고(blotted dry) 절반을 질소 액체에서 급속히 냉동시키고(snap frozen) -80 ℃에서 저장하였다. 나머지 절반을 후속적인 파라핀 포매(embedding) 및 조직 분석(histology)을 위해 4 % 포르말린에 고정시켰다.
조직 분석
4 % 포르말린에 고정된 폐 조직을 파라핀에 포매시키고 마이크로톰(microtome)(Leica SM200R)을 사용하여 5 ㎛로 자르고 폴리-L-라이신 코팅된 슬라이드에 놓았다. 이후 상기 부분을 슬라이드에서 건조시키고(60 ℃에서 2 시간) 실온에서 냉각되도록 두었다. 콜라겐 축적을 Masson 트리크롬 염색(Masson's Trichrome staining)을 사용하여 평가하였다.
결과
도 1A는 대조 그룹에서 수득된 결과를 나타내고, 이는 블레오마이신의 기관내 투여를 대신하여 식염수와 비이클을 수용한 것이다.
블레오마이신과 비이클이 기관내 투입된 래트에서 도 1B에 나타난 바와 같이 심각한 폐 섬유증이 발생되었다. 폐포가 주로 섬유모세포에 의해 대체되었고 세포외 기질 및 통상의 폐 구조가 거의 없어졌다.
50 mg/kg의 실시예 A(화합물 (134))로 블레오마이신-처리된 래트의 일일 치료는 상기 모델에서 지속적이고, 거의 완전한 폐 섬유증의 회복을 나타내었다. 전형적인 예가 도 1C에 나타나있다. 폐포는 손상되지 않고 섬유모세포 침윤 또는 세포외 기질 축적이 거의 일어나지 않는다. 통상의 폐 구조가 유지되고, 이는 도 1C와 도 1A의 비교에 의해 증명된다.
(B) 대표적인 화합물의 블레오마이신-유발 폐 섬유증에 따른 섬유성 마커 유전자의 발현에 대한 영향
mRNA 추출 및 cDNA의 합성
유전자 발현의 조사를 위한 냉동된 폐 조직의 한 부분을 무균 메스 칼날(scalpel blade)를 사용하여 작은 조각으로 잘랐다. 이후 약 100 mg의 조직을 2 ml의 에펜도르프 튜브에 넣고 1.5 ml의 Trizol(Invitrogen)을 첨가하였다. 이후 무균 텅스텐 카바이드 비드(Qiagen)를 튜브에 첨가하고 튜브를 8분 동안 30.0 Hz로 Retsch MM300 조직 분쇄기(Qiagen)에 두었다. 상기 시간 경과 후, 비드를 제거하고 샘플을 12000 rpm으로 10분 동안 원심분리하여 조직 조각을 제거하였다. RNA를 Trizol에 의해 공급된 변형된 버전의 제조자 프로토콜을 사용하여 추출하였다. 잠시동안, 0.3 ml 클로로포름을 튜브에 첨가하고 튜브를 세게 흔들고 실온에서 5분 동안 배양하고, 튜브를 15분 동안 12000 rpm으로 4 ℃에서 원심분리 하였다. 이어서 상층의 투명한 수성상을 모으고 750 ㎕ 이소프로판올에 첨가하였다. 이후 이를 세게 흔들고 -80 ℃에서 밤새 저장하였다. 이어서 상기 샘플을 실온에서 15분 동안 배양하고, 이를 40분 동안 12000 rpm으로 4 ℃에서 원심분리하였다. 이후 상청액을 제거하고 500 ㎕의 70 % 에탄올을 첨가하여 펠릿을 세척하고 샘플을 10분 동안 12000 rpm으로 4 ℃에서 원심분리 하고, 이러한 세척 과정을 2회 반복하고, 펠릿을 10-15분 동안 건조되도록 두었다. 마지막으로 펠릿을 RNase가 없는 물 20 ㎕에 다시 현탁시키고 -80 ℃에서 저장하였다. 각각의 샘플의 농도를 분광 광도계를 사용하여 측정하였다.
Superscript™III(Invitrogen, Paisley, UK) RT-제1 스트랜드 합성 키트를 사용하여, 2 ㎍의 각각의 mRNA 샘플을 생산자 프로토콜의 변형된 버전(modified version of the manufacturer's protocol)을 사용하여 역전사시켰다. 요약하면, 2 ㎍ RNA, 1 ㎕ 랜덤 헥사머 프라이머(50ng/㎕), 1 ㎕ dNTP 믹스(10 mM)의 혼합물을 DEPC-처리된 물로 10 ㎕가 되게 하고 5분 동안 65 ℃에서 배양하고, 5분 동안 얼음 위에 두었다. 이에 이어서, 각각의 반응에, 2 ㎕ RT 완충제(10X), 4 ㎕ MgCl2(25 mM), 2 ㎕ DTT(0.1M), 1 ㎕ RNaseOUT™(400 U/㎕) 및 1 ㎕ SuperScript™III 효소(200 U/㎕)를 첨가하고 혼합물을 25 ℃에서 10분 동안, 50 ℃에서 50분 동안 및 85 ℃에서 5분 동안 열 순환기(Applied Biosystems)에 둔 후, 1 ㎕의 RNase H를 첨가하고 37 ℃에서 20분 동안 배양하였다. RT 반응이 모든 mRNA를 cDNA로 전사시켰고 농도가 100 ng/㎕라는 가정 하에 합성된 cDNA를 5 ng/㎕로 희석시켰다.
실시간(real time) PCR을 사용한 유전자 발현의 조사
유전자 발현을 각각의 샘플에서 Applied Biosystems 7700 서열 분석 시스템을 사용하여 조사하였다. 18S 내부 조절을 위한 프라이머를 미리 제조된(pre-developed) 분석 시약 키트로서 구매한 반면, 프로-콜라겐 I 및 피브로넥틴에 대한 프라이머 및 프로브(probe)(하기 표 2 참조)를 PrimerExpress™(Applied Biosystems)를 사용하여 설계하였고, 이 때 각각의 세트에서 적어도 하나의 프라이머 또는 프로브가 인트론/엑손 접합(intron/exon junction)과 겹쳐서 cDNA 샘플의 임의의 오염 게놈 DNA의 증폭 가능성을 제거하도록 하였다. 구입된 PDAR은 또한 cDNA만을 증폭시켰다.
표적 | 서열 | |
피브로넥틴 | 정방향 | 5'-GAT GCC GAT CAG AAG TTT GGA-3' |
역방향 | 5'-TCG TTG GTC GTG CAG ATC TC-3' | |
프로브 | 5'-FAM-CTG CCC AAT GGC TGC CCA TGA-TAMRA-3' | |
프로-콜라겐 I | 정방향 | 5'-CAG ACT GGC AAC CTG AAG AAG TC-3' |
역방향 | 5'-TCG CCC CTG AGC TCG AT-3' | |
프로브 | 5'-FAM-CTG CTC CTC CAG GGC TCC AAC GA-TAMRA3' |
실시간 PCR을 25 ㎕의 반응물에서, 반응당 25 ng(5 ㎕)의 cDNA를 사용하여 수행하였다. 정량적 PCR 코어 키트를 구매하였고(Eurogentec) 마스터-믹스(master-mix)를 100회의 반응용으로 다음과 같이 구성하였다: 500 ㎕ 10X 반응 완충액, 500 ㎕ MgCl2 (50 mM), 200 ㎕ dNTP 혼합 용액(5 mM), 25 ㎕ Hot Goldstar 효소, 75 ㎕ 18S PDAR, 22.5 ㎕ 정방향 프라이머, 22.5 ㎕ 역방향 프라이머, 15 ㎕ 프로브 및 640 ㎕ DEPC 처리된 물. 이어서 상기 마스터-믹스의 20 ㎕를 25 ng(5 ㎕) 표적 cDNA에 첨가하였다. 각각의 분석을 3회 반복하였다.
유전자 발현을 정량하기 위해서, 각각의 프라이머 세트에 대해 표준 곡선을 만들었고 각각의 플레이트에 포함시켰다. 표준은 조사되는 모든 cDNA의 혼합물로 이루어졌다. 이러한 cDNA의 혼합물을 연속적으로 10, 20, 50, 100, 100회 희석시켰다. 표준 곡선을 희석 인자의 LOG10에 대한 수득된 CT(증폭이 고정 역치(set Threshold)에 도달한 시점의 사이클)로 구성하였다. 곡선을 표적 유전자 및 18S rRNA 내부 조절에 대해 그렸다. 이어서 각각의 샘플의 두 가지 표적 모두에 대한 CT값을 표준 곡선을 이용하여 배수 희석(fold dilution)으로 전환하였고 표적 유전자를 18S 유전자 값으로 표준화하였다.
통계
모든 통계적 분석을 GraphPad Prism V 4.02 소프트웨어를 사용하여 수행하였다. 비모수 T-검정(Mann-Whitney U 검정)을 사용하여 비교하였고 유의값(significant value)은 p = 0.05이었다.
결과
결과를 도 2(프로콜라겐 I) 및 3(피브로넥틴)에 나타내었다. 각각의 데이터 포인트는 래트 한 마리의 폐로부터 분리된 RNA를 나타낸다.
블레오마이신의 기관 내 투여 및 비이클의 후속적인 처리는 폐의 프로콜라겐 I의 증가를 보였고, 피브로넥틴 유전자 발현은, 도 2 및 3에 보이는 바와 같이, 도 1B에 보이는 조직학적으로 명백한 폐 섬유증과 일치한다.
50 mg/kg의 실시예 A (화합물 (134))로 처리된 블레오마이신 처리된 래트의 매일 치료는 도 2 및 3에 보이는 바와 같이, 상기 모델에서 섬유성 마커 유전자 발현의 상당한 (p ≤ 0.0001) 억제를 나타내었다.
따라서 상기 실험은 섬유성 마커의 발현, 및 이에 따른 세포외 기질의 축적이 실시예 A(화합물 (134))의 처리에 의해 급격하게 감소될 수 있다는 것을 증명한다.
따라서, 섬유성 마커의 발현, 및 이에 따른 세포외 기질의 축적이 본 발명에 따른 화합물의 처리에 의해 급격하게 감소될 수 있다.
본 발명에 따른 화합물은 이의 생물학적 특성 때문에 단독 요법으로 또는 다른 약학적으로 활성인 화합물과 함께 사용될 수 있다. 이러한 약학적으로 활성인 화합물은 예를 들어, 섬유증의 치료에서도 약학적으로 활성일 수 있다. 이러한 약학적으로 활성인 화합물은 또한 점액용해성(secretolytic), 기관지용해성(broncholytic) 및/또는 항염증성 활성을 갖는 물질일 수 있다.
본 발명에 따른 바람직한 양태에서, 이러한 약학적으로 활성인 화합물은 바람직하게는 항콜린제, 베타-2 미메틱, 스테로이드, PDE-IV 억제제, p38 MAP 키나제 억제제, NK1 길항제, LTD4 길항제, EGFR 억제제 및 엔도텔린-길항제로 이루어진 그룹으로부터 선택된다.
항콜린제는 바람직하게는 티오트로피움 염, 옥시트로피움 염, 플루트로피움 염, 이프라트로피움 염, 글리코피로늄 염 및 트로스피움 염으로 이루어진 그룹으로부터 선택될 수 있다.
베타-2 미메틱은 바람직하게는 예를 들어, 본원에 참조로서 인용된, US 4,460,581에 기재된 베타-2 미메틱으로부터 선택될 수 있다.
PDE-IV 억제제는 바람직하게는 엔프로필린(enprofyllin), 테오필린(theophyllin), 로플루미라스트(roflumilast), 아리플로(ariflo)(cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-디클로로-1-옥소-피리딘-4-일)-4-디플루오로메톡시-3-사이클로프로필메톡시벤즈아미드, NCS-613, 푸마펜틴(pumafentine), (-)p-[(4aR*,10bS*)-9-에톡시-1,2,3,4,4a,10b-헥사하이드로-8-메톡시-2-메틸벤조[s][1,6]나프티리딘-6-일]-N,N-디이소프로필벤즈아미드, (R)-(+)-1-(4-브로모벤질)-4-[(3-사이클로펜틸옥시)-4-메톡시페닐]-2-피롤리돈, 3-(사이클로펜틸옥시-4-메톡시페닐)-1-(4-N'-[N-2-시아노-S-메틸-이소티오우레이도]벤질)-2-피롤리돈, 시스[4-시아노-4-(3-사이클로펜틸옥시-4-메톡시페닐)사이클로헥산-1-카본산], 2-카보메톡시-4-시아노-4-(3-사이클로프로필메톡시-4-디플루오로메톡시페닐)사이클로헥산-1-온, 시스[4-시아노-4-(3-사이클로프로필메톡시-4-디플루오로메톡시페닐)사이클로헥산-1-올], (R)-(+)-에틸[4-(3-사이클로펜틸옥시-4-메톡시페닐)피롤리딘-2-일리덴]아세테이트, (S)-(-)-에틸[4-(3-사이클로펜틸옥시-4-메톡시페닐)피롤리딘-2-일리덴]아세테이트, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, 아로필린(arofyllin), 아티조람(atizoram), V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-사이클로펜틸-5,6-디하이드로-7-에틸-3-(2-티에닐)-9H-피라졸로[3,4-c]-1,2,4-트리아졸로[4,3-a]피리딘 및 9-사이클로펜틸-5,6-디하이드로-7-에틸-3-(3급-부틸)-9H-피라졸로[3,4-c]-1,2,4-트리아졸로[4,3-a]피리딘으로 이루어진 그룹으로부터 선택될 수 있다. 이러한 화합물은 가능한 경우, 이의 라세미체, 거울상 이성질체 또는 부분입체 이성질체의 형태, 또는 이의 약학적으로 허용되는 산 부가 염의 형태, 또는 이의 용매화물 및/또는 수화물의 형태로 존재할 수 있다.
스테로이드는 바람직하게는 프레드니솔론(prednisolone), 프레드니손(prednisone), 부틱소코르트프로피오네이트(butixocortpropionate), RPR-106541, 플루니솔리드(flunisolid), 베클로메타존(beclomethasone), 트리암시놀론(triamcinolone), 부데소니드(budesonid), 플루티카존(fluticasone), 모메타존(mometasone), 시클레소니드(ciclesonid), 로플레포니드(rofleponid), ST-126, 덱사메타존(dexamethasone), 6α,9α-디플루오로-17α-[(2-퓨라닐카보닐)옥시]-11β-하이드록시-16α-메틸-3-옥소-안드로스타-1,4-디엔-17β-카보티온산 (S)-플루오로메틸에스테르 및 6α,9α-디플루오로-11β-하이드록시-16α-메틸-3-옥소-17α-프로피오닐옥시-안드로스타-1,4-디엔-17β-카보티온산 (S)-(2-옥소-테트라하이드로-퓨란-3S-일)에스테르로 이루어진 그룹으로부터 선택될 수 있다. 이들 화합물은, 가능한 경우, 이의 라세미체, 거울상 이성질체 또는 부분입체 이성질체의 형태, 또는 이의 약학적으로 허용되는 산 부가 염의 형태, 또는 이의 용매화물 및/또는 수화물의 형태로 사용될 수 있다.
p38 MAP 키나제 억제제는 바람직하게는 예를 들어 미국 특허 US 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, 및 US 5,716,955 및 PCT 출원 WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921, WO 01/27089, DE 19842833, 및 JP 2000 86657에 기재된 p38 키나제 억제제로 이루어진 그룹으로부터 선택될 수 있고, 이들 문헌은 모두 전체가 본원에 참조로서 인용된다. 본 발명에 따른 배합물 중 특히 관심 대상은 US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO 00/55152, WO 00/55139 및 WO 01/36403에 기재된 p38 억제제이다. 바람직한 양태에서 p38 키나제 억제제는 WO 99/01131에 기재된 바와 같이 하기 화학식 (I)의 화합물 또는 이의 약학적으로 허용되는 염으로부터 선택된다.
화학식 (I)
상기 화학식 (I)에서
R1은 4-피리딜, 피리미디닐, 4-피리다지닐, 1,2,4-트리아진-5-일, 퀴놀릴, 이소퀴놀리닐 또는 퀴나졸린-4-일 환이고, 상기 환은 Y-Ra로, 또한 C1-4 알킬, 할로겐, 하이드록실, C1-4 알콕시, C1-4 알킬티오, C1-4 알킬술피닐, CH2OR12, 아미노, 모노 및 디- C1-6 알킬 치환된 아미노, N-헤테로사이클릴 환(환은 5 내지 7개의 원자를 갖고 산소, 황 또는 NR15 로부터 선택된 추가의 이종원자를 임의로 함유한다), N(R10)C(O)Rb 또는 NHRa로부터 선택된 추가의 독립적인 치환체로 임의로 치환되고,
Y는 산소 또는 황이고;
R4는 페닐, 나프트-1-일 또는 나프틸, 또는 헤테로아릴이고, 이는 1 또는 2개의 치환체에 의해 임의로 치환되고, 이들 각각은 독립적으로 선택되고, 이는 4-페닐, 4-나프트-1-일, 5-나프트-2-일 또는 6-나프트-2-일 치환체에 대해서는, 할로겐, 시아노, 니트로, C(Z)NR7R17, C(Z)OR16, (CR10R20)vCOR12, SR5, SOR5, OR12, 할로-치환된-C1 -4 알킬, C1 -4 알킬, ZC(Z)R12, NR10C(Z)R16 또는 (CR10R20)vNR10R20 이고, 다른 위치의 치환체에 대해서는 할로겐, 시아노, C(Z)NR13R14, C(Z)OR3, (CR10R20)m''COR3, S(O)mR3, OR3, 할로-치환된-C1 -4 알킬, C1 -4 알킬, (CR10R20)m''R10C(Z)R3, NR10S(O)m'R8, NR10S(O)m'NR7R17, ZC(Z)R3 또는 (CR10R20)m''NR13R14이고;
Z는 산소 또는 황이고;
n은 정수 1 내지 10이고;
m은 0, 또는 정수 1 또는 2이고;
m'는 정수 1 또는 2이고;
m''는 0, 또는 정수 1 내지 5이고;
v는 0, 또는 정수 1 내지 2이고;
R2는 -C(H) (A) (R22)이고;
A는 임의로 치환된 아릴, 헤테로사이클릴 또는 헤테로아릴 환이고, 또는 A는 치환된 C1 - 10알킬이고;
R22는 임의로 치환된 C1 -10 알킬이고;
Ra는 아릴, 아릴 C1 -6 알킬, 헤테로사이클릭, 헤테로사이클릴 C1 -6 알킬, 헤테로아릴, 헤테로아릴C1 - 6알킬이고, 여기서 이들 잔기 각각은 임의로 치환될 수 있고;
Rb는 수소, C1 -6 알킬, C3 -7 사이클로알킬, 아릴, 아릴 C1 -4 알킬, 헤테로아릴, 헤테로아릴C1-4 알킬, 헤테로사이클릴 또는 헤테로사이클릴C1 -4 알킬이고, 여기서 이들 잔기 각각은 임의로 치환될 수 있고;
R3는 헤테로사이클릴, 헤테로사이클릴 C1 -10 알킬 또는 R8이고;
R5는 수소, C1 -4 알킬, C2 -4 알케닐, C2 -4 알키닐 또는 NR7R17이고, 잔기 SR5는 SNR7R17가 아니고 SOR5는 SOH가 아니고;
R6는 수소, 약학적으로 허용되는 양이온, C1 -10 알킬, C3 -7 사이클로알킬, 아릴, 아릴 C1 -4 알킬, 헤테로아릴, 헤테로아릴 C1 -4 알킬, 헤테로사이클릴, 아릴, 또는 C1 -10 알카노일이고;
R7 및 R17는 각각 수소 또는 C1 -4 알킬로부터 독립적으로 선택되거나 R7 및 R17는 이들이 결합한 질소와 함께 5 내지 7원 헤테로사이클릭 환을 형성하고 상기 환은 산소, 황 또는 NR15로부터 선택된 추가의 이종원자를 임의로 함유하고;
R8는 C1 -10 알킬, 할로-치환된 C1 -10 알킬, C2 -10 알케닐, C2 -10 알키닐, C3 -7 사이클로알킬, C5 -7 사이클로알케닐, 아릴, 아릴 C1 -10 알킬, 헤테로아릴, 헤테로아릴 C1-10 알킬, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14이고, 여기서 아릴, 아릴알킬, 헤테로아릴, 헤테로아릴 알킬은 임의로 치환될 수 있고;
R9는 수소, C(Z) R11 또는 임의로 치환된 C1 -10 알킬, S(O)2R18, 임의로 치환된 아릴 또는 임의로 치환된 아릴 C1 -4 알킬이고;
R10 및 R20는 각각 독립적으로 수소 또는 C1 -4 알킬로부터 선택되고;
R11는 수소, C1 -10 알킬, C3 -7 사이클로알킬, 헤테로사이클릴, 헤테로사이클릴 C1-10 알킬, 아릴, 아릴C1 -10 알킬, 헤테로아릴 또는 헤테로아릴 C1 -10 알킬이고, 여기서 이들 잔기는 임의로 치환될 수 있고;
R12는 수소 또는 R16이고;
R13 및 R14는 각각 수소 또는 임의로 치환된 C1 -4 알킬, 임의로 치환된 아릴 또는 임의로 치환된 아릴C1 -4 알킬로부터 독립적으로 선택되거나, 이들이 결합한 질소와 함께 5 내지 7원 헤테로사이클릭 환을 형성하고, 상기 환은 산소, 황 또는 NR9로부터 선택된 추가의 이종 원자를 임의로 함유하고;
R15는 R10 또는 C(Z)-C1 -4 알킬이고;
R16은 C1 -4 알킬, 할로-치환된-C1 -4 알킬 또는 C3 -7 사이클로알킬이고;
R18은 C1 -10 알킬, C3 -7 사이클로알킬, 헤테로사이클릴, 아릴, 아릴1 -10 알킬, 헤테로사이클릴, 헤테로사이클릴- C1 - 10알킬, 헤테로아릴 또는 헤테로아릴1 - 10알킬이다.
NK1 길항제는 바람직하게는 N-[2-(3,5-비스-트리플루오로메틸-페닐)-에틸]-2-{4-사이클로프로필메틸-피페라진-1-일}-N-메틸-2-페닐-아세트아미드(BIIF 1149), CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968(Saredutant), SR 140333(Nolpitantium besilate/chloride), LY 303 870(Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, Aprepitant(MK-869), L-754030, CJ-11974, L-758298, DNK-33A, 6b-I, CJ-11974, TAK-637, GR 205171 및 화학식 (VIII)의 아릴글리신 아미드 유도체로 이루어진 그룹으로부터 선택되고
화학식 (VIII)
상기 화학식 (VIII)에서
R1 및 R2 는 이들이 결합된 질소 원자와 함께 화학식
의 환을 형성하고 또는,
여기서 r 및 s는 독립적으로 2 또는 3을 나타내고;
R6는 H, -C1-C5-알킬, C3-C5-알케닐, 프로피닐, 하이드록시(C2-C4)알킬, 메톡시(C2-C4)알킬, 디(C1-C3)알킬아미노(C2-C4)알킬, 아미노(C2-C4)알킬, 아미노, 디(C1-C3)알킬아미노, 모노플루오로- 내지 퍼플루오로(C1-C2)알킬, N-메틸피페리디닐, 피리딜, 피리미디닐, 피라지닐 또는 피리다지닐이고,
R7은 (a) 내지 (b)에 의해 정의된 임의의 그룹을 나타내고:
(a) 하이드록시,
(b) 4-피페리디노피페리딜,
(c)
여기서 R16 및 R17는 독립적으로 H, (C1-C4)알킬, (C3-C6)사이클로알킬, 하이드록시(C2-C4)알킬, 디하이드록시(C2-C4)알킬, (C1-C3)알콕시(C2-C4)알킬, 페닐(C1-C4)알킬 또는 디(C1-C3)알킬아미노(C2-C4)알킬을 나타내고,
R8는 H를 나타내고,
임의로 거울상 이성질체, 거울상 이성질체의 혼합물 또는 라세미체의 형태이다.
상술한 화학식 (VIII)의 화합물은 WO 96/32386, WO 97/32865 및 WO 02/32865에 기재되어 있다. 이러한 국제특허출원의 문헌은 전체가 본원에서 참조로서 인용되었다.
LTD4 길항제는 바람직하게는 몬테루카스트(montelukast), 1-(((R)-(3-(2-(6,7-디플루오로-2-퀴놀리닐)에테닐)페닐)-3-(2-(2- 하이드록시-2-프로필)페닐)티오)메틸사이클로프로판-아세테이트, 1-(((1(R)-3(3-(2-(2,3-디클로로티에노[3,2-b]피리딘-5-일)-(E)-에테닐)페닐)-3-(2-(1-하이드록시-1-메틸에틸)페닐)프로필)티오)메틸)사이클로프로판-아세테이트, 프란루카스트(pranlukast), 자피르루카스트(zafirlukast), 2-[[2-(4-3급-부틸-2-티아졸릴)-5-벤조퓨라닐]옥시메틸]페닐]아세테이트, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 및 L-733321로 이루어진 그룹으로부터 선택될 수 있다. 이들 화합물은 가능한 경우, 이의 라세미체, 거울상 이성질체 또는 부분입체 이성질체의 형태로, 또는 약학적으로 허용되는 이의 산 부가 염의 형태, 또는 이의 용매화물 및/또는 수화물의 형태로 사용될 수 있다.
EGFR 억제제는 바람직하게는 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(모르폴린-4-일)-1-옥소-2-부텐-1-일]-아미노}-7-사이클로프로필메톡시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디에틸아미노)-1-옥소-2-부텐-1-일]-아미노}-7-이클로프로필메톡시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디메틸아미노)-1-옥소-2-부텐-1-일]아미노}-7-사이클로프로필메톡시-키나졸린, 4-[(R)-(1-페닐-에틸)아미노]-6-{[4-(모르폴린-4-일)-1-옥소-2-부텐-1-일]-아미노}-7-사이클로펜틸옥시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{[4-((R)-6-메틸-2-옥소-모르폴린-4-일)-1-옥소-2-부텐-1-일]아미노}-7-사이클로프로필메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{[4-((R)-6-메틸-2-옥소-모르폴린-4-일)-1-옥소-2-부텐-1-일]아미노}-7-[(S)-(테트라하이드로퓨란-3-일)옥시]-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{[4-((R)-2-메톡시메틸-6-옥소-모르폴린-4-일)-1-옥소-2-부텐-1-일]아미노}-7-사이클로프로필메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[2-((S)-6-메틸-2-옥소-모르폴린-4-일)-에톡시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-({4-[N-(2-메톡시-에틸)-N-메틸-아미노]-1-옥소-2-부텐-1-일}아미노)-7-사이클로프로필메톡시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디메틸아미노)-1-옥소-2-부텐-1-일]아미노}-7-사이클로펜틸옥시-키나졸린, 4-[(R)-(1-페닐-에틸)아미노]-6-{[4-(N,N-비스-(2-메톡시-에틸)-아미노)-1-옥소-2-부텐-1-일]아미노}-7-사이클로프로필메톡시-키나졸린, 4-[(R)-(1-페닐-에틸)아미노]-6-({4-[N-(2-메톡시-에틸)-N-에틸-아미노]-1-옥소-2-부텐-1-일}아미노)-7-사이클로프로필메톡시-키나졸린, 4-[(R)-(1-페닐-에틸)아미노]-6-({4-[N-(2-메톡시-에틸)-N-메틸-아미노]-1-옥소-2-부텐-1-일}아미노)-7-사이클로프로필메톡시-키나졸린, 4-[(R)-(1-페닐-에틸)아미노]-6-({4-[N-(테트라하이드로피란-4-일)-N-메틸-아미노]-1-옥소-2-부텐-1-일}아미노)-7-사이클로프로필메톡시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디메틸아미노)-1-옥소-2-부텐-1-일]아미노}-7-((R)-테트라하이드로퓨란-3-일옥시)-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디메틸아미노)-1-옥소-2-부텐-1-일]아미노}-7-((S)-테트라하이드로퓨란-3-일옥시)-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-({4-[N-(2-메톡시-에틸)-N-메틸-아미노]-1-옥소-2-부텐-1-일}아미노)-7-사이클로펜틸옥시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N-사이클로프로필-N-메틸-아미노)-1-옥소-2-부텐-1-일]아미노}-7-사이클로펜틸옥시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디메틸아미노)-1-옥소-2-부텐-1-일]아미노}-7-[(R)-(테트라하이드로퓨란-2-일)메톡시]-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디메틸아미노)-1-옥소-2-부텐-1-일]아미노}-7-[(S)-(테트라하이드로퓨란-2-일)메톡시]-키나졸린, 4-[(3-에티닐-페닐)아미노]-6,7-비스-(2-메톡시-에톡시)-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-7-[3-(모르폴린-4-일)-프로필옥시]-6-[(비닐-카보닐)아미노]-키나졸린, 4-[(R)-(1-페닐-에틸)아미노]-6-(4-하이드록시-페닐)-7H-피롤로[2,3-d]피리미딘, 3-시아노-4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(N,N-디메틸아미노)-1-옥소-2-부텐-1-일]아미노}-7-에톡시-키놀린, 4-{[3-클로르-4-(3-플루오르-벤질옥시)-페닐]아미노}-6-(5-{[(2-메탄술포닐-에틸)아미노]메틸}-퓨란-2-일)키나졸린, 4-[(R)-(1-페닐-에틸)아미노]-6-{[4-((R)-6-메틸-2-옥소-모르폴린-4-일)-1-옥소-2-부텐-1-일]아미노}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-{[4-(모르폴린-4-일)-1-옥소-2-부텐-1-일]-아미노}-7-[(테트라하이드로퓨란-2-일)메톡시]-키나졸린, 4-[(3-클로르-4-플루오르페닐)아미노]-6-({4-[N,N-비스-(2-메톡시-에틸)-아미노]-1-옥소-2-부텐-1-일}아미노)-7-[(테트라하이드로퓨란-2-일)메톡시]-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-{[4-(5,5-디메틸-2-옥소-모르폴린-4-일)-1-옥소-2-부텐-1-일]아미노}-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-7-[(R)-(테트라하이드로퓨란-2-일)메톡시]-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-7-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-6-[(S)-(테트라하이드로퓨란-2-일)메톡시]-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{2-[4-(2-옥소-모르폴린-4-일)-피페리딘-1-일]-에톡시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[1-(3급-부틸옥시카보닐)-피페리딘-4-일옥시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(트랜스-4-아미노-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(트랜스-4-메탄술포닐아미노-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(테트라하이드로피란-3-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-메틸-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(모르폴린-4-일)카보닐]-피페리딘-4-일-옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(메톡시메틸)카보닐]-피페리딘-4-일-옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(피페리딘-3-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[1-(2-아세틸아미노-에틸)-피페리딘-4-일옥시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(테트라하이드로피란-4-일옥시)-7-에톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-((S)-테트라하이드로퓨란-3-일옥시)-7-하이드록시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(테트라하이드로피란-4-일옥시)-7-(2-메톡시-에톡시)-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{트랜스-4-[(디메틸아미노)술포닐아미노]-사이클로헥산-1-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{트랜스-4-[(모르폴린-4-일)카보닐아미노]-사이클로헥산-1-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{트랜스-4-[(모르폴린-4-일)술포닐아미노]-사이클로헥산-1-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(테트라하이드로피란-4-일옥시)-7-(2-아세틸아미노-에톡시)-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(테트라하이드로피란-4-일옥시)-7-(2-메탄술포닐아미노-에톡시)-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(피페리딘-1-일)카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-아미노카보닐메틸-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(시스-4-{N-[(테트라하이드로피란-4-일)카보닐]-N-메틸-아미노}-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(시스-4-{N-[(모르폴린-4-일)카보닐]-N-메틸-아미노}-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(시스-4-{N-[(모르폴린-4-일)술포닐]-N-메틸-아미노}-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(트랜스-4-에탄술포닐아미노-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-메탄술포닐-피페리딘-4-일옥시)-7-에톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-메탄술포닐-피페리딘-4-일옥시)-7-(2-메톡시-에톡시)-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[1-(2-메톡시-아세틸)-피페리딘-4-일옥시]-7-(2-메톡시-에톡시)-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(시스-4-아세틸아미노-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-[1-(3급-부틸옥시카보닐)-피페리딘-4-일옥시]-7-메톡시-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-(테트라하이드로피란-4-일옥시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(시스-4-{N-[(피페리딘-1-일)카보닐]-N-메틸-아미노}-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(시스-4-{N-[(4-메틸-피페라진-1-일)카보닐]-N-메틸-아미노}-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{시스-4-[(모르폴린-4-일)카보닐아미노]-사이클로헥산-1-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[2-(2-옥소피롤리딘-1-일)에틸]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(모르폴린-4-일)카보닐]-피페리딘-4-일옥시}-7-(2-메톡시-에톡시)-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-(1-아세틸-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-(1-메틸-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-(1-메탄술포닐-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-메틸-피페리딘-4-일옥시)-7(2-메톡시-에톡시)-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-이소프로필옥시카보닐-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(시스-4-메틸아미노-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{시스-4-[N-(2-메톡시-아세틸)-N-메틸-아미노]-사이클로헥산-1-일옥시}-7-메톡시-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-(피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-[1-(2-메톡시-아세틸)-피페리딘-4-일옥시]-7-메톡시-키나졸린, 4-[(3-에티닐-페닐)아미노]-6-{1-[(모르폴린-4-일)카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(시스-2,6-디메틸-모르폴린-4-일)카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(2-메틸-모르폴린-4-일)카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(S,S)-(2-옥사-5-아자-바이사이클로[2.2.1]헵트-5-일)카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(N-메틸-N-2-메톡시에틸-아미노)카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-에틸-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(2-메톡시에틸)카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-{1-[(3-메톡시프로필-아미노)-카보닐]-피페리딘-4-일옥시}-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[시스-4-(N-메탄술포닐-N-메틸-아미노)-사이클로헥산-1-일옥시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[시스-4-(N-아세틸-N-메틸-아미노)-사이클로헥산-1-일옥시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(트랜스-4-메틸아미노-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[트랜스-4-(N-메탄술포닐-N-메틸-아미노)-사이클로헥산-1-일옥시]-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(트랜스-4-디메틸아미노-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(트랜스-4-{N-[(모르폴린-4-일)카보닐]-N-메틸-아미노}-사이클로헥산-1-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-[2-(2,2-디메틸-6-옥소-모르폴린-4-일)-에톡시]-7-[(S)-(테트라하이드로퓨란-2-일)메톡시]-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-메탄술포닐-피페리딘-4-일옥시)-7-메톡시-키나졸린, 4-[(3-클로르-4-플루오르-페닐)아미노]-6-(1-시아노-피페리딘-4-일옥시)-7-메톡시-키나졸린, 세툭시맵(Cetuximab), 트라스투즈맵(Trastuzumab), ABX-EGF 및 Mab ICR-62로 이루어진 그룹으로부터 선택될 수 있다. 이들 화합물은 가능한 경우, 이의 라세미체, 거울상 이성질체 또는 부분입체 이성질체의 형태로, 또는 약학적으로 허용되는 이의 산 부가 염의 형태, 또는 이의 용매화물 및/또는 수화물의 형태로 사용될 수 있다. 이들 화합물은 종래 기술, 예를 들어 WO 96/30347, WO 97/02266, WO 99/35146, WO 00/31048, WO 00/78735, WO 01/34574, WO 01/61816, WO 01/77104, WO02/18351, WO 02/18372, WO 02/18373, WO 02/18376, WO 02/50043, WO 03/082290, Cancer Research 2004, 64:11 (3958-3965), Am J Health-Syst Pharm 2000, 57(15), 2063-2076, Clinical Therapeutics 1999, 21(2), 309-318, WO 98/50433 및 WO 95/20045에 기재되어 있다.
엔도텔린-길항제는 바람직하게는 테조센탄(tezosentan), 보센탄(bosentan), 엔라센탄(enrasentan), 식스타센탄(sixtasentan), T-0201, BMS-193884, K-8794, PD-156123, PD-156707, PD-160874, PD-180988, S-0139 및 ZD-1611로 이루어진 그룹으로부터 선택될 수 있다. 본 발명의 범주 내의 엔도텔린-길항제란 염, 바람직하게는 약학적으로 허용되는 산 부가 염, 또는 엔도텔린-길항제로부터 형성될 수 있는 유도체를 의미하는 것이다.
이들 배합물은 동시에 또는 연속적으로 투여할 수 있다.
본 발명에 따른 화합물의 약학적 용도는 바람직하게는 온혈 척추동물, 특히사람에 대해, 체중 1 kg 당 0.0001-100 mg의 용량으로 사용된다.
이들 화합물은 이들 자체로 또는 다른 활성 물질과 혼합되어 정맥내, 피하내, 근육내, 복막내 또는 비강 내 경로에 의해, 흡입에 의해, 또는 경피적으로, 또는 경구적으로 투여할 수 있지만, 특히 에어로졸 제형은 흡입에 적합하다.
투여를 위해 상기 제형은 하나 이상의 통상적인 비활성 고체, 반고체 또는 액체 담체, 예를 들어 전분, 서로 다른 유형의 셀룰로즈, 락토즈, 만니톨, 소르비톨, 글루코즈, 인산 칼슘, 경지방(hard fat), 지방산 알코올, 글리세롤, 중쇄 트리글리세라이드 및 관련 에스테르, 폴리에틸렌 글리콜, 정제된 특수유(specialty oils), 물, 물/에탄올, 물/글리세롤, 물/소르비톨, 물/폴리에틸렌 글리콜, 프로필렌 글리콜 및/또는 기능성 부형제, 예를 들어 폴리비닐-피롤리돈, 하이드록시프로필메틸셀룰로즈, 나트륨 카복시메틸-셀룰로즈, 나트륨 전분 글리콜레이트, 이산화규소, 폴리소르베이트, 폴리옥사머, 겔루사이어(gelucires), 스테아르산 마그네슘, 시트르산, 타르타르산 또는 이의 적합한 혼합물과 함께, 통상의 생약 제제(galenic preparation), 예를 들어 보통(plain) 또는 코팅된 정제, 캡슐, 파우더, 주입가능한 용액, 앰플, 현탁액, 용액, 스프레이 또는 좌제로 제형화된다.
다음의 제형의 예는 본 발명의 범주를 제한하지 않으면서 본 발명을 설명한다.
실시예 F1: 75 mg의 활성 물질을 함유하는 코팅된 정제
조성
정제 코어(core) 1개당 함유량:
활성 물질 75.0 mg
인산 칼슘 131.0 mg
폴리비닐피롤리돈 10.0 mg
카복시메틸셀룰로즈 나트륨 10.0 mg
이산화규소 2.5 mg
스테아르산 마그네슘 1.5 mg
230.0 mg
조제 (직접 압축)
활성 물질을 모든 성분과 함께 혼합하고, 체질하고, 정제 제조 기계에서 압 축시켜 목적하는 형태의 정제를 형성시킨다.
코어의 중량: 230 mg
코어의 외형: 9 mm, 양면이 볼록하다
이에 따라 생산된 정제 코어를 하이드록시프로필메틸셀룰로즈로 필수적으로 이루어진 막으로 코팅한다.
코팅된 정제의 중량: 240 mg.
실시예 F2: 100 mg의 활성 물질을 함유하는 정제
조성
정제 1개의 함유량:
활성 물질 100.0 mg
락토즈 80.0 mg
옥수수 전분 34.0 mg
하이드록시프로필메틸셀룰로즈 4.0 mg
스테아르산 마그네슘 2.0 mg
220.0 mg
조제 (습윤 과립)
활성 물질, 락토즈 및 전분을 함께 혼합하고 하이드록시프로필메틸셀룰로즈 수용액으로 균일하게 적신다. 습윤 조성물을 거르고(2.0 mm 메쉬 크기), 50 ℃에서 랙형(rack-type) 건조기에서 건조시킨 후, 이를 다시 거르고(1.5 mm 메쉬 크기) 윤활제를 첨가한다. 완성된 혼합물을 압축시켜 정제를 형성한다.
정제의 중량: 220 mg
정제의 외형: 10 mm, 평평하고 한쪽면에 비스듬한 가장자리와 쪼개진 홈이 있다.
실시예 F3: 150 mg의 활성 물질을 함유하는 정제
조성
정제 1개의 함유량:
활성 물질 150.0 mg
락토즈 85.0 mg
미정질 셀룰로즈 40.0 mg
폴리비닐피롤리돈 10.0 mg
이산화규소 10.0 mg
스테아르산 마그네슘 5.0 mg
300.0 mg
조제 (건조 과립)
활성 물질을 락토즈, 폴리비닐-피롤리돈 및 미정질 셀룰로즈의 일부와 혼합하고, 스테아르산 마그네슘을, 예를 들어 롤러 압축기로 압축한다. 리본을 메쉬 크기가 0.8 mm인 스크린을 통해 미세 미립으로 분쇄한다. 후속적으로 메쉬 크기가 0.5 mm인 스크린을 통해 걸러내고 잔여 성분과 혼합한 후, 혼합물로부터 정제를 가 압성형한다.
정제의 중량: 300 mg
정제의 외형: 10 mm, 평평하다
실시예 F4: 150 mg의 활성 물질을 함유하는 경질 젤라틴 캡슐
조성
캡슐 1개의 함유량:
활성 물질 150.0 mg
락토즈 85.0 mg
미정질 셀룰로즈 40.0 mg
폴리비닐피롤리돈 10.0 mg
이산화규소 10.0 mg
스테아르산 마그네슘 5.0 mg
300.0 mg
조제
활성 물질을 락토즈, 폴리비닐-피롤리돈 및 미정질 셀룰로즈의 일부와 혼합하고, 스테아르산 마그네슘를, 예를 들어 롤러 압축기로 압축한다. 리본을 메쉬 크기가 0.8 mm인 스크린을 통해 미세 미립으로 분쇄한다. 후속적으로 메쉬 크기가 0.5 mm인 스크린을 통해 걸러내고 잔여 성분과 혼합한 후, 완성된 혼합물을 크기1 의 경질 젤라틴 캡슐에 담는다.
캡슐 충전량: 약 300 mg
캡슐 껍질: 크기 1의 경질 젤라틴 캡슐.
실시예 F5: 150 mg의 활성 물질을 함유하는 좌제
좌제 1개의 함유량:
활성 물질 150.0 mg
폴리에틸렌글리콜 1500 800.0 mg
폴리에틸렌글리콜 6000 850.0 mg
폴리옥실 40 수소화 피마자유 200.0 mg
2,000.0 mg
조제
좌제 덩어리가 용해된 후 활성 물질을 균질하게 그 안에 분배시키고 용해물을 냉각된 형틀로 붓는다.
실시예 F6: 50 mg의 활성 물질을 함유하는 현탁액
100 ml의 현탁액 함유량
활성 물질 1.00 g
카복시메틸셀룰로즈 나트륨 0.10 g
메틸 p-하이드록시벤조에이트 0.05 g
프로필 p-하이드록시벤조에이트 0.01 g
글루코즈 0.00 g
글리세롤 5.00 g
70% 소르비톨 용액 20.00 g
향미제 0.30 g
증류수를 100 ml가 되도록 첨가한다.
조제
증류수를 70 ℃로 가열한다. 메틸 및 프로필 p-하이드록시벤조에이트를 글리세롤 및 카복시메틸셀룰로즈의 나트륨 염과 함께 그 안에 교반하면서 용해시킨다. 용액을 대기 온도로 냉각시키고 활성 물질을 첨가하고 그 안에 교반하면서 균질하게 분산시킨다. 설탕, 소르비톨 용액 및 향미제가 첨가되고 용해된 후, 현탁액을 교반하면서 진공으로 하여 공기를 제거한다.
따라서, 5 ml의 현탁액은 50 mg의 활성 물질을 함유한다.
실시예 F7: 10 mg의 활성 물질을 함유하는 앰플
조성
활성 물질 10.0 mg
0.01 N 염산 충분량
이중 증류수를 2.0 ml가 되도록 첨가한다.
조제
활성 물질을 0.01 N HCl의 필요량에 용해시키고, 염화나트륨과 등장으로 만 들고, 무균 여과하고, 2 ml 앰플에 옮겼다.
실시예 F8: 50 mg의 활성 물질을 함유하는 앰플
조성
활성 물질 50.0 mg
0.01 N 염산 충분량
이중 증류수를 10.0 ml가 되도록 첨가한다.
조제
활성 물질을 0.01 N HCl의 필요량에 용해시키고, 염화나트륨과 등장으로 만들고, 무균 여과하고, 10 ml 앰플에 옮겼다.
실시예 F9: 5 mg의 활성 물질을 함유하는 파우더 흡입용 캡슐
캡슐 1개의 함유량
활성 물질 5.0 mg
흡입용 락토즈 15.0 mg
20.0 mg
조제
활성 물질을 흡입용 락토즈와 혼합하였다. 혼합물을 캡슐 제조 기계에서 캡슐에 담았다(빈 캡슐의 중량 약 50 mg).
캡슐의 중량: 70.0 mg
캡슐 크기 = 크기 3
실시예 F10: 2.5 mg 활성 물질을 함유하는 소형 분무기용 흡입용 용액
스프레이 1개의 함유량
활성 물질 2.500 mg
벤즈알코늄 클로라이드 0.001 mg
1N 염산 충분량
에탄올/물 (50/50)을 15.000 mg가 되도록 첨가한다.
조제
활성 물질 및 벤즈알코늄 클로라이드를 에탄올/물 (50/50)에 용해시킨다. 용액의 pH를 1N 염산으로 조정한다. 생성 용액을 여과하고 소형 분무기(카트리지)에 사용되는 적합한 용기에 옮긴다.
용기의 함유량: 4.5 g
Claims (10)
- 만성 폐쇄성 폐질환에서의 섬유증 및 폐 조직의 리모델링, 만성 기관지염에서의 섬유증 및 폐 조직의 리모델링, 폐기종에서의 섬유증 및 폐 조직의 리모델링, 폐 섬유증 및 섬유성 성분을 갖는 폐 질환, 천식에서의 섬유증 및 리모델링, 류마티스 관절염에서의 섬유증, 바이러스 유발 간경변증, 방사선-유발 섬유증, 후 혈관성형 재협착(post angioplasty restenosis), 만성 사구체신염, 사이클로스포린을 수용하는 환자의 신장 섬유증 및 고혈압에 기인한 신장 섬유증, 섬유성 성분을 갖는 피부 질환 및 과다 흉터 형성으로 이루어진 그룹으로부터 선택된 섬유성 질환의 예방 또는 치료용 약제의 제조를 위한 화학식 I의 인돌리논, 이의 호변체, 부분입체 이성질체, 거울상 이성질체, 혼합물 및 이의 염의 용도.화학식 I상기 화학식 I에서,X는 산소 원자이고,R1은 수소 원자이고,R2는 불소, 염소 또는 브롬 원자 또는 시아노 그룹이고,R3는 페닐 그룹, 또는 불소, 염소, 브롬 또는 요오드 원자에 의하거나 C1 -3-알콕시 그룹에 의해 일치환된 페닐 그룹이고, 여기서 상술한 비치환되고 일치환된 페닐 그룹은 3- 또는 4-위치에서불소, 염소 또는 브롬 원자에 의해,시아노 그룹에 의해,C1 -3-알콕시 또는 C1 -2-알킬-카보닐-아미노 그룹에 의해,시아노-C1 -3-알킬, 카복시-C1 -3-알킬, 카복시-C1 -4-알콕시, 카복시-C1 -3-알킬아미노, 카복시-C1 -3-알킬-N-(C1 -3-알킬)-아미노, C1 -4-알콕시-카보닐-C1 -3-알킬, C1 -4-알콕시-카보닐-C1 -3-알콕시, C1 -4-알콕시-카보닐-C1 -3-알킬아미노, C1 -4-알콕시-카보닐-C1 -3-알킬-N-(C1 -3-알킬)-아미노, 아미노-C1 -3-알킬, 아미노카보닐-C1 -3-알킬, (C1-2-알킬아미노)-카보닐-C1 -3-알킬, 디-(C1 -2-알킬)-아미노카보닐-C1 -3-알킬, (C1 -2-알킬-카보닐)-아미노-C1 -3-알킬, (C1 -4-알콕시-카보닐)-아미노-C1 -3-알킬, (C3 -6-알킬-카보닐)-아미노-C1 -3-알킬, (페닐-카보닐)-아미노-C1 -3-알킬, (C3 -6-사이클로알킬-카보닐)-아미노-C1 -3-알킬, (C3 -6-사이클로알킬-C1 -3-알킬-카보닐)-아미노-C1 -3-알킬, (티오핀-2-일-카보닐)-아미노-C1 -3-알킬, (퓨란-2-일-카보닐)-아미노-C1 -3-알킬, (페닐-C1 -3-알킬-카보닐)-아미노-C1 -3-알킬, (2-(C1 -4-알콕시)-벤조일-카보닐)- 아미노-C1 -3-알킬, (피리딘-2-일-카보닐)-아미노-C1 -3-알킬, (피리딘-3-일-카보닐)-아미노-C1 -3-알킬-, (피리딘-4-일-카보닐)-아미노-C1 -3-알킬- 또는 C1 -3-알킬-피페라진-1-일-카보닐-C1 -3-알킬 그룹에 의해,카복시-C2 -3-알케닐, 아미노-카보닐-C2 -3-알케닐, (C1 -3-알킬-아미노)-카보닐-C2 -3-알케닐, 디-(C1 -3-알킬)-아미노-카보닐-C2 -3-알케닐 또는 C1 -4-알콕시-카보닐-C2 -3-알케닐 그룹에 의해 추가로 치환될 수 있고,여기서 상기 치환체는 동일하거나 상이할 수 있고,R4는 페닐 그룹 또는아미노, 구아니디노, 모노- 또는 디-(C1 -2-알킬)-아미노-, N-[ω-디-(C1 -3-알킬)-아미노-C2 -3-알킬]-N-(C1 -3-알킬)-아미노, N-메틸-(C3 -4-알킬)-아미노, N-(C1 -3-알킬)-N-벤질아미노, N-(C1 -4-알콕시카보닐)-아미노, N-(C1 -4-알콕시카보닐)-C1 -4-알킬아미노, 4-(C1 -3-알킬)-피페라진-1-일, 이미다졸-1-일, 피롤리딘-1-일, 아제티딘-1-일, 모르폴린-4-일, 피페라진-1-일 또는 티오모르폴린-4-일 그룹에 의해 말단이 치환된 C1 -3-알킬 그룹에 의해,디-(C1 -3-알킬)-아미노-(C1 -3-알킬)-술포닐, 2-[디-(C1 -3-알킬)-아미노]-에톡시, 4-(C1 -3-알킬)-피페라진-1-일-카보닐, {ω-[디-(C1 -3-알킬)-아미노]-(C2 -3-알 킬)}-N-(C1 -3-알킬)-아미노-카보닐, 1-(C1 -3-알킬)이미다졸-2-일, (C1 -3-알킬)-술포닐 그룹에 의해 또는화학식의 그룹에 의해 일치환된 페닐 그룹이고,여기서R7은 C1 -2-알킬, C1 -2-알킬-카보닐, 디-(C1 -2-알킬)-아미노-카보닐-C1 -3-알킬 또는 C1 -3-알킬술포닐 그룹이고,R8은 C1 -3-알킬, ω-[디-(C1 -2-알킬)-아미노]-C2 -3-알킬, ω-[모노-(C1 -2-알킬)-아미노]-C2 -3-알킬 그룹, 또는디-(C1 -2-알킬)-아미노, 피페라진-1-일 또는 4-(C1 -3-알킬)-피페라진-1-일 그룹에 의해 말단이 치환된 (C1 -3-알킬)-카보닐, (C4 -6-알킬)-카보닐 또는 카보닐-(C1 -3-알킬) 그룹이고,여기서 라디칼 R4에 존재하는 모든 디알킬아미노 그룹은 또한 4급 형태(quaternized form)로, 예를 들어 N-메틸-(N,N-디알킬)-암모늄 그룹으로 존재할 수 있고, 여기서 반대 이온은 바람직하게는 아이오다이드, 클로라이드, 브로마 이드, 메틸술포네이트, 파라-톨루엔술포네이트 및 트리플루오로아세테이트로 이루어진 그룹으로부터 선택되고,R5는 수소 원자이고,R6는 수소 원자이고,여기서 상술한 알킬 그룹은, 추가로 1 내지 3개의 수소 원자가 불소 원자에 의해 대체될 수 있는 직쇄 또는 측쇄 알킬 그룹을 포함하고,여기서 추가로, 존재하는 카복실, 아미노 또는 이미노 그룹은 생체내에서 제거가능한 라디칼에 의해 치환될 수 있거나, 프로드럭 라디칼의 형태, 예를 들어 생체내에서 카복실 그룹으로 전환될 수 있는 그룹의 형태 또는 생체내에서 이미노 또는 아미노 그룹으로 전환될 수 있는 그룹의 형태로 존재할 수 있다.
- 제1항에 있어서, 다음으로 이루어진 그룹으로부터 선택되는 화학식 I의 치환된 인돌린, 이의 호변체, 부분 입체 이성질체, 거울상 이성질체, 혼합물 및 이의 염의 용도:(a) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논(b) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(c) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(3-(2- 카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(d) 3-Z-[1-(4-(N-(4-메틸피페라진-1-일메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(e) 3-Z-[1-(4-(N-(2-디메틸아미노에틸)-N-메틸술포닐아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(f) 3-Z-[1-(4-(N-(3-디메틸아미노프로필)-N-아세틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(g) 3-Z-[1-(4-(1-메틸이미다졸-2-일)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(h) 3-Z-[1-(4-(N-(디메틸아미노메틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(i) 3-Z-[1-(4-(N-(2-디메틸아미노에틸카보닐)-N-메틸아미노)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(j) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(k) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-플루오로-2-인돌리논(l) 3-Z-[1-(4-(2-디메틸아미노에틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논(m) 3-Z-[1-(4-디메틸아미노메틸아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논(n) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-클로로-2-인돌리논(o) 3-Z-[1-(4-(피롤리딘-1-일메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논(p) 3-Z-[1-(4-(디메틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)페닐)메틸렌]-6-브로모-2-인돌리논 및(q) 3-Z-[1-(4-(디에틸아미노메틸)아닐리노)-1-(4-(2-카복시에틸)-메틸렌]-6-브로모-2-인돌리논.
- 제1항 또는 제2항에 있어서, 질환이 특발성 폐 섬유증, 거대 세포 사이질 폐렴(giant cell interstitial pneumonia), 사르코이드증(sarcodosis), 낭성 섬유증, 호흡 곤란 증후군, 약물-유발 폐 섬유증, 육아종증, 규폐증(silicosis), 석면증, 전신 경피증으로부터 선택된 섬유성 성분을 갖는 폐 섬유증 및 폐질환, C형 간염으로부터 유발된 간 경변으로부터 선택된 바이러스 유발 간경변증, 및 경피증, 사르코이드증 및 전신 홍반 루푸스로 이루어진 그룹으로부터 선택된 섬유성 성분을 갖는 피부 질환으로 이루어진 그룹으로부터 선택된 용도.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 질환이 특발성 폐 섬유증인 용도.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 치료가 항콜린제, 베타-2 미메틱, 스테로이드, PDE-IV 억제제, p38 MAP 키나제 억제제, NK1 길항제, LTD4 길항제, EGFR 억제제 및 엔도텔린-길항제로 이루어진 그룹으로부터 선택된 약학적으로 활성인 추가의 물질과의 병용 치료인 용도.
- 제1항 또는 제2항에 정의된 화학식 I의 치환된 인돌리논을 필요로 하는 환자에게 임의로 하나 이상의 약학적으로 허용되는 담체 또는 부형제와 함께 투여하는, 만성 폐쇄성 폐질환에서의 섬유증 및 폐 조직의 리모델링, 만성 기관지염에서의 섬유증 및 폐 조직의 리모델링, 폐기종에서의 섬유증 및 폐 조직의 리모델링, 폐 섬유증 및 섬유성 성분을 갖는 폐 질환, 천식에서의 섬유증 및 리모델링, 류마티스 관절염에서의 섬유증, 바이러스 유발 간경변증, 방사선-유발 섬유증, 후 혈관성형 재협착, 만성 사구체신염, 사이클로스포린을 수용하는 환자의 신장 섬유증 및 고혈압에 기인한 신장 섬유증, 섬유성 성분을 갖는 피부 질환, 과다 흉터 형성으로 이루어진 그룹으로부터 선택된 섬유성 질환의 예방 및 치료 방법.
- 제6항에 있어서, 질환이 특발성 폐 섬유증, 거대 세포 사이질 폐렴(giant cell interstitial pneumonia), 사르코이드증(sarcodosis), 낭성 섬유증, 호흡 곤란 증후군, 약물-유발 폐 섬유증, 육아종증, 규폐증(silicosis), 석면증, 전신 경 피증으로부터 선택된 섬유성 성분을 갖는 폐 섬유증 및 폐질환, C형 간염으로부터 유발된 간 경변으로부터 선택된 바이러스 유발 간경변증, 및 경피증, 사르코이드증 및 전신 홍반 루푸스로 이루어진 그룹으로부터 선택된 섬유성 성분을 갖는 피부 질환으로 이루어진 그룹으로부터 선택된 방법.
- 제7항에 있어서, 질환이 특발성 폐 섬유증인 방법.
- 제6항 내지 제8항 중 어느 한 항에 있어서, 치료가 항콜린제, 베타-2 미메틱, 스테로이드, PDE-IV 억제제, p38 MAP 키나제 억제제, NK1 길항제, LTD4 길항제, EGFR 억제제 및 엔도텔린-길항제로 이루어진 그룹으로부터 선택된 약학적으로 활성인 추가의 물질과의 병용 치료이고, 약학적으로 활성인 추가의 물질을 동시에 또는 연속적으로 투여하는 방법.
- 제1항 또는 제2항에 정의된 화학식 I의 치환된 인돌리논을 항콜린제, 베타-2 미메틱, PDE-IV 억제제, p38 MAP 키나제 억제제, NK1 길항제, LTD4 길항제 및 엔도텔린-길항제로 이루어진 그룹으로부터 선택된 약학적으로 활성인 추가의 물질, 임의로 하나 이상의 약학적으로 허용되는 담체 또는 부형제와 함께 함유하는 약학적 조성물.
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US7514468B2 (en) * | 2002-07-23 | 2009-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions |
US7169936B2 (en) * | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
WO2007057399A2 (en) * | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer with indole derivatives |
MY150753A (en) * | 2007-03-02 | 2014-02-28 | Mitsui Chemicals Inc | Non-woven fabric laminate |
EP2220079A2 (en) * | 2007-11-15 | 2010-08-25 | Boehringer Ingelheim International GmbH | Substituted amides, manufacturing and use thereof as medicaments |
US20090131359A1 (en) * | 2007-11-19 | 2009-05-21 | Atamas Sergei P | Antifibrotic therapy |
ES2394239T3 (es) * | 2008-01-25 | 2013-01-23 | Boehringer Ingelheim International Gmbh | Formas salinas de un derivado de 6-fluoro-1,2-dihidro-2-oxo-3H-indol-3-ilideno, procedimiento para su preparación y composiciones farmacéuticas que las contienen |
US8759010B2 (en) | 2008-09-26 | 2014-06-24 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Host cell kinases as targets for antiviral therapies against HCV infection |
WO2012103520A1 (en) * | 2011-01-28 | 2012-08-02 | Board Of Regents Of The University Of Nebraska | Methods and compositions for modulating cyclophilin d |
US10450295B2 (en) | 2013-08-09 | 2019-10-22 | Acclaim BioMed USA LLC | Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis |
CN114732910A (zh) | 2017-10-05 | 2022-07-12 | 弗尔康医疗公司 | P38激酶抑制剂降低dux4和下游基因表达以用于治疗fshd |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
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US6762180B1 (en) * | 1999-10-13 | 2004-07-13 | Boehringer Ingelheim Pharma Kg | Substituted indolines which inhibit receptor tyrosine kinases |
DE10117204A1 (de) * | 2001-04-06 | 2002-10-10 | Boehringer Ingelheim Pharma | In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
US7169936B2 (en) * | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
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ZA200703600B (en) | 2008-07-30 |
DK1835907T3 (da) | 2009-08-03 |
ATE429222T1 (de) | 2009-05-15 |
HRP20090312T1 (en) | 2009-07-31 |
IL184124A0 (en) | 2007-10-31 |
AU2005318136A1 (en) | 2006-06-29 |
NO20073830L (no) | 2007-07-23 |
DE602005014145D1 (de) | 2009-06-04 |
PT1835907E (pt) | 2009-06-16 |
CN101087604A (zh) | 2007-12-12 |
EP1835907B1 (en) | 2009-04-22 |
MX2007007676A (es) | 2007-08-14 |
TW200637544A (en) | 2006-11-01 |
EA200701181A1 (ru) | 2008-02-28 |
EP1835907A1 (en) | 2007-09-26 |
JP2008525374A (ja) | 2008-07-17 |
CA2591089A1 (en) | 2006-06-29 |
US20140128409A1 (en) | 2014-05-08 |
AR052439A1 (es) | 2007-03-21 |
BRPI0519351A2 (pt) | 2009-01-20 |
PL1835907T3 (pl) | 2009-08-31 |
RS50833B (sr) | 2010-08-31 |
WO2006067175A1 (en) | 2006-06-29 |
AU2005318136B2 (en) | 2012-02-09 |
US20120004202A1 (en) | 2012-01-05 |
PE20061155A1 (es) | 2006-12-16 |
CA2591089C (en) | 2014-02-11 |
US20060148883A1 (en) | 2006-07-06 |
JP5748386B2 (ja) | 2015-07-15 |
SI1835907T1 (sl) | 2009-10-31 |
ES2326277T3 (es) | 2009-10-06 |
CN101087604B (zh) | 2010-10-13 |
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