ES2326277T3 - Medicamentos para el tratamiento o prevencion de enfermedades fibroticas. - Google Patents
Medicamentos para el tratamiento o prevencion de enfermedades fibroticas. Download PDFInfo
- Publication number
- ES2326277T3 ES2326277T3 ES05823903T ES05823903T ES2326277T3 ES 2326277 T3 ES2326277 T3 ES 2326277T3 ES 05823903 T ES05823903 T ES 05823903T ES 05823903 T ES05823903 T ES 05823903T ES 2326277 T3 ES2326277 T3 ES 2326277T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- indolinone
- methylene
- phenyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000011282 treatment Methods 0.000 title claims abstract description 22
- 230000003176 fibrotic effect Effects 0.000 title claims abstract description 21
- 201000010099 disease Diseases 0.000 title claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 230000002265 prevention Effects 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 231
- -1 thiophene-2-ylcarbonyl Chemical group 0.000 claims abstract description 218
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 104
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 65
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 65
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 38
- 230000004761 fibrosis Effects 0.000 claims abstract description 35
- 239000000203 mixture Substances 0.000 claims abstract description 33
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- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 210000004072 lung Anatomy 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 20
- 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract description 19
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims abstract description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 16
- 238000001727 in vivo Methods 0.000 claims abstract description 16
- 238000007634 remodeling Methods 0.000 claims abstract description 16
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 15
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 15
- 239000011737 fluorine Substances 0.000 claims abstract description 15
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 14
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000460 chlorine Substances 0.000 claims abstract description 14
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims abstract description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000003277 amino group Chemical group 0.000 claims abstract description 11
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims abstract description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000004181 carboxyalkyl group Chemical group 0.000 claims abstract description 7
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 7
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- 208000006673 asthma Diseases 0.000 claims abstract description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims abstract description 6
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- 125000005111 carboxyalkoxy group Chemical group 0.000 claims abstract description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims abstract description 5
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 4
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 4
- 206010014561 Emphysema Diseases 0.000 claims abstract description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims abstract description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims abstract description 4
- 125000005019 carboxyalkenyl group Chemical group 0.000 claims abstract description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 claims abstract description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims abstract description 4
- 150000002500 ions Chemical class 0.000 claims abstract description 4
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims abstract description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims abstract description 4
- 206010006451 bronchitis Diseases 0.000 claims abstract 3
- 208000007451 chronic bronchitis Diseases 0.000 claims abstract 3
- 239000013543 active substance Substances 0.000 claims description 21
- 239000005557 antagonist Substances 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 210000004027 cell Anatomy 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 7
- LOQDUGXJZZMDJD-DQSJHHFOSA-N 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-(pyrrolidin-1-ylmethyl)anilino]methyl]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1C(\NC=1C=CC(CN2CCCC2)=CC=1)=C\1C2=CC=C(Cl)C=C2NC/1=O LOQDUGXJZZMDJD-DQSJHHFOSA-N 0.000 claims description 7
- 108050009340 Endothelin Proteins 0.000 claims description 7
- 102000002045 Endothelin Human genes 0.000 claims description 7
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
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- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 6
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 6
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 6
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims description 6
- RLJHTEFNMMMLKD-DQSJHHFOSA-N 3-[4-[(z)-(6-bromo-2-oxo-1h-indol-3-ylidene)-[4-(pyrrolidin-1-ylmethyl)anilino]methyl]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1C(\NC=1C=CC(CN2CCCC2)=CC=1)=C\1C2=CC=C(Br)C=C2NC/1=O RLJHTEFNMMMLKD-DQSJHHFOSA-N 0.000 claims description 5
- 239000000812 cholinergic antagonist Substances 0.000 claims description 5
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 claims description 5
- YVPMCULRLMBIGD-QPLCGJKRSA-N 3-[3-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoic acid Chemical compound C1=CC(CN(C)C)=CC=C1N\C(C=1C=C(CCC(O)=O)C=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O YVPMCULRLMBIGD-QPLCGJKRSA-N 0.000 claims description 4
- RHNANBOIVYNSLB-QPLCGJKRSA-N 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-[(dimethylamino)methyl]anilino]methyl]phenyl]propanoic acid Chemical compound C1=CC(CN(C)C)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(Cl)C=C2NC\1=O RHNANBOIVYNSLB-QPLCGJKRSA-N 0.000 claims description 4
- LSGCZBZIUYDZGH-RQZHXJHFSA-N 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-[2-(dimethylamino)ethyl]anilino]methyl]phenyl]propanoic acid Chemical compound C1=CC(CCN(C)C)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(Cl)C=C2NC\1=O LSGCZBZIUYDZGH-RQZHXJHFSA-N 0.000 claims description 4
- XFTLJHAGQCUBEX-QPLCGJKRSA-N 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(1-methylimidazol-2-yl)anilino]methyl]phenyl]propanoic acid Chemical compound CN1C=CN=C1C(C=C1)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O XFTLJHAGQCUBEX-QPLCGJKRSA-N 0.000 claims description 4
- APXPWTWQXBDIFW-DQSJHHFOSA-N 3-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-(pyrrolidin-1-ylmethyl)anilino]methyl]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1C(\NC=1C=CC(CN2CCCC2)=CC=1)=C\1C2=CC=C(F)C=C2NC/1=O APXPWTWQXBDIFW-DQSJHHFOSA-N 0.000 claims description 4
- 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
- MXJOFHZXYMJNPZ-QPLCGJKRSA-N 3-[4-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoic acid Chemical compound C1=CC(CN(C)C)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O MXJOFHZXYMJNPZ-QPLCGJKRSA-N 0.000 claims description 4
- MFWDNOIZFMTREW-DQSJHHFOSA-N 3-[4-[(z)-[4-[2-(dimethylamino)ethyl-methylsulfonylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoic acid Chemical compound C1=CC(N(CCN(C)C)S(C)(=O)=O)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O MFWDNOIZFMTREW-DQSJHHFOSA-N 0.000 claims description 4
- XPOQXQDIKYQOBM-ZIADKAODSA-N 3-[4-[(z)-[4-[3-(dimethylamino)propanoyl-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoic acid Chemical compound C1=CC(N(C)C(=O)CCN(C)C)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O XPOQXQDIKYQOBM-ZIADKAODSA-N 0.000 claims description 4
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- ZYANNCMTXFXGAV-DQSJHHFOSA-N 3-[4-[(z)-[4-[[2-(dimethylamino)acetyl]-methylamino]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoic acid Chemical compound C1=CC(N(C)C(=O)CN(C)C)=CC=C1N\C(C=1C=CC(CCC(O)=O)=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O ZYANNCMTXFXGAV-DQSJHHFOSA-N 0.000 claims description 3
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- 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
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- 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
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- 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
- PNUZAQZDSPPWMW-DQSJHHFOSA-N methyl 2-[3-[(z)-[4-[[2-(dimethylamino)acetyl]-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)CN(C)C)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 PNUZAQZDSPPWMW-DQSJHHFOSA-N 0.000 description 1
- HJRJKRJEAGPSMH-ZIADKAODSA-N methyl 2-[3-[(z)-[4-[acetyl-[2-(dimethylamino)ethyl]amino]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)C(C)=O)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 HJRJKRJEAGPSMH-ZIADKAODSA-N 0.000 description 1
- BMGLKNUVAQJCFC-FLWNBWAVSA-N methyl 2-[3-[(z)-[4-[acetyl-[3-(dimethylamino)propyl]amino]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(CCCN(C)C)C(C)=O)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 BMGLKNUVAQJCFC-FLWNBWAVSA-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
- 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
- FSOSVJYLBNJVAW-KTMFPKCZSA-N methyl 2-[4-[(z)-(6-fluoro-2-oxo-1h-indol-3-ylidene)-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]methyl]phenyl]acetate Chemical compound C1=CC(CC(=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 FSOSVJYLBNJVAW-KTMFPKCZSA-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
- PRCZUBRFZCBTSW-DQSJHHFOSA-N methyl 2-[4-[(z)-[4-[[2-(dimethylamino)acetyl]-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)CN(C)C)=C\1C2=CC=C(F)C=C2NC/1=O PRCZUBRFZCBTSW-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
- LBGHLBDMIFDSSF-FLWNBWAVSA-N methyl 2-[4-[(z)-[4-[acetyl-[3-(dimethylamino)propyl]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(CCCN(C)C)C(C)=O)=C\1C2=CC=C(F)C=C2NC/1=O LBGHLBDMIFDSSF-FLWNBWAVSA-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
- 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
- CJWDSCLUQYZRKQ-GMPMOFPVSA-N methyl 3-[3-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]prop-2-enoate Chemical compound COC(=O)C=CC1=CC=CC(C(\NC=2C=CC(CN(C)C)=CC=2)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 CJWDSCLUQYZRKQ-GMPMOFPVSA-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
- CLEIAVOFRQGEKU-ZIADKAODSA-N methyl 3-[3-[(z)-[4-[2-(dimethylamino)ethyl-methylsulfonylamino]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(CCN(C)C)S(C)(=O)=O)=C\2C3=CC=C(F)C=C3NC/2=O)=C1 CLEIAVOFRQGEKU-ZIADKAODSA-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
- CWLNRSIDJRHHRR-ZIADKAODSA-N methyl 3-[4-[(z)-(6-bromo-2-oxo-1h-indol-3-ylidene)-[4-(diethylaminomethyl)anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CN(CC)CC)=CC=C1N\C(C=1C=CC(CCC(=O)OC)=CC=1)=C/1C2=CC=C(Br)C=C2NC\1=O CWLNRSIDJRHHRR-ZIADKAODSA-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
- QIOQFSAFEUSMSN-DQSJHHFOSA-N methyl 3-[4-[(z)-(6-chloro-2-oxo-1h-indol-3-ylidene)-[4-[2-(dimethylamino)ethyl]anilino]methyl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1C(\NC=1C=CC(CCN(C)C)=CC=1)=C\1C2=CC=C(Cl)C=C2NC/1=O QIOQFSAFEUSMSN-DQSJHHFOSA-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
- JZTDEWUDDWOAHY-ZIADKAODSA-N methyl 3-[4-[(z)-[4-(diethylaminomethyl)anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)methyl]phenyl]propanoate Chemical compound C1=CC(CN(CC)CC)=CC=C1N\C(C=1C=CC(CCC(=O)OC)=CC=1)=C/1C2=CC=C(F)C=C2NC\1=O JZTDEWUDDWOAHY-ZIADKAODSA-N 0.000 description 1
- HXCBNQZMWSOEIK-ASDRPUQFSA-N methyl 3-[4-[(z)-[4-[(dimethylamino)methyl]anilino]-(6-fluoro-2-oxo-1h-indol-3-ylidene)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(F)C=C2NC/1=O HXCBNQZMWSOEIK-ASDRPUQFSA-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
- TUAWNQZBSWUTOS-FLWNBWAVSA-N methyl 3-[4-[(z)-[4-[3-(dimethylamino)propanoyl-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)CCN(C)C)=C\1C2=CC=C(F)C=C2NC/1=O TUAWNQZBSWUTOS-FLWNBWAVSA-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
- FXXQDYPNDZFBMV-UHFFFAOYSA-N methyl 5-cyano-5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-oxocyclohexane-1-carboxylate Chemical compound C1CC(=O)C(C(=O)OC)CC1(C#N)C1=CC=C(OC(F)F)C(OCC2CC2)=C1 FXXQDYPNDZFBMV-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
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Classifications
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
o de las indolinonas de la fórmula general ** ver fórmula** en las que X es un átomo de oxígeno R1 es un átomo de hidrógeno R 2 es un átomo de flúor, cloro o bromo o un grupo ciano, R 3 es un grupo fenilo o un grupo fenilo que está monosustituido por un átomo de flúor, cloro, bromo o yodo o por un grupo alcoxi C1-3, en el que los grupos fenilo no sustituido y monosustituido mencionados anteriormente pueden estar sustituidos adicionalmente en la posición 3 ó 4 por un átomo de flúor, cloro o bromo, por un grupo ciano, por un grupo alcoxi C1-3 o (alquil C1-2)carbonilamino, por un grupo cianoalquilo C1-3, carboxialquilo C1-3, carboxialcoxi C1-4, carboxi(alquil C1-3)amino, carboxi(alquil C 1-3)-N-(alquil C 1-3)amino, (alcoxi C 1-4)carbonilalquilo C 1-3, (alcoxi C 1-4)carbonilalcoxi C 1-3, (alcoxi C 1-4)carbonil(alquil C 1-3)amino, (alcoxi C 1-4)carbonil(alquil C 1-3)-N-(alquil C 1-3)amino, aminoalquilo C 1-3, aminocarbonilalquilo C1-3, ((alquil C1-2)amino)carbonilalquilo C1-3, di(alquil C1-2)amino-carbonilalquilo C1-3, ((alquil C1-2) carbonil)aminoalquilo C1-3, ((alcoxi C1-4)carbonil)aminoalquilo C1-3, ((alquil C3-6)carbonil)aminoalquilo C1-3, (fenilcarbonil)aminoalquilo C1-3, ((cicloalquil C3-6)carbonil)aminoalquilo C1-3, ((cicloalquil C3-6)(alquil C1-3) carbonil)aminoalquilo C 1-3, (tiofen-2-ilcarbonil)aminoalquilo C 1-3, (furan-2-ilcarbonil)-aminoalquilo C 1-3, (fenil (alquil C 1-3)carbonil)aminoalquilo C 1-3, (2-(alcoxi C 1-4)benzoil-carbonil)aminoalquilo C 1-3, (piridin-2-ilcarbonil) aminoalquilo C1-3, (piridin-3-ilcarbonil)aminoalquilo C1-3, (piridin-4-ilcarbonil)aminoalquilo C1-3 o (alquil C1-3) piperazin-1-ilcarbonilalquilo C1-3, por un grupo carboxialquenilo C2-3, aminocarbonilalquenilo C2-3, ((alquil C1-3)-amino)carbonilalquenilo C2-3, di (alquil C1-3)aminocarbonilalquenilo C2-3 o (alcoxi C1-4)-carbonilalquenilo C2-3, en el que los sustituyentes pueden ser idénticos o diferentes, R 4 es un grupo fenilo o un grupo fenilo que está monosustituido por un grupo alquilo C1-3 que está sustituido en el extremo por un grupo amino, guanidino, mono- o di(alquil C1-2) amino, N-[--di(alquil C 1-3)amino(alquil C 2-3)]-N-(alquil C 1-3)amino, N-metil(alquil C 3-4)amino, N-(alquil C 1-3)- N-bencilamino, N-((alcoxi C 1-4)-carbonil)amino, N-((alcoxi C 1-4)carbonil)(alquil C 1-4)amino, 4-(alquil C 1-3)piperazin-1-ilo, imidazol-1-ilo, pirrolidin-1-ilo, acetidin-1-ilo, morfolin-4-ilo, piperazin-1-ilo, tiomorfolin-4-ilo, por un grupo di(alquil C1-3)amino(alquil C1-3)sulfonilo, 2-[di(alquil C1-3)-amino]etoxi, 4-(alquil C1-3)piperazin- 1-ilcarbonilo, {omega-[di(alquil C1-3)amino](alquil C2-3)}-N-(alquil C1-3)aminocarbonilo, 1-(alquil C1-3)imidazol-2ilo, (alquil C1-3)sulfonilo, o por un grupo de la fórmula en el que R 7 es un grupo alquilo C1-2, (alquil C1-2)carbonilo, di(alquil C1-2)amino-carbonilalquilo C1-3 o (alquil C1-3)sulfonilo y R 8 es un grupo alquilo C 1-3, omega-[di(alquil C 1-2)amino]alquilo C 2-3, omega[mono(alquil C 1-2)amino]alquilo C 2-3, o un grupo (alquil C 1-3)carbonilo, (alquil C 4-6)carbonilo o carbonilalquilo C 1-3 que está sustituido en el extremo por un grupo di(alquil C1-2)amino, piperazin-1-ilo o 4-(alquil C1-3)piperazin-1-ilo, donde todos los grupos dialquilamino presentes en el radical R 4 pueden también estar presentes en forma cuaternizada, por ejemplo en forma de un grupo N-metil-(N,N-dialquil)amonio, donde el ión conjugado preferiblemente se selecciona del grupo que consiste en yoduro, cloruro, bromuro, metilsulfonato, para-toluenosulfonato y trifluoroacetato, R 5 es un átomo de hidrógeno y R 6 es un átomo de hidrógeno, donde los grupos alquilo mencionados anteriormente incluyen los grupos alquilo lineales y ramificados en los que además de uno a 3 átomos de hidrógeno pueden ser reemplazados por átomos de flúor, donde además un grupo carboxilo, amino o imino presente puede estar sustituido por un radical que puede escindirse in vivo o puede estar presente en forma de un radical de profármaco, por ejemplo en forma de un grupo que puede convertirse in vivo en un grupo carboxilo o en forma de un grupo que puede convertirse in vivo en un grupo imino o amino, los tautómeros, los diastereoisómeros, los enantiómeros, sus mezclas y sus sales, para la preparación de un medicamento para la prevención o el tratamiento de una enfermedad fibrótica que se selecciona del grupo que consiste en fibrosis y remodelación de tejido pulmonar en la enfermedad pulmonar obstructiva crónica, fibrosis y remodelación de tejido pulmonar en la bronquitis crónica, fibrosis y remodelación de tejido pulmonar en el enfisema, fibrosis pulmonar y enfermedades pulmonares con un componente fibrótico, fibrosis y remodelación en el asma.
Description
Medicamentos para el tratamiento o prevención de
enfermedades fibróticas.
La presente invención se refiere a un uso
novedoso de indolinonas de la fórmula general
\vskip1.000000\baselineskip
sustituidas en la posición 6, los
tautómeros, los diastereoisómeros, los enantiómeros, sus mezclas y
sus sales, en particular sus sales fisiológicamente
aceptables.
\vskip1.000000\baselineskip
Los compuestos de la fórmula general I anterior,
los tautómeros, los diastereoisómeros, los enantiómeros, sus
mezclas y sus sales, en particular sus sales fisiológicamente
aceptables, han sido descritas en el documento WO 04/009547 como
que tienen propiedades farmacológicas valiosas, en particular un
efecto inhibidor sobre diversas quinasas, especialmente las
tirosina quinasas de receptores tales como VEGFR1, VEGFR2, VEGFR3,
PDGFR\alpha, PDGFR\beta, FGFR1, FGFR3, EGFR, HER2,
c-Kit, IGF1R y HGFR, Flt-3, y sobre
la proliferación de células humanas cultivadas, en particular las
células endoteliales, por ejemplo en la angiogénesis, pero también
en la proliferación de otras células, en particular células
tumorales.
Sin embargo, no se ha descrito ninguno de estos
compuestos para su uso en el tratamiento o prevención de las
enfermedades fibróticas a las que se hace referencia en la presente
invención.
La remodelación es una respuesta normal a la
lesión tisular y a la inflamación que se observa en muchos tejidos
por todo el cuerpo. Cuando se ha resuelto la inflamación y
reparación del daño tisular, el tejido generalmente vuelve a su
estado original. Una reparación tisular sin control y excesiva o la
incapacidad de detener la remodelación cuando ya no es necesaria
conlleva la afección que se conoce como fibrosis. La fibrosis se
caracteriza por una deposición excesiva de los componentes de la
matriz extracelular y por el crecimiento excesivo de los
fibroblastos. La fibrosis puede tener lugar en todos los tejidos,
pero es especialmente dominante en órganos con una exposición
frecuente a agresiones químicas y biológicas, que incluyen el
pulmón, la piel, el tubo digestivo, el riñón y el hígado (Eddy,
1996, J Am Soc Nephrol, 7 (12):2495-503; Dacic y
cols., 2003, Am J Respir Cell Mol Biol, 29S: S5-9;
Wynn, 2004, Nat Rev Immunol, 4 (8):583-94). La
fibrosis a menudo pone en peligro la(s) función(es)
normal(es) del órgano y muchas enfermedades fibróticas, de
hecho, ponen en peligro la vida o producen desfiguraciones graves,
tales como la fibrosis pulmonar idiopática (IPF), cirrosis hepática,
esclerodermia, o fibrosis renal. Las opciones de tratamiento para
estas enfermedades a menudo se limitan al trasplante de órganos, un
procedimiento de riesgo y caro.
Un extenso corpus de bibliografía implica a las
familias de factores de crecimiento como factor de crecimiento
derivado de plaquetas (PDGF), factor de crecimiento de fibroblastos
(FGF), factor de crecimiento endotelial vascular (VEGF), factor de
crecimiento epidérmico (EGF), y factor de crecimiento transformante
beta (TGFb) en la inducción o persistencia de la fibrosis
(Levitzki, Cytokine Growth Factor Rev, 2004,
15(4):229-35; Strutz y cols., Kidney Intl,
2000, 57:1521-38; Strutz y cols., 2003, Springer
Semin Immunopathol, 24:459-76; Rice y cols., 1999,
Amer J Pathol, 155(1):213-221; Broekelmann y
cols., 1991, Proc Nat Acad Sci, 88:6642-6; Wynn,
2004, Nat Rev Immunol, 4(8):583-94).
Los miembros de las familias PDGF, EGF y FGF son
mitógenos potentes para las células mesenquimatosas tales como las
células del músculo liso, los miofibroblastos y los fibroblastos
(Benito y cols., 1993, Growth Regul
3(3):172-9; Simm y cols., 1998, Basic Res
Cardiol, 93(S3):40-3; Klagsburn, Prog Growth
Factor Res, 1989, 1(4):207-35; Kirkland y
cols., 1998, J Am Soc Nephrol, 9(8):1464-73),
las mismas células que suplantan al tejido normal en la fibrosis y
se cree que desempeñan un papel en la remodelación tisular (Abboud,
1995, Annu Rev Physiol., 57:297-309; Jinnin y
cols., 2004, J Cell Physiol, en línea; Martinet y cols., 1996, Arch
Toxicol 18:127-39; Desmouliere, Cell Biology
International, 1995, 19:471-6; Jelaska y cols.,
Springer Semin Immunopathol, 2000, 21:385-95).
\newpage
La inhibición de PDGF atenúa tanto la fibrosis
hepática como la fibrosis pulmonar en modelos experimentales, lo
que sugiere que la fibrosis en los diferentes órganos puede tener un
origen común (Borkham-Kamphorst y cols., 2004,
Biochem Biophys Res Commun; Rice y cols., 1999, Amer J Pathol,
155(1):213-221). Un inhibidor de la quinasa
del receptor EGF era también activo en este modelo de fibrosis
pulmonar. La expresión aumentada por un factor de tres de un
miembro de la familia EGF, HB-EGF, en los islotes de
páncreas de ratón fue suficiente para provocar el desarrollo de la
fibrosis tanto en los compartimentos exocrino como endocrino (Means
y cols., 2003, Gastroenterology,
124(4):1020-36).
De forma similar, los ratones sin FGF1/FGF2
muestran una fibrosis hepática dramáticamente disminuida tras la
exposición crónica a tetracloruro carbónico (CCl4) (Yu y cols.,
2003, Am J Pathol, 163(4):1653-62). La
expresión de FGF está aumentada en la fibrosis intersticial renal
humana en la que existe una fuerte correlación con la cicatrización
patológica intersticial (Strutz y cols., 2000, Kidney Intl,
57:1521-38) así como en un modelo de fibrosis
pulmonar experimental (Barrios y cols., 1997, Am J Physiol, 273 (2
Pt 1):L451-8), que de nuevo acredita la idea de que
la fibrosis en diversos tejidos tiene un base común.
Además, se han observado niveles elevados de
VEGF en diversos estudios en personas con asma (Hoshino y cols.,
2001, J Allergy Clin Immunol 107:1034-39; Hoshino y
cols., 2001, J Allergy Clin Immunol 107:295-301;
Kanazawa y cols., 2002, Thorax 57:885-8; Asai y
cols., J Allergy Clin Immunol 110:571-5, 2002;
Kanazawa y cols., 2004, Am J Respir Crit Care Med,
169:1125-30). La expresión inducible de VEGF en un
modelo de ratón transgénico induce un fenotipo tipo asma, edema,
angiogénesis e hiperplasia del músculo liso (Lee y cols., 2004,
Nature Med 10:1095-1103).
Finalmente, TGFb estimula la producción de
proteínas de matriz extracelular que incluyen fibronectina y
colágenos y se cree que desempeña un papel importante en la
fibrosis en muchos tejidos (Leask y cols., 2004, FASEB J
18(7):816-27; Bartram y cols., 2004, Chest
125(2):754-65; Strutz y cols., 2003, Springer
Semin Immunopathol, 24:459-76; Wynn, 2004, Nat Rev
Immunol, 4(8):583-94). Los inhibidores de la
producción de TGFb y de las rutas de señalización están activos en
un número de modelos de fibrosis en animales (Wang y cols., 2002,
Exp Lung Res, 28:405-17; Laping, 2003, Curr Opin
Pharmacol, 3(2):204-8).
Tal como se resume anteriormente, diversos
factores de crecimiento están regulados por aumento en la fibrosis,
y la inhibición de un único factor parece reducir la gravedad de la
fibrosis en los modelos de fibrosis.
Sorprendentemente, los inventores encontraron
que los compuestos de la fórmula general I anterior son eficaces en
el tratamiento o prevención de enfermedades fibróticas
específicas.
La presente invención así se refiere al uso de
los compuestos de la fórmula general I anterior para la preparación
de un medicamento para el tratamiento o prevención de enfermedades
fibróticas específicas.
La presente invención también se refiere a un
método para el tratamiento o prevención de enfermedades fibróticas
específicas, mediante la administración a un paciente que lo
necesite de una composición farmacéutica que comprende un compuesto
de la fórmula general I anterior, junto con un vehículo
farmacéuticamente adecuado. La expresión "paciente" se pretende
que comprenda el cuerpo de animales mamíferos, preferiblemente el
cuerpo humano.
La presente invención se refiere además a una
composición farmacéutica para el tratamiento o prevención de
enfermedades fibróticas específicas que comprende un compuesto de la
fórmula general I anterior solo o combinado con uno o más agentes
terapéuticos adicionales.
De acuerdo con la presente invención, los
compuestos de la fórmula general I son los compuestos
en los
que
\global\parskip0.930000\baselineskip
I. En la fórmula I anterior,
X es un átomo de oxígeno,
R^{1} es un átomo de hidrógeno,
R^{2} es un átomo de flúor, cloro o bromo o un
grupo ciano,
R^{3} es un grupo fenilo o un grupo fenilo que
está monosustituido por un átomo de flúor, cloro, bromo o yodo o por
un grupo alcoxi C_{1-3}, en el que los grupos
fenilo no sustituido y monosustituido mencionados anteriormente
pueden estar sustituidos adicionalmente en la posición 3 ó 4
por un átomo de flúor, cloro o bromo,
por un grupo ciano,
por un grupo alcoxi C_{1-3} o
(alquil C_{1-2})carbonilamino,
por un grupo cianoalquilo
C_{1-3}, carboxialquilo C_{1-3},
carboxialcoxi C_{1-4}, carboxi(alquil
C_{1-3})amino, carboxi(alquil
C_{1-3})-N-(alquil
C_{1-3})amino, (alcoxi
C_{1-4})carbonil-alquilo
C_{1-3}, (alcoxi
C_{1-4})carbonilalcoxi
C_{1-3}, (alcoxi
C_{1-4})carbonil(alquil
C_{1-3})amino, (alcoxi
C_{1-4})carbonil(alquil
C_{1-3})-N-(alquil
C_{1-3})amino, aminoalquilo
C_{1-3}, amino-carbonilalquilo
C_{1-3}, ((alquil
C_{1-2})amino)carbonilalquilo
C_{1-3}, di(alquil
C_{1-2})amino-carbonilalquilo
C_{1-3}, ((alquil
C_{1-2})carbonil)aminoalquilo
C_{1-3}, ((alcoxi
C_{1-4})carbonil)aminoalquilo
C_{1-3}, ((alquil
C_{3-6})carbonil)aminoalquilo
C_{1-3}, (fenilcarbonil)aminoalquilo
C_{1-3}, ((cicloalquil
C_{3-6})carbonil)aminoalquilo
C_{1-3}, ((cicloalquil
C_{3-6})(alquil
C_{1-3})carbonil)aminoalquilo
C_{1-3},
(tiofen-2-ilcarbonil)aminoalquilo
C_{1-3},
(furan-2-ilcarbonil)-aminoalquilo
C_{1-3}, (fenil(alquil
C_{1-3})carbonil)aminoalquilo
C_{1-3}, (2-(alcoxi
C_{1-4})benzoilcarbonil)aminoalquilo
C_{1-3},
(piridin-2-ilcarbonil)aminoalquilo
C_{1-3},
(piridin-3-ilcarbonil)aminoalquilo
C_{1-3},
(piridin-4-ilcarbonil)aminoalquilo
C_{1-3} o (alquil
C_{1-3})piperazin-1-ilcarbonilalquilo
C_{1-3},
por un grupo carboxialquenilo
C_{2-3}, aminocarbonilalquenilo
C_{2-3}, ((alquil (C_{1-3})-
amino)carbonilalquenilo C_{2-3},
di(alquil
C_{1-3})aminocarbonilalquenilo
C_{2-3} o (alcoxi
C_{1-4})-carbonilalquenilo
C_{2-3},
en los que los sustituyentes pueden ser
idénticos o diferentes,
R^{4} es un grupo fenilo o un grupo fenilo que
está monosustituido
por un grupo alquilo C_{1-3}
que está sustituido en el extremo por un grupo amino, guanidino,
mono- o di(alquil C_{1-2})amino,
N-[\omega-di(alquil
C_{1-3})amino(alquil
C_{2-3})]-N-(alquil
C_{1-3})amino,
N-metil(alquil
C_{3-4})amino, N-(alquil
C_{1-3})-N-bencilamino,
N-((alcoxi
C_{1-4})-carbonil)amino,
N-((alcoxi C_{1-4})carbonil)(alquil
C_{1-4})amino, 4-(alquil
C_{1-3})piperazin-1-ilo,
imidazol-1-ilo,
pirrolidin-1-ilo,
acetidin-1-ilo,
morfolin-4-ilo,
piperazin-1-ilo,
tiomorfolin-4-ilo,
por un grupo di(alquil
C_{1-3})amino(alquil
C_{1-3})sulfonilo, 2-[di(alquil
C_{1-3})ami-no]etoxi,
4-(alquil
C_{1-3})piperazin-1-ilcarbonilo,
{\omega-[di(alquil
C_{1-3})amino](alquil
C_{2-3})}-N-(alquil
C_{1-3})aminocarbonilo, 1-(alquil
C_{1-3})imidazol-2-ilo,
(alquil C_{1-3})sulfonilo, o
por un grupo de la fórmula
en el
que
R^{7} es un grupo alquilo
C_{1-2}, (alquil
C_{1-2})carbonilo, di(alquil
C_{1-2})ami-nocarbonilalquilo
C_{1-3} o (alquil
C_{1-3})sulfonilo y
R^{8} es un grupo alquilo
C_{1-3}, \omega-[di(alquil
C_{1-2})amino]alquilo
C_{2-3}, \omega-[mono(alquil
C_{1-2})amino]alquilo
C_{2-3}, o
un grupo (alquil
C_{1-3})carbonilo, (alquil
C_{4-6})carbonilo o carbonilalquilo
C_{1-3} que está sustituido en el extremo por un
grupo di(alquil C_{1-2})amino,
piperazin-1-ilo o 4-(alquil
C_{1-3})piperazin-1-ilo,
donde todos los grupos dialquilamino presentes
en el radical R^{4} pueden también estar presentes en forma
cuaternizada, por ejemplo en forma de un grupo
N-metil-(N,N-dialquil)amonio,
en el que el ión conjugado preferiblemente se selecciona del grupo
que consiste en yoduro, cloruro, bromuro, metilsulfonato,
para-toluenosulfonato y trifluoroacetato,
\global\parskip1.000000\baselineskip
R^{5} es un átomo de hidrógeno y
R^{6} es un átomo de hidrógeno,
donde los grupos alquilo mencionados
anteriormente incluyen los grupos alquilo lineales y ramificados en
los que además de uno a 3 átomos de hidrógeno pueden ser
reemplazados por átomos de flúor,
donde además un grupo carboxilo, amino o imino
presente puede estar sustituido por un radical que puede escindirse
in vivo o puede estar presente en forma de un radical de
profármaco, por ejemplo en forma de un grupo que puede convertirse
in vivo en un grupo carboxilo o en forma de un grupo que
puede convertirse en un grupo que puede convertirse in vivo
en un grupo imino o amino,
sus tautómeros, enantiómeros, diastereoisómeros,
sus mezclas y sus sales.
\vskip1.000000\baselineskip
II. Compuestos particularmente preferidos de la
fórmula I anterior son aquellos compuestos en los que X, R^{1},
R^{5} y R^{6} son tal como se definen en I. y:
II.i. R^{2} y R^{4} son tal como se definen
en I. y
R^{3} es un grupo fenilo o un grupo fenilo que
está monosustituido por un átomo de flúor, cloro, bromo o yodo o por
un grupo alcoxi C_{1-3}, en el que los grupos
fenilo no sustituido y monosustituido mencionados anteriormente
pueden estar sustituidos adicionalmente en la posición 3 ó 4
por un átomo de flúor, cloro o bromo,
por un grupo ciano,
por un grupo alcoxi C_{1-3} o
(alquil C_{1-2})carbonilamino,
por un grupo cianoalquilo
C_{1-3}, carboxialquilo C_{1-3},
carboxialcoxi C_{1-4}, carboxi(alquil
C_{1-3})amino, carboxi(alquil
C_{1-3})-N-(alquil
C_{1-3})amino, (alcoxi
C_{1-4})carbonil-C_{1-3}-alquilo,
(alcoxi C_{1-4})carbonilalcoxi
C_{1-3}, (alcoxi
C_{1-4})carbonil(alquil
C_{1-3})amino, (alcoxi
C_{1-4})carbonil(alquil
C_{1-3})-N-(alquil
C_{1-3})amino, aminoalquilo
C_{1-3}, amino-carbonilalquilo
C_{1-3}, (alquil
C_{1-2})amino)carbonilalquilo
C_{1-3}, di(alquil
C_{1-2})amino-carbonilalquilo
C_{1-3}, ((alquil
C_{1-2})carbonil)aminoalquilo
C_{1-3}, ((alcoxi
C_{1-4})carbonil)aminoalquilo
C_{1-3}, ((alquil
C_{3-6})carbonil)aminoalquilo
C_{1-3},
(fenilcarbonil)-aminoalquilo
C_{1-3}, ((cicloalquil
C_{3-6})carbonil)aminoalquilo
C_{1-3}, ((cicloalquil
C_{3-6})(alquil
C_{1-3})carbonil)aminoalquilo
C_{1-3},
(tiofen-2-ilcarbonil)aminoalquilo
C_{1-3},
(furan-2-ilcarbonil)aminoalquilo
C_{1-3}, (fenil(alquil
C_{1-3})carbonil)aminoalquilo
C_{1-3}, (2-(alcoxi
C_{1-4})benzoilcarbonil)aminoalquilo
C_{1-3},
(piridin-2-ilcarbonil)aminoalquilo
C_{1-3},
(piridin-3-ilcarbonil)aminoalquilo
C_{1-3},
(piridin-4-ilcarbonil)aminoalquilo
C_{1-3} o (alquil
C_{1-3})piperazin-1-ilcarbonilalquilo
C_{1-3},
por un grupo carboxialquenilo
C_{2-3}, aminocarbonilalquenilo
C_{2-3}, ((alquil
C_{1-3})-amino)carbonilalquenilo
C_{2-3}, di(alquil
C_{1-3})aminocarbonilalquenilo
C_{2-3} o (alcoxi
C_{1-4})-carbonilalquenilo
C_{2-3},
en los que los sustituyentes pueden ser
idénticos o diferentes;
\vskip1.000000\baselineskip
II.ii. R^{2} y R^{4} son tal como se definen
en I. y
R^{3} es un grupo fenilo que está
sustituido
por un grupo (alquil
C_{1-2})carbonilamino,
por un grupo carboxialquilo
C_{1-3}, carboxialcoxi C_{1-4},
(alcoxi C_{1-4})carbonilalquilo
C_{1-3}, (alcoxi
C_{1-4})carbonilalcoxi
C_{1-3}, aminocarbonilalquilo
C_{1-3}, ((alquil
C_{1-2})ami-no)carbonilalquilo
C_{1-3}, di(alquil
C_{1-2})aminocarbonilalquilo
C_{1-3}, ((alquil
C_{1-2})carbonil)aminoalquilo
C_{1-3}, ((alcoxi
C_{1-4})carbonil)aminoalquilo
C_{1-3}, (fenilcarbonil)aminoalquilo
C_{1-3}, ((cicloalquil
C_{3-6})carbonil)aminoalquilo
C_{1-3}, (cicloalquil
C_{3-6})(alquil
C_{1-3})carbonil)amino(alquilo
C_{1-3}),
(tiofen-2-ilcarbonil)amino(alquilo
C_{1-3}),
(furan-2-ilcarbonil)amino(alquilo
C_{1-3}),(fenil(alquil
C_{1-3})carbonil)amino(alquilo
C_{1-3}), (2-(alcoxi
C_{1-4})benzoilcarbonil)aminoalquilo
C_{1-3},
(piridin-2-ilcarbonil)aminoalquilo
C_{1-3},
(piridin-3-ilcarbonil)aminoalquilo
C_{1-3},
(piridin-4-ilcarbonil)aminoalquilo
C_{1-3} o (alquil
C_{1-3})piperazin-1-ilcarbonilalquilo
C_{1-3},
por un grupo aminocarbonilalquenilo
C_{2-3}, ((alquil
C_{1-3})amino)carbonilalquenilo
C_{2-3}, di(alquil
C_{1-3})aminocarbonilalquenilo
C_{2-3} o (alcoxi
C_{1-4})carbonilalquenilo
C_{2-3};
\vskip1.000000\baselineskip
II.iii. R^{2} y R^{4} son tal como se
definen en I. y
R^{3} es un grupo fenilo sustituido por un
grupo carboxialquilo C_{1-3} o (alcoxi
C_{1-4})carbonilalquilo
C_{1-3};
\vskip1.000000\baselineskip
II.iv. R^{3} y R^{4} son tal como se definen
en I. y
R^{2} es un átomo de flúor o cloro;
\vskip1.000000\baselineskip
II.v. R^{2} y R^{3} son tal como se definen
en I. y
R^{4} es un grupo fenilo o un grupo fenilo que
está monosustituido
por un grupo alquilo C_{1-3}
que está sustituido en el extremo por un grupo amino, guanidino,
mono- o di(alquil C_{1-2})amino,
N-[\omega-di(alquil
C_{1-3})amino(alquil
C_{2-3})]-N-(alquil
C_{1-3})amino,
N-metil(alquil
C_{3-4})amino, N-(alquil
C_{1-3})-N-bencilamino,
N-((alcoxi
C_{1-4})-carbonil)amino,
N-((alcoxi C_{1-4})carbonil)(alquil
C_{1-4})amino, 4-(alquil
C_{1-3})piperazin-1-ilo,
imidazol-1-ilo,
pirrolidin-1-ilo,
acetidin-1-ilo,
morfolin-4-ilo,
piperazin-1-ilo,
tiomorfolin-4-ilo,
por un grupo di(alquil
C_{1-3})amino(alquil
C_{1-3})sulfonilo, 2-[di(alquil
C_{1-3})ami-no]etoxi,
4-(alquil
C_{1-3})piperazin-1-ilcarbonilo,
{\omega-[di(alquil
C_{1-3})amino](alquil
C_{2-3})}-N-(alquil
C_{1-3})aminocarbonilo, 1-(alquil
C_{1-3})imidazol-2-ilo,
(alquil C_{1-3})sulfonilo, o
por un grupo de la fórmula
en el
que
R^{7} es un grupo alquilo
C_{1-2}, (alquil
C_{1-2})carbonilo, di(alquil
C_{1-2})amino-carbonilalquilo
C_{1-3} o (alquil
C_{1-3})sulfonilo y
R^{8} es un grupo alquilo
C_{1-3}, \omega-[di(alquil
C_{1-2})amino]alquilo
C_{2-3}, \omega-[mono(alquil
C_{1-2})amino]alquilo
C_{2-3}, o
un grupo (alquil
C_{1-3})carbonilo, (alquil
C_{4-6})carbonilo o carbonilalquilo
C_{1-3} que está sustituido en el extremo por un
grupo di(alquil C_{1-2})amino,
piperazin-1-ilo o 4-(alquil
C_{1-3})piperazin-1-ilo,
donde todos los grupos dialquilamino presentes
en el radical R^{4} pueden también estar presentes en forma
cuaternizada, por ejemplo en forma de un grupo
N-metil-(N,N-dialquil)amonio,
donde el ión conjugado preferiblemente se selecciona del grupo que
consiste en yoduro, cloruro, bromuro, metilsulfonato,
para-toluenosulfonato y trifluoroacetato,
\vskip1.000000\baselineskip
III. Subgrupos de compuestos particularmente
preferidos de la fórmula I anterior que deben mencionarse en
particular son aquellos en los que:
III.i. X, R^{1}, R^{2}, R^{5} y R^{6}
son tal como se definen en I., R^{3} es tal como se define en
II.i. y R^{4} es tal como se define en II.v.;
III.ii. X, R^{1}, R^{2}, R^{5} y R^{6}
son tal como se definen en I., R^{3} es tal como se define en
II.ii. y R^{4} es tal como se define en II.v.;
III.iii. X, R^{1}, R^{2}, R^{5} y R^{6}
son tal como se definen en I., R^{3} es tal como se define en
II.iii. y R^{4} es tal como se define en II.v.;
III.iv. X, R^{1}, R^{5} y R^{6} son tal
como se definen en I., R^{2} es tal como se define en II.iv.,
R^{3} es tal como se define en II.i., II.ii. o II.iii. y R^{4}
es tal como se define en II.v.
\vskip1.000000\baselineskip
Un grupo de compuestos más preferidos de la
fórmula I anterior son aquellos en los que
X es un átomo de oxígeno,
R^{1} es un átomo de hidrógeno,
R^{2} es un átomo de flúor, cloro o bromo o un
grupo ciano,
R^{3} es un grupo fenilo o un grupo fenilo que
está monosustituido por un átomo de flúor, cloro, bromo o yodo o por
un grupo alcoxi C_{1-3}, en el que los grupos
fenilo no sustituido y monosustituido mencionados anteriormente
pueden estar sustituidos adicionalmente en la posición 3 ó 4
por un átomo de flúor, cloro o bromo,
por un grupo alcoxi C_{1-3} o
(alquil C_{1-2})carbonilamino,
por un grupo carboxialquilo
C_{1-3}, aminocarbonilalquilo
C_{1-3}, ((alquil
C_{1-2})amino)-carbonilalquilo
C_{1-3}, di(alquil
C_{1-2})aminocarbonilalquilo
C_{1-3}, ((alquil
C_{1-2})carbonil)-aminoalquilo
C_{1-3} o (fenilcarbonil)aminoalquilo
C_{1-3},
en el que los sustituyentes pueden ser idénticos
o diferentes,
R^{4} es un grupo fenilo que está
sustituido
por un grupo alquilo C_{1-3}
sustituido en el extremo por un grupo di(alquil
C_{1-2})-amino, o
por un grupo de la fórmula
en el
que
R^{7} es un grupo alquilo
C_{1-2}, (alquil
C_{1-2})carbonilo, di(alquil
C_{1-2})amino-carbonilalquilo
C_{1-3} o (alquil
C_{1-3})sulfonilo y
R^{8} es un grupo alquilo
C_{1-3} o \omega-[di(alquil
C_{1-2})amino]alquilo
C_{2-3}, o
un grupo (alquil
C_{1-3})carbonilo sustituido en el extremo
por un grupo di(alquil
C_{1-2})amino, piperazino o 4-(alquil
C_{1-3})piperazin-1-ilo,
R^{5} es un átomo de hidrógeno y
R^{6} es un átomo de hidrógeno,
donde los grupos alquilo mencionados
anteriormente incluyen los grupos alquilo lineales y ramificados en
los que además de uno a 3 átomos de hidrógeno pueden ser
reemplazados por átomos de flúor,
donde además un grupo carboxilo, amino o imino
presente puede estar sustituido por un radical que puede escindirse
in vivo,
sus tautómeros, enantiómeros, diastereoisómeros,
sus mezclas y sus sales.
\vskip1.000000\baselineskip
Los siguientes compuestos de la fórmula I son
particularmente preferidos:
(a)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(b)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(c)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(d)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(e)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-
2-indolinona
2-indolinona
(f)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-in-
dolinona
dolinona
(g)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(h)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(i)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-
2-indolinona
2-indolinona
(j)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(k)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(l)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(m)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(n)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(o)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(p)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(q)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-carboxietil)metilen]-6-bromo-2-indolinona
donde además un grupo carboxilo, amino o imino
presente puede estar sustituido por un radical que puede escindirse
in vivo o puede estar presente en forma de un radical de
profármaco, por ejemplo en forma de un grupo que puede convertirse
in vivo en un grupo carboxilo o en forma de un grupo que
puede convertirse en un grupo que puede convertirse in vivo
en un grupo imino o amino,
sus tautómeros, enantiómeros, diastereoisómeros,
sus mezclas y sus sales.
\vskip1.000000\baselineskip
Un grupo que puede convertirse in vivo en
un grupo carboxilo debe entenderse que significa, por ejemplo, un
grupo hidroximetilo, un grupo carboxilo, un grupo que está
esterificado con un alcohol en el que el resto alcohólico es
preferiblemente un alcanol C_{1-6}, un
fenilalcanol C_{1-3}, un cicloalcanol
C_{3-9}, en el que un cicloalcanol
C_{5-8} puede estar adicionalmente sustituido por
uno o dos grupos alquilo C_{1-3}, un cicloalcanol
C_{5-8} en el que un grupo metileno en la posición
3 ó 4 es reemplazado por un átomo de oxígeno o por un grupo imino
opcionalmente sustituido por un grupo alquilo
C_{1-3}, fenilalquilo C_{1-3},
fenil(alcoxi C_{1-3})carbonilo o
(alquil C_{1-6})carbonilo y en el que el
resto cicloalcanol puede estar sustituido adicionalmente por uno o
dos grupos alquilo C_{1-3}, un cicloalquenol
C_{4-7}, un alquenol C_{3-5}, un
fenilalquenol C_{3-5}, un alquinol
C_{3-5}, o un fenilalquinol
C_{3-5}, con la condición de que ningún enlace al
átomo de oxígeno se origine en un átomo de carbono que porte un
enlace doble o triple, un (cicloalquil
C_{3-8})alcanol C_{1-3},
un bicicloalcanol que tiene un total de 8 a 10 átomos de carbono
que pueden estar sustituidos adicionalmente en el resto
bicicloalquilo por uno o dos grupos alquilo
C_{1-3}, un
1,3-dihidro-3-oxo-1-isobenzofuranol
o un alcohol de la fórmula
R_{a}-CO-O-(R_{b}CR_{c})-OH,
en el
que
R_{a} es un grupo alquilo
C_{1-8}, cicloalquilo C_{5-7},
fenilo o fenilalquilo C_{1-3},
R_{b} es un átomo de hidrógeno, un grupo
alquilo C_{1-3}, cicloalquilo
C_{5-7} o fenilo, y
R_{c} es un átomo de hidrógeno o un grupo
alquilo C_{1-3},
y un radical que puede escindirse in vivo
a partir de un grupo imino o amino debe entenderse como que
significa, por ejemplo, un grupo hidroxilo, un grupo acilo, tal
como el grupo benzoilo o piridinoilo, o un grupo (alquil
C_{1-16})carbonilo, tal como el grupo
formilo, acetilo, propionilo, butanoilo, pentanoilo o hexanoilo, un
grupo aliloxicarbonilo, un grupo (alcoxi
C_{1-16})carbonilo, tal como el grupo
metoxicarbonilo, etoxicarbonilo, propoxicarbonilo,
isopropoxicarbonilo, butoxicarbonilo,
terc-butoxicarbonilo, pentoxicarbonilo,
hexiloxicarbonilo, octiloxicarbonilo, noniloxicarbonilo,
deciloxicarbonilo, undeciloxicarbonilo, dodeciloxicarbonilo o
hexadeciloxicarbonilo, un grupo fenil(alcoxi
C_{1-6})carbonilo, tal como el grupo
benciloxicarbonilo, feniletoxicarbonilo o fenilpropoxicarbonilo, un
grupo (alquil
C_{1-3})sulfonil(alcoxi
C_{1-4})carbonilo, (alcoxi
C_{1-3})(alcoxi C_{2-4})(alcoxi
C_{2-4})carbonilo o
R_{a}CO-O-(R_{b}CR_{c})-O-CO-,
en el que
R_{a} es un grupo alquilo
C_{1-8}, cicloalquilo C_{5-7},
fenilo o fenilalquilo C_{1-3},
R_{b} es un átomo de hidrógeno, un grupo
alquilo C_{1-3}, cicloalquilo
C_{5-7} o fenilo, y
R_{c} es un átomo de hidrógeno, un grupo
alquilo C_{1-3} o
R_{a}CO-O-(R_{b}CR_{c})-O-, en
el que R_{a} a R_{c} son tal como se define anteriormente,
y además, para un grupo amino, el grupo
ftalimido, en el que los radicales éster que se mencionan
anteriormente pueden usarse también como un grupo que puede
convertirse in vivo en un grupo carboxilo.
\vskip1.000000\baselineskip
Radicales de profármacos preferidos para un
grupo carboxilo son un grupo (alcoxi
C_{1-6})carbonilo, tal como el grupo
metoxicarbonilo, etoxicarbonilo,
n-propiloxicarbonilo, isopropiloxicarbonilo,
n-butiloxicarbonilo,
n-pentiloxicarbonilo,
n-hexiloxicarbonilo o ciclohexiloxicarbonilo, o un
grupo fenil(alcoxi
C_{1-3})carbonilo, tal como el grupo
benciloxicarbonilo, y,
para un grupo imino o amino, un grupo (alcoxi
C_{1-9})carbonilo, tal como el grupo
metoxicarbonilo, etoxicarbonilo,
n-propiloxicarbonilo, isopropiloxicarbonilo,
n-butiloxicarbonilo,
n-pentiloxicarbonilo,
n-hexiloxicarbonilo, ciclohexiloxicarbonilo,
n-heptiloxicarbonilo,
n-octiloxicarbonilo o
n-noniloxicarbonilo, un grupo fenil(alcoxi
C_{1-3})carbonilo, tal como el grupo
benciloxicarbonilo, un grupo fenilcarbonilo opcionalmente sustituido
por un grupo alquilo C_{1-3}, tal como el grupo
benzoilo o 4-etil-benzoilo, un grupo
piridinoilo, tal como el grupo nicotinoilo, un grupo (alquil
C_{1-3})sulfonil-n-(alcoxi
C_{2-3})carbonilo o (alcoxi
C_{1-3})(alcoxi C_{2-3})(alcoxi
C_{1-4})carbonilo, tal como el grupo
2-metilsulfoniletoxicarbonilo o
2-(2-etoxi)etoxicarbonilo.
Los compuestos que se ejemplifican
anteriormente, sus tautómeros, sus estereoisómeros o sus sales
fisiológicamente aceptables, así como su procedimiento de
fabricación, han sido descritos en el documento WO 04/009547, cuyo
contenido se incorpora al presente documento por referencia.
La siguiente lista de compuestos específicos es
ilustrativa de la presente invención, sin constituir ninguna
limitación de su alcance:
(1)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(3-yodofenil)metilen]-6-cloro-2-indolinona
(2)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-yodofenil)metilen]-6-cloro-2-indolinona
(3)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-clorofenil)metilen]-6-cloro-2-indolinona
(4)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(4-clorofenil)metilen]-6-cloro-2-indolinona
(5)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-clorofenil)metilen]-6-cloro-2-
indolinona
indolinona
(6)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-clorofenil)metilen]-6-cloro-2-indolinona
(7)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-clorofenil)metilen]-6-cloro-2-indolinona
(8)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(3,4-dimetoxifenil)metilen]-6-cloro-2-indolinona
(9)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3,4-dimetoxifenil)metilen]-6-cloro-2-indolinona
(10)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3,4-dimetoxifenil)metilen]-6-cloro-2-
indolinona
indolinona
(11)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3,4-dimetoxifenil)metilen]-6-cloro-2-indolinona
(12)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilcarbamoil)anilino)-1-(3,4-dimetoxifenil)metilen]-6-cloro-2-indolinona
(13)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-cianofenil)metilen]-6-cloro-2-indolinona
(14)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-yodofenil)metilen]-6-fluoro-2-indolinona
(15)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-fluorofenil)metilen]-6-fluoro-2-indolinona
(16)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(3-fluorofenil)metilen]-6-fluoro-2-indolinona
(17)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-fluorofenil)metilen]-6-fluoro-2-indolinona
(18)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-acetilaminoetil)fenil)-metilen]-6-fluoro-2-indolinona
(19)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-(2-acetilaminoetil)fenil)metilen]-6-fluoro-2-indolinona
(20)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-acetilaminoetil)fenil)metilen]-6-fluoro-2-indolinona
(21)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(22)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-yodofenil)metilen]-6-fluoro-2-indolinona
(23)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(24)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-(N-terc-butoxicarbonil-amino-metil)fenil)metilen]-6-fluoro-2-indolinona
(25)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(26)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(27)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-cianometilfenil)metilen]-6-fluoro-2-indolinona
(28)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(N-terc-butoxicarbonilaminometil)fenil)metilen]-6-fluoro-2-indolinona
(29)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(N-terc-butoxicarbonilaminometil)fenil)metilen]-6-fluoro-2-in-
dolinona
dolinona
(30)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-(N-terc-butoxicarbonil-2-aminoetil)fenil)metilen]-6-fluoro-2-indolinona
(31)
3-Z-[1-(4-(N-acetil-N-metilamino)anilino)-1-(4-(2-metoxicarboniletil)fenil)-metilen]-6-fluoro-2-indolinona
(32)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-metoxicarboniletil)fenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(33)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(34)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(35)
3-Z-[1-(4-(N-terc-butoxicarbonilmetilaminometil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(36)
3-Z-[1-(4-(4-metilpiperazin-1-il-carbonil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(37)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-metoxicarboniletil)fenil)-metilen]-6-fluoro-2-indolinona
(38)
3-Z-[1-(4-metilsulfonilanilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(39)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(40)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(41)
3-Z-[1-(4-(4-metilpiperazin-1-il-carbonil)anilino)-1-(3-metoxicarbonil-metilfenil)metilen]-6-fluoro-2-indolinona
(42)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(43)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(44)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-
2-indolinona
2-indolinona
(45)
3-Z-[1-(4-(N-(4-dimetilamino-butilcarbonil)-N-metilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(46)
3-Z-[1-anilino-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(47)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-metoxicarbonilmetilfenil)-metilen]-6-fluoro-2-indolinona
(48)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(4-metoxicarbonilmetil-fenil)metilen]-6-fluoro-2-indolinona
(49)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(50)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(51)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(4-metoxicarbonilmetilfenil)-metilen]-6-fluoro-2-indolinona
(52)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(53)
3-Z-[1-(4-metilsulfonilanilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(54)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(55)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(56)
3-Z-[1-anilino-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(57)
3-Z-[1-(4-metilsulfonilanilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(58)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(59)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(60)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(61)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(62)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(2-metoxicarboniletil)fenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(63)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3-(2-metoxicarboniletil)fenil)metilen]-
6-fluoro-2-indolinona
6-fluoro-2-indolinona
(64)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(3-(2-metoxicarboniletil)fenil)metilen]-
6-fluoro-2-indolinona
6-fluoro-2-indolinona
(65)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(3-(2-metoxicarboniletil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(66)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(N-terc-butoxicarbonilaminometil)fenil)metilen]-6-fluoro-2-indolinona
(67)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(3-acetilaminometilfenil)-metilen]-6-cloro-2-indolinona
(68)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(3-acetilaminometilfenil)metilen]-6-cloro-2-indolinona
(69)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3-acetilaminometilfenil)metilen]-6-cloro-2-indolinona
\newpage
(70)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(3-acetilaminometilfenil)metilen]-6-cloro-2-indolinona
(71)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(72)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(73)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-
6-fluoro-2-indolinona
6-fluoro-2-indolinona
(74)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(75)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(76)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(77)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-
6-fluoro-2-indolinona
6-fluoro-2-indolinona
(78)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(79)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(4-(2-metoxicarboniletil)fenil)meti-
len]-6-fluoro-2-indolinona
len]-6-fluoro-2-indolinona
(80)
3-Z-[1-anilino-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(81)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-metoxicarboniletil)fenil)-metilen]-6-fluoro-2-indolinona
(82)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(83)
3-Z-[1-(4-(N-terc-butoxicarbonilaminometil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(84)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(3-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(85)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-metoxicarbonilmetilfenil)metilen]-6-fluoro-2-indolinona
(86)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(87)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-cloro-2-indolinona
(88)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-etoxicarboniletil)fenil)metilen]-6-cloro-2-indolinona
(89)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-cloro-2-indolinona
(90)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(91)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(3-(2-metoxicarboniletil)-fenil)metilen]-6-fluoro-2-indolinona
(92)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(3-(2-metoxicarboniletil)fenil)-metilen]-6-fluoro-2-indolinona
(93)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(4-(2-metoxicarboniletil)-fenil)metilen]-6-fluoro-2-indolinona
(94)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(95)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(96)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(97)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-cloro-2-indolinona
(98)
3-Z-[1anilino-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(99)
3-Z-[1-(4-(N-terc-butoxicarbonilaminometil)anilino)-1-(3-(2-etoxicarbonil-etil)fenil)metilen]-6-fluoro-2-indolinona
(100)
3-Z-[1-(4-(N-terc-butoxicarbonilmetilaminometil)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(101)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-metoxicarbonilmetoxifenil)metilen]-6-fluoro-2-indolinona
(102)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-metoxicarbonilmetoxifenil)metilen]-6-fluoro-2-indolinona
(103)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-etoxicarboniletoxi)fenil)metilen]-6-fluoro-2-indolinona
(104)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-bromo-2-indolinona
(105)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-bromo-2-indolinona
(106)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-bromo-2-indolinona
(107)
3-Z-[1-(3-dimetilaminometilanilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(108)
3-Z-[1-(3-dimetilaminometilanilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(109)
3-Z-[1-(3-dimetilaminometilanilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-cloro-2-indolinona
(110)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3,4-dimetoxifenil)metilen]-6-ciano-2-indolinona
(111)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(3-(2-metoxicarbonilvinil)fenil)metilen]-6-cloro-2-indolinona
(112)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-metoxicarbonilvinil)fenil)-metilen]-6-cloro-2-indolinona
(113)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-carbamoilvinil)fenil)metilen]-6-fluoro-2-indolinona
(114)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-metoxicarbonilvinil)fenil)-metilen]-6-fluoro-2-indolinona
(115)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-(2-metoxicarbonilvinil)fenil)-metilen]-6-fluoro-2-indolinona
(116)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-metoxicarboniletil)fenil)-metilen]-6-cloro-2-indolinona
(117)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(3-(2-metoxicarboniletil)fenil)metilen]-6-cloro-2-indolinona
(118)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(119)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-metoxicarboniletil)fenil)-metilen]-6-fluoro-2-indolinona
(120)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(121)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-aminometilfenil)metilen]-6-cloro-2-indolinona
(122)
3-Z-[1-(4-(N-((4-metilpiperazin-1-il)metilcarbonil)-N-metilamino)anilino)-1-(4-aminometilfenil)metilen]-
6-cloro-2-indolinona
6-cloro-2-indolinona
(123)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-aminometilfenil)metilen]-6-fluoro-2-indolinona
(124)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(3-(2-aminoetil)fenil)metilen]-6-fluoro-2-indolinona
(125)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-aminometilfenil)metilen]-6-fluoro-2-indolinona
(126)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-aminometilfenil)metilen]-6-fluoro-2-indolinona
(127)
3-Z-[1-(4-(metilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(128)
3-Z-[1-(4-(metilaminometil)anilino)-1-(4-(2-metilcarbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(129)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-aminometilfenil)metilen]-6-fluoro-2-indolinona
(130)
3-Z-[1-(4-(aminometil)anilino)-1-(4-(2-metoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(131)
3-Z-[1-(4-(aminometil)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(132)
3-Z-[1-(4-(metilaminometil)anilino)-1-(3-(2-etoxicarboniletil)fenil)metilen]-6-fluoro-2-indolinona
(133)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(134)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(135)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(136)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(137)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(138)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(139)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(140)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(141)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(142)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(143)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-
indolinona
indolinona
(144)
3-Z-[1-(4-(N-terc-butoxicarbonilmetilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-in-
dolinona
dolinona
(145)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(146)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(147)
3-Z-[1-(4-metilsulfonilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(148)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(3-carboximetilfenil)-metilen]-6-fluoro-2-indolinona
(149)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-carboximetilfenil)metilen]-
6-fluoro-2-indolinona
6-fluoro-2-indolinona
(150)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(151)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(152)
3-Z-[1-anilino-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(153)
3-Z-[1-(4-metilsulfonilanilino)-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(154)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(155)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(3-carboximetilfenil)metilen]-
6-fluoro-2-indolinona
6-fluoro-2-indolinona
(156)
3-Z-[1-anilino-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(157)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(158)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(4-carboximetilfenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(159)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(160)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(4-carboximetilfenil)-metilen]-6-fluoro-2-indolinona
(161)
3-Z-[1-(4-metilsulfonilanilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(162)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(163)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(4-carboximetilfenil)metilen]-
6-fluoro-2-indolinona
6-fluoro-2-indolinona
(164)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(165)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(4-carboximetilfenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(166)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(167)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(168)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(169)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(170)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-
indolinona
indolinona
(171)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(172)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(173)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(174)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(175)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-in-
dolinona
dolinona
(176)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(177)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(178)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(179)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(180)
3-Z-[1anilino-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(181)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(182)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(183)
3-Z-[1-(4-aminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(184)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(3-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(185)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-carboximetilfenil)metilen]-6-fluoro-2-indolinona
(186)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(187)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(188)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(189)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(190)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(191)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-
2-indolinona
2-indolinona
(192)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(193)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(194)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(195)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-
2-indolinona
2-indolinona
(196)
3-Z-[1anilino-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(197)
3-Z-[1-(4-aminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(198)
3-Z-[1-(4-metilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(199)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carboximetoxifenil)metilen]-6-fluoro-2-indolinona
(200)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carboximetoxifenil)fenil)metilen]-6-fluoro-2-indolinona
(201)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(202)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(203)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-carboxietil)metilen]-6-bromo-2-indolinona
(204)
3-Z-[1-(3-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(205)
3-Z-[1-(3-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(206)
3-Z-[1-(3-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(207)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carbamoiletil)fenil)metilen]-6-cloro-2-indolinona
(208)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-metilcarbamoiletil)fenil)metilen]-6-cloro-2-indolinona
(209)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-metilcarbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(210)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-dimetilcarbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(211)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(212)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-metilcarbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(213)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-dimetilcarbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(214)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(215)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-metilcarbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(216)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(217)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-dimetilcarbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(218)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-(4-metilpiperazin-1-ilcarbonil)etil)fenil)metilen]-6-fluoro-2-
indolinona
indolinona
(219)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-carbamoilmetilfenil)meti-
len]-6-fluoro-2-indolinona
len]-6-fluoro-2-indolinona
(220)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-carbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(221)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-dimetilcarbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(222)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-metilcarbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(223)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-metilcarbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(224)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-dimetilcarbamoilmetilfenil)metilen]-6-fluoro-2-indolinona
(225)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-metilcarbamoilmetilfenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(226)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(4-(2-metilcarbamoiletil)fenil)-metilen]-6-fluoro-2-indolinona
(227)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-metilcarbamoiletil)fenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(228)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-(2-metilcarbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(229)
3-Z-[1-(4-(N-terc-butoxicarbonilmetilaminometil)anilino)-1-(4-(2-metil-carbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(230)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-metilcarbamoiletil)fenil)-metilen]-6-fluoro-2-indolinona
(231)
3-Z-[1-(4-metilsulfonilanilino)-1-(4-(2-metilcarbamoiletil)fenil)metilen]-6-fluoro-2-indolinona
(232)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(4-(2-metilcarbamoil-etil)fenil)metilen]-6-fluoro-2-indolinona
(233)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(3-metilcarbamoilmetil-fenil)metilen]-6-fluoro-2-indolinona
(234)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-metilcarbamoilmetilfenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(235)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-acetilaminometilfenil)metilen]-6-cloro-2-indolinona
(236)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-acetilaminometilfenil)meti-
len]-6-cloro-2-indolinona
len]-6-cloro-2-indolinona
(237)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-benzoilaminofenil)metilen]-6-cloro-2-indolinona
(238)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-benzoilaminometilfenil)metilen]-6-cloro-2-indolinona
(239)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-acetilaminometilfenil)metilen]-6-fluoro-2-indolinona
(240)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-propionilaminometilfenil)metilen]-6-fluoro-2-indolinona
(241)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-benzoilaminometilfenil)metilen]-6-fluoro-2-indolinona
(242)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-fenilacetilaminometilfenil)metilen]-6-fluoro-2-indolinona
(243)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-acetilaminoetil)fenil)metilen]-6-fluoro-2-indolinona
(244)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-benzoilaminoetil)fenil)metilen]-6-fluoro-2-indolinona
(245)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-propionilaminoetil)fenil)metilen]-6-fluoro-2-indolinona
(246)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-fenilacetilaminoetil)fenil)metilen]-6-fluoro-2-indolinona
(247)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-acetilaminometilfenil)metilen]-6-fluoro-2-indolinona
(248)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-propionilaminometilfenil)metilen]-6-fluoro-2-indolinona
(249)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-fenilacetilaminometilfenil)metilen]-6-fluoro-2-indolinona
(250)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-acetilaminometilfenil)meti-
len]-6-fluoro-2-indolinona
len]-6-fluoro-2-indolinona
(251)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-propionilaminometilfenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(252)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-fenilacetilaminometilfenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(253)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-ciclopropilcarbonilaminometilfenil)metilen]-6-fluoro-2-indolinona
(254)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-ciclobutilcarbonilaminome-
tilfenil)metilen]-6-fluoro-2-indolinona
tilfenil)metilen]-6-fluoro-2-indolinona
(255)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(piridin-2-ilcarbonilamino-
metil)fenil)metilen]-6-fluoro-2-indolinona
metil)fenil)metilen]-6-fluoro-2-indolinona
(256)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-ciclohexilcarbonilaminometilfenil)metilen]-6-fluoro-2-indolinona
(257)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(piridin-3-ilcarbonilamino-
metil)fenil)metilen]-6-fluoro-2-indolinona
metil)fenil)metilen]-6-fluoro-2-indolinona
(258)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-isobutirilaminometilfenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(259)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(3-metilbutirilaminometilfenil)metilen]-6-fluoro-2-indolinona
(260)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-ciclohexilmetilcarbonilami-
nometilfenil)metilen]-6-fluoro-2-indolinona
nometilfenil)metilen]-6-fluoro-2-indolinona
(261)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-metoxiacetilaminometilfenil)metilen]-6-fluoro-2-indolinona
(262)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(2-metoxibenzoilaminome-
til)fenil)metilen]-6-fluoro-2-indolinona
til)fenil)metilen]-6-fluoro-2-indolinona
(263)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-terc-butilacetilaminometilfenil)metilen]-6-fluoro-2-indolinona
(264)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(2-tiofencarbonilaminometil)fenil)metilen]-6-fluoro-2-indolinona
(265)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-pivaloilaminometilfenil)metilen]-6-fluoro-2-indolinona
(266)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(2-furoilaminometil)fenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(267)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-acetilaminometilfenil)meti-
len]-6-fluoro-2-indolinona
len]-6-fluoro-2-indolinona
(268)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-propionilaminometilfenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(269)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-benzoilaminometilfenil)metilen]-6-fluoro-2-indolinona
(270)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-fenilacetilaminometilfenil)
metilen]-6-fluoro-2-indolinona
metilen]-6-fluoro-2-indolinona
(271)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-ciclopropilcarbonilamino-metilfenil)metilen]-6-fluoro-2-indoli-
nona
nona
(272)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-ciclobutilcarbonilaminometil-fenil)metilen]-6-fluoro-2-indolinona
(273)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(piridin-2-ilcarbonilaminometil)-fenil)metilen]-6-fluoro-2-indolinona
(274)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-ciclohexilcarbonilaminometil-fenil)metilen]-6-fluoro-2-indolinona
(275)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(piridin-3-ilcarbonilamino-metil)fenil)metilen]-6-fluoro-2-indolinona
(276)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-isobutirilaminometilfenil)-metilen]-6-fluoro-2-indolinona
(277)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(3-metilbutirilaminometilfenil)-metilen]-6-fluoro-2-indolinona
(278)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-ciclohexilmetilcarbonil-aminometilfenil)metilen]-6-fluoro-2-in-
dolinona
dolinona
(279)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-metoxiacetilaminometil-fenil)metilen]-6-fluoro-2-indolinona
(280)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-metoxibenzoil-aminometil)fenil)metilen]-6-fluoro-2-indolinona
(281)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-terc-butilacetilaminometil-fenil)metilen]-6-fluoro-2-indolinona
(282)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-tiofenocarbonil-aminometil)fenil)metilen]-6-fluoro-2-indoli-
nona
nona
(283)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-pivaloilaminometilfenil)metilen]-6-fluoro-2-indolinona
(284)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-furoilaminometil)fenil)metilen]-6-fluoro-2-indolinona
(285)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(piridin-4-ilcarbonilaminometil)-fenil)metilen]-6-fluoro-2-indolinona
(286)
3-Z-[1-(4-trimetilamoniometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
yoduro
(287)
3-Z-[1-(4-trimetilamoniometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
yoduro
(288)
3-Z-[1-(4-guanidinometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(289)
3-Z-[1-(4-guanidinometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(290)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-clo-
ro-2-indolinona
ro-2-indolinona
(291)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(292)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(293)
3-Z-[1-(4-(N-(2-metilaminoetil)-N-acetilamino)anilino)-1-(4-(2-carboxi-etil)fenil)metilen]-6-cloro-2-indolinona
(294)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-
indolinona
indolinona
(295)
3-Z-[1-(4-(N-(3-metilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-in-
dolinona
dolinona
(296)
3-Z-[1-(4-(3-dimetilaminopropil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(297)
3-Z-[1-(4-etilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(298)
3-Z-[1-(4-metilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(299)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(300)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(4-(2-carboxietil)-fenil)metilen]-6-cloro-2-indolinona
(301)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-
cloro-2-indolinona
cloro-2-indolinona
(302)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-propilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(303)
3-Z-[1-(4-aminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(304)
3-Z-[1-(3-(metilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(305)
3-Z-[1-(3-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(306)
3-Z-[1-(3-(3-dimetilaminopropil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(307)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(308)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-cloro-2-indolinona
(309)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(310)
3-Z-[1-(4-(N-(N-(2-dimetilaminoetil)-N-metilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(311)
3-Z-[1-(4-(2-dietilaminoetilsulfonil)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-cloro-2-indolinona
(312)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-clo-
ro-2-indolinona
ro-2-indolinona
(313)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(314)
3-Z-[1-(4-(2-dimetilaminoetoxi)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(315)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(316)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-
cloro-2-indolinona
cloro-2-indolinona
(317)
3-Z-[1-(4-(metiletilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(318)
3-Z-[1-(4-(metilpropilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(319)
3-Z-[1-(4-(metilbencilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(320)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(4-(2-carboxietil)fenilmetilen]-6-cloro-2-indolinona
(321)
3-Z-[1-(4-(acetidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(322)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(323)
3-Z-[1-(4-(piperazin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(324)
3-Z-[1-(4-(morfolin-4-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(325)
3-Z-[1-(4-(tiomorfolin-4-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(326)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(327)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(328)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-clo-
ro-2-indolinona
ro-2-indolinona
(329)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(3-(2-carboxi-etil)fenil)metilen]-6-cloro-2-in-
dolinona
dolinona
(330)
3-Z-[1-(4-(N-(2-metilaminoetil)-N-acetilamino)anilino)-1-(3-(2-carboxi-etil)fenil)metilen]-6-cloro-2-indolinona
(331)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-
indolinona
indolinona
(332)
3-Z-[1-(4-(N-(3-metilaminopropil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-in-
dolinona
dolinona
(333)
3-Z-[1-(4-(3-dimetilaminopropil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(334)
3-Z-[1-(4-etilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(335)
3-Z-[1-(4-metilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(336)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(337)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-cloro-2-indolinona
(338)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-
cloro-2-indolinona
cloro-2-indolinona
(339)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-propilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(340)
3-Z-[1-(4-aminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(341)
3-Z-[1-(3-(dimetilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(342)
3-Z-[1-(3-(metilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(343)
3-Z-[1-(3-(2-dimetilaminoetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(344)
3-Z-[1-(3-(3-dimetilaminopropil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(345)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(346)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(347)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-cloro-2-indolinona
(348)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-cloro-2-indolinona
(349)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(350)
3-Z-[1-(4-(N-(N-(2-dimetilaminoetil)-N-metilaminometilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(351)
3-Z-[1-(4-(2-dietilaminoetilsulfonil)anilino)-1-(3-(2-carboxietil)-fenil)metilen]-6-cloro-2-indolinona
\newpage
(352)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-clo-
ro-2-indolinona
ro-2-indolinona
(353)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(354)
3-Z-[1-(4-(2-dimetilaminoetoxi)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(355)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(356)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-
cloro-2-indolinona
cloro-2-indolinona
(357)
3-Z-[1-(4-(metiletilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(358)
3-Z-[1-(4-(metilpropilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(359)
3-Z-[1-(4-(metilbencilaminometil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-cloro-2-indolinona
(360)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(361)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(3-(2-carboxietil)fenilmetilen]-6-cloro-2-indolinona
(362)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(363)
3-Z-[1-(4-(acetidin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(364)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-cloro-2-indolinona
(365)
3-Z-[1-(4-(piperazin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(366)
3-Z-[1-(4-(morfolin-4-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(367)
3-Z-[1-(4-(tiomorfolin-4-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(368)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(369)
3-Z-[1-(4-(N-(2-metilaminoetil)-N-acetilamino)anilino)-1-(4-(2-carboxi-etil)fenil)metilen]-6-fluoro-2-indolinona
(370)
3-Z-[1-(4-(N-(3-metilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(371)
3-Z-[1-(4-(3-dimetilaminopropil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(372)
3-Z-[1-(4-etilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(373)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(374)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-propilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(375)
3-Z-[1-(3-(metilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(376)
3-Z-[1-(3-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(377)
3-Z-[1-(3-(3-dimetilaminopropil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(378)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(379)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(380)
3-Z-[1-(4-(N-(N-(2-dimetilaminoetil)-N-metilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(381)
3-Z-[1-(4-(2-dietilaminoetilsulfonil)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(382)
3-Z-[1-(4-(2-dimetilaminoetoxi)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(383)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(384)
3-Z-[1-(4-(metiletilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(385)
3-Z-[1-(4-(metilpropilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(386)
3-Z-[1-(4-(metilbencilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(387)
3-Z-[1-(4-(acetidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(388)
3-Z-[1-(4-(piperazin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(389)
3-Z-[1-(4-(morfolin-4-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(390)
3-Z-[1-(4-(tiomorfolin-4-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(391)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(3-(2-carboxi-etil)fenil)metilen]-6-fluoro-2-indolinona
(392)
3-Z-[1-(4-(N-(2-metilaminoetil)-N-acetilamino)anilino)-1-(3-(2-carboxi-etil)fenil)metilen]-6-fluoro-2-indolinona
(393)
3-Z-[1-(4-(N-(3-metilaminopropil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(394)
3-Z-[1-(4-(3-dimetilaminopropil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(395)
3-Z-[1-(4-etilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(396)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(397)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-
fluoro-2-indolinona
fluoro-2-indolinona
(398)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-propilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(399)
3-Z-[1-(3-(metilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(400)
3-Z-[1-(3-(2-dimetilaminoetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(401)
3-Z-[1-(3-(3-dimetilaminopropil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(402)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(403)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(404)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(405)
3-Z-[1-(4-(N-(N-(2-dimetilaminoetil)-N-metilaminometilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(406)
3-Z-[1-(4-(2-dietilaminoetilsulfonil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(407)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(408)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-
2-indolinona
2-indolinona
(409)
3-Z-[1-(4-(2-dimetilaminoetoxi)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(410)
3-Z-[1-(4-(metiletilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(411)
3-Z-[1-(4-(metilpropilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(412)
3-Z-[1-(4-(metilbencilaminometil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-fluoro-2-indolinona
(413)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(414)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(415)
3-Z-[1-(4-(acetidin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(416)
3-Z-[1-(4-(piperazin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(417)
3-Z-[1-(4-(morfolin-4-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(418)
3-Z-[1-(4-(tiomorfolin-4-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(419)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bro-
mo-2-indolinona
mo-2-indolinona
(420)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bro-
mo-2-indolinona
mo-2-indolinona
(421)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(422)
3-Z-[1-(4-(N-(2-metilaminoetil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(423)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(424)
3-Z-[1-(4-(N-(3-metilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(425)
3-Z-[1-(4-(3-dimetilaminopropil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(426)
3-Z-[1-(4-etilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(427)
3-Z-[1-(4-metilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(428)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(429)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(4-(2-carboxietil)-fenil)metilen]-6-bromo-2-indolinona
(430)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-
bromo-2-indolinona
bromo-2-indolinona
(431)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-propilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(432)
3-Z-[1-(4-aminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(433)
3-Z-[1-(3-(dimetilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(434)
3-Z-[1-(3-(metilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(435)
3-Z-[1-(3-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(436)
3-Z-[1-(3-(3-dimetilaminopropil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(437)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(438)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(439)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(440)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(441)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(442)
3-Z-[1-(4-(N-(N-(2-dimetilaminoetil)-N-metilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(443)
3-Z-[1-(4-(2-dietilaminoetilsulfonil)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(444)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(445)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(446)
3-Z-[1-(4-(2-dimetilaminoetoxi)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(447)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(448)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-
bromo-2-indolinona
bromo-2-indolinona
(449)
3-Z-[1-(4-(metiletilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(450)
3-Z-[1-(4-(metilpropilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(451)
3-Z-[1-(4-(metilbencilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(452)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(453)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(4-(2-carboxietil)-fenilmetilen]-6-bromo-2-indolinona
(454)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(455)
3-Z-[1-(4-(acetidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(456)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(4-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(457)
3-Z-[1-(4-(piperazin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(458)
3-Z-[1-(4-(morfolin-4-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(459)
3-Z-[1-(4-(tiomorfolin-4-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(460)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(461)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(462)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bro-
mo-2-indolinona
mo-2-indolinona
(463)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bro-
mo-2-indolinona
mo-2-indolinona
(464)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(465)
3-Z-[1-(4-(N-(2-metilaminoetil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(466)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
\newpage
(467)
3-Z-[1-(4-(N-(3-metilaminopropil)-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(468)
3-Z-[1-(4-(3-dimetilaminopropil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(469)
3-Z-[1-(4-etilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(470)
3-Z-[1-(4-metilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(471)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(472)
3-Z-[1-(4-(4-metilpiperazin-1-ilcarbonil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(473)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-
bromo-2-indolinona
bromo-2-indolinona
(474)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-propilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(475)
3-Z-[1-(4-aminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(476)
3-Z-[1-(3-(dimetilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(477)
3-Z-[1-(3-(metilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(478)
3-Z-[1-(3-(2-dimetilaminoetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(479)
3-Z-[1-(3-(3-dimetilaminopropil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(480)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(481)
3-Z-[1-(4-(N-(dimetilaminocarbonilmetil)-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(482)
3-Z-[1-(4-(N-metil-N-metilsulfonilamino)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(483)
3-Z-[1-(4-(N-metil-N-acetilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(484)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(485)
3-Z-[1-(4-(N-(N-(2-dimetilaminoetil)-N-metilaminometilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(486)
3-Z-[1-(4-(2-dietilaminoetilsulfonil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(487)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(488)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(489)
3-Z-[1-(4-(2-dimetilaminoetoxi)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(490)
3-Z-[1-(4-(N-(4-dimetilaminobutilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(491)
3-Z-[1-(4-(N-(3-dimetilaminopropilcarbonil)-N-metilamino)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-
bromo-2-indolinona
bromo-2-indolinona
(492)
3-Z-[1-(4-(metiletilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(493)
3-Z-[1-(4-(metilpropilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(494)
3-Z-[1-(4-(metilbencilaminometil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(495)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(496)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilaminometil)anilino)-1-(3-(2-carboxietil)fenilmetilen]-6-bromo-2-indolinona
(497)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(498)
3-Z-[1-(4-(acetidin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(499)
3-Z-[1-(4-((4-metilpiperazin-1-il)metil)anilino)-1-(3-(2-carboxietil)fenil)-metilen]-6-bromo-2-indolinona
(500)
3-Z-[1-(4-(piperazin-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(501)
3-Z-[1-(4-(morfolin-4-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(502)
3-Z-[1-(4-(tiomorfolin-4-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(503)
3-Z-[1-(4-(imidazol-1-ilmetil)anilino)-1-(3-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(504)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carboximetilaminofenil)metilen]-6-fluoro-2-indolinona
(505)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carboximetilaminofenil)metilen]-6-fluoro-2-indolinona
(506)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(N-metil-carboximetilamino)-fenil)metilen]-6-fluoro-2-indolinona
(507)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(N-metil-carboximetilamino)-fenil)metilen]-6-fluoro-2-indolinona
(508)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carboximetoxifenil)metilen]-6-cloro-2-indolinona
(509)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carboximetoxifenil)metilen]-6-cloro-2-indolinona
(510)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carboximetilaminofenil)metilen]-6-cloro-2-indolinona
(511)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carboximetilaminofenil)metilen]-6-cloro-2-indolinona
(512)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(N-metil-carboximetilamino)-fenil)metilen]-6-cloro-2-indolinona
(513)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(N-metil-carboximetil-amino)fenil)metilen]-6-cloro-2-indolinona
(514)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carboximetoxifenil)metilen]-6-bromo-2-indolinona
(515)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carboximetoxifenil)metilen]-6-bromo-2-indolinona
(516)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-carboximetilaminofenil)metilen]-6-bromo-2-indolinona
(517)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-carboximetilaminofenil)metilen]-6-bromo-2-indolinona
(518)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(N-metil-carboximetilamino)-fenil)metilen]-6-bromo-2-indolinona
(519)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(N-metil-carboximetilamino)-fenil)metilen]-6-bromo-2-indolinona,
así como sus tautómeros, sus estereoisómeros o
sus sales fisiológicamente aceptables.
\vskip1.000000\baselineskip
Los compuestos de la fórmula general I, sus
tautómeros, sus estereoisómeros o sus sales fisiológicamente
aceptables son así adecuados para la prevención o tratamiento de una
enfermedad fibrótica específica que se selecciona del grupo que
consiste en:
Fibrosis y remodelación del tejido pulmonar en
la enfermedad pulmonar obstructiva crónica (COPD), bronquitis
crónica, y enfisema;
fibrosis pulmonar y las enfermedades pulmonares
con un componente fibrótico que incluyen, pero sin limitación
fibrosis pulmonar idiopática (IPF), neumonía intersticial de células
gigantes (GIP), sarcodosis, fibrosis quística, síndrome disneico
(ARDS), granulomatosis, silicosis, fibrosis pulmonar inducida por
fármacos (por ejemplo, inducida por fármacos tales como bleomicina,
bis-cloronitrosourea, ciclofosfamida, amiodarona,
procainamida, penicilamina, oro o nitrofurantoina), silicosis,
asbestosis, esclerodermia sistémica;
fibrosis y remodelación en el asma.
\vskip1.000000\baselineskip
En una realización preferida, de acuerdo con la
presente invención, los compuestos de la fórmula general I, sus
tautómeros, sus estereoisómeros o sus sales fisiológicamente
aceptables son especialmente adecuados para la prevención o el
tratamiento de fibrosis pulmonar idiopática.
\vskip1.000000\baselineskip
Los siguientes resultados experimentales
ilustran la presente invención sin representar una limitación de su
alcance.
\vskip1.000000\baselineskip
DEPC (dietilpirocarbonato)
dNTP (desoxirribonucleotidotrifosfatos)
CT (ciclo en el cual la amplificación alcanza un
umbral fijado)
ADN (ácido desoxirribonucléico)
ADNc (ADN complementario)
ARN (ácido ribonucléico)
ARNm (ARN mensajero)
PCR (reacción en cadena de la polimerasa)
\vskip1.000000\baselineskip
En los siguientes experimentos del Ejemplo B1,
el Ejemplo A denota el compuesto
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona,
que es el compuesto (134) de la lista de compuestos y el compuesto
(b) de la lista de compuestos preferidos.
\vskip1.000000\baselineskip
(A) Efecto de un compuesto representativo sobre
la morfología pulmonar tras la fibrosis pulmonar inducida por
bleomicina.
\vskip1.000000\baselineskip
Se compró bleomicina sulfato (bleomicina
HEXAL^{TM}) en una farmacia local.
\vskip1.000000\baselineskip
Todos los experimentos se realizaron de acuerdo
con las directrices alemanas para el bienestar de los animales,
fueron realizados por personas tituladas para trabajar con animales
y fueron aprobados por las autoridades responsables. Se inyectó
bleomicina sulfato (10 U/kg peso corporal en 300 \mul de solución
salina) a ratas Wistar macho por vía intratraqueal o solución salina
sola (control de solución salina) usando un catéter (0,5 mm de
diámetro interno, 1,0 mm de diámetro externo) por la fosa nasal,
después de haber sido expuestas al anestésico Isofluorano durante 5
minutos. El día siguiente, las ratas fueron tratadas con el Ejemplo
A (compuesto (134)) o con solución salina suspendida en 1 ml de
Natrosol al 0,1% por vía oral. A las ratas de control se les
administró 1 ml de Natrosol al 0,1% (control de vehículo).
Se investigaron un total de 30 ratas y se
agruparon y trataron tal como se muestra en la Tabla 1.
Las ratas se sacrificaron 21 días después de la
instilación de bleomicina con una inyección intraperitoneal letal de
Narcoren^{TM} (Pentobarbital Sodio, Rhone Merieux). Se extirparon
los pulmones, se secaron con papel secante y la mitad se congeló
rápidamente en nitrógeno líquido y se almacenó a -80ºC. La otra
mitad se fijó en formalina al 4% para subsiguientemente embeberla en
parafina y realizar el examen histológico.
\vskip1.000000\baselineskip
Los tejidos de pulmón fijados en formalina al 4%
se embebieron en parafina y se cortaron secciones de 5 \mum usando
un microtomo(Leica SM200R) y se colocaron sobre portaobjetos
recubiertos de poli-L-lisina.
Después se secaron las secciones sobre los portas (60ºC 2 horas) y
después se dejaron enfriar a temperatura ambiente. Se evaluó la
deposición de colágeno usando la tinción tricromática de Masson.
\vskip1.000000\baselineskip
La Figura 1A muestra el resultado obtenido con
el grupo de control, que recibió solución salina y el vehículo en
lugar de bleomicina por vía intratraqueal.
Las ratas tratadas por vía intratraqueal con
bleomicina y el vehículo desarrollaron una fibrosis pulmonar grave,
tal como se observa en la Figura 1B. Los alvéolos en gran medida han
sido reemplazados por fibroblastos y matriz extracelular y la
estructura pulmonar normal está casi destruida.
El tratamiento diario de las ratas tratadas con
bleomicina con 50 mg/kg del Ejemplo A (compuesto (134)) mostró una
inversión consistente, casi completa de la fibrosis pulmonar en este
modelo. Un ejemplo típico se muestra en la Figura 1C. Los alvéolos
están intactos y se ha producido poca o ninguna infiltración de
fibroblastos ni deposición de matriz extracelular. Se ha mantenido
una estructura pulmonar normal, que se pone en evidencia al comparar
la Figura 1C con la Figura 1A.
\vskip1.000000\baselineskip
(B) Efecto de un compuesto representativo sobre
la expresión de genes marcadores de fibrosis tras la fibrosis
pulmonar inducida por bleomicina.
Una parte del tejido pulmonar congelado dedicado
a la investigación de la expresión génica se cortó en trozos
pequeños usando un escalpelo estéril. Después se colocaron
aproximadamente 100 mg de tejido en un tubo Eppendorf de 2 ml y se
añadieron 1,5 ml de Trizol (Invitrogen). Después, se añadió una
perla de carburo de tungsteno estéril (Qiagen) al tubo y el tubo se
introdujo en un aparato de disgregación tisular Retsch MM300
(Qiagen) a una frecuencia de 30,0 Hz durante 8 minutos. Después de
este tiempo, la perla se retiró y la muestra se centrifugó a 12000
rpm durante 10 minutos para eliminar los desechos de tejido. El ARN
se extrajo usando una versión modificada del protocolo del
fabricante proporcionado con Trizol. En pocas palabras, se añadieron
0,3 ml de cloroformo al tubo y el tubo se agitó vigorosamente y
después se dejó incubar a temperatura ambiente durante 5 minutos,
después de lo cual el tubo se centrifugó durante 15 minutos a 12000
rpm a 4ºC. Después se recolectó la fase acuosa incolora superior y
se añadió a 750 \mul de isopropanol. Esto después se agitó
vigorosamente y se almacenó a -80ºC hasta la mañana siguiente.
Después las muestras se incubaron a temperatura ambiente durante 15
minutos, después de lo cual se centrifugaron durante 40 minutos a
12000 rpm a 4ºC. Después se retiró el sobrenadante y se añadieron
500 \mul de etanol al 70% para lavar el sedimento, después la
muestra se centrifugó durante 10 minutos a 12000 rpm y 4ºC, esta
etapa de lavado se repitió dos veces, después de lo cual se dejó
secar el sedimento durante 10-15 minutos. Finalmente
el sedimento se resuspendió en 20 \mul de agua sin RNasa y se
almacenó a -80ºC. Después, la concentración de cada muestra se midió
usando un espectrómetro.
Usando el kit de síntesis de primera cadena TI
Superscript^{TM} III (Invitrogen, Paisley, Reino unido), se
realizó la transcripción inversa de 2 \mug de cada muestra de ARNm
usando una versión modificada del protocolo del fabricante. En
pocas palabras, una mezcla de 2 \mug de ARN, 1 \mul de hexámeros
cebadores aleatorios (50 ng/\mul), 1 \mul de mezcla de dNTP (10
mM) se completó hasta 10 \mul con agua tratada con DEPC y se
incubó a 65ºC durante 5 minutos, después de lo cual se introdujo en
hielo durante 5 minutos. Después de esto, a cada reacción, se
añadieron 2 \mul de tampón de TI (10X), 4 \mul de MgCl_{2}
(25mM), 2 \mul de DTT (0,1 M), 1 \mul de RNaseOUT^{TM} (40
U/\mul) y 1 \mul de enzima SuperScript^{TM} III (200
U/\mul) y la mezcla se introdujo en un ciclador térmico (Applied
Biosystems) con las condiciones siguientes: 25ºC durante 10
minutos, 50ºC durante 50 minutos y 85ºC durante 5 minutos, después
de lo cual se añadió 1 \mul de RNasa H y se incubó a 37ºC durante
20 minutos. El ADNc sintetizado se diluyó hasta 5 ng/\mul usando
el supuesto de que la reacción
de TI reacción transcribía completamente todo el ARNm en ADNc y tenía una concentración de 100 ng/\mul.
de TI reacción transcribía completamente todo el ARNm en ADNc y tenía una concentración de 100 ng/\mul.
\vskip1.000000\baselineskip
Se investigó la expresión génica en cada una de
las muestras usando el sistema de detección de secuencias Applied
Biosystems 7700. Se compraron los cebadores para el control endógeno
de 18S en forma de kits de reactivos de ensayo revelados
previamente, mientras que los cebadores y las sondas (véase la Tabla
2 a continuación) para procolágeno I y fibronectina se diseñaron
usando PrimerExpress^{TM} (Applied Biosystems), asegurándose de
que al menos uno de los cebadores o las sondas en cada conjunto se
superponía a una unión entre intrón y exón, eliminando así la
posibilidad de que se amplificara cualquier ADN genómico
contaminante en la muestra de ADNc. Los PDAR comprados también
amplificaban sólo ADNc.
La PCR en tiempo real se realizó en reacciones
de 25 \mul, usando 25 ng (5 \mul) de ADNc por reacción. Se
compró un kit esencial de PCR (Eurogentec) y se preparó una mezcla
maestra de la forma siguiente para 100 reacciones: 500 \mul 10 X
tampón de reacción, 500 \mul de MgCl_{2} (50 mM), 200 \mul de
solución de mezcla de dNTP (5 mM), 25 \mul de enzima Hot Goldstar,
75 \mul de 18S PDAR, 22,5 \mul de cebador directo, 22,5 \mul
de cebador inverso, 15 \mul de sonda y 640 \mul de agua tratada
con DEPC. Después, 20 \mul de esta mezcla maestra se añadieron a
25 ng (5 \mul) de ADNc diana. Cada análisis se realizó por
triplicado.
Para cuantificar la expresión génica, se
construyó una curva con estándares para cada conjunto de cebadores
y se incluyó en cada placa. Los patrones se prepararon con una
mezcla de todos los ADNc que se investigaban; se realizó una
dilución seriada de 10, 20, 50, 100, 100 veces de esta mezcla de
ADNc. Se construyó una curva de estándares del C_{T} obtenido
(ciclo en el que la amplificación alcanza un umbral fijado) en
función del LOG_{10} del factor de dilución. Las curvas se
representaron para el gen diana y el control endógeno de ARNr de
18S. El valor de C_{T} para ambas dianas para cada una de las
muestras se convirtió después en una dilución factorial usando la
curva de los patrones y se normalizó el valor del gen diana con el
valor del gen 18S.
\vskip1.000000\baselineskip
Todos los análisis estadísticos se realizaron
usando el programa GraphPad Prism V 4.02. Las comparaciones se
realizaron usando una prueba T no paramétrica (prueba U de
Mann-Whitney) y se consideró que un valor
significativo era p \leq 0,05.
\vskip1.000000\baselineskip
Los resultados se muestran en las Figuras 2
(procolágeno I) y 3 (fibronectina). Cada punto representa el ARN
aislado del pulmón de una sola rata.
La administración intratraqueal de bleomicina y
el tratamiento subsiguiente con vehículo sólo mostró grandes
aumentos de la expresión génica de procolágeno I y fibronectina en
el pulmón, tal como se observa en las Figuras 2 y 3, lo que es
consistente con la fibrosis pulmonar histológicamente aparente que
se observa en la Figura 1B.
El tratamiento diario de las ratas tratadas con
bleomicina con 50 mg/kg del Ejemplo A (compuesto (134)) mostró una
inhibición significativa (p \leq 0,0001) de la expresión de genes
marcadores fibróticos en este modelo, tal como se observa en las
Figuras 2 y 3.
Este experimento, demuestra así que la expresión
de marcadores fibróticos, y por lo tanto la deposición de matriz
extracelular, puede reducirse de forma dramática mediante el
tratamiento con el Ejemplo A (compuesto (134)).
Así, la expresión de marcadores fibróticos, y
por lo tanto la deposición de matriz extracelular, puede reducirse
de forma dramática mediante el tratamiento con los compuestos de
acuerdo con la presente invención.
Debido a sus propiedades biológicas, los
compuestos de acuerdo con la invención pueden usarse como
monoterapia o junto con otros compuestos farmacológicamente
activos. Tales compuestos farmacológicamente activos pueden ser
compuestos que son, por ejemplo, también farmacológicamente activos
en el tratamiento de la fibrosis. Tales compuestos
farmacológicamente activos pueden ser también sustancias con una
actividad secretolítica, bronquiolítica y/o antiinflamatoria.
En una realización preferida de acuerdo con la
presente invención, tales compuestos farmacológicamente activos
preferiblemente se seleccionan del grupo que consiste en agentes
anticolinérgicos, beta-2 miméticos, esteroides,
inhibidores de PDE-IV, inhibidores de p38 MAP
quinasa, antagonistas de NK_{1}, antagonistas de LTD4, inhibidores
de EGFR y antagonistas de endotelinas.
Los agentes anticolinérgicos pueden
seleccionarse preferiblemente del grupo que consiste en las sales de
tiotropio, sales de oxitropio, sales de flutropio, sales de
ipatropio, sales de glucopirronio y sales de trospio.
Los beta-2 miméticos
preferiblemente pueden seleccionarse de los beta-2
miméticos que se describen, por ejemplo, en el documento US
4.460.581, que se incorpora al presente documento por
referencia.
Los inhibidores de PDE-IV
preferiblemente pueden seleccionarse del grupo que consiste en
emprofilina, teofilina, roflumilast, ariflo (cilomilasto),
CP-325,366, BY343, D-4396
(Sch-351591),
AWD-12-281
(GW-842470),
N-(3,5-dicloro-1-oxo-piridin-4-il)-4-difluorometoxi-3-ciclopropilmetoxibenzamida,
NCS-613, pumafentina,
(-)p-[(4aR*,
10bS*)-9-etoxi-1,2,3,4,4a,10b-hexahidro-8-metoxi-2-metilbenzo[s][1,6]naftiridin-6-il]-N,N-diisopropilbenzamida,
(R)-(+)-1-(4-bromobencil)-4-[(3-ciclopentiloxi)-4-metoxi-fenil]-2-pirrolidona, 3-(ciclopentiloxi-4-metoxifenil)-1-(4-N'-[N-2-ciano-S-metil-isotio-ureido]bencil)-2-pirrolidona, ácido cis[4-ciano-4-(3-ciclopentiloxi-4-metoxifenil)ciclo-hexano-1-carbónico], 2-carbometoxi-4-ciano-4-(3-ciclopropilmetoxi-4-difluorometoxi-fenil)ciclohexan-1-ona, cis[4-ciano-4-(3-ciclopropilmetoxi-4-difluorometoxifenil)-ciclo-hexan-1-ol], (R)-(+)-etil[4-(3-ciclopentiloxi-4-metoxifenil)pirrolidin-2-iliden]acetato, (S)-(-)-etil[4-(3-ciclopentiloxi-4-metoxifenil)pirrolidin-2-iliden]acetato, CDP840,
Bay-198004, D-4418, PD-168787, T-440, T-2585, arofilina, atizoram, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-ciclopentil-5,6-dihidro-7-etil-3-(2-tienil)-9H-pirazolo[3,4-c]-1,2,4-triazolo[4,3-a]piridina y 9-ciclopentil-5,6-dihidro-7-etil-3-(terc-butil)-9H-pirazolo[3,4-c]-1,2,4-triazolo[4,3-a]piridina. Estos compuestos pueden usarse, según estén disponibles, en forma de sus racematos, enantiómeros o diastereoisómeros, o en forma de sus sales de adición de ácidos farmacológicamente aceptables, o en forma de sus solvatos y/o hidratos.
10bS*)-9-etoxi-1,2,3,4,4a,10b-hexahidro-8-metoxi-2-metilbenzo[s][1,6]naftiridin-6-il]-N,N-diisopropilbenzamida,
(R)-(+)-1-(4-bromobencil)-4-[(3-ciclopentiloxi)-4-metoxi-fenil]-2-pirrolidona, 3-(ciclopentiloxi-4-metoxifenil)-1-(4-N'-[N-2-ciano-S-metil-isotio-ureido]bencil)-2-pirrolidona, ácido cis[4-ciano-4-(3-ciclopentiloxi-4-metoxifenil)ciclo-hexano-1-carbónico], 2-carbometoxi-4-ciano-4-(3-ciclopropilmetoxi-4-difluorometoxi-fenil)ciclohexan-1-ona, cis[4-ciano-4-(3-ciclopropilmetoxi-4-difluorometoxifenil)-ciclo-hexan-1-ol], (R)-(+)-etil[4-(3-ciclopentiloxi-4-metoxifenil)pirrolidin-2-iliden]acetato, (S)-(-)-etil[4-(3-ciclopentiloxi-4-metoxifenil)pirrolidin-2-iliden]acetato, CDP840,
Bay-198004, D-4418, PD-168787, T-440, T-2585, arofilina, atizoram, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-ciclopentil-5,6-dihidro-7-etil-3-(2-tienil)-9H-pirazolo[3,4-c]-1,2,4-triazolo[4,3-a]piridina y 9-ciclopentil-5,6-dihidro-7-etil-3-(terc-butil)-9H-pirazolo[3,4-c]-1,2,4-triazolo[4,3-a]piridina. Estos compuestos pueden usarse, según estén disponibles, en forma de sus racematos, enantiómeros o diastereoisómeros, o en forma de sus sales de adición de ácidos farmacológicamente aceptables, o en forma de sus solvatos y/o hidratos.
\newpage
Los esteroides preferiblemente pueden
seleccionarse del grupo que consiste en prednisolona, prednisona,
butixocort propionato, RPR-106541, flunisolida,
beclometasona, triamcinolona, budesonida, fluticasona, mometasona,
ciclesonida, rofleponida, ST-126, dexametasona,
éster (S)-fluorometílico del ácido
6\alpha,9\alpha-difluoro-17\alpha-[(2-furanilcarbonil)oxi]-11\beta-hidroxi-16\alpha-metil-3-oxoandrosta-1,4-dien-17\beta-carbotiónico,
y éster
(S)-(2-oxotetrahidro-furan-3S-ílico)
del ácido
6\alpha,9\alpha-difluoro-11\beta-hidroxi-16\alpha-metil-3-oxo-17\alpha-propioniloxiandrosta-1,4-dieno-17\beta-carbotiónico.
Estos compuestos pueden usarse, según estén disponibles, en forma
de sus racematos, enantiómeros o diastereoisómeros, o en forma de
sus sales de adición de ácidos farmacológicamente aceptables, o en
forma de sus solvatos y/o hidratos.
Los inhibidores de p38 MAP quinasa
preferiblemente pueden seleccionarse del grupo que consiste en los
inhibidores de p38 quinasa que se describen por ejemplo en las
patentes de Estados Unidos 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, y US 5.716.955 y las solicitudes de patente PCT 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, los documentos DE 19842833, y JP
2000 86657 cuyas descripciones se incorporan todas al presente
documento por referencia en su totalidad. De interés particular
para las combinaciones de acuerdo con la invención son los
inhibidores de p38 que se describen en los documentos 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, y WO 01/36403. En una realización preferida
el inhibidor de p38 quinasa se selecciona de los compuestos de la
siguiente fórmula (I) tal como se describen en el documento WO
99/01131
en los
que
R_{1} es un anillo 4-piridilo,
pirimidinilo, 4-piridazinilo,
1,2,4-triazin-5-ilo,
quinolilo, isoquinolinilo, o
quinazolin-4-ilo, anillo que está
sustituido con Y-R_{a} y opcionalmente con un
sustituyente independiente adicional que se selecciona de alquilo
C_{1}-_{4}, halógeno, hidroxilo, alcoxi
C_{1}-_{4}, (alquil
C_{1}-_{4})tio, (alquil
C_{1}-_{4})sulfinilo, CH_{2}OR_{12},
amino, amino sustituido con monoalquilo y dialquilo
C_{1}-_{6}, un anillo
N-heterociclilo que tiene de 5 a 7 miembros y
opcionalmente contiene un heteroátomo adicional que se selecciona de
oxígeno, azufre o NR_{15},
N(R_{10})C(O)R_{b} o NHR_{a};
Y es oxígeno o azufre;
R_{4} es fenilo,
naft-1-ilo o naftilo, o un
heteroarilo, que está opcionalmente sustituido por uno o dos
sustituyentes, cada uno de los cuales se selecciona
independientemente, y que, para un sustituyente
4-fenilo,
4-naft-1-ilo,
5-naft-2-ilo o
6-naft-2-ilo, es
halógeno, ciano, nitro, C(Z)NR_{7}R_{17},
C(Z)OR_{16},
(CR_{10}R_{20})_{v}COR_{12}, SR_{5}, SOR_{5},
OR_{12}, alquilo C_{1-4} sustituido con halo,
alquilo C_{1-4}, ZC(Z)R_{12},
NR_{10}C(Z)R_{16}, o
(CR_{10}R_{20})_{v}NR_{10}R_{20} y que, para otras
posiciones de sustitución es halógeno, ciano,
C(Z)NR_{13}R_{14}, C(Z)OR_{3},
(CR_{10}R_{20})_{m''}COR_{3},
S(O)mR_{3}, OR_{3}, alquilo
C_{1-4} sustituido con halo, alquilo
C_{1-4},
(CR_{10}R_{20})_{m''}R_{10}C(Z)R_{3},
NR_{10}S(O)_{m'}R_{8},
NR_{10}S(O)_{m'}NR_{7}R_{17},
ZC(Z)R_{3} o
(CR_{10}R_{20})_{m''}NR_{13}R_{14};
Z es oxígeno o azufre;
n es un número entero que tiene un valor de 1 a
10;
m es 0, o un número entero 1 ó 2;
m' es un número entero que tiene un valor de 1 ó
2;
m'' es 0, o un número entero que tiene un valor
de 1 a 5;
v es 0, o un número entero que tiene un valor de
1 a 2;
R_{2} es -C(H) (A) (R_{22});
A es un anillo arilo, heterociclilo, o
heteroarilo opcionalmente sustituido, o A es alquilo
C_{1-10} sustituido;
R_{22} es un alquilo
C_{1-10} opcionalmente sustituido;
R_{a} es arilo, arilalquilo
C_{1-6}, heterociclo, heterociclilalquilo
C_{1-6}, heteroarilo, heteroarilalquilo
C_{1-6}, en el que cada uno de estos restos puede
estar opcionalmente sustituido;
R_{b} es hidrógeno, alquilo
C_{1-6}, cicloalquilo C_{3-7},
arilo, arilalquilo C_{1-4}, heteroarilo,
heteroarilalquilo C_{1-4}, heterociclilo, o
heterociclilalquilo C_{1-4}, en el que cada uno de
estos restos puede estar opcionalmente sustituido;
R_{3} es heterociclilo, heterociclilalquilo
C_{1-10} o R_{8};
R_{5} es hidrógeno, alquilo
C_{1-4}, alquenilo C_{2-4},
alquinilo C_{2-4} o NR_{7}R_{17}, excluyendo
que los restos SR_{5} sean SNR_{7}R_{17} y que SOR_{5} sea
SOH;
R_{6} es hidrógeno, un catión
farmacéuticamente aceptable, alquilo C_{1-10},
cicloalquilo C_{3-7}, arilo, arilalquilo
C_{1-4}, heteroarilo, heteroarilalquilo
C_{1-4}, heterociclilo, arilo, o alcanoilo
C_{1-10};
R_{7} y R_{17} se seleccionan cada uno
independientemente de hidrógeno o alquilo C_{1-4}
o R_{7} y R_{17} junto con el nitrógeno al que están unidos
forman un anillo heterocíclico de 5 a 7 miembros, anillo que
opcionalmente contiene un heteroátomo adicional que se selecciona de
oxígeno, azufre o NR_{15};
R_{8} es alquilo C_{1-10},
alquilo C_{1-10} sustituido con halo, alquenilo
C_{2-10}, alquinilo C_{2-10},
cicloalquilo C_{3-7}, cicloalquenilo
C_{5-7}, arilo, arilalquilo
C_{1-10}, heteroarilo, heteroarilalquilo
C_{1-10},
(CR_{10}R_{20})_{n}OR_{11},
(CR_{10}R_{20})_{n}S(O)_{m}R_{18},
(CR_{10}R_{20})_{n}
NHS(O)_{2}R_{18}, (CR_{10}R_{20})_{n}NR_{13}R_{14}; en el que el arilo, arilalquilo, heteroarilo, heteroarilalquilo pueden estar opcionalmente sustituidos;
NHS(O)_{2}R_{18}, (CR_{10}R_{20})_{n}NR_{13}R_{14}; en el que el arilo, arilalquilo, heteroarilo, heteroarilalquilo pueden estar opcionalmente sustituidos;
R_{9} es hidrógeno, C(Z) R_{11} o
alquilo C_{1-10} opcionalmente sustituido,
S(O)_{2}R_{18}, arilo opcionalmente sustituido o
arilalquilo C_{1-4} opcionalmente sustituido;
R_{10} y R_{20} se seleccionan cada uno
independientemente de hidrógeno o alquilo
C_{1-4};
R_{11} es hidrógeno, alquilo
C_{1-10}, cicloalquilo C_{3-7},
heterociclilo, heterociclilalquilo C_{1-10},
arilo, arilalquilo C_{1-10}, heteroarilo o
heteroarilalquilo C_{1-10}, en el que estos restos
pueden estar opcionalmente sustituidos;
R_{12} es hidrógeno o R_{16;}
R_{13} y R_{14} se seleccionan cada uno
independientemente de hidrógeno o
alquilo C_{1-4} opcionalmente
sustituido, arilo opcionalmente sustituido o arilalquilo
C_{1-4} opcionalmente sustituido, o junto con el
nitrógeno al que están unidos forman un anillo heterocíclico de 5 a
7 miembros, anillo que opcionalmente contiene un heteroátomo
adicional que se selecciona de oxígeno, azufre o NR_{9};
R_{15} es R_{10} o
C(Z)-alquilo C_{1-4};
R_{16} es alquilo C_{1-4},
alquilo C_{1-4} sustituido con halo, o
cicloalquilo C_{3-7};
R_{18} es alquilo C_{1-10},
cicloalquilo C_{3-7}, heterociclilo, arilo,
arilalquilo_{1-10}, heterociclilo,
heterociclilalquilo C_{1-10}, heteroarilo o
heteroarilalquilo C_{1-10};
o una de sus sales farmacéuticamente
aceptable.
\vskip1.000000\baselineskip
Los antagonistas de NK_{1} preferiblemente
pueden seleccionarse del grupo que consiste en
N-[2-(3,5-bis-trifluorometilfenil)etil]-2-{4-ciclopropilmetilpiperazin-1-il}-N-metil-2-fenilacetamida
(BIIF 1149), CP-122721, FK-888, NKP
608C, NKP 608A, CGP 60829, SR 48968 (Saredutant), SR 140333
(Nolpitantio besilato/cloruro), 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 y los
derivados de arilglicinamida de la fórmula general (VIII)
en los
que
R^{1} y R^{2} junto con el átomo de N al que
están unidos forman un anillo de la fórmula
en los
que
r y s independientemente denotan el número 2 ó
3;
R^{6} denota H, alquilo
C_{1}-C_{5}, alquenilo
C_{3}-C_{5}, propinilo, hidroxialquilo
C_{2}-C_{4}, metoxialquilo
C_{2}-C_{4}, di(alquil
C_{1}-C_{3})aminoalquilo
C_{2}-C_{4}, aminoalquilo
C_{2}-C_{4}, amino, di(alquil
C_{1}-C_{3})amino, monofluoro- hasta
perfluoroalquilo C_{1}-C_{2},
N-metilpiperidinilo, piridilo, pirimidinilo,
pirazinilo o piridazinilo,
R^{7} denota cualquiera de los grupos que se
definen en (a) a (d):
(a) hidroxi
(b) 4-piperidinopiperidilo,
(c)
en el que
R^{16} y R^{17} independientemente
denotan
H, alquilo C_{1}-C_{4},
cicloalquilo C_{3}-C6, hidroxialquilo
C_{2}-C_{4}, dihidroxialquilo
C_{2}-C_{4}, (alcoxi
C_{1}-C_{3})alquilo
C_{2}-C_{4}, fenilalquilo
C_{1}-C_{4} o di(alquil
C_{1}-C_{3})aminoalquilo
C_{2}-C_{4}, y
R^{8} denota H,
opcionalmente en forma de enantiómeros, mezclas
de enantiómeros o los racematos.
\vskip1.000000\baselineskip
Los compuestos de la fórmula (VIII) que se
mencionan anteriormente se describen en los documentos WO
96/
32386, WO 97/32865 y WO 02/32865. La descripción de estas solicitudes internacionales de patentes se incorpora al presente documento por referencia en su totalidad.
32386, WO 97/32865 y WO 02/32865. La descripción de estas solicitudes internacionales de patentes se incorpora al presente documento por referencia en su totalidad.
Los antagonistas de LTD4 preferiblemente pueden
seleccionarse del grupo que consiste en montelukast,
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinil)etenil)fenil)-3-(2-(2-
hidroxi-2-propil)fenil)tio)metilciclopropano
acetato,
1-(((1(R)-3(3-(2-(2,3-dicloro-tieno[3,2-b]piridin-5-il)-(E)-etenil)fenil)-3-(2-(1-hidroxi-1-metiletil)fenil)propil)tio)-metil)-ciclopropano
acetato, pranlukast, zafirlukast,
[2-[[2-(4-terc-butil-2-tiazolil)-5-benzofuranil]oximetil]fenil]acetato,
MCC-847 (ZD-3523),
MN-001, MEN-91507
(LM-1507), VUF-5078,
VUF-K-8707 y
L-733321. Estos compuestos pueden usarse, según
estén disponibles, en forma de sus racematos, enantiómeros o
diastereoisómeros, o en forma de sus sales de adición de ácidos
farmacológicamente aceptables, o en forma de sus solvatos y/o
hidratos.
Los inhibidores de EGFR preferiblemente pueden
seleccionarse del grupo que consiste en
4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(morfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-ciclopropilmetoxiquinazolina,
4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dietil-amino)-1-oxo-2-buten-1-il]amino}-7-ciclopropilmetoxiquinazolina,
4-[(3-cloro-4-fluoro-fenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-ciclopropilmetoxi-quinazolina,
4-[(R)-(1-feniletil)amino]-6-{[4-(morfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-ciclopentiloxiquinazolina,
4-[(3-cloro-4-fluorofe-
nil)amino]-6-{[4-((R)-6-metil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluoro-fenil)amino]-6-{[4-((R)-6-metil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-[(S)-(tetrahidro-
furan-3-il)oxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-((R)-2-metoxi-metil-6-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[2-((S)-6-metil-2-oxomorfolin-4-il)etoxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-({4-[N-(2-metoxietil)-N-metilamino]-1-oxo-2-
buten-1-il}amino)-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-
oxo-2-buten-1-il]amino}-7-ciclopentiloxiquinazolina, 4-[(R)-(1-feniletil)amino]-6-{[4-(N,N-bis-(2-metoxietil)ami-
no)-1-oxo-2-buten-1-il]amino}-7-ciclo-propilmetoxiquinazolina, 4-[(R)-(1-feniletil)amino]-6-({4-[N-(2-metoxietil)-N-etilamino]-1-oxo-2-buten-1-il}amino)-7-ciclopropilmetoxiquinazolina, 4-[(R)-(1-feniletil)amino]-6-({4-[N-(2-metoxietil)-N-metilamino]-1-oxo-2-buten-1-il}amino)-7-ciclopropilmetoxi-quinazolina, 4-[(R)-(1-feniletil)amino]-6-
({4-[N-(tetrahidropiran-4-il)-N-metilamino]-1-oxo-2-buten-1-il}amino)-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((R)-tetrahidrofuran-3-iloxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)quinazolina, 4-[(3-cloro-4-fluorofenil)-amino]-6-({4-[N-(2-metoxietil)-N-metilamino]-1-oxo-2-buten-1-il}ami-
no)-7-ciclopentil-oxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N-ciclopropil-N-metilamino)-1-oxo-2-buten-1-il]amino}-7-ciclopentiloxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-[(R)-(tetrahidrofuran-2-il)metoxi]-quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-[(S)-(tetrahidro-furan-2-il)metoxi]quinazolina, 4-[(3-etinilfenil)amino]-6,7-
bis-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-7-[3-(morfolin-4-il)propiloxi]-6-[(vinilcarbonil)
amino]-quinazolina, 4-[(R)-(1-feniletil)amino]-6-(4-hidroxifenil)-7H-pirro-lo[2,3-d]pirimidina, 3-ciano-4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-etoxi-quinolina, 4-{[3-cloro-4-(3-fluorobenciloxi)fenil]amino}-6-(5-{[(2-metanosulfoniletil)amino]metil}furan-2-il)quinazolina, 4-[(R)-(1-feniletil)ami-
no]-6-{[4-((R)-6-metil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-metoxiquinazolina, 4-[(3-cloro-4-fluoro-fenil)amino]-6-{[4-(morfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-[(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-
cloro-4-fluorofenil)amino]-6-({4-[N,N-bis-(2-metoxietil)amino]-1-oxo-2-buten-1-il}amino)-7-[(tetrahidrofuran-2-il)
metoxi]quinazolina, 4-[(3-etinilfenil)amino]-6-{[4-(5,5-dimetil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-qui-
nazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-7-metoxiquinazolina, 4-[(3-
cloro-4-fluorofenil)amino]-6-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-7-[(R)-(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-7-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-6-[(S)-(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{2-[4-(2-oxomorfolin-4-il)piperidin-1-il]-etoxi}-7-metoxiquinazoli-
na, 4-[(3-cloro-4-fluorofenil)amino]-6-[1-(terc-butiloxicarbonil)piperidin-4-iloxi]-7-metoxi-quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(trans-4-aminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-
(trans-4-metanosul-fonilamino-ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetrahi-
dropiran-3-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(morfolin-4-il)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(metoxi-metil)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)-amino]-6-(piperidin-3-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[1-(2-acetil-amino-etil)piperidin-4-iloxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetrahidropiran-4-iloxi)-7-etoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-((S)-tetrahidrofuran-3-iloxi)-7-hidroxiquinazolina, 4-[(3-cloro-4-fluorofenil)
amino]-6-(tetrahidro-piran-4-iloxi)-7-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{trans-4-[(di-
metilamino)sulfonilamino]ciclohexan-1-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{trans-4-
[(morfolin-4-il)carbonilamino]ciclohexan-1-iloxi}-7-etoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{trans-4-
[(morfolin-4-il)sulfonil-amino]ciclo-hexan-1-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetra-
hidropiran-4-iloxi)-7-(2-acetilaminoetoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetrahidropiran-4-iloxi)-7-(2-metanosulfonilaminoetoxi)quinazolina, 4-[(3-cloro-4-fluoro-fenil)ami-no]-6-{1-[(piperidin-1-il)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-aminocarbonilmetilpiperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(tetrahidropiran-4-il)carbonil]-N-metilamino}-ciclo-he-
xan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(morfolin-4-il)carbonil]-N-metil-
amino}ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(morfolin-4-il)sulfonil]-N-metilamino}ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(trans-4-etansulfonilamino-ciclo-hexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-etoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[1-(2-metoxiacetil)piperidin-4-iloxi]-7-(2-metoxietoxi)quinazolina,
4-[(3-cloro-4-fluoro-fenil)amino]-6-(cis-4-acetilaminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-etinil-fenil)
amino]-6-[1-(terc-butiloxicarbonil)piperidin-4-iloxi]-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-(tetrahidropi-
ran-4-iloxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)-amino]-6-(cis-4-{N-[(piperidin-1-il)carbonil]-N-metilamino}ciclohexan-1-iloxi)-7-metoxi-quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(4-metilpiperazin-1-
il)carbonil]-N-metilamino}ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{cis-4--
[(morfolin-4-il)carbonilamino]ciclohexan-1-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[2-(2-oxopirrolidin-1-il)etil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(morfolin-4-il)carbonil]piperidin-4-iloxi}-7-(2-metoxietoxi)quinazolina, 4-[(3-etinilfenil)amino]-6-(1-acetilpiperidin-4-iloxi)-7-metoxi-quinazolina, 4-[(3-etinilfenil)amino]-6-(1-metilpiperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metilpiperidin-4-iloxi)-7-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-isopropiloxicarbonil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-metilaminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{cis-4-[N-(2-metoxiacetil)-N-metilamino]-ciclohexan-1-iloxi}-7-metoxiquinazoli-
na, 4-[(3-etinilfenil)amino]-6-(piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-[1-(2-metoxiacetil)piperidin-4-iloxi]-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-{1-[(morfolin-4-il)carbonil]piperidin-4-iloxi}-7-
metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(cis-2,6-dimetil-morfolin-4-il)-carbonil]piperidin-4-ilo-
xi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(2-metil-morfolin-4-il)carbonil]piperidin-4-iloxi}-
7-metoxiquinazolina, 4-[(3-cloro-4-fluoro-fenil)amino]-6-{1-[(S,S)-(2-oxa-5-aza-biciclo[2.2.1]hept-5-il)carbonil]pi-
peridin-4-il-oxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(N-metil-N-2-metoxietil-amino)-car-
bonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-etil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(2-metoxi-etil)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina,
4-[(3-cloro-4-fluorofenil)-amino]-6-{1-[(3-metoxipropilamino)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-
[(3-cloro-4-fluorofenil)amino]-6-[cis-4-(N-metanosulfonil-N-metilamino)ciclohexan-1-iloxi]-7-metoxiquinazolina,
4-[(3-cloro-4-fluorofenil)amino]-6-[cis-4-(N-acetil-N-metilamino)ciclo-hexan-1-iloxi]-7-metoxiquinazolina, 4-[(3-
cloro-4-fluorofenil)amino]-6-(trans-4-metil-aminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)
amino]-6-[trans-4-(N-metanosulfonil-N-metilamino)ciclohexan-1-iloxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(trans-4-dimetilaminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-
(trans-4-{N-[(morfolin-4-il)carbonil]-N-metilamino}-ciclo-hexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-7-[(S)-(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-ciano-piperidin-4-iloxi)-7-metoxiquinazolina, Cetuximab, Tras-tuzumab, ABX-EGF y Mab ICR-62. Estos compuestos pueden usarse, según estén disponibles, en forma de sus racematos, enantiómeros o diastereoisómeros, o en forma de sus sales de adición de ácidos farmacológicamente aceptables, o en forma de sus solvatos y/o hidratos. Estos compuestos están descritos en la técnica anterior, por ejemplo en los documentos 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, y WO 95/20045.
nil)amino]-6-{[4-((R)-6-metil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluoro-fenil)amino]-6-{[4-((R)-6-metil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-[(S)-(tetrahidro-
furan-3-il)oxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-((R)-2-metoxi-metil-6-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[2-((S)-6-metil-2-oxomorfolin-4-il)etoxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-({4-[N-(2-metoxietil)-N-metilamino]-1-oxo-2-
buten-1-il}amino)-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-
oxo-2-buten-1-il]amino}-7-ciclopentiloxiquinazolina, 4-[(R)-(1-feniletil)amino]-6-{[4-(N,N-bis-(2-metoxietil)ami-
no)-1-oxo-2-buten-1-il]amino}-7-ciclo-propilmetoxiquinazolina, 4-[(R)-(1-feniletil)amino]-6-({4-[N-(2-metoxietil)-N-etilamino]-1-oxo-2-buten-1-il}amino)-7-ciclopropilmetoxiquinazolina, 4-[(R)-(1-feniletil)amino]-6-({4-[N-(2-metoxietil)-N-metilamino]-1-oxo-2-buten-1-il}amino)-7-ciclopropilmetoxi-quinazolina, 4-[(R)-(1-feniletil)amino]-6-
({4-[N-(tetrahidropiran-4-il)-N-metilamino]-1-oxo-2-buten-1-il}amino)-7-ciclopropilmetoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((R)-tetrahidrofuran-3-iloxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)quinazolina, 4-[(3-cloro-4-fluorofenil)-amino]-6-({4-[N-(2-metoxietil)-N-metilamino]-1-oxo-2-buten-1-il}ami-
no)-7-ciclopentil-oxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N-ciclopropil-N-metilamino)-1-oxo-2-buten-1-il]amino}-7-ciclopentiloxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-[(R)-(tetrahidrofuran-2-il)metoxi]-quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-[(S)-(tetrahidro-furan-2-il)metoxi]quinazolina, 4-[(3-etinilfenil)amino]-6,7-
bis-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-7-[3-(morfolin-4-il)propiloxi]-6-[(vinilcarbonil)
amino]-quinazolina, 4-[(R)-(1-feniletil)amino]-6-(4-hidroxifenil)-7H-pirro-lo[2,3-d]pirimidina, 3-ciano-4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-etoxi-quinolina, 4-{[3-cloro-4-(3-fluorobenciloxi)fenil]amino}-6-(5-{[(2-metanosulfoniletil)amino]metil}furan-2-il)quinazolina, 4-[(R)-(1-feniletil)ami-
no]-6-{[4-((R)-6-metil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-metoxiquinazolina, 4-[(3-cloro-4-fluoro-fenil)amino]-6-{[4-(morfolin-4-il)-1-oxo-2-buten-1-il]amino}-7-[(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-
cloro-4-fluorofenil)amino]-6-({4-[N,N-bis-(2-metoxietil)amino]-1-oxo-2-buten-1-il}amino)-7-[(tetrahidrofuran-2-il)
metoxi]quinazolina, 4-[(3-etinilfenil)amino]-6-{[4-(5,5-dimetil-2-oxomorfolin-4-il)-1-oxo-2-buten-1-il]amino}-qui-
nazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-7-metoxiquinazolina, 4-[(3-
cloro-4-fluorofenil)amino]-6-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-7-[(R)-(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-7-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-6-[(S)-(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{2-[4-(2-oxomorfolin-4-il)piperidin-1-il]-etoxi}-7-metoxiquinazoli-
na, 4-[(3-cloro-4-fluorofenil)amino]-6-[1-(terc-butiloxicarbonil)piperidin-4-iloxi]-7-metoxi-quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(trans-4-aminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-
(trans-4-metanosul-fonilamino-ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetrahi-
dropiran-3-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(morfolin-4-il)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(metoxi-metil)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)-amino]-6-(piperidin-3-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[1-(2-acetil-amino-etil)piperidin-4-iloxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetrahidropiran-4-iloxi)-7-etoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-((S)-tetrahidrofuran-3-iloxi)-7-hidroxiquinazolina, 4-[(3-cloro-4-fluorofenil)
amino]-6-(tetrahidro-piran-4-iloxi)-7-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{trans-4-[(di-
metilamino)sulfonilamino]ciclohexan-1-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{trans-4-
[(morfolin-4-il)carbonilamino]ciclohexan-1-iloxi}-7-etoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{trans-4-
[(morfolin-4-il)sulfonil-amino]ciclo-hexan-1-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetra-
hidropiran-4-iloxi)-7-(2-acetilaminoetoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(tetrahidropiran-4-iloxi)-7-(2-metanosulfonilaminoetoxi)quinazolina, 4-[(3-cloro-4-fluoro-fenil)ami-no]-6-{1-[(piperidin-1-il)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-aminocarbonilmetilpiperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(tetrahidropiran-4-il)carbonil]-N-metilamino}-ciclo-he-
xan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(morfolin-4-il)carbonil]-N-metil-
amino}ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(morfolin-4-il)sulfonil]-N-metilamino}ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(trans-4-etansulfonilamino-ciclo-hexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-etoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[1-(2-metoxiacetil)piperidin-4-iloxi]-7-(2-metoxietoxi)quinazolina,
4-[(3-cloro-4-fluoro-fenil)amino]-6-(cis-4-acetilaminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-etinil-fenil)
amino]-6-[1-(terc-butiloxicarbonil)piperidin-4-iloxi]-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-(tetrahidropi-
ran-4-iloxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)-amino]-6-(cis-4-{N-[(piperidin-1-il)carbonil]-N-metilamino}ciclohexan-1-iloxi)-7-metoxi-quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-{N-[(4-metilpiperazin-1-
il)carbonil]-N-metilamino}ciclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{cis-4--
[(morfolin-4-il)carbonilamino]ciclohexan-1-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[2-(2-oxopirrolidin-1-il)etil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(morfolin-4-il)carbonil]piperidin-4-iloxi}-7-(2-metoxietoxi)quinazolina, 4-[(3-etinilfenil)amino]-6-(1-acetilpiperidin-4-iloxi)-7-metoxi-quinazolina, 4-[(3-etinilfenil)amino]-6-(1-metilpiperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metilpiperidin-4-iloxi)-7-(2-metoxietoxi)quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-isopropiloxicarbonil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(cis-4-metilaminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{cis-4-[N-(2-metoxiacetil)-N-metilamino]-ciclohexan-1-iloxi}-7-metoxiquinazoli-
na, 4-[(3-etinilfenil)amino]-6-(piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-[1-(2-metoxiacetil)piperidin-4-iloxi]-7-metoxiquinazolina, 4-[(3-etinilfenil)amino]-6-{1-[(morfolin-4-il)carbonil]piperidin-4-iloxi}-7-
metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(cis-2,6-dimetil-morfolin-4-il)-carbonil]piperidin-4-ilo-
xi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(2-metil-morfolin-4-il)carbonil]piperidin-4-iloxi}-
7-metoxiquinazolina, 4-[(3-cloro-4-fluoro-fenil)amino]-6-{1-[(S,S)-(2-oxa-5-aza-biciclo[2.2.1]hept-5-il)carbonil]pi-
peridin-4-il-oxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(N-metil-N-2-metoxietil-amino)-car-
bonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-etil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-{1-[(2-metoxi-etil)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina,
4-[(3-cloro-4-fluorofenil)-amino]-6-{1-[(3-metoxipropilamino)carbonil]piperidin-4-iloxi}-7-metoxiquinazolina, 4-
[(3-cloro-4-fluorofenil)amino]-6-[cis-4-(N-metanosulfonil-N-metilamino)ciclohexan-1-iloxi]-7-metoxiquinazolina,
4-[(3-cloro-4-fluorofenil)amino]-6-[cis-4-(N-acetil-N-metilamino)ciclo-hexan-1-iloxi]-7-metoxiquinazolina, 4-[(3-
cloro-4-fluorofenil)amino]-6-(trans-4-metil-aminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)
amino]-6-[trans-4-(N-metanosulfonil-N-metilamino)ciclohexan-1-iloxi]-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(trans-4-dimetilaminociclohexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-
(trans-4-{N-[(morfolin-4-il)carbonil]-N-metilamino}-ciclo-hexan-1-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-[2-(2,2-dimetil-6-oxomorfolin-4-il)etoxi]-7-[(S)-(tetrahidrofuran-2-il)metoxi]quinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-metanosulfonil-piperidin-4-iloxi)-7-metoxiquinazolina, 4-[(3-cloro-4-fluorofenil)amino]-6-(1-ciano-piperidin-4-iloxi)-7-metoxiquinazolina, Cetuximab, Tras-tuzumab, ABX-EGF y Mab ICR-62. Estos compuestos pueden usarse, según estén disponibles, en forma de sus racematos, enantiómeros o diastereoisómeros, o en forma de sus sales de adición de ácidos farmacológicamente aceptables, o en forma de sus solvatos y/o hidratos. Estos compuestos están descritos en la técnica anterior, por ejemplo en los documentos 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, y WO 95/20045.
Los antagonistas de endotelinas preferiblemente
pueden seleccionarse del grupo que consiste en tezosentano,
bosentano, enrasentano, sixtasentano, T-0201,
BMS-193884, K-8794,
PD-156123, PD-156707,
PD-160874, PD-180988,
S-0139 y ZD-1611. Cualquier
referencia a antagonistas de endotelinas dentro del alcance de la
presente invención incluye una referencia a las sales,
preferiblemente las sales de adición de ácidos o derivados
farmacológicamente aceptables, que pueden formarse a partir de los
antagonistas de endotelinas.
Estas combinaciones pueden administrarse bien de
forma simultánea o secuencial.
Para uso farmacéutico, los compuestos de acuerdo
con la invención preferiblemente se usan para vertebrados de sangre
caliente, en particular seres humanos, en dosis de
0,0001-100 mg/kg de peso corporal.
Estos compuestos pueden administrarse o bien
solos o combinados con otras sustancias activas por vía intravenosa,
subcutánea, intramuscular, intraperitoneal o intranasal, por
inhalación, o por vía transdérmica u oral, mientras que las
formulaciones en aerosol son adecuadas en particular para la
inhalación.
Para la administración se formulan con uno o más
vehículos inertes, sólidos, semisólidos o líquidos convencionales,
por ejemplo con almidón, diferentes tipos de celulosa, lactosa,
manitol, glucosa, fosfato cálcico, grasas duras, alcoholes grasos,
glicerol, triglicéridos de cadena media y ésteres relacionados,
polietilenglicol, aceites de especialidades refinados, agua,
agua/etanol, agua/glicerol, agua/sorbitol, agua/polietilenglicol,
propilenglicol, y/o excipientes funcionales, por ejemplo con
polivinilpirrolidona, hidroxipropilmetilcelulosa,
carboximetilcelulosa sódica, almidónglicolato sódico, dióxido de
silicio, polisorbatos, poloxámeros, gelucires, estearato magnésico,
ácido cítrico, ácido tartárico o sus mezclas adecuadas en
preparaciones galénicas convencionales tales como comprimidos
simples o recubiertos, cápsulas, polvos, soluciones inyectables,
ampollas, suspensiones, soluciones, spray o supositorios.
Los siguientes ejemplos de formulaciones
ilustran la presente invención sin representar una limitación de su
alcance.
\vskip1.000000\baselineskip
1 núcleo de comprimido contiene:
\vskip1.000000\baselineskip
La sustancia activa se mezcla con todos los
componentes, se tamiza y se comprime en una máquina de formación de
comprimidos de la forma deseada.
- Peso del núcleo:
- 230 mg
- Aspecto del núcleo:
- 9 mm, biconvexo
\vskip1.000000\baselineskip
Los núcleos de comprimido así producidos se
recubren con una película que consiste esencialmente en
hidroxipropilmetilcelulosa.
- Peso del comprimido recubierto:
- 240 mg
\vskip1.000000\baselineskip
1 comprimido contiene:
La sustancia activa, la lactosa y el almidón se
mezclan y se humedecen uniformemente con una solución acuosa de la
hidroxipropilmetilcelulosa. Después de que se ha tamizado (2,0 mm de
tamaño de malla) la composición húmeda y se seca en un desecador de
tipo de rejilla a 50ºC se tamiza de nuevo (1,5 mm de tamaño de
malla) y se añade el lubricante. La mezcla terminada se comprime
formando comprimidos.
- Peso del comprimido:
- 220 mg
- Aspecto de comprimido:
- 10 mm, de caras planas con bordes biselados y hendidura de corte en un lado
\vskip1.000000\baselineskip
1 comprimido contiene:
\vskip1.000000\baselineskip
La sustancia activa mezclada con lactosa,
polivinilpirrolidona, y partes de la celulosa microcristalina,
estearato de magnesio se compacta por ejemplo con una compactadora
de rodillo. Las tiras se disgregan en gránulos finos a través de un
tamiz con un tamaño de malla de 0,8 mm. Después del subsiguiente
tamizado a través de un tamiz con un tamaño de malla de 0,5 mm y de
mezclar con el resto de los componentes, se comprimen los
comprimidos a partir de la mezcla.
- Peso del comprimido:
- 300 mg
- Aspecto de comprimido:
- 10 mm, plano
\vskip1.000000\baselineskip
1 cápsula contiene:
\newpage
La sustancia activa mezclada con lactosa,
polivinilpirrolidona, y partes de la celulosa microcristalina,
estearato magnésico se compacta por ejemplo en una compactadora de
rodillo. Las tiras se disgregan en gránulos finos a través de un
tamiz con un tamaño de malla de 0,8 mm. Después del subsiguiente
tamizado a través de un tamiz con un tamaño de malla de 0,5 mm y de
mezclar con el resto de los componentes, la mezcla terminada se
envasa en cápsulas de gelatina dura de tamaño 1.
- Relleno de la cápsula:
- aprox. 300 mg
- Valvas de la cápsula:
- cápsula de gelatina dura de tamaño 1.
\vskip1.000000\baselineskip
1 supositorio contiene:
Después de que se ha derretido la masa de
supositorio, se distribuye la sustancia activa de forma homogénea en
ella y la masa fundida se vierte en moldes enfriados.
\vskip1.000000\baselineskip
100 ml de suspensión contienen
El agua destilada se calienta a 70ºC. Los
p-hidroxibenzoatos metílico y propílico junto con el
glicerol y la sal sódica de carboximetilcelulosa se disuelven en
ella agitando. La solución se enfría a temperatura ambiente y se
añade la sustancia activa y se dispersa de forma homogénea en ella
agitando. Después de que se han añadido el azúcar, la solución de
sorbitol y el aroma y se han disuelto, la suspensión se evacua
agitando para eliminar el aire.
Así, 5 ml de suspensión contienen 50 mg de
sustancia activa.
\vskip1.000000\baselineskip
\vskip1.000000\baselineskip
La sustancia activa se disuelve en la cantidad
necesaria de HCl 0,01 N, se hace isotónica con cloruro sódico, se
esteriliza por filtración y se transfiere a una ampolla de 2 ml.
\vskip1.000000\baselineskip
\vskip1.000000\baselineskip
La sustancia activa se disuelve en la cantidad
necesaria de HCl 0,01 N, se hace isotónica con cloruro sódico, se
esteriliza por filtración y se transfiere a una ampolla de 10
ml.
\vskip1.000000\baselineskip
1 cápsula contiene
\vskip1.000000\baselineskip
La sustancia activa se mezcla con lactosa
inhalable. La mezcla se envasa en cápsulas en una máquina de
preparar cápsulas (peso de la cápsula vacía aprox. 50 mg).
peso de cápsula: 70,0 mg
tamaño de la cápsula = tamaño 3
\newpage
1 spray contiene
\vskip1.000000\baselineskip
La sustancia activa y el cloruro de benzalconio
se disuelven en etanol/agua (50/50). El pH de la solución se ajusta
con ácido clorhídrico 1 N. La solución resultante se filtra y se
transfiere a envases adecuados para usar en un nebulizador
manual(cartuchos).
Contenido del envase: 4,5 g
Claims (10)
1. Uso de las indolinonas de la fórmula
general
\vskip1.000000\baselineskip
\vskip1.000000\baselineskip
en las
que
X es un átomo de oxígeno,
R^{1} es un átomo de hidrógeno,
R^{2} es un átomo de flúor, cloro o bromo o un
grupo ciano,
R^{3} es un grupo fenilo o un grupo fenilo que
está monosustituido por un átomo de flúor, cloro, bromo o yodo o por
un grupo alcoxi C_{1-3}, en el que los grupos
fenilo no sustituido y monosustituido mencionados anteriormente
pueden estar sustituidos adicionalmente en la posición 3 ó 4
- \quad
- por un átomo de flúor, cloro o bromo,
- \quad
- por un grupo ciano,
- \quad
- por un grupo alcoxi C_{1-3} o (alquil C_{1-2})carbonilamino,
- \quad
- por un grupo cianoalquilo C_{1-3}, carboxialquilo C_{1-3}, carboxialcoxi C_{1-4}, carboxi(alquil C_{1-3})amino, carboxi(alquil C_{1-3})-N-(alquil C_{1-3})amino, (alcoxi C_{1-4})carbonilalquilo C_{1-3}, (alcoxi C_{1-4})carbonilalcoxi C_{1-3}, (alcoxi C_{1-4})carbonil(alquil C_{1}-3)amino, (alcoxi C_{1-4})carbonil(alquil C_{1-3})-N-(alquil C_{1-3})amino, aminoalquilo C_{1-3}, aminocarbonilalquilo C_{1-3}, ((alquil C_{1-2})amino)carbonilalquilo C_{1-3}, di(alquil C_{1-2})amino-carbonilalquilo C_{1-3}, ((alquil C_{1-2})carbonil)aminoalquilo C_{1-3}, ((alcoxi C_{1-4})carbonil)aminoalquilo C_{1-3}, ((alquil C_{3-6})carbonil)aminoalquilo C_{1-3}, (fenilcarbonil)aminoalquilo C_{1-3}, ((cicloalquil C_{3-6})carbonil)aminoalquilo C_{1-3}, ((cicloalquil C_{3-6})(alquil C_{1-3})carbonil)aminoalquilo C_{1-3}, (tiofen-2-ilcarbonil)aminoalquilo C_{1-3}, (furan-2-ilcarbonil)-aminoalquilo C_{1-3}, (fenil(alquil C_{1-3})carbonil)aminoalquilo C_{1-3}, (2-(alcoxi C_{1-4})benzoil-carbonil)aminoalquilo C_{1-3}, (piridin-2-ilcarbonil)aminoalquilo C_{1-3}, (piridin-3-ilcarbonil)aminoalquilo C_{1-3}, (piridin-4-ilcarbonil)aminoalquilo C_{1-3} o (alquil C_{1-3})piperazin-1-ilcarbonilalquilo C_{1-3},
- \quad
- por un grupo carboxialquenilo C_{2-3}, aminocarbonilalquenilo C_{2-3}, ((alquil C_{1-3})-amino)carbonilalquenilo C_{2-3}, di(alquil C_{1-3})aminocarbonilalquenilo C_{2-3} o (alcoxi C_{1-4})-carbonilalquenilo C_{2-3},
- \quad
- en el que los sustituyentes pueden ser idénticos o diferentes,
- \quad
- R^{4} es un grupo fenilo o un grupo fenilo que está monosustituido
- \quad
- por un grupo alquilo C_{1-3} que está sustituido en el extremo por un grupo amino, guanidino, mono- o di(alquil C_{1-2})amino, N-[\omega-di(alquil C_{1-3})amino(alquil C_{2-3})]-N-(alquil C_{1-3})amino, N-metil(alquil C_{3-4})amino, N-(alquil C_{1-3})-N-bencilamino, N-((alcoxi C_{1-4})-carbonil)amino, N-((alcoxi C_{1-4})carbonil)(alquil C_{1-4})amino, 4-(alquil C_{1-3})piperazin-1-ilo, imidazol-1-ilo, pirrolidin-1-ilo, acetidin-1-ilo, morfolin-4-ilo, piperazin-1-ilo, tiomorfolin-4-ilo,
- \quad
- por un grupo di(alquil C_{1-3})amino(alquil C_{1-3})sulfonilo, 2-[di(alquil C_{1-3})-amino]etoxi, 4-(alquil C_{1-3})piperazin-1-ilcarbonilo, {\omega-[di(alquil C_{1-3})amino](alquil C_{2-3})}-N-(alquil C_{1-3})aminocarbonilo, 1-(alquil C_{1-3})imidazol-2-ilo, (alquil C_{1-3})sulfonilo, o
\newpage
- \quad
- por un grupo de la fórmula
en el
que
- \quad
- R^{7} es un grupo alquilo C_{1-2}, (alquil C_{1-2})carbonilo, di(alquil C_{1-2})amino-carbonilalquilo C_{1-3} o (alquil C_{1-3})sulfonilo y
- \quad
- R^{8} es un grupo alquilo C_{1-3}, \omega-[di(alquil C_{1-2})amino]alquilo C_{2-3}, \omega-[mono(alquil C_{1-2})amino]alquilo C_{2-3}, o
- \quad
- un grupo (alquil C_{1-3})carbonilo, (alquil C_{4-6})carbonilo o carbonilalquilo C_{1-3} que está sustituido en el extremo por un grupo di(alquil C_{1-2})amino, piperazin-1-ilo o 4-(alquil C_{1-3})piperazin-1-ilo,
donde todos los grupos dialquilamino presentes
en el radical R^{4} pueden también estar presentes en forma
cuaternizada, por ejemplo en forma de un grupo
N-metil-(N,N-dialquil)amonio,
donde el ión conjugado preferiblemente se selecciona del grupo que
consiste en yoduro, cloruro, bromuro, metilsulfonato,
para-toluenosulfonato y trifluoroacetato,
R^{5} es un átomo de hidrógeno y
R^{6} es un átomo de hidrógeno,
donde los grupos alquilo mencionados
anteriormente incluyen los grupos alquilo lineales y ramificados en
los que además de uno a 3 átomos de hidrógeno pueden ser
reemplazados por átomos de flúor,
donde además un grupo carboxilo, amino o imino
presente puede estar sustituido por un radical que puede escindirse
in vivo o puede estar presente en forma de un radical de
profármaco, por ejemplo en forma de un grupo que puede convertirse
in vivo en un grupo carboxilo o en forma de un grupo que
puede convertirse in vivo en un grupo imino o amino,
los tautómeros, los diastereoisómeros, los
enantiómeros, sus mezclas y sus sales,
para la preparación de un medicamento para la
prevención o el tratamiento de una enfermedad fibrótica que se
selecciona del grupo que consiste en fibrosis y remodelación de
tejido pulmonar en la enfermedad pulmonar obstructiva crónica,
fibrosis y remodelación de tejido pulmonar en la bronquitis crónica,
fibrosis y remodelación de tejido pulmonar en el enfisema, fibrosis
pulmonar y enfermedades pulmonares con un componente fibrótico,
fibrosis y remodelación en el asma.
2. Uso de acuerdo con la reivindicación 1, en el
que la indolinona sustituida de la fórmula general I se selecciona
del grupo que consiste en:
(a)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(b)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(c)
3-Z-[1-(4-dimetilaminometilanilino)-1-(3-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(d)
3-Z-[1-(4-(N-(4-metilpiperazin-1-ilmetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(e)
3-Z-[1-(4-(N-(2-dimetilaminoetil)-N-metilsulfonilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(f)
3-Z-[1-(4-(N-(3-dimetilaminopropil)-N-acetilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-in-
dolinona
dolinona
(g)
3-Z-[1-(4-(1-metilimidazol-2-il)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(h)
3-Z-[1-(4-(N-(dimetilaminometilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
\newpage
(i)
3-Z-[1-(4-(N-(2-dimetilaminoetilcarbonil)-N-metilamino)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(j)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(k)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-fluoro-2-indolinona
(l)
3-Z-[1-(4-(2-dimetilaminoetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(m)
3-Z-[1-(4-dimetilaminometilanilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(n)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-cloro-2-indolinona
(o)
3-Z-[1-(4-(pirrolidin-1-ilmetil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona
(p)
3-Z-[1-(4-(dimetilaminometil)anilino)-1-(4-(2-carboxietil)fenil)metilen]-6-bromo-2-indolinona,
y
(q)
3-Z-[1-(4-(dietilaminometil)anilino)-1-(4-(2-carboxietil)metilen]-6-bromo-2-indolinona,
los tautómeros, los diastereoisómeros, los
enantiómeros, sus mezclas y sus sales.
3. Uso de acuerdo con una cualquiera de las
reivindicaciones 1 ó 2, en el que la enfermedad se selecciona del
grupo que consiste en la fibrosis pulmonar y las enfermedades
pulmonares con un componente fibrótico que se seleccionan de
fibrosis pulmonar idiopática, neumonía intersticial de células
gigantes, sarcodosis, fibrosis quística, síndrome disneico, fibrosis
pulmonar inducida por fármacos, granulomatosis, silicosis,
asbestosis, esclerodermia sistémica.
4. Uso de acuerdo con una cualquiera de las
reivindicaciones 1 a 3, en el que la enfermedad es fibrosis pulmonar
idiopática.
5. Uso de acuerdo con una cualquiera de las
reivindicaciones 1 a 4, en el que el tratamiento es un tratamiento
combinado con una sustancia farmacológicamente activa adicional que
se selecciona del grupo que consiste en agentes anticolinérgicos,
beta-2 miméticos, esteroides, inhibidores de
PDE-IV, inhibidores de p38 MAP quinasa, antagonistas
de NK_{1}, antagonistas de LTD4, inhibidores de EGFR y
antagonistas de endotelinas.
6. Una composición farmacéutica que comprende
una indolinona sustituida de fórmula I tal como se define en una
cualquiera de las reivindicaciones 1 ó 2, opcionalmente junto con
uno o más vehículos o excipientes farmacéuticamente aceptables, para
la prevención o el tratamiento de una enfermedad fibrótica que se
selecciona del grupo que consiste en fibrosis y remodelación de
tejido pulmonar en la enfermedad pulmonar obstructiva crónica,
fibrosis y remodelación de tejido pulmonar en la bronquitis crónica,
fibrosis y remodelación de tejido pulmonar en el enfisema, fibrosis
pulmonar y enfermedades pulmonares con un componente fibrótico,
fibrosis y remodelación en el asma, fibrosis inducida por
radiaciones.
7. La composición farmacéutica de acuerdo con la
reivindicación 6, en la que la enfermedad se selecciona del grupo
que consiste en la fibrosis pulmonar y las enfermedades pulmonares
con un componente fibrótico que se seleccionan de fibrosis pulmonar
idiopática, neumonía intersticial de células gigantes, sarcodosis,
fibrosis quística, síndrome disneico, fibrosis pulmonar inducida por
fármacos, granulomatosis, silicosis, asbestosis, esclerodermia
sistémica.
8. La composición farmacéutica de acuerdo con la
reivindicación 7, en la que la enfermedad es fibrosis pulmonar
idiopática.
9. La composición farmacéutica de acuerdo con
una cualquiera de las reivindicaciones 6 a 8, en la que el
tratamiento es un tratamiento combinado con una sustancia
farmacológicamente activa adicional que se selecciona del grupo que
consiste en agentes anticolinérgicos, beta-2
miméticos, esteroides, inhibidores de PDE-IV,
inhibidores de p38 MAP quinasa, antagonistas de NK_{1},
antagonistas de LTD4, inhibidores de EGFR y antagonistas de
endotelinas, administrándose dicha sustancia farmacológicamente
activa adicional de forma simultánea o secuencial.
10. Composición farmacéutica que contiene una
indolinona sustituida de la fórmula I tal como se define en una
cualquiera de las reivindicaciones 1 ó 2 combinada con una sustancia
farmacológicamente activa adicional que se selecciona del grupo que
consiste en agentes anticolinérgicos, beta-2
miméticos, inhibidores de PDE-IV, inhibidores de p38
MAP quinasa, antagonistas de NK_{1}, antagonistas de LTD4 y
antagonistas de endotelinas, opcionalmente junto con uno o más
vehículos o excipientes farmacéuticamente aceptables.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04030769 | 2004-12-24 | ||
EP04030769 | 2004-12-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
ES2326277T3 true ES2326277T3 (es) | 2009-10-06 |
Family
ID=35717457
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES05823903T Active ES2326277T3 (es) | 2004-12-24 | 2005-12-21 | Medicamentos para el tratamiento o prevencion de enfermedades fibroticas. |
Country Status (26)
Country | Link |
---|---|
US (3) | US20060148883A1 (es) |
EP (1) | EP1835907B1 (es) |
JP (1) | JP5748386B2 (es) |
KR (1) | KR20070092305A (es) |
CN (1) | CN101087604B (es) |
AR (1) | AR052439A1 (es) |
AT (1) | ATE429222T1 (es) |
AU (1) | AU2005318136B2 (es) |
BR (1) | BRPI0519351A2 (es) |
CA (1) | CA2591089C (es) |
DE (1) | DE602005014145D1 (es) |
DK (1) | DK1835907T3 (es) |
EA (1) | EA200701181A1 (es) |
ES (1) | ES2326277T3 (es) |
HR (1) | HRP20090312T1 (es) |
IL (1) | IL184124A0 (es) |
MX (1) | MX2007007676A (es) |
NO (1) | NO20073830L (es) |
PE (1) | PE20061155A1 (es) |
PL (1) | PL1835907T3 (es) |
PT (1) | PT1835907E (es) |
RS (1) | RS50833B (es) |
SI (1) | SI1835907T1 (es) |
TW (1) | TW200637544A (es) |
WO (1) | WO2006067175A1 (es) |
ZA (1) | ZA200703600B (es) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
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 |
EP2116367B1 (en) * | 2007-03-02 | 2018-04-04 | Mitsui Chemicals, Inc. | Layered nonwoven fabric |
WO2009063028A2 (en) * | 2007-11-15 | 2009-05-22 | 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 |
CA2712388A1 (en) * | 2008-01-25 | 2009-07-30 | Boehringer Ingelheim International Gmbh | Salt forms of a 6-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene derivative, process for their manufacture and pharmaceutical compositions containing same |
JP2012503619A (ja) | 2008-09-26 | 2012-02-09 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | Hcv感染に対する抗ウイルス治療のための標的としての宿主細胞キナーゼ |
US20140050728A1 (en) * | 2011-01-28 | 2014-02-20 | Board Of Regents Of The University Of Nebraska | Methods and compositions for inhibiting cyclophilin d for the treatment and prevention of obesity and kidney indications |
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 |
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 |
SG11202003035SA (en) | 2017-10-05 | 2020-04-29 | Fulcrum Therapeutics Inc | Use of p38 inhibitors to reduce expression of dux4 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1319090A (zh) * | 1998-09-25 | 2001-10-24 | 贝林格尔英格海姆法玛公司 | 新的取代的二氢吲哚酮、它们的制备方法和它们作为药物的用途 |
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 |
PE20040701A1 (es) * | 2002-07-23 | 2004-11-30 | Boehringer Ingelheim Pharma | Derivados de indolinona sustituidos en posicion 6 y su preparacion como medicamentos |
-
2005
- 2005-12-16 PE PE2005001477A patent/PE20061155A1/es not_active Application Discontinuation
- 2005-12-20 US US11/275,226 patent/US20060148883A1/en not_active Abandoned
- 2005-12-21 CN CN2005800446331A patent/CN101087604B/zh not_active Expired - Fee Related
- 2005-12-21 ES ES05823903T patent/ES2326277T3/es active Active
- 2005-12-21 AT AT05823903T patent/ATE429222T1/de active
- 2005-12-21 MX MX2007007676A patent/MX2007007676A/es active IP Right Grant
- 2005-12-21 RS RSP-2009/0245A patent/RS50833B/sr unknown
- 2005-12-21 SI SI200530719T patent/SI1835907T1/sl unknown
- 2005-12-21 WO PCT/EP2005/057013 patent/WO2006067175A1/en active Application Filing
- 2005-12-21 DE DE602005014145T patent/DE602005014145D1/de active Active
- 2005-12-21 EP EP05823903A patent/EP1835907B1/en active Active
- 2005-12-21 KR KR1020077017059A patent/KR20070092305A/ko not_active Application Discontinuation
- 2005-12-21 EA EA200701181A patent/EA200701181A1/ru unknown
- 2005-12-21 PL PL05823903T patent/PL1835907T3/pl unknown
- 2005-12-21 DK DK05823903T patent/DK1835907T3/da active
- 2005-12-21 JP JP2007547510A patent/JP5748386B2/ja not_active Expired - Fee Related
- 2005-12-21 PT PT05823903T patent/PT1835907E/pt unknown
- 2005-12-21 CA CA2591089A patent/CA2591089C/en not_active Expired - Fee Related
- 2005-12-21 BR BRPI0519351-6A patent/BRPI0519351A2/pt not_active IP Right Cessation
- 2005-12-21 AU AU2005318136A patent/AU2005318136B2/en not_active Ceased
- 2005-12-22 AR ARP050105467A patent/AR052439A1/es unknown
- 2005-12-23 TW TW094146423A patent/TW200637544A/zh unknown
-
2007
- 2007-05-04 ZA ZA200703600A patent/ZA200703600B/en unknown
- 2007-06-21 IL IL184124A patent/IL184124A0/en unknown
- 2007-07-23 NO NO20073830A patent/NO20073830L/no not_active Application Discontinuation
-
2009
- 2009-05-27 HR HR20090312T patent/HRP20090312T1/xx unknown
-
2011
- 2011-03-31 US US13/077,138 patent/US20120004202A1/en not_active Abandoned
-
2014
- 2014-01-13 US US14/153,542 patent/US20140128409A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
RS50833B (sr) | 2010-08-31 |
TW200637544A (en) | 2006-11-01 |
DK1835907T3 (da) | 2009-08-03 |
NO20073830L (no) | 2007-07-23 |
US20140128409A1 (en) | 2014-05-08 |
CN101087604A (zh) | 2007-12-12 |
CN101087604B (zh) | 2010-10-13 |
JP2008525374A (ja) | 2008-07-17 |
PL1835907T3 (pl) | 2009-08-31 |
PT1835907E (pt) | 2009-06-16 |
SI1835907T1 (sl) | 2009-10-31 |
ATE429222T1 (de) | 2009-05-15 |
EA200701181A1 (ru) | 2008-02-28 |
KR20070092305A (ko) | 2007-09-12 |
US20120004202A1 (en) | 2012-01-05 |
CA2591089C (en) | 2014-02-11 |
AR052439A1 (es) | 2007-03-21 |
BRPI0519351A2 (pt) | 2009-01-20 |
DE602005014145D1 (de) | 2009-06-04 |
CA2591089A1 (en) | 2006-06-29 |
AU2005318136A1 (en) | 2006-06-29 |
AU2005318136B2 (en) | 2012-02-09 |
IL184124A0 (en) | 2007-10-31 |
EP1835907A1 (en) | 2007-09-26 |
US20060148883A1 (en) | 2006-07-06 |
HRP20090312T1 (en) | 2009-07-31 |
ZA200703600B (en) | 2008-07-30 |
WO2006067175A1 (en) | 2006-06-29 |
MX2007007676A (es) | 2007-08-14 |
JP5748386B2 (ja) | 2015-07-15 |
PE20061155A1 (es) | 2006-12-16 |
EP1835907B1 (en) | 2009-04-22 |
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