Use of Nintedanib for the treatment of lung fibrosis

摘要

Treatment of immunological (or related) diseases involves administration of an active agent (I) selected from 37 specific (Z)-3-(1-(substituted amino)-1-phenyl-methylene)-2-indolinones and (4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methyl-piperidin-4-yl-methoxy)-quinazoline, optionally together with various other drugs (II). Treatment of immunological diseases or pathological states having an immunological component involves administration of a pharmaceutical composition containing an indolinone or quinazolinone compound (I), optionally together with at least one other drug (II) selected from non-steroidal antiinflammatories, steroids, disease modifying antirheumatic agents, immunosuppressants, biological reaction modifiers and antiinfective agents. (I) is selected from the following compounds and their tautomers, stereoisomers and salts: (1) (Z)-3-(1-(4-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(methylsulfonylamino)-2-indolinone; (2) (Z)-3-(1-(4-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; (3) (Z)-3-(1-(4-dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; (4) (Z)-3-(1-(4-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone; (5) (Z)-3-(1-(4-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(4-amino-phenylsulfonylamino)-2-indolinone; (6) (Z)-3-(1-(4-pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; (7) (Z)-3-(1-(4-(3-aminopropyl)-piperidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(ethylsulfonylamino)-2-indolinone; (8) (Z)-3-(1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methylamino)-phenylamino)-1-phenyl-methylene)-5-(phenylsulfonylamino)-2-indolinone; (9) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonylamino)-2-indolinone; (10) (Z)-3-(1-(4-(N-methyl-N-(piperidin-1-yl-methylcarbonyl)-amino)-phenylamino)-1-phenyl-methylene)-5-(N-methyl-N-phenylsulfonylamino)-2-indolinone; (11) (Z)-3-(1-(2-benzimidazolyl-amino)-1-phenyl-methylene)-5-amido-2-indolinone; (12) (Z)-3-(1-(4-N-methyl-propionylamino)-phenylamino)-1-phenyl-methylene)-5-amido-2-indolinone; (13) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone; (14) (Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-propionyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone; (15) (Z)-3-(1-(4-(dimethylamino-methyl)-phenylamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-indolinone; (16) (Z)-3-(1-(4-(dimethylamino-methyl)-phenylamino)-1-phenyl-methylene)-5-(naphth-1-ylmethyl-carbamoyl)-2-indolinone; (17) (Z)-3-(1-(4-dimethylamino-methyl)-phenylamino)-1-phenyl-methylene)-5-(N-butyl-N-phenyl-carbamoyl)-2-indolinone; (18) (Z)-3-(1-(4-(dimethylamino-methyl)-phenylamino)-1-phenyl-methylene)-5-(hexylcarbamoyl)-2-indolinone; (19) (Z)-3-(1-(4-(dimethylamino-methyl)-phenylamino)-1-phenyl-methylene)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; (20) (Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylene)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; (21) (Z)-3-(1-(4-butylamino-methyl)-phenylamino)-1-phenyl-methylene)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; (22) (Z)-3-(1-(4-pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylene)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; (23) (Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; (24) (Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; (25) (Z)-3-(1-(4-(diethanolamino-methyl)-phenylamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-indolinone; (26) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; (27) (Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-phenylamino)-1-phenyl-methylene)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; (28) (Z)-3-(1-(4-(butylaminomethyl)-phenylamino