Medicaments for the treatment or prevention of fibrotic diseases

Patent metadata

Field	Value
Publication number	US-2016136133-A1
Application number	US-201514982179-A
Country	US
Kind code	A1
Filing date	Dec 29, 2015
Priority date	Dec 24, 2004
Publication date	May 19, 2016
Grant date	—

Abstract

The present invention relates to the use of indolinones of general formula

substituted in the 6 position, wherein
R 1 to R 5 and X are defined as in claim 1 , the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.

First claim

What is claimed is:

1 . A method for preventing or treating a fibrotic disease selected from the group consisting of fibrosis and remodeling of lung tissue in chronic obstructive pulmonary disease, fibrosis and remodeling of lung tissue in chronic bronchitis, fibrosis and remodeling of lung tissue in emphysema, lung fibrosis and pulmonary diseases with a fibrotic component, fibrosis and remodeling in asthma, fibrosis in rheumatoid arthritis, virally induced hepatic cirrhosis, radiation-induced fibrosis, post angioplasty restenosis, chronic glomerulonephritis, renal fibrosis in patients receiving cyclosporine and renal fibrosis due to high blood pressure, diseases of the skin with a fibrotic component, and excessive scarring, which comprises administering a therapeutically effective amount of an indolinone of formula

substituted in the 6 position, wherein
X denotes an oxygen or sulphur atom,
R 1 denotes a hydrogen atom or a prodrug group,
R 2 denotes a carboxy group, a straight-chain or branched C 1-6 -alkoxy-carbonyl group, a C 4-7 -cycloalkoxy-carbonyl or an aryloxycarbonyl group,
a straight-chain or branched C 1-6 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C 1-3 -alkoxy-carbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,
a straight-chain or branched C 2-6 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C 1-3 -alkoxy, amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group,
an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group,
R 3 denotes a hydrogen atom, a C 1-6 -alkyl, C 3-7 -cycloalkyl, trifluoromethyl or heteroaryl group,
a phenyl or naphthyl group, a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C 1-3 -alkyl or C 1-3 -alkoxy group, whilst in the event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted
by a hydroxy, hydroxy-C 1-3 -alkyl or C 1-3 -alkoxy-C 1-3 -alkyl group,
by a cyano, carboxy, carboxy-C 1-3 -alkyl, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,
by a nitro group,
by an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino or amino-C 1-3 -alkyl group,
by a C 1-3 -alkylcarbonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkyl-carbonylamino, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, C 1-3 -alkyl-sulphonylamino, C 1-3 -alkylsulphonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino-C 1-3 -alkyl or aryl-C 1-3 -alkylsulphonylamino group,
by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneimino-C 1-3 -alkyl, cycloalkyleneiminocarbonyl-C 1-3 -alkyl or cycloalkyleneiminosulphonyl-C 1-3 -alkyl group having 4 to 7 ring members in each case, whilst in each case the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C 1-3 -alkyl) group,
or by a heteroaryl or heteroaryl-C 1-3 -alkyl group,
R 4 denotes a C 3-7 -cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,
or a phenyl group substituted by the group R 6 , which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-5 -alkyl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, amino, acetylamino, C 1-3 -alkyl-sulphonyl-amino, aminocarbonyl, C 1-3 -alkyl-aminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, aminosulphonyl, C 1-3 -alkyl-aminosulphonyl, di-(C 1-3 -alkyl)-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein
R 6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,
a cyano, nitro, amino, C 1-5 -alkyl, C 3-7 -cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group,
the group of formula

wherein the hydrogen atoms bound to a nitrogen atom may in each case be replaced independently of one another by a C 1-3 -alkyl group,
a C 1-3 -alkoxy group, a C 1-3 -alkoxy-C 1-3 -alkoxy, phenyl-C 1-3 -alkoxy, amino-C 2-3 -alkoxy, C 1-3 -alkylamino-C 2-3 -alkoxy, di-(C 1-3 -alkyl)-amino-C 2-3 -alkoxy, phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, C 5-7 -cycloalkyleneimino-C 2-3 -alkoxy or C 1-3 -alkylmercapto group,
a carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkyl-amino-carbonyl, N—(C 1-5 -alkyl)-C 1-3 -alkylaminocarbonyl, phenyl-C 1-3 -alkylamino-carbonyl,
N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino-carbonyl, piperazinocarbonyl or N—(C 1-3 -alkyl)-piperazinocarbonyl group,
a C 1-3 -alkylaminocarbonyl or N—(C 1-5 -alkyl)-C 1-3 -alkylaminocarbonyl group wherein an alkyl moiety is substituted by a carboxy or C 1-3 -alkoxycarbonyl group or in the 2 or 3 position by a di-(C 1-3 -alkyl)-amino, piperazino, N—(C 1-3 -alkyl)-piperazino or a 4- to 7-membered cycloalkyleneimino group,
a C 3-7 -cycloalkyl-carbonyl group,
wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,
a 4- to 7-membered cycloalkyleneimino group wherein
a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
the cycloalkylene moiety may be fused to a phenyl ring or
one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl group and/or
in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl,
sulphonyl, —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group,
a C 1-4 -alkyl group substituted by the group R 7 , wherein
R 7 denotes a C 3-7 -cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group or
in a 5- to 7-membered cycloalkyl group a —(CH 2 ) 2 group may be replaced by a —CO—NH group, a —(CH 2 ) 3 group may be replaced by a —NH—CO—NH or —CO—NH—CO group or a —(CH 2 ) 4 group may be replaced by a —NH—CO—NH—CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group,
an aryl or heteroaryl group,
a hydroxy or C 1-3 -alkoxy group,
an amino, C 1-7 -alkylamino, di-(C 1-7 -alkyl)-amino, phenylamino, N-phenyl-C 1-3 -alkyl-amino, phenyl-C 1-3 -alkylamino, N—(C 1-3 -alk

Assignees

• Boehringer Ingelheim Int

Inventors

• Park John Edward
• Roth Gerald Juergen
• Heckel Armin
• Chaudhary Nveed
• Brandl Trixi
• Dahmann Georg
• Grauert Matthias

Classifications

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D295/215

  Radicals derived from nitrogen analogues of carbonic acid · CPC title