MEDICAMENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES

• US 20100204211A1
• Filed: 12/22/2009
• Published: 08/12/2010
• Est. Priority Date: 12/24/2004
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: DAHMANN, Georg, ROTH, Gerald Juergen, CHAUDHARY, Nveed, PARK, John Edward, BRANDL, Trixi, HECKEL, Armin, GRAUERT, Matthias
• Application Number:
  US12/645,151
• Publication Number:
  US 20100204211A1
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61K 9/08 : Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/10 : Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/1623 : Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/2018 : Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2866 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/34 : in position 2
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/215 : Radicals derived from nitrogen analogues of carbonic acid
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links

Abstract

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

substituted in the 6 position, wherein

• R₁ to R₅ 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.

Claims

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

2. The method as recited in claim 1 wherein the substituent in the 6 position of the substituted indolinone of formula I comprises a substituted amido group.

3. The method as recited in claim 1 wherein the indolinone of formula I is selected from the group consisting of:

(a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,

(b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone,

(c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(d) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,

(e) 3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,

(f) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,

(g) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,

(h) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,

(i) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(j) 3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(k) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(l) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(m) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(n) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(o) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(p) 3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(q) 3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(r) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and

(s) 3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

or a salt of any of the above recited indolines.

4. The method as recited in claim 1 wherein the indolinone of formula I is selected from the group consisting of:

(t) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(u) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

(v) 3-Z-[1-(3-cyano-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(w) 3-Z-[1-(3-methoxy-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(x) 3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(y) 3-Z-[1-(4-(N—

(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(z) 3-Z-[1-(4-(N-(di-(2-hydroxy-ethyl)-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(aa) 3-Z-[1-(4-(N-(imidazol-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ab) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ac) 3-Z-[1-(4-(N-((4-methyl-[1,4]diazepan-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ad) 3-Z-[1-(4-(N-((1-methyl-piperidin-4-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ae) 3-Z-[1-(2,3-dimethyl-4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(af) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ag) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ah) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ai) 3-Z-[1-(4-(N-((3-dimethylamino-propyl)-aminocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(aj) 3-Z-[1-anilino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(ak) 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(al) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

(am) 3-Z-[1-(4-(4-methylpiperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(an) 3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(ao) 3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(ap) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(aq) 3-Z-[1-(4-(di-(2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(ar) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(as) 3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(at) 3-Z-[1-(4-(N—

(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(au) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone

(av) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-carboxy-2-indolinone

(aw) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

(ax) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

(ay) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

(az) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone

(ba) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bb) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bc) 3-Z-[1-((1-methyl-piperidin-4-yl)-amino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bd) 3-Z-[1-(trans-4-dimethylamino-cyclohexylamino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(be) 3-Z-[1-(4-(2-diethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bf) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bg) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bh) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bi) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bj) 3-Z-[1-(3-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bk) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bl) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bm) 3-Z-[1-anilino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bn) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bo) 3-Z-[1-(4-((2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bp) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bq) 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(br) 3-Z-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bs) 3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bt) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(bu) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(by) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(bw) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(bx) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(by) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(bz) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(ca) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(cb) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(cc) 3-Z-[1-(4-carbamoyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(cd) 3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(ce) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(cf) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(cg) 3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(ch) 3-Z-[1-(4-(N-ethyl-N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(ci) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-diethylcarbamoyl-2-indolinone

(cj) 3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(ck) 3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(cl) 3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone

(cm) 3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(cn) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone

(co) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone

(cp) 3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-methoxycarbonyl-2-indolinone

(cg) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone

(cr) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone

(cs) 3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone

(ct) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone, and

(cu) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone,

or a salt of any of the above recited indolines.

5. The method as recited in claim 1 wherein the indolinone of formula I is selected from 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone or the monoethanesulfonate salt thereof.

6. The method as recited in claim 1 wherein the disease is selected from the group consisting of the lung fibrosis and pulmonary diseases with a fibrotic component selected from idiopathic pulmonary fibrosis, giant cell interstitial pneumonia, sarcodosis, cystic fibrosis, respiratory distress syndrome, drug-induced lung fibrosis, granulomatosis, silicosis, asbestosis, systemic scleroderma, the virally induced hepatic cirrhosis selected from hepatitis C induced hepatic cirrhosis, and the diseases of the skin with a fibrotic component selected from scleroderma, sarcodosis and systemic lupus erythematosus.

7. The method as recited in claim 6 wherein the disease is idiopathic pulmonary fibrosis.

8. The method as recited in claim 1 further comprising administering an additional pharmacologically active substance selected from the group consisting of anticholinergic agents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK₁ antagonists, LTD4 antagonists, EGFR inhibitors and endothelin-antagonists in combination with the indoline of formula I.

9. A pharmaceutical composition comprising a substituted indolinone of formula I as recited in claim 1, an additional pharmacologically active substance selected from the group consisting of anticholinergic agents, beta-2 mimetics, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK₁ antagonists, LTD4 antagonists and endothelin-antagonists, and one or more pharmaceutically acceptable carriers or excipients.