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Medicaments for the Treatment or Prevention of Fibrotic Diseases

Inactive Publication Date: 2006-06-29
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] The present invention further relates to a pharmaceutical composition for the treatment or prevention of specific fibrotic

Problems solved by technology

Excessive uncontrolled tissue repair or the failure to stop remodeling when it is no longer required leads to condition known as fibrosis.
Fibrosis often severely compromises the normal function(s) of the organ and many fibrotic diseases are, in fact, life-threatening or severely disfiguring, such as idiopathic pulmonary fibrosis (IPF), liver cirrhosis, scleroderma, or renal fibrosis.
Treatment options for these diseases are often limited to organ transplantation, a risky and expensive procedure.

Method used

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  • Medicaments for the Treatment or Prevention of Fibrotic Diseases
  • Medicaments for the Treatment or Prevention of Fibrotic Diseases
  • Medicaments for the Treatment or Prevention of Fibrotic Diseases

Examples

Experimental program
Comparison scheme
Effect test

example b1

[1423] In the following experiments of Example B1, Example A denotes the compound 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, which is compound (m) of the list of the preferred compounds.

[1424] (A) Effect of a representative compound on lung morphology following bleomycin-induced pulmonary fibrosis.

[1425] Materials and Methods

[1426] Bleomycin sulfate (Bleomycin HEXAL™) was purchased from a local pharmacy.

[1427] Bleomycin Administration and Treatment Protocols

[1428] All experiments were performed in accordance with German guidelines for animal welfare, performed by persons certified to work with animals and approved by the responsible authorities. Male Wistar rats were intratracheally injected with Bleomycin sulfate (10 U / kg body weight in 300 μl saline) or saline alone (saline control) using a catheter (0.5 mm internal diameter, 1.0 mm external diameter) through the nasal passage, following exposure to th...

example b2

[1452] In the following experiments of Example B2, the compound 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, which is compound (u) of the list of the preferred compounds, was used.

[1453] All the methods employed are the same as the methods described in the experiments of Example B1, however using compound (u) instead of compound (m).

[1454] (A) Effect of a representative compound on lung morphology following bleomycin-induced pulmonary fibrosis.

[1455] Samples were prepared from rats treated as outlined in above Table 1 of experimental Example B1 (A).

[1456] Results

[1457]FIG. 4A shows the result obtained with the control group, which received saline and the vehicle instead of bleomycin intratracheally.

[1458] Rats treated intratracheally with bleomycin and the vehicle developed severe lung fibrosis, as seen in FIG. 4B. The alveoli have been largely replaced by fibroblasts and extracellular matr...

example f1

Coated Tablet Containing 75 mg of Active Substance

[1524]

[1525] Preparation (Direct Compression)

[1526] The active substance is mixed with all components, sieved and compressed in a tablet-making machine to form tablets of the desired shape.

Weight of core:230 mgAppearance of core:9 mm, biconvex

[1527] The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose.

Weight of coated tablet:240 mg.

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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.

Description

[0001] The present invention relates to a new use of indolinones of general formula substituted in the 6 position, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof. BACKGROUND [0002] Compounds of the above general formula I, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof, have been described in WO 01 / 27081 and WO 04 / 13099 as having valuable pharmacological properties, in particular an inhibiting effect on various kinases, especially receptor tyrosine kinases such as VEGFR2, PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as complexes of CDK's (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and to viral cyclin (cf. L. Mengtao in J. Viro...

Claims

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Application Information

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IPC IPC(8): A61K31/404
CPCA61K31/496A61K31/44A61K31/4045A61K31/4178A61K31/454C07D403/12A61K31/551A61K45/06C07D209/34A61K31/404A61K31/5377A61K31/445A61K31/495C07D401/12A61K2300/00C07D295/155C07D295/215A61P43/00A61K9/2866A61K9/2018A61K9/02A61K9/0031A61K9/10A61K9/0095A61K9/1623A61K9/08A61K9/0078A61K9/0075A61K47/10A61K47/38A61K9/0019C07D471/04
Inventor PARK, JOHN EDWARDROTH, GERALD JUERGENHECKEL, ARMINCHAUDHARY, NVEEDBRANDL, TRIXIDAHMANN, GEORGGRAUERT, MATTHIAS
Owner BOEHRINGER INGELHEIM INT GMBH
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