Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-06
2000-11-07
Seaman, D. Margaret
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142352, 514253, 544128, 544235, 544238, 544363, 544405, 154155, 154154, A61K 3147, A61K 31535, C07D41300, C07D21516, C07D21520
Patent
active
061437646
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/03229, filed Nov. 5, 1996.
FIELD OF THE INVENTION
The present invention relates to novel quinoline derivatives and quinazoline derivatives having an inhibitory action against abnormal cell growth and to their pharmaceutically acceptable salts. More specifically, the present invention relates to novel quinoline derivatives and quinazoline derivatives having an inhibitory action against autophosphorylation of the platelet-derived growth factor receptor and to their pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Growth factors such as insulin, the epidermal growth factor and the platelet-derived growth factor (hereinafter referred to as PDGF) have an important role in cell growth. In particular, PDGF is known to be a powerful cell growth factor related to the control of cell growth and division (Cell 46, 155 (1986)). However, in diseases or pathophysiological situations such as leukemia, cancers, psoriasis, glomerular nephritis, organofibrosis, atherosclerosis, restenosis after percutaneous coronary angioplasty or bypass surgery and rheumatoid arthritis, abnormal production of PDGF or PDGF receptor occurs at the pathophysiological sites, and abnormal cell growth is observed at the pathophysiological sites in such diseases. Namely, this is an excess of cell growth signals associated with overproduction of the PDGF or PDGF receptors. Thus, it is necessary to suppress cell growth signal transduction to improve these pathophysiological situations.
In one trial, it was reported that abnormal cell growth in pathophysiological situations was suppressed by administration of an anti-PDGF antibody (J. Exp. Med. 175, 1413 (1992)); however, there are problems such as in vivo stability and methods of administration as a therapeutic agent because the anti-PDGF antibody is a protein molecule.
On the other hand, in cells, PDGF is known to bind to the PDGF receptor to activate tyrosine kinase present in this receptor. This receptor tyrosine kinase relates to intracellular signal transduction via autophosphorylation of the receptor itself and plays an important role in cell growth. In pathophysiological situations, this intracellular signal transduction is considered to be excessive. Therefore, inhibition of PDGF receptor autophosphorylation can be considered as another possible strategy to suppress cell growth signal transduction.
Examples of suppressing cell growth using the PDGF receptor autophosphorylation inhibitors, which are low molecular weight compounds, are described in the literature (Cancer Research 54, 6106 (1994); Proc. Natl. Acad. Sci. USA. 92, 2558 (1995)). Therefore, PDGF receptor autophosphorylation inhibitors could be useful in many diseases such as leukemia, cancers, psoriasis, glomerular nephritis, organofibrosis, atherosclerosis, restenosis after percutaneous coronary angioplasty or bypass surgery and rheumatoid arthritis.
Examples of previously known PDGF receptor autophosphorylation inhibitors include 3-arylquinolines (J. Med. Chem. 37, 2627 (1994); J. Med. Chem. 37, 2129 (1994) and Publication of Japanese Patent Laid-open No. 94/507643), 3-arylquinoxalines (Cancer Research 54, 6106 (1994)), and 4-pyridyl-2-arylpyrimidines (Proc. Natl. Acad. Sci. USA. 92, 2558 (1995)).
However, as far as the present inventors know, compounds which have a structure in which an aryl group or heteroaryl group is bonded to position 4 of the quinoline backbone or quinazoline backbone via one oxygen atom, sulfur atom or carbon atom and which have a PDGF receptor autophosphorylation inhibitory activity are not known.
Furthermore, as to previously known quinoline derivatives, {4-[(7-chloro-4-quinolinyl)oxy]phenyl}(4-fluorophenyl)methanone is described in Publication of Examined Japanese Patent Application No. 89/246263. This known compound is used as a fungicide, and there are no reports as to its PDGF receptor autophosphorylation inhibitory activity.
Furthermore, 4-arylquinoline derivatives are described in J. Med. Chem. 14, 1060 (1971), Acta Chim. Hung 112, 241 (1983
REFERENCES:
patent: 5821244 (1998-10-01), Schaper
CA 122:9884, Schaper, 1994.
CA 120:299513, Kawashima, 1993.
CA 99:88018, Gall-Istok, 1983.
CA 76:42038, Wright, 1971.
Kato Shinichiro
Kobayashi Yoshiko
Kubo Kazuo
Murooka Hideko
Nishitoba Tsuyoshi
Kirin Beer Kabushiki Kaisha
Seaman D. Margaret
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