Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-06-25
1998-08-04
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514445, 514523, 549 66, 558401, 564340, 564342, 564344, 564345, A61K 31165, C07C23576
Patent
active
057894485
DESCRIPTION:
BRIEF SUMMARY
The present application is a 371 application of PCT/JP95/01475, filed Jul. 25, 1995.
TECHNICAL FIELD
This invention relates to a tyrosine kinase inhibitor, more specifically to a tyrosine kinase inhibitor containing a benzoylethylene derivative having specific structure or a pharmaceutically acceptable salt thereof as an active ingredient.
BACKGROUND ART
In chemotherapy of cancer, many substances have been practically used as a medicine. In many cases, however, they are not necessarily in a satisfactory situation since not only the effect of the substance as a medicine is insufficient but also the inhibitory activity thereof is not limited only to cancer cells and the substance shows potent toxicity so that side effects thereof are a great problem.
It has been known that a receptor of a growth factor controls function of differentiation and growth of cells and when a kind of aberration occurs, abnormal growth (excrescence) and differentiation of cells occur and the cells become cancerous. It has been clarified that tyrosine kinase type acceptors participate particularly in formation of cancer, and found that these acceptors show peculiar tyrosine-specific protein kinase (tyrosine kinase) activities and these activities are particularly accelerated in cancer cells (Cancer Research, 51, 4430-4435 (1991); Cancer Research, 52, 3636-3641 (1992); Cancer Chemother. Pharmacol., 32, 1-19 (1993), etc.). Based on these findings, it has been already proposed that an agent which specifically inhibits tyrosine kinase activity of a growth factor acceptor become to be a carcinostatic agent having novel function and mechanism with less side effect. In such a material, there are, for example, microorganism-derived Erbstatin, Lavendustin, Herbimycin A, Genistein, etc., and as chemically synthesized products, benzylidene malonic nitrile Journal of Medicinal Chemistry, 32, 2344 (1989); Ditto, 34, 1896 (1991)!, .alpha.-cyanocinnamide derivative (Japanese Provisional Patent Publication No. 222153/1988), 3,5-diisopropyl-4-hydroxystyrene derivative (Japanese Provisional Patent Publication No. 39522/1987), 3,5-di-t-butyl-4-hydroxystyrene derivative (Japanese Provisional Patent Publication No. 39523/1987), Erbstatin derivative compound (Japanese Provisional Patent Publication No. 277347/1987), and the like.
The conventional tyrosine kinase inhibitors are each insufficient in their inhibitory activities and they are not yet sufficient for using as a carcinostatic agent. An object of the present invention is to provide a novel compound useful as a carcinostatic agent which can be easily available, has high activity specifically as a tyrosine kinase inhibitor of a growth factor acceptor, and thus has no side effects which are possessed by the conventional carcinostatic agents. Also, it has been well known that tyrosine-specific protein kinase (tyrosine kinase) has central function in differentiation and growth of cells or in cell information transfer mechanism, and failure in control of tyrosine kinase activity in cells causes aberration in differentiation and growth mechanism of cells or in cell information transfer mechanism which is considered to directly participate in crisis of many diseases. For example, these diseases are arteriosclerosis (Am. J. Physiol., 260 (4-part 1), C721-C730 (1991); Biochem. Biophys. Res. Commun., 192 (3), 1319-1326 (1993), etc.), platelet aggregation (FEBS Letters, 263 (1), 104-108 (1990); FEBS Letters, 309 (1), 10-14 (1992), etc.), immune disorder (FEBS Letters, 279 (2), 319-322 (1991); J. Immunol., 146 (9), 2965-2971 (1991); Nature, 358, 253-255 (1992), etc.), inflammation (Molecular Pharmacology, 37, 519-525 (1990); International Immunology, a (4), 447-453 (1992), etc.) or the like. Thus, tyrosine kinase inhibitors are considered to be useful for treatment and prevention of these diseases.
DISCLOSURE OF THE INVENTION
The present inventors have intensively studied to solve the above problems and as a result, they have found that a benzoylethylene derivative with specific structure has potent t
REFERENCES:
patent: 3864344 (1975-02-01), Raabe et al.
patent: 4418079 (1983-11-01), Kojima et al.
European Journal of Med. Chem., vol. 23(1), pp. 45-52, (1988), Mario Bianchi, et al., "Gastric Anti-Secretory, Anti-Ulcer and Cytoprotective Properties of Substituted (E)-4-Phenyl- and Heteroaryl-4-Oxo-2-Butenoic Acids".
Collection of Czechoslovak Chemical Communications, vol. 28, pp. 3278-3289, (1963), M. Semonsky, et al., "Substanzen mit Antineoplastischer Wirksamkeit VI. Aminolyse Von .gamma.-Aryl-.alpha.,.beta.-Dihalogen-.DELTA..sup..alpha.,.beta. -Crotonlactonen; Einige Substituierte .beta.-Aroyl-.beta.-Halogen Acrylsaureamide und -Propionsaureamide Sowie .beta.-Aroylpropionsaureamide".
Collection of Czechoslovak Chemical Communications, vol. 41, pp. 3106-3112, (1976), V. Zikan, et al., "Synthesis and Saponification of Ethyl Esters of cis- and trans-.beta.-4-Alkoxybenzoyl-.beta.- and -.beta.-Bromoacrylic Acids".
Journal of the Chemical Society, vol. (B), pp. 156-160, (1971), K. Bowden, et al., "Reactions of Carbonyl Compounds in Basic Solutions. Part IV. The Mechanism of the Alkaline Hydrolysis of Methyl 3-Benzoylacrylates".
Journal of the Chemical Society, Perkin Transactions, vol. 1, pp. 2721-2728, (1990), Donald J. Coveney, et al., "Acylocobalt Salophen Reagents. Precursors to Acyl Radical Intermediates for Use in Carbon-To-Carbon Bond-Forming Reactions to Alkenes".
Journal of American Chemical Society, vol. 110, pp. 1557-1565, (1988), Antonio M. Echavarren, et al., "Palladium-Catalyzed Carbonylative Coupling of Aryl Triflates with Organostannanes".
Journal of the Chemical Society, Perkin Transactions I, pp. 1588-1594, (1978), John W. Apsimon, et al., "Synthesis of Some 2-Phenylpyrrole Derivatives".
Journal of Organic Chemistry of the USSR, vol. 8, No. 4, pp. 735-738, (1972), I.G. Tishchenko, et al., "Liquid-Phase Oxidation of .alpha.,.beta.-Unsaturated Ketones. X. Oxidation of Alkoxyisobutylidebeacetophenoes".
Hara Hiroto
Inokawa Haruki
Kitano Yasunori
Takayanagi Hisao
Umeki Hiroe
Mitsubishi Chemical Corporation
Raymond Richard L.
LandOfFree
Benzoylethylene derivative does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzoylethylene derivative, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzoylethylene derivative will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1177712