Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1991-10-17
1993-02-23
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...
5142312, 514255, 514325, 514385, 514401, 514403, 514429, 514617, 514629, 514654, 514655, 544155, 544381, 546203, 546204, 5483001, 5483471, 5483561, 548529, 564184, 564222, 564427, 564374, 564384, A61K 31135
Patent
active
051890658
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the use of derivatives of 9,10-dihydrophenanthrene for the preparation of an anti-tumor medicament and notably of an anti-cancer medicament, the use as medicaments of derivatives of 9,10-dihydrophenanthrene and products derived from this structure
The expression of oncogenes in a cell of a mammal leads to the transformation of types of normal cells into cancerous cells. Said transformation is caused by the infection of a cell by a retrovirus. There can be cited as a well-known example, the infection of hens by the Rous virus which leads to the appearance of a cancer. The corresponding oncogene which is responsible for the malignant transformation was named "SRC" gene (J. S. Grugge RL Erikson, Nature 269, 346-348 (1977).
Many oncogenes known up until now, are characterized by the expression of a protein possessing a kinase activity. These enzymes catalyse the transfer of the terminal phosphate group of ATP onto an amino acid. Contrary to many of the other proteinkinases which transfer the phosphate group onto a seryl or threonyl remainder, the majority of oncogene kinases phosphorylize a tyrosyl remainder of the protein chain. Moreover it is known that the oncogene products, namely those of v-mos, v-mil and v-raf oncogenes have a specific serine/threonine proteinkinase activity (K. Rolling et al., Nature (London) 312, 558-561 (1984), B. Singh et al., Journal of Virology 60, 1149-1152 (1986).
The tyrosinekinase activity plays an integral part in the function of certain growth factor receptors. New results show that the growth of many tumors depends on the presence of growth factors such as Epidermal Growth Factor (EGF), the "Transforming Growth Factor Alpha (TGFAlpha) or the "Platelet Derived Growth Factor" (PDGF) (A. S. Goustin, G. D. Shipley, H. L. Moses, Cancer Research 46, 1015-1029 (1986). As a consequence of the link between the growth factor and its receptor, the tyrosinekinase, which is a specific component of the growth factor receptor, is stimulated.
Therefore it is to be expected that an inhibitor of tyrosinekinase and also of serine/threoninekinase can inhibit the growth and the proliferation of tumors and can be used in anti-tumor therapy.
It has just been discovered, in a surprising fashion, that the products of formula (I) as defined hereafter are oncogene kinases inhibitors such as tyrosinekinase, serine/threoninekinase and tyrosinekinase of the growth factor receptor and are thus of use in the treatment of tumor-related illnesses. The products of formula (I) which have anti-proliferative, anti-oncotic and carcinostatic properties can, in particular, be used to inhibit the growth and proliferation of tumors and in tumor therapy.
Therefore a subject of the present invention is the use of products of general formula I): ##STR2## in which X and Y, identical of different, are chosen from hydrogen atoms and hydroxy radicals and alkyloxy radicals having 1 to 4 carbon atoms and R.sub.1 and R.sub.2, identical or different, are chosen from hydrogen atoms, alkyl, alkenyl or alkynyl radicals having at most 4 carbon atoms, arylalkyl and acyl radicals, or R.sub.1 and R.sub.2 from together with the nitrogen atom to which they are linked a heterocycle with five or six links capable of carrying an optionally substituted second heteroatom chosen from nitrogen, oxygen or sulphur atoms, as well as their addition salts with mineral or organic acids for the preparation of an anti-tumor medicament.
Among the values of X and Y there can be mentioned in addition to the hydrogen and hydroxy values, the following radicals: methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, sec-butyloxy, isobutyloxy, tert-butyloxy. The hydroxy value is preferred.
Among the values of R.sub.1 and R.sub.2, there can be mentioned in addition to the hydrogen values, the following radicals: linked, the following radicals: pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl or propylpiperazinyl.
The addition salts with mineral or organi
REFERENCES:
Freedman et al., Br. J. Pharm., vol. 67 (1979) pp. 143-152.
Petterson et al., J. Computer-Aided Molecular Design, No. 1 (1987) pp. 143-152.
Yasuda et al., J. Chem. Soc., No. 5 (May 1988) pp. 745-751.
Cannon et al., J. Med. Chem., vol. 18 (1975) pp. 108-110.
Nichols et al., J. Med. Chem. vol. 21 (1978) pp. 395-398.
Yasuda et al., J. Org. Chem., vol. 52 (1987) pp. 753-759.
Czech Jorg
Guillaume Jacques
Marchandeau Christian
Nedelec Lucien
Sedlacek Hans H.
Raymond Richard L.
Roussel Uclaf
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