Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1990-09-12
1993-06-01
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
554 56, 554 63, 554127, 562552, A61K 3124
Patent
active
052160238
DESCRIPTION:
BRIEF SUMMARY
This invention relates to polyunsaturated fatty acid derivatives and their salts with tyrosine kinase inhibitor activity having the Formula (I) ##STR2## wherein R.sub.1 is an alkyl chain consisting of 18 to 24 carbon atoms containing at least two unsaturated double bonds; consisting of 1 to 4 carbon atoms; found in living organisms or a group having the formula (II) ##STR3## where A is OH or one A is hydroxy and the other A is hydrogen, and k=0 or 1 ##STR4## where X is as described above, ##STR5## where n is as defined above;
Due to the immunostimulant and tyrosine kinase inhibitor activity, the compounds of the invention can be applied for stopping and suppressing the pathological cell proliferation, consequently, for treating the malignant neoplastic diseases.
According to recent investigations, the formation of malignant tumors is clearly the result of the abnormal activation of certain genes. The abnormal activation of these genes called proto-oncogenes and their transformation into oncogenes can be caused by several mechanisms independently of retroviruses. By definition, the term "oncogene" means that these genes permit the formation and survival of malignant neoplastic cells (Bradshaw, T.K.: Mutagenesis 1, 91-97 (1986).
In the present state of the art, the regulation of cell-division is carried out by a complex mechanism which consists of genomial information comprising proto-oncogenes and the finely adjusted interaction between different factors inducing growth and differentiation and endocrine and paracrine regulators. The close connection between oncogenes and growth factors is also supported by the fact that the major part of oncogenes encodes proteins which themselves are growth factors or growth factor receptors or which interact with the signal transduction mechanism induced by growth factors.
As each cell of an organism is part of a strictly regulated and systematic "cell society", it has long been presumed that, normally, cells only begin to divide as an effect of an extrinsic signal i.e. growth factor. Recent investigations have also provided that, in the permanently dividing neoplastic cells, a growth factor transduction pathway is always active but, in certain (pathological) cases, the exogene growth factor is replaced by an oncogene product [Winstein, B.; J. Cell. Biochem. 33, 213-224 (1987) and Paul, D.; Drug Res. 35, 772-779 (1985)].
Many of the consequent steps of the signal transduction mechanism are potential sites of oncogene intervention.
Under the physiological conditions of regulated cell-division such as embriogenesis or regeneration of injured tissue, proto-oncogenes which take part in the regulation of cell-division are activated by growth factors.
In transformed cells containing activated oncogenes, the complex interaction signals and regulating mechanisms which normally appear in a tissue have stronger effects because the organism and the microenvironment tend to control the cells that "break loose".
In the present state of the art, all the tumors are monoclonal, that is, they originate from one single transformed cell. Tumor progression begins when these transformed cells become able to divide permanently in this special, "hostile" microenvironment, and the divisions result in viable variants. To be able to survive and divide in this competitive environment, neoplastic cells have to possess special division parameters and other favorable features such as resistance to immune effects. Thus, in the permanently dividing neoplastic cells, there is a signal transduction mechanism constantly "on" which induces cell division and with which inhibitory regulating signals of the environment are unable to interact [Nicolson, G. L.: Cancer Research 47, 1473-1487 (1987)].
In the present state of the art, the regulation of cell division is carried out by three main transduction mechanisms: the stimulation or inhibition of the tyrosine kinase pathway, the phospholipid metabolism protein kinase C pathway, and/or the CAMP protein kinase A pathway.
The significance of the tyrosine kinase t
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Chemical Abstracts, vol. 113, #7, p. 59, 1990, 52513r.
Chem Abstracts 110:1415326.
Chem Abstracts 111:1208922.
Boross Maria
Keri Gyorgy
Literati Peter N.
Nemeth Gabor
Szilagyi Ildiko
Carr Deborah D.
Dees Jos,e G.
Dubno Herbert
Folligen Budapest Ltd.
Myers Jonathan
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