Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-20
2004-11-16
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06818780
ABSTRACT:
FIELD OF THE TECHNIQUE
Within the therapeutic group of non-steriod antiinflammatories propionic acid derivatives occupy an outstanding place from both the therapeutic and commercial points of view.
Within this subgroup we can distinguish first of all ibuprofen (1), which was the first of a series in which we can today find naproxen (2), ketoprofen (3) and fenbufen (4) among others.
The pharmacodynamic characteristics of all these products is similar, which they present in varying degrees of antiinflammatory, antithermic, analgesic and antiplatlet activity, all of them being non-selective inhibitors of ciclooxygenases (Cox I y Cox II) (
Terapéutica farmacológica del dolor. Jesús Flores
1993
. Ed. EUNSA. Pamplona
1993
. Colección clínica de la salud. Capitulo
5, pag: 121-156.).
The structural analogy between compounds (I) and (VI) (the latter being originally found and described from a fern “
Asplenium onopteris
”) has led us to a pharmacological study of the two series of functionalised molecules starting from
in accordance with that shown in diagrams 1 and 2.
The central idea of the present invention therefore consists of obtaining a series of molecules on the basis of an adequate functionalisation using compound VI of Diagram 1 and using the corresponding derivatives of the aromatic rings, benzene and naphthalene, as functionalised syntones.
ANTECEDENTS OF THE INVENTION
The cell, the structural and functional unit of all living beings, is governed by a series of mechanisms that take decisions which in turn determine different conducts: proliferation, differentiation, activation, senescence and apoptosis. In higher organisms, there are some tissues in which there exist stem cells that generate the functional mature cells by proliferation and differentiation.
Within the systems of higher organisms, the immunological system constitutes an essential defence mechanism for preserving the viability of the individual. Multicellular beings, including humans, find themselves in an environment with a great many microorganisms that can penetrate into their interior and use them for their own growth. The immune system is capable of recognising microorganisms and triggering an effector response leading to their destruction or functional cancellation. Moreover, multicellular beings undergo errors in cell proliferation processes and they accumulate mutations that lead to the tumoral transformation of some of their components. The immune system is also capable of recognising cells that have undergone neoplastic transformation and of successfully suppressing tumoral growth and dissemination. Nevertheless, the effector capacity of the immune system can provoke inflammatory tissue alterations with lesions to parenchymatous components. These processes are accompanied by infiltration and proliferation of cells from the immune system into the tissues. Some originate in the response to infectious agents and can be acute and systemic, such as sepsis and multiorganic inflammatory response, or they can be chronic and localised such as hepatitis, tubercular arthritis, etc. Other inflammatory processes mediated by the immune system are those known as autoimmune, which are triggered in the presence of the actual components of the organism, such as rheumatoid arthritis, inflammatory disease of the digestive tract, etc. As a cellular system, the immune system can also undergo tumoral transformations giving rise to malign lymphoproliferative syndromes. The immune system can also participate in aptogenis of tissue damage by chronic processes such as some demencias and arteriosclerosis.
In the analysis of immunological responses, a distinction is drawn between natural or non-specific immunity and acquired or specific immunity. The latter is in turn divided into tumoral immunity characterised by the production of antibodies by type B lymphocytes and in cell mediation response via T lymphocytes. The immunological response consists of a complex feedback network in which autocrine and paracrine mediators, cytokins, growth factors, etc., all play a role, in addition to the mediators responsible for connection with the endocrine system and the nervous system.
An essential element in the generation of the specific immunological response is the capacity to expand lymphocyte subpopulations by antigen stimulus determined via a complex process of recognition and processing of the antigen followed by a process of presentation to the effector cell that finally generates the response. This process can be summarised by saying that the proliferation of the subpopulations corresponding to the antigen is the essential property of mature lymphocytes (Assas A K, Lichtman A H, Pober J S. Cellular and Molecular Immunology. 2nd ed. W. B. USA: Sanders Company, 1994:31-3).
The cellular mechanisms for proliferation in turn imply a complex mechanism for the reception of signals external to the cell via membrane receptors, and the transmission of those signals to the cell nucleus in order to put into operation the mitotic mechanisms which likewise imply nuclear and cytoplasmatic processes (Metezeau P H, Ronot X, Le Loan-Merliquac Q, Ratinard M H. La Citometrie en Flux. In: Le Gorde Cellulaire. Paris: MEDSI/Mc Gram Hin, 1988:77-87).
The physiological mechanisms of the immunological system must necessarily include an availability of “defensive” cells at sites where their activity is needed, hence the existence of “call” mechanisms, circulation, recruitment and adhesion.
The efficiency of the immunological system is nevertheless subject to dysfunctions which can in general terms be separated into three fundamental types, as has been stated previously. Proliferative dysfunction, that in which a cell population or subpopulation proliferates out of control, giving rise to various types of leukaemias and lymphomas and other malign and benign lymphoproliferative syndromes. Functional dysfunction therefore implies an exacerbation of the response that gives to, for example, autoimmune pathologies due to errors in antigen recognition, or a decrease in the type of response giving rise to different situations of immunosuppression. One particular case consists of pathologies or situations of inflammation (chronic or acute) with the concomitant tissue destruction and functional alteration, which can be produced in the context of systemic autoimmune diseases or specific organs as well as in response to various infectious agents.
The pathology of the immunological system is in some aspects, and paradoxically so, parallel to the course of technological and social processes. For example, there can be no doubting the close relation between the development of the AIDS pandemic with social factors such as the enormous increase in displacements, the liberalisation of customs or the unemployment situation with its consequences of margination and drug addiction (Baiter M, Cohen J. International AIDs Meeting Infects a dose of realism. Science (New Fows) 1998;281:159-60., Mann J M, Tarantola D J. HIV 1998: the global picture. Sci Am 1998;279(1):82-3., Bartlett J G, Moore R D. Improving HIV therapy. Sci Am 1998;279(1):84-7).
Another important factor of immunological pathology is the development of the chemical industry and environmental contamination which propitiates the development of allergies and immunotoxicity (Descotes J. Immunotoxicology of drugs and chemicals. Elsevier Press, 1990., Herchman E, Kimber I, Purches IFH. Immunotoxicology: Suppressive and stimulatory effect of drugs and environmental chemicals on the immune system. Arch Toxicol 1989;63:257-73).
Finally, we can mention that, at least in developed countries, the increase in life expectancy, changes in nutrition, modifications to interactions with infectious agents, the present-day life-style, have all been associated with a greater incidence and prevalence of autoimmune disease and autoimmunity with inadequate recognition of tissues, which are seen as “not one's own”, as in rheumatoid arthritis (Lugmano R, Gordon C; Bacon P. Clinical Pharmacology and modificator of autoimmunity and infl
Barrera Jaime Bermejo
De Mon Melchor Álvarez
Pablo Pivel Ranieri Juan
Silva Margarita Hernández
Consejo Superior de Investigaciones Cientificas
Klauber & Jackson
Morris Patricia L.
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