Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen bonded directly to ring carbon of the purine ring...
Reexamination Certificate
1997-06-04
2001-04-10
Berch, Mark L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen bonded directly to ring carbon of the purine ring...
Reexamination Certificate
active
06214992
ABSTRACT:
DESCRIPTION
Use of theophylline derivatives for the treatment and prophylaxis of states of shock, novel xanthine compounds and processes for their preparation.
The present invention relates to the use of theophylline derivatives having at least one ether function in the structurally modified methyl radical in the 1-position for the production of pharmaceuticals for the treatment and prophylaxis of shock disorders, to new xanthine compounds having the above mentioned substitution pattern and to processes for their preparation.
Shock is defined as an acutely occurring condition of inadequate nutritive perfusion of vital organs, which always represents the highest danger to life (Med. Mo. Pharm. 1989, 12/9: 279-282).
The causes of shock are varied. Thus cardiogenic shock is caused by primary heart failure as a result of myocardial infarct, severe cardiac arrhythmias, cardiac muscle insufficiency or other cardiac disorders, of hypovolemic shock (hemorrhagic and traumatic shock and also burn and dehydration shock) due to fluid losses or displacements, of septic shock due to systemic infiltration of microbes (gram-negative and gram-positive bacteria, fungi, viruses, protozoa etc.) or their toxins and finally of anaphylactic shock due to generalized antigen-antibody reactions. Despite this variety of causes, however, the pathogenesis and clinical picture of the various forms of shock proves to be very uniform (Pschyrembel, klinisches Wörterbuch [Clinical dictionary], Walter de Gruyter-Verlag, 255th Edition, 1986, page 1513). A disorder of the cell functions always plays a key part as a result of inadequate supply of the tissue with oxygen and substrates (ischemia) and inadequate disposal of the toxic metabolic products (Medwelt 1989, 40: 519-522). Shock is a dynamic event whose course depends substantially on the duration of ischemia. In the first, compensated shock phase, the body reacts with a neuronally and hormonally controlled centralization of the circulation, by means of which the organs situated in the center of the body (heart, brain, lungs, liver, kidneys) are protected for the time being. The clinical picture is characterized by tachycardia, still normal or only slightly lowered blood pressure, hyperventilation with respiratory alkalosis and as a rule pale, cold and clammy skin; in septic shock fever also occurs, from time to time associated with shivering fits. If the compensation mechanisms are exhausted, the capillary perfusion of the central organs is also impaired to an increasing extent. This leads into the second, decompensated shock phase, which is characterized by progressive cell death and loss of function. The occurrence of shock is irreversible. The drastic increase in the vascular permeability in the microcirculation area leads through loss of fluid to a rise in the hematocrit, to interstitial edemas and to the release of mediators which, inter alia, cause a disseminated intravasal coagulation, for example in the form of a consumptive coagulopathy with obturating fibrin thrombi in the terminal vascular system. The constant reduction in cardiac output and blood pressure leads to complete circulatory collapse. At the end of the shock cascade death results due to acute failure of the heart, liver, kidneys or lungs (ARDS=Acute Respiratory Distress Syndrome) or due to multi-organ failure (MOF), if several organs simultaneously lose their function.
Conventional therapy is orientated to clinical symptomatology and includes immediate measures for eliminating the vital threat, such as volume substitution, artificial respiration for the prophylaxis of ARDS, administration of vasoactive pharmaceuticals to support the circulation, analgesia and sedation, correction of the disorders in the acid-based balance, heparin administration to avoid a consumptive coagulopathy and treatment with corticosteriods to reduce membrane permeability. Depending on the cause of shock, further therapeutic measures are indicated, for example operation and hemostasis in hemorrhagic shock, elimination of the focus of infection and antibiotic therapy in septic shock and possible treatment by means of cardiac pacemaker and aortal balloon counterpulsation in cardiogenic shock. In spite of all these therapeutic measures, the result of treatment, however, remains extremely unsatisfactory. Thus the mortality rates, for example, in cardiogenic shock on account of a cardiac infarct is 90% and in septic shock, the globally most frequent cause of death in intensive-care units, is more than 50%.
This makes understandable the demand by clinics for a more causally aligned therapy concept, which allows as early an interruption of the shock cascade as possible and thus distinctly improves the chance of survival. Promising starting points for this are offered by the complex pathophysiological processes which underlie the progressive course of the shock disorder. According to present knowledge, a number of mediator systems and inflammatorily competent cells are activated by the respective pathological stimulus both in septic and aseptic forms of shock (N. Engl. J. Med. 1993, 328/20: 1471-1477) and by this means an endothelial inflammation with diffuse inflammatory processes is caused, which is also designated (J. Amer. med. Ass. 1992, 268: 3452) as SIRS (Systemic Inflammatory Response Syndrome). At the center of this syndrome is the generalized pathological interaction between activated granulocytes and endothelial cells via complementary adhesion molecules which, with progressive vascular damage, leads to disorders in the microcirculation and organ damage with increasing functional impairment and finally ends up in a multi-organ failure. With triggering of the vascular wall-associated inflammatory processes by the granulocytic endothelial interaction, septic and aseptic events follow a common pathogenetic final route with the development of shock. Moreover, there are sound indications for the fact that in the course of aseptic forms of shock an invasion of bacteria or their toxic products into the blood stream described as bacterial translocation occurs via an initially nonmicrobally triggered barrier disorder in the lung and, in particular, gastrointestinal tract, so that aseptic and septic events overlap (Medwelt
1989, 40: 525-532).
More recent attempts at a causal therapeutic intervention now aim at specific interventions in the disease process supported by inflammatory mediators, in order to interrupt the pathological signal chain as early as possible and thus prevent the development of organ damage in time. In large-scale clinical studies, for example, murine and human monoclonal antibodies against the endotoxin (LP=Lipopolysaccharide) from the cell wall of gram-negative bacteria, humanized recombinant and both murine and human monoclonal antibodies against the cytokine TNF (tumor necrosis factor), soluble TNF receptors prepared by genetic engineering and other TNF binding proteins of the physiologically occurring interleukin-1 receptor antagonist Antril (IL-1-RA) produced by recombination as well as the bradykinin antagonist Bradycor have been investigated without a therapeutic breakthrough becoming apparent until now (Scrip Magazine, December 1994: 50-52). The intensive search for effective blockers of the extremely complex disease event therefore continues undiminished, the knowledge increasingly gaining acceptance that the switching-off of a specific mediator of the wide-ranging signal cascade only has low prospects of success and that therapeutic advances are most likely to be expected from a multifunctional intervention, be it just by combination of various selectively active pharmaceuticals or advantageously by a monopharmacon with as wide a pharmacological spectrum of action as possible.
For the testing of preparations for antishock action, various experimental animal models have been developed. A particularly practicable readily standardized and predictive model (Proc. Natl. Acad. Sci. U.S.A. 1979, 76/11: 5939-5943) is endotoxin lipoplysaccharide (LPS)-induced shock on C
Anagnostopulos Hiristo
Defossa Elisabeth
Gebert Ulrich
Grome John J.
Heinelt Uwe
Berch Mark L.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Hoechst Aktiengesellschaft
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