Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1996-12-27
1999-03-30
Barts, Samuel
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514550, 560150, 562556, A61K 31195
Patent
active
058890564
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB95/01378 filed Jun. 14, 1995.
The present invention relates to amidino sulphoxide and sulphone derivatives, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use as selective inhibitors of inducible nitric oxide synthase.
It has been known since the early 1980's that the vascular relaxation brought about by acetylcholine is dependent on the presence of the endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of glyceryl trinitrate as a vasodilator has been known for well over 100 years and it is now known that NO is the active component of amylnitrite, glyceryltrinitrite and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesised from the amino acid L-arginine by the enzyme NO synthase.
NO is the endogenous stimulator of the soluble guanylate cyclase enzyme and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al, Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al, Pharmacological Reviews, 43, 109-142 (1991)). It is now thought that excess NO production may be involved in a number of conditions, including conditions which involve systemic hypotension such as septic shock and therapy with certain cytokines, and many inflammatory diseases such as arthritis.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, N.sup.G -monomethyl-L-arginine (L-NMMA), and the therapeutic use of L-NMMA for the treatment of septic (toxic) shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three isoenzymes of NO synthase (reviewed in Knowles and Moncada, Biochem. J. (1994) 298, 249-258) as follows: present in vascular endothelial cells, and that releases NO in response to receptor or physical stimulation. in the brain and some peripheral nervous systems, that releases NO in response to receptor or physical stimulation. activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible NO synthase synthesises NO for long periods.
The NO released by eNOS and nNOS acts as a transduction mechanism underlying several physiological responses. The NO produced by iNOS acts as a cytotoxic molecule for invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation, vascular leakage and tissue damage, may result largely from the effects of NO synthesised by iNOS.
The NO synthase inhibitors proposed for therapeutic use so far, such as L-NMMA and nitroarginine, are non-selective in that they inhibit all the NO synthase isoenzymes. Use of such a non-selective NO synthase inhibitor requires that great care is taken in order to avoid the potentially serious consequences of over-inhibition of the eNOS including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of septic and/or toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, whilst non-selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit iNOS to a considerably greater extent than eNOS would be of even greater therapeutic benefit and much easier to use.
Patent application PCT/GB9202387 discloses a group o
Clark Helen Alice Rebecca
Davies Patricia Ifeyinwa
Drysdale Martin James
Franzmann Karl Witold
Hodson Harold Francis
Barts Samuel
Glaxo Wellsome Inc.
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