Amidino derivatives and their use as nitric oxide synthase inhib

Details Amidino derivatives and their use as nitric oxide synthase inhib Amidino derivatives and their use as nitric oxide synthase inhib

1994-06-22

1999-01-26

Shippen, Michael L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514529, 514531, 514534, 514549, 514550, 514551, 514562, 514563, 514564, 546332, 560 35, 560124, 560123, 560150, 560153, 560168, 562440, 562505, 562506, 562556, 562562, 562560, 562557, A61K 3144

Patent

active

058639314

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to amidino derivatives, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use as nitric oxide synthase inhibitors.
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 nitric oxide (NO) as a vasodilator has been known for well over 100 years and 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 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, particularly conditions which involve systemic hypotension such as toxic shock and therapy with certain cytokines.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of 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 two types of NO synthase as follows:
(i) a constitutive, Ca.sup.++ /calmodulin dependent enzyme that releases NO for response to receptor or physical stimulation.
(ii) a Ca.sup.++ independent enzyme which is induced after 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 the constitutive enzyme acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is as a cytotoxic molecule for tumour cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesised by the inducible NO synthase.
The NO synthase inhibitors proposed for therapeutic use so far, and in particular L-NMMA, are non-selective in that they inhibit both the constitutive and the inducible NO synthase. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypotension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of 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 the inducible NO synthase to a considerably greater extent than the constitutive NO synthase would be of even greater therapeutic benefit and much easier to use.
The present invention concerns amidino derivatives of the formula (I) ##STR2## and salts, and pharmaceutically acceptable esters and amides thereof, in which: alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-6 cycloalkyl group or a C.sub.3-6 cycloalkylC.sub.1-6 al

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