Aminoacid derivatives as no synthase inhibitors

Details Aminoacid derivatives as no synthase inhibitors Aminoacid derivatives as no synthase inhibitors

1996-03-18

1999-02-23

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

514538, 514619, 514620, 514438, 514447, 514472, 514481, 514345, 514352, 514369, 514370, 562439, 560 34, 564163, 564164, 549 68, 549 76, 549475, 549476, 549478, 549479, 546290, 546296, 546297, 546304, 546312, 548182, 548183, 548184, 548194, A61K 31195, A61K 3138, C07C24100, C07C23300

Patent

active

058744720

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/GB94/01325 Jun. 20, 1994.
The present invention relates to amino acid derivatives which contain an aromatic ring, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use as selective inhibitors of 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 nitric oxide (NO) as a vasodilator has been known for well over 100 years and NO is the active component of amyl nitrite, 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 three types of NO synthase isoenzymes as follows: endothelium, that releases NO in response to receptor or physical stimulation; brain, that releases NO in response to receptor or physical stimulation; 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 isoenzyme acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible isoenzyme acts as a cytoxic 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, such as L-NMMA and nitroarginine, are non-selective in that they inhibit both the constitutive and the inducible NO synthase. Use of such a non-selective NO synthase inhibitor would require great care to be taken in order to avoid the potentially serious consequences of over-inhibition of the other isoenzymes. 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 one NO-synthase isoenzyme to a considerably greater extent compared to one or both of the other isoenzymes would be of even greater therapeutic benefit and much easier to use.
Patent application PCT/GB9202387 discloses a class of amidino derivatives of the formula (0) ##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 cycloalkyl C.sub.1-6 alkyl group; and which may optionally be substituted by one or more C.sub.1-3 alkyl groups, 1 or 2 and X is S(O).sub.x where x is 0, 1 or 2, or X is O or NR.sup.2 where R.sup.

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