Triazolo [4,5-d]pyrimidine compounds, their use as medicaments,

Details Triazolo [4,5-d]pyrimidine compounds, their use as medicaments, Triazolo [4,5-d]pyrimidine compounds, their use as medicaments,

1998-09-30

2000-12-05

Powers, Fiona T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

544254, A61K 31505, C07D48704

Patent

active

061567566

DESCRIPTION:

BRIEF SUMMARY
The present invention provides new triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation. Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty is also compromised by platelet mediated occlusion or re-occlusion.
A number of converging pathways lead to platelet aggregation. Whatever the initial stimulus, the final common event is a cross linking of platelets by binding of fibrinogen to a membrane binding site, glycoprotein IIb/IIIa (GPIIb/IIa). The high anti-platelet efficacy of antibodies or antagonists for GPIIb/IIIa is explained by their interference with this final common event. However, this efficacy may also explain the bleeding problems that have been observed with this class of agent. Thrombin can produce platelet aggregation largely independently of other pathways but substantial quantities of thrombin are unlikely to be present without prior activation of platelets by other mechanisms. Thrombin inhibitors such as hirudin are highly effective anti-thrombotic agents, but again may produce excessive bleeding because they function as both anti-platelet and anti-coagulant agents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L. et. al. (1994) Circulation 90, pp.1638-1642).
It has been found that ADP acts as a key mediator of thrombosis. A pivotal role for ADP is supported by the fact that other agents, such as adrenaline and 5-hydroxytryptamine (5HT, serotonin) will only produce aggregation in the presence of ADP. The limited anti-thrombotic efficacy of aspirin may reflect the fact that it blocks only one source of ADP which is that released in a thromboxane-dependent manner following platelet adhesion (see e.g. Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 81-106; Antiplatelet Trialists Collaboration (1994), Br. Med. J. 308, pp.159-168). Aspirin has no effect on aggregation produced by other sources of ADP, such as damaged cells or ADP released under conditions of turbulent blood flow. ADP-induced platelet aggregation is mediated by the P.sub.2T -receptor subtype uniquely located on the platelet membrane. Recently it has been shown that antagonists at this receptor offer significant improvements over other anti-thrombotic agents. Accordingly there is a need to find P.sub.2T -antagonists as anti-thrombotic agents.
It has now been found that a series of triazolo[4,5-d]pyrimidine derivatives are P.sub.2T -antagonists. In a first aspect the invention therefore provides a compound of formula (I): ##STR1## wherein: R.sup.1 is a C.sub.1-6 alkyl, C.sub.3-8 -cycloalkyl or a phenyl group, each group being optionally substituted by one or more substituents selected from halogen, OR.sup.8, NR.sup.9 R.sup.10, SR.sup.11 or C.sub.1-6 alkyl (itself optionally substituted by one or more halogen atoms); substituents selected from halogen, OR.sup.8, NR.sup.9 R.sup.10, SR.sup.11, C.sub.3-8 -cycloalkyl, aryl (optionally substituted by one or more alkyl groups and/or halogen atoms), or C.sub.1-6 -alkyl; or R.sup.2 is a C.sub.3-8 -cycloalkyl group optionally substituted by one or more substituents selected from halogen, OR.sup.8, NR.sup.9 R.sup.10, SR.sup.11, C.sub.1-6 -alkyl or phenyl (the latter two being optionally substituted by one or more substituents selected from halogen, NO.sub.2, C(O)R.sup.8, OR.sup.8, SR.sup.11, NR.sup.12 R.sup.13, phenyl and C.sub.1-6 -alkyl which is optionally substitu

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