Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-21
2001-06-26
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S254000
Reexamination Certificate
active
06251910
ABSTRACT:
This application is a 371 National Stage application of PCT/SE90/01393, filed Jul. 15, 1998, which claims priority from Swedish applications 9702773-4, filed Jul. 22, 1997 and 9702775-9, filed Jul. 22, 1997.
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/IIIa). 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
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
2T
-antagonists as anti-thrombotic agents.
It has now been found that a series of triazolo[4,5-d]pyrimidine derivatives are P
2T
-receptor antagonists. In a first aspect the invention therefore provides a compound of formula (I):
wherein:
R
1
is a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
-cycloalkyl or a phenyl group, each group being optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
or C
1-6
alkyl (itself optionally substituted by one or more halogen atoms);
R
2
is C
1-8
alkyl optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
, C
3-8
-cycloalkyl, aryl (optionally substituted by one or more alkyl groups and/or halogen atoms), or C
1-6
-alkyl; or R
2
is a C
3-8
-cycloalkyl group optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
, C
1-6
-alkyl or phenyl, the latter two groups being optionally substituted by one or more substituents selected from halogen, NO
2
, C(O)R
8
, OR
8
, SR
11
, NR
12
R
13
, a fused 5- or 6-membered saturated ring containing one or two oxygen atoms, phenyl or C
1-6
-alkyl the latter two groups being optionally substituted by OR
8
, NR
9
R
10
or one or more halogen atoms;
one of R
3
and R
4
is hydroxy and the other is hydrogen, hydroxy or NR
9
R
10
;
R is a group (CR
5
R
6
)
m
OR
7
where m is 0 or 1, R
5
and R
6
are independently hydrogen, C
1-6
alkyl or phenyl the latter two groups being optionally substituted by halogen, and R
7
is hydrogen, C
1-6
alkyl or (CR
5
R
6
)
n
R
14
where R
5
and R
6
are as defined above, n is 1 to 3 and R
14
is COOH, OR
15
, NR
16
R
17
or CONR
16
R
17
;
or R is a C
1-4
alkyl or C
2-4
alkenyl group, each of which is substituted by one or more groups selected from ═S, ═O, ═NR
20
or OR
21
and optionally substituted by one or more groups selected from halogen, C
1-4
alkyl, phenyl, SR
21
, NO
2
or NR
22
R
23
(where R
21
, R
22
and R
23
are independently hydrogen, C
1-4
alkyl or phenyl; R
20
is OR
24
or NR
25
R
26
, where R
24
is hydrogen, C
1-4
alkyl or phenyl, and R
25
and R
26
are independently hydrogen, C
1-4
alkyl, aryl, C
1-6
acyl, arylsulphonyl or arylcarbonyl);
R
8
is hydrogen, C
1-6
alkyl optionally substituted by halogen or R
8
is phenyl optionally substituted by one or more substituents selected from halogen, NO
2
, C(O)R
6
, OR
6
, SR
9
, NR
10
R
11
;
R
9
, R
10
and R
11
are independently hydrogen or C
1-6
alkyl;
R
12
and R
13
are independently hydrogen, C
1-6
alkyl, acyl, alkyl sulfonyl optionally substituted by halogen, or phenyl sulfonyl optionally substituted by C
1
-C
4
alkyl; and
R
15
, R
16
and R
17
are independently hydrogen or C
1-6
alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
Alkyl groups, whether alone or as part of another group, can be straight chained or branched. Compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The invention also extends to any tautomeric forms and mixtures thereof.
Preferably the compound of formula (I) has the following stereochemistry:
Suitably R
1
is a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkenyl, C
3-8
-cycloalkyl or a phenyl group, each group being optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
or C
1-6
alkyl (itself optionally substituted by one or more halogen atoms). Preferably R
1
is C
1-4
alkyl or phenyl each of which can be substituted by trifluoromethyl. More preferably R
1
is propyl, butyl, trifluoromethylphenyl or 3,3,3,-trifluoropropyl.
Suitably R
2
is C
1-8
alkyl optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
, C
3-8
-cycloalkyl, aryl (optionally substituted by one or more alkyl groups and/or halogen atoms), or C
1-6
-alkyl; or R
2
is a C
3-8
-cycloalkyl group optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
, C
1-6
-alkyl or phenyl, the latter two groups being optionally substituted by one or more substituents selected from halogen, NO
2
, C(O)R
8
, OR
8
, SR
11
, NR
12
R
13
, a fused 5- or 6-membered saturated ring containing one or two oxygen atoms, phenyl or C
1-6
-alkyl the latter two groups being optionally substituted by OR
8
, NR
9
R
10
or one or more halogen atoms. Aryl groups include phenyl and naphthyl groups. Acyl groups include C(O)C
1-6
alkyl such as acetyl and 1-oxopropyl. Preferably R
2
is C
1-6
alkyl or a C
3-8
-cycloalkyl group optionally substituted by phenyl. More preferably R
2
is butyl or cyclopropyl optionally substituted by phenyl, the phenyl group itself being optionally substituted by one or more halogen, C
3-8
alkyl, alkoxy, phenoxy or phenyl groups.
Su
Guile Simon
Ingall Anthony
Springthorpe Brian
Willis Paul
AstraZeneca UK Limited
McKenzie Thomas
Nixon & Vanderhye
Shah Mukund J.
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