Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-25
2002-04-09
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S254000, C540S600000
Reexamination Certificate
active
06369064
ABSTRACT:
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, aryl or a thienyl 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, C
2-8
alkenyl or C
3-8
cycloalkyl each of which may be optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
, C
1-6
alkyl, C
3-8
cycloalkyl, pyridyl or aryl (the latter two of which may be optionally substituted by one or more substitutents selected from halogen, OR
20
, C(O)R
11
, NR
14
C(O)R
15
, NR
16
SO
2
R
17
, SO
2
NR
18
R
19
, nitro, NR
12
R
13
, SR
11
, methylenedioxy or C
1-6
alkyl which is optionally substituted by one or more halogen atoms);
R
3
and R
4
are both hydroxy;
R
5
is hydrogen or C
1-6
alkyl; R
6
is C
1-6
alkyl, optionally substituted by one or more groups selected from C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, halogen, OR
21
, C
3-6
cycloalkyl, or R
6
is C
3-6
cycloalkyl, or R
6
is —A-phenyl or —A-pyridyl each of which may be optionally substituted by one or more groups selected from C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, halogen, OC
1-6
alkyl, C
3-6
cycloalkyl, or methylenedioxy; or R
5
R
6
together with the nitrogen atom to which they are attached for a 5 to 7-membered saturated ring optionally substituted by C
1-6
alkyl;
A is a bond or C
1-6
alkyl;
R
8
is hydrogen, C
1-6
alkyl (which may be optionally substituted by one or more halogen atoms) or aryl (which may be optionally substituted by one or more substituents selected from halogen, nitro, C(O)R
11
, OR
20
, SR
11
, NR
12
R
13
, NR
14
C(O)R
15
, NR
16
SO2R
17
, SO2NR
18
R
19
);
R
9
is hydrogen, C
1-6
alkyl (which may be optionally substituted by one or more halogen atoms) or aryl (which may be optionally substituted by one or more substituents selected from halogen, nitro, C(O)R
20
, OR
20
, SR
11
, NR
12
R
13
, NR
14
C(O)R
15
, NR
16
SO
2
R
17
, SO
2
NR
18
R
19
);
R
10
is hydrogen, C
1-6
alkyl or C(O)C
1-6
alkyl;
R
12
and R
13
are independently hydrogen, C
1-6
alkyl or together with the nitrogen atom to which they are attached form a 4- to 8-membered ring;
R
15
is C
1-6
alkyl or phenyl;
R
11
, R
14
and R
16
are independently hydrogen or C
1-6
alkyl;
R
17
is C
1-6
alkyl or phenyl;
R
18
and R
19
are independently hydrogen, C
1-6
alkyl or phenyl;
R
20
is hydrogen, phenyl or C
1-6
alkyl (which may be optionally substituted by halogen);
R
21
is hydrogen or C
1-6
alkyl, provided that when R
21
is H, R
5
must be 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. Aryl groups include phenyl and naphthyl groups. Acyl groups include C(O)C
1-6
alkyl such as acetyl and 1-oxopropyl.
Suitably R
1
is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
-cycloalkyl, aryl or a thienyl 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
1-6
alkyl, thienyl, or trifluoromethylphenyl. More preferably R
1
is methyl, propyl, propenyl or thienyl.
Suitably R
2
is C
1-8
alkyl, C
2-8
alkenyl or C
3-8
cycloalkyl each of which may be optionally substituted by one or more substituents selected from halogen, OR
8
, NR
9
R
10
, SR
11
, C
1-6
alkyl, C
3-8
cycloalkyl, pyridyl or aryl (the latter two of which may be optionally substituted by one or more substituents selected from halogen, OR
20
, C(O)R
11
, NR
14
C(O)R
15
, NR
16
SO
2
R
17
, SO
2
NR
18
R
19
, nitro, NR
12
R
13
, SR
11
, methylenedioxy or C
1-6
alkyl which is optionally substituted by one or more halogen atoms); where R
8
, R
9
, R
10
, R
11
, R
14
, R
15
, R
16
, R
17
, R
18
and R
19
are as defined above. Preferably R
2
is C
1-6
alkyl or a C
3-8
-cycloalkyl group optionally substituted by phenyl which itself can be optionally substituted by halogen, OR
8
or C
1-6
-alkyl. More preferably R
2
is cyclopropyl optionally substituted by phenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-methylphenyl or 4-fluorophenyl.
Suitably R
5
is hydrogen or C
1-6
alkyl; R
6
is C
1-6
alkyl, optionally substituted by one or more groups selected from C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, halogen, OR
21
, C
3-6
cycloalkyl, or R
6
is C
3-6
cycloalkyl, or R
6
is -A-phenyl or -A-pyridyl each of which may be optionally substituted by one or more groups selected from C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, halogen, OC
1-6
alkyl, C
3-6
cycloalkyl, or methylenedioxy; or R
5
and R
6
together with the nitrogen atom to which they are attached for a 5 to 7-membered saturated ring optionally substituted by
Brown Roger
Pairaudeau Garry
Springthorpe Brian
Thom Stephen
Willis Paul
AstraZeneca AB
Nixon & Vanderhye
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