Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-19
2001-10-02
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212080, C514S228800, C514S258100, C540S488000, C540S524000, C544S063000, C544S254000
Reexamination Certificate
active
06297232
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 (SHT, 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;
X is OH or NHR
3
;
R
1
is C
1-6
-alkyl, C
3-8
-cycloalkyl or a phenyl group, each group being optionally substituted by one or more halogen atoms and/or OR
4
, NR
4
R
5
, C
1-6
-thioalkyl and/or C
1-6
-alkyl (itself optionally substituted by one or more halogen atoms);
R
2
is C
1-8
-alkyl or C
2-8
-alkenyl each of which is optionally substituted by one or more halogen atoms and/or OR
4
, NR
4
R
5
, C
1-6
-thioalkyl, C
3-8
-cycloalkyl, aryl and/or C
1-6
-alkyl groups; or R
2
is a C
3-8
-cycloalkyl group optionally substituted by one or more halogen atoms and/or OR
4
, NR
4
R
5
, C
1-6
-thioalkyl, phenyl and/or C
1-6
-alkyl groups; the optional phenyl substituent being further optionally substituted by one or more halogen atoms and/or NO
2
, C(O)R
4
, OR
4
, NR
4
R
5
, C
1-6
-thioalkyl and/or C
1-6
-alkyl groups;
R
3
is hydrogen or C
1-6
-alkyl substituted by one or more hydroxy and/or phenyl groups and optionally by one or more halogen atoms, wherein the phenyl group is substituted by one or more hydroxy groups and optionally substituted by one or more halogen atoms and/or NO
2
, C(O)R
4
, OR
4
, NR
4
R
5
, C
1-6
-thioalkyl and/or C
1-6
-alkyl groups, or R
3
is a C
1-6
-alkyl group substituted by a C(O)NR
4
R
5
or a COOH group and optionally by one or more halogen atoms and/or OR
4
, C(NH)NR
4
R
5
, C(O)NR
4
R
5
, phenyl and/or C
1-6
-alkyl groups, wherein the alkyl group is optionally substituted by one or more hydroxy and/or phenyl groups and wherein the phenyl group is optionally substituted as defined above for R
3
; or
R
3
is a lactam ring of formula (i):
wherein Q is a (CH
2
)
m
moiety wherein m is 1, 2 or 3, Z is O, C(O) or CH
2
;
R
4
and R
5
each independently represent hydrogen, phenyl or a C
1-6
-alkyl wherein the alkyl group is optionally substituted by one or more phenyl groups;
or a salt thereof.
Alkyl groups, whether alone or as part of another group, can be straight chained or branched.
Suitably R
1
is C
1-6
-alkyl, C
3-8
-cycloalkyl or a phenyl group, each group being optionally substituted by one or more halogen atoms and/or OR
4
, NR
4
R
5
, C
1-6
-thioalkyl and/or C
1-6
-alkyl (itself optionally substituted by one or more halogen atoms). Preferably R
1
is C
1-4
-alkyl, C
4-8
-cycloalkyl or a phenyl group optionally substituted by one or more halogen atoms or by a CF
3
group. More preferably R
1
is propyl, cyclohexyl or phenyl optionally substituted by two chlorine atoms or by a CF3 group. Most preferably R
1
is propyl or phenyl substituted in the 4-position by CF
3
.
Suitably R
2
is C
1-8
-alkyl or C
2-8
-alkenyl each of which is optionally substituted by one or more halogen atoms and/or OR
4
, NR
4
R
5
, C
1-6
-thioalkyl, C
3-8
-cycloalkyl, aryl and/or C
1-6
-alkyl groups; or R
2
is a C
3-8
-cycloalkyl group optionally substituted by one or more halogen atoms and/or OR
4
, NR
4
R
5
, C
1-6
-thioalkyl, phenyl and/or C
1-6
-alkyl groups; the optional phenyl substituent being further optionally substituted by one or more halogen atoms and/or NO
2
, C(O)R
4
, OR
4
, NR
4
R
5
, C
1-6
-thioalkyl and/or C
1-6
-alkyl groups. By the term ‘aryl’ is meant phenyl and naphthyl. Preferably R
2
is C
1-6
-alkyl optionally substituted by phenyl or C
1-6
-thioalkyl or R
2
is a C
3-8
-cycloalkyl group optionally substituted by phenyl. Most preferably R
2
is butyl or 2-phenylcyclopropyl.
Suitably X is OH or NHR
3
where R
3
is hydrogen or C
1-6
-alkyl substituted by one or more hydroxy and/or phenyl groups and optionally by one or more halogen atoms, wherein the phenyl group is substituted by one or more hydroxy groups and optionally substituted by one or more halogen atoms and/or NO
2
, C(O)R
4
, OR
4
, NR
4
R
5
, C
1-6
-thioalkyl and/or C
1-6
-alkyl groups, or R
3
is a C
1-6
-alkyl group substituted by a C(O)NR
4
R
5
or a COOH group and optionally by one or more halogen atoms and/or OR
4
, C(NH)NR
4
R
5
, C(O)NR
4
R
5
. phenyl and/or C
1-6
-alkyl groups, wherein the alkyl group is optionally substituted by one or more hydroxy and/or phenyl groups and wherein the phenyl group is optionally substituted as defined above, or R
3
is a lactam ring of formula (i).
Preferably R
3
is hydrogen or C
1-6
-alkyl substituted by hydroxy and optionally by C(O)NH
2
or di-fluoro; C
1-6
-alkyl substituted by C(O)NH
2
; C
1-6
-alkyl substituted by C(O)NHMe; C
1-6
-alkyl substituted by hydroxyphenyl and optionally by C(O)NR
4
R
5
or R
3
is a lactam ring of formula:
Most preferably R
3
is hydrogen.
Particularly preferred compounds of the invention include those exemplified herein, both in free base form and as pharmaceutically acceptable salts thereof.
According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises
(a) deprotecting a compound of formula (II):
wherein R
1
and R
2
are as defined above, P
1
is a protecting g
Bonnert Roger Victor
Ingall Anthony Howard
Springthorpe Brian
Willis Paul Andrew
Astrazeneca AB
McKenzie Thomas C.
Nixon & Vanderhye
Shah Mukund J.
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