Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-08
2003-02-25
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
Reexamination Certificate
active
06525060
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides new triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation.
BACKGROUND OF THE INVENTION
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) IIIa Investigators (1994)
Circulation
90, pp. 1631-1637; Neuhaus K. L. et. al. (1994)
Circulation
90, pp. 1638-1642).
It has been found that adenosine 5′-diphosphate (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 and 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 located on the platelet membrane. The P
2T
receptor (also known as P2Y
ADP
or P2T
AC
) is primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor which is as yet uncloned. The pharmacological characteristics of this receptor have been described, for example, in the references by Humphries et al.,
Br. J. Pharmacology (
1994), 113, 1057-1063, and Fagura et al.,
Br. J. Pharmacology (
1998) 124, 157-164. Recently it has been shown that antagonists at this receptor offer significant improvements over other anti-thrombotic agents (see
J. Med. Chem.
(1999) 42, 213). Accordingly there is a need to find further P
2T
(P2Y
ADP
or P2T
AC
) antagonists as anti-thrombotic agents.
International Patent Application WO 9905143 discloses generically a series of triazolo[4,5-d]pyrimidine compounds having activity as P
2T
(P2Y
ADP
or P2T
AC
) antagonists. It has now been found that certain compounds within the scope of International Patent Application WO 9905143 but not specifically disclosed therein exhibit high potency combined with surprisingly high metabolic stability and bioavailibility, such that the predicted therapeutic dose for prolonged inhibition of aggregation in man shows advantage.
DESCRIPTION OF THE INVENTION
In a first aspect the invention therefore provides a compound of formula (I):
wherein:
R
1
is C
3-5
alkyl optionally substituted by one or more halogen atoms;
R
2
is a phenyl group, optionally substituted by one or more fluorine atoms;
R
3
and R
4
are both hydroxy;
R is XOH, where X is CH
2
, OCH
2
CH
2
or a bond;
or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
provided that:
when X is CH
2
or a bond, R
1
is not propyl.
when X is CH
2
and R
1
is CH
2
CH
2
CF
3
, butyl or pentyl, the phenyl group at R
2
must be substituted by fluorine.
when X is OCH
2
CH
2
and R
1
is propyl, the phenyl group at R
2
must be substituted by fluorine.
Alkyl groups, whether alone or as part of another group are straight chained and fully saturated.
Suitably R
1
is a C
3-5
alkyl optionally substituted by one or more fluorine atoms. Preferably R
1
is C
3-5
alkyl optionally substituted on the terminal carbon by three fluorine atoms. More preferably R
1
is 3,3,3,-trifluoropropyl, butyl or propyl.
Suitably R
2
is phenyl or phenyl substituted by one or more fluorine atoms. Preferably R
2
is phenyl, 4-fluorophenyl or 3,4-difluorophenyl.
Suitably R is XOH where X is CH
2
, OCH
2
CH
2
or a bond.
Preferably R is CH
2
OH or OCH
2
CH
2
OH.
Particularly preferred compounds include:
[1R-[1&agr;,2&agr;,3&bgr;(1R*,2S*),5&bgr;]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
[1R-[1&agr;,2&agr;,3&bgr;(1R*,2S*),5&bgr;]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
[1S-(1&agr;,2&agr;,3&bgr;(1S*,2R*),5&bgr;]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;
[1R-[1&agr;,2&agr;,3&bgr;(1R*,2S*),5&bgr;]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
[1S-[1&agr;,2&bgr;,3&bgr;,4&agr;(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol;
[1S-(1&agr;,2&agr;,3&bgr;(1S*,2R*),5&bgr;)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;
[1S-[1&agr;,2&agr;,3&bgr;,5&bgr;(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol [1S-[1&agr;,2&bgr;,3&bgr;,4&agr;(1S*, 2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;
[1S-[1&agr;,2&agr;,3&bgr;(1S*,2R*),5&bgr;]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol;
and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts.
According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises:
(a) reacting a compound of formula (II):
where R, R
1
, R
3
and R
4
are as defined in formula (I), or are protected derivatives thereof, or R
3
and R
4
together form a bond in the 5-membered ring, o
Guile Simon
Hardern David
Ingall Anthony
Springthorpe Brian
Willis Paul
Astrazeneca UK Limited
Ford John M.
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