[1,2,3]-triazolo[4,5-d] pyrimidine...

Details [1,2,3]-triazolo[4,5-d] pyrimidine... [1,2,3]-triazolo[4,5-d] pyrimidine...

2002-05-13

2004-03-30

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

06713483

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides novel [1,2,3]-triazolo[4,5-d]pyrimidine analogues, 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 platelet-mediated occlusion or re-occlusion also compromises angioplasty.
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. 1631-30 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. 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. 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). There is a need to find P
2T
(P2Y
ADP
or P2T
AC
) antagonists as anti-thrombotic agents.
DESCRIPTION OF THE INVENTION
In a first aspect the invention provides a compound of formula (I):
wherein:
R
1
is OR
5
or CH
2
R
6
;
R
2
is alkyl C
1-6
or haloalkyl C
1-6
;
R
3
is cycloalkyl C
3-6
, optionally substituted by R
7
;
R
4
is alkyl C
1-6
;
R
5
is H or alkyl C
1-6
, optionally substituted by OH;
R
6
is OH, N
3
, or NHR
8
;
R
7
is phenyl, optionally substituted by one or more groups selected from alkyl C
1-6
, halogen, and OR
10
;
R
8
is H, alkyl C
1-6
, or COR
9
;
R
9
is alkyl C
1-6
;
R
10
is alkyl C
1-6
;
or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
Preferably the compound of formula (I) has the following stereochemistry:
Where R
3
is
the stereochemistry is preferably
Suitably R
1
is OH, O(CH
2
)
2
OH, CH
2
OH, CH
2
N
3
, CH
2
NH
2
, or CH
2
NHAc.
Suitably R
2
is n-Pr.
Suitably R
3
is cyclopropyl optionally substituted with phenyl, optionally substituted by one or more groups selected from alkyl C
1-6
, halogen and OR
10
.
Suitably R
4
is methyl.
Particularly preferred compounds of the invention include:
[1S-[1&agr;,2&agr;,3&bgr;,5&bgr;(1S*, 2R*)]]-3-(2-Hydroxyethoxy)-5-[7-[N-methyl-(2-phenylcyclopropyl)amino]-5-(propylthio)-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-[7-[N-Methyl-(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;
[1S-[1&agr;,2&agr;,3&bgr;,5&bgr;(1S*,2R*)]]-3-(Hydroxymethyl)-5-[7-[N-methyl-(2-phenylcyclopropyl)amino]-5-(propylthio)-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-[7-[N-[2-(3,4-Difluorophenyl)cyclopropyl]-N-methylamino]-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;
[1S-[1&agr;,2&bgr;,3&bgr;,4&agr;(1S*,2R*)]]4-[7-N-[2-(4Methoxyphenyl)cyclopropyl]-N-methylamino]-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3 -triol;
[1S-[1&agr;,2&agr;,3&bgr;,5&bgr;(1S*,2R*)]]-3-Azidomethyl-5-[7-[N-methyl-(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2-diol;
[1S-[1&agr;,2&agr;,3&bgr;,5&bgr;(1S*,2R*)]]-3-Aminomethyl-5-[7-[N-methyl-(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2-diol;
[1R-[1&agr;,2&agr;,3&bgr;,4&agr;(1R*,2S*)]]-N-[[2,3-Dihydroxy4-[7-[N-methyl-(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]cyclopentyl]methyl]acetamide;
or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises:
a. For compounds of formula (I) where R
1
is O(CH
2
)
2
OH, the reaction of a compound of formula(II)
where R
2
, R
3
and R
4
are defined in formula (I). P and P′ are protecting groups, for example CMe
2
, with 2-(2-bromoethoxy)-2H-tetrahydropyran, in the presence of dimethylsulphoxide and a phase transfer catalyst, such as a tetra-alkylammonium halide, preferably tetra-butylammonium bromide, and aqueous sodium hydroxide, in the presence of a water-immiscible organic solvent, preferably toluene, at a temperature of between about 50 and about 120° C., and optionally thereafter removing any protecting groups.
Protecting groups can be added and removed using known reaction conditions. The use of protecting groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).
Tetrahydropyranyl groups can be removed by the use of an acid, for example, trifluoroacetic acid, in water or aqueous acetonitrile, at a temperature between about 20 and about 50° C.
A compound of formula (II) can be prepared by reacting a compound of formula (III)
where P, P′, R
2
are defined above, with R
3
R
4
NH, in the presence of a base, preferably N,N-di-isopropylethylamine, in an inert ethereal solvent, preferably diethyl ether or tetrahydrofuran or a chlorocarbon solvent, preferably dichloromethane, at a temperature of between about 20 and about 50° C.
Where R
3
R
4
NH is
and R
7
is phenyl, the compound may be prepared as described by C. Kaiser et al, J. Org. Chem., 1962, 27, 768-773, using (1R-trans)-2-phenylcyclopropanamine, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described by L. A. Mitscher et al, J. Med. Chem., 1986, 29, 2044).
Where R
3
R
4
NH is
such compounds can be prepared by acylation of
(prepared as described in International Patent Application WO 9905143) with acetic anhyd

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