U.S. patent application number 13/423848 was filed with the patent office on 2013-03-21 for trisubstituted triazolopyrimidines for use in platelet aggregation inhibition.
This patent application is currently assigned to AstraZeneca. The applicant listed for this patent is Simon Guile, David Hardern, Anthony Ingall, Brian Springthorpe, Paul Willis. Invention is credited to Simon Guile, David Hardern, Anthony Ingall, Brian Springthorpe, Paul Willis.
Application Number | 20130072503 13/423848 |
Document ID | / |
Family ID | 26663448 |
Filed Date | 2013-03-21 |
United States Patent
Application |
20130072503 |
Kind Code |
A1 |
Hardern; David ; et
al. |
March 21, 2013 |
TRISUBSTITUTED TRIAZOLOPYRIMIDINES FOR USE IN PLATELET AGGREGATION
INHIBITION
Abstract
The invention provides new triazolo[4,5-d]pyrimidine compounds,
their use as medicaments, compositions containing them and
processes for their preparation.
Inventors: |
Hardern; David; (Sutton
Bonington, GB) ; Ingall; Anthony; (Loughborough,
GB) ; Springthorpe; Brian; (Loughborough, GB)
; Willis; Paul; (West Bridgford, GB) ; Guile;
Simon; (Loughborough, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hardern; David
Ingall; Anthony
Springthorpe; Brian
Willis; Paul
Guile; Simon |
Sutton Bonington
Loughborough
Loughborough
West Bridgford
Loughborough |
|
GB
GB
GB
GB
GB |
|
|
Assignee: |
AstraZeneca
London
GB
|
Family ID: |
26663448 |
Appl. No.: |
13/423848 |
Filed: |
March 19, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13137125 |
Jul 21, 2011 |
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13423848 |
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12591395 |
Nov 18, 2009 |
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13137125 |
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12149771 |
May 8, 2008 |
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12591395 |
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11711838 |
Feb 28, 2007 |
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12149771 |
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11230493 |
Sep 21, 2005 |
7250419 |
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11711838 |
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10323655 |
Dec 20, 2002 |
6974868 |
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11230493 |
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09508195 |
Mar 8, 2000 |
6525060 |
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10323655 |
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Current U.S.
Class: |
514/261.1 ;
544/254 |
Current CPC
Class: |
A61K 31/519 20130101;
A61P 7/00 20180101; A61P 25/00 20180101; A61P 7/02 20180101; A61P
43/00 20180101; C07D 239/48 20130101; A61P 35/02 20180101; A61P
11/00 20180101; C07D 487/04 20130101; A61P 1/04 20180101; A61P
13/12 20180101; A61P 9/00 20180101; A61P 29/00 20180101; A61P 9/10
20180101; C07C 211/40 20130101; A61P 35/00 20180101; A61P 25/06
20180101 |
Class at
Publication: |
514/261.1 ;
544/254 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 4, 1998 |
SE |
9804211-2 |
Apr 9, 1999 |
SE |
9901271-8 |
Dec 2, 1999 |
SE |
PCT/SE99/02256 |
Claims
1. A compound of formula (I) ##STR00014## wherein: R.sup.1 is
C.sub.3-5 alkyl optionally substituted by one or more halogen
atoms; R.sup.2 is a phenyl group, optionally substituted by one or
more fluorine atoms; R.sup.3 and R.sup.4 are both hydroxy; R is
XOH, where X is CH.sub.2, OCH.sub.2CH.sub.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.sub.2 or a bond, R.sup.1
is not propyl, when X is CH.sub.2 and R.sup.1 is CH.sub.2CH.sub.2
CF.sub.3, butyl or pentyl, the phenyl group at R.sup.2 must be
substituted by fluorine, when X is OCH.sub.2CH.sub.2 and R.sup.1 is
propyl, the phenyl group at R.sup.2 must be substituted by
fluorine.
2. A compound according to claim 1 in which R.sup.1 is
3,3,3,-trifluoropropyl, butyl or propyl.
3. A compound according to claim 1 in which R.sup.2 is phenyl or
4-fluorophenyl or 3,4-difluorophenyl.
4. A compound according to claim 1 in which R is CH.sub.2OH or
OCH.sub.2CH.sub.2 OH.
5. A compound according to claim 1 which is:
[1R-[.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-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.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-3-[7-[[2-(3,4-Difluorop-
henyl)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.alpha.,2.alpha.,3.beta.(1S*,2R*),5]]-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.alpha.,2.alpha.,3.beta.(1R*,2S*),5p]]-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.alpha.,2.beta.,3.beta.,4.alpha.(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.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[[2-(3,4-Difluorop-
henyl)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.alpha.,2.alpha.,3.beta.,5.beta.(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[-
7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-tri-
azolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol
[1S-[1.alpha.,2.beta.,3.beta.,4.alpha.(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.alpha.,2.alpha.,3.beta.(1S*,2R*),5]]-3-[5-(Butylthio)-7-[(2-phenyl-
cylopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethox-
y)-cyclopentane-1,2-diol; or pharmaceutically acceptable salts or
solvates thereof, or solvates of such salts.
6. A pharmaceutical composition comprising a compound according to
claim 1 in combination with a pharmaceutically acceptable diluent,
adjuvant and/or carrier.
7. A pharmaceutical composition comprising a compound according to
claim 1 for use in the treatment or prevention of myocardial
infarction, thrombotic stroke, transient ischaemic attacks, and/or
peripheral vascular disease.
8. A pharmaceutical composition comprising a compound according to
claim 1 for use in the treatment or prevention of unstable or
stable angina.
9. A compound according to claim 1 for use in therapy.
10. A compound according to claim 1 for use in the treatment or
prevention of myocardial infarction, thrombotic stroke, transient
ischaemic attacks, and/or peripheral vascular disease.
11. A compound according to claim 1 for use in the treatment or
prevention of unstable or stable angina.
12. The use of a compound according to claim 1 as an active
ingredient in the manufacture of a medicament for use in the
treatment or prevention of myocardial infarction, thrombotic
stroke, transient ischaemic attacks, and/or peripheral vascular
disease.
13. The use of a compound according to claim 1 as an active
ingredient in the manufacture of a medicament for use in the
treatment or prevention of unstable or stable angina.
14. A method of treatment or prevention of a platelet aggregation
disorder which comprises administering to a person suffering from
or susceptible to such a disorder a therapeutically effective
amount of a compound according to claim 1.
15. A method of treatment or prevention of myocardial infarction,
thrombotic stroke, transient ischaemic attacks, and/or peripheral
vascular disease, which comprises administering to a person
suffering from or susceptible to such a condition a therapeutically
effective amount of a compound according to claim 1.
16. A method of treatment or prevention of unstable or stable
angina which comprises administering to a person suffering from or
susceptible to such a condition a therapeutically effective amount
of a compound according to claim 1.
17. A process for the preparation of a compound of formula (I)
which comprises reacting a compound of formula (II): ##STR00015##
where R, R.sup.1, R.sup.3 and R.sup.4 are as defined in claim 1, or
are protected derivatives thereof, or R.sup.3 and R.sup.4 together
form a bond in the 5-membered ring, or R is CH.sub.2CH.sub.2 OR
where R is C.sub.1-6alkyl or benzyl, and L is a leaving group, with
a compound of formula (III): ##STR00016## where R.sup.2 is defined
in claim 1 or is a protected derivative thereof, in the presence of
a base in an inert solvent at ambient or elevated temperature, and
optionally thereafter and in any order: converting one or more
functional groups into further functional groups; removing any
protecting groups: forming a pharmaceutically acceptable salt or
solvate, or a solvate of such a salt.
18. The compounds:
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[7-[[2-(4-Fluoro-
phenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyri-
midin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol:
[[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[7-[[2-(4-Fluor-
ophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazo-
lo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-
-4-methanol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]-6-[7-[[2-(3,4-Diflu-
orophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-tria-
zolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-
le-4-methanol;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(propylthio)-3-
H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclope-
nta-1,3-dioxol-4-ol;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[[6-[7-Amino-5-(propylthio)-
-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclo-
penta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[[6-[7-Bromo-5-(propylthio)-
-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclo-
penta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-[[6-[7-[[2-(3,4-Di-
fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-py-
rimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ac-
etic acid, methyl ester;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[[7-[2-(3,4-Difl-
uorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimi-
din-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethan-
ol;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(propylthio-
)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclo-
penta-1,3-dioxole-4-methanol;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(propylsulfony-
l)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cycl-
openta-1,3-dioxole-4-methanol:
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(butylthio)-3H-
-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopent-
a-1,3-dioxole-4-methanol;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(butylthio)-3H-
-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-
-1,3-dioxole-4-methanol, acetate;
[3aR-[3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Bromo-5-(butylthio)-3H-
-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopent-
a-1,3-dioxole-4-methanol, acetate;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[5-(Butylthio)-7-
-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimi-
din-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,
acetate;
[3aR-[3a.alpha.,4.alpha.,6.alpha.,6a.alpha.(1S*,2R*)]]-6-[7-[[(4-
-Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]py-
rimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.,6a.alpha.(1S*,2R*)]]-6-[[7-[(4-Fluoroph-
enyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimi-
din-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.,6a.alpha.(1S*,2R*)]]-6-[7-[[(4-Fluoroph-
enyl)cyclopropyl]amino]-5-(butylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3--
yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;
[1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[[2-(3,4-Difluorop-
henyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrim-
idin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;
(1S-cis)-2-[[4-[[6-Chloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrim-
idinyl]amino]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl ester;
(1S-cis)2-[[4-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo-
[4,5-d]-pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl
ester;
[1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazol-
o[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl
ester;
[1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thiol-3H-1,2,3-triazol-
o[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy-1-ethanol;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-2-[6-[7-Amino-5-[(3,3,3-tri-
fluoropropyl)thiol-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-
-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-2-[6-[7-Bromo-5-[(3,3,3-tri-
fluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-
-dimethyl-4H-cyclopenta-1,3-dioxo]-4-yloxy]ethanol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*2S*),6a.alpha.]-2-[6-(7-Phenylcyclop-
ropyl)amino]5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimi-
din-3-yl]-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxy]ethanol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*2S*),6a.alpha.-6-[[7-[(3,4-Difluorop-
henyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin--
3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[[7-[(3,4-Difluo-
rophenyl)cyclopropyl]aminol-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyr-
imidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[5-(Butylthio)-7-
-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimi-
din-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol;
[3aS-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[Tetrahydro-6-hydroxy-2,2-d-
imethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl
ester;
[3aS-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)-[2,2-Dimethyl-6-(2-hydroxyet-
hoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid,
phenylmethyl ester;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)-2-[[6-Amino-2,2-dimethyl-tet-
rahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;
2-(Butylthio)-4,6-dichloropyrimidine-5-amine;
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-2-[[6-[[5-Amino-2-(butylthi-
o)-6-chloro-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,-
3-dioxol-4-yl]oxy]ethanol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-2-[6-[[5-(Butylthi-
o)-7-chloro-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethy-
l-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol;
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-2-[6-[[5-(Butylthi-
o)-7-[2-phenylcyclopropyl]amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-te-
trahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] to 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 is used to prevent or alleviate these conditions,
such as thrombolysis and angioplasty is also compromised by
platelet mediated occlusion or re-occlusion.
[0003] 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) Ea
Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L.
et. al. (1994) Circulation 90, pp. 1638-1642).
[0004] 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.
[0005] ADP-induced platelet aggregation is mediated by the P.sub.2T
receptor subtype located on the platelet membrane. The P.sub.2T
receptor (also known as P2Y.sub.ADP or P2T.sub.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.sub.2T (P2Y.sub.ADP
or P2T.sub.AC) antagonists as anti-thrombotic agents.
[0006] International Patent Application WO 9905143 discloses
generically a series of triazolo[4,5-d]-pyrimidine compounds having
activity as P.sub.2T (P2Y.sub.ADP or P2T.sub.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
[0007] In a first aspect the invention therefore provides a
compound of formula (I):
##STR00001##
[0008] wherein:
[0009] R.sup.1 is C.sub.3-5 alkyl optionally substituted by one or
more halogen atoms;
[0010] R.sup.2 is a phenyl group, optionally substituted by one or
more fluorine atoms;
[0011] R.sup.3 and R.sup.4 are both hydroxy;
[0012] R is XOH, where X is CH.sub.2, OCH.sub.2CH.sub.2 or a
bond;
[0013] or a pharmaceutically acceptable salt or solvate thereof, or
a solvate of such a salt.
[0014] provided that:
[0015] when X is CH.sub.2 or a bond, R.sup.1 is not propyl.
[0016] when X is CH.sub.2 and R.sup.1 is CH.sub.2CH.sub.2CF.sub.3,
butyl or pentyl, the phenyl group at R.sup.2 must be substituted by
fluorine.
[0017] when X is OCH.sub.2CH.sub.2 and R.sup.1 is propyl, the
phenyl group at R.sup.2 must be substituted by fluorine.
[0018] Alkyl groups, whether alone or as part of another group are
straight chained and fully saturated.
[0019] Suitably R.sup.1 is a C.sub.3-5 alkyl optionally substituted
by one or more fluorine atoms. Preferably R.sup.1 is C.sub.3-5
alkyl optionally substituted on the terminal carbon by three
fluorine atoms. More preferably R.sup.1 is 3,3,3,-trifluoropropyl,
butyl or propyl.
[0020] Suitably R.sup.2 is phenyl or phenyl substituted by one or
more fluorine atoms. Preferably R.sup.2 is phenyl, 4-fluorophenyl
or 3,4-difluorophenyl.
[0021] Suitably R is XOH where X is CH.sub.2, OCH.sub.2CH.sub.2 or
a bond.
[0022] Preferably R is CH.sub.2OH or OCH.sub.2CH.sub.2 OH.
[0023] Particularly preferred compounds include: [0024]
[1R-[1.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-3-[7-[[2-(4-Fluoropheny-
l)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: [0025]
[1R-[1.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-3-[7-[[2-(3,4-Difluorop-
henyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo-
[4,5-d]primidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
[0026]
[1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.]]-3-[7-[[2-(3,4-Difluorop-
henyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin--
3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol; [0027]
[1S-(1.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-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; [0028]
[1S-(1.alpha.,2.alpha.,3.beta.,4.alpha.(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; [0029]
[1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[(2-(3,4-Difluorop-
henyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo-
[4,5d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;
[0030]
[1S-[1.alpha.,2.alpha.,3.beta.,5.beta.(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[-
7-(2-phenylcyclopropyl)amino]5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-tria-
zolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol [0031]
[1S-[1.alpha.,2.beta.,3.beta.,4.alpha.(1S*,2R*)]]-4-[5-(Burylthio)-7-[[2--
(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-
-yl]cyclopentane-1,2,3-trial; [0032]
[1S-[1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.]]-3-[5-(Butylthio)-7-[(2--
phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydr-
oxyethoxy)-cyclopentane-1,2-diol; and pharmaceutically acceptable
salts or solvates thereof, or solvates of such salts.
[0033] 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):
##STR00002##
where R, R.sup.1, R.sup.3 and R.sup.4 are as defined in formula
(I), or are protected derivatives thereof, or R.sup.3 and R.sup.4
together form a bond in the 5-membered ring, or R is
CH.sub.2CH.sub.2 OR', where R' is C.sub.1-6 alkyl or benzyl, and L
is a leaving group such as halogen or SR, with a compound of to
formula (II):
##STR00003##
where R.sup.2 is as defined in formula (I), or is a protected
derivative thereof, or where X is a bond: (b) hydroxylation of a
compound of formula (IV):
##STR00004##
where R.sup.1 is defined in formula (I) and R.sup.8 is H or
CH.sub.2CH.sub.2OP.sup.3 where P.sup.3 is H or a protecting group
or R.sup.8 is CH.sub.2COOR' where R' is C.sub.1-6 alkyl or benzyl,
and Z is NH.sub.2 or
##STR00005##
where R.sup.2 is defined in formula (I). and for both (a) and (b)
optionally thereafter and in any order: converting one or more
functional groups into further functional groups; removing any
protecting groups; forming a pharmaceutically acceptable salt or
solvate, or a solvate of such a salt.
[0034] Compounds of formula (II) can be reacted with amines of
formula (III) in the presence of a base, such as a tertiary organic
amine, in an inert solvent, such as dichloromethane, at ambient or
elevated temperature. Other suitable bases include inorganic bases
such as potassium carbonate.
[0035] The hydroxy groups R.sup.3 and R.sup.4 can be protected as
groups OP.sup.1 and OP.sup.2 where P.sup.1 and P.sup.2 are
protecting groups. Examples of suitable protecting groups in
compounds of formula (II) are C.sub.1-6alkyl (preferably methyl),
benzyl, (C.sub.1-6alkyl).sub.3Si (preferably t-butyldimethylsilyl),
and a C(O)C.sub.1-6alkyl group such as acetyl. Preferably the two
groups P.sup.1 and P.sup.2 together with the atoms to which they
are attached form an alkylidene ring such as a methylidene or
isopropylidene ring. Alternatively P.sup.1 and P.sup.2 can form an
alkoxymethylidene ring such as ethoxymethylidene.
[0036] 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).
[0037] Ester protecting groups can be removed by basic hydrolysis,
for example by using a metal hydroxide, preferably an alkali metal
hydroxide, such as sodium hydroxide or lithium hydroxide, or
quaternary ammonium hydroxide in a solvent, such as aqueous ethanol
or aqueous tetrahydrofuran, at a temperature of from 10.degree. to
100.degree. C., preferably the temperature is around room
temperature: or by acidic hydrolysis using a mineral acid such as
HCl or a strong organic acid such as trichloroacetic acid in a
solvent such as aqueous 1,4-dioxane. Trialkylsilyl protecting
groups can be removed by the use of, for example, a fluoride ion
source, for example tetra-n-butylammonium fluoride or hydrogen
fluoride. When one or is both of P.sup.1 and P.sup.2 are C.sub.1-6
alkyl, deprotection can be achieved using boron tribromide. Benzyl
groups can be removed by hydrogenolysis using a transition metal
catalyst, for example palladium on charcoal, under an atmosphere of
hydrogen, at a pressure of from 1 to 5 bar, in a solvent, such as
acetic acid.
[0038] A compound of formula (II) can be prepared by diazotising a
compound of formula (V):
##STR00006##
wherein R.sup.1 is as defined in formula (I), and R is as defined
in formula (I), or is a protected derivative thereof, or is
OCH.sub.2CO.sub.2R', where R' is C.sub.1-6 alkyl or benzyl, and L
is as defined above and R.sup.3 and R.sup.4 are as defined in
formula (I) or are protected derivatives thereof or R.sup.3 and
R.sup.4 together form a bond in the 5-membered ring, with a metal
nitrite, for example an alkali metal nitrite, especially sodium
nitrite in dilute aqueous acid, for example 2M HCl, or with a
C.sub.1-6-alkyl nitrite, in an inert solvent, at a temperature of
from about -20 to about 100.degree. C. Preferred conditions are
isoamyl nitrite in acetonitrile at about 80.degree. C.
[0039] A compound of formula (V) wherein R is CH.sub.2OH, R.sup.3
and R.sup.4 are hydroxyl or protected derivatives thereof and L is
as defined above, can be prepared by reducing a compound of to
formula (VI):
##STR00007##
wherein R.sup.1, L, P.sup.1 and P.sup.2 are as defined above.
[0040] The reduction of the nitro group can be carried out for
example by using hydrogenation with a transition metal catalyst at
a temperature around room temperature, for example palladium on
charcoal under an atmosphere of hydrogen, preferably at a pressure
from 1 to atmospheres, in a solvent, for example ethanol, or by
using iron in an acidic solvent such as acetic acid at a
temperature of about 100.degree. C.
[0041] Reduction of the lactam can be carried out using complex
metal hydrides such as lithium aluminium hydride in a solvent such
as ether or preferably, by using sodium borohydride in a suitable
solvent such as methanol.
[0042] A compound of formula (VI) can be prepared by reacting a
compound of formula (VII):
##STR00008##
wherein L and R.sup.1 are as defined above and L.sup.1 is a leaving
group, for example a halogen atom, wherein L and L.sup.1 are
preferably the same, with a compound of formula (VIII):
##STR00009##
wherein P.sup.1 and P.sup.2 are as defined above, in the presence
of a base such as C.sub.1-6-alkyl-M or MH wherein M is a metal ion,
for example n-butyl lithium, in an inert solvent, such as
tetrahydrofuran, at a temperature of from about -10 to about
100.degree. C. Preferably sodium hydride is used in tetrahydrofuran
at room temperature.
[0043] One or more functional groups can be converted into further
functional groups using standard chemistry. A compound where X is a
bond can be converted to a compound where X is O(CH.sub.2): by
treatment with base followed by LY where L is a leaving group and Y
is (CH.sub.2).sub.2OH or a protected version thereof or Y is
CH.sub.2COOR' where R' is C.sub.1-6alkyl or benzyl. A compound
where R is CH.sub.2CH.sub.2 OR may be converted into a compound
where R is O(CH.sub.2).sub.2OH by reduction, for example using
DIBAL-H.RTM.. The group SR.sup.1 can be interconverted by oxidation
of the sulfur, for example using Oxone.TM. or mCBPA, followed by
treatment with a compound R.sup.1'--SM where R.sup.1' is a
different R.sup.1 group and M is a metal such as sodium.
Alternatively the product of the sulfur oxidation may be treated
with MSH where M is a metal such as sodium, followed by treatment
with a base and R.sup.1'X where R.sup.1' is a different R.sup.1
group and X is a leaving group. Suitable bases include
N,N-diisopropylethylamine.
[0044] A compound of formula (II) where R, R.sup.1, R.sup.3, and
R.sup.4 are as defined in formula (I) or are protected derivatives
thereof, or R.sup.3 and R.sup.4 together form a bond in the
5-membered ring, or R is OCH.sub.2CO.sub.2R' where R' is C.sub.1-6
alkyl or benzyl, and L is a leaving group such as halogen, may be
converted into a compound of formula (II) where R, R.sup.1,
R.sup.3, and R.sup.4 are defined above and L is NH.sub.2 by
treatment with a diazotizing agent in the presence of a
halogenating agent, preferably isoamyl-nitrite and carbon
tetrabromide.
[0045] A compound of formula (II) where R, R.sup.1, R.sup.3, and
R.sup.4 are defined above and L is NH.sub.2 may be prepared by
treating a compound of formula (II) where R, R.sup.1, R.sup.3, and
R.sup.4 are as defined above and L is a leaving group such as
halogen, with ammonia in a solvent such as methanol.
[0046] Compounds of formula (V) can also be prepared by treating a
compound of formula (XI)
##STR00010##
where R, R.sup.3 and R.sup.4 are as defined in formula (I) or are
protected derivatives thereof or R is OCH.sub.2CO.sub.2R' where R'
is C.sub.1-6 alkyl or benzyl, or R.sup.3 and R.sup.4 together form
a bond in the 5-membered ring, with a compound of formula (VII) as
defined above, followed by reduction of the nitro group. The
reaction is carried out in an inert solvent such as dichloromethane
or 1,4-dioxane, in the presence of a non-nucleophilic base, such as
N,N-diisopropylamine, at a temperature of about -20.degree. C. to
about 150.degree. C., preferably at ambient temperature.
[0047] Compounds of formula (II) where R is as defined in formula
(I), R.sup.3 and R.sup.4 together form a bond in the 5-membered
ring, and L is SR.sup.1, or a protected derivative thereof, can be
prepared by reacting a compound of formula (XII):
##STR00011##
where R.sup.1 groups are as defined in formula (I), with a compound
of formula (XIII):
##STR00012##
in which R.sup.7 is H or a protected derivative thereof. The
reaction can be carried out in the presence of a suitable
transition metal complex, preferably tetrakistriphenylphosphine is
palladium(0).
[0048] Compounds of formula (XII) can be prepared from compounds of
formula (XIV):
##STR00013##
by reacting with a compound R.sup.1X where R.sup.1 is as defined in
formula (I) and X is a leaving group such as halo, followed by
cyclisation.
[0049] Compounds of formula (XI) where R is OH or a protected
version thereof and R.sup.3 and R.sup.4 are as defined in formula
(I) or are protected derivatives thereof may be prepared from
compounds of formula (XIII) where R.sup.7 is H or a protecting
group by treatment with a bisester of imidodicarbamic acid using
palladium catalysis followed by hydroxylation of the double bond,
and optionally, deprotection of the nitrogen. Preferably
imidodicarbonic acid, bis-(1,1-dimethylethyl)ester and
tetrakistriphenylphosphine palladium(0) are used followed by osmium
terroxide and deprotection using hydrochloric acid in methanol.
[0050] Compounds of formula (XI), where R is OCH.sub.2CO.sub.2R'
where R' is C.sub.1-6alkyl and R.sup.3 and R.sup.4 together form a
bond in the 5-membered ring, may be formed from compounds of
formula (XIII), where R.sup.7 is H or a protecting group, by
treatment with an azide in the presence of a palladium catalyst,
followed by reduction of the azide and alkylation of the alcohol as
described previously.
[0051] Compounds of formula (XI) where R is OCH.sub.2CH.sub.2 OH
and R.sup.3 and R.sup.4 are as defined in formula (I) or are
protected derivatives thereof may be prepared from compounds of
formula (XI) where R is OH and R.sup.3 and R.sup.4 are as defined
in formula (I) or are protected derivatives thereof, by protection
of the nitrogen, alkylation of the alcohol using a 2-halo-acetic
acid ester, followed by reduction of the ester and deprotection of
the nitrogen. We prefer protection of the nitrogen as a
carbobenzyloxy derivative using benzyl chloroformate followed by
alkylation of the alcohol using ethyl bromoacetate and potassium
t-butoxide, reduction of the ester using lithiumm borohydride in
tetrahydrofuran and deprotection of the nitrogen by hydrogenation
in the presence of palladium on carbon. In addition we prefer the
case where the alcohols R.sup.3 and R.sup.4 are protected as an
isopropylidene ring.
[0052] The amines of formula (III) can be prepared using procedures
described in H Nishiyama et al, Bull. Chem. Soc., Jpn., 1995, 68,
1247, P. Newman, Optical Resolution Procedures for Chemical
Compounds, Vol. 1. Amines and Related Compounds: Optical Resolution
and Information Centre Manhattan College, Riverdale, N.Y., 1978, p
120, J. Vallgarda et al, J. Chem. Soc. Perkin 1, 1994, 461 or in
International Patent Application WO 9905143.
[0053] All novel intermediates form a further aspect of the
invention.
[0054] Salts of the compounds of formula (I) may be formed by
reacting the free acid, or a salt thereof, or the free base, or a
salt or a derivative thereof, with one or more equivalents of the
appropriate base (for example ammonium hydroxide optionally
substituted by C.sub.1-6-alkyl or an alkali metal or alkaline earth
metal hydroxide) or acid (for example a hydrohalic (especially
HCl), sulphuric, oxalic or phosphoric acid). The reaction may be
carried out in a solvent or medium in which the salt is insoluble
or in a solvent in which the salt is soluble, e.g. water, ethanol,
tetrahydrofuran or diethyl ether, which may be removed in vacuo, or
by freeze drying. The reaction may also be a metathetical process
or it may be carried out on an ion exchange resin. The non-toxic
physiologically acceptable salts are preferred, although other
salts may be useful, e.g. in isolating or purifying the
product.
[0055] The compounds of the invention act as P.sub.2T (P2Y.sub.ADP
or P2T.sub.AC) receptor antagonists. Accordingly, the compounds are
useful in therapy, including combination therapy, particularly they
are indicated for use as: inhibitors of platelet activation,
aggregation and degranulation, promoters of platelet
disaggregation, anti-thrombotic agents or in the treatment or
prophylaxis of unstable angina, primary arterial thrombotic
complications of atherosclerosis such as thrombotic or embolic
stroke, transient ischaemic attacks, peripheral vascular disease,
myocardial infarction with or without thrombolysis, arterial
complications due to interventions in atherosclerotic disease such
as angioplasty, including coronary angioplasty (PTCA),
endarterectomy, stent placement, coronary and other vascular graft
surgery, thrombotic complications of surgical or mechanical damage
such as tissue salvage following accidental or surgical trauma,
reconstructive surgery including skin and muscle flaps, conditions
with a diffuse thrombotic/platelet consumption component such as
disseminated intravascular coagulation, thrombotic
thrombocytopaenic purpura, haemolytic uraemic syndrome, thrombotic
complications of septicaemia, adult respiratory distress syndrome,
anti-phospholipid syndrome, heparin-induced thrombocytopaenia and
pre-eclampsialeclampsia, or venous thrombosis such as deep vein
thrombosis, venoocclusive disease, haematological conditions such
as myeloproliferative disease, including thrombocythaemia, sickle
cell disease; or in the prevention of mechanically-induced platelet
activation in vivo, such as cardio-pulmonary bypass and
extracorporeal membrane oxygenation (prevention of
microthromboembolism), mechanically-induced platelet activation in
vitro, such as use in the preservation of blood products, e.g.
platelet concentrates, or shunt occlusion such as in renal dialysis
and plasmapheresis, thrombosis secondary to vascular
damage/inflammation such as vasculitis, arteritis,
glomerulonephritis, inflammatory bowel disease and organ graft
rejection, conditions such as migraine. Raynaud's phenomenon,
conditions in which platelets can contribute to the underlying
inflammatory disease process in the vascular wall such as
atheromatous plaque formation/progression, stenosis/restenosis and
in other inflammatory conditions such as asthma, in which platelets
and platelet-derived factors are implicated in the immunological
disease process. Further indications include treatment of CNS
disorders and prevention of the growth and spread of tumours.
[0056] According to the invention there is further provided the use
of a compound according to the invention as an active ingredient in
the manufacture of a medicament for use in the treatment or
prevention of the above disorders. In particular the compounds of
the invention are useful for treating myocardial infarction,
thrombotic stroke, transient ischaemic attacks, peripheral vascular
disease and stable and unstable angina, especially unstable angina.
The invention also provides a method of treatment or prevention of
the above disorders which comprises administering to a person
suffering from or susceptible to such a disorder a therapeutically
effective amount of a compound according to the invention.
[0057] The compounds may be administered topically, e.g. to the
lung and/or the airways, in the form of solutions, suspensions, HFA
aerosols and dry powder formulations; or systemically, e.g. by oral
administration in the form of tablets, pills, capsules, syrups,
powders or granules, or by parenteral administration in the form of
sterile parenteral solutions or suspensions, by subcutaneous
administration, or by rectal administration in the form of
suppositories or transdermally.
[0058] The compounds of the invention may be administered on their
own or as a pharmaceutical composition comprising the compound of
the invention in combination with a pharmaceutically acceptable
diluent, adjuvant and/or carrier. Particularly preferred are
compositions not containing material capable of causing an adverse,
e.g. an allergic, reaction.
[0059] Dry powder formulations and pressurised HFA aerosols of the
compounds of the invention may be administered by oral or nasal
inhalation. For inhalation the compound is desirably finely
divided. The compounds of the invention may also be administered by
means of a dry powder inhaler. The inhaler may be a single or a
multi dose inhaler, and may be a breath actuated dry powder
inhaler.
[0060] One possibility is to mix the finely divided compound with a
carrier substance, e.g. a mono-, di- or polysaccharide, a sugar
alcohol or another polyol. Suitable carriers include sugars and
starch. Alternatively the finely divided compound may be coated by
another substance. The powder mixture may also be dispensed into
hard gelatine capsules, each containing the desired dose of the
active compound.
[0061] Another possibility is to process the finely divided powder
into spheres which break up during the inhalation procedure. This
spheronized powder may be filled into the drug reservoir of a
multidose inhaler, e.g. that known as the Turbuhaler.RTM. in which
a dosing unit meters the desired dose which is then inhaled by the
patient. With this system the active as compound with or without a
carrier substance is delivered to the patient.
[0062] The pharmaceutical composition comprising the compound of
the invention may conveniently be tablets, pills, capsules, syrups,
powders or granules for oral administration; sterile parenteral or
subcutaneous solutions, suspensions for parenteral administration
or suppositories for rectal administration.
[0063] For oral administration the active compound may be admixed
with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol,
mannitol, starches such as potato starch, corn starch or
amylopectin, cellulose derivatives, a binder such as gelatine or
polyvinylpyrrolidone, and a lubricant such as magnesium stearate,
calcium stearate, polyethylene glycol, waxes, paraffin, and the
like, and then compressed into tablets. If coated tablets are
required, the cores, prepared as described above, may be coated
with a concentrated sugar solution which may contain e.g. gum
arabic, gelatine, talcum, titanium dioxide, and the like.
Alternatively, the tablet may be coated with a suitable polymer
dissolved either in a readily volatile organic solvent or an
aqueous solvent.
[0064] For the preparation of soft gelatine capsules, the compound
may be admixed with e.g. a vegetable oil or polyethylene glycol.
Hard gelatine capsules may contain granules of the compound using
either the above mentioned excipients for tablets, e.g. lactose,
saccharose, sorbitol, mannitol, starches, cellulose derivatives or
gelatine. Also liquid or semisolid is formulations of the drug may
be filled into hard gelatine capsules.
[0065] Liquid preparations for oral application may be in the form
of syrups or suspensions, for example solutions containing the
compound, the balance being sugar and a mixture of ethanol, water,
glycerol and propylene glycol. Optionally such liquid preparations
may contain colouring agents, flavouring agents, saccharine and
carboxymethylcellulose as a thickening agent or other excipients
known to those skilled in art.
EXAMPLES
[0066] The invention is illustrated by the following non-limiting
examples.
[0067] In the examples the NMR spectra were measured on a Varian
Unity Inova 300 or 400 spectrometer and the MS spectra were
measured as follows: EI spectra were obtained on a VG 70-250S or
Finnigan Mat Incos-XL spectrometer, FAB spectra were obtained on a
VG70-250SEQ spectrometer. ESt and APCI spectra were obtained on
Finnigan Mat SSQ7000 or a Micromass Platform spectrometer.
Preparative HPLC separations were generally performed using a
Novapak.RTM., Bondapak.RTM. or Hypersil.RTM. column packed with
BDSC-18 reverse phase silica. Flash chromatography (indicated in
the Examples as (SiO.sub.2)) was carried out using Fisher Matrix
silica, 35-70 .mu.m. For examples which showed the presence of
rotamers in the proton NMR spectra only the chemical shifts of the
major rotamer are quoted.
Example 1
[1R-[1.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-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
a)
[3aS-[1(E),3a.alpha.,6.alpha.,7a.beta.]]-1-[3-(4-Fluorophenyl)-1-oxo-2--
propenyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-d-
ioxide
[0068] A mixture of 3-(4-fluorophenyl)-2-propenoic acid (3.0 g) and
thionyl chloride (5.0 ml) was stirred at 70.degree. C. for 1 hour,
the reaction mixture was then concentrated under reduced pressure.
The residue was azeotroped twice with dichloromethane then
dissolved in toluene (10 ml). To a suspension of sodium hydride
(60% dispersion in oil; 0.99 g) in toluene (40 ml) was added a
solution of
[3aS-(3a.alpha.,6.alpha.,7a.beta.)]-hexahydro-8,8-dimethyl-3H-3a,6-methan-
o-2,1-benzisothiazole-2,2-dioxide (3.89 g) in toluene (40 ml) and
the mixture stirred for 30 minutes. To the reaction mixture was
then added the solution described above and the resulting
suspension was stirred for 16 hours. Water (200 ml) was added, the
organics collected and the aqueous extracted into dichloromethane
(3.times.100 ml). The organics were combined, dried and
concentrated. Recrystallisation (ethanol) gave the subtitle
compound as colourless needles (5.92 g).
[0069] MS (APCI) 364 (M+H.sup.+, 100%)
b)
[3aS-[1(1S*,2S*),3a.alpha.,6.alpha.,7a.beta.]]-1-[[2-(4-Fluorophenyl)cy-
clopropyl]carbonyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothia-
zole-2,2-dioxide
[0070] A solution of diazomethane (2.9 g) in ether (150 ml)
(prepared as described in Vogel's Textbook of Practical Organic
Chemistry, Fifth Edition, Longman Scientific and Technical, p 432)
was added to a solution of the product of step a) (5.90 g) and
palladium(II) acetate (18 mg) in dichloromethane (350 ml) at
0.degree. C. and the reaction mixture stirred at 0.degree. C. for 5
hours. Acetic acid (5 ml) was added and the reaction mixture was
then washed with saturated sodium bicarbonate solution (200 ml) and
the organics filtered through a plug of silica. After concentrating
in vacuo, the residue was recrystallised (ethanol) to give the
subtitle compound as colourless needles (3.81 g).
[0071] MS (APCI) 378 (M+H.sup.+, 100%)
c) (1R-trans)-2-(4-Fluorophenyl)-cyclopropanecarboxylic acid
[0072] A suspension of the product from step b) (3.74 g) and
lithium hydroxide monohydrate (4.11 g) in tetrahydrofuran (100
ml)/water (3 ml) was stirred at 50.degree. C. for 24 hours. The
reaction mixture was concentrated in vacuo, and the residue
dissolved in water (100 ml), acidified with 2N HCl and extracted
into dichloromethane (3.times.75 ml). The organics were dried and
concentrated. Purification (SiO.sub.2, isohexane:diethylether 2:1
as eluant) gave the subtitle compound as a colourless solid (1.78
g).
[0073] MS (APCI) 179 (M-H.sup.+, 100%)
d) (1R-trans)-2-(4-Fluorophenyl)cyclopropanamine,
[R--(R*,R*)]-2,3-dihydroxybutanedioate (1:1)
[0074] To a solution of the product from step c) (1.78 g) and
triethylamine (2.7 ml) in acetone/water (10:1, 23 ml) at 0.degree.
C. was added ethyl chloroformate (2.0 ml) over 5 min. The solution
was maintained at 0.degree. C. for 30 minutes before addition of
sodium azide (1.52 g) in water (6 ml). After a further hour, water
(350 ml) was added and the reaction mixture extracted with toluene
(3.times.100 ml). The organic extracts were combined and dried,
then heated at reflux for 2 hours behind a blast screen. After
cooling the solution, 6N HCl (50 ml) was added and the mixture
heated at reflux for 3 hours. Water (150 ml) was added and the
aqueous phase basified with 2N NaOH (aq), then extracted into
dichloromethane (3.times.100 ml). The organic phase was dried and
concentrated. The amine was dissolved in ethanol (5 ml) and a
solution of L-tartaric acid (1.48 g) in ethanol (20 ml) was added.
After 20 minutes the solid was collected affording the subtitle
compound as colourless needles (1.12 g).
[0075] NMR .delta.H (d.sub.6-DMSO) 1.07-1.39 (1H, m), 1.22-1.29
(1H, m), 2.16-2.23 (1H, m), 2.64-2.70 (1H, m), 3.95 (2H, s),
7.06-7.19 (4H, m)
e)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[7-[[2-(4-Fluo-
rophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimid-
in-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol
[0076] N,N-Diisopropylethylamine (1.29 g) was added to a solution
of
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-chloro-5-(propylthio)--
3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclope-
nta-1,3-dioxole-4-methanol (prepared as described in International
Patent Application WO 9703084) (1.0 g) and the product of step d)
(0.75 g) in dichloromethane (25 ml). The reaction mixture was
stirred at room temperature for 3 hours, then washed with water,
dried and evaporated. The residue was purified (SiO.sub.2, ethyl
acetate:isohexane 1:1 as eluent) to afford the subtitle compound
(1.25 g).
[0077] MS (APCI) 515 (M+H.sup.+, 100%)
f)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[7-[[2-(4-Fluo-
rophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]py-
rimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol
[0078] 3-Chloroperoxybenzoic acid (70%, 1.8 g) was added to a
suspension of the product of step e) (1.25 g) in ethanol (25 ml)
and the resulting solution stirred at room temperature for 2 hours.
The reaction mixture was concentrated and the residue taken up in
ethyl acetate (500 ml), washed with 10% aqueous sodium
metabisulfite solution (2.times.100 ml) and 10% aqueous sodium
bicarbonate solution (2.times.100 ml) then dried and concentrated
to afford the subtitle compound (1.4 g).
[0079] MS (APCI) 547 (M+H.sup.+, 100%)
g)
[[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[7-[[2-(4-Flu-
orophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-tria-
zolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-
le-4-methanol
[0080] Sodium hydrosulfide hydrate (1.4 g) was added to a solution
of the product of step f) (1.4 g) in dimethyl sulphoxide (20 ml)
and the solution stirred at room temperature for 1.5 hours. Brine
(150 ml) was added and the mixture acidified with acetic acid then
extracted with ethyl acetate (3.times.100 ml). The organic phase
was dried and concentrated and the residue azeotroped with toluene
(3.times.100 ml). The residue was dissolved in
N,N-dimethylformamide (20 ml) then N,N-diisopropylethylamine (0.33
g) and 3,3,3-trifluoropropylbromide (0.48 g) added. After stirring
at 50.degree. C. for 30 minutes the reaction mixture was diluted
with ethyl acetate (100 ml) then washed with aqueous brine
(3.times.100 ml), dried and concentrated then the residue purified
(SiO.sub.2, isohexane:ethyl acetate 1:1 as eluant) to afford the
subtitle compound (1.4 g).
[0081] MS (APCI) 569 (M+H.sup.+, 100%)
h) [1R-[1.alpha.,
2.alpha.,3.beta.(1R*,2S*),5.beta.]]-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
[0082] A solution of the product from step g) (1.4 g) in
trifluoroacetic acid (10 ml) and water (2 ml) was stirred at room
temperature for 1 hour. The reaction mixture was diluted with ethyl
acetate (400 ml) then washed with sodium bicarbonate solution (400
ml), dried and evaporated. The residue was purified (SiO.sub.2,
methanol:chloroform 3:47 as eluant) to afford the title compound
(0.44 g).
[0083] MS (APCI) 529 (M+H.sup.+, 100%)
[0084] NMR .delta.H (d.sub.6-DMSO) 9.42 (1H, d), 7.27-7.22 (2H, m),
7.14-7.08 (2H, m), 5.01-4.95 (2H, m), 4.73-4.70 (2H, m), 4.44-4.41
(1H, m), 3.87-3.84 (1H, m), 3.50-3.45 (2H, m), 3.26-3.13 (3H, m),
2.60-2.55 (1H, m), 2.28-2.20 (2H, m), 2.10-2.06 (1H, m), 1.90-1.80
(1H, m), 1.49-1.46 (1H, m), 1.33-1.30 (1H, m).
Example 2
[1R-[1.alpha.,2.alpha.,3.beta.(1R*,2S*),5]]-3-[7-[[2-(3,4-Difluorophenyl)c-
yclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-
pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol
a)
[3aS-[1(E),3a.alpha.,6.alpha.,7a.beta.]]-1-[3-(3,4-Difluorophenyl)-1-ox-
o-2-propenyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2-
,2-dioxide
[0085] The subtitle compound was prepared according to the method
of Example 1, step a) using 3-(3,4-difluorophenyl)-2-propenoic
acid.
[0086] MS (APCI) 382 (M+H.sup.+, 100%)
b)
[3aS-[1(1S*,2S*),3a.alpha.,6.alpha.,7a.beta.]]-1-[[2-(3,4-Difluoropheny-
l)cyclopropyl]carbonyl]-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benziso-
thiazole-2,2-dioxide
[0087] The subtitle compound was prepared according to the method
of Example 1, step b) using the product of step a).
[0088] MS (APCI) 396 (M+H.sup.+, 100%)
c) (1R-trans)-2-(3,4-Difluorophenyl)-cyclopropane carboxylic
acid
[0089] The subtitle compound was prepared according to the method
of Example 1, step c) using the product of step b).
[0090] NMR .delta.H(CDCl.sub.3) 7.06 (1H, dt. J=10.0, J=8.5 Hz),
6.93-6.80 (2H, m), 2.58-2.52 (1H, m), 1.88-1.82 (1H, m), 1.66
(1H.dt, J=9.2, J=5.2 Hz), 1.34 (1H, ddd, J=8.5, J=6.5, J=4.8
Hz).
d) (1R-trans)-2-(3,4-Difluorophenyl)cyclopropanamine,
[R--(R*,R*)]-2,3-dihydroxybutanedioate (1:1)
[0091] The subtitle compound was prepared according to the method
of Example 1, step d) using the product of step c).
[0092] MS (APCI) 170 (M+H.sup.+, 100%)
e)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]-6-[7-[[2-(3,4-Dif-
luorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-tr-
iaz[4,5-d]pyrimidin-3-yl]-triazolo-2,2-dimethyl-4H-cyclopenta-1,3-dioxole--
4-methanol
[0093] Isoamyl nitrite (5.1 ml) was added to a solution of
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[[5-amino-6-Chloro-2-[(3,-
3,3-trifluoropropyl)thio]-4-pyrimidinyl]-amino]-tetrahydro-2,2-dimethyl-4H-
-cyclopenta-1,3-dioxole-4-methanol (prepared as described in
International Patent Application WO 9703084) (8.1 g) in
acetonitrile (1000 ml) and the solution heated at 70.degree. C. for
1 hour. The cooled reaction mixture was concentrated and purified
(SiO.sub.2, dichloromethane:ethyl acetate 4:1 as eluant) to afford
an intermediate which was converted to the subtitle compound by the
method of example 1, step e) using the product of step d).
[0094] MS (APCI) 587 (M+H.sup.+, 100%)
f)
[1R-[1.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-3-[7-[[2-(3,4-Difluor-
ophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazo-
lo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol
[0095] Prepared according to the method of example 1, step h) using
the product of step e).
[0096] MS (APCI) 547 (M+H.sup.+, 100%)
[0097] NMR .delta.H (d.sub.6-DMSO) 9.43 (1H, d), 7.35-7.28 (2H, m),
7.14-7.02 (1H, m), 5.01-4.96 (2H, m), 4.72-4.69 (2H, m), 4.42 (1H,
q), 3.87-3.84 (1H, m), 3.50-3.44 (2H, m), 3.25-3.12 (3H, m),
2.58-2.50 (2H, m), 2.28-2.21 (3H, m), 1.85-1.80 (1H, m), 1.52-1.50
(1H, m), 1.39-1.37 (1H, m).
Example 3
[1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[2-(3,4-Difluorophe-
nyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3--
yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol
a)
(1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbona-
te
[0098] To a suspension of ether washed sodium hydride (60%
dispersion in oil; 0.31 g) in tetrahydrofuran (30 ml) was added
imidodicarbonic acid bis-(1,1-dimethylethyl)ester (1.84 g). The
mixture was stirred at 40.degree. C. for 1 hour. To the mixture, at
ambient temperature, was then added
(1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) and
tetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction
mixture was stirred for 24 hours then purified (SiO.sub.2, ethyl
acetate:hexane 1:9 as eluant) to give the subtitle compound as a
colourless solid (0.90 g).
[0099] NMR .delta.H (d.sub.6-DMSO) 1.43 (18H, s), 1.61 (1H, ddd,
J=12.3, 7.7, 6.4 Hz), 2.54 (1H, dt, J=12.6, 7.4 Hz), 4.51-4.57 (1H,
m), 4.86 (1H, tq, J=8.0, 1.8 Hz), 4.91 (1H, d, J=5.4 Hz), 5.71-5.77
(2H, m).
b)
[1R-(1.alpha..2.beta.,3.beta.,4.alpha.)]-2,3,4-Trihydroxy-cyclopentenyl-
imidodicarbonic acid, bis(1,1-dimethylethyl)ester
[0100] To a solution of the product of step a) (17.1 g) in
tetrahydrofuran (500 ml)/water (50 ml) was added
N-methylmorpholine-N-oxide (9.4 g) followed by osmium tetroxide (10
ml, 2.5% solution in r-butanol). The mixture was stirred at room
temperature for 4 days then treated with sodium hydrosulphite (6.0
g). The suspension was filtered through celite and the product
purified (SiO.sub.2, ethyl acetate:hexane 1:1 as eluant) to afford
the subtitle compound (19.1 g).
[0101] NMR .delta.H (d.sub.6-DMSO) 1.44 (18H, s), 1.46-1.60 (1H,
m), 1.97-2.05 (1H, m), 3.55-3.58 (1H, m), 3.66-3.73 (1H, m),
4.11-4.21 (2H, m), 4.54 (1H, d, J=4.8 Hz), 4.56 (1H, d, J=5.9 Hz),
4.82 (1H, d. J=4.6 Hz)
c)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-Amino-tetrahydro-2,2-di-
methyl-4H-cyclopenta-1,3-dioxol-4-ol, hydrochloride
[0102] The product from step b) (17.4 g) in 6M HCl (100
ml)/methanol (500 ml) was stirred for 18 hours. The mixture was
evaporated and then azeotroped with toluene (4.times.200 ml) to
give a colourless powder (8.7 g). This solid was suspended in
acetone (250 ml) containing 2,2-dimethoxypropane (25 ml) and cHCl
(0.2 ml) then heated under reflux for 2 hours. The mixture was
cooled, evaporated and azeotroped with toluene (3.times.200 ml).
The residue was dissolved in 20% aqueous acetic acid and stirred
for 2 hours. The mixture was evaporated and azeotroped with toluene
(4.times.200 ml) to afford the subtitle compound (10.1 g).
[0103] MS (APCI) 174 (M+H.sup.+, 100%)
d)
[3aR-(3a.alpha.,4.alpha.,6a.alpha.)]-6-[[6-Chloro-5-nitro-2-(propylthio-
)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-
-ol
[0104] A solution of the product from step c) (10.0 g) and
N,N-diisopropylethylamine (35 ml) in tetrahydrofuran (600 ml) was
stirred for 1 hour. The mixture was filtered and the solution was
added over 1 hour to a solution of
4,6-dichloro-5-nitro-2-(propylthio)-pyrimidine (prepared as
described in International Patent Application WO 9703084) (25.6 g)
in tetrahydrofuran (1000 ml) and stirred for a further 2 hours. The
solvent volume was reduced in vacuo and ethyl acetate was added
(1000 ml). The mixture was washed with water and the organic layers
were dried, evaporated and purified (SiO.sub.2, isohexane-ethyl
acetate as eluant) to afford the subtitle compound (14.2 g).
[0105] MS (APCI) 405 (M+H.sup.+, 100%)
e)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[[5-Amino-6-Chloro-2-(p-
ropylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-
-dioxol-4-ol
[0106] Iron powder (3.0 g) was added to a stirred solution of the
product of step d) (2.7 g) in acetic acid (100 ml). The reaction
mixture was stirred at room temperature for 2 hours, concentrated
to half volume, diluted with ethyl acetate and washed with water.
The organic phase was dried and concentrated to afford the subtitle
compound (2.0 g).
[0107] MS (APCI) 375 (M+H.sup.+, 100%)
f)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Chloro-5-(propylthio-
)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cycl-
openta-1,3-dioxol-4-ol
[0108] Isoamyl nitrite (1.1 ml) was added to a solution of the
product of step e) (2.0 g) in acetonitrile (100 ml) and the
solution heated at 70.degree. C. for 1 hour. The cooled reaction
mixture was concentrated and purified (SiO.sub.2, ethyl
acetate:isohexane 1:3 as eluant) to afford the subtitle compound
(1.9 g).
[0109] MS (APCI) 386 (M+H.sup.+, 100%)
g) [3aR-(3a.alpha.,
4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo-
[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-
-ol
[0110] The product of step f) (13.2 g) in tetrahydrofuran (200 ml)
containing 0.88 ammonia (5 ml) was stirred for 2 hours then
concentrated to dryness and the residue partitioned between water
and ethyl acetate. The organics were dried and then concentrated to
afford the subtitle compound (12.5 g).
[0111] MS (APCI) 367 (M+H.sup.+, 100%).
h)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[[6-[7-Amino-5-(propylthi-
o)-3H-1,2,3-triazolo[4,S-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyc-
lopenta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester
[0112] To a solution of the product of step g) (0.50 g) in
tetrahydrofuran (25 ml) at 0.degree. C., was added butyllithium
(0.62 ml of 2.5N in hexanes). After 20 minutes, the suspension was
treated with a solution of trifluoromethanesulfonyloxy-acetic acid
methyl ester (0.34 g) (prepared according to the method of Biton,
Tetrahedron, 1995, 51, 10513) in tetrahydrofuran (10 ml). The
resulting solution was allowed to warm to room temperature then
concentrated and purified (SiO.sub.2, ethyl acetate:hexane 4:6 as
eluant) to afford the subtitle compound (0.25 g).
[0113] MS (APCI) 439 (M+H.sup.+, 100%).
i)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[[6-[7-Bromo-5-(propylthi-
o)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyc-
lopenta-1,3-dioxol-4-ol]oxy]acetic acid, methyl ester
[0114] The product from step h) (1.1 g) and isoamylnitrite (2.4 ml)
in bromoform (30 ml) was heated at 80.degree. C. for 30 minutes.
The cooled reaction mixture was purified (SiO.sub.2, ethyl
acetate:isohexane 1:4 as eluant) to afford the subtitle compound
(0.44 g).
[0115] MS (APCI) 502/4 (M+H.sup.+), 504 (100%).
j)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-[[6-[7-[[2-(3,4--
Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]--
pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-
acetic acid, methyl ester
[0116] To a mixture of the products from step i) (0.80 g) and
Example 2, step d) (0.61 g) in dichloromethane (25 ml) was added
N,N-diisopropylethylamine (0.85 ml). The resulting solution was
stirred at room temperature for 16 hours then concentrated in
vacuo. Purification (SiO.sub.2, isohexane:ethylacetate 3:1 as
eluant) gave the subtitle compound as a colourless foam (0.77
g).
[0117] MS (APCI) 591 (M-H.sup.+, 100%)
k)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-2-[6-[[7-[2-(3,4-
-Difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]p-
yrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]--
ethanol
[0118] DIBAL-H.RTM. (1.0M solution in hexanes, 5.15 ml) was added
to an ice-cooled solution of the product of step j) (0.76 g) in
tetrahydrofuran (1 ml) and the solution stirred at this temperature
for 2 hours. The reaction mixture was concentrated in vacuo and the
residue was dissolved in ethyl acetate (75 ml). A saturated aqueous
solution of sodium potassium tartrate (75 ml) was added and the
mixture stirred vigorously for 16 hours. The organics were
collected and the aqueous re-extracted with ethyl acetate
(2.times.50 ml). The combined organics were dried and concentrated
and the residue purified (SiO.sub.2, isohexane:ethylacetate 1:1 as
eluant) to give the subtitle compound (0.63 g).
[0119] MS (APCI) 563 (M+H.sup.-, 100%)
l)
[1S-[1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.]]-3-[7-(2-(3,4-Difluoro-
phenyl)cyclopropyamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-
-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol
[0120] Prepared according to the method of example 1, step h) using
the product of step k).
[0121] MS (APCI) 523 (M+H.sup.+, 100%)
[0122] NMR .delta.H (d.sub.6-DMSO) 8.95 (1H, d, J=3.3 Hz),
7.39-7.21 (2H, m), 7.10-7.00 (1H, m), 5.12 (1H, d, J=6.4 Hz), 5.05
(1H, d, J=3.6 Hz), 4.96 (1H, q, J=9.0 Hz), 4.62-4.54 (2H, m), 3.95
(1H, br s), 3.79-3.73 (1H, m), 3.55-3.47 (4H, m), 3.20-3.13 (1H,
m), 2.98-2.81 (2H, m), 2.63 (1H, dt. J=13.6, 8.5 Hz), 2.29-2.21 and
2.16-2.09 (1H, m), 2.07-2.00 (1H, m), 1.73-1.33 (4H, m), 0.99 (3H,
t, J=7.4 Hz).
Example 4
[1R-[1.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-3-[S-(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
a)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(propylthio)-
-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclop-
enta-1,3-dioxole-4-methanol
[0123] Prepared according to the method of Example 3, step g) using
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-chloro-5-(propylthio)--
3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclope-
nta-1,3-dioxole-4-methanol (prepared as described in International
Patent Application WO 9703084). The crude product was purified
(SiO.sub.2, methanol:dichloromethane 1:19 as eluant) to give the
subtitle compound.
[0124] MS (APCI) 381 (M+H.sup.+, 100%).
b)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(propylsulfo-
nyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cy-
clopenta-1,3-dioxole-4-methanol
[0125] Prepared according to the method of example 1, step f) using
the product of step a).
[0126] MS (APCI) 413 (M+H.sup.+, 100%).
c)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-3-(butylthio)--
3H-1,2,3-triazolo[4,S-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclope-
nta-1,3-dioxole-4-methanol
[0127] 1-Butanethiol (2.38 ml) in DMF (25 ml) was added to a
suspension of sodium hydride (60%, 1.09 g) in DMF (50 ml). After 1
hour a solution of the product of step b) (3.66 g) in DMF (65 ml)
was added dropwise and the resulting mixture was stirred overnight.
The reaction mixture was added slowly to saturated aqueous sodium
bicarbonate (1000 ml) and then is extracted into ethyl acetate
(3.times.200 ml). The organic phase was dried (MgSO.sub.4) and
concentrated in vacuo and the residue purified (SiO.sub.2,
methanol:dichloromethane 1:19 as eluant) to give the subtitle
compound (3.32 g).
[0128] MS (APCI) 395 (M+H.sup.+, 100%).
d)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Amino-5-(butylthio)--
3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclope-
nta-1,3-dioxole-4-methanol, acetate
[0129] To a solution of the product from step c) (3.3 g) in
dichloromethane (50 ml), was added pyridine (2.7 ml),
4-dimethylaminopyridine (0.4 g) and acetic anhydride (2.0 ml). The
mixture was stirred at room temperature overnight, concentrated
in-vacuo and purified (SiO.sub.2, diethyl ether:isohexane 3:2 as
eluent) to give the subtitle compound (2.7 g).
[0130] MS (APCI) 437 (M+H.sup.+, 100%).
e)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-[7-Bromo-5-(butylthio)--
3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclope-
nta-1,3-dioxole-4-methanol, acetate
[0131] Prepared according to the method of example 3, step i) using
the product of step d).
[0132] MS (APCI) 500/502 (M+H.sup.-), 500 (100%).
f)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[5-(Butylthio)-
-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyri-
midin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol,
acetate
[0133] Prepared according to the method of example 3, step j) using
the product of example 2, step d) and the product of step e).
[0134] MS (APCI) 589 (M+H.sup.+, 100%).
g)
[1R-[1.alpha.,2.alpha.,3.beta.(1R*,2S*),5.beta.]]-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
[0135] The product of step f) (0.64 g) in 80% aqueous acetic acid
(30 ml) was heated at 80.degree. C. for 1 hour. The cooled mixture
was poured into saturated sodium bicarbonate solution and extracted
into ethyl acetate. The organic phase was dried and concentrated in
vacuo to give a gum which was dissolved in methanol (50 ml)/10%
aqueous potassium carbonate solution (3 ml). The solution was
stirred for 30 minutes, neutralised with acetic acid, and
concentrated in vacuo. Purification (SiO.sub.2,
methanol:dichloromethane 1:19 as eluent) gave a solid which was
recrystallised (acetonitrile) to give the title compound (0.25
g).
[0136] MS (APCI) 507 (M+H.sup.+, 100%).
[0137] NMR .delta.H (d.sub.6-DMSO) 9.34 (1H, br), 7.40-7.23 (2H,
m), 7.11-7.00 (1H, m), 5.06-4.93 (2H, m), 4.76-4.67 (2H, m),
4.48-4.38 (1H, m), 3.91-3.84 (1H, m), 3.56-3.39 (2H, m), 3.21-3.08
(1H, m), 3.03-2.83 (2H, m), 2.32-2.17 (1H, m), 2.17-2.03 (2H, m),
1.91-1.77 (1H, m), 1.71-1.32 (4H, m), 1.32-1.17 (2H, m), 0.81 (3H,
t).
Example 5
[1S-[1.alpha.,2.beta.,3.beta.,4.alpha.(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(-
4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,d]pyrimidin-3-yl]-cy-
clopentane-1,2,3-triol
a) [3aR-[3a.alpha.,
4.alpha.,6.alpha.,6a.alpha.(1S*,2R*)]]-6-[7-[[(4-Fluorophenyl)cyclopropyl-
]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro--
2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol
[0138] Prepared according to the method of example 1, step e) using
the product of example 1, step d) and the product of example 3 step
f).
[0139] MS (APCI) 501 (M+H.sup.+, 100%).
b) [3aR-[3a.alpha.,
4.alpha.,6.alpha.,6a.alpha.(1S*,2R*)]]-6-[[7-[(4-Fluorophenyl)cyclopropyl-
]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrah-
ydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol
[0140] Prepared according to the method of example 1, step f) using
the product of step a).
[0141] MS (APCI) 532 (M+H.sup.+, 100%).
c)
[3aR-[3a.alpha.,4.alpha.,6.alpha.,6a.alpha.(1S*,2R*)]]-6-[7-[[(4-Fluoro-
phenyl)cyclopropyl]amino]-5-(butylthio)-3H-1,2,3-triazolo[4,-d]pyrimidin-3-
-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol
[0142] Prepared according to the method of example 4 step c) using
the product of step b).
[0143] MS (APCI) 515 (M+H.sup.+, 100%).
[1S-[1.alpha.,2.beta.,3.beta.,4.alpha.(1S*,2*)]]-4-[5-(Butylthio)-7-[[2-(4-
-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-c-
yclopentane-1,2,3-triol
[0144] Prepared according to the method of example 1 step h) using
the product of step c).
[0145] MS (APCI) 575 (M+H.sup.+, 100%).
[0146] NMR .delta.H (d.sub.6-DMSO) 7.26-7.22 (2H, m), 7.11 (2H, t),
4.99-4.90 (1H, m), 4.67-4.63 (1H, m), 3.93 (1H, s), 3.77 (1H, bs),
3.35-3.13 (1H, m), 3.00-2.80 (2H, m), 2.59-2.51 (1H, m), 2.15-2.11
(1H, m), 1.91-1.86 (1H, m), 1.53-1.41 (3H, m), 1.35-1.30 (1H, m),
1.22 (2H, sex), 0.80 (3H, t).
Example 6
[1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[[2-(3,4-Difluoroph-
enyl)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
a)
[1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[[2-(3,4-Difluor-
ophenyl)cyclopropyl]amino]-5-(propylsulphonyl)-3H-1,2,3-triazolo[4,5-d]pyr-
imidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol
[0147] The subtitle compound was prepared according to the method
of Example 1, step f) using the product of Example 3, step 1.
[0148] MS (APCI) 555 (M+H.sup.+, 100%)
b)
[1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[[2-(3,4-Difluor-
ophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazo-
lo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol
[0149] The title compound was prepared according to the method of
Example 1, step g) using the product of step a).
[0150] MS (APCI) 555 (M+H.sup.+, 100%)
[0151] NMR .delta.H (d.sub.6-DMSO) 9.45 (1H, d), 7.36-7.05 (3H, m),
5.05 (1H, d), 5.02 (1H, d), 4.95 (1H, m), 4.60 (2H, m), 3.95 (1H,
m), 3.86 (1H, m), 3.47 (4H, m), 3.30-3.11 (3H, m), 2.63-2.49 (3H,
m), 2.19 (1H, m), 2.00 (1H, m), 1.53 (1H, m), 1.40 (1H, m).
Example 7
[1S-[1.alpha.,2.alpha.,3.beta.,5.beta.(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-
-(2-phenylcyclopropyl)amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triaz-
olo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol
a)
(1S-cis)-2-[[4-[[6-Chloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio]-4-pyr-
imidinyl]amino]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl
ester
[0152] A solution of sodium azide (4.70 g) in degassed water (25
ml) was added to a solution of (1R,4S)-4-hydroxy-2-cyclopenten-1-yl
acetate (9.99 g) in tetrahydrofuran (60 ml) and stirred for 10 min.
Tetrakis(triphenylphosphine)palladium(0) (365 mg) was added and
stirred for min. The aqueous layer was separated and extracted
twice with ethyl acetate. The combined organic layers were dried
(MgSO.sub.4), concentrated and purified on a short column
(SiO.sub.2, ethyl acetate:isohexane 1:2 as eluant) to afford a
yellow oil. This was dissolved in tetrahydrofuran (25 ml) and
slowly added to a suspension of sodium hydride (2.94 g, 60%
dispersion in oil) in tetrahydrofuran (60 ml) at -78.degree. C. A
solution of ethyl bromoacetate (8.2 ml) in tetrahydrofuran (5 ml)
was added and the mixture was allowed to warm to 20.degree. C. and
stirred for 30 min. Aqueous ammonium chloride solution was added
and the mixture was extracted with ether. The organic layers were
dried (MgSO.sub.4), concentrated and purified (SiO.sub.2,
ether:isohexane 1:5 as eluant) to afford a colourless oil. A
solution of this oil and triphenylphosphine (17.89 g) in
tetrahydrofuran (90 ml) was stirred for 10 min. Water (15 ml) was
added and the solution was stirred for 18 hours. The solvent was
removed in vacuo and the residue azeotroped with toluene then
purified (SiO.sub.2, ethyl acetate then ethyl
acetate-methanol-ammonia (90:9:1) as eluant) to afford a pale
yellow oil (7.14 g).
[0153] A solution of this compound in tetrahydrofuran (50 ml) was
added over 25 min to a solution of
4,6-dichloro-5-nitro-2-[(3,3,3-trifluoropropyl)thio]pyrimidine
(prepared as described in International Patent Application WO
9703084) (24.8 g) and N,N-diisopropylethylamine (77.5 ml) in dry
tetrahydrofuran (100 ml) and then stirred for 30 minutes. Water was
added and the mixture was extracted with ether (three times). The
organic layers were dried (MgSO.sub.4), concentrated and purified
(SiO.sub.2, ethyl acetate:isohexane 1:4 as eluant) to afford the
subtitle compound (7.39 g).
[0154] MS (APCI) 367/9 (M-(EtO.sub.2CCH.sub.2O).sup.+), 367
(100%)
b) (1S-cis)
2-[[4-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]--
pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid, ethyl
ester
[0155] Prepared according to the method of example 3, steps e) and
f) using the product of step a).
[0156] MS (APCI) 348/50 (M-(EtO.sub.2CCH.sub.2O).sup.+), 348
(100%).
c)
[1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triaz-
olo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-acetic acid,
ethyl ester
[0157] Prepared according to the method of example 3, step g) using
the product of step b).
[0158] MS (APCI) 433 (M+H.sup.-, 100%).
d)
[1S-(cis)]2-[[4-[7-Amino-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triaz-
olo[4,5-d]pyrimidin-3-yl]-2-cyclopenten-1-yl]oxy]-1-ethanol
[0159] Prepared according to the method of example 3, step k) using
the product of step c).
[0160] MS (APCI) 391 (M+H.sup.-, 100%).
e)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-2-[6-[7-Amino-5-[(3,3,3-t-
rifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2-
,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol
[0161] A solution of the product from step d) (454 mg), osmium
tetroxide (0.17 ml of 0.1 M solution in t-butanol),
N-methylmorpholine N-oxide (2.10 mg) and pyridine (0.09 ml) in
acetone (5 ml) and water (1 ml) was heated at 70.degree. C. for 5
hours. Sodium hydrosulfite (330 mg) in water (1 ml) was added, the
solvent was remove in vacuo and the residue azeotroped with
toluene. A solution of this and p-toluenesulfonic acid (50 mg) in
acetone (5 ml) and 2,2-dimethoxypropane (2 ml) was stirred for 3 h.
The solvent was remove in vacuo, aq sodium hydrogen carbonate
solution added and the mixture was extracted with ethyl acetate.
The organic layers were dried (MgSO.sub.4), concentrated and
purified (SiO.sub.2,isohexane:acetone 5:2 as eluant) to afford the
subtitle compound as a white solid (367 mg).
[0162] MS (APCI) 465 (M+H.sup.-, 100%)
f)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-2-[6-[7-Bromo-5-[(3,3,3-t-
rifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2-
,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy]ethanol
[0163] Prepared according to the method of Example 3, step i) using
the product of step e).
[0164] MS (APCI) 528/30 (M+H.sup.-), 528 (100%)
g)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]-2-[6-(7-Phenylcyc-
lopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]py-
rimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxy]ethanol
[0165] Prepared according to the method of Example 3, step j) using
the product of step f) and (1R-trans)-2-phenyl-cyclopropanamine,
[R--(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described
by L. A. Mitscher et al., J. Med. Chem. 1986, 29, 2044).
[0166] MS (APCI) 581 (M+H.sup.+, 100%)
h) [1S-[1.alpha.,2.alpha.,
3.beta.,5.beta.(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
[0167] Prepared according to the method of Example 1, step h) using
the product of step g).
[0168] MS (APCI) 540 (M+H.sup.+, 100%).
[0169] NMR .delta.H (d.sub.b-DMSO) 7.35-7.16 (5H, m), 4.97 (1H, q),
4.62-4.54 (1H, m), 3.98-3.92 (1H, m), 3.78-3.72 (1H, m), 3.55-3.44
(4H, m), 3.26-3.19 (2H, m), 3.16-3.07 (1H, m), 2.70-2.61 (1H, m),
2.58-2.52 (1H, m), 2.23-2.18 (1H, m), 2.05-1.97 (1H, m), 1.86 (1H,
s), 1.54-1.46 (1H, m), 1.38-1.30 (1H, m).
Example 8
[1S-[1.alpha.,2.beta.,3.beta.,4.alpha.(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
a)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]-6-[[7-[(3,4-Diflu-
orophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimi-
din-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol
[0170] The subtitle compound was prepared according to the method
of Example 1, step e) using the product of Example 3, step f) and
the product of example 2, step d).
[0171] MS (APCI) 519 (M.+-.H.sup.+, 100%).
b)
[3aR-[3a.alpha.;4.alpha.,6.alpha.(1R*,2S*),6.alpha.]]-6-[[7-[(3,4-Diflu-
orophenyl)cyclopropyl]amino]-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]py-
rimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol
[0172] The subtitle compound was prepared according to the method
of Example 1, step f) using the product of step a).
[0173] MS (APCI) 551 (M+H.sup.+, 100%).
c)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-6-[5-(Butylthio)-
-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyri-
midin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol
[0174] The subtitle compound was prepared according to the method
of Example 4, step c) using the product of step b).
[0175] MS (APCI) 533 (M+H.sup.+, 100%)
d)
[1S-[1.alpha.,2.beta.,3.beta.,4.alpha.(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
[0176] The title compound was prepared according to the method of
Example 1, step h) using the product of step c).
[0177] NMR .delta.H (d.sub.6-DMSO) 7.15-6.98 (3H, m), 6.67 (1H, s),
5.11-5.09 (1H, m), 4.82-4.76 (1H, m), 4.34-4.21 (3H, m), 3.7 (1H,
s), 3.2-2.92 (4H, m), 2.77 (1H, m), 2.42-2.36 (1H, m), 2.2-2.18
(1H, m), 1.42-1.25 (6H, m), 0.9 (3H, q).
[0178] MS (APCI) 493 (M.+-.+H.sup.+, 100%)
Example 9
[1S-[1a.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.]]-3-[5-(Butylthio)-7-[(2--
phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydr-
oxethoxy)-cyclopentane-1,2-diol
a)
[3aS-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[Tetrahydro-6-hydroxy-2,2-
-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid,
phenylmethyl ester
[0179] Potassium carbonate (39.3 g) was added to a suspension of
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-6-amino-tetrahydro-2,2-dime-
thyl-4H-cyclopenta-1,3-dioxol-4-ol, hydrochloride, (prepared as
described in WO 9905142) (27.1 g) in 4-methyl-2-pentanone (500 ml).
Water (150 ml) was then added followed by dropwise addition of
benzyl chloroformate (23.1 g). The reaction mixture was stirred at
room temperature for 4 hours before the organic phase was
separated. The aqueous phase was extracted with
4-methyl-2-pentanone (2.times.50 ml). The combined organics were
concentrated and the residue was purified (SiO.sub.2,
dichloromethane:methanol, 95:5 to 90:10 as eluant) to give the
subtitle compound (39.23 g).
[0180] NMR .delta.H (CDCl.sub.3) 7.32 (5H, m), 5.65 (1H, br s),
5.10 (2H, br s), 4.59 (1H, d), 4.48 (1H, d), 4.27 (1H, m), 4.19
(1H, br m), 2.24 (1H, br s), 1.69 (1H, d), 1.41 (3H, s), 1.26 (3H,
s).
b)
[3aS-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[2,2-Dimethyl-6-(2-hydrox-
yethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid,
phenylmethyl ester
[0181] Potassium tert-butoxide (3.6 g) in tetrahydrofuran (20 ml)
was added over 5 minutes to a solution of the product from step a)
(39.23 g) in tetrahydrofuran (200 ml). After 15 minutes, ethyl
bromoacetate (3.7 ml) in tetrahydrofuran (10 ml) was added
dropwise. The mixture to was stirred at 0.degree. C. for 10
minutes, then further ethyl bromoacetate was added (3.7
ml.times.4). The reaction mixture was stirred at 0.degree. C. a
further 2 hours. Lithium borohydride (2.79 g) was then added
portionwise to the resulting suspension and the reaction mixture
was stirred at <5.degree. C. for 16 hours. Glacial acetic acid
(23 g) was added dropwise to the cold mixture. After stirring for
30 minutes, water (100 ml) was added dropwise and the resulting
mixture was stirred for 30 minutes. The phases were then separated
and the aqueous phase was extracted with ethyl acetate. The
combined organics were washed with saturated sodium bicarbonate and
brine, dried and concentrated. The residue was purified (SiO.sub.2,
ethyl acetate:hexane, 25:75 to 50:50 as eluant) to give the
subtitle compound (38.6 g).
[0182] MS (APCI) 218 (M+H.sup.+, 100%).
c))
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-2-[[6-Amino-2,2-dimethyl-
-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol
[0183] A slurry of 5% palladium on charcoal (4 g) in ethanol was
added to a solution of the product from step b) (39.96 g) in
ethanol (250 ml) and the mixture was hydrogenated at 1.2 bar for 20
hours. The catalyst was filtered off and the filtrate was
concentrated to give the subtitle compound (23.65 g).
[0184] MS (APCI) 160 (M+H.sup.+, 100%).
d) 2-(Butylthio)-4,6-dichloropyrimidine-5-amine
[0185] The subtitle compound was prepared according to the method
of example 3, step e) using
2-(butylthio)-4,6-dichloro-5-nitro-pyrimidine (prepared as
described in DE 2223644).
[0186] NMR .delta.H (CDCl.sub.3) 4.20 (2H, br s), 3.10 (2H, t),
1.70 (2H, m), 1.47 (2H, m), 0.95 (3H, t).
e)
[3aR-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-2-[[6-[[5-Amino-2-(butylt-
hio)-6-chloro-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta--
1,3-dioxol-4-yl]oxy]ethanol
[0187] The subtitle compound was prepared according to the method
of example 3, step d) using the products of steps c) and d).
[0188] MS (APCI) 433 (M+H.sup.+, 100%).
f)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(1R*,2S*),6a.alpha.]]-2-[6-[[5-(Butylt-
hio)-7-chloro-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimet-
hyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol
[0189] The subtitle compound was prepared according to the method
of Example 3, step f) using the product of step e).
[0190] NMR .delta.H (CDCl.sub.3) 5.53 (1H, m), 5.21 (1H, m), 4.88
(1H, d), 4.05 (1H, m), 3.59 (4H, m), 3.24 (2H, t), 2.70 (1H, m),
2.53 (1H, m), 2.13 (1H, t), 1.79 (2H, m), 1.55 (5H, m), 1.37 (3H,
s), 0.98 (3H, t).
g)
[3aR-[3a.alpha.,4.alpha.,6.alpha.(R*,2S*),6a.alpha.]]-2-[6-[[5-(Butylth-
io)-7-[2-phenylcyclopropyl]amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-t-
etrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol
[0191] The subtitle compound was prepared according to the method
of Example 3, step j) using the product of step f).
[0192] MS (APCI) 541 (M+H.sup.+, 100%).
h)
[1S-[1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.]]-3-[5-(Butylthio)-7-[(-
2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hy-
droxethoxy)-cyclopentane-1,2-diol
[0193] The title compound was prepared according to the method of
example 1, step h) using the product of step g).
[0194] MS (APCI) 501 (M+H.sup.+, 100%)
[0195] NMR .delta.H (d.sub.6-DMSO) 9.33 (1H, d), 7.30 (2H, m), 7.18
(3H, m), 5.12 (1H, d), 5.04 (1H, d), 4.96 (1H, q), 4.59 (2H, m),
3.94 (1H, s), 3.76 (1H, m), 3.51 (4H, m), 3.22 (1H, m), 2.98 (1H,
m), 2.86 (1H, m), 2.65 (1H, m), 2.14 (1H, m), 2.05 (1H, m),
1.21-1.53 (6H, m), 0.80 (3H, t).
Pharmacological Data
[0196] The preparation for the assay of the P.sub.2T (P2Y.sub.ADP
or P2T.sub.AC) receptor agonist/antagonist activity in washed human
platelets for the compounds of the invention was carried out as
follows.
[0197] Human venous blood (100 ml) was divided equally between 3
tubes, each containing 3.2% trisodium citrate (4 ml) as
anti-coagulant. The tubes were centrifuged for 15 minutes at 240G
to obtain a platelet-rich plasma (PRP) to which 300 ng/ml
prostacyclin was added to stabilize the platelets during the
washing procedure. Red cell free PRP was obtained by centrifugation
for 10 minutes at 125G followed by further centrifugation for 15
minutes at 640G. The supernatant was discarded and the platelet
pellet resuspended in modified, Calcium Free Tyrode solution (10
ml) (CFT), composition: NaCl 137 mM, NaHCO.sub.3 11.9 mM,
NaH.sub.2PO.sub.4 0.4 mM, KCl 2.7 mM, MgCl.sub.2 1.1 mM, dextrose
5.6 mM, gassed with 95% O.sub.2/5% CO.sub.2 and maintained at
37.degree. C. Following addition of a further 300 ng/ml PGI.sub.2,
the pooled suspension was centrifuged once more for 15 minutes at
640G. The supernatant was discarded and the platelets resuspended
initially in 10 ml CFT with further CFT added to adjust the final
platelet count to 2.times.10.sup.5/ml. This final suspension was
stored in a 60 ml syringe at 3.degree. C. with air excluded. To
allow recovery from PGI-inhibition of normal function, platelets
were used in aggregation studies no sooner than 2 hours after final
resuspension.
[0198] In all studies, 3 ml aliquots of platelet suspension were
added to tubes containing CaCl.sub.2 solution (60 .mu.l of 50 mM
solution with a final concentration of 1 mM). Human fibrinogen
(Sigma, F 4883) and 8-sulphophenyltheophylline (8-SPT which was
used to block any P.sub.1-agonist activity of compounds) were added
to give final concentrations of 0.2 mg/ml (60 .mu.l of 10 mg/ml
solution of clottable protein in saline) and 300 nM (10 .mu.l of 15
mM solution in 6% glucose), respectively. Platelets or buffer as
appropriate were added in a volume of 150 .mu.l to the individual
wells of a 96 well plate. All measurements were made in triplicate
in platelets from each donor.
[0199] The agonist/antagonist potency was assessed as follows.
[0200] Aggregation responses in 96 well plates were measured using
the change in absorbance given by the plate reader at 660 nm.
Either a Bio-Tec Ceres 900C or a Dynatech MRX were used as the
plate reader.
[0201] The absorbance of each well in the plate was read at 660 nm
to establish a baseline figure. Saline or the appropriate solution
of test compound was added to each well in a volume of 10 .mu.l to
give a final concentration of 0.0.01, 0.1, 1, 10 or 100 mM. The
plate was then shaken for 5 min on an orbital shaker on setting 10
and the absorbance read at 660 nm. Aggregation at this point was
indicative of agonist activity of the test compound. Saline or ADP
(30 mM; 10 .mu.l of 450 mM) was then added to each well and the
plate shaken for a further 5 min before reading the absorbance
again at 660 nm.
[0202] Antagonist potency was estimated as a % inhibition of the
control ADP response to obtain an IC.sub.50. Compounds exemplified
have pIC.sub.50 values of more than 5.0.
* * * * *