5,7-disubstituted thiazolo[4,5-D]pyrimidines as chemokine inhibitors
There are disclosed novel 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivatives of formula (I) wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the specification, and pharmaceutically acceptable salts thereof, together with processes for their preparation, pharmaceutical compositions comprising them and their use in therapy. The compounds of formula (I) are CX 3 CR1 receptor antagonists and are thereby particularly useful in the treatment or prophylaxis of neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain.
1. A method of treating rheumatoid arthritis in a person comprising administering to the person a therapeutically effective amount of a compound of formula (I),
wherein
R 1 is CH 3 or CH 3 CH 2 ;
R 2 is H, 2-F, 2-Cl, 3-F, 3-OCH 3 , 3-CN, 3-CF 3 , 3-CONH 2 or 3-SO 2 CH 3 ;
R 3 is H or CH 3 ;
R 4 is H or CH 3 ; and
R 5 is H; or, when R 4 is CH 3 , R 5 is H or F;
or a pharmaceutically acceptable salt thereof.
2. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein
R 1 is CH 3 or CH 3 CH 2 ;
R 2 is H, 2-F, 2-Cl, 3-F, 3-OCH 3 , 3-CN, 3-CF 3 , 3-CONH 2 or 3-SO 2 CH 3 ;
R 3 is H or CH 3 ;
R 4 is H or CH 3 ; and
R 5 is H; or, when R 4 is CH 3 , R 5 is H or F;
comprising
reacting a compound of formula (II):
wherein R 3 , R 4 and R 5 are as defined in formula (I);
with a compound of formula (III):
wherein R 1 and R 2 are as defined in formula (I) and L 1 is a leaving group;
to produce the compound of formula (I)
and optionally forming a pharmaceutically acceptable salt of the compound of formula (I).
3. A method of treating rheumatoid arthritis in a person comprising administering to the person a therapeutically effective amount of a compound that is (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol, or a pharmaceutically acceptable salt thereof.
4. A method of treating rheumatoid arthritis in a person comprising administering to the person a therapeutically effective amount of a compound that is:
(2R)-2-[(2-amino-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-({2-amino-5-[(1-phenylethyl)thio][1,3]thiazolo[4,5-d]pyrimidin-7-yl}amino)-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1R)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol;
3-{(1S)-1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)butyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-5-yl)thio]ethyl}benzonitrile;
(2R)-2-{[2-amino-5-({(1S)-1-[3-(methylsulfonyl)phenyl]ethyl}thio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino}-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol;
3-{(1S)-1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-5-yl)thio]ethyl})benzonitrile;
(2R)-2-({2-amino-5-[(1-phenylpropyl)thio][1,3]thiazolo[4,5-d]pyrimidin-7-yl}amino)-4-methylpentan-1-ol;
3-{1-[(2-amino-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-5-yl)thio]ethyl})benzamide;
(2R)-2-{[2-amino-5-({1-[3-(trifluoromethyl)phenyl]ethyl}thio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino}-4-methylpentan-1-ol;
(2R)-2-[{2-amino-5-[(1-phenylethyl)thio][1,3]thiazolo[4,5-d]pyrimidin-7-yl}(methyl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[1-(2-chlorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[1-(3-methoxyphenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-fluoro-4-methylpentan-1-ol;
(2R)-2-[(2-amino-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-fluoro-4-methylpentan-1-ol; or
(2R)-2-[(2-amino-5-{[(1S)-1-(3-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol;
or a pharmaceutically acceptable salt thereof.
5. A method of treating rheumatoid arthritis in a person comprising administering to the person a pharmaceutical formulation comprising (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol, or pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
6. A method of treating rheumatoid arthritis in a person comprising administering to the person a pharmaceutical formulation comprising at least one compound according to claim 4 , or pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
7. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein
R 1 is CH 3 or CH 3 CH 2 ;
R 2 is H, 2-F, 2-Cl, 3-F, 3-OCH 3 , 3-CN, 3-CF 3 , 3-CONH 2 or 3-SO 2 CH 3 ;
R 3 is H or CH 3 ;
R 4 is H or CH 3 ; and
R 5 is H; or, when R 4 is CH 3 , R 5 is H or F;
comprising
reacting a compound of formula (IV)
wherein R 1 and R 2 are as defined in formula (I) and L 2 is a leaving group;
with a compound of formula (V)
wherein R 3 , R 4 and R 5 are as defined in formula (I);
and optionally forming a pharmaceutically acceptable salt of the compound of formula (I).
8. The method of claim 1 , wherein the compound is (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol.