Fused pyrimidines as inhibitors of nucleoside phosphorylases and nucleosidases
View Patent ↗The present invention relates to compounds of the general formula (I) which are inhibitors of purine muclioside phosphorylases (PNP), purine phosphoribosyltransferases (PPRT), 5′-methylthioadenosine phosphorylases (MTAP), 5′-methylthioadenosine mucliosidases (MTAN) and/or nucleoside hydrolases (NH). The invention also relates to the use of these compounds in the treatment of diseases and infections including cancer, bacterial infections, protozoal infections, and T-cell mediated disease and to pharmaceutical compositions containing the compounds.
1. A compound of the formula (I):
wherein:
V is selected from CH 2 and NH, and W is NR 1 ; or V is NR 1 , and W is selected from CH 2 and NH;
X is selected from CH 2 and CHOH in the R or S-configuration;
Y is selected from hydrogen, halogen and hydroxy, except where V is selected from NH and NR 1 , then Y is hydrogen;
Z is selected from hydrogen, halogen, hydroxy, SQ, OQ and Q, where Q is an alkyl, aralkyl or aryl group;
R 1 is a radical of the formula (II)
A is N;
B is selected from OH, NH 2 , NHR 6 , SH, hydrogen and halogen, where R 6 is an alkyl, aralkyl or aryl group;
D is selected from OH, NH 2 , NHR 7 , hydrogen, halogen and SCH 3 , where R 7 is an alkyl, aralkyl or aryl group;
E is N;
G is selected from CH 2 and NH, or G is absent, provided that where W is NR 1 and G is NH then V is CH 2 , and provided that where V is NR 1 and G is NH then W is CH 2 ,
or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 , where Z is selected from hydrogen, halogen, hydroxy, SQ and OQ.
3. A compound as claimed in claim 1 , where V is CH 2 .
4. A compound as claimed in claim 1 , where X is CH 2 .
5. A compound as claimed in claim 1 , where G is CH 2 .
6. A compound as claimed in claim 1 , where Z is OH.
7. A compound as claimed in claim 1 , where Z is SQ.
8. A compound as claimed in claim 1 , where Z is Q.
9. A compound as claimed in claim 1 , where W is NR 1 .
10. A compound as claimed in claim 1 , where W is selected from NH and NR 1 , and X is CH 2 .
11. A compound as claimed in claim 1 , where V, X and G are all CH 2 , Z is OH and W is NR 1 .
12. A compound as claimed in claim 1 , where V, X and G are all CH 2 , Z is SQ and W is NR 1 .
13. A compound as claimed in claim 1 , where Y is hydrogen.
14. A compound as claimed in claim 1 , where Y is hydroxy.
15. A compound as claimed in claim 1 , where B is hydroxy.
16. A compound as claimed in claim 1 , where B is NH 2 .
17. A compound as claimed in claim 1 , where D is H.
18. A compound as claimed in claim 1 , where D is NH 2 .
19. A compound as claimed in claim 1 , which is:
(3R,4R)-1-[(8-aza-9-deazahypoxanthin-9-yl)methyl]-3-hydroxy-4-(hydroxymethyl)pyrrolidine;
(3R,4R)-1-[(8-aza-9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(hydroxymethyl)pyrrolidine;
(3R,4R)-3-hydroxy-4-hydroxymethyl-1-(hypoxanthin-9-yl)pyrrolidine; or
(3R,4S)-1-[(8-aza-9-deezaadenin-9-yl)methyl]-3-hydroxy-4-(benzylthiomethyl)pyrrolidine;
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a compound as claimed in claim 1 and a carrier.