Azetidine analogues of nucleosidase and phosphorylase inhibitors
View Patent ↗Disclosed are azetidine analogues of nucleosidase and nucleoside phosphorylase inhibitors, the use of these compounds as pharmaceuticals, pharmaceutical compositions containing the compounds, methods of treating certain diseases using the compounds, processes for preparing the compounds, and intermediates useful in the preparation of the compounds.
1. A compound of formula (I):
wherein:
W and X are each independently selected from hydrogen, CH 2 OH, CH 2 OQ and CH 2 SQ;
Y and Z are each independently selected from hydrogen, halogen, CH 2 OH, CH 2 OQ, CH 2 SQ, SQ, OQ and Q;
Q is an alkyl, aralkyl or aryl group each of which may be optionally substituted with one or more substituents selected from hydroxy, halogen, methoxy, amino, or carboxy;
R 1 is a radical of the formula (II)
A is selected from CH and CR 2 , where R 2 is selected from halogen, alkyl, aralkyl, aryl, OH, NH 2 , NHR 3 , NR 3 R 4 and SR 5 , where R 3 , R 4 and R 5 are each alkyl, aralkyl or aryl groups optionally substituted with hydroxy or halogen, and where R 2 is optionally substituted with hydroxy or halogen when R 2 is alkyl, aralkyl or aryl;
B is selected from hydroxy, NH 2 , NHR 6 , SH, hydrogen and halogen, where R 6 is an alkyl, aralkyl or aryl group optionally substituted with hydroxy or halogen;
D is selected from hydroxy, NH 2 , NHR 7 , hydrogen, halogen and SCH 3 , where R 7 is an alkyl, aralkyl or aryl group optionally substituted with hydroxy or halogen;
E is N;
G is a C 1-4 saturated or unsaturated alkyl group optionally substituted with hydroxy or halogen;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof.
2. A compound as claimed in claim 1 where W is CH 2 OH or CH 2 SQ.
3. A compound as claimed in claim 2 where W is CH 2 SCH 3 .
4. A compound as claimed in claim 1 where X is CH 2 OH or CH 2 SQ.
5. A compound as claimed in claim 4 where W is CH 2 SCH 3 .
6. A compound as claimed in claim 1 where Z is selected from hydrogen, halogen, CH 2 OH, CH 2 OQ and CH 2 SQ.
7. A compound as claimed in claim 6 where Y or Z is CH 2 OH.
8. A compound as claimed in claim 6 where Y or Z is CH 2 SQ or CH 2 OQ.
9. A compound as claimed in claim 1 where either or both of Y or Z is Q.
10. A compound as claimed in claim 6 where either or both of Y or Z is CH 2 OH.
11. A compound as claimed in claim 1 where W and X are both hydrogen.
12. A compound as claimed in claim 11 where either or both of Y or Z is CH 2 OH.
13. A compound as claimed in claim 11 where either or both of Y or Z is CH 2 SQ.
14. A compound as claimed in claim 1 where Y and Z are both hydrogen.
15. A compound as claimed in claim 1 where G is CH 2 .
16. A compound as claimed in claim 1 where B is hydroxy or NH 2 .
17. A compound as claimed in claim 1 where A is CH.
18. A compound as claimed in claim 1 where D is H or NH 2 .
19. A compound as claimed in claim 1 where, when any of Y, Z, B and D is halogen, each halogen is independently chlorine or fluorine.
20. A compound as claimed in claim 1 which is selected from the following:
i. 7-((2,4-bis(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
ii. 7-((3,3-bis(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
iii. 7-((2-(hydroxymethyl)azetidin-1-yl) methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
iv. 7-((3-(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
v. 7-((3-hydroxy-3-(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
vi. 7-((3-hydroxy-2-(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
vii. 2-amino-7-((2,4-bis(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
viii. 2-amino-7-((3,3-bis(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
ix. 2-amino-7-((2-(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
x. 2-amino-7-((3-(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
xi. 2-amino-7-((3-hydroxy-3-(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
xii. 2-amino-7-((3-hydroxy-2-(hydroxymethyl)azetidin-1-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one;
xiii. (1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-3-(methylthiomethyl)azetidin-3-yl)methanol;
xiv. 1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-3-(methylthiomethyl)azetidin-3-ol;
xv. (1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)azetidin-2-yl)methanol;
xvi. 7-((2-(methylthiomethyl)azetidin-1-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
xvii. 7-((3-(methylthiomethyl)azetidin-1-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; or
xviii. 1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-2-(methylthiomethyl)azetidin-3-ol.
21. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically effective excipient, diluent or carrier.
22. A pharmaceutical composition comprising a compound of claim 20 and a pharmaceutically effective excipient, diluent or carrier.