3-hydroxypyrrolidine inhibitors of 5′-methylthioadenosine phosphorylase and nucleosidase
View Patent ↗The present invention relates to 3-hydroxypyrrolidine compounds of the general formula (1) which are inhibitors of 5′-methylthioadenosine phosphorylase or 5′-methylthioadenosine nucleosidase. The invention also relates to the use of these compounds in the treatment of diseases or conditions in which it is desirable to inhibit 5′-methylthioadenosine phosphorylase or 5′-methylthioadenosine nucleosidase including cancer, and to pharmaceutical compositions containing the compounds.
1. A compound of the formula (Ia):
where:
X is ethyl;
A is CH;
B is NH 2 or NHR 5 ;
R 5 is an alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, or aryl group, each of which is optionally substituted with one or more halogen or hydroxy groups; and
D is H, OH, NH 2 , or SCH 3 ;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester prodrug form thereof.
2. A compound as claimed in claim 1 which is a compound of the formula (Ib):
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester prodrug form thereof.
3. A compound as claimed in claim 1 where B is NH 2 .
4. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 1 .
5. A method of inhibiting 5′-methylthioadenosine phosphorylase (MTAP) or 5′-methylthioadenosine nucleosidase (MTAN) in a subject comprising contacting the MTAP or MTAN with a compound as claimed in claim 1 in an amount effective to inhibit MTAP or MTAN.
6. The method of claim 5 , wherein the MTAP or MTAN is in a human subject.
7. The method of claim 6 , wherein the subject has cancer or a bacterial or protozoal infection.
8. A method of inhibiting 5′-methylthioadenosine phosphorylase (MTAP) or 5′-methylthioadenosine nucleosidase (MTAN) comprising contacting the MTAP or MTAN with a compound as claimed in claim 1 in an amount effective to inhibit MTAP or MTAN.