3-hydroxypyrrolidine inhibitors of 5′-methylthioadenosine phosphorylase and nucleosidase

Patent metadata

Field	Value
Publication number	US-9957272-B2
Application number	US-201615347944-A
Country	US
Kind code	B2
Filing date	Nov 10, 2016
Priority date	Jul 17, 2009
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Victoria Link Ltd
• Albert Einstein College Medicine Inc

Inventors

• Evans Gary Brian
• Longshaw Alistair Ian
• Schramm Vern L
• Tyler Peter Charles

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P31/04

  Antibacterial agents · CPC title