Dioxolane analogues of uridine for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10822360-B2
Application number	US-202016847477-A
Country	US
Kind code	B2
Filing date	Apr 13, 2020
Priority date	Aug 25, 2014
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The invention provides compounds of the formula:

R 1 is OR 11 , or NR 5 R 5′ ;
R 2 is H or F;
R 5 is H, C 1 -C 6 alkyl, OH, C(═O)R 6 , O(C═O)R 6 or O(C═O)OR 6 ;
R 5′ is H or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;
R 13 is H, phenyl, pyridyl, benzyl, indolyl or naphthyl wherein the phenyl, pyridyl, benzyl, indolyl and naphthyl is optionally substituted with 1, 2 or 3 R 22 ;

and the other variables are as defined in the claims,

which are of use in the treatment of cancer, and related aspects.

First claim

The invention claimed is:

1. A compound represented by formula Ia:

wherein:
R 1 is OR 11 , or NR 5 R 5′ ;
R 2 is F;
R 5 is H, C 1 -C 6 alkyl, OH, C(═O)R 6 , OC(═O)R 6 or OC(═O)OR 6 ;
R 5′ is H or C 1 -C 6 alkyl;
R 6 is C 1 -C 22 alkyl or C 3 -C 7 cycloalkyl;
R 11 is H or C 1 -C 6 alkyl;
R 13 is H, phenyl, pyridyl, benzyl, indolyl or naphthyl wherein the phenyl, pyridyl, benzyl, indolyl and naphthyl is optionally substituted with 1, 2 or 3 R 22 ;
R 15 is C 1 -C 3 alkyl;
R 16 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, benzyl, or phenyl, any of which is optionally substituted with 1, 2 or 3 groups, each independently selected from halo, OR 18 and N(R 18 ) 2 ;
each R 18 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 7 cycloalkyl;
each R 22 is independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, hydroxyC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, carboxyC 1 -C 6 alkyl, hydroxy, amino CN, and NO 2 , or any two R 22 groups attached to adjacent ring carbon atoms can combine to form —O—(CR 23 R 23′ ) 1-6 —O—;
R 23 and R 23′ are independently H or C 1 -C 3 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is NH 2 or NHC(═O)C 1 -C 6 alkyl.

3. A compound according to claim 1 , wherein R 1 is NH 2 .

4. A compound according to claim 1 , wherein R 15 is methyl.

5. A compound according to claim 1 , wherein R 16 is C 3 -C 10 alkyl.

6. A compound according to claim 1 , wherein R 16 is 2-propylpentyl or 2-ethylbutyl.

7. A compound according to claim 1 , wherein R 16 is benzyl.

8. A compound according to claim 1 , wherein R 16 is C 3 -C 7 cycloalky.

9. A compound according to claim 1 , wherein R 13 is phenyl or naphthyl, any of which is optionally substituted with one or two R 22 .

10. A compound according to claim 9 , wherein R 13 is phenyl.

11. A compound according to claim 7 , wherein R 16 is cyclopentyl or cyclohexyl.

12. A compound according to claim 1 , with the formula

or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 with the formula

or a pharmaceutically acceptable salt thereof.

Assignees

• Medivir Ab

Inventors

• Bethell Richard
• Eneroth Anders
• Klasson Bjorn
• Oberg Fredrik

Classifications

• C07F9/65586 Primary

  at least one of the hetero rings does not contain nitrogen as ring hetero atom · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K31/665

  having oxygen as a ring hetero atom, e.g. fosfomycin · CPC title

• C07D405/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title