Dioxolane analogues of uridine for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10654877-B2
Application number	US-201916459165-A
Country	US
Kind code	B2
Filing date	Jul 1, 2019
Priority date	Aug 25, 2014
Publication date	May 19, 2020
Grant date	May 19, 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 method for the treatment of liver cancer, comprising the oral administration to a warm blooded animal of a therapeutically effective amount of a compound of the formula Ia:

wherein:
R 1 is NH 2 ;
R 2 is H;
R 13 is phenyl, optionally substituted with 1, 2 or 3 R 22 ;
R 15 is methyl;
R 16 is 2-pentyl;
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 and/or solvate thereof.

2. The method according to claim 1 , wherein R 13 is substituted with one or two R 22 .

3. The method according to claim 1 , wherein R 13 is unsubstituted phenyl.

4. The method according to claim 1 , wherein the compound of formula Ia is:

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein the compound of formula Ia is

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 , wherein the compound of formula Ia is

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 , wherein the liver cancer is hepatocellular carcinoma.

8. The method according to claim 1 , wherein the liver cancer is a secondary liver cancer, that is a cancer that has originated in an organ elsewhere in the body and has metastasised to the liver.

9. The method according to claim 8 , wherein the cancer has metastasised to the liver from colon, lung or breast.

10. The method according to claim 1 , wherein the warm-blooded animal is a human.

11. A compound of the formula:

12. The compound according to claim 11 , which is at least 90% diastereomerically pure.

Assignees

• Medivir Ab

Inventors

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

Classifications

• A61K31/675

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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D405/04 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title