3-substituted 5-amino-6H-thiazolo[4,5-d]pyrimidine-2,7-dione compounds for the treatment and prophylaxis of virus infection

Patent metadata

Field	Value
Publication number	US-10040815-B2
Application number	US-201615207338-A
Country	US
Kind code	B2
Filing date	Jul 11, 2016
Priority date	Dec 8, 2014
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

The present invention relates to compounds of formula (I),

wherein R 1 , R 2 and R 3 are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.

First claim

We claim:

1. A compound of formula (I),

wherein
R 1 is hydroxy or C 1-6 alkylcarbonyl-O-;
R 2 is C 1-6 alkyl; and
R 3 is hydrogen or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

2. A compound according to claim 1 , wherein
R 1 is hydroxy or acetyloxy;
R 2 is ethyl or propyl; and
R 3 is hydrogen, acetyl or isobutyryl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

3. A compound of formula (Ia) according to claim 1 ,

wherein
R 1 is hydroxy or C 1-6 alkylcarbonyl-O-;
R 2 is C 1-6 alkyl; and
R 3 is hydrogen or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

4. A compound according to claim 3 , wherein
R 1 is hydroxy or acetyloxy;
R 2 is ethyl or propyl; and
R 3 is hydrogen, acetyl or isobutyryl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

5. A compound according to claim 1 selected from the group consisting of:
5-Amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxypropyl)tetrahydrofuran-2-yl]-6H-thiazolo [4,5-d]pyrimidine-2,7-dione;
[(2R,3R,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-(1-hydroxypropyl)tetrahydrofuran-3-yl] acetate;
[(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo [4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate;
5-Amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxybutyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione; and
[(1S)-1-[(2S,4R,5R)-5-(5-Amino-2,7-dioxo-6H-thiazolo [4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] 2-methylpropanoate;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

6. A compound of formula (II),

wherein
R 4 is hydroxy or C 1-6 alkylcarbonyl-O-;
R 5 is C 1-6 alkyl or C 3-7 cycloalkyl; and
R 6 is hydrogen or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

7. A compound according to claim 6 , wherein
R 4 is hydroxy or acetyloxy;
R 5 is ethyl or cyclopropyl; and
R 6 is hydrogen or acetyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

8. A compound of formula (IIa) according to claim 6 ,

wherein
R 4 is hydroxy or C 1-6 alkylcarbonyl-O-;
R 5 is C 1-6 alkyl or C 3-7 cycloalkyl; and
R 6 is hydrogen or C 1-6 alkylcarbonyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

9. A compound according to claim 8 , wherein
R 4 is hydroxy or acetyloxy;
R 5 is ethyl or cyclopropyl; and
R 6 is hydrogen or acetyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

10. A compound according to claim 6 selected from the group consisting of:
5-Amino-3-[(2R,3R,5S)-3-hydroxy-5-(1-hydroxypropyl)tetrahydrofuran-2-yl]thiazolo[4,5-d]pyrimidin-2-one;
[(2R,3R,5S)-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-5-(1-hydroxypropyl)tetrahydrofuran-3-yl] acetate; and
1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl acetate;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

11. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and a therapeutically inert carrier.

12. A pharmaceutical composition comprising a compound in according to claim 6 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and a therapeutically inert carrier.

13. A method for treating a Hepatitis B virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14. A method for treating a Hepatitis B virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

15. A method of activating the TLR7 receptor in a patient in need thereof comprising administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

16. A method of activating the TLR7 receptor in a patient in need thereof comprising administering an effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

17. A method of stimulating production of interferon-α comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

18. A method of stimulating production of interferon-a comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Assignees

• Hoffmann La Roche

Inventors

• Chen Dongdong
• Feng Song
• Gao Lu
• Li Chao
• Wang Baoxia
• Wang Lisha
• Yun Hongying
• Zheng Xiufang

Classifications

• A61P43/00

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

• A61P31/20

  for DNA viruses · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P1/16

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