Glucuronide prodrugs of Janus kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10745405-B2
Application number	US-201815986028-A
Country	US
Kind code	B2
Filing date	May 22, 2018
Priority date	May 23, 2017
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

Abstract

The invention relates to glucuronide prodrug compounds of Janus kinase (JAK) inhibitors having formula I:

where W 1 , R 1 and A 1 are as defined. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds to treat gastrointestinal inflammatory diseases; and processes and intermediates for preparing such compounds.

First claim

What is claimed is:

1. A compound of formula I:

wherein
R 1 is hydrogen or C 1-3 alkyl;
W 1 is selected from:

and A 1 is a group having the formula (iv)

wherein f is 2 or 3; R 5 is hydrogen or C 1-3 alkyl; and B 3 is selected from C 6-10 aryl and C 1-9 heteroaryl; wherein the heteroaryl group contains from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; the aryl or heteroaryl group is unsubstituted or substituted with 1 to 3 substituents independently selected from C 1-4 alkyl, C 1-3 alkoxy, amino, cyano, halo, hydroxy, nitro and trifluoromethyl;
or a pharmaceutically-acceptable salt thereof.

2. The compound of claim 1 , wherein W 1 has formula (1).

3. The compound of claim 1 , wherein W 1 has formula (2).

4. The compound of claim 1 , wherein W 1 has formula (3).

5. The compound of claim 1 having the formula VI:

wherein
f is 2 or 3;
q is 0, 1 or 2;
R 1 is hydrogen or C 1-3 alkyl;
R 5 is hydrogen or C 1-3 alkyl;
R 12 is hydrogen, C 1-4 alkyl, C 1-3 alkoxy, amino, cyano, halo, hydroxy, nitro or trifluoromethyl;
each R 13 , when present, is independently selected from C 1-4 alkyl, C 1-3 alkoxy, amino, cyano, halo, hydroxyl, nitro and trifluoromethyl; and
W 1 is selected from:

or a pharmaceutically-acceptable salt thereof.

6. The compound of claim 5 , wherein W 1 has formula (1).

7. The compound of claim 5 , wherein W 1 has formula (2).

8. The compound of claim 5 , wherein W 1 has formula (3).

9. The compound of claim 5 , wherein R 1 is methyl.

10. The compound of claim 5 , wherein f is 2.

11. The compound of claim 5 , wherein R 5 is methyl.

12. The compound of claim 5 , wherein q is 0.

13. The compound of claim 5 , wherein R 12 is hydrogen, C 1-4 alkyl, halo, nitro or trifluoromethyl.

14. The compound of claim 5 , wherein f is 2; q is 0; R 1 is methyl; R 5 is methyl; and R 12 is hydrogen, C 1-4 alkyl, halo, nitro or trifluoromethyl.

15. The compound of claim 1 having the formula VII:

wherein
R 12 is hydrogen, C 1-4 alkyl, C 1-3 alkoxy, amino, cyano, halo, hydroxy, nitro or trifluoromethyl; and
W 1 is selected from:

or a pharmaceutically-acceptable salt thereof.

16. The compound of claim 15 , wherein W 1 has formula (1).

17. The compound of claim 15 , wherein W 1 has formula (2).

18. The compound of claim 15 , wherein W 1 has formula (3).

19. The compound of claim 15 , where R 12 is hydrogen.

20. The compound of claim 15 , where R 12 is nitro.

21. A pharmaceutical composition comprising a pharmaceutically acceptable-carrier and a compound of claim 1 .

22. A method of treating a gastrointestinal inflammatory disease selected from the group consisting of ulcerative colitis, Crohn's disease and colitis associated with immune checkpoint inhibitor therapy, in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically acceptable-carrier and a compound of claim 1 .

23. The method of claim 22 , wherein the gastrointestinal inflammatory disease is ulcerative colitis.

24. The method of claim 22 , wherein the gastrointestinal inflammatory disease is Crohn's disease.

25. The method of claim 22 , wherein the gastrointestinal inflammatory disease is colitis associated with immune checkpoint inhibitor therapy.

26. A process for preparing a compound of claim 1 , the process comprising deprotecting a compound of formula 3:

wherein
R 1 , W 1 and A 1 are as defined in claim 1 ;
P 1 is a carboxy-protecting group; and
each P 2 is independently a hydroxyl-protecting group;
or a salt thereof;
to provide a compound of claim 1 .

27. A process for preparing a compound of claim 1 , the process comprising:
(a) contacting a compound of formula 1:

wherein
W 1 is as defined in claim 1 ;
L 1 is an acyl leaving group;
or a salt thereof;
with a compound of formula 2:

wherein
R 1 and A 1 are as defined in claim 1 ;
P 1 is a carboxy-protecting group; and
each P 2 is independently a hydroxyl-protecting group;
or a salt thereof;
to provide a compound of formula 3:

or a salt thereof; and
(b) deprotecting the compound of formula 3, or a salt thereof, to provide a compound of claim 1 .

28. A process for preparing a compound of claim 1 , the process comprising:
(a) contacting a compound of formula 4:

wherein W 1 is as defined in claim 1 ;
or a salt thereof;
with a compound of formula 5:

wherein
R 1 and A 1 are as defined in claim 1 ;
L 2 is an acyl leaving group;
P 1 is a carboxy-protecting group; and
each P 2 is independently a hydroxyl-protecting group;
or a salt thereof;
to provide a compound of formula 3:

or a salt thereof, and
(b) deprotecting the compound of formula 3, or a salt thereof, to provide a compound of claim 1 .

29. A compound of formula VII-1:

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1 , wherein the compound has the formula VII-2:

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1 , wherein the compound has the formula VII-3:

or a pharmaceutically acceptable salt thereof.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Long Daniel D
• Wilton Donna A A
• Loo Mandy M
• Hudson Ryan
• Brassil Patrick J

Classifications

• C07H17/02

  Heterocyclic radicals containing only nitrogen as ring hetero atoms · CPC title

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C07H13/12

  by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title