Prodrugs of a JAK inhibitor compound for treatment of gastrointestinal inflammatory disease

Patent metadata

Field	Value
Publication number	US-10961267-B2
Application number	US-201916555222-A
Country	US
Kind code	B2
Filing date	Aug 29, 2019
Priority date	Nov 24, 2015
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

Abstract

The invention provides compounds which are prodrugs of a JAK inhibitor agent for the targeted delivery of the JAK inhibitor to the gastrointestinal tract of a mammal. The invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds to treat gastrointestinal inflammatory diseases, and processes and intermediates useful for preparing the compounds.

First claim

What is claimed is:

1. A method of treating a gastrointestinal inflammatory disease in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically acceptable-carrier and a compound of formula (I):

wherein
n is 0, 1 or 2;
R 1 is selected from hydrogen, C 1-4 alkyl, C 1-3 alkoxy, amino, nitro, halo, cyano, hydroxy, and trifluromethyl;
each R 2 , when present, is independently selected from C 1-4 alkyl, C 1-3 alkoxy, amino, nitro, halo, cyano, hydroxyl, and trifluromethyl;
R 3 is hydrogen, methyl or ethyl;
R 4 is hydrogen, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof;
wherein the gastrointestinal inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, celiac sprue, microscopic colitis, pouchitis and colitis associated with immune checkpoint inhibitor therapy.

2. The method of claim 1 , wherein the gastrointestinal inflammatory disease is ulcerative colitis.

3. The method of claim 1 , wherein the gastrointestinal inflammatory disease is Crohn's disease.

4. The method of claim 1 , wherein the gastrointestinal inflammatory disease is colitis associated with immune checkpoint inhibitor therapy.

5. The method of claim 1 , wherein the gastrointestinal inflammatory disease is selected from the group consisting of celiac sprue, microscopic colitis, and pouchitis.

6. A method of delivering tofacitinib to the colon of a mammal, the method comprising orally administering to the mammal a glucuronide-containing prodrug of tofacitinib which prodrug is cleaved by β-glucuronidase in the colon to release tofacitinib, wherein the glucuronide-containing prodrug of tofacitinib is a compound of formula (I):

wherein
n is 0, 1 or 2;
R 1 is selected from hydrogen, C 1-4 alkyl, C 1-3 alkoxy, amino, nitro, halo, cyano, hydroxy, and trifluromethyl;
each R 2 , when present, is independently selected from C 1-4 alkyl, C 1-3 alkoxy, amino, nitro, halo, cyano, hydroxyl, and trifluromethyl;
R 3 is hydrogen, methyl or ethyl;
R 4 is hydrogen, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof.

7. The method of claim 6 , wherein the glucuronide-containing prodrug of tofacitinib is a compound of formula (II):

wherein
R 1 is selected from hydrogen, C 1-4 alkyl, C 1-3 alkoxy, amino, nitro, halo, cyano, hydroxy, and trifluromethyl;
or a pharmaceutically-acceptable salt thereof.

8. The method of claim 6 , wherein the glucuronide-containing prodrug of tofacitinib is a compound of formula 1:

or a pharmaceutically acceptable salt thereof.

9. A method of treating a gastrointestinal inflammatory disease in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically acceptable-carrier and a compound of formula (II):

wherein
R 1 is selected from hydrogen, C 1-4 alkyl, C 1-3 alkoxy, amino, nitro, halo, cyano, hydroxy, and trifluromethyl;
or a pharmaceutically-acceptable salt thereof;
wherein the gastrointestinal inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, celiac sprue, microscopic colitis, pouchitis and colitis associated with immune checkpoint inhibitor therapy.

10. The method of claim 9 , wherein the gastrointestinal inflammatory disease is ulcerative colitis.

11. The method of claim 9 , wherein the gastrointestinal inflammatory disease is Crohn's disease.

12. The method of claim 9 , wherein the gastrointestinal inflammatory disease is colitis associated with immune checkpoint inhibitor therapy.

13. The method of claim 9 , wherein the gastrointestinal inflammatory disease is selected from the group consisting of celiac sprue, microscopic colitis, and pouchitis.

14. A method of treating a gastrointestinal inflammatory disease in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically acceptable-carrier and a compound of formula 1:

or a pharmaceutically acceptable salt thereof;
wherein the gastrointestinal inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, celiac sprue, microscopic colitis, pouchitis and colitis associated with immune checkpoint inhibitor therapy.

15. The method of claim 14 , wherein the gastrointestinal inflammatory disease is ulcerative colitis.

16. The method of claim 14 , wherein the gastrointestinal inflammatory disease is Crohn's disease.

17. The method of claim 14 , wherein the gastrointestinal inflammatory disease is colitis associated with immune checkpoint inhibitor therapy.

18. The method of claim 14 , wherein the gastrointestinal inflammatory disease is selected from the group consisting of celiac sprue, microscopic colitis, and pouchitis.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• C12P17/165

  Heterorings having nitrogen atoms as the only ring heteroatoms · CPC title

• C07H15/26 Primary

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

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P29/00

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