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

Patent metadata

Field	Value
Publication number	US-10435428-B2
Application number	US-201615358462-A
Country	US
Kind code	B2
Filing date	Nov 22, 2016
Priority date	Nov 24, 2015
Publication date	Oct 8, 2019
Grant date	Oct 8, 2019

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 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.

2. The compound of claim 1 , or a pharmaceutically-acceptable salt thereof, wherein R 1 is hydrogen.

3. The compound of claim 1 , or a pharmaceutically-acceptable salt thereof, wherein R 1 is nitro.

4. The compound of claim 1 , or a pharmaceutically-acceptable salt thereof, wherein R 1 is amino.

5. The compound of claim 1 , or a pharmaceutically-acceptable salt thereof, wherein n is 0.

6. The compound of claim 1 , or a pharmaceutically-acceptable salt thereof, wherein n is 1.

7. 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 compound of claim 7 , or a pharmaceutically-acceptable salt thereof, wherein R 1 is selected from hydrogen, methyl, methoxy, amino, nitro, and chloro.

9. The compound of claim 7 , or a pharmaceutically-acceptable salt thereof, wherein R 1 is hydrogen.

10. The compound of claim 7 , or a pharmaceutically-acceptable salt thereof, wherein R 1 is amino.

11. A compound of formula 1:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 , wherein the compound is

13. The compound of claim 11 , wherein upon contact with a β-glucuronidase enzyme, a compound of formula 2:

or a salt thereof is produced.

14. A pharmaceutical composition comprising a pharmaceutically acceptable-carrier and a compound of any one of claims 1 , 7 , and 11 to 12 .

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• A61P29/00

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

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title