Prodrugs of a JAK Inhibitor Compound for Treatment of Gastrointestinal Inflammatory Disease

Patent metadata

Field	Value
Publication number	US-2019389895-A1
Application number	US-201916555222-A
Country	US
Kind code	A1
Filing date	Aug 29, 2019
Priority date	Nov 24, 2015
Publication date	Dec 26, 2019
Grant date	—

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

1 - 14 . (canceled)

15 . 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 any one of claims 1 , 7 , and 11 to

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

17 . The method of claim 15 , wherein the gastrointestinal inflammatory disease is Crohn's disease.

18 . The method of claim 15 , wherein the gastrointestinal inflammatory disease is colitis associated with immune checkpoint inhibitor therapy.

19 . 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.

20 . The method of claim 19 , 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.

21 - 24 . (canceled)

25 . The method of claim 19 , 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.

26 . The method of claim 19 , wherein the glucuronide-containing prodrug of tofacitinib is a compound of formula 1.

or a pharmaceutically acceptable salt thereof.

27 . The method of claim 15 , wherein the gastrointestinal inflammatory disease is selected from the group consisting of celiac sprue, microscopic colitis, and pouchitis.

28 . 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.

29 . The method of claim 28 , wherein the gastrointestinal inflammatory disease is ulcerative colitis.

30 . The method of claim 28 , wherein the gastrointestinal inflammatory disease is Crohn's disease.

31 . The method of claim 28 , wherein the gastrointestinal inflammatory disease is colitis associated with immune checkpoint inhibitor therapy.

32 . The method of claim 28 , wherein the gastrointestinal inflammatory disease is selected from the group consisting of celiac sprue, microscopic colitis, and pouchitis.

33 . 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.

34 . The method of claim 33 , wherein the gastrointestinal inflammatory disease is ulcerative colitis.

35 . The method of claim 33 , wherein the gastrointestinal inflammatory disease is Crohn's disease.

36 . The method of claim 33 , wherein the gastrointestinal inflammatory disease is colitis associated with immune checkpoint inhibitor therapy.

37 . The method of claim 33 , 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

• A61P29/00

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

• A61P1/00

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

• A61P1/04

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

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title