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

Patent metadata

Field	Value
Publication number	US-11608354-B2
Application number	US-202117249126-A
Country	US
Kind code	B2
Filing date	Feb 22, 2021
Priority date	Nov 24, 2015
Publication date	Mar 21, 2023
Grant date	Mar 21, 2023

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 process for preparing 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 trifluoromethyl;
each R 2 , when present, is independently selected from C 1-4 alkyl, C 1-3 alkoxy, amino, nitro, halo, cyano, hydroxyl, and trifluoromethyl;
R 3 is hydrogen, methyl or ethyl;
R 4 is hydrogen, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof, the process comprising deprotecting a compound of formula (I-A):

or a salt thereof; wherein each PG a is independently a hydroxyl protecting group; and PG b is a carboxyl protecting group; to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. The process of claim 1 , wherein R 1 is nitro; R 3 and R 4 are methyl; each PG a is acetyl; PG b is methyl; and n is 0.

3. A process for preparing a compound of formula 1:

or a pharmaceutically acceptable salt thereof, the process comprising:
(a) reacting a compound of formula 12′:

or a salt thereof; wherein each PCS is independently a hydroxyl protecting group, with a compound of formula 13;

to provide a compound of formula 14′:

and
(b) deprotecting the compound of formula 14′ to provide the compound of formula 1 or a pharmaceutically acceptable salt thereof.

4. The process of claim 1 , wherein each PG a is independently selected from the group consisting of acetyl, allyl, and tert-butyldimethylsilyl.

5. The process of claim 1 , wherein each PG a is acetyl.

6. The process of claim 1 , wherein PG b is methyl.

7. The process of claim 1 , wherein R 1 is nitro.

8. The process of claim 1 , wherein R 3 and R 4 are methyl.

9. The process of claim 1 , wherein n is 0.

10. The process of claim 3 , wherein each PG a is independently selected from the group consisting of acetyl, allyl, and tert-butyldimethylsilyl.

11. The process of claim 3 , wherein each PG a is acetyl.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• 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

• C12P17/165

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