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