Phenyloxadiazole derivatives as PGDS inhibitors
This invention is directed to a compound of formula (I): wherein R1, R2 and R3 are as defined herein, a pharmaceutical composition comprising the compound, intermediates and processes for making said compounds, and the use of the compound to treat allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD) and age-related macular degeneration (AMD).
1. A compound of formula (I):
wherein
R1 is hydrogen or C 1 -C 6 alkyl;
R2 is hydrogen, halogen or C 1 -C 3 alkyl; and
R3 is hydroxyalkyl.
2. The compound of claim 1 wherein R1 is hydrogen, R2 is hydrogen and R3 is hydroxyalkyl.
3. The compound of claim 2 which is 2-pyridin-2-yl-pyrimidine-5-carboxylic acid 3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-benzylamide.
4. The compound of claim 1 wherein R1 is C 1 -C 6 alkyl, R2 is hydrogen and R3 is hydroxyalkyl.
5. The compound of claim 4 selected from the group consisting of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid ((S)-1-{3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-phenyl}-ethyl)-amide and 2-pyridin-2-yl-pyrimidine-5-carboxylic acid ((R)-1-{3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-phenyl}-ethyl)-amide.
6. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
7. A method for treating an allergic or inflammatory disorder in a patient in need thereof, wherein the allergic or inflammatory disorder is selected from the group consisting of allergic rhinitis, asthma, and chronic obstructive pulmonary disease, the method comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 .
8. A process for preparing a compound of formula (I):
wherein
R1 is hydrogen or C 1 -C 6 alkyl;
R2 is hydrogen, halogen or C 1 -C 3 alkyl; and
R3 is hydroxyalkyl;
or a pharmaceutically acceptable salt thereof,
the process comprising the step of reacting a compound of formula XI
with an acid compound of formula
in the presence of a suitable coupling reagent.
9. The process of claim 8 wherein the compound of formula (I) is
and the compound of formula XI is
10. The process of claim 9 wherein the suitable coupling reagent is selected from the group consisting of DMTMM, CDI, and TBTU.
11. A process for preparing a compound of formula (I)
wherein
R1 is hydrogen or C 1 -C 6 alkyl;
R2 is hydrogen, halogen or C 1 -C 3 alkyl; and
R3 is hydroxyalkyl;
or a pharmaceutically acceptable salt thereof,
the process comprising the step of reacting a compound of formula XI
with an ester compound of formula
wherein R4 is C 1 -C 3 alkyl,
in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).
12. The process of claim 11 wherein the compound of formula (I) is
and the compound of formula XI is
13. The process of claim 12 wherein R4 of the ester compound is CH 3 .
14. A process for preparing a compound of formula (I):
wherein
R1 is hydrogen or C 1 -C 6 alkyl;
R2 is hydrogen, halogen or C 1 -C 3 alkyl; and
R3 is hydroxyalkyl;
or a pharmaceutically acceptable salt thereof,
the process comprising the step of reacting a compound of formula XI
with an acid chloride compound of formula
15. The process of claim 14 wherein the compound of formula (I) is
and the compound of formula XI is
16. A pharmaceutically acceptable salt of a compound of formula (I):
wherein
R1 is hydrogen or C 1 -C 6 alkyl;
R2 is hydrogen, halogen or C 1 -C 3 alkyl; and
R3 is hydroxyalkyl.
17. The pharmaceutically acceptable salt of claim 16 wherein R1 is hydrogen, R2 is hydrogen and R3 is hydroxyalkyl.
18. The pharmaceutically acceptable salt of claim 17 wherein the compound is 2-pyridin-2-yl-pyrimidine-5-carboxylic acid 3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-benzylamide.
19. The pharmaceutically acceptable salt of claim 16 wherein R1 is C 1 -C 6 alkyl, R2 is hydrogen and R3 is hydroxyalkyl.
20. The pharmaceutically acceptable salt of claim 19 wherein the compound is selected from the group consisting of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid ((S)-1-{3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-phenyl}-ethyl)-amide and 2-pyridin-2-yl-pyrimidine-5-carboxylic acid ((R)-1-{3-[5-(1-hydroxy-1-methyl-ethyl)-1,2,4-oxadiazol-3-yl]-phenyl}-ethyl)-amide.
21. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to claim 16 and a pharmaceutically acceptable carrier.
22. A method for treating an allergic or inflammatory disorder in a patient in need thereof, wherein the allergic or inflammatory disorder is selected from the group consisting of allergic rhinitis, asthma, and chronic obstructive pulmonary disease, the method comprising administering to the patient a pharmaceutically effective amount of the pharmaceutically acceptable salt according to claim 16 .