Non-steroidal glucocorticoid inhibitors and their use in treating inflammation, allergy and auto-immune conditions
The present invention provides compounds of formula (I): a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates and to use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation, allergy and/or autoimmune conditions.
1. A compound of formula (I):
wherein
R 1 is hydrogen;
R 2 and R 3 are each independently selected from bromine, chlorine, fluorine, —CHF 2 , —CF 3 and —OCHF 2 , or R 2 is —SO 2 CH 3 and R 3 is hydrogen;
n is an integer selected from 0, 1 and 2,
when n is 1, X is selected from chlorine and fluorine, and
when n is 2, each X is fluorine;
or a salt thereof.
2. A compound according to claim 1 wherein R 2 and R 3 are each independently selected from the group consisting of fluorine, chlorine, bromine, —OCHF 2 and —CHF 2 .
3. A compound according to claim 2 wherein R 2 and R 3 are each chlorine.
4. A compound according to claim 2 wherein R 2 and R 3 are each fluorine.
5. A compound according to claim 1 wherein n is 1.
6. A compound according to claim 5 wherein X is fluorine.
7. A compound of formula (IA):
wherein
R 1 is selected from hydrogen, methyl and ethyl; and
when R 1 is hydrogen or methyl, R 2 and R 3 are each independently selected from chlorine and fluorine, or
when R 1 is ethyl, R 2 and R 3 are each independently selected from chlorine and fluorine, or R 2 is —SO 2 CH 3 and R 3 is hydrogen;
or a salt thereof.
8. A compound selected from the group consisting of:
5-amino-N-[2-({[(2,6-dichlorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide;
5-amino-N-[2-({[(2,6-dichlorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 1);
5-amino-N-[2-({[(2,6-dichlorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2);
5-amino-N-(2-{[[(2,6-difluorophenyl)carbonyl](ethyl)amino}methyl]-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide;
5-amino-N-(2-{[[(2,6-difluorophenyl)carbonyl](ethyl)amino}methyl]-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 1);
5-amino-N-(2-{[[(2,6-difluorophenyl)carbonyl](ethyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2);
5-amino-N-[2-({[(2-chloro-6-fluorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide;
5-amino-N-[2-({[(2-chloro-6-fluorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 1);
5-amino-N-[2-({[(2-chloro-6-fluorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2);
5-amino-N-[2-({[(2-bromo-6-fluorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide;
5-amino-N-[2-({[(2-bromo-6-fluorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 1);
5-amino-N-[2-({[(2-bromo-6-fluorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2);
5-amino-N-(2-{[({2-chloro-6-[(difluoromethyl)oxy]phenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide;
5-amino-N-(2-{[({2-chloro-6-[(difluoromethyl)oxy]phenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 1);
5-amino-N-(2-{[({2-chloro-6-[(difluoromethyl)oxy]phenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2);
5-amino-N-{2-[({[2,6-bis(difluoromethyl)phenyl]carbonyl}amino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide;
5-amino-N-{2-[({[2,6-bis(difluoromethyl)phenyl]carbonyl}amino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 1);
5-amino-N-{2-[({[2,6-bis(difluoromethyl)phenyl]carbonyl}amino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2);
5-amino-N-(2-{[({2-[(difluoromethyl)oxy]-6-fluorophenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide;
5-amino-N-(2-{[({2-[(difluoromethyl)oxy]-6-fluorophenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 1);
5-amino-N-(2-{[({2-[(difluoromethyl)oxy]-6-fluorophenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2);
or a salt thereof.
9. A compound which is:
5-amino-N-[2-({[(2,6-dichlorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2); or
a salt thereof.
10. A compound which is:
5-amino-N-(2-{[[(2,6-difluorophenyl)carbonyl](ethyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2); or
a salt thereof.
11. A pharmaceutical composition comprising a compound of formula (I) as claimed claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable diluents or carriers.
12. A compound according to claim 9 which is:
5-amino-N-[2-({[(2,6-dichlorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2); or
a pharmaceutically acceptable salt thereof.
13. A compound according to claim 12 which is:
5-amino-N-[2-({[(2,6-dichlorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2); or
a pharmaceutically acceptable salt.
14. A compound according to claim 12 which is:
5-amino-N-[2-({[(2,6-dichlorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (Enantiomer 2) as the free base.
15. A pharmaceutical composition according to claim 11 in the form of eye drops for topical administration.
16. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 12 , or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable diluents or carriers.
17. A pharmaceutical composition according to claim 16 in the form of eye drops for topical administration.
18. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 13 , or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable diluents or carriers.
19. A pharmaceutical composition according to claim 18 in the form of eye drops for topical administration.
20. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 14 , or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable diluents or carriers.
21. A pharmaceutical composition according to claim 20 in the form of eye drops for topical administration.