Substituted pyridines as selective cyclooxygenase-2 inhibitors
View Patent ↗The invention encompasses the novel compound of Formula I as well as a method of treating COX-2 mediated diseases comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I. The invention also encompasses certain pharmaceutical compositions for treatment of COX-2 mediated diseases comprising compounds of Formula I.
1. A pharmaceutically acceptable salt of a compound of formula I
wherein:
R 1 is selected from the group consisting of:
(a) CH 3 ,
(b) NH 2 ,
(c) NHC(O)CF 3 and
(d) NHCH 3 ;
Ar is a mono-, di-, or trisubstituted pyridinyl or pyridinyl N-oxide, wherein the substituents are selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C 1-6 alkoxy,
(d) C 1-6 alkylthio,
(e) CN,
(f) C 1-6 alkyl,
(g) C 1-6 fluoroalkyl,
(h) N 3 ,
(i) —CO 2 R 3 ,
(j) hydroxy,
(k) —C(R 4 )(R 5 )—OH,
(l) —C 1-6 alkyl-CO 2 —R 6 and
(m) C 1-6 fluoroalkoxy;
R 2 is selected from the group consisting of:
(a) halo,
(b) C 1-6 alkoxy,
(c) C 1-6 alkylthio,
(d) C 1-6 alkyl,
(e) N 3 ,
(f) —CO 2 H,
(g) hydroxy,
(h) C 1-6 fluoroalkoxy,
(i) NO 2 ,
(j) NR 11 R 12 and
(k) NHCOR 13 ;
R 3 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , are each independently selected from the group consisting of:
(a) hydrogen and
(b) C 1-6 alkyl,
or R 4 and R 5 or R 11 and R 12 together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms.
2. The pharmaceutically acceptable salt of the compound according to claim 1 of formula Ic
wherein:
R 1 is selected from the group consisting of:
(a) CH 3 and
(b) NH 2 ,
R 2 is selected from the group consisting of:
(a) chloro and
(b) methyl,
and wherein there may be one, two or three groups X independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C 1-4 alkoxy,
(d) C 1-4 alkylthio,
(e) CN,
(f) C 1-4 alkyl and
(g) CF 3 .
3. The pharmaceutically acceptable salt of the compound according to claim 2 wherein:
R 1 is selected from the group consisting of:
(a) CH 3 and
(b) NH 2 ,
R 2 is chloro, wherein there is one group X independently selected from the group consisting of:
(a) hydrogen,
(b) F or Cl,
(c) methyl and
(d) ethyl.
4. The pharmaceutically acceptable salt of the compound according to claim 3 wherein:
R 1 is selected from the group consisting of:
(a) CH 3 and
(b) NH 2 ,
R 2 is chloro, wherein there is one group X independently selected from the group consisting of:
(a) hydrogen,
(b) F or Cl and
(c) methyl.
5. The pharmaceutically acceptable salt of the compound according to claim 4 wherein R 1 is methyl.
6. The pharmaceutically acceptable salt of the compound according to claim 1 of formula Ic
wherein:
R 1 is CH 3 or NH 2 ;
R 2 is selected from the group consisting of:
(a) halo,
(b) C 1-6 alkoxy,
(c) C 1-6 alkylthio,
(d) C 1-6 alkyl,
(e) N 3 ,
(f) —CO 2 H,
(g) hydroxy,
(h) C 1-6 fluoroalkoxy,
(i) NO 2 ,
(j) NR 11 R 12 and
(k) NHCOR 13 , and
X is hydrogen.
7. The pharmaceutically acceptable salt of the compound according to claim 1 of the formula
wherein:
R 1 is CH 3 or NH 2 ,
R 2 is selected from the group consisting of:
(a) halo,
(b) C 1-3 alkoxy,
(c) C 1-3 alkylthio,
(d) C 1-3 alkyl,
(e) N 3 ,
(f) —CO 2 H,
(g) hydroxy,
(h) C 1-3 fluoroalkoxy,
(i) NO 2 ,
(j) NR 11 R 12 and
(k) NHCOR 13 , and
X is methyl, ethyl, n-propyl, i-propyl or cyclopropyl.
8. The pharmaceutically acceptable salt of the compound according to claim 7 wherein X is methyl.
9. A pharmaceutical composition for treating an inflammatory disease susceptible to treatment with an non-steroidal anti-inflammatory agent comprising: a non-toxic therapeutically effective amount of the pharmaceutically acceptable salt of the compound according to claim 1 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition for treating cyclooxygenase mediated diseases advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 comprising: a non-toxic therapeutically effective amount of pharmaceutically acceptable salt of the compound according to claim 1 and a pharmaceutically acceptable carrier.
11. A method of treating an inflammatory disease susceptible to treatment with an non-steroidal anti-inflammatory agent comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of the pharmaceutically acceptable salt the compound according to claim 1 and a pharmaceutically acceptable carrier.
12. A method of treating cyclooxygenase mediated diseases advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of the pharmaceutically acceptable salt the compound according to claim 1 .