Patent EA-001444-B1 (EA)
Title: Substituted pyridines as selective cyclooxygenase-2 inhibitors
Inventor: DUBE DANIEL
IPC: C07D213/00
Filed: 1997-07-08
Abstract: 1. A compound of Formula I:   or a pharmaceutically acceptable salt thereof wherein: R<1> is selected from the group consisting of (a) CH3, (b) NH2, (c) NHC(O)CF3, (d) NHCH3; Ar is a mono-, di-, or tri-substituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of (a) hydrogen, (b) halo, (c) C1-6alkoxy, (d) C1-6alkylthio, (e) CN, (f) C1-6alkyl, (g) C1-6fluoroalkyl, (h) N3, (i) -CO2R<3>, (j) hydroxy, (k) -C(R<4>)(R<5>)-OH, (l)-C1-6alkyl-CO2R<6>, (m) C1-6fluoroalkoxy; R<2> is chosen from the group consisting of (a) halo, (b) C1-6alkoxy, (c) C1-6alkylthio, (d) CN, (e) C1-6alkyl, (f) C1-6fluoroalkyl, (g) N3, (h) -CO2R<7> (i) hydroxy, (j) -C(R<8>)(R<9>)-OH, (k) -C1-6alkyl-CO2-R<10>, (l) C1-6fluoroalkoxy, (m) NO2, (n) NR<11>R<12>, (o) NHCOR<13>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<9>, R<10>, R<11>, R<12>, R<13>, are each independently chosen from the group consisting of (a) hydrogen, and (b) C1-6alkyl, or R<4> and R<5>, R<8> and R<9> 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, provided that when Ar is fluorophenyl, R<2> is selected from (a), (b), (c) or (e) to (o) in the definition of R<2> above. 2. A compound according to claim 1 wherein Ar is a mono-, di- or trisubstituted 2-pyridinyl. 3. A compound according to claim 1 wherein Ar is a mono-, di or trisubstituted 3-pyridinyl. 4. A compound according to claim 1 wherein R<1> is CH3 or NH2. 5. A compound according to claim 1 wherein Ar is a mono-, di-, or trisubstituted 2-pyridinyl or 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b) halo, (c) C1-3alkoxy, (d) C1-3alkylthio, (e) C1-3alkyl, (f) CF3, and (g) CN. 6. A compound according to claim 1 wherein R<1> is CH3 or NH2; and Ar is a mono-, di-, or trisubstituted 2-pyridinyl or 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b) halo, (c) C1-3alkoxy, (d) C1-3alkylthio, (e) C1-3alkyl, (f) CF3, and (g) CN. 7. A compound according to claim 1 wherein R<2> is (a) halo, (b) C1-4alkoxy, (c) CN, (d) C1-3-alkyl, (e) C1-3-fluoroalkyl, (f) -CO2H, (g) -C1-3-alkyl-CO2H, (h) C1-3-fluoroalkoxy, or (i) NO2. 8. A compound according to claim 1 wherein R<2> is halo, CH3 or CF3. 9. A compound according to claim 1 wherein R<1> is CH3 or NH2; R<2> is halo, CH3 or CF3; and Ar is a mono-, di-, or trisubstituted 2-pyridinyl or 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b) halo, (c) C1-3-alkoxy, (d) C1-3-alkylthio, (e) C1-3-alkyl, (f) CF3, and (g) CN. 10. A compound according to claim 1 wherein R<1> is CH3 or NH2; R<2> is halo, CH3 or CF3; and Ar is a mono- or di- substituted 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b) halo, (c) C1-3-alkoxy, (d) C1-3-alkylthio, (e) C1-3-alkyl, (f) CF3, and (g) CN. 11. A compound according to claim 1 wherein R<1> is CH3 or NH2; R<2> is halo, CH3 or CF3; and Ar is a mono- or di-substituted phenyl and the substituents are selected from the group consisting of  (a) hydrogen, (b) halo, (c) C1-3-alkoxy, (d) C1-3-alkylthio, (e) C1-3-alkyl (f) CF3, and (g) CN. 12. A compound according to claim 1 of formula Ia:   or a pharmaceutically acceptable salt thereof wherein R<2> and Ar are selected together as follows:  R<2 >Ar (1) CF3 Ph (2) CF3 3-ClC6H4 (3) CF3 4-ClC6H4 (4) CF3 4-FC6H4 (5) CF3 2-(CMe2OH)C6H4 (6) CF3 3-(CMe2OH)C6H4 (7) CF3 3-pyr (8) CF3 5-(2-Me)pyr (9) CF3 5-(3-Br)pyr (10) CF3 5-(3-Cl)pyr (11) CF3 5-(2-OMe)pyr (12) CF3 2-(5-Br)pyr (13) Me Ph (14) Me 4-ClC6H4 (15) Me 3-pyr (16) Cl Ph (17) Cl 4-ClC6H4 (18) Cl 2-(CMe2OH)C6H4 (19) Cl 3-(CMe2OH)C6H4 (20) Cl 2-pyr (21) Cl 3-pyr (22) Cl 4-pyr (23) Cl 5-(2-Me)pyr (24) Cl 5-(3-Br)pyr (25) Cl 5-(3-Cl)pyr (26) Cl 5-(2-OMe)pyr (27) Cl 2-(5-Br)pyr (28) F Ph (29) F 3-pyr (30) F 5-(2-Me)pyr (31) Br Ph (32) Br 3-pyr (33) Br 5-(2-Me)pyr (34) NO2 Ph (35) NO2 3-pyr (36) NO2 5-(2-Me)pyr (37) OMe Ph (38) OMe 3-pyr (39) OMe 5-(2-Me)pyr (40) NHCOMe Ph (41) NHCOMe 3-pyr (42) NHCOMe 5-(2-Me)pyr (43) CO2Me 4-ClC6H4 (44) CO2H 4-ClC6H4 (45) CN 4-ClC6H4 13. A compound according to claim 12 wherein the pharmaceutically acceptable salt is an salt of citric, hydrobromic, hydrochloric, maleic, methanesulfonic, phosphoric, sulfuric or tartaric acid. 14. A compound according to claim 13, wherein the pharmaceutically acceptable salt is an acid-additive salt of hydrochloric or methanesulfonic acid. 15. A compound according to claim 1 of formula Ib   or a pharmaceutically acceptable salt thereof, wherein R<2> and Ar are selected together as follows:  R<2> Ar (48) CF3 Ph (49) CF3 4-ClC6H4 (5) CF3 4-FC6H4 (51) CF3 3-pyr (52) Me Ph (53) Me 4-ClC6H4 (54) Cl 3-pyr (55) Cl 5-(2-Me)pyr (56) CN 4-ClC6H4 (71) Cl 5-(2-ethyl)pyr (72) Cl 5-(2-Et)pyr-MeSO3H (73) Cl 5-(2-c-Pr)pyr (74) Cl 3-(2,6-Me2)pyr 16. A compound according to claim 15 wherein the pharmaceutically acceptable salt is a salt of citric, hydrobromic, hydrochloric, maleic, methanesulfonic, phosphoric, sulfuric or tartaric acid. 17. A compound according to claim 16 wherein the pharmaceutically acceptable salt is an acid-additive salt of hydrochloric or methanesulfonic acid. 18. 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 a compound according to claim 1 and a pharmaceutically acceptable carrier. 19. 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 a compound according to claim 1 and a pharmaceutically acceptable carrier. 20. 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 a compound according to claim 1 and a pharmaceutically acceptable carrier. 21. 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 a compound according to claim 1 and a pharmaceutically acceptable carrier. 22. A compound according to claim 1 wherein: R<2> is chosen from the group consisting of (a) halo, (b) C1-6-alkoxy, (c) C1-6-alkylthio, (d) C1-6-alkyl, (e) N3, (f) -CO2H, (g) hydroxy, (h) C1-6-fluoroalkoxy, (i) NO2, (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 chosen from the group consisting of' (a) hydrogen, and (b) C1-6-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. 23. A compound according to claim 22 of formula Ic   wherein: R<1> is selected from the group consisting of (a) CH3, (b) NH2, R<2> is chosen from the group consisting of (a) chloro, (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) C1-4-alkoxy, (d) C1-4-alkylthio, (e) CN, (f) C1-4-alkyl, (g) CF3. 24. A compound according to claim 23, wherein: 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, (d) ethyl. 25. A compound according to claim 24, wherein there is one group X independently selected from the group consisting of (a) hydrogen, (b) F or Cl, (c) methyl. 26. A compound according to claim 25, wherein R<1> is methyl. 27. A compound according to claim 1, of formula Ic   wherein R<1> is CH3 or NH2; R<2> is (a) halo, (b) C1-6-alkoxy, (c) C1-6-alkylthio, (d) C1-6-alkyl, (e) N3, (f) -CO2H, (g) hydroxy, (h) C1-6-fluoroalkoxy (i) NO2, (j) NR<11>R<12>, (k) NHCOR<13>, and X is hydrogen. 28. A compound according to claim 1, which is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)pyridine or a pharmaceutically acceptable salt thereof. 29. A compound according to claim 1, which is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)pyridine hydromethanesulfonate. 30. A compound according to claim 1, which is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)pyridine hydrochloride. 31. A compound according to claim 1, which is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine or a pharmaceutically acceptable salt thereof. 32. A compound according to claim 1, which is 5-chloro-3-(4-methylsulfonyl)phenyl-1-(2-ethyl-5-pyridinyl)pyridine hydromethanesulfonate. 33. A compound according to claim 1, of formula Ic   wherein: R<1> is CH3 or NH2 R<2> is (a) halo, (b) C1-3-alkoxy, (c) C1-3-alkylthio, (d) C1-3-alkyl, (e) N3, (f) -CO2H, (g) hydroxy, (h) C1-3-fluoroalkoxy, (i) NO2, (j) NR<11>R<12>, (k) NHCOR<13>, and X is methyl, ethyl, n-propyl, isopropyl or cyclopropyl. 34. A compound according to claim 33, wherein X is methyl. 35. A compound according to claim 33 which is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine or a pharmaceutically acceptable salt thereof. 36. A compound according to claim 33 which is 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine hydrochloride. 37. A compound according to claim 1 selected from: 3-(4-methylsulfonyl)phenyl-2-phenyl-5-trifluoromethylpyridine; 2-(3-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethylpyridine; 2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethylpyridine; 2-(4-fluorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethylpyridine; 5-methyl-3-(4-methylsulfonyl)phenyl-2-phenylpyridine; 2-(4-chlorophenyl)-5-methyl-3-(4-methylsulfonyl)phenylpyridine; 5-chloro-2-(4-chlorophenyl-3-(4-methylsulfonyl)phenylpyridine; 2-(4-(chlorophe