Claims
- 1. A compound of formula I ##STR216## or a pharmaceutically acceptable salt thereof wherein: X-Y-Z-is selected from the group consisting of:
- (a) --S--N.dbd.CH--,
- (b) --CH.dbd.N--S--,
- (c) --N.dbd.CR.sup.4 --S--, and
- (d) --S--CR.sup.4 .dbd.N--,
- when side b is a double bond, and sides a an c are single bonds; and
- X-Y-Z-is selected from the group consisting of:
- (a) .dbd.N--S--CH.dbd.,
- (b) .dbd.CH--S--N.dbd., and
- (c) .dbd.N--S--N.dbd.,
- when sides a and c are double bonds and side b is a single bond;
- R.sup.1 is selected from the group consisting of
- (a) S(O).sub.2 CH.sub.3,
- (b) S(O).sub.2 NH.sub.2,
- (c) S(O).sub.2 NHC(O)CF.sub.3,
- (d) S(O)(NH)CH.sub.3,
- (e) S(O)(NH)NH.sub.2,
- (f) S(O)(NH)NHC(O)CF.sub.3,
- (g) P(O)(CH.sub.3)OH, and
- (h) P(O)(CH.sub.3)NH.sub.2,
- R.sup.2 is selected from the group consisting of
- (a) C.sub.1-6 alkyl,
- (b) C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7, cycloalkyl,
- (c) mono-, di- or tri-substituted phenyl wherein the substituent is selected from the group consisting of
- (1) hydrogen,
- (2) halo,
- (3) C.sub.1-6 alkoxy,
- (4) C.sub.1-6 alkylthio,
- (5) CN,
- (6) CF.sub.3,
- (7) C.sub.1-6 alkyl,
- (8) N.sub.3,
- (9) --CO.sub.2 H,
- (10) --CO.sub.2 -- C.sub.1-4 alkyl,
- (11) --C(R.sup.5)(R.sup.6)--OH,
- (12) --C(R.sup.5)(R.sup.6)--O-- C.sub.1-4 alkyl, and
- (13) --C.sub.1-6 alkyl-CO.sub.2 --R.sup.5 ;
- (d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additional N atoms; or
- the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2 or 3 additional N atoms; said substituents are selected from the group consisting of
- (1) hydrogen,
- (2) halo, including fluoro, chloro, bromo and iodo,
- (3) C.sub.1-6 alkyl,
- (4) C.sub.1-6 alkoxy,
- (5) C.sub.1-6 alkylthio,
- (6) CN,
- (7) CF.sub.3,
- (8) N.sub.3,
- (9) --C(R.sup.5)(R.sup.6)--OH, and
- (10) --C(R.sup.5)(R.sup.6)--O-- C.sub.1-4 alkyl;
- R.sup.4 is selected from the group consisting of
- (a) hydrogen,
- (b) CF.sub.3,
- (c) CN,
- (d) C.sub.1-6 alkyl,
- (e) --Q,
- (f) --O--Q;
- (g) --S--Q, and
- (h) optionally substituted
- (1) --C.sub.1-5 alkyl-Q,
- (2) --O--C.sub.1-5 alkyl-Q,
- (3) --S--C.sub.1-5 alkyl-Q,
- (4) --C.sub.1-3 alkyl--O--C.sub.1-3 alkyl-Q,
- (5) --C.sub.1-3 alkyl--S--C.sub.1-3 alkyl-Q,
- (6) --C.sub.1-5 alkyl--O--Q, and
- (7) --C.sub.1-5 alkyl--S--Q,
- wherein the substituent resides on the alkyl and the substituent is C.sub.1-3 alkyl, and
- R.sup.5 and R.sup.6, R.sup.7 and R.sup.8 are each independently selected from the group consisting of
- (a) hydrogen, and
- (b) C.sub.1-6 alkyl,
- or R.sup.5 and R.sup.6 or R.sup.7 and R.sup.8 together with the carbon to which they are attached form a monocyclic saturated carbon ring of 3, 4, 5, 6 or 7 atoms; and
- Q is CO.sub.2 H, CO.sub.2 --C.sub.1-4 alkyl, tetrazolyl-5-yl, C(R.sup.7)(R.sup.8)(OH), or C(R.sup.7)(R.sup.8)(O--C.sub.1-4 alkyl).
- 2. A compound according to claim 1 wherein
- R.sup.1 is selected from the group consisting of
- (a) S(O).sub.2 CH.sub.3,
- (b) S(O).sub.2 NH.sub.2,
- (c) S(O).sub.2 NHC(O)CF.sub.3,
- (d) S(O)NHCH.sub.3,
- (e) S(O)NHNH.sub.2, and
- (f) S(O)NHNHC(O)CF.sub.3 ;
- R.sup.2 is selected from the group consisting of
- (a) C.sub.1-4 alkyl,
- (b) C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7, cycloalkyl,
- (c) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of
- (1) hydrogen,
- (2) fluoro, chloro, and bromo,
- (3) C.sub.1-4 alkoxy,
- (4) C.sub.1-4 alkylthio,
- (5) CN,
- (6) CF.sub.3,
- (7) C.sub.1-4 alkyl,
- (8) N.sub.3,
- (9) --CO.sub.2 H,
- (10) --CO.sub.2 --C.sub.1-3 alkyl,
- (11) --C(R.sup.5)(R.sup.6)--OH, and
- (12) --C(R.sup.5)(R.sup.6)--O--C.sub.1-3 alkyl,
- (d) mono- or di-substituted heteroaryl selected from the group consisting of
- (1) furanyl,
- (2) diazinyl, triazinyl and tetrazinyl,
- (3) imidazolyl,
- (4) isooxazolyl,
- (5) isothiazolyl,
- (6) oxadiazolyl,
- (7) oxazolyl,
- (8) pyrazolyl,
- (9) pyrrolyl,
- (10) thiadiazolyl,
- (11) thiazolyl,
- (12) thienyl,
- (13) triazolyl, and
- (14) tetrazolyl,
- wherein said substituents are selected from the group consisting of
- (a) hydrogen,
- (b) fluoro, chloro, bromo,
- (c) C.sub.1-4 alkoxy,
- (d) C.sub.1-4 alkylthio,
- (e) CN,
- (5) CF.sub.3,
- (6) C.sub.1-4 alkyl,
- (7) N.sub.3,
- (8) --C(R.sup.5)(R.sup.6)--OH,
- (9) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl.
- 3. A compound according to claim 2 wherein
- R.sup.2 is selected from the group consisting of
- (a) cyclohexyl, and
- (b) mono- or di-substituted phenyl, and wherein the substituents are selected from the group consisting of
- (1) hydrogen,
- (2) halo,
- (3) C.sub.1-4 alkoxy,
- (4) C.sub.1-4 alkylthio,
- (5) CN,
- (6) CF.sub.3,
- (7) C.sub.1-4 alkyl,
- (8) N.sub.3, and
- (9) --C(R.sup.5)(R.sup.6)--OH;
- R.sup.4 and R.sup.4' are each independently selected from the group consisting of
- (a) hydrogen,
- (b) CF.sub.3,
- (c) C.sub.1-3 alkyl,
- (d) CN,
- (e) chloro and fluoro; and
- R.sup.5 and R.sup.6, are each independently selected from the group consisting of
- (a) hydrogen,
- (b) methyl or ethyl,
- or R.sup.5 and R.sup.6 together with the carbon to which they are attached form a saturated carbon ring of 4, 5 or 6 atoms.
- 4. A compound according to claim 3 wherein
- R.sup.1 is selected from the group consisting of
- (a) S(O).sub.2 CH.sub.3,
- (b) S(O).sub.2 NH.sub.2,
- (c) S(O)NHCH.sub.3, and
- (d) S(O)NHNH.sub.2 ;
- R.sup.2 is selected from the group consisting of
- mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of
- (1) hydrogen,
- (2) halo, selected from the group consisting of fluoro, chloro and bromo,
- (3) C.sub.1-3 alkoxy,
- (4) C.sub.1-3 alkylthio,
- (5) CN, and
- (6) C.sub.1-3 alkyl.
- 5. A compound according to claim 4 wherein
- R.sup.1 is selected from the group consisting of
- (a) S(O).sub.2 CH.sub.3,
- (b) S(O).sub.2 NH.sub.2,
- (c) S(O)NHCH.sub.3, and
- (d) S(O)NHNH.sub.2 ;
- R.sup.2 is
- mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of
- (1) hydrogen,
- (2) halo, selected from the group consisting of fluoro, chloro and bromo,
- (3) methoxy, and
- (4) methyl.
- 6. A compound according to claim 5 wherein
- R.sup.1 is selected from the group consisting of
- (a) S(O).sub.2 CH.sub.3, and
- (b) S(O).sub.2 NH.sub.2,
- R.sup.2 is
- mono or di-substituted phenyl wherein the substitutents are selected from the group consisting of
- (1) hydrogen,
- (2) halo, selected from the group consisting of fluoro, chloro and bromo.
- 7. A compound according to claim 3 wherein
- R.sup.2 is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of
- (1) furanyl,
- (2) diazinyl, triazinyl, tetrazinyl,
- (3) imidazolyl,
- (4) isooxazolyl,
- (5) isothiazolyl,
- (6) oxadiazolyl,
- (7) oxazolyl,
- (8) pyrazolyl,
- (9) pyrrolyl,
- (10) thiadiazolyl,
- (11) thiazolyl,
- (12) thienyl,
- (13) triazolyl, and
- (14) tetrazolyl,
- wherein the substitutents are selected from the group consisting of
- (a) hydrogen,
- (b) fluoro or chloro,
- (c) C.sub.1-3 alkoxy,
- (d) C.sub.1-6 alkyl thio,
- (e) CN,
- (5) CF.sub.3,
- (6) C.sub.1-3 alkyl,
- (7) --C(R.sup.5)(R.sup.6)--OH;
- (8) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl.
- 8. A compound according to claim 7 wherein R.sup.2 is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of
- (1) 2-furanyl,
- (2) 3-furanyl,
- (3) 2-thienyl,
- (4) 3-thienyl,
- (5) 3-isoxazolyl,
- (6) 4-isoxazolyl,
- (7) 5-isoxazolyl,
- (8) 3-isothiazolyl,
- (9) 4-isothiazolyl,
- (10) 5-isothiazolyl,
- (11) 2-oxazolyl,
- (12) 4-oxazolyl,
- (13) 5-oxazolyl,
- (14) 2-thiazolyl,
- (15) 4-thiazolyl,
- (16) 5-thiazolyl,
- (17) 1,2,3-thiadiazol-4-yl,
- (18) 1,2,3-thiadiazol-5-yl,
- (19) 1,2,4-thiadiazol-3-yl,
- (20) 1,2,4-thiadiazol-5-yl,
- (21) 1,3,4-thiadiazol-2-yl,
- (22) 1,2,5-thiadiazol-3-yl,
- (23) 1,2,3-oxadiazol-4-yl,
- (24) 1,2,3-oxadiazol-5-yl,
- (25) 1,2,4-oxadiazol-3-yl,
- (26) 1,2,4-oxadiazol-5-yl,
- (27) 1,3,4-oxadiazol-2-yl,
- (28) 1,2,5-oxadiazol-3-yl,
- (29) pyrazol-4-yl,
- (30) pyrazol-5-yl,
- (31) 1,2,3-triadiazol-4-yl,
- (32) 1,2,3-triadiazol-5-yl,
- (33) 1,2,4-triadiazol-3-yl,
- (34) 1,2,4-triadiazol-5-yl,
- (35) 1,2-diazinyl,
- (36) 1,3-diazinyl,
- (37) 1,4-diazinyl,
- (38) 1,2,3,4-tetrazin-5-yl,
- (39) 1,2,4,5-tetrazin-4-yl,
- (40) 1,3,4,5-tetrazin-2-yl, and
- (41) 1,2,3,5-tetrazin-4-yl.
- 9. A compound according to claim 8 wherein the heteroaryl is selected from the group consisting of
- (1) 3-isoxazolyl,
- (2) 4-isoxazolyl,
- (3) 5-isoxazolyl,
- (4) 3-isothiazolyl,
- (5) 4-isothiazolyl,
- (6) 5-isothiazolyl,
- (7) 2-oxazolyl,
- (8) 4-oxazolyl,
- (9) 5-oxazolyl,
- (10) 2-thiazolyl,
- (11) 4-thiazolyl,
- (12) 5-thiazolyl,
- (13) 1,2,3-thiadiazol-4-yl,
- (14) 1,2,3-thiadiazol-5-yl,
- (15) 1,2,4-thiadiazol-3-yl,
- (16) 1,2,4-thiadiazol-5-yl,
- (17) 1,3,4-thiadiazol-2-yl,
- (18) 1,2,5-thiadiazol-3-yl,
- (19) 1,2,3-oxadiazol-4-yl,
- (20) 1,2,3-oxadiazol-5-yl,
- (21) 1,2,4-oxadiazol-3-yl,
- (22) 1,2,4-oxadiazol-5-yl,
- (23) 1,3,4-oxadiazol-2-yl,
- (24) 1,2,5-oxadiazol-3-yl,
- (25) 1,2-diazinyl,
- (26) 1,3-diazinyl, and
- (27) 1,4-diazinyl.
- 10. A compound according to claim 9 wherein the heteroaryl is selected from the group consisting of
- (1) 3-isothiazolyl,
- (2) 4-isothiazolyl,
- (3) 5-isothiazolyl,
- (4) 2-oxazolyl,
- (5) 4-oxazolyl,
- (6) 5-oxazolyl,
- (7) 2-thiazolyl,
- (8) 4-thiazolyl,
- (9) 5-thiazolyl,
- (10) 1,2-diazinyl,
- (11) 1,3-diazinyl, and
- (12) 1,4-diazinyl, and
- wherein the substitutents are selected from the group consisting of
- (1) hydrogen,
- (2) fluoro or chloro,
- (3) C.sub.1-3 alkoxy,
- (4) C.sub.1-3 alkylthio,
- (5) CN,
- (6) C.sub.1-3 alkyl, and
- (7) --C(R.sup.5)(R.sup.6)--OH,
- wherein R.sup.5 and R.sup.6 are each independently hydrogen, methyl or ethyl.
- 11. A compound according to claim 10 wherein
- R.sup.1 s selected from the group consisting of
- (a) S(O).sub.2 CH.sub.3,
- (b) S(O).sub.2 NH.sub.2,
- (c) S(O)NHCH.sub.3, and
- S(O)NHNH.sub.2,
- R.sup.3 is selected from the group consisting of
- (a) hydrogen,
- (b) CF.sub.3,
- (c) C.sub.1-3 alkyl and hydroxy C.sub.1-3 alkyl, and
- (d) CN.
- 12. A compound according to claim 11 wherein the hetereooaryl is selected from the group consisting of
- (1) 3-isothiazolyl,
- (2) 4-isothiazolyl,
- (3) 5-isothiazolyl,
- (4) 2-oxazolyl,
- (5) 4-oxazolyl,
- (6) 5-oxazolyl,
- (7) 2-thiazolyl,
- (8) 4-thiazolyl,
- (9) 5-thiazolyl,
- (10) 1,2-diazinyl,
- (11) 1,3-diazinyl, and
- (12) 1,4-diazinyl, and
- wherein the substitutents are selected from the group consisting of
- (1) hydrogen,
- (2) fluoro or chloro,
- (3) methoxy,
- (4) methylthio,
- (5) CF.sub.3,
- (6) methyl.
- 13. A compound according to claim 1 selected from the group consisting of
- (a) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl) phenyl)thiazole, and
- (b) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole, or a pharmaceutically acceptable salt thereof.
- 14. A compound according to claim 1 selected from the group consisting of ##STR217## or a pharmaceutically acceptable salt thereof.
- 15. A pharmaceutical composition for treating an inflammatory disease susceptable 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.
- 16. 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.
- 17. A method of treating an inflammatory disease susceptable 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.
- 18. 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.
RELATED U.S. APPLICATION DATA
This application is a Divisional of application U.S. Ser. No. 08/179,467, filed Jan. 10, 1994, now U.S. Pat. No. 5,474,995, which is a continuation-in-part of U.S. Ser. No. 08/082,196, filed Jun. 24, 1993 (abandoned).
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Divisions (1)
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Number |
Date |
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Parent |
179467 |
Jan 1994 |
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Continuation in Parts (1)
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Number |
Date |
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82196 |
Jun 1993 |
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