Nitric oxide releasing prodrugs of diaryl-2-(5h)-furanones as cyclooxygenase-2 inhibitors
View Patent ↗The invention encompasses novel compounds of Formula I, which are nitric oxide-releasing prodrugs of diaryl-2-(5H) furanones useful in the treatment of cyclooxygenase-2 mediated diseases. The invention also encompasses certain pharmaceutical compositions and methods for treatment of cyclooxygenase-2 mediated diseases comprising the use of compounds of Formula I. The above compounds may be used as a combination therapy with low-dose aspirin to treat chronic cyclooxygenase-2 mediated diseases or conditions while simultaneously reducing the risk of thrombotic cardiovascular events
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of:
(a) S(O) 2 CH 3 ,
(b) S(O) 2 NH 2 ,
(c) S(O) 2 NHC(O)CF 3 ,
(d) S(O)(NH)CH 3 ,
(e) S(O)(NH)NH 2 ,
(f) S(O)(NH)NHC(O)CF 3 ,
(g) P(O)(CH 3 )OH, and
(h) P(O)(CH 3 )NH 2 ;
R 2 and R 3 each are independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C 1-6 alkoxy,
(d) C 1-6 alkylthio,
(e) CN,
(f) CF 3 ,
(g) C 1-6 alkyl, and
(h) N 3 ;
R 4 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl, optionally substituted with 1–3 substituents independently selected from the group consisting of:
(i) halo,
(ii) phenyl, naphthyl or HET 1 , each of said phenyl, naphthyl or HET 1 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ,
(iii) N(R i )R ii , wherein R i and R ii are each independently selected from the group consisting of hydrogen and C 1-4 alkyl,
(iv) —CO 2 R iii , wherein R iii is hydrogen or C 1-4 alkyl,
(c) phenyl, naphthyl or HET 2 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 5 is selected from the group consisting of:
wherein:
each s is independently 1 or 2,
E is a bond, oxygen, sulfur or —C(O)—O—,
each W is independently selected from the group consisting of:
Ar is selected from the group consisting of: phenyl, naphthyl and HET 3 ,
each R a is independently selected from the group consisting of:
(1) halo,
(2) C 1-6 alkyl,
(3) C 1-6 alkoxy,
(4) C 1-6 alkylthio,
(5) OH,
(6) CN,
(7) CF 3 ,
(8) CO 2 R 7 , and
(9) C 0-6 alkyl-W—NO s ;
each Rb is independently selected from the group consisting of:
(1) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 4 , each of said phenyl, naphthyl or HET 4 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ; and
(2) phenyl, naphthyl or HET 5 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ;
R 6 , R 7 and R 8 are each independently selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl; and
HET 1 , HET 2 , HET 3 , HET 4 and HET 5 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
2. A compound according to claim 1 of Formula I
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of:
(a) S(O) 2 CH 3 ,
(b) S(O) 2 NH 2 ,
(c) S(O) 2 NHC(O)CF 3 ,
(d) S(O)(NH)CH 3 ,
(e) S(O)(NH)NH 2 ,
(f) S(O)(NH)NHC(O)CF 3 ,
(g) P(O)(CH 3 )OH, and
(h) P(O)(CH 3 )NH 2 ;
R 2 and R 3 each are independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C 1-6 alkoxy,
(d) C 1-6 alkylthio,
(e) CN,
(f) CF 3 ,
(g) C 1-6 alkyl, and
(h) N 3 ;
R 4 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 1 , each of said phenyl, naphthyl or HET 1 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
(c) phenyl, naphthyl or HET 2 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 5 is selected from the group consisting of:
wherein:
each s is independently 1 or 2,
E is a bond, oxygen, sulfur or —C(O)—O—,
each W is independently selected from the group consisting of:
Ar is selected from the group consisting of: phenyl, naphthyl and HET 3 ,
each R a is independently selected from the group consisting of:
(1) halo,
(2) C 1-6 alkyl,
(3) C 1-6 alkoxy,
(4) C 1-6 alkylthio,
(5) OH,
(6) CN,
(7) CF 3 ,
(8) CO 2 R 7 , and
(9) C 0-6 alkyl-W—NO s ;
each Rb is independently selected from the group consisting of:
(1) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 4 , each of said phenyl, naphthyl or HET 4 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ; and
(2) phenyl, naphthyl or HET 5 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ;
R 6 , R 7 and R 8 are each independently selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl; and
HET 1 , HET 2 , HET 3 , HET 4 and HET 5 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
3. The compound according to claim 2 wherein
R 1 is S(O) 2 CH 3 , and
R 2 and R 3 are both hydrogen.
4. The compound according to claim 3 wherein:
R 4 is C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 1 , each of said phenyl, naphthyl or HET 1 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 6 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl; and
HET 1 is selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
5. The compound according to claim 4 wherein R 4 is methyl, ethyl, propyl or isopropyl.
6. The compound according to claim 3 wherein:
R 4 is phenyl, naphthyl or HET 2 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 6 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl; and
HET 2 is selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
7. The compound according to claim 3 wherein R 5 is —NO s , wherein s is 1 or 2.
8. The compound according to claim 3 wherein R 5 is —C(O)—E—C 1-10 alkyl-W—NO s , wherein:
s is 1 or 2,
E is a bond, oxygen, sulfur or —C(O)—O—,
W is selected from the group consisting of:
each R b is independently selected from the group consisting of:
(1) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 4 , each of said phenyl, naphthyl or HET 4 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ; and
(2) phenyl, naphthyl or HET 5 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ;
R 8 is selected from the group consisting of
(a) hydrogen and
(b) C 1-6 alkyl; and
HET 4 and HET 5 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
9. The compound according to claim 8 wherein:
E is a bond or oxygen;
s is 2;
W is oxygen; and
R 4 is hydrogen, methyl, ethyl, propyl or isopropyl.
10. The compound according to claim 3 wherein R 5 is
wherein:
each s independently 1 or 2,
E is a bond, oxygen, sulfur or —C(O)—O—,
each W is independently selected from the group consisting of:
each R a is independently selected from the group consisting of:
(1) halo,
(2) C 1-6 alkyl,
(3) C 1-6 alkoxy,
(5) OH,
(6) CN,
(7) CF 3 ,
(8) CO 2 R 7 , and
(9) C 0-6 alkyl-W—NO s ;
each Rb is independently selected from the group consisting of:
(1) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 4 , each of said phenyl, naphthyl or HET 4 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ; and
(2) phenyl, naphthyl or HET 5 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ;
R 7 and R 8 is selected from the group consisting of
(a) hydrogen and
(b) C 1-6 alkyl; and
HET 4 and HET 5 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
11. A compound according to claim 2 of Formula II
or a pharmaceutically acceptable salt thereof, wherein
R 4 is selected from the group consisting of:
(a) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 1 , each of said phenyl, naphthyl or HET 1 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
(b) phenyl, naphthyl or HET 2 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 6 is selected from the group consisting of
(a) hydrogen and
(b) C 1-6 alkyl;
s is 1 or 2; and
HET 1 and HET 2 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
12. A compound according to claim 2 of Formula III
or a pharmaceutically acceptable salt thereof, wherein
R 4 is selected from the group consisting of:
(a) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 1 , each of said phenyl, naphthyl or HET 1 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
(b) phenyl, naphthyl or HET 2 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 6 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl;
R a is hydrogen or C 0-6 alkyl-W—NO s ;
each s is independently 1 or 2,
each W is independently selected from the group consisting of:
each Rb is independently selected from the group consisting of:
(1) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 4 , each of said phenyl, naphthyl or HET 4 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ; and
(2) phenyl, naphthyl or HET 5 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ;
R 8 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl; and
HET 1 , HET 2 , HET 4 and HET 5 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
13. A compound according to claim 2 of Formula IV
or a pharmaceutically acceptable salt thereof, wherein
R 4 is selected from the group consisting of:
(a) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 1 , each of said phenyl, naphthyl or HET 1 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
(b) phenyl, naphthyl or HET 2 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 6 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl;
R a is hydrogen or C 0-6 alkyl-W—NO s .
each s is independently 1 or 2;
each W is independently selected from the group consisting of:
each Rb is independently selected from the group consisting of:
(1) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 4 , each of said phenyl, naphthyl or HET 4 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ; and
(2) phenyl, naphthyl or HET 5 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ;
R 8 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl; and
HET 1 , HET 2 , HET 4 and HET 5 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
14. The compound according to claim 13 of Formula IVa
or a pharmaceutically acceptable salt thereof, wherein
R 4 is selected from the group consisting of:
(a) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 1 , each of said phenyl, naphthyl or HET 1 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
(b) phenyl, naphthyl or HET 2 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 6 ;
R 6 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl;
R a is hydrogen or C 0-6 alkyl-W—NO s ;
each s is independently 1 or 2;
each W is independently selected from the group consisting of:
each Rb is independently selected from the group consisting of:
(1) C 1-6 alkyl, optionally substituted with 1–3 halo groups or optionally substituted with phenyl, naphthyl or HET 4 , each of said phenyl, naphthyl or HET 4 being optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ; and
(2) phenyl, naphthyl or HET 5 , each optionally substituted with 1–3 substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, OH, CN, CF 3 , and CO 2 R 8 ;
R 8 is selected from the group consisting of
(a) hydrogen,
(b) C 1-6 alkyl; and
HET 1 , HET 2 , HET 4 and HET 5 are each independently selected from the group consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
15. The compound according to claim 1 wherein: R 4 is C 1-6 alkyl, mono-substituted with
(i) N(R i )R ii , wherein R i and R ii are each independently selected from the group consisting of hydrogen and C 1-4 alkyl or
(ii) —CO 2 R iii , wherein R iii is hydrogen or C 1-4 alkyl.
16. A compound selected from the following group:
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt thereof, and
17. A method for treating a chronic cyclooxygenase-2 mediated disease or condition and reducing the risk of a thrombotic cardiovascular event in a human patient in need of such treatment and at risk of a thrombotic cardiovascular event comprising orally concomitantly or sequentially administering to said patient a compound according to claim 1 in an amount effective to treat the cyclooxygenase-2 mediated disease or condition and aspirin in an amount effective to reduce the risk of the thrombotic cardiovascular event, wherein said chronic cyclooxygenase-2 mediated disease or condition is selected from the group consisting of pain, fever and inflammation of a condition selected from the group consisting of rheumatic fever, symptoms associated with influenza, common cold, low back pain, neck pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, neuralgia, synovitis, rheumatoid arthritis, osteoarthritis, gout, bursitis, burns, injuries, and pain and inflammation following surgical procedures and inhibition of the onset or progression of Alzheimer's disease.
18. A pharmaceutical composition comprising a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.