IP Library › Granted Patent US 7,442,716

Granted Patent B2

US 7,442,716 · App. 11/374,288 · Granted Oct 28, 2008

2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors

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Quick Facts

Patent No.: US 7,442,716
App. No.: 11/374,288
Granted: Oct 28, 2008
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention encompasses novel compounds of Formula I or pharmaceutically acceptable salts thereof. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful to treat pain and/or inflammation from a variety of diseases or conditions, such as osteoarthritis, rheumatoid arthritis and acute or chronic pain. Methods of treating diseases or conditions mediated by the mPGES-1 enzyme and pharmaceutical compositions are also encompassed.

Claims (1425)

1. A compound represented by Formula I

or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, wherein:

J is selected from the group consisting of —C(X 2 )— and —N—,

K is selected from the group consisting of —C(X 3 )— and —N—,

L is selected from the group consisting of —C(X 4 )— and —N—, and

M is selected from the group consisting of —C(X 5 )— and —N—,

with the proviso that at least one of J, K, L or M is other than —N—;

X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of: (1) H; (2) —CN; (3) F; (4) Cl; (5) Br; (6) I; (7) —OH; (8) —N 3 ; (9) C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein one or more of the hydrogen atoms attached to said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl may be replaced with a fluoro atom, and said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted with a hydroxy group; (10) C 1-4 alkoxy; (11) NR 9 R 10 —C(O)—C 1-4 alkyl-O—; (12) C 1-4 alkyl—S(O) k —; (13) —NO 2 ; (14) C 3-6 cycloalkyl, (15) C 3-6 cycloalkoxy; (16) phenyl, (17) carboxy; and (18) C 1-4 alkyl-O—C(O)—;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of: (1) H; (2) F; (3) Cl; (4) Br; (5) I; (6) —CN; (7) C 1-10 alkyl or C 2-10 alkenyl, wherein one or more of the hydrogen atoms attached to said C 1-10 alkyl or C 2-10 alkenyl may be replaced with a fluoro atom, or two hydrogen on adjacent carbon atoms may be joined together and replaced with —CH 2 — to form a cyclopropyl group, or two hydrogen atoms on the same carbon atom may be replaced and joined together to form a spiro C 3-6 cycloalkyl group, and wherein said C 1-10 alkyl or C 2-10 alkenyl may be optionally substituted with one to three substituents independently selected from the group consisting of: —OH, acetyl, methoxy, ethenyl, R 11 —O—C(O)—, R 35 —N(R 36 )—, R 37 —N(R 38 )—C(O)—, cyclopropyl, pyrrolyl, imidiazolyl, pyridyl and phenyl, said pyrrolyl, imidiazolyl, pyridyl and phenyl optionally substituted with C 1-4 alkyl or mono-hydroxy substituted C 1-4 alkyl; (8) C 3-6 cycloalkyl; (9) R 12 —O—; (10) R 13 —S(O) k —, (11) R 14 —S(O) k —N(R 15 )—; (12) R 16 —C(O)—; (13) R 17 —N(R 18 )—; (14) R 19 —N(R 20 )—C(O)—; (15) R 21 —N(R 22 )—S(O) k —; (16) R 23 —C(O)—N(R 24 )—; (17) Z-C≡C; (18) —(CH 3 )C═N—OH or —(CH 3 )C═N—OCH 3 ; (19) R 34 —O—C(O)—; (20) R 39 —C(O)—O—; and (21) phenyl, naphthyl, pyridyl, pyradazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl or furyl, each optionally substituted with a substituent independently selected from the group consisting of: F, Cl, Br, I, C 1-4 alkyl, phenyl, methylsulfonyl, methylsulfonylamino, R 25 —O—C(O)— and R 26 —N(R 27 )—, said C 1-4 alkyl optionally substituted with 1 to 3 groups independently selected from halo and hydroxy;

each Z is independently selected from the group consisting of: (1) H; (2) C 1-6 alkyl, wherein one or more of the hydrogen atoms attached to said C 1-6 alkyl may be replaced with a fluoro atom, and wherein

C 1-6 alkyl is optionally substituted with one to three substituents independently selected from: hydroxy, methoxy, cyclopropyl, phenyl, pyridyl, pyrrolyl, R 28 —N(R 29 )— and R 30 —O—C(O)—; (3) —(CH 3 )C═N—OH or —(CH 3 )C═N—OCH 3 ; (4) R 31 —C(O)—; (5) phenyl; (6) pyridyl or the N-oxide thereof; (7) C 3-6 cycloalkyl, optionally substituted with hydroxy; (8) tetrahydropyranyl, optionally substituted with hydroxy; and (9) a five-membered aromatic heterocycle containing 1 to 3 atoms independently selected from O, N or S and optionally substituted with methyl;

each R 9 , R 10 , R 15 , R 24 and R 32 is independently selected from the group consisting of: (1) H; and (2) C 1-4 alkyl;

each R 11 , R 12 , R 13 , R 14 , R 16 , R 23 , R 25 , R 30 , R 31 , R 34 and R 39 is independently selected from the group consisting of: (1) H; (2) C 1-4 alkyl, (3) C 3-6 cycloalkyl; (4) C 3-6 cycloalkyl-C 1-4 alkyl- (5) phenyl, (6) benzyl; and (7) pyridyl; said C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, phenyl, benzyl and pyridyl may each be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: OH, F, Cl, Br and I, and wherein said C 1-4 alkyl may be further substituted with oxo or methoxy or both;

each R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 26 , R 27 , R 28 , R 29 , R 35 , R 36 , R 37 and R 38 is independently selected from the group consisting of: (1) H; (2) C 1-6 alkyl; (3) C 1-6 alkoxy; (4) OH and (5) benzyl or 1-phenylethyl; and R 17 and R 18 , R 19 and R 20 , R 21 and R 22 , R 26 and R 27 , and R 28 and R 29 , R 35 and R 36 , and R 37 and R 38 may be joined together with the nitrogen atom to which they are attached to form a monocyclic ring of 5 or 6 carbon atoms, optionally containing one or two atoms independently selected from —O—, —S(O) k — and —N(R 32 )—; and

each k is independently 0, 1 or 2.

2. A compound according to claim 1 represented by Formula I

or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, wherein:

J is selected from the group consisting of —C(X 2 )— and —N—,

K is selected from the group consisting of —C(X 3 )— and —N—,

L is selected from the group consisting of —C(X 4 )— and —N—, and

M is selected from the group consisting of —C(X 5 )— and —N—,

with the proviso that at least one of J, K, L or M is other than —N—;

X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of: (1) H; (2) —CN; (3) F; (4) Cl; (5) Br; (6) I; (7) —H; (8) —N 3 ; (9) C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein one or more of the hydrogen atoms attached to said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl may be replaced with a fluoro atom, and said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted with a hydroxy group; (10) C 1-4 alkoxy; (11) NR 9 R 10 —C(O)—C 1-4 alkyl-O—; (12) C 1-4 alkyl-S(O) k —; (13) —NO 2 ; (14) C 3-6 cycloalkyl, (15) C 3-6 cycloalkoxy; (16) phenyl, (17) carboxy; and (18) C 1-4 alkyl-O—C(O)—;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of: (1) H; (2) F; (3) Cl; (4) Br; (5) I; (6) —CN; (7) C 1-6 alkyl or C 2-6 alkenyl, wherein one or more of the hydrogen atoms attached to said C 1-6 alkyl or C 2-6 alkenyl may be replaced with a fluoro atom, and wherein said C 1-6 alkyl or C 2-6 alkenyl may be optionally substituted with one to three substituents independently selected from the group consisting of: —OH, methoxy, R 11 —O—C(O)—, cyclopropyl, pyridyl and phenyl; (8) C 3-6 cycloalkyl; (9) R 12 —O—; (10) R 13 —S(O) k —, (11) R 14 —S(O) k —N(R 15 )—; (12) R 16 —C(O)—; (13) R 17 —N(R 18 )—; (14) R 19 —N(R 20 )—C(O)—; (15) R 21 —N(R 22 )—S(O) k —; (16) R 23 —C(O)—N(R 24 )—; (17) Z-C≡C;

(18) —(CH 3 )C═N—OH or —(CH 3 )C═N—OCH 3 ; and (19) phenyl, naphthyl, pyridyl, pyradazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl or furyl, each optionally substituted with a substituent independently selected from the group consisting of: F, Cl, Br, I, C 1-14 alkyl, phenyl, methylsulfonyl, methylsulfonylamino, R 25 —O—C(O)— and R 26 —N(R 27 )—, said C 1-4 alkyl optionally substituted with 1 to 3 groups independently selected from halo and hydroxy;

C 1-6 alkyl is optionally substituted with one to three substituents independently selected from: hydroxy, methoxy, cyclopropyl, phenyl, pyridyl, pyrrolyl, R 28 —N(R 29 )— and R 30 —O—C(O)—; (3) —(CH 3 )C═N—OH or —CH 3 )C═N—OCH 3 ; (4) R 31 —C(O)—; (5) phenyl; (6) pyridyl or the N-oxide thereof; (7) C 3-6 cycloalkyl, optionally substituted with hydroxy; (8) tetrahydropyranyl, optionally substituted with hydroxy; and (9) a five-membered aromatic heterocycle containing 1 to 3 atoms independently selected from O, N or S and optionally substituted with methyl;

each R 9 , R 10 , R 15 , R 24 and R 32 is independently selected from the group consisting of: (1) H; and (2) C 1-4 alkyl;

each R 11 , R 12 , R 13 , R 14 , R 16 , R 23 , R 25 , R 30 and R 31 is independently selected from the group consisting of: (1) H; (2) C 1-4 alkyl, (3) C 3-6 cycloalkyl; (4) phenyl, (5) benzyl; and (6) pyridyl; said C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, benzyl and pyridyl may each be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: OH, F, Cl, Br and I;

each R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 26 , R 27 , R 28 and R 29 is independently selected from the group consisting of: (1) H; (2) C 1-6 alkyl; (3) C 1-6 alkoxy; (4) OH and (5) benzyl or 1-phenylethyl; and R 17 and R 18 , R 19 and R 20 , R 21 and R 22 , R 26 and R 27 , and R 28 and R 29 may be joined together with the nitrogen atom to which they are attached to form a monocyclic ring of 5 or 6 carbon atoms, optionally containing one or two atoms independently selected from —O—, —S(O) k — and —N(R 32 )—; and

each k is independently 0, 1 or 2.

3. A compound according to claim 2 according to Formula A

or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug.

4. The compound according to claim 3 wherein:

X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of: (1) H; (2) —CN; (3) F; (4) Cl; (5) Br; and (6) 1.

5. The compound according to claim 3 , wherein X 2 , X 3 and X 4 are H, and X 5 is other than H.

6. The compound according to claim 5 , wherein X 5 is —CN.

7. The compound according to claim 3 , wherein at least one of R 1 or R 8 is other than H.

8. The compound according to claim 3 wherein at least one of R 2 or R 7 is other than H.

9. The compound according to claim 3 wherein at least one of R 4 or R 5 is other than H.

10. The compound according to claim 3 wherein:

at least one of R 3 or R 6 is other than H; and

R 1 , R 2 , R 4 , R 5 , R 7 and R 8 are H.

11. The compound according to claim 10 , wherein R 3 and R 6 are both other than H.

12. The compound according to claim 11 , wherein:

one of R 3 or R 6 is independently selected from the group consisting of: F, Cl, Br, and I; and

the other of R 3 or R 6 is Z-C≡C.

13. The compound according to claim 10 , wherein: R 3 and R 6 are independently selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, vinyl, cyclopropyl, —CO 2 i-Pr, —CO 2 CH 3 , —SO 2 CF 3 , 3-pyridyl, acetyl,

with the proviso that at least one of R 3 or R 6 is other than hydrogen.

14. The compound according to claim 2 according to Formula B:

or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug.

15. The compound according to claim 14 wherein:

one of R 3 or R 6 is independently selected from the group consisting of: F, Cl, Br, and I; and

the other of R 3 or R 6 is Z-C≡C.

16. A prodrug of a compound according to claim 1 of Formula C

or a pharmaceutically acceptable salt thereof, wherein:

Y 1 is selected from the group consisting of: (1) C 1-6 alkyl; (2) PO 4 —C 1-4 alkyl-; (3) C 1-4 alkyl-C(O)—O—CH 2 —, wherein the C 1-4 alkyl portion is optionally substituted with R 33 —O—C(O)—; and (4) C 1-4 alkyl-O—C(O)—; and

R 33 is selected from the group consisting of: (1) H; (2) C 1-4 alkyl, (3) C 3-6 cycloalkyl; (4) phenyl; (5) benzyl; and (6) pyridyl; said C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, benzyl and pyridyl may each be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: OH, F, Cl, Br and I.

17. A compound according to claim 1 selected from one of the following tables:

R 3 /R 6

R 6 /R 3

Y 1

CCl

CCN

CBr

CCl

3-pyridyl

CCN

CBr

CCN

CO 2 Et

CCN

H 2 PO 4 CH 2

CCN

SO 2 CH 3

CCN

cyclopropyl

CCN

vinyl

CCN

ethyl

CCN

cyclopropyl

CCN

CBr

CCN

SO 2 CF 3

CCN

CO 2 CH 3

CCN

CCl

100

CO 2 i-Pr

CCN

101

102

CCN

103

CCN

104

CCN

105

CCl

106

CCN

107

CCl

108

CCN

109

CCN

110

CCl

111

CCN

112

CCN

113

CCN

114

CCN

115

CCN

116

CCN

117

CCN

118

CH 3

CCN

119

CH 3

CCN

120

CH 3

CCN

121

CCN

122

CCN

123

CCN

124

CCN

125

CCN

126

CCN

127

CCN

128

CCN

129

CCN

130

CCN

131

CCN

132

CCN

133

CCN

134

CCN

135

CCN

136

CCN

137

CCN

138

CCN

139

CCN

140

CCN

141

CCN

142

CCN

143

CCN

144

CCN

145

CCN

146

CCN

147

CCN

148

CCN

149

CCN

150

CCN

151

CCN

152

CCN

153

CCN

154

CCN

155

CCN

156

CCN

157

CCN

158

CCN

159

CCN

160

CCN

161

CCN

162

CCN

163

CCN

164

CCN

165

CCN

166

CCN

167

CCN

168

CCN

169

CCN

170

CCN

171

CCN

172

CCN

173

CCN

174

CCN

175

CCN

176

CCN

177

CCN

178

CCN

179

CCN

180

CCN

181

CCN

182

CCN

183

CCN

184

CCN

185

CCN

186

CCN

187

CCN

188

CCN

189

CCN

190

CCN

191

192

193

194

or a pharmaceutically acceptable salt of any of the above compounds.

18. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

19. The compound according to claim 10 , wherein: R 3 and R 6 are independently selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, methoxy, ethyl, vinyl, cyclopropyl, propyl, butyl, —CO 2 i-Pr, —CO 2 CH 3 , —SO 2 CF 3 , 3-pyridyl, acetyl,

with the proviso that at least one of R 3 or R 6 is other than hydrogen.

20. The compound according to claim 1 according to Formula B:

or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, wherein:

21. The compound according to claim 20 wherein R 6 is R 12 —O.

22. The compound according to claim 21 wherein R 12 is selected from the group consisting of: (1) C 1-4 alkyl and (2) C 3-6 cycloalkyl-C 1-4 alkyl-, wherein said C 1-4 alkyl and C 3-6 cycloalkyl may each be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: OH, F, Cl, Br and I.

23. The compound according to claim 20 wherein R 6 is selected from F, Cl, Br and I.

24. The compound according to claim 17 which is

25. A pharmaceutical composition comprising a compound according to claim 24 and a pharmaceutically acceptable carrier.

26. The compound according to claim 17 which is

27. A pharmaceutical composition comprising a compound according to claim 26 and a pharmaceutically acceptable carrier.

Assignments (3)

CHANGE OF NAME Recorded Oct 17, 2018

From: MERCK FROSST CANADA LTD.

To: MERCK CANADA INC.

Reel/Frame 047246/0528 →

CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR NAME, PREVIOUSLY RECORDED ON REEL 021468 FRAME 0222. Recorded Sep 29, 2008

From: CHAU, ANH; COTE, BERNARD; DUCHARME, YVES; FRIESEN, RICHARD; GAGNON, MARC; GIROUX, ANDRE; WU, TOM; YU, HONGPING; MARTINS, EVELYN; FRENETTE, RICHARD

To: MERCK FROSST CANADA LTD.

Reel/Frame 021646/0786 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2008

From: CHAU, ANH; COTE, BERNARD; DUCHARME, YVES; FRIESEN, RICHARD; GAGNON, MARC; GIROUX, ANDRE; WU, TOM; XU, HONGPING; MARTINS, EVELYN; FRENETTE, RICHARD

To: MERCK FROSST CANADA LTD.

Reel/Frame 021468/0222 →