Phenanthrene derivatives as MPGES-1 inhibitors
The invention encompasses novel compounds of Formula 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.
1 . A compound represented by Formula I
or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug, wherein:
A is selected from the group consisting of: aryl, heteroaryl, heterocyclyl and cycloalkyl, or a fused analog of any of aforementioned;
B is selected from the group consisting of: aryl, heteroaryl, heterocyclyl and cycloalkyl, or a fused analog of any of the aforementioned;
with the proviso that A and B cannot both simultaneously be phenyl;
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 1 is selected from the group consisting of: (1) F; (2) Cl; (3) Br; (4) I; (5) —OH; (6) —N 3 ; (7) 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 or oxo group; (8) C 1-4 alkoxy; (9) NR 9 R 10 —, NR 9 R 10 —C(O)—C 1-4 alkyl-O— or NR 9 R 10 —C(O)—; (10) C 1-4 alkyl-S(O) k —; (11) —NO 2 ; (12) C 3-6 cycloalkyl, (13) C 3-6 cycloalkoxy; (14) phenyl, (15) carboxy; (16) C 4alkyl-O—C(O)—, and (17) —CN;
X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of: (1) H; (2) F; (3) Cl; (4) Br; (5) I; (6) —OH; (7) —N 3 ; (8) 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 or oxo group; (9) C 1-4 alkoxy; (10) NR 9 R 10 —, NR 9 R 10 —C(O)—C 1-4 alkyl-O— or NR 9 R 10 —C(O)—; (11) C 1-4 alkyl-S(O) k —; (12) —NO 2 ; (13) C 3-6 cycloalkyl, (14) C 3-6 cycloalkoxy; (15) phenyl, (16) carboxy; (17) C 1-4 alkyl-O—C(O)—, and (18) —CN;
each R 1 and R 2 is 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, acetyloxy, 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 1-14 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; (7) pyridyl and (8) pyridylmethyl; said C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, phenyl, benzyl, pyridyl and pyridylmethyl 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;
and when said compound of Formula I is a prodrug, said prodrug is represented by Formula A
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.
2 . 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:
W is O or S, X is CR 2 and b is a double bond, or
X is O or S, W is CR 2 and a is a double bond.
3 . The compound according to claim 2 wherein:
X 2 and X 4 are H;
K is CH or N;
M is —C(X 5 )—; and
X 1 and X 5 are independently selected from the group consisting of: (1) F; (2) Cl; (3) Br; (4) I; and (5) CN.
4 . The compound according to claim 3 wherein:
R 1 and R 2 are independently selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, methoxy, ethyl, vinyl, cyclopropyl, propyl, butyl, —SO 2 CF 3 , 3-pyridyl, acetyl, phenyl,
5 . The compound according to claim 4 selected from the following table
W
X
R 1
R 2
X 1
M
K
CH
S
H
H
Cl
CF
CH
S
CH
H
Cl
Cl
CF
CH
CH
O
H
H
Cl
CF
CH
S
CH
H
H
Cl
CF
CH
CH
S
CN
H
Cl
CF
CH
CH
S
Cl
H
Cl
CF
CH
CH
S
Cl
H
CN
CF
CH
CH
S
Cl
H
Br
CBr
CH
CH
S
Cl
H
CN
CCN
CH
CH
5
Cl
H
Br
CBr
N
CH
S
Cl
H
CN
CCN
N
CH
O
Cl
H
CN
CCN
CH
CH
O
Cl
H
Br
CBr
N
CH
O
Cl
H
CN
CCN
N
CH
S
Cl
Br
Cl
CF
CH
S
CH
H
Br
Cl
CF
CH
CH
S
Cl
Br
CN
CCN
CH
CH
S
Cl
CN
CCN
CH
CBr
S
Cl
Br
Br
CBr
CH
CH
S
Cl
Cl
CN
CCN
CH
CH
S
Br
Cl
Br
CBr
CH
CH
S
Br
Cl
CN
CCN
CH
CH
S
Cl
CN
CCN
CH
CBr
S
Cl
Cl
Br
CBr
CH
CBr
S
Cl
Cl
CN
CCN
CH
CCl
S
Br
Cl
Br
CBr
CH
CCl
S
Br
Cl
CN
CCN
CH
CCl
S
Cl
CN
CCN
CH
CCl
S
Cl
CN
CCN
CH
CH
S
Cl
CN
CCN
CH
CH
S
Cl
CN
CCN
CH
or a pharmaceutically acceptable salt of any of the aforementioned compounds.
6 . The compound according to claim 1 according to Formula C
wherein Y and Z are independently selected from the group consisting of: CH and N, or the N-oxide thereof.
7 . The compound according to claim 6 wherein
X 2 and X 4 are H;
K is CH or CF;
M is —C(X 5 )—; and
X 1 and X 5 are independently selected from the group consisting of: (1) F; (2) Cl; (3) Br; (4) I; and (5) CN.
8 . The compound according to claim 7 wherein
R 1 and R 2 are independently selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, methoxy, ethyl, vinyl, cyclopropyl, propyl, butyl, —SO 2 CF 3 , 3-pyridyl, acetyl, phenyl,
9 . The compound according to claim 8 selected from the following table
Y
Z
R 1
R 2
X 1
M
K
CH
N
H
H
Cl
CF
CH
N
CH
H
H
Cl
CF
CH
NO
CH
H
H
Cl
CF
CH
NH
CH
H
O
Cl
CF
CH
N
CH
H
H
Br
CBr
CH
N
CH
H
H
CN
CCN
CH
NO
CH
H
H
Br
CBr
CH
N
CH
H
Cl
CN
CCN
CH
N
CH
H
Ph
Br
CBr
CH
N
CH
H
Ph
CN
CCN
CH
N
CH
OCH3
Cl
Br
CBr
CH
N
CH
OCH3
Cl
CN
CCN
CH
N
CH
Br
CBr
CH
N
CH
CN
CCN
CH
N
CH
Cl
CN
CCN
CH
N
CH
CN
CCN
CH
N
CH
CN
CCN
CH
N
CH
CN
CN
CCN
CH
N
CH
CN
CCN
CH
N
CH
Cl
CN
CCN
CF
N
CH
CN
CCN
CH
N
CH
CN
CCN
CH
N
CH
Cl
CN
CCN
CH
N
CH
CN
CCN
CH
or a pharmaceutically acceptable salt of any of the aforementioned compounds.
10 . The compound according to claim 1 wherein:
X 1 is selected from the group consisting of: (1) F; (2) Cl; (3) Br; (4) I; and (5) CN; and
X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of: (1) H; (2) F; (3) Cl; (4) Br; (5) I; and (6) CN.
11 . The compound according to claim 1 wherein M is —C(X 5 )—.
12 . The compound according to claim 11 wherein X 5 is other than H.
13 . The compound according to claim 12 , wherein X 1 and X 5 are the same and selected from the group consisting of: (1) F; (2) Cl; (3) Br; (4) I and (5) CN.
14 . The compound according to claim 1 , wherein at least one of R 1 or R 2 is present and other than H.
15 . The compound according to claim 14 , wherein: R 1 and R 2 are independently selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, methoxy, ethyl, vinyl, cyclopropyl, propyl, butyl, —SO 2 CF 3 , 3-pyridyl, acetyl, phenyl
with the proviso that at least one of R 1 or R 2 is present and other than H.
16 . The compound according to claim 1 wherein
A is selected from the group consisting of: aryl and heteroaryl, or a fused analog of any of aforementioned;
B is selected from the group consisting of: aryl and heteroaryl, or a fused analog of any of the aforementioned;
with the proviso that A and B cannot both simultaneously be phenyl.
17 . The compound according to claim 1 selected from the following group:
or a pharmaceutically acceptable salt of any of the aforementioned compounds.
18 . A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.
19 . A method for treating a microsomal prostaglandin E synthase-1 mediated disease or condition in a human patient in need of such treatment comprising administering to said patient a compound according to claim 1 in an amount effective to treat the microsomal prostaglandin E synthase-1 mediated disease or condition.
20 . The method according to claim 19 wherein the disease or condition is selected from the group consisting of: acute or chronic pain, osteoarthritis, rheumatoid arthritis, bursitis, ankylosing sponylitis and primary dysmenorrhea.