Benzimidazole cyclooxygenase-2 inhibitors

Details Benzimidazole cyclooxygenase-2 inhibitors Benzimidazole cyclooxygenase-2 inhibitors

2001-08-08

2004-03-30

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S255030, C514S247000, C544S333000, C544S405000, C544S238000

Reexamination Certificate

active

06713482

ABSTRACT:

TECHNICAL FIELD
This invention relates to benzimidazole compounds and their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds. These compounds and compositions have cyclooxygenase-2 inhibitory activities, therefore they are useful as agents for treatment of inflammatory diseases of a mammalian subject, especially a human subject.
BACKGROUND ART
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in treating pain and the signs and symptoms of arthritis because of their analgesic and anti-inflammatory activity. It is accepted that common NSAIDs work by blocking the activity of cyclooxygenase (COX), also known as prostaglandin G/H synthase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandins, especially prostaglandin E2 (PGE
2
), which is the predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of biosynthesis of prostaglandins has been a therapeutic target of anti-inflammatory drug discovery. The therapeutic use of conventional NSAIDs is, however, limited due to drug associated side effects, including life threatening ulceration and renal toxicity. An alternative to NSAIDs is the use of corticosteriods, however, long tern therapy can also result in severe side effects. Recently, two forms of COX were identified, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, J. A.; Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtoll, J.; Willoughby, D. A. Proc. Natnl. Acad. Sci. USA, 1994, 91, 2046). COX-1 is thought to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and to be the predominant isoform present in inflammation conditions. A pathological role for prostaglandins has been implicated in a number of human disease states including rheumatoid and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer, and Alzheimer disease. The NSAIDs currently on market inhibit both isoforms of COX with little variation for selectivity, explaining their beneficial (inhibition of COX-2) and deleterious effects (inhibition of COX-1). It is believed that compounds that would selectively inhibit the biosynthesis of prostaglandins by intervention of the induction phase of the inducible enzyme cyclooxygenase-2 and/or by intervention of the activity of the enzyme cyclooxygenase-2 on arachidonic acid would provide alternate therapy to the use of NSAIDs or corticosteriods in that such compounds would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition.
A variety of imidazole compounds are known and are disclosed in several patent applications. Specifically, Japanese Kokai (laid-open) Publication number S49-81369 discloses 1-benzyl-benzimidazole compounds as anti-inflammatory agents. Japanese Kokai (laid-open) Publication Number S59-75257 and H06-194780 disclose a variety of benzimidazole compounds as electrophotographic materials.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula (I):
or a pharmaceutically acceptable salt thereof, wherein
Ar is heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
X
1
is independently selected from halo, C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, halo-substituted C
1
-C
4
alkyl, hydroxy-substituted C
1
-C
4
alkyl, (C
1
-C
4
alkoxy)C
1
-C
4
alkyl, halo-substituted C
1
-C
4
alkoxy, amino, N—(C
1
-C
4
alkyl)amino, N,N-di(C
1
-C
4
alkyl)amino, [N—(C
1
-C
4
alkyl)amino]C
1
-C
4
alkyl, [N,N-di(C
1
-C
4
alkyl)amino]C
1
-C
4
alkyl, N—(C
1
-C
4
alkanoyl)amino, N—(C
1
-C
4
alkyl)(C
1
-C
4
alkanoyl)amino, N—[(C
1
-C
4
alkyl)sulfonyl]amino, N-[(halo-substituted C
1
-C
4
alkyl)sulfonyl]amino, C
1
-C
4
alkanoyl, carboxy, (C
1
-C
4
alkoxy)carbonyl, carbamoyl, [N—(C
1
-C
4
alkyl)amino]carbonyl, [N,N-di(C
1
-C
4
alkyl)amino]carbonyl, cyano, nitro, mercapto, (C
1
-C
4
alkyl)thio, (C
1
-C
4
alkyl)sulfinyl, (C
1
-C
4
alkyl)sulfonyl, aminosulfonyl, [N—(C
1
-C
4
alkyl)amino]sulfonyl and [N,N-di(C
1
-C
4
alkyl)amino]sulfonyl;
X
2
is independently selected from halo, C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, halo-substituted C
1
-C
4
alkyl, hydroxy-substituted C
1
-C
4
alkyl, (C
1
-C
4
alkoxy)C
1
-C
4
alkyl, halo-substituted C
1
-C
4
alkoxy, amino, N—(C
1
-C
4
alkyl)amino, N,N-di(C
1
-C
4
alkyl)amino, [N—(C
1
-C
4
alkyl)amino]C
1
-C
4
alkyl, [N,N-di(C
1
-C
4
alkyl)amino]C
1
-C
4
alkyl, N—(C
1
-C
4
alkanoyl)amino, N—(C
1
-C
4
alkyl)—N—(C
1
-C
4
alkanoyl) amino, N—[(C
1
-C
4
alky)sulfonyl]amino, N-[(halo-substituted C
1
-C
4
alkyl)sulfonyl]amino, C
1
-C
4
alkanoyl, carboxy, (C
1
-C
4
alkoxy)carbonyl, carbamoyl, [N—(C
1
-C
4
alkyl)amino]carbonyl, [N,N-di(C
1
-C
4
alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (C
1
-C
4
alkyl)thio, (C
1
-C
4
alkyl)sulfinyl, (C
1
-C
4
alkyl)sulfonyl, aminosulfonyl, [N—(C
1
-C
4
alkyl)amino]sulfonyl and [N,N-di(C
1
-C
4
alkyl)amino]sulfonyl;
R
1
is selected from
hydrogen;
straight or branched C
1
-C
4
alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy, C
1
-C
4
alkoxy, amino, N—(C
1
-C
4
alkyl)amino and N,N-di(C
1
-C
4
alkyl)amino;
C
3
-C
8
cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, amino, N—(C
1
-C
4
alkyl)amino and N,N-di(C
1
-C
4
alkyl)amino;
C
4
-C
8
cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, amino, N—(C
1
-C
4
alkyl)amino and N,N-di(C
1
-C
4
alkyl)amino;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, halo-substituted C
1
-C
4
alkyl, hydroxy-substituted C
1
-C
4
alkyl, (C
1
-C
4
alkoxy)C
1
-C
4
alkyl, halo-substituted C
1
-C
4
alkoxy, amino, N—(C
1
-C
4
alkyl)amino, N,N-di(C
1
-C
4
alkyl)amino, [N—(C
1
-C
4
alkyl)amino]C
1
-C
4
alkyl, [N,N-di(C
1
-C
4
alkyl)amino]C
1
-C
4
alkyl, N—(C
1
-C
4
alkanoyl)amino, N—[(C
1
-C
4
alkyl)(C
1
-C
4
alkanoyl)]amino, N—[(C
1
-C
4
alkyl)sulfonyl]amino, N-[(halo-substituted C
1
-C
4
alkyl)sulfonyl]amino, C
1
-C
4
alkanoyl, carboxy, (C
1
-C
4
alkoxy)carbonyl, carbamoyl, [N—(C
1
-C
4
alkyl)amino]carbonyl, [N,N-di(C
1
-C
4
alkyl)amino]carbonyl, cyano, nitro, mercapto, (C
1
-C
4
alkyl)thio, (C
1
-C
4
alkyl)sulfinyl, (C
1
-C
4
alkyl)sulfonyl, aminosulfonyl, [N—(C
1
-C
4
alkyl)amino]sulfonyl and [N,N-di(C
1
-C
4
alkyl)amino]sulfonyl; and
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or
a 6membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl being optionally substituted with one to three substituent(s) selected from X
1
;
R
2
and R
3
are i

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