Heteroaryl phenyl pyrazole compounds as...

Details Heteroaryl phenyl pyrazole compounds as... Heteroaryl phenyl pyrazole compounds as...

2000-11-28

2003-11-18

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S269700, C546S271400, C546S275400

Reexamination Certificate

active

06649636

ABSTRACT:

TECHNICAL FIELD
This invention relates to heteroaryl-phenyl pyrazole derivatives and methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases. The compounds of this invention inhibit the biosynthesis of prostaglandins by intervention of the action of the enzyme cyclooxygenase on arachidonic acid, and are therefore useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock.
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 E
2
(PGE
2
), which is the predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of the 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 term therapy can also result in severe side effects.
The use of NSAIDs in the treatment or alleviation of inflammation and other inflammation associated disorders in dogs and cats has been more limited than that in humans: e.g., only three such NSAIDs have been approved by the Food and Drug Administration, Committee on Veterinary Medicine (FDA/CVM), for use in dogs in the United States, i.e., ETOGESIC® (etodolac), ARQUEL® (meclofenamic acid) and RIMADYL® (carprofen). Consequently, there is less experience and knowledge in veterinary medicine about safety and efficacy issues surrounding the use of NSAIDs in dogs. In veterinary medicine, for example, the most common indication for NSAIDs is the treatment of degenerative joint disease (DJD), which in dogs often results from a variety of developmental diseases, e.g., hip dysplasia and osteochondrosis, as well as from traumatic injuries to joints. In addition to the treatment of chronic pain and inflammation, NSAIDs are also useful in dogs for treating post-surgical acute pain, as well as for treating clinical signs associated with osteoarthritis.
Two forms of COX are now known, 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. Natl. 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 is believed 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 arthritis and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, dysmenorrhea, premature labour, nephritis, nephrosis, atherosclerosis, hypotension, shock, pain, cancer, and Alzheimer disease. It is believed that compounds that would selectively inhibit the biosynthesis of prostaglandins by intervention of activity of the enzyme COX-2 on arachidonic acid would provide alternate therapy to the use of conventional 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 sulfonylbenzene compounds which inhibit COX have been disclosed in patent publications (WO 97/16435, WO 97/14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO 96/936617, WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845, and EP 554829). Especially, International Publication Number WO 97/11704 discloses pyrazole compounds substituted with optionally substituted aryl.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of
(a) (5- to 6-membered)- heteroaryl containing 1 to 4 ring heteroatoms independently selected from —N═, —NR═, —O—, or —S—, wherein said heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-S—, amino, (C
1
-C
4
)alkylamino, di[(C
1
-C
4
)alkyl]amino, amido, (C
1
-C
4
)alkylamido, di[(C
1
-C
4
)alkyl]amido, (C
1
-C
4
)alkyl-(C═O)—O—, (C
1
-C
4
)alkyl-(C═O)—N(R′)—, formyl, (C
1
-C
4
)alkyl-(C═O)— and (C
1
-C
4
)alkoxy-(C═O)—; wherein R′ is hydrogen or (C
1
-C
4
)alkyl; wherein each of said (C
1
-C
4
)alkyl may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-S—, amino, (C
1
-C
4
)alkylamino, di[(C
1
-C
4
)alkyl]amino, amido, (C
1
-C
4
)alkylamido, di[(C
1
-C
4
)alkyl]amido, (C
1
-C
4
)alkyl-(C═O)—O—, (C
1
-C
4
)alkyl-(C═O)—N(R′)—, formyl, (C
1
-C
4
)alkyl-(C═O)— and (C
1
-C
4
)alkoxy-(C═O)—;
(b) (5- to 6-membered)-beteroaryl containing 1 to 2 ring heteroatoms independently selected from the group consisting of —N═, —NR′—, —S— or —O—; wherein said heteroaryl is fused to a saturated, partially saturated or aromatic (5- to 7-membered)-carbocyclic ring; wherein either of said (5- to 6-membered)-heteroaryl ring or said fused saturated, partially saturated or aromatic (5- to 7-membered)-carbocyclic ring may optionally be substituted with 1 to 2 substituents per ring, wherein said substituents are independently selected from the group consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-S—, amino, (C
1
-C
4
)alkylamino, di[(C
1
-C
4
)alkyl]amino, amido, (C
1
-C
4
)alkylamido, di[(C
1
-C
4
)alkyl]amido, (C
1
-C
4
)alkyl-(C═O)—O—, (C
1
-C
4
)alkyl-(C═O)—N(R′)—, formyl, (C
1
-C
4
)alkyl-(C═O)— and (C
1
-C
4
)alkoxy-(C═O)—; wherein R′ is hydrogen or (C
1
-C
4
)alkyl; wherein each of said (C
1
-C
4
)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-S—, amino, (C
1
-C
4
)alkylamino, di[(C
1
-C
4
)alkyl]amino, amido, (C
1
-C
4
)alkylamido, di[(C
1
-C
4
)alkyl]amido, (C
1
-C
4
)alkyl-(C═O)—O—, (C
1
-C
4
)alkyl-(C═O)—N(R′)—, formyl, (C
1
-C
4
)alkyl-(C═O)— and (C
1
-C
4
)alkoxy-(C═O)—; and
(c) (5- to 6-membered)-heteroaryl containing 1 to 2 ring heteroatoms independently selected from the group consisting of —N═, —NR′—, —S—, or —O—; wherein said heteroaryl is fused to a (5- to 6-membered)-heteroaryl containing 1 to 2 ring heteroatoms independently selected from the group consisting of —N═, —NR′—, —S— or —O—; wherein either of said (5- to 6-membered)-heteroaryl or said fused (5- to 6-membered)-heteroaryl is optionally substituted with one to two substituents per ring, wherein said substituents are independently selected from the group consisting of halo, hydroxy, cyano, mercapto, carboxy,

Affiliated with

Also associated with

Rating

Heteroaryl phenyl pyrazole compounds as... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Heteroaryl phenyl pyrazole compounds as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heteroaryl phenyl pyrazole compounds as... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3179974