Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-06-18
2004-04-27
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S365000, C514S369000, C514S372000, C514S374000, C514S396000, C514S398000, C514S427000, C548S193000, C548S203000, C548S205000, C548S214000, C548S235000, C548S240000, C548S300100, C548S316400, C548S341100, C548S400000, C548S577000, C549S029000, C549S062000, C549S065000, C549S263000, C549S295000, C549S323000
Reexamination Certificate
active
06727238
ABSTRACT:
TECHNICAL FIELD
This invention relates to compound 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, in mammals. This invention also relates to pharmaceutical compositions comprising such compounds.
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 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.
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. 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 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, dysmenorrhea, premature labour, nephritis, nephrosis, 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 COX-2 and/or by intervention of the activity of the enzyme COX-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 sulfonylbenzene compounds which inhibit COX have been disclosed in patents 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 by optionally substituted aryl.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or its pharmaceutically acceptable salt thereof, wherein
A is partially unsaturated or unsaturated five membered heterocyclic, or partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula (I) are attached to ring atoms of Ring A adjacent to each other;
R
1
is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R
1
is heteroaryl;
R
2
is C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkylamino, C
1-4
dialkylamino or amino;
R
3
, R
4
and R
5
are independently hydrogen, halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
2-5
alkenyl, C
2-5
alkynyl, C
1-4
alkoxy, hydroxy-C
1-4
alkyl, C
1-4
alkoxy C
1-4
alkyl, C
1-4
alkanoyl, cyano, nitro, cyano C
1-4
alkyl, carboxy, C
1-4
alkoxycarbonyl, aminocarbonyl, N—C
1-4
alkylaminocarbonyl, N,N-di-C
1-4
alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N—C
1-4
alkyl-N-arylamiocarbonyl, aryl, aryloxy, aryloxy-C
1-4
alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-C
1-4
alkyl, morpholino-carbonyl, C
1-4
alkoxyaminocarbonyl or C
1-4
alkyl-carbonylamino; or two of R
3
, R
4
and R
5
are taken together with atoms to which they are attached and form a 4-7 membered ring;
R
6
and R
7
are independently hydrogen, halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylthio, C
1-4
alkylamino, N,N-di C
1-4
alkylamino, hydroxyl-C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, C
1-4
alkyl-C
1-4
alkoxy, C
1-4
alkylamino-C
1-4
alkyl, hydroxy, amino-C
1-4
alkyl and N,N-di C
1-4
alkylamino-C
1-4
alkyl; and
m and n are independently 1, 2, 3 or 4.
The sulfonylbenzene compounds of the present invention exhibit inhibition of COX activity. Preferable compounds of this invention exhibit inhibitory activity against COX-2, with more preferable compounds having COX-2 selectivity.
Accordingly, the present invention also provides a pharmaceutical composition, useful for the treatment of a medical condition in which prostaglandins are implicated as pathogens, which comprises a compound of the formula (I) and the pharmaceutically acceptable salts thereof.
Further, the present invention provides a method for the treatment of a medical condition in which prostaglandins are implicated as pathogens, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of said pharmaceutical composition.
The medical conditions in which prostaglandins are implicated as pathogens, include the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout, ankylosing spondylitis, systemic lumpus erythematosus and juvenile arthritis, bursitis, burns, injuries following surgical and dental procedures.
The compounds and pharmaceutical composition of this invention may inhibit cellular neoplastic transformations and metastatic tumor growth and thus may be used in the treatment and/or prevention of cancers in the colon, breast, skin, esophagus, stomach, urinary bladder, lung and liver. The compounds and pharmaceutical composition of this invention were used in the treatment and/or prevention of cyclooxygenase-mediated proliferation disorders such as which occur in diabetic retinopathy and tumor angiogenesis.
The compounds and pharmaceutical composition of this invention may inhibit prostaniod-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids, and thus may be of use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders and in the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, and for the treatment of bone loss (treatment of osteoarthritis), stroke, seizures, migraine, multiple sclevosis, AIDS and encephaloathy.
By virtue of the COX-2 activity and/or specificity for COX-2 over COX-1, such compounds will prove useful as an alternative to conventional NSAIDs particularly where such NSAIDs
Ando Kazuo
Kato Tomoki
Kawai Akiyoshi
Nonomura Tomomi
Benson Gregg C.
Munchhof Martha G.
Patel Sudhaker B.
Pfizer Inc.
Richardson Peter C.
LandOfFree
Sulfonylbenzene compounds as anti-inflammatory/analgesic agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Sulfonylbenzene compounds as anti-inflammatory/analgesic agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sulfonylbenzene compounds as anti-inflammatory/analgesic agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3237921