Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-28
2001-10-16
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...
C514S314000, C514S414000, C514S415000, C546S146000, C546S168000, C548S454000, C548S469000
Reexamination Certificate
active
06303628
ABSTRACT:
TECHNICAL FIELD
This invention relates to bicycliccarbonyl indoles as pharmaceutical agents. This invention specifically relates to compounds, compositions and methods for the treatment or alleviation of pain, inflammation, other inflammation-associated disorders such as arthritis, and the like in humans, dogs, cats and the like.
BACKGROUND ART
Nonsteroidal antiinflammatory 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, nepbrotoxicity, 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 indole compounds are known and are disclosed in several patent applications. International Publication Number WO 96/32379 discloses N-substituted indole compounds as cGMP-PDE Inhibitors. International Publication Numbers WO 96/37467, WO 96/37469, UK Patent Publication GB 2283745 A and U.S. Pat. No. 5,510,368 disclose 2-methyl-N-substituted indole compounds as cyclooxygenase-2 Inhibitors. Also, a variety of indole compounds are disclosed as agents for controlling underwater fouling organisms in European Patent Publication Number 0 556 949 A2. International Publication Number WO 99/05104 discloses 3-amino-substituted indole compounds. Further, International Publication Number WO 97/09308 discloses indole compounds as neuropeptide receptor antagonists.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof wherein
A is C
1-6
alkylene or —NR
1
—;
Z is C(═L)R
2
, or SO
2
R
3
;
U is CH or N;
W and Y are independently selected from —CH
2
—, O, S and —N—R
1
;
m is 1, 2 or 3;
q and r are independently 0, 1 or 2;
X is independently selected from halogen, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, mono- or di-(C
1-4
alkyl)amino and cyano;
n is 0, 1, 2, 3 or 4;
L is oxygen or sulfur;
R
1
is hydrogen or C
1-4
alkyl;
R
2
is hydroxy, C
1-6
alkyl, halo-substituted C
1-6
alkyl, C
1-6
alkoxy, halo-substituted C
1-6
alkoxy, C
3-7
cycloalkoxy, C
1-4
alkyl(C
3-7
cycloalkoxy), —NR
4
R
5
, C
1-4
alkylphenyl-O— or phenyl-O—, said phenyl being optionally substituted with one to five substituents independently selected from halogen, C
1-4
alkyl, hydroxy, C
1-4
alkoxy and nitro;
R
3
is C
1-6
alkyl or halo-substituted C
1-6
alkyl; and
R
4
and R
5
are independently selected from hydrogen, C
1-6
alkyl and halo-substituted C
1-6
alkyl.
The indole compounds of the present invention exhibit inhibition of COX activity. Preferably 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 also provides compounds which can be used as intermediates of formula (I) where in
A is methylene;
Z is C(═O)OCH
3
;
U is CH or N;
W and Y are independently selected from —CH
2
—, O and N—R
1
;
m is 1, or 2;
q and r are independently 0 or 1;
X is independently selected from chloro, trifluoromethyl, and methoxy;
n is 1 or 2; and
R
1
is hydrogen or methyl.
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, dog, cat etc. 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 may be contra-indicated such as in patients with ulcers (such as peptic ulcers and gastric ulcers), gastritis, regional enterotis, ulcerative colitis, diverticulitis or with a recurrent history of GI lesions, GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, hemophilia and
Hayashi Shigeo
Nakao Kazunari
Stevens Rodney W.
Davis Zinna Northington
Djuardi Elsa
Ginsburg Paul H.
Pfizer Inc
Richardson Peter C.
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