Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-26
2001-08-21
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S233200, C514S254090, C514S422000, C514S423000, C544S143000, C544S144000, C544S373000, C546S278100, C548S465000, C548S483000
Reexamination Certificate
active
06277878
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel substituted indoles as pharmaceutical agents. This invention specifically relates to compounds, compositions and methods for the treatment or alleviation of pain and inflammation and other inflammation-associated disorders, such as arthritis.
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, 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.
Heterocyclylcarbonyl substituted benzofuranyl-ureas are disclosed in European patent publication number EP 0 779 291 A1.
A variety of indole compounds are known and are disclosed in several patent applications. The International Publication Numbers WO 96/37467, WO 96/37469, UK Patent Publication GB 2283745 A and US Publication Number 5510368 disclose 2-methyl-N-substituted indole compounds as cyclooxygenase-2 Inhibitors.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof wherein
R
1
is hydrogen or C
1-4
alkyl; R
2
is C(=L′)R
3
or SO
2
R
4
; Y is a direct bond or C
1-4
alkylene; L and L′ are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) C
1-6
alkyl,
(Q-b) halo-substituted C
1-4
alkyl,
(Q-c) C
3-7
cycloalkyl optionally substituted with one or two substituents independently selected from C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkoxy, hydroxy and halo,
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
, alkyl, hydroxy, C
1-4
alkoxy, nitro, halo-substituted C
1-4
alkoxy, S(O)
m
R
5
, SO
2
NH
2
, SO
2
N(C
1-4
alkyl)
2
, amino, C
1-4
alkylamino, di-(C
1-4
alkyl)amino, NR
1
C(O)R
5
, CN, C
1-4
alkyl-OH and C
1-4
alkyl-OR
5
,
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, amino, C
1-4
alkylamino, di-(C
1-4
alkyl)amino, C
1-4
alkyl-OH and C
1-4
, alkyl-OR
5
, and
(Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, amino, C
1-4
alkylamino, di-(C
1-4
alkyl)amino, C
1-4
alkyl-OH and C
1-4
alkyl-OR
5
;
R
3
is —OR
6
, —NR
7
R
8
, N(OR
1
)R
7
or a group of formula:
Z is a direct bond, oxygen, sulfur or NR
5
;
R
4
is C
1-6
, alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkyl-OH, —NR
7
R
8
, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy and halo-substituted C
1-4
, alkoxy;
R
5
is C
1-4
, alkyl or halo-substituted C
1-4
alkyl;
R
6
is C
1-4
alkyl, C
3-7
, cycloalkyl, C
1-4
alkyl-C
3-7
cycloalkyl, halo-substituted C
1-4
alkyl, C
1-4
alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, C
1-4
alkylthio, amino, di-(C
1-4
alkyl)amino and nitro;
R
7
and R
8
are independently selected from the following:
(a) hydrogen,
(b) C
1-6
alkyl optionally substituted with a substituent independently selected from halo, hydroxy, C
1-4
alkoxy, amino, C
1-4
alkylamino and di-(C
1-4
alkyl)amino,
(c) C
3-7
cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C
1-4
alkyl and C
1-4
alkoxy,
(d) C
1-4
alkyl-C
3-7
cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C
1-4
and C
1-4
alkoxy, and
(f) C
1-4
alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, di-(C
1-4
alkyl)amino and CN;
X is independently selected from halo, 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, di-(C
1-4
alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1, 2 or 3.
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 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
Kawamura Kiyoshi
Nakao Kazunari
Stevens Rodney W.
Uchida Chikara
Djuardi Elsa
Ginsburg Paul H.
Liu Hong
Pfizer Inc
Raymond Richard L.
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