Indole compounds as COX-2 inhibitors

Details Indole compounds as COX-2 inhibitors Indole compounds as COX-2 inhibitors

1999-12-03

2001-10-09

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...

C514S419000, C548S469000, C548S483000, C548S484000, C548S492000

Reexamination Certificate

active

06300363

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the National Stage filing under 35 U.S.C. §371 based on PCT/IB98/01026, filed internationally on Jul. 3, 1998, which claims priority from PCT/IB97/00917, filed Jul. 23, 1997.
TECHNICAL FIELD
This invention relates to novel indoles cyclooxygenase inhibitors. 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 in mammals. This invention also relates to pharmaceutical compositions comprising such compounds.
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 otherhand, 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-1inhibition.
A variety of indole compounds are known and are disclosed in several patent applications. Specifically, the International Publication Numbers WO 96/37467 and WO 96/37469 disclose N-benzylindole compounds as cyclooxyenase-2 inhibitors. Also, a variety of indole compounds are disclosed in Khim. Geterotsikl. Soedin. 1990, 11, 1569 by Tolkunov et.al.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
and the pharmaceutically acceptable salts thereof wherein
L is oxygen or sulfur; Y is a direct bond or C
1-4
alkylidene;
Q is
(a) C
1-6
alkyl or halosubstituted C
1-6
alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxy, C
1-4
alkoxy, amino and mono- or di-(C
1-4
alkyl)amino,
(b) C
3-7
cycloalkyl optionally substituted with up to three substituents independently selected from hydroxy, C
1-4
alkyl and C
1-4
alkoxy,
(c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to four substituents independently selected from
(c-1) halo, C
1-4
alkyl, halosubstituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halosubstituted C
1-4
alkoxy, S(O)
m
R
3
, SO
2
NH
2
, SO
2
N(C
1-4
alkyl)
2
, amino, mono- or di-(C
1-4
alkyl)amino, NHSO
2
R
3
, NHC(O)R
3
, CN, CO
2
H, CO
2
(C
1-4
alkyl), C
1-4
alkyl-OH, C
1-4
alkylOR
3
, CONH
2
, CONH(C
1-4
alkyl), CON(C
1-4
alkyl)
2
and —O—Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, C
1-4
alkyl, CF
3
, hydroxy, OR
3
, S(O)
m
R
3
, amino, mono- or di-(C
1-4
alkyl)amino and CN,
(d) a monocyclic aromatic group of 5 atoms, said aromatic group having one heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substitutents independently selected from
(d-1) halo, C
1-4
alkyl, halosubstituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halosubstituted C
1-4
alkoxy, C
1-4
alkyl-OH, S(O)
m
R
3
, SO
2
NH
2
, SO
2
N(C
1-4
alkyl)
2
, amino, mono- or di-(C
1-4
alkyl)amino, NHSO
2
R
3
, NHC(O)R
3
, CN, CO
2
H, CO
2
(C
1-4
alkyl), C
1-4
alkyl-OR
3
, CONH
2
, CONH(C
1-4
alkyl), CON(C
1-4
alkyl)
2
, phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF
3
, C
1-4
alkyl, hydroxy, C
1-4
alkoxy, OCF
3
, SR
3
, SO
2
CH
3
, SO
2
NH
2
, amino, C
1-4
alkylamino and NHSO
2
R
3
,
(e) a monocyclic aromatic group of 6 atoms, said aromatic group having one heteroatom which is N and optionally containing up to three atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substituents independently selected from the above group (d-1);
R
1
is hydrogen or C
1-6
alkyl optionally substituted with a substituent selected independently from hydroxy, OR
3
, nitro, amino, mono- or di-(C
1-4
alkyl)amino, CO
2
H, CO
2
(C
1-4
alkyl), CONH
2
, CONH(C
1-4
alkyl) and CON(C
1-4
alkyl)
2
;
R
2
is
(a) hydrogen,
(b) C
1-4
alkyl,
(c) C(O)R
5
wherein R
5
is selected from
(c-1) C
1-22
alkyl or C
2-22
alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from
(c-1-1) halo, hydroxy, OR
3
, S(O)
m
R
3
, nitro, amino, mono- or di-(C
1-4
alkyl)amino, NHSO
2
R
3
, CO
2
H, CO
2
(C
1-4
alkyl), CONH
2
, CONH(C
1-4
alkyl), CON(C
1-4
alkyl)
2
, OC(O)R
3
, thienyl, naphthyl and groups of the following formulae:
(c-2) C
1-22
alkyl or C
2-22
alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms,
(c-3) —Y—C
3-7
cycloalkyl or —Y—C
3-7
cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from
(c-3-1) C
1-4
alkyl, hydroxy, OR
3
, S(O)
m
R
3
, amino, mono- or di-(C
1-4
alkyl)amino, CONH
2
, CONH(C
1-4
alkyl) and CON(C
1-4
alkyl)
2
,
(c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents independently selected from
(c-4-1) halo, C
1-8
alkyl, C
1-4
alkyl-OH, hydroxy, C
1-8
alkoxy, halosubstituted C
1-8
alkyl, halosubstituted C
1-8
alkoxy, CN, nitro, S(O)
m
R
3
, SO
2
NH
2
, SO
2
NH(C
1-4
alkyl), SO
2
N(C
1-4
alkyl)
2
, amino, C
1-4
alkylamino, di-(C
1-4
alkyl)amino, CONH
2
, CONH(C
1-4
alkyl), CON(C
1-4
alkyl)
2
, OC(O)R
3
, and phenyl optionally substituted with up to three substituents independently selected from halo, C
1-4
alkyl, hydroxy, OCH
3
, CF
3
, OCF
3
, CN, nitro, amino, mono- or di-(C
1-4
alkyl)amino, CO
2
H, CO
2
(C
1-4
alkyl) and CONH
2
,
(c-5) a monocyclic aromatic group as defined in (d) and (e) above, said aromatic group being optionally substituted with up to three substituents independently selected from
(c-5-1) halo, C
1-8
alkyl, C
1-4
alkyl-OH, hydroxy, C
1-

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