Sulfonyl heteroaryl triazoles as anti-inflammatory/analgesic...

Details Sulfonyl heteroaryl triazoles as anti-inflammatory/analgesic... Sulfonyl heteroaryl triazoles as anti-inflammatory/analgesic...

2002-07-03

2004-06-22

Berch, Mark L (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S310000, C544S316000, C544S298000, C544S182000, C544S405000, C544S309000, C544S238000, C546S272400, C514S274000

Reexamination Certificate

active

06753332

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to sulfonyl heteroaryl triazoles, methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases.
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. Common NSAIDs work by blocking the activity of cyclooxygenase (COX), an enzyme that converts arachidonic acid into prostanoids. 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, et. al.,
Proc. Natl. Acad. Sci. USA,
1994, 91, 2046). COX-1 appears 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. The therapeutic use of conventional NSAIDs is, however, limited due to drug associated side effects, including life threatening ulceration and renal toxicity.
COX is also known as prostaglandin G/H synthase (PGHS). Prostaglandins, especially prostaglandin E
2
(PGE
2
), a predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. A pathological role for prostaglandins has been implicated in a number of human diseases including rheumatoid arthritis, osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, dysmenorrhea, premature labour, nephritis, nephrosis, atherosclerosis, hypotension, shock, pain, cancer and Alzheimer. Compounds that 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 triazole compounds which inhibit COX have been disclosed in U.S. Pat. Nos. 4,259,504, 4,962,119, 5,066,668, and 5,376,670; European Patent Publications EP 3895A1, EP 155486A, and EP 1099695; and scientific publication (
Eur. J. Med. Chem.
1990, 25, 95-101).
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein
is an aromatic heterocycle selected from the group consisting of
m is 0, 1 or 2, preferably m is 2;
X is CR
6
or N, preferably CR
6
wherein R
6
is hydrogen;
wherein R
1
is selected from the group consisting of:
(a) (C
1
-C
6
)alkyl (preferably branched (C
1
-C
6
)alkyl), (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylcarbonyl, formyl, formamidyl, (C
1
-C
6
)alkylcarbonyl, cyano, mercapto, nitro, hydroxycarbonyl, (C
1
-C
6
)alkoxycarbonyl, amino, N—(C
1
-C
6
)alkylamino, N,N—[(C
1
-C
6
)alkyl]
2
amino, N—(C
3
-C
7
)carbocyclylamino, N—(C
6
-C
10
)arylamino, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamino, N—(C
2
-C
9
)heteroarylamino, amido, N—(C
1
-C
6
)alkylamido, N,N—[(C
1
-C
6
)alkyl]
2
amido, N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamido, (C
1
-C
6
)alkoxyamido, (C
1
-C
6
)alkylthio, (C
3
-C
7
)carbocyclylthio, (C
6
-C
10
)arylthio, (C
2
-C
9
)heteroarylthio, (C
1
-C
6
)alkyl-S(═O)—, (C
1
-C
6
)alkyl-SO
2
—, (C
6
-C
10
)aryloxy, (C
2
-C
9
)heteroaryloxy, (C
2
-C
9
)heterocyclylcarbonyl, or (C
1
-C
6
)alkylcarbonyl-N(R
2
)—;
(b) phenyl optionally substituted by one to three substituents independently selected from the group consisting of halo (preferably fluoro), hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)carbocyclyl, (C
1
-C
6
)alkoxy, —OCF
3
, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkyl-S(═O)—, (C
1
-C
6
)alkyl-SO
2
—, amino, N—(C
1
-C
6
)alkylamino, N,N—[(C
1
-C
6
)alkyl]
2
amino, N—(C
3
-C
7
)carbocyclylamino, N—(C
6
-C
10
)arylamino, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamino, N—(C
2
-C
9
)heteroarylamino, amido, N—(C
1
-C
6
)alkylamido, N,N—[(C
1
-C
6
)alkyl]
2
amido, N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkoxyamido, (C
1
-C
6
)alkylcarbonyloxy, (C
1
-C
6
)alkylcarbonyl-N(R
2
)—, formyl, (C
1
-C
6
)alkylcarbonyl, (C
1
-C
6
)alkoxycarbonyl, (C
6
-C
10
)aryl and (C
2
-C
9
)heterocyclyl; preferably halo, most preferably one to three fluoro atoms;
(c) phenyl fused to a saturated, partially saturated or aromatic (5- to 7-membered)-carbocyclic ring;
wherein either of said phenyl or said fused saturated, partially saturated or aromatic (5- to 7-membered)-carbocyclic ring is optionally substituted by one to two substituents per ring, wherein said substituents are independently selected from the group consisting of halo (such as chloro, bromo, or fluoro), hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)carbocyclyl, (C
1
-C
6
)alkoxy, —OCF
3
, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkyl-S(═O)—, (C
1
-C
6
)alkyl-SO
2
—, amino, N—(C
1
-C
6
)alkylamino, N,N—[(C
1
-C
6
)alkyl]
2
amino, N—(C
3
-C
7
)carbocyclylamino, N—(C
6
-C
10
)arylamino, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamino, N—(C
2
-C
9
)heteroarylamino, amido, N—(C
1
-C
6
)alkylamido, N,N—[(C
1
-C
6
)alkyl]
2
amido, N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkoxyamido, (C
1
-C
6
)alkylcarbonyloxy, (C
1
-C
6
)alkylcarbonyl-N(R
2
)—, formyl, (C
1
-C
6
)alkylcarbonyl, (C
1
-C
6
)alkoxycarbonyl, (C
6
-C
10
)aryl and (C
2
-C
9
)heterocyclyl;
(d) phenyl fused to a saturated, partially saturated or aromatic (5- to 6-membered)-heterocyclyl containing one to two ring heteroatoms independently selected from the group consisting of —N═, —NR
2
—, —S—and —O—;
wherein either of said phenyl or said fused saturated, partially saturated or aromatic (5- to 6-membered)-heterocyclyl is optionally substituted with one to two substituents per ring;
wherein said substituents are independently selected from the group consisting of halo (such as chloro, bromo, or fluoro), hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)carbocyclyl, (C
1
-C
6
)alkoxy, —OCF
3
, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkyl-S(═O)—, (C
1
-C
6
)alkyl-SO
2
—, amino, N—(C
1
-C
6
)alkylamino, N,N—[(C
1
-C
6
)alkyl]
2
amino, N—(C
3
-C
7
)carbocyclylamino, N—(C
6
-C
10
)arylamino, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamino, N—(C
2
-C
9
)heteroarylamino, amido, N—(C
1
-C
6
)alkylamido, N,N—[(C
1
-C
6
)alkyl]
2
amido, N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkoxyamido, (C
1
-C
6
)alkylcarbonyloxy, (C
1
-C
6
)alkylcarbonyl-N(R
2
)—, formyl, (C
1
-C
6
)alkylcarbonyl, (C
1
-C
6
)alkoxycarbonyl, (C
6
-C
10
)aryl and (C
2
-C
9
)heterocyclyl;
(e) (3- to 7-membered)-carbocyclic optionally containing one or two double bonds, preferably the (3- to 7-membered)-carbocyclic contains no double bonds;
wherein said (3- to 7-membered)-carbocyclic may also be optionally substituted by one to three substituents independently selected from the group consisting of halo (such as chloro, bromo, or fluoro), hydroxy, cyano, mercapto, hydroxycarbonyl, nitro, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)carbocyclyl, (C
1
-C
6
)alkoxy, —OCF
3
, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkyl-S(═O)—, (C
1
-C
6
)alkyl-SO
2
—, amino, N—(C
1
-C
6
)alkylamino, N,N—[(C
1
-C
6
)alkyl]
2
amino, N—(C
3
-C
7
)carbocyclylamino, N—(C
6
-C
10
)arylamino, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamino, N—(C
2
-C
9
)heteroarylamino, amido, N—(C
1
-C
6
)alkylamido, N,N—[(C
1
-C
6
)alkyl]
2
amido, N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkyl-N—(C
6
-C
10
)arylamido, N—(C
1
-C
6
)alkoxyamido, (C
1
-C
6
)alkylcarbonyloxy, (C
1
-C
6
)alkylcarbonyl-N(R
2
)—, formy

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