Derivatives of benzosulphonamides as inhibitors of the enzyme cy

Details Derivatives of benzosulphonamides as inhibitors of the enzyme cy Derivatives of benzosulphonamides as inhibitors of the enzyme cy

1998-09-03

1999-12-21

Killos, Paul J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Para-n-benzene - sulfoxy-n containing doai, and said benzene...

514156, 514158, 514211, 5142228, 514605, 564 97, 564 99, 540544, 540546, 548136, 5483001, 548207, 546301, 546329, 546300, 549 66, 549 73, 549 72, A61K 3118

Patent

active

060049480

DESCRIPTION:

BRIEF SUMMARY
The invention relates to new derivatives of benzenesulphonic acids having anti-inflammatory activity.
Prostaglandins play a crucial part in inflammatory processes and the inhibition of prostaglandin formation, particularly the formation of PGG.sub.2, PGH.sub.2 and PGE.sub.2 is the property common to anti-inflammatory compounds. The known non-steroidal anti-inflammatory drugs (NSAIDs) which reduce prostaglandin-induced pain and swelling in inflammatory processes also influence prostaglandin-regulated processes which do not accompany inflammatory processes. Therefore, the majority of known NSAIDs cause undesirable side effects at higher doses, sometimes even life-threatening ulcers, particularly gastric ulcers, gastric bleeds and the like. This seriously restricts the therapeutic potential of these compounds.
Most known NSAIDs inhibit the formation of prostaglandins by inhibiting enzymes in human arachidonic acid metabolism, particularly by inhibiting the enzyme cyclooxygenase (COX). An enzyme of human arachidonic metabolism which has only recently been discovered is the enzyme cyclooxygenase II (COX-2). (Proc. Natl. Acad. Sci. USA, 89, 7384, 1992). COX-2 is induced by cytokines or endotoxins. The discovery of this inducible enzyme which plays a decisive role in inflammatory processes opens up the possibility of searching for selectively acting compounds with an anti-inflammatory effect which will inhibit the inflammatory process more effectively without influencing other prostaglandin-regulated processes and at the same time having fewer and less severe side effects.
From WO 94/13635, 5-methylsulphonamide-1-indanones are known which inhibit the enzyme cyclooxygenase II and can therefore be used for the treatment of inflammatory processes. The potential and side effects of these compounds have not yet been fully investigated. Moreover, these known compounds have poor solubility and therefore have significant disadvantages in formulation and use. Therefore, there is still a need for new cyclooxygenase II-selective compounds which are safe in terms of their activity and side effects profile and are effective in use in the treatment of inflammatory processes.
The aim of the present invention was therefore to prepare new non-steroidal anti-inflammatory drugs (NSAIDs) which selectively inhibit cyclooxygenase II (COX-2) and therefore have less and less severe undesirable side effects.
This aim was unexpectedly achieved by preparing new derivatives of benzenesulphonic acids. These new compounds, by virtue of their selective effect on the enzyme cyclooxygenase II, have excellent anti-inflammatory, analgesic, anti-pyretic and anti-allergic properties without having the extremely undesirable side effects of the known anti-inflammatories.
The present invention therefore relates to compounds of formula I ##STR2## wherein A denotes oxygen, sulphur or NH, polysubstituted by halogen, alkyl, CF.sub.3 or alkoxy ##STR3## R.sub.2 and R.sub.3 independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH.sub.2).sub.n --X, or seven-membered, saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, O or S, which may optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH.sub.2).sub.n --X, R.sub.2 ' denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH.sub.2).sub.n --X, --OCO.sub.2 R.sub.4, --CN, --CONR.sub.4 OR.sub.5, --CONR.sub.4 R.sub.5, --SR.sub.4, --S(O)R.sub.4, --S(O).sub.2 R.sub.4, --NR.sub.4 R.sub.5, --NHC(O)R.sub.4, --NHS(O).sub.2 R.sub.4 --CH.sub.2 --, --CH.sub.2 --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, --CH.sub.2 --CO--, --CO--CH.sub.2 --, --NHCO--, --CONH--, --NHCH.sub.2 --, --CH.sub.2 NH--, --N.dbd.CH--, --NHCH--, --CH.sub.2 --CH.sub.2 --NH--, --CH.dbd.CH--, >N--R.sub.3, >C.dbd.O, >S(O).sub.m, aralkyl or aryl, optionally be mono- or polysubstituted by halogen or alkoxy, or R.sub.6 denotes CF.sub.3, and
A denotes

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