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Abstract

This invention is directed to physiologically active compounds of formula (I) ##STR1## wherein ##STR2## represents a bicyclic ring system, of about 10 to about 13 ring members, in which the ring ##STR3## is an azaheterocycle, and the ring ##STR4## represents an azaheteroaryl ring, or an optionally halo substituted benzene ring; R.sup.1 represents hydrogen or a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms, optionally substituted by hydroxy or one or more halogen atoms, or when Z.sup.1 represents a direct bond R.sup.1 may also represent a lower alkenyl or lower alkynyl group, or a formyl group; R.sup.2 represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl, cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, hydroxy, --SO.sub.2 NR.sup.4 R.sup.5, --NR.sup.4 SO.sub.2 R.sup.5, --NR.sup.4 R.sup.5, --C(.dbd.O)R.sup.5, --C(.dbd.O)C(.dbd.O)R.sup.5, --C(.dbd.O)NR.sup.4 R.sup.5, --C(.dbd.O)OR.sup.5, --O(C.dbd.O)NR.sup.4 R.sup.5, or --NR.sup.4 C(.dbd.O)R.sup.5 ; R.sup.3 represents --C(.dbd.Z)--N(R.sup.7)R.sup.6, --C(.dbd.Z)--CHR.sup.12 R.sup.6, --C(.dbd.Z)--R.sup.6, --CR.sup.8.dbd.C(R.sup.9)(CH.sub.2).sub.p --R.sup.6, --C(R.sup.10).dbd.C(R.sup.11)R.sup.12, --C(R.sup.13)(R.sup.10)C(R.sup.11)(R.sup.14)R.sup.12, --C(R.sup.8)(R.sup.15)CH(R.sup.9)(CH.sub.2).sub.p --R.sup.6, --R.sup.6, --V(.dbd.Z)--R.sup.6, --C(R.sup.17).dbd.N--OC(.dbd.O)R.sup.18, --C(.dbd.O)--N(R.sup.19)OR.sup.20, --C.ident.C--R.sup.6, --CH.sub.2 --C(.dbd.Z)--R.sup.6, --C(.dbd.Z)--C(.dbd.Z)R.sup.6, --CH.sub.2 --NHR.sup.6, --CH.sub.2 --ZR.sup.6, --CH.sub.2 --SOR.sup.6, --CH.sub.2 --SO.sub.2 R.sup.6, --CF.sub.2 --OR.sup.6, --NH--CH.sub.2 R.sup.6, --Z--CH.sub.2 R.sup.6, --SO--CH.sub.2 R.sup.6, --SO.sub.2 --CH.sub.2 R.sup.6, --O--CF.sub.2 R.sup.6, --O--C(.dbd.Z)R.sup.6, --N.dbd.N--R.sup.6, --NH--SO.sub.2 R.sup.6, --SO.sub.2 --NR.sup.21 R.sup.22, --CZ--CZ--NHR.sup.6, --NH--CO--OR.sup.6, --O--CO--NHR.sup.6, --NH--CO--NHR.sup.6, --R.sup.23, --CX.sup.1.dbd.CX.sup.2 R.sup.6, --C(.dbd.NOR.sup.24), --(CH.sub.2).sub.q R.sup.6, --CH.sub.2 --CO--NH(CH.sub.2).sub.q R.sup.6, --CH.sub.2 --NH--CO(CH.sub.2).sub.q R.sup.6, --CH.sub.2 --CO--CH.sub.2 R.sup.6, --C(.dbd.NR.sup.25)--NH(CH.sub.2).sub.q R.sup.6, --C(X.sup.3).dbd.N--(CH.sub.2).sub.q R.sup.6 or --CH(X.sup.4)--CH.sub.2 R.sup.6 ; A.sup.1 represents a direct bond, or a straight or branched C.sub.1-6 alkylene chain optionally substituted by hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl, or A.sup.1 represents a straight or branched C.sub.2-6 alkenylene or C.sub.2-6 alkynylene chain; Z.sup.1 represents a direct bond, an oxygen or sulphur atom or NH; n and m each represent zero or 1, provided that n is 1 when m is zero and n is zero when m is 1; and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (I) and N-oxides thereof, and their prodrugs. Such compounds inhibit the production or physiological effects of TNF and inhibit cyclic AMP phosphodiesterase. The invention is also directed to pharmaceutical compositions comprising compounds of formula (I), their pharmaceutical use and methods for their preparation.

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First Claim