Inventors:
Paul Joseph Cox - Dagenham, GB
Shelley Bower - Dagenham, GB
David John Aldous - Dagenham, GB
Peter Charles Astles - Dagenham, GB
Daniel Gerard McGarry - King of Prussia PA
Christopher Hulme - Phoenixville PA
John Robinson Regan - Larchmont NY
Fu-Chih Huang - North Wales PA
Stevan Wakefield Djuric - Libertyville IL
Kevin Joseph Moriarty - Norristown PA
Rose Mappilakunnel Mathew - Phoenixville PA
Gregory Bernard Poli - Perkasie PA
Assignee:
Aventis Pharma Limited - Kent
International Classification:
A61K 3147
US Classification:
514314, 514308, 514309, 514312, 514313, 546169, 546140, 546141, 546146, 546153, 546156, 546158, 546159, 546165, 546166
Abstract:
This invention is directed to physiologically active compounds of formula (I) wherein represents a bicyclic ring system, of about 10 to about 13 ring members, in which the ring is an azaheterocycle, and the ring represents an azaheteroaryl ring, or an optionally halo substituted benzene ring; R 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 represents a direct bond R may also represent a lower alkenyl or lower alkynyl group, or a formyl group; R 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, âSO NR R , âNR SO R , âNR R , âC( O)R , âC( O)C( O)R , âC( O)NR R , âC( O)OR , âO(C O)NR R , or âNR C( O)R ; R represents âC( Z)âN(R )R , âC( Z)âCHR R , âC( Z)âR , âCR C(R )(CH ) âR , âC(R ) C(R )R , âC(R )(R )C(R )(R )R , âC(R )(R )CH(R )(CH ) âR , âR , âV( Z)âR , âC(R ) NâOC( O)R , âC( O)âN(R )OR , âCâCâR , âCH âC( Z)âR , âC( Z)âC( Z)R , âCH âNHR , âCH âZR , âCH âSOR , âCH âSO R , âCF âOR , âNHâCH R , âZâCH R , âSOâCH R , âSO âCH R , âOâCF R , âOâC( Z)R , âN NâR , âNHâSO R , âSO âNR R , âCZâCZâNHR , âNHâCOâOR , âOâCOâNHR , âNHâCOâNHR , âR , âCX CX R , âC( NOR ), â(CH ) R , âCH âCOâNH(CH ) R , âCH âNHâCO(CH ) R , âCH âCOâCH R , âC( NR )âNH(CH ) R , âC(X ) Nâ(CH ) R or âCH(X )âCH R ; A represents a direct bond, or a straight or branched C alkylene chain optionally substituted by hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl, or A represents a straight or branched C alkenylene or C alkynylene chain; Z 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.
