Aventis Pharma Limited

Rhone Poulenc Rorer

May & Baker, Ltd.

Garry Fenton

Malcolm Norman Palfreyman

Andrew David Morley

Andrew James Ratcliffe

Brian William Sharp

Sukanthini Thurairatnam

Tahir Nadeem Majid

Bernard Yvon Vacher

Michael J Ashton

Ian Michael McFarlane

David Riddell

Neil Victor Harris

Michael John Ashton

David J Lythgoe

Nigel Vicker

Susan Jacqueline Hills

Donald I Dron

Andrew W Bridge

Christopher G Newton

David Charles Cook

Christopher Smith

Keith A Stuttle

Keith Alfred Stuttle

Clive McCarthy

Robert Chapman

Robert K Chambers

Jonathan S Mason

Anthony H Loveless

Robert Edward MacKenzie

Bernard Yvon Jack Vacher

Malcolm P Toft

This invention is directed to a [di(ether or thioether)heteroaryl or fluoro substituted aryl] compound or an N-oxide thereof or a pharmaceutically acceptable salt thereof, which is useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF). Compounds within the scope of the present invention also inhibit cyclic AMP phosphodiesterase, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase, such disease states including inflammatory and autoimmune diseases, in particular type IV cyclic AMP phosphodiesterase. The present invention is therefore directed to their pharmacological use for inhibiting TNF and/or cyclic AMP phosphodiesterase, pharmacological compositions comprising the compounds and methods for their preparation.

Compounds as PDE IV and TNF inhibitors

A compound of formula XIX wherein R, R, Z, Z, Q, Qand Qas defined in the specification.

The invention is directed to physiologically active compounds of formula (I): wherein: Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (&#x3b1;4&#x3b2;1).

Substituted tetrahydroisoquinolines

The invention is directed to physiologically active compounds of general formula (I): wherein: represents (i) a saturated 3 to 6 membered carbocycle, optionally substituted by one or more alkyl groups, (ii) indanyl or (iii) a saturated 4 to 6 membered heterocyclic ring; Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (&#x3b1;4&#x3b2;1).

Substituted alkanoic acids

Compounds as PDE IV and TNF-inhibitors

Indane derivatives

This invention is directed to the pharmaceutical use of phenyl compounds, which are linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The invention is also directed to the compounds, their preparation and pharmaceutical compositions containing these compounds. Furthermore, this invention is directed to the pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase.

Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group

Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-

Compounds containing phenyl linked to aryl or heteroaryl by an

Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- o

1-Alkoxy-2-(alkoxy- or cycloalkoxy-)-4-(cyclothioalkyl- or

Therapeutically useful isoquinolinone derivatives of the formula A--X--R.sup.3, wherein A represents a group of the formula: ##STR1## wherein R.sup.1 and R.sup.2 represents cycloalkyl, alkyl, alkenyl or alkynyl optionally substituted by halogen or cycloalkyl, or represents optionally substituted aryl or heteroaryl, R.sup.4 represents hydrogen, halogen, optionally substituted alkyl, alkenyl or alkynyl, optionally substituted aryl or heteroaryl, or a group R.sup.6 O-- wherein R.sup.6 represents alkyl, aryl or arylalkyl, X represents ethylene or vinylene, R.sup.3 represents a group of the formula:

Isoquinolinones

Therapeutically useful pyrrolo[2,1-a]phthalazine derivatives of the formula: ##STR1## wherein R.sup.1 and R.sup.2 represent cycloalkyl, optionally substituted alkyl, alkenyl, alkynyl, aryl or heteroaryl, X represents ethylene or vinylene, R.sup.3 represents a group of the formula:

Pyrrolophthalazines

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West Malling, United Kingdom

Garry Fenton