Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents

A compound of formula I

• or a pharmaceutically acceptable salt or prodrug thereof, wherein
• R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, cycloalkyl, carboxaldehyde, a group of formula II defined as
• and wherein at least one of R1 or R3 is a pyrimidine;
• subject to the proviso that one or more than one of R1 or R3 is a group of formula II as defined above;
• D, B, Y and Z are each independently selected from the group consisting of —CR6═, —CR7R8—, —C(O)—, —O—, —SO2—, —S—, —N═, and —NR9—;
• n is an integer of zero to three;
• R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, hydroxyalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl and carboxyalkyl;
• and
• R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino;
• or
• R10 and R11 are taken together with N to form a three to seven membered unsubstituted heterocyclyl, or a three to seven membered substituted heterocyclyl ring, substituted with one or more than one substituent R13, wherein R13 is independently selected from the group consisting of alkyl, alkylene, alkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylalkylaminocarbonyl, hydroxy, hydroxyalkyl, hydroxyalkoxyalkyl, carboxy, carboxyalkyl, carboxycarbonyl, carboxaldehyde, alkoxycarbonyl, arylalkoxycarbonyl, aminoalkyl, aminoalkanoyl, aminocarbonyl, carboxamido, alkoxycarbonylalkyl, carboxamidoalkyl, cyano, tetrazolyl, alkanoyl, hydroxyalkanoyl, alkanoyloxy, alkanoylamino, alkanoyloxyalkyl, alkanoylaminoalkyl, sulfonate, alkylsulfonyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl and heterocyclylsulfonylaminocarbonyl;
• A is an unsubstituted aryl group, an unsubstituted heterocyclyl group, a substituted aryl group, or a substituted heterocyclyl group, substituted with one or more than one substituent R12, wherein R12, is independently selected from the group consisting of halogen, alkyl, aryl, haloalkyl, hydroxy, all oxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkoxy, hydroxyalkyl, aminoalkyl, aminocarbonyl, alkyl(alkoxycarbonylalkyl) aminoalkyl, heterocyclyl, heterocyclylalkyl, carboxaldehyde, carboxaldehyde hydrazone, carboxamido, alkoxycarbonylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, hydroxyalkylaminocarbonyl, cyano, amino, heterocyclylalkylamino, carboxythioalkoxy, carboxycycloalkoxy, thioalkoxy, carboxyalkylamino, trans-cinnamyl and heterocyclylalkylaminocarbonyl;
• and
• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are unsubstituted or substituted with one or more than one electron donating or electron withdrawing group
• wherein the heterocyclyl is chosen from 3-,4-,5-,6- and 7-membered rings containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
• the 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds, the heterocyclyl being optionally substituted with alkyl, halogen, hydroxy or alkoxy substituents,
• further wherein the heterocyclyl optionally comprises a group chosen from:
• (i) bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, and another monocyclic heterocyclic ring;
• (ii) bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group optionally selected from
• and
• (iii) compounds of the formula
• where X* and Z* are each independently selected from —CH2—, —CH2NH—, —CH2O—, —NH— and —O—, with the proviso that at least one of X* and Z* is not —CH2—, and Y* is selected from —C(O)— and —(C(R″)2)v -, where R″ is hydrogen or alkyl of one to our carbons, and v is 1-3.