2 cyclo(alkyl and alkenyl) phenyl-alkenylyl heteroaryl compounds and pharmaceutical compositions containing same

A compound of the formula ##STR14## wherein:

• x is an integer from 0 to 3;
• each of L.sup.1 and L.sup.2 is --C.dbd. or --N.dbd.;
• Y is halogen or --OR.sup.1, where R.sup.1 is an optionally substituted C.sub.1-6 alkyl group, said R.sup.1 substituent being halogen;
• X is --O--, --S-- or--N(R.sup.6)--;
• Z is --(CH.sub.2).sub.n --, where n is an integer of 0 to 3;
• R.sup.2 is an optionally substituted C.sub.3-8 cycloalkyl group or an optionally substituted C.sub.3-8 cycloalkenyl group, said R.sup.2 substituents being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
• R.sup.3 and R.sup.4 are independently hydrogen, an optionally substituted C.sub.1-6 alkyl group or a --CO.sub.2 R.sup.7, --CONR.sup.8 R.sup.9, --CSNR.sup.8 R.sup.9, --CN or --CH.sub.2 CN group, said optional C.sub.1-6 alkyl substituents being halogen, hydroxyl, C.sub.1-6 alkoxy, thiol or C.sub.1-6 alkylthio;
• R.sup.6 is hydrogen or a C.sub.1-6 alkyl group;
• R.sup.7, R.sup.8 and R.sup.9 are independently hydrogen or an optionally substituted C.sub.1-3 alkyl group, an optionally substituted C.sub.6-12 arylC.sub.1-3 alkyl group or an optionally substituted C.sub.6-12 aryl group, said R.sup.7, R.sup.8 and R.sup.9 substituents being independently R.sup.10 ;
• R.sup.10 is R.sup.11 or --Alk.sup.1 (R.sup.11).sub.m, wherein m is an integer of 0 to 3 and Alk.sup.1 is straight or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene group, said Alk.sup.1 group containing from zero to three --O--, --S--, --N(R.sup.6)-- or --S(O).sub.p -- groups, where p is 1 or 2;
• R.sup.11 is halogen or an amino (--NH.sub.2), substituted amino, nitro, cyano, hydroxyl (--OH), substituted hydroxyl, cycloalkoxy, formyl (HC(O)--), carboxyl (--CO.sub.2 H), esterified carboxyl, thiol (--SH), substituted thiol, C(O)R.sup.7, --SO.sub.3 H, --SO.sub.2 R.sup.7, --SO.sub.2 N(R.sup.7 R.sup.8), --CON(R.sup.7 R.sup.8), --NHSO.sub.2 R.sup.7, --N(SO.sub.2 R.sup.7).sub.2, --NHSO.sub.2 N(R.sup.7 R.sup.8), --NHC(O)R.sup.7 or --NHC(O)OR.sup.7 group;
• and
• R' and R" are hydrogen or are linked together to form the diradical --CH.dbd.CH--CH.dbd.CH--;
• or a salt, solvate, hydrate, prodrug or N-oxide thereof;
• with the proviso that one of L.sup.1 and L.sup.2 is --C.dbd. and the other of L.sup.1 and L.sup.2 is --N.dbd..

A compound of the formula ##STR15## wherein:

• Z is --(CH.sub.2).sub.n --, where n is an integer of 0 to 3;
• R.sup.2 is an optionally substituted C.sub.3-8 cycloalkyl group, said R.sup.2 substituent being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
• R.sup.3 and R.sup.4 are independently hydrogen, an optionally substituted C.sub.1-6 alkyl group or a --CO.sub.2 R.sup.7, --CONR.sup.8 R.sup.9, --CSNR.sup.8 R.sup.9, --CN or --CH.sub.2 CN group, said optional C.sub.1-6 alkyl substituents being halogen, hydroxyl, C.sub.1-6 alkoxy, thiol or C.sub.1-6 alkylthio;
• R.sup.5 is an imidazolyl or pyrazolyl group, or a benzo-fused ring derivative thereof, wherein each of said R.sup.5 groups is independently optionally substituted, said R.sup.5 substituent being R.sup.10 ;
• R.sup.7, R.sup.8 and R.sup.9 are independently hydrogen or an optionally substituted C.sub.1-3 alkyl group, an optionally substituted C.sub.6-12 arylC.sub.1-3 alkyl group or an optionally substituted C.sub.6-12 aryl group, said R.sup.7, R.sup.8 and R.sup.9 substituents being independently R.sup.10 ;
• R.sup.10 is R.sup.11 or --Alk.sup.1 (R.sup.11).sub.m, wherein m is an integer of 0 to 3 and Alk.sup.1 is straight or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene group, said Alk.sup.1 group containing from zero to three --O--, --S--, --N(R.sup.6)-- or --S(O).sub.p -- groups, where p is 1 or 2;
• and
• R.sup.11 is halogen or an amino (--NH.sub.2), substituted amino, nitro, cyano, hydroxyl (--OH), substituted hydroxyl, cycloalkoxy, formyl (HC(O)--), carboxyl (--CO.sub.2 H), esterified carboxyl, thiol (--SH), substituted thiol, --C(O)R.sup.7, --SO.sub.3 H, --SO.sub.2 R.sup.7, --SO.sub.2 N(R.sup.7 R.sup.8), --CON(R.sup.7 R.sup.8), --NHSO.sub.2 R.sup.7, --N(SO.sub.2 R.sup.7).sub.2, --NHSO.sub.2 N(R.sup.7 R.sup.8), --NHC(O)R.sup.7 or --NHC(O)OR.sup.7 group;
• or a salt, solvate, hydrate, prodrug or N-oxide thereof.

A pharmaceutical composition comprising a compound of formula (1) ##STR16## wherein:

• Y is a halogen atom or an --OR.sup.1 group, wherein R.sup.1 is an optionally substituted alkyl group;
• X is --O--, --S--, or --N(R.sup.6)--;
• Z is --(CH.sub.2).sub.n --, where n is an integer of 0 to 3;
• R.sup.2 is an optionally substituted cycloalkyl or cycloalkenyl group;
• R.sup.3 and R.sup.4 are independently a hydrogen atom or an optionally substituted alkyl, --CO.sub.2 R.sup.7, --CONR.sup.8 R.sup.9, --CSNR.sup.8 R.sup.9, --CN or --CH.sub.2 CN group;
• R.sup.5 is an imidazolyl or pyrazolyl group, or a benzo-fused ring derivative thereof, wherein each of said R.sup.5 groups is independently optionally substituted;
• R.sup.6 is a hydrogen atom or an optionally substituted alkyl group;
• and
• R.sup.7, R.sup.8 and R.sup.9 are independently a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group;
• or a salt, solvate, hydrate, prodrug or N-oxide thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents.

A method of preventing or treating an inflammatory disease in a patient comprising administering to said patient, in combination with a pharmaceutically acceptable carrier, a selective inhibitor of a phosphodiesterase (PDE) IV isoenzyme in an amount effective to elevate intracellular levels of adenosine 3', 5'-cyclic monophosphate (cAMP), said inhibitor comprising a compound of the formula:

• ##STR17## wherein:
• Y is a halogen atom or an --OR.sup.1 group, wherein R.sup.1 is an optionally substituted alkyl group;
• X is --O--, --S--, or --N(R.sup.6)--;
• Z is --(CH.sub.2).sub.n --, where n is an integer of 0 to 3;
• R.sup.2 is an optionally substituted cycloalkyl or cycloalkenyl group;
• R.sup.3 and R.sup.4 are independently a hydrogen atom or an optionally substituted alkyl, --CO.sub.2 R.sup.7, --CONR.sup.8 R.sup.9, --CSNR.sup.8 R.sup.9, --CN or --CH.sub.2 CN group;
• R.sup.5 is an imidazolyl or pyrazolyl group, or a benzo-fused ring derivative thereof, wherein each of said R.sup.5 groups is independently optionally substituted;
• R.sup.6 is a hydrogen atom or an optionally substituted alkyl group;
• and
• R.sup.7, R.sup.8 and R.sup.9 are independently a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group;
• or a salt, solvate, hydrate, prodrug or N-oxide thereof.