Styryl derivatives as anti-inflammatory agents

A pharmaceutical composition comprising a compound of formula (1) ##STR20## wherein Y represents a halogen atom or a group --OR.sup.1, where R.sup.1 is an C.sub.1-6 alkyl group optionally substituted by one or more halogen atoms;

• X is --O--, --S-- or --N(R.sup.6)--, where R.sup.6 is a hydrogen atom or an C.sub.1-6 alkyl group;
• R.sup.2 is a C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl group optionally substituted by one, two or three substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, hydroxyl, and C.sub.1-6 alkoxy;
• R.sup.3 and R.sup.4, which may be the same or different, is each a group --(CH.sub.2).sub.n Ar, where n is zero or an integer 1, 2 or 3, and Ar is a monocyclic or bicyclic C.sub.6-12 aryl group, or a monocyclic or bicyclic heteroaryl group which is a member selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl;
• and wherein the aryl and heteroaryl groups defining R.sup.3 and R.sup.4 are optionally substituted by one, two, three or more substituents selected from the group consisting of an atom or group R.sup.8 or --Alk.sup.1 (R.sup.8).sub.m wherein R.sup.8 is a halogen atom, 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)Alk.sup.1, --SO.sub.3 H, --SO.sub.2 Alk.sup.1, --SO.sub.2 NH.sub.2, --SO.sub.2 NHAlk.sup.1, --SO.sub.2 N[Alk.sup.1 ].sub.2, --CONH.sub.2, --CONHAlk.sup.1, C-ON[Alk.sup.1 ].sub.2, --NHSO.sub.2 H, --NHSO.sub.2 Alk.sup.1, --N[SO.sub.2 Alk.sup.1 ].sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHAlk.sup.1, --NHSO.sub.2 N[Alk.sup.1 ].sub.2, --NHC(O)Alk.sup.1, or --NHC(O)OAlk.sup.1 group;
• Alk.sup.1 is a straight or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene chain optionally interrupted by one, two, or three --O--, or --S-- atoms or --S(O)p--, where p is an integer 1 or 2, or --N(R.sup.6)-- as defined above;
• and m is zero or an integer 1, 2 or 3;
• and
• R.sup.5 is a hydrogen atom or an C.sub.1-6 alkyl group optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, and C.sub.1-6 alkoxy;
• or a salt, solvate, hydrate or N-oxide thereof;
• together with one or more pharmaceutically acceptable carriers, excipients or diluents.

A method of preventing or treating an inflammatory disease by means of the therapeutic effect achieved by elevating the intra-cellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) within inflammatory leukocytes of a patient suffering from such an inflammatory disease, comprising the step of administering to said patient an amount of a selective inhibitor of one or more of the phosphodiesterase (PDE) IV family of isoenzymes, which is sufficient to obtain said therapeutic effect, said inhibitor being one or more compounds of the formula:

• ##STR21## wherein Y represents a halogen atom or a group --OR.sup.1, where R.sup.1 is an C.sub.1-6 alkyl group optionally substituted by one or more halogen atoms;
• X is --O--, --S-- or --N(R.sup.6)--, where R.sup.6 is a hydrogen atom or an C.sub.1-6 alkyl group;
• R.sup.2 is a C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl group optionally substituted by one, two or three substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, hydroxyl, and C.sub.1-6 alkoxy;
• R.sup.3 and R.sup.4, which may be the same or different, is each a group --(CH.sub.2).sub.n Ar, where n is zero or an integer 1, 2 or 3, and Ar is a monocyclic or bicyclic C.sub.6-12 aryl group, or a monocyclic or bicyclic heteroaryl group which is a member selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl;
• and wherein the aryl and heteroaryl groups defining R.sup.3 and R.sup.4 are optionally substituted by one, two, three or more substituents selected from the group consisting of an atom or group R.sup.8 or --Alk.sup.1 (R.sup.8).sub.m, wherein R.sup.8 is a halogen atom, 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)Alk.sup.1, --SO.sub.3 H, --SO.sub.2 Alk.sup.1, --SO.sub.2 NH.sub.2, --SO.sub.2 NHAlk.sup.1, --SO.sub.2 N[Alk.sup.1 ].sub.2, --CONH.sub.2, --CONHAlk.sup.1, C--ON[Alk.sup.1 ].sub.2, --NHSO.sub.2 H, --NHSO.sub.2 Alk.sup.1, --N[SO.sub.2 Alk.sup.1 ].sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHAlk.sup.1, --NHSO.sub.2 N[Alk.sup.1 ].sub.2, --NHC(O)Alk.sup.1, or --NHC(O)OAlk.sup.1 group;
• Alk.sup.1 is a straight or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene chain optionally interrupted by one, two, or three --O--, or --S-- atoms or --S(O)p--, where p is an integer 1 or 2, or --N(R.sup.6)-- as defined above;
• and m is zero or an integer 1, 2 or 3;
• and
• R.sup.5 is a hydrogen atom or an C.sub.1-6 alkyl group optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, and C.sub.1-6 alkoxy;
• or a salt, solvate, hydrate or N-oxide thereof.