US 5,633,257 AGranted

Cyclo(alkyl and alkenyl)phenyl-alkenylyl(aryl and heteroaryl)compounds and pharmaceutical compositions containing them

AssigneeCelltech Therapeutics Limited

InventorsGraham J. Warrellow, Valerie A. Cole, Rikki P. Alexander

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Abstract

Compounds of general formula (1) ##STR1## are described wherein Y is a halogen atom or a group --OR.sup.1, wherein R.sup.1 is an optionally substituted alkyl group; X is --O--, --S--, or --N(R.sup.6), wherein R.sup.6 is a hydrogen atom or an optionally substituted alkyl group; R.sup.2 is an optionally substituted cycloalkyl or cycloalkenyl group; R.sup.3 and R.sup.4, which may be the same or different, is each a hydrogen atom or an optionally substituted alkyl, --CO.sub.2 R.sup.7 (wherein R.sup.7 is a hydrogen atom, am optionally substituted alkyl, aralkyl, aryl, aryloxyalkyl, alkanoyloxyalkyl or aroyloxyalkyl group), --CONR.sup.8 R.sup.9 (where R.sup.8 and R.sup.9, which may be the same or different, is as defined for R.sup.7), --CSNR.sup.8 R.sup.9, --CN or --CH.sub.2 CN group; Z is --(CH.sub.2).sub.n -- where n is zero or an integer 1, 2 or 3; R.sup.5 is an optionally substituted monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms; and the salts, solvates, hydrates, prodrugs and N-oxides thereof. Compounds according to the invention are potent and selective phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of diseases such as asthma where an unwanted inflammatory response or muscular spasm is present.

Claims26

Dependent claims

A compound of the formula ##STR13## wherein Y is halogen or --OR.sup.1, where R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, 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 substituted or unsubstituted C.sub.3-8 cycloalkyl or substituted or unsubstituted C.sub.3-8 cycloalkenyl, said R.sup.2 substituents being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
each of R.sup.3 and R.sup.4 is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, said C.sub.1-6 alkyl substituents being halogen, hydroxyl, C.sub.1-6 alkoxy, thiol or C.sub.1-6 alkylthio, --CO.sub.2 R.sup.7, --CONR.sup.8 R.sup.9, --CSNR.sup.8 R.sup.9, --CN or CH.sub.2 CN;
R.sup.5 is substituted or unsubstituted pyridyl, said R.sup.5 substituent being R.sup.10 ;
R.sup.6 is hydrogen or C.sub.1-6 alkyl;
each of R.sup.7, R.sup.8 and R.sup.9 is independently hydrogen, substituted or unsubstituted C.sub.1-3 alkyl, substituted or unsubstituted C.sub.6-12 arylC.sub.1-3 alkyl or substituted or unsubstituted C.sub.6-1 aryl;
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, said Alk.sup.1 group is optionally interrupted by one 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, 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 ;
or a salt, solvate, hydrate, prodrug or N-oxide thereof.

8 more elements

A pharmaceutical composition comprising a compound of the formula ##STR16## wherein Y is halogen or --OR.sup.1, where R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, 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 substituted or unsubstituted C.sub.3-8 cycloalkyl or substituted or unsubstituted C.sub.3-8 cycloalkenyl, said R.sup.2 substituents being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
each of R.sup.3 and R.sup.4 is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, said C.sub.1-6 alkyl substituents being halogen, hydroxyl, C.sub.1-6 alkoxy, thiol or C.sub.1-6 alkylthio, --CO.sub.2 R.sup.7, --CONR.sup.8 R.sup.9, --CSNR.sup.8 R.sup.9 --CN, or CH.sub.2 CN;
R.sup.5 is substituted or unsubstituted pyridyl, said R.sup.5 substituent being R.sup.10 ;
R.sup.6 is hydrogen or C.sub.1-6 alkyl;
each of R.sup.7, R.sup.8 and R.sup.9 is independently hydrogen, substituted or unsubstituted C.sub.1-3 alkyl, substituted or unsubstituted C.sub.6-12 arylC.sub.1-3 alkyl or substituted or unsubstituted C.sub.6-12 aryl;
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, said Alk.sup.1 group is optionally interrupted by one 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, 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 ;
or a salt, solvate, hydrate, prodrug or N-oxide thereof;
together with one or more pharmaceutically acceptable carriers, excipients or diluents.

9 more elements

Dependencies are inferred from the claim text.