US 5,849,770 A · Tri-substituted phenyl derivatives useful as PDE IV inhibitors

Abstract

Tri-substituted phenyl derivatives and pharmaceutical compositions containing them. In a preferred embodiment, the compounds have the general formula (2): ##STR1## wherein L is preferably --OR; R.sup.a is preferably an optionally substituted alkyl group; R is preferably an optionally substituted cycloalkyl group; R.sup.3 is preferably hydrogen; hydrogen, R.sup.4 is preferably --(CH.sub.2).sub.t Ar, --(CH.sub.2).sub.t --Ar--(L.sup.1).sub.n --Ar' or --(CH.sub.2).sub.t ArN(R.sup.b)CX.sup.1 N(R.sup.b)L.sup.2 (Alk).sub.m Ar; R.sup.5 is preferably --(CH.sub.2).sub.t Ar, --(CH.sub.2).sub.t --Ar--(L.sup.1).sub.n --Ar' or --(CH.sub.2).sub.t ArN(R.sup.b)CX.sup.1 N(R.sup.b)L.sup.2 (Alk).sub.m Ar; R.sup.6 and R.sup.7 are preferably hydrogen, L.sup.1 and L.sup.2 are preferably divalent linking groups; Ar is preferably a monocyclic or bicyclic aryl or heteroaryl group; and Ar' is preferably Ar or an Ar containing group. Compounds of the invention are potent and selective phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of various diseases, such as asthma, which are associated with an unwanted inflammatory response or muscular spasm.

A compound of formula (1):

##STR8## wherein:
Y is halogen or an alkyl or --XR.sup.a group;
X is --O--, --S(O).sub.p -- or --N(R.sup.b)--, where p is zero or an integer 1 or 2;
L is --XR, --C(R.sup.11).dbd.C(R.sup.1)(R.sup.2) or --(CHR.sup.11).sub.n CH(R.sup.1)(R.sup.2), where n is zero or the integer 1;
each of R.sup.a and R.sup.b is independently hydrogen or an optionally substituted alkyl group;
R is an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group;
each of R.sup.1 and R.sup.2, which may be the same or different, is hydrogen, fluorine, --CN, --NO.sub.2, or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, --CO.sub.2 R.sup.8, --CONR.sup.9 R.sup.10 or --CSNR.sup.9 R.sup.10 group, or R.sup.1 and R.sup.2, together with the carbon atom to which they are attached, are linked to form an optionally substituted cycloalkyl or cycloalkenyl group;
R.sup.3 is hydrogen, fluorine, hydroxy or an optionally substituted straight or branched alkyl group;
R.sup.4 is hydrogen, --(CH.sub.2).sub.t Ar, --(CH.sub.2).sub.t --Ar--(L.sup.1).sub.n --Ar' or --(CH.sub.2).sub.t ArN(R.sup.b)CX.sup.1 N(R.sup.b)L.sup.2 (Alk).sub.m Ar, where t is zero or an integer 1, 2 or 3;
R.sup.5 is --(CH.sub.2).sub.t Ar, --(CH.sub.2).sub.t --Ar--(L.sup.1).sub.n --Ar' or --CH.sub.2).sub.t ArN(R.sup.b)CX.sup.1 N(R.sup.b)L.sup.2 (Alk).sub.m Ar;
R.sup.b is hydrogen or an optionally substituted alkyl group;
R.sup.6 is hydrogen, fluorine, or an optionally substituted alkyl group;
R.sup.7 is hydrogen, fluorine, an optionally substituted straight or branched alkyl group, --OR.sup.c, where R.sup.c is hydrogen or an optionally substituted alkyl or alkenyl group, or a formyl, alkoxyalkyl, alkanoyl, carboxamido or thiocarboxamido group;
each of R.sup.8, R.sup.9 and R.sup.10, which may be the same or different, is hydrogen or an optionally substituted alkyl, aralkyl or aryl group;
R.sup.11 is hydrogen, fluorine or a methyl group;
X.sup.1 is an oxygen or sulphur atom;
L.sup.1 and L.sup.2 are independently divalent linking groups;
Ar is a monocyclic or bicyclic aryl group, optionally containing one or more heteroatoms selected from oxygen, sulphur and nitrogen atoms;
Ar' is Ar, --CO(Alk).sub.m Ar, --SO.sub.2 (Alk).sub.m Ar, --SO.sub.2 NH(Alk).sub.m Ar, --SO.sub.2 N(Alk.sup.1)(Alk).sub.m Ar, --SO.sub.2 N((Alk).sub.m Ar).sub.2, --CONH(Alk).sub.m Ar, --CON(Alk.sup.1)(Alk).sub.m Ar, --CON((Alk).sub.m Ar).sub.2, --N(Alk.sup.1)SO.sub.2 (Alk).sub.m Ar, --NHSO.sub.2 (Alk).sub.m Ar, --N(SO.sub.2 (Alk).sub.m Ar).sub.2, --NHSO.sub.2 NH(Alk).sub.m Ar, --N(Alk.sup.1)SO.sub.2 NH(Alk).sub.m Ar, --NHSO.sub.2 N(Alk.sup.1)(Alk).sub.m Ar, --N(Alk.sup.1)SO.sub.2 N(Alk.sup.1) (Alk).sub.m Ar, --NHSO.sub.2 N((Alk).sub.m Ar).sub.2, --N(Alk.sup.1)SO.sub.2 N((Alk).sub.m Ar).sub.2, --NHC(O)(Alk).sub.m Ar, --N(Alk.sup.1)C(O)(Alk).sub.m Ar, --N(C(O)(Alk).sub.m Ar).sub.2, --NHC(O)NH(Alk).sub.m Ar, --N(Alk.sup.1)C(O)NH(Alk).sub.m Ar, --NHC(O)N(Alk.sup.1)(Alk).sub.m Ar, --NAlk.sup.1 C(O)N(Alk.sup.1)(Alk).sub.m Ar, --NHC(O)O(Alk).sub.m Ar, --N(Alk.sup.1)C(O)O(Alk).sub.m Ar, --C(S)NH(Alk).sub.m Ar, --C(S)N(Alk.sup.1)(Alk).sub.m Ar, --C(S)N(Alk.sup.1)(Alk).sub.m Ar, --C(S)N((Alk).sub.m Ar).sub.2, --NHC(S)(Alk).sub.m Ar, --N(Alk.sup.1)C(S)(Alk).sub.m Ar, --N(C(S)(Alk).sub.m Ar).sub.2, --NHC(S)NH(Alk).sub.m Ar, --N(Alk.sup.1)C(S)NH(Alk).sub.m Ar, --NHC(S)N(Alk.sup.1)(Alk).sub.m Ar, --N(Alk.sup.1)C(S)N(Alk.sup.1)(Alk).sub.m Ar, --SO.sub.2 (Alk).sub.m NHet, --CO(Alk).sub.m NHet, --CS(Alk).sub.m NHet, --NHSO.sub.2 (Alk).sub.m NHet, --NHC(O)(Alk).sub.m NHet, --NHC(S)(Alk).sub.m NHet, --SO.sub.2 NH((Alk).sub.m Het'), --CONH((Alk).sub.m Het'), --CSNH((Alk).sub.m Het'), --NHSO.sub.2 NH((Alk).sub.m Het'), --NHC(O)NH(Alk).sub.m (Het') or --NHC(S)NH(Alk).sub.m (Het');
m is zero or the integer 1;
Alk is an optionally substituted, 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).sub.q -- or --N(R.sup.b)-- groups, where q is an integer 1 or 2;
Alk.sup.1 is an optionally substituted, straight or branched C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl chain optionally interrupted by one, two or three --O-- or --S-- atoms or --S(O).sub.q -- or --N(R.sup.b)-- groups;
NHet is an optionally substituted C.sub.5-7 heterocyclic amino group optionally containing one or more additional --O-- or --S-- atoms or --N(R.sup.b)--, --CO-- or --CS-- groups;
Het' is an optionally substituted C.sub.5-7 monocyclic carbocyclic group optionally containing one or more --O-- or --S-- atoms or --N(R.sup.b)-- groups:
or a salt, solvate, hydrate, prodrug or N-oxide thereof;
with the proviso that at least one of R.sup.4 and R.sup.5 is --(CH.sub.2).sub.t ArN(R.sup.b)CX.sup.1 N(R.sup.b)L.sup.2 (Alk).sub.m Ar.

23 more elements

Tri-substituted phenyl derivatives useful as PDE IV inhibitors

Life of this patent

Tri-substituted phenyl derivatives useful as PDE IV inhibitors

Life of this patent

Abstract

Claims28