US 5,859,034 AGranted

Tri-substituted phenyl compounds which have useful pharmaceutical activity

AssigneeCelltech Therapeutics Limited

InventorsGraham John Warrellow, Julien Alistair Brown

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Abstract

Tri-substituted phenyl derivatives having the general formula (I): ##STR1## In a preferred embodiment, Y is preferably an --XR.sup.a group, X is preferably --O--, Z is preferably an --XR.sup.5 group, R.sup.a is preferably hydrogen or an optionally substituted alkyl group, R.sup.1 is preferably an --NHC(--NCN)NHR.sup.13 or --NHC(.dbd.CHNO.sub.2)NHR.sup.13 group, R.sup.2, R.sup.3 and R.sup.4 are preferably hydrogen, R.sup.5 is preferably an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl or heterocycloalkyl group, R.sup.12 is preferably hydrogen or a C.sub.1-3 alkyl group, R.sup.13 is preferably hydrogen, a C.sub.1-3 alkyl group, an optionally substituted phenyl group or an optionally substituted phenylC.sub.1-3 alkyl group, Ar.sup.1 is preferably an optionally substituted nitrogen containing heteroaryl group, and Ar is preferably a phenyl 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.

Claims16

Dependent claims

A compound of formula (1):

##STR4## wherein:
Y is halogen or an --XR.sup.a group;
X is --O--, --S(O).sub.m -- or --N(R.sup.b)--, where m is zero or an integer 1 or 2;
Z is an --XR.sup.5, --C(R.sup.6).dbd.C(R.sup.7)(R.sup.8) or --(CHR.sup.6), CH(R.sup.7)(R.sup.8) group, 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.sup.1 is an --N(R.sup.12)C(.dbd.NCN)NHR.sup.13, --N(R.sup.12)C(.dbd.NCN)SR.sup.13, --N(R.sup.12)C(.dbd.CHNO.sub.2)NHR.sup.13 or --N(R.sup.12)C(.dbd.CHNO.sub.2)SR.sup.13 group;
R.sup.2 is hydrogen, fluorine, hydroxyl or an optionally substituted alkyl group;
R.sup.3 is hydrogen, fluorine or an optionally substituted alkyl group;
R.sup.4 is hydrogen, fluorine, an optionally substituted alkyl group, an alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group or --OR.sup.c, where R.sup.c is hydrogen or an optionally substituted alkyl or alkenyl group;
R.sup.5 is an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl or heterocycloalkyl group;
R.sup.6 is hydrogen, fluorine or a methyl group;
each of R.sup.7 and R.sup.8 is independently hydrogen, fluorine, --CN, NO.sub.2, or an optionally substituted alkyl, alkenyl, alkoxy, alkylthio, --CO.sub.2 R.sup.9, --CONR.sup.10 R.sup.11 or --CSNR.sup.10 R.sup.11 group, or R.sup.7 and R.sup.8, together with the carbon atom to which they are attached, are linked to form an optionally substituted cycloalkyl, cycloalkenyl or heterocycloalkyl group;
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or an optionally substituted alkyl, aralkyl or aryl group;
R.sup.12 is hydrogen or a C.sub.1-3 alkyl group;
R.sup.13 is hydrogen, a C.sub.1-3 alkyl group, an optionally substituted phenyl group or an optionally substituted phenylC.sub.1-3 alkyl group;
Ar.sup.1 is an optionally substituted monocyclic or bicyclic aryl group, optionally containing one or more heteroatoms selected from oxygen, sulphur and nitrogen atoms;
and
Ar is a monocyclic or bicyclic aryl group, optionally containing one or more heteroatoms selected from oxygen, sulphur and nitrogen atoms;
or a salt, solvate, hydrate, prodrug or N-oxide thereof.

16 more elements

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

##STR6## wherein:
Y is halogen or an --XR.sup.a group;
X is --O--, --S(O).sub.m -- or --N(R.sup.b)--, where m is zero or an integer 1 or 2;
Z is an --XR.sup.5, --C(R.sup.6).dbd.C(R.sup.7 (R.sup.8) or --(CHR.sup.6).sub.n CH(R.sup.7)(R.sup.8) group, 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.sup.1 is an --N(R.sup.12)C(.dbd.NCN)NHR.sup.13, --N(R.sup.12)C(.dbd.NCN)SR.sup.13, --N(R.sup.12)C(.dbd.CHNO.sub.2)NHR.sup.13 or --N(R.sup.12)C(.dbd.CHNO.sub.2)SR.sup.13 group;
R.sup.2 is hydrogen, fluorine, hydroxyl or an optionally substituted alkyl group;
R.sup.3 is hydrogen, fluorine or an optionally substituted alkyl group;
R.sup.4 is hydrogen, fluorine, an optionally substituted alkyl group, an alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group or --OR.sup.c, where R.sup.c is hydrogen or an optionally substituted alkyl or alkenyl group;
R.sup.5 is an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl or heterocycloalkyl group;
R.sup.6 is hydrogen, fluorine or a methyl group;
each of R.sup.7 and R.sup.8 is independently hydrogen, fluorine, --CN, NO.sub.2, or an optionally substituted alkyl, alkenyl, alkoxy, alkylthio, --CO.sub.2 R.sup.9, --CONR.sup.10 R.sup.11 or --CSNR.sup.10 R.sup.11 group, or R.sup.7 and R.sup.8, together with the carbon atom to which they are attached, are linked to form an optionally substituted cycloalkyl, cycloalkenyl or heterocycloalkyl group;
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or an optionally substituted alkyl, aralkyl or aryl group;
R.sup.12 is hydrogen or a C.sub.1-3 alkyl group;
R.sup.13 is hydrogen, a C.sub.1-3 alkyl group, an optionally substituted phenyl group or an optionally substituted phenylC.sub.1-3 alkyl group;
Ar.sup.1 is an optionally substituted monocyclic or bicyclic aryl group, optionally containing one or more heteroatoms selected from oxygen, sulphur and nitrogen atoms;
and
Ar is a monocyclic or bicyclic aryl group, optionally containing one or more heteroatoms selected from oxygen, sulphur and nitrogen atoms;
or a salt, solvate, hydrate, prodrug or N-oxide thereofl
together with one or more pharmaceutically acceptable carriers, excipients or diluents.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/984,198Filed 3 Dec 1997
Priority: GB 96251844 Dec 1996
Granted: 12 Jan 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 213/89
Having three double bonds between ring members or between ring members and non-ring members: with hetero atoms directly attached to the ring…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 11/00
Drugs for disorders of the respiratory system