US 5,965,570 AGranted

Tricyclic piperidinyl compounds useful as inhibitors of farnesyl-protein transferase

AssigneesSchering Corporation, Pharmacopeia, Inc.

InventorsAlan B. Cooper, Alan K. Mallams, Viyyoor M. Girijavallabhan, Ronald J. Doll, Arthur G. Taveras, F. George Njoroge, John J. Baldwin, John C. Reader

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Abstract

Novel tricyclic compounds and pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel tricyclic compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human.

Claims20

Dependent claims

A compound of the formula:

##STR138## or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or NR.sup.9 wherein R.sup.9 is O.sup.-, --CH.sub.3 or --(CH.sub.2).sub.n CO.sub.2 H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR.sup.1 or CR.sup.2 ;
or
each of a, b, c, and d are independently selected from CR.sup.1 or CR.sup.2 ;
each R.sup.1 and each R.sup.2 is independently selected from H, halo, --CF.sub.3, --OR.sup.10, --COR.sup.10, --SR.sup.10, --S(O).sub.t R.sup.11 (wherein t is 0, 1 or 2), --SCN, --N(R.sup.10).sub.2, --NR.sup.10 R.sup.11, --NO.sub.2, --OC(O)R.sup.10, --CO.sub.2 R.sup.10, --OCO.sub.2 R.sup.11, --CN, --NHC(O)R.sup.10, --NHSO.sub.2 R.sup.10, --CONHR.sup.10, --CONHCH.sub.2 CH.sub.2 OH, --NR.sup.10 COOR.sup.11, --SR.sup.11 C(O)OR.sup.11, --SR.sup.11 N(R.sup.75).sub.2 wherein each R.sup.75 is independently selected from H and --C(O)OR.sup.11, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, --OR.sup.10 or --CO.sub.2 R.sup.10 ;
R.sup.3 and R.sup.4 are the same or different and each independently represents H, any of the substituents of R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 taken together represent a saturated or unsaturated C.sub.5 -C.sub.7 fused ring to the benzene ring (Ring III);
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently represents H, --CF.sub.3, --COR.sup.10, alkyl or aryl, said alkyl or aryl optionally being substituted with --OR.sup.10, --SR.sup.10, --S(O).sub.t R.sup.11, --NR.sup.10 COOR.sup.11, --N(R.sup.10).sub.2, --NO.sub.2, --COR.sup.10, --OCOR.sup.10, --OCO.sub.2 R.sup.11, --CO.sub.2 R.sup.10, OPO.sub.3 R.sup.10, or R.sup.5 is combined with R.sup.6 to represent .dbd.O or .dbd.S and/or R.sup.7 is combined with R.sup.8 to represent .dbd.O or .dbd.S;
R.sup.10 represents H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl or --NR.sup.40 R.sup.42 wherein R.sup.40 and R.sup.42 independently represent H, aryl, alkyl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl;
R.sup.11 represents alkyl or aryl;
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent --NO.sub.2, --R.sup.10, halo, --OR.sup.11, --OCO.sub.2 R.sup.11 or --OC(O)R.sup.10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H.sub.2, --(OR.sup.11).sub.2, H and halo, dihalo, alkyl and H, (alkyl).sub.2, --H and --OC(O)R.sup.10, H and --OR.sup.10, oxy, aryl and H, .dbd.NOR.sup.10 or --O--(CH.sub.2).sub.p --O-- wherein p is 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5 or 6;
T is --CO--;
--SO--;
--SO.sub.2 --;
or --CR.sup.30 R.sup.31 -- wherein R.sup.30 and R.sup.31 independently represent H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
and
Z represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, --OR.sup.40, --SR.sup.40, --CR.sup.40 R.sup.42, --NR.sup.40 R.sup.42, ##STR139## wherein n, R.sup.40 and R.sup.42 are defined hereinbefore, m is 2, 3 4, 5, 6, 7 or 8;
q is 0, 1 or 2;
and R.sup.14 represents H, C.sub.1-6 alkyl, aralkyl, heteroaryl, acyl, carboxamido, carboxamidoalkyl, cyano, alkoxycarbonyl, aralkyloxycarbonyl, D- and L-amino acids covalently bonded through the carboxyl group, imido, imidamido, sulfamoyl, sulfonyl, dialkylphosphinyl, N-glycosyl, ##STR140## with the proviso that when T is --SO--, Z is not --NR.sup.40 R.sup.42.

16 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula:

##STR138## or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or NR.sup.9 wherein R.sup.9 is O.sup.-, --CH.sub.3 or --(CH.sub.2).sub.n CO.sub.2 H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR.sup.1 or CR.sup.2 ;
or
each of a, b, c, and d are independently selected from CR.sup.1 or CR.sup.2 ;
each R.sup.1 and each R.sup.2 is independently selected from H, halo, --CF.sub.3, --OR.sup.10, --COR.sup.10, --SR.sup.10, --S(O).sub.t R.sup.11 (wherein t is 0, 1 or 2), --SCN, --N(R.sup.10).sub.2, --NR.sup.10 R.sup.11, --NO.sub.2, --OC(O)R.sup.10, --CO.sub.2 R.sup.10, --OCO.sub.2 R.sup.11, --CN, --NHC(O)R.sup.10, --NHSO.sub.2 R.sup.10, --CONHR.sup.10, --CONHCH.sub.2 CH.sub.2 OH, --NR.sup.10 COOR.sup.11, --SR.sup.11 C(O)OR.sup.11, --SR.sup.11 N(R.sup.75).sub.2 wherein each R.sup.75 is independently selected from H and --C(O)OR.sup.11, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, --OR.sup.10 or --CO.sub.2 R.sup.10 ;
R.sup.3 and R.sup.4 are the same or different and each independently represents H, any of the substituents of R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 taken together represent a saturated or unsaturated C.sub.5 -C.sub.7 fused ring to the benzene ring (Ring III);
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently represents H, --CF.sub.3, --COR.sup.10, alkyl or aryl, said alkyl or aryl optionally being substituted with --OR.sup.10, --SR.sup.10, --S(O).sub.t R.sup.11, --NR.sup.10 COOR.sup.11, --N(R.sup.10).sub.2, --NO.sub.2, --COR.sup.10, --OCOR.sup.10, --OCO.sub.2 R.sup.11, --CO.sub.2 R.sup.10, OPO.sub.3 R.sup.10, or R.sup.5 is combined with R.sup.6 to represent .dbd.O or .dbd.S and/or R.sup.7 is combined with R.sup.8 to represent .dbd.O or .dbd.S;
R.sup.10 represents H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl or --NR.sup.40 R.sup.42 wherein R.sup.40 and R.sup.42 independently represent H, aryl, alkyl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl;
R.sup.11 represents alkyl or aryl;
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent --NO.sub.2, --R.sup.10, halo, --OR.sup.11, --OCO.sub.2 R.sup.11 or --OC(O)R.sup.10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H.sub.2, --(OR.sup.11).sub.2, H and halo, dihalo, alkyl and H, (alkyl).sub.2, --H and --OC(O)R.sup.10, H and --OR.sup.10, oxy, aryl and H, .dbd.NOR.sup.10 or --O--(CH.sub.2).sub.p --O-- wherein p is 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5 or 6;
T is --CO--;
--SO--;
--SO.sub.2 --;
or --CR.sup.30 R.sup.31 -- wherein R.sup.30 and R.sup.31 independently represent H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
and
Z represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, --OR.sup.40, --SR.sup.40, --CR.sup.40 R.sup.42, --NR.sup.40 R.sup.42, ##STR139## wherein n, R.sup.40 and R.sup.42 are defined hereinbefore, m is 2, 3 4, 5, 6, 7 or 8;
q is 0, 1 or 2;
and R.sup.14 represents H, C.sub.1-6 alkyl, aralkyl, heteroaryl, acyl, carboxamido, carboxamidoalkyl, cyano, alkoxycarbonyl, aralkyloxycarbonyl, D- and L-amino acids covalently bonded through the carboxyl group, imido, imidamido, sulfamoyl, sulfonyl, dialkylphosphinyl, N-glycosyl, ##STR140## with the proviso that when T is --SO--, Z is not --NR.sup.40 R.sup.42.

16 more elements