Methods for inhibiting neoproliferative changes in blood vessel walls

A method for deterring, inhibiting or reversing stenosis, restenosis or unwanted proliferation of an artery in a human or veterinary patient, said method comprising the step of:

• administering to the patient a compound having the structural formula
• Wherein,
• X, Y and Z are same or different and are independently selected from CH2, O, S, NR1, N═CH, CH═N and R2—C═C—R3, where R2 and R3 are H or may combine to form a saturated or unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more R groups;
• R1 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl and aroyl, optionally substituted with hydroxy, amino, substituted amino, cyano, alkoxy, halogen, trihaloalkyl, nitro, thio, alkylthio, carboxy and alkoxycarbonyl groups;
• R is selected from H, halogen, trihaloalkyl, hydroxy, acyloxy, alkoxy, alkenyloxy, thio, alkylthio, nitro, cyano, ureido, acyl, carboxy, alkoxycarbonyl, N—(R4)(R5) and saturated or unsaturated, chiral or achiral, cyclic or acyclic, straight or branched hydrocarbyl group with from 1 to 20 carbon atoms, optionally substituted with hydroxy, halogen, trihaloalkyl, alkylthio, alkoxy, carboxy, alkoxycarbonyl, oxoalkyl, cyano and N—(R4)(R5) group,
• R4 and R5 are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl and acyl or R4 and R5 may combine to form a ring, wherein a carbon may be optionally substituted by a heteroatom selected from O, S or N—R6,
• R6 is H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl or carboxyalkyl,
• n is 1-5;
• m is 1 or 2;
• with the proviso that
• when m is 1, Q is selected from OH, CN, carboxyalkyl, N—(R7)(R8), where R7 and R8 are selected from H, lower alkyl (1-4C), cycloalkyl, aryl, acyl, amido, or R7 and R8 may combine to form a saturated or unsaturated heterocylic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S;
• or
• —NH-heterocycle, where the heterocycle is represented by thiazole, oxazole, isoxazole, pyridine, pyrimidine, and purine and
• where U and V are selected from H and O;
• and
• when m is 2, Q is a spacer of from 2-10 carbons as a straight or branched, chiral or achiral, cyclic or acyclic, saturated or unsaturated, hydrocarbon group, such as phenyl;
• In the most preferred embodiment of this invention,
• X, Y, and Z are R2—C═C—R3, where R2 and R3 are H;
• R is selected from H and halogen, preferably, F and Cl;
• m is 1;
• and
• Q is —N—(R7)(R8), where R7 and R8 are selected from H, acyl, amido, and R7 and R8 combine to form a saturated or unsaturated heterocyclic ring, optionally substituted with up to three heteroatoms selected from N, O, or S, for example, pyrrolidine, piperidine, pyrazole, imidazole, oxazole, isoxazole, tetrazole, azepine, etc., which may be optionally substituted with a lower alkyl or amino group;
• wherein the compound is administered at a dose that effectively deters, inhibits or reverses stenosis, restenosis or unwanted proliferation of an artery but does not inhibit hepatic cytochrome P450 enzyme activity.