Substituted indolylmethylene-oxindole analogues as tyrosine kinase inhibitors

Indol-3-ylmethylene-2-oxindole derivative having the following formula (I) ##STR7## wherein one or two of R, R.sub.1, R.sub.2 and R.sub.3 are a substituent selected independently from:

• a) a --X--(CH.sub.2).sub.m --NH.sub.2, --X--(CH.sub.2).sub.m --NR.sub.4 R.sub.5, or --X--(CH.sub.2).sub.m ----NHR.sub.6 group, in which X is --O--, --S-- or --NH--, m is an integer of 1 to 4, one of R.sub.4 and R.sub.5 is hydrogen or C.sub.1 -C.sub.6 alkyl and the other is C.sub.1 -C.sub.6 alkyl or R.sub.4 and R.sub.5 taken together with the nitrogen atom to which they are linked form a C.sub.4 -C.sub.7 saturated heteromonocyclic ring, and R.sub.6 is C.sub.2 -C.sub.6 alkanoyl or the terminal carbonyl group of a peptidyl residue containing from 1 to 3 amino acids wherein the terminal amino group is either free or in a protected form or in an alkylated form to provide a --NR.sub.4 R.sub.5 group in which R.sub.4 and R.sub.5 are as defined above;
• b) a --NHC(NH)NH.sub.2, --NHC(NH)NR.sub.4 R.sub.5, --NHC(NH)NHR.sub.6, --N.dbd.CH--NH.sub.2, --N.dbd.CH--NR.sub.4 R.sub.5 or --N.dbd.CH--NHR.sub.6 group in which R.sub.4, R.sub.5 and R.sub.6 are as defined above;
• c) a --X--(CH.sub.2).sub.m --COR.sub.7 group wherein X and m are as defined above, R.sub.7 is hydroxy, amino, C.sub.1 -C.sub.6 alkoxy or --NR.sub.4 R.sub.5 in which R.sub.4 and R.sub.5 are as defined above, or R.sub.7 is the terminal amino group of a peptidyl residue containing from 1 to 3 aminoacids;
• d) a --COR.sub.a or COR.sub.8 group in which R.sub.a is the terminal amino group of a peptidyl residue containing from 1 to 3 aminoacids and R.sub.8 is C.sub.1 -C.sub.4 alkoxy unsubstituted or substituted by phenyl or R.sub.8 is a --(CH.sub.2).sub.n NH.sub.2, --(CH.sub.2).sub.n --NR.sub.4 R.sub.5 or --(CH.sub.2).sub.n --NHR.sub.6 group in which n is 1 or 2 and R.sub.4, R.sub.5 and R.sub.6 are as defined above;
• e) a --Y--CO--Y'--R.sub.9 group wherein each of Y and Y' which may be the same or different is --NH-- or --O-- and R.sub.9 is phenyl or C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by phenyl;
• and
• f) a --NHR.sub.6 or --NHR.sub.10 group in which R.sub.6 is as defined above and R.sub.10 is C.sub.1 -C.sub.6 alkyl substituted by 1 to 3 hydroxy groups;
• and the others are independently chosen from hydrogen, halogen, amino, hydroxy, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, carboxy, C.sub.1 -C.sub.6 alkoxy-carbonyl, C.sub.2 -C.sub.6 alkanoyloxy, cyano and --NR.sub.4 R.sub.5 in which R.sub.4 and R.sub.5 are as defined above, or a pharmaceutically acceptable salt of formula (I).