Substituted tetralymethylen-Oxindoles analogues as tyrosine kinase inhibitors

A tetralylmethylene-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, the said two being the same or different, are selected from:

• 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, in which X is --O--, --S-- or --NH--, m is an integer of 2 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 N atom to which they are linked form a 5 to 7 membered saturated heteromonocycle, and R.sub.6 is C.sub.2 -C.sub.6 alkanoyl or a C-terminally linked peptidyl group consisting of 1 to 3 aminoacids wherein the terminal amino group is either free or protected 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) --NH--C(.dbd.NH)--NR.sub.4 R.sub.5, --NH--C(.dbd.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 in which R.sub.4, R.sub.5 and R.sub.6 are as defined above;
• c) --X--(CH.sub.2).sub.n --COR.sub.7 wherein X is as defined above, n is an integer of 1 to 4, 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 a N-terminally linked peptidyl group consisting of from 1 to 3 aminoacids;
• d) --COR.sub.a or --COR.sub.8 in which R.sub.a is a N-terminally linked peptidyl group consisting of from 1 to 3 aminoacids and R.sub.8 is --(CH.sub.2).sub.p --NH.sub.2, --(CH.sub.2).sub.p --NR.sub.4 R.sub.5 or --(CH.sub.2).sub.p --NHR.sub.6 in which p is 1 or 2 and R.sub.4, R.sub.5 and R.sub.6 are as defined above;
• e) --Y--CO--Y'--R.sub.9 wherein each of Y and Y' which may be 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) --NHR.sub.6 or --NHR.sub.10 in which R.sub.6 is as defined above and R.sub.10 is an amino protecting group;
• and the remainder of R, R.sub.1, R.sub.2 and R.sub.3, which are the same or different, are selected 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 alkoxycarbonyl, 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 a salt forming derivative of formula (I) as defined above.