Substituted indolylmethylene-oxindole analogues as tyrosine kina

Details Substituted indolylmethylene-oxindole analogues as tyrosine kina Substituted indolylmethylene-oxindole analogues as tyrosine kina

1996-12-04

1998-12-15

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 19, 514323, 514414, 514418, 546201, 548455, 548469, 548486, 548490, A01N 4338, A61K 3140, C07D20914, C07D20934

Patent

active

058497102

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP96/01165 filed Mar. 14, 1996.
The present invention relates to new derivatives of substituted indolylmethylene-oxindoles, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular in treating a patient in need of tyrosine kinase inhibition.
International applications WO91/13055 and WO93/01182 disclose indolylmethylene-oxindole derivatives endowed with high in-vitro tyrosine kinase inhibiting activity. However, such methylen-oxindole derivatives, similarly to other known tyrosine kinase inhibitors, are characterized by high lipophylicity, low aqueous solubility and consequently low bioavailability.
However, the task to combine in the same molecule a high tyrosine kinase inhibiting activity and adequate hydrosolubility cannot be achieved by merely introducing hydrophilic groups into the structure of in-vitro active tyrosine kinase inhibitors, as this strategy results in most cases in a significant loss of inhibitory activity. Indeed, as known in the art, the therapeutic efficacy of all drugs is strongly influenced by different parameters that can affect their bioavailability. Object of the present invention is therefore to provide novel indolylmethylene-oxindole compounds endowed with improved bioavailability.
Accordingly, the present invention provides novel indol-3-ylmethylene-2-oxindole derivatives having the following general formula (I) ##STR1## wherein one or two of R, R.sub.1, R.sub.2 and R.sub.3 are a substituent selected independently from: 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 aminoacids 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; --N.dbd.CH--NH.sub.z, --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; 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; 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; 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 and R.sub.10 is C.sub.1 -C.sub.6 alkyl substituted by 1 to 3 hydroxy groups; 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, and the pharmaceutically acceptable salts of salt forming compounds of formula (I).
The invention includes within its scope all the possible isomers, stereoisomers, in particular Z- and E-isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
A --(CH.sub.2).sub.m -- group may be a branched or straight C.sub.1 -C.sub.4 alkylene chain, typically ##STR2## in particular --CH.sub.2 -- and --CH(CH.sub.3)--.
The alkyl groups, and the alkyl moiety in the alkanoyl groups, may be branched or straight alkyl chain. A C.sub.1 -C.sub.6 alkyl group is preferably a

REFERENCES:
patent: 5409949 (1995-04-01), Buzzetti et al.

Affiliated with

Also associated with

Rating

Substituted indolylmethylene-oxindole analogues as tyrosine kina does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted indolylmethylene-oxindole analogues as tyrosine kina, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted indolylmethylene-oxindole analogues as tyrosine kina will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1457955