Substituted tetralymethylen-Oxindoles analogues as tyrosine kina

Details Substituted tetralymethylen-Oxindoles analogues as tyrosine kina Substituted tetralymethylen-Oxindoles analogues as tyrosine kina

1998-01-12

2000-11-14

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514323, 514418, 544144, 546201, 548486, A61K 3154, C07D41306, C07D40106, C07D20934

Patent

active

061470732

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new derivatives of substituted tetralylmethylen-oxindoles, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular as tyrosine kinase inhibitors.
International applications W091/13055 and WO95/01349 disclose tetralylmethylen-oxindole derivatives endowed with high in vitro tyrosine kinase inhibiting activity. However, such tetralylmethylene-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 tetralylmethylen-oxindole compounds endowed with improved bioavailability.
Accordingly, the present invention provides novel substituted tetralylmethylene-2-oxindole derivatives having the following formula (I) ##STR2## 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 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 residue containing from 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; --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; 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 residue containing from 1 to 3 aminoacids; linked peptidyl residue containing from 1 to 3 aminoacids and R.sub.8 is a --(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 group in which p is 1 or 2 and R.sub.4, R.sub.5 and R.sub.6 are as defined above; 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 an amino protective group; and the others of R, R.sub.1, R.sub.2 and R.sub.3 are independently chosen from hydrogen, halogen, amino, hydroxy, C.sub.1 -C6 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, and the pharmaceutically acceptable salts of salt forming compounds of formula (I). The invention includes within its scope all the possible isomers, stereoisomers and in particular Z- and E-isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors (otherwise known as prodrugs) of the compounds of formula (I).
A--(CH.sub.2)--group may be a branched or straight C.sub.1 -C.sub.4 alkylene chain, typically --CH.sub.2 --, --CH(CH.sub.3)--, --CH.sub.2 CH.sub.2 -- and (CH.sub.3).sub.2 CH--CH< 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 chains. A C.sub.1 -C.sub.6 alkyl group is preferably a C.sub.1 -C.sub.4 alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or te

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

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