Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1998-01-29
1999-05-18
Ramsner, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
5142352, 514314, 546174, 546176, 546177, A61K31/47;31/535
Patent
active
059051493
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new derivatives of substituted quinolylmethylen-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 WO91/13055 and WO95/01349 disclose quinolylmethylen-oxindole derivatives endowed with high in vitro tyrosine kinase inhibiting activity. However, such quinolylmethylene-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 quinolylmethylen-oxindole compounds endowed with improved bioavailability.
Accordingly, the present invention provides novel substituted quinolylmethylen-oxindole derivatives having the following general formula (I) ##STR1## wherein R is H or --(CH.sub.2).sub.n --COR.sub.7 group in which n is an integer of 1 to 4 and R.sub.7 is hydroxy, amino, C.sub.1 -C.sub.6 alkoxy or --NR.sub.5 R.sub.6 in which one of R.sub.5 and R.sub.6 is hydrogen or C.sub.1 -C.sub.6 alkyl and the other is C.sub.1 -C.sub.6 alkyl or R.sub.7 and R.sub.6 taken together with the N atom to which they are linked form a 5 to 7 membered saturated heteromonocycle or R.sub.7 is a N-terminally linked peptidyl residue containing from 1 to 3 aminoacids in which the terminal carboxyl group may be present as such, as amide, as alkali metal salt or as a C.sub.1 -C.sub.4 alkyl ester; one or two of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are a substituent selected independently from: R.sub.6 or --X--(CH.sub.2).sub.m --NHR.sub.8 group, in which X is --O--, --S-- or --NH--, m is an integer of 2 to 4, R.sub.5 and R.sub.6 are as defined above, and R.sub.8 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.5 R.sub.6 group in which R.sub.5 and R.sub.6 are as defined above; --N.dbd.CH--NH.sub.2, --N.dbd.CH--NR.sub.5 R.sub.6 or --N.dbd.CH--NHR.sub.8 group in which R.sub.5, R.sub.6 and R.sub.8 are as defined above; defined above and n is an integer of 1 to 4; linked peptidyl residue containing from 1 to 3 aminoacids in which the terminal carboxyl group may be present as such, as amide, as alkali metal salt or as a C.sub.1 -C.sub.4 alkyl ester and R.sub.9 is a --(CH.sub.2).sub.p --NH.sub.2, --(CH.sub.2).sub.p --NR.sub.5 R.sub.6 or --(CH.sub.2).sub.p --NHR.sub.8 group in which p is 1 or 2 and R.sub.5, R.sub.6 and R.sub.8 are as defined above; or different) is --NH-- or --O-- and R.sub.10 is phenyl or C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by phenyl; and and R.sub.11 is an amino protective group; and the others of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently chosen from hydrogen, halogen, amino, hydroxy, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl-(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.5 R.sub.6 in which R.sub.5 and R.sub.6 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).
The oxindolidene substituent and R.sub.1 and R.sub.
Ballinari Dario
Battistini Carlo
Buzzetti Franco
Ermoli Antonella
Vioglio Sergio
Pharmacia & Upjohn S.p.A
Ramsner Robert W.
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