Bicyclic 4-aralkylaminopyrimidine derivatives as tyrosine kinase

Details Bicyclic 4-aralkylaminopyrimidine derivatives as tyrosine kinase Bicyclic 4-aralkylaminopyrimidine derivatives as tyrosine kinase

1998-02-06

2000-05-02

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544293, 544284, C07D23994, C07D47334, A61K 3170, A61K 31505

Patent

active

060573260

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel and known bicyclic 4-aralkylaminopyrimidine derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular as tyrosine kinase inhibitors.
Several N-substituted 4-aminopyrimidines are known in the art. For instance Japanese patent application JP92-270490 (C.A. 122: 133208) discloses the preparation of N-substituted 4-amino-pyrimidine derivatives useful as agrochemical fungicides, insecticides, nematocides and acaricides. French patent no. 1438006 (C.A.66: 11176e) claims 6-substituted purine compounds having kinetine activity. EP-A-0390112 discloses purine and pyrazolo-pyrimidine compounds which are selective adenosine receptor agents in particular adenosine antagonists. Phytochemistry 10(1), 23-8, 1971; and ibidem, 7(11), 1989-94, 1968 relate to cytokinin activity of substituted purines in plants. DE 4321029 (C.A.122: 160674) teaches the preparation of 4-substituted quinazolineamines useful as agrochemical fungicides.
The present invention provides, as a first aspect, the use of a compound having the following formula (I) ##STR2## wherein A is a benzene or imidazole ring; -C.sub.4)alkyl, hydroxy-(C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy-(C.sub.1 -C.sub.4)alkyl, (C.sub.2 -C.sub.4)acyloxy-(C.sub.1 -C.sub.4)alkyl, halobenzoyloxy-(C.sub.1 -C.sub.4)alkyl, carboxy, carbamoyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, cyano, (C.sub.1 -C.sub.4)alkylcarbonyl, carboxy-(C.sub.1 -C.sub.4)alkyl, carbamoyl-(C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxycarbonyl-(C.sub.1 -C.sub.4)alkyl, halo-(C.sub.1 -C.sub.4)alkyl, amino-(C.sub.1 -C.sub.4)alkyl, mono- or di-(C.sub.1 -C.sub.4)alkylamino-(C.sub.1 -C.sub.4)alkyl, sulfo-(C.sub.1 -C.sub.4)alkyl or sulfamido-(C.sub.1 -C.sub.4)alkyl; alkyl, C.sub.1 -C.sub.4 alkoxy, halogen or --NR.sub.5 R.sub.6 in which each of R.sub.5 and R.sub.6 independently is H or C.sub.1 -C.sub.4 alkyl; alkyl, halogen, hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, nitro, cyano or CF.sub.3 ; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as tyrosine kinase inhibitor.
It is evident to the people skilled in the art that when at the same time ring A is imidazole and one of R.sub.1 and R.sub.2 is C.sub.1 -C.sub.4 alkoxy, halogen or --NR.sub.5 R.sub.6 then such substituent is only linked to the carbon ring atoms of the imidazole moiety. Whereas when the substituents R.sub.1 and R.sub.2 are C.sub.1 -C.sub.4 alkyl they may be attached either to the carbon or nitrogen ring atoms of the imidazole moiety.
When the ring B is tetralin, indane or 2-oxindole the aminomethyl bridge may be located on either of the ring B moieties, preferably it is located on the benzene moiety.
The R.sub.3 and R.sub.4 substituents in tetralin and indane may be on either of the ring moieties, preferably they are attached to the benzene moiety. In 2-oxindole the R.sub.3 and R.sub.4 substituents can be located on the benzene moiety, whereas the C.sub.1 -C.sub.4 alkyl substituent may also be attached to the nitrogen ring atom of the pyrrole moiety, of course.
When in the synthesis optically active aralkylamino derivatives are employed, then the R substituent may be above or beneath the plane indicating an (R) or (S) configuration.
The invention includes within its scope all the possible isomers, stereoisomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors (otherwise known as prodrugs) of the compounds of formula (I).
An alkyl group or an alkyl moiety in a alkoxy, alkylcarbonyl or alkoxycarbonyl group may be a branched or straight alkyl chain.
A C.sub.1 -C.sub.4 alkyl group is preferably a C.sub.1 -C.sub.2 alkyl, that is ethyl or methyl.
A C.sub.1 -C.sub.4 alkoxy group is preferably a methoxy or ethoxy group.
A C.sub.1 -C.sub.4 alkylcarbonyl is preferably an acetyl.
A (C.sub.1 -C.sub.4)perfluoralkyl is preferably a trifluoromethyl.
A phenyl-(C.sub.1 -C.sub.4)alkyl is preferably benzyl.
A hydroxy-(C.sub.1 -C.sub.4)a

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