Dihydroxyindanone tyrosine kinase inhibitors

Details Dihydroxyindanone tyrosine kinase inhibitors Dihydroxyindanone tyrosine kinase inhibitors

1993-11-23

1995-10-10

O'Sullivan, Peter

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

514448, 514569, 514603, 514604, 514617, 514618, 514619, 514730, 514824, 549461, 549488, 549498, 562462, 564 86, 564 87, 564 92, 564162, 564166, 564168, A61K 3112, A61K 3118, C07C 49747, C07C31137

Patent

active

054572371

DESCRIPTION:

BRIEF SUMMARY
This invention relates to dihydroxyindanone compounds which are tyrosine kinase inhibitors useful for the control of cancer, antiangiogenesis and atherosclerosis.


BACKGROUND OF THE INVENTION

Tyrosine-specific protein kinases (tyrosine kinases) represent a family of enzymes which catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. The first members of this class to be identified were tyrosine kinases associated with viral genes (termed oncogenes) which were capable of cell transformation (i.e. pp60v-src and pp98v-fps). Later it was shown that there were normal cellular counterparts (i.e. pp60c-src and pp98c-fps) to these viral gene products. A third category of tyrosine kinases to be identified are those termed the growth factor receptors, which includes insulin, epidermal growth factor, and p185HER-2 receptors. All of these tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions.
Though the exact mechanisms of signal transduction have yet to be elucidated, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Therefore, inhibitors of these tyrosine kinases are useful for the prevention and chemotherapy of proliferative diseases dependent on these enzymes.


SUMMARY OF THE INVENTION

This invention is directed to dihydroxyindanone compounds that are useful as tyrosine kinase inhibitors. The compounds of this invention have the formula ##STR1## and pharmaceutically-acceptable salts and prodrugs thereof wherein
R.sub.2 is halo, COOH, NO.sub.2, H, ##STR2##
R.sub.4 is H, alkyl (C.sub.1 -C.sub.6 ) or phenyl;
R.sub.5 is phenyl, phenylalkyl (C.sub.1 -C.sub.3) , --NH-phenyl, hydroxyphenyl, --(C.sub.1 -C.sub.4 ) alkyl or thienyl;
R.sub.6 is (C.sub.1 -C.sub.6) alkyl, nitro, perhaloalkyl (C.sub.1 -C.sub.4) , halo, --SO.sub.2 -alkyl (C.sub.1 -C.sub.4 ), ##STR3## and
R.sub.7 is H, halo, perhaloalkyl(C.sub.1 -C.sub.4), alkoxy(C.sub.1 -C.sub.3); with the proviso that at least two of R.sub.2, R.sub.3 or R.sub.4 is H and when R.sub.3 and R.sub.4 are H, R.sub.2 can't be H.
A first group of preferred compounds of Formula I are compounds wherein R.sub.2 and R.sub.4 are H. Especially preferred within this first preferred group are compounds when R.sub.3 is halo, ##STR4## Preferred within this latter group are compounds wherein R.sub.7 is H, halo, trifluoromethyl or methoxy.
A second group of preferred compounds of Formula I are those wherein R.sub.2 and R.sub.3 are H. Especially, preferred within this second preferred group are compounds wherein R.sub.4 is phenyl or n-butyl.
A third group of preferred compounds of Formula I are those wherein R.sub.3 and R.sub.4 are H. A first group of especially preferred compounds within this third preferred group are compounds wherein R.sub.2 is halo, NO.sub.2, --CO.sub.2 alkyl(C.sub.1 -C.sub.4) or COOH. A second group of especially preferred compounds within this third preferred group of Formula I compounds are compounds wherein R.sub.2 is ##STR5## Preferred within this latter group are compounds wherein R.sub.5 is phenyl, phenethyl, --NH-phenyl, hydroxyphenyl, propyl or thiophene. Preferred within this group are compounds wherein R.sub.5 is phenyl, phenethyl, --NH-phenyl, 2-hydroxyphenyl, propyl or 3-thiophene. A third group of especially preferred compounds within this third preferred group of Formula I compounds are compounds wherein R.sub.2 is ##STR6## Preferred within this latter group are compounds wherein R.sub.2 is ##STR7## Preferred within this latter group are compounds wherein R.sub.6 is t-butyl, nitro, trifluoromethyl, -SO.sub.2 -methyl or H. A fourth group of especially preferred compounds within this third preferred group of Formula I compounds are compounds wherein R.sub.2 is ##STR8## Preferred within this latter group are compounds wherein R.sub.2 is ##STR9## Preferred within this latter group are compounds wherein R.sub.6 is t-butyl, nitro,

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