Styryl compounds which inhibit EGF receptor protein tyrosine kinase
AssigneeYissum Research Development Company of the Hebrew University of Jerusalem
InventorsAlexander Levitzki, Chaim Gilon, Michael Chorev, Aviv Gazit
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Abstract
A method of inhibiting cell proliferation in a patient suffering from such disorder comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, which is a substituted styrene compound which can also be a naphthalene, an indane or a benzoxazine; including nitrile and molononitrile compounds, and pharmaceutical compositions comprising, in admixture with a pharmaceutically acceptable carrier, a pharmaceutically-effective amount of such compound.
Claims21
A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis and restenosis comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
- (A) a substituted styrene compound having the formula ##STR13## wherein:
- one of R.sub.1 and R.sub.2 is alkyl, --H, --CN, --OH, --CONRR or --CSNRR;
- the other of R.sub.1 and R.sub.2 is alkyl, --H, --CN, --OH, --CONRR, --CSNRR, --CONHR.sub.9, --CONHCH.sub.2 CN, --CH.dbd.C(CN).sub.2, --C(NH.sub.2).dbd.C(CN).sub.2 or --NHCHO
- wherein R.sub.1 and R.sub.2 are not both alkyl, --H, --CN or --OH;
- R is alkyl or --H;
- R.sub.3 is alkyl, --H, --CN, --OH, --CONRR, --CSNRR, --CH.sub.2 CN or --CH.dbd.C(CN)COHN.sub.2 ;
- R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are each independently alkyl, --H, --CN, halo, --NO.sub.2 or --NHCOCH.sub.3 ;
- R.sub.3 and R.sub.7 together may be --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --or, starting from R.sub.3, --CONH--;
- R.sub.9 is, --CONH.sub.2, ##STR14## R.sub.10 is alkyl, halo or --NO.sub.2 ;
- R.sub.11 is alkyl, --CN, halo, --NO.sub.2 or --NHCOCH.sub.3 ;
- R.sub.12 is alkyl, --H, halo,;
- n is 0 to about 6;
- and
- m is 2 to about 10,
- provided that when one of R.sub.1 and R.sub.2 is --CH.dbd.C(CN).sub.2, at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 is not --H;
- (B) an .alpha.-substituted benzylidene malononitrile compound having the formula ##STR15## wherein:
- R.sub.3 is alkyl, --CN, --OH, --CONRR, --CSNRR, --CH.sub.2 CN or --CH.dbd.C(CN)CONH.sub.2 ;
- R is alkyl or --H;
- and
- R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are each independently alkyl, --H, --CN, halo, --NO.sub.2 or --NHCOCH.sub.3 ;
- (C) an .alpha.-unsubstituted benzylidene malononitrile compound having the formula ##STR16## wherein:
- at least one of R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 is C.sub.2 to about C.sub.6 alkyl or --CN;
- the remainder of R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are each independently alkyl, --H, --CN, halo, --NO.sub.2 or --NHCOCH.sub.3 ;
- and
- R is alkyl or --H;
- and
- (D) a bicyclic benzylidene malononitrile compound having the formula ##STR17## wherein:
- R.sub.3 and R.sub.7 together are --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --or, starting from R.sub.3, --CONH--;
- and
- R.sub.4, R.sub.5 R.sub.6 and R.sub.8 are each independently alkyl, --H, --CN, halo, --NO.sub.2 or --NHCOCH.sub.3.
A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis and restenosis comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
- (A) a substituted styrene compound having the formula ##STR26## wherein:
- R.sub.1 and R.sub.2 are each independently --CN or --CONH.sub.2 or one of R.sub.1 and R.sub.2 may be --CSNH.sub.2 or, when R.sub.1 is CN, R.sub.2 can also be the group --C(NH.sub.2).dbd.C(CN).sub.2, with the proviso that R.sub.1 and R.sub.2 are not both CN;
- R.sub.3 is --H, --CN.sub.3 or --OH;
- R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently alkyl of 1-5 carbons, --H, halo, or --NO.sub.2 ;
- and
- R.sub.8 is H;
- (B) an .alpha.-substituted benzylidene malononitrile compound having the formula ##STR27## wherein:
- R.sub.3 is --CH.sub.3 or --OH;
- R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently alkyl of 1-5 carbons, --H, halo or --NO.sub.2 ;
- and
- R.sub.8 is --H;
- or
- (C) an .alpha.-unsubstituted benzylidene malononitrile compound having the formula ##STR28## wherein:
- at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is alkyl or 2-5 carbons;
- the remainder of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently alkyl of 1-5 carbons, H, halo or --NO.sub.2 ;
- and
- R.sub.8 is --H;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.