Substituted amide derivatives

Details Substituted amide derivatives Substituted amide derivatives

1998-08-04

2000-04-11

Owens, Amelia

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

549496, A61K 3134

Patent

active

060488948

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates novel substituted amide derivatives. More particularly, the substituted amide derivatives of the present invention inhibit protein-farnesyl transferase (PFT) in vivo thereby to suppress function of oncogene protein Ras and thus present antitumor activities, etc., and they are thus useful in the pharmaceutical field.


BACKGROUND ART

The ras oncogene is activated by mutation, and its translation product Ras protein plays an important role in transformation of normal cells to cancer cells. Such activation of ras oncogene is observed in many cancers such as colorectal cancers or pancreatic cancers, and the proportion thereof is reported to reach about 20% of the total human cancers. Accordingly, it is expected that canceration can be suppressed and antitumor effects can be obtained by suppressing such activation of ras oncogene, by inhibiting the function of Ras protein as its product.
Recently, it has been found that farnesyl-modification of Ras protein itself is essential for function of Ras protein, and it is possible to suppress localization of Ras protein at the plasma membrane by inhibiting this farnesyl-modification and thereby to inhibit transformation to cancer cells. The protein-farnesyl transferase (PFT) is an enzyme which catalyses this farnesyl-modification of Ras protein, and by inhibiting this enzyme, it is possible to suppress function of carcinogenic Ras protein. Further, this enzyme contributes to farnesyl-modification of only very limited proteins in vivo. Accordingly, the inhibitor for such an enzyme is expected to be a safe and highly selective antitumor agent. From such a viewpoint, many PFT inhibitors have been developed in recent years (Cell, vol. 57, pp. 1167-1177 (1989); Proc. Natl. Acad. Sci., vol. 86, pp. 8323-8327 (1989); ditto, vol. 90, pp. 2281-2285 (1993); Science, vol. 245, pp. 379-385 (1989); ditto, vol. 260 pp. 1934-1937 (1993); ditto, vol. 260, pp. 1937-1942 (1993); J. Biol. Chem., vol. 266, pp. 15575-15578 (1991); J. Antibiotics, vol. 46, pp. 222-227 (1993); Natur Medicine, vol. 1, pp. 792-797 (1995); JP-A-5-201869; JP-A-5-213992).
Further, it has recently been found by a research by the present inventors that these PFT inhibitors can block the reactivation of static viruses by suppressing development of matured Ras proteins and are useful as anti-AIDS (HIV) agents (PCT/JP95/02489).
However, up to now, all of the reported PFT inhibitors have had some problems for development as medicines, such that the activities are low in cells, and the effects in vivo are inadequate.


DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a novel antitumor agent or an anti-AIDS agent which inhibits the protein-farnesyl transferase (PFT) thereby to inhibit functional manifestation of oncogene protein Ras and which thus provides antitumor or anti-AIDS effects.
The present inventors have found that a compound represented by general formula (I) or a pharmaceutically acceptable salt or ester thereof: ##STR3## [wherein each of ##STR4## which may be the same or different, is an aryl group or an aromatic heterocyclic group which may have substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower hydroxyalkyl group, a lower fluoroalkyl group, a lower alkoxycarbonyl group, a carbamoyl group and a lower alkylcarbamoyl group; A.sup.1 is a C.sub.1-6 chain hydrocarbon group which may have substituent(s) selected from the group consisting of a halogen atom, a lower alkyl group, an oxo group, a lower hydroxyalkyl group and a lower alkoxy group or a group represented by --A.sup.1a --W.sup.1 --A.sup.1b -- (wherein A.sup.1a is a C.sub.1-5 chain hydrocarbon group which may have substituent(s) selected from the group consisting of a halogen atom, a lower alkyl group, an oxo group, a lower hydroxyalkyl group and a lower alkoxy group; A.sup.1b is a single bond or a C.sub.1

REFERENCES:
patent: 5488149 (1996-01-01), Nomoto et al.

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