Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-08-04
1999-11-09
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514338, 514471, 5462837, 549 60, 549435, 549487, 560 20, 560 39, 560 41, 562444, 562450, C07D30754, A61K 3134
Patent
active
059815736
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates novel N,N-disubstituted amic acid derivatives. More particularly, the N,N-disubstituted amic acid 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 or 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: ##STR1## [wherein each of ##STR2## which are the same or different, is an aryl group or an aromatic heterocyclic group; A.sup.1 is a C.sub.2-6 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.1-4 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; W.sup.1 is an oxygen atom, a sulfur atom, an ethynylene group, a cyclopropylene group or a group represented by --NR.sup.W --; and R.sup.W is a hydro
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Aoyama Tetsuya
Arai Sachie
Iwasawa Yoshikazu
Kawakami Kumiko
Monden Yoshiaki
Banyu Pharmaceutical Co. Ltd.
Dentz Bernard
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