Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-10-07
2000-06-06
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514398, 546256, 5483241, C07D40114, A61K 3144, A61K 31415
Patent
active
060719354
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a series of novel derivatives of 2-(2-oxo-ethylidene)-imidazolidin-4-one that exhibit activity as inhibitors of the enzyme farnesyl protein transferase and are believed to be useful as anti-cancer and anti-tumor agents. This invention also relates to methods of using such compounds in the treatment or prevention of cancer in a mammal, in particular a human, and to pharmaceutical compositions containing such compounds.
Other compounds that inhibit farnesyl protein transferase and are believed to be useful as anti-cancer and anti-tumor agents are referred to in International Patent Application PCT/US92/11292, which designates the United States and was published on Jul. 22, 1993 as WO 93/14085, U.S. Pat. No. 4,876,259, which issued on Oct. 24, 1989, International Patent Application PCT/IB95/00189, which designates the United States and was filed on Mar. 20, 1995, U.S. patent application Ser. No. 08/236,743, which was filed on Apr. 29, 1994, and U.S. Provisional Application entitled "Adamantyl Substituted Oxindoles As Pharmaceutical Agents," which was filed on May 28, 1996, in the name of R. A. Volkmann and J. P. Lyssikatos. The foregoing patent and patent applications are incorporated herein by reference in their entireties.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260,1834 to 1837, 1993).
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula I ##STR2##
and to pharmaceutically acceptable salts thereof, wherein:
R.sub.1 and R.sub.2 are independently selected from the group consisting of --(CH.sub.2).sub.p (5-10 membered heterocyclyl), --(CH.sub.2).sub.p (C.sub.6 -C.sub.10 aryl), allyl, propargyl and C.sub.1 -C.sub.6 alkyl wherein p is 0 to 3, said alkyl and the alkyl moieties of said R.sub.1 and R.sub.2 groups are optionally substituted by 1 to 3 R.sub.9 substituents, and the aryl and heterocyclyl moieties of said R.sub.1 and R.sub.2 groups are optionally substituted by 1 to 3 substituents independently selected from halo and R.sub.9 ;
R.sub.3 is --(CH.sub.2).sub.m (1- or 2-adamantyl), --(CH.sub.2).sub.m (C.sub.3 -C.sub.10 cycloalkyl), --(CH.sub.2).sub.m (C.sub.6 -C.sub.10 aryl), C.sub.1 -C.sub.10 alkyl, ##STR3##
wherein m is 0 to 6, and said cycloalkyl and alkyl optionally contain 1 or 2 double or triple bonds;
X.sub.1, X.sub.2, and X.sub.3 are each independently C.sub.1 -C.sub.7 alkylene optionally containing 1 or 2 double or triple bonds, X.sub.4 is a bond or C.sub.1 -C.sub.7 alkylene optionally containing 1 or 2 double or triple bonds, and, in formula (Ib), the X.sub.4 moiety is attached to the X, moiety at any available carbon in the X, moiety;
R.sub.4 is C.sub.6 -C.sub.10 aryl, 5-10 membered heterocyclyl or C.sub.1 -C.sub.6 alkyl wherein each of said R.sub.4 groups is optionally substituted by 1 to 3 R.sub.5 substituents;
each R.sub.5 is independently selected from the group consisting of halo, nitro, cyano, phenyl, --C(O)OR.sub.6, --SO.sub.2 NR.sub.6 R.sub.7, --NR.sub.6 R.sub.8, --C(O)R.sub.6, --OR.sub.6, --C(O)NR.sub.6 R.sub.8, --OC(O)NR.sub.6 R.sub.8, --NR.sub.8 C(O)NR.sub.8
REFERENCES:
Graham et al, Journal of Medicinal Chemistry, vol. 37, No. 6, p. 725-732, Mar. 1994.
Davis Zinna Northington
Ginsburg Paul H.
Jacobs Seth
Pfizer Inc.
Richardson Peter C.
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