Hydantoin compounds and methods related thereto

Details Hydantoin compounds and methods related thereto Hydantoin compounds and methods related thereto

2000-03-30

2002-05-07

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S389000, C546S210000, C546S274400, C548S314400, C548S321100

Reexamination Certificate

active

06384061

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel hydantoin derivative represented by the following formula (I) which shows an inhibitory activity against farnesyl transferase, and thus can be used as an effective therapeutic agent against anti-proliferative diseases such as resfenosis, Rheumatitis arthrititis and particularly cancer:
or pharmaceutically acceptable salts thereof, in which R
1
, R
2
, R
3
and R
4
are defined as described below.
The present invention also relates to a process for preparation of the compound of formula (I) and to an anticancer composition comprising the compound of formula (I) as an active ingredient.
BACKGROUND ART
Mammalian Ras proteins act as molecular switches in the signalling events associated with cell growth and differentiation. The ras proto-oncogene family consists of three members, N-, K-, and H-ras, which code for highly homologous four types of proteins; i.e. H-, N-ras proteins of 189 residues and two isomorphic K-ras-4B and K-ras-4A proteins of 188 and 189 residues, respectively. The chemical basis for the switch mechanism involves cycling of the protein between the inactive (off) guanosine diphosphate (GDP) bound state and the active (on) guanosine triphosphate (GTP) bound state (Bourne. H. R.; Sanders, D. A.; McCormick, F.;
Nature,
1991, 349,117). Biochemical and structural studies have shown that point mutations of the residues 12, 13, and 61, positioned in the neighborhood of phosphoryl group of GTP, resulting in the decrease of guanosine triphosphatase activity are associated with many human cancers, particularly, pancreatic cancer, urinary bladder carcinoma, colon cancer, etc. (Bos, J. L., Cancel Res., 1989, 49, 4682).
Ras protein is synthesized as a cytosolic precursor that is ultimately localized to the cytoplasmic face of the plasma membrane after a series of posttranslational modification (Gibbs, J. B., Cell 1991, 65, 1). These series of biochemical modifications, by changing the electrical charge state or spacial structure to increase the hydrophobicity allow Ras protein to attach to cell membrane more easily. The first and obligatory step in the series is the addition of a farnesyl moiety to the cysteine residue of the C-terminal CAAX motif (C, cysteine, A, usually aliphatic residue; X, any other amino acid) in a reaction catalyzed by farnesyl protein transferase (FTase). This modifications is essential for Ras function, as demonstrated by the inability of Ras mutants lacking the C-terminal cysteine to be farnesylated, to localize to the plasma, and to transform mammalian cells in culture (Hancock, J. F., Magee, A. I., Child, J. E., Marshall, C. J., Cell 1989, 57, 1167). The subsequent posttranslational modifications, cleavage of the AAX residues, carboxyl methylation of the farnesylated cysteine, and palmitoylation of the cysteines located upstream of the CAAX motif in H-and N-ras proteins are not obligatory for Ras membrane association or cellular transforming activity. Interestingly, K-ras-4B, different from H- and N-ras, has a multiple lysine rich region named polybasic domain, instead of having cysteine required for palmitoylation, thereby facilitating the farnesylated ras protein to bind to anionic lipid layer of cell membrane. The inhibitors of FTase that catalyzes the obligatory modification have therefore been suggested as anticancer agents for tumors in which Ras oncogene contributes to transformation (Buses, J. E. et al., Chemistry & Biology, 1995, 2 787). A number of FTase inhibitors have recently identified demonstrated potent and specific ability to block Ras farnesylation. signalling and transformation in transformed cells and tumor cell lines both in vitro and in animal models (Koh, N. E. et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 914; Kohl, N. E. et al., Nature Medicine. 1995, 1 792). However, most of the inhibitors are related to CAAX motif as Ras substrate mimic and peptidie in nature or contain a sulfhydryl group (U.S. Pat. No. 5.141,851; Kohl, N. E. et al., Science, 1993, 260, 1934; PCT/US95/12224, Graham et al., Sebti, S. M. et al., J. Biol. Chem., 1995, 270, 26802; James, G. L. et al., Science, 1993 260, 1937; Bishop, W. R. et al., J. Biol. Chem., 1995, 270, 3061 1) Recently, a new type of peptidomimetic inhibitor imitating catalytic step of FTase has been reported (Poulter, C. D. et al., J. Am. Chem. Soc., 1996, 118,8761). The chemical basis of the inhibitor design relates to the reaction mechanism. That is, transferring prenyl group by the enzyme is electrophilic displacement and the reaction requires (+) charge in a transition state.
These inhibitors previously described however possess limited activity and selectivity for inhibition of the oncogenic function of Ras proteins, particularly K-ras-4B, which is found to be most common in human cancer. Therefore, new inhibitor having the ability of effectively inhibiting K-ras activity is required.
DISCLOSURE OF INVENTION
The present inventors have performed studies for developing a compound having the structure characteristics imitating transition state of catalytic reaction of farnesyl transferase and as a result, found that hydantoin derivatives according to the present invention can inhibit farnesyl transferase activity by imitating transition state of catalytic reaction of farnesyl transferase.
Therefore, the object of the present invention is to provide a hydantoin derivative of formula (I) which inhibits the activity of farnesyl transferase, process for preparation thereof, and anti-cancer composition comprising the compound of formula (I) as an active component.
BEST MODE FOR CARRYING OUT THE INVENTION
It is the first object of the present invention to provide a hydantoin derivative represented by the following formula (I) and pharmaceutically acceptable salt thereof which inhibit the activity of farnesyl transferase
in which
R
1
and R
2
independently of one another represent hydrogen; lower alkyl; monocyclic or bicyclic alkyl group which can be substituted by lower alkyl or halogen; heterocyclic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring member; or a radical having the following formula:
(wherein D represents alkoxy; hydroxy; amino acid residue; morpholine; thiomorpholine; piperazine, alkoxyalkylamine or alkyloxyalkylamine each of which is substituted or unsubstituted by lower alkyl, and m is selected from 0 to 2),
R
3
represents amino acid residue, or a radical having the following formula,
wherein
A represents hydrogen; lower alkyl; aryl group which is substituted by substituents selected from a group consisting of halogen, cyano (CN) nitro(NO
2
), carboxy(COOH), amide, thioamide, SR and lower alkyl; heterocyclic group which is substituted by substituents selected from a group consisting, of halogen, cyano, nitro, COOR, amide, thioamide, SR and lower alkyl and which comprises nitrogen or sulfur atom as ring member; lower alkyl substituted by the substituted aryl or heterocyclic group as mentioned above; or a radical having the following formula:
(in the definition for the substituent A, R represents hydrogen or lower alkyl, and E represents hydrogen or —F—G wherein F represents CH
2
, C═O, SO
2
, and G represents hydrogen; lower alkyl substituted or unsubstituted by phenyl or biphenyl: lower alkoxy; phenyl benzyl; benzyloxy; amine substituted or unsubstituted by lower alkyl, phenyl, benzyl, cycloalkyl or phenoxy alkyl),
B and C independently of one another represent hydrogen, halogen or lower alkyl.
n denotes an integer of 0 to 4,
R
4
represents hydrogen; aromatic group substituted or unsubstituted by lower alkyl or halogen; bicyclic aromatic group; heteroaromatic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring member; or a radical having the following formula:
wherein
R
5
represents aryl group substituted by lower alkoxy; or heterocyclic group containing hetero atoms selected from a group consisting of nitrogen, oxygen and sulfur as ring member,
R
6
represents hydrogen; lower alkyl; lower alkyl which is sub

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