Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2001-12-03
2002-10-29
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S058400, C544S128000, C544S130000, C544S133000, C544S139000, C544S370000, C546S205000, C548S200000, C548S236000, C548S311700, C548S312100, C548S312400, C548S314700
Reexamination Certificate
active
06472526
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel imidazole derivative represented by the following formula (1) which shows an inhibitory activity against farnesyl transferase:
in which A, n
1
and Y are defined as described below, or pharmaceutically acceptable salts or isomers thereof.
The present invention also relates to a process for preparation of the compound of formula (1), to intermediates which are used in the preparation of the compound of formula (1), and to a pharmaceutical composition comprising the compound of formula (1) 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 4 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 ground 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., Cancer Res., 1989, 49, 4682).
Ras protein is synthesized as a cytosolic precursor that 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 modification 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., Childs, J. E., Marshall, C. J., Cell 1989, 57, 1167). The subsequent posttranslational modifications, cleavage of the AAX residues, carboxyl methylation of the 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 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 (Kohl. N. E. et. al., Proc. Natl. Acad. Sci. USA. 1994, 91, 9141; 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 peptidic 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, 30611). 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. This 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.
With regard to the restenosis and vascular proliferative diseases, it has been shown that inhibition of cellular ras prevents smooth muscle proliferation after vascular injury in vivo (Indolfi C. et al., Nature Med., 1995, 1(6), 541-545). This report definitively supports a role for farnesyl transferase inhibitors in this disease, showing inhibition of accumulation and proliferation of vascular smooth muscle.
DISCLOSURE OF INVENTION
The present inventors have performed studies for developing a compound having the structural characteristics imitating an intermediate state of catalytic reaction of FTase and as a result found that imidazole derivatives according to the present invention can potently inhibit the enzyme.
Therefore, the object of the present invention is to provide an imidazole derivative of formula (1) which inhibits the activity of FTase, a process for preparation thereof, and an intermediate which can be used effectively for the preparation of the compound of formula (1).
It is another object of the present invention to provide a pharmaceutical composition comprising the compound of formula (1) as an active ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
It is the first object of the present invention to provide an imidazole derivative represented by the following formula (1) which inhibit the activity of farnesyl transferase:
in which
n
1
represents an integer of 1 to 4,
A represents hydrogen; straight-chain or branched C
1
-C
10
-alkyl which may be optionally substituted by C
3
-C
7
-cycloalkyl or lower alkoxy; or a radical selected from the following group:
wherein
R
1
and R
1
′ independently of one another represent hydrogen, halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy, phenyl, benzyloxy, or lower alkyl which may be optionally substituted by C
3
-C
6
-cycloalkyl,
R
2
represents hydrogen or lower alkyl, or represents —E—F wherein E is —CH
2
—, —C(O)— or —S(O)
2
— and F is hydrogen; lower alkyl which may be optionally substituted by phenoxy or biphenyl; lower alkoxy which may be optionally substituted by aryl; phenyl; benzyl; benzyloxy; or amino which may be optionally substituted by lower allyl, benzyl or C
5
-C
6
-cycloalkyl,
R
3
represents hydrogen, lower alkyl or phenyl,
R
4
represents a radical selected from the following group:
wherein
n
2
and n
3
independently of one another denote 0, 1, 2, 3 or 4,
R
5
and R
9
independently of one another represent hydrogen, lower alkyl, lower alkoxy, phenoxy, phenyl, hydroxy or halogen,
R
6
and R
8
independently of one another represent hydrogen, lower alkyl, lower alkoxy, phenoxy, phenyl, cyano, hydroxy or halogen,
R
7
represents hydrogen; lower alkyl which may be optionally substituted by C
3
-C
6
-cycloalkyl; lower alkoxy; hydroxy; C
3
-C
6
-cycloalkyl; di(lower alkyl)amino; phenyl; phenoxy; or halogen,
R
10
represents hydrogen, lower alkyl or lower alkoxy,
Y represents a radical selected from the following group:
wherein
X represents O or S,
B represents hydrogen, or lower alkyl which may be optionally substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl,
C represents hydrogen, or lower alkyl which may be optionally substituted by aryl; or represen
Ahn In Ae
Choi Tae Saeng
Chung Hyun Ho
Jeong Shin Wu
Jung Won Hee
Corless Peter F.
Edwards & Angell LLP
LG Chemical Ltd.
McKane Joseph K.
O'Day Christine C.
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