AU8464798A - Hydantoin derivatives having an inhibitory activity for farnesyl transferase - Google Patents
Hydantoin derivatives having an inhibitory activity for farnesyl transferase Download PDFInfo
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- AU8464798A AU8464798A AU84647/98A AU8464798A AU8464798A AU 8464798 A AU8464798 A AU 8464798A AU 84647/98 A AU84647/98 A AU 84647/98A AU 8464798 A AU8464798 A AU 8464798A AU 8464798 A AU8464798 A AU 8464798A
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- imidazol
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Description
WO 99/05117 PCT/KR98/00225 -1 HYDANTOIN DERIVATIVES HAVING AN INHIBITORY ACTIVITY FOR FARNESYL TRANSFERASE 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: [Formula I] O R 1 R<N2 R3 y O or pharmaceutically acceptable salts thereof, in which R1, 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 anti-cancer 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 WO 99/05117 PCT/KR98/00225 - 2 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., Cancer 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 WO 99/05117 PCT/KR98/00225 -3 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 (US Patent 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. 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 WO 99/05117 PCT/KR98/00225 4 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 famrnesyl transferase : [Formula I] o R2 R3'N NR 0 in which WO 99/05117 PCT/KR98/00225 - 5 R 1 and R 2 independently of one another represent hydrogen; lower alkyl; monocyclic or bicyclic aryl 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: 0 D (wherein D represents alkoxy; hydroxy; amino acid residue; morpholine; thiomorpholine; piperazine, alkoxyalkylamine or aryloxyalkylamine each of which is substituted or unsubstituted by lower alkyl, and m is selected from 0 to 2), R3 represents amino acid residue; or a radical having the following formula, A A BA\N, B N-,t N' wherein A represents hydrogen; lower alkyl; aryl group which is substituted by substituents selected from a group consisting of halogen, cyano(CN), nitro(NO2), 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: WO 99/05117 PCT/KR98/00225 - 6 N-E (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, R4 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: WO 99/05117 PCT/KR98/00225 -7 o 0 R5 NHR6 NH 0 R 6 0 R 6 0 N NH OR 9 NH RR I~n 0 OR X 6 wherein Rs 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, R6 represents hydrogen; lower alkyl; lower alkyl which is substituted by substituents selected from a group consisting of halogen, cyano, hydroxy, COOR, amide, thioamide, SR and SO 2 R; lower alkyl substituted by an aryl group which is substituted by substituents selected from a group consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl; heterocyclic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring member; heterocyclic group which is substituted by substituents selected from a group consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl and which contains hetero atoms selected from a group consisting of nitrogen and sulfur as ring member, wherein R represents WO 99/05117 PCT/KR98/00225 -8 lower alkyl, R7 and Rs independently of one another represent hydrogen, halogen, halogenoalkyl, cyano, amide, thioamide, alkoxy or phenoxy, or represent a radical having the following formula, 0n0 R 114-C -\ - I I/1 nR i o -N Z-Rio C-N Z wherein Z represents CH 2 , CO, O, S, SO2, NR 9 , NHSO 2 or NHCOO, Rio represents hydrogen, lower alkyl, halogenoalkyl, alkoxy, hydroxy, benzyloxycarbonyl or benzyl, R9 represents hydrogen or lower alkyl, or lower alkyl substituted by aromatic group, X represents CH 2 , CO, O, S or SO 2 , and n denotes an integer of 0 to 4. In the definitions for the substituents of the compound of formula (I), the term "lower alkyl" means a straight or branched alkyl having 1 to 4 carbon atoms which includes methyl, ethyl, isopropyl, isobutyl and t-butyl; the term "heterocyclic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring member" means mono- or bicyclic aliphatic or aromatic group containing one or two nitrogen or sulfur in the ring as ring member. The abbreviations for amino acids used in the present specification are consistent with IUPAC-IUB Commission on biochemical nomenclature of amino acid and peptide[Eur. J. Biochem., 1984, 158, 9-31]. Also, the compound of formula (I) according to the present invention can form a pharmaceutically acceptable salt. Such salt includes WO 99/05117 PCT/KR98/00225 - 9 non-toxic acid addition salt containing pharmaceutically acceptable anion, for example a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trofluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., or a salt with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; and metal addition salt for example a salt with alkali metal or alkaline earth metal such as lithium salt. Further, the present invention includes a solvate of the compound of formula (I) such as alcoholate, and hydrate thereof. Since the compound of formula (I) according to the present invention may have asymmetric carbon atoms depending on the substituents, they can be present in the form of racemate, diastereomer mixture or the individual diastereomers. Thus, the present invention also includes all of these stereoisomers and their mixtures. Among the compound of formula (I) according to the present invention, the preferred compounds include those wherein Ri represents hydrogen; monocyclic or bicyclic aryl group which can be substituted by lower alkyl or halogen; or a radical having the following formula: 0 >24~ D (wherein D represents alkoxy; hydroxy; amino acid residue; morpholine; thiomorpholine; piperazine or alkoxyalkylamine each of which is substituted or unsubstituted by lower alkyl, and m is selected from 0 to 1), WO 99/05117 PCT/KR98/00225 - 10 R2 represents hydrogen; lower alkyl; or a radical having the following formula: 0 D (wherein D represents alkoxy; hydroxy; amino acid residue; morpholine; thiomorpholine; piperazine or alkoxyalkylamine each of which is substituted or unsubstituted by lower alkyl, and m is selected from 0 to 1), R3 represents a radical having the following formula, A A N C wherein A represents hydrogen; aryl group which is substituted by substituents selected from a group consisting of halogen, cyano(CN), nitro(NO2), carboxy(COOH), amide, thioamide, SR and lower alkyl; or a radical having the following formula: -CN-E (in the definition for the substituent A, R represents hydrogen or lower alkyl, and E represents hydrogen or -F-G wherein F represents C=O, and G represents benzyloxy, lower alkoxy, or lower alkyl substituted or unsubstituted by phenyl), B and C independently of one another represent hydrogen, n denotes an integer of 1 to 3, R4 represents hydrogen; aromatic group substituted or unsubstituted by halogen; bicyclic aromatic group; heteroaromatic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring WO 99/05117 PCT/KR98/00225 - 11 member; or a radical having the following formula: o oo /(nRS( NH' R6N X NH OR9 R 6 o 0 R8 0 OR9 X wherein R5 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, R6 represents hydrogen; lower alkyl; lower alkyl which is substituted by substituents selected from a group consisting of halogen, cyano, hydroxy, COOR, amide, thioamide, SR and SO 2 R; lower alkyl substituted by an aryl group which is substituted by substituents selected from a group consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl; or heterocyclic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring member; heterocyclic group which is substituted by substituents selected from a group consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl and which contains hetero atoms selected from a group consisting of nitrogen and sulfur as ring member, wherein R represents lower alkyl,
R
7 and Rs independently of one another represent hydrogen, halogen, halogenoalkyl, cyano or phenoxy, or represent a radical having the WO 99/05117 PCT/KR98/00225 - 12 following formula, ZRCo -N Z-R - / R Z10 wherein Z represents O, S, SO 2 , NR 9 , NHSO 2 or NHCOO, Rio represents hydrogen, lower alkyl, halogenoalkyl, alkoxy, hydroxy or benzyloxycarbonyl, R9 represents hydrogen or lower alkyl, X represents O, S or SO 2 , and n denotes an integer of 1 to 3. Typical examples of the compound of formula (I) according to the present invention are presented in the following Tables la to lv.
WO 99/05117 PCT/KR98/00225 - 13 Table la COM. Formula Nomenclature NO. 2-(2- { 3-[3-(1H-imidazol-4-yl) Spropyl]-5-methyl-5-naphthalen 1 /-N 0 o 1-yl-2,4-dioxo-imidazolidin-1-y N y N yN NH OCH 3 1}-acetylamino)-4-methylsulfan o 0 yl-butyric acid methyl ester 2-(2-{ 3-[3-(1H-imidazol-4-yl) s propyl]-5-methyl-5-naphthalen 2 /N o 0 1-yl-2,4-dioxo-imidazolidin-1-y 2 \N N " N "--NH OH l }-acetylamino)-4-methylsulfan o o yl-butyric acid 2-(2-{ 3-[2-(1H-imidazol-4-yl)-e s thyl]-5-methyl-5-naphthalen-1 3 o- 0 yl-2,4-dioxo-imidazolidin-1-yl } HN__ N N NH OCH 3 -acetylamino)-4-methylsulfanyl o o -butyric acid methyl ester 2-(2- { 3-[2-(1H-imidazol-4-yl)-e s thyl]-5-methyl-5-naphthalen-1 4 o o yl-2,4-dioxo-imidazolidin-1-yl} HNN NH -acetylamino)-4-methylsulfanyl o o -butyric acid WO 99/05117 PCT/KR98/00225 - 14 Table lb COM. O. Formula Nomenclature NO. 2- { 2-[3-(3H-imidazol-4-yl-m I o ethyl)-5-methyl-5-naphthalen N -1-yl-2,4-dioxo-imidazolidin K' NH OCH 3 1 -yl]-acetylamino}-4-methyls So ulfanyl-butyric acid methyl ester S s2- {2-[3-(3H-imidazol-4-yl-m s ethyl)-5-methyl-5-naphthalen 6N. o o 6 I -1-yl-2,4-dioxo-imidazolidin HN N " N "" NH OH 1-yl]-acetylamino}-4-methyls o o ulfanyl-butyric acid 2-(2-{3-[3-(4-cyano-benzyl) | , imidazol-4-yl)-methyl]-5-met 7 N o hyl-5-naphthalen-1-yl-2,4-dio 7K N N OCH3 xo-imidazolidin-1-yl } -acetyla NC NNH mino)-4-methylsulfanyl-buty ric acid methyl ester 2-(2-{3-[3-(4-cyano-benzyl) | s imidazol-4-yl)-methyl]-5-met N o0 0 hyl-5-naphthalen-1-yl-2,4-dio 8/ N N OH xo-imidazolidin-1-yl}-acetyla NCN mino)-4-methylsulfanyl-buty I ric acid WO 99/05117 PCT/KR98/00225 -15 Table Ic COM. Formula Nomenclature NO. 2-(2- {3-[3-(3H-imidazol-4-yl) -'.... .- Spropyl]-5-methyl-5-naphthalen 9 N_ --yl -2,4-dioxo-i midazoli din- I NNN NHI O -yl I -acetylamino)-3-thiophen-2 0 0 -yl-propionic acid 10 N 3-[3-(3H-imidazol-4-yl)-propyl N ]-5-methyl -5-naphthalen- l-yl-l 1N 0~~ -(2-oxo-2-thiazolidin-3-yl-ethy S l)-imidazoli din-2,4-di one I1 -[2-(l, 1 -dioxo-thiazolidin-3-y N l)-3 -(3H-imidazol-4-yl)-propyl </N N ]-5-methyl-5-naphthalen- l-yl HN y s 0 imidazolidin-2,4-dione 3-[3 -(3H-imidazol-4-yl)-propyl ]-5-methyl-1-{2-[2-(2-methyls 12 </N 0 ulfanyl-ethyl)-thiazolidin-3-yl] HN "_J N-2-oxo-ethyll-5-naphthalen-1 HN I(0 yl-imidazolidin-2,4-dione WO 99/05117 PCT/KR98/00225 - 16 Table ld COM. Formula Nomenclature NO. 0 2-(2-{3-[3-(3H-imidazol-4-yl) So= propyl]-5-methyl-5-naphthalen 13 N I O o -1-yl-2,4-dioxo-imidazolidin-1 HN ~~N N NH OH -yl}-acetylamino)-4-methylsulf 0 o onyl-butyric acid 2-{2-[3-(3-imidazol-1-yl-propy s 1)-5-methyl-5-naphthalen-1-yl 14 NO o 2,4-dioxo-imidazolidin-1-yl]-a N N o N NH OH cetylamino} -4-methylsulfanyl 0 0 butyric acid < . s2-{ 2-[3-(2-imidazol- 1-yl-ethyl) s -5-methyl-5-naphthalen-1-yl-2, 15 o o 4-dioxo-imidazolidin- l-yl]-ace N- ' ' "/X',NH OH tylamino}-4-methylsulfanyl-bu No o 0 tyric acid < 1-benzyl-3-(3-imidazol-1-yl-pr 16 o opyl)-5-methyl-5-naphthalen-1 N N -yl-imidazolidin-2,4-dione o WO 99/05117 PCT/KR98/00225 - 17 Table le NO. Formula Nomenclature I 1-(pentafluoro-benzyl)-3-(3-im 17 N F idazol-1-yl-propyl)-5-methyl-5 N /\F -naphthalen-1I-yl-imidazolidin F 2,4-dione I 1-(3-pyridylmethyl)-3-(3-imida 18 N~1Nzol-1 -yl-propyl)-5-methyl-5-na N -N N N phthalen-1 -yl-imidazolidin-2,4 "if dione 1 -(3 -chloro-benzyl)-3 -(3 -imida 19 zol-I1 -yl-propyl)-5 -m ethyl -5 -na \,N N N phthalen- 1-yl-imidazolidin-2,4 Y dione 0 I 1-(3-bromo-benzyl)-3-(3-imida 20 zol- 1-yl-propyl)-5-methyl-5-na \ NN N phthalen- 1-yl-imidazolidin-2,4 N B 0 dione WO 99/05117 PCTJKR98/00225 - 18 Table If COM. N.Formula Nomenclature 1 -(4-bromo-benzyl)-3 -(3-imid 21 Br azol-1-yl-propyl)-5-methyl-5 N N naphthalen- 1 -yl-imi dazoli din "II 2,4-dione 1 -(3 -trifluoromethyl-benzyl)-3 22 I-(3 -imi dazol -1I-yl-propyl)- 5-m N ~ethyl -5 -naphthal en-1 lIma Y CF, zolidin-2,4-dione y-md 23 1-(3-trifluoromethoxy-benzyl)I N methyl-5-naphthalen- 1-yl-imid 1 azolidin-2,4-dione -~ ~ I 3-(3-imidazol-1-yl-propyl)-5 methyl-5-naphthalen-1-yl-1 -(4 24 0 0 -phenoxy-benzyl)-imidazolidi ~N~~N~ANn-2,4-dione WO 99/05117 PCT/KR98/00225 - 19 Table 1g COM. Formula Nomenclature NO. 3-(3-imidazol- 1-yl-propyl)-5 25N- omethyl-5-naphthalen-1-yl-1-(3 25 o -phenoxy-benzyl)-imidazolidi o0 n-2,4-dione 3-(3-imidazol-1-yl-propyl)- 1-( 26 N 4-methylsulfanyl-benzyl)-5-m N N N Nethyl-5-naphthalen-1-yl-imida o zolidin-2,4-dione 0 C' " 3-(3-imidazol-1-yl-propyl)-5 27 N ] omethyl-1-(4-methylsulfanylme 27 N thyl-benzyl)-5-naphthalen- 1-yl N Yo-imidazolidin-2,4-dione o 3-(3-imidazol-1 -yl-propyl)-5 N28 NzN I S 0 methyl- 1-(4-methylsulfonyl-be 2N 0 nzyl)-5-naphthalen-1-yl-imida zolidin-2,4-dione o WO 99/05117 PCT/KR98/00225 - 20 Table lh COM. Formula Nomenclature NO. 5-[3-(3-imidazol-1-yl-propyl) N i 5-methyl-5-naphthalen-1-yl-2, 29 sN 4-dioxo-imidazolidin- 1-ylmeth ,N - CN yl]-2-methylsulfanyl-benzonitr o ile 5-[3-(3-imidazol- I -yl-propyl) N 5-methyl-5-naphthalen-1-yl-2, sro 30 0 s 4-dioxo-imidazolidin-1-ylmeth N N , I " N N NcN yl]-2-methylsulfonyl-benzonitr o ile I lf 2-[3-(3-imidazol- 1 -yl-propyl) 31 5-methyl-5-naphthalen 1 -yl-2, 31N 4-dioxo-imidazolidin- 1-ylmeth CN yl]-benzonitrile S N 3-[3-(3-imidazol-1-yl-propyl) 032 o 5-methyl-5-naphthalen-1-yl-2, NIN cN 4-dioxo-imidazolidin- 1 -ylmeth -CN yl]-benzonitrile WO 99/05117 PCT/KR98/00225 - 21 Table li COM. Formula Nomenclature NO. 4-[3-(3-imidazol- 1-yl-propyl) 33 0CN -5-methyl-5-naphthalen- l-yl 33 2,4-dioxo-imidazolidin- 1-ylm 0 ethyl]-benzonitrile 1-(4-aminomethyl-benzyl)-3-( NH2 o34 3-imidazol-1-yl-propyl)-5-me N N N N thyl-5-naphthalen- 1-yl-imidaz o olidin-2,4-dione o N-{2-[3-(3-imidazol- 1 -yl-pro 3 pyl)-5-methyl-5-naphthalen-1 35 N-yl-2,4-dioxo-imidazolidin- 1 S1 ylmethyl]-benzyl } -methanesu
NH-S
II Ifonamide o N- { 3-[3-(3-imidazol-1-yl-pro I pyl)-5-methyl-5-naphthalen-1 3II ylmethyl]-benzyl } -methanesu O -0S-NH 0 Ifonamide WO 99/05117 PCT/KR98/00225 - 22 Table lj COM. Formula Nomenclature NO. SN-{4-[3-(3-imidazol-1-yl-pro NI pyl)-5-methyl-5-naphthalen-1 37 o -yl-2,4-dioxo-imidazolidin- 1 -N ^ N:_ ylmethyl]-benzyl }-methanesu o lfonamide .- I 4-[3-(3-imidazol-1-yl-propyl) Soo -5-methyl-5-naphthalen-1-yl 38 No No 2,4-dioxo-imidazolidin-1-ylm S* N ethyl]-benzoic acid methyl o ester 4-[3-(3-imidazol-1-yl-propyl) / OH o -5-methyl-5-naphthalen-1-yl 39 o N9 N "N - N..- 2,4-dioxo-imidazolidin- 1-ylm 0 ethyl]-benzoic acid 0 -( N C ] 3-(3-imidazol-1-yl-propyl)-1 o .__N -[3-(morpholine-4-carbonyl)-b 40 NN'N . 0 enzyl]-5-methyl-5-naphthale n-1-yl-imidazolidin-2,4-dione o WO 99/05117 PCT/KR98/00225 - 23 Table 1k COM. NO. Formula Nomenclature NO. o 4-[3-(3-imidazol- 1-yl-propyl) H -5-methyl-5-naphthalen-1-yl 41 0 2,4-dioxo-imidazolidin-1-ylm -N N ethyl]-N-(2-methoxy-ethyl)-b o enzamide 0 4-[3-(3-imidazol-1-yl-propyl) \-5-methyl-5-naphthalen-1-yl 42 o 2,4-dioxo-imidazolidin- 1-ylm N ,N . ethyl]-N-(2-methoxy-ethyl) o N-methyl-benzamide ~ o o 4-{4-[3-(3-imidazol-l1-yl-pro CN pyl)-5-methyl-5-naphthalen-1 43 -yl-2,4-dioxo-imidazolidin-1 " N ylmethyl]-benzoyl } -piperazin N0 e-1-carboxylic acid benzyl ' ester 3-(3-imidazol-1-yl-propyl)-1 N [3-(thiomorpholine-4-carbon 44 s yl)-benzyl]-5-methyl-5-napht ^ . halen- 1 -yl-imidazolidin-2,4-d o o ione WO 99/05117 PCT/KR98/00225 - 24 Table 11 COM. Formula Nomenclature NO. CN 4- { 5-[3-(4-methyl-4-naphthal " 0 en-1-yl-2,5-dioxo-imidazolidi 45 N n-1-yl)-propyl]-imidazol-1l-yl N |/ N YNH methyl }-benzonitrile 0 CN 4- { 5-[3-(3-methyl-4-methyl SN 4-naphthalen-1-yl-2,5-dioxo-i /N 46 0 midazolidin- 1 -yl)-propyl]-im N 1N idazol- 1-ylmethyl }-benzonitr Y ile 0 CN I - N4- { 5-[3-(3-ethyl-4-methyl-4 47 naphthalen-1-yl-2,5-dioxo-im 47 N1/ 0 idazolidin- 1-yl)-propyl]-imid N YN -Nw , azol- 1-ylmethyl }-benzonitrile 0 CN 4-{ 5-[3-(3-propyl-4-methyl-4 N -naphthalen-1-yl-2,5-dioxo-i 48 midazolidin-1-yl)-propyl]-im N /N idazol- 1 -ylmethyl } -benzonitr oile o WO 99/05117 PCT/KR98/00225 - 25 Table Im COM. Formula Nomenclature NO. CN 4-{5-[3-(3-butyl-4-methyl-4 49 naphthalen-1-yl-2,5-dioxo-im 49 .N o__ idazolidin-1-yl)-propyl]-imid N // N, azol-1-ylmethyl}-benzonitrile 0 CN 4-(5-{3-[3-(2-methoxy-ethox I ( ymethyl)-4-methyl-4-naphtha 50 0 len-1-yl-2,5-dioxo-imidazolid N 11- oin- 1-yl]-propyl}-imidazol- 1-y NY N'O O lmethyl)-benzonitrile o CN (3-{3-[3-(4-cyanobenzyl)-3H I -imidazol-4-yl]-propyl }-5-me 51 thyl-5-naphthalen- 1 -yl-2,4-di N ' o N No oxo-imidazolidin- 1-yl)-acetic
NY
N
l O j acid ethyl ester o CN (3-{ 3-[3-(4-cyanobenzyl)-3H I -imidazol-4-yl]-propyl )-5-me 52 thyl-5-naphthalen-1-yl-2,4-di //I ON o N O N oxo-imidazolidin- 1 -yl)-acetic N Y N ' - IOH acid 0 WO 99/05117 PCT/KR98/00225 - 26 Table in COM. Formula Nomenclature NO. CN 4-(5- { 3-[3-benzyl-4-methyl-4 -naphthalen-1-yl-2,5-dioxo-i 53 midazolidin- 1-yl]-propyl } -im NN N idazol-1-ylmethyl)-benzonitri le 0 CN 4-(5- { 3-[3-(3-cyano-benzyl) 4-methyl-4-naphthalen-1-yl-2 54 , 5-dioxo-imidazolidin- 1-yl]-p N I ropyl}-imidazol-1-ylmethyl) y
N
CN benzonitrile 0 CN 4-{ 5-[3 -(3-furan-2-ylmethyl I 4-methyl-4-naphthalen- 1-yl-2 55 ,5-dioxo-imidazolidin-1-yl)-p N N 0 ropyl]-imidazol-1-ylmethyl} NN benzonitrile 0 WO 99/05117 PCT/KR98/00225 - 27 Table lo COM. Formula Nomenclature NO. CN 4-(5-{3-[3-(furan-2-carbonyl) "' -4-methyl-4-naphthalen-1-yl 56 2,5-dioxo-imidazolidin-1-yl] SN 0 propyl}-imidazol-1-ylmethyl) .- -benzonitrile O o cN 2-[2-(3-{ 3-[3-(4-cyano-benzy SI 1)-3H-imidazol-4-yl]-propyl } 57 s -5-methyl-5-naphthalen-1-yl oN 0 2,4-dioxo-imidazolidin- l-yl) N\ _N N NH O\ acetylamino]-4-methylsulfan o o yl-butyric acid methyl ester cN 2-[2-(3-{ 3-[3-(4-cyano-benzy l)-3H-imidazol-4-yl]-propyl } 8 s -5-methyl-5-naphthalen-1-yl N 0 2,4-dioxo-imidazolidin-1-yl) Y NH OH acetylamino]-4-methylsulfan o o yl-butyric acid CN N 1-ylmethyl)-imidazol-1-ylme N YNH thyl]-benzonitrile 0 WO 99/05117 PCTIKR98/00225 - 28 Table Ip CO.Formula Nomenclature NO. CN -~ I ~4-[5-(3-methyl-4-methyl-4-n 60 Iaphthalen- l-yl-2, 5-dioxo-imi NN dazolidin- 1-ylmethyl)-imidaz - N YNI ol-1I-ylmethyl]-benzonitrile CN I ~4- [5-(3 -ethyl -4-methyl -4-nap 61 hthalen-1I-yl-2,5-dioxo-imida N 11'-N 0O- zolidin-1I-ylmethyl)-imidazol N N__,, I1-ylmethyl]-benzonitnile CN { 3-[3-(4-cyano-benzyl)-3H-i -~ ~'-midazol-4-ylmethyl]-5-methy 62 l-5-naphthalen-1I-yl-2,4-dioxo N\ -imidazolidin-1I-yl I}-acetic acid ethyl ester CN 4-f 5-[3-(3-cyanobenzyl)-4-m -~ ~ ethyl-4-naphthalen-1-yl-2,5-d 63 //-N ioxo-imidazolidin-1I-ylmethyl N N N 1 3-imidazol- 1 -ylmethyl I}bn CN onitrile WO 99/05117 PCT/KR98/00225 - 29 Table lq COM. Formula Nomenclature NO. - '-3-(3-imidazol-1-yl-propyl)-1 6 4 (4-methoxy-benzoyl)-5-meth 64 . yl-5-naphthalen- 1-yl-imidazo So lidin-2,4-dione I 3-(3-imidazol-1-yl-propyl)-5 65 0 methyl- -(morpholine-4-carb N N , N N N, onyl)-5 -naphthalen- 1 -yl-imid Sl oazolidin-2,4-dione 3 -(3-imidazol- 1-yl-propyl)-5 methyl-5 -naphthalen- 1 -yl-2,4 66 N/~ ' -dioxo-imidazolidine- 1-carbo N, N N NH CN xylic acid (3-cyano-phenyl) 00 amide N-(4-cyano-tetrahydropyran 0 4-yl)-2-[3-(3-imidazol-l-yl-p 67 No o ropyl)-5-methyl-5-naphthalen NN NH 'CN -1-yl-2,4-dioxo-imidazolidin 0 1-yl]-acetamide WO 99/05117 PCT/KR98/00225 - 30 Table Ir NO. Formula Nomenclature Br 3-f{3-[3-(4-bromo-benzyl)-3 68 H-imidazol-4-yl]-propyl }J-5 N\ Nmethyl-5-naphthalen- 1 -yl-imi N YNH dazolidin-2,4-dione Br I 3- {3-[3-(4-bromo-benzyl)-3 69 H-imidazol-4-yl]-propyl}1-1,5 N 11 N -dimethyl-5-naphthalen-1I-yl N Y Nl imidazolidin-2,4-dione Br (3-f{ 3 -[3 -(4-bromo-benzyl)-3 H-imidazol-4-yl]-propyl}J-5 70 methyl-5-naphthalen- I-yl-2,4 11--N0 N\ -dioxo-imidazolidin-1I-yl)acet N ic acid ethyl ester 0 I 3-[3-(3-imidazol-1-yl-propyl) 71 01 -5-methyl-5-phenyl-2,4-diox N N o-imidazolidin-1-ylmethyl]-b Y :_a CN efizonitrile WO 99/05117 PCT/KR98/00225 - 31 Table Is COM. NO. Formula Nomenclature NO. CN 4-[5-(3-naphthalen- 1-yl-2,5 72 dioxo-imidazolidin- 1-ylmeth 7N- yl)-imidazol-1-ylmethyl]-be - /N/ nzonitrile 0 Cl I 3-[3-(4-chloro-benzyl)-3H-i midazol-4-ylmethyl]- 1 -napht 1-N / halen-1-yl-imidazolidin-2,4 /\ \ -A Y\ dione 0 o o 4-[5-(3-naphthalen-1-yl-2,5 N dioxo-imidazolidin-1-ylmeth 74 yl)-imidazol- 1-ylmethyl]-pip / eridine-1-carboxylic acid N\ Sbenzyl ester CN I 4-[5-(3-naphthalen-1-ylmeth yl-2,5-dioxo-imidazolidin- 1 75 o 75N - A ylmethyl)-imidazol- 1-ylmeth NN N yl]-benzonitrile
O\
WO 99/05117 PCT/KR98/00225 - 32 Table It COM. Formula Nomenclature NO. o o 4-[5-(3-naphthalen-1-ylmeth N yl-2,5-dioxo-imidazolidin- 1 76 ylmethyl)-imidazol- 1-ylmeth N o yl]-piperidine-1 -carboxylic SNacid benzyl ester O CN { 1-[3-(4-cyano-benzyl)-3H-i S o midazol-4-ylmethyl]-3-napht o halen-1-ylmethyl-2,5-dioxo-i 77 0 7N midazolidin-4-yl}-acetic N\_ N N -~acid ethyl ester N CN { 1-[3-(4-cyano-benzyl)-3H-i OH midazol-4-ylmethyl]-3-napht 78 o halen-1-ylmethyl-2,5-dioxo-i N N midazolidin-4-yl }-acetic T acid O CN { 1-[3-(4-cyano-benzyl)-3H-i o midazol-4-ylmethyl]-3-napht 79 hal en- 1-ylmethyl-2,5-dioxo-i N - / N midazolidin-(4S)-yl}-acetic I acid methyl ester
O
WO 99/05117 PCTJKR98/00225 - 33 Table lu. COM. N .Formula Nomenclature CN 0 No 4-{ 5-[4-(2-morpholin-4-yl-2 0 -oxo-ethyl)-3-naphthalen-1-y 80 0 Imethyl-2,5-dioxo-imidazoli N. di-i-ylmethyl]-imidazol-1 - N Ndi y ylmethyl I-benzonitrile CN 0 No4- {(5 S)-[4-(2-morpholin-4-y N l-2-oxo-ethyl)-3-naphthalen 81 1-N 0 N 1 -ylmethyl-2, 5-dioxo-imidaz N\_ I ~.oii--ylmethyl]-imidazol T ~ I 1-ylmethyl} -benzonitrile 0 CN -N 2- { 1-[3-(4-cyano-benzyl)-3 NIT H-imidazol-4-ylmethyl]-3-na 82 0 0phthalen-1I-ylmethyl-2,5-dio //--Nxo-imidazolidin-4-yl)-N-(2-( N\ NYN -- N,N-dimethylamino)-ethyl) 0 N.acetamide Br -0 2-{ 1-[3-(4-bromo-benzyl)-3 N H-imidazol-4-ylmethyl]-3-na 83 0 0phthalen- 1 -ylmethyl-2, 5-dio N.N xo-imidazolidin-4-yI} -N-(2 - NyN I ~methoxy-ethyl)-N-methyl-ac 0. etamide WO 99/05117 PCTJKR98/00225 - 34 Table Iv COM. N.Formula Nomenclature CN N/ 4-((5S)-{4-112-(4-methyl-pipe No razin-l1-yl)-2-oxo-ethyl]-3-na 840o phthalen-1I-ylmethyl-2,5-diox 84 4N oo-imidazolidin- 1 -ylmethyl I -i N\, NYN midazol-1I-ylmethyl)-benzoni 0 trile CN 0 /(2S)-(2-{1 -[3-(4-cyano-benz NH _ yl)-3 H-imi dazol -4-ylm ethyl] 85 0 0\_3-naphthalen-1I-ylmethyl-2,5 N dioxo-imidazolidin-4-yl }-ace N YN tylamino)-4-methylsulfanyl-b 0 utyric acid methyl ester CN 0 (2S)-(2-{1 -[3-(4-cyano-benz OH- yl)-3H-imidazol-4-ylmethyl] 86 0 U3-naphthalen- 1-ylmethyl-2,5 11--N dioxo-imidazolidin-4-yl})-ace N\, N YN -,, tylamino)-4-methylsulfanyl-b 0 utyric acid N~~] 0+7 ~ 3 -(3 -imidazol- 1-yl-propyl)- 1 87 Y N naphthalen-1I-yl-imi dazoli din 0 I6 -2,4-dione WO 99/05117 PCT/KR98/00225 - 35 It is another object of the present invention to provide a process for preparing the hydantoin derivative of formula (I) as defined above. According to the present invention, the hydantoin derivative of formula (I) can be prepared by a process characterized in that 1) a compound represented by the following formula (II): [Formula II] o Ri )L R2 HN
NR
4 o wherein R 1 , R 2 and R4 are defined as previously described, is reacted under Mitsunobu reaction condition with an alcohol derivative represented by the following formula (III): [Formula III]
R
3 -OH wherein R 3 is defined as previously described, or 2) a compound represented by the following formula (IIa): [Formula IIa] O Ri R2 HN NH
O
WO 99/05117 PCT/KR98/00225 - 36 wherein Ri and R 2 are defined as previously described, is reacted with the alcohol derivative of formula (III) under Mitsunobu reaction condition to produce a compound represented by the following formula (Ia): [Formula Ia] O R, R2 R3"N
N
E O wherein R 1 , R 2 and R 3 are defined as previously described, then substituent R 4 ' is introduced into the resulting compound of formula (Ia) to produce a compound represented by the following formula (Ib): [Formula Ib] o RI -R2 R3,-N YN-s4 0 wherein R 1 , R 2 and R 3 are defined as previously described and R 4 ' is the same as R4 except that R 4 ' is not hydrogen. While, the starting compounds used in the above reaction may be prepared according to the processes depicted in the following Schemes 1 to 9. First, the compound of formula (IIa) can be synthesized by condensing a ketone compound with potassium cyanide and ammonium carbonate as represented in the following Reaction Scheme 1: WO 99/05117 PCT/KR98/00225 - 37 [Reaction Scheme 1] o R1
O=
R 1 -- R2 S+
(NH
4
)
2
CO
3 + KCN - IHN NH R2 O (2a) As represented in the following Reaction Scheme 2, the compound of formula (II) can be prepared from ethyl bromoacetate by alkylation of amine compound and cyclization: [Reaction Scheme 2] 0 0 Br + H 2
N-R
4 HN O Ns HNR KOCN HN N-R4 HR4 Y Further, the compound of formula (II) may be obtained by processes represented in the following Reaction Schemes 3 and 4. Specifically, a racemate can be obtained through the alkylation of an amine compound using fumarate and then cyclization as Reaction Scheme 3, and a stereospecific isomer can be obtained through the reductive amination of an aspartic acid having ester protecting group with an aldehyde compound and then cyclization as Reaction Scheme 4: WO 99/05117 PCT/KR98/00225 - 38 [Reaction Scheme 3] o 0 O O + H 2 N-R O O O O HNR 4 0 <R4 AcOH O0 - N 0 KOCN HN N-R 4 O [Reaction Scheme 4] o 0 O + OHC-R4 O O 0 NH 2 0 HNR 4 0 AcOH O KOCN HN N- The alcohol compound of formula (III) may be prepared by processes described in the following Reaction Schemes 5 to 9. That is, the compound 3 can be synthesized by forming imidazole moiety using dihydroxy acetone as Reaction Schemes 5 and 6, or by alkylating the existing imidazole methanol compound as Reaction Scheme 7. Also, the compound of formula (III) may be prepared by processes described in the following Reaction Schemes 8 and 9.
WO 99/05117 PCT/KR98/00225 - 39 [Reaction Scheme 5] Benzaldehyde 1. CbzCl
NH
2 HIN 2. KHSO 4
N
Cbz Cbz / / N N KSCN HNO 3 CbzN O OH OH
NH
2 HO OH HSN N H S -- , N'N [Reaction Scheme 6] Br Br Br KSCN \ / HNO 3 \ / O H HNH
NH
2 HO OH HSN N [Reaction Scheme 7] N OH Trt-Cl N OH /N OAc HN * H C I N (AcO) 2 0 N Trt Trt CN CN CN 4-Bromomethyl + TFA KOH benzonitrile Br OA c OAc OH Ti t OAc I OH N<N N Trt WO 99/05117 PCT/KR98/00225 - 40 [Reaction Scheme 8] 0 0 NH O N LOH [Reaction Scheme 9] 0 Br O LiAlH 4 OH In the above Reaction Schemes, AcOH represents acetic acid, Cbz-Cl represents benzyloxycarbonyl chloride, Trt-Cl represents chlorotriphenylmethane and TFA represents trifluoroacetic acid. The process for preparing the compound of formula (I), particularly the synthetic methods as described above will be more specifically explained by the following Preparations and Examples. As the coupling agent used in the above amidation reaction for preparing the compound of formula (I), a mixture of carbodiimides such as dicyclohexylcarbodiimide(DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbo diimide(EDC), 1,1'-dicarbonyldiimidazole(CDI), etc., and 1-hydroxybenzo trizole can be mentioned. Reaction conditions including the amount of reactants, temperature, reaction time, etc. can be easily determined by the person having ordinary skill in the art depending on the reactant used. Also, the free comopund of formula (I) produced in the WO 99/05117 PCT/KR98/00225 - 41 aforementioned reaction may be easily converted into a salt form thereof according to the conventionally known methods in this art. After the reaction is completed, the resulting product may be further separated and purified by usual work-up processes, such as for example, chromatography, recrystallization, etc. The compound of formula (I) shows an inhibitory activity against farnesyl transferase, and thus can be effectively used as an anti-cancer agent. Therefore, the present invention also provides an anti-cancer agent comprising the novel compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. When the active compound according to the present invention is used for clinical purpose, it is preferably administered in an amount ranging from 10mg to 4 0 mg per kg of body weight a day. The total daily dosage may be administered in one time or over several times. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight of the subject patient, sex, hygienic condition, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc. The compound of the present invention may be administered in the form of injections or oral preparations. Injections, for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent. Solvents which can be used for preparing WO 99/05117 PCT/KR98/00225 - 42 injections include water, Ringer's fluid and NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acid such as oleic acid may also be used for injections. As the solid preparation for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation. The solid preparations may be prepared by mixing the active compound of formula (I) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agent and binding agent. The present invention will be more specifically explained in the following examples. However, it should be understood that the following examples are intended to illustrate the present invention but not in any manner to limit the scope of the present invention. Processes for preparing the starting substances used for obtaining the compound of formula (I) will be explained in the following Preparations. Preparation 1 Synthesis of 5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione 30g(0.18 mol) of l'-acetonaphthone and 23g(0.35 mol) of potassium cyanide[KCN] were dissolved in 9 00 mg of methanol. Then, 169g(1.8 mol) of ammonium carbonate[(NH 4
)
2
CO
3 ] in 900mf of distilled water were added thereto and the resulting solution was stirred for 12 hours at 7 0 1C. The reaction solution was distilled under reduced WO 99/05117 PCT/KR98/00225 - 43 pressure to remove methanol and the residue was extracted with ethyl acetate(500m x 4). The extract was distilled under reduced pressure to remove ethyl acetate and 38.2g(Yield: 90%) of title compound was obtained. I H NMR(CDCl 3 ) a (ppm) 2.15(3H, s), 6.35(1H, s), 7.44(1H, t), 7.53(2H, min), 7.70(1H, d), 7.89(1H, d), 7.93(1H, d), 7.99(1H, d), 8.52(1H, br) FAB Mass(M+H) : 241 Preparation 2 Synthesis of 1-naphthalen-1-yl-imidazolidin-2,4-dione 2-1) Synthesis of (naphthalen-1-yl-amino)-acetic acid ethyl ester 19.3g(139 mmol) of potassium carbonate was added to 2 0 0 mg of dimethylformamide, and then the solution was heated to dissolve potassium carbonate. After cooling to room temperature, 8 mg( 7 0 mmol) of ethyl bromoacetate and 10g(70 mmol) of 1-naphthylamine were added to the solution, which was then stirred for 48 hours. DMF was removed under reduced pressure and ethyl actate was added to the residue. The ethyl acetate layer was washed with water 4 times and saturated sodium chloride solution. Ethyl acetate was removed under reduced pressure, and then column chromatography was performed using a mixed solution(9:1) of hexane and ethyl acetate as an eluent to obtain 12g of the title compound(Yield 75%, MW 229). SH NMR(CDCl 3 ) 8 (ppm) 1.33(3H, t), 4.07(2H, s), 4.30(2H, q), 6.24(1H, d), 7.30(1H, d), 7.34(1H, t), 7.47(2H, min), 7.80(1H, min), 7.95(1H, m) FAB (M+H) 230 WO 99/05117 PCT/KR98/00225 - 44 2-2) Synthesis of 1-naphthalen-1-yl-imidazolidin-2,4-dione 8.68g(37.9 mmol) of the compound prepared in Preparation 2-1) and 6.34g(75.8 mmol) of potassium isocyanate were added to 100rg of acetic acid and the solution was stirred for 24 hours at 110°C. Acetic acid was removed under reduced pressure and then ethyl acetate was added to the residue. The resulting solution was washed with water 3 times, IN HCI solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The solution was recrystallized from ethyl acetate to obtain 6.8g of the title compound(Yield 80%, MW 226). 'H NMR(CD 3 OD) (ppm) 4.49(2H, s), 7.52-7.61(4H, min), 7.89-7.98(3H, m) FAB (M+H) 227 Preparation 3 Synthesis of 1-(naphthalen-1-ylmethyl)-2,4-dioxo-imidazolidin-5-yl]acetic acid ethyl ester 3-1) Synthesis of 2-[(naphthalen-1-ylmethyl)-amino]succinic acid diethyl ester 3 .12m(1 9 .0 mmol) of diethyl fumarate and 3.0g(19 mmol) of 1-aminomethyl naphthalene were added to acetonitrile, and then the solution was refluxed for 12 hours. Acetonitrile was removed under reduced pressure and column chromatography was performed using a mixed solution of hexane and ethyl acetate(3:1) as an eluent to obtain 4.57g of the title compound(Yield 73%, MW 329). 1H NMR (CDCl 3 ) 8~(ppm) 1.19(3H, t), 1.30(3H, t), 2.18(1H, br), 2.70 (2H, 2dd), 3.79(1H, dd), 4.03-4.13(2H, min), 4.15(1H, d), 4.23(2H, WO 99/05117 PCT/KR98/00225 - 45 q), 4.35 (1H, d), 7.41(1H, t), 7.45-7.55(3H, min), 7.77(1H, d), 7.85(1H, d), 8.20(1H, d) FAB (M+H) 330 3-2) Synthesis of [1-(naphthalen- 1-ylmethyl)-2,4-dioxo-imidazolidin-5-yl]ace tic acid ethyl ester 4.57g(13.9 mmol) of the compound prepared in Preparation 3-1) and 3.38g(41.7 mmol) of potassium isocyanate were added to 150ni of acetic acid and the solution was stirred for 24 hours at 1101C. Acetic acid was removed under reduced pressure and ethyl acetate was added to the residue. The resulting solution was washed with water 3 times, IN HCl solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, respectively. Ethyl acetate was removed under reduced pressure and then column chromatography was performed using a mixed solution of hexane and ethyl acetate(1:1) as an eluent to obtain 3.85g of the title compound(Yield 85%, MW 326). IH NMR (CDCl 3 ) 3 (ppm) 1.08(3H, t), 2.70(2H, 2dd), 3.80(1H, min), 3.90 (2H, min), 4.80(1H, d), 5.30(1H, d), 7.38-7.46(2H, min), 7.51(1H, t), 7.57(1H, min), 7.83(1H, min), 7.87(1H, d), 8.10(1H, d), 9.27(1H, s) FAB (M+H) 327 Preparation 4 Synthesis of [1-(naphthalen-1-ylmethyl)-2,4-dioxo-imidazolidin-(5S)-yl]ac etic acid methyl ester 4-1) Synthesis of (2S)-[(naphthalen-1-ylmethyl)-amino]succinic acid diethyl ester 2.22g(11.2 mmol) of (S)-dimethyl aspartate hydrochloride and 1.6 mnt(11.2 mmol) of 1-naphthyl aldehyde were added to 50g of WO 99/05117 PCT/KR98/00225 - 46 dimethylformamide, and then the solution was stirred for 1 hour. 5.0g(22.4 mmol) of sodium triacetoxy borohydride was added to the solution and the resulting solution was stirred for 4 hours. Then, DMF was removed in vacuo and then ethyl acetate was added thereto. The solution was washed with water and saturated sodium chloride solution. Ethyl acetate was removed under reduced pressure and column chromatography was performed on the residue using a mixed solution of hexane and ethylacetate(3:1) as an eluent to obtain 3.00g of the title compound(Yield 89%, MW 301). 1H NMR (CDCl 3 ) 3 (ppm) 2.23(1H, br), 2.74(2H, 2dd), 3.60(3H, s), 3.77 (3H, s), 3.81(1H, dd), 4.15(1H, d), 4.34(1H, d), 7.41(1H, t), 7.44-7.55(3H, m), 7.77(1H, d), 7.84(1H, d), 8.18(1H, d) FAB (M+H) 302 4-2) Synthesis of [1-(naphthalen-1-ylmethyl)-2,4-dioxo-imidazolidin-(5S)-yl] acetic acid methyl ester 3.00g(9.96 mmol) of the compound prepared in Preparation 4-1) and 2.2g(26 mmol) of potassium isocyanate were added to 50ra of acetic acid and then the solution was stirred for 30 minutes at 110 C. Acetic acid was removed under reduced pressure and ethyl acetate was added to the residue. The resulting solution was washed with water 3 times, 1N HCI solution, saturated sodium bicarbonate solution and saturated sodium hydroxide solution, respectively. Ethyl acetate was removed under reduced pressure to obtain 2.87g of the title compound(Yield 92%, MW 312). 1H NMR (CD 3 OD+CDCl 3 ) a (ppm) 2.45(2H, 2dd), 3.09(3H, s), 3.75(1H, t), 4.79(2H, dd), 7.20(1H, min), 7.27-7.37(2H, min), 7.63(1H, d), 7.66(1H, d), 7.90 (1H, d) WO 99/05117 PCT/KR98/00225 - 47 FAB (M+H) 313 Preparation 5 Synthesis of 4-(5-hydroxymethyl-imidazol-1-ylmethyl)-piperidine-1-carbo xylic acid benzyl ester 5-1) Synthesis of 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester 22.2g(0.2 mol) of 4-aminomethyl piperidine was dissolved in 250 my of toluene and 21.2g(0.2 mol) of benzaldehyde was added thereto. The reaction mixture was heated to reflux for 3 hours with Dean-stack and then cooled down to 0OC. 34.2g(0.2 mol) of benzyl chloroformate was added dropwise while stirring. The reactants were stirred for 3 hours and 22 0 mg of 1N KHSO 4 was added at room temperature. The reaction solution was extracted with 20 0 myf of diethylether 3 times and the aqueous layer was basified with sodium hydroxide. After the aqueous solution was treated with saturated sodium chloride solution, it was extracted with 100t of dichloromethane 3 times, and the organic layer was dried over magnesium sulfate. Removal of dichloromethane under reduced pressure provided 38g of the title compound(Yield 91%, MW 248). 1H NMR(CDC13) 3(ppm) 1.11(2H, s), 1.49(3H, s), 1.70(2H, d), 2.57(2H, d), 2.78(2H, s), 4.20(2H, s), 5.12(2H, s), 7.34-7.35(5H, m) FAB (M+H) 249 5-2) Synthesis of 4-(5-hydroxymethyl-2-mercapto-imidazol-1-ylmethyl)-pipe ridine-l1-carboxylic acid benzyl ester 24.8g(0.1 mol) of the compound prepared in Preparation 5-1) was dissolved in 5 0mt of n-butanol with 6.0g(0.1 mol) of acetic acid. Above solution was added to 5 0mf of n-butanol solution in which 12.6g(0.13 WO 99/05117 PCT/KR98/00225 - 48 mol) of potassium thiocyanate, 15.2g(0.1 mol) of 1,3-dihydroxyacetone dimer and 10.0g(0.17 mol) of acetic acid were dissolved, and then the resulting solution was stirred for 48 hours. After stirring, the solvent was removed under the reduced pressure and 200m of ethyl acetate was added thereto. The resulting solution was washed with 100m of water 3 times and the organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain 27g of the title compound(Yield 75%, MW 361). H NMR(CDCl 3 ) a (ppm) 1.22(2H, d), 1.57(2H, d), 2.30(1H, s), 2.72(2H, s), 3.96(2H, s), 4.15(2H, d), 4.46(2H, s), 5.10(2H, s), 6.62(1H, s), 7.26-7.37(5H, m) FAB (M+H) 362 5-3) Synthesis of 4-(5-hydroxymethyl-imidazol- 1-ylmethyl)-piperidine- 1-car boxylic acid benzyl ester 18.05g(50 mmol) of the compound prepared in Preparation 5-2) was added to a mixed solution of 100mi of 10% nitric acid solution and 10ml of ethyl acetate at 01C. It was stirred for 3 hours at room temperature. The reaction solution was basified with 4N aqueous sodium hydroxide solution and then extracted with 100 my of ethyl acetate twice. The extracted organic solution was dried over magnesium sulfate. The solvent was removed under reduced pressure to give 12.3g of the title compound(Yield 75%, MW 329). 1H NMR(CDC1 3 ) a (ppm) 1.16(2H, d), 1.56(2H, d), 1.98(1H, s), 2.70(2H, s), 3.88(2H, d), 4.18(2H, s), 4.49(1H, s), 4.56(3H, s), 5.10(2H, s), 6.82 (1H, s), 7.27-7.40(5H, m) FAB (M+H) 330 WO 99/05117 PCT/KR98/00225 - 49 Preparation 6 Synthesis of 1-(4-bromobenzyl)-5-hydroxymethyl-imidazole 8.9g(40 mmol) of 4-bromobenzylamine hydrochloride and 4my of acetic acid were dissolved in 85 my of n-butanol. 5.19g(50 mmol) of potassium thiocyanate and 3.21g(20 mmol) of 1.3-dihydroxyacetone dimer were added to the solution. The resulting solution was stirred for 4 days and then filtered under reduced pressure to separate the precipitated solid, which was then washed with water and diethylether. The solid thus obtained was added to 10% nitric acid solution, and then the mixture was stirred for 3 hours, filtered under reduced pressure to remove the insoluble impurities. Then, the solution was basified with 4N sodium hydroxide solution to precipitate a solid product. This solid product was washed with water several times and dried under vacuum to give 6.7g of the title compound(Yield 60%, MW 266). 'H NMR(CDCl 3 ) 3 (ppm) 4.45(2H, s), 5.20(2H, s), 6.94(1H, s), 7.03(2H, d), 7.18(4H, m) FAB Mass (M+H) 267 Preparation 7 Synthesis of 4-(5-hydroxymethyl-imidazol-1-ylmethyl)-benzonitrile 7-1) Synthesis of 1-trityl-4-hydroxymethyl-imidazole 7.98g(59.2 mmnol) of hydroxymethyl imidazole hydrochloride was dissolved in a solvent mixture of 6 0ma of dimethylformnamide and 20m of triethylamine. 2 00m of dimethylformamide solution containing 18.7g (67 mmol) of triphenylmnethyl chloride was added slowly thereto. After 2 hours, 1000me of ice water was added thereto to obtain a solid. This solid was recrystallized from dioxane to give 17.6g of the title WO 99/05117 PCT/KR98/00225 - 50 compound(Yield 87%, MW 340). mp 227-229 oC. 7-2) Synthesis of 1-trityl-4-hydroxymethyl-imidazole acetate 10.0g(29.4 mmol) of the compound prepared in Preparation 7-1) was added to 2 0 0 mi of pyridine and then, 3.30g(32.4 mmol) of acetic anhydride was added. After stirring for 24 hous at room temperature pyridine was removed under reduced pressure. The residue was dissolved in 4 0 0 mg of ethylacetate, and then washed with 200 mg of saturated sodium chloride solution. After removal of ethyl acetate under reduced pressure, chromatography was performed on the residue using dichloromethane/ methanol(95:5) as an eluent to obtain 10.44g of the title compound(Yield 93%, MW 382). 'H NMR(CDCl 3 ) 8 (ppm) 2.01(3H, s), 4.95(2H, s), 6.88(1H, s), 7.08(5H, s), 7.27(10H, s), 7.45(1H, s) FAB (M+H) 383 7-3) Synthesis of 1-trityl-3-(4-cyanobenzyl)-imidazol-4-ylmethyl acetate bromide 10.0g(26.2 mmol) of the compound prepared in Preparation 7-2) was dissolved in 4 0r of dichloromethane and 5.64g(28.8 mmol) of 4-cyanobenzyl bromide was added thereto. The resulting solution was stirred for 60 hours at room temperature and dichloromethane was removed under reduced pressure. Column chromatography was performed with the residue using dichloromethane/methanol(95:5) as an eluent to obtain 10.62g of the title compound(Yield 70%, MW 578). H NMR(CDCl 3 /CD30D) (ppm) 1.95(3H, s), 4.95(2H, s), WO 99/05117 PCT/KR98/00225 - 51 5.45(2H, s), 7.11-7.40(18H, min), 7.65(2H, d), 8.21(1H, s) FAB (M+H) 579 7-4) Synthesis of 1-(4-cyanobenzyl)-imidazol-5-ylmethyl acetate 9.10g(15.7 mmol) of the compound prepared in Preparation 7-3) was dissolved in 500 mi of dichloromethane and 6 .06mn( 7 8
.
7 mmol) of trifluoroacetic acid and 1 2 .5m( 7 8
.
7 mmol) of triethylsilane were added slowly thereto at 0 °C. The resulting solution was stirred for 1 hour at room temperature. After removal of dichloromethane under reduced pressure, pH was adjusted to pH 10 using saturated potassium carbonate solution. This solution was extracted with 300m of ethyl acetate and ethyl acetate was removed under reduced pressure. Column chromatography was performed with the residue using ethyl acetate as an eluent to obtain 3.60g of the title compound(Yield 90%, MW 255). 1H NMR(CDCl 3 ) 8 (ppm) 1.90(3H, s), 4.97(2H, s), 5.25(2H, s), 7.14(2H, d), 7.21(1H, d), 7.67(1H, s), 7.75(2H, d) FAB (M+H) 256 7-5) Synthesis of 4-(5-hydroxymethyl-imidazol-1-ylmethyl)-benzonitrile 3.36g(13.2 mmol) of the compound prepared in Preparation 7-4) was dissolved in 16 0 mi of methanol and 3.60g(26.3 mmol) of K 2 CO3 was added thereto. After stirring for 20 minutes at room temperature, methanol was removed under reduced pressure and product was extracted with 25 0my of ethyl acetate. Column chromatography was performed using dichloromethane/methanol(95:5) as an eluent to obtain 2.55g of the title compound(Yield 91%, MW 213). 1H NMR (CDC1 3
/CD
3 OD) 3 (ppm) 4.28(2H, s), 5.18(2H, s), 6.84(1H, s), 7.12(2H, d), 7.42(1H, s), 7.55(2H, d) WO 99/05117 PCT/KR98/00225 - 52 FAB (M+H) 213 Preparation 8 Synthesis of 3-imidazol-1-yl-propanol 8-1) Synthesis of methyl 3-imidazol-1-yl-propionate 5.0g(73.4 mmol) of imidazole and 12.6g(148.6 mmol) of methyl acrylate were dissolved in 100mp of acetonitrile, and then refluxed for 8 hours. Acetonitrile and the excess methyl acrylate was removed under reduced pressure. Then, 2 0 0 mt of ethyl acetate was added to the residue and the solution thus obtained was washed with saturated sodium chloride solution. Removal of ethyl acetate under reduced pressure provided 11. lg(Yield: 90%) of the title compound. I H NMR(CDCl 3 ) a (ppm) 2.75(2H, t), 3.46(3H, s), 4.24(2H, t), 6.89(1H, s), 7.00(1H, s), 7.46(1H, s) FAB Mass(M+H) : 169 8-2) Synthesis of 3-imidazol-1-yl-propanol To the 1.1g(6.6 mmol) of the compound prepared in Preparation 8-1) in 50my of tetrahydrofuran was added 0.26g(6.6 mmol) of lithium aluminum hydride[LiAH4] and then the resulting mixture was refluxed for one hour. Then, 20my of IN sodium hydroxide solution was added to the reaction mixture which was then extracted with ethyl acetate. Removal of the organic solvent under reduced pressure provided 0.77g(Yield: 93%) of the title compound was obtained. 1H NMR(CDCl 3 ) 8 (ppm) 1.67(2H, min), 3.26(2H, t), 3.78(2H, t), 6.60(1H, s), 6.75(1H, s), 7.14(1H, s) FAB Mass(M+H) : 127 WO 99/05117 PCT/KR98/00225 - 53 Preparation 9 Synthesis of 2-imidazol-1-yl-ethanol 9-1) Synthesis of 2-imidazol-l-yl-acetic acid ethyl ester 5.0g(73.4 mmol) of imidazole and 3
.
3 6 mf( 29
.
4 mmol) of ethyl bromoacetate were dissolved in 5 0m of dimethylformamide and stirred for 4 hours. Dimethylformamide was removed in vacuo. Then, 100 m of ethyl acetate was added to the residue and it was washed with saturated sodium chloride solution. Removal of the organic solvent under reduced pressure provided 0.77g(Yield: 17%) of the title compound. H NMR(CDCl 3 ) a (ppm) 1.29(3H, t), 4.25(2H, q), 4.70(2H, s), 6.95(1H, s), 7.10(1H, s), 7.49(1H, s) FAB Mass(M+H) : 155 9-2) Synthesis of 2-imidazol-1-yl-ethanol To the 2 0mi of tetrahydrofuran solution of 0.77g(5.0 mmol) of the compound prepared in Preparation 9-1) was added 0.2g(5.0 mmol) of lithium aluminum hydride and then the resulting mixture was refluxed for one hour. Then, 10 m of IN sodium hydroxide solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic solvent was removed under reduced pressure and the residue was subjected to chromatography using a solvent mixture of methanol-methylene chloride(5:95) as the eluent to obtain 0.51g(Yield: 91%) of the title compound. 1H NMR(CDCl 3 ) 8 (ppm) 3.78(2H, t), 3.98(2H, t), 6.85(1H, s), 6.94(1H, s), 7.36(1H, s) WO 99/05117 PCT/KR98/00225 - 54 FAB Mass(M+H) : 113 Example 1 Synthesis of 2-(2-{3-[3-(1H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen -1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester(Compound 1) 1-1) Synthesis of 3-[3-(1-triphenylmethyl-imidazol-4-yl)-propyl]-5-methyl -5-naphthalen- 1 -yl-imidazolidin-2,4-dione 0.60g(2.51 mmol) of 5-methyl-5-naphthalen-1-yl-imidazolidin-2,4 dione prepared in Preparation 1, 1.02g(2.76 mmol) of 3-(1-triphenyl methyl-imidazol-4-yl)-propanol and 0.87g(3.3 mmol) of triphenylphosphine (Ph 3 P) were dissolved in 5 0ag of tetrahydrofuran. 0.52mf(3.3 mmol) of diethylazodicarboxylate[DEAD] was added thereto and the resulting solution was stirred for 24 hours. Tetrahydrofuran was removed under reduced pressure and the residue was subjected to chromatography using ethyl acetate the eluent to obtain 1.17g(Yield: 80%) of the title compound. 'H NMR(CDCl 3 ) (ppm) 2.04(5H, min), 2.60(2H, t), 3.67(2H, t), 6.59(1H, s), 7.05(1H, s), 7.15(6H, min), 7.32(9H, min), 7.37(1H, t), 7.44(2H, d), 7.63(1H, d), 7.79(1H, d), 7.86(1H, d), 7.91(1H, d) FAB Mass(M+H) : 591 1-2) Synthesis of 2- { 3-[3-(1 -triphenylmethyl-imidazol-4-yl)-propyl]-5-methyl -5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl}-acetic acid ethyl ester 0.082g(0.14 mmol) of 3-[3-(1-triphenylmethyl-imidazol-4-yl)-propyl] -5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione prepared in Example 1-1) and 0.023mg(0.21 mmol) of ethyl bromoacetate were dissolved in 5 mi of dimethylformamide. 0.017g(0.21 mmol) of sodium hydride [NaH] WO 99/05117 PCT/KR98/00225 - 55 was added thereto and the resulting solution was stirred for one hour. Dimethylformamide was removed under reduced pressure and the residue was dissolved in ethyl acetate and then washed with saturated sodium chloride solution. Removal of ethyl acetate under reduced pressure provided 0.092g(Yield: 99%) of title compound. IH NMR(CDCl 3 ) 3 (ppm) 1.10(3H, t), 2.02(3H, s), 2.15(2H, min), 2.70(2H, t), 3.80(2H, t), 4.02(2H, min), 4.10(2H, q), 6.60(1H, s), 7.13(6H, min), 7.33(11H, m), 7.46(3H, min), 7.69(1H, d), 7.89(2H, m) FAB Mass(M+H) : 677 1-3) Synthesis of 2-(2- {3-[3-(1-triphenylmethyl-imidazol-4-yl)-propyl]-5 methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazolidin- 1 -yl } -acetylamino)-4-methyl sulfanyl-butyric acid methyl ester 0.092g(0.14 mmol) of 2- {3-[3-(1-triphenylmethyl-imidazol-4-yl) propyl]-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazolidin- 1 -yl } -acetic acid ethyl ester prepared in Example 1-2) was dissolved in 4mj of a solvent mixture of tetrahydrofuran- distilled water(3:1). 0.0058g(0.14 mmol) of lithium hydroxide[LiOH] was added thereto and the resulting solution was stirred for one hour. The solvents were removed under reduced pressure and the residue was thoroughly dried under vacuum. The residue thus produced was dissolved in 5 my of dimethylformamide. Then, 0.041g (0.21 mmol) of methionine methyl ester, 0.037g(0.28 mmol) of N-hydroxy benzotriazole and 0.04g(0.28 mmol) of 3-ethyl-(dimethyl amino)-propylcarbodiimide hydrochloride were added to the resulting solution and stirred for 12 hours at room temperature. After removal of dimethylformamide under reduced pressure, 30m of ethyl acetate was added. The resulting solution was washed twice with 10ay of saturated potassium carbonate solution and 10 mg of saturated sodium chloride solution, sequentially. Then, chromatography using a WO 99/05117 PCT/KR98/00225 - 56 solvent mixture of ethyl acetate-hexane(1:1) as the eluent was carried out to obtain 0.11 g(0.13 mmol, Yield: 95%) of the title compound. H NMR(CDCl 3 ) a (ppm) 1.84(2H, min), 1.98(6H, min), 2.14(2H, min), 2.40(2H, t), 2.71(2H, t), 3.38(1H, dd), 3.62(3H, s), 3.80(2H, min), 4.46(1H, min), 6.64(1H, d), 6.75(1H, dd), 7.14(6H, min), 7.24-7.53(13H, min), 7.72(1H, d), 7.89(2H, m) FAB Mass(M+H) : 794 1-4) Synthesis of 2-(2- { 3-[3-(1H-imidazol-4-yl)-propyl]-5-methyl-5-naphtha len-1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester 0.1 lg(0.13 mmol) of 2-(2-{3-[3-(1-triphenylmethyl-imidazol-4-yl) propyl]-5-methyl-5-naphthalen-l1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino) -4-methylsulfanyl-butyric acid methyl ester prepared in Example 1-3) and 0.0 5 3 mi(0.
2 6 mmol) of triisopropylsilane were dissolved in 5Mo of methylene chloride. Then, 5 m of trifluoroacetic acid was added thereto and the resulting solution was stirred for one hour at room temperature. The organic solvent was removed under reduced pressure and saturated potassium carbonate[K2CO3] solution was added. The solution was extracted with 10 mJ of ethyl acetate and the solvent was removed under reduced pressure. The residue was subjected to chromatography using a solvent mixture of methanol-methylene chloride(5:95) as the eluent to obtain 0.068g(Yield: 95%) of the title compound. 1H NMR(CDCl 3 ) 3 (ppm) 1.88(2H, min), 2.00(3H, s), 2.06(3H, s), 2.14(2H, min), 2.45(2H, t), 2.76(2H, min), 3.38(1H, dd), 3.69(3H, d), 3.82(2H, m), 4.54(1H, min), 6.87(1H, d), 7.60-7.40(5H, min), 7.72(1H, d), 7.91(2H, m) FAB Mass(M+H) : 552 WO 99/05117 PCT/KR98/00225 - 57 Example 2 Synthesis of 2-(2-{3-[3-(1H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen -1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid(Compound 2) lithium salt 0.068g(0.12 mmol) of 2-(2- { 3-[3-(1H-imidazol-4-yl)-propyl]-5 methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-l-yl}-acetylamino)-4-methyl sulfanyl-butyric acid methyl ester prepared in Example 1 was dissolved in 4 m of a solvent mixture of tetrahydrofuran-distilled water(3:1). 0.005g(0.12 mmol) of lithium hydroxide was added thereto and stirred for one hour. After solvents were removed under reduced pressure, the residue was thoroughly dried under vacuum to obtain 0.06g(Yield 95%) of the title compound. ESI Mass(M+Li
+
) : 538 Example 3 Synthesis of 2-(2-{3-[2-(1H-imidazol-4-yl)-ethyl]-5-methyl-5-naphthalen 1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester(Compound 3) 0.032g of the title compound was prepared according to the same procedure as Example 1 except that 2-(1-triphenylmethyl-imidazol-4-yl) ethanol was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1). IH NMR(CDCl 3 ) (ppm) 1.88(2H, min), 2.01(3H, s), 2.08(3H, s), 2.20(1H, t), 2.45(1H, t), 3.20(2H, min), 3.37(1H, dd), 3.70(3H, d), 4.05(2H, min), 4.54(1H, min), 6.97(1H, s), 7.71-7.30(6H, m), 7.90(2H, m) FAB Mass(M+H) : 538 WO 99/05117 PCT/KR98/00225 - 58 Example 4 Synthesis of 2-(2- {3-[2-(1H-imidazol-4-yl)-ethyl]-5-methyl-5-naphthalen 1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid(Compound 4) lithium salt 0.02g of the title compound was prepared according to the same procedure as Example 2 using 0.03g(0.056 mmol) of 2-(2-{3-[2-(1H imidazol-4-yl)-ethyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1l-yl} -acetylamino)-4-methylsulfanyl-butyric acid methyl ester prepared in Example 3. ESI Mass(M-Li++2H) : 524 Example 5 Synthesis of 2-{2-[3-(3H-imidazol-4-yl-methyl)-5-methyl-5-naphthalen-1 yl-2,4-dioxo-imidazolidin-1-yl]-acetylamino}-4-methylsulfanyl-butyric acid methyl ester(Compound 5) 0.025g of the title compound was prepared according to the same procedure as Example 1 except that (3-triphenylmethyl-imidazol-4-yl) methanol was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1). 1H NMR(CDCl 3 ) 6 (ppm) 1.80(2H, min), 1.98(3H, s), 2.00(3H, s), 2.08(1H, t), 2.38(1H, t), 3.38(1H, dd), 3.67(3H, d), 4.45(1H, min), 4.88(2H, d), 6.80(1H, min), 7.08(3H, min), 7.34(1H, min), 7.45(1H, min), 7.68(1H, d), 7.82(2H, m) FAB Mass(M+l) : 524 WO 99/05117 PCT/KR98/00225 - 59 Example 6 Synthesis of 2-{2-[3-(3H-imidazol-4-yl-methyl)-5-methyl-5-naphthalen-1 yl-2,4-dioxo-imidazolidin-1-yl]-acetylamino}-4-methylsulfanyl-butyric acid (Compound 6) lithium salt 0.015g of the title compound was prepared according to the same procedure as Example 2 using 0.02g(0.038 mmol) of 2-{2-[3-(3H imidazol-4-yl-methyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazolidin-1-yl ]-acetylamino}-4-methylsulfanyl-butyric acid methyl ester prepared in Example 5. ESI Mass(M-Li++2H) : 510 Example 7 Synthesis of 2-(2-{3-[3-(4-cyano-benzyl)-imidazol-4-yl-methyl]-5-methyl 5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-m ethylsulfa nyl-butyric acid methyl ester(Compound 7) 0.04g of the title compound was prepared according to the same procedure as Example 1 except that 1-(4-cyanobenzyl)-5-hydroxymethyl imidazole prepared in Preparation 7 was used instead of 3-(1 triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1). 1H NMR(CDC1 3 ) 8 (ppm) 1.85(2H, min), 2.00(3H, s), 2.06(4H, min), 2.45(1H, t), 3.36(1H, dd), 3.71(3H, d), 4.50(1H, min), 4.71(2H, min), 5.48(2H, dd), 6.90(1H, min), 7.08(1H, min), 7.14(2H, min), 7.39-7.75(7H, min), 7.91(2H, inm) FAB Mass(M+H) : 639 Example 8 WO 99/05117 PCT/KR98/00225 - 60 Synthesis of 2-(2-{3-[3-(4-cyano-benzyl)-imidazol-4-yl-methyl]-5-methyl 5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfa nyl-butyric acid(Compound 8) lithium salt 0.025g of the title compound was prepared according to the same procedure as Example 2 using 0.03g(0.047 mmol) of 2-(2-{3-[3-(4-cyano benzyl)-imidazol-4-yl-methyl]-5-methyl-5-naphthalen-l1-yl-2,4-dioxo-imidazoli din- l-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester prepared in Example 7. FAB Mass(M+H) : 631 Example 9 Synthesis of 2-(2-{3-[3-(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen -1-yl-2,4-dioxo-imidazolidin-1-yl}-acetamino)-3-thiophen-2-yl-propionic acid(Compound 9) lithium salt 0.025g of the title compound was prepared according to the same procedure as Example 1 and Example 2 except that 3-thiophen-2-yl-propionic acid methyl ester was used instead of methionine methyl ester in Example 1-3). 1H NMR(CD30D) 3(ppm) 1.95(3H, d), 2.10(2H, m), 2.74(2H, min), 3.20(2H, m), 3.78(2H, t), 4.00(1H, dd), 4.71(1H, min), 6.68-6.90(3H, min), 7.12(1H, min), 7.34-7.54(5H, min), 7.59(1H, t), 7.99(2H, q) ESI Mass(M-Li++2H) : 560 Example 10 Synthesis of 3-[3-(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl 1-(2-oxo-2-thiazolidin-3-yl-ethyl)-imidazolidin-2,4-dione(Compound 10) WO 99/05117 PCT/KR98/00225 - 61 0.06g of the title compound was prepared according to the same procedure as Example 1 except that thiazolidine was used instead of methionine methyl ester in Example 1-3). 'H NMR(CDCl 3 ) 8 (ppm) 2.02(3H, s), 2.15(2H, m), 2.70(2H, t), 3.00(2H, br), 3.75(2H, t), 3.80(2H, t), 4.02(2H, m), 4.50(2H, t), 6.60(1H, s), 7.13(6H, m), 7.33(11H, m), 7.46(3H, m), 7.69(1H, d), 7.89(2H, m) FAB Mass(M+H) : 478 Example 11 Synthesis of 1-[2-(1,1-dioxo-thiazolidin-3-yl)-3-(3H-imidazol-4-yl)-propyl] -5-methyl-5-naphthalen-1 -yl-imidazolidin-2,4-dione(Compound 11) 0.05g of the title compound was prepared according to the same procedure as Example 1 except that 1,1-dioxo-thiazolidine was used instead of methionine methyl ester in Example 1-3). 'H NMR(CDCl 3 ) 8(ppm) 2.02(3H, s), 2.15(2H, m), 2.70(2H, t), 3.24(2H, t), 3.80(2H, t), 4.02(4H, m), 4.40(2H, br), 6.60(1H, s), 7.13(6H, m), 7.33(11H, m), 7.46(3H, m), 7.69(1H, d), 7.89(2H, m) FAB Mass(M+H) : 510 Example 12 Synthesis of 3-[3-(3H-imidazol-4-yl)-propyl]-5-methyl-1 -{2-[2-(2-methyl sulfanyl-ethyl)-thiazolidin-3-yl]-2-oxo-ethyl}-5-naphthalen-1-yl-imidazolidi n-2,4-dione(Compound 12) 0.055g of the title compound was prepared according to the same procedure as Example 1 except that 2-(2-methylsulfanyl-ethyl)-thiazolidine WO 99/05117 PCT/KR98/00225 - 62 was used instead of methionine methyl ester in Example 1-3). 1H NMR(CDCl 3 ) 3 (ppm) 1.90(1H, min), 2.05(4H, min), 2.15(2H, min), 2.57(2H, min), 2.70(2H, t), 2.85(2H, min), 2.96(1H, min), 3.32(1H, min), 3.80(2H, t), 4.02(2H, min), 4.52(1H, t), 6.60(1H, s), 7.13(6H, min), 7.33(11H, min), 7.46(3H, min), 7.69(1H, d), 7.89(2H, m) FAB Mass(M+H) : 552 Example 13 Synthesis of 2-(2-{ 3
-[
3
-(
3 H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen -1-yl-2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfonyl-butyric acid(Compound 13) lithium salt The same procedure as Example 1 was carried out except that 4-methyl sulfonyl-butyric acid methyl ester was used instead of methionine methyl ester in Example 1-3), and then the resulting product was treated according to the same procedure as Example 2 to obtain 0.024g of the title compound. FAB Mass(M+H) : 576 Example 14 Synthesis of 2- {2-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-yl]-acetylamino}-4-methylsulfanyl-butyric acid (Compound 14) lithium salt The same procedure as Example 1 was carried out except that 3-(imidazol-1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl- imidazol-4-yl)-propanol in Example 1-1), and then the resulting product was treated according to the same procedure as WO 99/05117 PCT/KR98/00225 - 63 Example 2 to obtain 0.024g of the title compound. ESI Mass(M-Li++2H) : 552 Example 15 Synthesis of 2-{2-[3-(2-imidazol-1-yl-ethyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-yl]-acetylamino}-4-methylsulfanyl-butyric acid (Compound 15) lithium salt The same procedure as Example 1-1) to 1-3) was carried out except that 2-(imidazol-1-yl)-ethanol prepared in Preparation 9 was used instead of 3-(1- triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1), and then the resulting product was treated according to the same procedure as Example 2 to obtain 0.027g of the title compound. ESI Mass(M-Li++2H) : 538 Example 16 Synthesis of 1-benzyl-3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen 1-yl-imidazolidin-2,4-dione(Compound 16) The title compound was prepared in a yield of 80% according to the same procedure as Example 1-1) to 1-2) except that 3 (imidazol-1-yl)-propanol was used instead of 3-(1-triphenylmethyl-imidazol -4-yl)-propanol in Example 1-1) and that benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) ~ (ppm) 1.86(3H, s), 2.27(2H, min), 3.77(2H, t), 4.07-4.20(3H, min), 4.31(1H, d), 6.78-6.85(2H, min), 6.87(1H, s), 7.03(1H, s), 7.09(3H, min), 7.21(1H, d), 7.32(1H, min), 7.42(1H, t), 7.48(1H, t), WO 99/05117 PCT/KR98/00225 - 64 7.57(1H, s), 7.63(1H, d), 7.82(1H, d), 7.87(1H, d) FAB Mass(M+H) :439 Example 17 Synthesis of 1-(pentafluoro-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl 5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 17) The title compound was prepared in a yield of 87% according to the same procedure as Example 1 except that 3-(imidazol-1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl imidazol-4-yl)-propanol in Example 1-1) and that pentafluoro-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) (ppm) 2.10(3H, s), 2.30(2H, min), 3.82(2H, t), 4.07-4.20(3H, min), 5.11(1H, d), 7.06(1H, s), 7.12(1H, s), 7.20(1H, d), 7.35-7.50(3H, min), 7.66(1H, d), 7.68-7.80(3H, m) FAB Mass(M+H) : 529 Example 18 Synthesis of 1-(3-pyridylmethyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5 naphthalen-1-yl-imidazolidin-2,4-dione(Compound 18) The title compound was prepared in a yield of 60% according to the same procedure as Example 1 except that 3-(imidazol-1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl imidazol-4-yl)-propanol in Example 1-1) and that 3-pyridylmethyl chloride was used instead of ethyl bromoacetate in Example 1-2). 1 H NMR(CDCl 3 ) ~ (ppm) 1.89(3H, s), 2.30(2H, min), 3.81(2H, min), 4.15(3H, min), 4.35(1H, d), 6.85(1H, min), 7.08-7.52(7H, min), 7.65(1H, d), WO 99/05117 PCT/KR98/00225 - 65 7.85(3H, min), 7.98(1H, s), 8.21(1H, d) FAB Mass(M+H) :440 Example 19 Synthesis of 1-(3-chloro-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5 naphthalen-1-yl-imidazolidin-2,4-dione(Compound 19) The title compound was prepared in a yield of 90% according to the same procedure as Example 1 except that 3-(imidazol-1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl imidazol-4-yl)-propanol in Example 1-1) and that 3-chlorobenzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) a (ppm) 1.86(3H, s), 2.27(2H, m), 3.77(2H, t), 4.02(1H, d), 4.10(2H, t), 4.35(1H, d), 6.76(2H, min), 6.90(1H, t), 6.97(1H, d), 7.06(1H, s), 7.11(1H, s), 7.21(1H, d), 7.32(1H, t), 7.42(1H, t), 7.50(1H, t), 7.63(1H, d), 7.68(1H, s), 7.82(1H, d), 7.88(1H, d) FAB Mass(M+H) : 473 Example 20 Synthesis of 1-(3-bromo-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5 naphthalen-1-yl-imidazolidin-2,4-dione(Compound 20) The title compound was prepared in a yield of 90% according to the same procedure as Example 1 except that 3-(imidazol-l-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl imidazol-4-yl)-propanol in Example 1-1) and that 3-bromo-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDC1 3 ) (ppm) 1.86(3H, s), 2.27(2H, min), 3.77(2H, t), WO 99/05117 PCT/KR98/00225 - 66 4.07-4.20(3H, min), 4.31(1H, d), 6.78-6.85(2H, min), 6.87(1H, s), 7.03(1H, s), 7.09(2H, min), 7.21(1H, d), 7.32(1H, min), 7.42(1H, t), 7.48(1H, t), 7.57(1H, s), 7.63(1H, d), 7.82(1H, d), 7.87(1H, d) FAB Mass(M+H) : 517 Example 21 Synthesis of 1-(4-bromo-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5 naphthalen-1-yl-imidazolidin-2,4-dione(Compound 21) The title compound was prepared in a yield of 95% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol-1 yl)-propanol prepared in Preparation 8 was used instead of 3-(1 triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 4-bromo -benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) a (ppm) 1.86(3H, s), 2.27(2H, min), 3.77(2H, t), 3.97(1H, d), 4.09(2H, t), 4.31(1H, d), 6.72(2H, d), 7.05(1H, s), 7.10(3H, min), 7.23(1H, d), 7.32(1H, t), 7.41-7.55(2H, min), 7.57-7.68(2H, min), 7.86(1H, d), 7.89(1H, d) FAB Mass(M+H) : 517 Example 22 Synthesis of 1-(3-trifluoromethyl-benzyl)-3-(3-imidazol-1-yl-propyl)-5 m ethyl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 22) The title compound was prepared in a yield of 92% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol-1 yl)-propanol prepared in Preparation 8 was used instead of 3-(1 triphenyhnlmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 3-tri fluoromethyl-benzyl bromide was used instead of ethyl bromoacetate in WO 99/05117 PCT/KR98/00225 - 67 Example 1-2). 1H NMR(CDCl 3 ) a (ppm) 1.86(3H, s), 2.30(2H, min), 3.80(2H, min), 4.10(2H, t), 4.30(2H, s), 6.94(1H, s), 7.00-7.15(4H, min), 7.20(1H, t), 7.29(1H, t), 7.40(1H, t), 7.48(1H, t), 7.62(1H, d), 7.72(1H, s), 7.78(1H, d), 7.85(1H, d) FAB Mass(M+H) : 507 Example 23 Synthesis of 1-(3-trifluoromethoxy-benzyl)-3-(3-imidazol-1-yl-propyl)-5 methyl-5-naphthalen-1-yi-imidazolidin-2,4-dione(Compound 23) The title compound was prepared in a yield of 80% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1 triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 3-tri fluoromethoxy-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) 8 (ppm) 1.80(3H, s), 2.30(2H, min), 3.80(2H, min), 4.00(1H, d), 4.10(2H, t), 4.44(1H, d), 6.72(1H, s), 6.79(1H, s), 6.89(1H, d), 7.00(1H, t), 7.06(1H, s), 7.10(1H, s), 7.22(1H, d), 7.33(1H, t), 7.43(1H, t), 7.49(1H, t), 7.62(1H, d), 7.67(1H, s), 7.83(1H, d), 7.88(1H, d) FAB Mass(M+H) : 523 Example 24 Synthesis of 3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-1-(4 phenoxy-benzyl)-imidazolidin-2,4-dione(Compound 24) WO 99/05117 PCT/KR98/00225 - 68 The title compound was prepared in a yield of 70% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphelnylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 4-phenoxy-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) a (ppm) 1.86(3H, s), 2.27(2H, min), 3.73-3.85(3H, min), 4.09(2H, t), 4.57(1H, d), 6.61(1H, s), 6.73(2H, t), 6.88(2H, d), 7.04(2H, min), 7.10(2H, min), 7.25-7.40(4H, min), 7.43-7.50(2H, min), 7.56-7.63(2H, min), 7.89(2H, t) FAB Mass(M+H) : 531 Example 25 Synthesis of 3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-1-(3 phenoxy-benzyl)-imidazolidin-2,4-dione(Compound 25) The title compound was prepared in a yield of 73% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 3-phenoxy-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) 8 (ppm) 1.86(3H, s), 2.27(2H, min), 3.73-3.85(3H, min), 4.09(2H, t), 4.57(1H, d), 6.60(1H, s), 6.72(2H, t), 6.88(2H, d), 7.00-7.12(4H, min), 7.25-7.40(4H, min), 7.43-7.50(2H, min), 7.57(1H, s), 7.60(1H, d), 7.89(2H, t) FAB Mass(M+H) : 531 WO 99/05117 PCT/KR98/00225 - 69 Example 26 Synthesis of 3-(3-imidazol-1-yl-propyl)-1-(4-methylsulfanyl-benzyl)-5 methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 26) The title compound was prepared in a yield of 85% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 4-methylsulfanyl-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) 8 (ppm) 1.86(3H, s), 2.27(2H, min), 3.73-3.85(3H, min), 4.09(2H, t), 4.57(1H, d), 6.88(2H, d), 6.99(2H, d), 7.04(1H, s), 7.08(1H, s), 7.29(1H, d), 7.34(1H, t), 7.45(1H, t), 7.51(1H, t), 7.58(1H, s), 7.62(1H, d), 7.86(1H, d), 7.90(1H, d) FAB Mass(M+H) :485 Example 27 Synthesis of 3-(3-imidazol-1-yl-propyl)-1-(4-methylsulfanylmethyl-benzyl) -5-methyl-5-naphthalen-1 -yl-imidazolidin-2,4-dione(Com pound 27) The title compound was prepared in a yield of 65% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 4-methylsulfanyhnlmethyl-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 'H NMR(CDC1 3 ) 8 (ppm) 1.86(3H, s), 2.27(2H, min), 3.55(2H, s), 3.73-3.85(3H, min), 4.09(2H, t), 4.57(1H, d), 6.88(2H, d), 6.99(2H, d), WO 99/05117 PCT/KR98/00225 - 70 7.04(1H, s), 7.08(1H, s), 7.29(1H, d), 7.34(1H, t), 7.45(1H, t), 7.51(1H, t), 7.58(1H, s), 7.62(1H, d), 7.86(1H, d), 7.90(1H, d) FAB Mass(M+H) :499 Example 28 Synthesis of 3-(3-imidazol-1-yl-propyl)-1-(4-methylsulfonyl-benzyl)-5 methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 28) The title compound was prepared in a yield of 70% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenyhnlmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 4-methylsulfonyl-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) 8 (ppm) 1.86(3H, s), 2.27(2H, m), 2.87(3H, s), 3.80(2H, t), 4.09(2H, t), 4.25(1H, d), 4.40(1H, d), 6.95(2H, d), 7.04(1H, s), 7.08(1H, s), 7.18(1H, d), 7.28(1H, t), 7.37-7.45(4H, m), 7.59(1H, s), 7.64(1H, d), 7.77(1H, d), 7.83(1H, d) FAB Mass(M+H) : 517 Example 29 Synthesis of 5-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1 -ylmethyl]-2-methylsulfanyl-benzonitrile(Com pou nd 29) The title compound was prepared in a yield of 50% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that WO 99/05117 PCT/KR98/00225 - 71 5-bromomethyl-2-methylsulfanyl-benzonitrile was used instead of ethyl bromoacetate in Example 1-2). IH NMR(CDCl 3 ) a~(ppm) 1.86(3H, s), 2.27(2H, min), 2.40(3H, s), 3.80(2H, t), 4.00(1H, d), 4.09(2H, t), 4.48(1H, d), 6.66(1H, d), 6.69(1H, d), 6.95(1H, dd), 7.04(1H, s), 7.05-7.12(2H, min), 7.25(1H, d), 7.40(1H, t), 7.49(1H, t), 7.59(1H, s), 7.64(1H, d), 7.78(1H, d), 7.87(1H, d) FAB Mass(M+H) : 510 Example 30 Synthesis of 5-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-ylmethyl]-2-methylsulfonyl-benzonitrile(Compou nd 30) The title compound was prepared in a yield of 72% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 5-bromomethyl-2-methylsulfonyl-benzonitrile was used instead of ethyl bromoacetate in Example 1-2). 1 H NMR(CDC1 3 ) ~ (ppm) 2.10(3H, s), 2.32(2H, m), 3.08(3H, s), 3.83(2H, m), 3.95(1H, d), 4.15(2H, t), 4.85(1H, d), 6.92(1H, s), 7.02-7.06(2H, min), 7.10-7.14(2H, min), 7.28(1H, t), 7.41(1H, t), 7.49(1H, d), 7.52(1H, d), 7.61(1H, s), 7.69(1H, d), 7.77(1H, d), 7.86(1H, d) FAB Mass(M+H) : 542 Example 31 Synthesis of 2-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4 -dioxo-imidazolidin-1-ylm ethyl]-benzonitrile(Com pound 31) WO 99/05117 PCT/KR98/00225 - 72 The title compound was prepared in a yield of 90% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 2-bromomethyl-benzonitrile was used instead of ethyl bromoacetate in Example 1-2). H NMR(CDCl 3 ) 8 (ppm) 1.86(3H, s), 2.30(2H, min), 3.80(2H, min), 4.09(2H, t), 4.43(1H, d), 4.73(1H, d), 6.89(1H, min), 6.95(1H, min), 7.03-7.10(4H, min), 7.22(1H, d), 7.30(1H, min), 7.36(1H, min), 7.43(1H, t), 7.59(1H, s), 7.67(1H, d), 7.70(2H, d) FAB Mass(M+H) :464 Example 32 Synthesis of 3-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4 -dioxo-imidazolidin-1-ylmethyl]-benzonitrile(Compound 32) The title compound was prepared in a yield of 80% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 3-bromomethyl-benzonitrile was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) a (ppm) 1.86(3H, s), 2.30(2H, min), 3.80(2H, t), 4.05-4.20(3H, min), 4.42(1H, d), 6.84(1H, s), 6.97(1H, t), 7.04(1H, s), 7.06-7.19(4H, m), 7.29(1H, min), 7.41(1H, t), 7.51(1H, t), 7.59(1H, s), 7.67(1H, d), 7.80(1H, d), 7.89(1H, d) FAB Mass(M+H) : 464 WO 99/05117 PCT/KR98/00225 - 73 Example 33 Synthesis of 4-[ 3
-(
3 -imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4 -dioxo-imidazolidin-1-ylm ethyl]-benzonitrile(Com pound 33) The title compound was prepared in a yield of 77% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenyhnlmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 4-bromomethyl-benzonitrile was used instead of ethyl bromoacetate in Example 1-2). 1 H NMR(CDCl 3 ) 8 (ppm) 2.10(3H, s), 2.32(2H, min), 3.08(3H, s), 3.83(2H, m), 3.95(1H, d), 4.15(2H, t), 4.85(1H, d), 6.92(1H, s), 7.02-7.06(2H, m), 7.10-7.14(2H, m), 7.28(1H, t), 7.41(1H, t), 7.49(1H, d), 7.52(1H, d), 7.61(1H, s), 7.69(1H, d), 7.77(1H, d), 7.86(1H, d) FAB Mass(M+H) : 542 Example 34 Synthesis of 1-( 4 -aminomethyl-benzyl)-3-(3-imidazol-1-yl-propyl)-5 methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 34) The title compound was prepared in a yield of 80% according to the same procedure as Example 1 except that 3-(imidazol-1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl -imidazol-4-yl)-propanol in Example 1-1) and that 4-[N-(t-butyloxy -carbonyl)-aminomethyl]-benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). IH NMR(CDCl 3 ) a (ppm) 1.88(3H, s), 2.29(2H, min), 2.80(3H, s), WO 99/05117 PCT/KR98/00225 - 74 3.58(2H, s), 3.79(2H, min), 3.91(1H, d), 4.09(2H, t), 4.44(1H, d), 6.86(2H, d), 6.98(2H, s), 7.06(2H, min), 7.25(1H, t), 7.33(1H, t), 7.44(1H, t), 7.48(1H, t), 7.57(1H, s), 7.60(1H, d), 7.83(1H, d), 7.88(1H, d) FAB Mass(M+H) : 468 Example 35 Synthesis of N- {2-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-ylmethyl]-benzyl}-methanesulfonamide(Compou nd 35) 35-1) Synthesis of 1-(2-aminomethyl-benzyl)-3-(3-imidazol-1-yl-propyl) -5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione The title compound was prepared in a yield of 83% according to the same procedure as Example 34 except that 2-[N-(t-butyloxycarbonyl) -aminomethyl]-benzylbromide was used instead of 4-[N-(t-butyloxy -carbonyl)-aminomethyl]-benzylbromide. 35-2) Synthesis of N-[2- {3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen -1-yl-2,4-dioxo-imidazolidin- 1 -ylmethyl } -benzyl]-methanesulfonamide 0.02 ml (0.24 mmol) of methansulfonyl chloride was added to 10 ml dichloromethane solution of 0.06 ml (0.4 mmol) of triethylamine and 0.10 g (0.2 mmol) of 1-( 2 -aminomethyl-benzyl)-3-(3-imidazol-1-yl-propyl) -5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione prepared in Example 35-1) at 0'C. After stirring for 1 hour at room temperature, it was washed with saturated potassium carbonate solution and saturated sodium chloride solution sequentially. After removal of dichloromethane, chromatography using a solvent mixture of methanol-dichloromethane (7:93) as the eluent was carried out to obtain 0.1 g (0.18 mmol, Yield: 87%) of the title compound.
WO 99/05117 PCT/KR98/00225 - 75 H NMR(CDCl 3 ) 3 (ppm) 1.76(3H, s), 2.29(2H, m), 2.78(3H, s), 3.79(2H, t), 4.04(1H, d), 4.10(2H, t), 4.16(2H, s), 4.67(1H, d), 6.55(1H, d), 6.95(1H, t), 7.04-7.18(4H, m), 7.25(1H, m), 7.40(1H, t), 7.44-7.55(2H, m), 7.60(2H, m), 7.85(1H, d), 7.90(1H, d) FAB Mass(M+H) : 546 Example 36 Synthesis of N-{3-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-ylmethyl]-benzyl}-methanesulfonamide(Compou nd 36) The title compound was prepared in a yield of 78% according to the same procedure as Example 35 except that 3-[N-(t-butyloxy -carbonyl)-aminomethyl]-benzylbromide was used instead of 4-[N-(t-butyloxycarbonyl)-aminomethyl]-benzylbromide. IH NMR(CDCl 3 ) 3 (ppm) 1.63(3H, s), 2.23-2.43(2H, m), 2.85(3H, s), 3.85-3.93(3H, m), 4.02-4.21(4H, m), 4.50(1H, d), 6.78(1H, d), 6.99(2H, d), 7.06(3H, m), 7.18(1H, m), 7.37(1H, m), 7.46(1H, t), 7.50(1H, t), 7.58(1H, d), 7.63(1H, s), 7.87(1H, d), 7.89(1H, d) FAB Mass(M+H) : 546 Example 37 Synthesis of N- {4-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-ylmethyl]-benzyl}-methanesulfonamide(Compou nd 37) The title compound was prepared in a yield of 83% according to the same procedure as Example 35-2) except that 1-(4-aminomethyl-benzyl)-3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen-1 WO 99/05117 PCT/KR98/00225 - 76 -yl-imidazolidin-2,4-dione prepared in Example 34 was used instead of 1-(2-aminomethyl-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1 -yl-imidazolidin-2,4-dione. 'H NMR(CDCl 3 ) 8 (ppm) 1.88(3H, s), 2.29(2H, min), 2.80(3H, s), 3.79(2H, min), 3.91(1H, d), 4.05-4.15(4H, min), 4.44(1H, d), 6.86(2H, d), 6.98(2H, s), 7.06(2H, min), 7.25(1H, t), 7.33(1H, t), 7.44(1H, t), 7.48(1H, t), 7.57(1H, s), 7.60(1H, d), 7.83(1H, d), 7.88(1H, d) FAB Mass(M+H) :546 Example 38 Synthesis of 4-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-ylmethyl]-benzoic acid methyl ester(Compound 38) The title compound was prepared in a yield of 71% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol prepared in Preparation 8 was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 4-bromomethyl-benzoic acid methyl ester was used instead of ethyl bromoacetate in Example 1-2). 'H NMR(CDC1 3 ) 8 (ppm) 1.80(3H, s), 2.28(2H, min), 2.72(2H, min), 3.79(3H, s), 3.95(1H, d), 4.08(2H, min), 4.48(1H, d), 6.94(2H, d), 7.03(1H, s), 7.10(1H, m), 7.25(1H, d), 7.35(1H, t), 7.45(2H, min), 7.60(1H, d), 7.65(1H, s), 7.68(2H, d), 7.82(1H, d), 7.88(1H, d) FAB Mass(M+H) : 497 Example 39 Synthesis of 4-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4 WO 99/05117 PCT/KR98/00225 - 77 -dioxo-imidazolidin-1-ylmethyl]-benzoic acid(Compound 39) The title compound was prepared in a yield of 93% according to the same procedure as Example 2 using 4-[3-(3-imidazol-1-yl-propyl) 5-methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-ylmethyl]-benzoic acid methyl ester prepared in Example 38. 'H NMR(CDCl 3 ) 8 (ppm) 483 Example 40 Synthesis of 3-(3-imidazol-1-yl-propyl)-1-[3-(morpholine-4-carbonyl) benzyl]-5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 40) The title compound was prepared in a yield of 90% from compound 38 according to the same procedure as Example 1-3) except that morpholine was used instead of methionine methyl ester. H NMR(CDCl 3 ) a (ppm) 1.89(3H, s), 2.38(2H, min), 3.20-3.88(10H, br), 4.13(1H, d), 4.45(1H, d), 6.92(2H, d), 7.30(2H, d), 7.33(1H, d), 7.35(3H, min), 7.41(1H, t), 7.50(1H, t), 7.65(1H, d), 7.82(1H, d), 7.88(1H, d), 9.30(1H, s) FAB Mass(M+H) : 552 Example 41 Synthesis of 4-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-ylmethyl]-N-(2-methoxy-ethyl)-benzamide(Comp ound 41) The title compound was prepared in a yield of 80% from compound 38 according to the same procedure as Example 1-3) except WO 99/05117 PCT/KR98/00225 - 78 that 2-methoxyethylamine was used instead of methionine methyl ester. 1 H NMR(CDCl 3 ) a (ppm) 1.85(3H, s), 2.35(2H, m), 3.40(3H, s), 3.61(4H, m), 3.80(2H, m), 4.01(1H, d), 4.35(2H, m), 4.52(1H, d), 6.40(1H, s), 6.93(2H, d), 7.21(1H, d), 7.30-7.53(7H, m), 7.62(1H, d), 7.84(1H, d), 7.89(1H, d), 8.92(1H, s) FAB Mass(M+H) :540 Example 42 Synthesis of 4-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4 -dioxo-imidazolidin-1-ylmethyl]-N-(2-methoxy-ethyl)-N-methyl-benzamide (Compound 42) The title compound was prepared in a yield of 90% from compound 39 according to the same procedure as Example 1-3) except that 2-methoxy-ethylmethylamine was used instead of methionine methyl ester. 1 H NMR(CDCl 3 ) 8~(ppm) 1.80(3H, s), 2.35(2H, m), 2.85(2H, s), 3.05(1H, s), 3.35(5H, m), 3.55-4.05(5H, m), 4.28(2H, m), 4.50(1H, m), 6.93(4H, d), 7.10(2H, m), 7.28(3H, m), 7.36(1H, t), 7.45(1H, m), 7.51(1H, t), 7.63(1H, d), 7.89(2H, m), 8.75(1H, s) FAB Mass(M+H) : 554 Example 43 Synthesis of 4- {4-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1l-yl 2,4-dioxo-imidazolidin-1-ylmethyl]-benzoyl}-piperazine-1 -carboxylic acid benzyl ester(Compound 43) The title compound was prepared in a yield of 70% from WO 99/05117 PCT/KR98/00225 - 79 compound 38 according to the same procedure as Example 1-3) except that piperazine 1-carboxylic acid benzyl ester was used instead of methionine methyl ester. 'H NMR(CDCl 3 ) 8 (ppm) 1.89(3H, s), 2.35(2H, min), 3.10-3.75(8H, br), 3.80(2H, min), 4.19(3H, min), 4.40(1H, d), 5.17(2H, s), 6.92(2H, d), 7.01(2H, d), 7.18(2H, d), 7.24(1H, d), 7.28-7.44(7H, min), 7.49(1H, t), 7.63(1H, d), 7.82(1H, d), 7.89(1H, d), 8.20(1H, s) FAB Mass(M+H) : 685 Example 44 Synthesis of 3-(3-imidazol-1-yl-propyl)-1-[3-(thiomorpholine-4-carbonyl) benzyl]-5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 44) The title compound was prepared in a yield of 86% from 3-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazoli din-1-ylmethyl]-benzoic acid methyl ester according to the same procedure as Example 1-3) except that thiomorpholine was used instead of methionine methyl ester. 1H NMR(CDCl 3 ) 8 (ppm) 1.82(3H, s), 2.35(2H, min), 2.55(4H, br), 3.45(2H, br), 3.80(5H, min), 4.26(2H, min), 4.54(1H, d), 7.00(2H, min), 7.09(2H, d), 7.25(3H, min), 7.63(1H, d), 7.89(2H, t), 8.51(1H, s) FAB Mass(M+H) : 568 Example 45 Synthesis of 4-{5-[3-(4-methyl-4-naphthalen-1 -yl-2,5-dioxo-imidazolidin 1-yl)-propyl]-imidazol-1-ylmethyl}benzonitrile(Compound 45) The title compound was prepared in a yield of 60% according to WO 99/05117 PCT/KR98/00225 - 80 the same procedure as Example 1-1) except that 4-[5-(3-hydroxy-propyl) imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl imidazol-4-yl)-propanol. 1H NMR(CDCl 3 ) (ppm) 1.95(2H, m), 1.98(3H, s), 2.36(2H, t), 3.63(2H, t), 5.00(2H, s), 6.87(1H, s), 6.94(2H, d), 7.39(2H, t), 7.45(3H, m), 7.53(1H, s), 7.63(1H, d), 7.83(1H, d), 7.88(1H, d), 7.90(1H, d) FAB Mass(M+H) :464 Example 46 Synthesis of 4- {5-[3-(3-methyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo imidazolidin-1-yl)-propyl]-imidazol-1-ylmethyl}-benzonitrile(Compound 46) The title compound was prepared in a yield of 75% according to the same procedure as Example 1-1) to 1-2) except that 4-[5-(3 hydroxy-propyl)-imidazol-1-yhnlmethyl]-benzonitrile was used instead of 3-(1-triphenyhnlmethyl-imidazol-4-yl)-propanol in Example 1-1) and that methyl iodide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDC1 3 ) ~ (ppm) 1.95(3H, s), 2.05(2H, t), 2.47(2H, t), 2.62(3H, s), 3.74(2H, m), 5.16(2H, dd), 7.03(1H, s), 7.06(2H, d), 7.23(1H, t), 7.35(1H, d), 7.43(1H, t), 7.47(1H, d), 7.52(1H, t), 7.66(1H, d), 7.90(2H, m), 8.24(1H, s) FAB Mass(M+H) :478 Example 47 Synthesis of 4- {5-[3-(3-ethyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo imidazolidin-1-yl)-propyl]-imidazol-1-ylm ethyl}benzonitrile(Compound 47) WO 99/05117 PCT/KR98/00225 - 81 The title compound was prepared in a yield of 78% according to the same procedure as Example 46 except that ethyl iodide was used instead of methyl iodide. 'H NMR(CDC13) a (ppm) 0.83(3H, t), 1.95(3H, s), 2.07(2H, t), 2.51(2H, t), 3.11(2H, min), 3.76(2H, min), 5.28(2H, dd), 7.13(3H, d), 7.20(1H, t), 7.32(1H, d), 7.42(1H, t), 7.47(2H, d), 7.53(1H, t), 7.70(1H, d), 7.90(1H, d), 7.92(1H, d), 9.04(1H, s) FAB Mass(M+H) :492 Example 48 Synthesis of 4-{5-[3-(3-propyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo im idazolidin-1-yl)-propyl]-im idazol-1-ylm ethyl}benzonitrile(Compound 48) The title compound was prepared in a yield of 62% according to the same procedure as Example 46 except that propyl iodide was used instead of methyl iodide. 1H NMR(CDCl 3 ) ( (ppm) 0.61(3H, t), 1.25(2H, min), 1.93(3H, s), 2.07(2H, t), 2.47(2H, t), 2.96(2H, min), 3.73(2H, min), 5.13(2H, dd), 7.00(1H, s), 7.04(2H, d), 7.22(1H, t), 7.32(1H, d), 7.41(1H, t), 7.68(1H, d), 7.90(2H, min), 7.99(1H, s) FAB Mass(M+H) : 506 Example 49 Synthesis of 4- {5-[3-(3-butyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo-imida zolidin-1-yl)-propyl]-imidazol-1-ylmethyl} benzonitrile(Compound 49) WO 99/05117 PCT/KR98/00225 - 82 The title compound was prepared in a yield of 61% according to the same procedure as Example 46 except that butyl iodide was used instead of methyl iodide. IH NMR(CDCl 3 ) ~ (ppm) 0.61(3H, t), 1.03(2H, min), 1.24(2H, min), 1.93(3H, s), 2.07(2H, min), 2.47(2H, t), 2.99(2H, min), 3.72(2H, min), 5.09(2H, dd), 7.00(1H, s), 7.03(2H, d), 7.22(1H, t), 7.32(1H, d), 7.42(1H, t), 7.48-7.53(3H, min), 7.68(1H, d), 7.83(1H, s), 7.88(1H, d), 7.91(1H, d) FAB Mass(M+H) : 520 Example 50 Synthesis of 4-(5-{3-[3-(2-methoxy-ethoxymethyl)-4-methyl-4-naphthalen 1-yl-2,5-dioxo-imidazolidin-1-yl]-propyl}-imidazol-1-ylmethyl)-benzonitrile (Compound 50) The title compound was prepared in a yield of 55% according to the same procedure as Example 46 except that 2-methoxy-ethoxymethyl bromide was used instead of methyl iodide. 'H NMR(CDCl 3 ) 8 (ppm) 2.15(3H, s), 2.31(2H, min), 3.30(4H, br), 3.41(1H, br), 3.56(1H, br), 3.70(1H, br), 3.76(2H, t), 4.16(3H, min), 4.98(1H, d), 7.09(1H, s), 7.13(1H, s), 7.28(1H, min), 7.40(1H, t), 7.45-7.60(2H, m), 7.80(1H, d), 7.85-8.0(3H, m) FAB Mass(M+H) :437 Example 51 Synthesis of (3-{3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl}-5-methyl -5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl)-acetic acid ethyl ester (Compound 51) WO 99/05117 PCT/KR98/00225 - 83 The title compound was prepared in a yield of 88% according to the same procedure as Example 1-1) to 1-2) except that 4-[5-(3 hydroxy-propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1). 1H NMR(CDCl 3 ) ~ (ppm) 1.88(3H, s), 2.12(2H, min), 2.54(2H, min), 3.80(2H, min), 4.10(1H, d), 4.39(1H, d), 5.20(2H, s), 6.88(1H, s), 6.96(1H, t), 7.03-7.22(7H, m), 7.36(1H, t), 7.48-7.57(3H, min), 7.66(1H, d), 7.80(1H, d), 7.89(1H, d), 8.11(1H, br) FAB Mass(M+H) : 579 Example 52 Synthesis of (3-{3-[ 3 -(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl}-5-methyl -5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl)-acetic acid lithium salt (Compound 52) The title compound was prepared in a yield of 81% according to the same procedure as Example 1-1) to 1-2) and Example 2 except that 4-[5-(3-hydroxy-propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1). FAB Mass(M+H) : 522 Example 53 Synthesis of 4-(5- {3-[3-benzyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo imidazolidin-1 -yl]-propyl}-imidazol-1-ylmethyl)-benzonitrile(Compound 53) The title compound was prepared in a yield of 81% according to the same procedure as Example 1-1) to 1-2) except that 4-[5-(3-hydroxy- WO 99/05117 PCT/KR98/00225 - 84 propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1 triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that benzyl bromide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) a (ppm) 1.68(3H, s), 2.09(2H, t), 2.50(2H, t), 3.76(3H, min), 4.75(1H, d), 5.23(2H, s), 6.90(2H, d), 7.06-7.22(8H, min), 7.38(1H, t), 7.45(3H, min), 7.59(1H, d), 7.85(1H, d), 7.90(1H, d), 8.46(1H, s) FAB Mass(M+H) :554 Example 54 Synthesis of 4-(5- {3-[3-(3-cyano-benzyl)-4-methyl-4-naphthalen-1l-yl-2,5 dioxo-imidazolidin-1-yl]-propyl}-imidazol-1-ylmethyl)-benzonitrile(Compo und 54) The title compound was prepared in a yield of 89% according to the same procedure as Example 1-1) to 1-2) except that 4-[5-(3 hydroxy-propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 3-bromomethylbenzonitrile was used instead of ethyl bromoacetate in Example 1-2). 1 H NMR(CDC1 3 ) 8(ppm) 1.88(3H, s), 2.12(2H, min), 2.54(2H, min), 3.80(2H, min), 4.10(1H, d), 4.39(1H, d), 5.20(2H, s), 6.88(1H, s), 6.96(1H, t), 7.03-7.22(7H, min), 7.36(1H, t), 7.48-7.57(3H, min), 7.66(1H, d), 7.80(1H, d), 7.90(1H, d), 8.11(1H, br) FAB Mass(M+H) : 579 Example 55 Synthesis of 4-{5-[3-(3-furan-2-ylmethyl-4-methyl-4-naphthalen-1-yl-2,5- WO 99/05117 PCT/KR98/00225 - 85 dioxo-imidazolidin-1-yl)-propyl]-imidazol-1-ylmethyl}-benzonitrile(Compo und 55) The title compound was prepared in a yield of 89% according to the same procedure as Example 1-1) to 1-2) except that 4-[5-(3 hydroxy-propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 2-bromomethylfuran was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) 8~(ppm) 1.78(3H, s), 2.07(2H, min), 2.48(2H, min), 3.76(3H, min), 4.58(1H, d), 5.16(2H, s), 5.84(1H, d), 6.08(1H, d), 7.03-7.22(6H, min), 7.32-7.52(5H, min), 7.65(1H, d), 7.90(2H, m), 8.23(1H, s) FAB Mass(M+H) : 544 Example 56 Synthesis of 4-(5- {3-[3-(furan-2-carbonyl)-4-methyl-4-naphthalen-1-yl 2,5-dioxo-imidazolidin-1-yl]-propyl}-imidazol-1-ylmethyl)-benzonitrile (Compound 56) The title compound was prepared in a yield of 89% according to the same procedure as Example 1-1) to 1-2) except that 4-[5-(3 hydroxy-propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 2-furoyl chloride was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) a~(ppm) 1.32(3H, t), 1.89(3H, s), 2.07(2H, min), 2.51(2H, min), 3.76(2H, min), 4.06(1H, d), 4.26(2H, q), 4.43(1H, d), WO 99/05117 PCT/KR98/00225 - 86 5.96(1H, d), 6.73(1H, d), 7.10-7.22(5H, min), 7.38(1H, t), 7.50(3H, min), 7.67(1H, d), 7.84(1H, d), 7.88(1H, d), 8.80(1H, s) FAB Mass(M+H) : 616 Example 57 Synthesis of 2-[2-(3- {3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl}-5 methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl)-acetylamino]-4-met hylsulfanyl-butyric acid methyl ester(Compound 57) The title compound was prepared in a yield of 60% according to the same procedure as Example 1-1) to 1-3) except that 4-[5-(3 hydroxy-propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1). FAB Mass(M+H) : 667 Example 58 Synthesis of 2-[2-(3-{3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl}-5 methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl)-acetylamino]-4-met hylsulfanyl-butyric acid lithium salt (Compound 58) The same procedure as Example 1-1) to 1-3) was carried out except that 4-[5-(3-hydroxy-propyl)-imidazol-1-ylmethyl]-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1), and then the resulting product was treated according to the same procedure as Example 2 to obtain the title compound in a yield of 70%. FAB Mass(M+H) : 652 Example 59 WO 99/05117 PCT/KR98/00225 - 87 Synthesis of 4-[5-(4-methyl-4-naphthalen-1-yl-2,5-dioxo-imidazolidin-1 -yl methyl)-imidazol-1-ylmethyl]-benzonitrile(Com pound 59) The title compound was prepared in a yield of 70% according to the same procedure as Example 1-1) except that 4-(5-hydroxymethyl imidazol-1-ylmethyl)-benzonitrile prepared in Preparation 7 was used instead of 3-(1-triphenyhnlmethyl-imidazol-4-yl)-propanol in Example 1-1). H NMR(CDCl 3 ) 8 (ppm) 1.93(3H, s), 4.54(2H, dd), 5.33(2H1, dd), 7.00(3H, min), 7.25(2H, min), 7.40-7.55(6H, min), 7.83(2H, m) FAB Mass(M+H) : 434 Example 60 Synthesis of 4-[5-(3-methyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo-imida zolidin-1-ylmethyl)-imidazol-1 -ylmethyl]-benzonitrile(Com pound 60) The title compound was prepared in a yield of 62% according to the same procedure as Example 1-1) to 1-2) except that 4-(5-hydroxy methyl-imidazol-1-ylmethyl)-benzonitrile was used instead of 3-(1 triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that methyl iodide was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) 8 (ppm) 1.92(3H, s), 2.58(3H, s), 4.65(2H, dd), 5.44(2H, dd), 6.97(1H, d), 7.09(3H, min), 7.39(1H, s), 7.42(1H, d), 7.48(1H, t), 7.56(3H, min), 7.64(1H, d), 7.87(2H, m) FAB Mass(M+H) :450 Example 61 Synthesis of 4-[5-(3-ethyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo-imida zolidin-1-ylmethyl)-imidazol-1 -ylmethyl]-benzonitrile(Compound 61) WO 99/05117 PCT/KR98/00225 - 88 The title compound was prepared in a yield of 72% according to the same procedure as Example 1-1) to 1-2) except that 4-(5 hydroxymethyl-imidazol-1-ylmethyl)-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that ethyl iodide was used instead of ethyl bromoacetate in Example 1-2). 1 H NMR(CDCl 3 ) ~ (ppm) 0.76(3H, t), 1.92(3H, s), 3.06(2H, q), 4.63(2H, dd), 5.46(2H, dd), 6.93(1H, d), 7.09(3H, m), 7.39(2H, d), 7.46(1H, t), 7.54(3H, m), 7.64(1H, d), 7.85(2H, m) FAB Mass(M+H) : 464 Example 62 Synthesis of {3-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-5-methyl 5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl)-acetic acid ethyl ester (Compound 62) The title compound was prepared in a yield of 77% according to the same procedure as Example 1-1) to 1-2) except that 4-(5 hydroxymethyl-imidazol-1-ylmethyl)-benzonitrile was used instead of 3-(1-triphenyhnlmethyl-imidazol-4-yl)-propanol in Example 1-1). 1H NMR(CDCl 3 ) 8 (ppm) 1.14(3H, t), 1.62(2H, s), 1.98(3H, s), 4.04(2H, m), 4.70(2H, dd), 5.46(2H, dd), 6.93(1H, d), 7.07(1H, t), 7.12(2H, d), 7.41(2H, m), 7.48(1H, t), 7.55(1H, s), 7.58(2H, d), 7.65(1H, d), 7.85(1H, d), 7.89(1H, d) FAB Mass(M+H) : 522 Example 63 Synthesis of 4
-{
5
-[
3 -(3-cyanobenzyl)-4-methyl-4-naphthalen-1-yl-2,5- WO 99/05117 PCT/KR98/00225 - 89 dioxo-imidazolidin-1-ylm ethyl]-imidazol-1-ylmethyl}-benzonitrile(Compou nd 63) The title compound was prepared in a yield of 74% according to the same procedure as Example 1-1) to 1-2) except that 4-(5 hydroxymethyl-imidazol-1-ylmethyl)-benzonitrile was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 3-bromomethylbenzonitrile was used instead of ethyl bromoacetate in Example 1-2). 1 H NMR(CDCl 3 ) a (ppm) 1.90(3H, s), 4.25(2H, dd), 4.72(2H, dd), 5.55(2H, dd), 6.68(1H, d), 6.80(1H, s), 6.90-7.35(6H, min), 7.40-7.90(8H, min), 8.10(1H, s) FAB Mass(M+H) : 551 Example 64 Synthesis of 3-(3-imidazol-1 -yl-propyl)-1 -(4-methoxy-benzoyl)-5-methyl 5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 64) The title compound was prepared in a yield of 80% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol was used instead of 3-(1-triphenylmethyl-imidazol-4-yl) propanol in Example 1-1) and that 4-methoxy-benzoyl chloride was used instead of ethyl bromoacetate in Example 1-2). 'H NMR(CDCl 3 ) ~ (ppm) 2.30(2H, min), 2.48(3H, s), 3.71-3.90(5H, min), 4.13(2H, t), 6.81(2H, d), 7.03(1H, s), 7.12(1H, s), 7.44-7.57(5H, min), 7.63(1H, d), 7.79(1H, s), 7.88(2H, t), 7.94(1H, d) FAB Mass(M+H) :483 WO 99/05117 PCT/KR98/00225 - 90 Example 65 Synthesis of 3-( 3 -imidazol-1-yl-propyl)-5-methyl-1-(morpholine-4-carbon yl)-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 65) The title compound was prepared in a yield of 61% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol was used instead of 3-(1-triphenylmethyl-imidazol-4 yl)-propanol in Example 1-1) and that morpholine-4-carbonyl chloride was used instead of ethyl bromoacetate in Example 1-2). 'H NMR(CDCl 3 ) 8~(ppm) 2.30(2H, p), 2.44(3H, s), 3.07(4H, br), 3.26(2H, br), 3.36(2H, br), 3.80(2H, m), 4.15(2H, t), 7.08(1H, s), 7.15(1H, s), 7.31(1H, d), 7.39(1H, t), 7.47(1H, t), 7.54(1H, t), 7.86(2H, m), 7.94(2H, d) FAB Mass(M+H) : 462 Example 66 Synthesis of 3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4 dioxo-imidazolidin-1-carboxylic acid (3-cyano-phenyl)-amide(Compound 66) The title compound was prepared in a yield of 58% according to the same procedure as Example 1-1) to 1-2) except that 3-(imidazol 1-yl)-propanol was used instead of 3-(1-triphenylmethyl-imidazol-4 yl)-propanol in Example 1-1) and that 3-isocyanatobenzonitrile was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) 8 (ppm) 2.35(5H, min), 3.84(2H, br), 4.20(2H, t), 7.10(1H, s), 7.20(1H, s), 7.32(3H, min), 7.40-7.55(3H, min), 7.60(1H, t), 7.81(1H, s), 7.84-7.98(3H, min), 8.29(1H, s), 10.21(1H, s) WO 99/05117 PCT/KR98/00225 - 91 FAB Mass(M+H) :493 Example 67 Synthesis of N-(4-cyano-tetrahydropyran-4-yl)-2-13-(3-imidazol-1l-yl p ropyl)-5-methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl]-acetamid e(Compound 67) The title compound was prepared in a yield of 67% according to the same procedure as Example 1-1) to 1-3) except that 3-(imidazol 1-yl)-propanol was used instead of 3-(1-triphenylmethyl-imidazol-4 yl)-propanol in Example 1-1) and that 4-amino-tetrahydropyran-4 carbonitrile was used instead of methionine methyl ester in Example 1-3). 1 H NMR(CDCl 3 ) ~ (ppm) 1.57(2H, min), 1.92-2.10(5H, min), 2.30(2H, min), 3.49-3.62(3H, m), 3.67-3.76(4H, min), 4.13(1H, d), 4.21(2H, t), 7.14(1H, s), 7.22(1H, s), 7.36(1H, d), 7.43(1H, m), 7.46(1H, t), 7.51(1H, t), 7.72(1H, d), 7.90(1H, t), 7.98(1H, br), 8.30(1H, s) FAB Mass(M+H) : 515 Example 68 Synthesis of 3-{3-[3-(4-bromo-benzyl)-3H-imidazol-4-yl]-propyl}-5-meth yl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 68) The title compound was prepared in a yield of 78% according to the same procedure as Example 1-1) except that 3-[3-(4-bromo benzyl)-3H-imidazol-4-yl]-propanol was used instead of 3-(1-triphenyl methyl-imidazol-4-yl)-propanol. H NMR(CDCl 3 ) 8 (ppm) 1.86(2H, min), 1.93(3H, s), 2.28(2H, min), WO 99/05117 PCT/KR98/00225 - 92 3.54(2H, t), 4.73(2H, s), 6.67(2H, d), 6.70(1H, s), 7.20-7.36(6H, min), 7.56(1H, d), 7.71(1H, d), 7.75(1H, d), 7.90(1H, d), 8.46(1H, s) FAB Mass(M+H) : 517 Example 69 Synthesis of 3-{3-[3-(4-bromo-benzyl)-3H-imidazol-4-yl]-propyl}-1,5-di methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione(Compound 69) The title compound was prepared in a yield of 70% according to the same procedure as Example 1-1) to 1-2) except that [3-(4-bromo benzyl)-3H-imidazol-4-yl]-propanol was used instead of 3-(1-triphenyl methyl-imidazol-4-yl)-propanol in Example 1-1) and that methyl iodide was used instead of ethyl bromoacetate in Example 1-2). 'H NMR(CDCl 3 ) 3 (ppm) 1.89(3H, s), 2.05(2H, min), 2.47(2H, min), 2.61(3H, s), 3.73(2H, t), 4.97(2H, min), 6.83(2H, d), 6.95(1H, s), 7.28(1H, d), 7.38(2H, d), 7.43(1H, t), 7.49(1H, t), 7.65(1H, d), 7.70(1H, s), 7.88(2H, t), 8.00(1H, s) FAB Mass(M+H) : 531 Example 70 Synthesis of (3- {3-[3-(4-bromo-benzyl)-3H-imidazol-4-yl]-propyl}-5 methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1-yl)-acetic acid ethyl ester(Compound 70) The title compound was prepared in a yield of 60% according to the same procedure as Example 1-1) to 1-2) except that [3-(4-bromo benzyl)-3H-imidazol-4-yl]-propanol was used instead of 3-(1-triphenyl methyl-imidazol-4-yl)-propanol in Example 1-1).
WO 99/05117 PCT/KR98/00225 - 93 H NMR(CDCl 3 ) a (ppm) 1.24(3H, t), 1.95-2.15(5H, min), 2.51(2H, min), 3.68(2H, t), 4.11(4H, min), 5.23(2H, s), 6.43(1H, s), 6.98(2H, d), 7.38-7.55(5H, min), 7.65(1H, d), 7.86(1H, d), 7.91(2H, min), 9.25(1H, s) FAB Mass(M+H) : 603 Example 71 Synthesis of 3-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-phenyl-2,4-dioxo imidazolidin-1-ylmethyl]-benzonitrile(Compound 71) The title compound was prepared in a yield of 53% according to the same procedure as Preparation 1 and Example 1-1) to 1-2) except that acetophenone was used intead of acetonaphthone in Preparation 1 and 3-(imidazol-1-yl)-propanol was used instead of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol in Example 1-1) and that 3-bromomethylbenzonitrile was used instead of ethyl bromoacetate in Example 1-2). 1H NMR(CDCl 3 ) a (ppm) 1.67(3H, s), 2.20(2H, min), 3.67(2H, t), 4.00(2H, t), 4.05(1H, d), 4.78(1H, d), 6.98(1H, s), 7.06(1H, s), 7.18(2H, min), 7.39(5H, min), 7.46(1H, d), 7.53(2H, m) FAB Mass(M+H) :414 Example 72 Synthesis of 4-[5-(3-naphthalen-1-yl-2,5-dioxo-imidazolidin-1-ylmethyl) imidazol-1-ylmethyl]-benzonitrile(Compound 72) 0.053g(0.24 mmol) of the compound prepared in Preparation 2, 0.051g(0.24 mmol) of the compound prepared in Preparation 7 and 0.079g(0.30 mmol) of triphenylphosphine were dissolved in 10my of tetrahydrofuran and 0.0 4 7 m(0.
3 0 mmol) of diethylazodicarboxylate was WO 99/05117 PCT/KR98/00225 - 94 added thereto. The solution was stirred for 24 hours and tetrahydrofuran was removed under reduced pressure. Column chromatography was performed on the residue using a solvent mixture of methanol and dichloromethanol(3:97) as an eluent to obtain 0.081g of the title compound(Yield 80%, MW 421.5). 1H NMR(CDCl 3 ) 6 (ppm) 4.31(2H, s), 4.64(2H, s), 5.57(1H, s), 7.22(2H, d), 7.39(2H, min), 7.47(1H, t), 7.54(2H, min), 7.61(2H, d), 7.66(2H, min), 7.87-7.93(2H, m) FAB Mass (M+H): 422 Example 73 Synthesis of 3-[3-(4-chloro-benzyl)-3H-imidazol-4-ylmethyl]-1-naphthal en-1-yl-imidazolidin-2,4-dione(Compound 73) 73-1) Synthesis of 1-(4-chlorobenzyl)-5-hydroxymethyl-imidazole The title compound was prepared according to the same procedure as Preparation 6 except that 4-chlorobenzylamine was used instead of 4-bromobenzylamine in 54% yield. IH NMR(CDCl 3 ) 8~(ppm) 2.78(1H, br), 4.49(2H, s), 5.20(2H, s), 6.93(1H, s), 7.07(2H, d), 7.32(2H, d), 7.45(1H, s) FAB Mass (M+H): 223 73-2) Synthesis of 3-[3-(4-chloro-benzyl)-3H-imidazol-4-ylmethyl]-1 naphthalen-1-yl-imidazolidin-2,4-dione 0.07g(Yield 85%, MW 430.9) of the title compound was prepared using 0.046g(0.21 mmol) of the compound prepared in Example 73-1) and 0.043g(0.19 mmol) of the compound prepared in Preparation 2 according to the same procedure as Example 72.
WO 99/05117 PCT/KR98/00225 - 95 H NMR(CDC1 3 ) a (ppm) 4.16(2H, s), 4.62(2H, s), 5.31(2H, s), 7.22(2H, d), 7.39(2H, m), 7.47(1H, t), 7.54(2H, m), 7.61(2H, d), 7.66(2H, m), 7.87-7.93(2H, m) FAB Mass (M+H): 431 Example 74 Synthesis of 4-[5-(3-naphthalen-1-yl-2,5-dioxo-imidazolidin-1-ylmethyl) imidazol-1-ylmethyl]-piperidine-1-carboxylic acid benzyl ester (Compound 74) 0.07g(Yield 81%, MW 537.6) of the title compound was prepared using 0.090g(0.23 mmol) of the compound prepared in Preparation 5 and 0.035g(0.16 mmol) of the compound prepared in Preparation 2 according to the same procedure as Example 72. 1H NMR(CDC1 3 ) 8 (ppm) 1.30(2H, br), 1.62(2H, br), 1.92(1H, m), 2.72(2H, br), 4.05-4.29(4H, br), 4.40(1H, s), 4.80(1H, s), 5.09(1H, s), 7.28-7.38(6H, m), 7.45-7.59(4H, m), 7.72(1H, m), 7.84-7.96(3H, m) FAB Mass (M+H): 538 Example 75 Synthesis of 4-[5-(3-naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-1-yl m ethyl)-imidazol-1-ylmethyl]-benzonitrile(Com pound 75) 75-1) Synthesis of (naphthalen-1-ylmethyl-amino)-acetic acid ethyl ester The title compound was prepared according to the same procedure as Preparation 2-1), except that 1-naphthyl methyl amine was used instead of 1-naphthylamine in 90% yield.
WO 99/05117 PCT/KR98/00225 - 96 1H NMR(CDCl 3 ) a (ppm) 1.29(3H, t), 1.98(1H, br), 3.51(2H, s), 4.22(2H, q), 4.26(2H, s), 7.43(1H, t), 7.46-7.52(2H, m), 7.55(1H, m), 7.78(1H, d), 7.86(1H, d), 8.23(1H, d) FAB Mass (M+H): 244 75-2) Synthesis of 1-(naphthalen-1-ylmethyl)-imidazolidin-2,4-dione The title compound was prepared using the compound prepared in Example 75-1), according to the same procedure as Preparation 2-2) in 92% yield. IH NMR(CDCl 3 ) a (ppm) 3.57(2H, s), 4.91(2H, s), 7.33(1H, d), 7.38(1H, t), 7.45-7.54(2H, m), 7.79(1H, d), 7.83(1H, d), 8.05(1H, d) FAB Mass (M+H): 241 75-3) Synthesis of 4-[5-(3-naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-1 ylmethyl)-imidazol- 1 -ylmethyl]-benzonitrile 0.077g of the title compound was prepared using 0.050g(0.21 mmol) of the compound prepared in Example 75-2) and 0.047g(0.22 mmol) of the compound prepared in Preparation 7 according to the same procedure as Example 72(Yield 84%, MW 435). 1H NMR(CDCl 3 ) 8 (ppm) 3.34(2H, s), 4.51(2H, s), 4.89(2H, s), 5.41(2H, s), 7.02(2H, d), 7.27(1H, s), 7.32(1H, d), 7.43(3H, m), 7.48(1H, s), 7.54 (2H, m), 7.89(2H, m), 8.05(1H, d) FAB Mass (M+H): 436 Example 76 Synthesis of 4-[5-(3-naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-1-yl methyl)-imidazol-1-ylmethyl]-piperidine-1-carboxylic acid benzyl ester (Compound 76) WO 99/05117 PCT/KR98/00225 - 97 0.10g of the title compound was prepared using 0.050g(0.21 mmol) of the compound prepared in Example 75-2) and 0.072g(0.22 mmol) of the compound prepared in Preparation 5 according to the same procedure as Example 72(Yield 87%, MW 551). IH NMR(CDCl 3 ) a (ppm) 1.24(2H, br), 1.75(3H, br), 2.71(2H, s), 3.57(2H, s), 3.99(2H, s), 4.22(1H, br), 4.64(2H, s), 4.99(2H, s), 5.12(2H, s), 7.17 (1H, s), 7.34-7.39(7H, min), 7.44(1H, t), 7.54(2H, min), 7.87(2H, min), 8.07(1H, d) FAB Mass (M+H): 552 Example 77 Synthesis of {1-[3-(4-cyano-benzyl)-3H-imidazo-4-ylmethyl]-3-naphthal en-1-ylmethyl-2,5-dioxo-imidazolidin-4-yl}-acetic acid ethyl ester (Compound 77) 1.58g(Yield 90%, MW 521) of the title compound was prepared using 1.10g(3.37 mmol) of the compound prepared in Preparation 3 and 0.86g(4.06 mmol) of the compound prepared in Preparation 7 according to the same procedure as Example 72. 1H NMR(CDCl 3 ) a (ppm) 1.01(3H, t), 2.61(2H, min), 3.59(1H, min), 3.67(1H, min), 3.80(1H, m), 4.55(2H, dd), 4.76(1H, d), 5.13(1H, d), 5.42(2H, dd), 7.11 (2H, d), 7.30(1H, s), 7.34(1H, d), 7.41(1H, min), 7.49-7.54(5H, min), 7.87(2H, min), 8.03(1H, m) FAB Mass (M+H): 552 Example 78 Synthesis of {1-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-naphth alen-1-ylmethyl-2,5-dioxo-imidazolidin-4-yl}-acetic acid(Compound 78) WO 99/05117 PCT/KR98/00225 - 98 0.7g(1.34 mmol) of the compound prepared in Example 77 was dissolved in a solvent mixture of tetrahydrofuran, methanol and water(3:2:1). 0.12g (2.68 mmol) of lithium hydroxide monohydrate was added thereto and the solution was stirred for 1 hour. The solvents were removed under reduced pressure to obtain 0.66g of the title compound(Yield 95%, MW 516). FAB Mass (M+H): 517 Example 79 Synthesis of {1-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-naphtha len-1-ylmethyl-2,5-dioxo-imidazolidin-(4S)-yl}-acetic acid methyl ester (Compound 79) 0.364g(Yield 78%, MW 507) of the title compound was prepared using 0.287g(0.920 mmol) of the compound prepared in Preparation 4 and 0.215g(1.01 mmol) of the compound prepared in Preparation 7 according to the same procedure as Example 72. 1H NMR(CDCl 3 ) 3 (ppm) 2.46(1H, dd), 2.63(1H, dd), 3.19(3H, s), 3.60(1H, min), 4.52(2H, s), 4.90(2H, dd), 5.40(2H, dd), 7.09(2H, d), 7.25(1H, s), 7.30 (1H, d), 7.37(1H, t), 7.45-7.49(4H, min), 7.53(1H, s), 7.79-7.85(2H, min), 8.00 (1H, d) FAB Mass (M+H): 508 Example 80 Synthesis of 4-{5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3-naphthalen-1-yl m ethyl-2,5-dioxo-imidazolidin- 1 -ylmethyl]-imidazo 1-1-ylmethyl}-benzo n itr ile(Compound 80) WO 99/05117 PCT/KR98/00225 - 99 0.073g(0.14 mmol) of the compound prepared in Example 78, 0.018n, (0.21 mmol) of morpholine and 0.038g(0.28 mmol) of N-hydroxybenzotriazole were dissolved in 10rn of dimethylformamide. 0.04g (0.21 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added thereto. The solution was strirred for 2 hours and dimethylformamide was removed under reduced pressure. 20pg, of ethylacetate was added to the residue and the organic layer was washed with water and saturated sodium bicarbonate solution. Then, ethylacetate was removed under reduced pressure. Column chromatography was performed using a solvent mixture of methanol and dichloromethane(3:97) as an eluent to obtain 0.061g of the title compound(Yield 78%, MW 562). 1H NMR(CDCl 3 ) 3 (ppm) 2.36(2H, min), 2.55(1H, min), 2.71(1H, min), 2.86(1H, min), 3.14(1H, min), 3.29(1H, min), 3.88(1H, t), 4.62(3H, min), 5.25(1H, d), 5.46 (2H, dd), 7.13(2H, d), 7.30(1H, s), 7.32(1H, d), 7.40(1H, t), 7.50-7.57(5H, min), 7.87(2H, min), 8.07 (1H, inm) FAB Mass (M+H): 563 Example 81 Synthesis of 4- {(5S)-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3-naphthalen-1l-yl methyl-2,5-dioxo-imidazolidin-1-ylmethyl]-imidazol-1-ylmethyl}-benzonitr ile(Compound 81) The same procedure as Example 78 was carried out using 0.071g(0.14 mmol) of the compound prepared in Example 79 and the resulting product was treated according to the same procedure as Example 80 to obtain 0.059g of the title compound(Yield 75%, MW 562).
WO 99/05117 PCT/KR98/00225 - 100 H NMR(CDC1 3 ) a (ppm) 2.32(1H, dd), 2.43-2.55(2H, m), 2.70(1H, m), 2.79 (1H, m), 3.16(1H, m), 3.20-3.36(4H, m), 3.96(1H, t), 4.60-4.70(3H, m), 5.27 (1H, d), 5.58(2H, dd), 7.29(2H, d), 7.35(1H, d), 7.39(1H, d), 7.42(1H, s), 7.52-7.55(2H, m), 7.60(2H, d), 7.85(1H, d), 7.88(1H, m), 8.06(1H, m), 8.28 (1H, s) FAB Mass (M+H): 563 Example 82 Synthesis of 2-{1-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-naphth alen-1-ylmethyl-2,5-dioxo-imidazolidin-4-yl}-N-(2-(N,N-dimethylamino) ethyl)-acetamide(Compound 82) 0.060g(Yield 78%, MW 550) of the title compound was prepared using 0.073g(0.14 mmol) of the compound prepared in Example 78 and 0.016m(0.1 8 mmol) of 2-(N,N-dimethylamino)ethylaine according to the same procedure as Example 80. 'H NMR(CDC13) 8~(ppm) 2.34-2.60(2H, m), 2.91(1H, m), 3.05(1H, m), 3.20 (2H, m), 3.27(3H, s), 3.68(1H, t), 4.57(2H, dd), 4.90(1H, d), 5.03(1H, d), 5.26(1H, s), 5.44(2H, dd), 7.12(2H, d), 7.29(1H, s), 7.36(1H, d), 7.42(1H, t), 7.48-7.53(5H, m), 7.87(2H, m), 8.09(1H, m) FAB Mass (M+H): 551 Example 83 Synthesis of 2-{1-[3-(4-bromo-benzyl)-3H-imidazol-4-ylmethyl]-3-naphth alen-1-ylmethyl-2,5-dioxo-imidazolidin-4-yl}-N-(2-methoxy-ethyl)-N-methy l-acetamide(Compound 83) WO 99/05117 PCT/KR98/00225 - 101 83-1) Synthesis of 2-{ 1-[3-(4-bromo-benzyl)-3H-imidazol-4-ylmethyl]-3 naphthalen- 1-ylmethyl-2,5-dioxo-imidazolidin-4-yl}-acetic acid The title compound was prepared using the compounds prepared in Preparations 6 and 3 according to the same procedures as Examples 72 and 78 in 83% yield. FAB Mass (M+H): 547 83-2) Synthesis of 2-{ 1-[3-(4-bromo-benzyl)-3H-imidazol-4-ylmethyl]-3 naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-4-yl}-N-(2-methoxy-ethyl)-N-m ethyl-acetamide 0.045g(Yield 73%, MW 617) of the title compound was prepared using 0.055g(0.10 mmol) of the compound prepared in Example 83-1) and 0.011g(0.12 mmol) of N-methyl-2-methoxyethylamine according to the same procedure as Example 80. 1 H NMR(CDCl 3 ) (ppm) 2.36(1.5H, s), 2.44(1H, min), 2.58(1.5H, s), 2.65 (0.5H, dd), 2.80(0.5H, min), 2.89(1H, min), 3.00-3.14(1H, min), 3.16(1H, t), 3.21 (1.5H, s), 3.25(1.5H, min), 3.63(1H, min), 3.84(0.5H, t), 4.65(2H, d), 4.74(1H, dd), 5.09(1H, dd), 5.37(2H, s), 6.98(2H, t), 7.32-7.55(8H, min), 7.77-7.88(2H, min), 8.08(1H, m) FAB Mass (M+H): 618 Example 84 Synthesis of 4
-((
5
S)-{
4 -[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-3 naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-1-ylmethyl}-imidazol-1-ylm ethyl)-benzonitrile(Compound 84) The same procedure as Example 78 was carried out using 0.14g(0.28 mmol) of the compound prepared in Example 79 and the WO 99/05117 PCT/KR98/00225 - 102 resulting product was reacted with 0.044mg(0.40 mmol) of N-methyl-piperazine according to the same procedure as Example 80 to obtain 0.11g of the title compound(Yield 71%, MW 575.7). 1H NMR(CDCl 3 ) 8 (ppm) 2.15(2H, br), 2.22(3H, s), 2.39(2H, min), 2.73(1H, br), 2.84(1H, br), 2.97(1H, br), 3.28(1H, br), 3.87(1H, t), 4.58(2H, d), 4.68 (1H, d), 5.17(1H, d), 5.44(2H, dd), 7.12(2H, d), 7.27(1H, s), 7.31(1H, d), 7.39(1H, t), 7.48-7.56(5H, min), 7.83(1H, d), 7.87(1H, min), 8.05(1H, m) FAB Mass (M+H): 576 Example 85 Synthesis of (2S)-(2- {1-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3 naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-4-yl}-acetamino)-4-methyl sulfanyl-butyric acid methyl ester(Compound 85) 0.17g(Yield 84 %, MW 638) of the title compound was prepared using 0.16g(0.31 mmol) of the compound prepared in Example 78 and 0.066g(0.35 mmol) of (L)-methionine methyl . ester hydrochloride according to the same procedure as Example 80. H NMR(CDCl 3 ) 8 (ppm) 1.80(1H, min), 1.96(1H, min), 2.05(3H, d), 2.32(1H, min), 2.38(1H, t), 2.52(1H, min), 2.65(1H, min), 3.73(4H, min), 4.29-4.40(1H, min), 4.55(2H, dd), 4.74(1H, min), 5.24(1H, t), 5.44(2H, min), 6.04(1H, s), 7.11(2H, t), 7.27(1H, d), 7.37(1H, d), 7.42(1H, t), 7.47-7.53(5H, min), 7.87(2H, min), 8.06(1H, m) FAB Mass (M+H): 639 Example 86 Synthesis of (2S)-(2-{1-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3- WO 99/05117 PCT/KR98/00225 - 103 naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-4-yI}-acetamino)-4-methyl sulfanyl-butyric acid(Compound 86) The title compound was prepared using the compound prepared in Example 85 according to the same procedure as Example 78 in 95% yield. FAB Mass (M+H): 625 Example 87 Synthesis of 3-(3-imidazol-1-yl-propyl)-1-naphthalen-1-yl-imidazolidin 2,4-dione(Compound 87) 0.13g(Yield 91%, MW 334) of the title compound was prepared using 0.10g(0.44 mmol) of the compound prepared in Preparation 2 and 0.055g(0.44 mmol) of the compound prepared in Preparation 8 according to the same procedure as Example 72. 1H NMR(CDC1 3 ) a~(ppm) 2.18(2H, min), 3.66(2H, t), 3.99(2H, t), 4.31(2H, s), 6.95(1H, s), 7.02(1H, s), 7.17(1H, s), 7.42(1H, t), 7.50(2H, min), 7.65 (1H, d), 7.85(1H, d), 7.92(2H, m) FAB Mass (M+H): 335 As mentioned above, compounds according to the present invention have an inhibitory activity against farnesyl transferase. In order to determine such inhibitory activity of the compounds, following experiments were performed. Experimental Example 1 Analysis of Ras farnesyl transferase inhibiting activity WO 99/05117 PCT/KR98/00225 - 104 In the present experiment, Ras farnesyl transferase produced by genetic recombination techniques by the improved Pompliano's method(Pompliano et al.; Biochemistry, 1992, 31, 3800) was used, Ras substrate (Ras-CVLS) protein was used by purifying by the known method(Chung et al., Biochemicia et Biophysica Act, 1992, 278, 1129). The enzyme reaction was performed in 50 of 50mM Sodium HEPES buffer solution containing 25mmol of potassium chloride, 25mmol of magnesium chloride, 10mmol of DTT and 50 mol of zinc chloride. 1.5 p mol of Ras substrate protein, 0.15 / mol of tritium farnesylpyrophosphate and 4.5nmol of farnesyl transferase were used. More specifically, in the initial step, farnesyl transferase was added to the above buffer solution, reaction was maintained for 30 minutes at 37C 0 and then the reaction was stopped by adding l4 of ethanol solution containing IM HC1. The formed precipitates were adsorbed to GF/B filter using Hopper harvestor(Hopper # 225V) for filter-binding, washed with ethanol, and then radioactivity of the dried filter was measured using LKB p counter. Enzyme titer was measured in the unsaturated state of substrate where the concentrations of Ras substrate protein and farnesyl transferase have quantitative relationship. Enzyme inhibiting activity was measured using less than 5% of total reaction solution of the compound according to the present invention dissolved in dimethylsulfoxide(DMSO) solution as a reagent. Enzyme inhibiting activity was represented by percentage of the amount of the farnesyl incorporated with the reagent to that without the reagent. IC 50 of the reagent was defined as the concentration inhibiting the enzyme activity by 50%.
WO 99/05117 PCT/KR98/00225 - 105 To evaluate the selective enzyme inhibiting activity of the compound according to the present invention, inhibiting activity on geranylgeranyl transferase was measured. Geranylgeranyl transferase was purified from bovine brain with the method modified from Schber's method(Schber et al., J. Biol. Chem. 1990, 265, 14701), and substantially the same experiment as that of famrnesyl transferase was performed using geranylgeranyl pyrophosphate and Ras-CVIL substrate protein under the similar condition to farnesyl transferase reaction. Experimental Example 2 Analysis of intracellular Ras farnesyl transferase inhibiting activity In the present experiment, Rat2 cell line which expresses C-Harvey-Ras protein having transforming activity and Rat2 cell line(Korean patent application No. 97-14409) which is transformed with fused protein of H-Ras substituted with polybasic lysine domain at C-terminus of K-Ras were used. The experiment was performed by the modified Declue's method(Declue. J. E. et al., Cancer Research, 1991, 51, 712). Hereinafter, the experimental method will be described in more detail. 3 x 105 cells of transformed Rat2 fibroblast cell line were sprayed on 60mm cell cultivation dish and cultivated for 48 hours in a cell incubator at 37°C and after 50% or more of density was reached, it was treated with a reagent. The compound according to the present invention dissolved in dimethylsulfoxide(DMSO) was used as the reagent. 1% of dimethylsulfoxide was used in both control and experimental groups. After 4 hours from the treatment of the reagent, methionine labeled with 150 p Ci of radioactive isotope, 3 S per 1M of medium, was added and after cultivating for 20 hours, the cells were washed with WO 99/05117 PCT/KR98/00225 - 106 physiological saline water. The cells were lysed using lm of cool cell lysis buffer solution(50mM of Sodium Herpiss buffer solution containing 5mmol of magnesium chloride, immol of DTT, 1% NP 40, Immol of EDTA, Immol of PMSF, 2 / mol of leupeptin, 2 / mol of pepstatin A and 2 / 1 mol of antipain) and the supernatant was obtained by high-velocity centrifugation of 12,000g x 5 minutes. The amount of the labeled radioisotope of the supernatent was measured and standardized to obtain a quantitative result in immunoprecipitation reaction and then, Y13-259, monoclonal antiboby specifically binding to Ras protein(Furth, M. E. et al., J. Virol, 1982, 43, 294) was added and reacted for 15 hours at 4°C. Protein A bound to goat anti-murine Immunoglobulin antibody-agarose suspension was added to the solution and reacted for 1 hour at 4 C and then, to remove unspecific binding product, immunoprecipitates were washed with buffer solution(50mM Tris chloride buffer solution containing 50mmol of sodium chloride, 0.5% of sodium dioxycolate, 0.5% of NP 40 and 0.1% of SDS). The precipitates were boiled in reagent buffer solution for electrophoresis and then, electrophoresis was performed using 13.5% of SDS polyacrylamide gel. Afer electrophoresis, the gel was fixed and dried. Then, the gel was exposed to X-ray film, developed and printed. From the result of the experiment, intensities of band of protein with and without farnesyl of Ras protein were measured, and the concentration of reagent inhibiting 50% of farnesyl binding was defined as CICso, an intracellular Ras farnesyl transferase inhibiting activity. For the compound according to the present invention, from the results of the experiment according to the above Experimental Examples 1 and 2, IC 50 was 50 PM or less and CIC 5 0 was 100 PM or less. The results are shown in the below table 2a to 2d.
WO 99/05117 PCT/KR98/00225 - 107 Table 2a Ftase GGtase Compound No. IC 50 so (nM) CICso (1 M) IC 50 so (/ M) 1 500 1 >10 2 0.8 5 3.4 3 2500 5 >10 4 4.8 10 0.7 5 190000 10 >10 6 61 7.3 >10 7 180 <20 >10 8 14 <20 >10 9 15 >1 80 10 >50000 <20 >10 11 >50000 <20 >10 12 5500 <20 >10 13 1.5 <20 >10 14 1 <20 >10 15 2 <20 >10 16 2500 <20 >10 17 1500 <20 >10 18 600 <20 >10 19 240 <20 >10 20 300 <20 >10 21 150 <20 >10 22 1700 <20 >10 23 3000 <20 >10 WO 99/05117 PCT/KR98/00225 - 108 Table 2b Ftase GGtase Compound No. IC5o (nM) CIC 5 0 (y M) IC 50 (M M) 24 750 <20 >10 25 720 <20 >10 26 700 <20 >10 27 210 <20 >10 28 1100 <20 >10 29 80 <20 >10 30 725 <20 >10 31 900 <20 >10 32 92 <20 >10 33 1300 <20 >10 34 2100 <20 >10 35 500 <20 >10 36 1200 <20 >10 37 350 <20 >10 38 250 <20 >10 39 200 <20 >10 40 1400 <20 >10 41 530 <20 >10 42 1000 <20 >10 43 5000 <20 >10 44 8000 <20 >10 45 5500 <20 >10 46 55 <20 >10 WO 99/05117 PCT/KR98/00225 - 109 Table 2c Ftase GGtase Compound No. IC 50 so (nM) CIC 50 so ( M) IC 50 so (1- M) 47 18 <20 >10 48 40 <20 >10 49 55 <20 >10 50 55 <20 >10 51 19 <20 >10 52 19 <20 >10 53 65 <20 >10 54 50 <20 >10 55 45 <20 >10 56 80 <20 >10 57 16 400 >10 58 14 <20 >10 59 440 <20 >10 60 160 <20 >10 61 160 <20 >10 62 50 <20 >10 63 50 <20 >10 64 700 <20 >10 65 4500 <20 >10 66 200 <20 >10 67 3600 <20 >10 68 5000 <20 >10 69 300 <20 >10 WO 99/05117 PCT/KR98/00225 - 110 Table 2d Ftase GGtase Compound No. IC 50 (nM) CIC 5 0 (LL M) IC 5 0 (U M) 70 5000 <20 >10 71 7000 <20 >10 72 20 <10 >10 73 800 <50 >10 74 4000 >50 >10 75 30 <10 >10 76 5000 >50 >10 77 50 <10 >10 78 100 <20 >10 79 40 <10 >10 80 90 <10 >10 81 110 <20 >10 82 150 <20 >10 83 1500 >50 >10 84 120 <20 >10 85 200 <50 >10 86 50 <10 >10 87 5000 >50 >10 As can be seen from the above results((ICs5o < 50 M, CIC50so > 100 M), the novel hydantoin derivative according to the present invention effectively inhibits the activity of farnesyl transferase in transfering farnesyl group of Ras protein. Thus, the compound of formula (I) can be advantageously used as an anti-cancer agent.
Claims (4)
1. A hydantoin derivative represented by the following formula (I): [Formula I] 0 R 1 1ZVR2 R3" " 0 or pharmaceutically acceptable salt thereof in which R 1 and R 2 independently of one another represent hydrogen; lower alkyl; monocyclic or bicyclic aryl 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: 0 (wherein D represents alkoxy; hydroxy; amino acid residue; morpholine; thiomorpholine; piperazine, alkoxyalkylamine or aryloxyalkylamine each of which is substituted or unsubstituted by lower alkyl, and m is selected from 0 to 2), R3 represents amino acid residue; or a radical having the following formula, WO 99/05117 PCT/KR98/00225 - 112 A A >N B 7N.. c NN wherein A represents hydrogen; lower alkyl; aryl group which is substituted by substituents selected from a group consisting of halogen, cyano(CN), nitro(NO2), 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: -N-E (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=0, 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, R4 represents hydrogen; aromatic group substituted or unsubstituted by WO 99/05117 PCT/KR98/00225 - 113 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: O 0 R5 NH' NH R 7 0 R60 R6 0 NH R RR O R 9 X X wherein R5 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, R6 represents hydrogen; lower alkyl; lower alkyl which is substituted by substituents selected from a group consisting of halogen, cyano, hydroxy, COOR, amide, thioamide, SR and SO 2 R; lower alkyl substituted by an aryl group which is substituted by substituents selected from a group consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl; heterocyclic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring member; heterocyclic group which is substituted by substituents selected from a group WO 99/05117 PCT/KR98/00225 - 114 consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl and which contains hetero atoms selected from a group consisting of nitrogen and sulfur as ring member, wherein R represents lower alkyl, R 7 and Rs independently of one another represent hydrogen, halogen, halogenoalkyl, cyano, amide, thioamide, alkoxy or phenoxy, or represent a radical having the following formula, _0 n(IZ"'Rfo -C-N Z-Ro -N Z wherein Z represents CH 2 , CO, O, S, SO2, NR 9 , NHSO 2 or NHCOO, Rio represents hydrogen, lower alkyl, halogenoalkyl, alkoxy, hydroxy, benzyloxycarbonyl or benzyl, R9 represents hydrogen or lower alkyl, or lower alkyl substituted by aromatic group, X represents CH 2 , CO, O, S or SO 2 , and n denotes an integer of 0 to 4.
2. The compound of claim 1 wherein Ri represents hydrogen; monocyclic or bicyclic aryl group which can be substituted by lower alkyl or halogen; or a radical having the following formula: 0 4 D (wherein D represents alkoxy; hydroxy; amino acid residue; morpholine; thiomorpholine; piperazine or alkoxyalkylamine each of which is substituted or unsubstituted by lower alkyl, and m is selected from 0 to 1), R2 represents hydrogen; lower alkyl; or a radical having the WO 99/05117 PCT/KR98/00225 - 115 following formula: O (wherein D represents alkoxy; hydroxy; amino acid residue; morpholine; thiomorpholine; piperazine or alkoxyalkylamine each of which is substituted or unsubstituted by lower alkyl, and m is selected from 0 to 1), R 3 represents a radical having the following formula, A A B> B Y- N(1rIX N B wherein A represents hydrogen; aryl group which is substituted by substituents selected from a group consisting of halogen, cyano(CN), nitro(NO2), carboxy(COOH), amide, thioamide, SR and lower alkyl; or a radical having the following formula: -CN-E (in the definition for the substituent A, R represents hydrogen or lower alkyl, and E represents hydrogen or -F-G wherein F represents C=O, and G represents benzyloxy, lower alkoxy, or lower alkyl substituted or unsubstituted by phenyl), B and C independently of one another represent hydrogen, n denotes an integer of 1 to 3, R4 represents hydrogen; aromatic group substituted or unsubstituted by 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: WO 99/05117 PCT/KR98/00225 - 116 o o o O R R5 k,)NH'R6 -X OR RX, o i 0 R 8 0 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, R6 represents hydrogen; lower alkyl; lower alkyl which is substituted by substituents selected from a group consisting of halogen, cyano, hydroxy, COOR, amide, thioamide, SR and SO 2 R; lower alkyl substituted by an aryl group which is substituted by substituents selected from a group consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl; or heterocyclic group containing hetero atoms selected from a group consisting of nitrogen and sulfur as ring member; heterocyclic group which is substituted by substituents selected from a group consisting of halogen, cyano, COOR, amide, thioamide, SR, SO 2 R and lower alkyl and which contains hetero atoms selected from a group consisting of nitrogen and sulfur as ring member, wherein R represents lower alkyl, R 7 and R 8 independently of one another represent hydrogen, halogen, halogenoalkyl, cyano or phenoxy, or represent a radical having the following formula, WO 99/05117 PCT/KR98/00225 - 117 0 0 R _ nZ'Ro -N Z-Ro CN RoZ wherein Z represents O, S, SO 2 , NR 9 , NHSO 2 or NHCOO, Rio represents hydrogen, lower alkyl, halogenoalkyl, alkoxy, hydroxy or benzyloxycarbonyl, R9 represents hydrogen or lower alkyl, X represents O, S or SO 2 , and n denotes an integer of 1 to 3.
3. The compound of claim 2 which is selected from a group consisting of: 2-(2-{3-[3-(1H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo-i midazolidin-1l-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester, 2-(2-{3-[3-(1H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo-i midazolidin-1-yl } -acetylamino)-4-methylsulfanyl-butyric acid, 2-(2-{3-[2-(1H-imidazol-4-yl)-ethyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo-im idazolidin-1l-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester, 2-(2-{3-[2-(1H-imidazol-4-yl)-ethyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo-im idazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid, 2- { 2-[3-(3H-imidazol-4-yl-methyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imid azolidin-1-yl]-acetylamino}-4-methylsulfanyl-butyric acid methyl ester, 2- {2-[3-(3H-imidazol-4-yl-methyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imid azolidin-1-yl]-acetylamino }-4-methylsulfanyl-butyric acid, 2-(2-{3-[3-(4-cyano-benzyl)-imidazol-4-yl-methyl]-5-methyl-5-naphthalen-1-yl -2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester, 2-(2-{3-[3-(4-cyano-benzyl)-imidazol-4-yl-methyl]-5-methyl-5-naphthalen-1-yl -2,4-dioxo-imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid, 2-(2- { 3 -[3-(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-i WO 99/05117 PCTIKR98/00225 - 118 midazolidin- l-yl }-acetylamino)-3 -thiophen-2-yl-propionic acid, 3 -[3 -(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen- i-yl-i -(2-oxo-2-tbiazo lidin-3 -yl-ethyl)-imidazolidin-2,4-dione, 1- [2-(l 1 -dioxo-thiazolidin-3 -yl)-3 -(3 H-imidazol-4-yl)-propyl] -5 -methyl-5 -nap hthalen- 1 -yl-imidazolidin-2,4-dione, 3- [3-(3 H-imidazol-4-yl)-propyl] -5-methyl-i- {2-[2-(2-methylsulfanyl-ethyl)-thi azolidin-3 -yl]-2-oxo-ethyl }-5-naphthalen- 1-yl-iinidazolidin-2,4-dione, 2-(2-1{3 -[3 -(3H-imidazol-4-yl)-propyl]-5-methyl-5 -naplithalen- 1-yl-2,4-dioxo-i midazolidin- i-yl }-acetylamino)-4-methylsulfonyl-butyric acid, 2- {2-13 -(3 -imidazol- 1-yl-propyl)-5-methyl-5-naphthalen- 1-yl-2,4-dioxo-imidaz olidin- 1-yl]-acetylamnino }-4-methylsulfanyl-butyric acid, 2- {2-[3 -(2-imidazol- 1-yl-ethyl)-5-methyl-5-naphthalen- 1-yl-2,4-dioxo-imidazo lidn- 1 -yl]-acetylamino }-4-methylsulfanyl-butyric acid, 1 -benzyl-3 -(3 -imidazol- 1-yl-propyl)-5-methyl-5 -naplithalen- 1-yl-imidazolidin 2,4-dione, 1 -(pentafluoro-benzyl)-3 -(3 -imidazol- 1-yl-propyl)-5-methyl-5 -naphthalen- l-yl imidazolidin-2,4-dione, 1 -(3 -pyridylmethyl)-3 -(3 -imidazol- 1-yl-propyl)-5-methyl-5 -naphthalen- 1-yl-im idazolidin-2,4-dione, 1 -(3 -chloro-benzyl)-3 -(3 -inidazol- 1-yl-propyl)-5-methyl-5-naphthalen- 1-yl-imi dazolidin-2,4-dione, 1 -(3 -bromo-benzyl)-3 -(3 -imidazol- 1-yl-propyl)-5-methyl-5 -naphthalen- i-yl-im idazolidin-2,4-dione, 1 -(4-bromo-benzyl)-3 -(3 -imidazol- 1-yl-propyl)-5-methyl-5 -naphthalen- 1-yl-im idazolidin-2,4-dione, 1 -(3 -trifluoromethyl-benzyl)-3 -(3 -imidazol- 1-yl-propyl)-5-methyl-5-naphthalen -1I -yl-imidazoiidin-2,4-dione, 1 -(3 -trifluoromethoxy-benzyl)-3 -(3 -imidazol- 1 -yl-propyl)-5 -methyl-5 -naphthal en-i -yl-imidazolidin-2,4-dione, 3 -(3 -imidazol- 1-yl-propyi)-5-methyl-5-naphthalen- i-yl-i -(4-phenoxy-benzyi)-i WO 99/05117 PCT/KR98/00225 - 119 midazolidin-2,4-dione, 3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen- l-yl-l1-(3-phenoxy-benzyl)-i midazolidin-2,4-dione, 3-(3-imidazol- 1 -yl-propyl)- 1-(4-methylsulfanyl-benzyl)-5-methyl-5-naphthalen -1-yl-imidazolidin-2,4-dione, 3-(3-imidazol- 1 -yl-propyl)-5-methyl- 1-(4-methylsulfanylmethyl-benzyl)-5 -nap hthalen-1-yl-imidazolidin-2,4-dione, 3-(3-imidazol-1-yl-propyl)-5-methyl-l-(4-methylsulfonyl-benzyl)-5-naphthalen -1-yl-imidazolidin-2,4-dione,
5-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1-ylmethyl]-2-methylsulfanyl-benzonitrile, 5-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1-ylmethyl]-2-methylsulfonyl-benzonitrile, 2-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1-ylmethyl]-benzonitrile, 3 -[3 -(3 -imidazol- 1 -yl-propyl)-5 -methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1-ylmethyl]-benzonitrile, 4-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1 -ylmethyl]-benzonitrile, 1-(4-aminomethyl-benzyl)- 3 -(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen-1 -yl-imidazolidin-2,4-dione, N- {2-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4-dioxo-imida zolidin- 1-ylmethyl]-benzyl}-methanesulfonamide, N-{3-[3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4-dioxo-imida zolidin- 1 -ylmethyl]-benzyl}-methanesulfonamide, N- {4-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imida zolidin-1-ylmethyl]-benzyl}-methanesulfonamide, 4-[3 -(3 -imidazol- 1 -yl-propyl)-5 -methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1-ylmethyl]-benzoic acid methyl ester, 4-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4-dioxo-imidazoli WO 99/05117 PCT/KR98/00225 - 120 din- 1-ylmethyl]-benzoic acid, 3-(3-imidazol-1-yl-propyl)-1-[3-(morpholine-4-carbonyl)-benzyl]-5-methyl-5-n aphthalen- 1-yl-imidazolidin-2,4-dione, 4- [3 -(3 -imidazol- 1 -yl-propyl)-5 -methyl-5 -naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1-ylmethyl]-N-(2-methoxy-ethyl)-benzamide, 4-[3 -(3 -imidazol- 1 -yl-propyl)-5 -methyl-5 -naphthalen- 1 -yl-2,4-dioxo-imidazoli din- 1-ylmethyl]-N-(2-methoxy-ethyl)-N-methyl-benzamide, 4-{ 4-[3-(3-imidazol- 1-yl-propyl)-5-methyl-5-naphthalen- 1-yl-2,4-dioxo-imidaz olidin-1-ylmethyl]-benzoyl}-piperazine- 1-carboxylic acid benzyl ester, 3-(3-imidazol-1-yl-propyl)-1-[3-(thiomorpholine-4-carbonyl)-benzyl]-5-methyl -5-naphthalen- 1 -yl-imidazolidin-2,4-dione, 4-{5-[3-(4-methyl-4-naphthalen-1-yl-2,5-dioxo-imidazolidin-1-yl)-propyl]-imi dazol- 1-ylmethyl}benzonitrile, 4- { 5-[3-(3-methyl-4-methyl-4-naphthalen- 1 -yl-2,5-dioxo-imidazolidin- 1 -yl)-pr opyl]-imidazol-1-ylmethyl}-benzonitrile, 4- { 5-[3-(3-ethyl-4-methyl-4-naphthalen- 1 -yl-2,5-dioxo-imidazolidin- 1 -yl)-prop yl]-imidazol- 1-ylmethyl }benzonitrile, 4- { 5-[3-(3-propyl-4-methyl-4-naphthalen- 1 -yl-2,5-dioxo-imidazolidin- 1-yl)-pr opyl]-imidazol- 1 -ylmethyl }benzonitrile, 4- { 5-[3-(3-butyl-4-methyl-4-naphthalen- 1 -yl-2,5-dioxo-imidazolidin- 1-yl)-prop yl]-imidazol-1-ylmethyl }benzonitrile, 4-(5-{3-[3-(2-methoxy-ethoxymethyl)-4-methyl-4-naphthalen- l-yl-2,5-dioxo-i midazolidin-1-yl]-propyl}-imidazol-1-yhnlmethyl)-benzonitrile, (3-{3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl}-5-methyl-5-naphthalen-1 yl-2,4-dioxo-imidazolidin-1-yl)-acetic acid ethyl ester, (3- { 3 -[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl} -5-methyl-5-naphthalen- 1 yl-2,4-dioxo-imidazolidin-1-yl)-acetic acid, 4-(5-{3-[3-benzyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo-imidazolidin-l1-yl]-pr opyl}-imidazol- 1-ylmethyl)-benzonitrile, 4-(5- { 3 -[3 -(3 -cyano-benzyl)-4-methyl-4-naphthalen- 1 -yl-2,5 -dioxo-imidazolidi WO 99/05117 PCT/KR98/00225 - 121 n-1 -yl]-propyl}-imidazol- 1 -ylmethyl)-benzonitrile, 4- { 5-[3-(3-furan-2-ylmethyl-4-methyl-4-naphthalen- 1-yl-2,5-dioxo-imidazolidi n-1-yl)-propyl]-imidazol-1-ylmethyl }-benzonitrile, 4-(5- {3-[3-(furan-2-carbonyl)-4-methyl-4-naphthalen-1-yl-2,5-dioxo-imidazoli din- 1-yl]-propyl } -imidazol- 1 -ylmethyl)-benzonitrile, 2-[2-(3- {3-[3-(4-cyano-benzyl)-3H-imidazol-4-yl]-propyl}-5-methyl-5-naphtha len- 1-yl-2,4-dioxo-imidazolidin- 1-yl)-acetylamino]-4-methylsulfanyl-butyric acid methyl ester, 2-[2-(3- { 3-[3-(4-cyano-benzyl)-3H-imidazol-4-yl]-propyl } -5-methyl-5-naphtha len-1-yl-2,4-dioxo-imidazolidin-1-yl)-acetylamino]-4-methylsulfanyl-butyric acid, 4-[5-(4-methyl-4-naphthalen-1-yl-2,5-dioxo-imidazolidin-1-ylmethyl)-imidazol -1 -ylmethyl]-benzonitrile, 4-[5-(3-methyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo-imidazolidin-1-ylmethyl) -imidazol- 1-ylmethyl]-benzonitrile, 4-[5-(3-ethyl-4-methyl-4-naphthalen-1-yl-2,5-dioxo-imidazolidin-1-ylmethyl)-i midazol- 1-ylmethyl]-benzonitrile, {3-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-5-methyl-5-naphthalen-1-yl 2,4-dioxo-imidazolidin-1-yl)-acetic acid ethyl ester, 4- { 5 -[3-(3-cyanobenzyl)-4-methyl-4-naphthalen- 1 -yl-2,5-dioxo-imidazolidin- 1 -ylmethyl]-imidazol-1-ylmethyl}-benzonitrile, 3-(3-imidazol-1-yl-propyl)-1-(4-methoxy-benzoyl)-5-methyl-5-naphthalen-1-yl -imidazolidin-2,4-dione, 3-(3-imidazol-1-yl-propyl)-5-methyl-l1-(morpholine-4-carbonyl)-5-naphthalen 1-yl-imidazolidin-2,4-dione, 3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin e-l1-carboxylic acid (3-cyano-phenyl)-amide, N-(4-cyano-tetrahydropyran-4-yl)-2-[3-(3-imidazol- 1-yl-propyl)-5-methyl-5-na phthalen- 1-yl-2,4-dioxo-imidazolidin- 1-yl]-acetamide, 3-{3-[3-(4-bromo-benzyl)-3H-imidazol-4-yl]-propyl}-5-methyl-5-naphthalen-1 WO 99/05117 PCT/KR98/00225 - 122 -yl-imidazolidin-2,4-dione, 3-{3-[3-(4-bromo-benzyl)-3H-imidazol-4-yl]-propyl}-1,5-dimethyl-5-naphthale n-1-yl-imidazolidin-2,4-dione, (3- { 3-[3-(4-bromo-benzyl)-3H-imidazol-4-yl]-propyl } -5-methyl-5-naphthalen 1-yl-2,4-dioxo-imidazolidin-1-yl)-acetic acid ethyl ester, 3-[3-(3-imidazol- 1 -yl-propyl)-5-methyl-5-phenyl-2,4-dioxo-imidazolidin- 1 -ylm ethyl]-benzonitrile, 4-[5-(3-naphthalen-1-yl-2,5-dioxo-imidazolidin- 1 -ylmethyl)-imidazol- 1 -ylmeth yl]-benzonitrile, 3-[3-(4-chloro-benzyl)-3H-imidazol-4-ylmethyl]- 1 -naphthalen- 1 -yl-imidazolidi n-2,4-dione, 4-[5-(3-naphthalen-1-yl- 2 ,5-dioxo-imidazolidin- 1 -ylmethyl)-imidazol- 1 -yhnlmeth yl]-piperidine-1-carboxylic acid benzyl ester, 4-[5-(3-naphthalen-1-yhnlmethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-imidazol-1 ylmethyl]-benzonitrile, 4-[5-(3-naphthalen-1-ylmethyl-2,5-dioxo-imidazolidin-l1-ylmethyl)-imidazol-1 ylmethyl]-piperidine-1-carboxylic acid benzyl ester, { 1-[3-(4-cyano-benzyl)-3H-imidazol-4-yhnlmethyl]-3-naphthalen-1-ylmethyl-2,5 dioxo-imidazolidin-4-yl}-acetic acid ethyl ester, { 1-[3-(4-cyano-benzyl)-3H-imidazol-4-yhnlmethyl]-3-naphthalen-1-ylmethyl-2,5 dioxo-imidazolidin-4-yl }-acetic acid, { 1-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-naphthalen-1-ylmethyl-2,5 dioxo-imidazolidin-(4S)-yl}-acetic acid methyl ester, 4- { 5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3 -naphthalen- 1 -ylmethyl-2,5-dioxo-imn idazolidin- 1-yhnlmethyl]-imidazol- 1 -ylmethyl}-benzonitrile, 4-{(5S)-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3-naphthalen- 1 -ylmnethyl-2,5-dioxo imidazolidin- 1 -ylmethyl]-imidazol- 1 -ylmethyl} -benzonitrile, 2- { 1 -[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-naphthalen- 1-ylmethyl-2, 5-dioxo-imidazolidin-4-yl}-N-(2-(N,N-dimethylamino)-ethyl)-acetamide, 2-{ 1-[3-(4-bromo-benzyl)-3H-imidazol-4-ylmethyl]-3-naphthalen- 1-ylmethyl-2 ,5-dioxo-imidazolidin-4-yl}-N-(2-methoxy-ethyl)-N-methyl-acetamide, 4-((5S)-{4-[2-(4-methyl-piperazin- 1-yl)-2-oxo-ethyl]-3-naphthalen- 1-ylmethyl 2,5-dioxo-imidazolidin-1-ylmethyl}-imidazol-1-ylmethyl)-benzonitrile, WO 99/05117 PCT/KR98/00225 - 123 (2S)-(2- { 1-[3-(4-cyano-benzyl)-3 H-imidazol-4-ylmethyl]-3-naphthalen- 1 -ylmet hyl-2,5-dioxo-imidazolidin-4-yl }-acetylamino)-4-methylsulfanyl-butyric acid methyl ester, (2S)-(2- { 1 -[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-naphthalen- 1 -ylmet hyl-2,5-dioxo-imidazolidin-4-yl }-acetylamino)-4-methylsulfanyl-butyric acid, and 3-(3-imidazol- 1 -yl-propyl)- 1 -naphthalen-1-yl-imidazolidin-2,4-dione. 4. A process for preparing a hydantoin derivative of formula (I) as defined in claim 1 characterized in that 1) a compound represented by the following formula (II): [Formula II] O R 1 HNY N-R4 o wherein R 1 , R 2 and R4 are defined as claim 1, is reacted under Mitsunobu reaction condition with an alcohol derivative represented by the following formula (III): [Formula III] R 3 -OH wherein R 3 is defined as claim 1, or 2) a compound represented by the following formula (IIa): [Formula IIa] WO 99/05117 PCT/KR98/00225 - 124 O R 1 +R2 HN NH O wherein Ri and R 2 are defined as previously described, is reacted with the alcohol derivative of formula (III) under Mitsunobu reaction condition to produce a compound represented by the following formula (la): [Formula Ia] o RI R2 R3<N sNH 0 wherein R 1 , R 2 and R 3 are defined as previously described, then substituent R4' is introduced into the resulting compound of formula (Ia) to produce a compound represented by the following formula (Ib): [Formula Ib] o R 1 +R2 R 3 -- NN NR4 ' O 0 wherein R 1 , R 2 and R 3 are defined as previously described and R4' is the same as R 4 except that R4' is not hydrogen. 5. An anti-cancer composition comprising the compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1997/35333 | 1997-07-26 | ||
| KR1019970035333A KR19990012061A (en) | 1997-07-26 | 1997-07-26 | HYDENTOIN DERIVATIVES USEFUL AS PANESSyltransferase inhibitor |
| PCT/KR1998/000225 WO1999005117A1 (en) | 1997-07-26 | 1998-07-24 | Hydantoin derivatives having an inhibitory activity for farnesyl transferase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8464798A true AU8464798A (en) | 1999-02-16 |
| AU729341B2 AU729341B2 (en) | 2001-02-01 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU84647/98A Ceased AU729341B2 (en) | 1997-07-26 | 1998-07-24 | Hydantoin derivatives having an inhibitory activity for farnesyl transferase |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1000036A1 (en) |
| JP (1) | JP2001510829A (en) |
| KR (2) | KR19990012061A (en) |
| AR (1) | AR015412A1 (en) |
| AU (1) | AU729341B2 (en) |
| WO (1) | WO1999005117A1 (en) |
| ZA (1) | ZA986623B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1372551A (en) | 1999-09-06 | 2002-10-02 | 株式会社Lgci | Process for preparing 1-substituted 5-hydroxymethyl imidazole |
| WO2003018554A1 (en) | 2001-08-24 | 2003-03-06 | Wyeth Holdings Corporation | 3-substituted-3-(substitutedsulfonyl or sulfanyl)pyrrolidine-2,5-diones useful for inhibition of farnesyl-protein transferase |
| WO2003018011A1 (en) | 2001-08-24 | 2003-03-06 | Wyeth Holdings Corporation | 5-(substituted)-5-(substitutedsulfonyl or sulfanyl)thiazolidine-2,4-diones useful for inhibition of farnesyl-protein transferase |
| WO2003018135A1 (en) * | 2001-08-24 | 2003-03-06 | Wyeth Holdings Corporation | Method of using 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones for inhibition of farnesyl-protein transferase |
| CA2492210A1 (en) * | 2002-07-31 | 2004-02-05 | Euro-Celtique S.A. | Aryl substituted hydantoin compounds and their use as sodium channel blockers |
| AU2003298889A1 (en) * | 2002-12-04 | 2004-06-23 | Merck & Co., Inc. | Spirocyclic ureas, compositions containing such compounds and methods of use |
| TW200621766A (en) | 2004-09-17 | 2006-07-01 | Hoffmann La Roche | Substituted hydantoins |
| US7612212B2 (en) * | 2006-02-22 | 2009-11-03 | Hoffmann-La Roche Inc. | Substituted hydantoins |
| JP2010536723A (en) | 2007-08-16 | 2010-12-02 | エフ．ホフマン−ラ ロシュ アーゲー | Substituted hydantoin |
| CA2739011A1 (en) * | 2007-10-29 | 2009-05-07 | The Regents Of The University Of California | Osteoarthritis gene therapy |
| US8063085B2 (en) * | 2007-12-20 | 2011-11-22 | Hoffmann-La Roche Inc. | Substituted hydantoins |
| WO2014019092A1 (en) * | 2012-08-01 | 2014-02-06 | The Hospital For Sick Children | Inhibitors of peptidyl arginine deiminase (pad) enzymes and uses thereof |
| JP6227149B2 (en) * | 2013-12-31 | 2017-11-08 | イプセン ファルマ ソシエテ パール アクシオン サンプリフィエＩｐｓｅｎ Ｐｈａｒｍａ Ｓ．Ａ．Ｓ． | Novel imidazolidine-2,4-dione derivatives |
| KR101593205B1 (en) | 2015-06-12 | 2016-02-11 | 김윤태 | A grass window cleaning apparatus |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0219363A (en) * | 1988-07-06 | 1990-01-23 | Fujisawa Pharmaceut Co Ltd | Imidazolidine derivative |
| DE4009506A1 (en) * | 1990-03-24 | 1991-09-26 | Hoechst Ag | hydantoin |
| DE4126277A1 (en) * | 1991-08-08 | 1993-02-11 | Cassella Ag | HYDANTO DERIVATIVES |
| JPH0931060A (en) * | 1995-07-25 | 1997-02-04 | Nissan Chem Ind Ltd | Production of cyclic urea compound |
| JP3449084B2 (en) * | 1995-12-25 | 2003-09-22 | 富士レビオ株式会社 | Hydantoin derivatives |
-
1997
- 1997-07-26 KR KR1019970035333A patent/KR19990012061A/en unknown
-
1998
- 1998-07-22 KR KR1019980029459A patent/KR100384116B1/en not_active IP Right Cessation
- 1998-07-24 JP JP2000504116A patent/JP2001510829A/en active Pending
- 1998-07-24 EP EP98935376A patent/EP1000036A1/en not_active Withdrawn
- 1998-07-24 ZA ZA986623A patent/ZA986623B/en unknown
- 1998-07-24 WO PCT/KR1998/000225 patent/WO1999005117A1/en not_active Application Discontinuation
- 1998-07-24 AU AU84647/98A patent/AU729341B2/en not_active Ceased
- 1998-07-27 AR ARP980103683A patent/AR015412A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU729341B2 (en) | 2001-02-01 |
| WO1999005117A1 (en) | 1999-02-04 |
| KR19990014070A (en) | 1999-02-25 |
| EP1000036A1 (en) | 2000-05-17 |
| ZA986623B (en) | 1999-01-26 |
| AR015412A1 (en) | 2001-05-02 |
| KR100384116B1 (en) | 2003-08-30 |
| JP2001510829A (en) | 2001-08-07 |
| KR19990012061A (en) | 1999-02-25 |
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