KR100236472B1 - Tropane derivatives as farnesyl transferase inhibitors - Google Patents

Abstract

The present invention relates to a novel tropane derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, and a preparation method thereof.

[Formula 1]

(In Formula 1, R ₁ , R ₂ and R ₃ are as defined in the specification.)

The tropan derivatives and pharmaceutically acceptable salts thereof can be usefully used as anticancer agents because they act to inhibit farnesyl transferase.

Description

Tropan derivatives useful as panesyl transferase inhibitors

The present invention relates to tropan derivatives and their pharmaceutically acceptable salts, their preparation and their use as panesyl transferase inhibitors.

More specifically, the present invention relates to a tropan derivative, a pharmaceutically acceptable salt thereof, and a method for preparing the same, which act to inhibit panesyl transferase, and the present invention may be useful as an anticancer agent. have. Panesyl transferase is an enzyme that transfers panesyl groups to Ras protein, and the compound of the present invention inhibits the action of Ras protein by inhibiting the action of panesyl transferase.

Ras protein is a 21 kDa protein that plays an important role in cell growth and differentiation. It binds to guanine nucleotides, hydrolyzes guanosine triphosphate (GTP) to guanosine diphosphate (G), or converts GDP to GTP. Phosphorylation. Since GTP activates G protein and GDP inhibits G protein, Ras protein acts as a molecular switch that regulates cellular signaling by G protein.

(Bourne, H. R, Sanders, D. A, McCormick, F., Nature, 1991, 349, 117).

Ras proteins are produced from three ras genes in mammalian cells and include the K-Ras-4B protein of 188 amino acids or the H-Ras, K-Ras4A and N-Ras proteins of 189 amino acids. The amino acids at positions 12, 13 and 61 in these proteins are in close proximity to the phosphate groups of GTP, and these amino acid residues affect the spatial position of the water molecules involved in the process of GTP hydrolysis, thus affecting the GTPase enzyme activity of the Ras protein. Plays an important role. Specifically, some cancer cells generated in the human body are observed to be mutated at the amino acid position. When this mutation inhibits the GTPase enzyme activity inherent in Ras protein, GTP binding is continued and abnormal growth signals are continuously transmitted. Carcinogenicity has been reported to be caused by abnormalities in these signaling systems. Indeed, these carcinogenic ras genes are known to be closely associated with pancreatic cancer, bladder cancer, lung cancer and skin cancer (Bos, J. L., Cancer Res., 49, 4682, 1989).

In order for Ras protein to be biologically active, it must be attached to the cell membrane, and in order for Ras protein to be attached to the cell membrane, it must first be able to easily bind to the lipid layer in the cell membrane. Ras proteins are hydrophobic through several stages of binding, specifically the process by Ras farnesyltransferase involved in panesylation, three amino acids present at the carboxy terminus of the Ras protein. AAX peptide cleavage process, methyl transferase and palmitoyl transferase process, and the like, the carboxy terminal of the Ras protein is modified by this process. The first of these processes, panesylation, is carried out by panenyl transferase, in which a peptide consisting of four amino acids, CA1A2X, present at the carboxy terminus of the Ras protein is used as a substrate. Where A1 and A2 are aliphatic amino acids with no electrical load and X is methionine, alanine and serine. This panesylation reaction takes place at the cysteine site to form sulfur ether bonds, especially in the case of H-Ras and In-Ras proteins, as well as palmitoylation of another cysteine near its carboxy terminus. As a result of this panesylation, the Ras protein is increased in hydrophobicity and can be attached to the cell membrane, and the panesylated Ras protein is methylated again when the peptide of the three amino acids AAX at its carboxy terminus is removed by a cleavage enzyme. It is known that the farnesyl groups of proteins readily bind to lipid layers or other receptors in cell membranes. Indeed, although all of the above modification steps are necessary for optimal attachment of Ras proteins to cell membranes, it is reported that panesylation alone is sufficient for Ras protein activity.

Therefore, blocking the panesylation process effectively inhibits the carcinogenicity of the Ras protein caused by mutations, and thus, studies are being actively conducted to inhibit panesylation (Buss, JE et al., Chemistry & Biology, 2, 787, 1995).

Previous studies have shown that inhibition of farnesyl transferase not only inhibits cell growth transformed with Ras protein but also improves cell traits modified by Ras protein. It has been shown to selectively inhibit the response of oncogenic Ras proteins by intracellular prenyl groups [Kokl, NE et al., Proc. Natl. Acad. Sci. USA, 91: 9141 (1994); Kokl, N. E. et al., Nature Medicine, 1: 792 (1995).

Inhibitors of the farnesyl transferase, which combines two substrates, the farnesyl group and the Ras protein to generate a reactant, can be classified into three types. First, a compound capable of competitively inhibiting the farnesyl group (FPP), second, a compound that inhibits the C-terminus of the Ras protein, and a farnesyl transferase mimic the activation stage of the catalytic reaction using two substrates. It is to apply a stable compound as an inhibitor.

Most of the inhibitors studied so far are related to the CAAX motif, which mediates the introduction of the prenyl group at the C-terminus of the Ras protein, and applies a competitive inhibitory mechanism of the farnesyl transferase to the Ras protein substrate. For example, Kokl, N. E. et al. Studied peptide variants containing cysteine thiol groups that mimic CAAX and inhibitors that improved them [US Pat. Nos. 5,141,851; Kokl, N. E. et al., Science 260: 1934 (1993); PCT / US95 / 12224, Graham et al., Septi S. M., et al., Studied panesyl transferase inhibitors in which the skeletal structure of peptides was modified with phenyl groups [Sebti S. M. et al., J. Biol. Chem, 270: 26802 (1995). In addition, a variant using a benzodiazepine as a turn simulation structure of a peptide has been reported in the psychotropic pharmaceutical framework [James, GL et al., Science 260: 1937 (1993)], and tricycline deviated from the peptide structure. Inhibitors based on organic compounds have been studied [Bishop WR et al., J. Biol. Chem. 270: 30611 (1995).

On the other hand, studies of inhibitors that mimic the catalysis of panesyl transferase suggest that Poulter CD et al suggest that the mechanism of action of panesyl transferase to transfer prenyl groups is electrophilic displacement. , CD et al., Poc. Natl. Acad. Sci. USA], focusing on the fact that a reaction requires a positive load in the transition state, a new type of inhibitor that links the positive load of the transition state to the prenyl group was studied [Poulter C. D. et al, J. Am. Chem. Soc. 118: 8761 (1996).

As a result of efforts to develop new farnesyl transferase inhibitors, the present inventors have completed the present invention by preparing a tropan derivative having excellent panesyl transferase inhibitory ability.

An object of the present invention is to provide a novel tropan derivative, which has a function of inhibiting panesyl transferase, a preparation method thereof, and a use as an anticancer agent.

In the present invention, there is provided a tropan derivative of Formula 1 having a anticancer effect by inhibiting panesyl transferase and a pharmaceutically acceptable salt thereof.

Wherein R ₁ is selected from aromatics containing aromatics, nitrogen and sulfur atoms substituted with aromatics, halogens, NO 2 _, OR and lower alkyl. R ₂ is selected from aromatics containing aromatics, nitrogen and sulfur atoms substituted by aromatic, halogen, NO ₂ , OR and lower alkyl.

R ₃ is selected from among residues of amino acids, lower alkyl, lower alkyl including nitrogen and oxygen, lower alkyl substituted with aromatic, lower alkyl substituted with aromatic containing nitrogen, oxygen and sulfur atoms, Can be displayed.

In Formula 2, A is halogen, CN, NO ₂ , COOH, amide, thioamide. SR and lower alkyl are selected from the group consisting of substituted aromatics, halogen, CN, NO ₂ , COOH amide, thioamide, SR and lower alkyl substituted aromatics, and aromatics contained in the ring of a nitrogen atom or lower aromatics substituted with such aromatics. , Where R means lower alkyl. B, C, D and E are each independently selected from hydrogen halogen, or lower alkyl, n is selected from 0-4.

As used herein, the term "lower alkyl" refers to straight or branched chain alkyl of 1 to 4 carbon atoms, including methyl, ethyl, isopropyl, isobutyl, t-butyl.

As used herein, the term “aromatic with nitrogen and sulfur atoms” means that one or two nitrogen or sulfur atoms are contained in the aromatic ring in the mono or dicyclic direction.

Abbreviations for amino acids as used herein are in accordance with the IUPAC-IUB consensus on biochemical nomenclature for amino acids and peptides [Eur. J. Biochem. 1984, 158, 9-31.

The compounds of the present invention may have asymmetric carbon centers and may exist as racemates, racemic compounds, diastereomeric mixtures and individual diastereoisomers, all of these isomeric forms being included in the present invention.

Representative compounds of the present invention include the following compounds.

1) 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (4-methoxy-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol

2) 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7-phenyl-8-azabicyclo [3.2.1] octane-α-3-ol

3) 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (3-chloro-4- pullo-phenyl) -8-azabicyclo [3.2.1] octane-α -3-ol

4) 6-p-tolyl-8-pyridin-3-ylmethyl-7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol

5) 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol

6) 6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (4-methoxy-phenyl) -8-azabicyclo [3.2.1] octane- α-3-ol

7) 6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7-phenyl-8-azabicyclo [3.2.1] octane-α-3-ol

8) 6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (3-chloro-4- pullo-phenyl) -8-azabicyclo [3.2. 1] octane-α-3-ol

9) 6-p-tolyl-8- (3H-imidazol-4-ylmethyl) -7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol

10) 6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane- α-3-ol

The preparation method of the compound of the present invention can be summarized in the following steps.

1) attaching trimethylsilylethyl 3-α-hydroxy-8-azabicyclo [3,2,1] octa-6-ene-8-carboxylate to the polystyrene resin,

2) reacting the compound attached to the resin with palladium tetrakis and aryl bromide to introduce the desired substituent at the 7-position of the tropane skeleton,

3) performing a Suzuki reaction with the aryl boronic acid to the compound to introduce a desired substituent at the 6-position of the tropane skeleton,

4) removing the trimethyl ethyl oxy carbonyl (Teoc) functional group from the compound, and

5) subjecting the compound to triamine in the presence of aldehyde and triacetoxy borohydride and cleaving it from the resin in the presence of trifluoroacetic acid-water.

In more detail, the compounds of the present invention may be prepared as shown in Scheme 1 below.

Scheme 1 is a compound of formula (III) wherein trimethylsilylethyl 3-α-hydroxy-8-azabicyclo [3,2,1] octa-6-ene-8-carboxylate of formula (IV) is Dihydropa refers to a process of reacting with derivatized polystyrene resin to obtain a bicyclo compound attached to the resin of structural formula (V). The exact reaction yield is obtained after cleavage from the resin in the presence of pyridine-p-toluene sulfonate and dichloromethane / n-butanol. Compounds of formula (V) serve as starting materials in the preparation of the tropan derivatives of the invention.

Scheme 2 shows a process for obtaining a desired tropan derivative in a solid phase reaction from a bicyclo compound attached to the resin of formula (V). The compound attached to the resin of formula (V) is reacted with palladium tetrakis and arylbromide, and the resin is washed well to obtain a compound of formula (VI) having an appropriate substituent introduced at the 7-position of the tropane skeleton. It is then subjected to Suzuki reaction with arylboronic acid to obtain a compound of formula (VII) having a suitable substituent introduced at the 6-position of the tropane skeleton. Tetrahydrofuran (THF) or anisole is used as the reaction solvent. Trimethyl ethyl oxy carbonyl (Teoc) functional groups are removed from the compound of formula (VII) to obtain a compound of formula (VIII), which produces triamine in the presence of aldehyde and triacetoxy chloride brohydride. The prepared tropane derivative is cleaved from the resin in the presence of trifluoroacetic acid-water (TFA / H ₂ O) to give the final product, the compound of formula (IX). The compound of formula (IX) is a compound of formula 1 which is the target compound of the present invention.

Hereinafter, the preparation method of the novel compound of the present invention will be described in detail. However, the following examples are only for illustrating the present invention and the present invention is not limited by the examples. Prior to Examples, the preparation method of a material used as a starting material to prepare a compound of the present invention will be described.

[Production Example 1]

[Preparation of Resin with Trimethylsilylethyl 3-α-hydroxy-8-azabicyclo [3,2,1] oct-6-ene-8-carboxylate

[Step 1]

Preparation of ethyl 3-oxo-8-azabicyclo [3-2-1] oct-6-ene-8-carboxylate

22.44 g (60 mmol) of tetrabromoacetone and 8.34 g (60 mmol) of ethylpyrrole-N-carboxylate were dissolved in benzene, dropped to 0 ° C., and 60 ml of diethylzinc 1M solution was slowly added dropwise for 1 hour. The reaction was stirred at 0 ° C. for 1 hour and at room temperature for 6 hours. After the reaction, ethyl acetate and saturated ethylene chloride diamine tetraacetate solution were added to separate an organic layer. The separated organic layer was washed with saturated ethylene chloride diamine tetraacetate solution and saturated brine and dried over magnesium sulfate. The organic solvent was distilled off under reduced pressure, a saturated ammonium chloride methanol solution (240 ml) was added thereto, and an active copper-zinc hybrid (36 g) was slowly added thereto. The reaction was stirred at room temperature for 3 hours and then filtered through kietose. Then, most of methanol was removed by distillation under reduced pressure, and then dichloromethane was added thereto. The organic layer was washed twice with 100 ml of saturated ethylenediamine tetraacetate solution. After distilling off the organic solvent under reduced pressure, 4.68 g of the title compound was obtained using ethyl acetate-hexane (9: 1).

[Step 2]

Preparation of ethyl 3-α-hydroxy-8-azabicyclo [3.2.1] oct-6-ene-8-carboxylate

After dissolving 5.85 g of the compound prepared in Step 1 in 150 ml of tetrahydrofuran, the temperature was lowered to -78 ° C and 30 ml of L-selectide 1M solution was slowly added. The reaction was stirred at -78 [deg.] C. for 1 hour and then 18 ml of 2M aqueous sodium hydroxide solution was added. 9 ml of 30% hydrogen peroxide was added thereto, and the temperature was gradually raised to room temperature. The reaction was acidified with 1N aqueous hydrochloric acid solution and extracted with ethyl ether. Then, the solvent was distilled off under reduced pressure to remove an organic solvent, and chromatography was performed using ethyl acetate-hexane as a solvent to obtain 3.84 g.

[Step 3]

Preparation of Trimethylsilylethyl 3-α-hydroxy-8-azabicyclo [3.2.1] oct-6-ene-8-carboxylate

3 g of the compound obtained in Step 2 was dissolved in methanol, and 8.5 g of sodium hydroxide was added thereto, followed by heating to reflux for 120 hours. After the reaction, the solvent was distilled off under reduced pressure, 50 ml of dichloromethane and 10 ml of water were added to remove the water layer, and the organic layer was separated.

Then, the organic solvent was removed by distillation under reduced pressure. 100 ml of acetonitrile, trimethylsilylethyl-4-nitrophenyl carbonate 5.04 g, and diisopropyl ethylamine 2.7 g were added to the resulting compound, followed by stirring at 60 ° C. for 12 hours. After removing the organic solvent and chromatographed with ethyl acetate-hexane (6: 4) to give the title compound 4g.

[Step 4]

Preparation of Resin Attached with Trimethylsilylethyl 3-α-hydroxy-8-azabicyclo [3.2.1] oct-6-ene-8-carboxylate

To 24 ml dichloromethane, 4.0 g (14.9 mmol) of the compound prepared in Step 3 and 7.7 g (0.48 meq / g, 3.7 mmol) of a resin attached with tetrahydrofuran were added thereto, followed by adding 0.64 g of paratoluene sulfonic acid at room temperature for 24 hours. Stirred slowly. After the reaction, the reacted resin was washed well with dichloromethane (2 × 100 ml), dichloromethane: triethylamine (99: 1, 3 × 60ml), and dichloromethane (2 × 100ml), and then dried under reduced pressure. After the reaction, 0.5 g of the resin was cleaved from the resin in the presence of pyridine paratoluenesulfonate and dichloromethane / n-butanol to obtain 44 mg of the title compound. The calculated sound level was 0.33 meq / g.

Example 1

Preparation of 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (4-methoxy-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol

To 9 ml of deoxygenated anisole, 0.40 g of the resin prepared in Step 4 of Preparation Example 1, 67 mg of bromoanisole, and 0.42 g of palladium tetrakis were added thereto. The suspension was reacted by heating to 66 ° C. under nitrogen for 48 hours. The reaction was stopped and the reacted resin was filtered off, washed four times with 10 ml of deoxygenated tetrahydrofuran and 9 ml of deoxygenated anisole was added. 91 mg (0.6 mmol) of 4-methoxybenzeneboronic acid, 6 ml of 2N sodium carbonate and 94 mg (0.36 mmol) of triphenylphosphine were added thereto, and the mixture was heated to 66 ° C. under nitrogen and stirred for 54 hours. The reaction was filtered to remove the solvent and then the reacted resin was diluted with 10 ml of dimethylformamide: water (1: 1, 3 × 10 ml), dimethylformamide (3 × 10 ml), tetrahydrofuran (3 × 10 ml) and dichloromethane. It was washed once and dried well under vacuum. The dried resin was suspended in 9 ml of tetrahydrofuran, and then 156 mg (0.60 mmol) of tetrabutylammonium fluoride was added thereto, followed by reaction at 50 ° C. for 20 hours. The reaction solvent was removed by filtration, washed three times with 10 ml of tetrahydrofuran (2 × 10 ml), methanol (1 × 10 ml) and chloroform and dried under vacuum. The dried resin and 3-pyridyl carboxy aldehyde were added to 9 ml of 1% dimethyl acetate, reacted for 1 hour, and 0.13 g (0.6 mmol) of triacetoxy sodium borohydride was added thereto. The suspension was stirred for 30 hours, 0.5 ml of methanol was added, and the reaction solution was filtered off. It was then washed three times with dimethylformamide: water (1: 1, 3 × 10 ml), dimethylformamide (3 × 10 ml), tetrahydrofuran (3 × 10 ml) and 10 ml of dichloromethane and dried well under vacuum. The dried resin was suspended in 5 ml of trifluoroacetic acid: water (95: 5), filtered and the remaining resin was washed with methylene chloride. The filtrate was distilled under reduced pressure to remove the organic solvent, the reaction was dissolved in methylene chloride and washed with 1T aqueous sodium hydroxide solution. The organic solvent was removed to obtain 33 mg (yield 67%) of the title compound.

Example 2

Preparation of 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7-phenyl-8-azabicyclo [3.2.1] octane-α-3-ol

25 mg of the title compound was obtained in the same manner as in Example 1, using phenyl boronic acid instead of 4-methoxy benzeneboronic acid.

Example 3

6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (3-chloro-4- pullo-phenyl) -8-azabicyclo [3.2.1] octane-α-3 Preparation of -ol

Using the 3-chloro-4- pullo-phenyl boronic acid instead of 4-methoxy benzeneboronic acid was prepared in the same manner as in Example 1 to obtain 37 mg of the title compound.

Example 4

Preparation of 6-p-tolyl-8-pyridin-3-ylmethyl-7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol

4-bromotoluene was used instead of bromoanisole, and 3-nitrobenzene boronic acid was used instead of 4-methoxy benzeneboronic acid in the same manner as in Example 1 to obtain 37 mg of the title compound.

Example 5

Preparation of 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol

38 mg of the title compound was obtained by the same method as Example 1, using 3-nitro-phenyl boronic acid instead of 4-methoxy benzeneboronic acid.

Example 6

6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (4-methoxy-phenyl) -8-azabicyclo [3.2.1] octane-α- Preparation of 3-ol

To 9 ml of deoxygenated anisole, 0.40 g of the resin prepared in Preparation Example 4, 67 mg of bromoanisole and 0.42 g of palladium tetrakis were added thereto. The suspension was reacted at a temperature of 66 ° C. under nitrogen for 48 hours. After the reaction was stopped, the reacted resin was filtered, washed four times with 10 ml of deoxygenated tetrahydrofuran, and 9 ml of deoxygenated anisole was added. 91 mg (0.6 mmol) of 4-methoxybenzeneboronic acid, 6 ml of 2N sodium carbonate, and 94 mg (0.36 mmol) of triphenylphosphine were added thereto, followed by stirring for 54 hours at 66 ° C. under nitrogen. The reaction was filtered to remove the solvent and then the reacted resin was dimethylformamide: water (1: 1, 3 × 10 ml), dimethylformamide (3 × 10 ml), tetrahydrofuran (3 × 10 ml) and 10 ml dichloromethane. Washed three times and dried well under vacuum. The dried resin was suspended in 9 ml of tetrahydrofuran, and then 156 mg (0.60 mmol) of tetrabutylammonium fluoride were added and reacted at 50 ° C. for 20 hours. The reaction solvent was filtered off and washed three times with 10 ml of tetrahydrofuran (2 × 10 ml), methanol (1 × 10 ml) and chloroform and dried under vacuum. The dried resin and 1-trityl-4-carboxy aldehyde halide imidazole were added to 9 ml of 1% dimethyl acetate, followed by reaction for 1 hour, and 0.13 g (0.6 mmol) of triacetoxy sodium borohydride was added thereto. . The suspension was stirred for 30 hours, 0.5 ml of methane was added and the reaction solution was filtered off. It was then washed three times with dimethylformamide: water (1: 1, 3 × 10 ml), dimethylformamide (3 × 10 ml), tetrahydrofuran (3 × 10 ml) and 10 ml of dichloromethane and dried well under vacuum. The dried resin was suspended in 5 ml of trifluoroacetic acid: water (95: 5), filtered and the remaining resin was washed with methylene chloride. The filtrate was distilled under reduced pressure to remove the organic solvent, the reaction was dissolved in methylene chloride and washed with 1N aqueous sodium hydroxide solution. The organic solvent was separated and removed and chromatographed with a solvent of ethyl acetate: methanol (9: 1) to obtain 25 mg of the title compound.

Example 7

Preparation of 6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7-phenyl-8-azabicyclo [3.2.1] octane-α-3-ol

Using the phenyl boronic acid instead of 4-methoxy benzene boronic acid in the same manner as in Example 6 to obtain the title compound 25mg.

Example 8

6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (3-chloro-4- pullo-phenyl) -8-azabicyclo [3.2.1] Preparation of Octane-α-3-ol

37 mg of the title compound was obtained in the same manner as in Example 6, using 3-chloro-4-pulro-phenyl boronic acid instead of 4-methoxy benzeneboronic acid.

Example 9

6- (p-tolyl) -8- (3H-imidazol-4-ylmethyl) -7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol Manufacture

4-bromotoluene was used instead of bromoanisole and 3-nitrobenzene boronic acid was used instead of 4-methoxy benzeneboronic acid in the same manner as in Example 6 to obtain 37 mg of the title compound.

Example 10

6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α- Preparation of 3-ol

38 mg of the title compound was obtained by the same method as Example 6, using 3-nitro-phenyl boronic acid instead of 4-methoxy benzeneboronic acid.

[Ras farnesyl transferase inhibitory activity assay]

In this experiment, Ras farnesyl transferase prepared by genetic recombination technology was improved by improving the method of Pompiano [Pompliano et al., Biochemistry 31. 3800 (1992)], Ras substrate (Ras-CVLS) protein Was purified by the previously reported method (Chung et al., Bichimica et Biophysica Acta 1129, 278 (1992)).

The enzymatic reaction was carried out in 50 μl 50 mM sodium hippie buffer solution containing 25 mmol potassium chloride, 25 mmol magnesium chloride, 10 mmol DTT and 50 μmol zinc chloride, 1.5 μmol Ras substrate protein, 0.15 μmol tritium-panesyl fatigue Phosphate and 4.5 nmol of farnesyl transferase were used.

In detail, the reaction was continued for 30 minutes at 37 ° C. after the addition of the farnesyl transferase, and the reaction was stopped by adding 1 ml of an ethanol solution containing 1 M hydrochloric acid, and the resulting precipitate was hopper harvester for filter binding (hopper Adsorption to GF / B filters using #FH 225V, followed by washing with ethanol and drying filters was performed by measuring radioactivity using an LKB beta counter. The concentration of was measured in a substrate unsaturated state showing a quantitative titer, and the synthesized compound was dissolved in a dimethyl sulfoxide (DMSO) solvent and added within 5% of the total reaction solution to evaluate the enzyme inhibitory activity. The amount of farnesyl introduced in the presence of the sample was expressed as a percentage of the farnesyl introduced to the Ras substrate protein in the state. The concentration that inhibited the enzyme activity was determined by IC ₅₀ of each sample. Geranylgeranyl transferase for evaluating the selective inhibitory ability of the sample was determined by Shaber et al., J. Biol chem. 265: 14701 (1990). )] Was modified and used from the cerebellum, and experiments were carried out using geranyl geranyl pyrophosphate and Ras-CVIL substrate protein, which are specific substrates of geranyl geranyl transferase under conditions similar to the panesyl transferase reaction. Was performed.

Table 1 below summarizes the inhibitory effects of representative compounds.

The compounds of the present invention are novel tropan derivatives that inhibit the action of Ras protein by inhibiting the action of panesyl transferase, an enzyme that transfers the farnesyl group of Ras protein. Tropan derivatives of the present invention can be usefully used as an anticancer agent by having an excellent panesyl transferase inhibitory ability.

Claims (4)

A tropan derivative and a pharmaceutically acceptable salt, hydrate or solvate thereof, represented by the following Chemical Formula 1. [Formula 1]

In Formula 1, 1) R ₁ , R ₂ may be selected from aromatics, aromatics substituted with straight or branched chain alkyl of C ₁ -C ₄ , aromatics containing nitrogen and sulfur atoms, and 2) R ₃ is represented by the following formula It may be represented by two. [Formula 2]

In Formula 2, A is halogen, CN, NO ₂ , COOH amide, thioamide, SR and C ₁ -C ₂ linear or branched alkyl substituted with a branched alkyl, or halogen, CN, NO ₂ , COOH amide, thioamide, SR and C ₁ -C ₄ linear or branched alkyl substituted with nitrogen and sulfur atoms substituted in the ring or may be selected from C ₁ -C ₄ linear or branched alkyl substituted with such an aromatic, wherein R is C _1- C ₄ linear or branched alkyl. B, C, D and E may each independently be selected from hydrogen halogen, or straight or branched chain alkyl of C ₁ -C ₄ , and n may be selected from 0 to 4. The compound of claim 1, wherein 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (4-methoxy-phenyl) -8-azabicyclo [3.2.1] octane-α 3-ol, 6- (4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7-phenyl-8-azabicyclo [3.2.1] octane-α-3-ol, 6- ( 4-methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (3-chloro-4-poolo-phenyl) -8-azabacyclo [3.2.1] octane-α-3-ol, 6- (p-tolyl) -8-pyridin-3-ylmethyl-7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol, 6- (4 -Methoxy-phenyl) -8-pyridin-3-ylmethyl-7- (3-nitrotrophenyl) -8-azabicyclo [3.2.1] octane-α-3-ol, 6- (4 -Methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (4-methoxy-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol, 6- (4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7-phenyl-8-azabicyclo [3.2.1] octane-α-3-ol, 6- ( 4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (3-chloro-4- pullo-phenyl) -8-azabicyclo [3.2.1] octane-α -3-ol, 6-p-tolyl-8- (3H-imidazol-4-ylmethyl) -7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3-ol or 6 -(4-methoxy-phenyl) -8- (3H-imidazol-4-ylmethyl) -7- (3-nitro-phenyl) -8-azabicyclo [3.2.1] octane-α-3 A tropan derivative characterized in that it is -ol and a pharmaceutically acceptable salt, hydrate or solvate thereof. 1) attaching trimethylsilylethyl 3-α-hydroxy-8-azabicyclo [3.2.1] octa-6-ene-8-carboxylate to the polystyrene resin, 2) attaching the compound attached to the resin Reacting palladium tetrakis with aryl bromide to introduce the desired substituent at the 7-position of the tropane skeleton, 3) reacting the compound with aryl boronic acid to introduce the desired substituent at the 6-position of the tropane skeleton, 4) removing the trimethyl ethyl oxy carbonyl (Teoc) functional group from the compound and 5) making the compound triamine in the presence of aldehyde and triacetoxy chloride borohydride, which is trifluoroacetic acid. A process for producing the tropan derivative of claim 1, comprising cutting from a resin in the presence of water. Tropan derivative of claim 1 for inhibitor of farnesyl transferase.