KR100384117B1 - Pyrrole derivatives useful for farnesyl transferase inhibitors and their preparations - Google Patents

Abstract

The present invention relates to a compound of formula 1, a pharmaceutically acceptable salt or isomer thereof that includes a pyrrole structure and is capable of inhibiting farnesyl transferase.

In the above formula

A, B and D are as defined in the specification.

Description

Pyrrole derivatives useful for farnesyl transferase inhibitors and their preparations}

The present invention relates to a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof, which includes a pyrrole structure and is capable of inhibiting farnesyl transferase.

[Formula 1]

In the above formula

A represents any of the following groups of structural formulas:

From here

m and m 'each independently represent an integer of 0 to 3,

n represents an integer of 0 to 5,

Y represents O, S, S = O or SO ₂ ,

R ₁ represents hydrogen or a saturated or unsaturated 3 to 6 membered heterocycle or bicyclic 9 to 10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or Represents any one selected from the group of the following structural formulas:

X represents hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy or phenoxy,

R ₂ represents a saturated or unsaturated 3 to 9 membered heterocycle or bicyclic 9 to 10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or Represents any one selected:

Wherein p represents an integer of 1 to 3, Y is as defined above, and R ₄ and R ₅ each independently represent lower alkyl unsubstituted or substituted by phenyl or naphthyl, or C ₃ -C ₇ -cycloalkyl, phenyl or naphthyl,

R ₃ represents lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or lower alkylsulfonyl, unsubstituted or substituted by phenyl or naphthyl, respectively, or sulfonyl substituted by phenyl or naphthyl,

B represents phenyl or naphthyl,

D represents any one selected from the group of the following structural formulas:

From here

R ₆ and R ₇ each independently represent hydrogen or lower alkyl,

Y is as defined above.

In particular, the compound according to the present invention not only has a specific structure different from the farnesyltransferase inhibitors known to date, but also contains no thiol groups at all.

The present invention also includes a method for preparing the compound of Formula 1, and contains an anticancer composition comprising a compound of Formula 1 as an active ingredient together with a pharmaceutically acceptable carrier. Therefore, these manufacturing methods and compositions are also the subject of this invention.

Ras protein is a 21kDa protein that plays an important role in cell growth and differentiation. It binds to guanine nucleotides and hydrolyzes guanosine triphosphate (GTP) to guanosine diphosphate (GDP). It is also known to act as a molecular switch that regulates specific GTPase circuits in cells (Bourne, HR, Sanders, DA, McCormick, F. Nature 1991, 349, 117).

Ras protein is produced by mammalian cells by three Ras genes as amino acids 188 K-Ras-4B or 189 H-Ras, K-ras-4A and N-Ras. The amino acids at positions 12, 13, and 61 of the protein are in close proximity to the phosphate groups of GTP, and these amino acid residues affect GTPase activity by affecting the spatial position of water molecules involved in the hydrolysis of GTP. When cancer occurs in the human body, mutations in amino acids at this position are observed, which eventually inhibits Ras protein's intrinsic GTPase activity and maintains GTP binding status, which is known to show carcinogenicity by continuously transmitting abnormal growth signals. have. Such a carcinogenic Ras gene is known to be particularly closely related to pancreatic cancer, bladder cancer, lung cancer and skin cancer (Bos, JL, Cancer Res ., 1989, 49, 4682).

In order for the Ras protein to be biologically active, it must be attached to the cell membrane. This requires a carbon term after protein transfer by Ras farnesyl transferase, three AAX peptide cleavage enzymes at the Ras protein carboxy terminus, methyl transferase and palmitoyl transferase. The modification of is required. The first step, panesylation, is achieved by farnesyl transferase (FTase). The substrate of the farnesyl transferase is four peptides, CA1A2X, at the carboxy terminus of the Ras protein, where A1 and A2 are aliphatic amino acids with no electrical load and X is methionine, alanine or serine. The farnesyl reaction occurs on cysteine to form sulfur ether bonds, and in the case of H-Ras and N-Ras, palmitoylation occurs at another cysteine near the carboxy terminus. As a result of the panesylation, the Ras protein increases in affinity and adheres to the cell membrane. The panesylated Ras protein is subsequently removed from the carboxy terminus by three AAX peptides removed and methylated so that the panesyl group is formed in the lipid layer or in the cell membrane. It is known to facilitate binding with other receptors. On the other hand, unlike H-Ras and N-Ras, K-Ras-4B has a site where several lysines, called poly basic domains, are arranged in place of cysteine required for palmitoylation. It is known that binding to lipids is facilitated. In order for Ras protein to adhere well to the cell membrane, all modification steps are required. However, the activation of Ras protein is known to be sufficient for panicylation alone. Therefore, studies are being actively conducted to inhibit Ras carcinogenicity by mutation by blocking this panicylation. (Bus, JE et al ., Chemistry Biology , 1995, 2, 787).

Previous studies have shown that inhibition of farnesyl transferase in Ras-transformed cells inhibits cell growth and improves the cell morphology modified by Ras.

Indeed, several inhibitors of farnesyl transferase have been shown to selectively inhibit the response of Ras oncogenic genes to intracellular prenyl groups (see Kohl, NE et al, Proc. Natl. Acad. Sci. USA , 91, 9141 (1994); Kohl, NE et al., Nature Medicine, 1, 792 (1995). The developed farnesyl transferase inhibitors include peptide variants containing cysteine thiol groups and similar structures to CAAX, and inhibitors that improve them (see US Patent No. 5,141,851; Kohl, NE et al., Science 260, 1934 (1993); Graham et al., PCT / US95 / 12224), peptides modified with phenyl groups (Sebti, SM, J. Biol. Chem. 270, 26802, 1995), benzodiazepines in the psychotropic pharmaceutical framework Variant (James, GL et al. , Science, 260, 1937, 1993), which was used as a turn simulation structure of the inhibitor, and inhibitors based on tricyclic organic compounds from the peptide structure (Bishop WR et al. , J. Biol. Chem., 270, 30611, 1995). In addition, since the mechanism by which Panesyl transferase transfers a prenyl group is an electrophilic displacement reaction, it is considered that a positive load is required in the transition state of the reaction, thereby connecting the positive load of the transition state to the prenyl group. New types of inhibitors have been proposed (Poulter, CD et al., J. Am. Chem. Soc ., 118, 8761, 1996).

However, K-Ras activation is a major cause in many cases of human cancer, and most prenyl transferase inhibitors developed to date activate K-Ras. Therefore, the inhibition of growth of cells transformed by K-Ras is lower than the growth inhibition of cells transformed by H-Ras and N-Ras, so the study of novel inhibitors that can effectively inhibit K-Ras activity Is getting attention.

Therefore, the present inventors established a new evaluation system for evaluating the enzyme activity inhibitory ability against K-Ras substrate and the inhibitory activity of intracellular K-Ras prenylation, and utilizing the same, thereby identifying the K-Ras as well as H-Ras and N-Ras substrates. Novel compounds that inhibit misfire were synthesized and their inhibitory ability evaluated. As a result, the present inventors have found that the compound of Formula 1 meets the intended purpose of the present invention and that they can be usefully used as an anticancer agent.

Accordingly, an object of the present invention is to provide a compound of formula 1 having a superior anticancer effect and a method for preparing the same.

The present invention also provides an anticancer composition comprising the compound of formula 1 as an active ingredient together with a pharmaceutically acceptable carrier.

The present invention relates to a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof, which includes a pyrrole structure and is capable of inhibiting farnesyl transferase.

[Formula 1]

In the above formula

A represents any of the following groups of structural formulas:

From here

m and m 'each independently represent an integer of 0 to 3,

n represents an integer of 0 to 5,

Y represents O, S, S = O or SO ₂ ,

R ₁ represents hydrogen or a saturated or unsaturated 3 to 6 membered heterocycle or bicyclic 9 to 10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or Represents any one selected from the group of the following structural formulas:

X represents hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy or phenoxy,

R ₂ represents a saturated or unsaturated 3 to 9 membered heterocycle or bicyclic 9 to 10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or Represents any one selected:

Wherein p represents an integer of 1 to 3, Y is as defined above, and R ₄ and R ₅ each independently represent lower alkyl unsubstituted or substituted by phenyl or naphthyl, or C ₃ -C ₇ -cycloalkyl, phenyl or naphthyl,

R ₃ represents lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or lower alkylsulfonyl, unsubstituted or substituted by phenyl or naphthyl, respectively, or sulfonyl substituted by phenyl or naphthyl,

B represents phenyl or naphthyl,

D represents any one selected from the group of the following structural formulas:

From here

R ₆ and R ₇ each independently represent hydrogen or lower alkyl,

Y is as defined above.

Among the compounds of the formula (1) exhibiting excellent farnesyl transferase inhibitory activity, preferred compounds are

A represents any of the following groups of structural formulas:

From here

m and m 'represent an integer of 0 to 3,

n represents an integer of 0 to 3,

Y represents O or S,

R ₁ represents hydrogen or any one selected from the group of the following structural formulas:

X represents hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy or phenoxy,

R ₂ represents a saturated or unsaturated 5-6 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen atoms,

R ₃ each represents lower alkyl unsubstituted or substituted by phenyl or naphthyl,

B represents phenyl or naphthyl,

D represents any one selected from the group of the following structural formulas:

From here

R ₆ and R ₇ each independently represent hydrogen or lower alkyl,

Y is O or S is a compound.

Particularly preferred compounds are those in which A is benzyloxypropyl, phenoxypropyl, phenylthiopropyl, ethylthiopropyl, morpholin-4-ylpropyl, thiophen-2-ylethyl, furan-2-ylmethyl or N-benzylpiperi Di-4-yl, B is naphthalen-1-yl, and D is N- (2-methoxyethyl) -N-methylamino, morpholin-4-yl or 4-methylpiperazin-1-yl to be.

Representative examples of the compound of formula 1 according to the present invention are illustrated below, and the structure of each compound is as shown in Tables 1a to 1b below:

1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (1);

1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (2);

1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl)- 1H-pyrrole (3);

3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazole-5- Il] methyl-1H-pyrrole (4);

3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-thiophenoxypropyl) -1H-imidazole- 5-yl] methyl-1H-pyrrole (5);

3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazol-5-yl] methyl-1H-pyrrole (6);

3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazol-5-yl] methyl- 1H-pyrrole 7;

3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-thioethoxypropyl) -1H-imidazole-5 -Yl] methyl-1H-pyrrole (8);

3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- {1- [3- (morpholin-4-yl) propyl] -1H-imidazol-5-yl} methyl- 4- (naphthalen-1-yl) -1H-pyrrole (9);

3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- {1- [2- (thiophen-2-yl) ethyl] -1H Imidazol-5-yl} methyl-1H-pyrrole (10);

3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1- {1- [2- (thiophen-2-yl) ethyl] -1H-imidazole- 5-yl} methyl-1H-pyrrole (11);

1- [1- (furan-2-yl) methyl-1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole 12;

1- [1- (1-benzylpiperidin-4-yl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4 -(Naphthalen-1-yl) -1H-pyrrole (13); And

1- [1- (1-benzylpiperidin-4-yl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl ) -1H-pyrrole (14).

The compound of formula 1 according to the present invention can be obtained by (a) coupling a compound of formula 2 with a compound of formula 3 to obtain a compound of formula 1, or (b) coupling a compound of formula 4a with a compound of formula 5 Ring to obtain a compound of formula 1a, or (c) coupling a compound of formula 4b with a compound of formula 6 to obtain a compound of formula 1b, wherein The production method is also an object of the present invention.

However, the preparation method of the compound according to the present invention is not limited to the following description, and can be easily prepared by arbitrarily combining various synthesis methods described in this specification or disclosed in the prior literature, and such combinations are It is a common technique generalized to those skilled in the art to which the invention belongs.

R ₂ H

In the above formula

A, B, D, m, m ', n, Y, R ₁ and R ₂ are as defined above.

The coupling reaction of (a) to (c) for preparing the compound of formula 1 according to the present invention may suitably be carried out in the presence of a base in a solvent. The solvent may be selected within a range that does not adversely affect the reaction, preferably one or more selected from dimethylformamide, dichloromethane, tetrahydrofuran, chloroform and dimethylacetamide may be used. As the base, one or more selected from sodium hydride, potassium t-butoxide, sodium bis (trimethylsilyl) amide, sodium amide and potassium bis (trimethylsilyl) amide can be used.

Meanwhile, the compounds of Formulas 2 to 4 used as starting materials in the method of preparing the compound of Formula 1 may be prepared according to the methods shown in Schemes 1 to 3 below.

First, the compound of Formula 2 may be synthesized by reacting an amine with dihydroxyacetone to prepare a thiolimidazole derivative, as shown in Scheme 1 below, followed by desulfurization and halogenation (see J. Med). Chem., 33, 1312-1329, 1990).

Where A is as defined above.

The compound of formula 3 may be synthesized from the aldehyde derivative represented by formula B-CHO according to the method shown in Scheme 2 below, wherein as a coupling agent usable in the final step of preparing the compound of formula 3 from pyrrolecarboxylic acid Carbodiimides such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), and 1,1'-dicarbonyldiimidazole (CDI) Preference is given to using a mixture of and 1-hydroxybenzotriazole.

In the above formula

B and D are as defined above,

TosMIC represents tosylmethyl isocyanide and is used hereinafter with the same meaning.

On the other hand, the compounds of formula 4a and 4b can be prepared from the amino alcohol derivative as shown in Scheme 3 below.

In the above formula

q represents m + 2 or n.

That is, the aminoalcohol derivative is reacted with phthalic anhydride in the presence of toluene to protect the amine and then the hydroxy moiety is protected by reacting with benzylbromide in the presence of sodium hydride. Compounds protected with both amino and hydroxy groups are reacted with hydrazine to remove phthalic protecting groups to yield amines with only hydroxy groups protected by benzyl groups. After reacting the amine compound in the same manner as in Scheme 1, the resulting compound is reacted with the compound of Formula 3 and deprotected to prepare a primary alcohol compound. The primary alcohol is reacted with methanesulfonylchloride to give the desired compound of formula 4a or 4b.

The compound of the present invention prepared according to the method as described above has an inhibitory effect on the farnesyl transferase as described above can be usefully used as an anticancer agent. Accordingly, another object of the present invention is to provide an anticancer composition containing a compound of formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier.

The total daily dose to be administered to the host in a single dose or in separate doses when administering a compound of the present invention for clinical purposes is preferably in the range of 10 to 100 mg / kg body weight, but the specific dose level for a particular patient will be The compound, the weight of the patient, sex, health condition, diet, the time of administration of the drug, the method of administration, the rate of excretion, the drug mixture and the severity of the disease can be changed.

The compounds of the present invention can be administered in injectable and oral formulations as desired. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing agents, wetting agents, or suspending agents according to known techniques. Solvents that can be used for this are water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are also commonly used as solvents or suspending media. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Particularly, capsules and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the active compound of formula 1 according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and a carrier such as a lubricant such as magnesium stearate, a disintegrant, a binder and the like. .

Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. In the following Preparation Example, a method for synthesizing an intermediate for preparing the final compound is described. In the Examples, a process for synthesizing the final compound through reaction with the compound obtained in the Preparation Example is described. However, these preparation examples and examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

Preparation Example 1 Preparation of 4- (naphthalen-1-yl) -1H-pyrrole-3-carboxylic acid

1-1) Preparation of 3- (naphthalen-1-yl) -acrylic acid ethyl ester

22.4 g (0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml of acetonitrile, and then 1,8-diazabicyclo [5.4.0] undec-7-ene (1,5-5) (DBU) 30.4 g (2 mol) was added slowly. 15.6 g (0.10 mol) of 1-naphthalaldehyde was dissolved in 20 ml of tetrahydrofuran and slowly added to the reaction solution, followed by stirring for 8 hours. The organic solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate and washed twice with water. After drying over magnesium sulfate and concentration, column chromatography (eluant: n-hexane / ethyl acetate = 95/5, v / v) was carried out to obtain 20.3 g (0.090 mol, 90% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.33 (t, 3H), 4.10 (q, 2H), 6.75 (q, 1H), 7.50 (m, 3H), 7.73 (d, 1H), 7.85 (m, 2H), 8.10 (d, 1 H), 8.21 (d, 1 H)

FAB 227 (M + H)

1-2) Preparation of Ethyl 4- (naphthalen-1-yl) -1H-pyrrole-3-carboxylate

5 g (18.9 mmol) of the compound obtained in Production Example 1-1) and 3.68 g (18.9 mmol) of tosylmethyl isocyanide were dissolved in 100 mL of tetrahydrofuran. To this was slowly added 2.55 g (22.7 mmol) of tetrahydrofuran 100 mL solution of potassium t-butoxide and refluxed for 30 minutes. 100 ml of water was added to the reaction mixture to stop the reaction, and the solvent was removed under reduced pressure. The residue was extracted with diethyl ether, washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v) to give 3.85 g (14.5 mmol, 77% yield) of the title compound. It was.

¹ H NMR (CDCl ₃ ) δ 1.27 (t, 3H), 4.07 (q, 2H), 6.76 (s, 1H), 7.28-7.47 (m, 5H), 7.59 (s, 1H), 7.82 (m, 2H ), 9.99 (s, 1H)

FAB 266 (M + H)

1-3) Preparation of 4- (naphthalen-1-yl) -1H-pyrrole-3-carboxylic acid

2.64 g (10 mmol) of the compound obtained in Preparation Example 1-2) was dissolved in 50 mL of 50% ethanol, and 2.24 g (40 mmol) of potassium hydroxide was added thereto and refluxed for 7 hours. After cooling the reaction solution to room temperature, the pH was adjusted to 4-5 and extracted with ethyl acetate. Dry over sodium sulfate and remove the solvent under reduced pressure to afford 1.62 g (8.1 mmol, 81% yield) of the title compound. The obtained compound was used for the next reaction without any further purification.

¹ H NMR (CDCl ₃ ) δ 6.60 (s, 1H), 7.32-7.49 (m, 5H), 7.54 (s, 1H), 7.84 (m, 2H), 9.92 (s, 1H)

FAB 238 (M + H)

Preparation Example 2 Preparation of 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole

234 mg (1 mmol) of the compound obtained in Preparation Example 1-3) was dissolved in 2 ml of dimethylformamide, 230 mg (1.2 mmol) of EDC, 101 mg (1 mmol) of triethylamine, and 162 mg (1.7 mmol) of HOBT were added, followed by 0 ° C. Stir at 5 min. To this was added 124 mg (1 mmol) of N- (2-methoxyethyl) -N-methylamine hydrochloride and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, 10 ml of saturated potassium carbonate solution was added, extracted with 20 ml of ethyl acetate, and then washed with 10 ml of 1N hydrochloric acid aqueous solution. Washed with brine and water, dried over sodium sulfate and concentrated to give 246 mg (0.79 mmol, yield 79%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.46 (s, 2H), 2.80-3.40 (m, 8H), 3.40 (s, 1H), 6.80 (s, 1H), 7.00 (s, 1H), 7.42 (m, 4H ), 7.73 (d, 1H), 7.81 (d, 1H), 8.17 (d, 1H), 10.66 (s, 1H)

FAB 309 (M + H)

Preparation Example 3 Preparation of 3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole

234 mg (1 mmol) of the compound obtained in Preparation Example 1-3) was dissolved in 2 ml of dimethylformamide, 230 mg (1.2 mmol) of EDC and 162 mg (1.7 mmol) of HOBT were added, followed by stirring at 0 ° C. for 5 minutes. 87 mg (1 mmol) of morpholine was added thereto and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, 10 ml of saturated potassium carbonate solution was added, extracted with ethyl acetate, and then washed with 10 ml of 1N hydrochloric acid aqueous solution. Washed with brine and water, dried over sodium sulfate and concentrated to give 243 mg (0.8 mmol, yield 80%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.13-3.52 (br, 8H), 6.54 (s, 1H), 7.31-7.51 (m, 5H), 7.53 (s, 1H), 7.81 (m, 2H), 9.93 (s , 1H)

FAB 307 (M + H)

Preparation Example 4 Preparation of 3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole

The compound obtained in Preparation Example 1-3) and 4-methylpiperazine were reacted according to the Preparation Example 2 to obtain the title compound in 75% yield.

¹ H NMR (CDCl ₃ ) δ 1.15 (br, 2H), 1.87 (br, 2H), 1.92 (s, 3H), 2.96 (br, 2H), 3.41 (br, 2H), 6.83 (s, 1H), 7.09 (s, 1H), 7.36-7.42 (m, 4H), 7.73 (d, 1H), 7.75 (d, 1H), 8.10 (d, 1H), 10.52 (s, 1H)

FAB (M + H): 320

Preparation Example 5: Preparation of 1- (3-benzyloxypropyl) -5-chloromethyl-1H-imidazole hydrochloride

5-1) Preparation of 3-hydroxypropyl phthalimide

15.2 g (0.2 mole) of 3-amino-1-propanol and 29.6 g (0.2 mole) of phthalic anhydride were reacted with 500 ml of toluene for 24 hours with reflux using a Deanstock (Tetrahedron Letter, 34, 2947, 1993). After the reaction, the solvent was removed under reduced pressure, dissolved in 300 ml of dichloromethane and washed with 100 ml of water. The organic layer was separated and dried over anhydrous sodium sulfate to give 33.6 g (yield 80%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.57 (m, 2H), 3.17 (t, 2H), 3.42 (t, 2H), 7.68 (m, 5H)

FAB (M + H): 206

5-2) Preparation of 3-benzyloxypropyl amine

20.5 g (0.1 mmol) of the compound obtained in Preparation Example 5-1) was added to 40 ml of dimethylformamide, followed by 4.4 g (0.11 mmol) of sodium hydride (60%). 18.9 g (0.11 mmol) of benzyl bromide was added thereto and reacted for 12 hours. After the reaction, the solvent was removed, dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and the solvent was removed. Then, 200 ml of ethanol and 12.5 g (0.25 mmol) of hydrazine hydrate were added and reacted under reflux for 3 hours. After the reaction, the solvent was removed under reduced pressure, dissolved in 200 ml of dichloromethane and washed with saturated sodium bicarbonate. 200 ml of 1N aqueous hydrochloric acid solution was added and the organic layer was removed. Dichloromethane 200ml was added to the aqueous layer, and the organic layer was separated by basifying with 6N sodium hydroxide, and the solvent was removed by distillation under reduced pressure to obtain 8.3 g (yield 50%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.76 (m, 2H), 2.30 (br, 2H), 2.83 (t, 2H), 3.54 (t, 2H), 4.49 (s, 2H), 7.32 (m, 5H)

FAB 166 (M + H)

Preparation Example 5-3) Preparation of 1- (3-benzyloxypropyl) -5-hydroxymethyl-1H-imidazole

Dihydroxyacetone dimer and the compound obtained in Preparation Example 5-2) were prepared by modifying the method described in J. Med. Chem ., 33, 1312-1329, 1990 as starting material. That is, 4.95 g (30 mmol) of 3-benzyloxypropylamine, 2.97 g (16.5 mmol) of dihydroxyacetone dimer, and 3.20 g (33 mmol) of potassium thiocyanide were added to 30 ml of isopropyl alcohol, followed by 6 ml of acetic acid. The reaction was carried out at room temperature for 48 hours. After the reaction, the solvent was removed, 100 ml of ethyl acetate was added, and the resultant was washed twice with 100 ml of water. The solvent was removed under reduced pressure, 30 ml of 30% nitric acid and 6.9 mg (0.1 mmol) of NaNO ₂ were added and allowed to react for 2 hours. 20 ml of ethyl acetate was added to the reaction to remove the organic layer, and 100 ml of ethyl acetate was added to the aqueous layer. After pH of the mixed solution was basified to 12 or less using 6N aqueous sodium hydroxide solution, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated by removing the solvent under reduced pressure. Column chromatography (eluent: dichloromethane / methanol = 93/7, v / v) was performed on the residue to give 2.5 g (yield 38%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.05 (m, 2H), 3.41 (t, 2H), 4.10 (t, 2H), 4.45 (s, 2H), 4.55 (s + br, 3H), 6.84 (s, 1H ), 7.32 (m, 5H), 7.42 (s, 1H)

FAB 247 (M + H)

Preparation Example 5-4) Preparation of 1- (3-benzyloxypropyl) -5-chloromethyl-1H-imidazole hydrochloride

246 mg (1 mmol) of the compound obtained in Preparation Example 5-3) was dissolved in 3 ml of chloroform, and 355 mg (3 mmol) of thionyl chloride was slowly added dropwise at 0 ° C. After stirring for 2 hours, the solvent was removed by distillation under reduced pressure and the remaining hydrochloride was removed to give the title compound in 95% yield. The obtained compound was used directly in the next reaction without purification.

Preparation Example 6 Preparation of 1- [2- (thiophen-2-yl) ethyl] -5-chloromethyl-1H-imidazole hydrochloride

6-1) Preparation of 1- [2- (thiophen-2-yl) ethyl] -5-hydroxymethyl-1H-imidazole

Prepared by modifying the method described in J. Med. Chem ., 33, 1312-1329, 1990 with dihydroxyacetone dimer and 2- (thiophen-2-yl) ethylamine as starting materials. It was. That is, 1.37 g (10 mmol) of 2- (thiophen-2-yl) ethylamine, 1.08 g (6 mmol) of dihydroxyacetone dimer, and 1.15 g (11 mmol) of potassium thiocyanide are added to 10 ml of isopropyl alcohol. After addition, 2 ml of acetic acid was added and reacted at room temperature for 48 hours. The reaction solution was filtered and the remaining solid was washed twice with 5 ml of isopropyl alcohol and twice with 5 ml of water. The filtered solid was added to 20 ml of 10% aqueous nitric acid solution, cooled to 0 ° C., and 10 mg of sodium nitrite was added to the reaction solution, and the mixture was reacted at room temperature for 1 hour. The aqueous solution was washed with 10 ml of ethyl acetate, and the aqueous solution was basified and recrystallized to obtain 1.16 g (yield 49%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 3.31 (t, 2H), 4.25 (t, 2H), 4.55 (s, 2H), 6.70 (d, 1H), 6.90 (m, 2H), 7.15 (d, 1H), 7.25 (s, 1 H)

FAB 233 (M + H), C10H12N2OS (M)

6-2) Preparation of 1- [2- (thiophen-2-yl) ethyl] -5-chloromethyl-1H-imidazole hydrochloride

233 mg (1 mmol) of the compound obtained in Preparation Example 6-1) was dissolved in 3 ml of chloroform, and 355 mg (3 mmol) of thionyl chloride was slowly added dropwise at 0 ° C. After stirring for 2 hours, the solvent was removed by distillation under reduced pressure and the remaining hydrochloride was removed to give the title compound in 95% yield. The obtained compound was used directly in the next reaction without purification.

Preparation Example 7 Preparation of 1- (furan-2-yl) methyl-5-chloromethyl-1H-imidazole hydrochloride

7-1) Preparation of 1- (furan-2-yl) methyl-5-hydroxymethyl-1H-imidazole

0.97 g (10 mmol) of perrylamine, 1.08 g (6 mmol) of dihydroxyacetone dimer, and 1.15 g (11 mmol) of potassium thiocyanide were added to 10 ml of isopropyl alcohol, and then 2 ml of acetic acid was added. The reaction was carried out for a time. The reaction solution was filtered and the remaining solid was washed twice with 5 ml of isopropyl alcohol and twice with 5 ml of water. The filtered solid was added to 20 ml of 10% aqueous nitric acid solution, cooled to 0 ° C., and 10 mg of sodium nitrite was added to the reaction solution, and the mixture was reacted at room temperature for 1 hour. The aqueous solution was washed with 10 ml of ethyl acetate, and the aqueous solution was basified and recrystallized to obtain 1.07 g (yield 60%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.63 (s + br, 3H), 5.29 (s, 2H), 6.37 (d, 1H), 6.40 (m, 1H), 6.99 (s, 1H), 7.41 (s, 1H ), 7.65 (s, 1 H)

FAB 179 (M + H), C9H10N2O2 (M)

7-2) Preparation of 1- (furan-2-yl) methyl-5-chloromethyl-1H-imidazole hydrochloride

205 mg (1 mmol) of the compound obtained in Preparation Example 7-1) was dissolved in 3 ml of chloroform, and 355 mg (3 mmol) of thionyl chloride was slowly added dropwise at 0 ° C. After stirring for 2 hours, the solvent was removed by distillation under reduced pressure and the remaining hydrochloride was removed to give the title compound in 95% yield. The obtained compound was used directly in the next reaction without purification.

Preparation Example 8 Preparation of 1- (1-benzylpiperidin-4-yl) -5-chloromethyl-1H-imidazole hydrochloride

8-1) Preparation of 1- (1-benzylpiperidin-4-yl) -5-hydroxymethyl-1H-imidazole

3.0 g (11.4 mmol) of 4-amino-1-benzylpiperidine hydrochloride, 1.00 g (5.7 mmol) of dihydroxyacetone dimer and 1.8 g (18.2 mmol) of potassium thiocyanide were added to 10 ml of isopropyl alcohol. 2 ml of acetic acid was added and reacted at room temperature for 48 hours. The reaction solution was filtered and the remaining solid was washed twice with 5 ml of isopropyl alcohol and twice with 5 ml of water. The filtered solid was added to 20 ml of 10% aqueous nitric acid solution, cooled to 0 ° C., and 10 mg of sodium nitrite was added to the reaction solution, and the mixture was reacted at room temperature for 1 hour. The aqueous solution was washed with 10 ml of ethyl acetate, and the aqueous solution was basified and recrystallized to obtain 1.2 g (yield 38%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.94 (m, 2H), 2.01 (m, 2H), 2.12 (m, 2H), 2.97 (d, 2H), 3.52 (s, 2H), 4.08 (m, 1H), 4.54 (s, 2H), 6.72 (s, 1H), 7.20-7.31 (m, 5H), 7.45 (s, 1H)

FAB 272 (M + H), C16H21N3O (M)

8-2) Preparation of 1- (1-benzylpiperidin-4-yl) -5-chloromethyl-1H-imidazole hydrochloride

271 mg (1 mmol) of the compound obtained in Preparation Example 8-1) was dissolved in 3 ml of chloroform, and 355 mg (3 mmol) of thionyl chloride was slowly added dropwise at 0 ° C. After stirring for 2 hours, the solvent was removed by distillation under reduced pressure and the remaining hydrochloride was removed to give the title compound in 95% yield. The obtained compound was used directly in the next reaction without purification.

Example 1: 1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Preparation of (naphthalen-1-yl) -1H-pyrrole (1)

620 mg (2 mmol) of the compound obtained in Preparation Example 2 was dissolved in 20 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C., followed by stirring for 5 minutes. To this was added 601 mg (2.2 mmol) of the compound obtained in Preparation Example 5-4) and stirred at room temperature for 3 hours. After the solvent was removed by distillation under reduced pressure, 30 ml of water was added thereto, and extracted twice with 100 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, column chromatography (eluant: dichloromethane / methanol = 95/5, v / v) was carried out to give 780 mg (yield 67%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.78 (m, 2H), 2.40 (br, 2H), 2.71 (br, 1H), 2.90-3.30 (m, 5H), 3.25-3.40 (m, 3H), 3.99 (t , 2H), 4.41 (s, 2H), 4.56 (br, 1H), 5.09 (s, 2H), 6.66 (s, 1H), 7.05 (s, 1H), 7.13 (s, 1H), 7.20-7.50 ( m, 9H), 7.62 (s, 1H), 7.72 (d, 1H), 7.81 (d, 1H), 8.05 (d, 1H)

FAB (M + H) 537, C33H36N4O3 (M)

Example 2: 1- [1- (3-benzyloxypropyl) -1 H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) Preparation of -1H-pyrrole (2)

620 mg (2 mmol) of the compound obtained in Preparation Example 3 was dissolved in 20 mL of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C., followed by stirring for 5 minutes. To this was added 601 mg (2.2 mmol) of the compound obtained in Preparation Example 5-4) and stirred at room temperature for 3 hours. After the solvent was removed by distillation under reduced pressure, 30 ml of water was added thereto, and extracted twice with 100 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, column chromatography (eluant: dichloromethane / methanol = 95/5, v / v) was carried out to give 810 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.79 (m, 2H), 2.60-3.30 (br, 8H), 3.36 (t, 2H), 4.00 (t, 2H), 4.42 (s, 2H), 5.11 (s, 2H ), 6.66 (s, 1H), 7.05 (s, 1H), 7.13 (s, 1H), 7.20- 7.50 (m, 9H), 7.62 (s, 1H), 7.72 (d, 1H), 7.81 (d, 1H), 8.05 (d, 1H)

FAB (M + H) 535, C33H34N4O3 (M)

Example 3: 1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalene-1 -Yl) -1H-pyrrole (3) Preparation

640 mg (2 mmol) of the compound obtained in Preparation Example 4 was dissolved in 20 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C., followed by stirring for 5 minutes. To this was added 601 mg (2.2 mmol) of the compound obtained in Preparation Example 5-4) and stirred at room temperature for 3 hours. After the solvent was removed by distillation under reduced pressure, 30 ml of water was added thereto, and extracted twice with 100 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, column chromatography (eluent: dichloromethane / methanol = 95/5, v / v) was carried out to give 750 mg (yield 68%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.07 (br, 2H), 1.76 (m, 2H), 1.90-2.05 (br + s, 5H), 3.00 (br, 1H), 3.10-3.60 (br + t, 5H) , 3.95 (t, 2H), 4.44 (s, 2H), 5.07 (s, 2H), 6.66 (d, 1H), 7.04 (s, 1H), 7.13 (s, 1H), 7.20-7.31 (m, 6H ), 7.32-7.50 (m, 4H), 7.75 (d, 1H), 7.80 (d, 1H), 8.00 (d, 1H)

FAB (M + H) 548, C34H37N5O2 (M)

Example 4: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazole-5- Preparation of methyl] H-pyrrole (4)

4-1) 1- [1- (3-hydroxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Preparation of (Naphthalen-1-yl) -1H-pyrrole

536 mg (1 mmol) of the compound obtained in Example 1, 20 mg of Pd / C (10%) and 2.2 g (47 mmol) of formic acid were added to 50 ml of methanol and reacted for 96 hours (see J. Org. Chem. 3443, 1979). After the reaction was filtered and the solvent was concentrated under reduced pressure. 20 ml of ethyl acetate was added thereto, washed with 10 ml of saturated aqueous sodium hydrogen carbonate solution, and then the solvent was removed. Column chromatography (eluent: dichloromethane / methanol = 93/7, v / v) was carried out on the residue to give 313 mg (yield 70%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.33 (m, 2H), 2.37 (s, 2H), 2.68 (m, 1H), 2.85-3.10 (m, 6H), 3.29 (br, 1H), 3.51 (t, 2H ), 4.04 (t, 2H), 5.03 (br, 1H), 5.12 (s, 2H), 6.71 (s, 1H), 7.12 (s, 1H), 7.20 (s, 1H), 7.25 (d, 1H) , 7.39 (m, 3H), 7.72 (d, 1H), 7.78 (m, 2H), 7.99 (d, 1H)

FAB (M + H) 447, C26H30N4O3 (M)

4-2) 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methanesulfonyloxypropyl) -1H-imidazol-5-yl] methyl- Preparation of 4- (naphthalen-1-yl) -1H-pyrrole

223 mg (0.5 mmol) of the compound obtained in Example 4-1) was added to 10 ml of dichloromethane in which 55 mg (0.55 mmol) of triethylamine and 63 mg (0.55 mmol) of methanesulfonyl chloride were dissolved and reacted for 4 hours. . 10 mL of water was added after reaction, and the organic layer was isolate | separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Column chromatography on the residue (eluent: dichloromethane / methanol = 90/10, v / v) afforded 160 mg (60% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.95 (m, 2H), 2.42 (s, 2H), 2.70 (m, 1H), 2.85-3.18 (m, 8H), 3.29 (s, 1H), 3.45 (m, 1H ), 4.19 (m, 4H), 5.25 (s, 2H), 6.80 (d, 1H), 7.17 (s, 1H), 7.20-7.60 (m, 5H), 7.73 (d, 1H), 7.75 (d, 1H), 7.99 (d, 1H), 8.42 (br, 1H)

FAB (M + H) 525, C27H32N4O5S (M)

4-3) 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imid Preparation of Dazol-5-yl] methyl-1H-pyrrole

4.8 mg (0.12 mmol) of sodium hydride (60%) and 10.3 mg (0.11 mmol) of phenol were added to 2 ml of dimethylformamide. 52 mg (0.1 mmol) of the compound obtained in Example 4-2) was added to the reaction and reacted at 60 ° C. for 2 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and 10 ml of ethyl acetate was added to the residue, followed by washing with saturated aqueous sodium hydrogen carbonate solution. The solution was concentrated and subjected to column chromatography (eluant: dichloromethane / methanol = 93/7, v / v) to give 23 mg (45% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.03 (m, 2H), 2.40 (br, 2H), 2.71 (br, 1H), 2.90-3.22 (br, 5H), 3.31 (br, 1H), 3.88 (t, 2H ), 4.18 (m, 3H), 5.15 (s, 2H), 6.72 (d, 1H), 6.78 (d, 2H), 6.93 (t, 1H), 7.10 (s, 1H), 7.21 (m, 3H) , 7.35 (s, 1H), 7.39 (m, 3H), 7.74 (d, 1H), 7.82 (d, 1H), 8.03 (m, 2H)

FAB (M + H) 523, C32H34N4O3 (M)

Example 5: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-thiophenoxypropyl) -1H Preparation of -Imidazol-5-yl] methyl-1H-pyrrole (5)

4.8 mg (0.12 mmol) of sodium hydride (60%) and 12.1 mg (0.11 mmol) of thiophenol were added to 2 ml of dimethylformamide. 52 mg (0.1 mmol) of the compound obtained in Example 4-2) was added to the reaction and reacted at 60 ° C. for 2 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and 10 ml of ethyl acetate was added to the residue, followed by washing with saturated aqueous sodium hydrogen carbonate solution. The solution was concentrated and subjected to column chromatography (eluent: dichloromethane / methanol = 93/7, v / v) to give 29.6 mg (yield 55%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.88 (m, 2H), 2.41 (br, 2H), 2.60-3.20 (m, 8H), 3.32 (br, 1H), 4.04 (m, 3H), 5.13 (s, 2H ), 6.70 (s, 1H), 7.05-7.60 (m, 11H), 7.73 (d, 1H), 7.82 (m, 2H), 8.03 (d, 1H)

FAB (M + H) 539, C32H34N4O2S (M)

Example 6: 3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazol-5-yl] methyl-1H-pyrrole (6) Preparation

The title compound was obtained in 90% yield by the same method as in Example 4, except that the compound of Example 2 was used instead of the compound of Example 1 in step 4-1).

¹ H NMR (CDCl ₃ ) δ 1.25 (m, 2H), 2.24 (m, 3H), 2.70-3.35 (br, 5H), 3.98 (t, 2H), 4.43 (t, 2H), 5.29 (s, 2H ), 6.77 (m, 2H), 6.90 (m, 1H), 7.15-7.50 (m, 10H), 7.75 (d, 1H), 7.79 (d, 1H), 7.98 (d, 1H)

FAB (M + H) 521, C32H32N4O3 (M)

Example 7: 3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazol-5-yl] methyl- Preparation of 1H-pyrrole 7

The title compound was obtained in 87% yield in the same manner as in Example 4, except that the compound of Example 3 was used instead of the compound of Example 1 in step 4-1).

¹ H NMR (CDCl ₃ ) δ 1.07 (br, 2H), 1.70-2.0 (br + m + s, 6H), 2.49 (br, 1H), 2.91 (br, 2H), 3.31 (br, 2H), 3.81 (t, 2H), 4.04 (t, 2H), 5.05 (s, 2H), 6.70 (d, 1H), 6.78 (m, 2H), 6.90 (m, 1H), 7.11 (m, 2H), 7.20 ( m, 2H), 7.29 (m, 1H), 7.37 (m, 3H), 7.49 (s, 1H), 7.73 (d, 1H), 7.80 (d, 1H), 8.00 (d, 1H)

FAB (M + H) 534, C33H35N5O2 (M)

Example 8: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-thioethoxypropyl) -1H- Preparation of Imidazol-5-yl] methyl-1H-pyrrole (8)

4.8 mg (0.12 mmol) of sodium hydride (60%) and 6.8 mg (0.11 mmol) of ethanethiol were added to 2 ml of dimethylformamide. 52 mg (0.1 mmol) of the compound obtained in Example 4-2) was added to the reaction and reacted at room temperature for 2 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and 10 ml of ethyl acetate was added to the residue, followed by washing with saturated aqueous sodium hydrogen carbonate solution. The solution was concentrated and subjected to column chromatography (eluent: dichloromethane / methanol = 93/7, v / v) to give 21 mg (yield 43%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.69 (t, 3H), 1.87 (m, 2H), 2.25-2.85 (m, 7H), 2.90-3.15 (m, 5H), 3.34 (br, 1H), 4.03 (t , 2H), 4.57 (br, 1H), 5.17 (s, 2H), 6.76 (s, 1H), 7.12 (s, 1H), 7.20 (s, 1H), 7.37-7.46 (m, 4H), 7.78 ( d, 1H), 7.84 (m, 2H), 8.08 (d, 1H)

FAB (M + H) 491

Example 9: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- {1- [3- (morpholin-4-yl) propyl] -1 H-imidazole-5- Preparation of methyl-4- (naphthalen-1-yl) -1H-pyrrole (9)

4.8 mg (0.12 mmol) of sodium hydride (60%) and 9.6 mg (0.11 mmol) of morpholine were added to 2 ml of dimethylformamide. 52 mg (0.1 mmol) of the compound obtained in Example 4-2) was added to the reaction and reacted at room temperature for 2 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and 10 ml of ethyl acetate was added to the residue, followed by washing with saturated aqueous sodium hydrogen carbonate solution. The solution was concentrated and subjected to column chromatography (eluant: dichloromethane / methanol = 93/7, v / v) to give 20 mg (41% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.84 (m, 2H), 2.30-2.80 (m, 8H), 2.85-3.40 (m, 6H), 3.65-3.85 (m, 6H), 4.00 (t, 2H), 5.21 (s, 2H), 6.80 (s, 1H), 7.10-7.50 (m, 6H), 7.61 (s, 1H), 7.75 (d, 1H), 7.91 (d, 1H), 8.07 (d, 1H)

FAB (M + H) 516, C30H37N5O3 (M)

Example 10: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- {1- [2- (thiophen-2-yl) Preparation of ethyl] -1 H-imidazol-5-yl} methyl-1 H-pyrrole (10)

The title compound was obtained in the yield of 71% by using the compound obtained in Preparation Example 2 and the compound obtained in Preparation Example 6-2) as starting materials, in the same manner as in Example 1.

¹ H NMR (CDCl ₃ ) δ 2.24 (br, 1H), 2.39 (br, 2H), 2.71 (br, 1H), 2.90-3.17 (m, 6H), 3.29 (m, 2H), 4.05 (t, 2H ), 4.88 (s, 2H), 6.61 (s, 1H), 6.70 (d, 1H), 6.90 (m, 1H), 7.04 (s, 1H), 7.10 (s, 1H), 7.14 (d, 1H) , 7.30-7.50 (m, 5H), 7.73 (d, 1H), 7.81 (d, 1H), 8.05 (d, 1H)

FAB (M + H) 499, C29H30N4O2S (M)

Example 11: 3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1- {1- [2- (thiophen-2-yl) ethyl] -1H-imidazole- Preparation of 5-yl} methyl-1H-pyrrole (11)

640 mg (2 mmol) of the compound obtained in Preparation Example 4 was dissolved in 20 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C., followed by stirring for 5 minutes. To this was added 570 mg (2.2 mmol) of the compound obtained in Preparation Example 6-2) and stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, 30 ml of water was added to the residue, followed by extraction twice with 100 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, the residue was subjected to column chromatography (eluent: dichloromethane / methanol = 95/5, v / v) to give 750 mg (yield 74%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.07 (br, 2H), 1.80-2.10 (s + br, 5H), 2.80-3.40 (br + t, 6H), 4.05 (t, 2H), 4.90 (s, 2H) , 6.63 (s, 1H), 6.71 (s, 1H), 6.87 (m, 1H), 7.11 (m, 2H), 7.25 (s, 1H), 7.31 (m, 1H), 7.37-7.50 (m, 4H ), 7.68 (d, 1 H), 7.82 (d, 1 H), 8.06 (d, 1 H)

FAB (M + H) 510, C30H31N5OS (M)

Example 12: 1- [1- (furan-2-yl) methyl-1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) Preparation of -1H-pyrrole 12

640 mg (2 mmol) of the compound obtained in Preparation Example 4 was dissolved in 20 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C., followed by stirring for 5 minutes. To this was added 450 mg (2.2 mmol) of the compound obtained in Preparation Example 7-2) and stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, 30 ml of water was added to the residue, followed by extraction twice with 100 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, the residue was subjected to column chromatography (eluent: dichloromethane / methanol = 95/5, v / v) to give 600 mg (yield 63%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.23 (br, 2H), 1.90-2.03 (s + br, 4H), 2.62 (br, 2H), 3.03 (br, 2H), 3.37 (br, 2H), 4.92 (s , 2H), 5.13 (s, 2H), 6.22 (d, 1H), 6.29 (d, 1H), 7.12 (s, 1H), 7.15 (s, 1H), 7.31 (m, 2H), 7.47 (m, 3H), 7.67 (s, 1H), 7.76 (d, 1H), 7.83 (d, 1H), 8.03 (d, 1H)

FAB (M + H) 480, C29H29N5O2 (M)

Example 13: 1- [1- (1-benzylpiperidin-4-yl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] Preparation of Carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (13)

The title compound was obtained in 70% yield by reacting the compound obtained in Preparation Example 2 and the compound obtained in Preparation Example 8-2) as starting materials in the same manner as in Example 1.

¹ H NMR (CDCl ₃ ) δ 1.69 (d. 2H), 1.92 (m, 2H), 2.00 (t, 2H), 2.17 (br, 1H), 2.37 (br, 2H), 2.70 (br, 1H), 2.90-3.15 (m, 7H), 3.30 (s, 1H), 3.48 (s, 2H), 3.72 (m, 1H), 5.10 (s, 2H), 6.71 (d, 1H), 7.07 (s, 1H) , 7.13 (s, 1H), 7.20-7.31 (m, 6H), 7.32-7.42 (m, 3H), 7.64 (d, 1H), 7.75 (d, 1H), 7.83 (d, 1H), 8.00 (d , 1H)

FAB (M + H) 562, C35H39N5O2 (M)

Example 14 1- [1- (1-benzylpiperidin-4-yl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalene Preparation of -1-yl) -1H-pyrrole 14

The title compound was obtained in 70% yield by reacting the compound obtained in Preparation Example 3 and the compound obtained in Preparation Example 8-2) as starting materials in the same manner as in Example 1.

¹ H NMR (CDCl ₃ ) δ 1.66 (d, 2H), 1.89 (m, 2H), 1.99 (m, 2H), 2.28 (br, 2H), 2.70-3.35 (br, 8H), 3.47 (s, 2H ), 3.71 (m, 1H), 5.12 (s, 2H), 6.71 (s, 1H), 7.14 (d, 2H), 7.20-7.32 (m, 6H), 7.33-7.50 (m, 3H), 7.64 ( s, 1H), 7.77 (d, 1H), 7.79 (d, 1H), 7.93 (d, 1H)

FAB (M + H) 560, C35H37N5O2 (M)

Experimental Example 1: Analysis of Ras farnesyl transferase inhibitory activity

In this experiment, the improved method of Pompiano et al. (Pompliano et al., Biochemistry 31, 3800, 1992) was used. In other words, Ras farnesyl transferase prepared by genetic recombination technology was used, and H-Ras (H-Ras-CVLS) as a substrate and H- which substituted the polybasic lysine domain present at the carboxy terminus of K-Ras. The binding protein with Ras (see Korean Patent Application No. 97-14409) was purified and used according to the previously reported method (Chung et al., Bichimica et Biophysica Acta 1129, 278, 1992).

Enzyme reactions were carried out in 50 μl of 50 mM sodium hippies buffer containing 25 mM potassium chloride, 25 mM magnesium chloride, 10 mM Diti (DTT) and 50 μM zinc chloride, 1.5 μM Ras substrate protein, 0.15 μM tritium-panesyl pyrophosphate And farnesyl transferase 4.5 nM was used. The reaction was stopped by the addition of farnesyl transferase and the reaction was continued at 37 ° C. for 30 minutes, followed by the addition of 1 ml of ethanol solution containing 1 M hydrochloric acid. The resulting precipitate was adsorbed onto a GF / B filter using a hopper harvester (Hopper #FH 225V) for filter binding, washed with ethanol and the radioactivity of the dried filter was measured using an LKB beta counter. The enzyme titer was measured in a substrate unsaturated state in which the concentration of Ras substrate protein and panesyl enzyme showed a quantitative titer relationship, and the compound synthesized according to the present invention was dissolved in dimethyl sulfoxide (DMSO) solvent to obtain 5 The enzyme inhibition was assessed by addition within%. The enzyme inhibitory activity was expressed as a percentage of the amount of farnesyl introduced in the presence of the test compound relative to the amount of farnesyl introduced into the Ras substrate protein in the absence of the test compound, and the concentration that inhibited the enzyme activity of 50% was determined by IC ₅₀ of each test compound. Determined. Geranylgeranyl transferase for evaluating the selective inhibitory activity of the test compound was used after purification from the cerebellum by modifying the method of Shaver et al. (Schaber et al. J. Biol Chem., 265, 14701, 1990) Experiments were carried out using geranylgeranyl pyrophosphate and Ras-CVIL substrate protein, which are specific substrates of geranylgeranyl transferase under conditions similar to the real transferase reaction. The experimental results are shown in Table 2 below.

Experimental Example 2 Analysis of Inhibitory Effect of Intracellular Ras Farnesyl Transferase

In this experiment, a rat2 cell line expressing a C-Harvey-Ras protein having a transgenic activity by mutation and a H-Ras binding protein transformed with a H-Ras binding protein substituted with a polybasic lysine domain at the K-Ras carboxy terminus (see: Korean Patent Application No. 97-14409) was used, and the experiment was performed by modifying the method of DeCru et al. (See Declue. JE et al., Cancer Research, 51, 712, 1991) as follows.

The transformed rat2 fibroblast cell line was seeded at a density of 3 × 10 ⁵ cells per dish in a 60 mm cell culture dish, grown to a density of 50% or more by incubating for 48 hours in a 37 ° C. cell culture medium, and then treated with a test compound. . At this time, dimethyl sulfoxide (DMSO) was used as a solvent of the test compound, and dimethyl sulfoxide concentration was used as 1% in both the control group and the test group. After 4 hours of treatment with the test compound, methionine labeled with 150 μCi of radioisotope [ ³⁵ S] per 1 ml of medium was added and cultured for 20 hours, and the cells were washed with physiological saline. 1 ml of cooled cell lysis buffer (Magnesium chloride 5 mM, Dity 1 mM, NP40 1%, EDTA 1 mM, PMSF 1 mM, Lupetin 2 μM, Peptstatin A 2 μM and 50 μM Sodium Hippies buffer solution 2 μM) After adding the cells to lysate, the supernatant in which the cells were lysed was obtained by high-speed centrifugation (12,000 g x 5 minutes). The radioisotope labeling amount of the supernatant was measured and normalized to obtain quantitative results in the immunoprecipitation reaction. Subsequently, a monoclonal antibody, Y13-259 (see Furth, ME et al., J. Virol. , 43, 294, 1982), which specifically binds to Ras protein, was added to the reaction solution at Reacted. To this solution was added a protein A-agarose suspension bound to an immunoglobulin antibody from a goth-derived mouse and reacted at 4 ° C for 1 hour, followed by a buffer solution (sodium chloride) to remove the nonspecific binding substance from the immunoreactive precipitate. 50 mM, sodium dioxycholate 0.5%, NP40 0.5% and SDS 0.1% SDS). In order to analyze the precipitate using the electrophoretic method, the precipitate was added to the electrophoretic sample buffer and boiled, followed by electrophoresis using 13.5% SDS polyacrylamide gel. After electrophoresis, the gel was fixed, dried, and then subjected to photo printing by exposing to an X-ray film. The inhibitory effect of intracellular Ras farnesyl transferase was expressed as the concentration of the test compound (CIC ₅₀ ) in which the farnesyl binding was inhibited by measuring the intensity of the non-bound bands of the farnesyl bound band of the Ras protein. Table 2 shows the inhibitory effect of the representative compounds according to the present invention. Here, IC ₅₀ is data obtained by performing Experimental Example 1 and CIC ₅₀ is data obtained by performing Experimental Example 2.

Claims (6)

A compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof: [Formula 1] In the above formula A represents any of the following groups of structural formulas: From here m and m 'each independently represent an integer of 0 to 3, n represents an integer of 0 to 5, Y represents O, S, S = O or SO ₂ , R ₁ represents hydrogen or a saturated or unsaturated 3 to 6 membered heterocycle or bicyclic 9 to 10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or Represents any one selected from the group of the following structural formulas: X represents hydrogen, halogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkoxy, nitro, cyano, hydroxy or phenoxy of 1 to 4 carbon atoms, R ₂ represents a saturated or unsaturated 3 to 9 membered heterocycle or bicyclic 9 to 10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or Represents any one selected: Wherein p represents an integer of 1 to 3, Y is as defined above, and R ₄ and R ₅ each independently represent a straight or branched chain alkyl having 1 to 4 carbon atoms unsubstituted or substituted by phenyl or naphthyl. Or C ₃ -C ₇ -cycloalkyl, phenyl or naphthyl, R ₃ is straight or branched chain alkyl having 1 to 4 carbon atoms, unsubstituted or substituted by phenyl or naphthyl, straight or branched chain alkylcarbonyl having 1 to 4 carbon atoms, straight or branched chain alkoxycarbonyl having 1 to 4 carbon atoms or carbon atoms, respectively Linear or branched alkylsulfonyl of 1 to 4, or sulfonyl substituted by phenyl or naphthyl, B represents phenyl or naphthyl, D represents any one selected from the group of the following structural formulas: From here R ₆ and R ₇ each independently represent hydrogen or straight or branched chain alkyl having 1 to 4 carbon atoms, Y is as defined above. The method of claim 1, A represents any of the following groups of structural formulas: From here m and m 'represent an integer of 0 to 3, n represents an integer of 0 to 3, Y represents O or S, R ₁ represents hydrogen or any one selected from the group of the following structural formulas: X represents hydrogen, halogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkoxy, nitro, cyano, hydroxy or phenoxy of 1 to 4 carbon atoms, R ₂ represents a saturated or unsaturated 5-6 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen atoms, R ₃ represents straight or branched chain alkyl having 1 to 4 carbon atoms unsubstituted or substituted by phenyl or naphthyl, respectively, B represents phenyl or naphthyl, D represents any one selected from the group of the following structural formulas: From here R ₆ and R ₇ each independently represent hydrogen or straight or branched chain alkyl of 1 to 4 carbon atoms, Y is O or S. 2. A compound according to claim 1, wherein A is benzyloxypropyl, phenoxypropyl, phenylthiopropyl, ethylthiopropyl, morpholin-4-ylpropyl, thiophen-2-ylethyl, furan-2-ylmethyl or N-benzyl Piperidin-4-yl, B is naphthalen-1-yl, D is N- (2-methoxyethyl) -N-methylamino, morpholin-4-yl or 4-methylpiperazin-1- One person compound. The method of claim 1, 1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (1); 1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (2); 1- [1- (3-benzyloxypropyl) -1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl)- 1H-pyrrole (3); 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazole-5- Il] methyl-1H-pyrrole (4); 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-thiophenoxypropyl) -1H-imidazole- 5-yl] methyl-1H-pyrrole (5); 3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazol-5-yl] methyl-1H-pyrrole (6); 3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1- [1- (3-phenoxypropyl) -1H-imidazol-5-yl] methyl- 1H-pyrrole 7; 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- [1- (3-thioethoxypropyl) -1H-imidazole-5 -Yl] methyl-1H-pyrrole (8); 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- {1- [3- (morpholin-4-yl) propyl] -1H-imidazol-5-yl} methyl- 4- (naphthalen-1-yl) -1H-pyrrole (9); 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- {1- [2- (thiophen-2-yl) ethyl] -1H Imidazol-5-yl} methyl-1H-pyrrole (10); 3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1- {1- [2- (thiophen-2-yl) ethyl] -1H-imidazole- 5-yl} methyl-1H-pyrrole (11); 1- [1- (furan-2-yl) methyl-1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole 12; 1- [1- (1-benzylpiperidin-4-yl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4 -(Naphthalen-1-yl) -1H-pyrrole (13); or 1- [1- (1-benzylpiperidin-4-yl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl ) -1H-pyrrole (14). A method of preparing a compound of formula 1 as defined in claim 1 characterized in that the compound of formula 4a is coupled with a compound of formula 5 to yield a compound of formula 1a: [Formula 4a] [Formula 5] [Formula 1a] In the above formula B, D, m, m ', Y and R ₁ are as defined in claim 1. An anticancer composition comprising the compound as defined in claim 1 as an active ingredient together with a pharmaceutically acceptable carrier.