KR20040066296A - 3-(2-amino-4-pyrimidinyl)-2-naphthol derivatives as inhibitors of cyclin dependent kinase - Google Patents

Abstract

PURPOSE: 3-(2-Amino-4-pyrimidinyl)-2-naphthol derivatives as inhibitors of cyclin dependent kinase are provided, thereby preventing and treating cancers associated with cyclin dependent kinase(CDK). CONSTITUTION: The 3-(2-amino-4-pyrimidinyl)-2-naphthol derivatives represented by formula (1), and pharmaceutically acceptable salts, hydrates, solvates and isomers thereof are provided, wherein R is hydrogen, hydroxy, cyano, halogen, C1-C4 alkyloxy, amino, aminosulfonyl or NH2-N-R1; and R1 is hydrogen or hydroxy. The method for preparing the 3-(2-amino-4-pyrimidinyl)-2-naphthol derivatives of formula (1) comprises reacting a compound of formula (10) with guanidine and sodium ethoxide.

Description

{3- (2-Amino-4-pyrimidinyl) -2-naphthol derivatives as inhibitors of cyclin dependent kinase} with 3- (2-amino-4-pyrimidinyl) -2-naphthol structure

The present invention relates to novel compounds of formula (I), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, useful as inhibitors of Cyclin Dependent Kinase (hereinafter referred to as "CDK").

[Formula 1]

In the above formula

R is hydrogen, hydroxy, cyano, halogen, C ₁ -C ₄ -alkyloxy, amino, aminosulfonyl or In which R ¹ is hydrogen or hydroxy.

The present invention also relates to a method for preparing a compound of Formula 1 and an anticancer composition comprising a compound of Formula 1 as an active ingredient together with a pharmaceutically acceptable carrier.

Full-scale research at the molecular level of cell division began to develop in the late 1980s through the study of frog egg division, characterization of various cell growths and radioactive mutations in yeast, and Rb, a tumor suppressor. As the mechanism of cell division manipulation began to be revealed in more detail in the 1990s, the fact that small cell growth regulators regulate cell division processes such as cell growth, differentiation, development, aging and apoptosis through its regulatory functions These findings have helped to better understand the pathology of many diseases. A representative example is cancer. In the process of transforming normal cells into cancer cells, cell growth regulation is often lost. In other words, many abnormal growth activity of cell growth regulators was found in cancer cells, and some of them showed deep correlation of invasion / metastasis, which is the most problematic problem in cancer pathology. In particular, inducing overexpression or knock-out of cell growth regulators using a transgenic animal results in cell cycle deregulation of cancer from these cancers. It can be seen that it is a direct cause.

Cell growth is under positive and negative control, as with all other biological controls. The major pathways of cell cycle regulation known to date are due to the activity of cyclin dependent kinases, which are subject to positive or negative regulation depending on the environment in which the cells are located. Many studies on cancer cells and carcinogenesis have shown that problems with positive or negative control of kinase activity often lead to cancer. That is, cancer may occur when balanced control is not achieved or timely control is not made.

Representative mammalian cyclin dependent kinases include cyclin dependent kinase 4 (CDK4), which is active in the mid-G1 phase of the cell cycle, CDK2, which is active in the mid-G1 and S phases, and CDC2, which is active in the G2-M phase ( CDK1). It is known that CDK4 and CDK2 are regulated by G1-S cell cycle checkpoint and CDC2 is regulated by G2-M checkpoint. Various cancer cells show abnormalities in the regulation of CDK4, CDK2, and CDC2 (CDK1), and it was confirmed that abnormalities of these enzymes, which are artificially induced in transgenic animals, actually cause cancer. Thus, these representative cyclin dependent kinases CDK4, CDK2, CDC2 (CDK1) are in very good positions as targets for anticancer agents.

The results reported so far regarding the association between these CDKs and cancer disease are described in more detail below.

The association between abnormal regulation of CDK4 activity and cancer development has been observed in several cancer tissues. Deletion of p16 and p15 genes or overexpression of cyclin D1 has been identified in several types of cancers, especially in the case of breast cancer metastasis, which is a malignant phenotype of cancer when CDK4 activity is not regulated. phenotype) may be present. In addition, p16 knockout mice have been reported to have a higher incidence of cancer than p53 knockout mice, indicating that the loss of p16 function in CDK4 regulation is the cause of cancer. These results suggest that p16 may play a role downstream in NIH 3T3 cells overexpressing Ras or src. Conversely, when the p16 or p21 were expressed in cells transformed with ras, it was observed that the modified phenotype is changed to the normal phenotype. These experimental evidences seem to prove that deregulation of CDK4 activity is a clear cause of cancer, and furthermore, it is likely to play a role in maintaining the phenotype of cancer cells. Therefore, the inhibitor of CDK4 is highly likely to show anticancer effect.

On the other hand, in the case of CDK2, overexpression of cyclin E is observed in some breast cancers, which is closely associated with metastasis of breast cancer, which inhibits cell death and reduces anchorage independent growth in serum conditions where cyclin E overexpression is low. Hyperproliferation of mammary epithelial cells was observed in transgenic animals overexpressing CDK2 using the MMTV promoter, which strongly suggests that CDK2 activity is involved in the process of cell transformation or its maintenance. This suggests that inhibitors of CDK2 can act as anticancer agents.

In addition, CDC2 (CDK1), CDK3, CDK5, CDK6, and CDK7 have been found to play an important role in each stage of cell division, and they are divided into cyclin dependent kinase (CDKs) families. In addition, in the case of cyclin, cyclins A, B, C, D2, D3, D4, F and G belong to the same family in addition to cyclin D1 or cyclin E mentioned above.

Based on the accumulated research, the development of these inhibitors has recently begun to be realized in the recognition that inhibitors that effectively inhibit these cyclin dependent kinases will be useful as anticancer agents.

Compounds effective as CDKs inhibitors developed so far include the flavopyridols of Formula 2 (see European Patent Nos. 0,241,003 (1987) and 0,366,061 (1990)).

In addition, CDKs inhibitors of formula (3) having a purine structure have recently been reported (WO 97/16447), and structurally completely different compounds of formula (4) have been reported to be effective CDK inhibitors (see WO 98). / 33798).

However, the CDK inhibitors developed so far have not yet had a sufficiently satisfactory effect. Therefore, the present inventors have conducted intensive studies on inhibitors of these CDKs enzymes. Neyl-naphthol derivatives have been found to effectively inhibit the CDKs enzymes described above and have completed the present invention.

Accordingly, an object of the present invention is to provide a novel compound that inhibits CDKs activity and an anticancer composition containing the compound as an active ingredient. CDKs include CDK2, CDK4 and CDC2 (CDK1), CDK3, CDK5, CDK6, CDK7, and the like, and cyclin cyclin D1 and cyclin E and cyclin A, B, C, D2, D3, D4, F, G It includes everything.

Hereinafter, the present invention will be described in detail.

It is an object of the present invention to provide novel compounds of formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, which exhibit anticancer effects by inhibiting CDKs activity:

[Formula 1]

In the above formula

R is hydrogen, hydroxy, cyano, halogen, C ₁ -C ₄ -alkyloxy, amino, aminosulfonyl or In which R ¹ is hydrogen or hydroxy.

The compound of formula 1 according to the present invention may have an asymmetric carbon center and may include a double bond, depending on the type of substituent, so that the compound may exist as individual enantiomers, diastereomers or geometric isomers. It may also be present as a mixture thereof. Such isomers or mixtures thereof are therefore also included within the scope of the present invention.

The compounds according to the invention can also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by and the like are included.

Among the compounds of formula 1, preferred are those wherein R is hydrogen, hydroxy, cyano, bromo, methoxy, amino, aminosulfonyl or Wherein R ¹ is hydrogen or hydroxy.

Representative compounds among the compounds of the formula (1) include the following compounds.

1. 3- (2-amino-4-pyrimidinyl) -2-naphthol;

2. 3- (2-amino-4-pyrimidinyl) -6-methoxy-2-naphthol;

3. 3- (2-amino-4-pyrimidinyl) -2,6-naphthalenediol;

4. 3- (2-amino-4-pyrimidinyl) -6-bromo-2-naphthol;

5. 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphthalenesulfonamide;

6. 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphtonitrile;

7. 7- (2-amino-4-pyrimidinyl) -N, 6-dihydroxy-2-naphthalenecarboxyimideamide;

8. 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphthalenecarboxyimideamide; And

9. 6-amino-3- (2-amino-4-pyrimidinyl) -2-naphthol.

On the other hand, the compound of formula 1 according to the present invention can be prepared according to the method as described below. However, the method for preparing the compound according to the present invention, for example, reaction conditions such as a reaction solvent, a base, and the amount of the reactant used, or a reaction sequence, is not limited to those described below, and described herein Various synthesis methods disclosed in the publicly known literature can be easily prepared by combining them, and such combinations are conventional techniques that are generalized to those skilled in the art.

The compound of formula 1 according to the present invention may be prepared by reacting a compound of formula 10 with guanidine and sodium ethoxide.

In which R is as defined above.

According to the above method, the process of preparing the compound of Formula 1 may be preferably performed in a solvent, and ethanol is particularly preferably used as the solvent. The reactants, guanidine and sodium ethoxide, are preferably used in an amount of 5 to 50 equivalents based on the compound of formula (10) as the starting material, and guanidine is preferably used in the form of hydrochloride. The reaction is usually carried out at reflux temperature of the solvent.

On the other hand, the compound of Formula 10 used as a starting material in the process of preparing a compound of Formula 1 according to the present invention can be prepared according to the method as shown in Scheme 1, for example.

In which R is as defined above.

First, the compound of formula 5 as a starting material is dissolved in N, N-dimethylformamide, 3 equivalents of potassium carbonate and an excess of methane iodide are added, stirred at room temperature for 3 hours, concentrated and hydrolyzed with lithium hydroxide to give a compound of formula 6 Get The compound is reacted with 2.5 to 3 equivalents of thionyl chloride in a dichloromethane solvent and then excess dimethylamine is added to give a compound of formula 7. This compound is reacted with 2.5 to 3 equivalents of methylmagnesium bromide for about 24 hours to obtain the compound of formula 8, followed by reaction with 3 equivalents of aluminum chloride in dichloromethane solvent to obtain the compound of formula 9. This compound is reacted with an excess of N, N-dimethylformamide diethylacetal to give the compound of formula 10.

Specific reaction conditions of the preparation method may refer to the following Preparation Examples and Examples.

After the reaction is completed, the product can be separated and purified by conventional workup methods such as chromatography, recrystallization and the like.

The compound of formula 1 according to the present invention can be usefully used as an anticancer agent because of its excellent inhibitory activity against CDKs. Accordingly, another object of the present invention is to provide an anticancer composition comprising a compound of Formula 1, a pharmaceutically acceptable salt, a hydrate, a solvate or an isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. It is done.

While 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 0.01 to 100 mg per kg of body weight, the specific dose level for a particular patient will be the specific compound to be used. May vary depending on body weight, sex, health status, diet, time of administration, method of administration, excretion rate, drug mixing and severity of disease.

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 include water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are conventionally employed as a solvent or suspending medium. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may be used in the preparation of injectables.

Solid dosage forms for oral administration may be capsules, tablets, pills, powders and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms are prepared by mixing the active compound of formula 1 according to the present invention with a carrier selected from one or more inert diluents such as sucrose, lactose, starch and the like, lubricants such as magnesium stearate, disintegrants and binders.

In the case where the compound of the present invention is to be clinically administered to obtain a desired anticancer effect, the active compound of Formula 1 may be administered simultaneously with at least one component selected from known anticancer agents. Anticancer agents that can be administered in combination with the compounds of the present invention in this manner include 5-fluorouracil, cisplatin, doxorubicin, taxol, gemcitabine, and the like.

However, the compound-containing preparation according to the present invention for the purpose of anticancer effect is not limited to those described above, and any agent useful for the treatment and prevention of cancer may be included.

Hereinafter, the present invention will be described in more detail by the following Preparation Examples, Examples and Experimental Examples. However, these preparation examples, examples and experimental examples are only intended to help the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

Preparation Example 1

Synthesis of 3-methoxy-2-naphthoic acid

After dissolving 10.0 g (53.0 mmol) of 3-hydroxy-2-naphthoic acid in 200 ml of N, N-dimethylformamide, 22 g (160 mmol) of potassium carbonate and 40 ml of iodide methane were added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated, 180 mL of tetrahydrofuran and 60 mL of methanol were added, and 6.70 g (160 mmol) of lithium hydroxide was dissolved in 60 mL of water, followed by stirring at room temperature for 2 hours. After completion of the reaction, 200 ml of 1 normal hydrochloric acid aqueous solution was added to form a white solid. This was filtered and dried to obtain 10.04 g (49.6 mmol, yield 93.6%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.78 (1H, s), 7.91 (1H, d), 7.78 (1H, d), 7.58 (1H, t), 7.45 (1H, t), 7.30 (1H, s), 7.25 (1H, s), 4.17 (3H, s)

ESI MS (m / e) = 203 [M + 1]

Preparation Example 2

Synthesis of 3-methoxy-N, N-dimethyl-2-naphtamide

10.04 g (49.6 mmol) of the compound obtained in Preparation Example 1 was dissolved in 150 mL of dichloromethane, and 9.04 mL (126 mmol) of thionyl chloride and 0.5 mL of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was completely concentrated, 100 mL of tetrahydrofuran was added, and 60 mL (120 mmol) of 2.0 mol dimethylamine methanol solution was added thereto. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, 150 ml of water was added, followed by extraction twice with 100 ml of ethyl acetate and concentrated again. 50 ml of diethyl ether was added to the residue, which was stirred for 30 minutes and filtered to obtain 7.08 g (30.8 mmol, 62.0% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.74-7.72 (2H, m), 7.71 (1H, s), 7.45 (1H, t), 7.35 (1H, t), 7.25 (1H, s), 7.15 (1H, s), 3.93 (3H, s ), 3.14 (3H, s), 2.83 (3H, s)

ESI MS (m / e) = 230 [M + 1]

Preparation Example 3

Synthesis of 1- (3-methoxy-2-naphthyl) -1-ethanone

6.24 g (27.2 mmol) of the compound obtained in Preparation Example 2 was dissolved in 100 mL of tetrahydrofuran, and then 28 mL (84 mmol) of 3 mol methylmagnesium bromide tetrahydrofuran solution was added thereto, and the mixture was stirred at room temperature for 27 hours. After completion of the reaction, the mixture was concentrated, 200 ml of water was added thereto, and 150 ml of ethyl acetate was extracted twice, and concentrated again. 100 ml of normal hexane was added to the residue, followed by stirring for 30 minutes, followed by filtration to obtain 5.34 g (26.6 mmol, yield 98%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.16 (1H, s), 7.82 (1H, d), 7.71 (1H, d), 7.50 (1H, t), 7.36 (1H, t), 7.18 (1H, s), 4.00 (3H, s), 2.67 (3H, s)

ESI MS (m / e) = 201 [M + 1]

Preparation Example 4

Synthesis of 1- (3-hydroxy-2-naphthyl) -1-ethanone

2.65 g (13.3 mmol) of the compound obtained in Preparation Example 3 was dissolved in 50 mL of dichloromethane, and 5.3 g (40 mmol) of aluminum chloride was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated, 100 ml of water was added thereto, stirred for 30 minutes, and filtered to obtain 2.23 g (12.0 mmol, 90.1%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 11.56 (1H, s), 8.34 (1H, s), 7.81 (1H, d), 7.67 (1H, d), 7.51 (1H, t), 7.33 (1H, t), 7.27 (1H, s), 2.78 (3 H, s)

ESI MS (m / e) = 187 [M + 1]

Preparation Example 5

Synthesis of (E) -3- (dimethylamino) -1- (3-hydroxy-2-naphthyl) -2-propen-1-one

To 2.05 g (11.0 mmol) of the compound obtained in Preparation Example 4, 20 ml of N, N-dimethylformamide diethyl acetal was added and stirred under reflux for 2 hours. After completion of the reaction, concentrated, 100ml of water was added, stirred for 30 minutes and filtered to give 2.32g (9.63mmol, 87.5% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.25 (1H, s), 7.92 (1H, d), 7.76 (1H, d), 7.63 (1H, d), 7.43 (1H, d), 7.27-7.23 (2H, m), 5.97 (1H, d ), 3.21 (3H, s), 3.04 (3H, s)

ESI MS (m / e) = 242 [M + 1]

Example 1

Synthesis of 3- (2-amino-4-pyrimidinyl) -2-naphthol

5 ml of ethanol was added to 200 mg (0.84 mmol) of the compound obtained in Preparation Example 5, 265 mg (2.775 mmol) of guanidine hydrochloride and 189 mg (2.775 mmol) of sodium ethoxide were added thereto, and the mixture was stirred under reflux for 4 hours. After completion of the reaction, the reaction solution was concentrated, 50 ml of water was added to the residue, stirred for 30 minutes, filtered and dried to obtain 160 mg (0.68 mmol, 80.4%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.66 (1H, s), 8.43 (1H, s), 7.89 (1H, d), 7.70 (1H, d), 7.48-7.45 (2H, m), 7.31 (1H, t), 7.27 (1H, s ), 7.20 (2H, s)

ESI MS (m / e) = 238 [M + 1]

Preparation Example 6

Synthesis of 3,7-dimethoxy-2-naphthoic acid

The reaction was carried out in the same manner as in Preparation Example 1, except that 1.54 g (7.06 mmol) of 3-hydroxy-7-methoxy-2-naphthoic acid was used instead of 3-hydroxy-2-naphthoic acid. Compound 1.60 g (6.89 mmol, yield 97.7%) was obtained.

¹ H NMR (CDCl ₃ , ppm); δ 8.10 (1H, s), 7.76 (1H, d), 7.39-7.37 (2H, m), 7.19 (1H, d), 3.87 (3H, s), 3.83 (3H, s)

ESI MS (m / e) = 233 [M + 1]

Preparation Example 7

Synthesis of 1- (3,7-dimethoxy-2-naphthyl) -1-ethanone

1.55 g (6.68 mmol) of the compound obtained in Preparation Example 6 were reacted in the order of Preparation Example 2 and Preparation Example 3 to obtain 1.01 g (4.39 mmol, 65.7% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.06 (1H, s), 7.62 (1H, d), 7.17 (1H, d), 7.14-7.12 (2H, m), 3.96 (3H, s), 3.88 (3H, s), 2.67 (3H, s )

ESI MS (m / e) = 231 [M + 1]

Preparation Example 8

Synthesis of 1- (3-hydroxy-7-methoxy-2-naphthyl) -1-ethanone

0.98 g (4.26 mmol) of the compound obtained in Preparation Example 7 were reacted in the same manner as in Preparation Example 4, to obtain 0.89 g (4.12 mmol, 96.7%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 11.44 (1H, s), 8.26 (1H, s), 7.59 (1H, d), 7.25-7.23 (2H, m), 7.09 (1H, s), 3.96 (3H, s), 2.76 (3H, s )

ESI MS (m / e) = 217 [M + 1]

Example 2

Synthesis of 3- (2-amino-4-pyrimidinyl) -6-methoxy-2-naphthol

250 mg (1.16 mmol) of the compound obtained in Preparation Example 8 were reacted in the order of Preparation Example 5 and Example 1 to obtain 170 mg (0.64 mmol, 54.9%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.54 (1H, s), 8.43 (1H, s), 7.64 (1H, d), 7.41 (1H, d), 7.30 (1H, s), 7.23 (1H, s), 7.16 (2H, s), 7.14 (1 H, d), 3.84 (3 H, s)

ESI MS (m / e) = 268 [M + 1]

Example 3

Synthesis of 3- (2-amino-4-pyrimidinyl) -2,6-naphthalenediol

20 ml of dichloromethane was added to 100 mg (0.37 mmol) of the compound obtained in Example 2, 1.0 ml of 2.0 mol boron tribromide was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated, 20 ml of diethyl ether was added thereto, stirred for 30 minutes, filtered and dried to obtain 80 mg (0.32 mmol, yield 84.5%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.61 (1H, s), 8.53 (1H, s), 7.74 (1H, d), 7.44 (1H, d), 7.33 (1H, s), 7.27 (1H, s), 7.20 (2H, s), 7.14 (1 H, d)

ESI MS (m / e) = 254 [M + 1]

Preparation Example 9

Synthesis of 7-bromo-3-hydroxy-2-naphthoic acid

10.61 g (30.7 mmol) of 1,6-dibromo-2-hydroxy-3-naphthoic acid and 3.64 g (30.7 mmol) of tin were dissolved in 162 ml of acetic acid and 38 ml of concentrated hydrochloric acid and stirred under reflux for 5 hours. After the completion of the reaction, the mixture was cooled to room temperature, 500 ml of water was added, stirred for 10 minutes, filtered, and dried to obtain 8.0 g (30.0 mmol, 98.8%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.53 (1H, s), 8.27 (1H, s), 7.75 (1H, d), 7.64 (1H, s), 7.35 (1H, s)

ESI MS (m / e) = 267 [M + 1]

Preparation Example 10

Synthesis of 7-bromo-3-methoxy-2-naphthoic acid

5.07 g (20.0 mmol) of the compound obtained in Preparation Example 9 were reacted in the same manner as in Preparation Example 1, to obtain 4.80 g (17.1 mmol, of 90.0%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.43 (1H, s), 8.21 (1H, s), 7.65 (1H, d), 7.59 (1H, s), 7.30 (1H, s), 4.02 (3H, s)

ESI MS (m / e) = 281 [M + 1]

Preparation Example 11

Synthesis of 7-bromo-3-methoxy-N, N-dimethyl-2-naphtamide

2.60 g (9.25 mmol) of the compound obtained in Preparation Example 10 were reacted by the method of Preparation Example 2, to obtain 2.56 g (8.34 mmol, 90.1%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.90 (1H, s), 7.60 (1H, s), 7.58 (1H, d), 7.53 (1H, d), 7.12 (1H, s), 3.92 (3H, s), 3.15 (3H, s), 2.83 (3H, s)

ESI MS (m / e) = 308 [M + 1]

Preparation Example 12

Synthesis of 1- (7-bromo-3-methoxy-2-naphthyl) -1-ethanone

2.55 g (8.27 mmol) of the compound obtained in Preparation Example 11 were reacted by the method of Preparation Example 3, to obtain 2.29 g (8.23 mmol, 99.6% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.04 (1H, s), 7.97 (1H, s), 7.59 (1H, d), 7.54 (1H, d), 7.14 (1H, s), 4.01 (3H, s), 2.67 (3H, s)

ESI MS (m / e) = 279 [M + 1]

Preparation Example 13

Synthesis of 1- (7-bromo-3-hydroxy-2-naphthyl) -1-ethanone

0.46 g (1.65 mmol) of the compound obtained in Preparation Example 12 were reacted by the method of Preparation Example 4, to obtain 0.43 g (1.63 mmol, 98.7%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 11.59 (1H, s), 8.29 (1H, s), 8.01 (1H, s), 7.60-7.58 (2H, m), 7.24 (1H, s), 2.78 (3H, s)

ESI MS (m / e) = 265 [M + 1]

Example 4

Synthesis of 3- (2-amino-4-pyrimidinyl) -6-bromo-2-naphthol

0.40 g (1.52 mmol) of the compound obtained in Preparation Example 13 were reacted by the method of Example 2, obtaining 0.38 g (1.21 mmol, 79.4%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.63 (1H, s), 8.47 (1H, d), 8.14 (1H, s), 7.71 (1H, d), 7.57 (1H, d), 7.42 (1H, d), 7.31 (1H, s)

ESI MS (m / e) = 316 [M + 1]

Preparation Example 14

Synthesis of 7-acetyl-6-methoxy-2-naphthalenesulfonamide

2.28 g (11.4 mmol) of the compound obtained in Preparation Example 3 were dissolved in 80 ml of dichloroethane, and 3 ml (45.7 ml) of chlorosulfonic acid was added thereto, followed by stirring under reflux for 1 hour. After completion of the reaction, the reaction mixture was cooled to 0 deg. This was filtered, washed with 30 ml of diethyl ether and dried to give 890 mg (3.19 mmol, yield 28.0%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.43 (1H, s), 8.29 (1H, s), 8.04 (1H, d), 7.84 (1H, d), 7.59 (1H, s), 7.42 (2H, s), 3.99 (3H, s), 2.60 (3H, s)

ESI MS (m / e) = 280 [M + 1]

Preparation Example 15

Synthesis of 7-acetyl-6-hydroxy-2-naphthalenesulfonamide

800 mg (2.87 mmol) of the compound obtained in Preparation Example 14 were reacted in the same manner as in Preparation Example 4, to obtain 730 mg (2.75 mmol, 96.0%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.51 (1H, s), 8.80 (1H, s), 8.47 (1H, s), 7.92 (1H, d), 7.88 (1H, d), 7.41 (2H, s), 7.39 (1H, s), 2.77 (3H, s)

ESI MS (m / e) = 266 [M + 1]

Example 5

Synthesis of 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphthalenesulfonamide

500 mg (1.89 mmol) of the compound obtained in Preparation Example 15 were reacted by the method of Example 2, to obtain 450 mg (1.42 mmol, 75.1%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.93 (1H, s), 8.48 (1H, d), 8.41 (1H, s), 7.89 (1H, d), 7.81 (1H, d), 7.52 (1H, d), 7.40 (2H, s), 7.37 (1 H, s), 7.28 (2 H, s)

ESI MS (m / e) = 317 [M + 1]

Preparation Example 16

Synthesis of 7-acetyl-6-methoxy-2-naphtonitrile

1.70 g (6.12 mmol) of the compound obtained in Preparation Example 12 was dissolved in 50 mL of N, N-dimethylformamide, and copper cyanide 660 mg (7.34 mmol) was added thereto, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the reaction mixture was concentrated and 150 ml of ammonia water was added and stirred for 20 minutes. The reaction solution was extracted twice with 50 ml of ethyl acetate and concentrated again. 50 ml of normal hexane was added to the residue, which was stirred for 10 minutes, filtered, washed with 10 ml of diethyl ether, and dried to obtain 1.35 g (6.0 mmol, 98.0%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.20 (1H, s), 8.17 (1H, s), 7.80 (1H, d), 7.61 (1H, d), 7.21 (1H, s), 4.03 (3H, s), 2.67 (3H, s)

ESI MS (m / e) = 226 [M + 1]

Preparation Example 17

Synthesis of 7-acetyl-6-hydroxy-2-naphtonitrile

1.28 g (5.69 mmol) of the compound obtained in Preparation Example 16 were reacted in the same manner as in Preparation Example 4, to obtain 1.11 g (5.26 mmol, of 92.5%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 11.82 (1H, s), 8.42 (1H, s), 8.22 (1H, s), 7.73 (1H, d), 7.60 (1H, d), 7.25 (1H, s), 2.82 (3H, s)

ESI MS (m / e) = 212 [M + 1]

Example 6

Synthesis of 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphtonitrile

1.10 g (5.21 mmol) of the compound obtained in Preparation Example 17 were reacted by the method of Example 2, to obtain 1.05 g (4.08 mmol, 76.9%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.67 (1H, s), 8.81 (1H, s), 8.50-8.48 (2H, m), 7.90 (1H, d), 7.67 (1H, d), 7.44 (1H, d), 7.40 (1H, s ), 7.28 (2H, s)

ESI MS (m / e) = 263 [M + 1]

Example 7

Synthesis of 7- (2-amino-4-pyrimidinyl) -N, 6-dihydroxy-2-naphthalenecarboxyimideamide

After dissolving 220 mg (0.84 mmol) of the compound obtained in Example 6 in 30 ml of ethanol, 580 mg (8.4 mmol) of hydroxyamine hydrochloride and 705 mg (8.4 mmol) of sodium bicarbonate were added thereto, and the mixture was stirred under reflux for 24 hours. After completion of the reaction, the solids were filtered out and concentrated. 50 ml of ethyl acetate was added, stirred for 30 minutes, and further filtered through a filter paper. The filtered ethyl acetate solution was concentrated and separated by column chromatography (eluent: methanol / dichloromethane = 1/9, v / v) to give 100 mg (0.34 mmol, yield 40.4%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.69 (1H, s), 8.74 (1H, s), 8.47-8.44 (2H, m), 8.18 (1H, s), 7.78 (1H, d), 7.74 (1H, d), 7.47 (1H, d ), 7.31 (1H, s), 7.22 (2H, s), 5.84 (2H, s)

ESI MS (m / e) = 296 [M + 1]

Example 8

Synthesis of 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphthalenecarboxyimideamide

250 mg (0.95 mmol) of the compound obtained in Example 6 was dissolved in 20 ml of pyridine and 5 ml of triethylamine, cooled, and passed through a hydrogen sulfide gas until saturated. After sealing completely, the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated, 30 ml of acetonitrile and 1 ml (16.1 mmol) of methane iodide were added, followed by stirring under reflux for 2 hours. Concentrated again, 30 ml of acetonitrile and 400 mg (5.18 mmol) of ammonium acetate were added thereto, followed by stirring under reflux for 6 hours. After completion of the reaction, concentrated, 30ml of water was added, stirred for 10 minutes, filtered and dried to give 150mg (0.54mmol, 56.6% yield) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.33 (1H, s), 9.07 (1H, s), 8.83 (1H, s), 8.50 (1H, d), 8.44 (1H, s), 7.94 (1H, d), 7.73 (1H, d), 7.51 (1H, d), 7.42 (1H, s), 7.29 (2H, s)

ESI MS (m / e) = 280 [M + 1]

Preparation Example 18

Synthesis of 4-bromo-3-hydroxy-2-naphthoic acid

4.24 g (22.5 mmol) of 3-hydroxy-2-naphthoic acid was dissolved in 100 mL of acetic acid, and then 1.16 mL (22.5 mmol) of bromine was diluted in 5 mL of acetic acid and added dropwise for 30 minutes. After dropping, the mixture was stirred at room temperature for 1 hour and concentrated. 250 ml of water was added thereto, stirred for 10 minutes, filtered and dried to obtain 4.80 g (18.0 mmol, yield 80.2%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.63 (1H, s), 8.08 (1H, d), 8.04 (1H, d), 7.73 (1H, t), 7.47 (1H, t)

ESI MS (m / e) = 267 [M + 1]

Preparation Example 19

Synthesis of 4-bromo-3-methoxy-2-naphthoic acid

4.0 g (15.0 mmol) of the compound obtained in Preparation Example 18 were reacted in the same manner as in Preparation Example 1, to obtain 4.01 g (14.3 mmol, the yield of 95.5%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.51 (1H, s), 8.01 (1H, d), 7.92 (1H, d), 7.61 (1H, t), 7.40 (1H, t), 4.02 (3H, s)

ESI MS (m / e) = 281 [M + 1]

Preparation Example 20

Synthesis of 4-bromo-3-methoxy-N, N-dimethyl-2-naphtamide

4.0 g (14.3 mmol) of the compound obtained in Preparation Example 19 were reacted by the method of Preparation Example 2, to obtain 4.05 g (13.2 mmol, yield 92.3%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.23 (1H, d), 7.80 (1H, d), 7.75 (1H, s), 7.67 (1H, t), 7.51 (1H, t), 3.94 (3H, s), 3.18 (3H, s), 2.87 (3H, s)

ESI MS (m / e) = 308 [M + 1]

Preparation Example 21

Synthesis of 1- (4-bromo-3-methoxy-2-naphthyl) -1-ethanone

3.90 g (12.7 mmol) of the compound obtained in Preparation Example 20 were reacted by the method of Preparation Example 3, to obtain 3.15 g (11.3 mmol, 89.2%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.21 (1H, d), 7.75 (1H, d), 7.72 (1H, s), 7.61 (1H, t), 7.45 (1H, t), 4.00 (3H, s), 2.60 (3H, s)

ESI MS (m / e) = 279 [M + 1]

Preparation Example 22

Synthesis of 1- (3-methoxy-7-nitro-2-naphthyl) -1-ethanone

1.57 g (5.63 mmol) of the compound obtained in Preparation Example 21 was dissolved in 100 mL of acetic anhydride, and 1.63 g (6.75 mmol) of copper nitrate was added thereto, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated, 100 ml of water was added, 50 ml of ethyl acetate was extracted twice, and concentrated again. Column chromatography (developing solution: ethyl acetate / normal hexane = 1/4, v / v) was separated to give 250 mg (1.02 mmol, yield 18.1%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.78 (1H, s), 8.30 (1H, s), 8.26 (1H, d), 7.84 (1H, d), 7.27 (1H, s), 4.08 (3H, s), 2.69 (3H, s)

ESI MS (m / e) = 246 [M + 1]

Preparation Example 23

Synthesis of 1- (7-amino-3-methoxy-2-naphthyl) -1-ethanone

200 mg (0.82 mmol) of the compound obtained in Preparation Example 22 was dissolved in 50 mL of methanol, followed by 80 mg of 10% palladium / carbon, followed by stirring under a hydrogen pressure with a balloon for 2 hours. The palladium / carbon solid was filtered off using celite and the filtrate was concentrated to give 170 mg (0.79 mmol, 96.4% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.91 (1H, s), 7.54 (1H, d), 7.07 (1H, s), 6.96 (1H, d), 6.94 (1H, s), 3.94 (3H, s), 2.65 (3H, s)

ESI MS (m / e) = 216 [M + 1]

Preparation Example 24

Synthesis of 1- (7-amino-3-hydroxy-2-naphthyl) -1-ethanone

160 mg (0.74 mmol) of the compound obtained in Preparation Example 23 were reacted in the same manner as in Preparation Example 4, to obtain 135 mg (0.67 mmol, 90.8% yield) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.13 (1H, s), 7.56 (1H, d), 7.20 (1H, s), 7.05 (1H, d), 6.99 (1H, s), 3.97 (2H, s), 2.79 (3H, s)

ESI MS (m / e) = 202 [M + 1]

Example 9

Synthesis of 6-amino-3- (2-amino-4-pyrimidinyl) -2-naphthol

110 mg (0.55 mmol) of the compound obtained in Preparation Example 24 were reacted by the method of Example 2, to obtain 95 mg (0.37 mmol, 68.0%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 12.01 (1H, s), 8.31-8.28 (2H, m), 7.72 (1H, s), 7.49 (1H, d), 7.30 (1H, d), 7.18 (1H, s), 7.11 (1H, d ), 7.09 (2H, s), 2.92 (2H, s)

ESI MS (m / e) = 253 [M + 1]

Experimental Example 1

Inhibitory Activity of CDK1 and CDK2

Inhibitory activity of CDK1 and CDK2 was determined by Kitagawa method [Kitagawa, M. et al., Oncogene 9 ; 2549, 1994].

First, CDK1 is a cyclin truncated at the human N-terminus produced by cleaving amino terminal 86 amino acids containing baculovirus expressing the CDK1 gene and a signal sequence cleaved by Ubquitin. ) Infected cells with baculovirus expressing B1 gene at the same time and purified activating enzyme were used. CDK2 is an insect that infects baculovirus expressing CDK2 gene and baculovirus expressing cyclin A gene at the same time. Cell extracts or activators purified therefrom were used. The substrates of CDK1 and CDK2 were histone H1 or Rb protein. Compounds diluted at different concentrations were added, and an appropriate amount of CDK1 / cycline B1 or CDK2 / cyclin A was added to the substrate protein and [Gamma- ³² P labeled] ATP, and then the substrate was separated to measure the radioactivity of the substrate. .

According to the method described above, the inhibitory capacity of each enzyme activity of the inhibitor according to the present invention, which was measured for CDK1 and CDK2, was expressed as an IC50 value. The results are as shown in Table 1 below.

Experimental Example 2

Measurement of growth inhibition of cells [SRB (Sulforhodamine B) assay]

Cancer cells (HCT-116, A549, or NCI-H460) grown with RPMI1640 medium containing 5% FBS in a 37 ° C. incubator containing 5% carbon dioxide were added to 2000-3000 cells per well in a 96-well plate. I grew up in a day. After diluting each compound with the same medium to make a 2x stock of the concentration to be treated, 100 μl of each was added to the wells and treated for 48 hours. Cells were then fixed by treatment with 100 μl of 4% formaldehyde solution per well. After leaving at room temperature for 1 hour or more, the solution was discarded, washed 3-4 times with tap water, and then dried in a 50 ° C. dryer. 50 μl of a 1% acetic acid stain solution containing 0.4% SRB was added to each well, and the cells were stained for about 1 hour. The dye solution was removed, and each well was washed 3-4 times with 1% acetic acid solution and dried again in a 50 ° C. dryer. 100 μl of a 10 mM Tris (pH 10.5) solution was added to each well to elute the SRB dye attached to the cells for 30 minutes. The 96-well plate was then transferred to a reader (specttraMax 340) to determine the amount of cells by measuring absorbance at 530 nm (reference wavelength 650 nm).

As a result of experiments on three cell lines according to the method described above, the growth inhibitory capacity of each cell line of the inhibitor according to the present invention was found to be in the range of GI50> 10 ~ 0.1 μM.

Claims (5)

Compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof: [Formula 1] In the above formula R is hydrogen, hydroxy, cyano, halogen, C ₁ -C ₄ -alkyloxy, amino, aminosulfonyl or In which R ¹ is hydrogen or hydroxy. The compound of claim 1 wherein R is hydrogen, hydroxy, cyano, bromo, methoxy, amino, aminosulfonyl or Wherein R ¹ is hydrogen or hydroxy. The method of claim 1, 3- (2-amino-4-pyrimidinyl) -2-naphthol; 3- (2-amino-4-pyrimidinyl) -6-methoxy-2-naphthol; 3- (2-amino-4-pyrimidinyl) -2,6-naphthalenediol; 3- (2-amino-4-pyrimidinyl) -6-bromo-2-naphthol; 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphthalenesulfonamide; 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphtonitrile; 7- (2-amino-4-pyrimidinyl) -N, 6-dihydroxy-2-naphthalenecarboxyimideamide; 7- (2-amino-4-pyrimidinyl) -6-hydroxy-2-naphthalenecarboxyimideamide; And 6-amino-3- (2-amino-4-pyrimidinyl) -2-naphthol. A process for preparing the compound of formula 1 as defined in claim 1 characterized by reacting a compound of formula 10 with guanidine and sodium ethoxide: [Formula 10] Wherein R is as defined in claim 1. An anticancer composition comprising a compound of formula (I), a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as defined in claim 1 as an active ingredient with a pharmaceutically acceptable carrier.