KR100377138B1 - Cyclin's Zonkinase Inhibitor with Purine Structure, Methods for Making the Same, and Anticancer Compositions Containing the Same - Google Patents

Abstract

The present invention relates to a cyclin dependent kinase inhibitor having a purine structure of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, a method for preparing the same, and an anticancer composition containing the same as an active ingredient. .

[Formula 1]

Where

R ₁ represents substituted or unsubstituted alkyl, substituted or unsubstituted benzyl or substituted or unsubstituted aryl,

R ₂ represents substituted or unsubstituted alkyl,

R ₃ represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl,

n is 0, 1 or 2.

Description

Cycline-dependent kinase inhibitors having a purine structure, a method for preparing the same, and an anticancer composition containing the same

The present invention relates to a compound of formula (1), more particularly, a novel cyclin dependent kinase (hereinafter referred to as 'CDK') inhibitor having a purine structure of formula (1), a pharmaceutically acceptable salt thereof, Hydrates, solvates and isomers, methods for preparing the same, and anticancer compositions containing the same as active ingredients.

[Formula 1]

Where

R ₁ represents substituted or unsubstituted alkyl, substituted or unsubstituted benzyl or substituted or unsubstituted aryl,

R ₂ represents a substituted or unsubstituted alkyl,

R ₃ represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl,

n is 0, 1 or 2.

The full-scale study at the molecular level of cell division began to develop in the late 1980s through the study of the division of frog eggs, characterization of cell growth or radioactive mutations in yeast, and the study of Rb, a tumor suppressor. Regulatory mechanisms of cell division began to be elucidated in the 1990s. Small cell growth regulators regulate cell growth, differentiation, development, aging and apoptosis through their cell growth regulation functions. Turned out to be. These findings have already helped to better understand the pathological phenomena of many diseases, and cancer is a prime example. In the process of transforming normal cells into cancer cells, the loss of the regulation of cell growth is frequently found. The analysis of cancer cells showed that the activity of cell growth regulators was different from that of normal cells, and in particular, there was a strong correlation with invasion and metastasis, which is the most problematic problem in cancer pathology. Induction of Overexpression or Knock-out of Cell Growth Regulators Using Transgenic Animals The induction of cancer in these animals is caused by cell cycle deregulation. Is a direct factor.

The cell growth process is subject to positive and negative regulation just like any other biological regulation. The main framework of cell cycle regulation known to date is determined by the activity of CDK, and the activity of CDK is positive or negative depending on the environment in which cells are located. Many studies of cancer cells or carcinogenic mechanisms have found problems with this regulation or side regulation. In other words, excessive excessive positive effects or loss of side regulation and timely regulation, an important aspect of cell growth regulation, have been pointed out as problems in cancer cells.

Representative CDKs in mammals can be classified into three types: CDK4, which is active in the medium-G1 phase of the cell cycle, CDK1, which is active in the CDK2 and G2-M phases, which are active in the phase-G1 and S phases. CDC2). Among them, CDK4 and CDK2 are known to be regulated by G1-S cell cycle check point and CDC2 is regulated by G2-M check point. Various cancer cells show abnormalities in the regulatory mechanisms of CDK4, CDK2 and CDC2 (CDK1), and in fact, artificially induced abnormalities in transgenic animals caused cancer. This proves that, among other CDKs, CDK4 and CDK2 and CDC2 (CDK1) are the most promising targets as anticancer agents.

With respect to the case of CDK4, the association between the ideal regulation of CDK4 activity and the induction of cancer is well demonstrated in various cancer tissues. Deletion of p16 and p15 has been reported in several cancers, in particular overexpression of Cyclin D1 is seen in several cancers, in particular associated with metastasis of breast cancer. This suggests that the activity of deregulated CDK4 is a factor in the malignant phenotype of cancer cells. The report that p16 knock-out mice are as cancerous as p53 knock-out mice demonstrates that p16 CDK4 dysregulation is responsible for cancer, and that downstream of NIH 3T3 cells overexpressing ras or src. This shows the possibility of playing that role in. Conversely, it was observed that the modified phenotype transforming p16 or P21 to ras was converted to the normal phenotype. The experimental evidence above demonstrates the clear fact that deregulation of CDK4 activity is a cause of cancer and further shows the possibility of playing a role in maintaining the phenotype of cancer cells. Therefore, it is assumed that inhibitors of CDK4 are very likely to have excellent anticancer effects.

In the case of CDK2, overexpression of Cycline E has been observed in some breast cancers, and it is well known that it is strongly associated with metastasis of breast cancer. Overexpression of Cycline E has been proposed to inhibit cell death under low serum conditions and to cause anchorage independent growth. Hyperproliferation (neoplasia) of breast epithelial cells was observed in CDK2 overexpressing transgenic animals using the MMTV promoter. This strongly suggests that CDK2 activity is involved in the process of cell transformation or its maintenance, demonstrating the high potential of CDK2 inhibitors as anticancer agents.

In addition, CDC2 (CDK1), CDK3, CDK5, CDK6, CDK7, etc. have also been found to play an important role in each step of the cell division process, and is divided into families of the same Cyclin CDKs. Also for cyclins, in addition to cyclin D1 or cyclin E, cyclins A, B, C, D2, D3, D4, F, and cyclin. G also belongs to the same family.

Based on the accumulated research results, recent researches have been conducted to develop inhibitors that effectively inhibit these CDKs as targets of anticancer drugs. Representative compounds that have been developed as effective CDK inhibitors to date, flavopyridols of formula (2) are disclosed in EP 0,241,003 (1987) and 0,366,061 (1990).

[Formula 2]

In addition, CDK inhibitors having a purine structure of Formula 3 have been disclosed in WO 97/16447.

[Formula 3]

Therefore, the present inventors conducted intensive studies on inhibitors of these CDKs, in particular, purine-based compounds. As a result, all of the known purine-based compounds have a structure in which position 2 is connected to a nitrogen atom. The novel compound of formula (I) having a sulfur-substituted structure was found to inhibit CDK very effectively and to complete the present invention.

Accordingly, it is an object of the present invention to provide a novel CDK inhibitor of formula (I) having a purine structure, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, and methods for their preparation.

Still another object of the present invention is to provide an anticancer composition containing the compound of Formula 1 as an active ingredient.

First, the present invention provides a compound of formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof.

[Formula 1]

Where

R ₁ represents substituted or unsubstituted alkyl, substituted or unsubstituted benzyl or substituted or unsubstituted aryl,

R ₂ represents substituted or unsubstituted alkyl,

R ₃ represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl,

n is 0, 1 or 2.

Wherein R ₁ represents substituted or unsubstituted benzyl or substituted or unsubstituted phenyl, R ₂ represents substituted or unsubstituted alkyl, R ₃ preferably represents substituted or unsubstituted alkyl, and Among them, R ₁ represents benzyl substituted with alkoxy or phenyl substituted with halo, carboxy or halo and carboxy, R ₂ represents unsubstituted alkyl, and R ₃ represents alkyl substituted with hydroxy or amino. desirable.

Representative compounds according to the invention include 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -ethanol; 1- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-2-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propane-1,2-diol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-1-ol; 2- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -ethanol; (2-aminoethylsulfanyl-9-isopropyl-9H-purin-6-yl)-(4-methoxy-benzyl) -amine; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfinyl] -ethanol; 3- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propan-2-ol; 3- [6- (3-chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propane-1,2-diol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfonyl] -ethanol; 2- [6- (3-chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfinyl] ethanol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-1-ol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -butan-1-ol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -3-methylbutan-1-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -butan-1-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -pentan-1-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -4-methylpentan-1-ol; 2- [6- (3-Chloro-4-carboxyl-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -ethanol; 3- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propan-1-ol; Or 3- [6- (3-chloro-4-carboxyl-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propan-1-ol.

Secondly, the present invention provides an anticancer agent composition containing an effective anticancer compound of Formula 1 as an active ingredient.

Third, the present invention is prepared by reacting a compound of formula 4 with a compound of formula 5 in the presence of a base to prepare a compound of formula 6, and reacting a compound of formula 6 with a compound of formula 7 in the presence of a base to prepare a compound of formula 8 It provides a process for the preparation of the compound of formula (1) comprising the step of reacting a compound of formula (8) with a compound of formula (9).

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

Wherein R ₁ , R ₂ , R ₃ and the same as defined above,

X represents a halogen.

Hereinafter, the present invention will be described in detail.

In the present invention, CDK includes CDK2, CDK4, CDC2 (CDK1), CDK3, CDK5, CDK6, CDK7, and the like. The concept includes both G and.

The compounds of formula (1) according to the invention may form pharmaceutically acceptable salts, such pharmaceutically acceptable salts include acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example Inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc. Acid addition salts formed by sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid and the like.

In addition, the compound of formula 1 according to the present invention may have an asymmetric carbon center and therefore may exist as racemic compounds, diastereomeric mixtures or individual diastereomers, all of these isomeric forms are also within the scope of the present invention.

As shown in Scheme 1, the compound of Formula 1 according to the present invention may be prepared from the compound of Formula 4 to the compound of Formula 6 and the compound of Formula 8 to n = 0.

Scheme 1

Wherein R ₁ , R ₂ , R ₃ and X are as defined above.

That is, the compound of formula 4 is ₃ to 17 at 90 ° C. using a solvent such as amine (Formula 5) and normal butanol having ₁ to 1.5 equivalents of R ₁ in the presence of a base capable of neutralizing the hydrochloric acid produced in this reaction. Reaction for a time gives a compound of formula 6. The compound was reacted with a halogen substance having R ₂ in the presence of a base such as sodium hydride (NaH) (Formula 7) in a dimethylformamide (DMF) solvent at 80 ° C. for 1 to 20 hours to obtain a compound of Formula 8 do. This compound was reacted with thiol (Formula 9) having the same equivalent to the same volume of solvent as R ₃ in a high boiling point solvent such as normal butanol, dimethyl sulfoxide or N-methylpyrrolidin for 1 to 48 hours at 50 to 170 ° C. Reaction to give the compound of formula 1. The compound of formula 1 thus obtained is a compound of n = 0.

In addition, as shown in Scheme 2, a sulfoxide or sulfone compound having n = 1 or 2 may be obtained by oxidizing a compound of Formula 1 having n = 0 with various oxidizing agents.

Scheme 2

Wherein R ₁ , R ₂ , and R ₃ are as defined above.

That is, when n = 0 is reacted with an oxidizing agent such as m-chloroperbenzoic acid, oxone, thibutylhydroperoxide, hydrogen peroxide, sodium periodinate (NaIO ₄ ), etc. Can be obtained.

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

Since the compound of the formula (1) according to the present invention has a potent CDK inhibitory activity, the composition containing it can be usefully used as an anticancer agent. For this purpose, the compound of formula (1) is combined with a carrier which is commonly accepted in the pharmaceutical field, and conventional formulations in the pharmaceutical field, such as tablets, capsules, troches, solutions, suspensions or the like preparations. Injectable preparations, ointments in the form of injectable solutions or suspensions, or ready-to-use injectable dry powders which can be prepared by injection into distilled water for injection. It can be formulated into various formulations, such as topical formulations such as creams and solutions. Carriers which can be used in the present invention are conventional in the pharmaceutical field, for example, in the case of oral preparations, binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments or There are fragrances, and in the case of injectables, there are preservatives, analgesics, solubilizers or stabilizers, and in the case of topical administration, there are bases, excipients, lubricants or preservatives. The pharmaceutical preparations thus prepared may be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally, or topically. In addition, in order to prevent the decomposition of the drug by gastric acid during oral administration, an antacid may be used in combination, or a solid preparation for oral administration such as tablets may be formulated into a formulation coated with enteric skin.

The dosage of the compound of formula 1 according to the present invention to the human body is appropriately selected depending on the absorption of the active ingredient in the body, the rate of inactivation and excretion, the age, sex and condition of the patient, the severity of the disease to be treated and the like. The unit dosage form thus formulated may be divided into several divided doses at regular time intervals or by using a specialized dosage method according to the judgment of an expert who monitors or observes the administration of the drug as needed and the needs of the individual.

EXAMPLE

The present invention is explained in more detail by the following examples and experimental examples, but the scope of the present invention is not limited in any way by these.

Preparation Example 1 Synthesis of (2-Chloro-9H-purin-6-yl)-(4-methoxy-benzyl) -amine

1 g (5.29 mmol) of 2,6-dichloropurine, 0.87 g (1.2 m equivalent) of 4-methoxybenzylamine and 1.5 ml of triethylamine were added to 30 ml of normal butanol, followed by stirring at 90 ° C. for 5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with 50 ml of ethyl acetate, and washed twice with 10 ml of water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained solid was added with a small amount of ethyl acetate and stirred, followed by filtration to obtain 1.4 g of a white target compound (yield 92%).

Preparation Example 2 Synthesis of (2-Chloro-9H-purin-6-yl)-(3-chloro-phenyl) -amine

In Preparation Example 1, 1 g (yield 70%) of the target compound was obtained by reacting the same method using 0.8 g (1.2 mol equivalent) of 3-chloroaniline instead of 4-methoxybenzylamine.

Preparation Example 3 Synthesis of (2-Chloro-isopropyl-9H-purin-6-yl)-(4-methoxy-benzyl) -amine

0.5 g (1.7 mmol) of the compound obtained in Preparation Example 1 was dissolved in 20 mL of DMF, and 0.25 g (1.2 mol equivalent) of 2-bromopropane was added thereto. 0.1 g (1.5 mol equivalent) of NaH was added thereto at room temperature, followed by stirring at 80 ° C. for 17 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and diluted with 50 ml of ethyl acetate. The organic solution was washed with 5 ml of 0.1 N aqueous hydrochloric acid solution and 20 ml of water and dried over anhydrous magnesium sulfate. After filtering, a small amount of ethyl acetate was added to the solid obtained by concentrating, stirring well, and filtering to obtain 0.5 g (yield 89%) of the target compound as a white solid.

Preparation Example 4 Synthesis of (2-Chloro-9-isopropyl-9H-purin-6-yl)-(3-chloro-phenyl) -amine

In Preparation Example 3, the compound obtained from Preparation Example 2 was used instead of the compound obtained in Preparation Example 1, and reacted in the same manner to obtain 0.35 g (yield 63%) of the title compound.

Example 1 Synthesis of 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -ethanol

0.1 g (0.3 mmol) of the compound obtained in Preparation Example 3 was dissolved in 1 ml of solvent N-methylpyrrolidine and 0.5 ml of reagent mercaptoethanol, and stirred at 170 ° C. for 20 hours. The reaction was cooled and diluted with 10 ml of ethyl acetate, and then washed 5 times with 1 ml of 0.1 N aqueous hydrochloric acid solution and 1 ml of water. The mixture obtained after concentration was purified using recovery plate chromatography (eluate ethyl acetate-hexane = 1: 1 volume ratio). As a result, 51 mg (45%) of the title compound as a white solid were obtained.

Example 2 Synthesis of 1- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-2-ol

In Example 1, 37 mg (yield 32%) of the title compound were obtained by reacting in the same manner using the reagent 1-mercapto-2-propanol instead of mercaptoethanol.

Example 3 Synthesis of 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propane-1,2-diol

In Example 1, 41 mg (yield 34%) of the target compound were obtained by reacting in the same manner using the reagent 3-mercapto-1,2-propanediol instead of mercaptoethanol.

Example 4 Synthesis of 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-1-ol

In Example 1, 55 mg of the target compound (yield 47%) was obtained by reacting in the same manner using the reagent 1-mercapto-3-propanol instead of mercaptoethanol.

Example 5 Synthesis of 2- [6- (chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -ethanol

In Example 1, 47 mg of the target compound (yield 42%) was obtained by reacting in the same manner using 0.1 g (0.31 mmol) of the compound obtained from Preparation Example 4 instead of the compound obtained from Preparation Example 3.

Example 6 Synthesis of (2-Aminoethylsulfanyl-9-isopropyl-9H-purin-6-yl)-(4-methoxy-benzyl) -amine

In Example 1, the reaction was carried out in the same manner using reagent 1-mercapto-2-ethylamine instead of mercaptoethanol. Here, the washing with an aqueous hydrochloric acid solution was omitted during the purification, and as a result, 59 mg (yield 53%) of the title compound was obtained.

Example 7 Synthesis of 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfinyl] -ethanol

10 mg (0.027 mmol) of the compound obtained in Example 1 was dissolved in 2 ml of methylene chloride, 13 mg (2 mol equivalent) of m-chloroperbenzoic acid (m-CPBA) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated and purified using column chromatography. As a result, 5.4 mg (yield 52%) of the title compound as a white solid were obtained.

Example 8 Synthesis of 3- [6- (3-chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propan-2-ol

According to the same method as in Example 5, the starting material obtained in Preparation Example 4 was reacted with 1-mercapto-2-propanol to obtain 47 mg (yield 39%) of the title compound.

Example 9 Synthesis of 3- [6- (3-chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propane-1,2-diol

According to the same method as in Example 5, the starting material obtained in Preparation Example 4 was reacted with 3-mercapto-1,2-propanediol to obtain 29 mg (yield 22%) of the title compound.

Example 10 Synthesis of 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfonyl] -ethanol

10 mg (0.027 mmol) of the compound synthesized in Example 1 was dissolved in 2 ml of methanol, and 58 mg (10 mol equivalent) of sodium periodinate (NaIO ₄ ) was added thereto, followed by heating to reflux for 10 hours. After the reaction was completed, the mixture was concentrated to a temperature and purified using column chromatography. 2.7 mg (25% yield) of the title compound as a white solid were obtained.

Example 11 Synthesis of 2- [6- (3-chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfinyl] -ethanol

20 mg (0.057 mmol) of the compound synthesized in Example 5 was dissolved in 3 ml of methylene chloride, 30 mg (2 mol equivalent) of m-chloroperbenzoic acid (m-CPBA) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated and purified using column chromatography. 10.5 mg (54% yield) of the title compound as a white solid were obtained.

Experimental Example 1 Inhibitory Activity of CDK2 and CDK4

Assays of CDK2 inhibitory effect followed the Kitagawa method (Kitagawa, M. et al .; Oncogene, 9: 2549, 1994), and CDK2 expresses baculovirus and cyclin A genes that express the CDK2 gene. Insect cell extracts infected with baculovirus or purified active enzymes were used, and histone H1 or Rb protein was used as a substrate of CDK2.

Assays of CDK4 inhibitory effects were followed by Carlson's method (Carlson, BA et al .; Cancer Research 56: 2473, 1996), and CDK4 was characterized by baculoviruses expressing the CDK4 gene and baculoviruses expressing the Cycline D1 gene. Simultaneously infected insect cell extract or an activator purified therefrom was used, and Rb protein was used as a substrate of CDK4.

A compound of formula 1 according to the present invention diluted in concentration was added and an appropriate amount of CDK2 / Cyclin A or CDK4 / Cyclin D1, substrate protein, and ³² P labeled ATP was added and reacted, and then the substrate was separated to determine the radioactivity contained in the substrate.

According to the above method, the enzyme activity inhibition capacity of the compound of formula 1 according to the present invention measured for CDK2 and CDK4 is expressed as an IC ₅₀ value. The results are as shown in Table 1. Compounds not included in the Examples (Compounds 11 to 19) were also synthesized and purified in the same manner as in Example to determine IC ₅₀ values.

TABLE 1

As shown in Table 1, the compound of Formula 1 according to the present invention exhibits an IC ₅₀ value of <1 to <250 μM for CDK2 and CDK4, which shows excellent CDK inhibitory activity.

Experimental Example 2 Acute Oral Toxicity Test

In order to measure the acute oral toxicity of the compounds obtained in Examples 1 and 4, solutions containing the compounds in different concentrations were orally administered to male mice of the ICR strain at a dose of 10 ml per kg. After oral administration, mortality and 7 days of symptoms were observed and the median lethal dose (LD ₅₀ , mg / kg) was calculated according to the Litchfield-Wilcoxon method, and the results are shown in Table 2.

As shown in Table 2, the LD ₅₀ value is> 3,000, indicating that the compounds according to the invention are safe compounds.

CDK inhibitors having a purine structure of Formula 1 according to the present invention, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof have a novel structure as compared to the previously known purine-based CDK inhibitors, and have excellent CDK inhibition. Because of its activity, it can be usefully used as an anticancer agent.

Claims (4)

Compounds of Formula 1, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof: [Formula 1] Where R ₁ represents benzyl substituted with alkoxy or phenyl substituted with halo, carboxy or halo and carboxy, R ₂ represents unsubstituted alkyl, R ₃ represents alkyl substituted with hydroxy or amino, n is 0, 1 or 2. 2. A compound of Claim 1 further comprising: 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -ethanol; 1- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-2-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propane-1,2-diol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-1-ol; 2- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -ethanol; (2-aminoethylsulfanyl-9-isopropyl-9H-purin-6-yl)-(4-methoxy-benzyl) -amine; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfinyl] -ethanol; 3- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propan-2-ol; 3- [6- (3-chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propane-1,2-diol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfonyl] -ethanol; 2- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfinyl] -ethanol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -propan-1-ol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -butan-1-ol; 2- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -3-methylbutan-1-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -butan-1-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -pentan-1-ol; 3- [9-isopropyl-6- (4-methoxy-benzylamino) -9H-purin-2-ylsulfanyl] -4-methylpentan-1-ol; 2- [6- (3-Chloro-4-carboxyl-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -ethanol; 3- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propan-1-ol; And 3- [6- (3-chloro-4-carboxyl-phenylamino) -9-isopropyl-9H-purin-2-ylsulfanyl] -propan-1-ol; a compound selected from the group consisting of: . An anticancer composition comprising an effective anticancer compound according to claim 1 as an active ingredient. Reacting a compound of formula 4 with a compound of formula 5 in the presence of a base to prepare a compound of formula 6, Reacting a compound of formula 6 with a compound of formula 7 in the presence of a base to prepare a compound of formula 8, A method of preparing a compound of Formula 1 comprising reacting a compound of Formula 8 with a compound of Formula 9 to produce a compound of Formula 1: [Formula 1] [Formula 4] [Formula 5] [Formula 6] [Formula 7] [Formula 8] [Formula 9] Wherein R ₁ , R ₂ , R ₃ and n are the same as defined in claim 1, X represents a halogen.