KR20010077073A - C-2,6,9 substituted isopropylpurine derivatives and a preparation thereof - Google Patents

Abstract

PURPOSE: Provided are novel adenine compounds which inhibit the cyclin dependent kinase (CDK), specifically, isopropylpurine derivatives with the substitution at C-2,6,9 positions and their preparation method. These adenine compounds are more effective than existing olomousine and roscovitine in CDK inhibition. CONSTITUTION: The compounds are represented by chemical formula 1, wherein R1 is piperidino, piperazino, pyrrolidino or thiomorpholino group which is substituted by one or more groups selected from hydroxyalkyl amino, hydroxy, hydroxyalkyl, carboxylic acid, aldehyde and oxim group. Most preferably R1 is hydroxyalkylamino or 4-carboxy-2-hydroxymethyl pyrrolidino group. The preparation process includes the steps of: reacting 2,6-dichloropurine with 3-chloroaniline in butanol solution; reacting the resultant compound with isopropyl halide in the presence of strong base and reacting the product, in 4:1 mixed solvent of n-butanol and DMSO, with piperidine, piperazino, pyrrolidino or thiomorpholino group which is substituted by one or more group selected from hydroxyalkyl amino, hydroxy, hydroxyalkyl, carboxylic acid, aldehyde and oxim group.

Description

Isopropylpurine derivative substituted in the C- 2, 6, Y position and its manufacturing method {C-2,6,9 SUBSTITUTED ISOPROPYLPURINE DERIVATIVES AND A PREPARATION THEREOF}

The present invention relates to novel adenine-based compounds useful as inhibitors of cyclin dependent kinases (CDKs). More specifically, the present invention relates to isopropylpurine derivatives substituted at the C-2,6,9 positions and methods for preparing the same.

Cell division circuits typically have two main phases, one of which is the S phase to replicate DNA and the other is the M phase where cell division occurs. The first stage, G1, is a step for synthesizing cells for DNA replication and G2 is a step for cell division. This cell division is controlled by a protein kinase called cyclin dependent kinase (CDK _S ).

Thus, protein kinases are important enzymes that must be present in cell division. Cyclin-dependent kinase (CDK) is a key component of cell division. In general, CDK consists of two subunits, one of which is catalytic, consisting of cdk1 (= cdc2) to cdk8, and the other is a subunit that controls cell division from cyclin A to cyclin H. These cdk proteins are controlled by various post-translational modifications (phosphorylation and dephosphorylation), either by translation and transcription of their subunits or by forming complex structures, interacting with various protein inhibitors. In addition, the crystal structure of cdk2 and cdk2 / cyclin A has recently been revealed, allowing a more accurate understanding of the mechanism and activity of enzymes.

Many examples of cdk non-control in primary tumors and tumor cell lines of humans have been disclosed, and this observation is hopeful for the study of selective chemical inhibitors of cdk protein and the use of natural inhibitors for effective gene therapy. A few years ago a simple screening was done with pure p34 cdc2 / cyclin B and 6-dimethylaminopurine was first identified as a cdc2 inhibitor (Ic ₅₀ (controllable concentration of 50): 120 μM). As purine derivatives of this nature are known, many derivatives thereafter have been synthesized.

Representative of this is olomousine; 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine] was identified as an excellent cdc2 inhibitor (IC ₅₀ : 7 μΜ). Olamusin was originally a compound designed as a cytokinin 7-glucosyltransferase inhibitor, but has been found to have a very good effect as a cdc2 inhibitor. Since the discovery of these compounds, many purine derivatives have been synthesized by combining various substituents at the N-9 and C-2 positions of the purines. Among them, roscovitine having a simple alkyl group in the N-9 position and a fatty alcohol group in the C-2 position is about 10 times more effective than olomusine. 2- (2-2-ethyl-2-hydroxyethylamino) -6-benzylamino-9-isopropylpurine, IC ₅₀ : 0.4 μM] was synthesized and disclosed.

Accordingly, it is an object of the present invention to provide an adenine-based compound having a more excellent effect than olomusine, lascobitin, which is known as a CDK inhibitor, and a method of preparing the same.

The present invention relates to isopropylpurine derivatives having the formula

Wherein R ₁ is a hydroxyalkylamino group or a piperidino group, a piperazino group, a pyrrolidino group optionally having one or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, carboxylic acid, aldehyde and oxime Or thiomorpholino group.

Alkyl in the hydroxyalkylamino group of R ₁ is preferably a lower alkyl group having 1-6 carbon atoms. More specifically, the substituent R ₁ is a hydroxyalkylamino group, a piperazino group, a 4- (2-hydroxyethyl) piperazino group, a 4-hydroxypiperidino group, a thiomorpholino group, one or two hydroxy groups More preferred are a pyrrolidino group having, a pyrrolidino group having an oxime group, a pyrrolidino group having a carboxyl group and a hydroxy group, and a 2-hydroxymethylpyrrolidino group. Most preferably, R ₁ is a hydroxyalkylamino group or 4-carboxy-2-hydroxymethylpyrrolidino group.

In addition, the present invention also relates to a method for preparing an adenine-based compound and isopropylpurine derivative substituted at the C-2,6,9 position, which is made as follows:

a) reacting 2,6-dichloropurine with 3-chloroaniline in a butanol solvent,

b) reacting the resulting 2-chloro-6- (3-chloroanilino) purine with isopropyl halide in the presence of a strong base,

c) the resulting 2-chloro-6- (3-chloroanilino) -9-isopropylpurine in the group consisting of hydroxyalkylamine or hydroxy, hydroxyalkyl, carboxylic acid, aldehyde and oxime React with piperidine, piperazine, pyrrolidine, or thiomorpholine optionally having one or more substituents selected from. Such a method for producing the adenine compound of the present invention is shown in the following scheme 1.

In the formula, R ₁ is as described above.

Particularly preferably, the step c) may be performed using a solvent in which n -butanol and dimethyl sulfoxide are mixed at 4: 1 as an organic solvent.

In addition, the isopropylpurine compound of the present invention in which R ₁ having an oxime group is substituted is introduced by introducing an R ₁ substituent having a hydroxy group at a corresponding position, and then reacting hydroxyamine after oxidatively converting the hydroxy group to an aldehyde group. Can be.

Of course, the adenine-based compounds of the present invention can be prepared through various routes by methods conventional in the art.

The invention is illustrated in more detail by the following examples and preparations, but is not intended to limit the invention thereto.

[Production example]

A specific preparation example for preparing the adenine compound of the present invention is shown in the following scheme 2. Generally, 2,6-dichloropurine is used as a starting material for synthesizing adenine derivatives, which are expensive reagents and are difficult to use, and thus, in the actual research process, as shown in Scheme 2, adenine is used as a starting material. , 6-dichloropurine was prepared and used directly.

As shown in Scheme 2, hypodensine 1-N-oxide (3) can be obtained by oxidizing adenine with hydrogen peroxide to form adenine 1-oxide (2) and then sandmer reaction with 30 acetic acid and sodium nitrite. . Chlorination of this with phosphoryloxychloride allows the synthesis of the desired 2,6-dichloropurine (4). By reacting the purine compound (4) with 3-chloroaniline at 90 ° C. under an n-butanol solvent, the purine compound (5) having 3-chloroaniline substituted at the carbon number 6 can be obtained. In this case, if the temperature is increased to 100 ° C. or more, the carbon may be substituted at the second carbon position, and temperature control is very important, and the reaction time (24 hours) may be extended to obtain a product. The compound (5) thus obtained can be reacted with (CH ₃ ) ₂ CH-I using sodium hydride (NaH) as a strong base to synthesize an isopropylpurine compound (6). The reaction temperature may be carried out at room temperature, and the reaction may be performed at 50 ° C. for about 10 hours to improve the yield. The isopropyl purine compound (6) may be reacted with an amine compound to be substituted at the carbon position 2 using n -butanol solvent as an organic solvent under a bath temperature of 170 ° C. to obtain a target compound (7). As described above, a good yield can be obtained by mixing n -butanol and dimethyl sulfoxide in a ratio of 4: 1 by using an organic solvent during the reaction.

On the other hand, a specific example of introducing a substituent having an oxime group at the carbon position 2 is shown in the following scheme 3. First, an isopropylpurine compound (7 g) having an alcohol-substituted pyrrolidino group is prepared, and then the alcohol group is converted into an aldehyde group (7j) using an oxalic chloride, and then the aldehyde group is reacted with hydroxy amine. The isopropylpurine compound (7k) which has an oxime group was obtained.

Example 1

Adenine 1-ene-oxide (2)

Adenine (40 g, 0.296 mol) and acetic acid (240 mL) were added to a round flask and refluxed for 1 hour. After adenine was dissolved, it was cooled to room temperature and 30 hydrogen peroxide (148 mL, 1.5 mol) was added dropwise at room temperature. After standing at room temperature for 3 days, a white solid was formed. It was filtered and dried at room temperature.

Yield: 31.3 g (69.9), Melting point:> 300 ° C

Example 2

Hypoxanthine 1-ene-oxide (3)

29 acetic acid (1500 mL) was added to a round flask and sodium nitrite (100 g, 1.45 mol) was dissolved. Adenine 1-ene oxide ( 2 , 20 g, 0.132 mol) was added thereto, stirred for 2 hours, and left to stand at room temperature for 4 days. The resulting yellow solid was filtered and dried at room temperature.

Yield: 13.25 g (66), Melting Point:> 300 ° C

Example 3

2,6-dichloropurine (4)

To the flask was added hypoxanthine 1-ene-oxide ( 3 , 1.0 g, 6.57 mmol), triethylamine (2.5 mL, 18 mmol) and phosphoryloxychloride (70 mL, 0.77 mol).

After refluxing for 6 hours, excess phosphoryloxychloride was removed by distillation. Water and ethyl ether were added to the remaining product, the organic layer was separated, the solvent was removed, and the residue was purified by column chromatography to obtain 2,6-dichloropurine compound ( 4 ) as a yellow solid.

Yield: 0.5 g (40.1), Melting point: 177-178 ° C

Example 4

6- (3-chloroanilino) -2-chloropurine (5)

2,6-dichloropurine ( 4 , 4.0 g, 20 mmol) was added to n -butanol and slightly heated to dissolve. 3-chloroaniline (7.2 mL, 56.7 mmol) was added thereto, and stirred at 90 ° C. for 24 hours. After completion of the reaction, water and ethyl acetate were added and the organic layer was separated. After removing the organic solvent, it was purified by column chromatography to give a white solid.

Yield: 4.8 g (81.0), Melting point:> 300 ° C

¹ H-NMR (DMSO d-6): δ 7.16 (d, 1H, J = 7.7 Hz), 7.38 (t, 1H, J = 8.1 Hz), 7.86 (d, 1H, J = 7.44 Hz), 8.07 ( s, 1 H), 8.99 (s, 1 H), 10.58 (s, 1 H).

Example 5

6- (3-chloroanilino) -9-isopropylpurine (6)

In a nitrogen atmosphere, sodium hydride (NaH, 0.03 g, 1.46 mmol) was added to the flask, and a solution of 6- (3-chloroanilino) -2-chloropurine ( 5 , 0.28 g, 1 mmol) in DMF was added to the flask. Dropped in

Isopropyliodine ((CH ₃ ) ₂ CH-I, 3.34 g, 2 mmol) was added by syringe and then stirred at 50 ° C. for 2 days. After the reaction was completed, water and ethyl acetate were added, the organic layer was separated, and the organic solvent was removed. It was purified by column chromatography and then the organic solvent was removed.

Yield: 0.31 g (94.0), Melting point: 102-105 ° C

¹ H-NMR (CDCl ₃ ): δ 1.63 (d, 6H, J = 9.99 Hz), 4.78 (m, 1H, J = 6.66 Hz), 7.11 (d, 1H), 7.28 (t, 1H), 7.78 ( d, 1H), 7.88 (s, 1H), 7.99 (s, 1H).

Example 6

6- (3-chloroanilino) -2- (2-hydroxyethylamino) -9-isopropylpurine (7a)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 100 mg, 0.31 mmol) was dissolved in a mixed solvent of n -butanol and DMSO (4: 1), followed by ethanolamine (370 mg, 0.6 mmol). Was added drop wise. The mixture was stirred at a bath temperature of 170 ° C. for 6 hours, water and ethyl acetate were added, the organic layer was separated, and the organic solvent was removed. Recrystallization with ethyl acetate and hexane gave a white solid.

Yield: 80 mg (74.3), Melting point: 130-132 ° C, Molecular weight: 347 (C ₁₄ H ₁₃ Cl ₂ N ₅ )

¹ H-NMR (CDCl ₃ ): δ 1.55 (d, 6H, J = 4.83 Hz), 3.66 (t, 2H, J = 3.27 Hz), 3.88 (t, 2H, J = 4.69 Hz), 4.70 (m, 1H), 5.77 (t, 1H), 7.05 (d, 1H), 7.23 (t, 1H, J = 8.55 Hz), 7.45 (d, 1H, J = 7.80 Hz), 7.6 (s, 1H), 7.85 ( s, 1 H), 8.06 (s, 1 H).

Example 7

6- (3-chloroanilino) -2- (1- (2-hydroxyethyl) piperazino) -9-isopropyl-

Purine (7b)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 200 mg, 0.62 mmol) was dissolved in a mixed solvent of n -butanol and DMSO (4: 1) and then 1- (2-hydroxyethyl) Piperazine (1.0 g, 7.7 mmol) was added dropwise. After stirring for 6 hours at 170 ℃ water bath, water and ethyl acetate was added, the organic layer was separated and the organic solvent was removed. This was recrystallized with ethyl acetate and hexane to give a white solid.

Yield: 150 mg (84.2), Melting Point: 125-130 ° C, Molecular Weight: 416 (C ₂₀ H ₂₆ ClN ₇ O)

¹ H-NMR (CDCl ₃ ): δ 1.55 (d, 6H, J = 7.68 Hz), 2.54 (M, 6H), 3.7 (t, 2H), 3.83 (t, 4H, J = 8.38 Hz), 4.63 ( m, 1H), 7.01 (d, 1H, J = 7.86 Hz), 7.22 (t, 1H, J = 8.17 Hz), 7.41 (d, 1H, J = 1.185 Hz), 7.60 (s, 1H), 7.89 ( s, 1H), 8.10 (s, 1H)

Example 8

6- (3-chloroanilino) -2- (4-hydroxypiperidino) -9-isopropylpurine (7c)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 200 mg, 0.62 mmol) was dissolved in a mixed solvent of n -butanol and DMSO (4: 1), followed by 4-hydroxypiperidine (800 mg, 7.9 mmol) was added dropwise. After stirring for 6 hours at 170 ℃ bath water, recrystallized with ethyl acetate and hexane to give a white solid.

Yield: 180 mg (74.1), Melting point: 190-193 ° C, Molecular weight: 387 (C ₁₉ H ₂₃ CIN ₆ O)

¹ H-NMR (CDCl ₃ ): δ 1.56 (d, 6H, J = 8.13 Hz), 1.4 (t, 4H, J = 7.62 Hz), 2.02 (t, 4H, J = 8.08 Hz), 3.98 (m, 1H), 4.49 (m, 1H), 7.24 (t, 1H), 7.38 (d, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.25 (s, 1H)

Example 9

6- (3-chloroanilino) -2-piperazino-9-isopropylpurine (7d)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 100 mg, 0.31 mmol) was dissolved in a mixed solvent of n -butanol and DMSO (4: 1) and then piperazine (500 mg, 5.8 mmol) Was added drop wise. After stirring at a bath temperature of 170 ° C. for 6 hours, water and ethyl acetate were added to separate the organic layer, and the organic solvent was removed. This was recrystallized with ethyl acetate and hexane to give a white solid.

Yield: 80 mg (71.0), Melting point: 150-152 ° C, Molecular weight: 372 (C ₁₈ H ₂₂ ClN ₇ )

¹ H-NMR (CDCl ₃ ): δ 1.54 (d, 6H, J = 6.69 Hz), 2.97 (t, 4H, J = 4.92 Hz), 3.69 (t, 4H, J = 6.60 Hz), 4.68 (m, 1H), 6.97 (D, 1H, J = 9.03 Hz), 7.21 (t, 1H, J = 8.07 Hz), 7.42 (d, 1H, J = 4.36 Hz), 7.60 (s, 1H), 8.07 (s, 1H), 8.17 (s, 1H)

Example 10

6- (3-chloroanilino) -2-thiomorpholino-9-isopropylpurine (7e)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 100 mg, 0.31 mmol) was dissolved in a mixed solvent of n -butanol and DMSO (4: 1), followed by thiomorpholine (500 mg, 4.85 mmol). ) Was added dropwise. After stirring for 6 hours at a bath temperature of 170 ° C., water and ethyl acetate were added to separate the organic layer, and the organic solvent was removed. This was recrystallized from ethyl acetate and hexane to give a white solid.

Yield: 70 mg (62.6), Melting point: 235-240 ° C, Molecular weight: 389 (C ₁₈ H ₂₁ ClN ₆ S)

¹ H-NMR (CDCl ₃ ): δ 1.68 (d, 6H, J = 6.81 Hz), 2.71 (m, 4H, J = 7.04 Hz), 4.20 (m, 4H, J = 2.54 Hz), 4.67 (m, 1H), 7.08 (d, 1H, J = 6.03 Hz), 7.27 (t, 1H, J = 8.21 Hz), 7.61 (d, 1H, J = 6.18 Hz), 8.21 (s, 1H), 8.52 (s, 1H).

Example 11

6- (3-chloroanilino) -2- (2-methanolpiperidino) -9-isopropylpurine (7f)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 150 mg, 0.46 mmol) was dissolved in a mixed solvent of n -butanol and DMSO (4: 1), followed by 2-hydroxymethylpiperidine ( 500 mg, 4.3 mmol) was added dropwise. After stirring for 6 hours at a bath temperature of 170 ° C, water and ethyl acetate were added, the organic layer was separated, and the organic solvent was removed. This was recrystallized from ethyl acetate and hexane to give a white solid.

Yield: 80 mg (42.1), Melting point: 195-200 ° C, Molecular weight: 401 (C ₂₀ H ₂₅ ClN ₆ O)

¹ H-NMR (CDCl ₃ ): δ 1.57 (d, 6H, J = 8.33 Hz), 3.15 (m, 2H), 3.37 (m, 2H), 3.79 (m, 2H), 4.11 (m, 2H), 4.67 (m, 1H), 4.74 (t, 2H), 5.02 (m, 1H), 7.03 (d, 1H), 7.25 (m, 3H), 7.38 (d, 1H), 7.58 (s, 1H), 8.15 (s, 1 H).

Example 12

6- (3-chloroanilino) -2- (2-hydroxymethylpyrrolidino) -9-isopropylpurine

(7 g)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 250 mg, 0.77 mmol) was dissolved in a mixed solvent of n -butanol and DMSO (4: 1), followed by 2-hydroxymethylpyrrolidine ( 2000 mg, 20 mmol) was added dropwise. After stirring for 6 hours at a bath temperature of 170 ° C, water and ethyl acetate were added, the organic layer was separated, and the organic solvent was removed. This was recrystallized from ethyl acetate and hexane to give a white solid.

Yield: 180 mg (60.2), Melting point: 185-188 ° C, Molecular weight: 387 (C ₂₀ H ₂₅ ClN ₆ O)

¹ H-NMR (CDCl ₃ ): δ 1.47 (d, 1H), 1.77 (m, 2H), 1.98 (m, 2H), 2.15 (m, 2H), 3.79 (m, 4H), 4.94 (m, 2H ), 4.58 (m, 1H, J = 6.83 Hz), 6.99 (d, 1H, J = 7.89 Hz), 7.22 (t, 1H, J = 8.09 Hz), 7.44 (d, 1H, J = 7.74 Hz), 7.56 (s, 1H), 8.06 (s, 1H), 8.19 (s, 1H)

Example 13

6- (3-chloroanilino) -2- (4-carboxy-2-hydroxymethylpyrrolidino) -9-iso-

Propylpurine (7h)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 100 mg, 0.31 mmol) is dissolved in a mixed solvent of n -butanol and DMSO (4: 1), and then 4-carboxy-2-hydroxymethyl Pyrrolidine (1.1 g, 8.54 mmol) was added dropwise. After stirring for 6 hours at a bath temperature of 170 ° C, water and ethyl acetate were added, the organic layer was separated, and the organic solvent was removed. This was recrystallized from ethyl acetate and hexane to give a white solid.

Yield: 60 mg (48.3), Melting point: 150-154 ° C, Molecular weight: 403 (C ₁₉ H ₂₃ ClN ₆ O ₂ )

¹ H-NMR (CDCl ₃ ): δ 1.38 (d, 6H), 1.48 (d, 2H, J = 6.36 Hz), 2.30 (m, 1H), 3.61 (m, 2H), 3.81 (d, 1H), 4.35 (t, 2H, J = 9.82 Hz), 4.56 (s, 1H), 6.83 (d, 1H, J = 7.68 Hz), 7.05 (t, 1H, J = 7.99 Hz), 7.22 (d, 1H, J = 7.83 Hz), 7.52 (s, 1H), 7,96 (s, 1H), 8.38 (s, 1H)

Example 14

6- (3-chloroanilino) -2- (4-hydroxy-2-hydroxymethylpyrrolidino) -9-iso-

Propylpurine (7i)

6- (3-chloroanilino) -9-isopropylpurine ( 6 , 100 mg, 0.31 mmol) is dissolved in a mixed solvent of n -butanol and DMSO (4: 1) and then 4-hydroxy-2-hydroxy Methylpyrrolidine (1.0 g, 8.54 mmol) was added dropwise. The mixture was stirred at a bath temperature of 170 ° C. for 6 hours, water and ethyl acetate were added, the organic layer was separated, and the organic solvent was removed. This was recrystallized from ethyl acetate and hexane to give a white solid.

Yield: 60 mg (47.8), Melting point: 113-115 ° C, Molecular weight: 403 (C ₁₉ H ₂₃ CIN ₆ O ₂ )

¹ H-NMR (CDCl ₃ ): δ 1.38 (d, 6H), 1.48 (d, 2H, J = 6.36 Hz), 2.30 (m, 1H), 3.61 (m, 2H), 3.81 (d, 1H), 4.35 (t, 2H, J = 9.82 Hz), 4.56 (s, 1H), 6.83 (d, 1H, J = 7.68 Hz), 7.05 (t, 1H, J = 7.99 Hz), 7.22 (d, 1H, J = 7.83 Hz), 7.52 (s, 1H), 7.96 (s, 1H), 8.38 (s, 1H)

Example 15

6- (3-chloroanilino) -2- (2-N-oximemethylpyrrolidino) -9-isopropylpurine

(7k)

Methylene chloride (10 mL) and oxaric chloride (39.3 mL, 0.3097 mmol) were added to a round bottom flask, and methylsulfoxide (44.36 mL, 0.568 mmol) dissolved in methylene chloride at -78 ° C was added dropwise. In this reaction mixture, 6- (3-chloroanilino) -2- (2-hydroxymethylpyrrolidino) -9-isopropylpurine ( 7 g , 100 mg, 0.258 mmol) was dissolved in methylene chloride, and then -78. It was added dropwise at ℃ and stirred for 1 hour. After triethylamine (13.03 mg, 1.29 mmol) was added, the temperature was gradually raised to room temperature (7j). After the reaction was completed, the reaction mixture was extracted with methylene chloride and the organic layer was washed with brine. The obtained material (7j) was dissolved in methanol (5 mL) and added dropwise to water in which hydroxyamine hydrochloride (11.7 mg, 0.17 mmol) and sodium carbonate (20.6 mg, 0.19 mmol) were dissolved. After stirring at room temperature for one day, the mixture was extracted with ethyl acetate. The solvent was removed and then recrystallized from methylene chloride and hexane.

Yield: 20 mg (16.0), Melting point: 154-160 ° C, Molecular weight: 400 (C ₁₉ H ₂₂ ClN ₇ O)

¹ H-NMR (CDCl ₃ ): δ 1.57 (d, 1H), 2.06 (m, 2H), 2.18 (m, 2H), 2.42 (m, 2H), 3.82 (m, 4H), 4.67 (m, 1H ), 5.26 (m, 1H), 6.92 (d, 1H), 7.17 (t, 1H), 7.27 (s, 1H), 7.61 (s, 1H), 8.21 (m, 3H), 11.88 (s, 1H)

IR: 3497, 1673 cm ^-1

Example 16

Inhibitory activity of the isopropylpurine derivatives of the present invention on CDK-2 is shown in Table 1 below. Roscovitine, known to be effective for CDK inhibition, is shown as a control. It can be seen that the isopropylpurine derivatives of the present invention not only show a similar CDK inhibitory effect as the conventional CDK inhibitors, but also show superior values.

Compound no. IC ₅₀ (μM) CDK2 CDK4 7a 0.35 7.1 7d 0.9 4.5 7f 0.9 6.9 7 g 0.9 7.8 7h 0.3 6.5 Roscovitine 0.5 -

As described above, in the present invention, 3-chloroaniline is substituted at the 6th carbon position, isopropyl is introduced at the N-9 position, and cyclic alkylamine such as hydroxyalkylamine, piperidine, and piperazine at the C-2 position. Substituting the group provides a novel adenine-based compound having excellent potency to CDK2.

Claims (5)

Isopropylpurine derivatives having the formula Formula 1 Wherein R ₁ is a hydroxyalkylamino group or a piperidino group, a piperazino group, a pyrroli, which may be substituted with one or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, carboxylic acid, aldehyde and oxime Dino group or thiomorpholino group. The method according to claim 1, wherein R ₁ is a hydroxyalkylamino group, a piperazino group, a 4- (2-hydroxyethyl) piperazino group, a 4-hydroxypiperidino group, a thiomorpholino group, one or two hydroxy groups An isopropyl derivative which is a pyrrolidino group having a, a pyrrolidino group having an oxime group, a pyrrolidino group having a carboxyl group and a hydroxy group, and a 2-hydroxymethylpyrrolidino group. The isopropyl derivative according to claim 2, wherein R ₁ is a hydroxyalkylamino group or a 4-carboxy-2-hydroxymethylpyrrolidino group. a) reacting 2,6-dichloropurine with 3-chloroaniline in a butanol solvent, b) reacting the resulting 2-chloro-6- (3-chloroanilino) purine with isopropyl halide in the presence of a strong base, c) the resulting 2-chloro-6- (3-chloroanilino) -9-isopropylpurine in the group consisting of hydroxyalkylamine or hydroxy, hydroxyalkyl, carboxylic acid, aldehyde and oxime A method for preparing an isopropylpurine derivative having the formula (I) consisting of reacting with piperidine, piperazine, pyrrolidine, or thiomorpholine, which may be substituted with one or more substituents selected from: Formula 1 In the formula, R ₁ is as described above. 4. The process according to claim 3, wherein step c) is carried out in a 4: 1 mixed solvent of butanol and dimethylsulfoxide.