KR910000442B1 - Novel 6-fluoro purine compounds and its preparation process - Google Patents

Abstract

6-Fluoropurine derivatives of formula (I) were prepared by (i) a nucleophilic substitution reaction of 6-chloropurine cpd. of formula (II) with trimethylamine in dimethylformamide solvent to produce purinetrimethyl ammonium of formula (III), and (ii) a nucleophilic substitution reaction of cpd. (III) with potassium fluoride in dimethylformamide solvent. In the formulas, X= O or S; and Y= H or hydroxymethyl.

Description

New 6-fluoropurine compounds and preparation method thereof

The present invention relates to a novel purine compound represented by the following general formula (I) having a fluoro group at the 6-position and a method for producing the same, more particularly, having an antiviral action by an enzyme present in a mammalian cell. It relates to a 6-fluoropurine compound useful as a prodrug acting as a compound, inorganic salts such as hydrochloric acid, sulfuric acid, phosphoric acid, organic salts such as acetic acid, lactic acid, fumaric acid, maleic acid, tartaric acid, and a method for producing the same. .

In the above formula, X represents an oxygen atom or a sulfur atom, and Y represents a hydrogen atom or a hydroxymethyl group.

The 6-fluoropurine compound represented by the general formula (I) is a purine compound represented by the following general formula (A) by adenosine deaminase, an enzyme abundantly present in mammalian cells. It is very useful as a prodrug of the purine compound represented by the following general formula (A), which is completely metabolized and has excellent antiviral action.

In the above formula, X and Y are as described above.

However, the purine compound represented by the general formula (A) has been widely used as an antiviral agent as a compound known in the art, but researches for improving the purine compound have been continued because of low solubility in water and low bioavailability.

Accordingly, the present inventors have studied for a long time to solve the above problems, and as a result, the water-soluble and bioavailability is superior to the conventional purine compound of the general formula (A). The 6-fluoropurine compound of I) was prepared to complete the present invention.

That is, an object of the present invention is to provide a 6-fluoropurine compound of the general formula (I) and a manufacturing method thereof.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel 6-fluoropurine compound represented by the following general formula (I).

In the above formula, X and Y are as described above. Moreover, this invention relates to the salt of the 6-fluoropurine compound represented by the said General formula (I).

In the present invention, examples of the salt of the 6-fluoropurine compound of the general formula (I) include inorganic acid salts such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acid salts such as acetic acid, lactic acid, fumaric acid, maleic acid and tartaric acid. Can be.

In addition, the present invention is a nucleophilic substitution reaction of 6-chloropurine compound of the following general formula (II) with trimethylamine (N (CH ₃ ) ₃ ) in dimethylformamide (DMF) solvent, represented by the following general formula (III) Method for producing a 6-fluoropurine compound represented by the general formula (I), characterized in that to prepare a purine trimethyl ammonium salt compound, which is then subjected to nucleophilic substitution reaction with potassium fluoride (KF) in a dimethylformamide solvent It is

In the above formula, X and Y are as described above.

Hereinafter, the present invention will be described in more detail.

The 6-fluoropurine compound of the general formula (I), which is the target compound of the present invention, is rapidly metabolized into the 6-purine compound of the following general formula (A) by adenosine deaminase in vivo. It has a viral effect.

In the above formula, X and Y are as described above.

On the other hand, in the 6-chloropurine compound of the general formula (II) used as a starting material in the present invention, a method for producing a compound in which X is an oxygen atom and Y is a hydrogen atom is Can. J. Chem. 60,547 (1982), wherein X is an oxygen atom and Y is a hydroxymethyl group. J. Chem. 62,241 (1984).

However, in the 6-chloropurine compound of the general formula (II) according to the present invention, compounds in which X is a sulfur atom and Y is a hydrogen atom or a hydroxymethyl group were prepared by applying the method introduced in the literature as a novel compound.

Further, the 6-fluoropurine compound of the general formula (I), the 6-chloropurine compound of the general formula (II), and the 6-aminopurine compound represented by the following general formula (IV) As a result of reacting with adenosine deaminase in a buffer of pH 7.5, respectively, the maximum reaction rate (Vmax) at which the 6-fluoropurine compound of the general formula (I) is metabolized to the purine compound of the general formula (A) ) Was about 7-35 times faster than the maximum reaction rate of 6-chloropurine compound of formula (II) and 6-aminopurine compound of formula (IV).

In the above formula, X and Y are as described above.

In the present invention, the results of experiments comparing the enzyme kinetics maximum metabolism maximum reaction rate for the 6-fluoropurine compound of the general formula (I) with other derivatives are shown in Table 1 below.

Therefore, the 6-fluoropurine compound represented by the general formula (I) according to the present invention as described above is a general anti-viral agent by the adenosine deaminase which is an enzyme abundantly present in the cells of the living body. Not only can it be metabolized quickly and safely to the purine compound of (A), it is also useful as a compound having high solubility in water and high bioavailability.

Example 1

Preparation of 2-amino-9-[(2-hydroxyethoxy) methyl] purine-6-trimethylammonium chloride

1.06 g of 2-amino-6-chloro-9-[(2-hydroxyethoxy) methyl] purine was dissolved in 35 ml of N, N-dimethylformamide dried over calcium hydride, and 5 ml of anhydrous trimethylamine was temporarily added thereto. After addition to the mixture, the mixture was refluxed under nitrogen stream for 3 hours at room temperature.

After adding 35 ml of anhydrous ether to the reaction mixture, the white precipitate was filtered.

The white precipitate was dissolved in 5 ml of distilled water, filtered and the filtrate was distilled under vacuum to remove the solvent.

Subsequently, the white solid thus obtained was washed with acetone and dried at 80 ° C. in a vacuum oven to obtain the target compound in a yield of about 81%.

mp: 156.5-157 ° C (dec)

IR (KBr): 3402,3298,3203,1639,1570,1528,1462,1377,1119,1103cm ^-1

¹ H NMR (DMSO-d ₆ ): δ8.58 (S, 1H, C ₈ H), 7.39 (S, 2H, NH ₂ ), 5.55 (S, 2H, NCH ₂ O), 4.82 (t, 1H, J = 5.3 Hz, CH), 3.75 (S, 9H, NMe ₃ ), 3.56-3.46 (1 m, 4H, CH ₂ CH ₂ ).

MS (EI): m / e 266 (M ⁺ -HCI), 252 (M ⁺ -CH ₃ CI), 222 (M ⁺ -C ₃ H ₉ CI), 207 (M ⁺ -CH ₃ CI-C ₂ H ₅ O), 191 (M ⁺ -CH ₃ CI-C ₂ H ₅ O ₂ ), 178 (M ⁺ -CH ₃ CI-C ₃ H ₆ O ₂ ), 149 (M ⁺ -C ₃ H ₅ CI-C ₃ H ₅ O ₂ ).

HRMS: C ₁₁ H ₁₈ N ₆ O _2, (M ⁺ -HCI) m / e 266.1482 (calcd 266.1491).

Example 2

Preparation of 2-amino-9-[(1.3-dihydroxy-2-propoxy) methyl] purin-6-trimethyl ammonium chloride

2.5 g of 2-amino-6-chloro-9-[(1.3-dihydroxy-2-propoxy) methyl] purine was dissolved in 100 ml of N, N-dimethylformamide dried over calcium hydride, and trimethyl anhydride was added thereto. 10 ml of amine was added at once and refluxed under nitrogen stream for 2 hours at room temperature.

The reaction mixture was distilled under vacuum to remove the solvent, and the resulting white solid was dissolved in 4 ml of distilled water and filtered.

200 ml of acetone was added to the filtrate, and the resultant white precipitate was filtered and dried in a vacuum oven at 80 ° C. for about several hours. The target compound was obtained in a yield of about 70%.

mp: 157-159 ℃ (dec)

IR (KBr): 3360,3275,3202,1632,1562,1532,1489,1404,1377,1366,1111,1080cm ^-1

¹ H NMR (DMSO-d ₆ ): δ8.58 (S, 1H, C ₈ H), 7.37 (S, 2H, NH ₂ ), 5.64 (S, 2H, NCH ₂ O), 4.78 (t, 2H, J = 5.6 Hz, 2OH), 3.73 (S, 9H, NMe ₃ ), 3.62 (m, 1H, CH), 3.4 5 (m, 2H, CH ₂ ), 3.32 (m, 2H, CH ₂ ).

MS (EI): m / e 296 (M ⁺ -HCI), 282 (M ⁺ -CH ₃ CI), 252 (M ⁺ -C ₃ H ₉ CI), 207 (M ⁺ -CH ₃ CI-C ₃ H ₇ O ₂ ), 191 (M ⁺ -CH ₃ CI-C ₃ H ₇ O ₃ ), 178 (M ⁺ -CH ₃ CI-C ₄ H ₈ O ₃ ), 149 (M ⁺ -C ₃ H ₉ CI- C ₄ H ₇ O ₃ ).

HRMS: C ₁₂ H ₂₀ N ₆ O _3, (M ⁺ -HCI) m / e 296.1557 (calcd 296.1597).

Example 3

Preparation of 2-amino-6-fluoro-9-[(2-hydroxyethoxy) methyl] purine

0.74 g of the compound prepared in Example 1 was added to 7 ml of N, N-dimethylformamide dried with calcium hydride, and 2.4 g of dried potassium fluoride was added thereto, followed by maintaining the vacuum at 100-300 mmHg. Heated to temperature for 1-3 hours.

The reaction mixture was filtered, and 20 ml of anhydrous toluene was added and vacuum distilled again to completely remove a small amount of N, N-dimethylformamide remaining in the white solid formed by vacuum distillation of the filtrate.

This operation was repeated two more times and then subjected to fresh chromatography using a solvent of chloroform: methyl alcohol = 9: 1 to obtain the target compound in about 60% yield.

mp: 169-170 ° C (dec)

IR (KBr): 3387,3318,3294,3229,3129,1643,1578,1524,1478,1389,1223,1115,1092cm ^-1

¹ H NMR (DMSO-d ₆ ): δ 8.24 (S, 1H, C ₈ H), 7.01 (S, 2H, NH ₂ ), 5.48 (S, 2H, NCH ₂ O), 4.69 (s, 2H, J = 5.3 Hz, OH), 3.47 (m, 4H, CH ₂ CH ₂ ).

MS (EI): m / e 227 (M ⁺ ), 209 (M ⁺ -H ₂ O), 197 (M ⁺ -HCHO), 182 (M ⁺ -C ₂ H ₅ O), 166 (M ⁺ -C ₂ H ₅ O ₂ ), 153 (M ⁺ -C ₃ H ₅ O ₂ ).

HRMS: C ₈ H ₁₀ FN ₅ O _2, m / e 227.0816 (calcd 227.0818).

Example 4

Preparation of 2-amino-6-fluoro-9-[(1.3-dihydroxy-2-propoxy) methyl] purine

1 g of the compound prepared in Example 2 was added to 50 ml of N, N-dimethylformamide dried with calcium hydride, and 4 g of dried potassium fluoride was added thereto, followed by 1 at a temperature of 80 ° C. while maintaining a vacuum of 100-300 mmHg. Heated for ˜3 hours.

After the reaction mixture was filtered, 20 ml of anhydrous toluene was added to the white solid formed by vacuum distillation of the filtrate, followed by vacuum distillation again.

This operation was repeated two more times and then subjected to fresh chromatography using a solvent of chloroform: methyl alcohol = 8: 2 to obtain the target compound in a yield of about 56%.

mp: 184-186 ° C. (dec)

IR (KBr): 3399,3333,3217,1651,1574,1532,1489,1416,1215,1069cm ^-1

¹ H NMR (DMSO-d ₆ ): δ 8.22 (S, 1H, C ₈ H), 6.98 (S, 2H, NH ₂ ), 5.57 (S, 2H, NCH ₂ O), 4.62 (t, 2H, J = 5.5 Hz, 2OH), 3.57 (m, 1H, CH), 3.43 (m, 2H, CH ₂ ), 3.30 (m, 2H, CH ₂ ).

MS (EI): 257 (M ⁺ ), 227 (M ⁺ -HCHO), 209 (M ⁺ -HCHO-H ₂ O), 182 (M ⁺ -C ₃ H ₇ O ₃ ), 166 (M ⁺ -C ₃ H ₇ O ₃ ), 153 (M ⁺ -C ₄ H ₈ O ₃ ).

HRMS: C ₉ H ₁₂ FN ₅ O _3, m / e 257.0910 (calcd 257.0924).

Claims (2)

6-fluoropurine compound represented by the following general formula (I)

In the above formula, X represents an oxygen atom or a sulfur atom, and Y represents a hydrogen atom or a hydroxymethyl group. The 6-chloropurine compound represented by the following general formula (II) was subjected to nucleophilic substitution reaction with trimethylamine in a dimethylformamide solvent to prepare a purine trimethyl ammonium salt compound represented by the following general formula (III), and this was again dimethylformamide. A process for producing a 6-fluoropurine compound represented by the following general formula (I), which is carried out by nucleophilic substitution reaction with potassium fluoride in a solvent.

In the above formula, X represents an oxygen atom or a sulfur atom, and Y represents a hydrogen atom or a hydroxymethyl group.