WO1989002438A1

WO1989002438A1 - 3'-deoxyarabinofuranosylpyrimidine nucleoside derivatives

Info

Publication number: WO1989002438A1
Application number: PCT/JP1988/000901
Authority: WO
Inventors: Manami Morozumi; Toyofumi Yamaguchi
Original assignee: Yamasa Shoyu Kabushiki Kaisha
Priority date: 1987-09-08
Filing date: 1988-09-08
Publication date: 1989-03-23
Also published as: KR910005899B1; KR890701608A; JPS6468395A

Abstract

Novel compounds of 3'-deoxyarabinofuranosylpyrimidine nucleoside derivatives of general formula (I), or salts thereof (wherein R1 represents an amino group or a hydroxy group, R2 represents a hydrogen atom, a halogen atom or an alkyl group when R1 represents an amino group, or R2 represents an alkyl group when R1 represents a hydroxy group) are disclosed. The compounds are expected to have antiviral activities, particularly an antiretroviral activity.

Description

Details

3'-Doxyara vino furanosylpyrimidine nucleoside derivative Technical field

The present invention relates to a novel compound, a 3′-dexarabinofuranosylpyrimidine nucleoside derivative o

Background technology

Conventionally, 3'-dexoxybongo resin (Japanese Patent Publication No. Sho 43-111457, Japanese Patent Publication No. Sho 43-111458), 5-halogeno-3'-de resin Oxisbongo resin (Japanese Patent Publication No. Sho 43-111459), 3'-deokin-3'-lower alkyl mercaptosporgin resin (Japanese Patent Publication No. Sho 222-2617) ), 3'-Doxy-3'-halogenosbon resin (Japanese Patent Publication No. 42-200300, Japanese Patent Publication No. 42-218618, Japanese Patent Publication No. 43-132) No. 14), 3'-Doxy-3'-Azidos-bongo pyridine (Japanese Patent Publication No. 42-200299), 3'-Doxy-3'-halogenos bongosite 20, 113 (1977)) and other nucleotide derivatives are already known.

These previously known compounds have antiviral activity themselves. It is important as a compound that can be expected to be active or as a synthetic intermediate of a compound having antiviral activity. However, the antiviral activity of these compounds or of compounds derived from these compounds has not always been satisfactory.

Accordingly, an object of the present invention is to provide a novel compound that can be expected as an antiviral agent, particularly an antiretroviral agent that has recently attracted attention in AIDS, ATL, and the like.

Disclosure of the invention

As a result of studying various compounds, the present inventors have discovered a novel 3′-deoxyarabinofuranosylpyrimidine; a cleioside derivative which can be expected to have antiviral activity, particularly antiviral activity. The compound is obtained by a known method for converting nucleosides from ribofuranosyl form to arabinofuranosyl form, i.e., a 2-2 'cyclo isomer is obtained, followed by hydrolysis of a 2-2' bond. The inventors have found that the method can be easily prepared by applying the method to a 3′-deoxyribofuranosylpyrimidine nucleoside derivative, and completed the present invention.

That is, the present invention is, 3 ^r represented by the following general formula [I] - Dokishiara Binofurano Shirupiri Mi Jin'nu click Leo shea de derivatives 'Ru' (hereinafter, the present invention referred to as compound) and Der provides a salt thereof - _t

C ί

Wherein, R ¹ represents a § Mi amino group or a hydroxyl group, R ² is a hydrogen atom when R ¹ is Amino group, a halogen atom or § alkyl group, indicates an alkyl group when R ¹ is a hydroxyl group You. ]

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the compound of the present invention will be described in detail.

The compound of the present invention is represented by the above general formula [I]. In the above general formula [I], examples of the halogen atom for R ² include chlorine, fluorine, bromine and iodine; Examples of the alkyl group for R ² include a lower alkyl group having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, and the like.

Specific examples of the compound of the present invention represented by the general formula (I) include 3′-doxyarabinofuranosylcytosine.

5-Black mouth-3 '-Doxylar vinofurano sill cytosine, 5-Fluoro-3'-Doxylar vino furanosyl sill.

Cytosine, 5-Bromo-3 '-Doxylar Vino Furano Sylcytosine, 5-Anode-3'-Doxylar Vinofu Lanosylcytosine, 5-Methyl-3'-Doxyarabinofuranosylcytosine, 5-Ethyl-3'-Doxylabinofuranosylcytosine, 5-Methyl-3'-Doxysarapinofuranosilodylacyl (3'-Doxyarabinofuranosylthymine) And 5-ethyl-3'-doxyrabinofurano sylperacyl, and 5-provyl-3'-deoxyarabinofuranosylperacyl. .

Among the compounds of the present invention, when R ¹ is an amino group, the compound may be in the form of a salt, and examples of such a salt include inorganic acids such as hydrochloric acid and sulfuric acid or citric acid; An acid addition salt with an organic acid such as an acid can be exemplified.

The compound of the present invention can be easily prepared, for example, by the first and second production methods shown below.

First manufacturing method

氺

Rl

*

Wherein R ¹ and R ² are as defined above, R ³ is a leaving group, R ⁴ is a protecting group, R ⁵ is a protecting group or a hydrogen atom, and R ¹ is an amino group having a hydroxyl group or a protecting group. The group R ¹ represents an oxo or imino group. ]

The starting compound (A) of the first production method of the present invention can be obtained, for example, by condensing a trimethylsilylated base and 3-hydroxypropyl-protected hydroxyl group in the presence of a Lewis acid, and then removing the protecting group. or ^{^{^{N 0, 0 2 0 5 -}}} . DOO Riashiru - or Ν 6 Ν 6 0 2 '0 5' after reacting the presence of Te preparative § sill Col Jise pin and trimethylsilyl reduction bases and Lewis acids, protecting groups Can be prepared by the method of removing No. 0893, JP-A-55-76889, Carbohydrate Research, 61.545 (1978), etc.).

In the first production method of the present invention, when the starting compound (A) has a protecting group at the 5′-hydroxyl group, a leaving group at the 2′-hydroxyl group and R ^{1 of the} base moiety is an amino group, the amino group This is a method for obtaining a compound of the present invention by introducing a protecting group into a group, treating the compound with an alkali to obtain a compound (C), hydrolyzing a 2-2 ′ bond of the compound (C), and removing the protecting group.

The protecting group for the 5′-hydroxyl group may be any one that is commonly used as a protecting group for a primary hydroxyl group. Specific examples include acetyl, propionol, butyryl, isobutyryl, benzoyl, toluoyl, and other acyl groups, benzyl, tritinole (triphenylmethyl), phenylethyl, tris (p-methoxyphenyl). An aralkyl group such as methyl and the like, and a silyl group such as t-butyldi: methylsilinole and trimethylsilyl can be mentioned, and an aralkyl group is particularly preferable.

The leaving group to be introduced into the hydroxyl group at the 2'-position may be any one which can be removed by alkali treatment. Examples thereof include alkyl or arylsulfonyl groups such as lysopropylpyrbenzensulfonyl, p-bromobenzenesulfonyl, and naphthalenesulfonyl. It is suitable.

When R ^{1 in} the base moiety of the starting compound (A) is an amino group, it is preferable to protect the amino group with a protecting group, and the protecting group is preferably acetyl. And acyl groups such as propionyl, butyryl, isobutylyl, benzoyl and toluoyl.

Introduction of the protecting group to the 5′-protecting group, the 2′-leaving group and the N ⁴ -amino group can be carried out by a conventional method. For example, a trityl group can be specifically introduced at the 5′-position by treating the starting compound (A) with trityl chloride in a solvent such as pyridine. Further, the introduction of a mesyl group into the 2′-hydroxyl group can be carried out by treating a compound (A) having the above-mentioned protecting group at the 5′-position in pyridine with methansulfonyl chloride. The introduction of an acetyl group into an amino group can be carried out by treating the compound (A) having a protecting group at the 5′-position and a leaving group at the 2′-position with acetic anhydride.

The compound (B) thus obtained is treated with alkali to obtain a 2-2 ′ cyclo compound (compound (C)). As the anodized metal used, it is possible to use an alcohol, an ammonia, a triethylamine or the like of an alkali metal such as sodium methoxide and sodium ethoxide. Alkali treatment conditions include reaction solvents (for example, alcohols such as ethanol, dioxane, acetonitril). Etc.), the reaction temperature can be appropriately selected from the reaction conditions of 0 to 50 and the reaction time of 1 minute to 1 hour.

Hydrolysis of the 2-2 'bond of compound (C) can be performed under acidic conditions using acids such as hydrochloric acid, sulfuric acid, chloric acid, nitric acid, etc. Al 0 reaction temperature 2 0-1 0 under basic conditions using force re ^e C such as carbonate diisocyanato Riumu can be carried out more 'in processing several minutes to several hours.

The compound (D) thus obtained is subjected to a conventional method (for example, ion exchange, adsorption, etc., various chromatographic methods, recrystallization, etc.). The compound of the present invention can be isolated and purified.

Second manufacturing method

Wherein R ² is as defined above. ]

The second production method of the present invention is a suitable method when R ^{1 in the} base moiety of the target compound is an amino group.

Starting compound (E) may, for example, N ⁴ - Ashirushi preparative Thin after derivatives was trimethylsilyl reduction, which 3 has a protecting group - by the presence Chijimigohan response of Dokishiribosu and Lewis acid, followed by protecting group for the hydroxyl group and It can be prepared by removing the amino-protecting group of the amino group (for example, see JP-A-55-76898).

In the second production method of the present invention, the starting compound (E) is reacted with polyphosphoric acid, and after the reaction, the pyrophosphoric acid bond is hydrolyzed to obtain a compound (F). This is a method for obtaining the compound of the present invention by hydrolyzing the 2 ′ bond and further removing the 5′-phosphate group of the compound (G) using a phosphatase. (For details, see J. Org. Cheni., 32, 816 (1967).) << The reaction between the starting compound (E) and polyphosphoric acid is based on the starting compound.

»One,

The reaction temperature is 100-120, and the reaction time is 3-6 hours. Can be implemented.

Hydrolysis of the pyrrolic acid bond can be carried out by adding water to the reaction solution and reacting at a reaction temperature of 60 to 110 ° C. for a reaction time of 10 minutes to 2 hours.

Hydrolysis of the 2-2 'bond can be accomplished by using an alkali (eg, sodium hydroxide, hydroxide hydroxide, lithium hydroxide, barium hydroxide, aqueous ammonia) under basic conditions. Specifically, it can be carried out by maintaining the condition of pH 9 to 11.

The removal of the 5′-phosphate group of the compound (G) may be performed according to a conventional method using phosphatase. For example, the pH of the reaction solution is adjusted to 4 to 6 using an acid (such as hydrochloric acid or sulfuric acid). To: After adjustment, overreact acid phosphatase! : More can be implemented.

The compound of the present invention thus obtained can be isolated and purified by a conventional method in the same manner as in the first production method.

Hereinafter, the present invention will be described in more detail with reference to Examples: ₍ Example 1

(1) Synthesis of 5'-0-tritinol-3--3-deoxyribofuranosiltimin

Dissolve 4.4 g of 3'-dexoxylipofuranosylthymine in 100 ml of pyridine, add 15 g of triphenylmethyl chloride (trityl chloride), and incubate at 4 ° C. The mixture was stirred and reacted for 40 hours. After concentrating the reaction mixture, the residue was The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine in that order, and the ethyl acetate layer was concentrated to dryness under reduced pressure. The residue was purified with a silica gel column (about 110 g, washed with chloroform: ethyl acetate = 8: 1, then eluted with chloroform: ethanol = 9: 1), and dried to dryness. A small amount of methanol was added to the residue to dissolve it, and isopropyl ether was added. Rate of 57.1%).

Proton nuclear magnetic resonance spectrum (one CDC)

5 ppi 10.32 (1H, s, NH), 7.76

(1H, s, H-6), 7.50 to 7.20 (m, H-trityl), 5.77 (1H, s, H-l '), 4.97 (1H, s, H-2 '), 4.66 (l H, m, H-4'),

4.52 (1 H, s, OH-2 '),

3.45 (2 H, m H-5 '), 2.13 (2 H, m, H-3), 1.43 (3 Η, s, C H 3-5)

② Synthesis of 5'-0-trityl-3 'dexarabinofunosylthymine

Dissolve 6.0 g of 5'-0-trityl-3'-deoxylibofuranosyl thymine in 30 ml of pyridine, add 2.0 ml of methylsulfonyl chloride and add 40 ml overnight. The mixture was stirred and reacted. After the reaction solution was concentrated to dryness, 200 ml of ethanol and 38 ml of a 1N aqueous solution of sodium hydroxide were added, and the mixture was refluxed for 30 minutes. 2N sulfuric acid was added to the reaction solution, neutralized and concentrated to dryness. The residue was extracted with ethyl acetate, and the ethyl acetate solution was washed with brine and concentrated to dryness. The obtained syrup is purified by a silica gel column (110 g, eluting with chloroform: ethanol = 9: 1), and concentrated to dryness to give 5'-0-trityl as a reddish brown syrup. -3'-doxyara vino furanosyl thymine 5. Og was obtained. ③ Synthesis of 3'-doxylar binofurano silthymine

The whole amount of 5'-0-trityl-3'-dexilarabinofuranosylthymine was dissolved in 50 ml of an 80% acetic acid solution and refluxed for 40 minutes. After allowing the reaction solution to cool, the deposited precipitate was removed, and the solution was concentrated to dryness.

The obtained syrup is purified by a silica gel column (eluted with silica gel 40%, chloroform: ethanol = 4: 1), and concentrated to obtain an syrup, which is dissolved in a small amount of ethanol. The reaction mixture was added with ethyl acetate, and the precipitated colorless needle crystals were collected and dried to obtain 0.97 g of 3′-doxyarabinofuranosiltimin crystal (yield: 32.3%). . With a melting point of 16.6 to 16.7

UV absorption ^{spectrum λ5ΝΗίΜ2} 6 9 nm

₂ 0.05NHC x 1

λ π.ΐη ^{2 3 6 nm} Proton nuclear magnetic resonance spectrum (DMSO-d :) «5 ppm 1 1.21 (1 H, bs, NH-3),

7.64 (1H, s, H-6), 5.86 (1H, d, H-1 ', J'2' =

4.89 Hz) x 5.33 (1 H, d, OH—2 '), 5.11 (1 H, t, OH-5'), 4.33 (1 H, m, H-2 ') ), 3.98 (1 H, m, H-4 '), 3, 57 (2H, m, H—5'), 1.76 (3H, s,

C H 3 5)

Example 2

3'-Doxycytidine 1 g was added to polyphosphoric acid 7 g,

After reacting at 100 ° C for 90 minutes, add water and add i o crc,

Heat for 90 minutes to hydrolyze the pyrrolinic acid bond, and convert the 3'-doxy-2,2'-hydroararabinofuranosylcytosine to 5'-phosphoric acid (3'-doxycyclocytidine) -5'-phosphoric acid) was synthesized. The pH of the reaction mixture was adjusted to pH 10 by adding sodium hydroxide, the 2,2'-bond was opened, and the 3'-dexarabinofuranosylcytosine-5'- After acidification, the reaction solution was adjusted to pH 4.0, added with 10 ng of acid phosphatase, and allowed to react for 4 hours. The reaction solution was adjusted to pH 2.0, adsorbed on an activated carbon column, washed with water, and eluted with 40% ethanol containing 0.1 N ammonia. Concentrate the eluate, add ethanol After cooling to a liquid crystal and cooling, 450 mg of 3′-dexoxybinofuranosylcytosine was obtained.

Melting point: 1 in 34

%

E C 26 0 n m, 0.0 5 N H C 1) 5 84

cm

Proton nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ ppis 88 (H-d, J = 4.39),

4.00 (H-2 m), 2.3 1 ~

2.2 1 (H-m), 1.7 ~

1.68 (H-1 m), 4.25 (H-4,, s), 3.56 (H-5'H-5's), 5.68 (H-5, d , J =

7.32), 7.67 (H-6, d, J

7

7. 3 2) 7. 1 0 ( NH 2, s), 5. 0 7 (0 H - 2 ', s), 5; 1

(0 H-5 /, d, J = 5.

Example

Dissolve 5.0 g of 5-ethyl-3'-deoxyribofuranosylperacil in 100 ml of pyrimidine, add 15 g of triphenylmethyl chloride, and stir at 40 ° C for 40 hours. After concentrating the reaction solution, the residue is extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine in that order, and the ethyl acetate layer is concentrated to dryness under reduced pressure. The residue was purified by silica gel column (eluent with chloroform: ethanol 9) and concentrated to dryness. Harden. After dissolving the obtained residue in methanol, isopropyl ether was added and the resulting precipitate was dried and dried.

5-Ethyl-5 '-0-Tritinole-3'-Deoxyribofuranosylsilazil.

Next, 6.5 g of 5-ethyl-5'-0-trityl-3'-deoxyribofuranosylperacil was dissolved in 30 ml of pyridine, and 2.0 ml of methanesulfonyl chloride was added. The reaction solution is concentrated to dryness overnight, and then 200 ml of ethanol and 38 ml of a 1N aqueous solution of sodium hydroxide are added, and the mixture is refluxed for 30 minutes. After the reflux, the reaction mixture is neutralized by adding 2N sulfuric acid and concentrated to dryness. The residue is extracted with ethyl acetate, the ethyl acetate layer is washed with brine, and further concentrated to dryness. The residue obtained is purified on a silica gel column (eluted with chloroform: ethanol = 9: 1), concentrated to dryness and concentrated to dryness to give 5-ethynole-5 '. obtain.

5.0 g of the thus obtained 5-ethynole-5'-0-trityl-3'-doxyarabinofuranosylperacil is dissolved in 80% acetic acid (5 Oml) and refluxed for 40 minutes. After the reaction, the reaction solution is allowed to cool, and the precipitate that forms is removed by f. The solution is concentrated to dryness. The residue is purified by a silica gel column '(eluted with chloroform: ethanol = 4: 1), dissolved in a small amount of ethanol, and added with ethyl acetate to precipitate out. Obtain the crystals of Shiruduracil.

Example 4

Add 1.5 g of 5-bromo-3'-deoxyribofuranosylcytosine to 7 g of polyphosphoric acid, react at 100 for 90 minutes, add water and heat at 100 for 90 minutes. Hydrolysis of the pyrrolinic acid bond yields 5-promo-3'-dexoxy-2,2'-hydrohydroarabinofuranosylcytosine-5'-phosphoric acid. After the reaction, sodium hydroxide is added to the reaction solution to adjust the pH to 10 to open the 2,2'-bond. Further, the pH of the reaction solution was adjusted to 4.0, 1 Omg of acid phosphatase was added, and the mixture was reacted at 40 for 4 hours. After the reaction solution was adjusted to pH 2, a silica gel column (clos-hole-methanol) was used. Elution with a mixed solvent) to obtain 5-bumo-3'-doxyarabinofuranosylcytosine c Example 5

5-Methyl-3'-deoxyribofuranosylcytosine 1.2 g was added to polyphosphoric acid 7 g, reacted at 100 for 90 minutes, then added water and heated at 100 for 90 minutes. Then, the pyrrolinate bond is hydrolyzed to obtain 5-methyl-3'-dexoxy-2,2'-anhydroarabinofuranosylcytosine-5'-phosphoric acid. After the reaction, the reaction solution is adjusted to pH 10 by adding sodium hydroxide to weaken the 2,2'-bond. Further, the pH of the reaction solution was adjusted to 4.0, and 10 mg of acid phosphatase was added thereto. C, react for 4 hours, After adjusting the pH of the reaction solution to 2, it is purified by silica gel column (eluted with a mixed solvent of chloroform and methanol) to obtain 5-methyl-3'-dexoxyarabinofuranosylcytosine. possibility

Since the compound of the present invention is a novel 3'-dexarabinofuranosylpyrimidine nucleoside derivative which can be expected to have antiviral activity, particularly antiretroviral activity, it is a novel antiviral agent, particularly The development of troviral agents is promising.

Claims

The scope of the claims

—General formula (: I)

Wherein, R ¹ represents a § Mi amino group or a hydroxyl group, a hydrogen atom when R ¹ is § Mi amino group, a halogen atom or § alkyl group, an alkyl group when R ¹ is a hydroxyl group] 3′-Doxyarabinofurano sylbylimidine nucleoside derivative represented by the formula: or a salt thereof.

2. The derivative or a salt thereof according to claim 1, wherein R ¹ is an amino group, and R ^ "is a hydrogen atom, a halogen atom or an alkyl group.

3. The derivative or a salt thereof according to claim 1, which is 3.3'-doxyarabinofuranosylcytosine.

4. The derivative according to claim 1, wherein R ¹ is a hydroxyl group and: ² is an alkyl group.

5.5.- The derivative according to claim 1, wherein the derivative is methyl-3'-deoxyarabinofuranosylduracil (3'-deoxyarabinofuranosylthymine).