JP5070550B2 - Nucleoside derivatives with anti-herpesvirus activity - Google Patents

Description

  The present invention relates to a drug for preventing or treating herpes virus infection.

  Herpesviruses include herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), which is already infected by 95% of Japanese, and varicella-zoster virus that causes chicken pox and shingles ( HHV3) and Kaposi's Sarcoma-associated Herpesvirus (KSHV). Antiviral drugs such as acyclovir, ganciclovir, and interferon are used for the treatment of these viral infections. However, these antiviral agents are not effective against EBV and KSHV, and no effective treatment has been established so far for EBV and KSHV infection.

  EBV is a virus isolated from a Burkitt lymphoma patient. Infection with EBV is generally subclinical, but an association with malignant tumors has been suggested. There are no effective treatments for opportunistic infections caused by EBV after organ transplantation, and immunotherapy has been attempted. KSHV is the causative virus for Kaposi's sarcoma. Infection with KSHV causes canceration of infected cells, and is known to develop Kaposi's sarcoma and phosphorus tumor, particularly in humans using immunosuppressants. For this reason, KSHV infection has become a serious problem not only in opportunistic infections in AIDS patients but also in organ transplantation. The currently used methods for the treatment of Kaposi's sarcoma are excision for skin lesions and radiotherapy or cryotherapy for selected sites. In addition, as chemotherapy, doxorubicin, an anthracycline anticancer agent, is effective for solid cancer Kaposi's sarcoma. With side effects.

  For example, the following are known as nucleoside derivatives having antiviral activity: AZT (anti-HIV drug) Antimicrobial agents and chemotherapy 1987 31 (2) 274-280, acyclovir (anti-herpes drug) Antiviral research 1984 4 (3) 99-117, BVDU (anti-herpes) Antimicrobial agents and chemotherapy 1980 17 (1) 8-12. However, no compound having anti-EBV activity or anti-KSHV activity has been known so far.

References cited in this specification are as follows. All the contents described in these documents are cited here as a part of this specification. None of these documents is admitted to be prior art to this specification.
Antimicrobial agents and chemotherapy 1987 31 (2) 274-280 Antiviral research 1984 4 (3) 99-117 Antimicrobial agents and chemotherapy 1980 17 (1) 8-12

  An object of the present invention is to provide a drug effective for the prevention or treatment of herpesvirus infections including EBV and KSHV, and a method for treating herpesvirus infections.

［式中、Ｒは、ヒドロキシ、Ｃ_１−６のアルコキシ、ハロゲン、ＮＲ^１Ｒ^２（ここで、Ｒ^１およびＲ^２は、独立して、水素またはＣ_１−３のアルキルである）、シアノまたはフェニルである］
で表される化合物またはその塩を提供する。本発明はまた、上記式Ｉの化合物またはその塩を有効成分として含有する、ヘルペスウイルス感染症を予防または治療するための医薬組成物を提供する。The present inventors have found that certain nucleoside analogues exhibit cytocidal activity specifically for herpes virus-infected cells. The present invention provides compounds of formula I:

Wherein R is hydroxy, C _1-6 alkoxy, halogen, NR ¹ R ² (wherein R ¹ and R ² are independently hydrogen or C _1-3 alkyl), cyano Or is phenyl]
Or a salt thereof. The present invention also provides a pharmaceutical composition for preventing or treating herpes virus infection, comprising the compound of formula I or a salt thereof as an active ingredient.

Preferably, in Formula I, R is hydroxy, C _1-6 alkoxy, halogen or amino. More preferably, the compound of formula I is 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-methoxypurine (1a), 9- (2 -C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -2,6-diaminopurine (1b), 2-amino-9- (2-C-cyano-2-deoxy-β-D -Arabinopentofuranosyl) -6-chloropurine (1c) and 9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) guanine (1 g) .

  In yet another aspect, the present invention provides a method for preventing or treating herpesvirus infection by administering a compound of formula I or a salt thereof.

FIG. 1 shows the growth inhibitory effect of the compound of the present invention on EBV-infected cells and KSHV-infected cells.

［式中、Ｒは、ヒドロキシ、Ｃ_１−６のアルコキシ、ハロゲン、ＮＲ^１Ｒ^２（ここで、Ｒ^１およびＲ^２は、独立して、水素またはＣ_１−３のアルキルである）、シアノまたはフェニルである］
で表される９−（２−Ｃ−シアノ−２−デオキシ−１−β−Ｄ−アラビノペントフラノシル）プリン誘導体である。好ましくは、式Ｉの化合物において、Ｒは、ヒドロキシ、Ｃ_１−３のアルコキシ、ハロゲンまたはアミノである。より好ましくは、式Ｉの化合物において、Ｒはヒドロキシ、メトキシ、クロロ、またはアミノである。The compounds of the present invention have the formula I:

Wherein R is hydroxy, C _1-6 alkoxy, halogen, NR ¹ R ² (wherein R ¹ and R ² are independently hydrogen or C _1-3 alkyl), cyano Or is phenyl]
9- (2-C-cyano-2-deoxy-1-β-D-arabinopentofuranosyl) purine derivative represented by the formula: Preferably, in the compound of formula I, R is hydroxy, C _1-3 alkoxy, halogen or amino. More preferably, in the compound of formula I, R is hydroxy, methoxy, chloro, or amino.

［式中、Ｒは式Ｉで定義したとおりであり、Ｐｇはヒドロキシル基の保護基である］
のグアノシン誘導体を製造する。次に、２’位にシアノ基を導入して式ＩＩＩ：

のシアノ化２‘デオキシグアノシン誘導体とし、最後にこれを脱保護することにより製造することができる。ヌクレオシドの３’および５’のヒドロキシル基の種々の保護基、およびその導入方法および脱保護方法は、当該技術分野においてよく知られている。なお、上記の方法は本発明を限定するものではなく、有機化学の分野の当業者であれば、他の方法を用いて本発明の化合物を容易に合成することができる。The 9- (2-C-cyano-2-deoxy-1-β-D-arabinopentofuranosyl) purine derivative of the formula I of the present invention can be prepared as follows. First, Formula II in which the 3 ′ and 5 ′ hydroxyl groups of guanosine are appropriately protected and the desired R group is introduced at the 6-position of the purine ring:

[Wherein R is as defined in formula I, and Pg is a protecting group for a hydroxyl group]
The guanosine derivative of Next, a cyano group is introduced at the 2 ′ position to give a compound of formula III:

It is possible to produce a cyanated 2′-deoxyguanosine derivative of the above and finally deprotecting it. Various protecting groups for the 3 ′ and 5 ′ hydroxyl groups of nucleosides and methods for their introduction and deprotection are well known in the art. Note that the above method does not limit the present invention, and those skilled in the field of organic chemistry can easily synthesize the compound of the present invention using other methods.

  The guanosine derivatives of formula II can be prepared by known methods starting from guanosine. The compound of formula II (2a) in which R is alkoxy starts from the commercially available 2-amino-6-chloropurine riboside and is described in the literature (Org. Biomol. Chem., 2004, 2, 120-126). Can be synthesized according to The compound of formula II (2b) in which R is amino can be synthesized by the method described in the literature (Tetrahedron 2000, 56, 1047-1056) starting from 2-amino-6-chloropurine riboside. . The compound of formula II (2c) in which R is halogen is a method described in the literature (Can. J. Chem., 1983, 61, 1911-1920) starting from 2-amino-6-chloropurine riboside. Can be synthesized. The compound of formula II (2d) in which R is monoalkylamino or dialkylamino can be easily synthesized by adding a protecting group to the corresponding 2-amino-6-alkylaminopurine riboside. Compounds of formula II in which R is cyano or phenyl can be easily derived from the halogenated compound (2c).

  The cyanated guanosine derivative of formula III can be synthesized by introducing a cyano group at the 2 'position of the guanosine derivative of formula II. Briefly, the 2'-hydroxyl group of a 6-substituted-2-aminopurine riboside in which the 3'-5'-hydroxyl group is protected with a tetraisopropyldisiloxane group is oxidized to lead to a ketone body. The ketone body is reacted with tetrabutylammonium cyanide to convert to cyanohydrin, and the resulting hydroxyl group is converted to thionocarbonate. Subsequently, by performing radical reduction using tributyltin hydride, a cyano group can be selectively introduced at the 2′-β position.

  The cyanated guanosine derivative of formula III can then be deprotected to give the desired compound of formula I. Further, the compound of formula I (1g) in which R is hydroxy can be produced by reacting adenosine deaminase with the compound (1a) in which R is methoxy.

  The compound of the present invention has an activity of inhibiting herpesvirus growth and is useful for the treatment of herpesvirus infection. As shown in the examples below, the compounds of the invention can significantly inhibit the growth of EBV and KSHV. Herpes viruses whose growth is inhibited by the compounds of the present invention include HSV, CMV, EBV, HHV3, KSHV and the like.

  The pharmaceutical composition of the present invention can be formulated by methods known to those skilled in the art. For example, the compound of the present invention can be converted into a pharmaceutically acceptable carrier or vehicle, specifically, sterilized water or physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient. The pharmaceutical composition can be formulated by mixing in an appropriate combination with a drug, vehicle, preservative, binder and the like in a unit dosage form generally required for pharmaceutical practice.

  For oral administration, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries are prepared by mixing a compound of the present invention or a salt thereof with a pharmaceutically acceptable carrier well known in the art. It can be formulated as a suspension or the like. As the carrier, those conventionally known in the art can be widely used. For example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, carbonic acid Disintegrating agents such as sodium hydrogen, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stear cocoa butter, hydrogenated oil; quaternary ammonium salts, La Absorption accelerators such as sodium rilsulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; abundant amounts of purified talc, stearate, boric acid powder, polyethylene glycol, etc. An agent or the like can be used. Furthermore, the tablet can be a tablet coated with a normal coating, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.

  For parenteral administration, the compounds of the invention or salts thereof can be formulated according to conventional pharmaceutical practice using pharmaceutically acceptable vehicles well known in the art.

  Examples of water-soluble vehicles for injection include isotonic solutions containing physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, and suitable solubilizing aids. An agent such as an alcohol, specifically ethanol, a polyalcohol such as propylene glycol, polyethylene glycol, a nonionic surfactant such as polysorbate 80 (TM), HCO-50 may be used in combination.

  Oily vehicles include sesame oil and soybean oil, and benzyl benzoate and benzyl alcohol may be used in combination as solubilizing agents. Moreover, you may mix | blend with buffer, for example, phosphate buffer, sodium acetate buffer, a soothing agent, for example, procaine hydrochloride, stabilizer, for example, benzyl alcohol, phenol, antioxidant. The prepared injection solution is usually filled into a suitable ampoule.

  Suitable administration routes for the pharmaceutical composition of the present invention include, but are not limited to, oral, rectal, transmucosal, or enteral administration, or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, Intravitreal, intraperitoneal, intranasal, or intraocular injection is included. The administration route can be appropriately selected in consideration of the age and medical condition of the patient, other drugs used in combination, and the like.

  The dosage of the pharmaceutical composition of the present invention can be selected in the range of 0.001 mg to 10 mg / kg body weight per administration. Alternatively, the dose can be selected in the range of 0.1 to 100 mg per administration, but is not necessarily limited to these values. The dosage and administration method can be appropriately selected by the doctor in charge taking into account the patient's weight, age, symptoms, other drugs used in combination, and the like.

  The contents of all patents and references explicitly cited herein are hereby incorporated by reference as part of the present specification. In addition, the contents described in the specification and drawings of Japanese Patent Application No. 2006-1111397, which is the application on which the priority of the present application is based, are cited herein as a part of this specification.

  EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1
9- [2-C-Cyano-2-deoxy-3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -6-methoxypurine (3a) Synthesis of

Under an argon atmosphere, CrO _{3 (} 490 mg, 4.86 mmol) and MS4A (1.3 g) were suspended in CH ₂ Cl _{2 (} 16 mL), pyridine (0.79 mL, 9.72 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. Ac ₂ O (0.92 ml, 9.72 mmol) was added and the mixture was further stirred for 20 minutes, and then a solution of 2a (875 mg, 1.62 mmol, Org. Biomol. Chem., 2004, ₂ , 120-126) in CH ₂ Cl _{2 (} 2 mL) was added dropwise. And stirred for 15 minutes. The reaction solution was added dropwise to Et ₂ O (50 mL), and the Et ₂ O solution was filtered through Celite-Floridyl. The filtrate was washed with 0.1N aqueous HCl and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in CH ₂ Cl _{2 (} 16 mL). Bu ₄ NCN (651 mg, 2.43 mmol) was added at 0 ° C., and the mixture was stirred for 15 minutes. The reaction mixture was diluted with Et ₂ O, and the organic layer was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure.

DMAP (297 mg, 2.43 mmol) and PhOSCCl (0.34 ml, 2.43 mmol) were added to CH ₂ Cl _{2 (} 16 mL) under an argon atmosphere, and the residue obtained at 0 ° C. and Et ₃ N (0.34 ml, 2.43 mmol) were added. ) Was added and stirred for 20 minutes. Saturated multistory water was added to the reaction solution to stop the reaction, and the mixture was vigorously stirred for 15 minutes. The organic layer was washed with saturated multilayer water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure, and the residue was roughly purified by silica gel column chromatography (φ4 × 10 cm, hexane: EtOAc = 3: 1), and the fractions containing the product were concentrated under reduced pressure to obtain a thin solution. A yellow foam was obtained.

The obtained foam was dissolved in toluene (6.3 mL), AIBN (156 mg, 0.95 mmol) and Bu ₃ SnH (0.22 ml, 0.94 mmol) were added, and the mixture was heated to 100 ° C. and stirred for 15 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (φ3 × 7 cm, hexane: EtOAc = 3: 1-2: 1) to obtain colorless foam 3a (122 mg, 14 steps 14%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.90 (s, 1H, H-8), 6.35 (d, 1H, H-1 ′, J _{1 ′, 2 ′} = 7.3 Hz), 5.07 (t, 1H, H -3 ', J _{3', 2 '} = J _{3', 4 '} = 8.5Hz), 4.87 (brs, 2H, N H ₂ ), 4.15 (dd, 1H, H-5'a, J _{5'a, 4 '} = _3.7Hz , J _{5'a, 5'b} = 12.0Hz, 4.10-4.05 (m, 4H, H-5'b, O Me ), 3.87 (ddd, 1H, J _{4', 3 '} = 8.5 Hz, J _{4 ', 5'a} = J _{4', 5'b} = 12.0Hz), 3.70 (dd, 1H, H-2 ', J _{2', 1 '} = 7.3Hz, J _{2', 3 '} = 8.5Hz), 1.18-0.98 (m, 28H, isopropyl x 4);
¹³ C NMR (CDCl ₃ , 125 MHz) δ 161.71, 159.44, 153.04, 136.50, 115.84, 115.27, 84.09, 80.78, 73.11, 60.07, 53.91, 42.90. 17.41, 17.31, 17.26, 17.24, 16.98, 16.89, 16.83, 13.40 , 12.99, 12.41.

Example 2
9- [2-C-cyano-2-deoxy-3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -2,6-diaminopurine ( Synthesis of 3b)

Under an argon atmosphere, CrO _{3 (} 490 mg, 4.86 mmol) and MS4A (1.3 g) were suspended in CH ₂ Cl _{2 (} 16 mL), pyridine (0.79 mL, 9.72 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. Ac ₂ O (0.92ml, 9.72mmol) was added After stirring for a further 20 minutes, 2b (875mg, 1.62mmol, Tetrahedron 2000,56,1047-1056) CH 2 Cl 2 (2mL) was added dropwise stirring 15 min did. The reaction solution was added dropwise to Et ₂ O (50 mL), and the Et ₂ O solution was filtered through Celite-Floridyl. The filtrate was washed with 0.1N aqueous HCl and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in CH ₂ Cl _{2 (} 16 mL). Bu ₄ NCN (651 mg, 2.43 mmol) was added at 0 ° C., and the mixture was stirred for 15 min. The reaction mixture was diluted with Et ₂ O, and the organic layer was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure.

Under an argon atmosphere, DMAP (297 mg, 2.43 mmol) and PhOSCCl (0.34 ml, 2.43 mmol) were added to CH ₂ Cl _{2 (} 16 mL), and the residue obtained at 0 ° C. and Et ₃ N (0.34 ml, 2.43 mmol) were added. ) Was added and stirred for 20 minutes. Saturated multistory water was added to the reaction solution to stop the reaction, and the mixture was vigorously stirred for 15 minutes. The organic layer was washed with saturated multilayer water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure, and the residue was roughly purified by silica gel column chromatography (φ4 × 10 cm, hexane: EtOAc = 3: 1), and then the fractions containing the product were concentrated under reduced pressure to obtain a thin solution. A yellow foam was obtained.

The obtained foam was dissolved in toluene (6.3 mL), AIBN (156 mg, 0.95 mmol) and Bu ₃ SnH (0.22 ml, 0.94 mmol) were added, and the mixture was heated to 100 ° C. and stirred for 15 minutes. The reaction mixture was concentrated and purified by silica gel column chromatography (3 × 7 cm, hexane: EtOAc = 3: 1-2: 1) to give colorless foam 3b (122 mg, 14 steps 14%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.81 (s, 1H, H-8), 6.34 (d, 1H, H-1 ′, J _{1 ′, 2 ′} = 7.5 Hz), 5.65 (brs, 2H, N H ₂ ), 5.03 (t, 1H, H-3 ', J _{3', 2 '} = J _{3', 4 '} = 8.5Hz), 4.81 (brs, 2H, N H ₂ ), 4.14 (dd, 1H, H-5'a, J _{5'a, 4 '} = 3.8Hz, J _{5'a, 5'b} = 13.0Hz, 4.06 (dd, 1H, H-5'b, J _{5'b, 4'} = 3.8 Hz, J _{5'b, 5'a} = 13.0Hz), 3.85 (ddd, 1H, J _{4 ', 3'} = _8.5Hz , J _{4 ', 5'a} = J _{4', 5'b} = 13.0Hz) , 3.70 (dd, 1H, H-2 ', J _{2', 1 '} = 7.5Hz, J _{2', 3 '} = 8.5Hz), 1.18-0.98 (m, 28H, isopropyl x 4);
¹³ C NMR (CDCl ₃ , 125 MHz) δ161.54, 157.55, 152.95, 136.81, 117.10, 115.93, 85.62, 82.24, 74.99, 62.39, 44.53, 18.99, 18.91, 18.87, 18.82, 18.61, 18.52, 18.49, 18.43, 15.03 , 14.59, 14.52, 14.01.

Example 3
2-Amino-9- [2-C-cyano-2-deoxy-3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl) -6-chloro Synthesis of purine (3c)

Under an argon atmosphere, CrO _{3 (} 245 mg, 2.45 mmol) and MS4A (0.70 g) were suspended in CH ₂ Cl _{2 (} 5.00 mL), pyridine (0.40 mL, 4.90 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. . Ac ₂ O (0.46 ml, 4.90 mmol) was added, and the mixture was further stirred for 20 minutes, and then 2c (380 mg, 0.70 mmol, Can. J. Chem., 1983, 61, 1911-1920) in CH ₂ Cl _{2 (} 1 mL) Was added dropwise and stirred for 15 minutes. The reaction solution was added dropwise to Et ₂ O (15.0 mL), and the Et ₂ O solution was filtered through Celite-Floridyl. The filtrate was washed with 0.1N HCl aqueous solution and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. After filtering the solution, CH ₂ Cl _{2 (} 16 mL) and Bu ₄ NCN (380 mg, 1.40 mmol) were added to the filtrate, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with Et ₂ O, and the organic layer was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure.

Under an argon atmosphere, DMAP (130 mg, 1.05 mmol) and PhOSCCl (0.15 ml, 2.05 mmol) were added to CH ₂ Cl _{2 (} 7.00 mL), and the residue obtained at 0 ° C. and Et ₃ N (0.15 ml, 1.05 mmol) was added and stirred for 20 minutes. Saturated multistory water was added to the reaction solution to stop the reaction, and the mixture was vigorously stirred for 15 minutes. The organic layer was washed with saturated multilayer water and dried over anhydrous sodium sulfate. After filtration of the solution, the filtrate was concentrated under reduced pressure, and the residue was roughly purified by silica gel column chromatography (φ3 × 8 cm, hexane: EtOAc = 5: 1-4: 1), and the fraction containing the product was reduced in pressure. Concentration was performed to obtain a light yellow foamy substance.

The obtained foam was dissolved in toluene (3.60 mL), AIBN (88 mg, 0.54 mmol) and Bu ₃ SnH (0.13 ml, 0.54 mmol) were added, and the mixture was heated to 100 ° C. and stirred for 15 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (φ3 × 10 cm, hexane: EtOAc = 5: 1-2: 1) to obtain colorless foam 3c (126 mg, 4 steps 33%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 8.07 (s, 1H, H-8), 6.37 (d, 1H, H-1 ′, J _{1 ′, 2 ′} = 7.5 Hz), 5.09 (brs, 2H, N H ₂ ), 5.02 (t, 1H, H-3 ', J _{3', 2 '} = J _{3', 4 '} = 9.0Hz), 4.16 (dd, 1H, H-5'a, J _{5'a, 4 '} = 3.0Hz, J _{5'a, 5'b} = 13.1Hz, 4.08 (dd, 1H, H-5'b, J _{5'b, 4'} = 3.0Hz, J _{5'b, 5'a} = 13.1Hz), 3.89 (ddd, 1H, J _{4 ', 3'} = 9.0Hz, J _{4 ', 5'a} = J _{4', 5'b} = 13.1Hz), 3.72 (dd, 1H, H-2 ' , J _{2 ', 1'} = 7.5Hz, J _{2 ', 3'} = 9.0Hz), 1.18-0.94 (m, 28H, isopropyl x 4);
¹³ C NMR (CDCl ₃ , 125 MHz) δ 160.14, 153.86, 152.58, 140.13, 126.02, 115.90, 84.63, 81.36, 72.97, 60.56, 42.85, 17.56, 17.42, 17.38, 17.31, 17.25, 16.99, 16.91, 16.85, 13.58 , 13.44, 12.95, 12.65.

Example 4
Synthesis of 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-methoxypurine (1a)

3a (200 mg, 0.37 mmol) was dissolved in THF (4.0 mL) at 0 ° C., AcOH (42 μL, 0.37 mmol) and Bu ₄ NF (0.73 mL, 0.73 mmol) were added, and the mixture was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (φ2 × 7 cm, CHCl ₃ : MeOH = 15: 1). The fraction containing the product was concentrated and crystallized with CHCl ₃ to obtain white crystals 1a (81 mg, 73%).
¹ H NMR (DMSO-d ₆ , 500MHz) δ 8.14 (s, 1H, H-8), 6.52 (brs, 2H, NH ₂ ), 6.35 (d, 1H, H-1 ', J _{1', 2 '} = 7.5Hz), 6.25 (brd, 1H, OH-3 ', J _{OH-3', 3 '} = 5.8Hz), 5.14 (brt, 1H, OH-5', J _{OH-5 ', 5'a} = J _{OH-5 ', 5'b} = 5.3Hz), 4.76 (ddd, 1H, H-3', J _{3 ', 2'} = 8.4Hz, J _{3 ', 4'} = 6.5Hz, J _{3 ', OH -3 '} = 5.8Hz), 4.03 (dd, 1H, H-2', J _{2 ', 1'} = 7.5Hz, J _{2 ', 3'} = 8.4Hz), 3.81-3.78 (m, 1H, H- 4 '), 3.77-3.73 (m, 1H, H-5'a). 3.69-3.65 (m, 1H, H-5'b);
¹³ C NMR (DMSO-d ₆ , 125 MHz) δ 160.67, 159.90, 153.36, 137.94, 117.05, 113.58, 113.49, 85.35, 84.89, 81.25, 80.20, 79.91, 71.17;
FAB-LRMS m / z 307.1 (MH ⁺ ); FAB-HRMS (DMSO) calculated: C ₁₂ H ₁₄ N ₆ O ₄ 306.277, measured: 307.1152 (MH ⁺ )

Example 5
Synthesis of 9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -2,6-diaminopurine (1b)

At 0 ° C., 3b (200 mg, 0.37 mmol) was dissolved in THF (4.0 mL), AcOH (42 μL, 0.37 mmol) and Bu ₄ NF (0.73 mL, 0.73 mmol) were added, and the mixture was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (φ2 × 7 cm, CHCl ₃ : MeOH = 15: 1). The fraction containing the product was concentrated and crystallized with CHCl ₃ to obtain white crystals 1b (81 mg, 73%).

¹ H NMR (DMSO-d ₆ , 500MHz) δ 7.96 (s, 1H, H-8), 6.76 (brs, 2H, NH ₂ ), 6.29 (d, 1H, H-1 ', J _{1', 2 '} = 7.4Hz), 6.23 (brd, 1H, OH-3 ', J _{OH-3', 3 '} = 5.8Hz), 5.81 (brs, 2H, NH ₂ ), 5.18 (brt, 1H, OH-5', J _{OH-5 ', 5'a} = J _{OH-5', 5'b} = 5.3Hz), 4.77 (dd, 1H, H-3 ', J _{3', 2 '} = 8.4Hz, J _{3', 4 '} = 5.3Hz), 3.99 (t, 1H, H-2', J _{2 ', 1'} = J _{2 ', 3'} = 7.4Hz), 3.95-3.76 (m, 1H, H-4 '), 3.73 -3.23 (m, 1H, H-5'a). 3.68-3.63 (m, 1H, H-5'b);
¹³ C NMR (DMSO-d ₆ , 125 MHz) δ 160.29, 156.17, 151.12, 135.79, 134.12, 117.19, 112.91, 85.23, 84.79, 81.08, 79.76, 71.71, 71.19;
FAB-LRMS m / z 292.1 (MH ⁺ ); FAB-HRMS (DMSO) calculated: C ₁₁ H ₁₃ N ₇ O ₃ 291.266, measured: 292.1154 (MH ⁺ );

Example 6
Synthesis of 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-chloropurine (1c)

3c (271 mg, 0.50 mmol) was dissolved in THF (5.0 mL) at 0 ° C., AcOH (62 μL, 1.08 mmol) and Bu ₄ NF (1.00 mL, 1.00 mmol) were added, and the mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by flash silica gel column chromatography (φ2 × 20 cm, CHCl ₃ : MeOH = 12: 1). Fractions containing the product were concentrated and crystallized from EtOAc.MeOH to give white crystals 1c (110 mg, 73%).
¹ H NMR (DMSO-d ₆ , 500MHz) δ 8.41 (s, 1H, H-8), 7.04 (brs, 2H, NH ₂ ), 6.38 (d, 1H, H-1 ', J _{1', 2 '} = 7.4Hz), 6.31 (brd, 1H, OH-3 ', J _{OH-3', 3 '} = 3.7Hz), 5.18 (brs, 1H, OH-5'), 4.77 (dd, 1H, H-3 ', J _{3', 2 '} = 7.4Hz, J _{3', 4 '} = 3.8Hz), 4.08 (t, 1H, H-2', J _{2 ', 1'} = J _{2 ', 3'} = 7.4Hz ), 3.82-3.80 (m, 1H, H-4 '), 3.77-3.74 (m, 1H, H-5'a). 3.69-3.65 (m, 1H, H-5'b);
¹³ C NMR (DMSO-d ₆ , 125 MHz) δ159.85, 153.21, 149.72, 141.31, 139.68, 123.19, 123.10, 117.01, 86.06, 81.37, 80.55, 71.32;
FAB-LRMS m / z 311.1 (MH ⁺ ); FAB-HRMS (DMSO) calculated: C ₁₁ H ₁₁ ClN ₆ O ₃ 310.696, found: 311.0633 (MH ⁺ ).

9-アミノ-6-メチルアミノ-9-(2’-デオキシ-β-D-アラビノペントフラノシル)プリン(1.39g, 4.68mmol)のピリジン(47mL)溶液に、アルゴン雰囲気下0℃にてTIPDSCl2(1.8mL, 5.62mmol)を滴下し、室温下6時間撹拌した。溶媒を減圧下留去し、残渣をEtOAcで希釈した後、有機層を飽和重曹水・飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(φ6.5×7cm, ヘキサン：EtOAc=1：1-1：3-1：5-0：1)にて精製し、白色泡状物質2d(2.13g, 92%)を得た。
¹H NMR(CDCl3, 500MHz) δ7.62(s, 1H, H-8), 5.85(s, 1H, H-1’), 5.59(brs, 1H, NHMe), 4.87(dd, 1H, H-3’, J3’,2’=5.5Hz, J3’,4’=6.1Hz), 4.68(brs, 2H, NH2), 4.54(d, 1H, H-2’, J2’,3’=5.5Hz), 4.09-4.02(m, 3H, H-4’, H-5’), 3.36(brs, 1H, OH-2’), 3.10(brs, 3H, NHMe), 1.11-1.00(m, 28H, イソプロピル×4); Example 7
Synthesis of 2-amino-9- [3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -6-methylaminopurine (2d)

9-Amino-6-methylamino-9- (2′-deoxy-β-D-arabinopentofuranosyl) purine (1.39 g, 4.68 mmol) in pyridine (47 mL) at 0 ° C. under argon atmosphere TIPDSCl2 (1.8 mL, 5.62 mmol) was added dropwise, and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, the residue was diluted with EtOAc, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (φ6.5 × 7 cm, hexane: EtOAc = 1: 1−1: 3-1: 5-0: 1), and white foam 2d (2.13 g, 92%) Got.
¹ H NMR (CDCl3, 500MHz) δ7.62 (s, 1H, H-8), 5.85 (s, 1H, H-1 '), 5.59 (brs, 1H, NHMe), 4.87 (dd, 1H, H- 3 ', J3', 2 '= 5.5Hz, J3', 4 '= 6.1Hz), 4.68 (brs, 2H, NH2), 4.54 (d, 1H, H-2', J2 ', 3' = 5.5Hz ), 4.09-4.02 (m, 3H, H-4 ', H-5'), 3.36 (brs, 1H, OH-2 '), 3.10 (brs, 3H, NHMe), 1.11-1.00 (m, 28H, Isopropyl x 4);

Example 8
2-Amino-9- [2-C-cyano-2-deoxy-3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -6-methyl Synthesis of aminopurine (3d)

Under an argon atmosphere, CrO _{3 (} 650 mg, 6.51 mmol) and MS4A (1.9 g) were suspended in CH ₂ Cl _{2 (} 10 mL), pyridine (1.00 mL, 13.0 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. Ac ₂ O (1.30 ml, 13.0 mmol) was added and the mixture was further stirred for 20 minutes, and then a solution of 2d (1.00 g, 1.86 mmol) in CH ₂ Cl _{2 (} 4 mL) was added dropwise and stirred for 15 minutes. The reaction solution was added dropwise to Et ₂ O (30 mL), and the Et ₂ O solution was filtered through Celite-Floridyl. The filtrate was washed with 0.1N aqueous HCl and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in CH ₂ Cl _{2 (} 16 mL), and Bu ₄ NCN (651 mg, 2.43 mmol) was added at 0 ° C., followed by stirring for 15 minutes. The reaction mixture was diluted with Et ₂ O, and the organic layer was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, and the solution was filtered. CH ₂ Cl _{2 (} 19 mL) and Bu ₄ NCN (1.25 g, 4.65 mmol) were added to the filtrate, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with Et ₂ O, and the organic layer was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure.

Under an argon atmosphere, DMAP (340 mg, 2.79 mmol) and PhOSCCl (0.39 ml, 2.79 mmol) were added to CH ₂ Cl _{2 (} 19 mL), and the residue obtained at 0 ° C. and Et ₃ N (0.39 ml, 2.79 mmol) were added. ) Was added and stirred for 20 minutes. Saturated multistory water was added to the reaction solution to stop the reaction, and the mixture was vigorously stirred for 15 minutes. The organic layer was washed with saturated multilayer water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure, and the residue was roughly purified by silica gel column chromatography (φ4 × 7 cm, hexane: EtOAc = 1: 1), and then the fractions containing the product were concentrated under reduced pressure to obtain a thin solution. A yellow foam was obtained.

The obtained foam was dissolved in toluene (1.0 mL), AIBN (25 mg, 0.15 mmol) and Bu ₃ SnH (0.035 ml, 0.15 mmol) were added, and the mixture was heated to 100 ° C. and stirred for 15 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (φ1 × 7 cm, hexane: EtOAc = 1: 1−1: 2) to obtain colorless foam 3d (19.2 mg, 4 steps 1.9%).
¹ H NMR (CDCl ₃ , 500 MHz) δ 7.73 (s, 1H, H-8), 6.33 (d, 1H, H-1 ′, J _{1 ′, 2 ′} = 7.3 Hz), 5.72 (brs, 1H, N H Me), 5.07 (t, 1H, H-3 ', J _{3', 2 =} J _{3 ', 4' =} 8.5Hz), 4.82 (brs, 2H, N H ₂ ), 4.14 (dd, 1H, H -5'a, J _{5'a, 4 '=} 4.3Hz, J _{5'a, 5'b =} 12.8Hz, 4.06 (dd, 1H, H-5'b, J _{5'b, 4' =} 4.5Hz , J _{5'b, 5'a =} 12.8Hz), 3.85 (ddd, 1H, J _{4 ', 3' = 8.3Hz} , J _{4 ', 5'a} = 4.3Hz, J _{4', 5'b} = 4.5 Hz), 3.69 (dd, 1H, H-2 ', J _{2', 1 '=} 7.3Hz, J _{2', 3 '=} 8.3Hz), 3.11 (brs, 3H, NH Me ), 1.23-1.03 (m , 28H, isopropyl x 4);
¹³ C NMR (CDCl ₃ , 125 MHz) δ158.88, 134.42, 115.52, 84.01, 80.57, 79.52, 73.63, 61.47, 60.95, 55.65, 43.03, 17.40, 17.32, 17.29, 17.24, 17.03, 16.95, 16.90, 16.85, 13.43 , 13.02, 12.92, 12.62, 12.42;
FAB-LRMS calculated: C ₂₄ H ₄₁ N ₇ O ₄ Si ₂ 533.771, measured: m / z 548.3 (MH ⁺ );

Example 9
Synthesis of 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-methylaminopurine (1d)

3d (18 mg, 0.033 mmol) was dissolved in THF (0.33 mL) at 0 ° C., AcOH (4.0 μL, 0.072 mmol) and Bu ₄ NF (72 μL, 0.072 mmol) were added, and the mixture was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified by PTLC (CHCl ₃ : MeOH = 3: 1) to obtain white crystals 1d (6.6 mg, 65%).
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 7.94 (s, 1H, H-8), 7.27 (brs, 1H, N H Me), 6.29 (d, 1H, H-1 ′, J _{1 ′, 2 '=} 7.5Hz), 6.29 (brs, 1H, OH-3'), 5.89 (brs, 2H, NH ₂ ), 5.21 (brs, 1H, OH-5 '), 4.77 (dd, 1H, H-3' , J _{3 ', 2' =} 7.5Hz, J _{3 ', 4' =} 8.2Hz), 4.00 (t, 1H, H-2 ', J _{2', 1 '=} J _{2', 3 '=} 7.5Hz) , 3.79-3.64 (m, 3H, H-4 ', H-5'), 2.87 (brs, 3H, NH Me) ;
¹³ C NMR (DMSO-d ₆ , 125 MHz) δ 160.29, 155.39, 135.37, 117.16, 85.16, 84.79, 81.04, 79.72, 71.66, 71.17, 59.49, 57.52;
FAB-LRMS calculated value: C ₁₂ H ₁₅ N ₇ O ₃ 305.293, measured value: m / z 306.3 (MH ⁺ );

Example 10
Synthesis of 2-amino-9- [3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -6-cyanopurine (2e)

In an argon atmosphere, 2c (54 mg, 0.1 mmol) was dissolved in MeCN ₍ 1.00 mL), Me ₃ NHCl (20 mg, 0.2 eq), Et ₄ NCN (24 mg, 0.15 eq) and Et ₃ N (56 μL, 0.4 eq) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (φ2 × 5 cm, hexane: EtOAc = 3: 1) to obtain white foam 2e (51 mg, 94%).
¹ H NMR (CDCl ₃ , 500MHz) δ 8.11 (s, 1H, H-8), 5.95 (d, 1H, H-1 ', J _{1', 2 '=} 1.1Hz), 5.33 (brs, 2H, N H ₂ ), 4.72 (dd, 1H, H-3 ', J _{3', 2 '=} 5.5Hz, J _{3', 4 '=} 8.0Hz), 4.48 (dd, 1H, H-2', J _{2 ' , 1 '=} 1.1Hz, J _{2', 3 '=} 5.5Hz), 4.16-4.04 (m, 3H, H-4', H-5 '), 3.08 (brs, 1H, OH-2'), 1.11 -1.01 (m, 28H, isopropyl x 4);
¹³ C NMR (CDCl ₃ , 125 MHz) δ159.61, 154.07, 143.33, 131.84, 130.21, 113.56, 88.87, 81.99, 74.70, 70.26, 61.13, 17.38, 17.34, 17.30, 17.23, 17.12, 17.04, 16.97, 16.86, 13.36 , 13.04, 12.88, 12.61;
FAB-LRMS calculated: C ₂₃ H ₃₈ N ₅ O ₅ Si ₂ 534.244, measured: m / z 535.4 (MH ⁺ );

Example 11
2-Amino-9- [2-C-cyano-2-deoxy-3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -6-cyano Synthesis of purine (3e)

Under an argon atmosphere, CrO _{3 (} 290 mg, 2.88 mmol) and MS4A (0.80 g) were suspended in CH ₂ Cl _{2 (} 4.00 mL), pyridine (0.47 mL, 5.76 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. . Ac ₂ O (0.54 ml, 5.76 mmol) was added and the mixture was further stirred for 20 minutes, and then a solution of 2e (440 mg, 0.82 mmol) in CH ₂ Cl _{2 (} 2 mL) was added dropwise and stirred for 15 minutes. The reaction solution was added dropwise to Et ₂ O (15.0 mL), and the Et ₂ O solution was filtered through Celite-Floridyl. The filtrate was washed with 0.1N aqueous HCl and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. After filtering the solution, CH ₂ Cl _{2 (} 8.0 mL) and Bu ₄ NCN (440 mg, 1.64 mmol) were added to the filtrate, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with Et ₂ O, and the organic layer was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure.

Under an argon atmosphere, DMAP (150 mg, 1.23 mmol) and PhOSCCl (0.17 ml, 1.23 mmol) were added to CH ₂ Cl _{2 (} 8.00 mL), the residue obtained at 0 ° C. and Et ₃ N (0.17 ml, 1.23 mmol) was added and stirred for 20 minutes. Saturated multistory water was added to the reaction solution to stop the reaction, and the mixture was vigorously stirred for 15 minutes. The organic layer was washed with saturated multilayer water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure, and the residue was roughly purified by silica gel column chromatography (φ3 × 8 cm, hexane: EtOAc = 3: 1), and then the fractions containing the product were concentrated under reduced pressure to obtain a thin A yellow foam was obtained.

The obtained foam was dissolved in toluene (8.0 mL), AIBN (202 mg, 1.23 mmol) and Bu ₃ SnH (0.29 ml, 1.23 mmol) were added, and the mixture was heated to 100 ° C. and stirred for 15 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (φ3 × 10 cm, hexane: EtOAc = 4: 1-3: 1−2: 1), and colorless foam 3e (145 mg, 4 steps 33%) was obtained. Obtained.
¹ H NMR (CDCl ₃ , 500MHz) δ 8.24 (s, 1H, H-8), 6.40 (d, 1H, H-1 ', J _{1', 2 '=} 7.2Hz), 5.24 (brs, 2H, N H ₂ ), 4.99 (t, 1H, H-3 ', J _{3', 2 '=} J _{3', 4 '=} 8.7Hz), 4.17 (dd, 1H, H-5'a, J _{5'a, 4 '=} 2.8Hz, J _{5'a, 5'b =} 13.2Hz), 4.09 (dd, 1H, H-5'b, J _{5'b, 4'} = 2.9Hz, J _{5'b, 5'a} = 13.1Hz), 4.09 (ddd, 1H, J _{4 ', 3' =} 8.7Hz, J _{4 ', 5'a} = 2.8Hz, J _{4', 5'b} = 2.9Hz), 3.72 (dd, 1H, H-2 ', J _{2', 1 '=} 7.2Hz, J _{2', 3 '=} 8.7Hz), 1.18-0.94 (m, 28H, isopropyl x 4);
¹³ C NMR (CDCl ₃ , 125 MHz) δ159.62, 154.19, 142.05, 132.19, 129.67, 115.05, 113.46, 84.37, 80.89, 72.45, 60.14, 42.66, 17.52, 17.38, 17.27, 17.22, 16.94, 16.86, 16.82, 13.58 , 13.45, 12.96, 12.73, 12.40;
FAB-LRMS m / z 544.4 (MH ⁺ ); FAB-HRMS (CHCl ₃ ) Calculated: C ₂₄ H ₃₇ N ₇ O ₄ Si ₂ 543.245, Found: 545.2520 (MH ⁺ );

Example 12
Synthesis of 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-cyanopurine (1e)

3e (44 mg, 0.08 mmol) was dissolved in THF (5.0 mL) at 0 ° C., AcOH (62 μL, 1.08 mmol) and Bu ₄ NF (1.00 mL, 1.00 mmol) were added, and the mixture was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified by flash silica gel column chromatography (φ2 × 15 cm, CHCl ₃ : MeOH = 10: 1). Fractions containing the product were concentrated and crystallized with EtOAc to give white crystals 1e (11.6 mg, 75%).
¹ H NMR (DMSO-d ₆ , 500MHz) δ 8.63 (s, 1H, H-8), 7.24 (brs, 2H, NH ₂ ), 6.42 (d, 1H, H-1 ', J _{1', 2 '} = 7.5Hz), 6.31 (brd, 1H, OH-3 ', J _{OH-3', 3 '} = 5.8Hz), 5.18 (brt, 1H, OH-5', J _{OH-5 ', 5'a' =} J _{OH-5 ', 5'b' =} 5.3Hz), 4.77 (dd, 1H, H-3 ', J _{3', 2 '=} 8.7Hz, J _{3', 4 '=} 5.7Hz), 4.10 ( dd, 1H, H-2 ', J _{2', 1 '=} 7.5Hz, J _{2', 3 '=} 8.7Hz), 3.84-3.82 (m, 1H, H-4'), 3.75-3.74 (m, 1H, H-5'a). 3.69-3.66 (m, 1H, H-5'b);
FAB-LRMS m / z 302.0 (MH ⁺ ); FAB-HRMS (DMSO) calculated: C ₁₂ H ₁₁ N ₇ O ₃ 301.092, measured: 302.1006 (MH ⁺ );

Example 13
Synthesis of 2-amino-9- [3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -6-phenylpurine (2f)

Under an argon atmosphere, a toluene (18 mL) solution of Pd (PPh ₃ ) Cl ₂ (130 mg, 0.184 mmol) and PPh _{3 (} 100 mg, 0.37 mmol) was stirred at room temperature for 1 hour. 2c (1.00 g, 1.84 mmol), phenylboronic acid (450 mg, 3.68 mmol) and K ₂ CO ₃ (380 mg, 2.76 mmol) were added, and the mixture was heated to reflux at 100 ° C. for 24 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (φ4 × 20 cm, hexane: EtOAc = 3: 1) to give a white foam 2f (723 mg, 72 %).
¹ H NMR (CDCl ₃ , 500MHz) δ 8.63-8.61 (m, 2H, Ph), 7.94 (s, 1H, H-8), 7.54-7.47 (m, 3H, Ph), 5.96 (d, 1H, H -1 ', J _{1', 2 '=} 1.6Hz), 4.99 (brs, 2H, N H ₂ ), 4.90 (t, 1H, H-3', J _{3 ', 2' =} J _{3 ', 4' =} 5.7Hz), 4.63 (dd, 1H, H-2 ', J _{2', 1 '=} 1.6Hz, J _{2', 3 '=} 5.7Hz), 4.12-4.06 (m, 3H, H-4', H-5 '), 3.15 (brd, 1H, OH-2', J _{OH-2 ', 2' =} 3.15Hz), 1.13-1.02 (m, 28H, isopropyl x 4);
FAB-LRMS m / z 586.3 (MH ⁺ ); FAB-HRMS (CHCl ₃ ) Calculated: C ₂₈ H ₄₃ N ₅ O ₅ Si ₂ 585.280, Found: 588.22885 (MH ⁺ );

Example 14
2-Amino-9- [2-C-cyano-2-deoxy-3,5-O- (tetraisopropyldisiloxane-1,3-diyl) -β-D-arabinopentofuranosyl] -6-phenyl Synthesis of purine (3f)

Under an argon atmosphere, CrO _{3 (} 341 mg, 3.41 mmol) and MS4A (1.0 g) were suspended in CH ₂ Cl _{2 (} 5.0 mL), pyridine (0.55 mL, 6.82 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes. . Ac ₂ O (0.65 ml, 6.82 mmol) was added, and the mixture was further stirred for 20 minutes. Then, a solution of 2f (570 mg, 0.97 mmol) in CH ₂ Cl _{2 (} 2.5 mL) was added dropwise and stirred for 15 minutes. The reaction solution was added dropwise to Et ₂ O (15.0 mL), and the Et ₂ O solution was filtered through Celite-Floridyl. The filtrate was washed with 0.1N aqueous HCl and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. After filtering the solution, CH ₂ Cl _{2 (} 8.0 mL) and Et ₄ NCN (305 mg, 1.94 mmol) were added to the filtrate, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with Et ₂ O, and the organic layer was washed with saturated brine. The solution was dried over anhydrous sodium sulfate, the solution was filtered, and the filtrate was concentrated under reduced pressure.

Under argon atmosphere, DMAP (180 mg, 1.46 mmol) and PhOSCCl (0.20 ml, 1.46 mmol) were added to CH ₂ Cl _{2 (} 10.0 mL), and the residue obtained at 0 ° C. and Et ₃ N (0.20 ml, 1.46 mmol) were added. mmol) was added and stirred for 20 minutes. Saturated multistory water was added to the reaction solution to stop the reaction, and the mixture was vigorously stirred for 15 minutes. The organic layer was washed with saturated multilayer water and dried over anhydrous sodium sulfate. After filtering the solution, the filtrate was concentrated under reduced pressure, and the residue was roughly purified by silica gel column chromatography (φ3 × 8 cm, hexane: EtOAc = 5: 1), and then the fractions containing the product were concentrated under reduced pressure to obtain a thin solution. A yellow foam was obtained.

The obtained foam was dissolved in toluene (4.4 mL), AIBN (108 mg, 0.66 mmol) and Bu ₃ SnH (0.15 ml, 0.66 mmol) were added, heated to 100 ° C., and heated to reflux for 15 minutes. The reaction mixture was concentrated and purified by silica gel column chromatography (φ3 × 10 cm, hexane: EtOAc = 4: 1) to give colorless foam 3f (80 mg, 14 steps 14%).
¹ H NMR (CDCl ₃ , 500MHz) δ 8.64 (d 2H, Ph, J = 7.0Hz), 8.06 (s, 1H, H-8), 7.54-7.48 (m, 3H, Ph), 6.45 (d, 1H , H-1 ', J _{1', 2 '=} 7.3Hz), 5.04 (brs, 2H, N H ₂ ), 5.10 (t, 1H, H-3', J _{3 ', 2' =} J _{3 ', 4 '=} 8.3Hz), 4.16 (dd, 1H, H-5'a, J _{5'a, 4' =} 4.1Hz, J _{5'a, 5'b =} 12.8Hz), 4.09 (dd, 1H, H -5'b, J _{5'b, 4 '=} 3.0Hz, J _{5'b, 5'a =} 12.8Hz), 3.90 (ddd, 1H, J _{4', 3 '=} 8.3Hz, J _{4', 5 'a} = 4.1Hz, J _{4', 5'b} = 3.0Hz), 3.74 (dd, 1H, H-2 ', J _{2', 1 '=} 7.3Hz, J _{2', 3 '=} 8.3Hz), 1.18-1.01 (m, 28H, isopropyl x 4);
¹³ C NMR (CDCl ₃ , 125 MHz) δ159.62, 154.19, 142.05, 132.19, 129.67, 115.05, 113.46, 84.37, 80.89, 72.45, 60.14, 42.66, 17.52, 17.38, 17.27, 17.22, 16.94, 16.86, 16.82, 13.58 , 13.45, 12.96, 12.73, 12.40;
FAB-LRMS m / z 595.4 (MH ⁺ ); FAB-HRMS (CHCl ₃ ) Calculated: C ₂₉ H ₄₂ N ₆ O ₄ Si ₂ 594.281, Found: 595.2897 (MH ⁺ );

Example 15
Synthesis of 9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-phenylpurine (1f)

3f (62 mg, 0.114 mmol) was dissolved in MeOH (1.1 mL), NH ₄ F (42 mg, 1.14 mmol) was added, and the mixture was heated to reflux at 60 ° C. for 1 hr. The reaction solution was concentrated, and the residue was purified by flash silica gel column chromatography (φ3 × 5 + 1 cm, CHCl ₃ : MeOH = 10: 1). Fractions containing the product were concentrated and crystallized with EtOAc to give white crystals 1f (17.5 mg, 44%).
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 8.70-8.68 (m 2H, Ph), 8.44 (s, 1H, H-8), 7.56-7.53 (m, 3H, Ph), 6.65 (brs, 2H, NH ₂ ), 6.46 (d, 1H, H-1 ', J _{1', 2 '=} 7.4Hz), 6.29 (brd, 1H, OH-3', J _{OH-3 ', 3'} = 5.9Hz), 5.18 (brt, 1H, OH-5 ', J _{OH-5', 5'a '=} J _{OH-5', 5'b '=} 5.4Hz), 4.82 (dd, 1H, H-3', J _{3 ', 2' =} 7.4Hz, J _{3 ', 4' =} 6.1Hz), 4.10 (t, 1H, H-2 ', J _{2', 1 '=} J _{2', 3 '=} 7.4Hz), 4.12- 4.06 (m, 1H, H-4 '. H-5');
FAB-LRMS m / z 353.1 (MH ⁺ ); FAB-HRMS (DMSO) calculated: C ₁₇ H ₁₆ N ₆ O ₃ 352.128, found: 352.1354 (MH ⁺ );

Example 16
Synthesis of 9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) guanine (1g)

Dissolve 1a (25 mg, 0.082 mmol) in KH ₂ PO ₄ -Na ₂ HPO ₄ buffer (pH = 7.0) (8.2 mL), add adenosine deaminase (0.125 mL), and incubate in a thermostat at 37 ° C for 24 hours did. Activated carbon was added to the reaction solution to adsorb the enzyme and the product, and the activated carbon was washed with H ₂ O. The product was eluted with MeOH, and MeOH was distilled off under reduced pressure. The residue was purified by C18 reverse phase HPLC (YMC-Pack D-ODS-5-A, 250 × 20 mm, 5% MeCN, 0.1% AcOH in H ₂ O) to obtain a white solid 1 g (5.1 mg, 22%). Obtained.
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 10.74 (brs, 1H, NH), 7.98 (s, 1H, H-8), 6.34 (brs, 2H, NH ₂ ), 6.28 (brs, 1H, OH- 3 '), 6.24 (d, 1H, H-1', J _{1 ', 2' =} 7.0Hz), 5.14 (brs, 1H, OH-5 '), 4.71 (t, 1H, H-3', J _{3 ', 2' =} J _{3 ', 4' =} 8.5Hz), 4.02 (dd, 1H, H-2 ', J _{2', 1 '=} 7.0Hz, J _{2', 3 '=} 8.5Hz), 3.78 -3.63 (m, 1H, H-4 '. H-5');
AB-LRMS calculated: C ₁₁ H ₁₂ N ₆ O ₄ 292.092, measured: m / z 293.14 (MH ⁺ );

Example 16
Evaluation of EBV and KSHV growth inhibitory effect The synthesized CNDAG derivatives 1a to g were evaluated for the growth inhibitory effect of KSHV-infected cells as follows. DG75 (EBV- KSHV-) and Raji (EBV + KSHV-) cells at a concentration of 5000 cells / well, BC2 (EBV + KSHV +) cells and BC3 (EBV-KSHV +) cells at a concentration of 10000 cells / well, 96-well plate Sowing. At the time of seeding, the compounds were added to their final concentrations. After culturing for 5 days, 10 μl of WST-8 (Cell counting kit, Dojindo) was added to each well and incubated for 3 hours, and then the absorbance (Ws: 450 nm, Wr: 650 nm) was measured. The results are shown in FIG. The SD obtained as a result of three times is indicated by an error bar.

  As a result, it was found that 1a, 1b, 1c, and 1g showed cytostatic effects on EBV-infected cells and KSHV-infected cells. Similarly, the activity of ganciclovir and acyclovir was also evaluated, but the growth inhibitory effect of EBV or KSHV-infected cells was not observed.

  The compounds of the present invention are useful for preventing infection when an immunosuppressant is administered during organ transplant surgery, and for treating opportunistic infections when HIV-infected patients develop AIDS.

Claims (7)

Formula I:

Wherein R is hydroxy, C _1-6 alkoxy, halogen, NR ¹ R ² (wherein R ¹ and R ² are independently hydrogen or C _1-3 alkyl), cyano Or is phenyl]
Or a salt thereof. The compound or a salt thereof according to claim 1, wherein in formula I, R is hydroxy, _C1-6 alkoxy, halogen or amino.   The compound is 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-methoxypurine, 9- (2-C-cyano-2-deoxy-β -D-arabinopentofuranosyl) -2,6-diaminopurine, 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-chloropurine, 2. The compound of claim 1 selected from the group consisting of and 9- (2-C-cyano-2-deoxy- [beta] -D-arabinopentofuranosyl) guanine. Formula I:

Wherein R is hydroxy, C _1-6 alkoxy, halogen, NR ¹ R ² (wherein R ¹ and R ² are independently hydrogen or C _1-3 alkyl), cyano Or is phenyl]
A pharmaceutical composition for preventing or treating herpes virus infection, comprising a compound represented by the formula: 5. The pharmaceutical composition according to claim 4, wherein in formula I, R is hydroxy, _C1-6 alkoxy, halogen or amino.   The compound is 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) -6-methoxypurine (1a), 9- (2-C-cyano-2- Deoxy-β-D-arabinopentofuranosyl) -2,6-diaminopurine (1b), 2-amino-9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) The medicament according to claim 4, which is selected from the group consisting of -6-chloropurine (1c) and 9- (2-C-cyano-2-deoxy-β-D-arabinopentofuranosyl) guanine (1g). Composition.   The pharmaceutical composition according to any one of claims 4 to 6, wherein the herpesvirus infection is Epstein-Barr virus infection or Kaposi's sarcoma-associated herpesvirus infection.

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