Cyclobutyl purine derivative or salt thereof

Pending Publication Date: 2021-05-20
FUJIFILM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The objective of this patent is to offer a substance that can fight against adenovirus and make an excellent anti-adenoviral treatment.

Problems solved by technology

On the other hand, cidofovir is known to be toxic upon systemic administration and ocular instillation administration (Antimicrobial Agents and Chemotherapy, vol.

Method used

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  • Cyclobutyl purine derivative or salt thereof
  • Cyclobutyl purine derivative or salt thereof
  • Cyclobutyl purine derivative or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0250]

[0251]First Step

[0252]Under a nitrogen atmosphere, a 2.0 M lithium aluminum hydride / tetrahydrofuran solution (25 mL) was added dropwise under ice-cooling to a mixture of ethyl cis-3-aminocyclobutane-1-carboxylate hydrochloride (4.3 g) and tetrahydrofuran (43 mL) which was then stirred at room temperature for 1 hour. Water (4 mL), a 15% aqueous sodium hydroxide solution (4 mL), and water (12 mL) were added to the reaction solution, and the resulting solid was filtered off and washed with tetrahydrofuran. The solvent was distilled off under reduced pressure to give (cis-3-aminocyclobutyl)methanol (4.4 g) as a colorless oil.

[0253]Second Step

[0254]A mixture of (cis-3-aminocyclobutyl)methanol (8.5 g) obtained in the first step, 2-amino-4,6-dichloro-5-formamidopyrimidine (17.4 g), N,N-diisopropylethylamine (73 mL), ethanol (255 mL), and N-methyl-2-pyrrolidone (8.5 mL) was stirred with heating under reflux for 6 hours. The solvent was distilled off under reduced pressure, and the obt...

reference example 2-1

[0261]

[0262]A 5 M sodium methoxide / methanol solution (0.5 mL) was added to a mixture of (cis-3-(2-amino-6-chloro-9H-purin-9-yl)cyclobutyl)methanol hydrochloride (336 mg) and methanol (4.0 mL) which was then stirred at 50° C. for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100, methanol:ethyl acetate=0:100 to 20:80) to give (cis-3-(2-amino-6-methoxy-9H-purin-9-yl)cyclobutyl)methanol (142 mg) as a white solid.

[0263]MS (ESI m / z): 250 (M+H)

[0264]RT (min): 0.54

reference example 2-2

[0265]

[0266]Cyclopropylamine (50 μL) was added to a mixture of (cis-3-(2-amino-6-chloro-9H-purin-9-yl)cyclobutyl)methanol hydrochloride (20 mg) and ethanol (0.5 mL) which was then irradiated with microwave (microwave reactor, 120° C., 1 hour, 2.45 GHz, 0 to 240 W). The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=50:50 to 0:100, methanol:ethyl acetate=0:100 to 20:80) to give (cis-3-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclobutyllmethanol (21 mg) as a white solid.

[0267]MS (ESI m / z): 275 (M+H)

[0268]RT (min): 0.55

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Abstract

An object of the present invention is to provide a compound exhibiting an excellent drug efficacy as an anti-adenoviral agent, and an anti-adenoviral agent. The present invention provides a compound represented by General Formula [1](in the formula, R1 represents a halogen atom, an amino group which may be substituted, a C1-6 alkoxy group which may be substituted, a hydroxyl group which may be protected, or the like; R2 represents a hydrogen atom or an amino protecting group; R3 represents a C1-20 alkoxy group which may be substituted, an aryloxy group which may be substituted, an amino group which may be substituted, or the like; R4 represents a C1-20 alkoxy group which may be substituted, an aryloxy group which may be substituted, an amino group which may be substituted, or the like); or a salt thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of PCT International Application No. PCT / JP2019 / 029448 filed on Jul. 26, 2019, which claims priority under 35 U.S.C § 119(a) to Japanese Patent Application No. 2018-141749 filed on Jul. 27, 2018. Each of the above application(s) is hereby expressly incorporated by reference, in its entirety, into the present application.BACKGROUND OF THE INVENTION1. Field of the Invention[0002]The present invention relates to a cyclobutyl purine derivative or a salt thereof and an anti-adenoviral agent containing the same.2. Description of the Related Art[0003]Adenovirus is a double-stranded linear DNA virus and is a causative virus that causes various pathological conditions such as respiratory infection, pharyngoconjunctival fever, epidemic keratoconjunctivitis, hepatitis, gastroenteritis, cystitis, and encephalitis.[0004]Although there is no pharmaceutical product approved as an anti-adenoviral agent, for example, cid...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616A61P31/20Y02P20/55A61K31/683
InventorKUNIYOSHI, HIDENOBUYAMANE, TAKEHIROYAMAKAWA, TAKAYUKITANABE, SHINTAROFUJIWARA, HIDEYASUKODAMA, EIICHI
OwnerFUJIFILM CORP