WO2020045628A1

WO2020045628A1 - Nucleic acid analog and anti-hepatitis b virus agent

Info

Publication number: WO2020045628A1
Application number: PCT/JP2019/034125
Authority: WO
Inventors: 智仁濱田; 秀幸池内; 佳菜子稲生; 洋介岸川; 正徳池田; 緑武田
Original assignee: ダイキン工業株式会社; 国立大学法人鹿児島大学
Priority date: 2018-08-31
Filing date: 2019-08-30
Publication date: 2020-03-05
Also published as: JPWO2020045628A1; JP7496132B2

Abstract

The present invention addresses the problem of providing a nucleic acid analog, and a pharmaceutical composition, an anti-hepatitis virus agent and a preventive or therapeutic agent for a hepatitis virus-related disease each comprising a nucleic acid analog as an active ingredient. This problem can be solved by a compound represented by formula (1) (wherein: R^a represents a hydrogen atom or an alkyl group and R^b represents an oxo group; or R^a represents a hydrogen atom, a halogen atom or an alkyl group and R^b represents an amino group), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate of the same.

Description

Nucleic acid analogs and anti-hepatitis B virus agents

The present disclosure relates to pharmaceutical compositions, anti-hepatitis virus agents (particularly anti-hepatitis B virus agents), and hepatitis virus-related diseases (particularly hepatitis B virus-related diseases) containing, for example, novel nucleic acid analogs and nucleic acid analogs as active ingredients. )).

As an active ingredient of an anti-liver tumor virus agent and a preventive or therapeutic agent for a liver tumor virus-related disease, for example, the following formula:

(In the formula, Z is fluorine or hydrogen.)
Is known (Patent Document 1).

International Publication No. 2017/155082

The present disclosure relates to a novel nucleic acid analog, a pharmaceutical composition, an anti-hepatitis virus agent (particularly an anti-hepatitis B virus agent), and a hepatitis virus-related disease (particularly a hepatitis B virus-related disease) containing the nucleic acid analog as an active ingredient. The purpose of the present invention is to provide a preventive or therapeutic agent.

The present disclosure includes the following aspects.
Item 1.
The following equation (1):

(Where
R ^a is a hydrogen atom or an alkyl group, and R ^b is an oxo group, or R ^a is a hydrogen atom, a halogen atom or an alkyl group, and R ^b is an amino group . )
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.
Item 2.
The following equation (1):

(Where
R ^a is a hydrogen atom or an alkyl group, and R ^b is an oxo group, or R ^a is a hydrogen atom, a halogen atom or an alkyl group, and R ^b is an amino group . )
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, for preventing or treating hepatitis B virus-related diseases.
Item 3.
Item 3. The prophylactic or therapeutic agent according to Item 2, wherein the hepatitis B virus-related disease is at least one selected from the group consisting of hepatitis B, cirrhosis B, and hepatoma B.
Item 4.
The following equation (1):

(Where
R ^a is a hydrogen atom or an alkyl group, and R ^b is an oxo group, or R ^a is a hydrogen atom, a halogen atom or an alkyl group, and R ^b is an amino group . )
A method for producing a compound represented by or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof,
Reacting a nucleobase selected from the group consisting of uracil, 5-alkyluracil, cytosine, 5-halocytosine, and 5-alkylcytosine with a silylating agent to obtain a silylated nucleobase A;
The silylated nucleobase is represented by the following formula (I):

(Wherein Q ¹ and Q ² are the same or different and are hydroxyl-protecting groups, and X is bromine or iodine.)
And a step C of deprotecting the hydroxyl-protecting group of the product obtained by the reaction of the step B.
Item 5.
2′-deoxy-2′-fluoro-β-D-cytidine or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
Item 6.
Item 6. A pharmaceutical composition comprising the compound according to Item 5 as an active ingredient.
Item 7.
Item 6. An anti-hepatitis virus agent comprising the compound according to Item 5 as an active ingredient.
Item 8.
An agent for preventing or treating a hepatitis virus-related disease, comprising the compound according to item 5 as an active ingredient.
Item 9.
Item 9. The prophylactic or therapeutic agent according to Item 8, wherein the hepatitis virus-related disease is one or more selected from the group consisting of chronic hepatitis, cirrhosis, and liver cancer.

The present disclosure further includes the following aspects.
A compound represented by the above formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof for use as a medicament for preventing or treating hepatitis B virus-related disease. Japanese food.
-2'-deoxy-2'-fluoro-β-D-cytidine or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament for preventing or treating hepatitis virus-related diseases. Or their solvates.
A compound represented by the above formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a medicament for preventing or treating hepatitis B virus-related disease. Use of things.
-2'-deoxy-2'-fluoro-β-D-cytidine or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating hepatitis virus-related disease. Use of those solvates.

According to the present disclosure, a pharmaceutical composition, an anti-hepatitis virus agent (particularly an anti-hepatitis B virus agent), and a hepatitis virus-related disease (particularly hepatitis B virus-related) containing a new nucleic acid analog, a nucleic acid analog as an active ingredient The present invention provides a prophylactic or therapeutic agent for (disease).

The above summary of the present disclosure is not intended to describe each disclosed embodiment or every implementation of the present disclosure.
The following description of the disclosure more specifically exemplifies illustrative embodiments.
In several places throughout the disclosure, guidance is provided through examples and the examples can be used in various combinations.
In each case, the exemplary groups can serve as non-exclusive and representative groups.
All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety.

Terminology The symbols and abbreviations used herein, unless otherwise limited, are to be understood in the context of the present specification, as commonly used in the art to which this disclosure pertains.
As used herein, the phrase "comprising" is used to encompass the phrase "consisting essentially of," and the phrase "consisting of."
Unless otherwise limited, the steps, treatments, or operations described herein may be performed at room temperature.
As used herein, room temperature can mean a temperature in the range of 10-40 ° C.
In the present specification, the notation “C _nm ” (where n and m are each a number) has a carbon number of n or more and m or less as generally understood by those skilled in the art. It represents that.
In the present specification, examples of the halogen atom include fluorine, chlorine, bromine, and iodine.
In the present specification, examples of the alkyl group include linear or branched C _1-20 alkyl [eg, methyl, ethyl, propyl (n-propyl, i-propyl), butyl (n-butyl, s-butyl) , I-butyl, t-butyl), pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl].
In this specification, examples of the cycloalkyl group include C _3-10 cycloalkyl [eg, cyclopentyl and cyclohexyl].
In this specification, examples of the aryl group include C _6-10 aryl [eg, phenyl, and naphthyl].
Examples of aralkyl groups herein include C _6-10 aryl-linear or branched C _1-10 alkyl [eg, benzyl, and phenethyl].
In the present specification, examples of the alkoxy group include a linear or branched C _1-10 alkyloxy [eg, methoxy, ethoxy, and propoxy].
In the present specification, examples of the alkoxyalkoxy group include linear or branched C _1-20 alkyloxy-linear or branched C _1-4 alkyloxy [eg, methoxymethoxy, methoxyethoxy, ethoxyethoxy) , Hexadecyloxypropoxy, and octadecyloxyethoxy].
In the present specification, examples of the acyloxy group include a linear or branched C _1-10 alkylcarbonyloxy [eg, methylcarbonyloxy, ethylcarbonyloxy, and propylcarbonyloxy].
Examples of the substituents that the alkyl group, cycloalkyl group, aryl group, aralkyl group, alkoxy group, alkoxyalkoxy group, acyloxy group, and steroid group may each have,
Halogen, and organic groups, and preferred examples thereof include:
Halogen, alkoxy, alkylcarbonyloxy, alkylcarbonylthio, alkyloxycarbonyl, and alkyldithio, and more preferred examples thereof include
Halogen, linear or branched C _1-20 alkyloxy, linear or branched C _1-10 alkylcarbonyloxy, linear or branched C _1-10 alkylcarbonylthio, linear or Includes branched C _1-10 alkyloxycarbonyl, and straight or branched C _1-10 alkyldithio.

Anti-hepatitis B virus agent In the present disclosure, “anti-hepatitis B virus agent” means an agent that delays or suppresses the growth of hepatitis B virus.
The hepatitis B virus may be a strain having resistance to existing anti-hepatitis B virus agents (eg, entecavir, tenofovir).
The term “strain having resistance to anti-hepatitis B virus” refers to a strain in which the anti-hepatitis B virus agent does not exhibit the effect of delaying or inhibiting the growth of normal strains expressed in normal strains, or the degree of expression of the effect, Means a strain that is lower than that of the stock.
The anti-hepatitis B virus agent of one embodiment of the present disclosure has the following formula (1):

(Where
R ^a is a hydrogen atom or an alkyl group, and R ^b is an oxo group, or R ^a is a hydrogen atom, a halogen atom or an alkyl group, and R ^b is an amino group . )
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.

<Compound represented by Formula (1) [Nucleic acid analog compound]>
In the formula (1), the nitrogen-containing heterocyclic ring bonded to the 1-position of the furanose ring shows aromaticity, and when R ^b is an oxo group,

And when R ^b is an amino group,

It is.
The combination of R ^a and R ^b is preferably
A combination wherein R ^a is an alkyl group and R ^b is an oxo group, or a combination wherein R ^a is a hydrogen atom or a halogen atom and R ^b is an amino group.
The combination of R ^a and R ^b is more preferably
A combination in which R ^a is a C _1-4 alkyl group and R ^b is an oxo group, or a combination in which R ^a is a hydrogen atom or a fluorine atom and R ^b is an amino group.
The combination of R ^a and R ^b is even more preferably
A combination wherein R ^a is a methyl group and R ^b is an oxo group;
A combination wherein R ^a is a fluorine atom and R ^b is an amino group, or a combination wherein R ^a is a hydrogen atom and R ^b is an amino group {2′-deoxy-2′-fluoro-β-D -Cytidine [alias: 4-amino-1-((2R, 3S, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidin-2 (1H) -one ]｝
It is.
The compound represented by the formula (1) has a high inhibitory activity on the proliferation of hepatitis B virus.

<Method for producing compound represented by formula (1)>
The method for producing the compound represented by the formula (1) is not particularly limited.
Step A ′ of preparing a nucleobase selected from the group consisting of uracil, 5-alkyluracil, cytosine, 5-halocytosine, and 5-alkylcytosine
Optionally, a step A of reacting the nucleobase with a silylating agent to obtain a silylated nucleobase;
The nucleobase or silylated nucleobase is represented by the following formula (I):

(Wherein Q ¹ and Q ² are the same or different and are hydroxyl-protecting groups, and X is bromine or iodine.)
And a step C of deprotecting the hydroxyl-protecting group of the product obtained by the reaction of the step B.

[Step A]
Examples of the silylating agent include N, O-bistrimethylsilylacetamide (BSA), N, O-bistrimethylsilyltrifluoroacetamide (BSTFA), trimethylchlorosilane, trimethylsilylimidazole, and hexamethyldisilazane (HMDS). These may be used as pure products or in the form of a base complex such as pyridine. These may be used alone or in combination of two or more at an arbitrary mixing ratio.
The amount of each of the nucleobase and the silylating agent is not particularly limited as long as the reaction proceeds, but the molar ratio of the nucleobase and the silylating agent is, for example, from 1: 2 to 1: 100, more preferably 1 to 1. : 3 to 1:80.
The silylating agent can be used as a reaction solvent.
The reaction of Step A is usually performed in the presence of a sulfate. Examples of the sulfate include ammonium sulfate, magnesium sulfate, iron sulfate, and sulfate of silica gel.
The amount of the sulfate used is not particularly limited, but the molar ratio of the nucleic acid base and the sulfate is, for example, in the range of 1: 0.01 to 1:10, and more preferably in the range of 1: 0.1 to 1: 1. Can be
The reaction temperature in step A is not particularly limited as long as the reaction proceeds, but may be, for example, a temperature in the range of 15 to 80 ° C.
As the reaction time in step A, a time during which the desired product can be sufficiently obtained can be employed, and the reaction can be carried out until the reaction is completed.

[Step B]
In the formula (I), each of Q ¹ and Q ² is not particularly limited as long as it is a functional group capable of protecting a hydroxyl group, and examples thereof include ether-type protecting groups (eg, t-butyl, Benzyl, trityl), acetal-type protecting groups (eg, tetrahydropyranyl), acyl-type protecting groups (eg, acetyl, benzoyl), and silyl ether-type protecting groups (eg, t-butyldimethylsilyl, etc.).
The amount of each of the compound represented by the formula (I) and the nucleobase or silylated nucleobase is not particularly limited as long as the reaction proceeds, but the compound represented by the formula (I) and the nucleobase or The molar ratio of the silylated nucleobase can be, for example, in the range of 1: 1 to 1: 5.
The reaction of Step B is usually performed in a solvent.
Examples of such solvents are
Halogen-based solvents (eg, dichloromethane, chloroform, dichloroethane),
Alcohol solvents (eg, ethanol, propanol, butanol, pentanol),
Includes nitrile solvents (eg, acetonitrile) and mixed solvents thereof.
The reaction temperature in step B is not particularly limited as long as the reaction proceeds, but may be, for example, a temperature in the range of 15 to 80 ° C.
As the reaction time in the step B, a time during which the desired product can be sufficiently obtained can be adopted, and the reaction can be performed until the reaction is completed.

[Step C]
The method and conditions for deprotecting the protecting group for the hydroxy group of the product obtained by the reaction in Step B can be appropriately selected depending on the type of the protecting group. For example, in the case of a benzoyl group, a metal alkoxide (sodium Methoxide, etc.), ammonia and methanol, and the like.
The reaction temperature in step C is not particularly limited as long as the reaction proceeds, but may be, for example, a temperature in the range of 15 to 80 ° C.
As the reaction time in the step C, a time during which the target substance can be sufficiently obtained can be adopted, and the reaction can be performed until the reaction is completed.

生成 The products obtained by the reactions of Steps A to C may be purified by a technique such as filtration or column chromatography, if desired.

The method for producing the compound represented by the formula (I) is not particularly limited, but for example, the following formula (II):

(Wherein Q ¹ and Q ² are as defined above, respectively, and Q ³ is a protecting group for a hydroxyl group.)
And reacting the compound represented by with hydrogen bromide or hydrogen iodide.
The amount of each of the compound represented by the formula (II) and hydrogen bromide or hydrogen iodide is not particularly limited as long as the reaction proceeds, but the compound represented by the formula (II) and hydrogen bromide or iodine are used. The molar ratio of the hydride is, for example, in the range of 1: 1 to 1: 5.
The reaction of the compound represented by the formula (II) and hydrogen bromide or hydrogen iodide is usually performed in a solvent.
Examples of the solvent include a halogen-based solvent (eg, dichloromethane, chloroform, dichloroethane), a carboxylic acid-based solvent (eg, acetic acid), and a mixed solvent thereof.
The reaction temperature is not particularly limited as long as the reaction proceeds, but may be, for example, a temperature in the range of 15 to 30 ° C.

<Prodrug>
The prodrug of the compound represented by the formula (1) is not particularly limited as long as it can be converted into an active metabolite or a compound represented by the formula (1) in a living body. What is used as can be used arbitrarily.
Representative examples of such prodrugs include esters and ester amides.
Examples of the ester include a phosphate ester. A preferred example is:

(Wherein, R ^a and R ^b have the same meanings as described above, respectively, and R ¹ and R ² are the same or different and are each a hydrogen atom or an alkyl group optionally having one or more substituents. A cycloalkyl group optionally having one or more substituents, an aryl group optionally having one or more substituents, or an aralkyl group optionally having one or more substituents Or together with each other to form a ring together with the phosphorus and oxygen atoms constituting the phosphate moiety in the structural formula.)
And a phosphoric acid monoester represented by the following formula:

(Where
R ^a and R ^b are each the same as defined above,
R ³ and R ⁴ in each occurrence are the same or different and are each a hydrogen atom, an alkyl group optionally having one or more substituents, or a cycloalkyl optionally having one or more substituents Group, an aryl group optionally having one or more substituents, or an aralkyl group optionally having one or more substituents,
R ⁵ is an alkyl group optionally having one or more substituents, an alkoxy group optionally having one or more substituents, an alkoxy group optionally having one or more substituents An alkoxy group, an acyloxy group optionally having one or more substituents, or a steroid group optionally having one or more substituents (such as cyclopentaphenanthrein or hydrogenated cyclopentaphenanthrein). And n is 1 or 2. )
And phosphoric acid di- or tri-esters represented by
R ¹ is preferably an alkyl group optionally having one or more substituents, and more preferably a substituent selected from the group consisting of alkoxy, alkylcarbonyloxy, alkylcarbonylthio, and alkyldithio. It is an alkyl group which may have a group.
R ² is preferably a hydrogen atom, an alkyl group optionally having one or more substituents, an aryl group optionally having one or more substituents, or one or more substituents. An aralkyl group which may be possessed, and more preferably, a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group.
The ring formed by R ¹ and R ² together with the phosphorus atom and the oxygen atom constituting the phosphoric acid ester moiety can be a single ring or a condensed ring.
The number of atoms constituting the ring is, for example, an integer in the range of 6 to 10.
Specific examples of the ring are represented by the following formula:

And a ring represented by
The ring may have one or more substituents. Examples of such substituents include halogen, alkyl, cycloalkyl, aryl, and aralkyl.
R ³ and R ⁴ are preferably a hydrogen atom, an alkyl group optionally having one or more substituents, an aryl group optionally having one or more substituents, or one or more An aralkyl group which may have a substituent, more preferably a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group.
R ⁵ is preferably an alkyl group, an alkoxy group, an alkoxyalkoxy group, an acyloxy group, or a steroid group.
Specific examples of the ester amide include, for example, phosphoric ester amide. A preferred example is:

(Where
R ^a and R ^b are each the same as defined above,
R ⁸ is —NR ^8a R ^8b , or —OR ^8c , and R ⁶ , R ⁷ , R ^8a , R ^8b , and R ^8c are the same or different and each have a hydrogen atom and one or more substituents. An alkyl group which may have, a cycloalkyl group which may have one or more substituents, an aryl group which may have one or more substituents, or one or more substituents. It is an aralkyl group which may be possessed. )
And a compound represented by the formula:
R ⁶ and R ^8a are preferably an alkyl group optionally having one or more substituents, and more preferably have a substituent selected from the group consisting of halogen and alkyloxycarbonyl. Is an alkyl group which may be
R ⁷ and R ^8b are preferably a hydrogen atom or an alkyl group optionally having one or more substituents, and more preferably a hydrogen atom or an alkyl group.
R ^8c preferably has a hydrogen atom, an alkyl group optionally having one or more substituents, an aryl group optionally having one or more substituents, and one or more substituents. And an aralkyl group which may have one or more substituents, more preferably a hydrogen atom, an alkyl group, an aryl group or an aralkyl group.
Further preferred examples of the prodrug include a compound represented by the following formula.

(Where
R ^1a , R ^6a , and R ^8d are each an alkyl group;
R ^1b is a halogen or an alkyl group,
R ² and R ⁷ are as defined above,
Ar is an aryl group,
Nu is given by the following equation:

(Wherein, R ^a and R ^b are each the same as defined above).
m1 is an integer in the range of 1-18, and m2 is an integer in the range of 1-10. )
The production of the prodrug can be carried out based on common general technical knowledge by referring to a known method (for example, the method described in Chemical Reviews 2014, 114, 9154-9218) according to the chemical structure.

<Salt>
Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) or a prodrug thereof include (1) an inorganic acid [eg, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, Salts with nitric acid, pyrosulfuric acid, and metaphosphoric acid, etc .; and (2) organic acids [eg, citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, and sulfonic acid (eg, methanesulfonic acid, (p-toluenesulfonic acid and naphthalenesulfonic acid)] and (3) alkali metal salts [eg: sodium salt and potassium salt]
Is included.

<Solvate>
Examples of solvates of the compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof include hydrates and organic solvates (eg, methanol solvate, ethanol solvate) Dimethylsulfoxide and the like).

<Other active ingredients>
The anti-hepatitis B virus agent may further contain other active ingredients.
Examples of such "other active ingredients" include other nucleic acid analogs (such as 2'-deoxy-2'-fluoro-nucleosides) and other anti-hepatitis B virus agents.
The anti-hepatitis B virus agent may contain two or more formulations.
The compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof is formulated into a separate formulation from the “other active ingredient”. May be used.
The compound represented by the formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof is simultaneously, sequentially, or alternately with the “other active ingredient”. It may be administered to a subject.

<Content of active ingredient>
From the viewpoint of activity, the lower limit of the content of the active ingredient is, for example, 0.001% by mass, preferably 0.01% by mass, more preferably 0.05% by mass based on the total mass of the anti-hepatitis B virus agent. % Can be set. The upper limit of the content of the active ingredient is not particularly limited, but is set to, for example, 99.99% by mass, preferably 90% by mass, more preferably 80% by mass, based on the total mass of the anti-hepatitis B virus agent. be able to. The content of the active ingredient is within a range in which the lower limit and the upper limit are arbitrarily selected, for example, 0.001 to 99.99% by mass, preferably 0.01 to 90% by mass, and more preferably 0.05 to 80% by mass. It can be in the range of mass%.

<Additives>
The anti-hepatitis B virus agent may contain a pharmaceutically acceptable additive.
Examples of forms of anti-hepatitis B virus agent include solid preparations (eg, granules, powders, tablets, capsules, dry syrups), semi-solid preparations (eg, creams, ointments, gels), and liquid preparations (Eg, solutions, suspensions).
The solid preparation may be, for example, a mixture of active ingredients and additives (eg, excipients, binders, disintegrants, lubricants, coloring agents), and if desired, granulation, sizing, compression, and / or Alternatively, it can be produced by coating.
Examples of such excipients include lactose, lactose hydrate, sucrose, mannitol, sorbitol, crystalline cellulose, starch (eg, corn starch), hydrous silicon dioxide, and combinations thereof.
Examples of such binders include agar, acacia, hyaluronic acid, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and combinations thereof.
Examples of the disintegrant include alginic acid, carboxymethylcellulose (carmellose), croscarmellose sodium, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone (povidone), crospovidone, and combinations thereof.
Examples of such lubricants include stearic acid, magnesium stearate, calcium stearate, talc, and combinations thereof.
Examples of the coloring agent include iron sesquioxide, titanium oxide, and combinations thereof.
The semi-solid preparation can be produced, for example, by mixing an active ingredient, a semi-solid carrier, and other optional additives.
The liquid preparation includes, for example, an active ingredient, a liquid carrier [eg, an aqueous carrier (eg, purified water), an oily carrier], and other additives (eg, an emulsifier, a dispersant, a suspending agent, a buffer, An antioxidant, a surfactant, an osmotic pressure regulator, a chelating agent, an antibacterial agent) are mixed, and if necessary, sterilized.

<Form of administration>
The administration method of the anti-hepatitis B virus agent can be oral administration or parenteral administration (eg, intravenous administration, intramuscular administration, subcutaneous administration).
The method for administering the anti-hepatitis B virus agent may be local administration.
The subject to which the anti-hepatitis B virus agent is administered may be any of humans, non-human mammals (eg, monkeys, sheep, dogs, mice, rats), and non-mammals.
The number of administrations of the anti-hepatitis B virus agent can be appropriately selected depending on the age, weight, medical condition, and the like of the administration subject. For example, once, twice, or three times a day, once every two days, It can be once every three days or once a week.
The single dose of the anti-hepatitis B virus agent can be in the range of 0.1 mg to 1000 mg depending on the administration subject and the number of administrations.
A preferred example of the anti-hepatitis B virus agent is a formulation for oral administration, and specific examples thereof include:
Tablets containing the active ingredient, crystalline cellulose, hydroxypropylmethylcellulose, povidone, magnesium stearate, and titanium oxide; and hard gelatin capsules include capsules containing the active ingredient, povidone, and magnesium stearate.

The agent for preventing or treating hepatitis B virus-related disease "hepatitis B virus-related disease" means a disease that develops due to hepatitis B virus infection. The hepatitis B virus-related disease can be, for example, one or more selected from the group consisting of hepatitis B (eg, acute hepatitis B, chronic hepatitis B), cirrhosis B, and hepatoma B. .
The agent for preventing or treating hepatitis B virus-related disease according to one embodiment of the present disclosure is a compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Substance as an active ingredient.
Other active ingredients and additives that can be included in the prophylactic or therapeutic agent, as well as the dosage form of the prophylactic or therapeutic agent and the mode of administration (eg, administration route, administration target, number of administrations, and dosage) are as follows: For example, it can be selected from those described for the anti-hepatitis B virus agent.

A method for delaying or suppressing the growth of hepatitis B virus, or a method for preventing or treating a hepatitis B virus-related disease A method for delaying or suppressing the growth of hepatitis B virus according to one embodiment of the present disclosure, or The method for preventing or treating hepatitis B virus-related disease includes the step of treating a compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as necessary. Administering to the subject.
The mode of administration (eg, administration route, administration subject, administration frequency, and dosage) can be selected, for example, from those described for the anti-hepatitis B virus agent.

Pharmaceutical Composition A pharmaceutical composition according to one embodiment of the present disclosure comprises 2'-deoxy-2'-fluoro-β-D-cytidine or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof. Contains a Japanese product as an active ingredient.
The content of the active ingredient in the pharmaceutical composition, other active ingredients, and additives, and the dosage form and administration form of the pharmaceutical composition are selected, for example, from those described for the anti-hepatitis B virus agent. Can be.

Anti-hepatitis virus agent In the present disclosure, “anti-hepatitis virus agent” means an agent that delays or suppresses the growth of hepatitis virus.
The anti-hepatitis virus agent of one embodiment of the present disclosure is 2'-deoxy-2'-fluoro-β-D-cytidine or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. As an active ingredient.
The content of the active ingredient in the hepatitis virus agent, other active ingredients, and additives, and the dosage form and administration form of the hepatitis virus agent should be selected, for example, from those described for the anti-hepatitis B virus agent. Can be.

The agent for preventing or treating a hepatitis virus-related disease “hepatitis virus-related disease” means a disease that develops due to hepatitis virus infection.
Specific examples of hepatitis virus-related diseases include, for example, chronic hepatitis, cirrhosis, and liver cancer.
The agent for preventing or treating a hepatitis virus-related disease according to one embodiment of the present disclosure is 2'-deoxy-2'-fluoro-β-D-cytidine or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or These solvates are contained as active ingredients.
An agent for preventing or treating a hepatitis virus-related disease according to another embodiment of the present disclosure comprises the above-mentioned pharmaceutical composition.
The content of the active ingredient in the preventive or therapeutic agent for hepatitis virus-related diseases, other active ingredients, and additives, and the dosage form and administration form of the hepatitis virus agent are described, for example, with respect to the anti-hepatitis B virus agent. You can choose from

A method for delaying or suppressing the growth of hepatitis virus, or a method for preventing or treating a hepatitis virus-related disease A method for delaying or suppressing the growth of hepatitis virus, or a method for preventing or treating a hepatitis virus-related disease according to an embodiment of the present disclosure. The method of treating comprises administering the compound or the pharmaceutical composition to a subject in need thereof.
The mode of administration can be selected, for example, from those described for the anti-hepatitis B virus agent.

Hereinafter, one embodiment of the present disclosure will be described in more detail with reference to Examples, but the present disclosure is not limited thereto.

Example 1 (Synthesis example)
(1)
Dissolve 2 g of 2-Deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose in 20 mL of dichloromethane, add 4 mL of a hydrogen bromide acetic acid solution (5.1 mol / L), and stir. did. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to neutralize unreacted HBr.
Thereafter, the solution was separated, the solution extracted with dichloromethane was concentrated, and 1.7 g of 1-Bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranose was obtained. Obtained.
This was used for the next step.
(2) Reaction with thymine 0.3 g of thymine and 23 mg of ammonium sulfate were dispersed in hexamethyldisilazane (HMDS). Thereafter, the mixture was concentrated by heating and stirring.
To this, 0.4 g of crude 1-Bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranose dissolved in dichloroethane was added dropwise, followed by heating and stirring.
After the completion of the reaction, the mixture was diluted with methanol and the solid component was filtered. Then, the filtrate was concentrated and purified by column chromatography.
235 mg of a reaction product (2'-deoxy-2'-fluoro-3 ', 5'-di-O-benzoyl-β-D-tymidine) was obtained.
(3) Deprotection 100 mg of 2′-deoxy-2′-fluoro-3 ′, 5′-di-O-benzoyl-β-D-tymidine was dissolved in ammonia (methanol solution) and stirred.
After completion of the reaction, the reaction product was purified by preparative TLC to obtain 34 mg of 2′-deoxy-2′-fluoro-β-D-thymidine (the following formula).

¹ H NMR (acetone-d ₆ ): 7.88 and 7.86 (dd, 1H), 7.00 and 6.92 (br d, 2H), 6.17-6.12 (m, 1H), 5.14 and 5.00 (dd, 1H), 5.13 (br s, 1H), 4.42-4.37 (m, 1H), 4.27 (br s, 1H), 3.95-3.94 (m, 1H), 3.90-3.70 (m, 2H);
¹⁹ F NMR (acetone-d ₆ ): -170.80 to -170.87 (m), -199.89 to -200.13 (m)

Example 2 (Synthesis example)
(1)
The same operation as in step (2) of Example 1 was carried out except that 5-fluorocytosine was used instead of thymine, and 331 mg of 2′-deoxy-2′-fluoro-3 ′, 5′-di-O -benzoyl-β-5-fluoro-D-cytidine was obtained.
(2) Deprotection 100 mg of 2'-deoxy-2'-fluoro-3 ', 5'-di-O-benzoyl-β-5-fluoro-D-cytidine was dissolved in ammonia (methanol solution) and stirred.
After the completion of the reaction, the reaction product was purified by preparative TLC to obtain 38 mg of 2′-deoxy-2′-fluoro-β-5-fluoro-D-cytidine (the following formula).

¹ H NMR (acetone-d ₆ ): 7.88 and 7.86 (dd, 1H), 7.00 and 6.92 (br d, 2H), 6.17-6.12 (m, 1H), 5.14 and 5.00 (dd, 1H), 5.13 (br s, 1H), 4.42-4.37 (m, 1H), 4.27 (br s, 1H), 3.95-3.94 (m, 1H), 3.90-3.70 (m, 2H);
¹⁹ F NMR (acetone-d ₆ ): -167.50 (d), -199.89 to -200.13 (m)

Example 3 (Synthesis example)
(1)
Dissolve 2 g of 2-Deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose in 20 mL of dichloromethane, add 4 mL of hydrogen bromide acetic acid solution (5.1 mol / L), and stir. did. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to neutralize unreacted HBr.
Thereafter, the solution was separated, the solution extracted with dichloromethane was concentrated, and 1.7 g of 1-Bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranose was obtained. Obtained.
This was used for the next step.
(2) Reaction with cytosine 1 g of cytosine was dispersed in a co-solvent of dichloroethane: acetonitrile.
To this was added potassium t-butoxide, heated to 50 ° C., and stirred for a while to dissolve.
To this, 1.7 g of crude 1-Bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranose was dropped and reacted.
After completion of the reaction, the mixture was diluted with dichloroethane and filtered to remove solid components. The filtrate was concentrated, and purified by column chromatography.
170 mg of the reaction product (2'-deoxy-2'-fluoro-3 ', 5'-di-O-benzoyl-β-D-cytidine) was obtained.
(3) Deprotection 170 mg of 2′-deoxy-2′-fluoro-3 ′, 5′-di-O-benzoyl-β-D-cytidine was dissolved in methanol, and 12 mg of sodium methoxide was added and stirred.
After completion of the reaction, the reaction product was purified by preparative TLC to obtain 60 mg of 2'-deoxy-2'-fluoro-β-D-cytidine (the following formula).

¹ H NMR (CD3OD, 400 MHz) δ 3.734-3.839 (2H, m), 3.950-3.985 (1H, m), 4.270-4.325 (1H, m), 4.972-5.115 (1H, m), 5.911 (1H, d, J = 7.6Hz), 6.208 (1H, dd, J = 18.4, 3.6Hz), 7.835 (1H, d, J = 7.6Hz)

Comparative Example 1 (Synthesis Example)
The same operation as in Example 1 was carried out except that 2,6-dichloropurine was used in place of 2-amino-6-chloropurine in step (2) of Example 1, to give 2,6-dichloro-9- ((2R, 3S, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -9H-purine (the following formula) was obtained.

¹ H NMR (400 MHz, DMSO-D6) δ 8.53 (s, 1H), 6.41 (dd, J = 12.3, 4.6 Hz, 1H), 5.97 (s, 1H), 5.25 (dt, J = 52.8, 4.6 Hz , 1H), 5.09 (t, J = 5.5 Hz, 1H), 4.38-4.43 (m, 1H), 3.81-3.91 (m, 1H), 3.58-3.68 (m, 2H)

Test Example 1 (anti-HBV activity)
Evaluation of the anti-HBV activity was performed by using the HepG2.2.15 cell line, which is an HBV-producing cell obtained by introducing a gene twice as long as the HBV genome into the human hepatoma cell line HepG2, using the HBV DNA amount on the 7th day after the addition of the drug. Was evaluated by a quantitative PCR method. In PCR of HBV DNA, Forward primer (HBV-S190F; 5'-GCT CGT GTT ACA GGC GGG-3 ': SEQ ID NO: 1) and Reverse primer (HBV-S703R; 5'-GAA CCA CTG AAC AAA TGG CAC TAG TA- 3 ′: SEQ ID NO: 2) was used. PCR was performed for 35 cycles with 95 ° C 10 sec to 62 ° C 10 sec to 72 ° C 30 sec as one reaction.
Specifically, HepG2.2.15 cells were seeded at 1 × 10 ⁵ cells / well. 24 hours later, the compounds of Example 1 and Comparative Example 1 were diluted to 0, 0.49, 0.97, 1.95, 3.90, 7.81, 15.6, 31.3, 62.5, 125, 250, 500, and 1000 nM, and added to the cells. did. After culturing the cells for 7 days, the cytoplasmic fraction was collected and DNA was purified by phenol / chloroform extraction. The amount of intracellular HBV DNA was measured by quantitative PCR using 20 ng of the purified DNA.

Test Example 2 (Cytotoxicity test)
HepG2 NTCP-myc cells were seeded at 2 × 10 ⁴ cells / well. Twenty-four hours later, the compound of Example 1 was diluted to 0, 0.49, 0.97, 1.95, 3.90, 7.81, 15.6, 31.3, 62.5, 125, 250, 500, and 1000 nM, and added to the cells. HepG2 NTCP-myc cells were cultured for 7 days. After the culture, 10 μl of Premix WST-1 Cell Proliferation Assay System (TaKaRa) was added, and the mixture was cultured at 37 ° C. for 2 hours, and the absorbance was measured at 450 nm using a microplate reader.

Result 1. Anti-HBV activity EC ₅₀ (50% effective concentration) was calculated from a graph showing the relationship between compound concentration and anti-HBV activity. Table 1 shows the EC ₅₀ of the compounds of the examples and comparative examples.

From the results in Table 1, it can be seen that the compounds of Examples 1 to 3 have higher anti-HBV activity than the compound of Comparative Example 1.
2. Cytotoxicity CC ₅₀ (50% cytotoxicity concentration) was calculated from a graph showing the relationship between compound concentration and cytotoxicity. The CC ₅₀ against HepG2 NTCP-myc cells of the compound of Example shown in Table 2.

The results in Table 2 show that the compounds of Examples 1 to 3 have low cytotoxicity.

Claims

The following equation (1):

(Where
R a is a hydrogen atom or an alkyl group, and R b is an oxo group, or R a is a hydrogen atom, a halogen atom or an alkyl group, and R b is an amino group . )
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.
The following equation (1):

(Where
R a is a hydrogen atom or an alkyl group, and R b is an oxo group, or R a is a hydrogen atom, a halogen atom or an alkyl group, and R b is an amino group . )
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, for preventing or treating hepatitis B virus-related diseases.
The preventive or therapeutic agent according to claim 2, wherein the hepatitis B virus-related disease is at least one selected from the group consisting of hepatitis B, cirrhosis B, and hepatoma B.
The following equation (1):

(Where
R a is a hydrogen atom or an alkyl group, and R b is an oxo group, or R a is a hydrogen atom, a halogen atom or an alkyl group, and R b is an amino group . )
A method for producing a compound represented by or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof,
Reacting a nucleobase selected from the group consisting of uracil, 5-alkyluracil, cytosine, 5-halocytosine, and 5-alkylcytosine with a silylating agent to obtain a silylated nucleobase A;
The silylated nucleobase is represented by the following formula (I):

(Wherein Q 1 and Q 2 are the same or different and are hydroxyl-protecting groups, and X is bromine or iodine.)
And a step C of deprotecting the hydroxyl-protecting group of the product obtained by the reaction of the step B.
2′-deoxy-2′-fluoro-β-D-cytidine or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
A pharmaceutical composition comprising the compound according to claim 5 as an active ingredient.
An anti-hepatitis virus agent comprising the compound according to claim 5 as an active ingredient.
An agent for preventing or treating a hepatitis virus-related disease, comprising the compound according to claim 5 as an active ingredient.
The preventive or therapeutic agent according to claim 8, wherein the hepatitis virus-related disease is one or more selected from the group consisting of chronic hepatitis, cirrhosis, and liver cancer.