JPH10101591A - Preventing and therapeutic agent for viral infectious disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzene derivative, having selective strong antiviral activities against only viruses without affecting a host cell, and useful as a preventing and therapeutic agent for viral diseases (e.g. a hepatitis C virus). SOLUTION: This compound is represented by formula I [A is O, S, NH, CH,, etc.; X and Y are each H or, together, are a single bond, O, S, etc.; R<1> to R<8> are each H, a group represented by the formula C(U<1> )R9 (U<1> is 0 or S; R<9> is H, OH, a halogen, etc.), etc.], its salt or a hydrate thereof, e.g. 2,7-bis[2-(4- morpholino)ethyloxy]fluorenone. A compound, represented by formula II and belonging to the compound represented by formula I is obtained by reacting a compound represented by formula III with a compound represented by formula IV (X is OH or a halogen) in the presence of a base such as sodium hydride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicament comprising a benzene derivative or a pharmacologically acceptable salt thereof or a hydrate thereof which is useful as a prophylactic / therapeutic agent for a viral infectious disease.

[0002]

[Prior art]

<Background of the Invention> Viruses parasitize host cells unique to each, and cause the host energy or replication, transcription,
Proliferate using a translation system. The virus causes cell damage, cell proliferation, and various diseases in the host organism with the propagation of the virus. However, unlike infectious diseases of bacterial species and closely related infectious agents (mycoplasma, leptospira), there has been no effective drug until recently. While there is no cure, Jenner (Edward J
enner) 's invention of the smallpox vaccine paved the way for the prevention of viral diseases by vaccination. But,
Vaccines are those that cause mild infections or immunize with the protein antigens of the virus, and which do not respond to the host immune system or neutralizing antibodies to the virus (antigen-specific binding to the viral organism Has no effect on viruses whose recognition site is a hypervariable region.

[0003] As described above, hepatitis C virus (HCV) is a virus without a vaccine.
Diseases caused by this virus have become a global problem.
HCV has low cytotoxicity and low antigenicity due to the virus itself, and thus often becomes persistently infected and chronic in the host. In fact, it is considered that the antigen portion of the hepatitis C virus envelope, which is the target of the neutralizing antibody, has a high mutation rate and avoids recognition by the antibody. In general, persistent HCV infection causes liver damage following acute hepatitis, but subsides in a few years. Hepatitis recurs again after 20-30 years of asymptomatic persistent infection. If more severe liver damage persists, it will progress from chronic active hepatitis to cirrhosis, eventually leading to hepatocellular carcinoma.

<Conventional technology> Under such a background, a drug [antiviral chemotherapeutic agent (antiviral agent)] for a viral infection has been long-awaited, but acyclovir has recently appeared, and herpes virus infection has been developed. Had a dramatic effect on For HCV, interferon (IFN), a highly selective toxic drug, has emerged as a causative therapy,
It is currently used as a first-line drug for the treatment of hepatitis C.
In addition, glycyrrhizin, a licorice extract component, which is a hepatic protectant (can be expected to calm hepatitis and prevent the development of liver lesions) is used as a symptomatic drug.

[0005]

However, nucleoside derivatives such as acyclovir are also called nucleic acid-related antimetabolites, and the emergence of virus having strong side effects and drug resistance is a problem. Also, HCV
Compared to IFN, which is currently frequently used as the only therapeutic agent, only about half of the patients are generally effective, but half of them have improved their condition. Even in cases, if treatment is stopped, the disease recurs within six months. In addition, there are quite a few cases in which it is not improved by administration of IFN. In addition, there are also problems such as high drug prices and side effects. Drugs for such cases where IFN does not work have not yet been developed. Therefore, in order to overcome the above problems of antiviral agents, it is essential to develop an antiviral agent that works by a novel mechanism.

By the way, in 90% or more of eukaryotic mRNA, 40S ribosome binds to the 5-terminal cap structure,
Cap-dependent protein synthesis that moves to the nearest AUG and starts translation. However, poliovirus (poliovirus) and encephalomyocarditis virus (EMC vi
rus), foot-and-mouth disease virus (foot-and-mouth disease viru)
s), the genome of picornavirus genus such as rhinovirus, and the genome of hepatitis C virus (hepatitis C virus) are plus single-stranded RNA.
It has no cap structure at the 5 terminus and has a long 5-sided untranslated region (5UTR) (about 750 bases in poliovirus). In addition, multiple AUGs exist in 5UTR, and H
The 5UTR of CV-RNA is also long, about 340 bases, and contains 2-3 AUGs
Exists. Translation in these viruses is 5U
TR structure is a mechanism involved in ribosome recognition, such as the prokaryote Shine-Dargano sequence, ie, the ribosome recognizes the inside of the 5UTR and starts translation.
It is known that protein synthesis is performed by a new mechanism independent of cap called internal initiation, and the site recognized by this ribosome is IRES (Intern
al Ribosome Entry Site). HCV-RNA5UT
The structural features of R are thought to be closer to those of mRNAs that initiate internal rather than cap-dependent protein synthesis. Therefore, if the growth of the virus can be inhibited on the IRES, a drug selective for the virus can be created without affecting the host cell.

The inventors of the present invention have conducted intensive studies to solve the above problems based on such findings, and as a result, the benzene derivative of the present invention has a strong antiviral activity under a completely novel mechanism of action. The present invention has been found to be useful as a medicine.

[0008]

That is, the present invention provides a compound represented by the following general formula:

Embedded image [Wherein -A- is a formula

Embedded image X and Y each independently represent a hydrogen atom or together form a single bond or a formula;

Embedded image Wherein R ^{1 to} R ⁸ are the same or different and are 1) a hydrogen atom, 2) a general formula

Embedded image (In the formula, U ¹ represents an oxygen atom or a sulfur atom, and R ⁹ is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group optionally having a substituent, a lower group optionally having a substituent. An alkoxy group, an aryl group optionally having a substituent and optionally having one or more heteroatoms, or a general formula

Embedded image [In the formula, n represents an integer of 0 to 6, and R ¹⁰ and R ¹¹ are the same or different and are each a hydrogen atom, a lower alkyl group which may have a substituent, or a group which may have a substituent. Which means an aryl group optionally having one or more heteroatoms], 3) a general formula

Embedded image (In the formula, m represents an integer of 0 to 6, and R ¹² and R ¹³ are the same or different and are each independently a hydrogen atom, a lower alkyl group which may have a substituent, or a group which may have a substituent. (It means an aryl group which may have one or more hetero atoms or a cycloalkyl group which may have a substituent and may have one or more hetero atoms.)
A group represented by 4) a general formula

Embedded image (In the formula, U ² represents an oxygen atom or a sulfur atom, and R ¹⁴ represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group optionally having a substituent, or a lower group optionally having a substituent. An alkoxy group, an aryl group optionally having a substituent and optionally having one or more heteroatoms, or a general formula

Embedded image [Wherein, R ¹⁵ and R ¹⁶ are the same or different and are each a hydrogen atom, a lower alkyl group optionally having a substituent, an optionally substituted heteroatom having at least one hetero atom. A group represented by the following formula: 5) a group represented by the general formula:

Embedded image (Wherein, U ³ stands for an oxygen atom, a nitrogen atom or a sulfur atom, V is an optionally substituted C ₀ ~ ₆ alkylene group, an optionally C ₂ ~ be substituted ₆ Alkenylene group,
Or have a substituent means a good C ₂ ~ ₆ alkynylene group, W is a) hydrogen atom, b) a halogen atom, c) formula

Embedded image [Wherein, R ¹⁷ and R ¹⁸ are the same or different and are each a hydrogen atom, a lower alkyl group optionally having a substituent, an optionally substituted heteroatom having at least one hetero atom. An aryl group, or a cycloalkyl group which may have a substituent together and may have one or more heteroatoms], d) a cyano group,
e) a cycloalkyl group which may have a substituent and may have one or more hetero atoms, f) may have a substituent and may have one or more hetero atoms An aryl group, g) an acyl group which may have a substituent, h) a hydroxyl group,
i) a hydroxyl group protected by a protecting group, or j) azido group), 6) a hydroxyl group, 7) a hydroxyl group protected by a protecting group, 8) an amino group, 9) a protecting group. Amino group,
Or 10) General formula

Embedded image (Wherein, R ¹⁹ and R ²⁰ are the same or different and are a) a hydrogen atom, b) a lower alkyl group which may have a substituent,
c) a lower alkoxy group optionally having a substituent, d) an aryl group optionally having a substituent and optionally having one or more hetero atoms, or e) a general formula

Embedded image [Wherein, U ⁴ represents an oxygen atom or a sulfur atom, and R ^{21 s} are the same or different and are i) a hydrogen atom, ii) a lower alkyl group which may have a substituent, iii) a substituent. A cycloalkyl group optionally having one or more hetero atoms, iv) an aryl group optionally having a substituent and optionally having one or more hetero atoms, v) substituted An aryloxy group optionally having a group and optionally having one or more heteroatoms, or vi) a general formula

Embedded image Wherein R ²² and R ²³ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, or an aryl group which may have a substituent. A benzene derivative represented by the following formula: or a pharmacologically acceptable salt thereof, or a hydrate thereof. The medicament comprising the above-mentioned benzene derivative or a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the medicament is a prophylactic / therapeutic agent for a viral disease;
A medicament comprising the benzene derivative or a pharmacologically acceptable salt thereof or a hydrate thereof, which is the hepatitis virus,

Embedded image [Where A ² is a formula

Embedded image And R ²⁵ and R ²⁸ are the same or different and are each a hydrogen atom, a hydroxyl group, a thiol group, a lower alkoxy group, a lower alkylthio group, a lower acyl group, a lower alkyl (thiocarbonyl) group, a lower acyloxy group, a lower alkyl ( Thiocarbonyl) oxy group, or a general formula

Embedded image (In the formula, U ¹⁰ represents an oxygen atom or a sulfur atom, and V ¹⁰ has a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent, Means a lower alkynylene group which may be represented by W ¹⁰ is a general formula,

Embedded image [Wherein R ²⁹ and R ³⁰ may be the same or different and each may be a hydrogen atom, a lower alkyl group, or may be substituted together;
A cycloalkyl group optionally having a heteroatom as described above], a cyano group, an azide group, a halogen atom, a hydroxyl group, a hydroxyl group protected by a protective group, A cycloalkyl group optionally having the above hetero atom, or a cycloalkyl group optionally having a substituent,
R ²⁶ and R ^{27 each} represent a hydrogen atom, or an aryl group which may have a hetero atom described above.
Hydroxyl group, thiol group, lower alkoxy group, lower alkylthio group, lower acyl group, lower alkyl (thiocarbonyl) group, lower acyloxy group, lower alkyl (thiocarbonyl) oxy group, or a general formula

Embedded image (Wherein, U ²⁰ represents an oxygen atom or a sulfur atom, and V ²⁰ has a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent, W ²⁰ represents a cyano group, an azido group, a halogen atom, a hydroxyl group, a hydroxyl group protected by a protecting group, a substituted or unsubstituted hetero atom which may have one or more hetero atoms. A cycloalkyl group, an aryl group optionally having a substituent and optionally having one or more heteroatoms) or a salt thereof. Or a hydrate thereof, having the general formula

Embedded image [Where A ³ is the formula

Embedded image And A ⁴ is the formula

Embedded image R ^{31 to} R ³⁴ are the same or different and each represents a hydrogen atom,
Thiol group, lower alkoxy group, lower alkylthio group,
A lower acyl group, a lower alkyl (thiocarbonyl) group, a lower acyloxy group, a lower alkyl (thiocarbonyl) oxy group, or a general formula

Embedded image (In the formula, U ³⁰ represents an oxygen atom or a sulfur atom, and V ³⁰ has a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent, W ³⁰ represents a lower alkynylene group which may be represented by the general formula

Embedded image [Wherein, R ³⁵ and R ³⁶ are the same or different and represent a hydrogen atom, a lower alkyl group, or a cycloalkyl group which may be substituted together and have one or more hetero atoms. ], A cyano group, an azide group,
A halogen atom, a hydroxyl group, a hydroxyl group protected by a protecting group, a 4- or more-membered cycloalkyl group which may be substituted and may have one or more hetero atoms, and may have one or more substituents Which means an aryl group which may have a hetero atom).] Or a salt or hydrate thereof.

Next, compounds useful as agents for preventing or treating a pharmaceutical or viral disease according to the present invention are listed below.
Preferably, the general formula

Embedded image [Wherein, A, X, Y, R ^{1 to} R ⁸ represent the same groups as defined above. The same applies hereinafter. Is a group of compounds represented by, for example,

Embedded image

A group of compounds, more preferably

Embedded image [Wherein A ^{2 to} A ⁴ represent the same groups as defined above. And more preferably

Embedded image

More preferably,

Embedded image And particularly preferably a compound group consisting of

[0012]

Embedded image A group of compounds consisting of

[0013]

Embedded image A compound selected from the group consisting of

Hereinafter, the terms used in the present specification will be described in detail.

The following general formula

Embedded image The case where X and Y together represent a single bond, that is, the following general formula:

Embedded image Means a compound represented by

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group,
n-butyl group, i-butyl group, sec-butyl group, t-butyl group,
n-pentyl, i-pentyl, sec-pentyl, t-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n -Hexyl group, i-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-
Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2 -Ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1
-Ethyl-2-methylpropyl group and the like, preferably, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl Group, n-pentyl group, i-pentyl group, sec-pentyl group, t-
Pentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, i-hexyl group, more preferably methyl group, Ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, most preferably methyl group, ethyl group, n-propyl group, i -A propyl group.

The cycloalkyl group is a cyclic alkyl group corresponding to the lower alkyl group, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, and a cyclopentyl group is preferred. And cyclohexyl groups.

The lower alkoxy group refers to a group corresponding to the lower alkyl group, specifically, for example, a methoxy group,
Ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, sec-pentyloxy , T-pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,
1-dimethylpropoxy group, 1,2-dimethylpropoxy group,
n-hexyloxy group, i-hexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethyl Propoxy group, 1,2,2-trimethylpropoxy group, 1-ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group and the like, preferably methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyloxy group, sec-pentyloxy group, t-pentyloxy group,
Neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, n-hexyloxy group, i-hexyloxy group, more preferably Methoxy, ethoxy, n-
A propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, and a t-butoxy group.

The lower alkylthio group is a group corresponding to the lower alkyl group, and specifically includes, for example, a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, sec-butylthio group, t-butylthio group, n-pentylthio group, i-pentylthio group, sec-pentylthio group, t-pentylthio group, neopentylthio group, 1-methylbutylthio group, 2-methylbutylthio group, 1 , 1-dimethylpropylthio group, 1,2-dimethylpropylthio group, n-hexylthio group, i-hexylthio group,
1-methylpentylthio group, 2-methylpentylthio group, 3-
Methylpentylthio group, 1,1-dimethylbutylthio group, 1,
2-dimethylbutylthio group, 2,2-dimethylbutylthio group,
1,3-dimethylbutylthio group, 2,3-dimethylbutylthio group, 3,3-dimethylbutylthio group, 1-ethylbutylthio group, 2-ethylbutylthio group, 1,1,2-trimethylpropylthio Group, 1,2,2-trimethylpropylthio group, 1-ethyl-1
-Methylpropylthio group, 1-ethyl-2-methylpropylthio group and the like, preferably methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, sec-butylthio group, t-butylthio group, n-pentylthio group, i-pentylthio group, se
c-pentylthio group, t-pentylthio group, neopentylthio group, 1-methylbutylthio group, 2-methylbutylthio group,
1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, n-hexylthio group, i-hexylthio group, more preferably methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n -Butylthio, i-butylthio, sec-butylthio and t-butylthio, and most preferably methylthio, ethylthio, n-propylthio and i-propylthio.

Heteroatoms are specifically oxygen, sulfur, nitrogen, phosphorus, arsenic, antimony, silicon,
Germanium, tin, lead, boron, mercury and the like, preferably an oxygen atom, a sulfur atom, a nitrogen atom,
More preferably, it is a nitrogen atom.

The term "optionally substituted" means, for example, a hydroxyl group; a thiol group; a nitro group; a morpholino group; a thiomorpholino group;
A halogen atom such as a bromine atom and an iodine atom; a nitrile group; an azide group; a formyl group; an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group;
Alkenyl groups such as vinyl group, allyl group and propenyl group; alkynyl groups such as ethynyl group, butynyl group and propargyl group; alkoxy groups such as methoxy group, ethoxy group, propoxy group and butoxy group corresponding to lower alkyl groups; A halogenoalkyl group such as a group, a difluoromethyl group, a trifluoromethyl group, or a fluoroethyl group: a hydroxyalkyl group such as a hydroxymethyl group, a hydroxyethyl group, or a hydroxypropyl group; a guanidino group; a formimidoyl group; Carbamoyl group; thiocarbamoyl group; carbamoylalkyl group such as carbamoylmethyl group, carbamoylethyl group; thiocarbamoylalkyl group such as thiocarbamoylmethyl group, thiocarbamoylethyl group; methylcarbamoyl group, dimethyl Alkylcarbamoyl groups such as carbamoyl group, methylethylcarbamoyl group and diethylcarbamoyl group; alkylthiocarbamoyl groups such as methylthiocarbamoyl group, dimethylthiocarbamoyl group, methylethylthiocarbamoyl group and diethylthiocarbamoyl group; carbamide groups; acyl such as acetyl group Groups; amino groups; alkylamino groups such as methylamino group, ethylamino group and isopropylamino group; dialkylamino groups such as dimethylamino group, methylethylamino group and diethylamino group; aminomethyl group, aminoethyl group and aminopropyl group Carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group; methoxycarbonylmethyl group, ethoxy Alkoxycarbonylalkyl groups such as cicarbonylmethyl group, propoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group, propoxycarbonylethyl group; methyloxymethyl group, methyloxyethyl group, ethyloxymethyl group, ethyloxyethyl group Alkylthioalkyl groups such as methylthiomethyl group, methylthioethyl group, ethylthiomethyl group and ethylthioethyl group; aminoalkylaminoalkyl groups such as aminomethylaminomethyl group and aminoethylaminomethyl group; methyl Alkylcarbonyloxy groups such as carbonyloxy group, ethylcarbonyloxy group, and isopropylcarbonyloxy group;
Arylalkoxyalkoxyalkyl groups such as oxymethyl group and benzyloxyethyloxyethyl group; hydroxyalkoxyalkyl groups such as hydroxyethyloxymethyl group and hydroxyethyloxyethyl group; benzyloxymethyl group, benzyloxyethyl group and benzyloxypropyl group Arylalkoxyalkyl groups; quaternary ammonium groups such as trimethylammonio group, methylethylmethylammonio group and triethylammonio group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group;
Cycloalkenyl groups such as cyclopropenyl group, cyclobutenyl group, cyclopentenyl group and cyclohexenyl group; aryl groups such as phenyl group, pyridinyl group, thienyl group, furyl group and pyrrolyl group; methylthio group, ethylthio group, propylthio group and butylthio group Alkylthio groups such as phenylthio group, pyridinylthio group, thienylthio group, furylthio group and pyrrolylthio group; aryl lower alkyl groups such as benzyl group, trityl group and dimethoxytrityl group; sulfonyl group, mesyl group and p-toluenesulfonyl A substituted sulfonyl group such as a group; an aryloyl group such as a benzoyl group; a halogenoaryl group such as a fluorophenyl group and a bromophenyl group; an oxyalkoxy group such as a methylenedioxy group. The term "optionally having one or more substituents" means that these groups may be present in any combination, for example, hydroxyl, thiol, nitro, morpholino, thiomorpholino, halogen May be substituted with any group such as an atom, a nitrile group, an azide group, a formyl group, an amino group, an alkylamino group, a dialkylamino group, a carbamoyl group, a sulfonyl group, an acetyl group, an alkyl group, and an alkoxy group. means.

Specific examples of the aryl group include a phenyl group, a pentenyl group, an indenyl group, a naphthyl group, and a fluorenyl group, and a phenyl group is preferred.

The aryl group optionally having one or more hetero atoms includes, for example, pyranyl group, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, furyl group, thienyl group, pyrrolyl group, oxazolyl group. Group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, pyrazolyl group, furazanyl group, thiadiazolyl group, indolyl group and the like, and preferably pyridyl group, imidazolyl group, triazolyl group and the like. .

The aryloxy group corresponds to the above-mentioned aryl group, and specifically includes, for example, a phenyloxy group, an indenyloxy group, a naphthyloxy group and the like, and preferably a phenyloxy group. The aryloxy group optionally having one or more hetero atoms refers to an aryloxy group optionally having one or more hetero atoms, and specifically includes, for example, a pyranyloxy group, a pyridyloxy group. Group, pyridazyloxy group, pyrimidyloxy group, pyrazyloxy group, furyloxy group, thienyloxy group, pyrrolyloxy group, oxazolyloxy group, isoxazolyloxy group, thiazolyloxy group, isothiazolyloxy group, imidazolyloxy group, triazolyl group Oxy group, tetrazolyloxy group, pyrazolyloxy group, furazanyloxy group, thiadiazolyloxy group, indolyloxy group and the like, and preferably pyridyloxy group, imidazolyloxy group, triazolyloxy group and the like. .

The alkylene group is a divalent group derived by removing one hydrogen atom from each of carbon atoms at both chain ends of a linear saturated hydrocarbon, and specifically includes, for example, a methylene group, an ethylene group , A trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and the like, and preferably, a methylene group, an ethylene group, a trimethylene group, and the like.

The alkenylene group is a divalent group derived by removing one hydrogen atom from each carbon atom at both chain ends of a linear unsaturated hydrocarbon, and specifically includes, for example, a vinylene group and a propenylene Group, butenylene group, pentenylene group,
Hexenylene group and the like, preferably a vinylene group,
It is a propenylene group, a butenylene group or a pentenylene group, more preferably a vinylene group, a propenylene group or a butenylene group, further preferably a vinylene group or a propenylene group, and most preferably a vinylene group.

The alkynylene group refers to a divalent group derived by removing one hydrogen atom from each carbon atom at both chain ends of a linear unsaturated hydrocarbon, and specifically includes, for example, an ethynylene group, a propynylene Group, butynylene group, pentynylene group,
Hexinylene group and the like, preferably ethynylene group, propynylene group, butynylene group, pentynylene group, more preferably ethynylene group, propynylene group,
Butynylene group, more preferably ethynylene group,
It is a propynylene group, most preferably an ethynylene group.

The acyl group specifically includes, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, octanoyl group, lauroyl group,
Palmitoyl group, stearoyl group, oleoyl group, acryloyl group, methacryloyl group, crotonyl group, chloroformyl group, pyrvoyl group, oxalo group, methoxalyl group, ethoxylyl group, benzoyl group, toluoyl group, cinnamoyl group, naphthoyl group, phthaloyl group, etc. Is mentioned. The lower acyl group specifically includes, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, acryloyl group, methacryloyl group, crotonyl group, chloroformyl group , A pyruvoyl group,
Oxaro, methoxalyl, ethoxalyl and the like. A lower acyloxy group specifically includes, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyl Examples include an oxy group, a methacryloyloxy group, a crotonyloxy group, a chloroformyloxy group, a pyrvoyloxy group, an oxaloxy group, a methoxalyloxy group, and an ethoxyloxy group.

The lower alkyl (thiocarbonyl) group is
Shows those corresponding to the lower alkyl group, specifically, for example, methylthiocarbonyl group, ethylthiocarbonyl group, n-propylthiocarbonyl group, i-propylthiocarbonyl group, n-butylthiocarbonyl group, i-butylthio Carbonyl group, sec-butylthiocarbonyl group, t-butylthiocarbonyl group, n-pentylthiocarbonyl group, i-pentylthiocarbonyl group, sec-pentylthiocarbonyl group, t-pentylthiocarbonyl group, neopentylthiocarbonyl group , 1-methylbutylthiocarbonyl group, 2-methylbutylthiocarbonyl group, 1,1-dimethylpropylthiocarbonyl group, 1,2-dimethylpropylthiocarbonyl group, n-hexylthiocarbonyl group, i-hexylthiocarbonyl group , 1-methylpentylthiocarbonyl group, 2-methylpentylthiocarbonyl group, 3-methyl Pentylthiocarbonyl group, 1,1-dimethylbutylthiocarbonyl group,
2-dimethylbutylthiocarbonyl group, 2,2-dimethylbutylthiocarbonyl group, 1,3-dimethylbutylthiocarbonyl group, 2,3-dimethylbutylthiocarbonyl group, 3,3-dimethylbutylthiocarbonyl group, 1- Ethylbutylthiocarbonyl group, 2-ethylbutylthiocarbonyl group, 1,1,2-trimethylpropylthiocarbonyl group, 1,2,2-trimethylpropylthiocarbonyl group, 1-ethyl-1-methylpropylthiocarbonyl group, 1-ethyl-2-methylpropylthiocarbonyl group and the like, preferably, methylthiocarbonyl group, ethylthiocarbonyl group, n-propylthiocarbonyl group, i-propylthiocarbonyl group, n-butylthiocarbonyl group, i -Butylthiocarbonyl group, sec-
Butylthiocarbonyl group, t-butylthiocarbonyl group,
n-pentylthiocarbonyl group, i-pentylthiocarbonyl group, sec-pentylthiocarbonyl group, t-pentylthiocarbonyl group, neopentylthiocarbonyl group, 1-methylbutylthiocarbonyl group, 2-methylbutylthiocarbonyl group, 1,1-dimethylpropylthiocarbonyl group, 1,2-
Dimethylpropylthiocarbonyl group, n-hexylthiocarbonyl group, i-hexylthiocarbonyl group, more preferably methylthiocarbonyl group, ethylthiocarbonyl group, n-propylthiocarbonyl group, i-propylthiocarbonyl group, n- Butylthiocarbonyl group, i-butylthiocarbonyl group, sec-butylthiocarbonyl group, t-butylthiocarbonyl group, most preferably methylthiocarbonyl group, ethylthiocarbonyl group, n-propylthiocarbonyl group, i-propyl It is a thiocarbonyl group.

The lower alkyl (thiocarbonyl) oxy group means a group corresponding to the lower alkyl (thiocarbonyl) group, and specifically includes, for example, a methylthiocarbonyloxy group, an ethylthiocarbonyloxy group and an n-propylthiocarbonyl group. Oxy group, i-propylthiocarbonyloxy group, n-butylthiocarbonyloxy group, i-butylthiocarbonyloxy group, sec-butylthiocarbonyloxy group, t-butylthiocarbonyloxy group, n-pentylthiocarbonyloxy group A, i-pentylthiocarbonyloxy group, sec-pentylthiocarbonyloxy group, t-pentylthiocarbonyloxy group, neopentylthiocarbonyloxy group, 1-methylbutylthiocarbonyloxy group,
2-methylbutylthiocarbonyloxy group, 1,1-dimethylpropylthiocarbonyloxy group, 1,2-dimethylpropylthiocarbonyloxy group, n-hexylthiocarbonyloxy group, i-hexylthiocarbonyloxy group, 1-methyl Pentylthiocarbonyloxy group, 2-methylpentylthiocarbonyloxy group, 3-methylpentylthiocarbonyloxy group, 1,1-dimethylbutylthiocarbonyloxy group, 1,2-dimethylbutylthiocarbonyloxy group, 2,
2-dimethylbutylthiocarbonyloxy group, 1,3-dimethylbutylthiocarbonyloxy group, 2,3-dimethylbutylthiocarbonyloxy group, 3,3-dimethylbutylthiocarbonyloxy group, 1-ethylbutylthiocarbonyloxy group , 2-ethylbutylthiocarbonyloxy group, 1,1,2-trimethylpropylthiocarbonyloxy group, 1,2,2-trimethylpropylthiocarbonyloxy group, 1-ethyl-1-
Methylpropylthiocarbonyloxy group, 1-ethyl-2-
Methylpropylthiocarbonyloxy group and the like, preferably, methylthiocarbonyloxy group, ethylthiocarbonyloxy group, n-propylthiocarbonyloxy group, i-propylthiocarbonyloxy group, n-butylthiocarbonyloxy group, i -Butylthiocarbonyloxy group, sec-butylthiocarbonyloxy group, t-butylthiocarbonyloxy group, n-pentylthiocarbonyloxy group, i-pentylthiocarbonyloxy group, sec-pentylthiocarbonyloxy group, t-pentyl Luthiocarbonyloxy group, neopentylthiocarbonyloxy group, 1-
Methylbutylthiocarbonyloxy group, 2-methylbutylthiocarbonyloxy group, 1,1-dimethylpropylthiocarbonyloxy group, 1,2-dimethylpropylthiocarbonyloxy group, n-hexylthiocarbonyloxy group, i-hexylthio Carbonyloxy group, more preferably methylthiocarbonyloxy group, ethylthiocarbonyloxy group, n-propylthiocarbonyloxy group, i-propylthiocarbonyloxy group, n-butylthiocarbonyloxy group, i-butylthiocarbonyloxy Group, sec-butylthiocarbonyloxy group, t-butylthiocarbonyloxy group, most preferably methylthiocarbonyloxy group, ethylthiocarbonyloxy group, n-propylthiocarbonyloxy group, i-propylthiocarbonyloxy group is there.

The term "hydroxyl group protected with a protecting group" means a hydroxyl group protected with a protecting group for a hydroxyl group. To be specific, a hydroxyl group protected by a protecting group for organic synthesis is generally used. Any group may be used as long as it is a hydroxyl group, and examples thereof include, but are not particularly limited to, a hydroxyl group-protecting group such as a lower alkylsilyl group such as a trimethylsilyl group or a t-butyldimethylsilyl group; Lower alkoxymethyl group; for example, tetrahydropyranyl group; for example, benzyl group, p-methoxybenzyl group, 2,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, aralkyl group such as trityl group; for example, formyl An acyl group such as a group or an acetyl group;
For example, t-butoxycarbonyl group, 2-iodoethoxycarbonyl group, lower alkoxycarbonyl group such as 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, Alkenyloxycarbonyl groups such as 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnamyloxycarbonyl group; for example, benzyloxycarbonyl group, p And aralkyloxycarbonyl groups such as -methoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group.

The amino group protected with a protecting group means an amino group protected with a protecting group for an amino group. Specific examples of the protecting group for an amino group generally include the protection of an amino group in organic synthesis. Any group may be used as long as it is known as a group, and examples thereof include, but are not limited to, formyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, phenylacetyl, phenoxyacetyl, and thienylacetyl groups. Substituted or unsubstituted lower acyl group; substituted or unsubstituted lower alkoxycarbonyl group such as benzyloxycarbonyl group, t-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group; methyl group, t-butyl group, 2,2 , 2-trichloroethyl group, trityl group, p-methoxybenzyl group, p-nitrobenzyl group,
Substituted lower alkyl groups such as diphenylmethyl group and pivaloyloxymethyl group; substituted silyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; trimethylsilylmethoxymethyl group, trimethylsilylethoxymethyl group and t-butyldimethylsilylmethoxymethyl group And substituted silylalkoxyalkyl groups such as t-butyldimethylsilylethoxymethyl group; benzylidene group, salicylidene group, p-nitrobenzylidene group, m-chlorobenzylidene group, 3,5-di (t-butyl) -4-hydroxybenzylidene And substituted or unsubstituted benzylidene groups such as 3,5-di (t-butyl) benzylidene group.
The elimination of these protecting groups can be performed by a conventional method such as hydrolysis or reduction depending on the type of the protecting group used.

In the present invention, the type of the salt is not particularly limited, but specific examples thereof include, for example, hydrofluoric acid,
Addition salts of inorganic acids such as hydrochloride, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrobromide, hydroiodide; acetate, maleate, Fumarate,
Addition salts of organic carboxylic acids such as oxalate, lactate, tartrate, trifluoroacetate; methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, Benzenesulfonate, toluenesulfonate,
Addition salts of organic sulfonic acids such as taurine salts; trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine salts, N,
N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt, amine addition salt such as phenethylbenzylamine salt; sodium salt, potassium salt and the like Addition salts of alkaline earth metals such as magnesium salts and calcium salts; addition salts of amino acids such as arginine salts, lysine salts, serine salts, glycine salts, aspartates and glutamates; it can.

The pharmacologically acceptable salt is not particularly limited, but may be, for example, hydrochloride, sulfate, carbonate,
Addition salts of inorganic acids such as bicarbonate, hydrobromide, hydroiodide; acetate, maleate, lactate, tartrate,
Addition salts of organic carboxylic acids such as trifluoroacetate; methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, benzenesulfonate,
Addition salts of organic sulfonic acids such as toluenesulfonic acid salt and taurine salt; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine Addition salts of amines such as salts, diethanolamine salts, triethanolamine salts, tris (hydroxymethylamino) methane salts, phenethylbenzylamine salts; arginine salts, lysine salts, serine salts, glycine salts, aspartates, glutamates, etc. Examples thereof include amino acid addition salts.

All isomers such as tautomers, optical isomers and geometric isomers are also included in the present invention.

Next, a method for producing the compound according to the present invention will be described.

The compound according to the present invention can be produced by a known technique, but a general production method is illustrated below for reference. For example, the following production method 1

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[0039]

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For example, the following production method 2

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For example, the following production method 3

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[0043]

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For example, the following production method 4

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[0045]

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For example, the following manufacturing method 5

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[0047]

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For example, the following manufacturing method 6

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[0049]

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For example, the following production method 7

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[0051]

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For example, the following production method 8

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[0053]

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For example, the following production method 9

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[0055]

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In addition, the following compounds can be produced by applying these methods or by a conventional method.

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The solvent that can be used in the above-mentioned production method is not particularly limited as long as it does not inhibit the reaction, and may be any solvent that is generally used in organic synthesis. Lower alcohols such as propanol and butanol, polyalcohols such as ethylene glycol and glycerin, ketones such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone, diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, 1,2 Ethers such as dimethoxyethane, acetonitrile, nitriles such as propionitrile, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, esters such as diethyl phthalate,
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbons such as dichloroethane, trichloroethylene, tetrachloroethylene, benzene, toluene, xylene, monochlorobenzene, nitrobenzene,
Aromatics such as indene, pyridine, quinoline, collidine, phenol, pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzene, hydrocarbons such as petroleum ether, ethanolamine, diethylamine, triethylamine, pyrrolidine,
Amines such as piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine, toluidine, formamide, N-methylpyrrolidone, N, N-
Amides such as dimethylimidazolone, N, N-dimethylacetamide, N, N-dimethylformamide, phosphoric amides such as hexamethylphosphoric triamide, hexamethylphosphorous triamide, water, and other commonly used solvents One or more mixed solvents can be mentioned, and the mixing ratio is not particularly limited.

Specific examples of the base which can be used in the above reaction include, but are not particularly limited to, any one which is generally known as a base in organic synthesis. Examples of the base include sodium carbonate, sodium hydrogen carbonate, and carbonate. Potassium, sodium hydride, potassium hydride, potassium t-butoxy, pyridine, dimethylaminopyridine, trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N -Dimethylaniline, 1,8-diazabicyclo [5,4,0] undeca-
7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline, sodium hydroxide, potassium hydroxide, lithium hydroxide, butyllithium, sodium methylate, potassium methylate, sodium ethylate, etc. And sodium or potassium alcoholates of the formula (I).

For the reduction, a reducing agent commonly used in organic synthesis can be used, and is not particularly limited.
H ₄ , LiBH ₄ , Zn (BH ₄ ) ₂ , Me ₄ NBH (OAc) ₃ , NaBH ₃ CN, Select
_{ride, Super Hydride (LiBHEt 3)} , LiAlH 4, DIBAL, LiAlH
In addition to (t-BuO) ₃ , Red-al and binap, reducing agents such as catalytic hydrogenation catalysts such as platinum, palladium, rhodium, ruthenium and nickel can be used.

For the halogenation, phosgene, diphosgene (phosgene dimer), triphosgene (phosgene trimer),
Thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl
Halogenating agents usually used in the synthesis of acid halides, such as chloroformate, oxalyl chloride, and Vilsmeier reagent obtained by reacting these amides or phosphoric amides with these halogenating agents, can be used. .

In the above reaction, if necessary, a functional group is synthesized using a protecting group ordinarily used in organic synthesis, and purified by a conventional method such as column chromatography or crystallization using a suitable silica gel and the like, followed by a deprotection reaction. It is also possible to attach

The dose of the medicament according to the present invention depends on the degree of the symptom,
Depending on age, gender, body weight, dosage form, type of disease, etc., it is usually 1 mg to 5 g per day for an adult, and is administered once or several times. The administration form of the medicament according to the present invention is not particularly limited, and it can be administered orally or parenterally by a commonly used method.

For the preparation of these medicines, commonly used excipients, binders, lubricants, coloring agents, flavoring agents, etc., and if necessary, stabilizers, emulsifiers, absorption promoters, surfactants, etc. It can be used, and it is formulated by a conventional method by blending components generally used as raw materials for pharmaceutical preparations.

These components include, for example, animal and vegetable oils (soy oil, tallow, synthetic glyceride, etc.), hydrocarbons (liquid paraffin, squalane, solid paraffin, etc.), ester oils (octyldodecyl myristate, isopropyl myristate, etc.), Higher alcohols (setosteryl alcohol, behenyl alcohol, etc.), silicone resin, silicone oil, surfactants (polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hardened castor oil, polyoxy Water-soluble polymers (hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, poly Nylpyrrolidone, methylcellulose, etc.), alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene glycol, sorbitol, etc.), sugars (glucose, sucrose, etc.), inorganic powders (silicic anhydride, silica, etc.) Aluminum magnesium silicate, aluminum silicate, etc.), purified water and the like. For pH adjustment, inorganic acids (such as hydrochloric acid and phosphoric acid), alkali metal salts of inorganic acids (such as sodium phosphate), inorganic bases (such as sodium hydroxide), and organic acids (lower fatty acids, citric acid,
Lactic acid), alkali metal salts of organic acids (sodium citrate, sodium lactate, etc.), organic bases (arginine,
Ethanolamine). Further, a preservative, an antioxidant and the like can be added as required.

Examples of pharmacological experiments of the compound according to the present invention will be shown below to clarify the usefulness of the compound according to the present invention. Pharmacological Experimental Example The antiviral activity of the compound of the present invention due to IRES-dependent translation inhibitory activity was measured by the following method. The results are shown in Table 1 below. <Method for measuring the inhibitory activity of ellagic acid and its derivatives on cap-dependent translation and IRES-dependent translation by in vitro translation> 1) Background reactivity (test without Capped-globin mRNA or IRES-HCV mRNA) Test to see tube) Master Cocktail (Of the factors required for a cell-free translation system,
The necessary components other than the host protein, mRNA and salt in the cell are mixed in advance and stocked. ATP, GTP,
Dithiothreitol, creatine phosphate, creatine kinase, spermine tetrahydrochloride), Mg (CH ₃ CO
O) RRL of host factors (rabbit reticulocyte lysate, rabbits were injected several times with phenylhydrazine subcutaneously without addition of protein translation template to the reaction mixture containing ₂ ) CH ₃ COOK, ³⁵ S methionine, etc. Prepared by whole blood collection) and incubate at 30 ° C for 50 minutes. Here, translation of protein does not occur at all because mRNA is not originally present, but a slight translation product may appear as a background reaction. The value here is assumed to be “A”.

2) (Capp as a positive control
ed-globin mRNA or IRES-HCV mRNA was added) A test to see the reactivity. Master cocktail, Mg (CH ₃ COO) ₂ , CH ₃ COOK, ³⁵ S methionine and capped-globin mRNA or IRES-HCV mRNA were mixed. The reactivity of the reaction solution was measured in the same manner as in 1) above. Here, since the mRNA is present and no drug is added, it is considered that the reaction has progressed 100%. Assuming that the protein synthesis reaction value that has now appeared is “B”, the true translation reaction value “C” here is a value obtained by subtracting A from B. That is, C = BA ₃ ) a test to see the inhibitory activity of the test drug Master cocktail, Mg (CH ₃ COO) ₂ , CH ₃ COOK, ³⁵ S methionine and capped-globin mRNA or IRES-HCV mRNA, The reactivity of the reaction solution mixed with the test drug was measured in the same manner as in 1) above.

When the obtained protein synthesis reaction value is “D”, the true translation reaction value “E” is D to A
Is subtracted. That is, E = DA, and the inhibitory activity of the test drug is obtained using the following equation. Inhibition activity (% of inhibition) = (1-E / C) × 10
0 When capped-globin is used as mRNA, g
Inhibition against lobin, and when IRES-HCV is used, inhibition activity against HCV.

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[Table 1] [In the table, “Globin inhibition rate” indicates the cap-dependent translation inhibition rate of globin, and “IRES-HCV inhibition rate” indicates the IRES-dependent translation inhibition rate of hepatitis C virus. ]

In the above table, the relationship between the compound number and the structure is as follows.

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Therefore, the compound according to the present invention is represented by IRES
It can be seen that the compound has a selectivity that strongly inhibits the translation dependent on the cap, and does not inhibit the translation dependent on the cap.
Thus, the compounds according to the present invention have excellent antiviral activity and are useful for preventing and treating viral infections. In particular, a prophylactic / therapeutic agent for a viral infectious disease comprising a derivative of the present invention having a xanthone or fluorenone skeleton, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient is very useful.

The compound of the present invention exhibits an antiviral effect based on a novel mechanism of action different from IFN. Specifically, in the course of virus propagation, ribosomes inhibit the site (IRES) that recognizes viral RNA, thereby inhibiting translation (transcription) of viral genes and exerting antiviral activity.

In order to explain the present invention in more detail, some production examples of the compound according to the present invention are shown below, but the present invention is not limited to these.
Also, in the production examples, ¹ HN.M.R.
It was measured by FT NMR (400 MHz).

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EXAMPLES Preparation Example 1 4,4'-Dimethoxybiphenyl-2-carboxylic acid

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4,4'-dihydroxybiphenyl-2-
2.3 g of carboxylic acid was dissolved in a 4N aqueous solution of sodium hydroxide, 1.7 ml of dimethyl sulfate was added thereto, and the mixture was stirred at 0 ° C. for 20 minutes. Thereto was further added 1.7 ml of dimethyl sulfate, and the mixture was heated under reflux for 7.5 hours. Thereafter, the mixture was neutralized by adding 1N-hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to obtain 2.31 g of the title compound.

Mp = 153 ° C. MH ⁺ = ¹ H-NMR (CDCl ₃ ) δ ppm: 3.84 (s, 3H), 3.87 (s, 3)
H), 6.91 (d, 2H, J = 8.4Hz), 7.08 (dd, 1H, J = 8.4,2.8Hz), 7.23
(d, 2H, J = 8.4Hz), 7.26 (d, 1H, J = 8.4Hz), 7.44 (d, 1H, J = 2.8H
z)

Example 1 2,7-dimethoxyfluorenone

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518 mg of 4,4'-dimethoxybiphenyl-2-carboxylic acid was suspended in 10 ml of dichloromethane, and 1.32 ml of trifluoroacetic anhydride was added thereto, followed by stirring at room temperature overnight. Thereafter, the mixture was concentrated under reduced pressure, dissolved again in dichloromethane, and filtered through silica gel. The filtrate was concentrated under reduced pressure to obtain 448 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.84 (6H,
s), 6.94 (2H, dd, J = 8.0,2.8Hz), 7.16 (2H, dd, J = 2.8Hz), 7.2
9 (2H, d, J = 8.0Hz)

Example 2 2,7-dihydroxyfluorenone

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6.533 g of 2,7-dimethoxyfluorenone and 26.132 g of pyridine hydrochloride were mixed and melted by heating at 180 ° C. for 2.5 hours. After cooling to room temperature, water was added, and the precipitated solid was collected by filtration and washed with water to obtain 5.628 g of the title compound.

M ⁺ = 212 ¹ H-NMR (DMSO-d ₆ ) δppm: 6.84 (2H, dd, J = 8.
0,2.4Hz), 6.86 (2H, d, J = 2.4Hz), 7.36 (2H, d, J = 8.0Hz), 9.8
1 (2H, s)

Production Example 2 2- (2,4-dimethoxybenzoyl) amino-2-me
Chill-1-propanol

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To 9.11 g of 2,4-dimethoxybenzoic acid was added 11 ml of thionyl chloride, and the mixture was stirred at room temperature for 45 minutes and concentrated under reduced pressure. The product was dissolved in 10 ml of dichloromethane, and a solution of 9.8 ml of 2-amino-2-methyl-1-propanol in 20 ml of dichloromethane was added under ice-cooling, followed by stirring. The product was washed once with water, once with 7% hydrochloric acid, and then twice with water.
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by silica gel column chromatography (hexane-
(Eluted with ethyl acetate) to give 2.0 g of the desired product.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.37 (6H,
s), 3.65 (2H, d; J = 6.0 Hz), 3.85 (3H, s), 3.93 (3H, s), 5.51 (1
H, t; J = 6.0Hz), 6.47 (1H, d; J = 2.4Hz), 6.59 (1H, dd; J = 2.4H)
z, 8.8Hz), 8.01 (1H, br.s), 8.12 (1H, d; J = 8.8Hz)

Production Example 3 2- (2,4-dimethoxyphenyl) -4,4-dimethyl
Luoxazoline

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2.01 g of 2- (2,4-dimethoxybenzoyl) amino-2-methyl-1-propanol was dissolved in 20 ml of dichloromethane, 3 ml of thionyl chloride was added, and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, diethyl ether was added, and the product was collected by filtration. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluted with hexane-ethyl acetate) to obtain 1.565 g of the desired product.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.37 (6H,
s), 3.82 (3H, s), 3.86 (3H, s), 4.05 (2H, s), 6.47 (1H, s), 6.4
8 (1H, d; J = 8.8Hz), 7.71 (1H, d; J = 8.8Hz)

Production Example 4 2- (2- (3-methoxyphenyl) -4-methoxyphenyl
Enyl) -4,4-dimethyloxazoline

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3-bromo-1-methoxyphenol 2.17
2- (2,4-dimethoxyphenyl) was added to a solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran (12.5 ml) prepared from 1 ml of magnesium and 449 mg of magnesium pieces.
A solution of 3.95 g of -4,4-dimethyloxazoline in 31 ml of tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. A solution of 3-methoxyphenylmagnesium bromide prepared from 1.1 ml of 3-bromo-1-methoxyphenol and 225 mg of magnesium in tetrahydrofuran (5.
ml) was further added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized by adding an aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluted with hexane-ethyl acetate) to give 2.71 of the desired product
mg was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (6H,
s), 3.78 (2H, s), 3.83 (3H, s), 3.85 (3H, s), 6.70 to 9.91 (3H,
m), 6.94 (1H, dd; J = 2.2Hz, 2.4Hz), 6.97 (1H, ddd; J = 2.2Hz,
2.4Hz, 8.4Hz), 7.29 (1H, t; J = 8.8Hz), 7.69 (1H, d; J = 8.8Hz)

Production Example 5 2- (3-methoxyphenyl) -4-methoxybenzoic acid

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2- (2- (3-methoxyphenyl) -4
-Methoxyphenyl) -4,4-dimethyloxazoline
A mixture of 1.802 g and 3.6 ml of methyl iodide was added at room temperature for 5.5 minutes.
After stirring for an hour, the mixture was concentrated under reduced pressure. The product is methanol 14
Dissolve in 20 ml, add 14 ml of 20% aqueous sodium hydroxide,
The mixture was stirred at 80 ° C. overnight. After the reaction solution was concentrated under reduced pressure, 200 ml of water and 5 ml of acetic acid were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.422 g of the desired product.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.83 (3H,
s), 3.88 (3H, s), 6.84 (1H, d; J = 2.4Hz), 6.88 (1H, dd; J = 2.0H
z, 2.4Hz), 6.90-6.94 (3H, m), 7.31 (1H, t; J = 8.0Hz), 7.99 (1H
(H, d; J = 8.8Hz)

Example 3 3,6-Dimethoxyfluorenone

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After dissolving 1.422 g of 2- (3-methoxyphenyl) -4-methoxybenzoic acid in 14 ml of dichloromethane, a solution of 1.16 ml of trifluoroacetic anhydride in 5 ml of dichloromethane was added dropwise at an internal temperature of -12 ° C. Stirred at room temperature for 1 hour. After adding an aqueous solution of sodium hydrogen carbonate to the reaction solution, the mixture was extracted twice with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluted with hexane-ethyl acetate system) gave 755 mg of the desired product.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.91 (6H,
s), 6.75 (3H, dd; J = 2.2Hz, 8.2Hz), 7.00 (1H, d; J = 2.2Hz), 7.
59 (1H, d; J = 8.2Hz)

Example 4 3,6-dihydroxyfluorenone

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A mixture of 755 mg of 3,6-dimethoxyfluorenone and 2.5 g of pyridine hydrochloride was heated at 200 ° C. for 1.5 hours, and then cooled to room temperature. Water was added, and the precipitated solid was collected by filtration, washed with water, and then with hexane. Drying under reduced pressure in a desiccator gave 664 mg of the desired product.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 6.6
2 (2H, dd; J = 8.8Hz), 7.01 (2H, d; J = 2.0Hz), 7.36 (2H, d; J = 8.
8Hz), 10.45 (2H, s)

Production Example 6 N, N-diethyl-2-methoxybenzamide

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5.0 g of 2-methoxybenzoic acid was added to 70 ml of toluene.
And 4.4 ml of thionyl chloride and several drops of dimethylformamide were added dropwise. After stirring at 60 ° C. for 2 hours, the mixture was cooled to room temperature. To this solution were added 100 ml of tetrahydrofuran and 12.5 ml of diethylamine, and the mixture was stirred overnight at room temperature. The reaction mixture was added to water, extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 4.3 g (yield 63%) of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.02 (3H,
t, J = 7.1Hz), 1.23 (3H, t, J = 7.1Hz), 3.13 (2H, q, J = 7.1Hz),
3.48-3.64 (2H, m), 3.81 (3H, s), 6.89 (1H, d, J = 8.4Hz), 6.9
6 (1H, ddd, J = 7.5Hz, 7.5Hz, 0.9Hz), 7.23 (1H, dd, J = 7.5Hz,
2.0Hz), 7.30 (1H, ddd, J = 8.4Hz, 7.5Hz, 2.0Hz)

Production Example 7 2-Diethylcarbamoyl-3-methoxyphenylborough
acid

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Under a nitrogen atmosphere, 4.3 ml of tetramethylethylenediamine was dissolved in 130 ml of anhydrous tetrahydrofuran.
Cooled to -60 ° C. After slowly dropping 22.2 ml of a 1.3 M cyclohexane solution of S-butyllithium, the mixture was heated at -60 ° C.
Stirred for 10 minutes. To this solution was added 5.0 g of N, N-diethyl-2-methoxybenzamide in tetrahydrofuran (13 ml).
After the solution was added dropwise, the mixture was stirred at -65 ° C for 1 hour. 7.5 ml of trimethoxyborane was added thereto, the temperature was slowly raised to room temperature, and the mixture was stirred overnight. 100 ml of 1N hydrochloric acid under ice-cooling
In addition, the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate and methanol system) to give 5.2 g of the title compound.
(85% yield) as an oil.

Production Example 8 2-Diethylcarbamoyl-3,3'-dimethoxybifu
Henil

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Under a nitrogen atmosphere, 278 mg of palladium tetrakistriphenylphosphine was dissolved in 80 ml of dimethoxyethane, and 881 mg of 3-methoxybromobenzene was added thereto, followed by stirring at room temperature for 40 minutes. Thereafter, a solution of 1775 mg of 2-diethylcarbamoyl-3-methoxyphenylboronic acid obtained from the previous reaction in methanol (6 ml) was added to this solution.
4.4 ml of a 2 M aqueous sodium carbonate solution was added, and the mixture was heated under reflux for 12 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to give the title compound (1530 mg, yield 69%) as an oil.

¹ H-NMR (CDCl ₃ ) δ ppm: 0.77-0.
86 (6H, m), 2.68 ~ 2.78 (1H, m), 2.92 ~ 3.05 (2H, m), 3.74 ~
3.82 (1H, m), 3.81 (3H, s), 6.84-6.87 (1H, m), 6.92 (1H, dd,
J = 8.4,0.8Hz), 6.98 ~ 7.00 (1H, m), 7.04 ~ 7.08 (2H, m), 7.2
5 (1H, dd, J = 8.4,8.4Hz), 7.29 ~ 7.38 (1H, m)

Example 5 1,8-Dimethoxyfluorenone

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Under a nitrogen atmosphere, diisopropylamine 6.05
ml was dissolved in 15 ml of anhydrous tetrahydrofuran and cooled to -20 ° C. To this solution, 0.85 ml of a 1.6 M hexane solution of n-butyllithium was added dropwise, and the mixture was stirred at 0-5 ° C for 40 minutes.
The solution was cooled again to -10 ° C, and a solution of 761 mg of 2-diethylcarbamoyl-3,3'-dimethoxybiphenyl in tetrahydrofuran (5 ml) was added dropwise, followed by slowly rising to room temperature. 10 ml of a saturated aqueous ammonium chloride solution was added to the reaction mixture. Thereafter, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate-methanol system) to give 330 mg (57%) of the title compound.
Was obtained as crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.85 (6H,
s), 7.01 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 7.2 Hz), 7.51 (2H, d
d, J = 8.4,7.2Hz)

Example 6 1,8-dihydroxyfluorenone

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129 mg of 1,8-dimethoxyfluorenone and 1016 mg of pyridine hydrochloride were mixed in a solid state and heated at 200 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added,
The resulting precipitate was separated by filtration, and dried by heating under reduced pressure to give the title compound (60 mg).
(Yield 53%) as crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 6.77 (2H,
d, J = 7.6Hz), 7.12 (2H, d, J = 7.2Hz), 7.36 (1H, dd, J = 7.6,7.2
Hz)

Example 7 2,7-bis [2- (4-morpholino) ethyloxy]
Fluorenone

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2,7-dihydroxyfluorenone 110 mg
Was dissolved in 5 ml of N, N-dimethylformamide, and 135 mg of sodium hydride (60% dispersion in mineral oil) and 373 mg of 2-morpholinoethyl chloride hydrochloride were sequentially added thereto.
Stirred for hours. Water was added, the mixture was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane-methanol system) gave 158 mg of the title compound.

MH ⁺ = 439 ¹ H-NMR (CDCl ₃ ) δ ppm: 2.58 (8H, t, J = 4.8 Hz),
2.81 (4H, t, J = 5.6Hz), 3.74 (8H, t, J = 4.8Hz), 4.14 (4H, t, J =
5.6Hz), 6.95 (2H, dd, J = 8.4,2.4Hz), 7.16 (2H, d, J = 2.4Hz),
7.28 (2H, d, J = 8.4Hz)

Example 8 2,7-bis [2- (1-pyrrolidinyl) ethyloxy
Shi) fluorenone

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2,7-dihydroxyfluorenone 105 mg
Was dissolved in 5 ml of N, N-dimethylformamide, and 141 mg of sodium hydride (60% dispersion in mineral oil) and 2- (1-
342 mg of pyrrolidinyl) ethyl chloride hydrochloride were sequentially added, and the mixture was stirred at 80 ° C. overnight. Water was added, extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane-methanol system) gave 47 mg of the title compound and 43 mg of B, respectively.
(Title compound B: compound described in Example 9)

MH ⁺ = 407 ¹ H-NMR (CDCl ₃ ) δ ppm: 1.81 to 1.85 (8H, m), 2.6
4 ~ 2.68 (8H, m), 2.93 (4H, t, J = 6.0Hz), 4.15 (4H, t, J = 6.0H
z), 6.97 (2H, dd, J = 8.0,2.4Hz), 7.16 (2H, d, J = 2.4Hz), 7.28
(2H, d, J = 8.0Hz)

Example 9 7-Hydroxy-2- (1-pyrrolidinyl) ethyloxo
Cyfluorenone

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MH ⁺ = 310 ¹ H-NMR (CDCl ₃ ) δppm: 1.90-1.96 (4H, m), 2.8
1-2.87 (4H, m), 2.98 (2H, t, J = 6.0Hz), 4.04 (2H, t, J = 6.0H
z), 6.62 to 6.65 (1H, m), 6.71 to 6.74 (3H, m), 6.96 to 6.99 (2
H, m)

Example 10 2,7-bis (2-diisopropylaminoethyloxy)
Shi) fluorenone

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2,7-dihydroxyfluorenone 106 mg
Was dissolved in 6 ml of N, N-dimethylformamide, and 140 mg of sodium hydride (60% dispersion in mineral oil) and 398 mg of 2-diisopropylaminoethyl chloride hydrochloride were sequentially added thereto, followed by stirring at 80 ° C. for 16 hours. Water was added, extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane-ethyl acetate system) gave 24 mg of the title compound.

MH ⁺ = 467 ¹ H-NMR (CDCl ₃ ) δ ppm: 1.04 (12H, s), 1.06 (12
H, s), 2.83 (4H, t, J = 7.2Hz), 3.02 ~ 3.09 (4H, m), 3.92 (4H,
t, J = 7.2Hz), 6.92 (2H, dd, J = 8.4,2.4Hz), 7.15 (2H, d, J = 2.4
Hz), 7.26 (2H, d, J = 8.4Hz)

Example 11 2,7-bis (3-dimethylaminopropyloxy) phenyl
Luorenone dihydrochloride

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2,7-dihydroxyfluorenone 104 mg
Was dissolved in 6 ml of N, N-dimethylformamide, and 141 mg of sodium hydride (60% dispersion in mineral oil) and 320 mg of 3-dimethylaminopropyl chloride hydrochloride were sequentially added thereto.
Stirred at 120 ° C for 12 hours, then at 120 ° C for 3 hours. Water was added and extracted with ethyl acetate, washed with water and then with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. Silica gel column chromatography (dichloromethane-
After purifying with methanol, the solution was converted to hydrochloric acid with a 1N hydrogen chloride diethyl ether solution to obtain 100 mg of the title compound.

MH ⁺ = 383 ¹ H-NMR (D ₂ O) δ ppm: 2.06 2.14 (4H, m), 2.81 (12
H, s), 3.21-3.26 (4H, m), 3.99 (4H, t, J = 6.0Hz), 6.76-6.8
3 (4H, m), 7.05 (2H, d, J = 8.0Hz)

Example 12 2,7-bis (2-dimethylaminoethyloxy) fur
Orenone

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2,7-dihydroxyfluorenone 107 mg
Was dissolved in 6 ml of N, N-dimethylformamide, and 144 mg of sodium hydride (60% dispersion in mineral oil) and 290 mg of 2-dimethylaminoethyl chloride hydrochloride were sequentially added thereto.
For 4.5 hours. Add water and extract with ethyl acetate,
The extract was washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane-methanol system) gave 133 mg of the title compound.

MH ⁺ = 355 ¹ H-NMR (CDCl ₃ ) δppm: 2.34 (12H, s), 2.73 (4H,
t, J = 5.6Hz), 4.09 (4H, t, J = 5.6Hz), 6.97 (2H, dd, J = 8.0,2.4
Hz), 7.16 (2H, d, J = 2.4Hz), 7.27 (2H, d, J = 8.0Hz)

Example 13 3,6-bis- (2-diethylaminoethoxy) -fur
Orenone

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3,6-dihydroxyfluorenone 214 mg
And 860 mg of diethylaminoethyl chloride hydrochloride were dissolved in 2 ml of dimethylformamide, and 300 ml of sodium hydride was dissolved.
g was added and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane-methanol-aqueous ammonia) to obtain 190 mg of the desired product. An analytical sample was obtained by recrystallization from dichloromethane-diisopropyl ether.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.09 (12
H, t; J = 7.2Hz), 2.66 (8H, q; J = 7.2Hz), 2.91 (4H, t; J = 6.2H
z), 4.14 (4H, t; J = 6.2Hz), 6.74 (1H, dd; J = 2.0Hz, 8.0Hz), 7.
00 (1H, d; J = 2.0Hz), 7.56 (1H, d; J = 8.0Hz)

Example 14 1,8-Bis (N, N-diethylaminoethoxy) -phenyl
Luorenone

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67 mg of 1,8-dihydroxyfluorenone and 127 mg of 2-diethylaminoethyl chloride hydrochloride were added to N,
After dissolving in 5.0 ml of N-dimethylformamide and cooling with ice, 60 mg of sodium hydride (60% dispersion in mineral oil) was added. The reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol-concentrated aqueous ammonia) to give 57 mg (yield 47%) of the title compound as crystals.

MH ⁺ = 411 ¹ H-NMR (CDCl ₃ ) δppm: 1.08 (12H, t, J = 7.2Hz),
2.67 (8H, q, J = 7.2Hz), 2.97 (4H, t, J = 6.4Hz), 4.20 (4H, t, J =
6.4Hz), 6.82 (2H, d, J = 8.4Hz), 7.09 (2H, d, J = 7.2Hz), 7.37
(2H, dd, J = 8.4,7.2Hz)

Example 15 1,8-bis (4-morpholinoethoxy) -fluoreno
N

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60 mg of 1,8-dihydroxynaphthalene and 4
158 mg of morpholinoethyl chloride hydrochloride was dissolved in 5.0 ml of N, N-dimethylformamide, 67 mg of sodium hydride (60% dispersion in mineral oil) was added, and the mixture was heated at 70 ° C. for 3.0 hours. The reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (dichloromethane-methanol system) to give 31 mg of the title compound.
(Yield 25%) as crystals.

MH ⁺ = 439 ¹ H-NMR (CDCl ₃ ) δ ppm: 2.66 (8H, t, J = 4.6 Hz),
2.90 (4H, t, J = 5.9Hz), 3.74 (8H, t, J = 4.6Hz), 4.29 (4H, t, J =
5.9Hz), 6.83 (2H, d, J = 8.4Hz), 7.13 (2H, d, J = 7.2Hz), 7.40
(2H, dd, J = 8.4,7.2Hz)

Example 16 1,8-bis (1-piperidinoethoxy) -fluoreno
N

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100 mg of 1,8-dihydroxynaphthalene and 341 mg of 1-piperidinoethyl chloride hydrochloride were added to N, N-
It was dissolved in 22 ml of dimethylformamide, added with 151 mg of sodium hydride (60% dispersion in mineral oil), and heated at 100 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (dichloromethane-methanol system) to give the title compound (130m).
g (yield 63%) was obtained as crystals.

MH ⁺ = 435 ¹ H-NMR (CDCl ₃ ) δppm: 1.44 to 1.54 (4H, m), 1.6
4 to 1.76 (8H, m), 2.62 to 2.82 (8H, m), 2.94 to 3.06 (4H, m), 4.
32 ~ 4.40 (4H, m), 6.83 (2H, d, J = 8.8Hz), 7.12 (2H, d, J = 7.6H
z), 7.40 (2H, dd, J = 8.8,7.6Hz)

Example 17 2- (2-diethylamino) ethoxy-9-fluoreno
N

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196 mg of 2-hydroxy-9-fluorenone
And 206 mg of 2-diethylaminoethyl chloride were dissolved in 2 ml of dimethylformamide, and sodium hydride (60%
(Dispersed in mineral oil) (100 mg) and stirred at room temperature for 7 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed twice with water and once with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluted with methanol / dichloromethane) to obtain 219 mg of the desired product. A sample for physiological activity measurement was prepared by treating the product with a hydrogen chloride ether solution and converting it to a hydrochloride.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.08 (6H,
t; J = 7.2Hz), 2.65 (4H, q; J = 7.2Hz), 2.90 (2H, t; J = 6.0Hz),
4.10 (2H, t; J = 6.0Hz), 6.99 (1H, dd; J = 2.8Hz, 8.0Hz), 7.20
(1H, td; J = 2.4Hz, 7.2Hz), 7.20 (1H, d; J = 2.4Hz), 7.38-7.4
6 (3H, m), 7.60 (1H, dt; J = 1.2Hz, 7.2Hz)

Example 18 2,8-Diacetyldibenzofuran

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5.0 g of dibenzofuran and acetyl chloride 5.
83 g was dissolved in 100 ml of dichloromethane and cooled to -30 ° C. 8.38 g of aluminum chloride was added to this solution, and the temperature was slowly raised to room temperature with vigorous stirring, followed by stirring overnight. The organic layer was washed sequentially with 1N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to give the title compound (3.3 g, yield 44%) as crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.70 (6H,
s), 7.86 (2H, d, J = 8.8Hz), 8.17 (2H, dd, J = 8.8,1.8Hz), 9.01
(2H, d, J = 1.8Hz)

Example 19 2,8-Diacetoxydibenzofuran

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3.23 g of 2,8-diacetyldibenzofuran
Was dissolved in 30 ml of dichloromethane and 0.3 m of trifluoroacetic acid was dissolved.
l was added and cooled on ice. To this solution was added m-700 perbenzoic acid 8.28
g was added, and the mixture was gradually warmed to room temperature and stirred for 11 hours.
Since the reaction was not completed, 2.76 g of m-700 perbenzoic acid was further added, and the mixture was stirred at room temperature overnight. The reaction mixture was added to a mixture of a saturated aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium thiosulfate, and extracted with dichloromethane. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 4.7 g (yield / quantitative) of the title compound as crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.36 (6H,
s), 7.19 (2H, dd, J = 8.8,2.4Hz), 7.55 (2H, d, J = 8.8Hz), 7.63
(2H, d, J = 2.4Hz)

Example 20 2,8-dihydroxydibenzofuran

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4.7 g of 2,8-diacetoxydibenzofuran
To the mixture was added 100 ml of a 5% aqueous sodium hydroxide solution, and the mixture was heated under reflux for 5 hours. The reaction mixture was ice-cooled, 1N hydrochloric acid was added,
The pH was adjusted to 1 and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
It was concentrated under reduced pressure. The residue was adsorbed on silica gel and purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 1.2 g (36% yield) of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 6.8
7 (1H, dd, J = 8.8,2.4Hz), 7.28 (1H, d, J = 2.4Hz), 7.37 (1H, d,
J = 8.8Hz), 9.32 (2H, br-s)

Example 21 2,8-bis (N, N-diethylaminoethoxy) dibe
Nzofuran

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2,8-dihydroxydibenzofuran 129m
g and 1,2-diethylaminoethyl chloride hydrochloride 244 mg
Was dissolved in 5 ml of N, N-dimethylformamide, 65 mg of sodium hydride (60% dispersion in mineral oil) was added, and the mixture was heated and stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, the solvent was distilled off, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 173 mg (68%) of the title compound.

MH ⁺ = 399 ¹ H-NMR (CD ₃ OD) δppm: 1.12 (12H, t, J = 7.1H)
z), 2.73 (8H, q, J = 7.3Hz), 2.94-3.00 (4H, m), 4.16-4.22
(4H, m), 7.06 (1H, dd, J = 8.8,2.8Hz), 7.43 (1H, d, J = 8.8Hz),
7.55 (1H, d, J = 2.8Hz)

Example 22 2,8-Bis (cyanoethoxy) dibenzofuran

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2,8-dihydroxydibenzofuran 122m
g was dissolved in 7.0 ml of N, N-dimethylformamide and stirred at room temperature for 5 minutes. To this solution was added 97 μl of chloroacetonitrile, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to give the title compound (29 mg, yield 17%) as crystals.

MH ⁺ = 278 ¹ H-NMR (DMSO-d ₆ ) δppm: 5.25 (4H, s), 7.24
(2H, dd, J = 8.4,2.4Hz), 7.68 (2H, d, J = 8.8Hz), 7.86 (2H, d, J
= 2.4Hz)

Example 23 2- (2-diethylamino) ethoxycarbazole

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366 mg of 2-hydroxycarbazole and 757 mg of diethylaminoethyl chloride hydrochloride were dissolved in 3.5 ml of dimethylformamide, 176 mg of sodium hydride was added, and the mixture was stirred at room temperature for 16 hours. 176mg sodium hydride
After stirring at 100 ° C. for 2 hours and then at room temperature for 3 hours, water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed twice with water, once with saturated brine, and dried over anhydrous sodium chloride. After drying over magnesium sulfate, the mixture was dried under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 1% methanol / dichloromethane → 2.5% → 5% → 10%) to give 262 mg of the desired product. The product was treated with a hydrogen chloride diethyl ether solution and then dried under reduced pressure to obtain a physiological activity measurement sample.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.10 (6H,
t; J = 7.2Hz), 2.68 (4H, q; J = 7.2Hz), 2.94 (2H, t; J = 6.4Hz),
4.15 (2H, t; J = 6.4Hz), 6.85 (1H, dd; J = 2.4Hz, 8.0Hz), 6.92
(1H, q; J = 2.4Hz), 7.20 (1H, t; J = 7.2Hz), 7.33 (1H, t; J = 7.2H
z), 7.38 (1H, d; J = 8.4Hz), 7.92 (1H, d; J = 8.4Hz), 7.96 (1H,
d; J = 8.4Hz), 7.97 ~ 8.00 (1H, br.s)

Example 24 2,2 ', 5,5'-Tetramethoxybenzophenone

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1.82 g of 2,5-dimethoxybenzoic acid was dissolved in 20 ml of dichloromethane, 7.3 ml of thionyl chloride was added, and the mixture was heated under reflux for 4 hours. After that, it was concentrated under reduced pressure and
2.69 g of 5-dimethoxybenzoic acid chloride was obtained. It was dissolved in 10 ml of 1,2-dichloroethane, and 2.1 g of aluminum chloride and 1.85 g of 1,4-dimethoxybenzene were added to 1,2
-It was added dropwise to a solution of 20 ml of dichloroethane at 0 ° C. After raising the temperature to room temperature and stirring for 1 hour, the reaction solution was poured into an ice-cooled 1N aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude waxy product was recrystallized from diisopropyl ether to give 1.464 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.61 (6H,
s), 3.80 (6H, s), 6.85 (2H, d, J = 9.2Hz), 6.99 (2H, dd, J = 9.2,
3.2Hz), 7.09 (2H, d, J = 3.2Hz)

Example 25 2,5,5'-Trimethoxy-2'-hydroxybenzo
Phenon

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Under a nitrogen atmosphere, 8.41 g of 2,2 ′, 5,5′-tetramethoxybenzophenone was added to 80 ml of dichloromethane.
And cooled to -78 ° C. There, boron trichloride (1.
45 mL of a 0 M dichloromethane solution was slowly added dropwise, and the mixture was heated to room temperature and stirred for 2 hours. Cool down to -78 ° C again,
After adding 40 ml of methanol, the mixture was heated to room temperature and concentrated under reduced pressure. Ethyl acetate was added, and the mixture was washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 8.79 g of a crude product of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.65 (3H,
s), 3.74 (3H, s), 3.79 (3H, s), 6.83 (1H, d, J = 3.2Hz), 6.85 (1
H, d, J = 3.2Hz), 6.94 (1H, d, J = 8.8Hz), 6.98 (1H, d, J = 8.8H
z), 7.02 (1H, dd, J = 8.8,3.2Hz), 7.12 (1H, dd, J = 8.8,3.2H
z), 11.74 (1H, s)

Example 26 2,7-dimethoxyxanthone

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8.79 g of 2,5,5'-trimethoxy-2'-hydroxybenzophenone was added to 180 ml of methanol and 90 ml of water.
Dissolved in a mixed solvent of
The mixture was refluxed for 3 hours. Water was added and the precipitated solid was collected by filtration to obtain 6.57 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.94 (6H,
s), 7.34 (2H, dd, J = 9.2,3.2Hz), 7.45 (2H, d, J = 9.2Hz), 7.71
(2H, d, J = 3.2Hz)

Example 27 2,7-dihydroxyxanthone

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250 mg of 2,7-dimethoxyxanthone and 3 g of pyridine hydrochloride were mixed, and heated and melted at 190 ° C. for 10.5 hours. After cooling to room temperature, water was added, and the precipitated solid was collected by filtration and washed with water to obtain 217 mg of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 7.2
8 (2H, dd, J = 9.2,2.8Hz), 7.42 (2H, d, J = 2.8Hz), 7.49 (2H, d,
J = 9.2Hz), 9.88 (2H, s)

Example 28 2,7-bis (2-diethylaminoethyloxy) oxa
Tonton

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127 mg of 2,7-dihydroxyxanthone was dissolved in 5 ml of N, N-dimethylformamide, 81 mg of sodium hydride (60% dispersion in mineral oil) and 221 mg of 2-diethylaminoethyl chloride hydrochloride were added, and the mixture was stirred at 80 ° C. for 14 hours. . Water was added, extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purify by silica gel column chromatography (dichloromethane-methanol system) to obtain the title compound 12
0 mg was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.01-1.
18 (12H, m), 2.64 ~ 2.75 (8H, m), 2.92 ~ 3.01 (4H, m), 4.18 ~
4.24 (4H, m), 7.37 (2H, dd, J = 9.2,3.2Hz), 7.45 (2H, d, J = 9.2
Hz), 7.73 (2H, d, J = 3.2Hz)

Example 29 2,7-bis (3-dimethylaminopropyloxy) ki
Sandton

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73 mg of 2,7-dihydroxyxanthone was dissolved in 3 ml of N, N-dimethylformamide, and 50 mg of sodium hydride (60% dispersion in mineral oil) and 120 mg of 3-dimethylaminopropyl chloride hydrochloride were sequentially added thereto. In 2
Stirred for 0 hours. Water was added, extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purified by silica gel column chromatography (dichloromethane-methanol system)
30 mg of the title compounds A and 30 mg of B were obtained, respectively. (Title compound B: compound described in Example 30)

MH ⁺ = 399 ¹ H-NMR (CD ₃ OD) δ ppm: 2.02 to 2.07 (4H, m), 2.
33 (12H, s), 2.58 ~ 2.62 (4H, m), 4.13 (4H, t, J = 6.0Hz), 7.40
(2H, dd, J = 9.2,2.8Hz), 7.51 (2H, d, J = 9.2Hz), 7.62 (2H, d, J
= 2.8Hz)

Example 30 2- (3-dimethylaminopropyloxy) -7-hydride
Roxyxanthone

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MH ⁺ = 314 ¹ H-NMR (CD ₃ OD) δ ppm: 2.02 to 2.08 (2H, m), 2.
38 (6H, s), 2.64-2.68 (2H, m), 4.14 (2H, t, J = 6.0Hz), 7.30
(1H, dd, J = 9.2,3.2Hz), 7.40 (1H, dd, J = 9.2,3.2Hz), 7.46 (1
H, d, J = 9.2Hz), 7.51 (1H, d, J = 9.2Hz), 7.54 (1H, d, J = 3.2H
z), 7.63 (1H, d, J = 3.2Hz)

Example 31 2,7-bis-[(1-methyl-4-piperidinyl) o
[Xylene] xanthone

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Under ice-cooling, 2,7-dihydroxyxanthone
100 mg was suspended in 5 ml of tetrahydrofuran, and 113 mg of 4-hydroxy-1-methylpiperidine, 252 mg of triphenylphosphine and 167 mg of diethylazodicarboxylate were added. Thereafter, the mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol system) to obtain the above compound (88 mg).

MH ⁺ = 423 ¹ H-NMR (CDCl ₃ ) δppm: 1.84 to 1.93 (4H, m), 2.0
4 ~ 2.11 (4H, m), 2.29 ~ 2.39 (10H, m), 2.69 ~ 2.77 (4H, m),
4.44 ~ 4.51 (2H, m), 7.32 (2H, dd, J = 9.0,3.1Hz), 7.42 (2H, m
d, J = 9.0Hz), 7.70 (2H, d, J = 3.1Hz)

Example 32 2,7-bis-[(1-tert-butoxycarbonyl)-
4-piperidinyl] oxyxanthone

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Under ice cooling, 2,7-dihydroxyxanthone
100 mg was suspended in 5 ml of tetrahydrofuran, and 1-tert-
Butoxycarbonyl-4-hydroxypiperidine 194 mg
253 mg of triphenylphosphine and 168 mg of diethyl azodicarboxylate were added. Thereafter, the mixture was stirred at room temperature for 1 hour, added with water, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate system) to give 133 mg of the above compound.
Obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.49 (18
H, s), 1.74 ~ 1.82 (4H, m), 1.95 ~ 2.03 (4H, m), 3.32 ~ 3.40
(4H, m), 3.69-3.77 (4H, m), 4.59-4.66 (2H, m), 7.33 (2H, d
d, J = 9.2,3.1Hz), 7.44 (1H, d, J = 9.2Hz), 7.71 (1H, d, J = 3.1H
z)

Example 33 2,7-Bis-[(4-piperidinyl) oxy] xanane
T

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At room temperature, 133 mg of 2,7-bis-[(1-t-butoxycarbonyl) -4-piperidinyl] oxyxanthone was dissolved in 5 ml of dry dichloromethane, 5 ml of trifluoroacetic acid was added, and the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with 1N-sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue, and the crystals were filtered to obtain 62 mg of the above compound.

MH ⁺ = 395 ¹ H-NMR (CDCl ₃ ) δppm: 1.65 to 1.75 (4H, m), 2.0
5 to 2.13 (4H, m), 2.75 to 2.84 (4H, m), 3.13 to 3.21 (4H, m), 4.
49 ~ 4.57 (2H, m), 7.32 (2H, dd, J = 9.0,3.0Hz), 7.43 (2H, d, J
= 9.0Hz), 7.71 (2H, d, J = 3.0Hz)

Example 34 2,7-bis-[(2S) -2-pyrrolidinyl] methoxy
Xanthone dihydrochloride

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Under room temperature, 2,7-dihydroxyxanthone
200 mg was suspended in 6 ml of tetrahydrofuran, and (2S)-
1- (tert-butoxycarbonyl) -2-pyrrolidine methanol 370 mg, diethyl azodicarboxylate 320 m
g and triphenylphosphine (497 mg) were added, and the mixture was stirred for 12 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane-ethyl acetate system) to obtain an intermediate product. 5 ml of methanol obtained at room temperature
And 2 ml of a 4N hydrochloric acid / dioxane solution was added thereto, followed by stirring for 12 hours. The precipitated crystals were collected by filtration, and 171 mg of the above compound was collected.
I got

MH ⁺ = 395 ¹ H-NMR (D ₂ O) δ ppm: 1.79 to 1.90 (2H, m), 1.90 to
2.09 (4H, m), 2.14 ~ 2.23 (2H, m), 3.27 (4H, t, J = 6.1Hz), 3.9
3 ~ 4.06 (4H, m), 4.17 ~ 4.22 (2H, m), 7.17 (2H, bs), 7.25 (4
H, bs)

Example 35 2,7-bis-[(2S) -2-pyrrolidinyl] methoxy
Xanthone dihydrochloride

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At room temperature, 2,7-dihydroxyxanthone
200 mg was suspended in 6 ml of tetrahydrofuran, and (2R)-
1- (tert-butoxycarbonyl) -2-pyrrolidine methanol 370 mg, diethyl azodicarboxylate 320 m
g and triphenylphosphine (497 mg) were added, and the mixture was stirred for 12 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane-ethyl acetate system) to obtain an intermediate product. The intermediate product obtained at room temperature was treated with methanol 5
in 4 ml of a 4N hydrochloric acid / dioxane solution,
Stir for 12 hours. The precipitated crystals were collected by filtration, and the compound 15
8 mg were obtained.

MH ⁺ = 395 ¹ H-NMR (D ₂ O) δppm: 1.78-1.92 (2H, m), 1.90-
2.08 (4H, m), 2.12 ~ 2.21 (4H, m), 3.26 (4H, t, J = 7.0Hz), 3.9
3 ~ 4.07 (4H, m), 4.21 (2H, dd, J = 10.5 ~ 2.9Hz), 7.22 (H, b
s), 7.26 ~ 7.29 (4H, m)

Example 36 2,7-bis-[(2S), (4R) -4-hydroxy
-2-piperidinyl] methoxyxanthone dihydrochloride

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At room temperature, 2,7-dihydroxyxanthone
120 mg was suspended in 5 ml of tetrahydrofuran, and (2S),
(4R) -1- (tert-butoxycarbonyl) -4-
(Tert-butyldimethylsilyloxy) -2-pyrrolidine methanol 367 mg, diethylazodicarboxylate
193 mg and triphenylphosphine 300 mg were added and stirred for 12 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane-ethyl acetate system) to obtain an intermediate product. At room temperature, the intermediate product was dissolved in 10 ml of methanol, 2 ml of a 4N hydrochloric acid / dioxane solution was added, and the mixture was stirred for 12 hours. The precipitated crystals were collected by filtration to obtain the above compound (108 mg).

MH ⁺ = 427 ¹ H-NMR (D ₂ O) δ ppm: 2.01 to 2.09 (2H, m), 2.14 to
2.22 (2H, m), 3.26 (2H, d, J = 11.5Hz), 3.29 (2H, dd, J = 11.5,
4.4Hz), 4.00 ~ 4.07 (2H, m), 4.18 ~ 4.25 (4H, m), 4.59 ~ 4.6
5 (2H, m), 7.15 (2H, bs), 7.23 (4H, bs)

Production Example 9 (2-Hydroxyethyl) pivalate

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[0203] 20 g of ethylene glycol was dissolved in 100 ml of pyridine and cooled to 0 ° C. There pivaloyl chloride 20
180 ml of dichloromethane solution was added and stirred at room temperature. After disappearance of pivaloyl chloride on TLC, water was added, and the organic layer was washed with water, 1N-hydrochloric acid, and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 19.05 g of the crude title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.22 (9H,
s), 3.82 (2H, t, J = 4.8Hz), 4.20 (2H, t, J = 4.8Hz)

Production Example 10 (2-Pivaloyloxyethyl) methylsulfonate

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(2-Hydroxyethyl) pivalate 3.22
g in 50 ml of dichloromethane and cooled to 0 ° C.
9.5 ml of triethylamine, 2.6 of methanesulfonyl chloride
ml were sequentially added and stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate, and washed sequentially with 1N-hydrochloric acid, 1N-aqueous sodium hydroxide solution, water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give the crude title compound.
55 g were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.23 (9H,
s), 3.05 (3H, s), 4.32 ~ 4.35 (2H, m), 4.41 ~ 4.43 (2H, m)

Example 37 2,7-Bis [2- (pivaloyloxy) ethyloxy
X) Xanthone

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458 mg of 2,7-dihydroxyxanthone was dissolved in 10 ml of N, N-dimethylformamide, and 178 mg of sodium hydride (60% dispersion in mineral oil) and 2 g of (2-pivaloyloxyethyl) methylsulfonate were sequentially added thereto. And stirred at 80 ° C. for 15 hours. Water was added, the mixture was extracted with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane) gave 580 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.21 (18
H, s), 4.31 (4H, dd, J = 5.2,4.4Hz), 4.47 (4H, dd, J = 5.2,4.4H
z), 7.35 (2H, dd, J = 9.2,2.8Hz), 7.45 (2H, d, J = 9.2Hz), 7.71
(2H, d, J = 2.8Hz)

Example 38 2,7-Bis (2-hydroxyethyloxy) xanthate
N

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2,7-bis [2- (pivaloyloxy)
Ethyloxy] xanthone (580 mg) was dissolved in tetrahydrofuran-methanol 1: 1 mixed solvent (20 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at 50 ° C for 15 hours. The mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was recrystallized from methanol to obtain 158 mg of the title compound.

MH ⁺ = 317 ¹ H-NMR (CDCl ₃ ) δ ppm: 4.01 to 4.05 (4H, m), 4.2
3 (4H, t, J = 4.4Hz), 7.38 (2H, dd, J = 9.2,3.2Hz), 7.46 (2H, d,
J = 9.2Hz), 7.72 (2H, d, J = 3.2Hz)

Example 39 2,7-bis [2- (methanesulfonyloxy) ethyl
[Oxy] xanthone

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152 mg of 2,7-bis (2-hydroxyethyloxy) xanthone was dissolved in 3 ml of pyridine and cooled to 0 ° C. Thereto was added 0.1 ml of methanesulfonic acid chloride, and the mixture was heated to room temperature and stirred for 3 hours. Water was added, the mixture was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 320 mg of the crude title compound.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.
25 (6H, s), 4.37 ~ 4.40 (4H, m), 4.55 ~ 4.58 (4H, m), 7.52 (2
H, dd, J = 9.2,3.2Hz), 7.59 (2H, d, J = 3.2Hz), 7.65 (2H, d, J =
(9.2Hz)

Example 40 2,7-Bis (2-azidoethyloxy) xanthone

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150 mg of 2,7-bis [2- (methanesulfonyloxy) ethyloxy] xanthone was dissolved in 5 ml of N, N-dimethylformamide, and 62 mg of sodium azide was dissolved.
Was added and stirred at 80 ° C. for 2 hours. Water was added, the mixture was extracted with ethyl acetate, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 70 mg of the crude title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.67 (4H,
t, J = 4.8Hz), 4.29 (4H, t, J = 4.8Hz), 7.39 (2H, dd, J = 9.2,2.8
Hz), 7.48 (2H, d, J = 9.2Hz), 7.70 (2H, d, J = 2.8Hz)

Example 41 2,7-bis (2-aminoethyloxy) xanthone

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2,7-bis (2-azidoethyloxy)
70 mg of xanthone was dissolved in 10 ml of methanol. 15% 10% palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. After filtration through celite, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane-methanol system) to obtain 50 mg of the title compound.

MH ⁺ = 315 ¹ H-NMR (CDCl ₃ ) δ ppm: 3.15 (4H, t, J = 5.2 Hz),
4.12 (4H, t, J = 5.2Hz), 7.36 (2H, dd, J = 9.2,3.2Hz), 7.45 (2
(H, d, J = 9.2Hz), 7.71 (2H, d, J = 3.2Hz)

Example 42 2,7-bis (2-bromoethyloxy) xanthone

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510 mg of 2-bromoethanol, 1.08 g of triphenylphosphine, 0.65 ml of diethyl azodicarboxylate
Was dissolved in 10 ml of tetrahydrofuran and cooled to 0 ° C.
A suspension of 228 mg of 2,7-dihydroxy-9-xanthone in 10 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 23 hours. The precipitated solid was collected by filtration to obtain 84 mg of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.8
4 (4H, t, J = 5.2Hz), 4.45 (4H, t, J = 5.2Hz), 7.52 (2H, dd, J = 9.
2,3.2Hz), 7.57 (2H, d, J = 3.2Hz), 7.65 (2H, d, J = 9.2Hz)

Example 43 2,7-Bis [2- (1-imidazolyl) ethyloxo
X) Xanthone

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2,7-bis (2-bromoethyloxy)
Dissolve 80 mg of xanthone in 5 ml of N, N-dimethylformamide, add 40 mg of imidazole sodium, and add
Stirred for hours. Water and ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 45 mg of the title compound.

MH ⁺ = 417 ¹ H-NMR (DMSO-d ₆ ) δppm: 4.35 to 4.42 (8H,
m), 6.88 (2H, br-s), 7.27 (2H, br-s), 7.45 (2H, dd, J = 9.2,3.
2Hz), 7.53 (2H, d, J = 3.2Hz), 7.60 (2H, d, J = 9.2Hz), 7.70 (2
H, br-s)

Example 44 2,7-bis- [3- (4-pyridyl) propoxy] ki
Sandton

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Under ice-cooling, 2,7-dihydroxyxanthone
60 mg was suspended in 10 ml of tetrahydrofuran, and 74 mg of 3- (4-pyridyl) -1-propanol, 139 mg of triphenylphosphine, and 93 mg of diethylazodicarboxylate were added. Thereafter, the mixture was stirred at room temperature for 30 minutes, added with water, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate-hexane system) to obtain 44 mg of the above compound.

MH ⁺ = 467 ¹ H-NMR (CDCl ₃ ) δ ppm: 2.15 to 2.23 (4H, m), 2.8
5 (4H, t, J = 7.5Hz), 4.11 (4H, t, J = 6.0Hz), 7.17 (4H, bd, J = 6.
1Hz), 7.32 (2H, dd, J = 9.2,3.4Hz), 7.45 (2H, d, J = 9.2Hz), 7.
67 (2H, d, J = 3.4Hz), 8.52 (4H, bd, J = 6.1Hz)

Example 45 2,7-bis- (2-dimethylamino) ethoxy
Nchion

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167 mg of 2,7-bis- (2-dimethylamino) ethoxyxanthone and 94 mg of Lawesson's reagent were dissolved in 5 ml of toluene and stirred at 80 ° C. for 30 minutes. After cooling, water was added and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, and the crystals were collected by filtration to obtain the above compound (100 mg).

MH ⁺ = 387 ¹ H-NMR (CDCl ₃ ) δ ppm: 2.40 (12H, s), 2.80-2.
87 (4H, m), 4.20 (4H, t, J = 6.2Hz), 6.84 (2H, s), 6.97 (2H, d, J
= 9.5Hz), 8.71 (2H, d, J = 9.5Hz)

Example 46 2- (2-Diethylamino) ethoxy thioxanthone

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At room temperature, 2-hydroxythioxanthone 14
0 mg was dissolved in 4 ml of dimethylformamide, and then 50 mg of sodium hydride (60%) and 107 mg of 2-diethylaminoethyl chloride hydrochloride were added, followed by stirring at 80 ° C. for 30 minutes. After cooling, water was added and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate system) to obtain 178 mg of the above compound.

MH ⁺ = 328 ¹ H-NMR (CDCl ₃ ) δppm: 1.08 (6H, t, J = 7.0Hz),
2.65 (4H, q, J = 7.0Hz), 2.86 ~ 2.95 (2H, m), 4.15 (2H, t, J = 6.
5Hz), 6.98 (1H, d, J = 2.3Hz), 7.03 (1H, dd, J = 8.9,2.3Hz), 7.
46 (1H, ddd, J = 8.1,7.2,1.8Hz), 7.53 (1H, dd, J = 8.1,1.8H
z), 7.58 (1H, ddd, J = 8.1,7.2,1.8Hz), 8.54 (1H, d, J = 8.9H
z), 8.60 (1H, dd, J = 7.2,1.8Hz)

Example 47 2,7-Diacetyl-fluorene

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130 g of aluminum chloride was added to dichloroethane 60
The mixture was suspended in 0 ml, and 45.4 ml of acetic anhydride was added thereto under ice-cooling, and the reaction solution was heated to room temperature to obtain a brown solution. A solution of 19.0 g of fluorene dissolved in 30 ml of dichloroethane was added to give a green solution. The mixture was heated under reflux for 1 hour, and the obtained red-purple solution was cooled to room temperature. A mixture of concentrated hydrochloric acid and ice was added to separate an organic layer, which was further washed with brine. The solvent was distilled off, and ethanol was added to the residue, followed by filtration. The obtained solid was dissolved in dichloromethane, silica gel was added, and the mixture was filtered and washed with dichloromethane. The solvent was distilled off from the combined filtrate, ethanol was further added, and the insoluble solid was collected by filtration to obtain 20.0 g of the title compound as needles.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.66 (6H,
s), 4.02 (2H, s), 8.03 (2H, dd, J = 0.9Hz, 8.1Hz), 8.12 (2H, d,
J = 8.1Hz), 8.20 (2H, d, J = 0.9Hz)

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/38 A61K 31/38 31/40 31/40 31/415 31/415 31/435 31/435 31/44 31/44 31/445 31/445 31/535 ACS 31/535 ACS C07C 13/547 C07C 13/547 39/17 39/17 39/23 39/23 43/257 43/257 C 49/643 49/643 49/784 49/784 211/44 211/44 211/54 211/54 211/57 211/57 217/90 217/90 217/92 217/92 219/34 219/34 225/22 225/22 323/18 323/18 C07D 207 / 48 C07D 207/48 209/88 209/88 219/04 219/04 219/06 219/06 219/10 219/10 295/08 295/08 Z 307/91 307/91 311/86 311/86 335 / 16 335/16 405/14 207 405/14 207 211 211 211 213 213 233 233 (72) Inventor Tadashi Tsukada 9-7 Inari-mae, Tsukuba City, Ibaraki Pref. 2-23-5 Amakubo, Tsukuba City Maison Gakuen 302

Claims (8)

[Claims] 1. A compound of the general formula [Wherein -A- is a compound of the formula: Wherein X and Y each represent a hydrogen atom or together form a single bond or a formula; Wherein R ^{1 to} R ⁸ are the same or different and are 1) a hydrogen atom, 2) a general formula: (In the formula, U ¹ represents an oxygen atom or a sulfur atom, and R ⁹ is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group optionally having a substituent, a lower group optionally having a substituent. An alkoxy group, an aryl group optionally having a substituent and optionally having one or more heteroatoms, or a compound represented by the general formula: [In the formula, n represents an integer of 0 to 6, and R ¹⁰ and R ¹¹ are the same or different and are each a hydrogen atom, a lower alkyl group which may have a substituent, or a group which may have a substituent. Which means an aryl group optionally having one or more heteroatoms]. 3) a group represented by the general formula: (In the formula, m represents an integer of 0 to 6, and R ¹² and R ¹³ are the same or different and are each independently a hydrogen atom, a lower alkyl group which may have a substituent, or a group which may have a substituent. (It means an aryl group which may have one or more hetero atoms or a cycloalkyl group which may have a substituent and may have one or more hetero atoms.)
A group represented by the general formula: 4) (In the formula, U ² represents an oxygen atom or a sulfur atom, and R ¹⁴ represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group optionally having a substituent, or a lower group optionally having a substituent. An alkoxy group, an aryl group optionally having a substituent and optionally having one or more heteroatoms, or a compound represented by the general formula: [Wherein, R ¹⁵ and R ¹⁶ are the same or different and are each a hydrogen atom, a lower alkyl group optionally having a substituent, an optionally substituted heteroatom having at least one hetero atom. Which means a group represented by the following formula: 5) a group represented by the general formula: (Wherein, U ³ stands for an oxygen atom, a nitrogen atom or a sulfur atom, V is an optionally substituted C ₀ ~ ₆ alkylene group, an optionally C ₂ ~ be substituted ₆ Alkenylene group,
Or substituted means which may C ₂ ~ ₆ alkynylene group, W is a) hydrogen atom, b) a halogen atom, c) general formula 10] [Wherein, R ¹⁷ and R ¹⁸ are the same or different and are each a hydrogen atom, a lower alkyl group optionally having a substituent, an optionally substituted heteroatom having at least one hetero atom. An aryl group, or a cycloalkyl group which may have a substituent together and may have one or more heteroatoms], d) a cyano group,
e) a cycloalkyl group which may have a substituent and may have one or more hetero atoms, f) may have a substituent and may have one or more hetero atoms An aryl group, g) an acyl group which may have a substituent, h) a hydroxyl group,
i) a hydroxyl group protected by a protecting group, or j) azido group), 6) a hydroxyl group, 7) a hydroxyl group protected by a protecting group, 8) an amino group, 9) a protecting group. Amino group,
Or 10) the general formula (Wherein, R ¹⁹ and R ²⁰ are the same or different and are a) a hydrogen atom, b) a lower alkyl group which may have a substituent,
c) a lower alkoxy group optionally having a substituent, d) an aryl group optionally having a substituent and optionally having one or more heteroatoms, or e) a general formula: [Wherein, U ⁴ represents an oxygen atom or a sulfur atom, and R ^{21 s} are the same or different and are i) a hydrogen atom, ii) a lower alkyl group which may have a substituent, iii) a substituent. A cycloalkyl group optionally having one or more hetero atoms, iv) an aryl group optionally having a substituent and optionally having one or more hetero atoms, v) substituted An aryloxy group optionally having a group and optionally having one or more heteroatoms, or vi) a general formula: Wherein R ²² and R ²³ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, or an aryl group which may have a substituent. A group represented by the following formula: benzene derivative or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 2. The medicament comprising the benzene derivative according to claim 1, which is a prophylactic / therapeutic agent for a viral disease, or a pharmacologically acceptable salt thereof or a hydrate thereof. 3. The medicament comprising the benzene derivative according to claim 2, wherein the virus is hepatitis C virus, a pharmacologically acceptable salt thereof, or a hydrate thereof. 4. A compound represented by the following general formula (I) or (II): Embedded image [Wherein, R ^{1 to} R ⁸ are the same or different and are 1) a hydrogen atom, 2) a general formula: (In the formula, U ¹ represents an oxygen atom or a sulfur atom, and R ⁹ is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group optionally having a substituent, a lower group optionally having a substituent. An alkoxy group, an aryl group optionally having a substituent and optionally having one or more heteroatoms, or a compound represented by the general formula: [In the formula, n represents an integer of 0 to 6, and R ¹⁰ and R ¹¹ are the same or different and are each a hydrogen atom, a lower alkyl group which may have a substituent, or a group which may have a substituent. Which means an aryl group which may have one or more heteroatoms). 3) a general formula: (In the formula, m represents an integer of 0 to 6, and R ¹² and R ¹³ are the same or different and are each independently a hydrogen atom, a lower alkyl group which may have a substituent, or a group which may have a substituent. (It means an aryl group which may have one or more hetero atoms or a cycloalkyl group which may have a substituent and may have one or more hetero atoms.)
A) a group represented by the general formula: 4) (In the formula, U ² represents an oxygen atom or a sulfur atom, and R ¹⁴ represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group optionally having a substituent, or a lower group optionally having a substituent. An alkoxy group, an aryl group optionally having a substituent and optionally having one or more heteroatoms, or a compound represented by the general formula: [Wherein, R ¹⁵ and R ¹⁶ are the same or different and are each a hydrogen atom, a lower alkyl group optionally having a substituent, an optionally substituted heteroatom having at least one hetero atom. Which means a group represented by the following formula: 5) a group represented by the general formula: (Wherein, U ³ stands for an oxygen atom, a nitrogen atom or a sulfur atom, V is an optionally substituted C ₀ ~ ₆ alkylene group, an optionally C ₂ ~ be substituted ₆ Alkenylene group,
Or substituted means which may C ₂ ~ ₆ alkynylene group, W is a) hydrogen atom, b) a halogen atom, c) general formula 22] [Wherein, R ¹⁷ and R ¹⁸ are the same or different and are each a hydrogen atom, a lower alkyl group optionally having a substituent, an optionally substituted heteroatom having at least one hetero atom. An aryl group, or a cycloalkyl group which may have a substituent together and may have one or more heteroatoms], d) a cyano group,
e) a cycloalkyl group which may have a substituent and may have one or more hetero atoms, f) may have a substituent and may have one or more hetero atoms An aryl group, g) an acyl group which may have a substituent, h) a hydroxyl group,
i) a hydroxyl group protected by a protecting group, or j) azido group), 6) a hydroxyl group, 7) a hydroxyl group protected by a protecting group, 8) an amino group, 9) a protecting group. Amino group,
Or 10) the general formula (Wherein, R ¹⁹ and R ²⁰ are the same or different and are a) a hydrogen atom, b) a lower alkyl group which may have a substituent,
c) a lower alkoxy group optionally having a substituent, d) an aryl group optionally having a substituent and optionally having one or more hetero atoms, or e) a general formula: [Wherein, U ⁴ represents an oxygen atom or a sulfur atom, and R ^{21 s} are the same or different and are i) a hydrogen atom, ii) a lower alkyl group which may have a substituent, iii) a substituent. A cycloalkyl group optionally having one or more hetero atoms, iv) an aryl group optionally having a substituent and optionally having one or more hetero atoms, v) substituted An aryloxy group optionally having a group and optionally having one or more heteroatoms, or vi) a general formula: Wherein R ²² and R ²³ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, or an aryl group which may have a substituent. Benzene derivative selected from the group of compounds represented by) or a pharmacologically acceptable salt thereof, or water thereof. A prophylactic / therapeutic agent for viral diseases consisting of Japanese products. 5. The method according to claim 4, wherein the virus is hepatitis C virus. 6. The following structural formulas (III), (IV):
(V), (VI), (VII), or (VIII) Embedded image Embedded image Embedded image Embedded image Embedded image A prophylactic / therapeutic agent for hepatitis C virus disease, comprising a benzene derivative selected from the group of compounds represented by or a pharmaceutically acceptable salt thereof or a hydrate thereof. 7. A compound of the formula (IX) [Wherein A ² is a compound of the formula: R ²⁵ and R ²⁸ are the same or different and are each a hydrogen atom, a hydroxyl group, a thiol group, a lower alkoxy group, a lower alkylthio group, a lower acyl group, a lower alkyl (thiocarbonyl) group, a lower acyloxy group, a lower alkyl ( A thiocarbonyl) oxy group or a compound of the general formula (In the formula, U ¹⁰ represents an oxygen atom or a sulfur atom, and V ¹⁰ has a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent, means which may lower alkynylene group optionally, W ¹⁰ is the general formula, embedded image [Wherein R ²⁹ and R ³⁰ may be the same or different and each may be a hydrogen atom, a lower alkyl group, or may be substituted together;
A cycloalkyl group optionally having a heteroatom as described above], a cyano group, an azide group, a halogen atom, a hydroxyl group, a hydroxyl group protected by a protective group, A cycloalkyl group optionally having the above hetero atom, or a cycloalkyl group optionally having a substituent,
R ²⁶ and R ^{27 each} represent a hydrogen atom, or an aryl group which may have a hetero atom described above.
A hydroxyl group, a thiol group, a lower alkoxy group, a lower alkylthio group, a lower acyl group, a lower alkyl (thiocarbonyl) group, a lower acyloxy group, a lower alkyl (thiocarbonyl) oxy group, or a general formula (Wherein, U ²⁰ represents an oxygen atom or a sulfur atom, and V ²⁰ has a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent, W ²⁰ represents a cyano group, an azido group, a halogen atom, a hydroxyl group, a hydroxyl group protected by a protecting group, a substituted or unsubstituted hetero atom which may have one or more hetero atoms. A cycloalkyl group, an aryl group optionally having a substituent and optionally having one or more heteroatoms) or a salt thereof. Or their hydrates. 8. A compound of the formula (X) [Wherein A ³ is the formula: And A ⁴ is of the formula R ^{31 to} R ³⁴ are the same or different and each represents a hydrogen atom,
Thiol group, lower alkoxy group, lower alkylthio group,
A lower acyl group, a lower alkyl (thiocarbonyl) group, a lower acyloxy group, a lower alkyl (thiocarbonyl) oxy group, or a general formula (In the formula, U ³⁰ represents an oxygen atom or a sulfur atom, and V ³⁰ has a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent, W ³⁰ represents a lower alkynylene group which may be represented by the following general formula: [Wherein, R ³⁵ and R ³⁶ are the same or different and represent a hydrogen atom, a lower alkyl group, or a cycloalkyl group which may be substituted together and have one or more hetero atoms. ], A cyano group, an azide group,
A halogen atom, a hydroxyl group, a hydroxyl group protected by a protecting group, a 4- or more-membered cycloalkyl group which may be substituted and may have one or more hetero atoms, and may have one or more substituents A benzotetralin derivative or a salt thereof, or a hydrate thereof.