JP2010248111A - Hydroxydiallylcarboxylic acid derivative, method for producing the same and anti-influenza virus agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new hydroxydiallylcarboxylic acid derivative, and to provide an anti-influenza virus agent. <P>SOLUTION: There are provided a compound represented by formula (I) (wherein, R<SB>1</SB>is H or OH; R<SB>2</SB>is OH, 1 to 3C alkoxy or NR<SB>3</SB>R<SB>4</SB>), a pharmaceutically acceptable salt, solvate or ester thereof; a method for producing the compound; and an anti-influenza virus agent containing the compound or a pharmaceutically acceptable salt, solvate or ester thereof as an active ingredient. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel hydroxybiallylcarboxylic acid (HBCA) derivative, a method for producing the same, and an anti-influenza virus agent containing such a hydroxybiallylcarboxylic acid derivative as an active ingredient.

  Influenza is an acute infectious disease caused by influenza virus, and symptoms are characterized by respiratory tract inflammation, fever, chills, muscle pain, weakness and malaise. Influenza cures in about 7 to 10 days for healthy adults, but in infants and the elderly, or patients with chronic illness, pneumonia and influenza encephalopathy may also occur and lead to death.

  Vaccinations are carried out every year to prevent influenza infection, but influenza viruses tend to change their antigenicity, making it difficult to prevent epidemics by vaccination alone. Therapeutic agents currently used as anti-influenza drugs include amantadine, oseltamivir phosphate, and zanamivir. However, because of the safety and risk of side effects in children and the emergence of resistant viruses, the development of other drugs that are effective against influenza viruses and highly safe is required.

JP-A-3-101623 discloses an influenza virus infection preventive agent containing tea polyphenol as an active ingredient. In addition, the present inventors previously dideoxyepigallocatechin gallate:
Was found to have anti-influenza virus activity equivalent to that of natural epigallocatechin gallate (JP 2008-156324, Furuta T. et al., Bioorg. Med. Chem. Lett. 2007, 17 (11): 3095). -8).

JP-A-3-101623 JP 2008-156324 A

Furuta T. et al., Bioorg. Med. Chem. Lett. 2007, 17 (11): 3095-8

  An object of the present invention is to provide a novel compound having anti-influenza virus activity.

  As a result of the chemical synthesis of various derivatives of catechins and theaflavins, which are components of tea, and the correlation between the structure and anti-influenza virus activity, the present inventors measured the activity. In particular, it has been found that certain hydroxybiallylcarboxylic acid derivatives (HBCA derivatives) have high anti-influenza virus activity.

That is, the present invention relates to the general formula (I):
Formula (I):
[In the formula, _{R 1} is H or OH, _{R 2} is, _OH, an alkoxy group, or _NR 3 _{R 4} of _{C 1-3, R 3} is an alkyl group of H or _{C 1-3} , R ₄ are H, C _1-6 alkyl group, phenyl group or benzyl group, and these groups are selected from the group consisting of halogen, C _1-3 alkoxy group and C _1-3 acetyl group R ₃ and R ₄ together with N to which they are attached form a pyrrolidine ring, piperidine ring or morpholine ring, The pyrrolidine ring, piperidine ring or morpholine ring may be substituted with 1 to 3 groups selected from halogen and C _1-3 alkyl]
Or a pharmaceutically acceptable salt, solvate or ester thereof.

Preferably, in formula (I), R ₂ is the following group:
Selected from the group consisting of

  In another aspect, the present invention provides an anti-influenza virus agent comprising a compound represented by the above general formula (I) or a pharmaceutically acceptable salt, solvate or ester thereof as an active ingredient.

In still another aspect, the present invention provides a method for producing the compound represented by the above general formula (I). Of the compounds of formula (I), general formula (Ia) wherein R ₂ is OCH ₃ :
[Wherein R ₁ is H or OH]
The method for producing the compound comprises the following steps:
After protecting the phenolic hydroxyl group of catechol or pyrogallol and brominating it, it is reacted with trialkylboron to give formula (III):
[Wherein R ₁ is H or OR ₅ and R ₅ is a protecting group for a phenolic hydroxyl group]
Producing an organoboronic acid of
By protecting the phenolic hydroxyl group of methyl gallate followed by bromination, formula (IV):
Generate a bromo body of
Formula (V) from an organoboronic acid of formula (III) and a bromide of formula (IV) by Suzuki-Miyaura coupling:
To give a compound of formula (Ia) by deprotecting the compound of formula (V).

Of the compounds of formula (I), general formula (II) wherein R ₂ is OH:
The method for producing the compound comprises the following steps:
Formula (V) above:
[Wherein R ₁ is H or OR ₅ and R ₅ is a protecting group for a phenolic hydroxyl group]
The methyl ester part of the compound represented by is hydrolyzed and then deprotected.

Among the compounds of formula (I), _{R 2} is a _NR 3 _{R 4} (Ib):
[Wherein, R ₁ is H or OH, R ₃ is H or a C _1-3 alkyl group, and R ₄ is H, C _1-6 alkyl group, phenyl group or benzyl group. And these groups may be substituted with 1 to 3 groups selected from the group consisting of halogen, C _1-3 alkoxy groups and C _1-3 acetyl groups, or R ₃ and R ₄ together with N to which they are attached forms a pyrrolidine ring, piperidine ring or morpholine ring, wherein the pyrrolidine ring, piperidine ring or morpholine ring is selected from halogen and C _1-3 alkyl. Optionally substituted with 1 to 3 groups]
The method for producing a compound represented by the formula includes the following steps:
Formula (II):
[Wherein R ₁ is H or OH]
Protecting the phenolic hydroxyl group of the compound represented by formula (VI):
[Wherein R ₁ is H or OR ₅ and R ₅ is a protecting group for a phenolic hydroxyl group]
Forming a compound represented by:
A compound of formula (VII) is represented by formula (VIII):
NHR ₃ R ₄
Formula (IX):
[Wherein R ₁ , R ₃ , R ₄ and R ₅ are as defined above]
Forming a compound represented by:
Deprotecting the compound of formula (IX), formula (Ib):
[Wherein R ₁ , R ₃ and R ₄ are as defined above]
Is formed.

In each of the above formulas, R ₅ is a protecting group for a phenolic hydroxyl group, and any group generally used as a protecting group for a hydroxyl group may be used. For example, methanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group, nitrobenzenesulfonyl group, acetyl group, trichloroacetyl group, trifluoroacetyl group, benzoyl group, pivaloyl group, linear or branched C _{1 -4} alkyl group, benzyl group, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group and the like.

  According to the present invention, it is possible to provide a novel hydroxybiallylcarboxylic acid derivative (HBCA derivative) exhibiting anti-influenza virus activity.

The present invention relates to general formula (I):
[Wherein R ₁ is H or OH, R ₂ is OH, a C _1-3 alkoxy group or NR ₃ R ₄ , and R ₃ is H or a C _1-3 alkyl group. , R ₄ are H, C _1-6 alkyl group, phenyl group or benzyl group, and these groups are selected from the group consisting of halogen, C _1-3 alkoxy group and C _1-3 acetyl group R ₃ and R ₄ together with N to which they are attached form a pyrrolidine ring, piperidine ring or morpholine ring, The pyrrolidine ring, piperidine ring or morpholine ring may be substituted with 1 to 3 groups selected from halogen and C _1-3 alkyl]
Or a pharmaceutically acceptable salt, solvate or ester thereof. In the present invention, it has been found that the HBCA derivative of formula (I) has a high anti-influenza virus agent.

Of the compounds of general formula (I) above, formula (Ia) wherein R ₂ is OCH ₃ :
[Wherein R ₁ is H or OH]
These compounds are also useful as synthetic intermediates for other compounds of general formula (I) of the present invention. The compound of formula (Ia) can be synthesized from catechol or pyrogallol and a gallate ester as follows.

First, the phenolic hydroxyl group of catechol (9a) or pyrogallol (9b) is protected to 10a, b and then brominated using NBS to form bromide 11a, b. Next, after reacting with n-BuLi or i-PrMgBr · LiCl, (i-PrO) ₃ B is reacted. By hydrolysis with hydrochloric acid, boronic acids 7a, b corresponding to catechol and pyrogallol can be obtained (Scheme 1). In each of the following schemes, a benzyl group (Bn) is used as an example of a hydroxyl-protecting group, but any group represented by R ₅ in the above formula (III) is used as the protecting group. May be.

Bromine body 8, another fragment of biaryl body, is obtained by benzyl-protecting the phenolic hydroxyl group of methyl gallate (12) to 13 and then brominating with NBS (Scheme 2).

Thus to boronic acid 7a-b and bromine body 8 synthesized, as shown in Scheme _{3, Pd (PPh 3) 4} , sodium carbonate, Suzuki using lithium chloride - by performing Miyaura coupling, Biaryl form 6a-b is obtained.
Subsequent deprotection yields the compound of formula (Ia).

Among the compounds of the general formula (I), the compound in which R ₂ is OC ₂ H ₅ or OC ₃ H ₇ is obtained by reacting the compound 6a-b with ethanol or propanol in the presence of carbodiimide and dimethylaminopyridine. It can be synthesized by reacting followed by deprotection by catalytic hydrogenation.

Of the compounds of general formula (I) above, formula (II) wherein R ₂ is OH:
This compound can be synthesized as shown in Scheme 4. The methyl ester part of the above compound 6a-b is hydrolyzed to carboxylic acid 14a-b. Next, carboxylic acid 14a-b can be deprotected by catalytic hydrogenation to synthesize biphenyl derivative 15a-b having a carboxylic acid unit.

Among the compounds of the general formula (I) of the present invention, compounds in which R ₂ is NR ₃ R ₄ can be synthesized according to Scheme 5 starting from 14a-b carboxylic acid. First, the 14a-b compound is condensed with an amine in the presence of a suitable coupling agent. Next, it can be deprotected to obtain the amino derivative of the present invention.

As the amine, aqueous ammonia or any primary or secondary amine can be used. Examples of amines include, but are not limited to, alkylamines such as methylamine, ethylamine, propylamine, and butylamine, dialkylamines such as dimethylamine and methylethylamine, and arylamines such as aniline and benzylamine. Alternatively, the aryl group may be substituted with a halogen, a C _1-3 alkoxy group, or a C _1-3 acetyl group. Or cyclic secondary amines, such as a pyrrolidine ring, a piperidine ring, or a morpholine ring, may be sufficient. Preferred examples of the amine are methylamine, dimethylamine, butylamine, pyrrolidine, aniline, benzylamine, morpholine and dimethylamine.

  The condensation of the carboxylic acid and the amine can be performed by reacting the amine and the carboxylic acid using carbodiimide in the presence of 1-hydroxybenzotriazole (HOBt). As the carbodiimide, for example, EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diisopropylcarbodiimide, dicyclohexylcarbodiimide, etc. can be used, or DMT-MM which is a condensing agent for producing carboxyamide. (4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride) may be used for coupling.

  The compound of the formula (I) of the present invention has an activity of suppressing the growth of influenza virus. The anti-influenza virus activity of the compound of the present invention can be measured according to a conventional method. As an example, a dilution series solution of a test compound and an influenza virus suspension are mixed, incubated for a predetermined time, and then added to a plate on which test cells such as MDCK cells are cultured. After incubation for a certain period of time, the cells are washed, and the number or percentage of cells infected with the virus is measured by plaque assay, immunostaining, enzyme activity assay, and the like.

  In the present invention, the anti-influenza virus agent is a pharmaceutical composition comprising an HBCA derivative according to the present invention or a pharmaceutically acceptable salt, solvate or ester thereof together with a pharmaceutically acceptable carrier or excipient. Represents. The anti-influenza virus agent of the present invention can prevent and / or treat diseases associated with influenza virus infection, such as reducing or eliminating symptoms of diseases associated with influenza virus infection, It can inhibit the growth of influenza virus, reduce the activity of the virus, and / or eliminate or reduce the virus.

  The pharmaceutically acceptable salt is not particularly limited as long as it is pharmacologically acceptable. For example, it may be an alkali metal or alkaline earth metal such as sodium, potassium or calcium, ammonia or various organic bases. Salts obtained by the reaction, or inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, citric acid , Salt obtained by reaction with maleic acid, succinic acid, tartaric acid. Solvates represent, for example, hydrates, alcohol solvates and the like.

  The anti-influenza virus agent of the present invention can be formulated by methods known to those skilled in the art. For example, a pharmaceutically acceptable carrier or excipient, specifically, sterile water or saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, vehicle, preservative, binding It can be formulated by mixing in appropriate unit dosage forms required for generally accepted pharmaceutical practice, in appropriate combination with drugs and the like.

  Suitable routes of administration of the anti-influenza virus agent of the present invention include, but are not limited to, oral, rectal, transmucosal, or enteral administration, or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous , Intravitreal, intraperitoneal, intranasal, or intraocular injection. The administration route and administration method can be appropriately selected depending on the age and symptoms of the patient. Oral or nasal administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops. For inhalation, the compounds of the invention can be formulated as a dry powder or a suitable solution, suspension, or aerosol. Powders and solutions can be formulated with suitable additives known in the art. For parenteral administration, a compound of the invention or a pharmaceutically acceptable salt, solvate or ester thereof is formulated according to conventional pharmaceutical practice using pharmaceutically acceptable vehicles well known in the art. can do.

  The dose of the anti-influenza virus agent of the present invention can be selected, for example, in the range of 0.0001 mg to 1000 mg per kg of body weight at a time. Alternatively, for example, the dose can be selected in the range of 0.001 to 100,000 mg / body per patient, but is not necessarily limited to these values. The dose and administration method vary depending on the patient's weight, age, symptoms, etc., but those skilled in the art can appropriately select them.

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

Example 1 Synthesis of di-O-benzylcatechol (10a)
To a stirred suspension of 9a (30.0 g, 272 mmol) and K ₂ CO ₃ (150 g, 1.09 mol) in DMF (270 mL) was added BnBr (72.0 mL, 599 mmol) at room temperature. The mixture was stirred at 100 ° C. for 2 hours and filtered through a celite pad. The filtrate was added to H ₂ O and extracted with AcOEt. The organic layer was washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by recrystallization from AcOEt to give 10a (56.9 g, 72%) as white needles.
10a: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.25-7.46 (m, 10H), 6.87-6.96 (m, 4H), 5.21 (s, 4H)

Example 2 Synthesis of 4-bromo-1,2-di-O-benzylcatechol (11a)
To a stirred solution of 10a (30.0 g, 103 mmol) in DMF (100 mL) was added NBS (19.3 g, 108 mmol) in DMF (30.0 mL) dropwise at room temperature and the mixture was stirred at room temperature for 12 hours. . The reaction mixture was added to H ₂ O and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by recrystallization from AcOEt / hexane to give 11a (27.1 g, 71%) as a white solid.
11a: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.28-7.47 (m, 10H), 7.07 (d, 1H, J = 2.5 Hz), 6.98 (dd, 1H, J = 2) .5 Hz, 8.6 Hz), 6.79 (d, 1H, J = 8.6 Hz), 5.12 (brs, 4H)

Example 3 Synthesis of 3,4-di-O-benzylbenzeneboric acid (7a)
To a stirred solution of 11a (19.0 g, 51.5 mmol) in THF (237 mL) n-BuLi (29.7 mL, 77.2 mmol, 2.6 M solution in hexane) was added dropwise at −78 ° C. and the mixture Was stirred at −78 ° C. for 1 hour. Triisopropyl borate (41.6 mL, 180 mmol) was added to the reaction mixture at −78 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to 2N HCl and extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ : MeOH = 95: 5) and recrystallized from CHCl ₃ / hexane to give 7a (5.81 g, 34%) as a white solid Obtained.
7a: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.69-7.73 (m, 2H), 7.22-7.52 (m, 10H), 7.04 (d, 1H, J = 8.6 Hz) ), 5.27 (brs, 4H)

Example 4 Synthesis of (benzene-1,2,3-triyltris (oxy)) tris (methylene) tribenzene (10b)
To a stirred suspension of 9b (20.0 g, 159 mmol) and K ₂ CO ₃ (132 g, 952 mmol) in DMF (150 mL) was added BnBr (75.3 mL, 634 mmol) at room temperature. The mixture was stirred at 100 ° C. for 2 hours and filtered through a celite pad. The filtrate was added to H ₂ O and extracted with AcOEt. The organic layer was washed with _{H 2} O and brine, dried over anhydrous _Na 2 SO _4, and concentrated under reduced pressure. The residue was purified by recrystallization from AcOEt to give 10b (52.9 g, 84%) as white needles.
10b: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.25-7.45 (m, 15H), 6.93 (t, 1H, J = 8.5 Hz), 6.63 (d, 2H, J = 8) .5Hz), 5.11 (s, 4H), 5.07 (s, 2H)

Example 5 Synthesis of (4-bromobenzene-1,2,3-triyl) tris (oxy) tris (methylene) tribenzene (11b)
To a stirred solution of 10b (40.0 g, 101 mmol) in DMF (100 mL) was added NBS (18.9 g, 106 mmol) in DMF (50.0 mL) dropwise at room temperature and the mixture was stirred at room temperature for 14 hours. . The reaction mixture was added to H ₂ O and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by recrystallization from AcOEt / hexane to give 11b (44.6 g, 93%) as a white solid.
11b: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.20-7.52 (m, 15H), 6.67 (d, 2H, J = 9.2 Hz), 5.08 (s, 2H), 5. 06 (s, 2H), 5.05 (s, 2H)

Example 6 Synthesis of 2,3,4-tris (benzoyloxy) phenylboronic acid (7b)
To a stirred solution of 11b (1.00 g, 2.10 mmol) in THF (10.0 mL) i-PrMgBr.LiCl (11.3 mL, 14.7 mmol, 1.3 M solution in THF) was added dropwise at 0 ° C. And the mixture was stirred at room temperature for 3 hours. Next, triisopropyl borate (1.7 mL, 7.35 mmol) was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to 2N HCl and extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 9: 1 to 7: 3) and recrystallized from AcOEt / hexane to give 7b (661 mg, 66%) as a white solid.
7b: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.52 (d, 1H, J = 8.6 Hz), 7.26-7.46 (m, 15H), 6.84 (d, 1H, J = 8) .6 Hz), 5.54 (s, 1 H), 5.16 (d, 4 H, J = 3.9 Hz), 5.07 (s, 2 H)

Example 7 Synthesis of 3,4,5-tris-benzoyloxy-benzoic acid methyl ester (13)
To a stirred suspension of 12 (20.0 g, 109 mmol) and K ₂ CO ₃ (90.1 g, 652 mmol) in DMF (200 mL) was added BnBr (51.7 mL, 434 mmol) and the mixture was added at 100 ° C. at 3 ° C. Stir for hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was washed with MeOH to give 13 (44.4 g, 90%) as a white solid.
^{13: 1 H NMR (270MHz,} CDCl 3) δ7.27-7.47 (m, 15H), 7.25 (s, 2H), 5.14 (s, 4H), 5.11 (s, 2H) , 3.89 (s, 3H)

Example 8 Synthesis of methyl 3,4,5-tris (benzoyloxy) -2-bromobenzoate (8)
To a stirred solution of 13 (11.6 g, 25.5 mmol) in DMF (60 mL) was added NBS (4.77 g, 26.8 mmol) in DMF (20 mL) dropwise at room temperature and the mixture at room temperature overnight. Stir. The reaction mixture was added to H ₂ O and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by recrystallization from AcOEt / hexane to give 8 (11.3 g, 83%) as a white solid.
7: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.26-7.52 (m, 16H), 5.11 (s, 2H), 5.09 (s, 2H), 5.04 (s, 2H) , 3.93 (s, 3H)

Example 9 Synthesis of methyl 3 ′, 4,4 ′, 5,6-pentakis (benzoyloxy) biphenyl-2-carboxylate (6a)
7a (2.26 g, 6.75 mmol), 8 (3.00 g, 5.62 mmol), Pd (PPh ₃ ) ₄ (325 mg, 0.281 mmol) and LiCl (358 mg, 8.40 mmol) in DMF (30 mL). To a suspension of was added Na ₂ CO ₃ (894 mg, 8.40 mmol) in H ₂ O (6 mL) at room temperature. The mixture was degassed and stirred at 80 ° C. for 19 hours. The reaction mixture was added to H ₂ O and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 9: 1 to 85:15) to give 6a (1.06 g, 58%) as a white solid.
6a: ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.18-7.48 (m, 25 H), 6.95 (d, 1 H, J = 8.6 Hz), 6.88 (d, 1 H, J = 8 .6 Hz), 6.86 (brs, 1H), 6.76 (dd, 1H, J = 2.4 Hz, 8.6 Hz), 5.22 (s, 2H), 5.16 (s, 2H), 5.12 (s, 2H), 5.06 (s, 2H), 4.61 (s, 2H), 3.46 (s, 3H)

Example 10 Synthesis of 3 ', 4,4', 5,6-pentakis (benzoyloxy) biphenyl-2-carboxylic acid (14a)
To a solution of 6a (2.42 g, 3.26 mmol) in THF (29 mL) was added NaOH (432 mg), MeOH (29 mL) and H ₂ O (8 mL). The mixture was refluxed for 9 hours. The reaction mixture was quenched with 2N HCl and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 7: 3 to 3: 7) and recrystallized from AcOEt / hexane to give 14a (1.83 g, 77%) as a white solid.
14a: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 6.84-7.60 (m, 29H), 5.29 (s, 2H), 5.19 (s, 2H), 5.18 (s, 2H), 5.04 (s, 2H), 4.68 (s, 2H)

Example 11 Synthesis of 3 ', 4,4', 5,6-pentahydroxybiphenyl-2-carboxylic acid (15a)
To a solution of 14a (100 mg, 0.137 mmol) in a mixture of THF / MeOH (2.4 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 96.3 mg, 69.0 μmol). . The mixture was stirred at room temperature for 2.5 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was washed with CH ₂ Cl ₂ to give 15 (31.3 mg, 82%) as a white amorphous.
15a: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.01 (s, 1H), 6.75 (d, 1H, J = 7.9 Hz), 6.71 (d, 1H, J = 2.0 Hz) ), 6.51 (dd, 1H, J = 2.0 Hz, 7.9 Hz)

Example 12 Synthesis of (3 ′, 4,4 ′, 5,6-pentahydroxybiphenyl-2-yl) (pyrrolidin-1-yl) methanone (16a)
CH ₂ Cl ₂ (1mL) solution of 14a (100mg, 0.137mmol), EDCI hydrochloride (31.6 mg, 0.165 mmol), and HOBt (3.70mg, 27.4μmol) To a suspension of at room temperature Pyrrolidine (15.0 μL, 0.178 mmol) was added. The mixture was stirred at room temperature for 19 hours. The reaction mixture was quenched with 2N HCl, neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH: CH ₂ Cl ₂ = 97: 3) to give a white amorphous substance (73.1 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.4 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 64.6 mg, 46.0 μmol). The mixture was stirred at room temperature for 1.5 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 85: 15) to obtain 16a (21.0 mg, 46%, 2 steps) as a white amorphous.
16a: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.63 (d, 1 H, J = 8 Hz), 6.89 (d, 1 H, J = 2.0 Hz), 6.74 (dd, 1 H, J = 2.0 Hz, 7.9 Hz), 6.36 (s, 1H), 3.15-3.20 (m, 2H), 2.88-2.92 (m, 2H), 1.48-1 .59 (m, 4H)

Example 13 Synthesis of 3 ', 4,4', 5,6-pentahydroxy-N-phenylbiphenyl-2-carboxamide (16b)
To a suspension of 14a (100 mg, 0.137 mmol), EDCI hydrochloride (31.6 mg, 0.165 mmol), and HOBt (3.70 mg, 27.4 μmol) in CH ₂ Cl ₂ (1 mL) at room temperature. Aniline (16.6 mg, 0.178 mmol) was added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with 2N HCl, neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 4: 1) to obtain white amorphous (81.7 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.8 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 70.1 mg, 49.9 μmol). The mixture was stirred at room temperature for 2 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 85: 15) to obtain 16b (24.9 mg, 51%, 2 steps) as a white amorphous.
16b: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 8.06 (s, 1H), 6.95-7.34 (m, 5H), 6.87 (d, 1H, J = 2.0 Hz), 6.82 (d, 1H, J = 8.0 Hz), 6.72 (dd, 1H, J = 2.0 Hz, 8.0 Hz)

Example 14 Synthesis of morpholino (3 ′, 4,4 ′, 5,6-pentahydroxybiphenyl-2-yl) methanone (16c)
To a suspension of 14a (100 mg, 0.137 mmol), EDCI hydrochloride (31.6 mg, 0.165 mmol), and HOBt (3.7 mg, 27.4 μmol) in CH ₂ Cl ₂ (1 mL) at room temperature. Morpholine (15 μL, 0.178 mmol) was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with 2N HCl, neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH: CH ₂ Cl ₂ = 1: 99) to give a white amorphous (69.0 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.4 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 60.8 mg, 43.3 μmol). The mixture was stirred for 4 hours at room temperature under an atmosphere of H _2. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 85: 15) to obtain 16c (22.2 mg, 47%, 2 steps) as a white amorphous.
16c: ¹ H NMR (270 MHz, CD ₃ OD) δ 6.84 (d, 1 H, J = 2.0 Hz), 6.77 (d, 1 H, J = 7.9 Hz), 6.71 (dd, 1 H, J = 2.0 Hz, 7.9 Hz), 6.31 (s, 1H), 3.54-3.57 (m, 3H), 3.17-3.24 (m, 1H), 2.93- 3.02 (m, 3H), 2.65-2.72 (m, 1H)

Example 15 Synthesis of N-butyl-3 ′, 4,4 ′, 5,6-pentahydroxybiphenyl-2-carboxamide (16d)
To a suspension of 14a (100 mg, 0.137 mmol), EDCI hydrochloride (31.6 mg, 0.165 mmol), and HOBt (3.70 mg, 27.4 μmol) in CH ₂ Cl ₂ (1 mL) at room temperature. n-Butylamine (18 μL, 0.178 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with 2N HCl, neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 3: 7) to give a white amorphous substance (62.0 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.2 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 55.5 mg, 39.5 μmol). The mixture was stirred at room temperature under H ₂ atmosphere for 3.5 hours. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 9: 1) to obtain 16d (17.7 mg, 39%, 2 steps) as a white amorphous.
16d: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 6.82 (d, 1 H, J = 8.0 Hz), 6.78 (d, ¹ H, J = 2.0 Hz), 6.77 (s, 1 H ), 6.60 (dd, 1H, J = 2.0 Hz, 8.0 Hz), 3.29 (s, 1H), 3.02-3.05 (m, 2H), 1.02-1.17 (M, 4H), 0.79 (t, 3H, J = 7.1 Hz)

Example 16 Synthesis of 3 ', 4,4', 5,6-pentahydroxy-N, N-dimethylbiphenyl-2-carboxamide (16e)
Of 14a (100 mg, 0.137 mmol), DMT-MM (49.5 mg, 0.178 mmol), and 15% NaOH (55.0 μL, 0.206 mmol) in THF / MeOH (1.4 mL, 1: 1). To the suspension was added dimethylamine hydrochloride (14.5 mg, 0.178 mmol) at room temperature. The mixture was stirred at room temperature for 14 hours. The reaction was concentrated under reduced pressure, saturated NH ₄ Cl was added and extracted with EtOAc. The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 3: 7 to 3: 2) to give a white amorphous (55.5 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 49.3 mg, 35.1 μmol). The mixture was stirred for 1 hour at room temperature under an atmosphere of H _2. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 85: 15) to obtain 16e (14.0 mg, 33%, 2 steps) as a white amorphous.
16e: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 6.86 (d, 1 H, J = 2.0 Hz), 6.76 (d, 1 H, J = 7.9 Hz), 6.70 (dd, 1 H , J = 2.0 Hz, 7.9 Hz), 6.35 (s, 1H), 2.67 (s, 3H), 2.50 (s, 3H)

Example 17 Synthesis of methyl 2- (4,4 ′, 5,5 ′, 6-pentahydroxybiphenyl-2-ylcarboxamide) acetate (16f)
Suspension of 14a (100 mg, 0.137 mmol), DMT-MM (49.5 mg, 0.178 mmol), and 15% NaOH (55 μL, 0.206 mmol) in THF / MeOH (1.4 mL, 1: 1) To the solution was added glycine methyl ester hydrochloride (25.8 mg, 0.206 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, saturated NH ₄ Cl was added and extracted with AcOEt. The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 3: 7 to 3: 2) to give a white amorphous (68.0 mg).

To a white amorphous reaction mixture in a mixture of THF / MeOH (1.6 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 58.0 mg, 41.7 μmol). The mixture was stirred at room temperature for 2 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 85: 15) to obtain 16f (10.0 mg, 21%, 2 steps) as a white amorphous.
16f: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.9 (s, 1 H), 6.80 (d, 1 H, J = 8.0 Hz), 6.78 (d, 1 H, J = 2.0 Hz) ), 6.62 (dd, 1H, J = 2.0 Hz, 8.0 Hz), 3.80 (brs, 2H), 3.60 (s, 3H)

Example 18 Synthesis of 3 ', 4,4', 5,6-pentahydroxy-N-methylbiphenyl-2-carboxamide (16 g)
Suspension of 14a (100 mg, 0.137 mmol), DMT-MM (49.5 mg, 0.178 mmol), and 15% NaOH (55 μL, 0.206 mmol) in THF / MeOH (1.4 mL, l: 1) To the solution was added methylamine hydrochloride (13.9 mg, 0.178 mmol) at room temperature. The mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, saturated NH ₄ Cl was added and extracted with AcOEt. The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 3: 7 to 3: 2) to give a white amorphous (64.3 mg).

To a white amorphous reaction mixture in a mixture of THF / MeOH (1.6 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 57.7 mg, 41.1 μmol). The mixture was stirred at room temperature for 1 hour under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography _{(CH 2 Cl 2: MeOH =} 85: 15) to afford 16g (11.6mg, 29%, 2 steps) as a white amorphous.
16 g: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 6.68 (d, 1 H, J = 7.9 Hz), 6.66 (s, 1 H), 6.58 (d, ¹ H, J = 2.0 Hz) ), 6.50 (dd, 1H, J = 2.0 Hz, 7.9 Hz), 2.38 (d, 3H, J = 5.2 Hz)

Example 19 Synthesis of methyl 2 ', 3', 4,4 ', 5,6-hexakis (benzoyloxy) biphenyl-2-carboxylate (6b)
7b (30.0 mg, 68.1 μmol), 8 (30.3 g, 56.8 μmol), Pd (PPh ₃ ) ₄ (3.30 mg, 2.84 μmol) and LiCl (3. To a suspension of 61 mg, 85.2 μmol) was added Na ₂ CO ₃ (9.03 mg, 85.2 μmol) in H ₂ O (0.1 mL) at room temperature. The mixture was degassed and stirred at 80 ° C. for 18 hours. The reaction mixture was poured into H ₂ O and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 9: 1 to 85:15) to give 6b (12.4 mg, 31%) as a white solid.
6b: ¹ H NMR (270 MHz, CDCl ₃ ) δ 6.96-7.18 (m, 30H), 6.88-6.92 (m, 2H), 6.85 (s, 1H), 5.18 ( d, 4H, J = 7.3 Hz), 5.04 (s, 2H), 4.99 (s, 2H), 4.88 (d, 2H, J = 5.0 Hz), 4.74 (s, 2H), 3.55 (s, 3H)

Example 20 Synthesis of 2 ', 3', 4,4 ', 5,6-hexakis (benzoyloxy) biphenyl-2-carboxylic acid (14b)
To a solution of 6b (327 mg, 0.385 mmol) in THF (3.5 mL) was added NaOH (100 mg), MeOH (3.5 mL) and H ₂ O (0.85 mL). The mixture was refluxed for 6 hours. The reaction mixture was quenched with 2N HCl and extracted with AcOEt. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 9: 1 to 7: 3) to give 14b (286 mg, 77%) as a white solid.
14b: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 6.78-7.50 (m, 33H), 5.18 (s, 2H), 5.15 (s, 2H), 5.05 (s, 2H), 4.99 (s, 2H), 4.88 (d, 2H, J = 7.0 Hz), 4.71 (s, 2H)

Example 21 Synthesis of 2 ', 3', 4,4 ', 5,6-hexahydroxy-N-phenylbiphenyl-2-carboxamide (17a)
CH ₂ Cl ₂ (1mL) solution of 14b (100mg, 0.119mmol), EDCI hydrochloride (27.6 mg, 0.165 mmol), and HOBt (3.70mg, 27.4μmol) To a suspension of at room temperature Aniline (16.6 μL, 0.144 mmol) was added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with 2N HCl, neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 3: 7 to 1: 1) to give a white amorphous (75.1 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.4 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 57.9 mg, 41.3 μmol). The mixture was stirred at room temperature for 3 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 9: 1) to obtain 17a (19.9 mg, 45%, 2 steps) as a white amorphous.
17a: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.43-7.44 (m, 2H), 7.19-7.22 (m, 2H), 6.98-7.00 (m, 1H) ), 6.91 (s, 1H), 6.49 (d, 1H, J = 8.0 Hz), 6.43 (d, 1H, J = 8.0 Hz)

Example 22 Synthesis of N-benzyl-2 ', 3', 4,4 ', 5,6-hexahydroxybiphenyl-2-carboxamide (17b)
To a suspension of 14b (100 mg, 0.119 mmol), EDCI hydrochloride (27.6 mg, 0.165 mmol), and HOBt (3.70 mg, 27.4 μmol) in CH ₂ Cl ₂ (1 mL) at room temperature. BnNH ₂ (16.0μL, 0.144mmol) was added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with 2N HCl, neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 3: 7 to 1: 1) to obtain a white amorphous (61.8 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.0 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 46.9 mg, 33.4 μmol). The mixture was stirred at room temperature for 2 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 85: 15) to obtain 17b (14.1 mg, 31%, 2 steps) as a white amorphous.
17b: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.42 (brs, 1H), 7.15-7.21 (m, 3H), 7.00-7.03 (m, 2H), 6. 69 (s, 1H), 6.42 (d, 2H, J = 2.0 Hz), 4.33 (d, 2H, J = 6.0 Hz)

Example 23 Synthesis of (2 ', 3', 4,4 ', 5,6-hexahydroxybiphenyl-2-yl) (pyrrolidin-1-yl) methanone (17c)
To a suspension of 14b (124 mg, 0.149 mmol), EDCI hydrochloride (34.3 mg, 0.179 mmol), and HOBt (4.03 mg, 29.8 μmol) in CH ₂ Cl ₂ (1.2 mL), Pyrrolidine (32.6 μL, 0.388 mmol) was added at room temperature. The mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with 2N HCl, neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 2: 3 to 1: 1) to give a white amorphous (105 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.0 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 83.3 mg, 59.3 μmol). The mixture was stirred at room temperature for 1.5 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 9: 1) to obtain 17c (23.7 mg, 46%, 2 steps) as a white amorphous.
17c: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 6.49 (d, 1 H, J = 7.9 Hz), 6.41 (s, 1 H), 6.39 (d, 1 H, J = 7.9 Hz) ), 3.12-3.20 (m, 2H), 2.85-2.91 (m, 2H), 1.49-1.61 (m, 4H)

Example 24 Synthesis of 2 ', 3', 4,4 ', 5,6-hexahydroxybiphenyl-2-carboxamide (17d)
A suspension of 14b (150 mg, 0.179 mmol) and DMT-MM (99.6 mg, 0.359 mmol) in THF / MeOH (1.2 mL, 1: 1) at room temperature with 25% NH ₃ (50. 0 μL, 0.718 mmol) was added. The mixture was stirred at room temperature for 20 hours. The reaction was concentrated under reduced pressure, saturated NH ₄ Cl was added and extracted with EtOAc. The organic layer was washed with H ₂ O and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 3: 7) to obtain a white amorphous substance (114 mg).
To a white amorphous reaction mixture in a mixture of THF / MeOH (2.4 mL, 1: 1) was added Pd (OH) ₂ (10%, dry, 96.2 mg, 68.5 μmol). The mixture was stirred at room temperature for 2.5 hours under H ₂ atmosphere. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 9: 1 to 85:15) to give 17d (23.8 mg, 45%, 2 steps) as a white amorphous.
17d: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 8.45 (d, 1 H, J = 8.0 Hz), 7.42 (s, 1 H), 6.82 (d, 1 H, J = 8.0 Hz) )

Example 25 Synthesis of 3 ', 4,4', 5,6-pentahydroxybiphenyl-2-carboxamide (16h)
In the same manner as in Example 24, 14a to 16h were obtained.
16h: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.30-8.30 (brs, 5H), 6.86 (s, 1H), 6.81 (d, 1H, J1 = 8 Hz), 6. 79 (d, 1H, J1 = 2 Hz), 6.64 (dd, 1H, J1 = 2 Hz, J2 = 8 Hz), 6.27 (brs, 1H), 5.83 (brs, 1H)

Example 26 Synthesis of methyl 2 ', 3', 4,4 ', 5,6-hexahydroxybiphenyl-2-carboxylate (18)
18 was obtained by deprotecting 6b in the same manner as in Example 11.
18: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 8.36 (s, 1H), 8.32 (s, 1H), 7.32 (s, 1H), 6.87 (s, 1H), 6 .71 (d, 1H, J = 9 Hz), 6.24 (d, 1H, J = 9 Hz), 3.36 (s, 3H)

Example 27 Synthesis of ethyl-3 ', 4,4', 5,6-pentahydroxybiphenyl-2-carboxylate (19a)
To a mixture of 14a (150 mg, 0.206 mmol), WSCI.HCl (51.3 mg, 0.268 mmol), and DMAP (2.5 mg, 0.0206 mmol), EtOH / CH ₂ Cl ₂ (1: 1, 1 mL) Was added at room temperature. The mixture was stirred at room temperature for 20 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with H ₂ O and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 85: 15) to obtain a white amorphous.
The white amorphous was dissolved in a mixture of THF / MeOH (1: 1, ₄ mL) and hydrogenated with 10% Pd (OH) _{2 /} C (90.2 mg, 0.642 mmol) at room temperature for 1 hour. The reaction mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 92: 8 to 9: 1) to give 19a (41.9 mg, 67%, 2 steps) as a white amorphous.
19a: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.50-8.10 (brs, 5H), 6.91 (s, 1H), 6.78 (d, 1H, J ₁ = 8 Hz), 6 .69 (d, ₁ H, J ₁ = 2 Hz), 6.51 (dd, ₁ H, J ₁ = 2 Hz, J ₂ = 8 Hz), 3.90 (q, 2 H, J ₁ = 7 Hz), 0.92 ( t, 3H, J ₁ = 7Hz)
¹³ C NMR (68MHz, acetone -d ₆₎ δ168.6,145.2,145.0,144.5,143.9,136.7,129.4,123.9,122.9,122.5 , 118.2, 115.6, 109.6, 60.5, 14.0
FAB-MS m / z 307, C ₁₅ H ₁₅ O ₇ (M + H) ⁺

Example 28 Synthesis of propyl-3,4,4 ', 5,6-pentahydroxybiphenyl-2-carboxylate (20a)
14a to 20a were obtained in the same manner as in Example 27.
20a: ¹ H NMR (270 MHz, acetone-d ₆ ) δ 7.40-8.10 (brs, 5H), 6.93 (s, 1H), 6.77 (d, 1H, J ₁ = 8 Hz), 6 .70 (d, ₁ H, J ₁ = 2 Hz), 6.51 (dd, ₁ H, J ₁ = 2 Hz, J ₂ = 8 Hz), 3.90 (t, 2 H, J ₁ = 7 Hz), 1.34 ( _{sext, 2H, J 1 = 7Hz} ), 0.72 (t, 3H, J 1 = 7Hz)
¹³ C NMR (68 MHz, acetone-d ₆ ) δ 168.7, 145.2, 145.0, 144.5, 143.9, 136.7, 129.4, 124.0, 122.9, 122.5 118.2, 115.6, 109.7, 66.3, 22.4, 10.7
FAB-MS m / z 320, C ₁₆ H ₁₆ O ₇ (M)

Example 29 Anti-influenza virus activity test of HBCA derivative Each compound (1 mg / ml) dissolved in a serum-free medium (hybridoma-SFM complete DPM, Invitrogen Corp. NY, USA) was serially diluted 2-fold. 75 μl of each diluted solution was mixed with 75 μl of an influenza virus (A / Memphis / 1/71 (H1N1)) suspension (100 FFU) and reacted at 4 ° C. for 1 hour.

  Add 100 μl of test compound and influenza virus mixture at room temperature to MDCK (Madine-Darby canine kidney) cells cultured in a monolayer on a 96-well microtiter plate (Corning Costar Corporation, Cambridge, MA) and react at 34 ° C for 1 hour. Thereafter, the supernatant was removed and washed 3 times with PBS. Subsequently, 100 μl of SFM was added and cultured at 34 ° C. for 16 hours. The cultured cells were washed 3 times with PBS, MeOH was added and fixed at room temperature for 5 minutes. After washing with PBS three times, virus-infected cells were detected by an enzyme antibody method using an anti-NP monoclonal antibody and a goat anti-mouse immunoglobulin G + M (IgG + M) antibody conjugated with horseradish peroxidase. The virus-infected cells were calculated as the average value of triplicate measurement of the number of cells stained blue in one well. The 50% inhibitory concentration of virus infection was determined from a graph plotting percent inhibition against sample concentration.

The results are shown in the table below. All of the compounds of the present invention showed very high IC ₅₀ (mM) values compared to epigallocatechin (EGC).

  The compounds of the present invention are useful as anti-influenza virus agents.

Claims (6)

Formula (I):
[Wherein R ₁ is H or OH, R ₂ is OH, a C _1-3 alkoxy group or NR ₃ R ₄ , and R ₃ is H or a C _1-3 alkyl group. , R ₄ are H, C _1-6 alkyl group, phenyl group or benzyl group, and these groups are selected from the group consisting of halogen, C _1-3 alkoxy group and C _1-3 acetyl group R ₃ and R ₄ together with N to which they are attached form a pyrrolidine ring, piperidine ring or morpholine ring, The pyrrolidine ring, piperidine ring or morpholine ring may be substituted with 1 to 3 groups selected from halogen and C _1-3 alkyl]
Or a pharmaceutically acceptable salt, solvate or ester thereof. In the formula (I), R ₂ is the following group:
The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof selected from the group consisting of: An anti-influenza virus agent comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt, solvate or ester thereof as an active ingredient. Formula (Ia):
[Wherein R ₁ is H or OH]
A process for producing a compound of
After protecting the phenolic hydroxyl group of catechol or pyrogallol and brominating it, it is reacted with trialkylboron to give formula (III):
[Wherein R ₁ is H or OR ₅ and R ₅ is a protecting group for a phenolic hydroxyl group]
Producing an organoboronic acid of
By protecting the phenolic hydroxyl group of methyl gallate followed by bromination, formula (IV):
[Wherein R ₅ is a protecting group for a phenolic hydroxyl group]
Generate a bromo body of
Formula (V) from an organoboronic acid of formula (III) and a bromide of formula (IV) by Suzuki-Miyaura coupling:
[Wherein R ₁ is H or OR ₅ and R ₅ is a protecting group for a phenolic hydroxyl group]
To yield a compound of formula (Ia) by deprotecting the compound of formula (V)
The method including each process of these. Formula (II):
A process for preparing a compound of formula (V) as defined in claim 4:
[Wherein R ₁ is H or OR ₅ and R ₅ is a protecting group for a phenolic hydroxyl group]
Hydrolysis of the methyl ester moiety of the compound represented by
The method including each process of these. General formula (Ib):
[Wherein, R ₁ is H or OH, R ₃ is H or a C _1-3 alkyl group, and R ₄ is H, C _1-6 alkyl group, phenyl group or benzyl group. There, these groups, a halogen may be substituted by one to three groups selected from the group consisting of an acetyl group an alkoxy group and C _1-3 of C _1-3, or, R ₃ and R ₄ together with N to which they are attached forms a pyrrolidine ring, piperidine ring or morpholine ring, wherein the pyrrolidine ring, piperidine ring or morpholine ring is selected from halogen and C _1-3 alkyl. Optionally substituted with 1 to 3 groups]
Wherein the compound represented by formula (II):
[Wherein R ₁ is H or OH]
Protecting the phenolic hydroxyl group of the compound represented by formula (VI):
[Wherein R ₁ is H or OR ₅ and R ₅ is a protecting group for a phenolic hydroxyl group]
Forming a compound represented by:
A compound of formula (VII) is represented by formula (VIII):
NHR ₃ R ₄
Formula (IX):
[Wherein R ₁ , R ₃ , R ₄ and R ₅ are as defined above]
Forming a compound represented by:
Deprotecting the compound of formula (IX), formula (Ib):
[Wherein R ₁ , R ₃ and R ₄ are as defined above]
Form a compound of
The method including each process of these.