JPH07242655A - 1,4-benzodioxane derivative - Google Patents

Abstract

PURPOSE:To obtain a low toxic, orally administrable new derivative having excellent liver-protective activity, lipid peroxidationsuppressive activity and antiviral activity, thus useful as a therapeutic agent for hepatopathy. CONSTITUTION:The objective derivative (or a salt thereof) is expressed by formula I [R<1> is H, a lower alkyl or benzyl; R<2> is H or a lower alkyl; R<3> and X each is H, OH or benzyloxy; (n) is 0 or 1; A is a lower alkylene; Y is NHCOR<4> or COR<5> (R<4> is a lower alkyl; R<5> is a protected sulfur-contg. amino acid or phenyl-substituted amino)], e.g. N-[3-(3,4-dihydroxyphenyl)-2,3-dihydro-6-(2- hydroxyethyl)-1,4-benzoxyn-2-yl]-acetamide. This derivative of formula I (where, R<2> is H; Y is NHCOR<4>) can be obtained, for example, by reaction between a compound of formula II and a compound of formula III in a solvent, such as methanol in the presence of an oxidizing agent such as silver oxide pref. at room temperature to 50 deg.C for 1-24hr.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 1,4-benzodioxane derivative.

[0002]

2. Description of the Related Art The liver is an important organ responsible for most of the metabolism and regulation of substances in the living body. When this organ is damaged by alcohol, drugs, viruses, etc., it causes liver diseases such as drug-induced liver injury, alcoholic liver injury and viral hepatitis, and if these disorders are prolonged, cirrhosis and liver cancer result.

However, no drug effective against these liver disorders has been developed so far, and interferon (IFN), which is the only antiviral agent developed, does not exhibit the expected effect (hepatobiliary-pancreatic pancreas). , 24, 1
07-116 (1992)). In addition, since IFN is an injection, it causes a great physical pain to the patient.

Therefore, there is a demand for the development of a drug which can be administered orally, has low toxicity, suppresses liver damage and also suppresses virus growth.

Examples of the compound having a 1,4-benzodioxane skeleton which can be used as an active ingredient of a therapeutic agent for liver diseases include, for example, JP-B-55-38948 and JP-A-5-38948.
Although the compounds described in JP-A-5-59182 are known, compounds which are sufficiently satisfactory as therapeutic agents for liver diseases have not yet been obtained.

Further, N- [3- (3,4-dihydroxyphenyl) -2,3-dihydro-7- (2-hydroxyethyl) -1,4-benzodioxin-2-yl] -acetamide was added to Adv. Mass Spectrom 1
980 (8B) 1269 to 1273, Insect B
iochem Vol 11, 1980 25-31 and Biomed. Mass Spectrom Vol
8, No. 174-178 (1981), N- [3- (3,4-dihydroxyphenyl)-
2,3-Dihydro-1,4-benzodioxin-2-yl] acetamide is described in Arch. Insect Bioc
hem. Physiol. , Vol14 (2), 93-
109 (1990), it is not known that these compounds can be used as therapeutic agents for liver diseases.

[0007]

DISCLOSURE OF THE INVENTION As a result of intensive studies conducted by the present inventors to solve these problems, the novel 1,4-benzodioxane derivative represented by the following general formula (I) is excellent. It has a hepatoprotective action, a lipid peroxidation inhibitory action and an antiviral action, and was found to be useful as a therapeutic agent for liver diseases, and the present invention has been completed here.

[0008]

The present invention has the general formula (I)

[0009]

[Chemical 2]

[Wherein R ¹ represents a hydrogen atom, a lower alkyl group or a benzyl group, R ² represents a hydrogen atom or a lower alkyl group, and R ³ represents a hydrogen atom, a hydroxyl group or a benzyloxy group. X represents a hydrogen atom, a hydroxyl group or a benzyloxy group, n is 0 or 1, and A represents a lower alkylene group. Y represents a ^four or -COR ⁵ radical -NHCOR.
Here, R ⁴ represents a lower alkyl group, and R ⁵ represents a protected sulfur-containing amino acid residue or a phenyl-substituted amino group.
However, R ¹ , R ² and R ³ are hydrogen atoms, Y is an acetamido group, and-(A) n-X is substituted with a hydroxyethyl group at the 7-position and a hydrogen atom is excluded. . ] The 1,4-benzodioxane derivative represented by the following and a pharmaceutically acceptable salt thereof.

The compound of the present invention represented by the above general formula (I) has an excellent hepatoprotective action, lipid peroxidation inhibitory action and antiviral action, and can be suitably used for the treatment of liver diseases.

[0012] Examples of liver diseases include viral hepatitis,
Examples thereof include alcoholic liver injury and drug-induced liver injury.

In the above general formula (I), R ¹ , R ² , R ³ ,
More specifically, each group defined by R ⁴ , R ⁵ , A, X and Y and the other groups described in the present specification are as follows.

As the lower alkyl group, for example, methyl,
1 to 10 carbon atoms such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl groups
The linear or branched alkyl group of 6 can be exemplified.

Examples of the lower alkylene group include lower alkylene groups having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, methylmethylene, 2-methyltrimethylene, propylene, butylene, pentylene and hexylene groups. .

The sulfur-containing amino acid residue is a residue formed by removing a hydrogen atom from the amino group of an amino acid,
Examples of the amino acid residue include S-ethylcarbamoylcysteine methyl ester, S-ethylcarbamoylcysteine ethyl ester, S-ethylcarbamoylcysteine benzohydryl ester, S-ethylcarbamoylcystine methyl ester, S-ethylcarbamoylcystine ethyl ester, S Examples thereof include ethylcarbamoylcystine benzohydryl ester.

Examples of the phenyl-substituted amino group include 2
Examples thereof include lower alkoxycarbonylphenylamino group, 2-lower alkoxycarbonylmethylcarbamoylphenyl group and 4- (3-loweralkoxy-2-hydroxypropoxy) phenylamino group.

Examples of the lower alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy and n-.
Butoxy, isobutoxy, sec-butoxy, tert
Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as -butoxy, n-pentyloxy, isopentyloxy, and n-hexyloxy groups.

The lower alkoxycarbonylphenylamino group is an ester group based on a specific group of the above lower alkyl group of a carboxyl group, and the ester group includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, Isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert
-A lower alkoxycarbonylphenylamino group having a linear or branched alkoxy group having 1 to 6 carbon atoms such as butoxycarbonyl group, n-pentyloxycarbonyl group, isopentyloxycarbonyl group, and n-hexyloxycarbonyl group Can be illustrated.

The lower alkoxycarbonylmethylcarbamoylphenylamino group is a carbamoyl group derived from a glycine ester derivative of a carboxyl group, and the carbamoyl group is, for example, a methoxycarbonylmethylcarbamoyl group, an ethoxycarbonylmethylcarbamoyl group or an n-propoxycarbonylcarbamoyl group. , Isopropoxycarbonylcarbamoyl group, n-butoxycarbonylcarbamoyl group, isobutoxycarbonylcarbamoyl group, sec-butoxycarbonylcarbamoyl group, tert-butoxycarbonylcarbamoyl group, n
-Lower alkoxycarbonylmethylcarbamoylphenyl having a linear or branched alkoxycarbonylmethylcarbamoyl group having 1 to 6 carbon atoms such as a pentyloxycarbonylcarbamoyl group, an isopentyloxycarbonylcarbamoyl group, and an n-hexyloxycarbonylcarbamoyl group An amino group can be exemplified.

The 3-lower alkoxy-2-hydroxypropoxyphenylamino group is an ether group consisting of the hydroxyl group at the 3-position of the 2,3-dihydroxypropoxy group and the specific group of the above lower alkyl group. Is, for example, a 3-methoxy-2-hydroxypropyl group,
3-ethoxy-2-hydroxypropyl group, 3- (n-
Propoxy) -2-hydroxypropyl group, 3-isopropoxy-2-hydroxypropyl group, 3- (n-butoxy) -2-hydroxypropyl group, 3-isobutoxy-2-hydroxypropyl group, 3- (sec-butoxy) ) -2-Hydroxypropyl group, 3- (tert-butoxy) -2-hydroxypropyl group, 3- (n-pentyloxy) -2-hydroxypropyl group, 3-isopentyloxy-2-hydroxypropyl group, 3 -(N-
Hexyloxy) -2-hydroxypropyl group or the like having a linear or branched ether group having 1 to 6 carbon atoms 3-
A lower alkoxy-2-hydroxypropoxyphenylamino group can be exemplified.

1,4-represented by the general formula (I) of the present invention
Examples of the salt of the benzodioxane derivative include a base salt obtained by acting a pharmaceutically acceptable basic compound. Examples of the base salt include a salt of a compound of the general formula (I) with an acidic group, particularly a phenolic hydroxyl group, for example, a salt of an alkali metal such as sodium, potassium, magnesium or calcium, or an alkaline earth metal, ammonia, methyl. Examples thereof include organic salts such as amines such as amine, dimethylamine, piperidine, cyclohexylamine and triethylamine.

The 1,4-benzodioxane derivative represented by the above general formula (I) includes the following compounds.

R ¹ is a hydrogen atom or a lower alkyl group, R ²
Is a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or a hydroxyl group, X is a hydrogen atom or a hydroxyl group, n is 0 or 1, A is a methylene group, Y is an acetamide group or a -COR ⁵ group (R ⁵
Is a protected sulfur-containing amino acid residue or a phenyl-substituted amino group), a 1,4-benzodioxane derivative.

R ¹ is a hydrogen atom or a lower alkyl group, R ²
And R ³ is a hydrogen atom, X is a hydrogen atom or a hydroxyl group, n is 0, Y is an acetamide group or a -COR ⁵ group (R ⁵ is a protected sulfur-containing amino acid residue or a phenyl-substituted amino group)
Which is a 1,4-benzodioxane derivative.

In the compound represented by the above general formula (I), R ¹ , R ² and R ³ are preferably hydrogen atoms. Further, it is preferable that R ¹ is a methyl group and R ² and R ³ are hydrogen atoms.

Particularly preferred compounds are R ¹ , R ² and R
^A compound in which ³ is a hydrogen atom, n is 0, X is a hydroxyl group, Y is an acetamide group, and R ¹ is a methyl group, R ² and R ³
Is a hydrogen atom, n is 0, X is a hydrogen atom, and Y is a -COR ⁵ group (R ⁵ is a protected sulfur-containing amino acid residue or a phenyl-substituted amino group).

1, represented by the above general formula (I) of the present invention
The 4-benzodioxane derivative can be produced by using various compounds as raw materials.

For example, the 1,4-benzodioxane derivative of the present invention can be produced according to the method shown in the following reaction process formula-A or reaction process formula-B.

[0030]

[Chemical 3]

[Wherein R ¹ , R ³ , R ⁴ , A, X and n are the same as defined above. R ⁶ represents a lower alkyl group. More specifically, each step in the above reaction process formula-A is carried out as follows.

(Step 1) The compound represented by the general formula (Ia) is, for example, Journal of Chemical Society Parkin I, 775 (1980) and Journal of Biological Chemistry, Volume 262, No. 22, 105.
46-10549 (1987) according to the method described in
In the presence of an oxidizing agent such as silver oxide in a suitable solvent, the compound of general formula (I
It is produced by reacting the compound of I) with the compound of general formula (III).

The solvent is not particularly limited as long as it does not participate in the reaction, for example, methanol, ethanol, 1
-Propanol, 2-propanol, 1-butanol,
Alcohols such as 2-butanol, halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, acetic acid esters such as methyl acetate, ethyl acetate and butyl acetate, benzene , Aromatic hydrocarbons such as toluene and the like, aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethylsulfoxide, etc., alone or in combination of two or more thereof.

Examples of the oxidizing agent include oxidases such as mushroom tyrosinase, silver oxide and the like. Such an oxidizing agent is usually used in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to 1 mol of the compound of the general formula (III).

Compounds of general formula (II) and general formula (II
The ratio of the compound I) to the compound used is not particularly limited, but the former is usually 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents relative to the latter.

The reaction temperature of this reaction is usually about 0 to 100 ° C, preferably room temperature to 50 ° C. The reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours.

The compound represented by the general formula (II) was synthesized according to Reference Examples 1 to 4, and the compound represented by the general formula (III) was prepared as described in Org. Pr
ep. Proced. Int. 20 (20,1-2),
191 (1988) and Synthesis, 19, 523 (1
987) and according to Reference Examples 5 to 10.

Further, the benzyl compound (R
A compound of the general formula (Ia) in which ³ is a benzyloxy group is obtained by performing a debenzylation reaction in the presence of a catalyst in an inert solvent to give an alcohol compound (the general formula (I in which R ³ is a hydroxyl group). -A) compound). The inert solvent used here is not particularly limited as long as it does not participate in the reaction, and for example, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, acetic acid, etc. may be used alone or in combination of two or more thereof. Can be used.

Examples of the catalyst include palladium carbon, platinum and the like. Such a catalyst is usually 0.01 to 2 g, preferably 0.1 to 1 g of the compound of the general formula (Ia).
~ 0.5g should be used.

The hydrogen pressure in this reaction is usually 1 to 5 kg / cm.
² , preferably 1 to 3 kg / cm ² . The reaction temperature of the reaction is usually about 0 to 100 ° C., preferably room temperature to
It is 70 ° C., and the reaction time is usually 0.5 to 12 hours, preferably 1 to 4 hours.

The compound of the general formula (Ia) thus obtained has a liver damage-suppressing action by itself, but it may be isolated as an intermediate material or used in the next step 2 without isolation. You can

(Step 2) The compound represented by the general formula (Ib) is usually obtained by alkylating the compound represented by the general formula (Ia) by a known and conventional method, for example, an inert solvent. In, it is produced by reacting an alkylating agent in the presence of a basic compound.

The inert solvent is not particularly limited as long as it does not participate in the reaction, and for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, dichloromethane, chloroform. Halogenated hydrocarbons such as, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, acetic acid esters such as methyl acetate, ethyl acetate and butyl acetate, aromatic hydrocarbons such as benzene and toluene, acetone, methyl ethyl ketone , Alkyl ketones such as methyl isobutyl ketone,
Aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethylsulfoxide can be exemplified, and these can be used alone or in combination of two or more kinds.

Examples of the basic compound include trialkylamines such as triethylamine and diisopropylamine, carbonates such as sodium carbonate, potassium carbonate and silver carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and hydrogen. Examples thereof include inorganic basic compounds such as alkali metal hydrides such as sodium hydride and potassium hydride. . Such a basic compound is usually 1 to 5 molar equivalents, preferably 1 to 1 mol, relative to 1 mol of the compound of the general formula (Ia).
It is advisable to use 2 molar equivalents.

Examples of the alkylating agent include alkyl halides such as alkyl iodide. Such an alkylating agent is usually used in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to 1 mol of the compound of the general formula (Ia).

The reaction temperature for this alkylation is usually 0 ° C. to about the boiling point of the solvent, preferably room temperature to 100 ° C., and the reaction time is usually 1 to 48 hours, preferably 1 to 24 hours.

Further, the benzyl compound (R
The compound of the general formula (Ib) in which ³ is a benzyloxy group is subjected to the same debenzylation reaction as in Step 1 to give an alcohol compound (the general formula (I- in which R ³ is a hydroxyl group).
b)).

[0048]

[Chemical 4]

[Wherein R ¹ , R ² , R ³ , R ⁵ , A, X and n are the same as defined above. ] More specifically, the reaction in the above reaction process formula-B is carried out as follows. That is, the compound represented by the general formula (I-c) is usually a compound of Chemishberichte, 148.
2 (1975) and Chemish Berichte, 3664 (1
977), a carboxylic acid derivative represented by the general formula (IV) and a known compound represented by the general formula (V) are synthesized in a suitable solvent in the presence of a dehydration condensing agent. It is produced by reacting below.

The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, methyl acetate and ethyl acetate. , Acetic acid esters such as butyl acetate, aromatic hydrocarbons such as benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide, etc., alone or in combination of two or more thereof. Can be used.

The dehydrating condensing agent is not particularly limited as long as it activates a carboxylic acid compound, and examples thereof include dicyclohexylcarbodiimide, carbonyldiimidazole, diethyl cyanophosphate and the like. The amount of such dehydration condensing agent to be used is usually 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to the compound of general formula (IV).

The ratio of the compound of the general formula (IV) to the compound of the general formula (V) is not particularly limited, but the latter is usually 1 to 5 molar equivalents, preferably 1 to the former. It is preferable to use 2 molar equivalents.

The reaction temperature of this reaction is usually about 0 to 100 ° C., preferably room temperature to 50 ° C., and the reaction time is usually 1
It is about 48 hours, preferably 1 to 24 hours.

The compound of the present invention (I
Each of -a), (Ib) and (Ic) can be easily isolated and purified from the reaction mixture by a usual separation and purification means such as column chromatography, recrystallization and vacuum distillation.

In using the compound of the present invention as a medicine, various dosage forms can be adopted depending on the purpose of prevention or treatment, and examples of the dosage form include pills, tablets, powders, capsules and granules. It may be any of oral agents such as agents, injections, suppositories, ointments, patches, parenteral agents such as aerosols, eye drops, nasal drops, etc., and these administration forms are known to those skilled in the art. It can be manufactured by the manufacturing method.

In the case of preparing a solid oral preparation, after adding an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. to the compound of the present invention, Tablets, coated tablets, granules, powders, capsules and the like can be produced by a conventional method. Such additives may be those commonly used in the art, and examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch,
Calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, etc., as the binder, water, ethanol, propanol,
Simple syrup, glucose solution, starch solution, gelatin solution,
Carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc., as disintegrants, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearin. Acid monoglyceride, lactose, etc., lubricants such as purified talc, stearate, borax, polyethylene glycol, etc., coloring agents such as titanium oxide,
Examples of the flavoring / flavoring agents include iron oxide and the like, and sucrose, orange peel, citric acid, tartaric acid and the like can be exemplified.

When preparing an oral liquid preparation, an oral solution, syrup, elixir and the like are prepared by adding a flavoring agent, a flavoring agent, a buffering agent, a stabilizer and the like to the compound of the present invention by a conventional method. You can In this case, the flavoring / flavoring agents may be those listed above, the buffering agents include sodium citrate, and the stabilizing agents include tragacanth, gum arabic, gelatin, and the like.

When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc. are added to the compound of the present invention, and the compound is subcutaneously, intramuscularly or intravenously prepared by a conventional method. Injectables can be manufactured. In this case, sodium citrate, sodium acetate, sodium phosphate, etc. are used as the pH adjuster and buffer, and sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. are used as the stabilizer.
Examples of the isotonicity agent include sodium chloride and glucose, and examples of the local anesthetic include procaine hydrochloride, lidocaine hydrochloride and the like.

When a suppository is prepared, the compound of the present invention may be added to the compound of the present invention by a carrier known in the art, such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, and if necessary, Tween (registered trademark). It can be produced by a conventional method after adding a surfactant or the like.

In the case of preparing an ointment, the base, stabilizer, wetting agent, preservative and the like usually used in the compound of the present invention are blended, if necessary, and mixed and formulated by a conventional method. . Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.

In the case of producing a patch, the above-mentioned ointment, cream, gel, paste and the like may be applied to an ordinary support by a conventional method. As the support, a woven or non-woven fabric made of cotton, staple fiber or chemical fiber, or a film or foam sheet of soft vinyl chloride, polyethylene, polyurethane or the like is suitable.

The amount of the compound of the present invention to be blended in each dosage unit form described above is not constant depending on the symptoms of the patient to which it is applied, the dosage form thereof, etc. The dosage is preferably 1 to 1000 mg, the injection is 0.1 to 500 mg, and the suppository is 5 to 1000 mg. The daily dose of the drug having the above dosage form cannot be unconditionally determined depending on the patient's symptoms, body weight, sex, etc., but is usually 0.1 to 500 per adult per day.
It may be 0 mg, preferably 1 to 1000 mg, and it is preferable to administer this once or in 2 to 4 divided doses.

[0063]

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

Reference Example 1 Synthesis of 3,4-dihydroxyphenylacetic acid methyl ester 200 g of methanol was added to 10 g of 3,4-dihydroxyphenylacetic acid, and then while introducing hydrogen chloride gas, 6
Heated to reflux for hours. After cooling, the methanol was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 7.17 g (yield 66%) of 3,4-dihydroxyphenylacetic acid methyl ester.

¹ H-NMR (DMSO-d ₆ ): δ 3.43 (2H, s), 3.57 (3H, s), 6.4
0 to 6.66 (3H, m), 8.77 (2H, bro
ds).

Reference Example 2 Synthesis of 3,4-dimethoxymethoxyphenethylbenzyl ether 2.59 g of 3,4-dihydroxyacetic acid methyl ester obtained in Reference Example 1 and diisopropylethylamine 7.
To a solution of 43 ml of methylene chloride (26 ml), 3.24 ml of methoxymethyl chloride was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. After completion of the reaction, methylene chloride was distilled off, the obtained residue was distributed between diethyl ether and water, the organic layer was washed with a 1N-NaOH aqueous solution and then washed with water, and the separated organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 2.90 g (yield 76%) of 3,4-dimethoxymethoxyphenylacetic acid methyl ester.

Next, a suspension of 618 mg of lithium aluminum hydride in dry tetrahydrofuran (60 ml) was added to 2.20 g of methyl tetrahydrofuran of 3,4-dimethoxymethoxyphenylacetic acid (20 m).
l) The solution was added dropwise at room temperature and stirred at the same temperature for 1 hour. After completion of the reaction, hydrous tetrahydrofuran was added, the precipitated insoluble matter was filtered on Hyflo Supercel, and the filtrate was concentrated,
1.95 mg (yield 99%) of 3,4-dimethoxymethoxyphenethyl alcohol was obtained.

Next, 1.92 g of 3,4-dimethoxymethoxyphenethyl alcohol was dissolved in 20 ml of dry tetrahydrofuran, and 60% sodium hydride 4 was added under ice cooling.
75 mg was added in small portions. 20 minutes at the same temperature, 4 at room temperature
After stirring for 0 minutes, 1 ml of benzyl bromide and 60 ml of tetrabutylammonium iodide were added, and the mixture was further stirred at room temperature for 5 hours. After completion of the reaction, the insoluble matter was filtered on Hyflo Super Cell, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography,
2.11 mg (yield 80%) of 3,4-dimethoxymethoxyphenethyl benzyl ether was obtained.

¹ H-NMR (CDCl ₃ ): δ 2.79 (2H, t, J = 7.08 Hz), 3.51
(6H, s), 3.68 (2H, t, J = 7.08H
z), 4.52 (2H, s), 5.20 (4H, s),
6.76-7.35 (8H, m).

Reference Example 3 Synthesis of 3,4-dihydroxyphenethylbenzyl ether 2.10 g of 3,4-dimethoxymethoxyphenethylbenzyl ether obtained in Reference Example 2 was added to 2 ml of ethyl acetate.
After being dissolved in water, 5.6 ml of a 2.6 M hydrogen chloride-ethyl acetate solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, ethyl acetate was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 1.25 mg of 3,4-dihydroxyphenethylbenzyl ether (yield 8
5%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 2.78 (2H, t, J = 7.08 Hz), 3.65
(2H, t, J = 7.08Hz), 4.53 (2H,
s), 6.53 to 6.76 (3H, m), 7.30 (5
H, s).

Reference Example 4 Synthesis of benzhydryl (2-hydroxy-5-formyl) phenyl succinate 3,4-diluted in 200 ml of 0.5N aqueous sodium hydroxide solution
After 13.8 g of dihydroxybenzaldehyde was added and dissolved, 15 g of succinic anhydride was added under ice cooling, stirred for 5 minutes, neutralized with 50 ml of 2N hydrochloric acid, and extracted with ethyl acetate. Next, 200 ml of a methylene chloride solution containing 19.4 g of diphenyldiazomethane was added dropwise to this extract under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 21.43 g (yield 53%) of benzhydryl (2-hydroxy-5-formyl) phenylsuccinate. It was

¹ H-NMR (CDCl ₃ ): δ 2.88 to 3.00 (4H, m), 5.72 (1H,
s), 6.92 (1H, s), 7.25 to 7.80 (1
3H, m).

Reference Example 5 Synthesis of 3-hydroxy-4-methoxymethoxybenzaldehyde Benzhydryl (2-hydroxy-5-formyl) phenyl succinate 20.2 obtained in Reference Example 4
g and 7.74 g of diisopropylamine were dissolved in 200 ml of methylene chloride, 20 ml of a methylene chloride solution of 4.83 g of methoxymethyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off, the resulting residue was distributed between diethyl ether and water, the separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off.
22.4 g of residue was obtained.

Next, the residue obtained is treated with 200 m of methanol.
After dissolving in 1 l, 22 ml of 5N sodium hydroxide aqueous solution was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, methanol was distilled off, the obtained residue was distributed between diethyl ether and water, the separated aqueous layer was neutralized with 6N-hydrochloric acid 18 ml, extracted with diethyl ether, dried over anhydrous magnesium sulfate and then used as a solvent. Was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 9.0 g of 3-hydroxy-4-methoxymethoxybenzaldehyde.
(Yield 98%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 3.53 (3H, s), 5.32 (2H, s), 5.9
8 (1H, broad), 7.26 to 7.48 (3H,
m), 9.86 (1H, s).

Reference Example 6 Synthesis of 3-benzyloxy-4-methoxymethoxybenzaldehyde 1.82 g of 3-hydroxy-4-methoxymethoxybenzaldehyde obtained in Reference Example 5 and potassium carbonate 1.4
5 g and benzyl bromide 1.8 g were added to acetone 36 m.
The mixture was heated to reflux in 1 for 2 hours. After cooling, the insoluble material was filtered off, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography to obtain 2.58 g (yield 94%) of 3-benzyloxy-4-methoxymethoxybenzaldehyde.

¹ H-NMR (CDCl ₃ ): δ 3.52 (3H, s), 5.20 (2H, s), 5.3
2 (2H, s), 7.26 to 7.49 (8H, m),
9.83 (1H, s).

Reference Example 7 N-Acetyl-3-benzyloxy-4-hydroxy-β
Synthesis of styrylamine To 2.27 g of 3-benzyloxy-4-methoxymethoxybenzaldehyde obtained in Reference Example 6 was added a catalytic amount of zinc iodide and 1.2 ml of trimethylsilyl cyanide,
After stirring at room temperature for 1.5 hours, dry diethyl ether 15 ml
Dissolved in. This solution was added dropwise to a suspension of lithium aluminum hydride (758 mg) in dry diethyl ether (75 ml) at room temperature, and the mixture was heated under reflux for 2 hours. After cooling
Water under ice cooling 1 ml, 2N-sodium hydroxide aqueous solution 1 m
l, insoluble matter was filtered on Hyflo Super Cell,
The ether layer was separated from the filtrate, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 1.64 g of (3-benzyloxy-4-methoxymethoxy) phenylethanolamine.
(Yield 65%) was obtained.

¹ H-NMR (DMSO-d ₆ / D
₂ O): δ 2.60 to 2.80 (2H, m), 3.36 (3H,
s), 4.40 to 4.60 (1H, m), 5.08 (2
H, s), 5.12 (2H, s), 6.80 to 7.52
(8H, m).

Reference Example 8 Synthesis of O, N-diacetyl- (3-benzyloxy-4-methoxymethoxy) phenylethanolamine 4.13 g of (3-benzyloxy-4-methoxymethoxy) phenylethanolamine obtained in Reference Example 7 , 4.0 ml of triethylamine and 1 of dimethylaminopyridine
Under ice-cooling, 12.8 ml of acetic anhydride was added dropwise to 0 mg, and after the heat generation stopped, the mixture was stirred at room temperature for 1 hour. Next, acetic anhydride was distilled off under reduced pressure, water was added to the residue, and the precipitate was collected by filtration.
After drying under reduced pressure, 5.02 g (yield 95%) of O, N-diacetyl- (3-benzyloxy-4-methoxymethoxy) phenylethanolamine was obtained.

¹ H-NMR (CDCl ₃ ): δ 1.92 (3H, s), 2.02 (3H, s), 3.4
8 (3H, s), 3.46 to 3.64 (2H, m),
5.12 (2H, s), 5.18 (2H, s), 5.6
4 to 5.76 (1H, m), 6.80 to 7.48 (8
H, m).

Reference Example 9 Synthesis of O, N-diacetyl- (3-benzyloxy-4-acetoxy) phenylethanolamine O, N-diacetyl- (3-benzyloxy-4-methoxymethoxy) obtained in Reference Example 8 Toluenesulfonic acid monohydrate 95m to phenylethanolamine 1.94g
g, acetic anhydride 2.4 ml and acetic acid 12 ml were added, and 10
Stirred at 0 ° C. for 2 hours. After cooling, the acetic acid was distilled off under reduced pressure, the obtained residue was distributed between ethyl acetate and water, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and the solvent was distilled off. Diethyl ether was added to the residue, and the mixture was stirred under ice-cooling to precipitate crystals, and 1.34 g (yield 69%) of O, N-diacetyl- (3-benzyloxy-4-acetoxy) phenylethanolamine was obtained.

¹ H-NMR (CDCl ₃ ): δ 1.94 (3H, s), 2.07 (3H, s), 2.2
7 (3H, s), 3.52 to 3.66 (2H, m),
5.10 (2H, s), 5.73 to 5.86 (1H,
m), 6.89-7.43 (8H, m).

Reference Example 10 N-Acetyl-3-benzyloxy-4-hydroxy-β
-Styrylamine Synthesis 3.16 g of O, N-diacetyl- (3-benzyloxy-4-acetoxy) phenylethanolamine obtained in Reference Example 9 and 2.95 g of potassium carbonate were stirred in 24 ml of dimethyl sulfoxide at 110 ° C for 2 hours. did. After cooling
It was poured into ice water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated. Carbon tetrachloride was added to the obtained residue to precipitate crystals, and 1.00 g of N-acetyl-3-benzyloxy-4-hydroxy-β-styrylamine was added.
(Yield 40%) was obtained.

¹ H-NMR (DMSO-d ₆ ): δ 1.94 (3H, s), 5.12 (2H, s), 5.9
8 (1H, d, J = 14.9 Hz), 6.92 to 7.5
8 (9H, m), 8.96 (1H, s), 10.06
(1H, broad-d, J = 5.6 Hz).

Example 1 N- [3- (3,4-dihydroxyphenyl) -2,3
-Dihydro-6- (2-hydroxyethyl) -1,4-
Synthesis of Benzodioxin-2-yl] -acetamide (Compound 1) 4- (Hydroxyethyl) catechol 1 synthesized from the 3,4-dihydroxyphenethylbenzyl ether obtained in Reference Example 3 by a known debenzylation reaction
2.2 g and N-acetyl-3-obtained in Reference Example 10
Benzyloxy-4-hydroxy-β-styrylamine 1
4.15 g of benzene 600 ml and methanol 120
The mixture was stirred for 20 hours at room temperature in the presence of 11.58 g of silver oxide in ml. After filtering the insoluble matter on Hyflo Super Cell,
The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (benzene / ethyl acetate = 2/1) to obtain 10.94 g of a mixture of regioisomers. 10.94 g of the obtained mixture was dissolved in 200 ml of methanol, 5.46 g of 5% palladium carbon was added, and the mixture was shaken under a hydrogen stream (initial pressure of 2.8 kg / cm ² ) at room temperature for 24 hours. After filtering on Hyflo Super Cell, concentrate the filtrate,
The obtained residue was purified by HP-20 column chromatography and freeze-dried to obtain 4.09 g (yield 24%) of the title compound (Compound 1).

FAB-MS: m / z 346 (M + H)
^{+ 1} H-NMR (DMSO-d ₆ ): δ 1.77 (3H, s), 2.62 (2H, t, J = 7H)
z), 3.56 (2H, t, J = 7Hz), 4.55
(1H, br-s), 4.71 (1H, d, J = 7H
z), 5.55 (1H, d, J = 8Hz), 6.65
6.80 (6H, m), 8.85 (1H, br-d, J
= 9 Hz), 8.97 (2H, br-s).

Example 2 N- [3- (3-benzyloxy-4-hydroxyphenyl) -2,3-dihydro-6- (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide Synthesis of (Compound 2) 244 mg of 3,4-dihydroxyphenethyl benzyl ether obtained in Reference Example 3 and N obtained in Reference Example 10
-Acetyl-3-benzyloxy-4-hydroxy-β-
In the presence of 232 mg of silver oxide, 283 mg of styrylamine,
The mixture was stirred at room temperature for 24 hours in a mixed solvent of 12 ml of benzene and 2.4 ml of methanol. The insoluble matter was filtered through Hyflo Supercel and the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 295 mg (yield 56%) of the title compound (Compound 2).

¹ H-NMR (CDCl ₃ ): δ 1.94 (3H, s), 2.84 (2H, t, J = 5.
1Hz), 3.64 (2H, t, J = 5.1Hz),
4.52 (2H, s), 4.85 (1H, d, J = 5.
1Hz), 5.04 (2H, s), 5.75 (1H,
s), 6.04 (1H, dd, J = 5.1, 9.5H)
z), 6.20 (1H, d, J = 9.5 Hz), 6.7.
8-7.38 (16H, m).

Example 3 N- [3- (3-methoxy-4-hydroxyphenyl)
-2,3-Dihydro-6- (2-benzyloxyethyl)
Synthesis of -1,4-benzodioxin-2-yl] acetamide (Compound 3) In the same manner as in Example 2, instead of N-acetyl-3-benzyloxy-4-hydroxy-β-styrylamine,
The reaction was performed using N-acetyl-3-methoxy-4-hydroxy-β-styrylamine to obtain the title compound (Compound 3) in a yield of 33%.

¹ H-NMR (CDCl ₃ ): δ 1.92 (3H, s), 2.82 (2H, t, J = 6.
8Hz), 3.62 (2H, t, J = 6.8Hz),
3.80 (3H, s), 4.48 (2H, s), 4.8
2 (1H, d, J = 5.1Hz), 5.72 (2H,
s), 6.00 (1H, dd, J = 5.1, 9.6H)
z), 6.30 (1H, d, J = 9.6 Hz), 6.7.
2 to 6.90 (6H, m), 7.30 (5H, s).

Example 4 N- [3- (3,5-dibenzyloxy-4-hydroxyphenyl) -2,3-dihydro-6- (2-benzyloxyethyl) -1,4-benzodioxin-2-yl ] Synthesis of Acetamide (Compound 4) In the same manner as in Example 2, instead of N-acetyl-3-benzyloxy-4-hydroxy-β-styrylamine,
The reaction was carried out using N-acetyl-3,5-dibenzyloxy-4-hydroxy-β-styrylamine to obtain the title compound (Compound 4) with a yield of 75%.

¹ H-NMR (CDCl ₃ ): δ 1.89 (3H, s), 2.82 (2H, t, J = 6.
8Hz), 3.64 (2H, t, J = 6.8Hz),
4.51 (2H, s), 4.80 (1H, d, J = 6.
8Hz), 5.07 (4H, s), 5.66 (1H,
s), 6.00 (1H, dd, J = 6.8, 9.6H)
z), 6.20 (1H, d, J = 9.6 Hz), 6.6
7 (2H, s), 6.78 to 7.38 (18H, m).

Example 5 N- [3- (3-benzyloxy-4-hydroxyphenyl) -2,3-dihydro-1,4-benzodioxin-
Synthesis of 2-yl] acetamide (Compound 5) In the same manner as in Example 2, the reaction was performed using catechol instead of 3,4-dihydroxyphenethylbenzyl ether, to give the title compound (Compound 5) in a yield of 31. Earned in%.

¹ H-NMR (CDCl ₃ ): δ 1.89 (3H, s), 4.80 (1H, d, J = 6.
8Hz), 5.00 (2H, s), 6.00 (1H, d
d, J = 6.8, 9.6 Hz), 6.32 (1H, d,
J = 9.6 Hz), 6.82 to 6.96 (7H, m),
7.32 (5H, s).

Example 6 N- [3- (3-benzyloxy-4-hydroxyphenyl) -8-benzyloxy-2,3-dihydro-1,4-
Synthesis of Benzodioxin-2-yl] acetamide (Compound 6) In the same manner as in Example 2, 2,3-dihydroxybenzyl ether was used in place of 3,4-dihydroxyphenethylbenzyl ether to carry out the reaction. The compound (compound 6) was obtained with a yield of 36%.

¹ H-NMR (CDCl ₃ ): δ 1.68 (3H, s), 4.72 (1H, d, J = 5.
1Hz), 5.00 (2H, s), 5.02 (2H,
s), 5.82 (1H, s), 6.02 (1H, dd,
J = 5.1, 9.5 Hz), 6.50 to 7.00 (6
H, m), 7.20 (5H, s), 7.32 (5H,
s).

Example 7 N- [3- (3-Benzyloxy-4-methoxyphenyl) -2,3-dihydro-6- (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide Synthesis of (Compound 7) N- [3- (3-benzyloxy-4 obtained in Example 2
-Hydroxyphenyl) -2,3-dihydro-6- (2
-Benzyloxyethyl) -1,4-benzodioxin-
2-yl] acetamide (Compound 2) 525 mg and methyl iodide 284 mg were heated under reflux in acetone 12 ml for 3 hours in the presence of potassium carbonate 207 mg. After cooling, the insoluble matter was filtered on Hyflo Super Cell and the filtrate was concentrated.
The obtained residue was distributed between diethyl ether and water, the organic layer was separated, dried over anhydrous magnesium sulfate and the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography to give the title compound (Compound 7). Was obtained in an amount of 329 mg (yield 61%).

¹ H-NMR (CDCl ₃ ): δ 1.90 (3H, s), 2.83 (2H, t, J = 6.
8Hz), 3.64 (2H, t, J = 6.8Hz),
3.80 (3H, s), 4.42 (2H, s), 4.8
2 (1H, d, J = 5.1Hz), 5.20 (2H,
s), 5.98 (1H, dd, J = 5.1, 9.6H)
z), 6.28 (1H, d, J = 9.6 Hz), 6.7.
4 to 7.40 (16H, m).

Example 8 N- [3- (3,4-dimethoxyphenyl) -2,3-
Dihydro-6- (2-benzyloxyethyl) -1,4-
Synthesis of benzodioxin-2-yl] acetamide (Compound 8) In a manner similar to Example 7, N- [3- (3-benzyloxy-4-hydroxyphenyl) -2,3-dihydro-6-
Instead of (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide, N- [3- (3-methoxy-4-hydroxyphenyl) -2,3 obtained in Example 3 was used. -Dihydro-6- (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide (Compound 3) was reacted to give the title compound (Compound 8) in 90% yield. It was

¹ H-NMR (CDCl ₃ ): δ 1.94 (3H, s), 2.83 (2H, t, J = 6.
8Hz), 3.65 (2H, t, J = 6.8Hz),
3.83 (3H, s), 3.85 (3H, s), 4.5
2 (2H, s), 4.88 (1H, d, J = 5.1H
z), 6.00 (1H, dd, J = 5.1, 9.6H
z), 6.42 (1H, d, J = 9.6 Hz), 6.6
7-6.90 (6H, m), 7.30 (5H, s).

Example 9 N- [3- (3-hydroxy-4-methoxyphenyl)
-2,3-Dihydro-6- (2-hydroxyethyl)-
Synthesis of 1,4-Benzodioxin-2-yl] acetamide (Compound 9) N- [3- (3-Benzyloxy-4 obtained in Example 7
-Methoxyphenyl) -2,3-dihydro-6- (2-
Benzyloxyethyl) -1,4-benzodioxin-2
183 mg of -yl] acetamide (Compound 7) and 92 mg of 5% palladium carbon were shaken in 5 ml of methanol under hydrogen flow (initial pressure of 2.8 kg / cm ² ) at room temperature for 1 hour. The insoluble matter is filtered off, the filtrate is concentrated, and the resulting residue is treated with HP.
Purify by -20 column chromatography and freeze-dry to give 113 mg of the title compound (Compound 9) (yield 93
%)Obtained.

¹ H-NMR (pyridine-d ₅ ): δ 1.93 (3H, s), 2.94 (2H, t, J = 6.
7Hz), 3.67 (3H, s), 4.05 (2H,
t, J = 6.7 Hz), 5.20 (1H, t, J = 6.
8 Hz), 6.51 (1H, dd, J = 9.6, 6.8)
Hz), 6.90 (1H, dd, J = 8.3, 1.9H)
z), 6.95 (1H, d, J = 8.3 Hz), 7.0
7 (1H, d, J = 8.3Hz), 7.08 (1H,
d, J = 1.9 Hz), 7.13 (1H, dd, J =
8.3, 2.1 Hz), 7.49 (1H, d, J = 2.
1 Hz), 9.96 (1H, d, J = 9.6 Hz), 1
1.21 (1H, br-s).

Example 10 N- [3- (4-hydroxy-3-methoxyphenyl)
-2,3-Dihydro-6- (2-hydroxyethyl)-
Synthesis of 1,4-benzodioxin-2-yl] acetamide (Compound 10) By a method similar to that in Example 9, N- [3- (3-benzyloxy-4-methoxyphenyl) -2,3-dihydro-6- was used.
Instead of (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide (Compound 7),
N- [3- (3-Methoxy-4-hydroxyphenyl) -2,3-dihydro-6- (2-benzyloxyethyl) -1,4-benzodioxin-2-obtained in Example 3
The reaction was carried out using [yl] acetamide (Compound 3) to obtain the title compound (Compound 10) in a yield of 79%.

¹ H-NMR (pyridine-d ₅ ): δ 1.94 (3H, s), 2.96 (2H, t, J = 6.
8 Hz), 3.7 (3H, s), 4.06 (2H, t,
J = 6.8 Hz), 5.19 (1H, d, J = 7.1H)
z), 6.54 (1H, dd, J = 9.6, 7.2H
z), 6.92 (1H, dd, J = 8.1, 1.9H
z), 7.10 (1H, d, J = 8.1 Hz), 7.1
2 (1H, d, J = 1.9 Hz), 7.18 (1H, d
d, J = 8.1, 1.9 Hz), 7.22 (1H, d,
J = 8.1 Hz), 7.30 (1H, d, J = 1.7H)
z), 9.94 (1H, d, J = 9.6 Hz), 11.
3 (1H, br-s).

Example 11 N- [3- (3,4-dimethoxyphenyl) -2,3-
Dihydro-6- (2-hydroxyethyl) -1,4-benzodioxin-2-yl] acetamide (Compound 1
Synthesis of 1) In the same manner as in Example 9, N- [3- (3-benzyloxy-4-methoxyphenyl) -2,3-dihydro-6-
Instead of (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide (Compound 7),
N- [3- (3,4-dimethoxyphenyl) -2,3-dihydro-6- (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide (obtained in Example 8) The reaction was performed using compound 8) to obtain the title compound (compound 11) in a yield of 76%.

¹ H-NMR (pyridine-d ₅ ): δ 1.96 (3H, s), 2.96 (2H, t, J = 6.
8 Hz), 3.69 (3H, s), 3.73 (3H,
s), 4.07 (2H, t, J = 6.8Hz), 5.2
1 (1H, d, J = 7.0 Hz), 6.52 (1H, d
d, J = 9.4, 7.0 Hz), 6.92 (1H, d,
J = 8.1 Hz), 6.93 (1H, dd, J = 8.
1,1.9 Hz), 7.10 (1H, d, J = 8.1H
z), 7.12 (1H, d, J = 2.1 Hz), 7.2
0 (1H, dd, J = 8.1, 1.9Hz), 7.27
(1H, d, J = 1.9 Hz), 9.95 (1H, br
-S).

Example 12 N- [3- (3,4,5-trihydroxyphenyl)-
2,3-dihydro-6- (2-hydroxyethyl)-
Synthesis of 1,4-benzodioxin-2-yl] acetamide (Compound 12) By a method similar to that in Example 9, N- [3- (3-benzyloxy-4-methoxyphenyl) -2,3-dihydro-6- was used.
Instead of (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide (Compound 7),
N- [3- (3,5-dibenzyloxy-4-hydroxyphenyl) -2,3-dihydro-6 obtained in Example 4
The reaction was performed using-(2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide (Compound 4) to obtain the title compound (Compound 12) in a yield of 80%.

¹ H-NMR (pyridine-d ₅ ): δ 1.89 (3H, s), 2.90 (2H, t, J = 6.
8Hz), 4.02 (2H, t, J = 6.8Hz),
5.17 (1H, d, J = 6.8Hz), 6.55 (1
H, dd, J = 9.6, 6.8 Hz), 6.85 (1
H, dd, J = 8.1, 2.1 Hz), 7.02 (1
H, d, J = 8.1 Hz), 7.15 (2H, s),
9.96 (1H, d, J = 9.6Hz).

Example 13 N- [3- (3,4-dihydroxyphenyl) -2,3
Synthesis of -dihydro-8-hydroxy-1,4-benzodioxin-2-yl] acetamide (Compound 13) N- [3- (3-Benzyloxy-4-methoxyphenyl) -2 was prepared in the same manner as in Example 9. , 3-dihydro-6-
Instead of (2-benzyloxyethyl) -1,4-benzodioxin-2-yl] acetamide (Compound 7),
N- [3- (3-benzyloxy-4 obtained in Example 6
-Hydroxyphenyl) -8-benzyloxy-2,3-
The reaction was performed using dihydro-1,4-benzodioxin-2-yl] acetamide (Compound 6) to obtain the title compound (Compound 13) in a yield of 60%.

¹ H-NMR (pyridine-d ₅ ): δ 1.77 (3H, s), 4.69 (1H, d, J = 7.
27 Hz), 5.55 ((1H, t, J = 7.27,
9.19 Hz), 6.36 to 6.78 (6 H, m),
8.86 (1H, d, J = 9.19 Hz).

Example 14 N- {2- [N- (methoxycarbonylmethyl) carbamoyl] phenyl} -3- (3-methoxy-4-hydroxyphenyl) -2,3-dihydro-1,4-benzodioxin- Synthesis of 2-Carboxylic Acid Amide (Compound 14) 3- (3-Methoxy-4-methoxymethoxyphenyl)
-2,3-Dihydro-1,4-benzodioxin-2-
Carboxylic acid 100 mg and carbonyldiimidazole 52
mg and tetrahydrofuran were stirred in 1 ml of tetrahydrofuran at room temperature for 2 hours. After 2 hours, a solution of 66 mg of 2-aminobenzoylglycine methyl ester in 1 ml of methylene chloride was added, and the mixture was stirred at room temperature for 18 hours. After distilling off the solvent, 2 ml of methanol was added to the obtained residue, 0.1 ml of 4N-hydrogen chloride ethyl acetate solution was further added, and the mixture was stirred at room temperature for 1.5 hours. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography to give the title compound (compound 1
4) was obtained in 75 mg (53% yield).

¹ H-NMR (CDCl ₃ ): δ 3.78 (3H, s), 3.82 (3H, s), 4.1
6 (1H, d, J = 6Hz), 4.73 (1H, d, J
= 5 Hz), 5.27 (1H, d, J = 5 Hz), 5.
81 (1H, s), 7.85 to 8.57 (11H,
m), 8.47 (1H, d, J = 9 Hz).

Example 15 N- [4- (3-Ethoxy-2-hydroxypropoxy) phenyl] -3- (methoxy-4-hydroxyphenyl) -2,3-dihydro-1,4-benzodioxin-2- Synthesis of Carboxylic Acid Amide (Compound 15) In the same manner as in Example 14, 2-aminobenzoylglycine methyl ester was used in place of 2-aminobenzoic acid methyl ester for reaction, and the title compound (Compound 15) was obtained. Obtained with a yield of 50%.

¹ H-NMR (CDCl ₃ ): δ 1.21 (3H, t, J = 9 Hz), 3.45 to 4.2
1 (7H, m), 3.85 (3H, s), 4.73 (1
H, d, J = 6Hz), 5.21 (1H, d, J = 6H)
z), 5.72 (1H, s), 6.72 to 7.36 (1
1H, m), 7.88 (1H, br-s).

Example 16 N- (2-methoxycarbonylphenyl) -3- (3-
Synthesis of methoxy-4-hydroxyphenyl) -2,3-dihydro-1,4-benzodioxin-2-carboxylic acid amide (Compound 16) In the same manner as in Example 14, instead of 2-aminobenzoylglycine methyl ester. , P- (3-ethoxy-2
The reaction was performed using -hydroxy) propoxyaniline to obtain the title compound (Compound 16) in a yield of 40%.

¹ H-NMR (CDCl ₃ ): δ 3.83 (3H, s), 3.92 (3H, s), 4.7
6 (1H, d, J = 6Hz), 5.28 (1H, d, J
= 6 Hz), 5.64 (1 H, s), 6.71 to 8.0
0 (11H, m), 8.58 (1H, d, J = 9H
z).

Example 17 N-[(1-Methoxycarbonyl-2-ethylcarbamoylthio) ethyl] -3- (3-methoxy-4-hydroxyphenyl) -2,3-dihydro-1,4-benzodioxin- Synthesis of 2-Carboxylic Acid Amide (Compound 17) In the same manner as in Example 14, S-ethylcarbamoylthiocysteine methyl ester was used instead of 2-aminobenzoylglycine methyl ester to carry out the reaction.
A diastereomeric mixture of the title compound (Compound 17) was obtained with a yield of 70%.

¹ H-NMR (CDCl ₃ ): δ 1.08, 1.16 (both 3H, t, J = 8H
z), 3.14 to 3.34 (4H, m), 3.67,
3.71 (both3H, s), 3.86 (3H,
s), 4.54 to 4.77 (2H, m), 5.03 to
5.14 (1H, m), 5.23 to 5.54 (1H, b
r), 5.74 (1H, br), 6.80-8.10.
((7H, m), 7.40 to 7.80 (1H, br).

The contents of the present invention will be described in more detail below with reference to the results of pharmacological tests.

In these experiments, no deaths were observed in each compound-administered group, and no change in appearance was observed.

Pharmacological Test Example 1 In Vitro D-Galactosamine Evaluation of Effect in Hepatopathy Model Primary cultured hepatocytes (hereinafter hepatocytes) were prepared according to the method of Nakamura et al.
Nucleic Acid / Enzyme Separate Volume, No. 24, 55-76). That is, male Wistar rats (7 weeks old)
The liver was perfused with 0.05% collagenase to disperse the hepatocytes, and centrifugation (50 × G, 1 minute) was repeated 3 times to collect only hepatocytes. 2 x 10 ⁶ obtained hepatocytes were added to 3
A 5 mm dish was inoculated on a Williams' E medium containing 10% calf serum, and statically cultured at 37 ° C. for 2 hours in 5% CO ₂ . After culturing, the medium was replaced with a new medium, a compound dissolved in ethanol was added, and the mixture was treated with 1 mM D-galactosamine (GAL), and after 24 hours, the glutamate-pyruvate transaminase (GPT) leaked to the medium was transaminase. C-II Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.) was used for measurement, and the morphology of hepatocytes was also observed with a phase contrast microscope.
The inhibitory effect on hepatocyte damage was examined. The results obtained are shown in Table 1.

[0124]

[Table 1]

As shown in Table 1, the effect was observed with all the compounds.

Pharmacological Test Example 2 Effect of Active Ingredient in In Vitro t-BHP Liver Injury Model 2 × 10 ⁶ hepatocytes obtained in the same manner as in Pharmacological Test Example 1 were treated with 35% dish of 5% calf serum. The cells were seeded on William's E medium containing 5% CO ₂ and incubated at 37 ° C. for 20 hours in static culture. After culturing, the medium was replaced with a new medium, the compound dissolved in ethanol was added, and after 1 hour, 1 mM tert.
-Butyl hydroperoxide (t-BHP),
After 1 hour, the culture supernatant was collected, lactate dehydrogenase (LDH) was measured using lactate dehydrogenase C-II Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.), and the morphology of hepatocytes was also observed with a phase contrast microscope. The inhibitory effect on hepatocyte damage was examined. The obtained results are shown in Table 2.

[0127]

[Table 2]

As shown in Table 2, the effect was observed with all the compounds.

Hepatocytes remaining in the dish obtained in the same manner were recovered, and lipid peroxide was added to the stain (Stac
ey, N.N. H) and other methods (Toxico
l. Appl. Pharmacol. , 53, 470
480 (1980)) and also the morphology of hepatocytes was observed with a phase contrast microscope to determine the effect. The results obtained are shown in Table 3.

[0130]

[Table 3]

As shown in Table 3, the effect was observed with all the compounds.

Pharmacological test example 3 γ-interferon production enhancing action in mouse splenocytes Spleens were isolated from male ddY mice (5 weeks old), and splenocytes were separated. The obtained spleen cells were seeded on a 24-well microplate in RPMI1640 medium containing 10% fetal bovine serum so that the cell density was 10 ⁷ cells / well, and 5% C was added.
Incubation was carried out in O ₂ at 37 ° C. for 1 hour. After culturing, splenocytes were stimulated with concanavalin A (ConA: 5 μg / ml), and then a compound dissolved in ethanol was added. 48
After a lapse of time, the culture supernatant was collected, and γ-interferon (γ
-IFN) by ELISA (Holland biot)
technology). The results obtained are shown in Table 4.

[0133]

[Table 4]

As can be seen in Table 4, the compounds of the present invention are C
2 times more than γ-IF compared with the case where only onA was stimulated
Enhanced N production.

Pharmacological Test Example 4 Effect in GAL Liver Injury Model in vivo 50 Wistar male rats were bred for 1 week and used in groups of 10 10 rats each. Rats (7 weeks old) were administered with Compound 16 which was heated and dissolved, and then GAL was added to 400 mg.
After subcutaneous administration at a dose of / kg, fasting was performed, and 24 hours later, blood was collected from the inferior vena cava to measure GPT in plasma, and the inhibitory effect on hepatocyte damage was examined. The results obtained are shown in Table 5.

[0136]

[Table 5]

From the results in Table 5, it was found that 1
At a dose of 00 mg / kg, and 200 mg by oral administration
The effect was confirmed at a dose of / kg, and it was shown to be a therapeutic agent for liver disease that can be treated even by oral administration.

Pharmacological Test Example 5 Antiviral Activity The antiviral activity was examined using mouse leukemia virus (MLV) and herpes simplex virus (HSV) as models of hepatitis virus. Operation is low (R
owe, W.W. P. ) Et al. (Virology, 4
2, 1136 to 1139 (1970)). That is, SC cells were inoculated into a 24-well plate in 0.8 ml of 3.5 × 10 ⁴ cells / ml in a MEM medium containing 10% fetal bovine serum and cultured for 1 day. After 1 day, 0.1 ml of solutions of various concentrations of compound and 20-40 p. f. u's M
Add 0.1 ml of LV-containing medium at 37 ° C in 5% CO _2.
The cells were cultured for 5 days. 5 days later, 3 at 175 Wcm ² intensity
The infected cells were killed by UV irradiation for a minute, and XC cells were inoculated on the cells at a concentration of 0.8 × 10 ⁵ cells and cultured at 37 ° C. for 4 days. After 4 days, the cells were washed with physiological phosphate buffer solution (PBS) and stained with 0.05% crystal violet to count the number of plaques. The effect was determined by the% inhibitory drug concentration (MIC ₅₀ ). In addition, the same operation was performed using HSV, staining was performed with 0.05% neutral red, the number of plaques was counted, and the effect was determined by MIC ₅₀ . The obtained results are shown in Table 6.

[0139]

[Table 6]

From Table 6, it was shown that the antiviral activity of the compound of the present invention is remarkable.

[0141]

The 1,4-benzodioxane derivative of the present invention is extremely effective as a therapeutic agent for liver diseases including viral hepatitis, alcoholic liver injury and drug-induced liver injury.

Claims (7)

[Claims] 1. A compound represented by the general formula (I): [Wherein R ¹ represents a hydrogen atom, a lower alkyl group or a benzyl group, R ² represents a hydrogen atom or a lower alkyl group, R ^2
3 represents a hydrogen atom, a hydroxyl group or a benzyloxy group. X
Represents a hydrogen atom, a hydroxyl group or a benzyloxy group, n represents 0 or 1, and A represents a lower alkylene group. Y is-
An NHCOR ⁴ group or a -COR ⁵ group is shown. Here, R ⁴ represents a lower alkyl group, and R ⁵ represents a protected sulfur-containing amino acid residue or a phenyl-substituted amino group. However, R ¹ ,
Except when R ² and R ³ are hydrogen atoms, Y is an acetamide group, and — (A) n—X is substituted with a hydroxyethyl group at the 7-position and is a hydrogen atom. ] The 1,4-benzodioxane derivative represented by these, and its pharmaceutically acceptable salt. 2. R ¹ is a hydrogen atom or a lower alkyl group, R
² is a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or a hydroxyl group, X is a hydrogen atom or a hydroxyl group, n is 0 or 1, A is a methylene group, Y is an acetamide group or a -COR ⁵ group (R
^5. A 1,4-benzodioxane derivative and a pharmaceutically acceptable salt thereof according to claim 1, wherein ⁵ is a protected sulfur-containing amino acid residue or a phenyl-substituted amino group). 3. R ¹ is a hydrogen atom or a lower alkyl group, R 1
² and R ³ are hydrogen atoms, X is a hydrogen atom or a hydroxyl group, n is 0, Y is an acetamide group or a -COR ⁵ group (R ⁵ is a protected sulfur-containing amino acid residue or a phenyl-substituted amino group)
The 1,4-benzodioxane derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 4. The 1,4-benzodioxane derivative and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ , R ² and R ³ are hydrogen atoms. 5. The 1,4-benzodioxane derivative and the pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a methyl group and R ² and R ³ are hydrogen atoms. 6. The 1,4-benzodioxane derivative according to claim ¹ , wherein R ¹ , R ² and R ³ are hydrogen atoms, n is 0, X is a hydroxyl group and Y is an acetamido group, and a pharmaceutically acceptable derivative thereof. Salt. 7. R ¹ is a methyl group, R ² and R ³ are hydrogen atoms, n is 0, X is a hydrogen atom, and Y is a —COR ⁵ group (R 5 is a protected sulfur-containing amino acid residue or phenyl-substituted amino group). The 1,4-benzodioxane derivative according to claim 1 and a pharmaceutically acceptable salt thereof.