JP2588193B2 - Benzodioxole derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a benzodioxole derivative having an excellent action as a therapeutic drug for liver disease.

[Background of the Invention and Prior Art]

The etiology, pathology, and pathophysiology of liver disease are not uniform, and there are many unclear points. Therefore, it is presently extremely difficult to develop a therapeutic drug for liver disease.

At present, glycyrrhizin preparations can be mentioned as typical drugs widely used for treatment and prevention of this liver disease and evaluated clinically. However, glycyrrhizin preparations are said to be effective for liver damage, cirrhosis, hepatitis, liver protection after surgery, etc., but their medicinal effects are not so strong and there is a problem that they have steroid-like side effects. Furthermore, glycyrrhizin preparations are intravenous preparations, but have the drawback of being ineffective orally.

Under such circumstances, there is a need for the development of a highly safe and orally effective drug.

In view of such circumstances, the present inventors have started exploratory research in order to develop a new therapeutic agent for liver disease.

The present inventors have conducted long-term research on plants used in the private sector as a material, and as a result, have found that Petivelia alliacea L. and Cinnamomum porrectum (Roxb.) Kos.
term.)
[(Phenylmethyl) trithio] ethanol (A) and Cubevin (B) were found to be active compounds effective as therapeutic agents for liver diseases.

Subsequently, the present inventors have made these compounds as basic compounds, synthesized various compounds, and conducted intensive studies on the pharmacological activities thereof. As a result, the benzodioxol derivative represented by the following general formula (I) or The present inventors have found that the pharmacologically acceptable salt is a compound having higher safety and being more effective as a therapeutic agent for liver disease, and completed the present invention.

The following two patent applications have been published for the treatment of liver disease, but differ in chemical structure from the benzodioxole derivative of the present invention.

That is, the compounds disclosed in JP-A-62-29522 are compounds in which a saturated alkyl group is bonded to the phenyl ring of benzodioxole, and are mostly known compounds.

Japanese Patent Application Laid-Open No. 62-39583 discloses a (1,3-benzodioxol-5-yl) methylthio derivative, but the compound bonded to S is pyridine, pyrimidine, thiadiazole or the like. It is a heterocyclic ring and has a significantly different structure from the compound of the present invention.

As described above, the present invention was inspired by the compounds (A) and (B) discovered by the present inventors themselves from plant components, and led to the present invention compound (I) described below.
The idea is different from the inventions disclosed in the publications, and accordingly, the chemical structure is different from the two patent applications.

[Structure and effect of the invention]

The target compound of the present invention is a benzodioxole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ and R ² represent the same or different hydrogen atoms or lower alkyl groups.

R ³ is a hydrogen atom, a lower alkyl group or a formula-(CH ₂ ) _n COOH
(Wherein, n represents an integer of 1 to 3).

R ⁴ and R ⁵ represent the same or different hydrogen atoms or lower alkyl groups.

X is a group represented by the formula -S-, A group represented by or Means a group represented by

A is a group represented by the formula — (CH ₂ ) _n ′ -Het (where n ′ represents an integer of 1 to 3, and Het represents a substituted or unsubstituted nitrogen-containing heterocyclic ring); A group represented by A group represented by (Wherein, R ⁶ and R ⁷ represent the same or different hydrogen atoms or lower alkyl groups), a group represented by the formula —CH ₂ —CN, Wherein R ⁸ represents a lower alkyl group, or (Wherein p represents an integer of 1 to 3, and R ⁹ and R ¹⁰ represent the same or different lower alkyl groups). Where A is (Wherein R ⁶ and R ⁷ have the same meanings as above), except when all of R ^{1 to} R ⁵ are hydrogen atoms.

In the above definition of the compound (I) of the present invention,
The lower alkyl group found in the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is a straight or branched chain having 1 to 6 carbon atoms. A branched alkyl group, for example, a methyl group, an ethyl group,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,
1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3
-Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethyl Butyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,
It means a 1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group, and the like. Among these, preferred groups include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

The heterocycle (Het) in the definition of A means a nitrogen-containing heterocyclic group, and specifically, for example, pyridine, pyrazine, pyrimidine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole ring, and the like. Can be mentioned. These rings may be substituted with a lower alkyl group such as a methyl group, a hydroxyl group, or the like. Among these heterocyclic groups, preferred examples include a pyridyl group, an imidazolyl group, an isoxazolyl group, and the like.

The pharmacologically acceptable salts are conventional non-toxic salts, for example, alkali metal salts such as sodium salt, potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, trimethylamine salt, triethylamine salt, Organic amine salts such as pyridine salts, picoline salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, and ammonium salts. In the target substance (I), A is When represented by, the sodium salt is most preferred. Further, depending on the substituent, for example, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, phosphate, etc., for example, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfone Organic acid salts such as acid salts, and salts with amino acids such as arginine, aspartic acid and glutamic acid can be exemplified. In addition, some compounds may form hydrates.

The compound of the present invention has an asymmetric carbon depending on the type of the substituent, and may have optical isomers, but it goes without saying that these belong to the scope of the present invention.

Production Method Although various methods for producing the compound of the present invention can be considered, typical methods are described below.

Production method A [in the case where X is a group represented by the formula -S- in the general formula (I)] [In the formulas (II)-(IV), Y represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and A, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as those described above. Has the meaning of That is, the thiol represented by the general formula (II) and the thiol represented by the general formula (II)
By reacting with the compound represented by I), compound (IV), which is one of the target substances, can be obtained. In particular,
Without solvent or for example, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as tetrahydrofuran and dioxane, acetone, ketones such as methyl ethyl ketone, alcohols such as methanol and ethanol, chloroform, carbon tetrachloride and the like Halogenated hydrocarbons, further acetonitrile, N, N- dimethylformamide, dimethyl sulfoxide In an organic solvent not involved in the reaction selected from the reaction under ice cooling or room temperature ~ heating for several hours by a conventional method. Do. In this case, sodium bicarbonate, potassium carbonate, alkali metal carbonates such as sodium carbonate, or carbonates, sodium hydroxide, alkali hydroxides such as potassium hydroxide, or triethylamine, pyridine, diethylaniline The reaction proceeds easily by using such organic bases, furthermore, sodium hydride or the like as a dehydrohalogenating agent, a demethansulfonic acid agent or a de-p-toluenesulfonic acid agent.

Production method B [in the case where X is a group represented by the formula -S- in the general formula (I)] [In the formulas (IV) to (VI), Y represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and A, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as those described above. That is, the compound represented by the general formula (V) and the compound represented by the general formula (VI)
Is reacted under the same conditions as in Production Method A to give compound (IV), one of the target substances. Also in this case, it is preferable to use the base shown in Production method A.

In the production methods A and B, the halogen atom includes chlorine, bromine, iodine and the like, but usually bromine and iodine are used.

Production Method C [In the case where X is a group represented by the formula -S- in the general formula (I)] Wherein A, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as described above. That is, the compound represented by the general formula (VII) and the compound represented by the general formula (V
The compound (IV) as one of the target substances can be obtained by reacting with the thiol represented by (I). Specifically, without solvent, or for example, aromatic hydrocarbons such as benzene, toluene, xylene, tetrahydrofuran, ethers such as dioxane, dichloromethane, chloroform,
In a solvent selected from halogenated hydrocarbons such as carbon tetrachloride, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, and further acetonitrile and N, N-dimethylformamide under ice cooling. Alternatively, the reaction is performed by a conventional method from room temperature to heating under reflux.

When the reaction progresses slowly, a catalyst such as a peroxide such as benzoyl peroxide or azobisisobutyronitrile can be added.

Production method D [in the case where X is a group represented by the formula -S- in the general formula (I)] [Wherein, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the same meaning as described above. That is, a cyano compound represented by the general formula (VIII), which is one of the target substances, is reacted with carbon dioxide in the presence of a base to produce a carboxylic acid represented by the general formula (IX), which is one of the target substances. Is what you get. Specifically, the compound (VIII) is dissolved without solvent or in an ether-based anhydrous solvent such as anhydrous ether, anhydrous tetrahydrofuran, or anhydrous ethylene glycol dimethyl ether, and dried under dry ice-alcohol cooling to ice cooling. Compound (IX) can be obtained by reacting a strong base such as butyllithium, phenyllithium, lithium diisopropylamide, or sodium amide, and then reacting carbon dioxide under dry ice-alcohol cooling to ice cooling.

In the compound (IX), in the general formula (I), X is represented by the formula -S-, and A is And one of the target substances of the compound of the present invention.

Production Method E [In the general formula (I), when X is a group represented by the formula -S-] [Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , R ¹⁰ , and p have the same meanings as described above] That is, sodium sulfonate represented by the general formula (X) Is suspended in a solvent such as benzene or chloroform, and then the mixture is added with, for example, thionyl chloride and reacted under heating and reflux to obtain an acid chloride of the compound (X). Below or water, methanol, ethanol, benzene, dichloromethane, tetrahydrofuran,
The compound (XII) which is one of the target substances can be obtained by reacting in a solvent such as N, N-dimethylformamide in the presence of a base. In this case, examples of the base used include amine (XI) itself, pyridine, N, N-dimethylaniline and triethylamine.

In the compound (XII), in the general formula (I), X is represented by the formula -S-, and A is And one of the target substances of the compound of the present invention.

Production method F [In the general formula (I), X is If it is a group represented by [Wherein A, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the above-mentioned meanings] The present reaction is, for example, the reaction of one of the target compounds (IV) obtained by the above-mentioned method. Oxidation gives (XIII), one of the target compounds. Specifically, compound (IV) is converted into aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, and alcohols such as water, methanol and ethanol. , Further dissolved in a solvent selected from ethyl acetate, acetone, acetic acid, etc., under cooling with dry ice-alcohol or ice water,
An equimolar amount of an oxidizing agent such as, for example, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite is added, and the mixture is reacted by a conventional method to give a sulfoxide compound (XIII), one of the target compounds. Obtainable.

Production method G [In the general formula (I), X is If it is a group represented by [Wherein A, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the above-mentioned meanings] The present reaction is, for example, the reaction of one of the target compounds (IV) obtained by the above-mentioned method. Oxidation gives (XIV), one of the target compounds. Specifically, the compound (I
V), for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, and further ethyl acetate; Acetone, dissolved in a solvent selected from acetic acid and the like, and at least 2 equivalents of hydrogen peroxide under ice-cooling or room temperature,
An oxidizing agent such as peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite, sodium m-periodate, etc. is added and reacted to obtain a sulfone compound (XIV) as one of the target compounds. Can be.

Further, as another production method, for example, the sulfoxide compound (XIII) obtained by the method of Production Method F may be dissolved in a solvent such as chloroform, and an oxidizing agent such as m-chloroperbenzoic acid may be added and reacted. it can.

The target substance (I), which is one of the target substances of the present invention,
When producing a pharmacologically acceptable salt of, for example, in the general formula (I), A is Wherein R ³ is-(CH ₂ ) _n COOH or A is Is reacted with sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. to produce a pharmacologically acceptable salt such as the aforementioned sodium salts and potassium salts. be able to.

Next, pharmacological experimental examples will be described in order to explain the effects of the compound of the present invention in detail.

Pharmacological Experimental Example Experimental Example 1 Effect on D-Galactosamine Liver Injury Model Experimental Method D-galactosamine was applied to male Fischer ( _F344 ) rats weighing around 180 g
Galactosamine 300 mg / kg was administered subcutaneously to induce liver damage. Each test compound is dissolved in distilled water or suspended in 0.5% methylcellulose aqueous solution, and a dose of 50 mg / kg is added to D-
Oral administration was performed 1 hour after galactosamine administration.

Forty-eight hours after the administration of D-galactosamine, blood was collected from the tail of the rat, and the blood clotting time was measured by a hepaplastin test (HPT), and the GPT activity in plasma was measured by an enzymatic method.

Table 1 shows the inhibitory rate of each test compound against liver damage caused by D-galactosamine.

To prepare a pathology intraperitoneal administration carbon tetrachloride 0.5 ml / kg in Experiment 2 carbon tetrachloride (CC1 ₄₎ acting Experimental method weighing 180g around the Fischer based on liver injury model (F ₃₄₄₎ male rats. Carbon tetrachloride was diluted with olive oil to a final concentration of 0.25 ml / ml.

Each test compound is dissolved in distilled water or suspended in 0.5% methylcellulose aqueous solution.
A dose of 100 mg / kg was administered orally.

Twenty-four hours after the administration of carbon tetrachloride, blood was collected from the tail of the rat, and the GPT activity in plasma was measured by an oxygen method as an indicator of liver damage. Table 2 shows the inhibition rate of liver damage by carbon tetrachloride of each test compound.

Experimental Example 3 Toxicity test Using 7-week-old ddy male mice weighing around 30 g, Table 1
Orally administered for 4 days (dose 800 mg /
kg), none of the compounds died.

It is clear from Experimental Examples 1 and 2 that the compound of the present invention significantly suppresses liver damage caused by D-galactosamine and carbon tetrachloride, and has high utility as a therapeutic agent for liver disease.

Therefore, the compound of the present invention is useful as a therapeutic / prophylactic agent for various liver disorders in animals including humans, and specifically, for example, chronic hepatitis, acute hepatitis, drug-toxic liver disorder, viral hepatitis, alcoholic hepatitis , Jaundice, and the treatment or prevention of liver cirrhosis, which is the terminal image thereof.

Furthermore, the compound of the present invention has extremely low toxicity and high safety, as is clear from Experimental Example 3. Therefore, the compound of the present invention often requires continuous administration for a long period of time due to the nature of the disease. In this sense, the present invention is highly valuable.

When the compound of the present invention is administered as a therapeutic or prophylactic agent for liver disease, it may be administered orally as tablets, powders, granules, capsules, syrups and the like, or sprays, suppositories,
It may be administered parenterally as an injection, an external preparation, or a drip. The dosage varies significantly depending on the severity of symptoms, age, type of liver disease, etc., but usually about 0.1 mg to 1,000 mg per adult per day.
mg, preferably 2 mg to 500 mg, more preferably 5 to 100 mg
Is administered once to several times a day.

At the time of formulation, it is manufactured by an ordinary method using a usual formulation carrier.

That is, when preparing a solid preparation for oral use, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, if necessary, and then a tablet, Coated tablets, granules, powders, capsules, etc.

As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., as binders, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, doxtrin, pectin, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. Is approved, but as flavoring agents, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain,
For example, cinnamon powder is used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizing agent, and the like are added to the main drug, if necessary, to give a subcutaneous, intramuscular, or intravenous injection according to a conventional method.

Next, examples of the present invention will be described. However, it is needless to say that the present invention is not limited to these examples.

Production methods for starting materials used in producing the compound of the present invention are shown in Production Examples 1 to 9.

Production Example 1 2- (1,3-benzodioxol-5-yl) ethanethiol 750 g of 5- (2-bromoethyl) -1,3-benzodioxole was dissolved in ethanol 1, 312 g of thiourea was added, and the mixture was heated and refluxed on a boiling water bath for 2 hours. After cooling the reaction solution, a solution prepared by dissolving 300 g of sodium hydroxide in water 1 was added, and the mixture was heated under reflux on a boiling water bath for 45 minutes. After cooling, 3 l of water was added and extracted with 5 l of ethyl acetate, which was washed with diluted hydrochloric acid. Next, the solution was washed with water until the solution became almost neutral, dried over anhydrous sodium sulfate, and the solvent was distilled off at 40 ° C. to obtain about 570 g of a yellowish oily substance. This was subjected to column chromatography using about 3 kg of silica gel (hexane: benzene =
2: 1) to give 310 g of the title compound as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.36 (m, 1H), 2.6~2.9
(M, 4H), 5.87 (s, 2H), 6.50-6.74 (m, 3H) Production Example 2 3-acetoxy-4- (2-hydroxyethyl) -5
Methyl isoxazole 7.8 g of 4- (2-hydroxyethyl) -5-methylisoxazol-3-ol was dissolved in tetrahydrofuran 1, and 1.70 g of sodium hydride was added thereto under ice-cooling.
After stirring for 0 minutes, the mixture was ice-cooled again, 4.7 g of acetyl chloride was added, and the mixture was stirred at room temperature. After evaporating the solvent, water was added, the mixture was extracted with chloroform, washed with brine, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue is subjected to silica gel column chromatography (chloroform).
Purification afforded 2.96 g of the title compound as colorless prisms. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.30 (s, 3H), 2.49 (t, J =
6.1 Hz, 2H), 2.56 (s, 3H), 3.76 (t, J = 6.1 Hz, 2H) Production Example 3 5- (2-hydroxyethyl) -2-methyl-1,3-benzodioxole 1.0 g of 3,4-dihydroxyphenylacetic acid and 1.4 g of vinyl acetate
g, 6 mg of mercury oxide (yellow) and 0.03 ml of boron fluoride / ethyl etherate in 9 ml of toluene were stirred at room temperature for 14 hours. The reaction solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The obtained oil was dissolved in 10 ml of tetrahydrofuran, and added dropwise to a suspension of 0.5 g of lithium aluminum hydride in tetrahydrofuran under ice-cooling. After stirring at room temperature for 1 hour, 0.5 ml of water and 0.5% of 15% aqueous sodium hydroxide solution were added under ice-cooling.
ml and then 1.5 ml of water were added in this order, and the insoluble matter was removed by filtration. The filtrate is concentrated and subjected to silica gel column chromatography (ethyl acetate /
Separation with hexane = 1: 1) yielded 0.8 g of the title compound as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.66 (d, J = 5Hz, 3H), 1.74
(M, 1H), 2.73 (t, J = 6Hz, 2H), 3.72 (m, 2H), 6.14
(Q, J = 5 Hz, 1H), 6.59 (s, 3H) Production Example 4 2,2-dimethyl-5 (2-hydroxyethyl) -1,3-benzodioxole 1.7 g of 3,4-dihydroxyphenylacetic acid and a catalytic amount of p-
Toluenesulfonic acid in 18 ml of acetone 10 ml and benzene 10 ml
Heated to reflux for an hour. The reflux liquid was dehydrated with molecular sieves 4A. The reaction solution was concentrated, and the resulting black-brown oil was dissolved in 20 ml of tetrahydrofuran and added to a suspension of 0.8 g of lithium aluminum hydride in 30 ml of tetrahydrofuran under ice-cooling. After stirring at room temperature for 1 hour, the mixture was cooled with ice water and water was added.
8 ml, 0.8 ml of 15% sodium hydroxide and 2.4 ml of water were added in this order, and insolubles were removed by filtration. The filtrate was concentrated and separated by silica gel column chromatography (ethyl acetate / n-hexane = 1: 1) to obtain 1.1 g of the title compound as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.67 (s, 6H), 1.7 (m, 1
H), 2.73 (t, J = 6 Hz, 2H), 3.75 (bt ,, J = 6 Hz, 2H),
6.56 (m, 3H) Production Example 5 2- (6-methyl-1,3-benzodioxol-5-yl) ethanol (A) 5- (2-benzyloxyethyl) -6-bromo-1,3-benzodioxole Dissolve 15.0 g of 5- (2-acetoxyethyl) -1,3-benzodioxole in 10 ml of carbon tetrachloride and add bromine 4.6 under ice-cooling.
g was added, and the mixture was heated to room temperature and reacted for 2 hours. To this was added aqueous sodium bicarbonate, and extracted with chloroform. The extract was washed with an aqueous sodium thiosulfate solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude bromide as brown needles.

This was added without purification to methanol in which 8.6 g of sodium hydroxide was dissolved, and reacted at 60 ° C. for 1.5 hours. The methanol was removed, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a yellow oily residue.

This was added unpurified to a solution of 3.8 g of sodium hydride in 150 ml of dimethylformamide, stirred at 60 ° C. for 30 minutes, and cooled to room temperature. This is benzyl chloride
13.7 g was added dropwise and reacted again at 60 ° C. for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain crude benzyl ether. This was purified by silica gel column chromatography (ethyl acetate / hexane = 3: 97) to obtain 12.0 g of the title compound as a pale yellow oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.98 (t, J = 7Hz, 2H), 3.66
(T, J = 7Hz, 2H), 4.54 (s, 2H), 5.95 (s, 2H), 6.82
(S, 1H), 7.02 (s, 1H), 7.34 (s, 5H) (b) 5- (2-benzyloxyethyl) -6-methyl-1,3-benzodioxole 5- (2-benzyloxyethyl) -6-bromo-1,
Dissolve 3.0 g of 3-benzodioxole in 100 ml of anhydrous ether and 8.5 ml of 1.6 M n-butyllithium hexane solution at -78 ° C.
Was added and reacted at -50 ° C for 2 hours. The mixture was cooled again to -78 ° C, 6.4 g of methyl iodide was added, and the temperature was gradually raised to room temperature. Methanol and water were added to the reaction solution, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude methyl form. This was subjected to silica gel column chromatography (ethyl acetate / hexane = 2:98).
Purification afforded 1.9 g of the title compound as a pale yellow oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.20 (s, 3H), 2.82 (t, J =
7Hz, 2H), 3.58 (t, J = 7Hz, 2H), 4.48 (s, 2H), 5.82
(S, 2H), 6.56 (s, 1H), 6.60 (s, 1H), 7.44 (s, 5H) (c) 2- (6-methyl-1,3-benzodioxol-5-yl) ethynol 5- (2-benzyloxyethyl) -6-methyl-1,
Dissolve 1.9 g of 3-benzodioxole in 80 ml of ethanol, add 0.2 g of 10% palladium-carbon (50% water-containing product) and 4 ml
Acetic acid was added, and the mixture was catalytically reduced at 3 atm / cm ² for 1 hour. After filtering off the palladium-carbon and evaporating the ethanol, silica gel column chromatography (ethyl acetate / hexane = 2:
Purification in 3) yielded 1.0 g of the title compound as a pale yellow oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.88 (bs, 1H), 2.32 (s, 3
H), 2.88 (t, J = 7 Hz, 2H), 3.88 (t, J = 7 Hz, 2H), 5.9
6 (s, 2H), 6.76 (bs, 2H) Production Example 6 2- (6-ethyl-1,3-benzodioxol-5-yl) ethanol (A) (6-Ethyl-1,3-benzodioxole-5
-Yl) acetic acid Hydrogen chloride gas was blown into a mixture of 500 ml of concentrated hydrochloric acid, 1 of ethyl acetate and 900 ml of an aqueous formaldehyde solution.
-Ethyl-1,3-benzodioxole 600 g in ethyl acetate 3
A solution dissolved in 00 ml was dropped and allowed to react for 1 hour. Benzene was added thereto, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude chloro form as a pale yellow oil.

Dissolve the crude chloro form in 4 l of dimethyl sulfoxide, add 400 g of well ground sodium cyanide at room temperature,
Stir for 12 hours. To this, added to water, extracted with ethyl acetate, the extract was washed with water, dried over magnesium sulfate,
After concentration under reduced pressure, a crude cyano compound was obtained as a brown oil.

To a solution in which 800 g of sodium hydroxide was dissolved, a solution in which the crude cyano body was dissolved in 2 l of ethinol was added, and the mixture was heated under reflux for 16 hours. Ethanol was distilled off from the reaction solution, water was added thereto, and the mixture was washed with ether. The aqueous layer was acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.

Recrystallize the residual solid from ethyl acetate to give the title compound.
400 g were obtained as colorless crystals. ^{mp;. 114~115 ℃ 1 H-} NMR (90MHz, CDC1 3) δ; 1.16 (t, J = 7Hz, 3H), 2.52
(Q, J = 7Hz, 2H), 3.54 (s, 2H), 5.84 (s, 2H), 6.62
(S, 2H) (b) 2- (6-ethyl-1,3-benzodioxol-5-yl) ethanol A solution prepared by suspending 62 g of lithium aluminum hydride in 1.5 l of anhydrous tetrahydrofuran and dissolving 200 g of (6-ethyl-1,3-benzodioxol-5-yl) acetic acid in 200 ml of tetrahydrofuran at 0 ° C. was added dropwise. For 12 hours. After completion of the reaction, water was added, the precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / hexane = 1: 4) to obtain 169 g of the title compound as a pale yellow oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.16 (t, J = 7Hz, 3H), 2.80
(Bs, 1H), 2.54 (q, J = 7 Hz, 2H), 2.78 (t, J = 7 Hz, 2
H), 3.74 (t, J = 7 Hz, 2H), 5.84 (s, 2H), 6.60 (s, 1
H), 6.62 (s, 1H) Production Example 7 2- (6-propyl-1,3-benzodioxol-5-
Il) ethanol (A) (6-propyl-1,3-benzodioxole-
5-yl) acetonitrile 15 g of piperonyl butoxide and 300 ml of concentrated hydrochloric acid in benzene 10
It was dissolved in 0 ml and heated under reflux for 3 hours. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 6-
12 g of propyl-5-chloromethyl-1,3-benzodioxole were obtained as a light brown oil.

Of these, 2.0 g was dissolved in 30 ml of dimethyl sulfoxide, and 1.5 g of well ground sodium cyanide was added.
The reaction was performed at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / hexane = 7: 93) to obtain 1.7 g of the title compound as colorless needle crystals.

^{mp;. 66 ℃ ~67 ℃ 1} H-NMR (90MHz, CDC1 3) δ; 0.98 (t, J = 7Hz, 3H), 1.60
(Sext, J = 7Hz, 2H), 2.52 (t, J = 7Hz, 2H), 3.64 (s, 2H
H), 5.96 (s, 2H), 6.72 (s, 1H), 6.84 (s, 1H) (b) 2- (6-propyl-1,3-benzodioxol-5-yl) ethanol 1.7 g of (6-propyl-1,3-benzodioxol-5-yl) acetonitrile was added to a solution of 1.7 g of potassium hydroxide in 40 ml of 50% aqueous ethanol, and the mixture was heated under reflux for 14 hours. Ethanol was distilled off from the reaction solution under reduced pressure, water was added to the residue, washed with ether, the aqueous layer was acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 2- (6-propyl-1,3-benzodioxol-5-yl) acetic acid.

This was added to a solution of 0.64 g of lithium aluminum hydride in 20 ml of tetrahydrofuran at 0 ° C. and reacted for 1 hour.
Water was added to the reaction solution, the precipitate was filtered off, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / hexane = 3: 7) to obtain 1.4 g of the title compound as a colorless oil. . ^{1 H-NMR (90MHz, CDC1} 3) δ; 0.96 (t, J = 7Hz, 3H), 1.56
(Sext, J = 7Hz, 2H), 2.52 (t, J = 7Hz, 2H), 2.80 (t, J
= 7Hz, 2H), 3.78 (t, J = 7Hz, 2H), 5.89 (s, 2H), 6.6
8 (s, 2H) Production Example 8 1- (1,3-benzodioxol-5-yl) -2-methyl-1-propene 62.5 ml of a 1.6 M butyllithium / hexane solution was added to 500 ml of anhydrous ether, 38.5 g of isopropyltriphenylphosphonium bromide was added under a stream of nitrogen gas, and the mixture was stirred for 4 hours. 18 g of piperonal was added to the reaction solution, and the mixture was stirred for 5 hours. The reaction solution was filtered, washed with ether 1, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane / ethyl acetate 10: 1) to obtain 13.1 g of the title compound as a colorless oil. ¹ H-NMR (90 MHz, CDCL ₃ ) δ; 1.83 (d, J = 1 Hz, 3H), 1.86
(D, J = 1Hz, 3H), 5.92 (s, 2H), 6.15 (m, 1H), 6.56
-6.82 (m, 3H) Production Example 9 2-[{2- (1,3-benzodioxol-5-yl) ethyl} thio] ethanesulfonyl chloride (A) 2-[｛2- (1,3-benzodioxole-5
-Yl) ethyl {thio] ethanesulfonic acid sodium salt 15 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 17.4 g of sodium 2-bromoethanesulfonate were dissolved in a mixture of 280 ml of ethanol and 120 ml of water, and 3.3 g of sodium hydroxide was added. Heated to reflux for an hour. The reaction solution was concentrated, and 500 ml of ethyl acetate and 500 ml of water were added to carry out liquid separation. The aqueous layer was acidified with hydrochloric acid, extracted with n-butanol, washed with saturated saline, and then the solvent was distilled off to obtain 19 g of a yellowish residue. 2.94 g of sodium hydroxide
Was re-dissolved in a diluted methanol solution of the above to give 14.7 g of the title compound as colorless crystals. ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 2.72 (s, 8H), 5.94 (s,
2H), 6.56-6.88 (m, 3H) (b) 2-[{2- (1,3-benzodioxol-5-yl) ethyl} thio] ethanesulfonyl chloride 2-[{2- (1,3-benzodioxol-5-yl) -2-ethyl} thio] ethanesulfonic acid sodium salt (1.9 g) was suspended in N, N-dimethylformamide (4 ml), and the suspension was cooled under ice-water cooling. 0.89 g of thionyl was added dropwise. The mixture was stirred for 20 minutes under cooling with water, ice water was added to the reaction solution, and 200 ml of chloroform and 200 ml of water were added to carry out liquid separation. Wash the chloroform layer with water,
After drying over anhydrous sodium sulfate and evaporating the solvent, 2.1 g of the title compound was obtained as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.83 (s, 4H), 2.92~3.15
(M, 2H), 3.65-3.94 (m, 2H), 5.94 (s, 2H), 6.56-
6.85 (m, 3H) Example 1 [{2- (1,3-benzodioxol-5-yl) ethyl} thio] propan-2-one 90% of 10 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 5.1 g of 1-chloro-2-propanone
After dissolving in 200 ml of ethanol, 2.2 g of sodium hydroxide was added thereto, and reacted under heating and reflux for 10 minutes. The reaction solution was concentrated under reduced pressure, 200 ml of ethyl acetate was added, dissolved and washed three times with water. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (benzene / ethyl acetate = 30: 1) to obtain 11.1 g of the title compound as a colorless oily substance. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.25 (s, 3H), 2.50~2.90
(M, 4H), 3.17 (s, 2H), 5.85 (s, 2H), 6.40-6.75
(M, 3H) Example 2 MS m / z; 238 (M ⁺ ), 149 [{2- (1,3-benzodioxol-5-yl) ethyl} thio] acetonitrile By a method similar to that in Example 1, 8.5 g of the title compound was obtained as a colorless oil from 10 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 4.2 g of chloroacetonitrile. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.76~3.03 (m, 4H), 3.22
(S, 2H), 5.91 (s, 2H), 6.56 to 6.82 (m, 3H) MS m / z; 221 (M ⁺ ), 135 Example 3 2-Methyl-2-[｛2- (1,3 -Benzodioxol-5-yl) ethyl {thio] propionic acid By the same method as in Example 1, 6 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 4.6 g of 2-bromo-2-methylpropionic acid were used to give 6 g of the title compound as a colorless oil. Obtained. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.53 (s, 6H), 2.70~2.90
(M, 4H), 5.90 (s, 2H), 6.52 to 6.80 (m, 3H) Example 4 2-Methyl-2-[{2- (1,3-benzodioxol-5-yl) ethyl} Thio] propionic acid sodium acid A solution prepared by dissolving 0.90 g of sodium hydroxide in 9.0 ml of water in 6 g of 2-methyl-2-[{2- (1,3-benzodioxol-5-yl) ethyl} thio] propionic acid. In addition, after dissolution, 100 ml of ethanol was added and the solvent was distilled off. Ether was added to the residue, washed, filtered and dried under reduced pressure to obtain 6 g of the title compound as a white powder.

mp .; 261 to 265 ° C ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.32 (s, 6H), 2.52 to 2.
82 (m, 4H), 5.90 (s, 2H), 6.48 to 6.80 (m, 3H) MS (FAB) m / z; 313 (MNa ⁺ ), 291 (MH ⁺ ) Example 5 2-oxo-3- [{2- (1,3-benzodioxol-5-yl) ethyl} thio] propionic acid In the same manner as in Example 1, 0.21 g of the title compound was converted to keto-enol tautomerism from 0.50 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 0.43 g of 3-bromopyruvic acid hydrate. A pale yellow crystal was obtained as a mixture having a volume ratio of 2: 1.

^{mp;. 131~132 ℃ 1 H-} NMR (90MHz, CDC1 3 -DMSO-D 6) δ; 2.40~3.08 (m, 2
H + 1H x 1/3), 5.87 (s, 2H), 6.20 (s, 1H x 2/3), 6.4
0 to 6.84 (m, 3H), 8.10 (bs, 1H) MS m / z; 268 (M ⁺ ) Example 6 2- (1,3-benzodioxol-5-yl) ethyl (pyridine-4- Yl) methyl sulfide Dissolve 3.30 g of 2- (1,3-benzodioxol-5-yl) ethanethiol in 30 ml of ethanol, add 1.65 g of sodium hydroxide, and then 2.70 g of 4-picolyl chloride hydrochloride, and then at 70 ° C. for 30 minutes. The mixture was heated and stirred. After evaporating the solvent, water was added, and the mixture was extracted with ethyl acetate. 1N Hydrochloric acid was added to make the aqueous layer acidic, and the aqueous layer was separated and washed with ethyl acetate.
Next, potassium carbonate was added to the aqueous layer to adjust the pH to 8, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography (ethyl acetate / ethyl acetate).
Purification with hexane = 1: 4) gave 2.69 g of the title compound as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.4~2.87 (m, 4H) 3.60 (s,
2H), 5.86 (s, 2H), 6.35 to 6.75 (m, 3H), 7.05 to 7.25
(M, 2H), 8.25 to 8.57 (m, 2H) MS (FD) m / z; 273 (M ⁺ ) Example 7 2- (1,3-benzodioxol-5-yl) ethyl (pyridine- 2-yl) methyl sulfide 2.3 g of the title compound was obtained as a colorless oil from 3.0 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 2.7 g of 2-picolyl chloride hydrochloride in the same manner as in Example 6. Was. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.55~2.9 (m, 4H) 3.86 (s,
2H), 5.91 (s, 2H), 6.45-6.8 (m, 3H), 7.0-7.3
(M, 1H), 7.33 (bd, J = 7.9Hz, 1H), 7.61 (td, J = 7.9a)
nd 2.2 Hz, 1 H), 8.51 (bd, J = 5.8 Hz, 1 H) MS (FD) m / z; 273 (M ⁺ ) Example 8 2- (1,3-benzodioxol-5-yl) Ethyl (imidazol-4-yl) methyl sulfide 40 ml of thionyl chloride was added to 2.50 g of 4-vitroxyethylimidazole hydrochloride, and the mixture was heated and stirred at 70 ° C. for 1 hour.
Thionine chloride was distilled off, and 3.39 g of 2- (1,3-benzodioxol-5-yl) ethanethiol, 40 ml of ethanol and 1.50 g of sodium hydroxide were added thereto.
The mixture was heated and stirred for an hour. After evaporating the solvent, water was added, extracted with chloroform containing 5% methanol, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography (methanol / chloroform = 1: 49) to give 1.94 g of the title compound as colorless prisms.

^{mp;. 81~83 ℃ 1 H-} NMR (90MHz, CDC1 3) δ; 2.45~2.9 (m, 4H) 3.68 (s,
2H), 5.84 (s, 2H), 5.8-6.9 (broad, 1H), 6.4-6.7
5 (m, 3H), 6.86 (bs, 1H), 7.53 (bs, 1H) MS m / z; 262 (M ⁺ ) Example 9 4- [2- {2- (1,3-benzodioxole) -5-yl) ethyl {thio] ethyl-5-methylisoxazol-3-ol 3-acetoxy-4- (2-hydroxyethyl) -5
-Tetrahydrofuran 1 in 2.84 g of methyl isoxazole
To the mixture, 00 ml and 4.66 g of triethylamine were added, and 4.39 g of methanesulfonyl chloride was added dropwise at -15 ° C, followed by stirring at 0 ° C or lower for 1 hour. After evaporating the solvent, ice water was added, the mixture was extracted with chloroform, washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting methanesulfonate was converted to 2- (1,
3-benzodioxol-5-yl) ethanethiol 4.1
9 g, 30 ml of ethanol and 1.53 g of sodium hydroxide were added to the solution, and the mixture was heated and stirred at 70 ° C. After evaporating the solvent, water was added, and the mixture was extracted with chloroform containing 5% methanol, washed with brine, and dried over anhydrous magnesium sulfate. This was filtered, the filtrate was concentrated, purified by silica gel column chromatography, and recrystallized from ethyl acetate-hexane to obtain 0.96 g of the title compound as colorless needles.

^{mp;. 81~81.5 ℃ 1 H-} NMR (90MHz, CDC1 3) δ; 2.25 (s, 3H), 2.35~2.85
(M, 8H), 5.87 (s, 2H), 5.4 to 6.5 (br, 1H), 6.45 to
6.75 (m, 3H) MS m / z; 307 (M ⁺ ) Example 10 4- [2- {2- (1,3-benzodioxol-5-yl) ethyl} thio] ethyl-5-methyl Isoxazol-3-ol sodium salt In the same manner as in Example 4, 4- [2- {2- (1,
From 3-benzodioxol-5-yl) ethyl {thio] ethyl-5-methylisoxazol-3-ol 0.95, 1.01 g of the title compound was obtained as a white powder.

mp .; 144 to 152 ° C (dec.) ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.98 (s, 3H), 2.1 to 2.8
(M, 4H), 2.68 (bs, 4H), 5.88 (s, 2H), 6.48-6.9
(M, 3H) MS (FAB) m / z 352 (MNa ⁺ ), 330 (MH ⁺ ) Example 11 [{2- (2-methyl-1,3-benzodioxole-5)
-Yl) ethyl {thio] acetic acid 5- (2-hydroxyethyl) -2-methyl-1,3-
0.97 g of methanesulfonyl chloride was added dropwise to a methylene chloride (10 ml) solution of 0.76 g of benzodioxole and 1.2 ml of triethylamine under ice cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was diluted with chloroform, washed with cold water, saturated sodium hydrogen carbonate and brine in that order, and dried over magnesium sulfate. After distilling off the solvent, 0.9 g of mercaptoacetic acid, 10 ml of 10% sodium hydroxide and 10 ml of ethanol were added to the oily substance (mesylate) obtained.
The mixture was added and heated at 80 ° C. for 30 minutes. The reaction solution was concentrated, and the aqueous layer was washed with ethyl ether and then acidified with dilute hydrochloric acid. The aqueous layer was extracted with chloroform and dried over magnesium sulfate,
The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol / chloroform = 1: 99) to obtain 1.0 g of the title compound as a slightly brown oily substance. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.66 (d, J = 5Hz, 3H), 2.84
(S, 4H), 3.24 (s, 2H), 6.20 (q, J = 5Hz, 1H), 6.63
(M, 3H), 9.95 (m, 1H) Example 12 [{2- (2-methyl-1,3-benzodioxol-5)
-Yl) ethyl {thio] acetic acid sodium salt In the same manner as in Example 4, 0.7 g of the title compound was obtained as a white powder from 1.0 g of [{2- (2-methyl-1,3-benzodioxol-5-yl) ethyl} thio] acetic acid. .

mp .; 200-250 ° C (dec.) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.58 (d, J = 4.8 Hz, 3
H), 2.68 (m, 4H), 2.96 (s, 2H), 6.28 (q, J = 4.8Hz,
1H), 6.62 to 6.75 (m, 3H) MS (FAB) m / z 299 (MNa ⁺ ), 276 (MH ⁺ ) Example 13 [{2- (2,2-dimethyl-1,3-benzodioxy) Sole-
5-yl) ethyl {thio] acetic acid By the same method as in Example 11, 2,2-dimethyl-5-
(2-hydroxyethyl) -1,3-benzodioxole
From 4.3 g, 3.4 g of the title compound was obtained as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.65 (s, 6H), 2.84 (s, 4
H), 3.25 (s, 2H), 6.61 (m, 3H), 9.84 (m, 1H) Example 14 [{2- (2,2-dimethyl-1,3-benzodioxole-
5-yl) ethyl {thio] acetic acid sodium salt According to a method similar to that of Example 4, [{2- (2,2-dimethyl-1,3-benzodioxol-5-yl) ethyl}
From 3.3 g of [thio] acetic acid, 3.3 g of the title compound was obtained as a white powder.

mP .: 199 to 202 ° C (dec.) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.60 (s, 6H), 2.68
(S, 4H), 2.95 (s, 2H), 6.60 to 6.71 (m, 3H) MS (FAB) m / z 313 (MNa ⁺ ), 291 (MH ⁺ ) Example 15 [{2- (6-methyl) -1,3-benzodioxole-5
-Yl) ethyl {thio] acetic acid In the same manner as in Example 11, 2- (6-methyl-1,
From 1.5 g of 3-benzodioxol-5-yl) ethanol, 1.5 g of the title compound was obtained as a white powder. ^{1 H-NMR (90MHz, CDC1} 3) δ; 2.22 (s, 3H), 2.82 (s, 4
H), 3.26 (s, 2H), 5.88 (s, 2H), 6.66 (s, 2H), 10.
56 (bs, 1H) Example 16 [{2- (6-methyl-1,3-benzodioxol-5)
-Yl) ethyl {thio] acetic acid sodium salt In the same manner as in Example 4, [2- (6-methyl-
1,3-benzodioxol-5-yl) ethyldithio]
1.6 g of the title compound was obtained as a white powder from 1.5 g of acetic acid.

mp .; 194 to 195 ° C ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 2.17 (s, 3H), 2.59 to
2.63 (m, 2H), 2.67 to 2.72 (m, 2H), 2.96 (s, 2H), 5.
90 (s, 2H), 6.70 (s, 1H), 6.75 (s, 1H) MS (FAB) m / z; 277 (MH ⁺ ) Example 17 [{2- (6-ethyl-1,3-benzo) Dioxol-5
-Yl) ethyl {thio] acetic acid In the same manner as in Example 11, 2- (6-ethyl-1,1,
From 169 g of 3-benzodioxol-5-yl) ethanol, 85 g of the title compound was obtained as a white powder.

^{mp;. 63~64 ℃ 1 H-} NMR (90MHz, CDC1 3) δ; 1.16 (t, J = 7Hz, 3H), 2.52
(Q, J = 7Hz, 2H), 2.82 (s, 4H), 3.24 (s, 2H), 5.84
(S, 2H), 6.58 (s, 1H), 6.60 (s, 1H), 9.80 (bs, 1
H) Example 18 [{2- (6-ethyl-1,3-benzodioxole-5)
-Yl) ethyl {thio] acetic acid sodium salt By the same method as in Example 4, 91 g of the title compound was obtained as a white powder from 85 g of {{2- (6-ethyl-1,3-benzodioxol-5-yl) ethyl} thioacetic acid.

mp .; 193 to 196 ° C (dec.) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 1.10 (t, J = 7 Hz, 3H),
2.51 (q, J = 7Hz, 2H), 2.60-2.65 (m, 2H), 2.69-2.7
4 (m, 2H), 2.79 (s, 2H), 5.91 (s, 2H), 6.71 (s, 1
H), 6.75 (s, 1H) MS (FAB) m / z; 291 (MH ^<+> ) Example 19 [{2- (6-propyl-1,3-benzodioxole-
5-yl) ethyl {thio] acetic acid According to a method similar to that in Example 11, 2- (6-propyl-
1.4 g of 1,3-benzodioxol-5-yl) ethanol
Gave 1.4 g of the title compound as colorless crystals.

^{mp;. 72.5~73.5 ℃ 1 H-} NMR (90MHz, CDC1 3) δ; 0.96 (t, J = 7Hz, 3H), 1.56
(Sext, J = 7 Hz, 2H), 2.52 (t, J = 7 Hz, 2H), 2.84 (s, 4
H), 3.48 (s, 2H), 5.90 (s, 2H), 6.64 (s, 2H) Example 20 [{2- (6-propyl-1,3-benzodioxole-
5-yl) ethyl {thio] acetic acid sodium salt In the same manner as in Example 4, 1.5 g of the title compound was obtained as a white powder from 1.4 g of [{2- (6-propyl-1,3-benzodioxol-5-yl) ethyl] thio] acetic acid.

mp .; 189 to 190 ° C ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 0.96 (t, J = 7 Hz, 3H),
1.49 (sext, J = 7Hz, 2H), 2.46 (t, J = 8Hz, 2H), 2.62
~ 2.64 (m, 2H), 2.69 ~ 2.27 (m, 2H), 3.00 (s, 2H),
5.90 (s, 2H), 6.69 (s, 1H), 6.75 (s, 1H) MS (FAB) m / z; 305 (MH ⁺ ) Example 21 [[{2- (1,3-benzodioxole) -5-yl)-
1,1-dimethyldiethyl] thio] acetic acid 1- (1,3-benzodioxol-5-yl) -2-
30 g of benzene were added to 5 g of methyl-1-propene, 2.6 g of mercaptoacetic acid and a catalytic amount of α, α'-azobis-isobutyronitrile, and the mixture was refluxed for 2 days.
And refluxed for one week. 200 ml of ethyl acetate and 200 ml of water were added to the reaction solution, and the mixture was separated.An aqueous sodium carbonate solution was added to the ethyl acetate layer to extract the desired product.The aqueous layer was acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with water and dried. Dried over sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate / acetic acid =
80: 20: 1). This was dissolved in ethyl acetate, washed with water to remove acetic acid, dried over anhydrous sodium sulfate, and evaporated to give 3.33 g of the title compound as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.29 (s, 6H), 2.78 (s, 2
H), 3.29 (s, 2H), 5.92 (s, 2H), 6.52-6.80 (m, 3
H) Example 22 [[{2- (1,3-benzodioxol-5-yl)-
1,1-dimethyldiethyl] thio] acetic acid sodium salt In the same manner as in Example 4, 2.1 g of the title compound was obtained as colorless crystals from 3.33 g of [[{2- (1,3-benzodioxol-5-yl) -1,1-dimethyl} ethyl] thio] acetic acid. Was obtained as

mp .; 206-210 ° C ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.14 (s, 6H), 2.68 (s,
2H), 3.02 (s, 2H), 5.94 (s.2H), 6.52 to 6.88 (m, 3
H) MS (FD) m / z; 313 (MNa ⁺ ), 291 (MH ⁺ ) Example 23 [[{1- (1,3-benzodioxol-5-yl) methyl} propyl] thio] acetic acid 5- (1-butenyl) -1,3-benzodioxole 2.2
g and 5.4 g of mercaptoacetic acid were heated at 60 ° C. for 3 hours. The reaction product was diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was separated by silica gel column chromatography (chloroform) to obtain 1.8 g of the title compound as a colorless oil. ^{1 H-NMR (90MHz, CDC1} 3) δ; 1.00 (t, J = 7Hz, 3H), 1.54
(M, 2H), 2.69-3.00 (m, 3H), 3.14 (s, 2H), 5.87
(S, 2H), 6.62 (m, 3H), 8.7 (m, 1H) Example 24 [[1-{(1,3-benzodioxol-5-yl) methyl} propyl] thio] acetic acid sodium salt By a method similar to that of Example 4, 1.7 g of the title compound was obtained as a white powder from 1.7 g of [[1-{(1,3-benzodioxol-5-yl) methyl} propyl] thio] acetic acid.

184-188 ° C (dec); ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 0.89 (t, J = 7.3 Hz, 3
H), 1.31 (m, 1H), 1.48 (m, 1H), 2.43-2.59 (m, 1
H), 2.80-2.90 (m, 2H), 2.90 and 2.96 (ABq, J = 13.
2Hz, 2H), 5.96 (m, 2H), 6.65 (m, 1H), 6.77-6.82
(M, 2H) MS (FAB) m / z; 291 (MH ^<+> ) Example 25 [{2- (1,3-benzodioxol-5-yl) ethyl} thio] cyanoacetic acid 5.0 g of [{2- (1,3-benzodioxol-5-yl) ethyl} thio] acetonitrile was dissolved in 50 ml of anhydrous ether, and 1.6 M n-butyllithium chihesane solution 2 was added at -78 ° C.
2 ml was added and the mixture was stirred at -50 ° C for 2 hours. It was cooled again to -78 ° C, 10 g of dry ice was added, and the temperature was raised to room temperature. Water was added to the reaction solution, extracted with chloroform, and the extract was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform), and recrystallized from ethyl acetate-hexane to give the title compound (0.70 g) as colorless needles.

mp .; 106 to 107 ° C ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 2.62 to 3.10 (m, 4H), 5.
12 (s, 1H) 5.90 (s, 2H), 6.50 to 6.86 (m, 3H) MS (FAD) m / z; 265 (MH ⁺ ) Example 26 [{2- (1,3-benzodioxole) -5-yl) ethyl {thio] cyanate sodium salt [{2- (1,3-benzodioxol-5-yl) ethyl} thio] cyanacetic acid was obtained in the same manner as in Example 4.
From 0.70 g, 0.59 g of the title compound was obtained as a white powder.

mp .; 202 to 208 ° C (dec.) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 2.80 to 2.84 (m, 2H),
2.88 to 2.92 (m, 2H), 4.25 to 4.50 (bs, 1H), 5.97 (s, 2
H), 6.70-6.86 (m, 3H) MS (FAB) m / z; 310 (MNa ⁺ ) Example 27 N, N-dimethyl-2-[{2- (1,3-benzodioxole-5) -Yl) -2-ethyl {thio] ethanesulfonamide 2-[{2- (1,3-benzodioxol-5-chloride)
4 g of yl) ethyl {thio] ethanesulfonyl was dissolved in chloroform, dimethylammon gas was passed through with stirring, the chloroform solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. ). This was reconstituted from isopropyl ether-ethanol to give the title compound 3.
0 g was obtained as colorless crystals.

^{mp;. 93~94.5 ℃ 1 H-} NMR (90MHz, CDC1 3) δ; 2.75 (s, 4H), 2.83 (s, 6
H), 2.68-3.19 (m, 4H), 5.86 (s, 2H), 6.48-6.76
(M, 3H) MS m / z; 317 (M ⁺ ), 149, 135 Example 28 [{2- (1,3-benzodioxol-5-yl) ethyl} sulfinyl] propan-2-one 4 g of [{2- (1,3-benzodioxol-5-yl) ethyl} thio] propan-2-one in 70 ml of chloroform
Under cooling with ice water, 3.2 g of 90% m-chloroperbenzoic acid was added, and the mixture was stirred for 40 minutes. 150 ml of chloroform and an aqueous solution of sodium carbonate were added to the reaction solution, and the mixture was separated. The chloroform layer was washed three times with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was reconstituted with isopropyl ether to give the title compound 3.
5 g were obtained as colorless crystals.

^{. mp; 82~84.5 ℃ 1 H-} NMR (90MHz, CDC1 3) δ: 2.32 (s, 3H), 2.99 (s, 4
H), 3.65 and 3.77 (ABq, J = 13.5Hz, 2H), 5.89 (s, 2
H), 6.50-6.77 (m, 3H) MS (FAB) m / z; 255 (MH ^<+> ), 149 Example 29 [{2- (1,3-benzodioxol-5-yl) ethyl} sulfinyl Acetonitrile By a method similar to that in Example 28, 3.0 g of the title compound was obtained as colorless crystals from 3 g of {{2- (1,3-benzodioxol-5-yl) ethyl} thioacetonitrile.

^{mp;. 57~59.5 ℃ 1 H-} NMR (90MHz, CDC1 3) δ; 2.76~3.34 (m, 4H), 3.53
and 3.69 (ABq, J = 16.4Hz, 2H), 5.90 (s, 2H), 6.52 ~
6.79 (m, 3H) MS (FAB) m / z; 238 (M ⁺ ), 149 Example 30 [{2- (1,3-benzodioxol-5-yl) ethyl} sulfonyl] propane-2- on 4 g of [{2- (1,3-benzodioxol-5-yl) ethyl} thio] propan-2-one in 70 ml of chloroform
Was added to the mixture, and 8.1 g of 90% m-chloroperbenzoic acid was added thereto under cooling with ice water, followed by stirring for 2 hours. 150 ml of chloroform and an aqueous solution of sodium carbonate were added to the reaction solution. After liquid separation, the chloroform layer was washed three times with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was reconstituted with ethyl acetate-isopropyl ether to give the title compound 4.1 g was obtained as colorless crystals.

^{. mp; 97~99 ℃ 1 H-} NMR (90MHz, CDC1 3) δ: 2.39 (s, 3H), 2.88~3.47
(M, 4H), 3.92 (s, 2H), 5.89 (s, 2H), 6.50-6.77
(M, 3H) MS (FAB) m / z; 270 (M ⁺ ), 149 Example 31 [{2- (1,3-benzodioxol-5-yl) ethyl} sulfonyl] acetonitrile In the same manner as in Example 30, 2.95 g of the title compound was obtained as colorless crystals from 3 g of [{2- (1,3-benzodioxol-5-yl) ethyl} thio] acetonitrile.

^{. mp; 93~95 ℃ 1 H-} NMR (90MHz, CDC1 3) δ: 2.95~3.30 (m, 2H) 3.33~
3.67 (m, 2H), 3.75 (s, 2H), 5.91 (s, 2H), 6.56 to 6.
88 (m, 3H) MS m / z; 253 (M ⁺ ), 149.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location C07D 317/54 C07D 317/54 317/58 317/58 317/60 317/60 405/12 207 405 / 12 207 213 213 413/12 317 413/12 317 (72) Inventor Naoyuki Shimomura 2-23-5 Maiku Gakuen, 2-23-5 Sakuramura, Akumamura, Ibaraki Pref., Japan 207 (72) Inventor Toshihiko Kaneko, Yatabe-cho, Tsukuba-gun, Ibaraki 4-18-4 Kasuga Apartment Market No. 203 (72) Inventor Dingji Yamanaka Shimohirooka 725-25, Sakuramura, Niigata-gun, Ibaraki Prefecture (72) Inventor Yuharu Hishinuma 3-4 Kubogaoka, Moriya-cho, Kitasoma-gun, Ibaraki Prefecture −8 (72) Inventor Junichi Nagakawa 2-15-3, Sakuramura Umezono, Shinji-gun, Ibaraki Prefecture (72) Inventor Kazuo Hirota 4-19-13 Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture Eisai Mt. Prefecture Shinji 2-8-9 Okura Apartment No.3, Sakuramura-gun, Gunori No.3 (72) Inventor Toru Horie 25-4 Nishigo, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture (72) Inventor Yasuo Wakabayashi 368 Motoyoshida-cho, Mito-shi (56) References JP Akira 63-250374 (JP, A) US Patent 2,486,445 (US, A) US Patent 2,486,579 (US, A)

Claims (10)

(57) [Claims] 1. The compound of the general formula (I) [Wherein, R ¹ and R ² represent the same or different hydrogen atoms or lower alkyl groups. R ³ is a hydrogen atom, a lower alkyl group or a formula-(CH ₂ ) _n COOH
(Wherein, n represents an integer of 1 to 3). R ⁴ and R ⁵ represent the same or different hydrogen atoms or lower alkyl groups. X is a group represented by the formula -S-, A group represented by or Means a group represented by A is a group represented by the formula — (CH ₂ ) _n ′ -Het (where n ′ represents an integer of 1 to 3, and Het represents a substituted or unsubstituted nitrogen-containing heterocyclic ring); A group represented by the formula A group represented by Wherein R ⁶ and R ⁷ represent the same or different hydrogen atoms or lower alkyl groups, a group represented by the formula —CH ₂ —CN, Wherein R ⁸ represents a lower alkyl group, or (Wherein p represents an integer of 1 to 3, and R ⁹ and R ¹⁰ represent the same or different lower alkyl groups). Where A is (Wherein R ⁶ and R ⁷ have the same meanings as above), except when all of R ^{1 to} R ⁵ are hydrogen atoms. ] The benzodioxole derivative represented by these, or its pharmacologically acceptable salt. 2. In the general formula (I), A is The benzodioxole derivative according to claim 1, which is a group represented by the formula (wherein, R ⁸ represents a lower alkyl group) or a pharmaceutically acceptable salt thereof. 3. In the general formula (I), A is a group represented by the formula —CH ₂ —CN.
The benzodioxole derivative according to claim 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof. 4. In the general formula (I), A is The benzodioxole derivative according to claim 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof. 5. In the general formula (I), A is Wherein R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a lower alkyl group. 4. The benzodioxole derivative according to claim 1, Acceptable salt. 6. In the general formula (I), A is The benzodioxy according to claim 1, wherein p is an integer of 1 to 3, and R ⁹ and R ¹⁰ are the same or different lower alkyl groups. A sole derivative or a pharmacologically acceptable salt thereof. 7. In the general formula (I), A is a group represented by the formula — (CH ₂ ) _n ′
The benzodioxy group according to claim 1, which is a group represented by -Het (wherein, n 'represents an integer of 1 to 3, and Het represents a substituted or unsubstituted nitrogen-containing heterocyclic ring). A sole derivative or a pharmacologically acceptable salt thereof. 8. The benzodioxole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein in the general formula (I), X is a group represented by the formula —S—. 9. In the general formula (I), X is A group represented by or The benzodioxole derivative according to claim 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof. 10. A compound of the formula (I) [Wherein, R ¹ and R ² represent the same or different hydrogen atoms or lower alkyl groups. R ³ is a hydrogen atom, a lower alkyl group or a formula-(CH ₂ ) _n COOH
(Wherein, n represents an integer of 1 to 3). R ⁴ and R ⁵ represent the same or different hydrogen atoms or lower alkyl groups. X is a group represented by the formula -S-, A group represented by or Means a group represented by A is a group represented by the formula — (CH ₂ ) _n ′ -Het (where n ′ represents an integer of 1 to 3, and Het represents a substituted or unsubstituted nitrogen-containing heterocyclic ring); A group represented by the formula A group represented by (Wherein, R ⁶ and R ⁷ represent the same or different hydrogen atoms or lower alkyl groups), a group represented by the formula —CH ₂ —CN, Wherein R ⁸ represents a lower alkyl group, or (Wherein p represents an integer of 1 to 3, and R ⁹ and R ¹⁰ represent the same or different lower alkyl groups). Where A is (Wherein R ⁶ and R ⁷ have the same meanings as above), except when all of R ^{1 to} R ⁵ are hydrogen atoms. ] A therapeutic or prophylactic agent for liver disease, comprising a benzodioxole derivative represented by the following formula or a pharmacologically acceptable salt thereof as an active ingredient.