JP2535533B2 - 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, pathophysiology, and pathophysiology of liver diseases are not uniform, and there are many unclear points. Therefore, the development of therapeutic agents for liver diseases is extremely difficult at present.

A glycyrrhizin preparation can be mentioned as a typical drug currently widely used for the treatment and prevention of this liver disease and clinically evaluated. However, although the glycyrrhizin preparation is said to be effective for liver damage, liver cirrhosis, hepatitis, liver protection after surgery, etc., its medicinal effect is not so strong and there is a problem that it has steroid-like side effects. Further, although the glycyrrhizin preparation is an intravenous preparation, it has a drawback that it is ineffective orally.

Under such circumstances, there is a strong demand for the development of an orally effective drug having high safety.

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

The inventors of the present invention have used a plant that is used in the private sector as a material and have conducted research over a long period of time. As a result, Petivelia alliacea L. and Cinnamomum porrectum (Roxb.) Kost
erm.) shown by the following chemical structure formulas 2-
It has been found that [(phenylmethyl) trithio] ethanol (A) and cubevin (B) are active compounds effective as therapeutic agents for liver diseases.

Then, the present inventors synthesized various compounds using these compounds as basic compounds, and conducted extensive studies on their pharmacological activities. As a result, the benzodioxole derivative represented by the following general formula (I) or They have found that the pharmacologically acceptable salt is a compound having higher safety and being more effective as a therapeutic agent for liver diseases, and completed the present invention.

The following two patent applications have been published for the purpose of treating liver diseases, but they are different 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 most of them are known compounds.

Further, JP-A-62-39583 discloses a (1,3-benzodioxol-5-yl) methylthio derivative, which is remarkably different in structure from the compound of the present invention.

As described above, the present invention is derived from the plant components by obtaining the hints from the compounds (A) and (B) found by the present inventors themselves to reach the compound (I) of the present invention described below.
The invention is different from the invention seen in the publication of the case, and accordingly the chemical structure is different from the two patent applications.

[Structure and Effect of Invention]

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

(In the formula, X represents a group represented by the formula —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —CH ₂ —, or a group represented by the formula Means a group represented by.

R ¹ represents a hydrogen atom or a lower alkyl group, Y represents a hydrogen atom, an alkyl group, a hydroxyl group, a carboxyl group, an aryl group, a heteroarylcarbonyloxy group, or a formula Means a group represented by. ) In the above definition of the compound (I) of the present invention, R ¹
The lower alkyl group in the definition of is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert. -Butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like groups are mentioned, but the most preferable examples are methyl, ethyl and n-propyl groups.

The alkyl group in the definition of Y is, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl,
n-pentyl, 1-ethylpropyl, isoamyl, n-
Hexyl, n-heptyl, n-octyl, n-nonyl,
It means a linear or branched alkyl group such as n-decyl.

Further, the aryl group in the definition of Y means, for example, a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group and the like, and the most preferable example among them is a phenyl group. Examples of the heteroarylcarbonyloxy group include a heteroarylcarbonyloxy group derived from a 5- to 6-membered ring containing a nitrogen atom such as pyridine, pyrimidine, pyrrole, pyrazole and imidazole, thiazole and oxazolefuran. However, preferred examples thereof include a nicotinoyloxy group and the like.

The pharmacologically acceptable salt is a conventional non-toxic salt, and examples thereof include hydrochloride, sulfate, hydrobromide, maleate, acetate and the like.

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

Production Method There are various methods for producing the compound of the present invention, and a typical method is as follows.

Manufacturing method A [In the formula, X, R ¹ and Y have the above-mentioned meanings] That is, the thiol represented by the general formula (II) and the general formula (II
The target substance (I) can be obtained by reacting with a thiol represented by I).

Specifically, the compound (II) and the compound (III) are used in the absence of a solvent or in a solvent selected from alcohols such as methanol, ethanol and propanol, acetic acid and an aqueous solution of potassium iodide that do not participate in the reaction. Under ice cooling or under room temperature to heating, iodine, hydrogen peroxide, lead dioxide, oxygen, copper sulfate, ferric chloride, potassium permanganate, potassium ferricyanide, sulfuryl chloride, dimethyl sulfoxide, sulfur dioxide, phosphorus pentachloride Such an oxidizing agent can be added and the reaction can be carried out by a conventional method to obtain the desired compound (I).

Manufacturing method B [Wherein X represents the same group as described above, R ² represents a lower alkyl group, an aryl group, or a heteroaryl group, and Hal represents a halogen atom] That is, represented by the general formula (IV) For example, pyridine, triethylamine, N, N-dimethylaniline, sodium carbonate, carbonic acid is used as a dehydrohalogenating agent by dissolving the alcohol compound in the absence of solvent or in benzene, dichloromethane, chloroform, tetrahydrofuran, N, N-dimethylformamide or the like. A base such as sodium hydrogen is used, and an acid halide represented by the general formula (V) is added thereto to carry out a reaction to obtain a compound (VI) which is one of the target compounds.
In this case, pyridine can also be used as a solvent and dehydrohalogenating agent. The reaction is carried out under cooling with water or under heating under reflux.

The target substance (I), which is one of the target substances of the present invention,
When a pharmaceutically acceptable salt of is prepared, for example, in the general formula (I), Y is In this case, hydrochloric acid, sulfuric acid, hydrobromic acid, etc. can be reacted to produce the above-mentioned hydrochloride, sulfate, hydrobromide, and other pharmaceutically acceptable salts.

Next, examples of pharmacological experiments are shown to explain the effects of the compounds 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 400 mg / kg was subcutaneously administered to induce liver damage. Each test compound was suspended in a 0.5% aqueous methylcellulose solution, and a dose of 100 mg / kg was orally administered 1 hour after the administration of D-galactosamine.

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

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

Experimental Example 2 Action on carbon tetrachloride (CCl ₄ ) liver injury model Experimental method 0.5 mg / kg of carbon tetrachloride was intraperitoneally administered to male Fischer (F ₃₄₄ ) rats weighing about 180 g to prepare the pathological condition. Carbon tetrachloride was diluted with olive oil to a final concentration of 0.25 ml / ml.

Each test compound was suspended in a 0.5% methylcellulose aqueous solution, and 100 mg / kg was orally administered 1 hour before the administration of carbon tetrachloride.

Blood was collected from the rat tail 24 hours after carbon tetrachloride administration, and GPT activity in plasma was measured by an enzymatic method as an index of liver damage. Table 2 shows the inhibition rate of liver damage due to carbon tetrachloride for each test compound.

Experimental Example 3 Toxicity test Using 7-week-old ddy male mice weighing around 30 g, Table 1
When the compounds 1, 3, 6, 7 among the compounds of the present invention shown in (4) were orally administered for 4 days (dose 400 mg / kg), none of the compounds died.

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

Therefore, the compound of the present invention is useful as a therapeutic / preventive 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 further, it can be used for the treatment or prevention of 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 due to the nature of the disease, and the present invention is also valuable in this sense.

When the compound of the present invention is administered as a therapeutic / preventive agent for liver diseases, it may be orally administered as tablets, powders, granules, capsules, syrups, etc., 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.

When formulating, a usual pharmaceutical carrier is used and it is manufactured by a conventional method.

That is, in the case of preparing a solid preparation for oral use, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules, etc.

As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide, etc., as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin, etc., lubricants such as magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils, etc., should be added to medicines as colorants. What is allowed is, as a flavoring agent, cocoa powder, peppermint, aromatic acid, peppermint oil, Borneolum,
Cinnamon powder is used. Of course, these tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating, if necessary.

When preparing an injection, a pH adjusting agent, a buffering agent, a stabilizer, a solubilizing agent, etc. are added to the main drug as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.

Next, examples of the present invention will be described, but it goes without saying that the present invention is not limited thereto.

The production methods of the starting materials used in producing the compound of the present invention are shown in Production Examples 1 to 3.

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 (90 MHz, CDCl ₃ ) δ; 1.36 (m, 1H), 2.6 to 2.9 (m, 4H), 5.87 (s, 2H), 6.50 to
6.74 (m, 3H) Production Example 2 3- (1,3-benzodioxol-5-yl) propanethiol 25 g of thioacetic acid was added little by little to 53.5 g of safrole while stirring from room temperature to ice water, and the mixture was reacted for 30 minutes. A solution prepared by dissolving 20 g of sodium hydroxide in a mixed solution of 100 ml of water and 200 ml of ethanol was added to the reaction solution, and the mixture was heated under reflux for 20 minutes. After cooling, dilute sulfuric acid was added to the reaction solution to neutralize it, and then benzene 1 was added.
Was added, extracted, washed with water, the benzene layer was dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (hexane) to obtain 42.8 g of the title compound as a colorless oil.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.20 to 1.46 (m, 1H), 1.68 to 2.10 (m, 2H), 2.34 to 2.78
(M, 4H), 5.84 (s, 2H), 6.44 to 6.75 (m, 3H) Production Example 3 2- (1,3-benzodioxol-5-yl) -1-methylethanethiol 5 g of anhydrous tin chloride was added to 100 g of Safrole, and hydrochloric acid gas was bubbled under ice cooling for 1 hour and 30 minutes. Ethyl acetate (2 L) was added to the reaction solution to dissolve it, then the solution was washed twice with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is purified by silica gel column chromatography (hexane / benzene = 10: 1) to give 5
-(2-Chloropropyl) -1,3-benzodioxole 4
1.7 g was obtained as a colorless oil. This is ethanol 15
0 ml was dissolved, 48 g of thiourea was added, and the mixture was heated under reflux for 7 days.
After cooling, the reaction solution was filtered, and a solution prepared by dissolving 12.8 g of sodium hydroxide in 100 ml of water was added to the filtrate and heated under reflux for 2 hours. After cooling, the reaction solution was acidified with dilute sulfuric acid, and benzene 1 was added.
And water 1 were added for liquid separation, the benzene layer was washed twice with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / benzene = 10: 1) to give 8.5 g of the title compound as a colorless oil.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.32 (d, J = 6 Hz, 3 H), 1.54 (d, J = 6 Hz, 1 H), 2.61 to 2.
84 (m, 2H), 2.90 ~ 3.35 (m, 1H), 5.86 (s, 2H), 6.46 ~
6.76 (m, 3H) Example 1 (Compound 1) 2-[{2- (1,3-benzodioxol-5-yl)
Ethyl} dithio] ethanol 150 ml of 35 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 75 g of 2-mercaptoethanol
Was dissolved in ethanol, 43 g of iodine was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 2 liters of ethyl acetate and 2 liters of water, the layers were separated, and the ethyl acetate layer was washed twice with water, then washed twice with 1% aqueous sodium hydrogen sulfite solution 1 and further washed with water 3 times, and then with anhydrous sulfuric acid. Dry with sodium. This was filtered, the solvent was evaporated, and the residue was purified by silica gel column chromatography (benzene / ethyl acetate = 10: 1) to give 11.5 g of the title compound as a colorless oil.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.98 (t, J = 7 Hz, 1 H), 2.85 (t, J = 7 Hz, 2 H), 2.91 (s,
4H), 3.89 (q, J = 7Hz, 2H), 5.92 (s, 2H), 6.55 to 6.84
(M, 3H) MSm / z; 258 (M ⁺ ), 149 Example 2 (Compound 2) Bis {2- (1,3-benzodioxol-5-yl) ethyl} disulfide By the same method as in Example 1, 2 g of the title compound was obtained as colorless crystals from 3 g of 2- (1,3-benzodioxol-5-yl) ethanethiol.

・ Melting point (℃); 76 to 78 ・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.87 (s, 8H), 5.90 (s, 4H), 6.51 to 6.81 (m, 6H) ・ MSm / z; 362 (M ⁺ ), 149 Example 3 (Compound 3) Nicotinic acid 2-[{2- (1,3-benzodioxole-
5-yl) ethyl} dithio] ethyl 4-[{2- (1,3-benzodioxol-5-yl) ethyl} dithio] ethanol obtained in Example 1 4 g
Was added to a mixed solution of 20 ml of pyridine and 50 ml of benzene to dissolve,
To this was added 4 g of nicotinic acid chloride hydrochloride, and the mixture was heated under reflux for 2 hours. The reaction mixture was poured into ice water, sodium hydrogen carbonate was added to make it weakly alkaline, ethyl acetate was added thereto for liquid separation, and the ethyl acetate layer was washed 5 times with water. After drying over anhydrous sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 1) to obtain 5.4 g of the title compound as a colorless oily substance.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.92 (s, 4 H), 3.06 (t, J = 7 Hz, 2 H), 4.62 (t, J = 7 Hz,
2H), 5.92 (s, 2H), 6.40 ~ 6.86 (m, 3H), 7.30 ~ 7.50
(M, 1H), 8.20 ~ 8.41 (m, 1H), 8.68 ~ 8.85 (m, 1H), 9.1
4 to 9.34 (m, 1H) MSm / z; 363 (M ⁺ ), 149 Example 4 (Compound 4) Nicotinic acid 2-[{2- (1,3-benzodioxole-
5-yl) ethyl} dithio] ethyl hydrochloride Nicotinic acid 2-[{2- (1,3-
2.5 g of benzodioxol-5-yl) ethyl} dithio] ethyl was dissolved in 20 ml of ethyl acetate, a solution of hydrochloric acid in ethyl acetate was added, and the solvent was evaporated. After being dissolved in a mixed solution of methanol-ethanol, the mixture was filtered, the solution was concentrated, and ethanol /
When the mixture was recrystallized by adding an isopropyl ether mixed solution, 2.5 g of the title compound was obtained as colorless crystals.

・ Melting point (° C); 113 to 122 ・¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 2.66 to 3.00 (m, 4 H), 3.11 (t, J = 7 Hz, 2 H), 4.53 (t, J
= 7Hz, 2H), 5.90 (s, 2H), 6.48 ~ 6.92 (m, 3H), 7.62 ~
7.91 (m, 1H), 8.36 ~ 8.60 (m, 1H), 8.78 ~ 9.02 (m, 1
H), 9.02 to 9.24 (m, 1H) ・ MSm / z; 363,149 ・ Elemental analysis value: C ₁₇ H ₁₇ O ₄ NS ₂・ HCl as C H N Cl theoretical value (%) 51.06 4.54 3.50 8.87 Measured value (%) ) 51.05 4.51 3.59 8.84 Example 5 (Compound 5) 2-[{3- (1,3-benzodioxol-5-yl)]
Propyl} dithio] ethanol In the same manner as in Example 1, 27.8 g of 3- (1,3-benzodioxol-5-yl) propanethiol and 2- (1,3-benzodioxol-5-yl) propanethiol were added.
From 5.5 g of mercaptoethanol, 8.4 g of the title compound was obtained as a colorless oil.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.72 to 2.14 (m, 3H), 2.48 to 2.72 (m, 4H), 2.80 (t, J
= 7Hz, 2H), 3.84 (q, J = 7Hz, 2H), 5.85 (s, 2H), 6.44〜
6.74 (m, 3H) MSm / z; 272 (M ⁺ ), 135 Example 6 (Compound 6) 3- (1,3-benzodioxol-5-yl) propylphenethyl disulfide By a method similar to that in Example 1, 1.5 g of the title compound was obtained as a colorless oily product from 5 g of 3- (1,3-benzodioxol-5-yl) propanethiol and 5 g of phenethyl mercaptan.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.70 to 2.20 (m, 2H), 2.50 to 2.80 (m, 4H), 2.92 (s, 4
H), 5.85 (s, 2H), 6.44 ~ 6.78 (m, 3H), 7.00 ~ 7.52 (m,
5H) MSm / z; 332 (M ⁺ ) Example 7 (Compound 7) Nicotinic acid 2-[{3- (1,3-benzodioxole-
5-yl) propyl} dithio] ethyl 2 obtained in Example 5 by the same method as in Example 3
From 50 g of-[{3- (1,3-benzodioxol-5-yl) propyl} dithio] ethanol and 50 g of nicotinic acid chloride hydrochloride, 56.1 g of the title compound was obtained as a colorless oil.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.72 to 2.12 (m, 2 H), 2.65 (q, J = 7 Hz, 4 H), 3.00 (t, J
= 7Hz, 2H), 4.56 (t, J = 7Hz, 2H), 5.85 (s, 2H), 6.42 ~
6.70 (m, 3H), 7.20 ~ 7.40 (m, 1H), 8.10 ~ 8.30 (m, 1
H), 8.58 to 8.78 (m, 1H), 9.06 to 9.22 (m, 1H) MS m / z; 377 (M ⁺ ) Example 8 (Compound 8) Nicotinic acid 2-[{3- (1,3- Benzodioxole
5-yl) propyl} dithio] ethyl hydrochloride In the same manner as in Example 4, nicotinic acid 2-[{3- (1,3-benzodioxole-5] obtained in Example 7 was obtained.
From 46.1 g of -yl) propyl} dithio] ethyl, 48.5 g of the title compound was obtained as colorless crystals.

・ Melting point (° C); 105 to 110 ・¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.68 to 2.08 (m, 2 H), 2.71 (q, J = 7 Hz, 4 H), 3.13 (t, J
= 7Hz, 2H), 4.58 (t, J = 7Hz, 2H), 5.96 (s, 2H), 6.54 ~
6.87 (m, 3H), 7.69 ~ 7.90 (m, 1H), 8.44 ~ 8.64 (m, 1
H), 8.87 to 9.02 (m, 1H), 9.12 to 9.24m, 1H) ・ MSm / z; 377 ・ Elemental analysis value: C ₁₈ H ₁₉ O ₄ NS ₂・ HCl theoretical value as C H N Cl (%) 52.23 4.87 3.38 8.56 Actual value (%) 52.32 4.80 3.47 8.58 Example 9 (Compound 9) 3- (1,3-benzodioxol-5-yl) propylnonyl disulfide By the same method as in Example 1, 6.2 g of the title compound was obtained as a colorless oil from 10 g of 3- (1,3-benzodioxol-5-yl) propanethiol and 5 g of nonylmercaptan.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.74 to 1.02 (m, 3H), 1.08 to 1.48 (bs, 14H), 1.80 to 2.
12 (m, 2H), 2.50 ~ 2.76 (m, 6H), 5.86 (s, 2H), 6.46 ~
6.75 (m, 3H) MSm / z; 354 (M ⁺ ) Example 10 (Compound 10) Nicotinic acid 2-[{(1,3-benzodioxole-5-
Iyl) methyl} dithio] ethyl In the same manner as in Example 3, 2-[{(1,3-benzodioxol-5-yl) methyl} dithio] ethanol (2 g) and nicotinic acid chloride hydrochloride (2.2 g) were used to give the title compound.
2.8 g was obtained as a colorless oil.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.76 (t, J = 7 Hz, 2 H), 3.82 (s, 2 H), 4.45 (t, J = 7 Hz,
2H), 5.89 (s, 2H), 6.52 ~ 6.91 (m, 3H), 7.12 ~ 7.42
(M, 1H), 8.10 to 8.34 (m, 1H), 8.64 to 8.87 (m, 1H), 9.0
7 to 9.28 (m, 1H) MSm / z; 349 (M ⁺ ) Example 11 (Compound 11) Bis {2- (1,3-benzodioxol-5-yl)-
1-methylethyl} disulfide By the same method as in Example 1, 4 g of 2- (1,3-benzodioxol-5-yl) -1-methylethanethiol was added.
Thus, 3.5 g of the title compound was obtained as a colorless oil.

・¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.24 (d, J = 7 Hz, 6 H), 2.32 to 2.71 (m, 2 H), 2.72 to 3.1
6 (m, 4H), 5.91 (s, 4H), 6.48 to 6.82 (m, 6H) MSm / z; 390 (M ⁺ ) Example 12 (Compound 12) 2-[{2- (1,3- Benzodioxol-5-yl)
-1-Methylethyl} dithio] ethanol By the same method as in Example 1, 2- (1,3-benzodioxol-5-yl) -1-methylethanethiol 8.
The title compound 5.0 from 4g and 2.24g of 2-mercaptoethanol
g was obtained as a colorless oil.

^{· 1 H-NMR (90MHz,} CDCl 3) δ; 1.27 (d, J = 7Hz, 3H), 1.80~2.20 (br, 1H), 2.40~2.
80 (m, 1H), 2.68 ~ 3.25 (m, 4H), 3.60 ~ 4.10 (br, 2H),
5.90 (s, 2H), 6.50 to 6.88 (m, 3H) ・ MSm / z; 272 (M ⁺ )

Claims (9)

(57) [Claims] 1. A general formula (I) (In the formula, X represents a group represented by the formula —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —CH ₂ —, or a group represented by the formula Means a group represented by. R ¹ represents a hydrogen atom or a lower alkyl group, Y represents a hydrogen atom, an alkyl group, a hydroxyl group, a carboxyl group, an aryl group, a heteroarylcarbonyloxy group, or a formula Means a group represented by. ) A benzodioxole derivative represented by or a pharmacologically acceptable salt thereof. 2. A general formula (I), X has the formula -CH ₂ -, a group represented by the formula -CH ₂ -CH ₂ -, a group represented by the formula -CH ₂ -C
H ₂ —CH ₂ — group or a formula The benzodioxole derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is a heteroarylcarbonyloxy group. 3. The general formula (I), X has the formula -CH ₂ -, a group represented by the formula -CH ₂ -CH ₂ -, a group represented by the formula -CH ₂ -C
H ₂ —CH ₂ — group or a formula The benzodioxole derivative according to claim 1, wherein Y is a hydroxyl group, or a pharmaceutically acceptable salt thereof. 4. In the general formula (I), X is a group represented by the formula —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —, a group represented by the formula —CH ₂ —C.
H ₂ —CH ₂ — group or a formula The benzodioxole derivative according to claim 1 or a pharmacologically acceptable salt thereof, wherein Y is an aryl group. 5. In the general formula (I), X is a group represented by the formula —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —, or a group represented by the formula —CH ₂ —C.
H ₂ —CH ₂ — group or a formula A benzodioxole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is a hydrogen atom. 6. The general formula (I), X has the formula -CH ₂ -, a group represented by the formula -CH ₂ -CH ₂ -, a group represented by the formula -CH ₂ -C
H ₂ —CH ₂ — group or a formula Is a group represented by The benzodioxole derivative according to claim 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof. 7. The general formula (I), X has the formula -CH ₂ -, a group represented by the formula -CH ₂ -CH ₂ - group represented by or formula -CH ₂
The benzodioxole derivative according to claim 1, which is a group represented by —CH ₂ —CH ₂ —, and Y is a heteroarylcarbonyloxy group, or a pharmaceutically acceptable salt thereof. 8. The general formula (I), X has the formula -CH ₂ -, a group represented by the formula -CH ₂ -CH ₂ - group represented by or formula -CH ₂
A benzodioxole derivative according to claim ¹ , which is a group represented by —CH ₂ —CH ₂ —, R ¹ is a hydrogen atom, and Y is a heteroarylcarbonyloxy group, or a pharmacological agent thereof. Acceptable salt. 9. General formula (I) (In the formula, X represents a group represented by the formula —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —, a group represented by the formula —CH ₂ —CH ₂ —CH ₂ —, or a group represented by the formula Means a group represented by. R ¹ represents a hydrogen atom or a lower alkyl group, Y represents a hydrogen atom, an alkyl group, a hydroxyl group, a carboxyl group, an aryl group, a heteroarylcarbonyloxy group, or a formula Means a group represented by. ) A therapeutic / preventive agent for liver diseases, which comprises a benzodioxole derivative represented by: or a pharmacologically acceptable salt thereof as an active ingredient.