JP2535532B2 - 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 present inventors have made use of plants used in the private sector as materials, and as a result of repeated research over a long period of time, as a result, Petivelia alliacea L. and Cinnamomum porrectum (Roxb.) Kos
2) shown by the following chemical structural formulas respectively.
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 The inventors have found that the pharmacologically acceptable salt is a compound having higher safety and being more effective as a better therapeutic agent for liver disease, 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, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkoxy lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ³ represents a hydrogen atom or a lower alkyl group. And R ⁴ represents a hydrogen atom or a lower alkyl group, and R ¹ and R ² or R ¹ and R ³ may be taken together to form a 5- to 7-membered ring, provided that R Except when any of ¹ , ¹ , R ² and R ³ is a hydrogen atom.) 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 and R ⁴ is
A linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group,
2-methylbutyl group, 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-dimethylbutyl group, 1-ethylbutyl group,
2-ethylbutyl group, 1,1,2-trimethylpropyl group,
It means a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group and the like. Of these, preferable groups include a methyl group, an ethyl group, a propyl group and an isopropyl group.

Further, the lower alkoxy group in the definition of R ² is a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group. Group, isobutoxy group, sec-
Butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, hexyloxy It means a group. Of these, preferable groups include a methoxy group and an ethoxy group.

Further, the lower alkoxy lower alkyl group found in the definition of R ¹ is, for example, methoxymethyl group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, ethoxyethyl group, ethoxypropyl group, propoxymethyl group,
It means a propoxyethyl group, a propoxypropyl group or the like. Of these, preferable groups include a methoxymethyl group and an ethoxymethyl group.

R ¹ and R ² may be combined with each other to form a 5- to 7-membered ring, and specifically, the case is as shown in Example 13 below. In this case, the 5- to 7-membered ring includes a ring containing only carbon and a ring containing an oxygen atom.

Similarly, R ¹ and R ³ may be combined together to form a 5- to 7-membered ring, but specifically, it refers to the case as seen in Example 11 below.

The pharmacologically acceptable salt is a conventional non-toxic salt, for example, an alkali metal salt such as sodium salt and potassium salt, calcium salt, alkaline earth metal salt such as magnesium salt, trimethylamine salt, triethylamine salt, Examples thereof include pyridine salts, picoline salts, dicyclohexylamine salts, organic amine salts such as N, N′-dibenzylethylenediamine salts, ammonium salts and the like.
The most preferable salt is R ⁴ in the target substance (I).
When is a hydrogen atom, that is, a carboxylic acid, a sodium salt of the carboxylic acid can be mentioned. In addition, some compounds may form hydrates.

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.

Production Method A [When R ⁴ is a hydrogen atom in the general formula (I)] [In the formula, R ¹ , R ² and R ³ have the same meanings as described above] That is, the dicarboxylic acid represented by the general formula (II) is heated to 150 ° C. or higher in the absence of a solvent, It is possible to obtain the carboxylic acid (I) ′.

Production method B [when R ⁴ is a hydrogen atom in the general formula (I)] [In the formula, R ¹ , R ² and R ³ have the same meanings as described above] That is, the nitrile represented by the general formula (III) is hydrolyzed by a conventional method to obtain a carvone which is one of the target substances. The acid (I) 'can be obtained.

Specifically, it is appropriately selected from water or alcohols such as methanol, ethanol and ethylene glycol, hydrous alcohols such as hydrous methanol, hydrous ethanol, hydrous ethylene glycol, hydrous diethylene glycol and hydrous ethylene glycol monoethyl ether. It is hydrolyzed by a conventional method in the presence of a base in a solvent. In this case, examples of the base include potassium hydroxide, sodium hydroxide, barium hydroxide and the like.

Production Method C In the general formula (I), when R ¹ is a lower alkoxy lower alkyl group, the target substance can also be produced by the following method.

[In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. X
Means a halogen atom, M means an alkali metal atom, and Alkyl means a lower alkyl group. The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms as described above. Further, Alkylene means an alkylene group, and the alkylene group means an alkylene group derived from the aforementioned Alkyl group. That is, the halide represented by the general formula (IV) and the alcoholate represented by the general formula (V) are mixed in an organic solvent selected from, for example, tetrahydrofuran, dimethylformamide, methanol, ethanol and 1-propanol. In the usual manner, the reaction can be carried out under ice-cooling or at room temperature to under heating to obtain (VI) which is one of the target substances. In this case, examples of the halogen atom include bromine, chlorine and iodine. Further, examples of the alkali metal atom include potassium and sodium.

The compound (VI) obtained by the above method is a compound in which R ¹ is represented by the formula —Alkylene—O—Alkyl in the general formula (I), and is one of the target compounds of the present invention.

Production Method D In the general formula (I), R ¹ is a lower alkoxy lower alkyl group and is represented by the formula —CH ₂ —O—Alkyl (wherein Alkyl represents a lower alkyl group having 1 to 6 carbon atoms). When the group is a group represented by the following formula, the target substance can also be produced by the following method.

[In the formula, R ² , R ³ , R ⁴ and Alkyl have the same meanings as described above] That is, the acetoxymethyl compound represented by the general formula (VII) is present in the presence of an acid catalyst at room temperature to under heating. By reacting with a compound represented by the general formula (VIII), a compound represented by the general formula (IX), which is one of the target substances, is obtained. This reaction is usually preferably carried out in the presence of lower alcohol. Examples of lower alcohols include methanol, ethanol, 1-propanol, 2-propanol and the like.

Examples of the acid catalyst include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, D-10-camphorsulfonic acid and the like.

The compound (IX) obtained by the above method is a compound in which R ¹ is represented by the formula —CH ₂ —O—Alkyl in the general formula (I), and is one of the target substances of the present invention.

When the production method E R ¹ and R ³ together form a ring, the production can be performed by the following method.

[In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. n
Means an integer of 1 to 3] That is, the compound (XI), which is one of the target substances, can be obtained by intramolecular cyclization of the acrylic acid derivative represented by the general formula (X). This reaction is carried out without solvent or in an organic solvent selected from, for example, benzene, ethanol, tetrahydrofuran, dimethylformamide, etc. under ice cooling or room temperature to heating for several hours by a conventional method. In this case, the reaction proceeds easily by using a base such as sodium ethylate, potassium t-butoxide, sodium hydride and the like.

The compound (XI) obtained by the above method is one of the target compounds of the present invention.

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 300 mg / kg was administered subcutaneously to induce liver damage. Each test compound was dissolved in distilled water, and a dose of 50 mg / kg was orally administered 1 hour after administration of D-galactosamine.

Forty-eight hours after D-galactosamine administration, blood was collected from the rat tail, blood coagulation time was measured by a hepaplastin test (HPT), and GPT activity in plasma was measured by an oxygen 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 dissolved in distilled water and orally administered at a dose of 100 mg / kg 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 as an index of liver injury was measured by an enzymatic method. 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
Orally administered for 4 days (dose 800 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 listed, but it goes without saying that the present invention is not limited thereto.

Example 1 3- (6-Propyl-1,3-benzodioxol-5-yl) propionic acid (1) Synthesis of 5-chloromethyl-6-propyl-1,3-benzodioxole 22 g of 37% aqueous formaldehyde solution and 20 ml of ethyl acetate were added to 10 ml of concentrated hydrochloric acid, and the mixture was heated to 55 ° C, and 10.9 g of 5-propyl-1,3-benzodioxole was dissolved in 100 ml of ethyl acetate while bubbling hydrochloric acid gas. The solution was added dropwise and stirred for 2 hours and 45 minutes. After adding 300 ml of ethyl acetate and 300 ml of water and separating the layers,
The ethyl acetate layer was washed with water three times, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 16.1 g of a crude purified product of the title compound as a colorless oil. ¹ H-NMR (90MHz, CDCl ₃ ) δ; 0.99 (t, J = 7.2Hz, 3H), 1.36 to 1.86 (m, 2H), 2.64 (t, J
= 7.2Hz, 2H), 4.57 (s, 2H), 5.95 (s, 2H), 6.70 (s, 1
H), 6.83 (s, 1H) (2) (6-propyl-1,3-benzodioxole-5
-Yl) Synthesis of diethyl methylmalonate To 16.1 g of a crude product of 5-chloromethyl-6-propyl-1,3-benzodioxole, 24.3 g of diethyl malonate, 42 g of potassium carbonate, 300 ml of acetone and a catalytic amount of tetrabutylammonium bromide were added, and the mixture was kept for 25 hours Heated to reflux. The reaction solution was filtered, the residue was washed with acetone and combined with the filtrate.
The solvent was distilled off, 500 ml of ethyl acetate and 500 ml of water were added for liquid separation, the ethyl acetate layer was washed 3 times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 16.5 g of a crude product of the title compound.
Was obtained as a colorless oily substance. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.96 (t, J = 7.2 Hz, 3 H), 1.22 (t, J = 7.2 Hz, 6 H), 1.30 ~
1.80 (m, 2H), 2.32 to 2.60 (m, 2H), 3.10 (d, J = 7.2Hz, 2
H), 3.50 (t, J = 7.2Hz, 1H), 4.14 (q, J = 7.2Hz, 4H), 5.
83 (s, 2H), 6.58 (s, 2H) (3) (6-propyl-1,3-benzodioxole-5
-Yl) Synthesis of methylmalonic acid Diethyl (6-propyl-1,3-benzodioxol-5-yl) methylmalonate (16.5 g) was dissolved in ethanol (150 ml), sodium hydroxide (20 g) and water (50 ml) were added, and the mixture was heated on a boiling water bath for 30 minutes. The reaction solution is concentrated and ethyl acetate is added.
300 ml and 30 ml of water were added and the layers were separated. The aqueous layer was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed 3 times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 15.2 g of the title compound as a white powder. ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 0.91 (t, J = 7.2 Hz, 3H), 1.31 to 1.66 (m, 2H), 2.50 (t, J
= 7.2Hz, 2H), 2.98 (d, J = 7.2Hz, 2H), 3.47 (t, J = 7.2H)
z, 1H), 5.94 (s, 2H), 6.74 (s, 2H), 12.7 (bs, 2H) (4) 3- (6-propyl-1,3-benzodioxole-
Synthesis of 5-yl) propionic acid After heating 10 g of (6-propyl-1,3-benzodioxol-5-yl) methylmalonic acid on an oil bath at 150 to 160 ° C. for 1 hour, silica gel column chromatography (chloroform / methanol = 20: 1). ) And recrystallized from isopropyl ether to obtain 6.9 g of the title compound as colorless crystals. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.95 (t, J = 7.0 Hz, 3 H), 1.28 to 1.80 (m, 2 H), 2.08 to 3.0
0 (m, 6H), 5.85 (s, 2H), 6.58 (s, 2H) Example 2 3- (6-Propyl-1,3-benzodioxol-5-yl) propionic acid sodium salt 3- (6-propyl-1,3-benzodioxole-5-
1) N-sodium hydroxide aqueous solution to 6.9 g of propionic acid
After 29.2 ml and 100 ml of ethanol were added and dissolved, the solvent was distilled off, ether was added to the residue, and the resulting precipitate was collected by filtration and dried to give 7.5 g of the title compound as a colorless powder.

Melting point (° C); 213-216 ¹ H-NMR (90MHz, DMSO-d ₆ ) δ; 0.90 (t, J = 7.4Hz, 3H), 1.20-2.71 (m, 2H), 1.92-2.2
2 (m, 2H), 2.26 ~ 2.80 (m, 4H), 5.82 (s, 2H), 6.57 (s,
1H), 6.64 (s, 1H) MS (FAB) m / z; 281 (MNa ⁺ ), 259 (MH ⁺ ) Example 3 3- (6-Ethyl-1,3-benzodioxol-5-yl ) Propionic acid By the same method as in Example 1, 1.42 g of the title compound was obtained as colorless crystals from 5.4 g of 5-ethyl-1,3-benzodioxole. ¹ H-NMR (90MHz, CDCl ₃ ) δ; 1.20 (t, J = 7Hz, 3H), 2.32 to 3.08 (m, 6H), 5.84 (s, 2
H), 6.60 (s, 1H), 6.64 (s, 1H) Example 4 3- (6-Ethyl-1,3-benzodioxol 5-yl)
Propionic acid sodium salt By the same method as in Example 2, 3- (6-ethyl-1,3
-Benzodioxol-5-yl) propionic acid 1.42 g
From this, 1.53 g of the title compound was obtained as colorless crystals.

Melting point (° C); 202-204 (decomposition) ¹ H-NMR (400MHz, DMSO-d ₆ ) δ; 1.10 (t, J = 7Hz, 3H), 2.06 (t, J = 8Hz, 2H), 2.51 (q , J
= 7Hz, 2H), 2.66 (t, J = 8Hz, 2H), 5.88 (s, 2H), 6.68
(S, 1H), 6.71 (s, 1H) MS (FAB) m / z; 245 (MH ⁺ ) Example 5 3- (6-Methyl-1,3-benzodioxol-5-yl) propionic acid By the same method as in Example 1, 80 g of the title compound was obtained as colorless crystals from 150 g of 5-methyl-1,3-benzodioxole.

Melting point (° C); 129 to 132 ¹ H-NMR (90MHz, CDCl ₃ ) δ; 2.20 (s, 3H), 2.36 to 2.98 (m, 4H), 5.81 (s, 2H), 6.56
(S, 2H), 11.24 (bs, 1H) Example 6 3- (6-Methyl-1,3-benzodioxol-5-yl) propionic acid sodium salt By the same method as in Example 2, 3- (6-methyl-1,3
-Benzodioxol-5-yl) propionic acid 0.54 g
From this, 0.59 g of the title compound was obtained as a white powder.

Melting point (° C); 209 to 212 ¹ H-NMR (90MHz, DMSO-d ₆ ) δ; 2.54 (s, 3H), 1.86 to 2.84 (m, 4H), 5.80 (s, 2H), 6.56
(S, 1H), 6.63 (s, 1H) MS (FAB) m / z; 253 (MNa ⁺ ), 231 (MH ⁺ ) Example 7 3- (6-methoxymethyl-1,3-benzodioxole −
5-yl) propionic acid 1.6 g of 3- (6-acetoxymethyl-1,3-benzodioxol-5-yl) propionic acid was dissolved in 100 ml of methanol, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 4 hours and 15 minutes. After that, the solvent of the reaction solution was distilled off. To the residue, 1 g of sodium hydroxide, 5 ml of water and 45 ml of ethanol
Was added and the mixture was heated under reflux for 20 minutes, the reaction mixture was concentrated, 200 ml of ethyl acetate and 200 ml of water were added, the mixture was acidified with concentrated hydrochloric acid, separated, washed 3 times with water and dried over anhydrous sodium sulfate. . When the solvent was distilled off, 1.25 g of the title compound was obtained as a white powder. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.24 to 3.10 (m, 4H), 3.34 (s, 3H), 4.33 (s, 2H), 5.86
(S, 2H), 6.64 (s, 1H), 6.74 (s, 1H) Example 8 3- (6-methoxymethyl-1,3-benzodioxole-
5-yl) sodium propionate By the same method as in Example 2, 1.3 g of the title compound was obtained as a white powder from 1.25 g of 3- (6-methoxymethyl-1,3-benzodioxol-5-yl) propionic acid.

Melting point (° C); 155-159 ¹ H-NMR (90MHz, DMSO-d ₆ ) δ; 1.88-2.90 (m, 4H), 3.23 (s, 3H), 4.28 (s, 2H), 5.87
(S, 2H), 6.71 (s, 1H), 6.74 (s, 1H) MS (FAB) m / z; 283 (MNa ⁺ ), 261 (MH ⁺ ) Example 9 3- (6-ethoxymethyl-1) , 3-benzodioxole-
5-yl) propionic acid Dissolve 0.6 g of metallic sodium in 100 ml of ethanol, and then 3-
(6-chloromethyl-1,3-benzodioxole-5-
2.0 g of (propionic acid) was added little by little. After heating at 50 ° C. for 2 hours, the solvent was distilled off, the mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate, evaporated, and then separated by silica gel column chromatography (chloroform) to obtain 0.73 g of the title compound as colorless crystals.

Melting point (° C); 97 to 98 ¹ H-NMR (90MHz, CDCl ₃ ) δ; 1.23 (t, J = 7Hz, 3H), 2.61 (m, 2H), 2.91 (m, 2H), 3.51
(Q, J = 7Hz, 2H), 4.38 (s, 2H), 5.87 (s, 2H), 6.64 (s,
1H), 6.76 (s, 1H) Example 10 3- (6-Ethoxymethyl-1,3-benzodioxole-
5-yl) sodium propionate By the same method as in Example 2, 0.71 g of 3- (6-ethoxymethyl-1,3-benzodioxol-5-yl) propionic acid was obtained to obtain 0.7 g of the title compound as colorless crystals.

Melting point (° C); 165-282 (decomposition) ¹ H-NMR (400MHz, DMSO-d ₆ ) δ; 1.13 (t, J = 7.0Hz, 3H), 2.07 (m, 2H), 2.68 (m, 2H) , 3.
45 (q, J = 7.0Hz, 2H), 4.36 (s, 2H), 5.92 (s, 2H), 6.78
(S, 1H), 6.81 (s, 1H) MS (FAB) m / z; 297 (MNa ⁺ ), 275 (MH ⁺ ) Example 11 (5,6-methylenedioxyindan-2-yl) carboxylic acid (1) Synthesis of 5,6-methylenedioxyindene 1-hydroxy-5,6-methylenedioxyindane 10.
A solution of 8 g and 15 ml of acetic acid in toluene (100 ml) was heated under reflux for 4 hours. Water and a small amount of potassium carbonate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. After distilling off the solvent, the residue was separated by silica gel column chromatography (chloroform / hexane = 1: 3) to obtain 9.0 g of the title compound as colorless crystals.

Melting point (° C); 85-86 ¹ H-NMR (90MHz, CDCl ₃ ) δ; 3.29 (m, 2H), 5.92 (s, 2H), 6.43 (dt, J = 2Hz and 6Hz,
1H), 6.74 (m, 1H), 6.86 (s, 1H) 6.95 (s, 1H) (2) Synthesis of 5,6-methylenedioxyindan-2-ol A solution of 9.0 g of 5,6-methylenedioxyindene in tetrahydrofuran (23 ml) was cooled to 0 ° C. under a nitrogen atmosphere, and
A solution of 0.0M borane-methyl sulfide complex (2.2 ml) in tetrahydrofuran (5 ml) was added dropwise. The temperature was raised from 0 ° C. to room temperature over 4 hours, and 1.8 ml of water was added dropwise.
Further, while cooling with ice, 7.4 ml of 3M aqueous sodium hydroxide solution, and then 3
5.5 ml of 5% hydrogen peroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with brine and dried over magnesium sulfate. After distilling off the solvent, the residue was crystallized with ethyl acetate to obtain 6.4 g of the title compound as colorless crystals.

Melting point (° C); 99 to 100 ¹ H-NMR (90MHz, CDCl ₃ ) δ; 1.73 (m, 1H), 2.79 (dd, J = 4Hz and 16Hz, 2H), 3.14 (d
d, J = 6Hz and 16Hz, 2H), 4.68 (m, 1H), 5.91 (s, 2H),
6.71 (s, 2H) (3) Synthesis of 2-cyano-5,6-methylenedioxyindane To a solution of 5.8 g of 5,6-methylenedioxyindan-2-ol and 9.1 ml of triethylamine in dichloromethane (150 ml), 7.45 g of methanesulfonyl chloride was added dropwise under ice cooling.
Stirred at 0 ° C. for 1 hour. Ice water was added to the reaction solution, which was washed with a saturated aqueous solution of sodium hydrogen carbonate and then dried over magnesium sulfate. When the solvent was distilled off, 8.0 g of methanesulfonic acid ester was obtained. This was used as it was in the next reaction without purification.

Methanesulfonic acid ester 2.6g and sodium cyanide 1.0g
A catalytic amount of sodium iodide in dimethylformamide (20 ml) was heated at 80 ° C. for 6 hours. Water was added to the reaction solution and extracted with ether. The organic layer was washed with water and brine and dried over magnesium sulfate. When the solvent was distilled off and the resulting residue was separated by silica gel column chromatography,
0.4 g of the title compound was obtained as colorless crystals.

Melting point (° C); 124 to 125 ¹ H-NMR (90MHz, CDCl ₃ ) δ; 3.19 (m, 5H), 5.87 (s, 2H), 6.60 (s, 2H) (4) (5,6-methylenedi Oxyindan-2-yl)
Synthesis of carboxylic acids 2-cyano-5,6-methylenedioxyindane 1.4 g and 3
To a mixture of 50 ml of 0% potassium hydroxide aqueous solution and 50 ml of ethanol, 3.9 ml of 35% hydrogen peroxide solution was added dropwise under ice cooling. After the dropping, the mixture was heated at 60 ° C for 2 hours, and the solvent was distilled off. Dilute hydrochloric acid was added to the residue and extracted with chloroform. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was recrystallized from diisopropyl ether to give 1.4 g of the title compound as colorless crystals.

Mp ^{(℃); 168~169 1 H-} NMR (90MHz, CDCl 3) δ; 3.00~3.44 (m, 5H), 5.85 (s, 2H), 6.60 (s, 2H), 10.0
(Bs, 1H) Example 12 (5,6-Methylenedioxyindan-2-yl) carboxylic acid sodium salt By the same method as in Example 2, 1.5 g of the title compound was obtained as colorless crystals from 1.4 g of (5,6-methylenedioxyindan-2-yl) carboxylic acid.

Melting point (° C);> 270 ¹ H-NMR (400MHz, DMSO-d ₆ ) δ; 2.77 to 3.04 (m, 5H), 5.89 (m, 2H), 6.68 (s, 2H) MS (FAB) m / z 251 (MNa ⁺ ), 229 (MH ⁺ ) Example 13 (7,8-dihydro-5H-1,3-dioxolo [4,5-g]
[2] Benzopyran-5-yl) acetic acid (1) (7,8-dihydro-5H-1,3-dioxolo [4,5-g]
[2] Synthesis of benzopyran-5-yl) ethyl acetate 1.3 g of ethyl 3- {6- (2-hydroxyethyl) -1,3-benzodioxol-5-yl} acrylate was dissolved in 30 ml of ethanol, a catalytic amount of sodium ethylate was added, and the mixture was heated under reflux for 2 hours. did. After distilling off the solvent, 1N hydrochloric acid and water were added, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 85 : 15) to obtain 0.78 g of the title compound as a colorless oily substance. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.27 (t, J = 7.2 Hz, 3 H), 2.35 to 3.1 (m, 4 H), 3.5 to 4.37
(M, 2H), 4.17 (q, J = 7.2Hz, 2H), 5.09 (dd, J = 7.2Hz a
nd J = 5.6Hz, 1H), 5.85 (s, 2H), 6.46 (s, 1H), 6.51
(S, 1H) (2) (7,8-dihydro-5H-1,3-dioxolo [4,5-g]
[2] Synthesis of benzopyran-5-yl] acetic acid (7,8-dihydro-5H-1,3-dioxolo [4,5-g]
[2] 0.78 g of benzopyran-5-yl) ethyl acetate was dissolved in 20 ml of ethanol and 0.35 g of sodium hydroxide was added to 4 ml of water.
The solution dissolved in was added, and the mixture was heated with stirring at 60 ° C. After the solvent was distilled off, water was added and the mixture was washed with ethyl acetate, acidified with 1N hydrochloric acid, extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. This was filtered, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (chloroform) to give 0.67 g of the title compound as colorless crystals. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.35 to 3.20 (m, 4H), 3.5 to 3.95 (m, 1H), 3.92 to 4.28
(M, 1H), 4.95 to 5.25 (m, 1H), 5.87 (s, 2H), 6.46 (s, 1
H), 6.52 (s, 1H), 7.2 to 8.6 (br, 1H) Example 14 (7,8-dihydro-5H-1,3-dioxolo [4,5-g]
[2] Benzopyran-5-yl) acetic acid sodium salt In the same manner as in Example 2, (7,8-dihydro-5H
-1,3-Dioxolo [4,5-g] [2] benzopyran-5-
From 0.66 g of (yl) acetic acid, 0.69 g of the title compound was obtained as colorless crystals.

Melting point (° C); 257.5 to 258 (decomposition) ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 2.26 (d, J = 6.5 Hz, 2H), 2.3 to 2.55 (m, 2H), 3.35 to 4.05
(M, 2H), 4.89 (t, J = 6.5Hz, 1H), 5.83 (s, 1H), 6.52
(S, 1H), 6.75 (s, 1H) MS (FAB) m / z; 281 (MNa ⁺ ), 259 (MH ⁺ )

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Naoyuki Shimomura 2-23-5 Sakurakumura, Shinji-gun, Ibaraki Prefecture Maison Gakuen No. 207 (72) Inventor Toshihiko Kaneko 4-18-4 Kasuga Yatabe-cho, Tsukuba-gun, Ibaraki Market Apartment No. 203 (72) Inventor Kanji Yamanaka 725-25 Shimohirooka, Sakuramura, Shinji-gun, Ibaraki Prefecture (72) Inventor Uharu Nishinuma 3-4-8 Kubogaoka, Moriya-cho, Kitasoma-gun, Ibaraki (72) Invention Person Nagaichi Junichi 2-15-3 Umezono, Sakuramura, Shinji-gun, Ibaraki Prefecture (72) Inventor Kazuo Hirota 4-19-13 Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture Eisai Shioyama Dormitory (72) Inventor Kaname Miyamoto 2 -8-9 Daiho Apartment No. 3 (72) Inventor Toru Horie 25-4 Saigo, Yatabe Town, Tsukuba-gun, Ibaraki Prefecture (72) Inventor Yoshio Wakabayashi 368 Motoyoshida Town, Mito City

Claims (4)

(57) [Claims] 1. A general formula (I) (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkoxy lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ³ represents a hydrogen atom or a lower alkyl group. And R ⁴ represents a hydrogen atom or a lower alkyl group, and R ¹ and R ² or R ¹ and R ³ may be taken together to form a 5- to 7-membered ring, provided that R ¹⁾ , (R ²⁾ and (R ³⁾ are all hydrogen atoms.), Or a pharmaceutically acceptable salt thereof. 2. The benzodioxole according to claim 1, wherein in the general formula (I), R ¹ is a lower alkyl group or a lower alkoxy lower alkyl group, and R ² and R ³ are both hydrogen atoms. Derivatives or pharmaceutically acceptable salts thereof. 3. In the general formula (I), R ¹ and R ² or R ¹ and R ³
The benzodioxole derivative or the pharmaceutically acceptable salt thereof according to claim 1, which together form a 5- to 7-membered ring. 4. The general formula (I) (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkoxy lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ³ represents a hydrogen atom or a lower alkyl group. And R ⁴ represents a hydrogen atom or a lower alkyl group, and R ¹ and R ² or R ¹ and R ³ may be taken together to form a 5- to 7-membered ring, provided that R ^A compound for treating and preventing liver diseases comprising a benzodioxole derivative represented by the formula ( ¹⁾ , R ² or R ^{3 as} a hydrogen atom, or a pharmaceutically acceptable salt thereof as an active ingredient.