JP2777146B2 - Benzodioxole derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a benzodioxole derivative and a pharmacologically acceptable salt thereof having excellent action as a medicine.

[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 research over a long period of time using plants used in the private sector as materials, and as a result, have found that Petivelia alliacea L. and Cinnamomum porrectum (Roxb.)
rm.), each of which is represented by the following chemical structural formula.
[(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.

Furthermore, Japanese Patent Application Laid-Open No. 62-39583 discloses a (1,3-benzodioxol-5-yl) methylthio derivative, which is significantly different in 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) and a pharmaceutically acceptable salt thereof.

[Wherein X represents an alkylene group having 1 to 6 carbon atoms, and a lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group.

A is a group represented by the formula —O—Y—OR ¹ (wherein Y represents an alkylene group having 1 to 6 carbon atoms, and 1
A lower alkyl group may be attached to one or more carbon atoms. R ¹ represents a hydrogen atom, a lower alkyl group, or a tetrahydropyranyl group. A group represented by the formula: —O—Z—COOR ² (wherein Z represents an alkylene group having 1 to 6 carbon atoms;
A lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group. R ² represents a hydrogen atom or a lower alkyl group. ), (Wherein E represents an alkylene group having 1 to 6 carbon atoms,
A lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group. R ³ and R ⁴ represent the same or different hydrogen atoms, lower alkyl groups, or carboxymethyl groups. A group represented by the formula: —O—G—R ⁵ (wherein G represents an alkylene group having 1 to 6 carbon atoms, and one or more carbon atoms constituting the alkylene group is a lower alkyl group; R ⁵ represents a succinimide group, a phthalic imide group, or a 1,2-cyclohexanedicarboximide group), or a group represented by the formula —O—R ⁶ ( In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group). In the above definition of the compound (I) of the present invention, R
^{1, R 2, R 3,} R 4, R 5, R 6, X, Y, Z, and lower alkyl group found at E and G represents a linear or branched alkyl group having 1 to 6 carbon atoms E.g., methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl,
It means tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like.

X, Y, Z, E, Representative alkylene groups G has the formula -CH ₂
−, − (CH ₂ ) ₂ −, − (CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, −
(CH ₂ ) ₅ − and − (CH ₂ ) ₆ − can be shown. Also,
The lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group, specifically, for example, A group represented by A group represented by 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 salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, ammonium salt and the like, and further depending on the substituent, for example, hydrochloride, hydrobromide, sulfate, phosphoric acid Inorganic salts such as salts, for example acetate, maleate, tartrate,
Organic acid salts such as methanesulfonate, benzenesulfonate, toluenesulfonate, or, for example, arginine,
Examples thereof include salts with amino acids such as aspartic acid and glutamic acid. 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 general formula (I), A is a group represented by the formula -OY-OR ¹ (wherein
Y and R ^{1 each} have the same meaning as defined above) (Production Method 1) Y represents an alkylene group having 1 to 6 carbon atoms, and one of the alkylene groups constituting the alkylene group Alternatively, a lower alkyl group may be bonded to more carbon atoms, but the carboxylic acid corresponding to the target substance is used as a starting material, and reduced by a conventional method to obtain an alcohol (R ¹ = H).

When reducing, usually, for example, LiAlH ₄ , LiAlH (OCH ₃ ) ₃ ,
_{AlH (i-C 4 H 9} ) 2, NaBH (OCH 3) 3, NaAlH 2 (OCH 2 CH 2 OC
H ₃₎ the reaction is carried out in the presence of a reducing agent such as _2. As the solvent used at this time, ether, tetrahydrofuran, 1,2
-Dimethoxyethane, benzene and the like.

(Production method 2) (when R ¹ is H) (In the series of formulas, X and Y have the same meanings as described above, and Hal means a halogen atom.) That is, the alcohol represented by the formula (II)
The halogenated compound represented by I) is reacted by a conventional method to obtain a compound (IV). This reaction is usually performed in the presence of sodium hydride.

Any solvent may be used as long as it does not participate in the reaction, and examples thereof include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, and 1,2-dimethoxyethane.

Examples of the halogen include chlorine, bromine and iodine, and bromine is most preferable. Further, the compound (I
V) can be dissolved in a solvent such as methanol or ethanol and reacted with an acid catalyst such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid to obtain the desired product (V).

Production Method B [In the general formula (I), A is a group represented by the formula -O-Z-COOR ² (wherein
Z and R ^{2 each} have the same meaning as described above) (Production Method 1) Z represents an alkylene group having 1 to 6 carbon atoms, and one or more of the alkylene groups constituting the alkylene group Although a lower alkyl group may be bonded to more carbon atoms, an alcohol corresponding to the target substance is used as a starting substance, which is oxidized by a conventional method to obtain a carboxylic acid as the target substance.

For oxidation, for example, chromium oxide-sulfuric acid or chromium oxide-pyridine complex (Sarett oxidation) is suitable.

The carboxylic acid can be further esterified by a conventional method.

(Manufacturing method 2) That is, the alcohol represented by the general formula (II) is reacted with the halogen represented by the general formula (VI) to obtain a target compound represented by the general formula (VII).

This reaction is usually performed in the presence of sodium hydride, sodium amide, potassium carbonate, triethylamine, sodium hydroxide, silver oxide and the like. Any solvent may be used as long as it does not participate in the reaction, and examples thereof include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, and 1,2-dimethoxyethane. Examples of the halogen include chlorine, bromine and iodine, and bromine is most preferable.

When R ² is a lower alkyl group, compound (VII) is an ester, which is obtained by reacting a carboxylate formed in the reaction system with an alkyl halide such as methyl iodide. If necessary, this is hydrolyzed by a conventional method to obtain a carboxylic acid (R ² = H).

That is, the compound (VII) is hydrolyzed with an alcohol such as methanol or ethanol as a solvent and an alkali hydroxide such as sodium hydroxide or potassium hydroxide to obtain a carboxylic acid as a target substance.

Production method C [In the general formula (I), A is (Wherein, E, R ³ and R ⁴ have the same meanings as described above). (Production method 1) That is, a carboxylic acid represented by the general formula (VIII) or a reactive derivative thereof and an amine compound represented by the general formula (IX) are subjected to an amidation reaction by a conventional method to obtain a compound represented by the general formula An amide compound represented by (X).

Examples of the reactive derivative of the compound (VIII) include acid halides such as acid chloride and acid bromide; acid azide; active esters with N-hydroxybenzotriazole and N-hydroxysuccinimide; symmetric acid anhydrides; -Mixed acid anhydrides with toluenesulfonic acid and the like.

When a free carboxylic acid is used as the compound (VIII), the reaction is preferably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.

In the reaction, compound (VIII) or a reactive derivative thereof and compound (IX) are used in almost equimolar amounts or in a slightly excessive molar amount, and an organic solvent inert to the reaction, for example, pyridine, tetrahydrofuran, dioxane, ether, benzene, The reaction is performed in a solvent such as toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate, or acetonitrile.

Depending on the type of the reactive derivative, the addition of a base such as triethylamine, pyridine, picoline, lutidine, N, N-dimethylaniline, potassium carbonate, or sodium hydroxide during the reaction is advantageous for smoothly proceeding the reaction. There are cases.

The reaction temperature varies depending on the type of the reactive derivative, and is not particularly limited.

(Production Method 2) [When either R ³ or R ⁴ is a carboxymethyl group] That is, after dissolving compound (VIII) in a solvent such as benzene, chloroform, and dimethylformamide,
For example, thionyl chloride, oxalic acid chloride, phosphorus oxychloride, phosphorus pentachloride and the like are added, and reacted under ice-cooling or at room temperature to heating under reflux to obtain an acid chloride of compound (VIII). For example, aqueous sodium hydrogen carbonate solution,
An aqueous solution of sodium carbonate or an aqueous solution of sodium hydroxide is poured under ice water cooling and stirring, and reacted to obtain glycinamide (XII), which is one of the target substances.

Production Method D [In the general formula (I), A is a group represented by the formula -O-G-R ⁵ (wherein
G and R ⁵ have the same meanings as described above) That is, the compound (XIII) is dissolved in a solvent that does not participate in a reaction such as tetrahydrofuran or dioxane,
The target compound (XV) can be obtained by adding succinimide, phthalic imide, 1,2-cyclohexanecarboximide, and the like, and reacting with triphenylphosphine and diethyl azodicarboxylate.

Production Method E [In the case where A in the general formula (I) is a group represented by the formula -OR ⁶ (wherein R ⁶ has the same meaning as described above)] That is, the alcohol compound represented by the compound (II) and the halogen compound represented by the compound (XVI) are reacted by a conventional method to obtain a compound (XVII). This reaction is usually performed in the presence of sodium hydride, sodium amide, potassium carbonate, triethylamine, sodium hydroxide and the like.

Any solvent may be used as long as it does not participate in the reaction, and examples thereof include dimethylformamide, dimethylsulfoxide, 1,2-dimethoxyethane, and tetrahydrofuran. Examples of the halogen include chlorine, bromine, and iodine.

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

0.5 Pharmacological Experimental Example Experimental Example 1 D- galactosamine action 1. longitudinal Experimental method weighing 180g for hepatopathy model Fisher (Fischer type) (F ₃₄₄₎ male rats D- galactosamine 400 mg / kg administered subcutaneously 1 hour after each test compound % Methylcellulose liquid (100mg / k
g) was administered orally. D-galactosamine is dissolved and diluted with physiological saline, and then the pH is adjusted with a 10N aqueous potassium hydroxide solution.
Adjusted to 7.0 to a final concentration of 200 mg / ml.

48 hours after the administration of D-galactosamine, blood was collected from the tail of the rat, and the blood coagulation time of the whole blood was determined by the hepaplastin test (HP
In addition to T), GPT activity in plasma was measured by an enzymatic method.

Table 1 shows the inhibition rates of D-galactosamine-induced liver damage of each test compound.

Experimental Example 2 Effect on carbon tetrachloride (CCl ₄ ) liver injury model 1. Experimental method A test compound suspended in a 0.5% methylcellulose solution (100 mg / kg) was weighed around 180 g by Fischer.
Oral administration to male rats, 1 hour later 0.5m of carbon tetrachloride
l / kg was administered intraperitoneally. Carbon tetrachloride was diluted with olive oil to a final concentration of 0.25 ml / ml.

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

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.

When the compound of the present invention is administered as a therapeutic or prophylactic agent for liver disease, it may be administered orally as a powder, granule, capsule, syrup, or the like, or as a suppository, injection, external preparation, or infusion. It may be administered parenterally. The dose varies remarkably depending on the degree of symptoms, age, type of liver disease, etc., but usually about 0.1 mg to 1,000 mg, preferably 2 mg to 500 mg, more preferably 5 to 100 mg per day for an adult once to several times a day. Administer separately.

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 an excipient, for example, lactose, corn starch, sucrose, glucose, sorbite, crystalline cellulose, silicon dioxide, and the like, as a binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils, 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.

〔Example〕

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

Example 1 2-[[2- (1,3-benzodioxol-5-yl)
Ethoxy] ethane-1-ol (Production Method 1) A solution of lithium aluminum hydride (340 mg, 10 mmol) in tetrahydrofuran was prepared. In this, at 0 ° C [2
-(1,3-benzodioxol-5-yl) ethoxy]
5 ml of a solution of 1.20 g (5 mmol) of acetic acid in tetrahydrofuran is added to 15
The mixture was added over minutes, and stirred at room temperature for 2 hours. Ethyl acetate,
Water and a 1N aqueous hydrochloric acid solution were added, and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (developing solvent; ethyl acetate / hexane = 3: 7) to obtain 1.0 g (yield: 86%) of the target title compound.

(Production method 2) (a) 2- (1,3-benzodioxol-5-yl)
To a solution of 4.0 g of ethanol and 0.3 g of potassium iodide in 50 ml of dimethylformamide, add 2.0 g of 60% sodium hydride and add
After 10 minutes, 9.0 g of 2- (tetrahydropyran-2-yloxy) ethyl bromide was added. After completion of the reaction, the solvent was distilled off, water was added to the residue, and the mixture was extracted twice with ethyl acetate.
The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The resulting brown oil was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 1).
Purification was performed in 9) to obtain 3.3 g of a pale yellow liquid.

(B) 3.3 g of the liquid obtained in (a) was dissolved in 50 ml of methanol, 10 ml of 1N hydrochloric acid was added, and the mixture was heated at 60 ° C. for 15 minutes.
The solvent was distilled off from the reaction solution, and the residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residual oil was purified by silica gel column chromatography (Rover C column, ethyl acetate / n
-Hexane = 1: 1) to give 1.87 g of the title compound as a colorless transparent liquid.

NMR (ppm, CDCl ₃ ) δ: 2.81 (2H, t, J = 7 Hz), 3.08 to 3.76 (4H, m), 3.65 (2H,
t, J = 7Hz), 5.91 (2H, s), 8.70 (3H, m) ・ MASS m / e; 210 (M ⁺ ) ・ Elemental analysis value; C ₁₁ H ₁₄ O ₄ .1 / 4H ₂ O as C H Theoretical value (%) 61.53 6.80 Actual value (%) 61.74 6.52 Example 2 The following compound was obtained in the same manner as in (Production method 2) of Example 1.

4- [2- (1,3-benzodioxol-5-yl) ethoxy] butan-1-ol _{· NMR (ppm, CDCl 3)} δ; 1.57~1.74 (4H, m), 2.79 (2H, t, J = 7Hz), 3.40~3.6
8 (6H, m), 5.90 (2H, s), 6.57 to 6.78 (3H, m) MASS m / e; 238 (M ⁺ ) Example 3 [2- (1,3-benzodioxol-5) -Yl) ethoxy] acetic acid (Production Method 1) A solution of 360 mg (9 mmol) of sodium hydride in 6 ml of dimethylformamide was prepared, and 1.0 g (6 mmo) of 2- (1,3-benzodioxol-5-yl) ethan-1-ol was prepared therein.
2 ml of a dimethylformamide solution of l) was added dropwise at room temperature for 5 minutes. After the dropwise addition, the mixture was stirred at 50 ° C. for 10 minutes. The reaction solution was cooled to room temperature, and iodoacetic acid and sodium salt 1.87 g (9.0 mmo
l) was added. After the exotherm subsided, the mixture was again stirred at 50 ° C. for 3 hours. At room temperature, water and a 1N aqueous hydrochloric acid solution were added, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (developing solvent; ethyl acetate /
Hexane = 3: 7) to give 1.23 g of the title compound (83% yield)
I got

(Production Method 2) 2- [2- (1,3-benzodioxole-5) was added to a suspension prepared from 188 ml of anhydrous pyridine and 18.8 g of chromium trioxide.
-Yl) ethoxy] ethanol (8.0 g) was added and the mixture was stirred at room temperature overnight. After adding 300 ml of ether to the black-brown reaction solution with stirring, the resulting precipitate was collected by filtration, washed with ether, and the solvent was distilled off from the combined filtrate and washings. Ethyl acetate was added to the residue, and the mixture was extracted with a 10% aqueous sodium carbonate solution.The aqueous layer was washed with ethyl acetate, cooled with ice, and adjusted to pH 1.0 with concentrated hydrochloric acid.
Extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform / methanol / formic acid = 1000: 10: 1).
3.6 g of the title compound were obtained as a colorless oil.

NMR (ppm, CDCl ₃ ) δ; 2.84 (2H, t), 3.72 (2H, t), 4.12 (2H, s), 5.88 (2H,
s), 6.70 (3H, m) MASS m / e; 224 (M ⁺ ) Example 4 [2- (1,3-benzodioxol-5-yl) ethoxy] acetic acid sodium salt [2- (1,3-benzodioxol-5-yl) ethoxy] crystal was formed when 16 ml of 1N sodium hydroxide was added to a solution of 3.6 g of acetic acid in 50 ml of ethanol. This was collected by filtration, washed successively with ethanol and ether, and dried to obtain 2.6 g of the title compound as white crystals.

Melting point (℃); 208~209 · NMR ( ppm, DMSO-d 6) δ; 2.70 (2H, t, J = 7Hz), 2.47~3.62 (4H, m), 5.94 (2H,
s), 6.60 to 6.82 (3H, m) MASS (Fab) m / e; 247 (RCOONa H ⁺ ) Example 5 The following compound was obtained in the same manner as in (Production method 1) of Example 3 above. .

3- [2- (1,3-benzodioxol-5-yl) ethoxy] propionic acid NMR (ppm, CDCl ₃ ) δ; 2.63 (2H, t, J = 7 Hz), 2.80 (2H, t, J = 7 Hz), 3.64 (2
H, t, J = 7Hz), 3.73 (2H, t, J = 7Hz), 5.91 (2H, s), 6.59
6.76.79 (3H, m) MASS m / e; 238 (M ⁺ ) Example 6 The following compound was obtained in the same manner as in Example 4.

3- [2- (1,3-benzodioxol-5-yl) ethoxy] propionic acid sodium salt Melting point (° C); 190 to 195 NMR (ppm, DMSO-d ₆ · D ₂ O) δ; 2.17 (2H, t, J = 7 Hz), 2.70 (2H, t, J = 7 Hz), 3.50 (2
H, t, J = 7Hz), 3.64 (2H, t, J = 7Hz), 5.94 (2H, s), 6.62
MASS (Fab) m / e; 261 (RCCONa · H ⁺ ) Example 7 The following compound was obtained in the same manner as in (Production method 2) of Example 3 above.

4- [2- (1,3-benzodioxol-5-yl) ethoxy] butyric acid NMR (ppm, CDCl ₃ ) δ: 1.90 (2H, m), 2.44 (2H, t, J = 7 Hz), 2.78 (2H, t, J = 7)
Hz), 3.48 (2H, t, J = 7 Hz), 3.60 (2H, t, J = 7 Hz), 5.92
(2H, s), 6.58 to 6.80 (3H, m) MASS m / e; 252 (M ⁺ ) Example 8 4- [2- (1,3-benzodioxol-5-yl) ethoxy] k Herbic acid 1) Methyl 4- [2- (1,3-benzodioxol-5-yl) ethoxy] valerate 10 g of 2- (1,3-benzodioxol-5-yl) ethanol was dissolved in 300 ml of dimethylformamide, 60% sodium hydride was added, and the mixture was stirred at 40 ° C. for 1 hour and 20 minutes. Under ice-cooling, 22.46 g of 5-bromovaleric acid was added thereto, and the mixture was stirred for 40 minutes and then at 40 ° C. for 4 hours. The mixture was ice-cooled, 10 ml of methyl iodide was slowly added dropwise, the mixture was stirred at 40 ° C. for 1 hour, ice water was added, 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 to obtain 4.55 g (yield 27%) of the title compound.

2) 4- [2- (1,3-benzodioxol-5-yl) ethoxy] valeric acid 4.55 g of methyl ether obtained in 1) was dissolved in 50 ml of methanol, and 32.5 ml of 1N sodium hydroxide was added.
Stirred at C for 1 hour. The solvent was concentrated, methanol was removed, the aqueous layer was washed with ethyl acetate, acidified with 2N hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. This was filtered and the solvent was distilled off to give 4.05 g (yield 9
4%) of the title compound were obtained.

Melting point (° C.); 146 to 150 NMR (ppm, CDCl ₃ ) δ; 1.50 to 1.90 (4H, m), 2.2 to 2.3 (2H, m), 2.79 (2H, t, J
= 6.8Hz), 3.25-3.6 (2H, m), 3.58 (2H, t, J = 6.8Hz),
5.90 (2H, s), 6.55 to 6.9 (3H, m) MASS m / z; 266 (M ⁺ ) Example 9 2- [2- (1,3-benzodioxol-5-yl) ethoxy] Butan-1-ol 1) 2- [2- (1,3-benzodioxol-5-yl) ethoxy] butyric acid ethyl ester 1.87 g of 60% sodium hydride was added to a solution of 6.0 g of 2- (1,3-benzodioxol-5-yl) ethanol in 40 ml of dimethylformamide, and the mixture was stirred at 40 ° C. for 30 minutes. To this, 10.6 g of ethyl 2-bromobutyrate was added. After the exothermic reaction was completed, dimethylformamide was distilled off from the reaction solution. Ice water and 1N hydrochloric acid were added to the residue, and the mixture was extracted with ethyl acetate.
The organic layer was washed sequentially with water and brine, and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 19) to obtain 5.71 g of the title compound as a colorless transparent liquid.

NMR (ppm, CDCl ₃ ) δ; 0.94 (3H, t, J = 7 Hz), 1.27 (3H, t, J = 7 Hz), 1.87 (2
H, t, J = 7Hz), 2.80 (2H, t, J = 7Hz), 3.51 (1H, q, J = 7H)
z), 3.79 (2H, m), 4.09 (2H, q, J = 7Hz), 5.91 (2H, s),
6.69 (3H, m) 2) 2- [2- (1,3-benzodioxol-5-yl) ethoxy] butan-1-ol A solution of 1.35 g of the ester obtained in the above 1) in 10 ml of tetrahydrofuran was added dropwise to a suspension of 0.14 g of lithium aluminum hydride in 5 ml of tetrahydrofuran under ice cooling. After completion of the dropwise addition, the temperature was returned to room temperature, water, 15% sodium hydroxide and water were added, and the resulting precipitate was filtered through celite. The solvent was distilled off from the filtrate, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 3: 1) to obtain 1.0 g of the title compound as a colorless transparent liquid.

NMR (ppm, CDCl ₃ ) δ; 0.88 (3H, t, J = 7 Hz), 1.48 (2H, m), 2.80 (2H, t, J = 7)
Hz), 3.16 to 3.84 (5H, m), 5.92 (2H, s), 6.72 (3H, m) MASS m / e; 238 (M ⁺ ) Example 10 2- [2- (1,3-benzo Dioxol-5-yl) ethoxy] butyric acid sodium salt 2- [2- (1,3-benzodioxol-5-yl)
[Ethoxy] 12.5 ml of 1N sodium hydroxide was added to a solution of ethyl butyrate in 12.5 ml of methanol, and the solvent was distilled off. Ethanol was added to the residue, and the solvent was distilled off again. Addition of ether to the residue causes precipitation. The residue obtained by decanting the supernatant was added with ethanol, and the solvent was distilled off. Ether was added to the residue, and the resulting supernatant of the precipitate was decanted off. The remaining precipitate was dissolved in water and freeze-dried to obtain 2.3 g of the title compound as a colorless solid.

Melting point (° C.); 180 to 190 NMR (ppm, DMSO-d ₆ .D ₂ O) δ; 0.83 (3H, t, J = 7 Hz), 1.41 to 1.74 (2H, m), 2.76 (2H,
t, J = 7Hz), 3.21 ~ 3.85 (3H, m), 5.93 (2H, s), 6.68 ~
6.89 (3H, m) MASS (Fab) m / e; 275 (RCOONa.H ⁺ ), 297 (RCOONa.Na ⁺ ) Example 11 2- [3- (1,3-benzodioxol-5-) Il) propane-2-oxy] ethanol 1) [2- (1,3-benzodioxol-5-yl)
-1-methyl] ethyl-2- (tetrahydropyran-2
-Yloxy) -ethyl ether 5 g of 3- (1,3-benzodioxol-5-yl) propan-2-ol was dissolved in 50 ml of dimethylformamide, and 5.55 g of 60% sodium hydride was added at room temperature.
Stirred for 0 minutes. This was cooled on ice, 23.2 g of 1-bromo-2- (tetrahydropyran-2-yloxy) ethane was added dropwise over 20 minutes, and the mixture was stirred at 40 ° C for 2 hours. After evaporating the solvent, water was added, the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. After filtration and evaporation under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 6.09 g (yield 71%) of the title compound.

2) 2- [3- (1,3-benzodioxol-5-yl) propane-2-oxy] ethanol To 6.09 g of the ether compound obtained in 1) above, 60 m of methanol was added.
l, 20 ml of 2N hydrochloric acid was added, and the mixture was stirred at 60 ° C for 1 hour and 15 minutes. After evaporating the solvent, water was added, the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. After filtration and evaporation under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 3.93 g (89% yield) of the title compound.

NMR (ppm, CDCl ₃ ) δ; 1.19 (3H, d, J = 5.8 Hz), 1.8 to 1.05 (1H, m), 2.58 (2
H, dd, J = 13.7Hz and 5.8Hz), 2.80 (2H, dd, J = 13.7Hz a
nd 5.8Hz), 3.25-3.80 (5H, m), 5.92 (2H, s), 6.55-
6.85 (3H, m) MASS m / z; 224 (M ⁺ ) Example 12 N- [2- {2- (1,3-benzodioxol-5-yl) ethoxy} ethyl] succinimide 2- [2- (1,3-benzodioxol-5-yl)
Ethoxy) ethanol 15 g, triphenylphosphine 20.
25 g, 10.71 g of succinimide in 400 ml of tetrahydrofuran
Then, 13.45 g of diethyl azodicarboxylate dissolved in 70 ml of tetrahydrofuran was slowly added dropwise thereto, and the mixture was stirred for 12 hours. After evaporating the solvent, 300 ml of a 5% aqueous potassium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate. The ethyl acetate layer was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline in this order, and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the residue was subjected to silica gel column chromatography to obtain crude crystals. The crystal was recrystallized several times to remove impurities as crystals to some extent, and then subjected to silica gel column chromatography again to obtain 2.01 g (yield 9%) of the title compound.

Melting point (° C.); 61.5 to 63 NMR (ppm, CDCl ₃ ) δ; 2.66 (4H, s), 2.74 (2H, t, J = 6.5 Hz), 3.48 to 3.84 (6
H, m), 5.91 (2H, s), 6.54 to 6.80 (3H, m) MASS m / z; 291 (M ⁺ ) Example 13 2- [2- (1,3-benzodioxol-1) -Yl) methoxy] ethanol (A) A solution of 60% sodium hydride at 40 ° C. in a solution of 20.0 g of piperonyl alcohol in 100 ml of dimethylformamide.
9 g was added, and the mixture was stirred at 40 ° C. for 30 minutes. 90 g of 2- (tetrahydropyran-2-yloxy) ethyl bromide was added thereto.
added. After completion of the exothermic reaction, dimethylformamide was distilled off from the reaction solution, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate / n-hexane =
1: 4) to obtain 31.8 g of a pale yellow liquid.

(B) 31.8 g of the liquid obtained in (a) is added to 300 ml of methanol.
, And 90 ml of 1N hydrochloric acid was added thereto, followed by heating at 60 ° C. for 5 minutes. The solvent was distilled off from the reaction solution, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 3) to obtain 15.5 g of the title compound as a pale yellow liquid.

NMR (ppm, CDCl ₃ ) δ; 3.48 to 3.84 (4H, m), 4.44 (2H, s), 5.92 (2H, s), 6.8
0 (3H, m) MASS m / e; 196 (M ⁺ ) Example 14 [4- (1,3-benzodioxol-5-yl) butoxy] acetic acid 1) 4- (1,3-benzodioxol-5-yl) butanol 7.3 g of (1,3-benzodioxol-5-yl) acetaldehyde and 14.7 g of (carbethoxymethylene) triphenylphosphoramine were dissolved in 200 ml of tetrahydrofuran and refluxed for 6 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: 10% ethyl acetate / hexane). The resulting oil was subjected to medium pressure catalytic reduction using 0.1 g of palladium carbon (hydrated product) in ethanol. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained oil was dissolved in tetrahydrofuran (10 ml).
The solution was added dropwise to a suspension of 0.8 g of lithium aluminum hydride in tetrahydrofuran (50 ml) cooled with ice water. After stirring for 30 minutes, 0.8 ml of water, 0.8 ml of a 15% aqueous sodium hydroxide solution and then 2.4 ml of water were sequentially added, and the resulting suspension was filtered. The filtrate is concentrated under reduced pressure, and silica gel column chromatography (eluent: 35% ethyl acetate / hexane)
Purification afforded 4.1 g (yield 45%) of the title compound as a colorless oil.

_{· NMR (ppm, CDCl 3)} δ; 1.3~1.9 (5H, m), 2.56 (2H, m), 3.65 (2H, m), 5.90
(2H, s), 6.68 (3H, m)-MASS m / z; 194 (M ⁺ ) 2) [4- (1,3-benzodioxol-5-yl)
Butoxy) acetic acid 0.8 g of 60% sodium hydride was added to a solution of 2.0 g of 4- (1,3-benzodioxol-5-yl) butanol obtained in 1) above in dimethylformamide (10 ml).
Heated at ℃ for 30 minutes. After cooling to room temperature, 4.1 g of sodium iodoacetate was added as crystals. When the exothermic reaction was completed, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and passed through a short silica gel column chromatography (eluent: ethyl acetate). The eluate was concentrated, dissolved in ether, and extracted with a 1N aqueous sodium hydroxide solution. The aqueous layer was acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and purified by silica gel column chromatography (eluent: 40% ethyl acetate / hexane). The obtained crystals were recrystallized from ethyl acetate / hexane to give the title compound (1.4 g, yield 54%).
%)was gotten.

Melting point (℃); 73~74 · NMR ( ppm, CDCl 3) δ; 1.65 (4H, m), 2.54 (2H, m), 3.53 (2H, m), 4.10 (2H,
s), 5.91 (2H, s ), 6.65 (3H, m), 9.0 (1H, m) · MASS m / z; 253 (M + +1) · Elemental analysis; C ₁₃ C H Theoretical as H ₁₆ O ₅ Value (%) 61.89 6.39 found value (%) 62.01 6.51 Example 15 [[4- (1,3-benzodioxol-5-yl) butyl] oxy] acetic acid 4- (1,3-benzodioxol-5-yl) pentan-1-ol 2.0 g (9.6 m) was added to 15 ml of dimethylformamide.
mol) and add 0.58g (14mm) of sodium hydride
ol) was added at room temperature. The reaction was carried out at 50 ° C for 20 minutes, and 3.0 g (14 mmol) of sodium iodoacetate was added in 1 minute. 50 more
After allowing the reaction to proceed at room temperature for 1 hour, the mixture was cooled to room temperature, and water and a 1N aqueous hydrochloric acid solution were added. The mixture was extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was recrystallized from isopropyl ether to give 1.6 g (yield 63%) of the target title compound.

Melting point (℃); 79~79.5 · NMR ( ppm, CDCl 3) δ; 1.62 (6H, m), 2.58 (2H, t, J = 7Hz), 3.58 (2H, t, J = 7
Hz), 4.14 (2H, s), 5.94 (2H, s), 6.70 (3H, m) MASS; 266 (M ⁺ ) Example 16 5- (3-methoxypropyl) -1,3-benzodioxy Sole 1.8 g of 60% sodium hydride was added to a solution of 5.0 g of 2- (1,3-benzodioxol-5-yl) ethanol and 18-crown-60.1 g in 50 ml of dimethylformamide, and the mixture was stirred at 40 ° C. for 30 minutes. . 8.5 g of methyl iodide was added thereto, and after the completion of the heating reaction, dimethylformamide was distilled off, and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate / n
-Hexane = 1: 50) to give 4.5 g of the title compound as a colorless liquid.

NMR (ppm, CDCl ₃ ) δ; 1.78 (2H, m), 2.57 (2H, t, J = 7 Hz), 3.28 (3H, s), 3.
32 (3H, t, J = 7 Hz), 5.85 (2H, s), 6.65 (3H, m) MASS m / e; 194 (M ⁺ ) Example 17 3- [3- (1,3-benzodioxide Xol-5-yl) propoxy] propan-1-ol To a solution of 50.0 g of 3- (1,3-benzodioxol-5-yl) propan-1-ol in 1.0 l of dimethylformamide, a catalytic amount of sodium iodide, 60% sodium hydride
1.7 g was added, and the mixture was heated at 40 ° C. for 60 minutes. After cooling to room temperature, 153 g of 3- (tetrahydropyran-2-yloxy) propyl bromide was added thereto. After the heating reaction,
The solvent was distilled off from the reaction solution, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. 50 ml of 1N hydrochloric acid in the residue,
200 ml of ethanol was added, and the mixture was heated at 60 ° C. for 5 minutes. The solvent was distilled off from the reaction solution, the residue was dissolved in ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1: 3) to give the title compound 2
1.5 g were obtained as a colorless oil.

NMR (ppm, CDCl ₃ ) δ; 1.84 (2H, m), 2.60 (2H, t, J = 7 Hz), 3.42 (2H, t, J = 7)
Hz), 3.60 (2H, t, J = 7Hz), 3.79 (2H, t, J = 7Hz), 5.91
(2H, s), 6.54 to 6.78 (3H, m) MASS m / e; 238 (M ⁺ ) Example 18 The following compound was obtained in the same manner as in Example 17 above.

4- [3- (1,3-benzodioxol-5-yl) propoxy] -butan-1-ol NMR (ppm, CDCl ₃ ) δ; 1.62 to 2.00 (6H, m), 2.61 (3H, t, J = 7 Hz), 3.36 to 3.7
6 (6H, m), 5.92 (2H, s), 6.54 to 6.88 (3H, m) MASS m / e; 252 (M ⁺ ) Example 19 3- [3- (1,3-benzodioxole -5-yl) propoxy] propionic acid (Production method 1) 3- [3- (1,3-benzodioxol-5-yl) propoxy] propane- was added to an orange viscous suspension prepared from 580 ml of anhydrous pyridine and 58.2 g of chromic anhydride at 40 ° C. 20.0 g of 1-ol was added, and the mixture was stirred overnight at the same temperature. 2.0 l of ether was added to the reaction mixture, and the resulting precipitate was filtered off after stirring. After evaporating the solvent from the filtrate, a 10% aqueous sodium carbonate solution was added to the residue to dissolve it, and the residue was washed with ethyl acetate. The aqueous layer was ice-cooled, adjusted to pH 1.0 with 6N hydrochloric acid, and extracted with ethyl acetate.
The organic layer was washed with brine, dried over magnesium sulfate,
The solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain 11.8 g of the title compound. Recrystallization from diisopropyl ether gave an elemental analysis sample.

Melting point (℃); 49~50 · NMR ( ppm, CDCl 3) δ; 1.82 (2H, m), 2.60 (2H, t, J = 7Hz), 2.64 (2H, t, J = 7
Hz), 3.44 (2H, t, J = 7 Hz), 3.70 (2H, t, J = 7 Hz), 5.91
(2H, s), 6.54 to 6.78 (3H, m) MASS m / e; 252 (M ⁺ ) Elemental analysis value: C ₁₃ H ₁₆ O ₅ CH theoretical value (%) 61.90 6.39 Actual measurement value (%) 62.03 6.36 (Production method 2) To 54 g of 3- (1,3-benzodioxol-5-yl) propanol, 0.3 ml of Triton B (40% methanol solution) was added, and 21.7 ml of acrylonitrile was added dropwise. After stirring at room temperature for 1 hour, the mixture was cooled with ice water, 450 ml of a 30% aqueous potassium hydroxide solution and 300 ml of ethanol were added, and 126 ml of 35% aqueous hydrogen peroxide was added dropwise over 30 minutes. After stirring at room temperature for 6.5 hours, the mixture was heated at 60 ° C. for 3 hours. The reaction solution was washed with benzene, and the aqueous layer was made acidic with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain a pale brown oil. Diisopropyl ether was added thereto and crystallized to obtain 33 g of crude crystals. The product was further purified by silica gel column chromatography (eluent: hexane / ether / acetic acid = 20: 5: 0.01), recrystallized from diisopropyl ether, and 16.7 g of the title compound (yield 2).
2%).

Example 20 The following compound was obtained in the same manner as in Example 19 above.

4- [3- (1,3-benzodioxol-5-yl) propoxy] butyric acid NMR (ppm, CDCl ₃ ) δ; 1.83 (2H, m), 1.90 (2H, m), 2.47 (2H, t, J = 7Hz), 2.
60 (2H, t, J = 7Hz), 3.41 (2H, t, J = 7Hz), 3.46 (2H, t, J
= 7Hz), 5.91 (2H, s), 6.62 (1H, dd, J = 8Hz and 1.5H
z), 6.67 (1H, d, J = 1.5 Hz), 6.72 (1 H, d, J = 8 Hz) MASS m / e; 266 (M ⁺ ) Example 21 [3- (1,3-benzodioxy) Sole-5-yl) propoxy] acetic acid 1) Methyl 3- (1,3-benzodioxol-5-yl) propoxyacetate 6 g of 3- (1,3-benzodioxol-5-yl) propanol was dissolved in 90 ml of dimethylformamide, and 60% hydrogen was added. After adding 2 g of sodium iodide and stirring at 50 ° C for 30 minutes, add 10.48 g of sodium iodoacetate under ice cooling, and add 3.5 g at 50 ° C.
Reacted for hours. After adding 4.2 ml of methyl iodide under ice cooling and stirring at room temperature for 1 hour, the solvent was distilled off, ice water was added, the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. This was filtered off and evaporated, and the residue was subjected to column chromatography to obtain a crude oil containing some impurities. Further, the product was subjected to rover column chromatography to obtain 5.17 g (yield: 62%) of the pure title compound.

2) [3- (1,3-benzodioxol-5-yl)
Propoxy] acetic acid 3- (1,3-benzodioxol-5-yl) propanol (13 g) was dissolved in dimethylformamide (130 ml) and dissolved in 60%
4.33 g of sodium hydride was added, and the mixture was stirred at 50 ° C for 30 minutes.
Under ice cooling, 15.15 g of sodium iodoacetate was added, and the mixture was stirred at 50 ° C. for 3 hours. After cooling, water was added, the mixture was washed with chloroform, adjusted to pH 2 with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate.
This was filtered off, and the solvent was distilled off, thereby obtaining 15.71 g (yield: 91%) of the title compound.

Melting point (℃); 146~150 · NMR ( ppm, DMSO-d 6) δ; 1.45~1.95 (2H, m), 2.51 (2H, t, J = 7.6Hz), 3.34 (2
H, t, J = 6.5Hz), 3.60 (2H, s), 5.87 (2H, s), 6.44-6.8
0 (3H, m) MASS m / z; 238 (M ⁺ ) Example 22 [3- (1,3-benzodioxol-5-yl) propoxy] acetamidoacetic acid 20 ml of a benzene solution of 4.0 g (17 mmol) of [3- (1,3-benzodioxol-5-yl) propoxy] acetic acid was prepared. 4.0 g (34 mmol) of thionyl chloride was added dropwise thereto,
The mixture was heated to reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude acid chloride.

Separately, 3.4 g (45 mmol) of glycine and 1.8 g of sodium hydroxide
(45 mmol) of an aqueous solution (11.2 ml) was prepared, and at 0 ° C., 10 ml of a tetrahydrofuran solution of acid chloride was added dropwise over 1 minute. The reaction solution was stirred for 15 minutes at 10 ° C., water 11 ml, 12N hydrochloric acid
4.5 ml was added. White smoke was generated and a solid precipitated. Recrystallization from water-ethanol gave 2.7 g (54% yield) of the title compound.

Melting point (℃); 90~90.5 · NMR ( ppm, CD 3 OD) δ; 1.94 (2H, quint, J = 7Hz), 2.70 (2H, t, J = 7Hz), 3.58
(2H, t, J = 7Hz), 4.02 (4H, s), 5.92 (2H, s), 6.76 (3
H, s) MASS; 295 (M ⁺ ) Example 23 Methyl 4- [3- (1,3-benzodioxol-5-yl) propoxy] valerate The title compound was obtained in the same manner as in Example 8 above.

・ Melting point (° C.); 65-66 ・ NMR (ppm, CDCl ₃ ) δ; 1.40-2.00 (6H, m), 2.36 (2H, t, J = 7 Hz), 2.58 (2H,
t, J = 7Hz), 3.36 (4H, m), 5.84 (2H, s), 6.60 (3H, m),
9.30 (1H, bs)-MASS; 280 (M ⁺ )

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Naoyuki Shimomura 2-23-5 Mekuso Gakuen 207-5-23, Akubo, Tsukuba, Ibaraki Prefecture (72) Inventor Toshihiko Kaneko 4-10-20 Sejuru, Kasuga, Tsukuba City, Ibaraki Prefecture 202 Kasuga (72) Inventor Dinji Yamanaka 725-25 Shimohirooka, Tsukuba, Ibaraki Pref. 2-15-3 Umezono, Tsukuba, Japan (72) Inventor Kazuo Hirota 4-19-13, Kasuga, Tsukuba, Ibaraki Pref. No. 3 (72) Inventor Toru Horie 25-4 Saigo, Tsukuba City, Ibaraki Prefecture (72) Inventor Yasuo Wakabayashi 368 Motoyoshida-cho, Mito City, Ibaraki Prefecture (56) References JP-A 61-24585 (JP, A) 1983-110504 JP, A) JP-A-60-224604 (JP, A) JP-A-57-136533 (JP, A) U.S. Pat. No. 3,796,726 (US, A) U.S. Pat. No. 3,918,844 (US, A) Journal of Organism Chemistry, Vol. 48. , (1983) p. 3653-3657 Journal of Economic Entology, Vol. , No. 1, (1971) p. 238-241 (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 317/54 A61K 31/36 CA (STN)

Claims (2)

(57) [Claims] (1) General formula [Wherein X ′ represents an alkylene group having 2 to 6 carbon atoms, and a lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group. A is a group represented by the formula —O—Y—OR ¹ (wherein Y represents an alkylene group having 1 to 6 carbon atoms, and a lower alkyl group is bonded to one or more carbon atoms constituting the alkylene group. R ¹ represents a hydrogen atom, a lower alkyl group or a tetrahydropyranyl group), a group represented by the formula: —O—Z—COOR ² (wherein Z is a group having 1 to 6 carbon atoms) Means an alkylene group,
A lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group. R ² represents a hydrogen atom or a lower alkyl group. ), (Where E represents an alkylene group having 1 to 6 carbon atoms, and a lower alkyl group may be bound to one or more carbon atoms constituting the alkylene group. R ³ and R ⁴ are the same or different hydrogen atom, a lower alkyl group, or carboxy refers to a methyl group.), a group of the formula -O-G-R ⁵ (wherein G denotes an alkylene group having 1 to 6 carbon atoms, A lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group, and R ⁵ is a succinimide group, a phthalic imide group,
Or, it means a 1,2-cyclohexanedicarboximide group. ) Or a group represented by the formula -OR ⁶ (wherein R ⁶ represents a hydrogen atom or a lower alkyl group). ] The benzodioxole derivative represented by these, or its pharmacologically acceptable salt. 2. The general formula [Wherein X represents an alkylene group having 1 to 6 carbon atoms, and a lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group. A is a group represented by the formula —O—Y—OR ¹ (wherein Y represents an alkylene group having 1 to 6 carbon atoms, and a lower alkyl group is bonded to one or more carbon atoms constituting the alkylene group. R ¹ represents a hydrogen atom, a lower alkyl group or a tetrahydropyranyl group), a group represented by the formula: —O—Z—COOR ² (wherein Z is an alkylene having 1 to 6 carbon atoms) A lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group, and R ² represents a hydrogen atom or a lower alkyl group.) , (Where E represents an alkylene group having 1 to 6 carbon atoms, and a lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group. R ³ and R ⁴ are the same or different hydrogen atom, a lower alkyl group, or carboxy refers to a methyl group.), a group of the formula -O-G-R ⁵ (wherein G denotes an alkylene group having 1 to 6 carbon atoms, A lower alkyl group may be bonded to one or more carbon atoms constituting the alkylene group, wherein R ⁵ is a succinimide group, a phthalic imide group,
Or, it means a 1,2-cyclohexanedicarboximide group. ) Or a group represented by the formula -OR ⁶ (wherein R ⁶ represents a hydrogen atom or a lower alkyl group). ] 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.