JPH0543570A - 1,3-benzodioxole-2-thione derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as preventive and therapeutic agents for hepatopathy. CONSTITUTION:A compound, e.g. 5-isopropoxy-1,3-benzodioxole-2-thione expressed by formula I [X is O, S or SO2; R is H, lower alkyl, (substituted) aryl, etc.; R1 is H, lower alkyl, (substituted) aryl, etc.; R2 to R4 are H, halogen, nitro, lower alkyl, etc.; m is 0-3, provided that R1 is not H, when X is O; m is O and R2 to R4 are H; the lower alkyl is not methyl, when R1 is lower alkyl at the 4-position]. The compound expressed by formula I is obtained by reacting 1,2-dihydroxybenzene expressed by formula II with thiophosgene expressed by the formula CSCl2 in a mixture solution of an organic solvent such as chloroform and water containing sodium hydroxide, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 1,3-benzodioxol-2-useful as a therapeutic and preventive agent for liver diseases.
It relates to a thione derivative.

[0002]

2. Description of the Related Art The liver is the largest organ in the human body and is an important organ that controls metabolism in the living body.
well known. Although the liver is a tough organ, it is sometimes damaged by viruses and harmful substances invading from the outside of the body to cause diseases such as acute hepatitis, chronic hepatitis, fatty liver and cirrhosis. As for the liver disease, there are many unclear points because its etiology, pathology, and pathophysiology are not uniform.
Therefore, under the present circumstances, it is extremely difficult to develop a therapeutic agent for liver diseases. At present, 1,3-dithiol derivatives typified by malotilate and glycyrrhizin preparations are widely used in the treatment and prevention of this liver disease and clinically evaluated, but their effects are not yet satisfactory. There is ongoing development of superior drugs that are sufficient, safe, and orally effective.

The present inventors have found that the novel 1,3-benzodioxole-2-thione derivative represented by the general formula (I) described below is useful as a therapeutic and preventive agent for liver diseases. It was Conventionally, as a 1,3-benzodioxole-2-thione derivative, those containing a halogen atom, an alkoxycarbonyl group or an alkanoyl group have been reported to have a pesticidal action in West German Patent No. 2104247. , These compounds have a structurally different structure from the compound (I) of the present invention, and this publication does not suggest that they are useful for the treatment and prevention of liver diseases.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have synthesized various benzodioxole derivatives, and as a result of diligent researches on their pharmacological activity, the novel 1,3-benzodioe represented by the general formula (I) was obtained. The present inventors have completed the present invention by finding that a xol-2-thione derivative is effective as an excellent therapeutic agent for liver diseases. That is, the present invention provides a 1,3-benzodioxole-2-thione derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

[0005]

[Chemical 2] [Wherein, X is O; S; or SO ₂ , and R is a hydrogen atom; a lower alkyl group; an aryl group optionally substituted with a lower alkoxy group; or an optionally substituted lower alkyl group. A good arylalkyl group, R (1) is a hydrogen atom; a lower alkyl group; a hydrogen atom, a halogen atom,
Hydroxyl group, carboxyl group, lower alkoxy group, lower alkanoyl group, lower alkanoyloxy group, aryl group optionally substituted with lower alkyl group, carbamoyl group optionally having alkyl group on nitrogen atom, and nitrogen atom A substituted lower alkyl group; a lower alkenyl group; a lower alkanoyl group; an arylalkanoyl group; an aroyl group; A heteroaroyl group; or an aryl group which may be substituted with a lower alkoxy group, wherein R (2), R (3) and R (4) are the same or different and each is a hydrogen atom; a halogen atom; a nitro group; a lower alkyl Group; lower alkoxyalkyl group; arylalkyl group optionally substituted with lower alkyl group; lower alkoxy group; lower alkyl Hexanoyl group; mono- - or di -
A lower alkanoylamino group; or an alkoxycarbonyl group, and m is an integer of 0 to 3.

In the above definition, the aryl group means a 6-membered ring compound containing only a nitrogen atom as a hetero atom or a benzothiazole ring, and lower means a straight or branched chain having 1 to 6 carbon atoms. -Shaped carbon chain. However,
In the above definition, X is oxygen, m is 0,
When R (2), R (3) and R (4) are all hydrogen atoms,
R (1) is not a hydrogen atom, and when R (1) is a lower alkyl group at the 4-position, the lower alkyl group is not a methyl group. In the above definition, the lower alkyl group is
A linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
It means n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl and the like, and preferable examples include a methyl group and an ethyl group.

The lower alkanoyl group, the arylalkanoyl group, the aroyl group and the heteroaroyl group are residues of an organic acid such as an aliphatic saturated carboxylic acid, an aliphatic unsaturated carboxylic acid, a carbocyclic carboxylic acid or a heterocyclic carboxylic acid. Specific examples include lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, arylalkanoyl groups such as phenylacetyl, benzoyl, and the like.
Aroyl groups such as toluoyl and naphthoyl, furoyl,
Heteroaroyl groups such as nicotinoyl and isonicotinoyl can be mentioned.

The pharmacologically acceptable salts are conventional non-toxic salts, and examples of such salts include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, and aluminum. Salt with inorganic base, ethylamine, propylamine, diethylamine, triethylamine, morpholine, piperidine, N-
Salts with organic bases such as ethylpiperidine, diethanolamine, cyclohexylamine, salts with basic amino acids such as lysine, ornithine, ammonium salts, mineral salts such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, Oxalic acid,
Examples thereof include salts with organic acids such as succinic acid, citric acid, maleic acid, malic acid, fumaric acid, tartaric acid, picric acid, methanesulfonic acid and ethanesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid.

The compound of the present invention has 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.

The compound of the present invention can be produced, for example, according to the following reaction formula.

[Chemical 3] [In the formula, X, R, R (1), R (2), R (3), R (4) and m have the same meanings as described above. ] That is, 1,2-dihydroxybenzene represented by the general formula (II) and thiophosgene (III)
Compound (I) which is a target substance can be obtained by reacting with. Specifically, for example, in a mixture of an organic solvent not involved in the reaction selected from chloroform, dichloromethane and the like and water containing an alkali hydroxide such as sodium hydroxide and potassium hydroxide under ice cooling or under room temperature to heating under reflux. The reaction of (II) and (III) is carried out by a conventional method.

Isolation of the desired product from the reaction mixture is carried out by the usual separation and purification operations such as concentration, extraction, column chromatography, recrystallization and the like. Compound (II) is a known compound or is prepared by a method similar to the method in the known literature [Jouou of the Chemical Society (Jou
rnal of the Chemical Society), page 1514 (1
953), Organic Reactions (Organic Re
actions), vol. 9, page 73 (1957), the Journey of Organic Chemistry (the Jour
nal of Organic Chemistry), 37, 3368 (1972), Helvetica Kimika Actor (Helvetic)
a Chimica Acta), Volume 59, Page 2551 (197)
6) etc.].

The compound of the present invention can also be produced by using the compound (I) as a starting material and converting a part thereof by an appropriate means. That is, the compound (I) in which R (1) has a group represented by an acyl group can be produced by reacting the compound (I) in which R (1) is a hydrogen atom with an acylating agent. As the acylating agent, acetic anhydride,
Acetyl chloride, n-butyryl chloride, benzoyl chloride or the like or a combination of these organic acids and a suitable condensing agent is used. The chemical names of typical compounds (I) of the present invention are shown in Table 1 below, and their structural formulas are shown in Table 2.

[0013]

Table 1 Compound name No. 1 5-isopropoxy-1,3-benzodioxole-2-thione 2 5-methoxy-1,3-benzodioxole-2-thione 3 5-ethoxy-1,3 -Benzodioxole-2-thione 45-butoxy-1,3-benzodioxole-2-thione 5 5-allyloxy-1,3-benzodioxole-2-thione 6 5-benzyloxy-1 , 3-Benzodioxole-2-thione 7 5-p-tolylmethoxy-1,3-benzodioxole-2-thione 8 5- (2-oxopropoxy) -1,3-benzodioxole- 2-Thion 9 5-methoxymethoxy-1,3-benzodioxole-2-thione 10 5-N, N-diethylcarbamoylmethoxy-1,3-benzodioxole-2-thione 11 5-hydroxycarbonylmethoxy -1 , 3-Benzodioxole-2-thione 12 5-methoxycarbonylmethoxy-1,3-benzodioxole-2-thione 13 4,6-dimethoxy-1,3-benzodioxole-2-thione 14 5-Methoxy-6-nitro-1,3-benzodioxole-2-thione 15 5-Acetyl-6-methoxy-1,3-benzodioxole-2-thion 16 5-acetoxy-1,3 -Benzodioxole-2-thione 17 5-phenylacetoxy-1,3-benzodioxole-2-thione 18 5-benzoyloxy-1,3-benzodioxole-2-thione 19 4-acetoxy- 1,3-benzodioxole-2-thione 20 4-butyryloxy-1,3-benzodioxole-2-thione 21 4-nicotinoyloxy-1,3-benzodioxole-2-thione 22 5 -M Luthio-1,3-benzodioxole-2-thione 23 5-Methanesulfonyl-1,3-benzodioxole-2-thione 24 5-Phenoxy-1,3-benzodioxole-2-thione 25 5- (4-methoxyphenyloxy) -1,3-benzodioxole-2-thione 26 5-ethyl-6-methoxy-1,3-benzodioxole-2-thione 27 5-ethoxy-4, 6,7-Trimethyl-1,3-benzodioxole-2-thione 28 5-ethoxy-6-p-tolylmethyl-1,3-benzodioxole-2-thione 29 5-bromo-6-methoxy- 1,3-benzodioxole-2-thione 30 4-hydroxymethyl-1,3-benzodioxole-2-thione 31 5-hydroxymethyl-1,3-benzodioxole-2-thione 32 5 -(2-hydroxy) eth -1,3-benzodioxole-2-thione 33 5- (benzothiazol-2-yl) thiomethyl-1,3-benzodioxole-2-thione 34 5-methylthiomethyl-1,3-benzodioxy Sole-2-thione 35 4- (2-hydroxyethoxy) methyl-1,3-benzodioxole-2-thione 36 4- (3-methoxy) propyl-1,3-benzodioxole-2-thio 37 4-methoxy-6-methoxycarbonyl-1,3-benzodioxole-2-thione 38 5-acetylamino-6-methoxy-1,3-benzodioxole-2-thione 39 4-methoxymethoxy Methyl-1,3-benzodioxole-2-thione 40 5-methoxymethoxymethyl-1,3-benzodioxole-2-thione 41 4- (2-pyridyl) methoxymethyl-1,3- Benzodi Oxole-2-thione 42 4- (2-morpholinoethoxy) methyl-1,3-benzodioxole-2-thione 43 5- (2-methoxy) ethyl-1,3-benzodioxole-2-thione 44 4- (2-methoxy) ethyl-1,3-benzodioxole-2-thione 45 5- (2-methoxymethoxy) ethyl-1,3-benzodioxole-2-thione 46 5-methoxymethyl 1,3-Benzodioxole-2-thione 47 5-Ethoxymethyl-1,3-benzodioxole-2-thione 48 4-Methoxymethyl-1,3-benzodioxole-2-thione 49 5 -(2-Benzyloxy) ethyl-1,3-benzodioxole-2-thione 50 4-methoxy-6-methoxymethyl-1,3-benzodioxole-2-thione 51 5- [1- ( 1,3-benzodioxole-5 Yl) -1-methoxy] methyl-1,3-benzodioxole-2-thione 52 5- [1- (1,3-benzodioxol-5-yl) -1-ethoxy] methyl- 1,3-benzodioxole-2-thione 53 5- (1-methoxy-2-p-tolyl) ethyl-1,3-benzodioxole-2-thione 54 5- (1-ethoxy) ethyl-1 , 3-Benzodioxole-2-thione 55 5- (1-methoxy) ethyl-1,3-benzodioxole-2-thione 56 4-acetoxymethyl-1,3-benzodioxole-2- Thione 57 5- (3-acetoxy) propyl-1,3-benzodioxole-2-thione 58 5- (2-acetoxy) ethyl-1,3-benzodioxole-2-thion 59 5- Anisoyloxymethyl-1,3-benzodioxole-2-thione 60 4-butyryl o Cimethyl-1,3-benzodioxole-2-thione 61 4- (2-chloroethoxy) methyl-1,3-benzodioxole-2-thione 62 4- (2-morpholinoethoxy) methyl-1, 3-benzodioxole-2-thione hydrochloride

[0014]

[Table 2] CompoundFormula (I) Number-[CH (R)] mXR (1) R (2) R (3) R (4)  1 5-O-CH (CH₃)₂ H 2 5-O-CH₃ H 3 5-O-CH₂CH₃ H 4 5-O-CH₂CH₂CH₂CH₃ H 5 5-O-CH₂CH = CH₂ H 6 5-O-CH₂C₆H_Five H 7 5-O-CH₂-p-tolyl H 8 5-O-CH₂COCH₃ H 9 5-O-CH₂OCH₃ H 10 5-O-CH₂CON (CH₂CH₃)₂ H 11 5-O-CH₂CO₂H H 12 5-O-CH₂CO₂CH₃ H 13 4-O-CH₃ 6-OCH₃  14 5-O-CH₃ 6-NO₂  15 6-O-CH₃ 5-COCH₃  16 5-O-COCH₃ H 17 5-O-COCH₂C₆H_Five H 18 5-O-COC₆H_Five H 19 4-O-COCH₃ H 20 4-O-COCH₂CH₂CH₃ H 21 4-O-CO- (3-pyridyl) H 22 5-S-CH₃ H 23 5-SO₂-CH₃ H 24 5-O-C₆H_Five H 25 5-O-C₆H_Four-p-OCH₃ H 26 6-O-CH₃ 5-CH₂CH₃  27 5-O-CH₂CH₃ 4,6,7- (CH₃)₃  28 5-O-CH₂CH₃ 6-CH₂-p-tolyl 29 6-O-CH₃ 5-Br 30 4-CH₂-O-H H 31 5-CH₂-O-H H 32 5- (CH₂)₂-O-H H 33 5-CH₂-S- (2-benzothiazoyl) H 34 5-CH₂-S-CH₃ H 35 4-CH₂-O-CH₂CH₂OH H 36 4- (CH₂)₃-O-CH₃ H 37 4-O-CH₃ 6-CO₂CH₃  38 6-O-CH₃ 5-NHCOCH₃  39 4-CH₂-O-CH₂OCH₃ H 40 5-CH₂-O-CH₂OCH₃ H 41 4-CH₂-O-CH₂-(2-Pyridyl) H 42 4-CH₂-O-CH₂CH₂-Morpholino H 43 5- (CH₂)₂-O-CH₃ H 44 4- (CH₂)₂-O-CH₃ H 45 5- (CH₂)₂-O-CH₂OCH₃ H 46 5-CH₂-O-CH₃ H 47 5-CH₂-O-CH₂CH₃ H 48 4-CH₂-O-CH₃ H 49 5- (CH₂)₂-O-CH₂C₆H_Five H 50 4-O-CH₃ 6-CH₂OCH₃  51 5-CH- [5- (1,3-Benzodioxolyl)]-O-CH₃ H 52 5-CH- [5- (1,3-Benzodioxolyl)]-O-CH₂CH₃ H 53 5-CH (CH₂-p-tolyl) -O-CH₃ H 54 5-CH (CH₃) -O-CH₂CH₃ H 55 5-CH (CH₃) -O-CH₃ H 56 4-CH₂-O-COCH₃ H 57 5- (CH₂)₃-O-COCH₃ H 58 5- (CH₂)₂-O-COCH₃ H 59 5-CH₂-O-p-Anisoyl H 60 4-CH₂-O-COCH₂CH₂CH₃ H 61 4-CH₂-O-CH₂CH₂Cl H 62 4-CH₂-O-CH₂CH₂-Morpholino
 H

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. The physical properties of the products obtained in each example are shown in Table 3 below.

[0016]Example 1 5-isopropoxy-1,3-benzodioxole-2
-Thion  (Compound 1) 2 ', 4'-dihydroxyacetophenone 1.
0 g, 2-bromopropane 1.1 g and potassium carbonate 1.4
g to 10 ml of dried N, N-dimethylformamide
In addition, the mixture is heated and stirred at 110 ° C. for 45 minutes. Reaction mixture after cooling
After filtering the mixture, adding 50 ml of water to the filtrate, dilute hydrochloric acid was added.
Acidify and extract with 120 ml of ether. Wash the extract with water
And dried over anhydrous magnesium sulfate. Evaporate the solvent under reduced pressure
After that, 2'-hydroxy-4'-isopropoxyacetophe
Non-1.3 g is obtained as a brown oil.

1.3 g of this brown oily substance was added to 24 ml of a 0.5N aqueous sodium hydroxide solution and 9 ml of pyridine to form a uniform solution, which was then stirred at room temperature in an argon atmosphere. Next, 4.9 ml of 7.5% hydrogen peroxide solution is slowly added dropwise so that the temperature of the reaction solution does not exceed 40 ° C. After 30 minutes, the reaction solution was slowly poured into 80 ml of diluted hydrochloric acid and 200 ml of ethyl acetate was added.
To extract. The extract is washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, 1.1 g of 1,2-dihydroxy-4-isopropoxybenzene was obtained as a brown oil.

1.1 g of this dark brown oily substance is dissolved in 14 ml of chloroform and stirred at room temperature. To this solution, 0.51 ml of thiophosgene was added, and then 8.6 ml of 1.6N aqueous sodium hydroxide solution was added dropwise, and the mixture was stirred for 1 hour. After the reaction, the chloroform layer was separated and the aqueous layer was washed with ethyl acetate (30 m).
Extract with l. The organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. After the solvent is distilled off under reduced pressure, the obtained residue is purified by silica gel column chromatography (n-hexane: chloroform = 1: 1) to obtain 0.71 g of the title compound as white crystals.

Instead of 2-bromopropane in the above example, methyl iodide, ethyl iodide, n-butyl iodide, allyl bromide, benzyl chloride, α-bromo-p-xylene, bromoacetone, chloromethyl methyl ether. , N, N-diethyl chloroacetamide and methyl chloroacetate are subjected to the same reaction to obtain Compound 2 to Compound 12.

[0020]Example 2 4,6-dimethoxy-1,3-benzodioxole-2
-Thion  (Compound 13) In the same manner as in Example 1, 2 ',
Is it 5.2 g of 4 ', 6'-trihydroxyacetophenone?
3.4 g of the title compound are obtained as white crystals. As well
To 2-hydroxy-4-methoxy-5-nitroa
Compound 14 is obtained from cetophenone.

[0021]Example 3 5-acetyl-6-methoxy-1,3-benzodioxo
Ru-2-Thion  (Compound 15) 1.4 g of titanium tetrachloride was added to 1,2-dichloro
Dissolve in 5.3 ml of loethane and cool with ice. Nothing in this solution
Hydroacetic acid 0.6 g and 5-methoxy-1,3-benzodioxy
1.0 g of sole-2-thione is added to 1,2-dichloroethane
Do not stir the solution dissolved in 1.0 ml under an argon atmosphere.
Gradually add dropwise and stir for 2 hours under ice cooling. Reaction liquid
Is poured into 40 ml of water and extracted with 120 ml of ethyl acetate
It The extract was washed with water and saturated saline and washed with anhydrous sodium sulfate.
Dry with gnesium. The residue obtained after distilling off the solvent under reduced pressure
The residue is subjected to silica gel column chromatography (n-hexa
(Chloroform = 4: 1) to give the title compound.
0.13 g of the compound is obtained as white crystals.

[0022]Example 4 5-acetoxy-1,3-benzodioxole-2-thi
on  (Compound 16) Hydroxyhydroquinone 4.0 g
Obtained by reacting with thiophosgene according to the method of Example 1
5-hydroxy-1,3-benzodioxol-2-thio
1.5g acetic anhydride and 1.0ml pyridine to 1.7g on
And stir at room temperature for 20 minutes. The crystals that precipitate are collected by filtration
After washing with water, dry it with diphosphorus pentoxide in a vacuum desiccator.
It This crystal is recrystallized from n-hexane-benzene.
This gives 1.4 g of the title compound as yellow crystals. Up
Instead of acetic anhydride in the above example, phenylacetyl chloride, anhydrous
A similar reaction was carried out using benzoic acid to give compound 17,
Compound 18 is obtained.

[0023]Example 5 4-acetoxy-1,3-benzodioxole-2-thi
on  (Compound 19) Instead of the hydroxyhydroquinone of Example 4
By using 4.0 g of pyrogallol, acetic anhydride and pyridinium
When the same reaction is carried out with
Obtained as colored crystals. Instead of acetic anhydride in the above example, salt
Reaction using n-butyryl chloride and nicotinoyl chloride
By carrying out, compound 20 and compound 21 are obtained.

[0024]Example 6 5-methylthio-1,3-benzodioxol-2-thi
on  (Compound 22) 5-methylthio-1,3-benzodioki
1.0 g of sole in 150 ml of dry dichloromethane
Dissolve the boron trichloride while stirring under an argon atmosphere.
Add 12 ml of dichloromethane solution (1.0 M) and let it stand at room temperature.
After stirring for 6 hours, 12 ml of methanol was added, and the solvent
Was distilled off under reduced pressure to give 1,2-dihydroxy-4-methylthio.
1.1 g of benzene are obtained as a dark blue oil.

1.1 g of this dark blue oily substance was reacted with thiophosgene according to the method of Example 1 to obtain 0.93 g of the title compound as pale yellow crystals. Instead of 5-methylthio-1,3-benzodioxole in the above example, 5-methanesulfonyl-1,3-benzodioxole, 5-phenoxy-1,3-benzodioxole, 5
-(4-Methoxyphenyloxy) -1,3-benzodioxole, 5-ethyl-6-methoxy-1,3-benzodioxole, 5-ethoxy-4,6,7-trimethyl-1,3 -Benzodioxole, 5-ethoxy-6-
p-tolylmethyl-1,3-benzodioxole, 5-
A similar reaction is performed using bromo-6-methoxy-1,3-benzodioxole to give compound 23 to compound 29.

[0026]Example 7 4-hydroxymethyl-1,3-benzodioxole-
2-thion  (Compound 30) 19 g of 2,3-dihydroxybenzoic acid
75 g of potassium carbonate and 84 ml of benzyl chloride were dried
In addition to 250 ml of N, N-dimethylformamide, 10
Heat and stir at 0 ° C. for 2 hours. After allowing to cool, the reaction mixture was mixed with water (3).
Pour into 00 ml and extract with 900 ml of ethyl acetate. Extraction
The eluate was washed with water and saturated saline and washed with anhydrous magnesium sulfate.
Dry with um. After evaporating the solvent under reduced pressure, the resulting residue is dried.
Dissolve in 100 ml of dried ether.

400 ml of ether obtained by drying 14 g of lithium aluminum hydride in an argon atmosphere of this solution
To the solution added to the above was added dropwise under ice cooling. After stirring for 1 hour, 200 ml of hydrous ether was added, and after stirring for a while, Celite and anhydrous magnesium sulfate were added. After the precipitate was filtered off, the solvent was distilled off under reduced pressure to obtain slightly yellow crystals, which were recrystallized from n-hexane-ethyl acetate to give 1,2-
Dibenzyloxy-3-hydroxymethylbenzene 39
g are obtained as white crystals.

3.0 g of this white crystal was added to 60 m of ethanol.
1 and tetrahydrofuran (15 ml), 10% palladium carbon (0.26 g) is added, and hydrogenation is carried out at room temperature and atmospheric pressure for 2.5 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure,
1.3 g of 1,2-dihydroxy-3-hydroxymethylbenzene are obtained as white crystals. This white crystal 1.
When 3 g is reacted with thiophosgene according to the method of Example 1, 0.86 g of the title compound is obtained as yellow needle crystals. When the same reaction is carried out using 3,4-dihydroxybenzoic acid and 3,4-dihydroxyphenylacetic acid instead of 2,3-dihydroxybenzoic acid in the above example, compound 31 and compound 32 are obtained.

[0029]Example 8 5- (benzothiazol-2-yl) thiomethyl-1,
3-benzodioxole-2-thione  (Compound 33) 1.3 g of 3,4-dihydroxybenzoic acid
And 20 g of potassium carbonate in 80 ml of dry acetone
In addition, while stirring at room temperature, chloromethyl methyl ether 8.4m
1 is added dropwise, and the mixture is heated under reflux for 6 hours. After allowing to cool, the precipitate is filtered off.
Separate, concentrate the filtrate under reduced pressure, and pour the residue into 300 ml of water.
And extract with 800 ml of ethyl acetate. Extract the water and
Washed with saturated saline and dried over anhydrous magnesium sulfate.
It After evaporating the solvent under reduced pressure, the residue obtained was washed with silica gel.
Chromatography (chloroform: ethyl acetate = 2)
Purification by 4: 1) gives 3,4-bis (methoxymeth).
Toxy) 2.2 g of methoxymethyl benzoate is a colorless transparent oil.
Obtained as a substance. 2.2 g of this colorless transparent oily substance
According to the method of Example 7, lithium aluminum hydride and
When the reaction is carried out, 1-hydroxymethyl-3,4-bis
1.7 g of (methoxymethoxy) benzene is a colorless transparent oil.
It is obtained as a thing.

1.7 g of this colorless transparent oily substance is dissolved in 33 ml of dry dichloromethane, and then 2.2 g of 2,4,6-collidine and 0.62 g of lithium chloride are added. Carefully add 100 mg of methanesulfonyl chloride at 0 ° C. with stirring under an argon atmosphere and stir for 4.5 hours. The reaction mixture is poured into 300 ml of water and extracted with 800 ml of ether. The extract is washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue is dissolved in 10 ml of dry acetone.

1.6 g of 2-mercaptobenzothiazole
20m of dry acetone and 1.3g of anhydrous potassium carbonate
Add to 1 and stir under ice cooling. Acetone solution of the residue is added dropwise to this solution, and the mixture is stirred overnight under water cooling. The reaction mixture with water 3
Pour into 00 ml and extract with 800 ml of ethyl acetate. The extract is washed with water and saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give 1- (benzothiazol-2-yl) thiomethyl-3,4-bis (methoxy). 2.2 g of (methoxy) benzene are obtained as pale yellow crystals.

2.2 g of this pale yellow crystal was added to chloroform 9
ml, isopropanol 23 ml, concentrated hydrochloric acid 32 ml, and the mixture is stirred at room temperature overnight. The reaction mixture with water 3
Pour into 00 ml and extract with 800 ml of ethyl acetate. The extract is washed with water and saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, 1.6 g of 1,2-dihydroxy-4- (benzothiazol-2-yl) thiomethylbenzene was obtained as red-orange crystals.

1.6 g of this red-orange crystal was prepared in the following Example 1.
The reaction with thiophosgene according to the method described in (1) gives 1.0 g of the title compound as orange crystals. Compound 34 is obtained by performing the same reaction by using methanethiol instead of 2-mercaptobenzothiazole in the above example.

[0034]Example 9 4- (2-hydroxyethoxy) methyl-1,3-ben
Zodioxole-2-thione  (Compound 35) 1,2 obtained as an intermediate in Example 7
-Dibenzyloxy-3-hydroxymethylbenzene
3.0 g of dried N, N-dimethylformamide 15
0.2 ml of sodium hydride
And 20 ml of dried N, N-dimethylformamide
The mixture is added dropwise at room temperature and stirred for 20 minutes. Then chloro
Add 1.0 ml of methyl acetate and stir overnight. In the reaction solution
200 ml of water was added and extracted with 600 ml of ethyl acetate,
The extract is washed with water and dried over anhydrous magnesium sulfate. Melting
After distilling off the medium under reduced pressure, the resulting residue is subjected to silica gel column chromatography.
Matography (n-hexane: ethyl acetate = 5: 1)
Purified by 1,2-dibenzyloxy-3-
(Methoxycarbonylmethoxymethyl) benzene 1.1
g is obtained as a pale yellow oil.

1.1 g of this pale yellow oily substance was reacted with lithium aluminum hydride according to the method of Example 7 and the benzyl group was eliminated, and then reacted with thiophosgene according to the method of Example 1. The title compound 0.97
g are obtained as white crystals.

[0036]Example 10 4- (3-methoxy) propyl-1,3-benzodioki
Saul-2-Thion  (Compound 36) 2,3-dihydride according to the method of Example 8
1-Hydroxymethyl-obtained from Roxybenzoic acid
0.78 g of 2,3-bis (methoxymethoxy) benzene
And 1.5 g of pyridinium dichromate dried dichloro
Add to 20 ml of methane and stir at room temperature for 42 hours, then precipitate
Is filtered off and the solvent is distilled off. The residue obtained is filtered over silica gel.
Rum chromatography (n-hexane: ethyl acetate =
Purified by 1: 1), 2,3-bis (methoxymeth)
Toxyl) benzaldehyde (0.78 g) as colorless oil
Obtained.

A solution obtained by dissolving 0.16 g of sodium hydride in 4.0 ml of dried benzene is cooled to 0 ° C., and 0.77 ml of ethyl diethylphosphonoacetate is slowly added dropwise. After the foaming has subsided, a solution of 0.73 g of 2,3-bis (methoxymethoxy) benzaldehyde dissolved in 4.0 ml of dried benzene is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into 50 ml of ice water, and ethyl acetate was added to 30 ml.
Extract with 0 ml. The extract is washed with water and saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, 1.2 g of ethyl 2,3-bis (methoxymethoxy) cinnamate is obtained as a yellow oil.

1.2 g of this yellow oily substance was reacted with lithium aluminum hydride according to the method of Example 7 to obtain 0.72 g of 2,3-bis (methoxymethoxy) cinnamyl alcohol as a colorless transparent oily substance. Obtained as. Next, a solution prepared by adding 0.14 g of sodium hydride to 4.0 ml of dried diethylene glycol dimethyl ether was added-
Cool to 5 ° C. and add 0.72 g of 2,3-bis (methoxymethoxy) cinnamyl alcohol. After 15 minutes, 0.30 ml of methyl iodide is added and the reaction is carried out for 2 hours. After that, the reaction solution was poured into 50 ml of water, and 200 ml of chloroform was added.
To extract. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 1,2-bis (methoxymethoxy) -3- (3-methoxy-1-). 0.48 g of propenyl) benzene is obtained as a yellow oil.

0.48 g of this yellow oily substance was added to a liquid obtained by suspending 70 mg of platinum dioxide in 5 ml of ethanol, and hydrogenated at room temperature and atmospheric pressure for 3 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and then 1,2-bis (methoxymethoxy) -3-
0.46 g of (3-methoxy) propylbenzene is obtained as a colorless transparent oil. This colorless transparent oil 0.46
When g is removed of the methoxymethyl group according to the method of Example 8 and then reacted with thiophosgene according to the method of Example 1, 0.28 g of the title compound is obtained as white crystals.

[0040]Example 11 4-methoxy-6-methoxycarbonyl-1,3-ben
Zodioxole-2-thione  (Compound 37) 7.0 g of gallic acid was added to 5% sodium borate.
Solution (670 ml) and stirred at room temperature. In this solution
18 ml of dimethyl sulfate and 4N sodium hydroxide aqueous solution 4
7 ml of each is added dropwise, and the mixture is stirred at room temperature for 3 hours. reaction
50 ml of 3N hydrochloric acid was added to the solution to acidify it, and then ethyl acetate
Extract with 800 ml. The extract was washed with saturated saline,
Dry over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue obtained is subjected to silica gel column chromatography.
Purify with (chloroform: methanol = 10: 1)
Then, 3,4-dihydroxy-5-methoxybenzoic acid
1.8 g of chill are obtained as brown crystals. This brown crystal
1.8 g of thiophosgene was then prepared according to the method of Example 1.
When reacted with, 1.5 g of the title compound was obtained as white crystals.
can get.

[0041]Example 12 5-acetylamino-6-methoxy-1,3-benzodi
Oxole-2-thione  (Compound 38) In accordance with Example 7, 3,4-dihydroxy
React -6-methoxynitrobenzene with benzyl chloride
3,4-dibenzyloxy-6-methoxy obtained by
Dissolve 34 g of nitrobenzene in 300 ml of ethanol
Then, add 21 g of iron powder and 48 ml of 6N hydrochloric acid and heat it back for 2 hours.
After flowing, filter. The residue obtained by concentrating the filtrate is 10N
Add 300 ml of aqueous sodium hydroxide and add ether
Extract with 1.0 l. Wash the extract with saturated saline and
Dry over magnesium sulfate. After distilling off the solvent under reduced pressure, obtain
The residue obtained is subjected to silica gel column chromatography (
Purified by Loloform), 3,4-dibenzylo
14 g of xy-6-methoxyaniline was obtained as a brown oily substance.
Obtained.

14 g of this dark brown oily substance was added to 140 g of acetic anhydride.
g and 130 ml of pyridine, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is poured into 850 ml of ice water and extracted with 1.7 l of ethyl acetate. The extract is washed with 2N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, 13 g of 3,4-dibenzyloxy-6-methoxyacetanilide is obtained as dark brown crystals. 13 g of this dark brown crystal was removed of the benzyl group according to the method of Example 7, and then reacted with thiophosgene according to the method of Example 1, to give 0.80 g of the title compound as a brown needle crystal. Obtained as.

[0043]Example 13 4-methoxymethoxymethyl-1,3-benzodioxo
Ru-2-Thion  (Compound 39) 1,2 obtained as an intermediate in Example 7
-Dibenzyloxy-3-hydroxymethylbenzene
1.1 g of dried N, N-dimethylformamide 10
0.1 ml of sodium hydride
And 10 ml of dried N, N-dimethylformamide
The mixture is added dropwise and stirred at room temperature for 20 minutes. Then chloro
Add 0.3 ml of methyl methyl ether and stir for 2 hours
It 30 ml of water was added to the reaction solution, and 200 ml of ethyl acetate was added.
To extract. The extract is washed with water and dried over anhydrous magnesium sulfate.
dry. After evaporating the solvent under reduced pressure, the resulting residue is treated with silica gel.
Column chromatography (n-hexane: ethyl acetate
1 = 2-dibenzylo
1.1 g of xy-3-methoxymethoxymethylbenzene
Obtained as a colorless transparent oil.

1.1 g of this colorless transparent oily substance was removed of the benzyl group according to the method of Example 7 and then reacted with thiophosgene according to the method of Example 1 to give the title compound 1. 0 g is obtained as white crystals. Compound 40 is obtained by performing the same reaction using 1,2-dibenzyloxy-4-hydroxymethylbenzene instead of 1,2-dibenzyloxy-3-hydroxymethylbenzene in the above example. When a similar reaction is performed using 2-chloromethylpyridine and N- (2-chloroethyl) morpholine instead of chloromethyl methyl ether in the above example,
Compound 41 and compound 42 are obtained.

[0045]Example 14 5- (2-methoxy) ethyl-1,3-benzodioxo
Ru-2-Thion  (Compound 43) By the same method as in Example 7, 3,4-di
1,2-dibenzyl obtained from hydroxyphenylacetic acid
Luoxy-4- (2-hydroxy) ethylbenzene 2.
0 g and 1.0 g of methyl iodide are used in the following method of Example 10.
The reaction was carried out according to
The benzyl group is removed, and the chiral group is removed according to the method of Example 1.
When reacted with ophosgene, 1.0 g of the title compound is white.
Obtained as crystals. 1,2-dibenzyloxy of the above example
Instead of cy-4- (2-hydroxy) ethylbenzene,
1,2-dibenzyloxy-3- (2-hydroxy) eth
When a similar reaction was performed using tylbenzene, compound 44 was obtained.
Is obtained. Instead of methyl iodide in the above example,
When a similar reaction is performed using tyl methyl ether, the compound
The product 45 is obtained.

[0046]Example 15 5-methoxymethyl-1,3-benzodioxole-2
-Thion  (Compound 46) 1-hi obtained as an intermediate in Example 8
Droxymethyl-3,4-bis (methoxymethoxy) be
2.6 g of benzene and 1.9 g of methyl iodide were used in Example 10.
When the reaction is performed according to the method, 1-methoxymethyl-3,
2.8 g of 4-bis (methoxymethoxy) benzene is yellow
Obtained as an oil. 2.8 g of this yellow oil is meta
Add to a mixture of 30 ml of Nord and 1.0 ml of concentrated hydrochloric acid,
Stir at room temperature for 2 hours. Pour the reaction mixture into 100 ml of water
And extract with 150 ml of ethyl acetate. Wash the extract with water
And dried over anhydrous magnesium sulfate. Evaporate the solvent under reduced pressure
Then, the resulting residue was subjected to thiolation according to the method of Example 1 below.
When reacted with phosgene, 1.3 g of the title compound becomes white.
Obtained as crystals.

Compound 47 is obtained by the same reaction using ethyl iodide instead of methyl iodide in the above example. When 1-hydroxymethyl-2,3-bis (methoxymethoxy) benzene was used in place of 1-hydroxymethyl-3,4-bis (methoxymethoxy) benzene in the above example and a similar reaction was carried out, compound 48 was obtained. Is obtained. Further, instead of 1-hydroxymethyl-3,4-bis (methoxymethoxy) benzene and methyl iodide in the above example, 1-
A similar reaction is performed using (2-hydroxy) ethyl-3,4-bis (methoxymethoxy) benzene and benzyl chloride to give compound 49.

[0048]Example 16 4-methoxy-6-methoxymethyl-1,3-benzodi
Oxole-2-thione  (Compound 50) 3, which is obtained as an intermediate in Example 11,
Carry out methyl 4-dihydroxy-5-methoxybenzoate
Reaction with chloromethyl methyl ether according to the method of Example 8
Then, according to the method of Example 7, lithium aluminum hydride.
1-hydroxymethyl-3-me obtained by reaction with
Toxy-4,5-bis (methoxymethoxy) benzene
5.4 g of iodinated methyl ester was prepared according to the method of Example 10.
Reaction with meth.
The xymethyl group is eliminated, and the method of Example 1 is followed.
When reacted with thiophosgene, 0.72 g of the title compound
Are obtained as white crystals.

[0049]Example 17 5- [1- (1,3-benzodioxol-5-yl)
-1-Methoxy] methyl -1,3-benzodioxole-2-thione  (Compound 51) Scraped magnesium under argon atmosphere
0.47 g into 1.5 ml of dry tetrahydrofuran
Suspended and treated with 5-bromo-1,3-benzodioxole.
Add 50 g and warm. After the reaction starts, the remaining 5
-Bromo-1,3-benzodioxole 3.3 g (total
3.8 g) in 10 ml of dry tetrahydrofuran
Slowly add the thawed solution. Heat for 30 minutes after the addition is complete
To do. After allowing the reaction solution to cool, 3,4-bis (methoxy)
Cytometh) benzaldehyde 2.9g dried tet
A solution dissolved in 23 ml of lahydrofuran was added dropwise, and 10 minutes
Stir for a while. Saturated ammonium chloride solution 1 in the reaction solution
Add 5 ml slowly and stir for a while.
Extraction with 120 ml of water and the extract with water and saturated saline.
Wash and dry over anhydrous magnesium sulfate. Depressurize the solvent
After evaporation, the residue obtained is purified by silica gel column chromatography.
Fee (n-hexane: ethyl acetate: chloroform =
Purified by 3: 1: 1), 1,2-bis (methoxy)
Cymethoxy) -4- [1- (1,3-benzodioxo-
Lu-5-yl) -1-hydroxy] methylbenzene 3.
2 g are obtained as an orange oil.

3.2 g of this orange oily substance was used in the following Example 1.
When the reaction with methyl iodide was performed according to the method of Example 0, the methoxymethyl group was removed according to the method of Example 15, and the reaction with thiophosgene was further performed according to the method of Example 1, the title compound was obtained. 0.36 g is obtained as a yellow oil. Compound 52 is obtained by performing the same reaction by using ethyl iodide instead of methyl iodide in the above example. Compound 53 is obtained by performing the same reaction by using α-bromo-p-xylene instead of 5-bromo-1,3-benzodioxole in the above example.

[0051]Example 18 5- (1-ethoxy) ethyl-1,3-benzodioxo
Ru-2-Thion  (Compound 54) Magnesium shaving under argon atmosphere
0.36 g was suspended in 15 ml of dry tetrahydrofuran.
Turn cloudy and add methyl bromide at -5 ° C. Sharpened magnesiu
After the solution was dissolved and the solution became uniform, 3,4-dibenzyl
Tetrahydr obtained by drying 3.9 g of oxybenzaldehyde
A solution dissolved in 21 ml of lofran is added dropwise. 30 minutes later,
Pour into 300 ml of 2N hydrochloric acid and extract with 900 ml of ethyl acetate.
Put out. Wash the extract with saturated aqueous sodium hydrogen carbonate, water and saturated brine.
Clean and dry over anhydrous magnesium sulfate. Distill the solvent under reduced pressure
After removal, the residue obtained is purified by silica gel column chromatography.
(N-hexane: ethyl acetate = 4: 1)
Then, 1,2-dibenzyloxy-4- (1-hydro)
Xy) ethylbenzene (1.7 g) as a colorless transparent oily substance
can get.

1.7 g of this colorless transparent oily substance was added to 36 ml of ethanol and 9 ml of tetrahydrofuran, and then 10
% Palladium carbon (180 mg) is added, and hydrogenation is performed at room temperature and normal pressure for 3 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure,
0.93 g of 1- (1-ethoxy) ethyl-3,4-dihydroxybenzene is obtained as a pale purple oil. 0.93 g of this pale purple oily substance was reacted with thiophosgene according to the method of Example 1 to give 0.60 g of the title compound.
As a yellow oil. Compound 55 is obtained by the same reaction using methanol instead of ethanol in the above example.

[0053]Example 19 4-acetoxymethyl-1,3-benzodioxole-
2-thion  (Compound 56) According to the method of Example 4, 4-hydroxy
Cimethyl-1,3-benzodioxole-2-thione
1.2 g of the title compound was obtained as white crystals from 1.0 g.
Be done. 4-hydroxymethyl-1,3-benzo of the above example
Instead of dioxole-2-thione, 5- (3-hydro)
Xy) propyl-1,3-benzodioxole-2-thi
A similar reaction was performed using ON to give compound 57.
It

[0054]Example 20 5- (2-acetoxy) ethyl-1,3-benzodioki
Saul-2-Thion  (Compound 58) According to the method of Example 7, 3,4-dihi
1,2-dibenzyl obtained from droxyphenylacetic acid
Oxy-4- (2-hydroxy) ethylbenzene 1.0
g was dissolved in 4.0 ml of pyridine, and 2.0 g of acetic anhydride was added.
Add and stir for 45 minutes. Pour the reaction mixture into 200 ml of water
And extract with 300 ml of ethyl acetate. Wash the extract with water
And dried over anhydrous magnesium sulfate. Evaporate the solvent under reduced pressure
Thereafter, the residue obtained was benzenated according to the method of Example 7.
The dil group was eliminated, and then the procedure of Example 1 was repeated.
1.2g of the title compound is white when reacted with ophosgene.
Obtained as crystals.

[0055]Example 21 5-anisoyloxymethyl-1,3-benzodioxo
Ru-2-Thion  (Compound 59) 1,2-dibenzyloxy of Example 20
-4- (2-hydroxy) ethylbenzene and acetic anhydride
Instead, 1,2-dibenzyloxy-4-hydroxymeth
7.6 g of chlorobenzene and 4.4 g of p-anisoyl chloride were added.
When the same reaction is performed using the above compound, 1.0 g of the title compound is white.
Obtained as crystals.

[0056]Example 22 4-butyryloxymethyl-1,3-benzodioxo
Le-2-Thion  (Compound 60) 1,2-dibenzyloxy of Example 20
-4- (2-hydroxy) ethylbenzene and acetic anhydride
Instead, 1,2-dibenzyloxy-3-hydroxymeth
Using 3.0 g of chillbenzene and 1.2 g of n-butyryl chloride
Then, 0.81 g of the title compound is pale yellow.
Obtained as a colored oil.

[0057]Example 23 4- (2-chloroethoxy) methyl-1,3-benzodio
Xol-2-Thion  (Compound 61) 4- (2-hydroxy) obtained in Example 9
Ciethoxy) methyl-1,3-benzodioxole-2
-2.4 g of thione in 56 ml of dry dichloromethane
Dissolve, add 0.2 ml of thionyl chloride and stir at room temperature for 1 hour.
Stir. After evaporating the solvent under reduced pressure, the resulting residue is purified by silica gel.
Purified by column chromatography (chloroform)
This gave 1.0 g of the title compound as a pale yellow oil.
Be done.

[0058]Example 24 4- (2-morpholinoethoxy) methyl-1,3-ben
Zodioxole-2-thione hydrochloride  (Compound 62) 4- (2-morpholinoethoxy) methyl
-1,3-benzodioxole-2-thione 0.72 g
Is dissolved in 60 ml of dry ether. Salt in this solution
Stir for 30 minutes at room temperature while injecting hydrogen chloride gas.
The precipitated crystals are collected by filtration, washed with acetone and dried.
Then, 0.78 g of the title compound is obtained as white crystals.
Table 3 below shows the physical properties of the compounds shown in the examples. table
3 Infrared absorption spectrum unless otherwise specified
(IR) is the thin film method for oily substances and KB for solid substances
Value measured by r method, hydrogen nuclear magnetic resonance spectrum (¹H-
NMR) indicates compound 11, compound 14, compound 23, compound
31 (measured with deuterated acetone), compound 38 and
And compound 62 (these are measured with heavy dimethyl sulfoxide.
Values other than the above) indicate values measured with deuterated chloroform.

[0059]

[Table 3]Compound Melting point (℃) IR (cm ^-1 ) ¹ H-NMR (δ)  1 70.5 to 71.5 1340,1300 7.30 to 7.05 (m, 1H), 6.93 to 6.62 (m, 2H), 4.50 (sep, J = 6.0Hz, 1H), 1.36 (d, J = 6.0Hz, 6H) 2 119.5 ~ 120.5 1340, 1306, 7.28 ~ 7.09 (m, 1H), 6.97 ~ 6.63 (m, 2H), 1283 3.83 (s, 3H) 3 95.5 ~ 97.0 1333, 1300 7.32 ~ 7.08 (m, 1H), 6.96 ~ 6.64 (m, 2H), 4.05 (q, J = 7.0Hz, 2H), 1.42 (t, J = 7.0Hz, 3H) 4 58.0 ~ 59.0 1339,1304 7.32 ~ 7.09 (m, 1H), 6.98 ~ 6.68 (m , 2H), 3.99 (t, J = 6.0Hz, 2H), 2.10 to 1.18 (m, 4H), 1.01 (t, J = 6.0Hz, 3H) 5 88.0 to 88.5 1338,1305 7.39 to 7.10 (m, 1H ), 6.98 ~ 6.70 (m, 2H), 6.51 ~ 5.70 (m, 1H), 5.63 ~ 5.17 (m, 2H), 4.67 ~ 4.45 (m, 2H) 6 107.5 ~ 108.5 1330, 1305, 7.41 (s, 5H ), 7.31 ~ 7.10 (m, 1H), 1280 6.98 ~ 6.75 (m, 2H), 5.09 (s, 2H) 7 128.5 ~ 129.5 1337, 1301 7.48 ~ 6.67 (m, 7H), 5.02 (s, 2H), 2.36 (s, 3H) 8 119.0 to 120.5 1727,1330, 7.35 to 7.10 (m, 1H), 6.94 to 6.69 (m, 2H), 1282 4.57 (s, 2H), 2.25 (s, 3H) 9 75.5 to 76.0 1338, 1309, 7.23 (d, J = 8.0Hz, 1H), 7.10 to 6.81 (m, 2H), 1285 5.18 (s, 2H), 3.52 (s, 3H) 10 100.0 to 101.0 1648,1340, 7.40 to 7.10 (m, 1H), 7.00 to 6.75 (m, 2H), 1305 4.75 (s, 2H), 3.41 (q, J = 6.0Hz, 4H), 1,25 (t, J = 6.0Hz, 3H), 1.15 (t, J = 6.0Hz, 3H) 11 161.0 ~ 162.0 3420,1730, 7.44 (d, J = 8.0Hz, 1H), 7.21 (d, J = 2.0Hz, 1H), 1368,1305 7.00 (dd, J = 8.0,2.0Hz, 1H), 4.80 (s , 2H) 12 89.0 to 90.0 1752,1332, 7.39 to 7.12 (m, 1H), 7.02 to 6.71 (m, 2H), 1290 4.69 (s, 2H), 3.85 (s, 3H) 13 151.0 to 152.0 1290 6.46 ( d, J = 1.6Hz, 1H), 6.39 (d, J = 1.6Hz, 1H), 3.99 (s, 3H), 3.86 (s, 3H) 14 139.0 to 141.0 1528,1338, 8.12 (s, 1H), 7.63 (s, 1H), 4.07 (s, 3H) 1285 15 119.0 to 121.0 1665,1357, 7.70 (s, 1H), 6.97 (s, 1H), 3.96 (s, 3H), 1318,1278 2.62 (s, 3H) 16 85.5 ~ 87.0 1750,1306, 7.26 (d, J = 8.0Hz, 1H), 7.16 ~ 6.82 (m, 2H), 1290 2.30 (s, 3H) 17 116.0 ~ 117.0 1757,1346, 7.32 (s, 5H), 7.30 ~ 6.81 (m, 3H), 1302 3.85 (s, 2H) 18 126.0 ~ 126.5 1730, 1351, 8.32 ~ 8.02 (m, 2H), 7.88 ~ 7.00 (m, 6H) 1304 19 98.5 ~ 99.5 1773 , 1350, 7.41 to 6.99 (m, 3H), 2.39 (s, 3H) 1278 20 66.5 to 67.0 1768,1351, 7.51 to 6.91 (m, 3H), 2.64 (t, J = 7.0Hz, 2H), 1290 2.18 ~ 1.50 (m, 2H), 1.08 (t, J = 7.0Hz, 3H) 21 125.5 ~ 126.0 1765,1360, 9.48 (d, J = 2.0Hz, 1H), 8.98 (dd, J = 4.0,2.0 1291 Hz , 1H), 8.55 (dt, J = 7.0,2.0Hz, 1H), 7.58 (dd, J = 7.0,4.0Hz, 1H), 7.45 to 7.20 (m, 3H) 22 104.0 to 105.0 1344,1304 7.22 (s , 3H), 2.5 2 (s, 3H) 23 176.0 to 177.0 1358,1306, 8.08 (d, J = 2.0Hz, 1H), 8.02 (dd, J = 8.0,2.0 1280 Hz, 1H), 7.73 (d, J = 8.0Hz, 1H), 3.20 (s, 3H) 24 85.5 ~ 86.5 1348,1295 7.70 ~ 6.80 (m, 8H) 25 82.5 ~ 83.0 1341,1284 7.36 ~ 7.00 (m, 1H), 7.00 ~ 6.64 (m, 6H), 3.83 (s, 3H) 26 169.0 to 169.5 1344,1311, 7.11 (s, 1H), 6.81 (s, 1H), 3.88 (s, 3H), 2.67 1296 (q, J = 7.0Hz, 2H), 1.18 (t , J = 7.0Hz, 3H) 27 58.0 to 59.0 1345,1318 3.82 (q, J = 7.0Hz, 2H,), 2.30 (s, 6H), 2.22 (s, 3H), 1.43 (t, J = 7.0Hz , 3H) 28 158.5 ~ 159.0 1341,1299 7.08 (s, 4H), 6.98 (s, 1H), 6.79 (s, 1H), 4.01 (q, J = 7.0Hz, 2H), 3.93 (s, 2H), 2.35 (s, 3H), 1.44 (t, J = 7.0Hz, 3H) 29 About 200 (sublimation) 1331,1289 7.56 (s, 1H), 6.94 (s, 1H), 3.96 (s, 3H) 30 91.5〜 93.0 3225,1348, 7.45 ~ 7.15 (m, 3H), 4.85 (s, 2H), 1290 2.52 (brs, 1H) 31 96.5 ~ 97.5 3230,1337, 7.61 ~ 7.40 (m, 3H), 4.75 (brs, 2H) ), 1308,1283 2.81 (brs, 1H) 32 95.0 to 96.0 3300,1290 7.29 (s, 3H), 3.92 (t, J = 6.4Hz, 2H), 2.95 (t, J = 6.4Hz, 2H), 1.60 (brs, 1H) 33 70.0 to 71.0 1350,1315, 8.05 to 7.22 (m, 7H), 4.64 (s, 2H) 1291 34 96.0 to 97.0 1350,1308 7.41 to 7.16 (m, 3H), 3.75 (s, 2H) ), 2.02 (s, 3H) 35 41.0 3400,1350, 7.42 7.12 (m, 3H), 4.72 (s, 2H), 1308,1285 3.95 ~ 3.50 (m, 4H), 2.03 (brs, 1H) 36 44.5 ~ 45.0 1355,1287 7.32 ~ 7.08 (m, 3H), 3.40 ( t, J = 7.0Hz, 2H), 3.34 (s, 3H), 3.10 to 2.72 (m, 2H), 2.20 to 1.70 (m, 2H) 37 161.0 to 162.0 1725,1345, 7.58 (s, 2H), 4.08 (s, 3H), 3.92 (s, 3H) 1295 38 248.5 ~ 249.5 3310,1665, 9.55 ~ 9.25 (brs, 1H), 8.30 (s, 1H), 1325,1280 7.55 (s, 1H), 3.95 (s , 3H), 2.15 (s, 3H) 39 40.0 1350,1278 7.46 to 7.16 (m, 3H), 4.73 (s, 4H), 3.42 (s, 3H) 40 66.5 to 67.0 1350,1310 7.40 to 7.25 (m, 3H), 4.71 (s, 2H), 4.65 (s, 2H), 3.40 (s, 3H) 41 85.0 ~ 86.0 1349, 1295 8.70 ~ 8.50 (m, 1H), 7.90 ~ 7.05 (m, 6H), 4.81 ( s, 2H), 4.75 (s, 2H) 42 Oil 1351,1286 7.40 to 7.11 (m, 3H), 4.70 (s, 2H), 3.90 to 3.55 (m, 6H), 2.80 to 2.40 (m, 6H) 43 83.0 ~ 84.0 1342,1300 7.23 (s, 3H), 3.63 (t, J = 6.0Hz, 2H), 3.35 (s, 3H), 2.95 (t, J = 6.0Hz, 2H) 44 Oil 1353,1285 7.18 ( s, 3H), 3.70 (t, J = 6.6Hz, 2H), 3.35 (s, 3H), 3.05 (t, J = 6.6Hz, 2H) 45 55.5 ~ 57.0 1338,1310 7.28 (s, 3H), 4.61 (s, 2H), 3.80 (t, J = 6.4Hz, 2H), 3.30 (s, 3H), 2.98 (t, J = 6.4Hz, 2H) 46 85.5 ~ 86.5 1350,1310 7.40 ~ 7.20 (m, 3H ), 4.49 (s, 2H), 3.41 (s, 3H) 47 51.0 ~ 52.0 1339,130 0 7.50 to 7.20 (m, 3H), 4.59 (s, 2H), 3.60 (q, J = 7.0Hz, 2H), 1.28 (t, J = 7.0Hz, 3H) 48 69.5 to 70.0 1348,1305 7.40 to 7.10 (m, 3H), 4.59 (s, 2H), 3.45 (s, 3H) 49 98.0 to 98.5 1333,1305 7.40 to 7.00 (m, 8H), 4.48 (s, 2H), 3.67 (t, J = 6.4Hz , 2H), 2.92 (t, J = 6.4Hz, 2H) 50 90.0 to 91.0 1350,1323, 6.94 to 6.72 (m, 2H), 4.45 (s, 2H), 4.02 1280 (s, 3H), 3.42 (s , 3H) 51 Oil 1291 7.37 ~ 7.16 (m, 3H), 6.70 (s, 3H), 5.90 (s, 2H), 5.14 (s, 1H), 3.34 (s, 3H) 52 Oil 1291 7.39 ~ 7.07 (m , 3H), 6.70 (s, 3H), 5.90 (s, 2H), 5.29 (s, 1H), 3.49 (q, J = 7.0Hz, 2H), 1.25 (t, J = 7.0Hz, 3H) 53 Oil 1329,1284 7.30 ~ 6.75 (m, 7H), 4.40 (t, J = 7.0Hz, 1H), 3.25 (s, 3H), 3.19 ~ 2.79 (m, 2H), 2.32 (s, 3H) 54 Oil 1357, 1325, 7.32 ~ 7.15 (m, 3H), 4.47 (q, J = 6.0Hz, 1H), 1290 3.38 (q, J = 7.0Hz, 2H), 1.42 (d, J = 6.0Hz, 3H), 1.18 ( t, J = 7.0Hz, 3H) 55 Oil 1325,1285 7.38 ~ 7.20 (m, 3H), 4.37 (q, J = 6.0Hz, 1H), 3.25 (s, 3H), 1.45 (d, J = 6.0Hz , 3H) 56 53.0 1739,1351, 7.32 (s, 3H), 5.28 (s, 2H), 2.14 (s, 3H) 1305 57 70.0 ~ 71.0 1745,1340, 7.38 ~ 7.05 (m, 3H), 4.10 (t , J = 6.0Hz, 2H), 1290 2.98 to 2.60 (m, 2H), 2.08 (s, 3H), 2.25 to 1.80 (m, 2H) 58 85.0 to 85.5 1735,1349, 7.45 to 7.08 (m, 3H), 4.32 (t, J = 6.4Hz, 2H), 1315 3.03 (t, J = 6.4Hz, 2H), 2.03 (s, 3H) 59 168.0 to 169.0 1710,1349, 8.01 (d, J = 9.0Hz, 2H), 7.52 to 7.12 (m, 3H), 1311,1285 6.91 (d, J = 9.0Hz, 2H), 5.37 (s, 2H), 3.87 (s, 3H) 60 Oil 1739,1353, 7.45 ~ 7.10 (m, 3H), 5.30 (s, 2H), 1285 2.38 (t, J = 7.0Hz, 2H), 2.05 ~ 1.35 (m, 2H), 0.98 (t, J = 7.0Hz, 3H) 61 Oil 1355,1285 7.40 ~ 7.11 (m, 3H), 4.68 (s, 2H), 4.45 ~ 3.92 (m, 2H), 3.92 ~ 3.69 (m, 2H) 62 184.0 ~ 186.0 1356,1290 7.78 ~ 7.32 (m, 3H), 4.75 (s, 2H), 4.12 to 3.78 (m, 6H), 3.54 to 3.20 (m, 6H)

Pharmacological test The efficacy test as a therapeutic agent for liver diseases is usually carried out by administering a test substance and a hepatic disorder-inducing substance to a test animal and examining the hepatic disorder-suppressing action thereof. Although carbon tetrachloride, chloroform, thioacetamide, D-galactosamine and the like are known as hepatopathy-inducing substances, in this test, they are similar to human viral hepatitis in a light microscope and are accompanied by a strong inflammatory reaction. The known D-galactosamine was used. In addition, the liver damage inhibitory effect of the test substance,
Glutamic Oxaloacetic Transaminase (GO in Serum Increases Reflecting Hepatocyte Degeneration / Necrosis
T) Activity was searched as an index.

The animals used in the test were male Wistar rats, and 5 rats were used per group. 4 weeks old, weight 80 ~
Purchase 100g, and keep constant temperature and humidity (23 ± 1 ℃, 55
(± 5%) in a breeding room, fed with solid feed (MF: Oriental Yeast Co., Ltd.) and water freely and preliminarily breeded for 1 week,
Among them, those with good growth were selected and used for the test. The test substance was suspended in a 5% aqueous solution of gum arabic, and 12.5 mg
Gavage was administered at / 10 ml / kg. After 30 minutes, 3 times of D-galactosamine hydrochloride dissolved in physiological saline was added.
00 mg (250 mg as D-galactosamine) / 3
It was intraperitoneally administered at a rate of ml / kg four times every 3 hours.
Then, 39 hours after the final administration of D-galactosamine hydrochloride, blood was collected from the abdominal aorta and centrifuged (3000 rpm, 1
Serum was separated by 0 min) and its GOT activity was measured. The test animals were
The animals were fasted until the final administration of D-galactosamine hydrochloride. The GOT activity in serum was determined by the enzyme method of Lippi et al. [Clinica Chimica Acta, 28
Vol., P. 431 (1970)].

Table 4 shows the inhibition rate of liver damage by D-galactosamine for each test substance.

[Table 4] As is clear from Table 4, the compound of the present invention remarkably suppresses liver damage caused by D-galactosamine, and is therefore useful as a therapeutic agent for liver diseases.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Hironori Tanaka Inventor Hironori Tanaka 370 Mita-cho, Kishiwada City, Osaka Prefecture Shin Nihon Pharmaceutical Co., Ltd.Technical Division (72) Inventor Kazuo Matsumoto 370 Mita-cho, Kishiwada City, Osaka Shin Nihon Pharmaceutical Co., Ltd. Inside the Technology Headquarters (72) Inventor Zoji Hirase 370 Mita-cho, Kishiwada City, Osaka Prefecture Shin-Nippon Pharmaceutical Co., Ltd. (72) Takeshi Togawa, 370 Mita-cho, Kishiwada-shi, Osaka Prefecture, Technology Department, Shin-Nippon Pharmaceutical Co., Ltd. (72) Hiroichi Oshima, 370, Mita-cho, Kishiwada-shi, Osaka Prefecture, Technology Department, Shin-Nihon Pharmaceutical Co., Ltd. (72) Inventor Minoru Nishino 370 Mita-cho, Kishiwada-shi, Osaka Prefecture Shin-Nippon Pharmaceutical Co., Ltd.Technology Division (72) Inventor Miwa Okui 370 Mita-cho, Kishiwada-shi, Osaka Japan Shinakabu, Ltd. technology headquarters in

Claims (1)

[Claims] 1. A compound represented by the general formula (I): [Wherein, X is O; S; or SO ₂ ; R is a hydrogen atom; a lower alkyl group; an aryl group optionally substituted with a lower alkoxy group; or an optionally substituted lower alkyl group A good arylalkyl group, R (1) may be substituted with a hydrogen atom; a lower alkyl group; a halogen atom, a hydroxyl group, a carboxyl group, a lower alkoxy group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkyl group. A group selected from the group consisting of an aryl group, a carbamoyl group which may have an alkyl group on the nitrogen atom, and an amino group which may form a ring by combining the substituent on the nitrogen atom with the nitrogen atom. Substituted lower alkyl group; lower alkenyl group; lower alkanoyl group; arylalkanoyl group; aroyl group; heteroaroyl group; or lower alkoxy group R (2), R (3) and R (4) are the same or different and each is a hydrogen atom; a halogen atom; a nitro group; a lower alkyl group; a lower alkoxyalkyl group. An arylalkyl group optionally substituted with a lower alkyl group; a lower alkoxy group; a lower alkanoyl group; a mono- or di-lower alkanoylamino group; or an alkoxycarbonyl group, and m is an integer of 0 to 3. .. In the above definition, the aryl group means a 6-membered ring compound or a benzothiazole ring containing only a nitrogen atom as a hetero atom, and lower means a straight or branched carbon chain having 1 to 6 carbon atoms. Means However, in the above definition, X is oxygen,
When m is 0 and R (2), R (3) and R (4) are all hydrogen atoms, R (1) is not a hydrogen atom and R (1)
Is a lower alkyl group at the 4-position, the lower alkyl group is not a methyl group. ] The 1,3-benzodioxole-2-thione derivative represented by these and its pharmacologically acceptable salt.