JPS6327488A - Substituted-1,3-dithiolane derivative and use thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> and R<2> represent H, OH or lower alkanoyloxy; R<3> and R<4> represent lower alkyl, aralkyl, lower alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, (substituted) aryl or heterocyclic group or R<3> and R<4> may link with each other to form (substituted) alkylene). EXAMPLE:2-(1,3-Dithiolan-2-ylidene)-1-phenyl-1,3-butanedione. USE:A remedy for liver diseases. PREPARATION:For example, a compound expressed by formula II (M represents alkali metal or ammonium) is reacted with a 1,2-dihalogenoethane expressed by formula III (X represents halogen atom) normally in an inert solvent such as benzene, etc., at a temperature between room temperature and boiling point of the solvent for 1-24hr.

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel substituted-1,3-dithiolane derivative and the use of the compound as a therapeutic agent for liver diseases in the pharmaceutical field. BACKGROUND OF THE INVENTION It is known that the liver suffers from acute or chronic damage due to various causes such as alcohol, nutritional deficiencies, viruses, chemicals, toxins, etc., and the number of potential patients is extremely large. However, treatment for patients with these liver diseases is extremely difficult;
Only a few symptomatic treatments, such as diet therapy or artificial nutrition, or steroid therapy, such as adrenocortical hormone, which is a drug with strong side effects, are being used. Recently, as a therapeutic agent for these liver diseases, 1 typified by malotylate.
, 3-dithiol derivatives have been reported to be effective (see Japanese Patent Publications No. 56-18576, No. 56-18577, and No. 56-18578). (The following is a blank space) Problems to be Solved by the Invention The above-mentioned known 1,3-dithiol derivatives require large clinical doses and are still insufficiently effective. Means for Solving the Problems The inventors synthesized various compounds in order to develop therapeutic agents for liver diseases, and investigated their effects on suppressing liver disorders. As a result, the present invention was completed by discovering that the compound of the present invention exhibits a remarkable hepatotoxicity-suppressing effect that exceeds that of malotyrate in an experimental hepatopathy model. The present invention relates to a hydrogen atom, a hydroxyl group, or a lower alkanoyloxy group represented by the general formula [wherein R1 and R may be the same or different, and R3
and ridges may be the same or different, and represent a lower alkyl group, an aralkyl group, a lower alkoxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or an aryl group or a heterocyclic group that may have a substituent. Each is shown below. In addition, R3 and the ridge may be bonded to each other to form an alkylene group which may have a substituent. Regarding therapeutic agents. Next, various terms described in this specification will be explained. Lower alkanoyloxy groups include, for example, acetoxy groups,
It is a lower alkanoyloxy group consisting of 2 to 6 carbon atoms such as propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, pivaloyloxy group. The lower alkyl group is an alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group. Aralkyl groups include, for example, benzyl group, phenethyl group,
It is an aralkyl group consisting of 7 to 11 g of carbon atoms, such as a (1-naphthyl)methyl group or a (2-naphthyl)methyl group. The cycloalkyl group is, for example, a 3- to 7-membered cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group. A lower alkoxyalkyl group is a group having 2 to 6 carbon atoms, such as a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group, a 1-methoxyethyl group, a 2-ethoxyethyl group, a 3-methoxypropyl group, etc. It is an alkoxyalkyl group. The alkenyl group is an alkenyl group consisting of 2 to 6 carbon atoms, such as a vinyl group, an allyl group, a 1-propenyl group, a 1-butenyl group, a 1,3-pentagenyl group, and the like. The alkynyl group is an alkynyl group consisting of 2 to 6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a 1-butynyl group, a 1-pentynyl group, and the like. Aryl groups that may have substituents include, for example, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, methylthio group, ethylthio group, hydroxyl group, fluorine atom, chlorine atom, bromine atom, etc. An aryl group such as a phenyl group or a naphthyl group which may have a substituent. A heterocyclic group which may have a substituent is, for example, a heterocyclic group having a substituent such as a methyl group, an ethyl group, a methoxy group, an ethoxy group, a hydroxyl group, a methylthio group, an ethylthio group, a fluorine atom, a chlorine atom, a bromine atom, etc. It is a heterocyclic group such as a pyridyl group, a furyl group, a chenyl group, an imidazolyl group, a quinolyl group, an isoquinolyl group, etc., which may be The alkylene group optionally having a substituent, which is formed by R3 and the ridge bonding to each other, is an ethylene group, a trimethylene group, or a group with the formula CH2-CH(CH3) -CH-1-.
CH-C(CH3) is a fullkylene group such as a group represented by 2-CH2-. Typical examples of the compounds represented by the general formula r provided by the present invention include the following compounds. However, the present invention is not limited to these representative examples. Furthermore, some of the compounds represented by the general formula CII have various stereoisomers,
That is, isomers such as cis/trans isomers or optical isomers may exist, but the present invention also includes all these stereoisomers and mixtures thereof. 2- <1,3-dithiolane-2-ylidene)-1-phenyl-1,3-butanedione 2- (1,3-dithiolane-2-ylidene)-1-(
4-methoxyphenyl)-1,3-butanedione 3-(1,3-dithiolan-2-ylidene)-2,4-
Pentanedione 3- (1,3-dithiolane-2-ylidene)-1-phenyl-2,4-pentanedione 2- (1,3-dithiolane-2-ylidene)-1,3-cyclohexanedione 2-(1 ,3-dithiolane-2-ylidene)-5,5-
Dimethyl-1,3-cyclohexanedione 3-(4-hydroxy-1,3-dithiolan-2-ylidene)-2,4-pentanedione 2-(4-hydroxy-1,3-dithiolan-2-ylidene)- 1-phenyl-1,3-butanedione 2-(4-hydroxy-1,3-dithiolane-2-ylidene)-1-(4-chlorophenyl)-1,3-butanedione 2-(4-hydroxy-1,3 -・dithiolane-2-ylidene)-1-(4-methylphenyl)-1,3-butanedione 2-(4-hydroxy-1,3-dithiolane-2-ylidene)-1-(4-hydroxyphenyl)- 1,3-Butanedione 2-(4-hydroxy-1,3-dithiolane-2-ylidene)-1-(4-methoxyphenyl)-1,3-butanedione 2-(4-hydroxy-1,3-dithiolane- 2-ylidene)-1-(1-naphthyl)-1゜3-butanedione 2-(4-hydroxy-1,3-dithiolane-2-ylidene)-1-(2-naphthyl)-1゜3-butanedione 2 -(4-hydroxy-1,3-dithiolan-2-ylidene)-1-(3-pyridyl)-1゜3-butanedione 2-(4-hydroxy-1,3-dithiolan-2-ylidene)-1- (4-pyridyl)-1゜3-butanedione 2-(4-hydroxy-1,3-dithiolan-2-ylidene)-1-(2-furyl)-1゜3-butanedione 3-(4-hydroxy-1 ,3-dithiolan-2-ylidene)-1-phenyl-2,4-pentanedione 2-(4-hydroxy-1,3-dithiolan-2-ylidene)-1,3-cyclohexanedione 2-(4-hydroxy- 1,3-dithiolane-2-ylidene)-5,5-dimethyl-1,3-cyclohexanedione 3-(4-acetoxy-1,3-dithiolane-2-ylidene)-2,4-pentanedione 2-( 4-acetoxy-1,3-dithiolane-2-ylidene)-1-phenyl-1,3-butanedione 2-(4-acetoxy-1,3-dithiolane-2-ylidene)-1-(4-methylphenyl) -1,3-butanedione 2-(4-acetoxy-1,3-dithiolane-2-ylidene) -1-(4-methoxyphenyl)-1,3-butanedione 2-(4-acetoxy-1,3-dithiolane) -2-ylidene)-1-(1-naphthyl)-1゜3-butanedione 2-(4-acetoxy-1,3-dithiolane-3-butanedione 2-(4-acetoxy-1,3-dithiolane-2- ylidene)-1-(4-pyridyl)-1゜3-butanedione 2-(4-acetoxy-1,3-dithiolane-2-ylidene)-1-(2-furyl)-1゜3-butanedione 3-( 4-acetoxy-1,3-dithiolane-2-ylidene)-1-phenyl-2,4-pentanedione 2-(4-acetoxy-1,3-dithiolane-2-ylidene)-1,3-cyclohexanedione 2 -(4-acetoxy-1,3-dithiolane-2-ylidene)-5,5-dimethyl-1,3-cyclohexanedione 3-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-2,4-pentanedione 3-(4,5-dihydroxy-1,3-dithio 3-(4
,5-dihydroxy-1,3-dithiolane-2-ylidene)-2,4-hexanedione 3-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-6-methyl-2,4-hebutanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-phenyl-1゜3-butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(4-chlorophenyl)-1,3-
Butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(4-methylphenyl)-1,3-
Butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(4-hydroxyphenyl)-1,
3-butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(4-methoxyphenyl)-1,3
-butanedione 2-(4,,5-dihydroxy-1,3-dithiolane-
2-ylidene)-1-(3,4-dimethoxyphenyl)
-1,3-butanedione 2-(4,5-dihydroxy-
1,3-dithiolane-2-ylidene)-1-(4-hydroxy-3-methoxyphenyl)-1,3-butanedione 2-<4.5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(1-naphthyl)-1,3-butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(2-naphthyl)-1,3-butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(2-furyl)-1,3-butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-Ylidene)-1-(2-chenyl)-1,3-butanesionran-2-ylidene)-1-(3-pyridyl)-1,3
-butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(4-pyridyl)-1,3-butanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-phenyl-5-methyl-1,3-hexanedione 3-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-6-hebutene-2゜4-dione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-cyclohexyl-1,3-butanedione 3-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-ethoxy-2゜4-pentanedione 3-<4.5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-phenyl-2゜4-pentanedione 4-pentanedione 2-(C5-dihydroxy-1,3-dithiolane-2-
ylidene)-1,3-cyclohexanedione 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-5,5-dimethyl-1,3-cyclohexanedione 3-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-2,4-pentanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(4-methylphenyl)-1,3-
Butanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(4-methoxyphenyl)-1,3
-butanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(4-acetoxyphenyl)-1,
3-butanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(2-furyl)-1,3-butanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(3-pyridyl)-1,3-butanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(2-naphthyl)-1,3-butanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-phenyl-5-methyl-1,3-hexanedione 3-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-phenyl-2゜4-pentanedione 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1,3-cyclohexanedione 2-(4,5-diace1-xy1,3-dithiolane-
2-Ylidene)-5,5-dimethyl-1,3'-cyclohexanedione Next, the method for producing the compound of the present invention will be specifically explained. The compound [II of the present invention] can be produced, for example, by the method shown in the following reaction formula. Manufacturing method 1 [II] [Iee] [1
a] Separation method [II] [IV] [Ib
1 Manufacturing method 3 [E] [V] [Work 0]
Manufacturing method 4 [Idl [VI] [Eng. 8
] [In the formula, M is an alkali metal atom or an ammonium group, X is a halogen atom, R is a hydrogen atom or an active group of a xyl group, R is a hydrogen atom or a group RbC00 (in the formula,
b has the above-mentioned meaning), and Taku and Takashi have the above-mentioned meaning] The compound represented by the general formula [ff] used in the reactions of the above production methods 1 to 3 is represented by the following reaction formula. Synthesized by the method shown. [In the formula, R3, M and M have the above-mentioned meanings, i.e., β-diketones represented by the general formula [■] and carbon disulfide are reacted in an inert solvent under preservation of a base. A compound represented by the general formula [IN is obtained. Examples of the base group include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, ammonia, etc., and examples of the inert solvent include aprotic hydroxides such as dimethyl sulfoxide and dimethyl formamide. Examples include polar organic solvents and mixed solvents of these and water. Each manufacturing method will be specifically explained below. Production method 1 is a method for synthesizing dithiolanes [■8] in which R1 and R are both hydrogen atoms among the compounds represented by the general formula [E],
This compound is a compound represented by general formula [II] with 1.2-
Obtained by reaction with dihalogenoethane. This reaction is usually carried out in a solvent that does not affect the reaction.
Examples of such solvents include, for example, benzene, chloroform, tetrahydrofuran, acetone, dimethylformamide, dimethylsulfoxide, water and mixtures thereof. Although the reaction temperature and reaction time are not particularly limited, the reaction is usually carried out at a temperature range from air temperature to the boiling point of the solvent for 1 to 24 hours. The reaction molar ratio is appropriately such that 1,2-dihalogenoethane [111] is equivalent to or slightly in excess of the starting material compound [n]. Next, production method 2 and production method 3 will be explained as general synthesis methods for alcohol compounds [1'] and [1] in which R1 and/or both of R1 and M are hydroxyl groups among compounds of general formula [I]. . This reaction is usually carried out in the presence of an acid in an inert solvent, and examples of the acid include inorganic acids such as sulfuric acid and hydrochloric acid, and organic acids such as acetic acid. Further, as the solvent, an aprotic aliphatic solvent similar to that used in Production Method 1, or a mixture of these and water can be used. The reaction temperature is preferably 50° C. or lower, particularly room temperature or lower. The reaction time is usually 1 to 24 hours. Regarding the reaction molar ratio, halogenoaldehyde CrV ] is used in production method 2, and glyoxal [V] is used in production method 3 in equimolar or slightly excessive molar ratios to the raw material compound [I[ ]. Next, production method 4 will be explained as a method for synthesizing a compound of the general formula r18 in which both or one of R1 and R is a lower alkanoyloxy group among the compounds of the general formula ''. This reaction is a reaction in which the alcohol compound [■dco] produced by the above-mentioned production method 2 or 3 is acylated with an acylating agent represented by the general formula [■]. Acylating agent used at this time [■
l is an activated derivative of carboxylic acids corresponding to the desired lower alkanoyl group, such as acid halides or acid anhydrides of these carboxylic acids. The reaction is carried out in an inert solvent or with an excess of the acyl stopper itself as a solvent under conventional acylation conditions, e.g. in the presence of a base.
The reaction is carried out for 1 to 24 hours at low temperatures below 0C. The reaction molar ratio is usually an equimolar to excess molar amount of the acylating agent [■] to the raw material alcohol [1j]. The target compound [I] produced by the above-mentioned production method can be obtained by organic chemical synthesis (known common methods such as filtration,
It is separated from the reaction solution by solvent extraction, solvent distillation, etc., and purified by recrystallization, column chromatography, etc., if necessary. When the compound of the present invention is used as a therapeutic agent for liver diseases, the dosage regimen varies depending on the patient's weight, age, sex, physical condition, medical condition, etc., but in the case of oral administration, it is administered at
．． 1-50 mg/Ky of body weight for parenteral administration
It is 0.05 to 25 μ per day. In order to formulate the compound of the present invention, it is formulated into a dosage form such as a tablet, granule, powder, suspension, capsule, injection, isotonic solution, etc. by a conventional method in the technical field of formulation. When manufacturing oral solid preparations, after adding excipients to the main drug, and further adding condensing agents, disintegrants, lubricants, coloring agents, and flavoring agents as necessary, tablets, coated tablets, and Form into granules, powders, and capsules. When preparing an injection, a pH adjuster, a buffer, a solubilizing agent, a stabilizer, a preservative, etc. are added to the main drug as necessary, and the preparation is made into a subcutaneous, intramuscular, or intravenous injection using a conventional method. Pharmacological test examples and toxicity test examples are given below to clarify the usefulness of the compounds of the present invention. Pharmacological Test Example A test drug (drug symbol is the same as the compound symbol in Examples) was dissolved or suspended in olive oil and orally administered to mice (ddY male, body size M23±29, n=5) for 6 hours after drug administration. Afterwards, 0.05 kg/kg of carbon tetrachloride was orally administered. 24 hours after administration of carbon tetrachloride, BSP (sodium sulfobromophthalein) 1100 rn/Kl was administered into the tail vein, and 30 minutes later cardiac blood was collected to determine the concentration of G in plasma.
PT (glutamic bilvic transaminase) activity and BSP residual amount were measured. In addition, liver damage was visually observed immediately after blood collection and was measured using the following evaluation method. Liver damage index Liver symptoms 0 - Normal liver 2 Slight damage 4 Obviously damage 6 Significant damage As shown in Table 1, the compound of the present invention is carbon tetrachloride alone It has a remarkable effect of suppressing liver damage compared to the administered group, and its effect is greater than that of malochilate, which was used as a control. (Left below) Table 1 Effect unit on carbon tetrachloride-induced acute liver injury
(P-GPT), μg/In1(8SP)] f. Toxicity Test Example A test drug (drug symbol is the same as the compound symbol in Examples) was dissolved or suspended in olive oil and administered orally to mice (ddY male, body weight 23±29, n=5), one week after administration. The acute toxicity value (LD5o) was determined from the mortality rate. The toxicity of the test compounds (compounds A, 1.Q, R, and S) is extremely low, and their LD5o values are all 2 g/Kg or higher. The present invention will be specifically described below with reference to Examples. Example 1 1.6 g of benzoylacetone was mixed with 3 g of dimethyl sulfoxide.
Dissolve in 0d and add 1ON potassium hydroxide aqueous solution 2 under water cooling.
．． 2d and 0.7d of carbon disulfide were added and stirred at air temperature for 1 hour. 2.0 g of 1,2-dibromoethane while cooling with water again.
After the addition is complete, stir at air temperature for 3 hours. The reaction solution is poured into 200 d of ice water, and the precipitated crystals are collected by filtration and recrystallized from benzene-hexane to form the compound AM2. 1 g (yield 81x) m, p, 130-
Obtained as pale yellow needles at 131°C. NMRδ (CD C1,): 1.97 (3H, s),
3.33 (4H, m). 7.40-7.90 (5H, m) According to Example 1, the following compound was obtained. 2-(1,3-dithiolane-2-ylidene)-5,5
-dimethyl-1,3-cyclohexanedione

[Compound 8
N m, p, '202.5-203.5℃ (benzene-hexane reconsolidation) IIlax1143,90O NHRδ (CD CI, l): 1.02 (6H, s)
, 2.44 (4H, s). 3, 39 (4H, s) Example 3 7.5 g of benzoylacetone was dissolved in dimethyl sulfoxide 7.
Dissolved in 0- and cooled with water while keeping it at 110-15°C.
ON potassium hydroxide aqueous solution 9.3% and carbon disulfide 2.9%
Add -. After stirring for 1 hour at V temperature, cool again with water and bring the internal temperature to 15
While maintaining the temperature at °C, 4.21 nl of acetic acid and 9.37 mL of a 40% aqueous chloroacetaldehyde solution were added, and the mixture was stirred at the same temperature for 6 hours. Pour the reaction solution into 200 d of ice water and add 1 ml each of chloroform.
After extraction twice by adding 20d, the extract is washed with water and then dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off under reduced pressure, the residue was treated with aqueous methanol, and the precipitate was collected by filtration and recrystallized from benzene-hexane to obtain 2-(
4-hydroxy-1,3-dithiolan-2-ylidene)
-1-phenyl-1,3-butanedione cis. Trans mixture [Compound CI 5.3g (yield 41%)
) is obtained as pale yellow needle-like crystals with m, p, 121-122°C. (Left below) NHRδ (CD CI, ): 1.95. 1.9
8 (3H, 5x2), 3.42-〇3.56 (2) 1. m), 4.40-5.00 (IH. br), 5.78-5.92 (1M, ml, 7.
20-7.90 (51 (, m) Examples 4 to 7 were carried out according to Example 3 to obtain the following compounds. Example 4 2-(4-hydroxy-1,3-dithiolane) -2-ylidene)-5,5-dimethyl-1,3-cyclohexanedione compound D]m, p, 221-223°C (dec
, ) (Chloroform-hexane reconsolidation) (the following margins) NMR δ (CD 00): 1.02 (6H,S),
2.05 (4H, s). 3.45-3.58 (2H, m), 5.90 (IH, t
J=3Hz) Example 5 Compound E Nm, 0. 134
-135. ．． 5℃ (water-containing ethanol reconsolidation) NMI? δ(
CD CI, ): 1.96-2.00 (3H, 5x
2), 3.44-3, 56 (2H, dx 2 J=3H
z). 4.27(1)1. br), 5.81-5.90(
1) 1゜tx2 J=3Hz), 7.41-8.44
(7H. m) Example 6 Cis-trans mixed crab compound of 2-(4-hydroxy-1,3-dithiolan-2-ylidene)-1-(4-pyridyl)-1,3-butanedione FI m , p. 11
5-120℃ (purified by silica gel column chromatography) max 1240, 1171, 1055, 850, 688
° River δ (CD C13): 1.94-1.98 (3H
, 5x2), 3.56-3.64 (2H, dx2 J=
3Hz), 5.51 (IH, br), 5.92-6.0
0 (IH, m). 7.50-7.71 (2H, m), 8.63-8.89
(2H, m) Example 7 3-(4-hydroxy-1,3-dithiolan-2-ylidene)-1-phenyl-2,4-pentanedione [Compound G] m, p, 141-144°C ( Purified by silica gel column chromatography) N)IRδ(CD C13): 2.15(1)+(,
s), 3.43(2)1. d J=3H2), 3.
97 (2H, S), 4.12 (IH. br), 5.28 (IH, t J=3H2), 7.05
-7.45 (5H, m) Example 8 2.8 g of 2-(4-hydroxy-1゜3-dithiolan-2-ylidene)-1-phenyl-1,3-butanedione obtained in Example 3 was dissolved in 30% of chloroform, 1.6 g of acetic anhydride and 1.77 g of pyridine were added to the solution, and the mixture was stirred at room temperature for 4 hours. The reaction solution is poured into 20 ml of ice water, and the organic layer is separated and washed sequentially with 20 ml of 1N hydrochloric acid, 20-11 N aqueous sodium hydroxide solution, and 20 ml of water, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (100 g of Wakogel C-100, elution solvent benzene/ethyl acetate = 10/1) and then recrystallized from benzene-hexane. -(4-acetoxy-1゜3
-dithiolane-2-ylidene)-1-phenyl-1,3
-Butanedione [compound 12.6g (yield 81%) m
, p, obtained as pale yellow needles at 185-188°C. NMR δ (d6-DHSO): 1.87 (3H, s),
3.22 (3H, s). 3.71 (2H, d J = 3Hz), 6.60 (1) 1
゜t J=3NZ), 7.40-7.91 (5) 1. m
) Examples 9 to 11 were carried out according to Example 8 to obtain the following compounds. Example 9 2-(4-acetoxy-1,3-dithiolane-2-ylidene)-5,5-dimethyl-1,3-cyclohexanedione [Compound 11 m, p, 147-149°C (benzene-hexane reagent) Conclusion) NHRδ (CD C13): 1.12 (6H, S),
1.98 (3H, S). 2.43 (4H, s), 3.50 (2H, d J=3H
2), 6.51 (IH, t J□3Hz) Implementation
Example 10 2-(4-acetoxy-1,3-dithiolane-2-ylidene)-1-(2-naphthyl)-1,3-butanedione (compound J] m, p, 168-171°C (benzene-hexane re- Conclusion) NHRδ (CD C13): 2-01 (3) 1.S
), 2-08 (3H, S). 3.53 (2H, d J = 3H2), 6.58 (IH. t J = 3Hz), 7.28-8.41 (7H, m) Example 11 3-(4-acetoxy-1,3 -dithiolane-2-ylidene)-1-phenyl-2,4-pentanedione
2°N) IRδ (CD C13): 2. Ql(3H,
s), 2.22 (3B, s). 3.51 (2H, d J = 3Hz), 3.98° (2H
, s), 8°48 (1M, t J = 3Hz). 7.01-7.49 (5H, m) Example 12 Benzoylacetone 2. Og to dimethylformamide 2
Dissolved in 0d and cooled with water while maintaining the internal temperature of 10~15℃.
ON potassium hydroxide aqueous solution 2.5d and carbon disulfide 0.7
Add 4rd and stir at air temperature for 1 hour. Separately, vinegar 11.
41d and 1.8d of a 40% glyoxal aqueous solution were dissolved in dimethylformamide 6rd, and the above ketene mercaptide solution was added dropwise to this solution over a period of 20 minutes while keeping the internal temperature at 15° C. or less on water cooling. After the dropwise addition was completed, the mixture was stirred at air temperature for 1 hour, and then the reaction solution was poured into 300 d of ice water and extracted three times with 100 d of ethyl acetate each. The extract is washed with water, dried over anhydrous magnesium sulfate, the desiccant is filtered off, and the solvent is distilled off. If the residue is purified by silica gel column chromatography (Wako gel C-2002009, elution solvent ethyl acetate/methylene chloride = 2/'1), 2-(4,5-
dihydroxy-1,3-dithiolan-2-ylidene)-
Compound L11. to 1-phenyl-1,3-butanedione.
189 (yield 32x) is m, p, 103-107
Obtained as a white crystalline powder at °C. NMR δ (d6-DMSO): 1.93 (3H, s),
3.42 (2H, br). 5.51 (1H, d J = 2Hz), 5.61 (1N. d J = 2H2), 7.41-8.02 (5H, m) Examples 13 to 16 proceed to Example 12. The following compound was obtained. Example 13 2-(4,5-dihydroxy-1,3-dithiolane-
2-ylidene)-1-(4-meth-1-xyphenyl)-1
, 3-butanedione I compound M] m, p, 63-6
8°C (purified by silica gel column chromatography) NMR δ (d6-DMSO): 1.95 (3H, s),
3.84 (3H, s). 5.60 (IH, d J=2Hz), 5.71 (IH. d J=2Hz), 6°19 (2H, br), 7.07
(28, d J=9H2), 7.85 (2H, d J=
9H2) Example 14 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-1-(4-methylphenyl)-1,β-
Compound N in butanedione ] m, p, 73-76°C
Purified by silica gel column chromatography) max1420.1285.1240.1070,84
5°N) IRδ (d6-DMSO): 1.94 (3N,
s), 2.40 (3H, s). 5.56 (2H, d J = 2Hz), 5.66 (2H. d J = 2Hz), 6.72 (2H, br), 7.38
(2M, d J = 9Hz), 7.76 (2N, d J =
9Hz) h-15 2-(4,5-dihydroxy-1,3-dithiolane-2
-ylidene)-5-methyl-1-phenyl-1,3-hexanedione with compound 0] m,, p, 44-4
8°C (purified by silica gel column chromatography) N) IRδ (d6-DMSO): 0.73 (6H, d
J=6Hz), 1.76-2.20 (3H, m), 5.
49 (IH, d J = 2 Hz), 5.58 (18, d
J=2Hz), 6.52 (28, br), 7.36-
8.12 (5H, m) Example 16 2-(4,5-'j humanOxy1.,3-dithiolane-2-yliden)L5.5-dime≠ru1゜3-cyclohexanedione

[Compound P] m, p, 195
-197°C (chloroform-hexane recondensation after purification by silica gel column chromatography) maX1078.897 NHRδ (d6-0830): 0.96 (6M, s),
2.45 (4M, sl. 5.52 (2H, d J=5Hz), 6.69 (28
゜d J=5)1z) Example 17 2-(4,5-dihydroxy-1 obtained in Example 12)
,3-dithiolane-2-ylidene)-1-phenyl-1
, 1.2 g of 3-butanedione to pyridine 8&! After adding 1.1 d of acetic anhydride, the mixture was stirred at air temperature for 2 hours. Pour the reaction solution into 200 ml of ice water and add 701 ml of methylene chloride each.
1! ! and extract twice. The extracts are combined and washed twice with 100 ml each of 1N hydrochloric acid, 100 d of a 5% aqueous sodium bicarbonate solution, and 100 d of water, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the residue was recrystallized from benzene-hexane to give 2-(4,5-diacetoxy-1,3-
dithiolane-2-ylidene)-1-phenyl-1,3-
Butanedione compound i 1.1g (yield 66%) was m,
p, 165.5-167, obtained as a white amorphous product at 5°C. NHRδ (CD C13): 2.01 (3N, s),
2.04(,>H,s). 2゜09 (3H, s), 6.32 (IH, d, +=2
Hz), 6.46 (IH, dJ=2Hz). 7, 44-7', 95 (5H, m) Examples 18 to 21 were carried out according to Example 17 to obtain the following compounds. Example 18 2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(4-me!xyphenyl)-1,
Compound R1 is 3-butanedione! m, I). 154-155°C (benzene-hexane reconsolidation) (blank below) Br IRν cm-1: 3000.1775.1642.1
619.1466゜"ax1222.1055.865 3.85 (3H, s), 6.28 (IH, d J=2H
z), 6.42 (IH, dJ=2Hz). 6.92 (2H, d J = 911Z), 7.79 (2H
. d J-9H2) IJ2'(-1dan2-(4,5-diacetoxy-1,3-dithiolane-2
-ylidene)-1-(4-methylphenyl)-1,3-
Butanedione [Compound 33 m, p, 145.5-14
7.5℃ (methanol reconsolidation)”×1222.1040.
855 N) IRδ (CD CI ): 2.02 (6H, s
), 2.09 (3H,s,). 2.41 (3H, s), 6.29 (11 (, d J-2
8z), 6.42 (IH, d J-2Hz), 7.
24 (2H, d J=9Hz), 7.72 (2H, d
J-9Hz) l2-λdan2-(4,5-acetoxy-1,3-dithiolane-2-
ylidene)-5-methyl-1-phenyl-1,3-hexanedione to compound T] m, p, 114.5-11
6℃ (hydrated methanol reconsolidation) NMrδ (CD CL
): 0.79 (6H, d J = 6Hz), 1.85-
2.30 (3H, m), 2.05 (3H, s). 2.08 (3H, s), 6.28 (IH, d-J・?H
z), 6.42 (IH, d J=2Hz), 7.35-
7.95(5)1. m) Example 21 2-(4,5-diacetoxy-1,3-dithiolane-2
-Ylidene)-5,5-dimethyl-1°3-cyclohexanedione with the compound t1m,p. 197, 5-199℃ (benzene-hexane reconsolidation) NH
Rδ (CD C13): 1.05 (6H, S), 2.
09 (6H, S). 2.53 (4N, s), 6.42 (2N, s) 1 inhalation, 2 and] The compound of the present invention has been shown to reduce plasma GPT activity and plasma BSP residue in an experimental liver injury model induced by carbon tetrachloride. However, it significantly suppresses the increase in liver damage and has a remarkable effect of suppressing liver damage. Therefore, the compounds of the present invention are useful as agents for treating or preventing liver diseases, such as liver disorders accompanied by necrosis of hepatic parenchymal cells.

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] [In the formula, R^1 and R^2 may be the same or different, and R ^3 and R^4 may be the same or different, and are a lower alkyl group, an aralkyl group, a lower alkoxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or an aryl group or a hetero group that may have a substituent. Each ring group is shown. Note that R^3 and R^4 may be bonded to each other to form an alkylene group that may have a substituent. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [I] [In the formula, R^1 and R^2 may be the same or different, and represent a hydrogen atom, hydroxyl group, or lower alkanoyloxy group, R^3 and R^4 may be the same or different, and are a lower alkyl group, an aralkyl group, a lower alkoxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or an aryl group that may have a substituent. or each represents a heterocyclic group. In addition, R^3 and R^4 may be bonded to each other to form an alkylene group which may have a substituent. Liver diseases using a substituted-1,3-dithiolane derivative represented by therapeutic agent.