JPH0459315B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel 1,3-dithiol compound. (Prior art) General formula In the 1,3-dithiol compound represented by, R' is a lower alkyl group, for example, the 1,3-dithiol compound represented by
It is a known compound described in JP-A-51-144734 and JP-A-52-83751, etc., and is reported to be effective as a drug for liver diseases, but it has been pointed out that its problem is that it causes gastrointestinal disorders. . (Problems to be Solved by the Invention) An object of the present invention is to provide a novel 1,3-dithiol compound that has a better therapeutic effect on liver diseases and has reduced side effects of gastrointestinal disorders. (Means for solving the problems) The present invention is based on the general formula (In the formula, R is

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The present invention relates to a 1,3-dithiol compound represented by the following formula. The 1,3-dithiol compound of the present invention represented by the above general formula (1) is a novel compound that has not been described in any literature, and has a liver function improving effect and is useful as a therapeutic agent for liver diseases. The 1,3-dithiol compound represented by the general formula (1) of the present invention is produced, for example, by the following method. 2-methylthio-1,3-dithiolium iodide (3) is allowed to act on the compound represented by general formula (2) in a solvent in the presence of a base such as calcium hydride, lithium diisopropylamine, or sodium hydride. This method is expressed by the following reaction formula. (In the formula, R is the same as above.) Examples of the solvent used in the reaction include dioxane, tetrahydrofuran (THF), 1,2-
Ethers such as dimethoxyethane are preferably used. Furthermore, it is advantageous to use equal amounts of compounds (2) and (3). Although the reaction temperature may be selected appropriately, it is generally advantageous to carry out the reaction at a temperature of about 0°C to room temperature. The compound (2) used as a starting material in this reaction is a new compound that has not been described in any literature, and is produced, for example, from malonic acid dichloride (4) by the steps shown below. (In the formula, R is the same as above.) That is, compound (2) is obtained by reacting alcohol (5) with compound (4) in the presence of a base. Isolation and purification of the compound (1) of the present invention obtained by the above method is carried out by conventional operations such as extraction, recrystallization, column chromatography, and the like. (Example) Synthesis examples of the 1,3-dithiol compound of the present invention will be described below as examples, and further synthesis examples of starting material compounds will be described as reference examples. Reference example 1 1,3-dioxolane-4-methanol 3.12g
Dissolve in 50 ml of dry dichloromethane and add 4.60 ml of triethylamine. Under ice cooling, a solution of 1.60 ml of malonic acid dichloride dissolved in 2.0 ml of dry dichloromethane is added dropwise. Stirring is carried out at room temperature for 3 hours, and after the reaction, the mixture is poured into ice water, and the organic layer is separated and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off and the residue was separated and purified by column chromatography (developing solvent: chloroform:acetone=5:1) to obtain 2.77 g (67%) of an oil [Compound A]. Furthermore, ¹ H−
Table 1 shows the analysis results by NMR (proton nuclear magnetic resonance). Reference example 2 N-methylpiperidine-3-methanol 3.0g
was dissolved in 50 ml of dry dichloromethane, and 1.24 ml of malonic acid dichloride was dissolved in 8 ml of dry dichloromethane under ice-cooling.
Drop the solution dissolved in ml. After stirring at room temperature for 20 hours, a 5N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off. The residue [Compound B] was used in the next reaction without being purified. Furthermore, ¹ H−
Table 1 shows the results of NMR analysis. Reference Examples 3 to 7 Compounds C, D,
G, H, and I were synthesized. Incidentally, the analysis results by ¹ H-NMR are shown in Table 1. Reference Example 8 10 g of 1-piperazine ethanol and 15.5 g of α-bromoacetophenone were stirred in 70 ml of dichloromethane at room temperature for 18 hours. After the precipitate is filtered off, the crystals are added to 3N sodium hydroxide solution and extracted with chloroform. After drying the extract, the solvent was distilled off to obtain 15 g (79%) of crystals of 4-benzoylmethyl-1-piperazineethanol. Dissolve 5 g of 4-benzoylmethyl-1-piperazine ethanol in 100 ml of dry dichloromethane,
Add 1.5 g of malonyl dichloride dropwise while cooling on ice.
After stirring at the same temperature for 2 hours, 2N sodium hydroxide solution was added, the dichloromethane layer was separated, the separated layer was washed with water, dried, the solvent was distilled off, and the residue was subjected to column chromatography. Separation and purification using E (developing solvent; chloroform:ethanol = 8:1) yielded 3.0 g (27%) of an oil [Compound E]. Incidentally, the analysis results by ¹ H-NMR are shown in Table 1. Reference example 9 1-benzyloxycarbonyl-pyrrolidine-
24 g of 2-carboxylic acid to 120 g of dimethylformamide
ml, add 15.6 g of carbonyldiimidazole, and stir at 40°C for 1 hour. Next, 14.4 g of tert.-butanol and 1,8-diazabicyclo[5,4,
0]-7-Undecene (DBU) (14.6 g) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with ether. The extract was washed with 1N hydrochloric acid and then with water, dried, the solvent was distilled off, and tert.-butyl 1
-benzyloxycarbonyl-pyrrolidine-2-
26 g (88%) of carboxylate are obtained. tert.-butyl 1-benzyloxycarbonyl-
Dissolve 15 g of pyrrolidine-2-carboxylate in 150 ml of methanol, and dissolve 3 g of 10% palladium-carbon.
and hydrogenate at normal pressure. The reaction solution was filtered and the filtrate was concentrated to obtain 6.5 g (77%) of tert.-butyl pyrrolidine-2-carboxylate. 3.3 g of tert.-butyl pyrrolidine-2-carboxylate is dissolved in 50 ml of ethanol, and 1.3 g of propylene oxide is added dropwise under ice cooling. After dripping,
Stir for 2 days at room temperature. After the reaction, it is concentrated and extracted with benzene. After washing the extract with water and drying, the solvent was distilled off to obtain 3.7 g (84%) of tert.-butyl 1-(2-hydroxypropyl)pyrrolidine-2-carboxylate. tert.-butyl 1-(2-hydroxypropyl)
3.7 g of pyrrolidine-2-carboxylate was dissolved in 40 ml of dichloromethane, and 1.4 g of malonyl dichloride was added dropwise under ice cooling. After the addition, the mixture was stirred at room temperature for 4 hours. After the reaction, 1N sodium hydroxide solution is added and shaken, the dichloromethane layer is separated, dried, and the solvent is distilled off. The residue was separated and purified by column chromatography (developing solvent: chloroform:acetone = 7:1) to obtain an oil [Compound F] 2.1
g (25%). Incidentally, the analysis results by ¹ H-NMR are shown in Table 1.

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[Table] Example 1 60% sodium hydride 0.4 in dry THF (12 ml)
g, and 2.77 g of bis[(1,3-dioxoden-4-yl)-methyl][Compound A] was added dropwise under ice cooling. Next, the mixture was stirred at room temperature for 1 hour, cooled on ice again, 2.77 g of 2-methylthio-1,3-dithiolium iodide was added, and the mixture was stirred at room temperature for 3 hours. Add water to the reaction solution and extract twice with 60 ml of ethyl acetate.
After drying over anhydrous magnesium sulfate, the solvent is distilled off and the residue is crystallized from ether. The crude crystals were collected by filtration and recrystallized from ethyl acetate, mp110-112℃.
0.6 g (16%) of crystals [Compound 1] were obtained. Examples 2 to 5 and Examples 7 to 9 Compounds B to E,
Compounds 2 to 5 and 7 to 9 were synthesized using G to I as raw materials. Note that Compounds 2 to 5 and 7 to 8 were purified as maleate salts, and Compound 9 was purified as hydrochloride. Example 6 0.2 50% sodium hydride in dry THF (50 ml)
g, and then slowly add compound F (2.1 g) under ice cooling. Next, after stirring at room temperature for 2 hours, cooling on ice again,
Add 1.2 g of -methylthio-1,3-dithiolium iodide and stir at room temperature for 3 hours. After the reaction,
The solvent was distilled off and the residue was extracted twice with CHCl ₃ (50 ml).
After drying over anhydrous magnesium sulfate, the solvent is distilled off. The residue was subjected to silica gel column chromatography (developing solvent: chloroform:acetone = 10:
1) to obtain an oily bis[(2-tert-butoxycarbonyl-pyrrolidin-1-yl)-2-
1.5 g (60%) of propyl]1,3-dithiol-2-ylidene malonate was obtained. Add 2 ml of trifluoroacetic acid to 0.2 g of the above compound and stir at room temperature for 18 hours. After the reaction, the solvent was distilled off, and the residue was adjusted to pH 8 to 9 with sodium hydrogen aqueous solution, and separated and purified using MCI gel (manufactured by Mitsubishi Kasei). The eluate was lyophilized and 0.1g of compound 6 with mp131-133℃
(56%) obtained. ¹ H-NMR and elemental analysis values of Compounds 1 to 9 are shown in Table 2. In ¹ H-NMR in Table 2, (a) indicates that _CDCl3 , (b) DMSO- _d6 , and (c) _D2O were used as solvents. Also, in elemental analysis (C)
indicates the calculated value, and (F) indicates the analytical value.

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Claims (1)

[Claims] 1. General formula (In the formula, R is [formula] [formula] [formula] [formula] A 1,3-dithiol compound represented by [Formula] [Formula] [Formula] or [Formula].