JPH0584317B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a 1,2-dithiol-3-thione compound or a salt thereof having an immunomodulating effect, and a novel immunomodulating agent containing the same as an active ingredient. [Prior art] In general, immunomodulatory effects have little effect when the immune system is functioning normally;
It is understood that the function is to enhance immune function when it is low, and conversely to decrease it when immune function is hyperactive, correcting abnormalities in immune function and returning it to a normal state. Immune hyperactivity is also caused by a decline in the suppressive mechanism, but on the other hand, a state of decreased immune function can also be caused by an enhanced suppressive mechanism. Actions that act in the direction of correction can be called immunomodulatory actions. [Problem to be solved by the invention] Conventional immunomodulators include levamisole,
Thymus hormones are known, and many side effects have been reported in treatments using them. For example, with levamisole, nausea, rash,
Blood disorders have been reported, and the most serious side effect is granulocytopenia, which disappears when the drug is discontinued, but when administering this drug for a long period of time, strict monitoring of the white blood cell count is required. Tracking must be done. For this reason, there is a strong need for new immunomodulators that do not have the serious side effects normally observed in known immunomodulators. In recent years, efforts have been made to restore immune function that has been suppressed due to various causes, restore enhanced immune function to normal, and further strengthen and maintain normal immune function to prevent in-vivo infection and proliferation of pathogenic parasites such as viruses and bacteria. to oppose,
In addition, the importance of immunomodulators that strengthen resistance to the growth of foreign substances in the body such as cancer is increasing significantly. Such drugs are also desired to be applied to diseases such as various allergies, rheumatoid arthritis, diabetes, immunodeficiency, multiple sclerosis, and Guillain-Barre syndrome. [Means for Solving the Problems] As a result of searching for various immunomodulators to be used for this purpose, the present inventors found that lipoic acid (thioctic acid dl form), which is widely used in the treatment of liver diseases. discovered that it had an excellent immunomodulatory effect (Yamamoto, Pharmaceutical Society of Japan, 104th Annual Meeting, Abstracts, p. 397 (1984)), and after further intensive study, developed a specific dithiol compound as an active ingredient. The present invention was based on the discovery that it sometimes has an excellent immunomodulatory effect. That is, the present invention is a compound represented by the following general formula () or a salt thereof, and an immunomodulator containing the compound as an active ingredient.

〔Example〕

Examples will be explained below. 5-Methyl-1,2-dithiol-3-thione used as a raw material was produced by Bull.Soc.Chim.France 1962
2182, p. 2182 (Thurllier, A.). Reference example 1 4,4-di(methylmercapto)-3-buten-2-one 60% sodium hydride in 500 ml of anhydrous benzene 40
g (1.0 mol) and added 88.2 g (1.0 mol) of tert-amyl alcohol while ensuring that the internal temperature did not exceed 60°C.
mol) was added dropwise, the mixture was heated and stirred under reflux for 2 hours, and then left at room temperature overnight. Next, while keeping the internal temperature below 10°C, add 29 g (0.5 mol) of acetone and 38.1 g (0.5 mol) of carbon disulfide.
After the mixed solution was added dropwise and stirred at room temperature for 5 hours, 141.9 g (1.0 mol) of methyl iodide was added dropwise while stirring under ice cooling. Thereafter, the mixture was stirred at room temperature for 3 hours, and then left overnight. Water was added to the reaction mixture, and the organic layer was separated, washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and hexane was added to the resulting residue for crystallization to obtain 59.7 g of crude crystals. Recrystallized from ethanol to give 4,4-di(methylmercapto)-
3-Buten-2-one was obtained as yellow needles. Yield 51.9g (Yield 61.4%) Melting point 65-66.5℃ Reference example 2 3-Methyl-4,4-di(methylmercapto)
-3-Buten-2-one 20% sodium hydride in 700ml of anhydrous benzene
g (0.5 mol), heated to 60°C, and added 44.1 g (0.5 mol) of tert-amyl alcohol while stirring.
was dripped. After dropping, the mixture was stirred at 60°C for 4 hours. This is combined with 19 g (0.25 mol) of carbon disulfide and methyl ethyl ketone.
18 g (0.25 mol) of the mixed solution was added dropwise to the above reaction solution while keeping the temperature below 10°C. After the dropwise addition, the mixture was stirred at room temperature for 4 hours, and then 71 g (0.5 mol) of methyl iodide was added dropwise under ice cooling, followed by stirring at room temperature for 4 hours.
Insoluble matters were removed by filtration, the mother liquor was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow oil. Purification was performed by silica gel column chromatography (solvent n-hexane:ethyl acetate = 10:1) to obtain a yellow oil. Yield 31.4g (yield 71%) NMR (CDCl ₃ , δppm) 2.10 (3H, s), 2.30 (3H, s), 2.34 (3H, s),
2.38 (3H, s) Reference example 3 3-ethyl-4,4-di(methylmercapto)
-3-Buten-2-one The title compound was prepared in the same manner as in Reference Example 1 except that methylpropylketone was used instead of acetone and the reaction scale was changed to 10.8g (0.13mol) as the amount of methylpropylketone used. Obtained as an oil. Yield 17.6g (yield 74%) NMR (CDCl ₃ , δppm) 1.04 (3H, s), 2.28 (3H, s), 2.32 (3H,
s), 2.38 (3H, s), 2.62 (2H, q) Synthesis Example 1 5-Methyl-1,2-dithiol-3-thione (Compound No. 1) 130 g (0.58 mol) of phosphorus pentasulfide in 1.3 xylene
4,4 produced in Reference Example 1 was suspended and refluxed.
A solution of 51.9 g (0.32 mol) of -di(methylmercapto)-3-buten-2-one in 200 ml of xylene was added dropwise. After heating under reflux for 30 minutes, the reaction mixture was poured into 1.5 liters of diethyl ether. Insoluble materials were removed by filtration, and the mother liquor was washed with water and then with a 1% aqueous sodium hydroxide solution. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purified by silica gel column chromatography (hexane: ethyl acetate = 10:1), 5-methyl-1,
2-dithiol-3-thione was obtained as a red oil. Yield 21.9g (yield 46.0%) NMR (CDCl ₃ , δppm) 7.0 (1H, s), 2.54 (3H, s) Synthesis example 2 4,5-dimethyl-1,2-dithiol-3-
Thione (Compound No. 2) 31 g of 3-methyl-4,4-di(methylmercapto)-3-buten-2-one produced in Reference Example 2
(0.18 mol) was dissolved in 100 ml of xylene and added dropwise over 30 minutes to a refluxed solution of 700 ml of xylene in which 65 g (0.3 mol) of phosphorus pentasulfide was suspended. After the dropwise addition, the mixture was refluxed for 30 minutes, cooled to room temperature, 700 ml of ethyl ether was added, and insoluble matter was filtered off. After washing the mother liquor with water, it was dried using anhydrous magnesium sulfate. After distilling off the solvent, 17 g of crude crystals were obtained. Recrystallization from ethyl acetate gave orange crystals. Yield 9.7g (yield 35%) Melting point 95.5-97°C Synthesis example 3 4-ethyl-5-methyl-1,2-dithiol-3-thione (compound No. 3) 3-ethyl- produced in Reference example 3 4,4-di(methylmercapto)-3-buten-2-one 17g
(90 mol) was treated in the same manner as in Synthesis Example 1,
The title compound was obtained as a black oil. Yield 6.8g (yield 43%) NMR (CDCl ₃ , δppm) 1.05 (3H, t), 2.52 (3H, s), 2.68 (2H, q) Synthesis example 4 5-methyl-4-phenyl-1,2 -dithiol-3-thione (compound No. 4) (1) 3-phenyl-4,4-di(methylmercapto)-3-buten-2-one 60% sodium hydride in 150 ml of anhydrous benzene
Suspend 6.6g (0.17mol) and add 18ml (0.17mol) of tert-amyl alcohol while keeping the internal temperature at 60℃.
was added dropwise while stirring. After dropping, reflux for 3 hours, cool on ice, and remove carbon disulfide at an internal temperature of 10°C or less.
g (82 mmol), phenylacetone 11 g (82
A mixed solution of 1 mmol) was added dropwise. 5 at room temperature after dropping
After stirring for an hour, 24.1 g of methyl iodide was cooled on ice.
(0.17 mol) was added dropwise. After stirring at room temperature for 3 hours, 200 ml of water and 400 ml of ethyl acetate were added to the reaction solution, and the target product was extracted into the organic layer, which was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography to obtain the desired product as a yellow oil. Yield 13.2g (yield 67.6%) NMR (CDCl ₃ , δppm) 2.20 (3H, s), 2.26 (3H, s), 2.44 (3H, s), 7.38 (5H, bs) (2) 5-Methyl- 4-Phenyl-1,2-dithiol-3-thione Treated in the same manner as in Synthesis Example 1 using 13.1 g (55 mmol) of 3-phenyl-4,4-di(methylmercapto)-3-buten-2-one. The title compound was obtained as orange crystals. Yield 6.0g (yield 48.3%) Melting point 85-86℃ NMR (CDCl ₃ , δppm) 2.40 (3H, s), 7.10-7.30 (2H, m), 7.40-7.60 (3H, m) Synthesis example 5 5- [2-(4-methoxyphenyl)ester]
-1,2-dithiol-3-thione (compound no.
5) 5-methyl-1,2-dithiol-3-thione
0.40 g (2.7 mmol) and p-methoxybenzaldehyde 0.40 g (2.9 mmol) in methanol 6
ml, 0.05 ml of piperidine was added, and the mixture was heated and stirred under reflux for 5 hours. After cooling, the precipitated crude crystals were collected by filtration and recrystallized from benzene-ethanol to obtain the desired product as red crystals. Yield 0.18g (yield 25.0%) Melting point 129-131℃ NMR (DMSO- _d6 , δppm) 7.64 (2H, d), 7.16-7.52 (3H, m), 6.94 (2H, d), 3.79 (3H, s, -OCH ₃ ) Synthesis Example 6 5-[2-(4-chlorophenyl)ethenyl]-
1,2-dithiol-3-thione (compound no.
6) 5-methyl-1,2-dithiol-3-thione
0.40 g (2.7 mmol) and 0.40 g (2.8 mmol) of p-chlorobenzaldehyde in 6 ml of methanol
0.05 ml of piperidine was added, and the mixture was heated and stirred under reflux for 5 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from penzene-ethanol to obtain the desired product as red crystals. Yield 0.28g (yield 38.3%) Melting point 156-157℃ NMR (DMSO-d ₆ , δppm) 7.75 (2H, d), 7.58-7.67 (3H, m), 7.52 (2H, d) Synthesis example 7 5- [2-(4-methoxyphenyl)ethenyl]
-4-Methyl-1,2-dithiol-3-thione (Compound No. 7) 4,5-dimethyl-1,2-dithiol-3-
0.8 g (5 mmol) of thione in ethyl alcohol
Dissolve 0.7 g (5 mmol) of paramethoxybenzaldehyde and 80 mg of piperidine in 40 ml of
was added and refluxed for 8 hours. After cooling to room temperature, red crystals were obtained. Recrystallization from a benzene-ethyl alcohol mixture gave black plate-like crystals. Yield 0.58g (Yield 41%) Synthesis Example 8 4-phenyl-5-[2-(2-furyl)ethenyl]-1,2-dithiol-3-thione (Compound No. 8) Add 5-phenyl-5-[2-(2-furyl)ethenyl]-1,2-dithiol-3-thione (compound No. 8) to 30 ml of ethyl alcohol. Methyl-4-phenyl-1,2-dithiol-3-thione 1.9g
(8.5 mmol), 0.9 g (9.4 mmol) of furfural, and 0.1 g of piperidine were added, and the mixture was refluxed for 10 hours. After cooling to room temperature, crude crystals were obtained. Benzene-
The target compound was obtained by recrystallization from ethyl alcohol. Yield 1.3g (yield 50.4%) Melting point 169-170℃ NMR (CDCl ₃ , δppm) 6.36-6.56 (2H, m), 6.64 (1H, α) 7.08-7.60 (7H, m) 5-methyl -1,2-dithiol-
Using 3-thione or 4,5-dimethyl-1,2-dithiol-3-thione as a starting material, compounds No. 12-
28 compounds were synthesized. The physical property values are summarized in Table 3. Also, 5-(4-methoxyphenyl)-1,2-
Dithiol-3-thione (anethole trithione) (Compound No. 9) 5-phenyl-1,2-dithiol-3-thione) (Compound No. 10) 5-(4-dimethylaminophenyl)-1,2 −
dithiol-3-thione) (compound No. 11) using a known method, for example, J.Am.Chem.Soc 1962
Manufactured according to page 2941 (Erwin.K). Example 1 A Effect on mouse splenocyte blastogenesis Concanavalin A in mouse splenocytes
The effect of this compound on DNA synthesis induced by Concanavalin A (hereinafter referred to as Con A) was investigated. BALB/C mouse (female 10 weeks old) splenocyte 1
×10 ⁵ pieces with ConA 2μg/ml and this compound 10 ^-6 ,
After culturing in RPMI 1640 medium containing 10% fetal bovine serum with 10 ^-3 or 10 ^-4 M at 37° C. and 5% CO ₂ for 48 hours, ³ -H thymidine was added and the cells were further cultured for 18 hours. The cultured cells were harvested using a harvester, and the amount of ³ -H thymidine taken into the cells was measured using a liquid scintillation counter. The results are shown in Table-1. The displayed value is a relative value when the uptake amount of the control well is set as 100. B. Antibody Production Enhancement Effect The effect of this compound on antibody production against sheep red blood cells (SRBC) in mice was investigated. A group of 4 ICR mice (female, 7 weeks old) was used and 5 x 10 ⁷ SRBCs were injected into the tail vein of the mice for immunization. This compound was administered at 0.5% twice on the day of immunization and the next day.
It was suspended in methylcellulose and administered orally. Three days after immunization, the number of anti-SRBC antibody producing cells (PFC number) in the mouse splenocytes was measured by the method of Jerne (Science, vol. 140, p. 405, 1963). The results are shown in Table-2. The displayed value is a relative value when the PFC number of the control group is set to 100. C. Acute toxicity test Acute toxicity in mice was investigated using the oral administration method. The present compound was suspended in 0.5% methylcellulose and orally administered to five ddY mice (male, 7 weeks old) per group. The progress was observed for 14 days after administration, and the number of deaths was determined. When Compound No. 6 was used, there were no deaths at 500 mg/Kg administration, and no effect on body weight fluctuation was observed. On the other hand, 3 out of 4 animals died when lipoic acid was administered at 500 mg/Kg. D Formulation Example Tablets containing 20 mg of active compound and having the following composition were prepared by conventional techniques. Compound No. 3 20mg Lactose 78mg Cornstarch 50mg Magnesium stearate 2mg Other compounds of the present invention can be formulated in the same manner.

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Claims (1)

[Claims] 1. A compound represented by the following general formula () or a salt thereof. [Chemical formula] (In formula (), R ₁ represents a hydrogen atom or a lower alkyl group, and R ₃ represents a phenyl group substituted with a halogen atom, a lower alkyl group, a nitro group, a lower alkoxy group, or a hydroxyl group. However,
(Except when R ₃ is phenyl substituted only with a lower alkyl group, a halogen atom, or a lower alkoxy group)