KR900000968B1 - 1,2-dithiol-3-thione derivative composition and their preparation - Google Patents

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1,2-dithiol-3-thione derivatives, preparation method and composition thereof

The present invention relates to novel 1,2-dithiol-3-thione derivatives having immunomodulatory properties, methods for preparing the same, and immunomodulatory compositions containing them as active ingredients.

Immune regulation has little effect on the organism when the organism's immune system is normal, but it stimulates when the immune system is weak and inhibits it when the immune system is overactive.

The overactivity of the immune system is due to the low activity of the immunosuppressive mechanism, whereas the under activity of the immune system is due to the overactivity of the immunosuppressive mechanism. Therefore, as immunomodulation, the immunosuppressive mechanism of the immunosuppressive mechanism is regulated regularly to normalize the mechanism.

Immunomodulators such as levamisol and thymus hormone have been reported to have a number of side effects when used clinically. Levamisol, for example, has granulocytopenia, as well as vomiting, rash and blood disorders, as well as the most serious side effects. Although granulocytopenia is lost by discontinuation of levamisol, the number of leukocytes should be closely tracked after prolonged administration. Thus, there is a need for immunomodulators that do not exhibit serious side effects.

Recently, there is an increasing need for immunomodulators that inhibit the infection of heart and organisms in pathogenic parasites such as viruses and bacteria and enhance resistance to foreign substances such as cancer cells. There is also a need for immunomodulators for use in the treatment of various allergies, rheumatoid arthritis, diabetes, immunodeficiency syndrome, multiple sclerosis, and Gillian-Ber syndrome.

The inventors have found that riponic acid (DL-thioctynic acid), which is variously used for the treatment of liver disease, has been published and released with excellent immunomodulatory effect. (Japanese Pharmacy Society, 104th Annual Meeting, Collection of Lectures 1984, 397) )

It is an object of the present invention to provide an immunomodulator that has a stronger immunomodulatory effect than a conventional immunosuppressant and does not cause side effects.

The inventors have found that the novel 1,2-dithiol-3-thione derivatives are very safe to use and that the present invention has a strong immunomodulatory effect similar to that of riphonic acid in completion. Therefore, the present invention relates to a 1,2, -dithiol-3-thione derivative of the following formula (I),

R is a hydrogen, halogen, lower alkoxy, lower alkyl, amino, lower-alkyl substituted amino or lower alkoxy carbonyl group.

Immunomodulators of the present invention containing a compound of formula (I) as an active ingredient include autoimmune diseases including chronic rheumatoid arthritis, systemic lupus erythematosus, nephritis, diabetes, immunodeficiency, multiple sclerosis, and Gillian Ber syndrome; Direct and modified allergies; It is used extensively in the treatment of immunodeficiencies, including malignant tumors and serious infectious diseases.

In the formula (I) described above, "lower" means their structural isomers such as methyl, ethyl, propyl and butyl and isopropyl, isobutyl and t-butyl.

Among the compounds of formula (I), the preferred ones are as follows:

5- (4-phenyl-1,3-butadienyl) -1,2-dithiol-3-thione, 5- {4- (4-chlorophenyl) -1,3-butadienyl} -1, 2-dithiol-3-thione, 5- {4- (4-methoxyphenyl) -1,3-butadienyl} -1,2-dithiol-3-thione, 5- {4- (p- Toluyl) -1,3-butadienyl} -1,2-dithiol-3-thione, 5- {4- (o-chlorophenyl) -1,3-butadienyl} -1,2-dithi All-3-thione, 5- {4- (m-toluyl) -1,3-butadienyl} -1,2-dithiol-3-thione.

The immunomodulatory composition of the present invention contains a compound of formula (I) together with an existing pharmaceutically acceptable carrier or diluent and is formulated into tablets, capsules, powders and particles, injections and suppositories for oral administration. Dosage is 0.1-500 mg for each dose. Administration is usually once a day, but may be given more than once a day, depending on the patient's condition.

The novel 1,2-dithiol-3-thione derivatives of the present invention are prepared by converting a cinnamic aldehyde derivative of formula (II) to a 5-methyl-1,2-dithiol-3-thione derivative in an organic solvent in the presence of a base. It is made by condensation

R is a hydrogen, halogen, lower alkoxy, lower alkyl, amino, lower-alkyl substituted amino or lower alkoxy carbonyl group.

In this step, aliphatic and aromatic hydrocarbons, halogenated hydrocarbons, alcohols and ether groups are used as the organic solvent. Preferred organic solvents include hexane, toluene and methanol.

Preferred bases include lower alkoxides of alkali and alkaline metals, tertiary amines and 1,8-diazabicyclo 5,4,0-unde-7-can (DBU). The amount of base used in this process is 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to 5-methyl-1,2-dithiol-3-thione.

This process is -10 degreeC-100 degreeC; Preferably it is carried out at a temperature of 0 ℃ to 50 ℃. The reaction is complete by stirring in the reaction medium for about 1 hour.

It is a novel method to produce novel 1,2-dithiol-3-thione derivatives by condensation of aliphatic aldehyde derivatives with 5-methyl-1,2-dithiol-3-thione.

The present invention will be described in detail as a preferred embodiment.

The present embodiments are illustrative only and do not limit the present invention. The starting material, 5-methyl-1,2-dithiol-3-thione, in this example was prepared as described in Tnurllier, A, Bull. Soc. Chim. France (1962), 2182.

Reference Example 1

4,4-di (methyl mercapto) -3-buten-2-one

Suspend 40 g (1.0 mole) of 60% sodium hydroxide in 500 ml of anhydrous benzene. 88.2 g (1.0 mole) of t-amyl alcohol is added dropwise to the suspension while maintaining the temperature of the suspension below 60 ° C. The mixture is then heated to reflux under stirring for 2 hours and left overnight at room temperature. A mixture of 29 g (0.5 mole) acetone and 38.1 g (0.5 mole) carbon disulfide is added dropwise while maintaining the temperature of the mixture below 10 ° C. After stirring the reaction mixture for 5 hours at room temperature, 141.9 g (1.0 mole) of methyl iodide was added dropwise with cooling while cooling in ice water. After stirring for 3 hours at room temperature, the mixture was allowed to stand overnight. Water was added to the reaction mixture and the organic phase was separated. The organic phase was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and crystallized by adding hexane to the residue to give 59.7 g of crude crystals. The crude crystals were recrystallized from ethanol to yield 51.9 g (61.4%) of yellow needles, 4,4-di (methyl mercampto) -3-buten-2-one. Melting point: 65-66.5 ℃

Reference Example 2

5-methyl-1,2-dithiol-3-thione

Suspend 130 g (0.58 mole) of phosphorus pentasulfite in 1.3 l of xylene and 200 ml of xylene embedded with 51.9 g (0.32 mole) of 4,4-di (methyl mercapto) -3-buten-2-one Was added dropwise under reflux. After heating at reflux for 30 minutes, the reaction mixture is poured into 1.5 l of diethyl ether. The insolubles were filtered off, the mother liquor was washed and washed with 1% sodium hydroxide solution. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. Transcription was purified by silica gel chromatography (nucleic acid; ethyl acetate = 10: 1) to yield 21.9 g (46.0%) of red oily 5-methyl-1,2-dithiol-3-thione.

NMR (CDCl ₃ , δ ppm) 7.0 (1H, s) 25.4 (3H, s)

Example 1

5- (4-phenyl-1,3-butadienyl) -1,2-dithiol-3-thione

Compound number 1

600 mg (24 mg atom) magnesium metal was added to 40.1 methanol, and the mixture was heated at reflux for 1 hour to dissolve the magnesium metal. While cooling the mixture in ice water, 1.4 g (10 mmol) cinnamic aldehyde and 1.56 g (10 mmol) 5-methyl-1,2-dithiol-3-thione were sequentially added to the mixture and the mixture was stirred at room temperature for 1 hour. The separated crystals were collected by filtration and 300 ml of ethyl acetate was added. The insolubles were filtered off and the mother liquor was washed and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting crude crystals were recrystallized from benzene-ethanol to give 0.53 g (19.2) of dark red crystals, 5- (4-phenyl-1,3-butadienyl) -1,2-dithiol-3-thione. %) Was calculated. Melting Point: 160-161 ℃

NMR (DMSO-d ₆ , δ ppm) 7.3-7.7 (5H, s) 6.8-7.28 (5H, m)

Cinnamic aldehyde derivatives corresponding in a similar manner as in Example 1 (ie 4-chloro-cinna aldehyde, 4-methoxy-cinna aldehyde, 4-dimethylamino-cinna aldehyde, p-methyl-cinna aldehyde, o-chloro- Cinnamic aldehyde or m-methyl-cinnamic aldehyde) was reacted with 5-methyl-1,2-dithiol-3-thione to prepare the following compounds.

5- {4- (4-chlorophenyl) -1,3-butadienyl} -1,2-dithiol-3-thione

Compound number 2

Shape: Red Crystal

Yield: 18.9%

Melting Point: 144-145 ℃

NMR (DMSO-d ₆ , δppm) 6.80-7.25 (4H, m) 7.30-7.79 (5H, m)

5- {4- (4-methoxyphenyl) -1,3-butadienyl} -1,2-dithiol-3-thione

Compound number 3

Shape: Black Crystal

Yield: 13.6%

Melting Point: 147-148 ℃

NMR (DMSO-d ₆ , δ ppm) 7.28-7.69 (4H, m) 6.78-7.12 (5H, m) 3.79 (3H, s)

5- {4- (4-dimethylaminophenyl) -1,3-butadienyl} -1,2-dithiol-3-thione

Compound number 4

Geometry: Black Green Crystals

Yield: 5.3%

Melting Point: 133-134 ℃

5- {4- (p-toluyl) -1,3-butadienyl} -1,2-dithiol-3-thione

Compound number 5

Shape: Black Crystal

Yield: 26.7%

Melting Point: 144-145 ℃

NMR (DMSO-d ₆ , δppm) 2.44 (3H, s) 6.50-7.50 (9H, m)

Elemental Analysis (C ₁₄ H ₁₂ S ₃ )

Output: C; 60.83, H; 4.38, S; 34.79

Found: C; 60.73, H; 4.41, S; 35.05

5- {4- (o-chlorophenyl) -1,3-butadienyl} -1,2-dithiol-3-thione

Compound number 6

Shape: Dark Red Crystal

Yield: 11.0%

Melting Point: 161-162 ℃

NMR (DMSO-d ₆ , δppm) 7.87 (1H, s) 6.84-7.70 (8H, m)

5- {4- (m-methylphenyl) -1,3-butadienyl} -1,2-dithiol-3-thione

Compound number 7

Shape: Dark Red Crystal

Yield: 23.1%

Melting Point: 143.5-144.5 ℃

NMR (DMSO-d ₆ , δppm) 2.36 (3H, s) 6.95-7.51 (9H, m)

Examples of test results and structures of the compounds of the present invention will be described in detail below.

[Exam 1]

Activity on Mouse Cell Splenocytes

The activity of the compounds of the present invention on the DNA synthesis of mouse splenocytes, a synthesis derived from Concanavalin A (hereinafter referred to as ConA), was tested.

1 × 10 ⁵ splenocytes from BALB / C mice (female, 10 weeks old) were embedded with 2 μg / ml ConA and 10 ⁻⁶ , 10 ⁻⁵ or 10 ⁻⁴ M of the compound of the present invention, 48 hours incubation in 37 ℃ RPMI1640 medium containing serum albumin, the atmosphere was adjusted to contain 5% CO ₂ . Then 3H-thymidine was added to the medium, and the medium was incubated for another 18 hours.

Cultured cells were collected with harvesters and 3H-thymidine treated as cells was measured using a flame counter.

The results are listed in Table 1. The activity in the table indicates the relative activity when the control activity is 100.

TABLE 1

[Exam 2]

Antibody production-enhancing activity

The activity of the compounds of the present invention in the production of antibodies in mice against positive red blood cells (SRBC) was tested.

Mice were immunized by injecting 5 × 10 ⁷ SRBC into the tail vein of an ICR mouse (female, 7 weeks old, 4 mice in each group). Compounds of the invention suspended in 0.5% methylcellulose solution were administered orally twice on the day immunized and the day following. Three days after immunization, the number of splenocytes producing anti-SRBC antibodies (PFC count) was determined by Jerne method (Science Vol. 140, page 145 (1963)).

The results are listed in Table 2. In Table 2, activity indicates the relative number of PFCs when the control PFC number is 100.

TABLE 2

[Exam 3]

Activity against rat allergic encephalomyelitis (EAE) Chronic recurrent lap EAE, a model of autoimmune diseases such as multiple sclerosis, was produced according to the Feuer method followed by testing the compounds of the invention against rat EAE. .

0.2 ml consisting of 10 mg lyophilized spinal cord and Freund's complete adjuvant (containing 2 mg tuberculous bacillus H37RA species) in the hind pads of each Lewis rat (female, 7 males, 8 rats per group) Adhesion solution was separated and inoculated.

The compounds of the present invention were suspended in 0.5% methyl cellulose solution and the suspension was injected subcutaneously 8 copies 7 days before and 7 days after inoculation. The clinical status of the rats was observed up to 50 days of inoculation and measured 0-5 according to Feuer's method. Mortality was measured 50 days after inoculation.

The results are listed in Table 3. The average number of measurements calculated when the rat survives shows that Compound 1 of the present invention has excellent inhibitory properties against rat EAE.

TABLE 3

Mean Standard Horseshoe p <0.01

[Exam 4]

Acute toxicity

Oral properties of the compounds of the invention were measured for mice.

Compounds of the present invention were suspended in 0.5% methyl cellulose solution and suspension eggs were orally administered to ddY mice (male, 7 weeks old, 6 per group). The condition of the mice was observed and mortality was measured 14 days after administration. No mice died when 500 mg / kg of Compound (I) was administered and did not affect the body weight of the mice. In addition, one of six mice died when 300 mg / kg of riponic acid was administered.

Preparation Example (Tablet)

Tablets consisting of the following composition containing 20 mg of active ingredient were prepared by conventional methods.

20 mg of compound 1

Lactose 78mg

Cornstarch 50mg

Magnesium Stearate 2mg

Other compounds according to the invention were also purified in the same way.

Claims (4)

1,2-dithiol-3-thione derivative of the following formula (I)

Wherein R is hydrogen, halogen, lower alkoxy, lower alkyl, amino, lower-alkyl substituted amino or lower alkoxy carbonyl group. The method of claim 1, wherein 5- (4-phenyl-1,3-butadienyl) -1,2-dithiol-3-thione, 5- {4- (4-chlorophenyl) -1,3-buta Dienyl} -1,2-dithiol-3-thione, 5- {4- (4-methoxyphenyl) -1,3-butadienyl} -1,2-dithiol-3-thione, 5- {4- (p-toluyl) -1,3-butadienyl} -1,2-dithiol-3-thione, 5- {4- (o-chlorophenyl) -1,3-butadienyl} Derivatives which are -1,2-dithiol-3-thione, 5- {4- (m-methylphenyl) -1,3-butadienyl} -1,2-dithiol-3-thione. 1,2-dithiol-3- of formula (I), consisting of condensing an aldehyde compound of formula (II) with a 5-methyl-1,2-dithiol-3-thione derivative in an organic solvent in the presence of a base: Method for preparing thion derivatives.

Wherein R is hydrogen, halogen, lower alkoxy, lower alkyl, amino, lower alkyl substituted amino or lower alkoxy carbonyl. An immunomodulatory composition comprising an effective amount of a 1,2-dithiol-3-thione derivative of formula (I) of claim 1 and a pharmaceutically acceptable carrier.