JPH04117377A - 1,2-dithiol-3-thione derivative and antirheumatic agent containing the same as active ingredient - Google Patents

Abstract

NEW MATERIAL:5-{4-(4-Carboxyphenyl)-1,3-butadienyl}-1,2-dithiol-3-thione expressed by formula I. USE:An antirheumatic agent having immunological regulating action with high safety and hardly any side effects. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by the formula CH3COOK and the resultant product is then reacted with OH<-> to afford a compound expressed by formula III, which is subsequently oxidized and reacted with a compound expressed by the formula Ph3P=CH- CHO. The obtained product is then reacted with a compound expressed by formula IV and Mg(OCH3)2 to provide a compound expressed by formula V, which is subsequently reacted with H<+>.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a 1,2-dithiol-3-thione derivative and an antirheumatic agent containing the same as an active ingredient.

[Conventional technology]

In recent years, drugs with immunomodulatory effects have been widely used in clinical settings as therapeutic agents for autoimmune diseases, especially as antirheumatic agents for the treatment of rheumatoid arthritis.

In general, immunomodulatory effects have little effect when the immune function is functioning normally, but when the immune function is weakened, it is enhanced, and when the immune function is hyperactive, it is decreased, and each It is understood to be an action that corrects abnormalities in immune function and returns it to a normal state.

Immune hyperactivity is also caused by a decline in suppressive mechanisms, but
On the other hand, a state of decreased immune function can also be caused by the enhancement of the suppressive mechanism, so an action that acts in a regulatory manner to correct disturbances in suppression of the immunoregulatory mechanism can be said to be an immunomodulatory effect.

Many side effects have been reported in treatments using conventional anti-rheumatic agents (levamisole, D-penicillamine, etc.) that have immune function.

For example, nausea, rash, blood disorders, etc. have been reported with levamisole. Among these, the most serious side effect is granulocytopenia, which disappears upon discontinuation of treatment, but when using this autopsy over a long period of time, the white blood cell count must be closely monitored. Also, skin rash and taste disturbance have been reported as side effects of D-penicillamine.

For this reason, there is a strong desire for a new antirheumatic agent that has immunomodulatory effects and does not have serious side effects.

(Problems to be Solved by the Invention) An object of the present invention is to provide a highly safe antirheumatic agent with few side effects that is effective for the treatment of autoimmune diseases.

The present inventors previously discovered that a new 1,2-dithiol-3-thione derivative has an excellent immunomodulatory effect (Japanese Patent Application Laid-Open No. 10785/1985), but as a result of further intensive studies, we found that It is effective for collagen arthritis and is widely used as a compound that suppresses collagen arthritis at an extremely low dose compared to the compound described in JP-A-63-10785 (typically, compound No. 1 described in Example 1 thereof). The present invention was achieved by discovering a 12-dithiol-3-1,000-one derivative that exhibits an action and is safe.

[Means for Solving the Problems] That is, the present invention provides a 1,2-dithiol-3-1,000-one derivative represented by (1) or a physiologically acceptable salt thereof, and an anti-inflammatory drug containing the same as an active ingredient. It is a rheumatism drug. The compounds of the present invention have excellent anti-arthritic effects and high safety, and are extremely useful as active ingredients of anti-rheumatic agents.

Physiologically acceptable salts of the 1,2-dithiol-3-thione derivatives of the present invention include alkali metal salts such as sodium salts and potassium salts, calcium salts, magnesium salts,
Examples include salts made of inorganic bases such as alkaline earth metal salts such as aluminum salts, and salts made of organic bases such as triethylamine and ethanolamine.

of the present invention 12-Diolet-3-thione derivative teeth, It can be obtained by the production route shown below.

The dose of the 1,2-dithiol-3,000one derivative of the present invention for treated patient-1 depends on the symptoms to be treated and the administration method, but is usually 0.1 to 500 μl per dose for adults. , may also be administered once or more per day. Dosage forms include capsules, tablets, fine granules, syrups,
It can be administered orally or parenterally by means of an oral preparation such as a powder, an injection type, or a herbal medicine. Additives for formulations include excipients (lactose, cornstarch, sugar, sorbitol, calcium phosphate, etc.), binders (silo, 7p, gum arabic, gelatin, sorbitol, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.), lubricants ( (magnesium stearate, curcum, polyethylene glycol, silica, etc.), disintegrants (potato starch, carboquine methyl cellulose, etc.), wetting agents (sodium lauryl sulfate, etc.), etc. are used as appropriate according to the dosage form.

〔Example〕

The present invention will be explained in detail below using Reference Examples, Examples, Test Examples, and Formulation Examples.

5-methyl 1,2- used as a raw material in Example 5
Dithiol-3-thione, Bull, 3oc
Chim, France 1962, p. 2182 (
Thurllier, A) (Reference Example 1.2).

60% sodium hydride 40% in 500 mN of anhydrous heinine
g (1.0 mol) and 88.2 g of t-amyl alcohol, making sure that the internal temperature does not exceed 60'C.
(1.0 mol) was added dropwise.

After the dropwise addition, the mixture was heated and stirred under reflux for 2 hours and left at room temperature overnight. While keeping the internal temperature below 10°C, add acetone 29
g (0,5 mol) and carbon disulfide 38.1 g (0,
5 mol) mixture was added dropwise. After stirring at room temperature for 5 hours, 141.9 g (1.0 mol) of methyl iodide was added dropwise while stirring while cooling with water. After stirring at room temperature for 3 hours, it was left to stand overnight.

Water was added to the reaction mixture, and the organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and hexane was added to the resulting residue to crystallize it, giving 597 crude crystals.
I got g. Recrystallization from ethanol gave 4,4-di(methylmercapto)-3=buten-2-one as yellow needle-like crystals.

Yield 51.9g (yield 61.4%) Melting point 65~
66.5°C Reference Example 2 5-Methyl-1,2-dithiol-3-Celestial 2 130 g of phosphorus trisulfide in 1.31 xylene (0.58
mol) and suspended under reflux 51.9 g of 4,4-di(methylmercapto)-3-buten-2-one (0,
A solution of 200-related xylene (32 mol) was added dropwise. After heating under reflux for 30 minutes, the reaction mixture was poured into 1.5 J2 diethyl ether. Insoluble matter was filtered off, 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. Silica gel column chromatography (hexane;
Purified with ethyl acetate = 101) to give 5-methyl-1,2
-dithiol-3-thione was obtained as a red oil.

Yield 21.9g (yield 46.0%) NMR (CD
Ch, δp,, ) 7.0 (18, s) 2.54
(3)1. s) Example 14-acetoxymethyl t
-7 methyl ester dimethylformamide 150 4-bromomethylbenzoic acid t-butyl ester (22.7 g <84 mmol) and anhydrous potassium acetate 8.2 g (84 mmol)
was added and stirred at room temperature for 8 hours. After filtering out insoluble matter,
The solvent was distilled off, water was added to the residue, and the product was extracted using ethyl acetate. After drying the organic layer using anhydrous sodium sulfate, the solvent was distilled off to obtain an oil. Purification was performed by silica gel chromatography (solvent: n-hexane:ethyl acetate = 70:1) to obtain the title compound as a colorless oil.

Yield 11.3g (yield 54.0%) Example 24-
Hydroxymethyl tert-butyl ethyl 11.3 g (45 mmol) of the ester produced in Example 1 was dissolved in 2.7 g (low mmol) of sodium hydroxide in a methanol-water mixed solvent (2:1).
After adding 120 mff and stirring for 30 minutes under water cooling, water was added and neutralized using dilute hydrochloric acid. It was extracted with chloroform (twice) and dried with anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound as a colorless oil.

Yield: 7.7 g (yield 97%) 13 g (60 mmol) of pyridinium chlorochromate was suspended in 200 mm of dry dichloromethane, and a dichloromethane solution of 7.7 g (37 mmol) of the ester produced in Example 2 was added dropwise under water cooling. . After stirring for 5 hours at room temperature, it was set up overnight. After filtering off insoluble matter, the solvent was distilled off and chromatographed on silica gel (solvent: n-beef san:
Purification was performed using ethyl acetate (50:1) to obtain the title compound as colorless crystals.

Yield 6.8g (yield 89.0%) Melting point 51-5
3°C N gate R (D?l5O-d δppm) 7.90 (2H
, d, J=8Hz, aromatic proton) 8.16 (2H,
d, J=8Hz, aromatic proton) 10.1<1)1.
s, aldehyde proton) 4- to 120 m of benzene
7.3g t-butoxycarbonylbenzaldehyde
(35.4 mmol) and 12.0 g (39.5 mmol) of formylmethylenetriphenylphosphorane were added, and the mixture was heated under reflux for 16 hours.

The solvent was distilled off, 200% of n-hexane was added to the residue, insoluble matter was filtered off, and n-hexane was distilled off under reduced pressure. Silica gel chromatography (solvent: n-hexane: ethyl acetate-20:
1) to obtain the title compound as colorless crystals.

Yield 5g (yield 60.6%) Melting point 69-71°C NMR (CDCl2.δppn) 6.7 (1B, dd, J=8)1z, 4Hz)7.
5 (IH, d, J = 8Hz) 7.5-7.7 (2Bm) 7.9-8.1 (28m) 9.7 (IH, d, J = 4Hz) 0.8g of metallic magnesium in 50Id of methanol was added and heated under reflux for 1 hour to prepare magnesium methoxide. 4 prepared in Example 4 was added to this methanol solution under water cooling.
-t-butoxycarbonylcinnamaldehyde 4.5g
(19,4 mmol) and 5-methyl-1,2-
Dithiol-3-thione 3.2 g (21.6 mmol)
was added and reacted for 7 hours. The precipitated crystals were collected by filtration, added to 300 ml of benzene, and insoluble matter was removed by filtration. The benzene solution was washed with water and then dried using anhydrous sodium sulfate. After distilling off the benzene, the residue was recrystallized from 15 m of benzene,
The red title compound was obtained.

Yield: 1.3 g (19% yield) Melting point: 183-185°C 0.5 g of ester produced in Example 5 (1,38
0.4 d of 6N sulfuric acid and 3.5 d of dioxane
was added to the mixed solvent, and reacted at 80 to 90'C for 2 hours.

After cooling to room temperature, the precipitated crystals were collected by filtration and washed with dioxane and then water to obtain the red title compound.

Yield 0.4g (yield 94.6%) Melting point 282~
283°C Elemental analysis (C,,H,.0□S3) Calculated value (%)C;54.88)1;3.29S
;31.99 Actual value (%) C;54.6B)1
;3.34S;31.50 Test Example (1) Collagen Arthritis Suppressing Effect The arthritis suppressing effect of Compound 1 was compared with D-penicillamine using a colchicine-loaded collagen-induced arthritis model according to the following method.

Female Lewis rats (7 to 8 weeks) were intraperitoneally administered with 1 μg of colchicine/kg, and then 0.8 d of FIA emulsion containing 1.5 μl of bovine Type II collagen was inoculated intradermally at the base of the dorsal ridge. Compound 1, Compound No. 1
and D-penicillamine were orally administered at the doses shown in Table 1 every other day from day 2 to day 26 after antigen inoculation for a total of 13 times. After antigen inoculation, 8 days (before onset of symptoms), 15.19 and 27
The volume of both hind limbs was measured on a day-to-day basis and used as an index of arthritis.

The onset of arthritis was observed on the gold side 10 to 12 days after antigen inoculation.

As a result of observation for 4 weeks after antigen inoculation in the compound 1 administration group,
Although no suppression of the incidence rate was observed, there was a tendency to suppress hindlimb swelling (Figure 1). After that, rearing was continued, and 800Hz paw volume was measured after antigen inoculation, and a significant (p < o, os) suppression of swelling was observed in the Compound I and Compound No. 1 administration groups compared to the colchicine pretreatment group. It was done. On the other hand, no inhibitory effect was observed in the D-penicillamine administration group. Note that the paw volume of the colchicine non-treated group was significantly reduced compared to the colchicine pretreated group. The above results are shown in Table 1.

Table 1 Inhibition of swelling after antigen (collagen) 1 and 0 days Compound 1 Compound No. 1 * p <0.05 Significant difference with respect to colchicine pretreatment group n = 6 (2) Acute toxicity in elephants and sexual toxicity test mice was investigated using the oral administration method. d
The compound of the present invention was suspended in 0.5% methylcellulose and orally administered to dY mice (male, 7 weeks old) in groups of 5 mice.

The progress was observed for 7 days after administration, and the number of deaths was determined.

Compound 1 caused no deaths when administered at 200 d/kg, and no effect on body weight fluctuation was observed.

Tablets containing the active compound of Formulation Example 10 and having the following composition were prepared by conventional techniques.

Compound 1 10 ■ Milk Il! 78
■ Cornstarch 60 ■ Magnesium stearate 2 ■ [Effects of the invention] As a result of comparing the 1,2-dithiol-3-thione derivative of the present invention with D-penicillamine, which is widely used clinically, in an arthritis model, D- It showed anti-arthritic effects at much lower doses than penicillamine.

The 1,2-dithiol-3-thione derivatives and physiologically acceptable salts thereof of the present invention can be used not only for rheumatoid arthritis but also for autoimmune diseases such as systemic lupus erythematosus, nephritis and multiple sclerosis, and other immediate-onset diseases. It can be widely used in the treatment of delayed-type allergic diseases, malignant tumors, severe infectious diseases, immunodeficiency diseases, immunocompromised diseases, and the like.

[Brief explanation of drawings]

FIG. 1 is a diagram showing the swelling suppression effect after antigen inoculation. Patent applicant: Mitsui Toatsu Chemical Co., Ltd. Figure 1 Suppression of swelling up to 27 days after antigen vaccination ○：Control Antigen vaccination days (days) Hiraitoe Soho Seisho, published by Hat) August 23, 1991

Claims (2)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A 1,2-dithiol-3-thione derivative represented by: (2) An antirheumatic agent containing the 1,2-dithiol-3-thione derivative of claim (1) or a physiologically acceptable salt thereof as an active ingredient.