JPS6222779A - Novel dithiolane derivative and immunological regulator containing said derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (n is 1 or 2; R is H or methyl). EXAMPLE:(E)-3-(1,2-Dithiolan-3-yl)-acrylic acid. USE:An immunological regulator effective for diseases under immunosuppressive conditions, e.g. infectious diseases or cancer, and further for diseases requiring immunological regulation, e.g. various allergies. PREPARATION:2,2-Dimethyl-1,3-dithiane-4-carboxylic acid as a starting raw material is subjected to several steps to give a novel compound expressed by formula 3, which is then reacted with a Witting reagent in a solvent to afford a compound expressed by formula 9 (R3 is lower alkoxy, etc.). The result compound expressed by formula 9 is then hydrolyzed with an acid or alkali in a solvent, e.g. tetrahydrofuran (THF), to give a compound expressed by formula 10, which is then oxidized to afford a compound expressed by formula 11. The resultant compound expressed by formula 11 is dissolved in a solvent and reacted in the presence of an acid catalyst to give the aimed compound expressed by formula 12.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel dithiolane compound having an immunomodulating effect and a novel immunomodulating agent containing the same as an active ingredient.

To explain the above in more detail, the novel dithiolane compounds having immunomodulatory effects referred to in the present invention are the compounds numbered 12,1517.19.21 and 23 among the compounds shown in FIGS. 1 to 3. The immunomodulator of the present invention contains these compounds or physiologically acceptable salts thereof as active ingredients.

FIGS. 1 to 5 are simple illustrations of synthetic routes for obtaining these compounds.

To further explain each of these figures, Compounds 6 and 5 are also new, but they are each derived from Compound 1 through a human process to form Compound 2, and then through Step B or Step C, respectively. In compound 2, R1 represents a lower alkoxy group or a primary or secondary amine group. Compound 5 can also be derived from compound 4 by step D.

Compounds 7 and 8 are also new, but both are more E than compound 4.
After the step F, the product is guided through the G step if necessary. Note that in compound 8, R2 represents a lower alkoxy group.

The above route for obtaining Compound 3.5.7 or 8 will be referred to as Toilet Production Route I, which will be explained later.

The production route (■) shown in FIG. 2 consists of novel compounds 11, 12.
5 or 17, and as shown in the figure, steps H, L, M, and N include steps I1. T.

K are used in combination.

Similarly, production route (2) shown in FIG. 6 starts from new compound 5 to step 0. Novel compound 19. by P, Q, ■, J and K.
This will be explained with an explanation indicating that it leads to 21 or 2.

In general, immunomodulatory effects mean that the immune system functions normally.
It has almost no effect when the immune system is weakened, but when the immune system is weakened, it is strengthened, and when the immune system is hyperactive, it is decreased, correcting abnormalities in the immune system and returning it to its normal state. It is understood as action.

The restoration of immune function may also be caused by a decline in the suppressive mechanism, and on the other hand, the state of decreased immune function may also be caused by the restoration of the suppressive mechanism. It can be said that immunomodulatory action works to correct this.

Many side effects have been reported in treatments using conventional immunomodulators (levamisole, thymus hormone, etc.). For example, nausea, rash, blood disorders, etc. have been reported with levamisole, and the most serious side effect is granulocytopenia, which disappears when treatment is discontinued. must be closely tracked.

For this reason, there is a strong need for new immunomodulators that do not have the severe side effects normally observed in known immunomodulators.

In recent years, by restoring immune function that has been suppressed due to various causes, restoring normal immune function, and further strengthening and maintaining normal immune function, it is possible to prevent in-vivo infection and proliferation of pathogenic parasites such as viruses and bacteria. The importance of immunomodulators that increase resistance to the growth of xenobiotics such as cancer is increasing significantly. Such drugs are also desired to be applied to diseases such as various allergies and rheumatoid arthritis.

The present inventors searched for various immunomodulators to be used for this purpose and found that lipoic acid (thioctic acid DL form), which is widely used in the treatment of liver diseases, has excellent immunomodulatory effects. (Pharmaceutical Society of Japan, 104th Annual Pension, Collection of Lecture Abstracts 1984, p. 697, Yamamoto).

As a result of further intensive studies, we arrived at the present invention and found that the compound of the present invention represented by the general formula (1) (in which n is 1 or 2 and R is a hydrogen atom or a methyl group) is surprisingly useful. In particular, it is highly safe and lipoic acid (thioctic acid DL form)
discovered that it has an excellent immunomodulatory effect that exceeds that of
This has led to the completion of the present invention.

A specific example of the compound represented by the general formula (1) is (E
)-3-(1,2-dithioran-3-yl)-acrylic acid [Figure 2 or 3 Compound 12 (the same applies hereinafter)] (2E, 1
)-3-Methyl-5-(1,2-dithiolan-3-yl)2,4-pentadienoic acid [Compound 15] (E)-3-
Methyl-5-(1,2-dithiolan-ro-yl)-acrylic acid [Compound 19] (2F,4F)-5-(1,2-dithiolan-3-yl)-2,4-pentadienoic acid [Compound 19] 'v! J17〕(2
F,4E)-5-(1,2-dithiolan-3-yl)-
2,4-hexadienoic acid [Compound 21] (2E, 4F)
-5-(1,2-dithiolan-3-yl)-3-methyl-2,4-hexadienoic acid [Compound 23] is mentioned.

Physiologically acceptable salts of these compounds are also included within the scope of the present invention. Such salts include alkali metal salts such as lithium salts, sodium salts, potassium salts, etc., alkaline earth metal salts such as calcium salts, magnesium salts, etc., lysine salts, arginine salts, ornithine salts, etc. Amino acid salts, preferably basic amino acid salts, common organic base salts such as triethylamine salts, benzylamine salts, prolactin salts, etc. can be mentioned.

The compounds of the present invention can be produced by the production routes 1, IT, and II shown in Section. The method will be explained below.

2,2-dimethyl-1, which is the starting material for the compound of the present invention,
3-Dithian-4-carboxylic acid [Compound 1] was prepared from γ-butyrolactone by a known method (JuStuSLi-ebi
gs Annalen der Chemie Bd,
666, 1965.

p. 201, Ulrich Schmidt et al.).

In addition, a cyclic 1,3-dithiane compound (compound C in reaction formula I below) such as compound 1 or compound 4 is generally prepared by combining 1,3-dithiol (compound A in reaction formula I) with an aliphatic aldehyde or an aromatic aldehyde, preferably an aliphatic aldehyde or an aromatic aldehyde. Cyclic 1,3-dithiane (compound C of reaction formula 1) produced from an aliphatic ketone or aromatic ketone (compound B of reaction formula 1) by the reaction of reaction formula 1 in the presence of an acid catalyst and substituted with an aldehyde or ketone residue
).

(In the formula, X represents hydrogen or a carboxyl group, and Y and Z represent aldehyde or ketone residues.) The aldehyde or ketone used in reaction formula 1 is 1.3-
It is used to protect the two thiol groups of dithiol (compound A), and as shown in the following reaction formula (2), after going through an oxidation step, a small ring step is performed to form the general formula (
It is used as a protecting group to obtain the 1,2-dithiolane compound shown in 1).

(In the formula, YX Z represents an aldehyde or ketone residue) By the reaction of reaction formula , aliphatic and aromatic aldehydes such as acetaldehyde and benzaldehyde, and aliphatic and aromatic ketones such as acetone, methyl ethyl ketone, acetophenone, and benzophenone.The compounds used as these protecting groups are represented by the reaction formula (2). It is preferably an aldehyde or ketone that can be easily separated from the compound of the present invention represented by the general formula (1) since it is a by-product in a ring step.

With this in mind, the present inventors have conducted intensive studies on various aldehydes or ketones, and have found that they can be used industrially in large quantities and at low cost, are less dangerous to the human body, and are expressed by the general formula (1). It has been found that acetone is the most preferable compound B used in Reaction Scheme I among easily separable compounds of the present invention.

In Figure 1, Compound 3 can be produced from Compound 1 produced using acetone as a protecting group via Steps A and B, Compound 5 can be produced via Steps A and C, and Compound 4 can be produced via Steps E and F. Compounds 7 are all new compounds, and are extremely useful intermediates for producing the compound of the present invention represented by general formula (I).

Next, the dithiolane compound 12,15.17゜19 of the present invention, which is represented by the general formula (I) and is a cyclic disulfide compound.
．． The manufacturing method of Nos. 21 and 23 will be explained.

Generally, when producing a disulfide compound, the desired compound is obtained by oxidizing two thiol groups using various oxidizing agents. However, if a compound having a thiol group has a double bond in its molecule that is highly reactive with a thiol group, such as a double bond in an α,β-unsaturated carbonyl group, the disulfide The production of the compound involves an inter- or intramolecular addition reaction of a thiol group to a double bond as a side reaction. Furthermore, depending on the oxidizing agent used, not only the formation of disulfide bonds but also the oxidation reaction of double bonds occur due to side reactions, making it extremely difficult to obtain only the desired disulfide compound.

Therefore, the compound of the present invention represented by the general formula (I), that is, an intramolecular cyclic disulfide compound having a highly reactive double bond in the molecule, can be prepared by the method via the oxidation reaction of two free thiol groups. It is a compound that cannot be obtained by any means.

The present invention was accomplished by inventing a new method for producing an intramolecular cyclic disulfide compound without using two thiol groups.

That is, after subjecting a 1,3-dithiane compound having an unsaturated fatty acid as a substituent to an oxidation step, a 1,2-dithiolane compound, which is an intramolecular disulfide compound, can be produced in high yield through a small ring step. It is.

Next, the manufacturing routes T, I, (2) and the steps H to Q shown in FIGS. 1 to 6 will be specifically explained.

Production route 1 A step; R1 of compound 2 represents a lower alkoxy group or an amine group and a substituted amine. If it is an ester, it can be produced by reacting Compound 1 with a lower alcohol (methanol, ethanol, etc.) in the presence of an acid catalyst (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid) at a temperature in the range of 0° to 100°C. When R is an amide, a reactive derivative of compound 1 (acid chloride, mixed acid anhydride, etc.), a primary amine, preferably a secondary amine, and an organic solvent, i.e., an aliphatic or aromatic hydrocarbon, a halogenated It can be produced by reacting in a solvent such as a hydrocarbon or ether at a temperature of -10°C to 20°C.

Step B: Compound 2 (ester or amide) produced in Step A is added to an equimolar amount or a small amount in an organic solvent such as an aliphatic or aromatic hydrocarbon or ether, preferably a solvent such as hexane, toluene, or tetrahydrofuran. 4-formyl-2,2-dimethyl-1,3, which is an intermediate for producing the compound of the present invention represented by general formula m, by reducing with excess diisobutylaluminum hydride in the range of -78° to 50°. -dithiane (compound 3
) can be manufactured.

Step C: Compound 2 (amide) produced in Step A is heated in an organic solvent such as ether, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc., preferably in the range of -78° to 50°. 178
4-acetyl-2,2-dimethyl-1,3-dithiane (compound 5 ) can be produced. This compound 5 can also be produced by Step D as follows.

Step D: Compound 4 (2,2
-dimethyl-1,3-dithiane) is added to 1,3-propanedithiol in the presence of an acid catalyst in an organic solvent, such as an aliphatic or aromatic hydrocarbon, a hydrogenated hydrocarbon, or an ether, preferably hexane. Specifically, it can be produced by reacting acetone in a solvent such as benzene, dichloromethane, or tetrahydrofuran in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or boron trifluoride diethyl ether. It can also be produced under conditions using acetone as a solvent.

Compound 4 (2,2-dimethyl-1,3-dithiane) thus produced was treated with an aliphatic hydrocarbon, in a solvent such as ether, preferably in a solvent such as hexane or tetrahydrofuran ethyl ether at -78°-50 4-acetyl-2,2-dimethyl- 1,3-dithiane (compound 5) can be produced.

Step E; 2,2-dimethyl-1,3-dithiane (compound 4) is dissolved in 5-10 times the amount of methanol or ethanol, and the temperature is in the range of 0° to 50°, preferably in the range of 5° to 15°. and an oxidizing agent (e.g. sulfur metaperiodic acid,
(e.g., methachloroperbenzoic acid, hydrogen peroxide, etc.)
By oxidizing using 15 times the molar amount, 2,2-dimethyl-1,3=dithiane-1-oxide (compound 6) can be produced.

FT process: 2,2-dimethyl-1,3-dithiane-1-oxide (compound 6) is mixed with an aliphatic or aromatic hydrocarbon, a solvent such as ether, preferably diethyl ether, tetrahydrofuran, 1,2-simethoxy Dissolved in a solvent such as ethane at a temperature of -78° to 30°, preferably -78°.
It can be produced by reacting an acetate, preferably ethyl acetate, in the presence of a base such as potassium t-butoxy, lithium butyl lithium, lithium diisopropylamide, or sodium hydride in the range of 8° to 0°.

Step G: The acetyl compound (compound 7) produced in Step F is treated with alcohols, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ethers, etc.
Wittig reagent (
Compound 8 can be produced by reacting with phosphoranes (phosphoranes, phosphonic acid derivatives). 0 to 1 for phosphoranes
At 50°C, preferably in the range of 10 to 120°, equi-E/l/ to 10 times the mole relative to the acetyl form (compound 7),
Preferably, it can be produced by reacting equimolar to 3 times the molar amount. In the case of phosphonic acid derivatives, -78 to 100'
C, preferably in the presence of a base (e.g. t-butoxypotassium, sodium methoxide, lithium diisopropylamide, sodium hydride, etc.) at -20 to 30°C, equimolar to the acetyl form (compound 7). It is a novel compound that becomes an intermediate for the compound of the present invention by acting on a 10-fold mole, preferably an equimolar to 6-fold mole.
(E) -3-methyl-3-(2,2-dimethyl-1,
6-cythian-1-oxide-6-yl)-acrylic acid ethyl ester (compound 8) can be produced. R2 represents a lower alkyl (methyl, ethyl, t-butyl, etc.) group.

Production route ■ H step; 4-formyl-2,2-dimethyl = 1.6
- dithiane (compound 3) as an aliphatic or aromatic hydrocarbon,
Wittig reagents (e.g. phospholanes, phosphonates) in step G in a solvent such as a halogenated hydrocarbon, ether or alcohol, preferably benzene, toluene, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. Compound 9 can be produced by reacting under similar conditions. R in compound 9
3 is a lower alkoxy group or a -grade amino group, preferably 2
represents a class amine group.

Step (2) Compound 9 is subjected to acid hydrolysis (e.g., hydrochloric acid, sulfuric acid, etc.) or alkaline hydrolysis (e.g., thorium hydroxide, potassium hydroxide, ammonium hydroxide, etc.) (E) −
5-(2,2-dimethyl-1,6-cythian-4-yl)acrylic acid (compound 10) can be produced.

J step s (''') 3 (2,2-dimethyl-1,3-dithian-4-yl)acrylic acid (compound 1
S-
An oxide compound (compound 11) can be produced.

In the present invention, the oxidized product can generally be used in the next step without purification.

K step; converting compound 11 to an aliphatic or aromatic hydrocarbon,
Solvents such as halogenated hydrocarbons, esters, and ethers,
It is preferably dissolved in benzene, toluene, dichloromethane, ethyl acetate, tetrahydrofuran, dioxane, isopropyl ether, etc., and heated at 0° to 150°, preferably 30° to 100°, in the presence of an acid catalyst (e.g., hydrochloric acid, sulfuric acid, perchloric acid, etc.). By reacting with a mineral acid or an aqueous solution thereof and an organic acid such as acetic acid, methanesulfonic acid, para-toluenesulfonic acid, etc. for 1 to 24 hours, preferably 2 to 5 hours, ring reduction occurs. Invention compound (E) -
3-(1,2-dithiolan-6-yl)acrylic acid (compound 12) can be produced in good yield.

Step L: Compound 3 is treated with a Wittig reagent, e.g. dimethyl-(2-oxo-propyl), under the same conditions as Step G.
- Phosphonone-1, acetylmethylenetriphenylphosphorane, etc., can be used to create a new substance (
E) -4-(2,2-dimethyl-1,3-dithiane-
4-yl)-6-puten-2-one (compound 13) can be produced.

Step M: Compound 13 is treated with a Wittig reagent, such as t-butyl diethylphosphonoacetate, under the same conditions as in Step G.
By reacting with ethyl diethylphosphonoacetate or the like, a novel 4=compound 14) can be produced. R4 represents a lower alkyl group (eg, methyl, ethyl, t-butyl group, etc.). I and J described above from this compound 14.

The compound of the present invention (2E
, 4E) -5-(1,2-dithiolan-6-yl)-
3-Methyl-2,4-pencudienoic acid (compound 15) can be produced.

N step; 4-formyl-2,2-dimethyl-1
, 3-dithiane (compound 5) under the same conditions as in step G with a Wittig reagent, such as ethyl γ-diethylphosphorotonate or t-butyl ester, to form a new compound 16 as a cis-trans mixture. It can be manufactured as R5 represents a lower alkyl group (eg, methyl, ethyl, t-butyl group, etc.). This compound 1
6 is the compound of the present invention (2E, 4F)-5-(1,2-dithiolan-3-yl)-2,4-pentadienoic acid (compound 1
7) can be manufactured. Production route ■ 0 step; 4-acetyl-2,2-dimethyl-1,3
- Dithiane (compound 5) was treated with a Wittig reagent, such as ethyl diethylphosphonoacetate or t
- Compound 1 can be obtained by reacting with butyl ester, etc.
8 can be manufactured.

R6 represents a lower alkyl group (methyl, ethyl, t-butyl group, etc.). From the present compound, the present compound (E)-3 was obtained by the same treatment in the same order as the steps 1, J, and 2 described above.
-(1,2-dithiolan-6-yl)-3-methyl-acrylic acid (compound 19) can be produced.

The compound of the present invention (compound 19) can also be obtained from compound 18 by the same treatment in the order of J step (oxidation step) K step (ring wire reduction step) without hydrolyzing the ester □.
can be manufactured.

P step; 4-acetyl-2,2-dimethyl-1,3
Compound 20 can be produced by reacting -dithiane (compound 5) with a Wittig reagent, such as ethyl γ-diethylphosphonocrotonate or t-butyl ester, under the same conditions as in Step G. R7 represents a lower alkyl group (methyl, ethyl, t-butyl group, etc.). This compound 2o
Then, by performing the same processing in the order of steps 1, J, and 2, genuine 2
1) can be manufactured.

Q step; 4-acetyl-2,2-dimethyl-1,6
-dithiane (compound 5) under similar conditions as in step G with Wittig's reagent, e.g. 4-diethylphosphono-6-methyl-
Compound (22) can be produced by reacting 2-butenoic acid t-butyl ester. R8 represents a lower alkyl group (methyl, ethyl, t-butyl group, etc.). From this compound 22, the compound of the present invention (2E, 4F)-5-(1,2-dithiolan-ro-yl)-6-methyl-2,4- was obtained by performing the same treatment in the order of steps ①, J, and . Example 1
4=(N-phenyl-N-methylcarbamoyl)-2
, 2-dimethyl-1,3-dithiane (Compound 2) production (Example of Step A) 2.2-Dimethyl-1,3-dithiane-4-carboxylic acid (Compound 1) 3.5.9 (18, 2 mmol) was dissolved in voml of anhydrous monoisolated methylene, 4.13.9 (20 mmol) of dicyclohexylcarbodiimide was added, stirred for 5 minutes under water cooling, and then 2.14 g of N-methylaniline was added.
(2o milJ mol) was added and stirred at room temperature for 5 hours. Insoluble matter was removed, and the P solution was washed with dilute hydrochloric acid and then dilute aqueous sodium bicarbonate solution, the solvent was distilled off, and the residue was chromatographed on silica gel (solvent: chloroform:methanol-50:1).
The target product (compound 2) was purified by 3.2 g (6
2%) was obtained as crystals. Melting point: 87-89°C (recrystallized from hexane) NMR (100MHz, CDC13) 699m
: 7.2-7.5 (5H, m) 3.6-3.8 (
IT (, m), 3.26 (3H, s), 2.7-2.9
(2H, m), 1.8-2.4 (2H, m) Experimental example 2
4-formyl-2,2-dimethyl-1,3 (11,4 mmol) in 20 ml of tetrahydrofuran! The solution was cooled to -78°C with dry ice-acetone under a nitrogen stream, and 7.5ml (11.4 mmol) of a 1.54M diisobutylaluminum hydride toluene solution was added to -78°C.
Stir at 8°C for 15 hours.

Next, the reaction solution was added to 50ml of 5% hydrochloric acid, stirred for 15 minutes, extracted with ethyl ether, washed with a saturated aqueous solution of 1-lium chloride, and dried. After distilling off the solvent, the residue was purified by silica gel chromatography (solvent: chloroform) to obtain 1.65y (s2%) of the target product (compound 3) as a colorless oil.

NMR (100MHz, CDC15) δpI)m
: 9.6 (IJs).

5.62 (I H, ad, J = 4Hz, 6Hz)
, 2.6-3.2 (2H.

m), 2.1-2.4 (2H, m), 1.69 (3H
,s), 1.66(5H,s) Experimental example 4-(pyrrolidinocarbamoyl)-2,2
-Dimethyl-1,3-dithiane (Example of Step A) 2.2-
2 g of pyrrolidine in dimethyl-1,3-dithiane-4-carboxylic acid ethyl ester 44II (20-, lJ mol)
・(28 mmol) was added and heated at 70° C. for 10 hours. After cooling, it was dissolved in ethyl ether, washed with dilute hydrochloric acid and dilute aqueous alkaline solution, the solvent was distilled off, and purified by silica gel chromatography (solvent: chloroform:methanol - 50:1) to obtain the desired product (32165%) as crystals. Ta.

Melting point: 72°-74°G.

NMR (100MHz, CDC13) δT)T)m:
3.6-3.9 (2H, m) 3.5-36 (3H, m
); 2.9-3.1 (2H, m), 1.8=2.3
(6I(,m), 1.83(3H,s), 165(!+
H, s) From this compound, by the same treatment as in Example 2,
4-formyl-2,2-dimethyl-1,3-dithiane (
Compound 6) can be obtained.

Experimental example 4 4-formyl-2,2-dimethyl-1,3-
Dithiane (Compound 3) (Example of Step B) 2.2-dimethyl-1,3-dithiane-4-carboxylic acid ethyl ester 1
1.9 (50 mmol) in 40 ml of toluene solution,
Cool to -78°C under a nitrogen stream, add 1.56M diisobutylaluminum hydride toluene solution at 35 mA (54 mI
J mol) was added dropwise.

After reacting at -78°G for 1 hour, the mixture was poured into 100 ml of 5% hydrochloric acid and allowed to stand at room temperature for 50 minutes. The organic layer was separated, the solvent was distilled off, and the target product (compound 3) was purified by silica gel column chromatography (solvent: chloroform)5. y (57%)
was obtained as a colorless oil.

Experimental example 5 4-acetyl-2,2-dimethyl-1,32
1oom11 of 8,1# (0,1 mol)! The tetrahydrofuran solution was cooled to -78°C and diluted with 15M under nitrogen stream.
132 ml (0.2 mol) of methyllithium ethyl ether solution was added and stirred for 2 hours. The reaction solution was poured into water-cooled diluted hydrochloric acid, the organic layer was separated, washed with water, dried, concentrated, and subjected to silica gel column chromatography (solvent: hexane: ethyl acetate-1).
0:1) to obtain 15 g (79
%) was obtained as a colorless oil.

NMR (ID DMHZ, CD (J3) 699
m: 3.55 (IH, t, J=5T(z), 2.
5-3.2 (2H, m), 2.23 (3H, s) 1.9
-2.2 (2H, m), 168 (3H, s), 162 (
'3H,s) The compound obtained in Example 5 is as follows in Example 6.
It can also be obtained by

Experimental example 6 4-acetyl-2,2-dimethyl-1,6-
Dithiane (Compound 5) (Example of Step D) 2,2-dimethyl-1,6-dithiane (Compound 4) 1,48.9 (10
1. mmol) in 10 ml of tetrahydrofuran solution under ice cooling. <5M7L-butyllithium hexane solution 13.5
mA! (20 mmol) was added and left overnight at room temperature under a nitrogen stream. After cooling to -78°C, 4 ml (43 mmol) of dry N,N dimethylacetamide was added at once, and the mixture was gradually warmed to room temperature over 2 hours. Pour into 50ml of saturated ammonium chloride aqueous solution, separate the organic layer,
The product was purified by silica gel column chromatography (solvent: hexane:ethyl acetate-20=1), and 05 g of starting dithiane was recovered to obtain 1.29 (63%) of the target compound (compound 5) as a colorless oil.

Experimental Example 7 2,2-dimethyl-1,3-dithiane-1-
Oxide (Compound 6) (Example of Step E) 2.2-dimethyl-1,3-dithiane (Compound 4) isy (o, i mol)
was dissolved in 750 ml of methanol, and while keeping the reaction temperature at 20°C, 22.5.9 (0
, 1 mol) was added dropwise over 15 minutes. After the addition, the mixture was vigorously stirred at the same temperature for 30 minutes. After removing the insoluble matter, the mother liquor was concentrated under reduced pressure, extracted using chloroform, the organic layer was dried over magnesium sulfate, and purified by silica gel column chromatography (solvent: ethyl acetate) to obtain compound 6 as a colorless oil. .6.9 (89%) was obtained.

NMR (100M)TZ, CDCl5)δT)T)
m: 1.54 (3H, s).

1.62 (5H, s), 1.9-3.1 (6H, m)
Experimental example 8 6-acetyl-2,2-dimethyl-1,3-
Dithiane-1-oxide (Compound 7) (Example of Step F) 7.5 ml (52.8 mmol) of diisopropylamine was added to 60 ml of dry tetrahydrofuran, and the mixture was cooled to -20° C. using a dry ice-acetone bath. 1 for this
．． 6M 7L-butyllithium hexane solution 30ml
(48 mmol) was added and stirred at the same temperature for 40 minutes.

Next, the mixture was cooled to -78 DEG C., and a solution of 2,2-dimethyl-1,3-dithiane-1-oxide 7,9,li' (48 mmol) in 20 ml of tetrahydrofuran was added at the same temperature. After stirring for 1 hour, add 24 ml of dry ethyl acetate (24
1 mol of Mi) was added thereto, and the mixture was further stirred at the same temperature for 15 hours. Next, 2.8 ml (49: IJ mol) of acetic acid was added, and after the temperature was returned to room temperature, the insoluble matter was removed with F, the solvent was distilled off, and the mixture was purified by silica gel column chromatography (solvent: n-hexane, ethyl acetate = 2:1). Purify and obtain the desired product (compound 7) 3.8
19 was obtained as a colorless oil.

NMR (100MHz, CDC13) δppm:
1.55 (3H, s).

1.68 (3H, s), 2.36 (roH, s), 2.1
-2.5 (2H, m) 2.6-3.0 (2H, m)
, 3.5-5-37 (1H2 Experimental Example 9 (E)-
3-Methyl-3-(2,2-dimethyl-1,ro-dithian-1-oxide-6-yl)acrylic acid ethyl ester (Compound 8) (Example of Step G) To 730 ml of dry 1,2-dimethoxyetha 6096 Sodium hydride 0.5619 (14.1 mmol) = 29
- Add ethyl diethylphosphonoacetate to this 3.
A solution of 1511 (14.1 mmol) in 1 oml of 1,2-dimeteitokiethane was added dropwise under ice cooling. After stirring at room temperature for 30 minutes, the S-
Oxide (compound 7) 2.9# (14.1 mmol) of 1,2-dine 162F15 was added dropwise and stirred at room temperature for 6 hours. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to precipitate crystals.

This was washed with hexane, and the target product (compound 8
) 1. 519 (33.6%) is obtained as colorless crystals.

Melting point 170-171℃ Elemental analysis value (C12 H2O o, s2) Calculated value (@
C 52.13 H 7.31 S
23.19 Analysis value (%) C 51.77 H 7
．． 48 S 2!1.05NMR (100MH
z, CDC13) δppm: 1.2B (3H, t, J=
8Hz) 160 (3H, s), 1.7 (3H, s),
2.34 (3H, s).

2, 2-2.6 (2H, m), 2.7-3.08 (IH
, m), 4.14 (2H, q, J-8Hz), 5.9
4(IH,s), 3.1-3.32(IH,m) Reference Example 1 Ethoxycarbonylmethylenetriphenylphosphorane (manufacture of Wittig reagent used in step H) Triphenylphosphine 524g benzene 200ml
334 g of ethyl bromoacetate was added dropwise to the solution, and the mixture was stirred at room temperature for 6 hours. The precipitated phosphonium salt was collected in an oven and dried. This was added to 1.5 A' of water, and a dilute aqueous potassium hydroxide solution was added until the coexisting phenolphthalein turned red. The mixture was vigorously stirred for 1 hour, and the precipitate was collected, thoroughly washed with water, and dried to obtain the desired product 52111 (75%). Melting point 124-126°C (recrystallized from ethyl acetate) Experimental example 10 (E) -3-(2,2-dimethyl-1
,3-dithian-4-yl)ethyl acrylate (compound 9) (Example of step H) 4-formyl-2,2-dimethyl-1,3-dithiane 0
．． Phosphorane 2.08.9 (6 mmol) synthesized in Reference Example 1 was added to a solution of 88 g (5 mmol) in 10 ml of benzene, stirred at room temperature for 1 hour, and then refluxed for 8 hours. After concentration under reduced pressure, the residue was purified by silica gel color chromatography (solvent: hexane: ethyl acetate = 10:1) to obtain 0.95.9 (77%) of the target product (compound 9) as a colorless oil.

NMR (100MHz, CDCl4B) δppm
:6.82 (IH, dd, J=16Hz, I!5H2)
, 5.95 (IH, d, J = 16Hz), 4.18 (
2H, q, J=6Hz), 3.6-3.9 (IH, m
), 2.6-3.2 (3H, m), 2.1-2.4
(IH, m), 1.84 (3H, s).

1, /12 (3H, m), 1.30 (3H, t, J=
6Hz) Experimental Example 11 (E) -3-(2,2-dimethyl-1,3-dithian-4-yl)acrylic acid (compound 10) was dissolved in 40ml of dioxane, and 6N
Sulfuric acid2. s ml was added and heated at 1.90'C for 6 hours. The reaction solution was poured into water, extracted with ethyl acetate, the solvent was distilled off, and purified by silica gel column chromatography (solvent: dichloromethane-ethyl acetate mixed solvent) to obtain 159 g (77%) of the target product (compound io). was obtained as an oil.

NMR (100MH2, CDC13) δppm: 16
2 (3H, s, CH3) 1.84 (3H, s, CH3)
, 2.1-2.4 (IH, m), 26-3.3 (3H,
m), 3.7 4.0 (IH, m), 5.96 (IH,
d.

J=16Hz), 6.93(IH, aa, J=16.7
Hz), 10.6 (iH, bs) Experimental Example 12 (E) -3-(2,2-dimethyl-1
,3-dithian-4-yl)acrylic acid-1-oxy21
229 mol) was dissolved in 15 mA' of methanol, a catalytic amount of sodium tungstate was added, and 1 ml of 28-hydrogen peroxide was added dropwise while cooling with water. - After leaving at room temperature overnight, H2
O was added, extracted using ethyl acetate, and the solvent was distilled off.
0.8 g of crude crystals (47.5% dithiane-8-oxide) were obtained. This compound was used in the next reaction without purification.

Experimental Example 13 (E)-3-(1,2-dithiolane-6
-yl)acrylic acid (Compound 12) (Example of K step) 4g of the carboxylic acid synthesized in Example 12 was added to 50% of dioxane.
2 ml of 6N sulfuric acid was added thereto, and the mixture was heated at 95° C. for 15 hours. After cooling, 50 rnl of ethyl acetate was added, washed with water and a saturated chloride solution, dried over anhydrous sodium sulfate, and concentrated to 10 ml. After purification and separation using short silica gel chromatography (solvent: ethyl acetate), the product was crystallized from ethyl ether-hexane to obtain 2ig (76%) of the desired product (compound 12) as pale yellow crystals.

Melting point 96-97°C NMR (100MHz, CDCJ3) δppm: 1
0.5 (IH, b, S) 7.0 (IH, dd, J=16
．． 9Hz), 5.98 (IH, d, J=16Hz), 4
．． 25 (IH, m), 3.0-3.4 (2H, m).

2.6 (IH, m), 2.16 (IH, m) Experimental example 14
(E)-4-(2,2-dimethyl-1,3-dithian-4-yl)-3-buten-2-one (compound 13)
(Example of L process) a) 60% purity sodium hydride 3.22 & (8
0.5 mmol) in anhydrous tetrahydrofuran (5 oorn)
A solution of dimethyl-(2-oquin-propyl)-phosphonate 14.119 (81 mmol) in 1 DO ml of methyl-1,3
- A solution of 11.8 g (67 mmol) of dithiane in 100 ml of tetrahydrofuran is added dropwise and stirred for 6 hours. The reaction mixture is poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (solvent: hexane: ethyl acetate - 9:1) to obtain the desired product (compound 13) as an oily substance. .5 f9 (82,9 section) obtained.

NMR (100MHz, CDCl5) δrlTl
1m: 662 (IH, dd, J=15Hz, 7Hz
), 6.15 (IH, d, J=15Hz)', 3.80
(1H, m), 240-332 (4H, m), 2.25
(IH, s) 1.82 (IH, s), 1.6'1 (IH
,5)b) 4-formyl-2,2-dimethyl-1,
A solution of 8.4 g (47 mmol) of 3-dithiane and 17.0 g (53 mmol) of cetylmethylenetriphenylphosphorane in 8'Oml of benzene is stirred under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (solvent: -xane:ethyl acetate-9,1) to obtain 4,89 (49,8) of the target product (compound 13).

Experimental example 154- (4-t-butoxycarbonyl-3
-Methyl-1,3-butadienyl)-2,2-dimethyl-1,3-dithiane (Compound 14) (Example of Step M) 60% thorium hydride 0.8B,! i' (22 mmol) was suspended in 50 ml of anhydrous tetrahydrofuran, and diethylphosphonoacetic acid t-butyl ester 66 was added under water cooling.
7 g (26 mmol) was added dropwise. After making a homogeneous solution, it was cooled to -20 °C and transferred to the workplace in 4.8.9 of Compound 16 prepared in Example 14 ('23
A solution of 10 ml of tetrahydrofuran (mmol) in tetrahydrofuran was added dropwise thereto, and the mixture was stirred at the same temperature for 60 minutes and then for 2 hours while cooling with water. The reaction mixture was poured into dilute hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent, silica gel column chromatography (solvent; hexane:
3.1. Purify with ethyl acetate-1'o:1) to obtain the target product (compound 14) as colorless crystals. ! F (44%) was obtained.

Melting point 3B-40°C NMR (100MHz, CDCl)s) δppm
: 660(1i(', t), 5.88(IH,
'd), 5.62 (IH, s), 50 (IH, m),
2.4-3.2'(3'H, m), 2.14 (
RoH,s),'1.88-2.0(1)1. m) 1.7
8 (3H, s), 1.48 (12H) Experimental example 17S
(2E,4E)-5-(1,2-dithiolan-3-yl)-2,4-pencudienoic acid (compound 17) (N
, I, J, example of each step)'4-formyl-2,2-
Dimethyl-1,ro-dithiane (compound 5) 791! (4
A 20 ml tetrahydrofuran solution containing 12.5 g (50 mmol) of ethyl γ-diethylphosphonocrotonate and 12.5 g (50 mmol) of ethyl γ-diethylphosphonocrotonate was added dropwise to a 4 Bml tetrahydrofuran solution containing 2 g ('sc + mmol) of sodium 60 thihydride under water cooling, and the mixture was stirred for 2 hours. . Add 100 mJ of water, extract with ethyl acetate, distill off the solvent, and purify with silica gel column chromatography (hexane/acetic acid 10:1).
)6. '9 g' (56%) was obtained as an oil (cis-trans mixture).

6 g of this compound was dissolved in 40 ml of dioxane, 5 ml of 6N sulfuric acid was added, and the mixture was stirred at 90-100°G for 15 hours for hydrolysis.

Add 100 m/+ of water, extract with ethyl acetate, distill off the solvent, and purify with silica gel column chromatography (solvent: ethyl hexane diacetate = 4:'1).
Obtained 59 (65%) as an oil.

Obtained carboxylic acid (cis-trans mixture) 3, 4
Ioomg of sodium tungstate was added to a 4Bm, 1 methanol solution of g (1' 4 mmol), and 28q6 hydrogen peroxide solution 1.7 F (14 mmol) was added under water cooling, followed by stirring for 30 minutes. After concentrating this product under reduced pressure, it was purified by silica gel column chromatography (solvent: chloroform:methanol-21): 8-oxide 3.0
．． 9 (83%).

Next, 390 g of this S-oxide was dissolved in 40 ml of dioxane, 2 ml of 6N sulfuric acid was added, and the mixture was stirred at 70° C. for 15 hours. 50 ml of water was added, extracted with ethyl acetate, dried and concentrated to about 10 ml. This product was then subjected to silica gel column chromatography (solvent: hexane, ethyl acetate - 1:1).
) and crystallized using ethyl ether-hexane to obtain yellow crystals 052II (section 22). NMR analysis revealed that the product was only trans and trans isomers.

Melting point 140-142°C NMR (100MHz, CD (J3 + DMSO) δpp
m: 12.6 (IH.

bs), 7.16 (IH, dd, J=16.10Hz)
, 6.30 (IH, dd, J=16.11)Hz),
6.1 (IH, dd, J=16.10Hz), 5.7
8 (IH, d, J = 14Hz), 4.28 (IH, dd
, J=16.8Hz), Ro-34(2H,m)+2.
3-2.7 (IH, m), 1.9-2.3 (IH, m)
Experimental Example 17 (E)-3-Methyl-ro-(2,2-dimethyl-1,3-dithian-4-yl) t-butyl acrylate (Compound i 5) (Example of step o) Purity 60% 9.9.9 (0.25 mol) of sodium hydride was suspended in 500 ml of anhydrous tetrahydrofuran, and while stirring under water cooling, diethylphosphonoacetic acid was prepared using 4-acetyl-2,2-dimethyl-1 synthesized in Example 5. ,6-dithiane 47.3 g (0
, 25 mol) in 100 ml of tetrahydrofuran is added dropwise. After stirring for 1 hour at the same temperature and then 1 hour under cooling with water, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate.

The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (solvent: ethyl hexanediacetate-10:
Purify according to 1). An oily mixture of the E form and the two forms was obtained, but only the E form was crystallized by rubbing the wall of the container with a spatula, yielding 39.1 g (546%) of the desired product as colorless needle crystals. Melting point 3B-40℃ NMR (100MHz, CDCl3) δ1) pm
: 5.79 (1H, s).

360 (IH, dd, J=2.5Hz, -10Hz),
263.5 (2H, m), 2-20 (3H, s), 1.
95-2.2 (2H, m) 1.85 (3H, s), 1.
65 (3H, s), 1.48 (9H, s) Experimental Example 18 (
E) -3-Methyl-3-(1,2-dithiolan-6-yl)acrylic acid (compound 19) 781 g (0.27 mol) of t-butyl ester obtained in Experimental Example 17 in dioxane 50
6N sulfuric acid in 0ml solution! Add 14.5 ml and heat to 90℃
Stir for 5 hours.

The solvent is distilled off under reduced pressure, and when the amount of the solvent is reduced to about one-fourth, water is added, and the precipitated crystals are separated and washed with water. After drying, 587 g of (E)-3-methyl-3-(2,2-dimethyl-1,3-dithian-4-yl)acrylic acid was obtained as colorless crystals by NMR (100 MHz, CDC).
l! 3) δI) 1) m: 10.4 (IH, bs)
.

5.96 (IH, s), 361 (IH, dd, J=
12Hz, 25Hz) 2.23 (3H, s), 1.8
4 (5H, s), 1.61 (3H, s).

16-3.4 (4H, m) 110 g of sodium tungstate is added to a solution of 58.7 g (0.25 mol) of this carboxylic acid in 500 ml of methanol.
Add 28% hydrogen peroxide solution 30.5.9 while cooling with water and stirring.
(0.27 mol) was added dropwise and stirred at the same temperature for 30 minutes.

The precipitated crystals were collected and washed with water to obtain 400 g (608%) of (E)-3-methyl-3-(2,2-dimethyl-1,3-dithian-1-oxide-4-yl)acrylic acid. was obtained as a colorless powder.

To a solution of S-oxide 15.011 (60.4 mmol) in dioxane j75,'Oml with a melting point of 216-217°, 8 ml of 6N sulfuric acid are added and stirred for 9 hours at 90°C. Pour this into water,
Extract with ethyl acetate, wash the organic layer with water, and distill off the solvent under reduced pressure. The resulting residue was purified by silica gel chromatography (solvent: hexane:ethyl acetate-1:1), converted to ether, and crystallized from xane to give (E)-3-methyl-3-
4.4 # (43.6%) of (1,,,2-dithiolan-3-yl)acrylic acid is obtained as a pale yellow powder.

Melting point 96-98°C NMR (100MHz, CD (J3) δppm: 1
1.0 (, IH, bs).

5.85 (IH, s), 4.20 (IH, t,, r=7
Hz), 2.9-3.5 (2H, m), 2.4-2.8
(IH, m), 2.25 (RoH2S), 192.2 (1
B, m) Experimental Example 19 (2E,1)-5-(1,2-dithiolan-6-yl)-2,4-hexadienoic acid (compound 21
) Examples of each step of CP, I, J, etc.) 1.119 (27.5 mmol) of sodium hydride with a purity of 60q6 was finely suspended in 22 ml of anhydrous tetrahydrofuran, and the mixture was cooled with water and stirred to produce the 4 obtained in Example 5. -Acetyl-
2,2-dimethyl-1,3-dithiane (compound 5)
4.7.9 (24,6 mmol) and t-butyl trans-4-diethylphosphono-crotonate 7,6 El
(27,5 mmol) of anhydrous tetrahydrofuran 11 m
1. Add the mixed solution dropwise.

After stirring at the same temperature for 2 hours and at room temperature for 13 hours, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the resulting residue was chromatographed on silica gel (solvent: hexane: ethyl acetate-1).
(2E,4F)-5-(2,
2-dimethyl-1,5-dithian-4-yl) -2,
t-Butyl 4-hexadienoate (compound 20) was purified as a colorless oil to obtain 4.9ji (62.6%).

NMR (100MHz, CDCls)δT)T)
m: 7.45 (IH, q, J=15Hz.

10Hz), 6.15 (IH%, J=10Hz),
5.80 (IH.

a, J=15T(z), 368(IH,Q), 2.7-
3.2 (2H, m) 2.0-2.2 (2H, m), 1
．． 95 (3H, s), 1.85 (3H, s) 1.62
(3H,s), 1.50 (9H,s) of this t-butyl ester 4.91 (154 mmol) of dioxane 32
Add 32 ml of 6N sulfuric acid to the ml solution, heat to 90° C., and stir for 6 hours.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and hexane was added to crystallize it to give (2J4E)-5-(2,2-dimethyl-
2.05 g (51.3 g) of 1,3-dithian-4-yl)-2,4-hexadienoic acid was obtained as pale yellow crystals.

Melting point 163-1<55°C NMR (100MHz, CDCJ3) δI)pm
: 11.10 (IH, bs) 768 (IH, Q, J=
15Hz, 11Hz), 6.25 (IH, d.

J=11Hz), 5.87(II(,d, J=15Hz
), Ro70 (IH.

m), 263.4 (5H, m), 2.10 (IH, m)
, 2.01 (1°s), 1.90 (3H,'s), 1.
62 (3H, s) To a solution of 20 g (70 mmol) of this carboxylic acid in 23 ml of methanol was added 60 μm of sodium tungstate, and while stirring while cooling with water, 0.2% hydrogen peroxide solution was added.
96 El (7.9 mmol) was added dropwise, and 3
Stir for 0 minutes.

The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (solvent: chloroform:methanol = 30:1), and the solvent was distilled off under reduced pressure to obtain (2E,
4E)-5-(2,2-dimethyl-1,3-dithiane-
1,3119 (60, 1) was obtained as a colorless powder of 1-oxide-4-yl)-2,4-hexadienoic acid.

Add 0.9 ml of 6N sulfuric acid to a 20 ml dioxane solution of 1.3# (4.7 mmol) of S-oxide compound with a melting point of 75-76°,
Stir at 0°C for 8 hours. Add water and extract with ethyl acetate. The organic layer is washed with water and the solvent is distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (solvent: hexane-ethyl acetate-1:1) and crystallized from ether-hexane to give (2E, 41B)-5-(1,2-dithiolane-3-y). Ii) -2,4-hexadienoic acid (compound 21) as pale yellow powder 21 off! g(2o,
s%) obtained.

Melting point 123-125°C NMR (100MHz, CI) CA', ) δppm
: 11.8 (IH, bs), 7.45 (IH, q
, J=15Hz, 10Hz), 6.25(IH, d
, J-10Hz), 5.82 (IH, d, J=15
Hz), 2.40 (IH, m) 2.9-3.5 (2H,
m), 2.28-2.72 (IH, m), 2.02-2
．． 30 (IH, m), 1.93 (IH, s) Experimental example (E)-1-Methyl-3-(1,2-dithiolane-3
-yl)acrylic acid (compound 19) t obtained in Experimental Example 17
- Dissolve 4.89 (17 mmol) of butyl ester in 36 ml of methanol and dissolve 70 ml of sodium tungstate.
21 g of 28% hydrogen peroxide aqueous solution (
17:: IJ mol) was added and stirred for 30 minutes. Solvent 46 was distilled off to obtain S-oxide 639. Dissolve this in 40ml of dioxane, add 2.8ml of 6N sulfuric acid,
Stir at 0°C for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate.

Silica gel chromatography (solvent; hexane: acetic acid)
1/=2:1) and crystallized from ether-hexane to give the desired product (compound 1
9) 1.2 # was obtained.

Melting point 96-98℃ NMR (100MHz, CD0A!,)δpT)m
: 11.0 (IH, bs).

5.85 (IH, s), 4.20 (IH, t, J=7
Hz), 2.9-3.5 (2H, m), 2.4-2.
8(IH,m), 2.25(roH,s)2toi-1,ro-dithian-4-yl)-3-methyl-2,4
-tert-butyl hexadienoate (compound 22) (Q
Example of process) 1.1 g (28 mmol) of sodium 60 thihydride was subjected to WJA in 50 ml of anhydrous tetrahydrofuran, and tert of 4-diethylphospho-3-methyl-2-butenoic acid was added.
~8.2 g (28 mmol) of butyl was added dropwise with stirring under water cooling, and the mixture was stirred at the same temperature for 1 hour. Subsequently, 4.8 g of the acetyl compound (compound 5) synthesized in Experimental Example 5 was added under water cooling and stirring.
(25-: IJ mol) of tetrahydrofuran'20m
1 solution was added dropwise, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

The resulting residue was subjected to silica gel column chromatography (
Solvent: hexane:ethyl acetate (20:1) to give a colorless oil (2F,4E)-5-(2,2-dimethyl-
1,3-dithian-4-yl)-ro-methyl-2,4-
Tert-butyl hexadienoate was obtained. Yield 1.97
11 (Yield 24%) NMR (CD (J3.δppm): 5.92 (IH
, s), 5.58 (IH, 5) 655 (1H2dd),
27-63 (3H, m), 2.17 (3H.

s), 1,952.05 (IH, m), 1.88 (3H
,s), 1.85(3H,s), 1.59(3H,s
), 1.48 (9H, s) Experiment example (2E, 4m,
) = 5- (2,2-dimethyl-16-dithylone-4
-yl)-3-methyl-2,4-hexadienoic acid (2E, 4F) -5-(2
,2-dimethyl-1,ro-dithian-4-yl)-3-
tert-phthyl methyl-2,4-hexadienoate 1,
91? (5.8 mmol) was dissolved in 13 ml of dioxa, 2.4 ml of 6+=+ sulfuric acid was added, and the mixture was heated and stirred at 80° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was crystallized by adding hexane to give colorless crystals of (2, 4 g)-5-(2
,2-dimethyl-1,3-dithian-4-yl)-6-
Methyl-2,4-hexadienoic acid was obtained. Yield 1.44
．． 9 (yield 914%) Melting point 108-109°C (decomposition) NMR (CDCA, , δI) pm): 10.7 (
IH, bs), 5.99 (IH, s) 5.72 (IH,
s), 3.60 (IH, ad), 2.7-3.4 (
+H.

m), 2.26 (!IH, S), 1.90 (3H, s)
, 1.83(3H,S) 1.61(3H,s) Experimental example stand (2F, 4E) -5-(1,2-dithiolan-3-yl)-3-methyl-2,1-1\ Sodium xadienoate (Compound 23) Dissolve 1.49 (5.5 mmol) of monodimethyl-1,3-dithian-4-yl)-6-methyl-2,4-hexadienoic acid in 10 ml of methanol, and dissolve 301 Qg of sodium tungstate. (9X10'''5 moles) was added.

28% hydrogen peroxide solution 0.65 g (5.5
mmol] and stirred at the same temperature for 30 minutes. The catalyst was removed and the solvent was distilled off under reduced pressure to give (2F, 4E)-5-
(2,2-dimethyl-1,3-dithian-1-oxide-4-yl)-3-methyl-2,4-hexadienoic acid was obtained as colorless crystals. Yield 1.5.9 (yield ioo%
) Melting point: 161-165°G (decomposition) 1.519 (5.2 mmol) of the S-oxide obtained in this way was dissolved in 15 ml of dioxane, and 1.5 ml of 6N sulfuric acid was added.
．． 5 ml was added thereto, and the mixture was heated and stirred at 75°C for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sulfuric acid and concentrated under reduced pressure.

It was purified by silica gel column chromatography (solvent: hexane: ethyl acetate = 1:1) to give a colorless oil (2E
, 4F)-5-(1,'2-dithiolane-ro-yl)-
6-methyl-2,4-hexadienoic acid was obtained. Yield 0,
52 g (yield 688 cm) NMT ((CD73.δT)T)m): 9.5 (IH
, bs), 6.03 (IH, s) 5.75 (IH, s)
, 4.24 (IH, t), 2.8 3.5 (3H, m)
234 (3H, s), 2.10 (IH, m), 1.9
Didiolane obtained on 8(3H,s) 0.29,
? (1.3 mmol) to sodium hydrogen carbonate 0.10
A 2 ml aqueous solution of 6 & (1.3 mmol) was added.

Insoluble matter was removed and freeze-dried to obtain a yellow powder (2E, l
) -5-(1,2-dithiolan-3-yl)-3-methyl-2,4-hexadienoate was obtained. Yield 0.27.9 (yield 84.5%) Melting point 161°-13
3°C (decomposition) Biological test example 1 (effect on blastogenesis using mouse tile cells) Using BALB/C mouse tile cells, mitogen (mit
ogen: Concanavalin A (hereinafter referred to as Co
The effects of each compound of the present invention and lipoic acid on the lymphocyte blastogenesis response induced by stimulation (abbreviated as nA) were investigated.

That is, 1×10” infant spores of BALB/C mice (female, 10 to 14 weeks old) were added to 0.2 ml of RPMI-1640 medium supplemented with 10% beef fat serum, along with 2 μ9/ml of ConA and the test compound Yoshi. Bake 1 CO2 ink using a microculture plate (5% CO2,
The cells were cultured for 48 hours at 37°C.

Then, 05 μC] of 3H-thymidine ('H-TdR) was added, and after further culturing for 18 hours, the cells were collected in a cell harvester and the radioactivity of 3H-'rdR taken into the cells was measured. did. The results are shown in Table 1.

As is clear from Table 1, Co, a T cell mitogen,
When stimulated with nA, all of the compounds of the present invention exhibited a significant promoting effect, which was stronger than that of lipoic acid.

Biological Test Example 2 (Antibody Production Enhancement Effect) The effect on anti-5RBC (sheep red blood cell) antibody production response was investigated using TCR mice.

Namely, ICR mice (female, 7-9 weeks old, 4 mice per group) were immunized by injecting 5×107 antigen 5RBC into the tail vein. Immediately after and 24 hours later, compound 17.19 suspended in 05-thimethylcellulose solution was used. 2., 10 each
ff1g/kl? was administered orally. Six days after immunization, the spleen was removed and the number of antibody-producing cells that appeared was calculated using Jerne's PF.
C (Plaque Forming Ce1l) method (S
science, Vol. 140, p. 405, 1963).

The results are shown in Table 2.

As evident from Table 2, compound 17.19 enhanced antibody production at doses of 2 and 10 mg/kg.

Table 1 3HTdR radioactivity value in MI cyst circle is 2μm
The 3HTdR uptake value in the 1/ml ConA addition system was set to 1.
It is shown as a relative value when set to 00.

Biological Test Example 6 (Acute Toxicity) 'Compound 19 or lipoic acid suspended in 05% methylcellulose solution was orally administered to 4 to 5 male and female ddY mice weighing 20 to 2611 mm, and the mice were administered orally for 7 days. It was observed and the LD50 value was determined. Compound 19 and lipoic acid L
The D50 values were both 600 to 500 mg/kg.

As mentioned above, the compound of the present invention exhibits immunostimulatory activity.
Since it is a compound with low toxicity, it can be effectively used against diseases where immunosuppression is present, such as infectious diseases and cancer.

In addition, it is widely recognized that compounds with immunostimulatory effects such as the compounds of the present invention have both immunosuppressive effects depending on the dose, and therefore they can be used to treat various allergies, chronic rheumatoid arthritis, etc. that require immunomodulation. It can also be effectively used as a medicine for the following diseases.

Formulation Test Examples The compounds of the present invention can be administered orally or parenterally using conventional formulations. For oral use, it is used as a pharmaceutical preparation such as a tablet, granule, capsule, or powder, and for parenteral use, it is used as an injection for subcutaneous, intravenous, or intramuscular injection. It is desirable that the administration method and dosage form be appropriately selected depending on the type of disease, patient's condition, etc.

The appropriate dosage is 1 to 30 mg/kg body weight for oral administration, 1 to 10 mg for intravenous administration, and 11 to 10 mg for subcutaneous or intramuscular administration.
ng to 30111 g are appropriate, but it is desirable to select a more appropriate dose depending on the type of disease, patient condition, etc. Further, it is also possible to use the main principle together with other drugs such as anti-51A agents, antibacterial agents, and anti-inflammatory agents.

Examples of formulations are illustrated below.

Formulation Example 1 Composition of 1 tablet containing (E)-3-methyl-3-(1,2-dithiolan-ro-yl)acrylic acid (Compound 19) as the active ingredient Active ingredient 10@mg lactose
68■)・Corn starch 35mg crystalline cellulose
20111 g Hydroxypropyl cellulose 5 mg Magnesium stearate 2 mg Tablets containing the above ingredients were obtained by compression tableting.

Formulation Example 2 Capsules containing (E)-3-methyl-3-(1,2-dithiolan-3-yl)acrylic acid (Compound 19) Composition of 1 capsule Active ingredient 10Q mg Lactose 95q Corn starch 60111 g Crystalline cellulose 401T1g total Senshuku■ The above ingredients were filled into hard gelatin capsules to obtain capsules.

[Brief explanation of drawings]

Figures 1 to 6 are all diagrams showing synthetic routes for the compounds of the present invention. Figure 1 shows production route 11, Figure 2 shows production route (1), and Figure 3 shows production route (2).

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, n is 1 or 2, and R is a hydrogen atom or a methyl group) Represented by compound. 2. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, n and R are the same as above) A compound represented by the formula and a physiologically acceptable salt thereof as an active ingredient Immunomodulators.