JPH0881309A - Inclusion compound - Google Patents

Abstract

PURPOSE: To obtain an inclusion compound effective as a bactericidal agent which is free from skin irritation, stimulating smell and powder solidification during storage, accordingly excellent in handleability and capable of exhibiting excellent workability such as no corrosiveness caused by the vaporization, etc. CONSTITUTION: This is a cyclodextrin inclusion compound of a tetrahydrothiophene-1,1-dioxide derivative of the formula (X is H or a halogen), preferably 3,3,4,4-tetrafluorotetrahydrothiophene-1,1--dioxide. β-Cyclodextrin is preferable as the cyclodextrin. The inclusion compound is easily produced by dissolving each of a compound of the formula and a cyclodextrin in an appropriate solvent and mixing the obtained solutions to each other. In order to obtain the effect to prevent skin stimulation, etc., a compound of the formula is preferably included in a mole ratio of 0.1-2, especially 0.5-1 based on the cyclodextrin.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cyclodextrin inclusion compound of a tetrahydrothiophene-1,1-dioxide derivative useful as a bactericide.

[0002]

2. Description of the Related Art With the increasing demand for industrial water, the use of recirculation water systems is being actively used, and the control and suppression of the growth of microorganisms is an important problem in such use. In addition to these industrial water sources, with the diversification of industrial materials,
There are a wide range of disasters caused by the proliferation of microorganisms and fungi. In particular, water in the paper manufacturing process, industrial cooling water, or lubricating oil for metal processing, aqueous emulsion, paper, wood, plywood, glue, pulp, slime problems such as bacteria, yeast, algae parasitic on fibers, etc., There is an urgent need to take measures against microbial disasters. Recently, tetrahydrothiophene-1,1-dioxide derivatives are often used for the purpose of preventing or eliminating the generation of these microorganisms. Tetrahydrothiophene-1,1-dioxide derivatives have a wide pH range.
Has a broad spectrum of antibacterial activity in areas such as bacteria,
This is because it has an excellent antibacterial action against yeast, mold, etc., and has a very long-lasting effect, and is useful as a bactericide.

[0003]

However, the tetrahydrothiophene-1,1-dioxide derivative is liable to cause skin irritation, irritating odor, inconvenience in handling due to solidification of powder during storage, and further, volatilization due to volatilization. There are problems such as acid corrosion, and improvements are desired.

[0004]

[Means for Solving the Problems] In view of the above problems, the present inventors have conducted diligent research, and as a result, by including a tetrahydrothiophene-1,1-dioxide derivative with a cyclodextrin, skin irritation and irritation were obtained. The problems such as odor, inconvenience in handling due to solidification of powder during storage, and acid corrosion due to volatilization can be solved, and the present invention has been completed. That is, the present invention provides (1) the general formula (1)

Embedded image (In the formula, X is the same or different and represents a hydrogen atom or a halogen atom.) A cyclodextrin clathrate compound of the compound represented by the formula. (2) The clathrate compound according to (1), wherein the halogen atom of X is a chlorine atom. (3) The compound represented by the general formula (1) is 3, 3, 4, 4
-The inclusion compound according to (1), which is tetrachlorotetrahydrothiophene-1,1-dioxide. (4) The inclusion compound according to (1), wherein the cyclodextrin is β-cyclodextrin. (5) A fungicide containing the inclusion compound according to claim 1. Regarding

Tetrahydrothiophene-1, 1 of the present invention
-Dioxide derivatives have the general formula (1)

[Chemical 3] (In the formula, X is the same or different and represents a hydrogen atom or a halogen atom.). Examples of the halogen atom of X include fluorine, chlorine, bromine and iodine,
Chlorine is preferred. Specifically, 3, 3,
4,4-tetrachlorotetrahydrothiophene-1, 1
-Dioxide, 3,3,4,4-tetrabromotetrahydrothiophene-1,1-dioxide, 3,4-dichlorotetrahydrothiophene-1,1-dioxide, 3,
3,4-trichlorotetrahydrothiophene-1,1-
Dioxide, 3,3,4-tribromotetrahydrothiophene-1,1-dioxide and the like, 3,3,
4,4-tetrachlorotetrahydrothiophene-1, 1
-Dioxides are preferably used. Cyclodextrins of the present invention include cyclodextrins and branched cyclodextrins. Examples of the cyclodextrin include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like. Preferably, β-cyclodextrin is used. The branched cyclodextrin is a cyclodextrin ring having a branch such as glutose or maltose, and is a G1-β-cyclodextrin or G1-γ-cyclodextrin having a glucose dextrose having one glucose bonded to the cyclodextrin ring. Glucosyl cyclodextrins such as dextrin, G2-α-cyclodextrin, G2-β-cyclodextrin, and G2-in which two maltose glucoses are bound.
G to which maltosyl cyclodextrin such as γ-cyclodextrin and maltotriose of 3 glucose are bound
3-α-cyclodextrin, G3-β-cyclodextrin, G3-γ-cyclodextrin, etc. G1-Gl-, Gl-G2-, G2-G2 in which a maltotriosyl group is bonded to the 2-position or higher of cyclodextrin. And other maltotriosyl cyclodextrins and the like. Preferred are glucosyl cyclodextrin and maltosyl cyclodextrin. In addition to the above, as cyclodextrins, tetrahydrothiophene-
Any size may be used as long as it has a size of 4 to 12 angstroms, preferably 6 to 10 angstroms, in which the 1,1-dioxide derivative is included.

The inclusion compound of the present invention can be easily obtained by dissolving a tetrahydrothiophene-1,1-dioxide derivative and a cyclodextrin in an appropriate solvent and mixing them. −
Dioxide derivatives are included in cyclodextrins,
To obtain effects such as preventing skin irritation, tetrahydrothiophene-1, 1 is added to cyclodextrins.
It is desirable that the -dioxide derivative is included in a molar ratio of 0.1 to 2, more preferably 0.5 to 1.
For the specific preparation method, a direct method of the saturated aqueous solution method,
Any known method such as a solvent method, a spray drying method such as a drying method, or a freeze drying method may be used. Among these known preparation methods, the saturated aqueous solution method, the kneading method, and the drying method are preferable considering that the tetrahydrothiophene-1,1-dioxide derivative is difficult to disperse in water. For example, in the solvent method of the saturated aqueous solution method, it is 1 to 50 relative to cyclodextrins.
20 times by weight, preferably 5 to 30 times by weight of water
A saturated aqueous solution of cyclodextrins is prepared at -80 ° C, preferably 40-60 ° C. Next, it is 0.1 to 2 times mol, preferably 0.5 to 1 times the molar amount of cyclodextrins.
0.1 to 50 times the molar amount of the tetrahydrothiophene-1,1-dioxide derivative with respect to the tetrahydrothiophene-1,1-dioxide derivative, preferably 1 to 1
Dissolve with 5 times the weight of solvent. The solution of the tetrahydrothiophene-1,1-dioxide derivative is mixed with a saturated aqueous solution of cyclodextrins and stirred for 0.5 to 24 hours, preferably 1 to 10 hours to precipitate crystals. In this case, immediately after preparing a saturated aqueous solution of cyclodextrin, a solution of the tetrahydrothiophene-1,1-dioxide derivative is added, the temperature is gradually returned to room temperature, and further,
It is preferable to crystallize by cooling at about -10 to 10 ° C. The crystallized crystals are separated from the solution by filtration or the like,
The cyclodextrin clathrate compound can be obtained in the form of powder by drying under reduced pressure or the like.

The solvent for dissolving the tetrahydrothiophene-1,1-dioxide derivative is not particularly limited as long as it dissolves the tetrahydrothiophene-1,1-dioxide derivative and does not hinder inclusion. Water, for example, , Methanol, ethanol, n-propanol, iso-propanol, tert-butanol and other alcohol solvents such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol. 1,4-butanediol, 1,5-
Pentanediol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glycol solvents such as tripropylene glycol monomethyl ether, for example, ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc., for example, dioxane, tetrahydrofuran, ethyl ether, etc. Ether solvents, for example, ethyl acetate, butyl acetate, ester solvents such as isobutyl acetate, for example, benzene, toluene, xylene, methylnaphthalene, aromatic solvents such as solvent naphtha, for example, methylene chloride, carbon tetrachloride,
Halogenated hydrocarbon solvents such as chloroform, for example,
Examples thereof include polar solvents such as dimethylformamide, dimethylsulfoxide and acetonitrile. You may mix 2 or more types of these solvents. Further, the clathrate compound of the present invention may be added with known additives such as a bactericidal agent, a surfactant, an antioxidant, etc., for its purpose and application.

Examples of the bactericide include isothiazoline compounds such as 1,2-benzisothiazoline-3.
-One, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, 4,5-dichloro-2-octyl-4-isothiazolin-3-one, 2-octyl-4-isothiazolin -3-ON etc. are mentioned. Examples of the haloacetamide compound include 2,2-dibromo-3-nitrilopropanamide and 2,2-dibromo-3-nitrilo N-methyl-propanamide. Examples of the carbamate-based compound include 3-iodo 2-propynylbutyl carbamate and methyl-2-benzimidazole carbamate. As an alcohol compound,
For example, 2,2-dibromo-2-nitroethanol, 2
Examples include -bromo-2-nitropropane-1,3-diol. Examples of the dithiol compound include 4,
5-dichloro-1,2-dithiol-3-one may be mentioned. Two or more kinds of these bactericides may be used in combination, and the mixing ratio varies depending on the dosage form, purpose of use, application, etc., but is generally 0.1 to 99.9% by weight in the preparation. Mixing is desirable. Specifically, for example, 0.1 to 20% by weight for a solution and 10 to 10 for a wettable powder.
It is preferably 80% by weight, and 10 to 99.9% by weight for powders. The surfactant may be any known surfactant such as soaps, nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, polymer surfactants and the like. . Among them, nonionic surfactants and anionic surfactants are preferably used.

Examples of the nonionic surfactants include polyoxyalkylene aryl phenyl ethers, polyoxyethylene nonyl phenyl ethers, ethylene oxide / propylene oxide block copolymers and the like. Examples of the anionic surfactant include alkylbenzene sulfonic acid metal salt, alkylnaphthalene sulfonic acid metal salt, polycarboxylic acid type surfactant, dialkylsulfosuccinic acid ester metal salt, polyoxyethylene distyrenated phenyl ether sulfate ammonium salt, lignin. Examples of the metal salt include sulfonic acid metal salt, and examples of the metal salt include sodium salt and potassium salt. Examples of the antioxidant include 2,6-di-t-butyl-4-
Phenolic antioxidants such as methylphenol, 2,2'-methylenebis [4-methyl-6-t-butylphenol], alkyldiphenylamine, N, N'-di-s
Examples thereof include amine-based antioxidants such as -butyl-p-phenylenediamine. These surfactants and antioxidants are generally used in an amount of 0.02 to 0.
It is preferably used in an amount of about 3 parts by weight, or 5 to 80% by weight based on the total amount of the preparation. Further, these additives may be added when preparing the clathrate compound, or may be added immediately after preparation or after drying. The thus obtained cyclodextrin inclusion compound of the present invention has a broad antibacterial spectrum in a wide pH range, and includes bacteria, yeast,
It has an excellent antibacterial action against mold and the like, and has a very long-lasting effect, so that it is useful as a bactericide.
Specifically, it can be used as a slime control agent in a paper pulp mill, a cooling water circulation process, a sterilizing detergent, and an industrial bactericide such as a metalworking oil agent, casein, a starch coating solution, and a preservative for water-based paints.

[0010]

INDUSTRIAL APPLICABILITY Tetrahydrothiophene-1 of the present invention,
Cyclodextrin clathrates of 1-dioxide derivatives have no skin irritation, no irritating odor, are easy to handle without powder solidification during storage, and have no acid corrosion due to volatilization. It is effectively used as an excellent germicide.

[0011]

EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to the examples. Example 1 100 g of water was added to 4 g of β-cyclodextrin (manufactured by Wako Pure Chemical Industries, Ltd., hereinafter the same), and dissolved at 50 ° C. 3, 3, 4, dissolved in 2 ml of methanol,
4-tetrachlorotetrahydrothiophene-1,1-dioxide (manufactured by Takeda Pharmaceutical Co., Ltd., the same applies hereinafter) 0.2
4 g was added. Stir for about 4 hours while returning to room temperature, then 5
The mixture was stirred at 0 ° C for 2 hours. The resulting crystals were suction filtered and dried under reduced pressure to give white crystals. The white crystals were odorless and did not irritate the skin when handled with bare hands.
In addition, it was confirmed by powder X-ray analysis that 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide was clathrated with β-cyclodextrin. The powder X-ray peak interplanar spacing (Å) of the clathrate compound obtained in Example 1; 5.029 (I / I ₀ ; 100), 5.824 (I / I ₀ ; 6)
5), 6.458 (I / I ₀ ; 30), 4.422 (I / I ₀ ; 20)

Example 2 15 g of water was added to 4 g of γ-cyclodextrin (manufactured by Wako Pure Chemical Industries, Ltd., the same applies below), and heated to 40 ° C. to dissolve. 3,3 dissolved in 2 ml of methanol,
4,4-tetrachlorotetrahydrothiophene-1, 1
-0.2 g of dioxide was added. About 4 while returning to room temperature
The mixture was stirred for an hour and further at 5 ° C. for 2 hours. The resulting crystals were suction filtered and dried under reduced pressure to give white crystals. The white crystals were odorless and did not irritate the skin when handled with bare hands. The powder X-ray peak interplanar spacing (Å) of the clathrate compound obtained in Example 2; 5.029 (I / I ₀ ; 100), 5.824 (I / I ₀ ; 6)
5), 6.458 (I / I ₀ ; 30), 4.422 (I / I ₀ ; 20)

Example 3 To 4 g of β-cyclodextrin, 100 g of water was added, and 50
It melted at ℃. To this was added 0.24 g of 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide dissolved in 1.5 ml of carbon tetrachloride. While returning to room temperature, the mixture was stirred for about 4 hours and further at 5 ° C. for 2 hours. The resulting crystals were suction filtered and dried under reduced pressure to give white crystals. The white crystals were odorless and did not irritate the skin when handled with bare hands. Further, as in Example 1, it was confirmed by powder X-ray analysis that 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide was clathrated with β-cyclodextrin. Example 4 15 g of water was added to 4 g of γ-cyclodextrin, and the mixture was heated to 40 ° C.
It was heated to dissolve. To this was added 0.2 g of 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide dissolved in 1.5 ml of methylene chloride. While returning to room temperature, the mixture was stirred for about 4 hours and further at 5 ° C. for 2 hours. The resulting crystals were suction filtered and dried under reduced pressure to give white crystals. The white crystals were odorless and did not irritate the skin when handled with bare hands. Further, as in Example 2, it was confirmed by powder X-ray analysis that 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide was clathrated with γ-cyclodextrin.

Test Example 1 (Storage stability test) The sample contains the β-cyclodextrin inclusion compound of 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide obtained in Experimental Example 1 as a sample. White crystals and unoccluded 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide were used as comparative examples. About 500 g of each sample was placed in a 500 ml brown bottle and left at room temperature. Both samples did not solidify on the day of preparation, but when observed one month later, the white crystals of Example 1 did not change at all, but the uninclusions of Comparative Example 3, 3 and 3,
4,4-tetrachlorotetrahydrothiophene-1, 1
-The dioxide had solidified. Test Example 2 (Measurement of antibacterial activity) Bacteria was 33 in a multiple dilution method using glucose agar medium.
The minimum inhibitory concentration (MIC, μg / ml) was determined by culturing the fungi and yeast for 18 hours at 28 ° C. for 3 days at 28 ° C. A white crystal containing a β-cyclodextrin inclusion compound of 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide obtained in Experimental Example 1 as a sample,
As a comparative example, unoccluded 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide was used.
In addition, the amount of 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide was the same for both measurements. Table 1 shows the test bacteria and the measurement results.

[0015]

[Table 1] It can be seen that the antibacterial activity is the same regardless of the inclusion or non-inclusion.

Claims (5)

[Claims] 1. A general formula (1): (In the formula, X is the same or different and represents a hydrogen atom or a halogen atom.) A cyclodextrin clathrate compound of the compound represented by the formula. 2. The clathrate compound according to claim 1, wherein the halogen atom of X is a chlorine atom. 3. A compound represented by the general formula (1) is 3, 3,
4,4-tetrachlorotetrahydrothiophene-1,1
-The inclusion compound according to claim 1, which is a dioxide. 4. The inclusion compound according to claim 1, wherein the cyclodextrin is β-cyclodextrin. 5. A fungicide containing the clathrate compound according to claim 1.