JPS63227578A - Thiazole compound and antibacterial and mildew-proofing agent - Google Patents

Abstract

NEW MATERIAL:A thiazole compound shown by formula I (R<1> is 10-18C alkyl; R<2> is H or 1-6C alkyl; R<3> is H, formyl, methyl, vinyl or -CH2CH2OR<4>; R<4> is H or group shown by formula II; R is H or 1-9C alkyl; X is anion). EXAMPLE:N-Decyl-5-hydroxyethyl-4-methylthiazolium iodide. USE:Useful as an antibacterial and mildew-proofing agent. Showing excellent antimicrobial actions on both fungi and bacteria in a wide range and usable for various uses such as blending with coating compounds, synthetic resin products, paper products and fibrous products, preventing slime of service water for paper and pulp industry, sterilization and disinfection of animal skin, sterilization and disinfection of houses. PREPARATION:For example, a thiazole compound is quaternized with an alkyl halide to give a compound shown by formula I. Or 5-hydroxyethyl-4- methylthiazole is reacted with formic acid in the presence of an acid catalyst and quaternized to give the compound shown by formula I wherein R<3> is -CH2 CH2OCHO.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to a thiazole compound and an antibacterial/antifungal agent.

[Conventional technology]

Conventionally, organometallic compounds, halodanated aromatic compounds, organic nitrogen compounds, organic sulfur compounds, quaternary ammonium salt compounds, and the like have been used as antibacterial or antifungal agents.

However, these antibacterial and antifungal agents exhibit strong toxicity to humans, animals, and fish, have a high tendency to accumulate in the body, emit bad or strange odors, and are insufficiently effective. Alternatively, they have drawbacks such as a narrow range of application to bacterial species.

For this reason, currently 2.
-(4-thiazolyl)benzimidazole, chlorhexidine gluconate, panzalkonium chloride, etc. are used.

[Problem that the invention seeks to solve]

2-(4-thiazolyl)benzimidazole has low toxicity and good efficacy, but is only effective against fungi;
It shows no efficacy against bacteria. Additionally, this drug is highly unstable to sunlight, and bacteria that are resistant to this drug are also beginning to emerge.

Chlorhexidine gluconate also has low toxicity and exhibits excellent effects, but is only effective against some bacteria and has little effect on fungi. Additionally, this drug is unstable when exposed to sunlight, and the emergence of resistant bacteria has been observed.

Quaternary ammonium salt compounds such as pendelkonium chloride are also called inverse soaps, and are drugs that have been put into practical use for a long time. This also shows excellent antibacterial activity against bacteria, but is less effective against fungi, especially those in spore form. Furthermore, as with the two drugs mentioned above, the emergence of resistant bacteria has been observed.

As described above, even if conventional drugs have low toxicity, there are few that exhibit antibacterial activity against both fungi and bacteria at the same time.

By the way, the fungi that occur in the human living environment are rarely either fungi or bacteria, and often a combination of both types of fungi occurs. For such complex fungi, a combination of multiple types of drugs that have antibacterial activity against each type of fungi is usually used. but,
In this case, there are issues of contraindications between drugs, differences in optimal values for individual drugs, and differences in interactions such as adhesion with other substances such as proteins and polysaccharides. It is often difficult to exert antibacterial action.

Therefore, an object of the present invention is to provide a novel compound useful as an antibacterial/antifungal agent that exhibits excellent antibacterial activity against a wide range of both fungi and bacteria.

Another object of the present invention is to provide an antibacterial and antifungal agent containing such a novel compound as an active ingredient.

[Failure to solve the problem]

As a result of intensive research to achieve the above object, the present inventors found that the general formula (where R is an alkyl group having 10 to 18 carbon atoms, R2 is hydrogen or 1 to 6 carbon atoms) an alkyl group having atoms, R3 is hydrogen, formyl group, methyl group, vinyl group or -CH2CH20R4 group, R4 is hydrogen or 10R group, R is hydrogen or an alkyl group having 1 to 9 carbon atoms, or The present invention was completed by discovering that thiazole compounds represented by anion (especially halodane anion) are effective.

The compound represented by the above general formula (1) is a known thiazole, 4-methylthiazole, 5-methylthiazole, 4,5-dimethylthiazole, 5-hydroxyethyl-4-methylthiazole or 4-methyl-5- It can be manufactured from vinylthiazole and the like. That is, when these known thiazole compounds are converted to alkyl halides (RlX), the thiazole compounds of the present invention in which R1 corresponding to the 3-position nitrogen is introduced can be obtained. In general formula (1), R3 is -CH2CH
The compound that is 20CHO is 5-hydroxyethyl-4
- Obtained by first reacting methylthiazole with formic acid in the presence of an acid catalyst and quaternizing the product obtained as described above. Alternatively, the compound represented by general formula (1) can be prepared by reacting 5-hydroxyethyl-4-1fkf azole with the corresponding fatty acid in the presence of an acid catalyst, and quaternizing the resulting product in the same manner as above. obtained by

The thiazole compound of this invention can be widely applied to various uses for the purpose of controlling contamination by microorganisms including bacteria and fungi. For example, it can be blended into paints, synthetic resin products, paper products, textile products, wood and wood products, mechanical processing oils, agricultural products, and the like. It can also be attached for the purpose of preventing slime in industrial water such as paper/pulp industrial water and various types of cooling water, as well as for sterilizing and disinfecting human and animal skin, and for sterilizing and disinfecting various medical instruments and facilities, houses, vehicles, etc. It can also be used for disinfection.

Furthermore, the thiazole compound of the present invention can be used as an antibacterial and fungicidal agent in the form of powder, solution, or ointment, and can be used in various forms such as sprays, coatings, adhesives, etc. in addition to other carriers. Can be used in any form suitable for the purpose.

The amount of the thiazole compound used in this invention varies depending on the application, but examples include 0.01 to 1100 pp for paper and pulp industrial water, and 0.1 to 1100 pp for industrial cooling water.
100 ppm for metal processing oils, textile oils, paints, stings and stains, and 10 to 200,000 ppm, and 0.1 to 5% for skin solutions such as drops, hands, and fingers. is desirable.

Furthermore, the thiazole compound of the present invention can be mixed with various compounding agents such as other antibacterial agents, carriers, regulators, and surfactants as long as their antibacterial activity is not inhibited.

The thiazole compound of the present invention is soluble in solvents such as water, alcohols, pe/zene, toluene, xylene, and esters.

〔Example〕

5-hydroxyethyl-4-methylthiazole 1.43
(0.01 mol), 2.68 g (0.01 mol) of decyl iodide, and 25 ml of ethanol were placed in a 100 ml eggplant-shaped flask, purged with nitrogen, sealed tightly, and heated in an oil bath at 80°C for 24 hours. The time was hot. After the reaction, it was concentrated under reduced pressure using a rotary evaporator, and 50 ml of ethyl ether was added and cooled on ice. The precipitated crystals were recrystallized with a mixed solvent of ethanol and ethyl ether in a volume ratio of 1:4 to obtain N-decyl iodide. -5-hydroxyethyl-4-methylthiazolium was obtained (Example 1).

The corresponding thiazole compound was prepared by carrying out exactly the same operation as above, except that the same molar amounts of lauryl iodide, listyl iodide, cetyl iodide, and stearyl iodide were used in place of decyl iodide. were obtained (Examples 2 to 5).

Five types of N-alkyl-5- and droxyethyl-4-methylthiazolium iodides (abbreviated as T-n) were thus obtained.

Table 1 shows the elemental analysis values, melting point, yield, and crystalline state of (n represents the number of carbon atoms in the alkyl group at the 3-position nitrogen). In addition, 1H-NMR (in CDCl3, internal standard: tetramethylsila/) of these compounds is shown in Table 2.

The elemental analysis values are in good agreement with the calculated values within 0.3 inches. Furthermore, the results of thin layer chromatography (TLC) using ethyl acetate as a developing solvent confirmed that these thiazole compounds were synthesized in a pure manner.

-11ω- Antibacterial test The antibacterial spectrum of the thiazole compound of this invention against seven types of bacteria was measured according to the minimum growth concentration (MIC) measurement method of the Japanese Society of Chemotherapy.

Mieller-Hinton's agar medium was used as the medium, and bacteria were inoculated using a microplate.

As inoculum, Bactodryptone (1%), yeast extract (0.5%) and salt (0.5%) were used as PH7,
A bacterial suspension prepared by pre-cultivating bacterial cells for 24 hours using a liquid medium (L-Pros) of 0.0 and diluting them to 106 cells/ml with the same medium was used. The MIC was measured after culturing at 37° C. for 24 hours, and the minimum drug concentration that inhibited the formation of clear colonies was defined as the MIC. The results are shown in Table 3. Note that the MIC value is the average value of the values obtained by performing the experiment five times and excluding the maximum value and minimum value.

From the results in Table 3, it can be seen that the thiazole compound of the present invention exhibits strong antibacterial activity against both Durum-negative and Durum-positive bacteria, and has a remarkable effect against Staphylococcus nigra.

On the other hand, the antibacterial spectra of six types of mold were measured using Sabouraud's liquid medium by the test tube dilution method. The MIC was determined by visually determining the presence or absence of proliferation after culturing at 30° C. for 48 hours, and the minimum concentration that inhibited proliferation was defined as the MIC. The results are shown in Table 4.

Note that the MIC value is the average value of the values obtained by performing the experiment five times and excluding the maximum value and minimum value.

From the results in Table 4, it can be seen that the thiazole compound of the present invention exhibits strong antibacterial activity against molds (fungi) as well as against bacteria.

In addition, when compared with TBZ, which is currently in practical use as an antifungal agent with excellent antibacterial activity, it was confirmed that the thiazole compound of this invention has a broader antibacterial spectrum than TBZ.

〔Effect of the invention〕

As described above, the present invention provides a thiazole compound that exhibits excellent antibacterial activity against both fungi and bacteria. It is also possible to produce a derivative that firmly binds to fibers and leather products by reacting this thiazole 41 compound with a glycidyl compound.

Applicant's agent Patent attorney Takehiko Suzue, Commissioner of the Patent Office
Kunio Ogawa 1. Display of the case Japanese Patent Application No. 62-58350 2 Name of the invention Thiazole compound and antibacterial/antifungal agent 3 Person making the amendment Relationship to the case Patent applicant Midori Kagaku Co., Ltd. (and 1 other person) 4. Agent Address: UBE Building, 3-7-2 Kasumigaseki, Chiyoda-ku, Tokyo Address: 100 Phone: 03 (502) 31817 Contents of amendment (1) The line after "Confirmed." on page 16, line 7 of the specification. Insert the following text again.

Example 6 (1) Synthesis of N-alkylthiazolium iodide 0.85 g of thiazole (0.85 g
.

After the reaction, 10 ml of diethyl ether was added and the precipitated crystals were separated, and N-alkylthiazolium iodide (hereinafter abbreviated as TH-n, n is alkyl) was added from a mixture of ethyl alcohol and diethyl ether (1:4). The number of carbon atoms in the chain) was recrystallized.

The obtained compound was confirmed by elemental analysis, TLC and NMR. Elemental analysis values, molecular weight and melting point are shown in Table 5 below.
Shown below.

Table 5 Compound -〇 Molecular weight Melting point TH-n HCN ℃TH-10
8,11843,1103,72353,31073-
76(8,85)(44,14)(3,98)TH-
127,5846,983,9B 381.3E14
88-100 (7,40) (47,24) (3,8
7) TH-147, 9548, 853, 1740L41
8 97-102 (7,88) (49,87) (3,
42) T) t-188,5751,9B 3.41
437.472 138-100 (8,29) (52,
17) (3,20)TI-188,8953,842
,86485,52El 8B-E128.8B
54.18 3.01 Values in parentheses are calculated values (2) Antibacterial test An antibacterial test was conducted in the same manner as in Examples 1 to 5. The results are shown in Table 6 below.

Example 7 (1) Synthesis of N-alkyl 4-methylthiazolium iodide (4T-n) Synthesis was performed according to the synthesis method of Example 6. The identification results are shown in Table 7 below.

Table 7 Compound -〇 Zero molecular weight Melting point 4T-n HCN '04T-8
8,2842,214,29339,2838l-82
(8,53) (42,48) (4,13)4T-10
8,11345,503,543B7.337 108
-107 (7,13) (45,78) (3,81)4
T-127,5848,1B 3.85 31115
．． 381 104-107 (7,85) (48,80)
(3,54)4T-148,2350,733,50
423,444104-107(8,09)(51,0
8) (3,31)4T-16813553,013,
31451, 498108-110 (8,45053,
21) (3,10)4T-18LO454,533,
224713,552108-1108,8355,1
02,82 (2) Antibacterial test An antibacterial activity test was conducted in the same manner as in Examples 1 to 5. The results are shown in Table 8 below.

Example 8 (1) Synthesis of N-furkyl-4,5-dimethylthiazolium iodide (4,5T-n) Synthesis was performed according to the synthesis method of Example 6. The identification results are shown in Table 9 below.

Table 9 Compound -〇 Molecular weight Melting point 45T-n HCN "04.5T
-107,4746,893,8Et 381.38
4 8B-87 (7,47) (47,24) (3,8
7) 4.5T-127, 6348, 823, 22409
,41873(7,88)(48,87)(3,42
)4.5T-148, 4251, 1153, 38437
,47283-85(8,29)(52,17)(3
,20) 4.5T-1fl 8.91 53.91
3.22 4B5.525 88-80(e,ee)(
s4. ts) (3,01)4.5T-18i3.02
55.57 2.74 483.580 82-H8
, f38 55.87 2.84 (2) Antibacterial test An antibacterial activity test was conducted in the same manner as in Examples 1 to 5. The results are shown in Table 1O below.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, R^1 is an alkyl group having 10 to 18 carbon atoms, and R^2 is hydrogen or 1 to 6 carbon atoms. an alkyl group having R^3 is hydrogen, formyl group, methyl group, vinyl group or -CH_2CH_2OR
A thiazole compound represented by a ^4 group, R^4 is hydrogen or a ▲ mathematical formula, chemical formula, table, etc. ▼ group, R is hydrogen or an alkyl group having 1 to 9 carbon atoms, and X is an anion). (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, R^1 is an alkyl group having 10 to 18 carbon atoms, R^2 hydrogen or 1 to 6 carbon atoms. The alkyl group R^3 has is hydrogen, formyl group, methyl group, vinyl group or -CH_2CH_2OR^
4 groups, R^4 is hydrogen or ▲ mathematical formula, chemical formula, table, etc. ▼ group, R is hydrogen or an alkyl group having 1 to 9 carbon atoms, X is an anion) as an active ingredient. Antibacterial and antifungal agent.