JPH0610121B2 - Antibacterial agent - Google Patents

Description

The present invention relates to a terpene-based iodopropargyl ether represented by the general formula ROCH ₂ C≡CI (wherein R represents a terpene group defined in detail later) as an active ingredient. The present invention relates to antibacterial agents contained as.

2. Description of the Related Art It is conventionally known that some terpenes have an antibacterial action or an insecticidal action. For example, En
cyelopaedia of the Terpenoids (John S. Glasby, 19
This is also described in 1982, published by John Wiley & Sons (pages 2,645-2,646 of the same magazine). On the other hand, some iodopropargyl ethers are known to have strong antibacterial properties (Japanese Patent Publication Nos. 39-19791 and 41-1).
9077 and 42-13860 and JP-A-56-43243 and 58-183672).

However, regarding the terpene-based iodopropargyl ethers, there is no description of antibacterial action or insecticidal action.

Problems to be Solved by the Invention In recent years, it has excellent effects, is inexpensive and safe for medical use,
There is a strong demand for agricultural and industrial antibacterial agents. For example, as an antibacterial agent for medical use, there is a demand for a remedy for infectious diseases caused by bacteria, as well as for diseases caused by molds such as genus Kyandeida, Trichophyton, Cryptococcus, etc. There is a demand for bactericides, seed disinfectants, soil bactericides and the like for controlling plant diseases caused by genus. On the other hand, in the industrial field, there are problems such as deterioration of product quality and decrease of commercial value due to growth of bacteria and fungi, and it is required to solve these problems.

Means for Solving Problems, Actions and Effects The inventors of the present invention continued to search from various compounds in order to meet the above-mentioned expectations, and found that a certain compound having a terpene group had a strong antibacterial action. The present invention has been completed by confirming that these compounds are present and confirming that these compounds are excellent as antibacterial agents.

Therefore, according to the present invention, the general formula [I]: ROCH ₂ C≡CI [I] (wherein R is 3,7-dimethyloct-2-trans-
An antibacterial agent comprising a terpene iodopropargyl ether represented by 6-dienyl group, bornane group, paramenta-1,8-diene group or paramenta-1-ene group) as an active ingredient is provided.

Typical examples of the terpene-based iodopropargyl ether compound represented by the above general formula [I] include compound Nos. Shown below. 5, No. 6, No. 7 and No. There are 8 compounds each. The novel compound of the present invention represented by the general formula [I] is a terpene propargyl ether of the following general formula [II]: ROCH ₂ C≡CH [II] (wherein R has the above-mentioned meaning), Specifically, the compound No. shown below is used. 1,
No. 2, No. 3 and No. It can be produced by using each compound of 4 as a raw material and reacting these with iodine in a methanolic potassium hydroxide solution. Compound No. Compound name 1 (3,7-Dimethyloct-2-trans-6-dienyl) -2-propynyl ether 2 (bornan-2-yl) -2-propynyl ether (bp 74-78 ° C / 5 mmHg) 3 (paramenta -1,8-Dien-7-yl) -2-propynyl ether (bp. 74-75 ° C / 5mmHg) 4 (paramenta-1-en-8-yl) -2-propynyl ether (bp 77-78 ° C / 4 mmHg) 5 3-iodo- (3,7-dimethyloct-2-trans-6-dienyl) -2-propynyl ether (bp 94-96 ° C./3 mmHg) 6 3-iodo- (bornan-2-yl) -2 -Propynyl ether [IR spectrum (nudijol) cm ^-1 : 2920, 1450, 1350, 1100, 1070] 7 3-iodo- (paramenta-1,8-dien-7-yl) -2-propynyl ether [IR spectrum (Nujiyo Le) c
m ⁻¹ : 2900, 2820, 1635, 1430, 1060, 890] 8 3-iodo- (paramenta-1-en-8-yl) -2-propynyl ether [IR spectrum (nudijol) cm ⁻¹ : 2860, 1480 , 1380, 1060, 910] The above compound numbers are obtained in the following examples (formulation examples and test examples).
Also used in.

Of the compounds represented by the general formula [I] used as the active ingredient in the present invention and the starting compounds represented by the general formula [II], the compound No. All compounds except 1 are novel compounds not listed in the literature. Compound No. With respect to 1, it is disclosed in US Pat. No. 3,773,797 that the compound can be obtained by reacting propargyl alcohol with geranyl bromide in the presence of sodium hydride, but there is no suggestion as to its usefulness. Actually, this method is not practical because it requires the use of sodium hydride, which requires careful handling, and the yield is low, and no further progress has been reported.

The starting compounds of the general formula [II] can be produced safely and in high yields by the following methods, and thus economically.

Method for producing starting material compound of general formula [II]: (1) Condensation reaction of corresponding terpene alcohol and propargyl halide, for example, propargyl bromide in the presence of phase transfer catalyst such as tris (3,6-dioxaheptyl) amine. Let

(2) The corresponding terpene hydrocarbon and propargyl alcohol are subjected to an addition reaction in the presence of an acid catalyst such as Amberlyst-15.

The production examples of the novel compounds of the general formulas [I] and [II] are shown below.

Production Example 1 Production of Paramenta-1,8-dien-7-yl) -2-propynyl ether (Compound No. 3) Perillyl alcohol 45 g, normal hexane 120
g, tris (3,6-dioxaheptyl) amine (hereinafter abbreviated as TDA-1) 6 cc, 50 as a phase transfer catalyst
45 g of propargyl bromide was added dropwise to a mixed solution of 62 g of an aqueous caustic soda solution at 35 ° C., and the mixture was reacted at the same temperature for 6 hours with stirring.

After the reaction solution was washed with water, normal hexane was distilled off to obtain a crude reaction oil. The crude reaction oil was distilled to obtain (paramenta-1,8
45 g of an oil of -dien-7-yl) -2-propynyl ether was obtained. Yield 80%, Boiling point 74 ~ 75 ℃ / 5mm
Hg.

IR-Spectrum (Nujioru) cm ^-1 : 3280, 2920, 284
0, 1640, 1435, 1070, 890 Elemental analysis value: Calculated as C ₁₃ H ₁₈ O (212.2): C, 85.8; H, 8.55% Analysis value: C, 88.6; H, 8.05% Production example 2 (paramentor) Production of 1-en-8-yl) -2-propynyl ether (Compound No. 4) 54 g of β-pinene, 30 g of propargyl alcohol, 3 g of strongly acidic cation exchange resin (Amberlyst-15),
A solution of 300 cc of benzene was stirred overnight at room temperature to react. After removing Amberlyst-15 separately, benzene was distilled off to obtain a crude reaction oil. The crude reaction oil was distilled to obtain (paramenta-1-en-8-yl) -2-
42 g of an oil of propynyl ether was obtained. Yield 55
%, Boiling point 77 to 78 ° C./4 mmHg.

IR-spectrum (Nujioru)) cm ^-1 : 3280, 2875, 29
20, 1480, 1360, 1380, 1060, 910 Elemental analysis value: Calculated as C ₁₃ H ₂₀ O (214.3): C, 84.99; H, 9.41% Analytical value: C, 85.61; H, 9.31% Production example 3 3 -Iodo- (3,7-dimethyloct-2-trans-6-dienyl) -2-propynyl ether (Compound N
o. 5) Production of geraniol 45 g, normal hexane 120 g, 50
45 g of propargyl bromide was added dropwise to a mixed solution of 62 g of an aqueous caustic soda solution and 6 ml of TDA-1 at 35 ° C., and the mixture was reacted by stirring at the same temperature for 6 hours. After the reaction solution was washed with water, normal hexane was distilled off to obtain a crude reaction oil. This crude reaction oil was distilled to obtain 49 g of an oily substance of (3,7-dimethyloct-2-trans-6-dienyl) -2-propynyl ether. Yield 88%, boiling point 94-96 ° C / 3
mmHg.

To a solution of 150 g of methanol and 21 g of potassium hydroxide, 19 g of (3,7-dimethyloct-2-trans-6-dienyl) -2-propynyl ether was added. To this solution, gradually add 26 g of iodine, and at the room temperature after the addition is complete,
We reacted day and night. Methanol was distilled off from the reaction solution, benzene was extracted and washed with water, and then benzene was distilled off to obtain a crude reaction oil. The crude reaction oil was purified by silica gel chromatography, and the benzene: hexane = 2: 1 eluate was used to
Iodo- (3,7-dimethyloct-2-trans-6
-Dienyl) -2-propynyl ether was obtained. Yield 6
5%.

IR-spectrum (Nujioru) cm ^-1 : 2860, 1660, 143
0, 1370, 1340, 1050, 910 Elemental analysis value: Calculated as C ₁₃ H ₁₉ OI (340.15): C, 53.53; H, 5.63; I, 37.31% Analysis value: C, 55.41; H, 5.41; I, 36.91% For more details on the production method of these compounds and the physical properties of the obtained compounds, refer to Japanese Patent Application Laid-Open No. 62-26524
See Japanese Patent Application No. 61-106850, which is incorporated herein by reference.

Further, the antibacterial agent of the present invention containing the compound of general formula [I] as an active ingredient can be applied to a wide range of uses. First, it has been found that the antibacterial agent of the present invention is extremely useful for medical purposes. For example, the antibacterial agent is applied as a therapeutic agent for external diseases caused by molds such as genus Cajundeida, genus Aspergillus, genus Trichophyton, and genus Cryptococcus to the affected area in a use form such as a liquid agent and an ointment You can reach your purpose. In this case, the content of the active ingredient in the preparation can vary widely depending on the form of the preparation, but is generally 0.
It is suitable to mix in the range of 1 to 5%, preferably 0.5 to 2%. It can also be used as an antibacterial agent for animals such as pet animals or livestock. Further, it may be contained as a disinfectant or other active ingredient for machine tools for the purpose of preventing the growth of pathogenic bacteria and molds for medical purposes and maintaining a sterile environment. Further, the antibacterial agent of the present invention is used as an antibacterial agent in a wide range of fields of agriculture and industry, such as seeds, seedlings, agricultural and horticultural crops, wood, woodwork, paper crafts, leather,
It can be used to eradicate harmful bacteria and molds that attack agricultural products and industrial products including fibers, adhesives, paints, synthetic resins and the like. Further, it can also be used for the purpose of maintaining the quality and production of products and products in these fields and preserving the manufacturing environment.

As the form of use of the antibacterial agent of the present invention in these agricultural and industrial fields, a formulation retained on a commonly used carrier,
Examples thereof include oil solvents, emulsions, pastes, powders, wettable powders, granules, aerosols, antifungal paints and antifungal adhesives. Examples of the carrier used include inorganic solid carriers such as clay, talc, bentonite, kaolin, silicic acid anhydride, and calcium carbonate, organic solvent-based carriers such as kerosene, ligroin, xylene, dimethylformamide, and dimethylsulfoxide, dimethyl ether, freon gas, and the like. Examples of the gas carrier include, as an auxiliary agent for further enhancing the effect of the preparation, an appropriate one usually used, for example, an ionic or nonionic surfactant and a polymer compound such as polyvinyl acetate or methyl cellulose. is there. Further, these antibacterial agents of the present invention can also be used in combination with other antiseptic / antifungal agents such as siabendazole, insecticide / miticide, fungicides, herbicides, plant growth regulators and the like. The content of the active ingredient compound in these formulations may vary widely depending on the formulation form, but is generally 0.01-9.
A range of 5% by weight, preferably 0.2-40% by weight is suitable.

Examples Next will be described formulation examples of an antibacterial agent and test examples exemplifying the effect as an excellent antibacterial agent as examples of the present invention, but the present invention is not limited to the following examples, and here It goes without saying that many variations or modification means not exemplarily described in the above can be adopted. Formulation Examples 1 to 4 show formulation examples of medical antibacterial agents, and Formulation Examples 5 to 9 show formulation examples of agricultural and horticultural, household and industrial antibacterial agents.

Formulation Example 1 (Liquid formulation) Ingredients by weight Compound No. 5 1 Diethyl sebacate 10 Ethanol 80 Water 9 By uniformly mixing and dissolving the above ingredients, a liquid preparation containing 1% of the active ingredient is obtained.

Formulation Example 2 (ointment) compounding ingredients by weight Compound No. 5 1 Liquid paraffin 10 White petrolatum 89 The above components are uniformly mixed and kneaded to obtain an ointment containing 1% of the active ingredient.

Formulation Example 3 (Rocheon) Compounding Part by Weight Compound No. 5 1 Stearyl alcohol 4 Liquid paraffin 35 Sodium lauryl sulphate 1 Sorbitan monolaurate 5.5 Polyoxyethylene sorbitan monolaurate 2.5 Propylene glycol 1 Methyl paraoxybenzoate 0.05 Propyl paraoxybenzoate 0.025 Water 49.925 Effective if the above ingredients are mixed uniformly. A lotion containing 1% of the ingredients is obtained.

Formulation Example 4 (Suppository) Ingredients by Weight Compound No. 5 1 Higher fatty acid glyceride 99 After the above ingredients are uniformly mixed, they are poured into a metal mold, cooled and solidified, and then taken out from the mold to obtain a suppository containing 1% of the active ingredient.

Formulation Example 5 (Emulsion) Ingredients by Weight Compound No. 5 20 N, N-Dimethylformamide 20 Xylene 45 Polyoxyethylene alkylphenyl ether 12 Calcium alkylbenzenesulfonate salt 3 By uniformly mixing and dissolving the above components, an emulsion containing 20% of the active ingredient is obtained.

Formulation example 6 (powder) formulation parts by weight compound No. 6 3 Calcium stearate 1 Silica powder 20 Clay 28 Talc 48 The above ingredients are uniformly mixed and pulverized to obtain a powder containing 3% of the active ingredient.

Formulation Example 7 (Wettable powder) Ingredients by weight Compound No. 5 10 Clay 10 Silicic anhydride powder 75 Lignin sulfonic acid calcium salt 3 Polyoxyethylene alkylaryl ether 2 By uniformly mixing and grinding the above components, a wettable powder containing 10% of the active ingredient is obtained.

Formulation Example 8 (Granule) Ingredients by Weight Compound No. 7 10 Clay 77 Silicic anhydride powder 10 Carboxymethyl cellulose 3 Mixing the above components, adding an appropriate amount of water, kneading and synthesizing, and drying, a granule containing 10% of the active ingredient is obtained.

Formulation Example 9 (Flowable Agent) Compounding Ingredients by Weight Compound No. 5 25 Machine oil 57 Kerosene 10 Polyoxyethylene alkylphenyl ether 5 Calcium salt of alkylbenzene sulfonic acid 3 By mixing and dissolving the above components uniformly, a flowable agent containing 25% of the active ingredient is obtained.

Test Example 1 Antibacterial test against medicinal fungi Minimum inhibitory concentration (MIC) of test compound against medicinal fungi
Was measured by the agar plate dilution method (Sabouraud agar medium). The results are shown in Table 1. Each of the test compounds had a broad antifungal spectrum.

Test Example 2 Antibacterial test against phytopathogenic fungi The phytopathogenic fungi described in Table 2 were used as test bacteria to examine the presence or absence of growth of hyphae on an agar plate, and the minimum growth inhibitory concentration was determined. That is, a test compound was mixed in a Valeilyo decoction agar medium to prepare a dilution series, which was poured into a Petri dish and solidified to prepare an agar plate. The test bacteria were inoculated on the agar plate, and after culturing at 25 ° C. for 72 hours, the presence or absence of growth of the test bacteria was observed. The results of measurement of the minimum growth inhibitory concentration are shown in Table 2. All of the test compounds exhibited antibacterial activity against phytopathogenic bacteria.

Test Example 3 Antibacterial test against harmful bacterium of industrial material The harmful bacterium of industrial material described in Table 3 was tested as a test bacterium in the same manner as in Test Example 2, and after culturing for 10 days, the minimum inhibitory concentration was determined. All of the test compounds showed strong antibacterial action against harmful bacteria of industrial materials.

Test Example 4 Experimental therapeutic effect on Trichophyton infection Trichophyton mentaglophytes (Trichophyton) on two compartments of dorsal skin of guinea pigs (tested for 5 animals per group) that had been plucked
mentagrophytes) 530324 inoculated with experimental Trichophyton cinerea infected foci, compound No. 5% 1% liquid (Compound No.
5: 1 g, diethyl sebacate: 10 ml, ethanol:
80 ml, water: 10 ml) twice a day from the second day after inoculation,
It was applied for 10 days. On the day after the final treatment, autopsy was performed, and 5 skin pieces per section from the infected site were collected and subjected to a culture test, which was used as an index for determining the therapeutic effect together with the macroscopic findings. The results are shown in Tables 4 and 5. That is, in the culture test, as in the case of the control drug, the negative rate was 100%, and the macroscopic observation result exceeded that, showing an excellent therapeutic effect. As a control drug, Kozak S (2% tolnaftate, external solution, commercially available product) was used.

One group consists of 5 animals, and the average value is shown. -Almost normal, ± extremely mild, + mild, ++ moderately strong, +++ strength Test Example 5 Rice blast disease control test Four-leaf stage rice seedlings (cultivar "Tokuseki") were grown in plastic pots with a diameter of 6.5 cm, 8 each. The emulsion prepared according to Preparation Example 5 above was prepared into a spray solution having a predetermined concentration, and sprayed at a rate of 40 ml / 3 pot using a spray gun.
After air-drying the rice seedlings, a conidia suspension of rice blast fungus was uniformly sprayed and inoculated, and the rice seedlings were kept in a humid chamber at 24 ° C. overnight. After that, it was transferred to an artificial weather room at 25 ° C. to cause disease, and 7 days after the inoculation, the number of lesions was counted and counted, and the control value was calculated by the following formula.

The results are shown in Table 6. All of the test compounds showed high control effect.

Test Example 6 Rice scab seedling disease seed disinfection test A chemical solution having a predetermined concentration was prepared using the wettable powder produced according to the above-mentioned Formulation Example 7, and rice paddy seedling disease fungus-infected rice paddy (variety "Kinki No. 33") was prepared. ) Was immersed at 25 ° C. for 24 hours.
After the dipping treatment, the rice paddy is air-dried and then soaked at 10 ° C.,
Furthermore, it was germinated at 32 ° C. The germinated rice paddy was placed on the rice scab seedling disease selective medium in a Petri dish, the culture was continued as it was at 25 ° C., and two weeks later, the presence or absence of the rice scab seedling fungus that had formed around the rice paddy was examined. The results are shown in Table 7. All the test compounds showed high seed disinfecting effect.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Kuniomi Matsumoto 760 Meiji Seika Co., Ltd., Meiji Seika Co., Ltd., Kohoku Ward, Yokohama City, Kanagawa Prefecture (72) Inventor Tetsuro Watanabe 760 Meiji Seika, Shimooka Town, Kohoku Ward, Yokohama City, Kanagawa Prefecture Pharmaceutical Research Institute Co., Ltd. (72) Inventor Yuzo Kazuno 760 Meiji Seika Co., Ltd., Kohoku-ku, Yokohama City, Kanagawa Prefecture Meiji Seika Co., Ltd. (72) Inventor Takashi Inagaki 1-4-10 Wakihamacho, Chuo-ku, Kobe-shi, Hyogo Prefecture Nihonhon Terpene Chemical Co., Ltd. (72) Inventor Hiroyuki Takeuchi 1-4-10 Wakihama-cho, Chuo-ku, Kobe-shi, Hyogo Nihon Terpene Chemical Co., Ltd.

Claims (5)

[Claims] 1. General formula [I]: ROCH ₂ C≡CI [I] (wherein R is 3,7-dimethyloct-2-trans-
An antibacterial agent containing a terpene iodopropargyl ether represented by 6-dienyl group, bornane group, paramenta-1,8-diene group or paramentha-1-ene group) as an active ingredient. 2. The antibacterial agent according to claim 1, wherein the active ingredient is 3-iodo- (3,7-dimethyloct-2-trans-6-dienyl) -2-propynyl ether. 3. The active ingredient is 3-iodo- (bornane-2-
The antibacterial agent according to claim 1, which is yl) -2-propynyl ether. 4. The active ingredient is 3-iodo (paramentor).
The antibacterial agent according to claim 1, which is 1,8-dien-7-yl) -2-propynyl ether. 5. The active ingredient is 3-iodo- (paramenta-1).
The antibacterial agent according to claim 1, which is -en-8-yl) -2-propynyl ether.