JPS6242917B2 - - Google Patents

Description

[Detailed description of the invention]

[] Background of the Invention The present invention relates to a new antibiotic, a method for producing the same, and a plant disease control agent containing this substance as an active ingredient, particularly a fungicide for agricultural and horticultural use. [] Summary of the Invention The present inventors have discovered that a substance having antibacterial activity against rice sheath blight bacteria, Gram-positive bacteria, and Gram-negative bacteria is produced in a culture of a certain strain belonging to the genus Streptomyces. We discovered the active substance, isolated it from the culture, determined its physicochemical properties, and named it SF-2111. It was also confirmed that this substance and its acid addition salt are effective as plant disease control agents such as agricultural and horticultural fungicides. Therefore, the antibiotic SF-2111 substance and its acid addition salt according to the present invention are characterized in that the hydrochloride thereof is a water-soluble basic antifungal and antibacterial substance having the following physical and chemical properties. It is. (1) Appearance White amorphous powder (2) Melting point No clear melting point, foams and decomposes at 189-193°C. (3) Elemental analysis values (wt%) C 42.42% H 6.23% N 16.19% Cl 4.14% (4) Ultraviolet absorption spectrum There is no characteristic ultraviolet absorption maximum between 220 nm and 370 nm in aqueous solution. (5) Infrared absorption spectrum Potassium bromide tablets have the infrared absorption spectrum shown in Figure 1. (6) Solubility Easily soluble in water, sparingly soluble or insoluble in methanol, ethanol, n-butanol, acetone, ethyl acetate, chloroform, benzene, and ether. (7) Stability Stable in acidic to neutral conditions, but unstable in alkaline conditions. (8) Color reactions Positive for ninhydrin, Remieux, Tollens, and sulfuric acid reactions, negative for ferric chloride, silver nitrate, and Biuretz reactions. (9) Rf value of silica gel thin layer chromatogram Developing solvent Rf value n-butanol/acetic acid/water 0.14 (2:1:1) n-propanol/pyridine/acetic acid/water 0.56 (15:10:3:12) ( 10) Specific optical rotation (in aqueous solution) [α] ²³ _D -55.5° (Cl, H ₂ O) Furthermore, the method for producing the antibiotic SF-2111 substance according to the present invention is a method for producing SF-2111, which belongs to the genus Streptomyces.
From the culture obtained by culturing 2111 substance-producing bacteria,
It is characterized by collecting SF-2111 substance. Furthermore, the plant disease control agent according to the present invention includes:
It is characterized by containing SF-2111 substance or its acid addition salt as an active ingredient. [] Detailed description of the invention 1 Production of antibiotic SF-2111 substance 1 SF-2111 substance-producing bacteria SF-2111 substance is obtained by culturing SF-2111 substance-producing bacteria belonging to the genus Streptomyces. The SF-2111 substance-producing bacteria used in the method of the present invention are those that have the ability to produce a sufficient amount of SF-2111 substance to be collected into the culture. Examples of such strains include SF-, which was newly isolated from soil by the present inventors.
There are 2111 stocks. Strain SF-2111 was isolated from soil at the edge of a pond in Gojome Town, Minamiakita District, Akita Prefecture in May 1971. The mycological properties of SF-2111 strain are as shown below. Morphology Aerial fungi generally have poor adhesion, but on starch agar they adhere abundantly and spore formation is good.
The branches are simple and no axle branches are seen. Basal hyphae usually do not divide. The tips of aerial hyphae are straight or slightly wavy. When observed with an electron microscope, the surface structure of the spores is smooth. The spores are oval or cylindrical in shape, and the size is
0.4-0.6 x 0.9-1.2 microns, usually 10 or more spores in chains. Growth status on various media When cultured on various media at 28℃ for 14 to 21 days
The growth status of SF-2111 strain is shown in Table 1. The standard colors shown in [ ] in the table are Color
Harmony Manual (Container Corporation of
This is based on the color classification by America Corporation).

[Table] Physiological properties (1) Growth temperature range: 15 to 40 on starch agar
It grows in a temperature range of 25°C to 37°C. (2) Liquefaction of gelatin: Positive (20℃, 14 days of culture) (3) Starch hydrolysis: Positive (28℃, 14 days of culture) (4) Peptonization of skim milk: Positive (28℃, 14 days of culture) ) Coagulation of skim milk: Strong peptonization, coagulation unknown (5) Nitrate reduction: Negative (28℃, 14 days culture) (6) Salt tolerance: Grows at 4.0%, but not at 5.0%. (7) Production of melanin-like pigment: negative Availability of carbon source (using Pridham-Gotzlieb agar) D-glucose, D-fructose, D-xylose, D-mannitol, L-arabinose,
L-rhamnose, i-inositol, raffinose, and sucrose are all commonly utilized. Cell wall composition Method of Becker et al. [Appl.
Microbiol. 13: 236 (1965)] showed that diaminopimelic acid in the cell wall composition was of the LL type. To summarize the above properties, strain SF-2111 belongs to the genus Streptomyces, the tips of the aerial hyphae are straight to wavy, and the spore surface structure is smooth. The color tone of aerial mycelia is mainly gray-pink, with occasional yellow tones. The underside is light yellow to light brown, and no soluble pigment is produced in any medium. The present inventors used the SF-2111 strain as Streptomyces sp.
SF-2111). This strain has been deposited with the Institute of Microbial Technology, Agency of Industrial Science and Technology (Feikoken), and its accession number is Fiber Science and Technology Research Institute No. 5350. 2. Cultivation In the method of the present invention, SF-2111 substance-producing bacteria of the genus Streptomyces, such as the above-mentioned strain, are cultured in a medium containing nutrients that can be used by ordinary microorganisms. As the nutrient source, any known nutrient source conventionally used for culturing Streptomyces bacteria can be used. For example, as a carbon source, glucose, glycerol, starch, starch syrup, molasses, sucrose,
Dextrin, soybean oil, etc. can be used. As the nitrogen source, soybean flour, wheat germ, cottonseed meal, meat extract, pebtone, corn stable liquor, yeast extract, urea, ammonium sulfate, sodium nitrate, etc. can be used. others,
Calcium carbonate, sodium chloride, as needed.
In addition to adding inorganic salts such as phosphates, various organic and inorganic substances that can support the growth of bacteria and promote the production of SF-2111 substances can be appropriately added. The most suitable culture method is the deep culture method under aerobic conditions, similar to the method used for general antibiotic production. The appropriate temperature for culturing is 25-37℃, but 28℃
It is often cultivated nearby. Production of SF-2111 substance reaches its maximum accumulation in 2 to 7 days for both shaking culture and tank culture. 3 Assay The following method is used for assaying SF-2111 substances. Glucose 2.5% as assay medium;
Sodium nitrate 0.2%, phosphoric acid - potassium 0.1%, magnesium sulfate 0.05%, potassium chloride 0.05%, ferrous sulfate
A medium with a composition of 0.01% agar and 1.5% agar is used. Pericularia sasakii is used as the test bacterium. SF-2111 substance is 125 in the assay using this.
mg/ml to 16 mg/ml, the relationship between the logarithm of the concentration and the inhibition circle diameter shows a linear relationship, 42.5 to 22.3, respectively.
Give a stopping circle diameter of mm (paper disk plate method). 4 Collection SF-2111 substance obtained by the present invention is a water-soluble basic antibiotic. When collecting this from the culture, it is extracted and purified using activated carbon powder and products such as "Amberlite Adsorption of nonionic cross-polystyrene polymer by adsorption resin, “Amberlite 1RC”
-50" (Rohm & Haas, USA), "Amberlite CG-50" (Rohm & Haas, USA), and other cation exchange resins; Pharmacia Huain Chemical Co.), “Biogel P-
Chromatography using a gel-permeable resin such as "2" (Bio-Rad Co., Ltd.) is used. Specifically, the following collection method is efficient.
That is, the active ingredients accumulated in the culture solution are adsorbed onto "Diaion HP-20" and eluted with a 50% acetone aqueous solution. The eluate is concentrated under reduced pressure to remove acetone. This is further changed to “CM―
High purity SF-2111 substance can be obtained by appropriately combining ``Sephadex'' (Na <sup>+</sup> type), activated carbon adsorption, ``Sephadex LH 20'', ``Sephadex G-10'' column chromatography, etc. The SF-2111 substance obtained by the above method is obtained as a white amorphous powder hydrochloride by freeze-drying. 2 SF-2111 Substance 1 Free Base and Acid Addition Salt As mentioned above, SF-2111 substance is a water-soluble basic antibiotic. Therefore, SF-2111 substances are capable of forming acid addition salts. Examples of acid addition salts include, in addition to the above-mentioned hydrochlorides, salts with pharmaceutically acceptable inorganic acids such as hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, as well as acetic acid, citric acid, benzoic acid, There are salts with pharmaceutically acceptable organic acids such as ascorbic acid. 2 Physical and chemical properties SF-2111 substance has the following physical and chemical properties as its hydrochloride. 1 Appearance: White amorphous powder 2 Melting point: Gradually turns brown from around 174℃, 189~
Foaming decomposes at 193℃. 3 Elemental analysis values: C 42.42% H 6.23% N 16.19% Cl 4.14% 4 Ultraviolet absorption spectrum: 220 nm ~ in aqueous solution
There is no characteristic ultraviolet absorption maximum at 370 nm. 5 Infrared absorption spectrum: SF-2111 substance (hydrochloride) measured in potassium bromide tablets
Figure 1 shows the infrared absorption spectrum of . 6 Solubility: Easily soluble in water, poorly soluble or insoluble in methanol, ethanol, n-butanol, acetone, ethyl acetate, chloroform, benzene, and ether. 7 Stability: Stable in acidic to neutral conditions, but unstable in alkaline conditions. 8 Color reaction: Positive for ninhydrin, Remieux, Tollens and sulfuric acid reactions, negative for ferric chloride, silver nitrate and Biuret reactions. 9 R ₊ value of silica gel thin layer chromatography (Merck & Co. “Kiesel 60F-254”): Developing solvent R ₊ value n-butanol/acetic acid/water 0.14 (2:1:1) n-propanol/pyridine/acetic acid/ Water 0.56 (15:10:3:12) n-propanol/acetic acid/water 0.08 (4:1:1) 10 Specific optical rotation: [α] ²³ _D -55.5° (Cl, H ₂ O) 11 High pressure paper electricity Electrophoresis: Using Toyo Paper No. 51, PH
When electrophoresis is performed at 3500V for 30 minutes with the pyridine-acetate buffer (200 ml of pyridine and 8 ml of acetic acid dissolved in 3 liters of water) buffer described in 6.4, SF appears on the cathode side.
-2111 substance moves 11.3cm, DL-alanine moves 3.1cm, L-lysine moves 21.0cm
Each moved. 12 Hydrogen nuclear magnetic resonance spectrum measured in heavy water (100MHz, TMS external standard): As shown in Figure 2. 13 Molecular weight: Molecular weight estimated to be 650-700 by titration. 3. Antibacterial activity The antibacterial activity of the SF-2111 substance against various microorganisms was shown using the paper disc method, and the results are as follows.

【table】

[Table] The antifungal spectrum (indicating the minimum inhibitory concentration) obtained by the agar dilution method using Czapetsk medium is as follows.

【table】

[Table] 4 Toxicity In an acute toxicity test using SF-2111 substance in mice, 50% survived when administered intravenously at 50 mg/Kg. In addition, in a fish toxicity test using Japanese medaka, no abnormalities were observed in the fish at 5ppm. 5. Use as an antibiotic As mentioned above, substance SF-2111 or its acid addition salt has antibacterial activity against Gram-positive and Gram-negative bacteria, and therefore is useful for the prevention and treatment of infectious diseases caused by these microorganisms. It can be used as a pharmaceutical or veterinary drug. When the antibiotic SF-2111 of the present invention is used as a medicine for the prevention and treatment of infectious diseases, the dosage and route of administration should be determined by considering the above-mentioned antibacterial properties and toxicity, and depending on the patient's condition. It may be determined as appropriate in the same manner as in the case of antibiotics caused by Streptomyces bacteria. 3. Plant disease control agent Since the antibiotic SF-2111 according to the present invention has strong antibacterial activity against plant pathogenic bacteria, the SF-2111 substance or its acid addition salt can be used as a plant disease control agent such as a fungicide for agriculture and horticulture. It is possible. The plant disease control agent according to the present invention may be in any form that can be used as an agricultural or horticultural agent, especially a fungicide, except that the active ingredient is the SF-2111 substance or its acid addition salt. It can be used in various ways. Specifically, for example, the SF-2111 substance of the present invention or its acid addition salt may be used as is or diluted with water, solid powder, or other suitable carrier, and if necessary, an auxiliary agent such as a spreading agent may be added. Use in addition or
Alternatively, various liquid or solid carriers may be mixed using methods commonly used in agricultural chemical manufacturing, and if necessary, supplements such as wetting agents, spreading agents, dispersing agents, emulsifiers, fixing agents, and lubricants may be added. Adding agents, hydrating agents, liquid agents,
It can be used in various formulations such as emulsions, powders, granules, and fine granules. In producing these preparations, the liquid carrier used is one that serves as a solvent for the SF-2111 substance of the present invention or its acid addition salt, or one that can be dispersed or dissolved with an auxiliary agent.
For example, water, aromatic hydrocarbons, aliphatic hydrocarbons, alcohols, esters, ketones, highly polar dimethylformamide, dimethyl sulfoxide, etc. Solid carriers include clay, kaolin, talc, diatomaceous earth, Mineral powders such as bentonite, calcium carbonate, and silica, sand and gravel, wood flour, and other organic powders and granules can be used. Examples of auxiliary agents include nonionic, anionic, cationic, and amphoteric surfactants, ligninsulfonic acid or its salts, gums, fatty acid salts, and thickeners such as methyl cellulose. The pesticidal agent according to the present invention can be used by spraying on the foliage of crops, and can also be applied to water surfaces, water, soil surfaces, and soil.
In this case, compatible agricultural and horticultural chemicals or fertilizers may be used. Examples of such agricultural and horticultural chemicals include fungicides, insecticides, herbicides, and plant growth regulators. When the plant disease control agent of the present invention is used as a liquid agent, it is desirable that the compound of the present invention be contained in the spray solution at a concentration of 10 to 1000 ppm (in the case of concentrated small amount spraying, aircraft spraying, etc.). If necessary, it can be used as a more concentrated spray solution), but when used as a powder, granule, fine granule, etc., it is desirable to have a content of 0.1 to 30%. The amount of application varies depending on the type and severity of the target disease, the type of target crop, the mode of application, etc., but for example, when applying to soil, for example, 50% of a hydrating powder (20% active ingredient) per 10 ares. ~200 liters, for example 50~ for water solvent (10% active ingredient)
Appropriate application amounts are generally 200 liters, 2 to 6 kg for granules (5% active ingredient), and 2 to 6 kg for powders (2% active ingredient). 4 Experimental Examples The present invention is not limited to the following examples, and it goes without saying that many modifications and modification means not exemplified here can be adopted. 1. Production of SF-2111 substance (1) Cultivation Spores of Streptomyces sp. SF-2111 strain (NIFE accession number 5350) were placed in 1200 ml of a liquid medium containing 1% starch and 3% soybean flour (PH7).
(Use 12 500ml Erlenmeyer flasks) and culture with shaking at 28°C for 40 hours, and use as seed mother. Glucose 1.0%, starch syrup 4.0%, "Sungrain" 0.5%, soy flour 2.5%, yeast extract 0.2%, soybean oil 0.2%, cobalt chloride 0.0001%, ferrous sulfate
The seed mother was inoculated into 35 liters of a liquid medium having a composition of 0.001% (PH7), and cultured with aeration at 28°C for 90 hours. (2) Extraction After completion of the culture, the culture was filtered by adding a supernatant "Hyflo Super Cell", and a water washing solution was added to obtain 40 liters of solution. When this liquid is passed through a 6 liter column of "Diaion HP-20", the SF-2111 substance is adsorbed by the resin. After washing with 30 liters of water, elution was carried out with 20 liters of 50% acetone water and fractionated into 5 liters each.
The active fraction was obtained in the second 5 liters. This was concentrated under reduced pressure to obtain 2 liters of an aqueous solution. Add 2 liters of an aqueous solution containing the SF-2111 substance to cation exchange resin “CM Sefadex C-25” (Na ⁺
Type) Adsorb onto a 500 ml column, wash with 2.5 liters of water, elute with 1.5 liters of 0.2M saline, adsorb this solution onto a 50 ml column of activated carbon, and remove 250 ml.
After washing with water, elute with 500ml of 50% acetone water,
Concentrate to 50 ml under reduced pressure, freeze-dry, and prepare SF-
Obtained 2.67 g of pale yellowish white powder containing substance 2111 (purity
40%). (3) Dissolve 2.5g of crude powder containing purified SF-2111 substance in a small amount of water and prepare "CM Cephadex C-25 (Na ⁺ type)".
Place it on top of a 100ml column and wash with 500ml of water.
When developed and eluted with 0.01M saline, the fraction was divided into 10ml fractions.
An active classification was obtained between numbers 160 and 360. Adsorb 2 liters of active fraction onto a 60ml column of activated carbon, then add 300ml
After washing with water, the product was eluted with 600 ml of 50% acetone water, concentrated under reduced pressure, and lyophilized to obtain 487 mg of white powder (purity 90%). Dissolve 450 mg of this white powder in a small amount of water, place it on the top of a "Sephadex G-10" column (350 ml), and develop it with water.
No. 16 showed a single spot on silica gel thin layer chromatography using various solvents. This solution was freeze-dried to obtain 152 mg of white powder of SF-2111 substance. 2. Formulation Some of the formulations of the agricultural and horticultural disease control agent using the SF-2111 substance of the present invention are as follows, for example. Formulation example 1 Wettable powder Part by weight SF-2111 substance 20 Clay 10 Diatomaceous earth 65 Lignin sulfonic acid 3 Polyoxyethylene alkyl allyl ether 2 If the above ingredients are uniformly ground and mixed, water containing 20% of the active ingredient is obtained. Obtain Japanese medicine. Formulation example 2 Part by weight of water solvent SF-2111 substance 10 Polyoxyethylene alkyl allyl ether 2 Water 98 If the above ingredients are mixed and dissolved, the active ingredient will be 10%.
to obtain an aqueous solvent containing. Formulation example 3 Granules by weight SF-2111 substance 5 Clay 92 Carboxymethyl cellulose 3 Mix the above ingredients, add an appropriate amount of water, knead and dry to form granules containing 5% of the active ingredient. get. Formulation Example 4 Powder Part by Weight SF-2111 Substance 2 Calcium Stearate 1 Silicic Anhydride Powder 1 Clay 48 Talc 48 The above components are uniformly ground and mixed to obtain a powder containing 2% of the active ingredient. 3 Medicinal efficacy test Test example 1 Rice sheath blight control effect test The above formulation example 2 was applied to paddy rice (cultivar "Jukoku") at the earing stage grown in a 1/5000 are Wagner pot.
The aqueous solution manufactured by
cm ² ) at a rate of 70 ml/3 pots. Immediately after air-drying, the sheath blight bacteria obtained by plating on a peptone-added potato decoction agar medium for 48 hours were grown.
Inoculation was performed by inserting a piece of mycelium-containing agar punched with a 0.5 cm cork borer into the center of the plant, 15 cm from the ground surface. After inoculation, each pot was covered with a vinyl cylinder to encourage the invasion of the sheath blight fungus and left in a glass greenhouse at 30°C during the day and 24°C at night to develop the disease. Ten days after inoculation, the infected stems were examined. The lesion length was measured and the control value was calculated according to the following formula. In addition, the occurrence of drug damage is
At the same time, this was done by visual observation. Control value (%) = (1 - average lesion length of treated area/average lesion length of untreated area) x 100 The results were as shown in Table 4.

[Table] Test Example 2 Seedling damping-off control test Seedling damping-off fungus (Rhizoctonia type IA fungus) was cultured on a potato decoction agar medium and mixed and ground with 3 culture volumes of rice bran to prepare an inoculum. Ivy. Using tomatoes (variety ``Hikari'') and cucumbers (variety ``Satsuki Midori'') as test crops, 20 sprouted seeds per pot were sown and covered with soil in 1/5000 Ahl Wagner pots filled with sterilized field soil. Inoculation was carried out by uniformly spraying a mixture of equal amounts of the inoculum and sterilized field soil onto the mixture. After inoculation, let stand in a constant temperature room at 28°C for 48 hours, then prepare the hydrating powder prepared in Formulation Example 1 to a specified concentration and use it as an irrigation solution, and pipette 100 ml of this solution per pot evenly onto the ground surface. It was applied under pouring. Thereafter, in order to facilitate the progress of invasion of the inoculum, the plants were transported to a glass greenhouse at a temperature of 30°C to 28°C, and the soil in the pot was kept in a slightly dry state to develop the disease. In the investigation, the number of germination and the number of healthy seedlings up to 3 weeks after sowing were investigated, and the germination rate relative to the number of sown grains and the percentage of healthy seedlings relative to the number of germination were calculated. The results were as shown in Table 5.

[Table] Test Example 3 Powdery mildew control test on cucumbers Using water produced according to Formulation Example 1, three cucumber seedlings (cultivar "Satsuki Midori") in the second true leaf stage were grown in No. 3 clay pots. Prepare the medicinal solution so that it has the prescribed concentration and spray it with a spray gun.
Sprayed 35ml per pot, air-dried, moved to an artificial climate room, uniformly sprayed with a conidial suspension of powdery mildew of cucumber, and inoculated. After 14 days, the disease developed to the same extent as in the non-sprayed area. The degree of disease onset was investigated by assigning a disease index of 3, with no disease observed at all as a disease index of 0, and those in between, a disease index of 1 or 2, and the control value was calculated using the following formula. Control value (%) = (1 - average disease index of sprayed plots/average disease index of non-sprayed plots) x 100 The results were as shown in Table 6.

[Table] Test Example 4 Anthracnose control effect test on cucumber An aqueous solution produced according to Formulation Example 2 using cucumber seedlings (cultivar "Satsuki Midori") at the second true leaf development stage grown in three seedlings in a No. 3 clay pot. Prepare the chemical solution to a specified concentration and spray it with a spray gun.
Spray 40ml per pot, air dry, place in a humid room at 24°C, inoculate by evenly spraying conidial suspension of melon anthracnose, keep in the humid room overnight, and then place in an artificial climate room. It was transferred and caused the disease. The degree of disease onset was determined 5 days after vaccination.
0 for those without any disease, 1 or more lesions per leaf
5 items have an index of 1, 6 to 15 items have an index of 2, 16 to 30 items have an index of 3, 31 to 50 items have an index of 4, and 51 or more items have an index of 4. An index of 5 was given to each species, and the pesticidal value was calculated using the following formula. Control value (%) = (1 - average disease index of sprayed plots/average disease index of non-sprayed plots) x 100 The results were as shown in Table 7.

【table】 [Brief explanation of the drawing]

Figure 1 is a reproduction of the infrared absorption curve of SF-2111 substance hydrochloride using the potassium bromide tablet method. Figure 2 is a reproduction of the hydrogen nuclear magnetic resonance spectrum (100MHz) of SF-2111 substance hydrochloride measured in heavy water.

Claims (1)

[Scope of Claims] 1. Antibiotic SF-2111 substance and its acid addition salt, characterized in that the hydrochloride salt is a water-soluble basic antifungal and antibacterial substance having the following physical and chemical properties. (1) Appearance White amorphous powder (2) Melting point No clear melting point, foams and decomposes at 189-193°C. (3) Elemental analysis values (wt%) C 42.42% H 6.23% N 16.19% Cl 4.14% (4) Ultraviolet absorption spectrum There is no characteristic ultraviolet absorption maximum between 220 nm and 370 nm in aqueous solution. (5) Infrared absorption spectrum Potassium bromide tablets have the infrared absorption spectrum shown in Figure 1. (6) Solubility Easily soluble in water, sparingly soluble or insoluble in methanol, ethanol, n-butanol, acetone, ethyl acetate, chloroform, benzene, and ether. (7) Stability Stable in acidic to neutral conditions, but unstable in alkaline conditions. (8) Color reactions Positive for ninhydrin, Remieux, Tollens, and sulfuric acid reactions, negative for ferric chloride, silver nitrate, and Biuretz reactions. (9) Rf value of silica gel thin layer chromatogram Development medium Rf value n-Butanol/acetic acid/water 0.14 (2:1:1) n-propanol/pyridine/acetic acid/water 0.56 (15:10:3:12) (10) Specific optical rotation (in aqueous solution) [α] ²³ _D -55.5° (Cl, H ₂ O) 2 SF-2111 substance-producing bacteria belonging to the genus Streptomyces was cultivated, and SF-
Antibiotics characterized by collecting 2111 substances
SF-2111 Substance manufacturing method. 3. A plant disease control agent characterized by containing SF-2111 substance or its acid addition salt as an active ingredient.