JP2006213703A - New fermentation product - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound useful as an antibacterial agent against bacteria of the genus Propionibacterium. <P>SOLUTION: The new cyclic compound is isolated from Streptomyces sp. Q47152 strain and has an excellent antibacterial activity against bacteria of the genus Propionibacterium. A drug composition containing the compound as an active ingredient is useful as an antibacterial agent, particularly a treating agent for acne vulgaris and the like. A new strain which produces the compound and a method for producing the compound by using the strain are provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel fermented product useful as an antibacterial agent against pharmaceuticals, particularly Propionibacterium spp.

Acne vulgaris is a chronic inflammatory disease of sebaceous hair follicles that mainly develops around puberty. Acne vulgaris is an increase in androgen secretion, increased sebum secretion, formation of comedones due to narrowing of the pores due to abnormal keratinization of the hair follicle funnel, and Proponibacterium spp., Particularly Propionibacterium It develops with the involvement of extracellular enzymes such as lipase produced by bacteria in hair follicles such as acnes (Propionibacterium acnes) and inflammatory substances such as neutrophil migration factor. After onset, comedones and abscesses are formed, with pigmentation and small scars remaining. In this treatment, various antibacterial agents such as sulfur, salicylic acid, resorcin, and macrolide antibiotics are used to control the growth of P. acnes along with the removal of the stratum corneum blocking the pores. Yes. However, with the emergence of resistant bacteria to widely used macrolide antibiotics and the like, the development of effective therapeutic agents is still eagerly desired.
There are reports of cyclic fermentation products having an anti-inflammatory effect (for example, Patent Documents 1 and 2 and Non-Patent Document 1). However, there is no disclosure of a compound having an excellent antibacterial activity for Propionibacterium species.
JP2005-200324 WO95 / 22339 J. Am. Chem. Soc., 1999, 121, p11273-11276

  The creation of a new therapeutic agent for acne vulgaris that has excellent antibacterial activity against the species of the genus Propionibacterium, in particular, Propionibacterium acnes is eagerly desired.

（式中、R¹は水素原子又は水酸基を、R²は水素原子又はクロロ原子を、R³並びにR⁴は一方が水酸基で、他方がメトキシメチル又はクロロメチル基を意味するか、R³とR⁴が一体となって、式

で示される基を意味する。以下同様。） As a result of diligent search for physiologically active substances obtained from various microorganisms, the present inventors have found that a novel cyclic compound having antibacterial activity superior to Propionibacterium species than Streptomyces sp. The present invention has been completed.
That is, the present invention relates to a cyclic compound represented by the following formula (I) or a salt thereof. The present invention also relates to a pharmaceutical composition containing the compound as an active ingredient, particularly an antibacterial agent, a novel strain producing the compound, and a method for producing the compound using the strain.

(Wherein, the R ¹ is a hydrogen atom or a hydroxyl group, an R ² represents a hydrogen atom or a chloro atom, one R ³ and R ⁴ has a hydroxyl group, or the other means a methoxymethyl or chloromethyl group, with R ³ R ⁴ is united

Means a group represented by The same applies hereinafter. )

  The compound of the present invention has excellent antibacterial activity against Propionibacterium species, in particular, Propionibacterium acnes, and is useful for the treatment of acne vulgaris as an antibacterial agent.

  The cyclic compound of the present invention is obtained by a conventional method from a culture in which the substance-producing bacteria belonging to the genus Streptomyces are cultured in a nutrient medium and the substance is accumulated. Any microorganism can be used as long as it is a microorganism belonging to the genus Streptomyces and capable of producing the substance. Examples of such microorganisms include Streptomyces sp. Strain Q47152 belonging to the genus Streptomyces isolated from soil in Hateruma (Hateruma Island), Taketomi Town, Yaeyama District, Okinawa Prefecture.

Mycological properties of Streptomyces sp. Strain Q47152 Form This strain grows slightly in various organic and inorganic media, and the color of the basic mycelium is ash brown to dark yellow brown. The aerial hyphae are best formed on starch / inorganic salt agar and have white to bluish gray. The spore chain is coiled and more than 50 spores are chained together. When observed with an electron microscope, the spore has a cylindrical shape, a size of 1.0 to 1.5 × 0.4 to 0.8 μm, and its surface is spiny. There is no fragmentation of the basic mycelium in liquid culture. Special organs such as spores and motile spores are not observed.

2. Properties on various agar media Properties on various agar media are as shown below. Unless otherwise specified, the cells were cultured at 28 ° C. for 21 days and observed according to a conventional method. Color descriptions are based on color standards (Japan Color Research Institute).

（注）生育温度範囲及び至適生育温度は各温度（5,10,15,20,24,28,32,37,40,45,50℃）で、7〜21日までの観察結果（脱脂牛乳に対する作用は37℃で3〜21日までの観察結果）である。それ以外は、特に指摘のない限り、28℃で2週間後の観察結果を示す。 3. Physiological properties

(Note) Growth temperature range and optimum growth temperature are each temperature (5,10,15,20,24,28,32,37,40,45,50 ℃), and observation results from 7 to 21 days (degreasing The effect on milk is the observation result at 37 ° C for 3-21 days). Unless otherwise indicated, the observation results after 2 weeks at 28 ° C. are shown unless otherwise indicated.

4). Assimilation of carbon source (Prideham Godolib agar medium, 28 ° C culture)

5. Chemical analysis of bacterial cell components
Results of analysis of acid hydrolyzate of this strain according to the method of LECHVALIER et al. (LECHVALIER, MP. Et al; PP277-238 in DIETZ, A et al ed., Actinomycete Taxonomy, SIM Special Publication No. 6, 1980) , LL-diaminopimelic acid was detected. The main cell menaquinone was MK-9 (H8).
When bacterial species having the above properties are searched by various literatures (Bergey's Manual of Systematic Bacteriology vol.4, 1989, etc.), this strain is determined to belong to the genus Streptomyces. Therefore, this strain was named Streptomyces sp. Q47152. This strain has been deposited with the Patent Biological Deposit Center (IPOD), National Institute of Advanced Industrial Science and Technology (AIST), 1-1 1-1 Higashi, Tsukuba City, Ibaraki, Japan, 305-8566 Japan, as receipt number FERM BP-10436 ing. In addition, since microorganisms are likely to be artificially or naturally mutated, Streptomyces sp. Q47152 strain used in the present invention is not only isolated from natural microorganisms but also artificially irradiated with ultraviolet rays, X-rays, chemical agents, etc. Mutated ones and natural mutants thereof are also included.

(Production method)
The compound of the present invention belongs to the genus Streptomyces and can be obtained by culturing a microorganism having the ability to produce the compound of the present invention. Culturing is performed according to the culture method of general microorganisms.
The medium used for the culture may be any medium containing a nutrient source used by a microorganism belonging to the genus Streptomyces having the ability to produce the compound of the present invention, such as Streptomyces sp. A synthetic or natural medium is used. Known nutrients to be added to the medium can be used. The composition of the medium includes, for example, carbon sources such as D-glucose, L-arabinose, D-xylose, D-fructose, sucrose, rhamnose, raffinose, inositol, mannitol, D-galactose, D-mannose, maltose, trehalose, Starch, glucose, dextrin, glycerin, vegetable oil, potato starch and the like can be mentioned. Nitrogen sources include meat extract, peptone, gluten meal, cottonseed meal, soybean meal, peanut meal, fish meal, corn steep liquor, dry yeast, yeast extract, ammonium chloride, ammonium sulfate, ammonium nitrate, uric acid and other organic and inorganic nitrogen sources Is used. As metal salts, sulfates such as sodium, potassium, magnesium, calcium, zinc, iron and cobalt, nitrates, carbonates, phosphates and the like are added as necessary. Furthermore, if necessary, a production promoting substance or an antifoaming agent such as methionine, cysteine, cystine, thiosulfate, methyl oleate, lard oil, silicone oil, and surfactant can be added.
As the culture conditions, it is generally advantageous to perform the culture under aerobic conditions, and the culture temperature is in the range of 15 to 45 ° C, preferably in the vicinity of 20 to 40 ° C. Good results are obtained when the pH of the medium is adjusted to a range of about 5-9, preferably about 6-8. The culture period is appropriately set according to the composition of the medium and the temperature conditions, but is usually about 1 to 14 days, preferably about 3 to 8 days.

(Isolation method)
Isolation of the compound of the present invention can be carried out by appropriately utilizing the usual means for extraction and purification when isolating a physiologically active substance from a natural product. Since the compound of the present invention is easily soluble in alcohols such as methanol, ethanol and butanol, and acetone, it is preferable to extract with these solvents. The compound of the present invention dissolves in an organic solvent such as ethyl acetate and chloroform but is difficult to dissolve in water. Therefore, the compound of the present invention can be extracted and purified by a liquid separation operation using water and ethyl acetate or chloroform.
Further, the active compound of the present invention can be purified by contacting the fraction containing the active ingredient with an appropriate carrier to adsorb the active ingredient and then eluting with a suitable solvent. Preferably, Sephadex (registered trademark) LH-20, Amberlite (registered trademark) XAD-2, Diaion (registered trademark) HP-20, Diaion (registered trademark) CHP-20, or Diaion (registered trademark) The compound of the present invention is eluted with an organic solvent such as methanol, ethanol, acetone, butanol, acetonitrile, chloroform, or water, or a mixture thereof, after contacting and adsorbing on a porous adsorption resin such as SP-900. be able to. At this time, it may be advantageous to change the mixing ratio of the organic solvent and water stepwise or continuously. Further, the fraction containing the compound of the present invention can be obtained by various purification methods obvious to those skilled in the art such as column chromatography using silica gel, ODS, etc., centrifugal liquid-liquid partition chromatography, high performance liquid chromatography (HPLC) using ODS, etc. Can also be purified. It may be advantageous to separate and purify a pure compound by appropriately combining these various operating methods.

The compounds of the present invention can form acid addition salts. Such salts are pharmaceutically acceptable salts, specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or formic acid, acetic acid, Examples thereof include organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid.
Further, since the compound of the present invention has an asymmetric carbon atom, there exist stereoisomers (racemate, optical isomer, diastereomer, etc.) based on this. The present invention includes a mixture or an isolated form of these stereoisomers. The present invention also includes hydrates and various solvates of the compounds of the present invention. Furthermore, the present invention includes crystals of the compound of the present invention such as crystalline polymorphs.

A pharmaceutical composition containing the compound of the present invention as an active ingredient is prepared using carriers, excipients, and other additives that are usually used for formulation.
Administration is oral by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral by injections such as intravenous injections, intramuscular injections, suppositories, transdermal agents, nasal agents or inhalants. Either form may be sufficient.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the compound of the present invention or a salt thereof may contain at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. Mixed with magnesium acid etc. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert solvents such as purified water, ethanol, etc. . In addition to the inert solvent, the composition may contain adjuvants such as solubilizers, wetting agents, and suspending agents, sweeteners, corrigents, fragrances, and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like. Such a composition may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

  The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the administration subject, sex, etc., but usually 0.1 to 1500 mg for oral administration per day for adults, 0.01 to 0.1 mg for parenteral administration About 500 mg is appropriate and is administered once to several times a day. Since the dosage varies depending on various conditions, an amount smaller than the above dosage range may be sufficient. When used as an external preparation, an external preparation containing 0.001 to 20%, preferably 0.01 to 10% of the compound (I) is preferable. This is administered locally one to several times a day depending on the symptoms.

Hereinafter, the present invention will be described in more detail based on examples. The compounds of the present invention are not limited to the following examples.
Example 1
Dispense 100 ml each of 1% glucose, 2% potato starch, 0.5% polypeptone, 0.5% yeast extract, and 0.4% calcium carbonate (pH 7.0 before sterilization) into a 500 ml Erlenmeyer flask at 121 ° C for 20 minutes Sterilized. This medium was inoculated by scraping and inoculating Streptomyces sp. Q47152 strain well grown on a Bennett agar medium, and cultured with shaking at 28 ° C. and 220 rpm for 4 days to obtain a seed culture solution. Next, 100 ml of the medium having the same composition was dispensed into 50 500 ml Erlenmeyer flasks and sterilized at 121 ° C. for 20 minutes. 2 ml of the seed culture solution was inoculated into this medium, and cultured with shaking at 28 ° C. and 220 rpm for 6 days.
20 L of acetone was added to 5 L of the culture solution of the Q47152 strain cultured in this manner, and after sufficient stirring, filtered. About 25 L of the filtrate was concentrated under reduced pressure, adjusted to pH 7.0, and extracted with about 5 L of ethyl acetate. The organic solvent layer was concentrated under reduced pressure and subjected to silica gel column chromatography (20 g). After washing with 100 ml of chloroform solution, elution was performed with 100 ml of chloroform-methanol (9: 1) and (7: 3) solutions. The eluate was concentrated under reduced pressure and subjected to ODS column chromatography (6 g). After washing with 50 ml each of 50% and 60% (v / v) aqueous methanol solution, elution was performed with 50 ml each of 70%, 80% and 90% (v / v) aqueous methanol solution. The eluate was concentrated under reduced pressure to obtain about 455 mg of a crude extract. The crude extract was subjected to ODS HPLC (L-column, 20 x 250 mm, Chemical Substance Evaluation Research Organization), eluted with acetonitrile-6.5 mM ammonium acetate (pH 5.5) (55:45), 10 ml, and detected at UV266 nm. The target peak was collected. The separated solution was concentrated under reduced pressure and extracted with ethyl acetate to obtain Compound E (68 mg).

Physicochemical properties (Compound E)
Color and shape: white powder Molecular formula: C ₅₂ H ₆₄ ClN ₉ O ₁₆
High resolution ESIMS: m / z 1106.4232 ([M + H] ⁺ , Δ -0.6 mmu)
UV absorption (MeOH): λ _max (ε) 263 nm (ε 9,000)
Optical rotation [α] _D ^24.7 = -34.7 ° (c 0.0144, MeOH)
NMR data: One-dimensional charts of ¹ H NMR and ¹³ C NMR measured in CDCl ₃ are shown in FIGS.
Infrared absorption data: Figure 3 shows a chart of the infrared absorption spectrum.

Example 2
Dispense 30 ml of a medium consisting of 1% glucose, 2% potato starch, 0.5% polypeptone, 0.5% yeast extract, 0.4% calcium carbonate (pH 7.0 before sterilization) into a 100 ml Erlenmeyer flask at 121 ° C for 30 minutes Sterilized. This medium was inoculated by scraping and inoculating Streptomyces sp. Strain Q47152 well grown on a Bennett agar medium, and cultured with shaking at 30 ° C. and 250 rpm for 3 days to obtain a first-stage seed culture solution. Next, 100 ml of a medium having the same composition was dispensed into a 500 ml Erlenmeyer flask and sterilized at 121 ° C. for 30 minutes. The medium was inoculated with 2% of the first stage seed culture solution at 30 ° C. and 250 rpm for 3 days to obtain a second stage seed culture solution. Dispense MS # 3600 7%, dry yeast 1%, wheat germ 2%, cobalt sulfate 10ppm, defoamer 0.1% (pH 6.5 before sterilization) into 20L each 30L jar fermenter, sterilize at 123 ° C for 30 minutes did. 2% of the second-stage seed culture was inoculated and aerated and stirred for 3 days at 30 ° C.
Equal amount of acetone was added to 30L of the culture solution of Q47152 strain cultured in this way, and a filter aid (Radiolite # 600, Showa Chemical Industry Co., Ltd.) was added, and after sufficient stirring and extraction, filtration was performed. did. Add 30L of water to the filtrate, approx. 60L, adjust to pH2.5, and separate it into Sepabeads SP-850 (2L: Mitsubishi Chemical Corporation) equilibrated with 20% acetone aqueous solution (containing 0.01N HCl). Provided. After washing with 6 L of 75% aqueous methanol (containing 0.01 N HCl), elution was performed with 16 L of 100% methanol (containing 0.01 N HCl). An equal amount of water was added to the methanol-eluted fraction and subjected to ODS-B (50 mm φx 1,000 mmL: Daiso Corporation Daiso Gel SP-120-15 / 30-ODS-B) column chromatography. Elution was performed with 52% acetonitrile aqueous solution (containing 0.05% TFA), and fractionation was performed at regular intervals. Fractions containing the target compound were concentrated under reduced pressure and replaced with water, followed by extraction with ethyl acetate. The ethyl acetate extract was concentrated under reduced pressure and evaporated to dryness, and 728 mg of the crude extract was dissolved in a small amount of methanol. Using an ODS column (20φ x 250 mmL: Daiso Pack SP-120-5-ODS-BP), a 52% acetonitrile aqueous solution ( HPLC fractionation was carried out at 10 ml / min, containing 50 mM potassium dihydrogen phosphate. Fractions containing the target compound were concentrated and replaced with water, followed by extraction with ethyl acetate to obtain Compound F (13.5 mg) and Compound G (17.1 mg). In addition, an equal amount of water was added to the fraction containing the other target compound and subjected to chromatography on Diaion HP-20-SS (1.2L: Mitsubishi Chemical Corporation), 70% aqueous methanol solution (0.5% ammonium acetate) Elution), concentration under reduced pressure and substitution with water, followed by extraction with ethyl acetate to obtain Compound H (80 mg).

Physicochemical properties (Compound F)
Color and shape: white powder Molecular formula: C ₅₃ H ₆₈ ClN ₉ O ₁₇
High resolution ESIMS: m / z 1138.4500 ([M + H] ⁺ , Δ -0.1 mmu)
UV absorption (MeOH): λ _max (ε) 267 nm (ε 26,600)
Optical rotation [α] _D ^24.7 = -106.8 ° (c 0.02, MeOH)
NMR data: ¹ H NMR and ¹³ C NMR one-dimensional charts measured in CDCl ₃ are shown in FIGS.

(Compound G)
Color and shape: White powder Molecular formula: C ₅₂ H ₆₄ ClN ₉ O ₁₅
High resolution ESIMS: m / z 1090.4293 ([M + H] ⁺ , Δ 0.1 mmu)
UV absorption (MeOH): λ _max (ε) 263 nm (ε 25,100)
Optical rotation [α] _D ^24.7 = -96.8 ° (c 0.02, MeOH)
NMR data: ¹ H NMR and ¹³ C NMR one-dimensional charts measured in CDCl ₃ are shown in FIGS.

(Compound H)
Color and shape: white powder Molecular formula: C ₅₂ H ₆₅ Cl ₂ N ₉ O ₁₆
High resolution ESIMS: m / z 1142.4001 ([M + H] ⁺ , Δ -0.3 mmu)
UV absorption (MeOH): λ _max (ε) 264 nm (ε 22,000)
Optical rotation [α] _D ^24.3 = -52.6 ° (c 0.02, MeOH)
NMR data: One-dimensional charts of ¹ H NMR and ¹³ C NMR measured in CDCl ₃ are shown in FIGS.

Example 3
Dispense 100 ml each of 1% glucose, 2% potato starch, 0.5% polypeptone, 0.5% yeast extract, and 0.4% calcium carbonate (pH 7.0 before sterilization) into a 500 ml Erlenmeyer flask at 121 ° C for 20 minutes Sterilized. This medium was inoculated by scraping and inoculating Streptomyces sp. Q47152 strain well grown on a Bennett agar medium, and cultured with shaking at 28 ° C. and 220 rpm for 4 days to obtain a seed culture solution. Next, 100 ml of the medium having the same composition was dispensed into 50 500 ml Erlenmeyer flasks and sterilized at 121 ° C. for 20 minutes. 2 ml of the seed culture solution was inoculated into this medium, and cultured with shaking at 28 ° C. and 220 rpm for 6 days.
10 L of the culture solution of the Q47152 strain cultured in this manner was filtered and adjusted to pH 7.0. About 8 L of the filtrate was extracted and added with 10 L of ethyl acetate and subjected to silica gel chromatography (20 mmφ100 mmL). After washing with 100 ml of chloroform solution, elution was performed with 100 ml of chloroform-methanol (9: 1) and (7: 3) solutions. The eluate was concentrated under reduced pressure and subjected to ODS column chromatography (6 g). After washing with 50 ml each of 50% and 60% (v / v) aqueous methanol solution, elution was performed with 50 ml each of 70%, 80% and 90% (v / v) aqueous methanol solution. The eluate was concentrated under reduced pressure to obtain a fraction containing the target compound. The crude extract was subjected to ODS HPLC (L-column, 20 x 250mm, Chemical Substance Evaluation Research Organization), and the target peak was fractionated with 55% acetonitrile aqueous solution (containing 0.05% TFA) to obtain Compound I (3mg) .

Physicochemical properties (Compound I)
Color and shape: White powder Molecular formula: C ₅₂ H ₆₅ N ₉ O ₁₆
High resolution ESIMS: m / z 1072.4642 ([M + H] ⁺ , Δ 0.9 mmu)
UV absorption (MeOH): λ _max (ε) 267 nm (ε 14,700)
Optical rotation [α] _D ^24.0 = -252 ° (c 0.001, MeOH)
NMR data: One-dimensional charts of ¹ H NMR and ¹³ C NMR measured in CDCl ₃ are shown in FIGS.

From the physicochemical properties, the compounds obtained in Examples 1 to 3 were identified as compounds having a structure represented by the following formula.

Example 2
The minimum growth inhibitory concentration (MIC) for Propionibacterium spp. Was determined by measuring the presence or absence of growth after incubation at 37 ° C for 24 hours under anaerobic conditions using a GAM agar medium. The MIC of the compound (I) of the present invention against Propionibacterium acnes JCM6425 and Propionibacterium granulosum GAI7414 is as shown in the table below.

¹ is a diagram showing a ¹ H-NMR spectrum of compound E. FIG. 3 is a diagram showing a ¹³ C-NMR spectrum of compound E. FIG. 2 is an infrared absorption spectrum of Compound E. FIG. FIG. 2 shows a ¹ H-NMR spectrum of compound F. FIG. 6 shows a ¹³ C-NMR spectrum of compound F. FIG. 2 shows a ¹ H-NMR spectrum of compound G. 4 is a diagram showing a ¹³ C-NMR spectrum of compound G. FIG. FIG. 2 shows a ¹ H-NMR spectrum of compound H. FIG. 6 shows a ¹³ C-NMR spectrum of compound H. ¹ is a diagram showing a ¹ H-NMR spectrum of compound I. FIG. 2 is a diagram showing a ¹³ C-NMR spectrum of compound I. FIG.

Claims (5)

The cyclic compound or its salt shown by following formula (I).

(Wherein, the R ¹ is a hydrogen atom or a hydroxyl group, an R ² represents a hydrogen atom or a chloro atom, one R ³ and R ⁴ has a hydroxyl group, or the other means a methoxymethyl or chloromethyl group, with R ³ R ⁴ is united

Means a group represented by ) A cyclic compound represented by the formula (I) according to claim 1 or a salt thereof,

A microorganism belonging to the genus Streptomyces and capable of producing the compound according to claim 1 is cultured, and the compound according to claim 1 is isolated from the culture. A method for producing the compound. The method according to claim 3, wherein the microorganism belonging to the genus Streptomyces is Streptomyces sp. Q47152 strain. Streptomyces sp. Q47152 strain and mutants thereof capable of producing the compound according to claim 1.

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