JP2011116662A - New antibiotic sf2876 substance, method for producing the same, and pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new antibacterial agent, and a method for producing the same. <P>SOLUTION: There are disclosed a new thiopeptide compound produced by an actinomycete belonging to the genus Nonomuraea, i.e. a compound represented by formula (1), a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound or the pharmacologically acceptable salt thereof as an effective component, and a method of producing the same. In the formula, R<SB>1</SB>represents -OH, -H, or =O; R<SB>2</SB>represents -Cl, -OH, or -H, provided that R<SB>2</SB>may form -O- in combination with R<SB>1</SB>; R<SB>3</SB>represents -OH or -H; R<SB>4</SB>represents -CH<SB>3</SB>or -H; and R<SB>5</SB>represents didehydroalanine, provided that R<SB>5</SB>may form a didehydroalanine ester bond: [-NH-C(=CH<SB>2</SB>)CO-NHC(=CH<SB>2</SB>)CO-O-] in combination with -NH<SB>2</SB>or R<SB>2</SB>. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel antibiotic SF2876 substance, a pharmaceutical composition containing the compound as an active ingredient, and a method for producing the compound.

  Conventionally, various beta-lactam antibiotics, aminoglycosides, macrolides, glycopeptides, quinolones, etc. have been used for the prevention and treatment of bacterial infections, but recently, the number of infectious bacteria resistant to these antibiotics has increased. And antibiotics different from the conventional type are craved.

As antibacterial agents having a protein synthesis inhibitory effect, macrolide antibacterial agents, aminoglycosides, linezolid and the like are used. Thiopeptide antibacterial agents are also known to specifically inhibit protein synthesis, and GE2270s, amitiamycins, GE37468A, etc. have been reported (Non-patent Document 1, Non-patent Document 2 and Non-patent document 3).
J. Antibiotics, 1991, 44, p. 693-701 J. Antibiotics, 1994, 47, p. 668-674 J. Antibiotics, 1995, 48, p. 780-786

  An object of the present invention is to provide a new antibacterial drug having a chemical structure different from that of existing antibacterial drugs and effective against various resistant bacteria in order to overcome the intractability of infectious diseases caused by resistant bacteria.

  As a result of earnest search research to find antibiotics having the above properties, the present inventors have found a novel compound in the culture solution of actinomycetes, and the compound has antibacterial activity based on protein synthesis inhibition. In addition, it has been found that it has no cross-resistance with conventional types of drugs and has an excellent antibacterial activity compared to conventionally known compounds, and has established a method for producing the compounds, thereby completing the present invention. .

  That is, the present invention provides a novel antibiotic SF2876 represented by the following formula (1). The present invention also provides a method for producing the compound of the present invention, which comprises culturing the strain SF2876, which produces the compound of the present invention, and collecting the target compound from the culture solution. Furthermore, this invention provides the pharmaceutical composition containing this invention compound, and provides the antibacterial agent containing this invention compound in detail.

（1）
（式中、R₁は-OH、-H、＝Oを、
R₂は-Cl、-OH、-H、R₁と一緒になって-O-を形成、
R₃は-OHまたは-Hを、
R₄は-CH₃または-Hを、
R₅はジデヒドロアラニン、-NH₂、またはR₂と一緒になってジデヒドロアラニンエステル結合（-NH-C(=CH₂)CO-NHC(=CH₂)CO-O-）を形成する、を示す。）
好ましくは以下の化合物である。
２．R₁およびR₂が一緒になって-O-を、R₃が-OH、R₄が-CH₃、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
３．R₁が-OH、R₂が-Cl、R₃が-OH、R₄が-CH₃、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
４．R₁が-OH、R₂が-OH、R₃が-OH、R₄が-CH₃、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
５．R₁が-OH、R₂が-H、R₃が-OH、R₄が-H、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
６．R₁が-H、R₂が-OH、R₃が-OH、R₄が-CH₃、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
７．R₁が-OH、R₂が-H、R₃が-OH、R₄が-CH₃、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
８．R₁が=O、R₂が-H、R₃が-OH、R₄が-CH₃、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
９．R₁が-H、R₂が-H、R₃が-H、R₄が-CH₃、且つR₅が-NH₂である上記（1）記載の化合物またはその製薬学的に許容される塩。
１０．R₁が-H、R₂が-H、R₃が-H、R₄が-CH₃、且つR₅がジデヒドロアラニンである上記（1）記載の化合物またはその製薬学的に許容される塩。
１１．下記式（２）であらわされる化合物またはその製薬学的に許容される塩。

（2）
本発明の別の態様としては、
１２．放線菌ノノムラエ属に属し、1記載の化合物を生産する能力を有する微生物を培養し、その培養物から請求項1記載の化合物を単離することを特徴とする、１記載の化合物の製造法、
１３．１記載の化合物またはその製薬学的に許容される塩を、有効成分として含有することを特徴とする医薬組成物、
１４．製薬学上許容しうる担体とともに含んでなる１３記載の医薬組成物。
１５．抗菌剤である１３または１４記載の医薬組成物。
１６．放線菌ノノムラエ属に属する微生物が、Nonomuraea sp. SF2876株（FERM P-２１４９４）又はその変異株である１２記載の製造法。
１７．１記載の化合物を生産する能力を有することを特徴とするNonomuraea sp.SF2876株（FERM P-２１４９４）又はその変異株、
である。 That is, the present invention
1. The present invention relates to a thiopeptide compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(1)
(Wherein R ₁ represents —OH, —H, ═O,
R ₂ together with -Cl, -OH, -H, R ₁ forms -O-,
R ₃ is -OH or -H,
R ₄ represents -CH ₃ or -H,
R ₅ together with didehydroalanine, —NH ₂ , or R ₂ forms a didehydroalanine ester bond (—NH—C (═CH ₂ ) CO—NHC (═CH ₂ ) CO—O—) , Indicate. )
The following compounds are preferred.
2. R ₁ and R ₂ together represent —O—, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine, or a pharmaceutically acceptable salt thereof Acceptable salt.
3. R ₁ is —OH, R ₂ is —Cl, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine or a pharmaceutically acceptable compound thereof salt.
4). R ₁ is —OH, R ₂ is —OH, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine or a pharmaceutically acceptable compound thereof salt.
5). The compound or a pharmaceutically acceptable salt thereof according to (1), wherein R ₁ is —OH, R ₂ is —H, R ₃ is —OH, R ₄ is —H, and R ₅ is didehydroalanine. .
6). R ₁ is -H, R ₂ is -OH, R ₃ is -OH, R ₄ is -CH _3, is and R ₅ is (1) a compound according or a pharmaceutically and didecyl hydro alanine acceptable salt.
7). R ₁ is —OH, R ₂ is —H, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine or a pharmaceutically acceptable compound thereof salt.
8). The compound according to the above (1), wherein R ₁ is ═O, R ₂ is —H, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine, or a pharmaceutically acceptable salt thereof salt.
9. R ₁ is -H, R ₂ is -H, R ₃ is -H, R ₄ is -CH _3, is and R ₅ is allowed the above (1) The compound according or a pharmaceutically and -NH ₂ salt.
10. R ₁ is -H, R ₂ is -H, R ₃ is -H, R ₄ is -CH _3, is and R ₅ is (1) a compound according or a pharmaceutically and didecyl hydro alanine acceptable salt.
11. A compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

(2)
As another aspect of the present invention,
12 A method for producing a compound according to claim 1, wherein the microorganism belongs to the genus Actinomyces Nonomurae and has the ability to produce the compound according to 1, culturing a microorganism, and isolating the compound according to claim 1 from the culture,
13. A pharmaceutical composition comprising the compound according to 13.1 or a pharmaceutically acceptable salt thereof as an active ingredient,
14 14. A pharmaceutical composition according to 13, comprising a pharmaceutically acceptable carrier.
15. 15. The pharmaceutical composition according to 13 or 14, which is an antibacterial agent.
16. 13. The production method according to 12, wherein the microorganism belonging to the genus Actinomyces Nonomurae is Nonomuraea sp. SF2876 strain (FERM P-21494) or a mutant thereof.
17. Nonomuraea sp. SF2876 strain (FERM P-21494) or a mutant thereof characterized by having the ability to produce the compound described in 17.1
It is.

  The novel antibiotic SF2876 of the present invention does not have cross-resistance with conventional types of drugs, and has an excellent antibacterial activity compared to conventionally known compounds, thus preventing or treating bacterial infections It is useful as an active ingredient in pharmaceuticals.

In the compound represented by the formula (1) of the present invention, R ₁ and R ₂ are combined to form —O—, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine. "SF2876A substance" of the compound is, R ₁ is -OH, R ₂ is -Cl, R ₃ is -OH, R ₄ is -CH _3, and "SF2876B substance" compounds wherein R ₅ is didecyl hydro alanine, A compound in which R ₁ is —OH, R ₂ is —OH, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine is referred to as “substance SF2876C”, R ₁ is —OH, and R ₂ is A compound in which -H, R ₃ is -OH, R ₄ is -H, and R ₅ is didehydroalanine is a `` SF2876D substance '', R <sub>1</sub> is -H, R <sub>2</sub> is -OH, R <sub>3</sub> is -OH, R <sub>A</sub> compound in which <sub>4</sub> is —CH <sub>3</sub> and R <sub>5</sub> is didehydroalanine is “SF2876E substance”, R <sub>1</sub> is —OH, R <sub>2</sub> is —H, R <sub>3</sub> is —OH, R <sub>4</sub> is —CH <sub>3</sub> , and R <sub>5</sub> `` SF2876F substance '', wherein R ₁ is ═O, R ₂ is —H, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine. SF2876G substance ”, a compound in which R ₁ is —H, R ₂ is —H, R ₃ is —H, R ₄ is —CH ₃ , and R ₅ is —NH ₂ , and“ SF2876H substance ”, R ₁ is —H , R ₂ is —H, R ₃ is —H, R ₄ is —CH ₃ , and R ₅ is didehydroalanine as “SF2876I substance”, and the compound represented by formula (2) as “SF2876J substance”. Named (following this designation in the description herein).

Suitable salts of the SF2876 substance represented by the formula (1) of the present invention include conventional pharmaceutically acceptable salts, that is, salts with various bases and acid addition salts. More specifically, salts with inorganic bases such as alkali metal salts (for example, sodium salts, potassium salts, cesium salts, etc.), alkaline earth metal salts (for example, calcium salts, magnesium salts, etc.), ammonium salts, Salts with organic bases such as organic amine salts (for example, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt), inorganic acid Addition salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic carboxylic acid addition salts or organic sulfonic acid addition salts (eg, formate, acetate, trifluoroacetate, maleic acid) Salt, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.), basic amino acid or acidic amino acid Salt (such as arginine, lysine, aspartic acid, glutamic acid etc.) and the like can be mentioned.

  The SF2876 substance can be produced by culturing a SF2876 substance-producing bacterium belonging to the genus Nonomurae, collecting the SF2876 substance from the culture, and purifying it. Examples of the SF2876 substance-producing bacterium include SF2876 strain belonging to the genus Actinomycetes Nomurae isolated from a soil sample of Kagoshima Prefecture by the present inventors. The bacteriological properties, culture method and purification method of SF2876 substance of this strain are as follows.

  The SF2876 substance-producing bacterium used in the present invention is not limited to the specific microorganism described in the present specification. Any bacteria may be used as the SF2876 substance-producing bacteria as long as it has the ability to produce the SF2876 substance. Examples of microorganisms that can be used include the SF2876 strain, its subcultures, artificial mutants, natural mutants, and genetically modified strains.

The bacteriological properties, culture method and purification method of SF2876 substance of this strain are as follows.
1. Taxonomic properties of SF2876 strain
The morphological properties, culture properties, physiological properties, chemical taxonomic properties of SF2876 strain and taxonomic analysis by analysis of 16S rRNA gene are described in "Classification and Identification of Actinomycetes" The method described in the administrative center (2001) was followed.

(a) Morphological properties
SF2876 strain was extracted from yeast extract / starch agar medium (yeast extract 0.2%, starch 1.0%, agar 18 g, purified water 1 L, pH 7.0) and tyrosine agar medium (ISP medium No.7: glycerin 15 g, L-tyrosine 0.5 g, L-asparagine 1g, K ₂ HPO ₄ 0.5g, MgSO ₄ · 7H ₂ O 0.5g, NaCl 0.5g, FeSO ₄ · 7H ₂ O 0.01g, agar 18g, purified water 1L, pH 7.2) at 28 ° C for 14 days The cells were cultured and observed with an optical microscope and a scanning electron microscope. The basic mycelium develops well and branches irregularly, but does not break. The aerial hyphae are thinly grown on starch / inorganic salt agar medium (ISP-4) and glycerin / asparagine agar medium (ISP-5), and about 3 to 4 spore chains are formed on it. The form of the spore chain is linear or helical. The spores are oval and 0.4 to 0.6 X 0.7 to 1.0 μm. The surface is smooth or slightly rough, and no spore sac or motile spore is observed.

(b) Culture properties
The growth of SF2856 strain after 14 days of culture at 28 ° C, the aerial hyphae state and color, and the color of the back of the colony are as follows. In addition, the soluble pigment | dye was not recognized by all the culture media. The color display was in accordance with the Color Harmony Manual (Container Corporation of America, 1958).
(1) Yeast / malt agar medium (ISP-2): Growth is good and aerial mycelium is hardly observed. The back side is light yellow.
(2) Oatmeal agar medium (ISP-3): Growth is good and aerial hyphae is hardly observed. The back side has an ocher color.
(3) Starch / inorganic salt agar medium (ISP-4): Growth is good and aerial hyphae is slightly yellow. The back side has an ocher color.
(4) Glycerin / asparagine agar medium (ISP-5): Growth is good and aerial hyphae is slightly ivory. The back side is light yellow.
(5) Peptone / Yeast / Iron Agar (ISP-6): Growth is normal and aerial hyphae is hardly observed. The back side has an ocher color.
(6) Tyrosine agar medium (ISP-7): Growth is normal, and aerial hyphae is slight and pale pink. The back side has an ocher color.
(7) Yeast extract / starch agar medium: Growth is normal and almost no aerial hyphae is observed. The reverse side is a wheat color.
(8) Glucose / asparagine agar medium: Growth is weak and almost no aerial mycelium is observed. The reverse side is a wheat color.

(c) Physiological properties (1) Production of melanin-like pigments: No melanin-like pigments are produced on peptone, yeast, iron agar (ISP-6) and tyrosine agar (ISP-7).
(2) Gelatin liquefaction: gelatin is not liquefied.
(3) Milk coagulation / peptonization: Skim milk is not coagulated and peptone.
(4) Starch hydrolysis: Starch is weakly hydrolyzed.
(5) Reduction of nitrate: Nitrate is not reduced.
(6) Growth temperature range: It grows weakly at 15 ° C and 42 ° C, and grows well at 28 ° C to 37 ° C. The optimum temperature for growth is around 28 ° C.
(7) Salt tolerance: When yeast extract / starch agar medium is used as a basic medium, it grows weakly at a salt concentration of 1.5% and does not grow at 3%.
(8) Utilization of carbon source: D-glucose, D-xylose, D-fructose, sucrose, D-mannitol, L-rhamnose, L-arabinose and trehalose are frequently used, and raffinose is weakly utilized. Do not use myo-inositol.

(D) Chemical taxonomic properties Meso-diaminopimelic acid was confirmed in the cell wall, and majurose and ribose were detected in the hydrolyzate of the whole cell. It was. The phospholipid composition was PIV, and the major menaquinones were MK-9 (H ₄ ) and MK-9 (H ₆ ). Cellular fatty acids were the largest with iso-C16: 0 at 23%, followed by iso or anteiso C18: 1 and 2OH-C16: 0 branched fatty acids, 2-hydroxy acid.
These morphological and chemical taxonomic properties strongly suggested that the SF2876 strain belongs to the genus Nonomuraea.

(E) 16S rRNA gene analysis
As a result of decoding the partial base sequence (569bp) of 16S rRNA gene of SF2876 strain and searching the database, the homology with Nonomuraea spiralis (DQ491195) and Nonomuraea rubescens (AY039255) was the highest at 99%, and Nonomuraea Included in the genus cluster.

  Based on the above, the SF2876 strain is considered to belong to the genus Nonomurae, and this strain was designated as Nonomuraea sp. SF2876. This strain was deposited with the Patent Organism Depositary of the National Institute of Advanced Industrial Science and Technology under the accession number FERM P-21494 dated January 29, 2008.

2. Cultivation of SF2876 Substance-Producing Bacteria In the method of the present invention, SF2876 substance-producing bacteria such as the SF2876 strain are cultured in a nutrient medium containing an appropriate carbon source and nitrogen source. The medium used may be either a natural medium or a synthetic medium. As the carbon source, carbohydrates such as glucose, fructose, sucrose, molasses, starch or starch hydrolyzate, or organic acids such as propionic acid are used. On the other hand, as the nitrogen source, usually peptone, meat extract, yeast extract, corn steep liquor, oatmeal, wheat germ, casein hydrolyzate, soybean meal or soybean meal hydrolyzate are used, but ammonium, ammonium sulfate, ammonium nitrate or phosphorus Inorganic nitrogen compounds such as ammonium acid, or organic nitrogen compounds such as urea or amino acids are also effective. These carbon sources and nitrogen sources can be used in combination.

  If necessary, add potassium phosphate, potassium phosphate, magnesium phosphate, magnesium sulfate, sodium chloride, ferrous sulfate, manganese sulfate, copper sulfate, calcium carbonate, or other inorganic salts to the medium. May be. Moreover, when a culture medium foams, liquid paraffin, animal oil, vegetable oil, mineral oil, or silicon can be added.

  The SF2876 substance-producing bacteria are cultured under aerobic conditions such as by shaking culture or deep aeration stirring culture. The culture temperature can be appropriately changed within the range in which the SF2876 substance-producing bacterium produces the target substance, but preferably 25 to 37 ° C. The culture time is usually 1 to 14 days.

3. Collection and purification of SF2876 substance When collecting and purifying the SF2876 substance of the present invention from a microorganism culture solution, conventional separation means using its properties, for example, solvent extraction, ion exchange resin reports, adsorption or distribution chromatography It is possible to isolate and purify by appropriately combining gel filtration method, dialysis method, precipitation method and the like.

  Specifically, after the organic solvent of the extract was distilled off and concentrated, the concentrate was extracted with ethyl acetate or n-butanol, the extract was concentrated under reduced pressure, and the resulting concentrate was dissolved in methanol. / Chloroform, acetone / hexane, ethyl acetate / hexane, methanol / water, or acetonitrile / water repeatedly in a solvent system such as silica gel chromatography (eg Wakogel C-300, manufactured by Wako Pure Chemical Industries), or ODS chromatography (eg inertosyl) ODS-2, manufactured by GL Sciences Inc.) and the like. If necessary, it can be isolated and purified by elution with methanol, water, etc. using gel filtration column chromatography such as Sephadex LH-20 (Amersham Biosciences AB). .

  The SF2876 substance of the present invention or a pharmaceutically acceptable salt thereof has an antibacterial activity as shown in Test Examples, and a pharmaceutical composition containing the SF2876 substance as an active ingredient can be used for animals including humans. It is useful to administer as an antibacterial agent. The target bacteria when the SF2876 substance is used as an antibacterial agent is not particularly limited as long as the SF2876 substance shows an antibacterial activity, but exhibits an excellent antibacterial activity particularly against gram-positive bacteria.

  As the medicament of the present invention, one or two or more substances selected from the group consisting of the SF2876 substance and pharmaceutically acceptable salts thereof may be used by themselves. It is desirable to produce and administer a pharmaceutical composition comprising one or more of the above substances and one or more pharmaceutically acceptable single substances. The medicament of the present invention can be administered orally or by a parenteral administration route such as rectal, subcutaneous, intramuscular, intravenous, transdermal, transmucosal, inhalation, nasal drop, ear nose and the like.

  Various conventionally known methods can be applied to the method for producing and administering the medicament of the present invention. As the pharmaceutically acceptable simple substance used for the production of the pharmaceutical composition, an inorganic or organic pharmaceutically acceptable simple substance can be used. The pharmaceutical composition is preferably formulated in the form of a solid, semi-solid or liquid as an oral administration agent or a parenteral administration agent such as an external preparation, an injection, or a suppository. Further, solid preparations for rectal administration include suppositories containing the active ingredient of the present invention and a pharmaceutically acceptable simple substance and produced by a usual method.

  For oral administration, solid or liquid formulations can be prepared. Examples of solid preparations include tablets, dragees, pills, soft / hard capsules, powders, fine granules, powders, and granules. In such a solid preparation, for example, the SF2876 and a pharmaceutically acceptable salt thereof are mixed with a pharmaceutically acceptable carrier such as sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, It can be mixed with carboxymethylcellulose or the like. The operation for formulation can be carried out by a conventional method. At that time, additives for formulation other than the above simple substance, for example, a lubricant such as calcium stearate and magnesium stearate may be added to the formulation. Good.

  In addition, an enteric film such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer, or methacrylic acid, methyl methacrylate copolymer is applied to the solid preparation as described above. It can also be made into an enteric preparation. Solid preparations such as powders and granules can also be wrapped in enteric capsules.

  Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, pellets, syrups or elixirs. These preparations contain SF2876, which is the active ingredient of the medicament of the present invention, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable simple substances such as water or liquid paraffin. In addition, as a carrier component other than these, an oily base such as coconut oil, fractionated coconut oil, soybean oil, corn oil and the like can also be contained. As a pharmaceutically acceptable carrier, a commonly used adjuvant, fragrance, stabilizer, preservative and the like may be contained as necessary. Liquid formulations may also be enclosed in capsules made of a substance that can be absorbed in the body, such as gelatin.

The preparations for parenteral administration include injections, drops, infusions, ointments, lotions, tonics, sprays, suspensions, oils, emulsifiers, suppositories, transdermal absorption agents, transmucosal absorption agents, inhalants, eye drops Nasal drops, ear drops, inhalants and the like, and are administered as a sterile aqueous or non-aqueous liquid, suspension or emulsifier.
In non-aqueous solutions, suspensions or emulsifiers, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil or soybean oil, injectable organic acid esters such as ethyl oleate are pharmaceutically acceptable. It can be used as a carrier. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents. These solutions, suspensions, and emulsifiers can be sterilized by appropriately performing treatments such as filtration through a bacteria retaining filter, heating, blending of a bactericide, or ultraviolet irradiation. Alternatively, a sterile solid preparation containing the active ingredient can be produced and dissolved in sterile water or a sterile solvent for injection just before use. In addition, water is added to a uniform solution of vegetable oil such as soybean oil and phospholipid such as lecithin and active ingredients, for example, a pressure jet homogenizer. Fat emulsions homogenized by a homogenizer such as an ultrasonic homogenizer can also be used as injections.

  Examples of the dosage form for transdermal administration include ointments and creams. These are produced by conventional methods. In addition to the above, in order to formulate the active ingredient of the present invention, surfactants, penalizing agents, coloring agents, fragrances, preservatives, stabilizers, buffering agents, suspending agents, isotonic agents, and other are commonly used. Can be used as appropriate.

  The dose of the medicament of the present invention can be appropriately selected depending on the type of disease, administration method, patient age and symptoms, treatment time, etc. 0.01 to 100 mg / kg (body weight) can be administered as the amount of the above active ingredient, and 0.01 to 100 mg / kg (body weight) in the case of intramuscular administration, and 0.05 to 500 mg / kg (in the case of oral administration). Body weight). However, the dose is not limited to the above amount and can be appropriately increased or decreased. The medicament of the present invention can be administered once to several times a day or every several days.

EXAMPLES Examples and test examples of the present invention are shown below, but the present invention is not limited to these examples, and includes all the modifications or modification means not shown here.
Example 1
Seed medium containing 1.0% glucose, 2.0% soluble starch, 0.3% yeast extract, 0.5% polypeptone, 0.6% wheat germ, 0.2% soybean meal and 0.2% calcium carbonate, adjusted to pH 7.0 with 6 N sodium hydroxide Was dispensed into eight 100 mL Erlenmeyer flasks each at 20 mL and sterilized at 120 ° C. for 20 minutes. To this, SF2876 strain (FERM P-21494) in agar plate culture was inoculated one by one, and shake-cultured at 28 ° C. for 3 days to obtain a seed culture solution.
On the other hand, it contains 2.0% glucose, 1.0% starch, 1.5% soybean meal, 0.8% wheat germ, 0.1% polypeptone, 0.1% NaCl, 0.2% calcium carbonate, and 0.05% trace metals. 80 mL of the prepared production medium was dispensed into 100 500 mL Erlenmeyer flasks and sterilized at 120 ° C. for 20 minutes. 2% of the seed culture solution was inoculated into this production medium and cultured at 28 ° C. for 5 days with stirring at 200 rpm.

  An equal amount of acetone was added to the obtained culture (16.0 L) and stirred, and then the cells were filtered. Acetone was distilled off from the obtained filtrate under reduced pressure to obtain a concentrated liquid (8.0 L). The concentrate was adjusted to pH 2 with hydrochloric acid, and the active component was extracted with ethyl acetate (8.0 L). The solvent was distilled off under reduced pressure to obtain an oily substance (2.43 g). This oily substance was placed on the top of a silica gel column (silica gel 60 (spherical) (neutral), Nacalai Tesque, 100 g), hexane, 10% acetone-hexane, 50% acetone-hexane, 60% acetone-hexane, 80% acetone-hexane, acetone, 10% methanol-chloroform, 20% methanol-chloroform, 30% methanol-chloroform, 40% methanol-chloroform, 60% methanol-chloroform and methanol were developed as 300 ml each. Of these developing solvents, 80% acetone-hexane, acetone, 10% methanol-chloroform, 20% methanol-chloroform, and 30% methanol-chloroform were combined and concentrated to dryness to give 978 mg of an oily substance. Obtained.

  The resulting oily substance was placed on top of Sephadex LH-20 column chromatography (Amersham Biosciences AB, 450 ml), developed with methanol-acetone (10: 1), and the active fraction was concentrated to dryness. A solid oily substance 486 mg was obtained. 25 mg of the obtained oily substance was subjected to ODS-HPLC (Cosmocil 5C18-AR-II, φ20 mm x 250 mm, manufactured by Nacalai Tesque), and the flow rate was 49% acetonitrile-0.01% trifluoroacetic acid aqueous solution as a developing solvent. The active substance peak was collected under conditions of 10 ml / min and a detection wavelength of 210 nm, and 7.2 mg of the present compound SF2876B was isolated.

Example 2
Seed medium containing 1.0% glucose, 2.0% soluble starch, 0.3% yeast extract, 0.5% polypeptone, 0.6% wheat germ, 0.2% soybean meal and 0.2% calcium carbonate, adjusted to pH 7.0 with 6 N sodium hydroxide Was dispensed into three 100 mL Erlenmeyer flasks in 20 mL portions and sterilized at 120 ° C. for 20 minutes. To this, SF2876 strain (FERM P-21494) in agar plate culture was inoculated one by one, and shake cultured at 28 ° C. for 3 days to obtain a primary seed culture. Next, a 2 L Erlenmeyer flask into which 500 ml of the seed medium was dispensed was sterilized at 120 ° C. for 20 minutes, inoculated with 10 ml of the primary seed, and cultured with shaking at 28 ° C. for 3 days to obtain a secondary seed culture solution. In addition, 50 L of seed medium was prepared, and the secondary seed was inoculated at a rate of 2% into a sterilized 100 L jar fermenter, and cultured with aeration and stirring at 28 ° C. for 2 days. It was.
On the other hand, it contains 2.0% glucose, 1.0% starch, 1.5% soybean meal, 0.8% wheat germ, 0.1% polypeptone, 0.1% NaCl, 0.2% calcium carbonate, and 0.05% trace metals. 7 L of the above-mentioned tertiary seed culture solution was inoculated into two 600 L culture tanks charged with 350 L of the adjusted production medium and sterilized, and cultured at 28 ° C. for 4 days with aeration and agitation (100-330 rpm).

  4% of a filter aid was added to 610 L of the culture broth, followed by filtration using a filter press machine. 610 L of methanol was added to the remaining 123 kg of cells, stirred for 4 hours, and allowed to stand overnight to obtain 570 L of methanol extract using BaSKet. The resulting methanol extract was concentrated to 150 L using a pan-type concentrator while adding 40 L of ion-exchanged water on the way. The pH was adjusted to 3.0 with 200 ml of 50% sulfuric acid, 70 L of ethyl acetate was added, and the mixture was stirred and allowed to stand overnight. The ethyl acetate layer was separated, sodium sulfate was added and the ethyl acetate extract was dehydrated, and then sodium sulfate was separated and discarded. The remaining ethyl acetate extract was concentrated using a 50 L QVF concentrator, and silica gel C200 (Wako Pure Chemical Industries, 640 g) was added on the way, and the solvent was distilled off under reduced pressure. The obtained silica gel mixture was dried at 40 ° C. for 17 hours and placed on top of a silica gel column C200 (manufactured by Wako Pure Chemical Industries, 4.0 L). Hexane, 20% acetone-hexane, 40% acetone-hexane, 60% acetone-hexane and acetone were developed as 20 L each, and the acetone fraction was concentrated to dryness to obtain 45.0 g of a dried product.

  After adding 500 ml of ethanol to the obtained dried product and stirring, the precipitate was collected by filtration to obtain 25.4 g of a precipitate. 1.0 g of the resulting precipitate was divided into 10 portions of 100 mg each and subjected to ODS-HPLC (Inertosyl ODS-3, φ50 mm x 500 mm, manufactured by GL Sciences), 30% acetonitrile-0.1% trifluoroacetic acid From an aqueous solution, the active substance peak was fractionated under the conditions of a flow rate of 80 ml / min and a detection wavelength of 210 nm using a 100% acetonitrile gradient system as a developing solvent, and divided into the following 7 fractions and concentrated to dryness (fractions). 1: 33.4 mg, fraction 2: 69.9 mg: SF2876F, fraction 3: 52.8 mg, fraction 4-methanol soluble part: 133.0 mg, fraction 4-methanol insoluble part: 99.9 mg, fraction 5: 80.0 mg, fraction 6: 98.0 mg).

  Fraction 4-Methanol insoluble part: 50 mg out of 99.9 mg was subjected to ODS-HPLC (Inertosyl ODS-2, φ20 mm x 250 mm, manufactured by GL Sciences Inc.), 65% acetonitrile-0.01% trifluoroacetic acid aqueous solution as developing solvent The active ingredient was concentrated to dryness under the conditions of a flow rate of 10 ml / min and a detection wavelength of 210 nm to obtain 5.9 mg of SF2876A.

  Fraction 4-Methanol soluble part: 133.0 mg was subjected to ODS-HPLC (Inertosyl ODS-2, φ20 mm x 250 mm, manufactured by GL Sciences), flow rate 10 using 35% acetonitrile-0.01% trifluoroacetic acid aqueous solution as developing solvent The active ingredient was concentrated to dryness under the conditions of ml / min and detection wavelength of 210 nm to obtain 20.6 mg of SF2876C.

  Fraction 1: 33.4 mg and fraction 3: 52.8 mg were subjected to ODS-HPLC (Inertosyl ODS-2, φ20 mm x 250 mm, manufactured by GL Sciences Inc.), flow rate using 50% acetonitrile-0.01% trifluoroacetic acid aqueous solution as developing solvent The active ingredient was concentrated to dryness under the conditions of 10 ml / min and a detection wavelength of 210 nm to obtain SF2876D 4.7 mg, SF2876E 4.5 mg, and SF2876G 4.8 mg.

  Fraction 5: 80.0 mg was subjected to ODS-HPLC (Inertosyl ODS-2, φ20 mm x 250 mm, GL Sciences), 65% acetonitrile-0.01% trifluoroacetic acid aqueous solution as a developing solvent, detection rate of 10 ml / min The active ingredient was concentrated to dryness under a wavelength of 210 nm to obtain 7.0 mg of SF2876H and 14.2 mg of SF2876I.

  Fraction 6: To 98.0 mg, 100 ml of ethyl acetate and 100 ml of ion exchange water were added and dissolved, adjusted to pH 2.0 with 6N-hydrochloric acid, stirred and allowed to stand, and then the ethyl acetate layer was concentrated to dryness. 3 ml of methanol was added to the obtained ethyl acetate extract, and the mixture was separated into a methanol soluble part and an insoluble part. The obtained methanol-insoluble part was designated as SF2876J (14.3 mg).

1. Physicochemical properties of SF2876A substance (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₀ N ₁₄ O ₁₂ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1339.2119 (M + H) ⁺ , calculated value 1339.2135
(4) Specific rotation: [α] _D ²⁶ = + 96.5 ° (c = 0.329, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 207 (520), 222 / s (450), 250 / s (285), 304 (185), 345 / s (65)
[0.1N HCl-MeOH]: 208 (440), 224 (420), 250 / s (300), 304 (180), 345 / s (65)
[0.1N NaOH-MeOH]: 214 (1030), 246 / s (360), 300 (200), 345 / s (90)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3389, 2940, 1661, 1534, 1516, 1500, 1456, 1427
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 1.13 (d, 3H), 1.90 (m, 1H), 2.14 (dd, 1H), 2.51 to 2.61 (m, 2H) , 2.67 (s, 3H), 3.20 to 3.33 (m, 2H), 4.64 (d, 1H), 4.82 (m, 1H), 5.14 (m, 1H), 5.20 (m, 1H), 5.33 (m, 1H ), 5.46 (m, 1H), 5.84 (s, 1H), 5.87 (s, 1H), 6.10 (s, 1H), 6.43 (s, 1H), 6.59 (d, 2H), 6.89 (d, 2H) , 6.97 (m, 1H), 7.18-7.20 (m, 4H), 7.37 (s, 1H), 7.44 (d, NH), 7.69 (d, NH), 8.13 (s, 1H), 8.19 (s, 1H ), 8.35 (d, 1H), 8.50 (d, 1H), 8.54 (s, 1H), 8.60 (d, NH), 8.63 (s, 1H), 8.76 (d, NH), 9.38 (s, NH) , 10.03 (s, NH)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 174.3 s, 171.8 s, 171.3 s, 168.6 s, 167.4 s, 165.1 s, 164.5 s, 164.1 s, 162.2 s, 161.2 s , 160.1 s, 160.0 s, 159.9 s, 158.7 s, 158.7 s, 155.6 s, 153.2 s, 150.3 s, 150.2 s, 149.7 s, 149.4 s, 147.0 s, 146.9 s, 141.6 s, 140.7 d, 139.6 s, 139.4 s, 134.4 s, 133.3 s, 129.8 d, 129.8 d, 128.2 d, 127.8 s, 127.2 d, 127.2 d, 127.0 s, 126.2 d, 126.2 d, 126.1 d, 125.0 d, 122.3 d, 118.3 d, 115.4 d, 115.0 d, 115.0 d, 111.3 t, 105.4 t, 71.6 d, 66.3 d, 57.3 d, 55.0 d, 51.5 d, 48.7 d, 42.5 t, 39 d, 37.9 t, 37.7 t, 15.5 q, 11.7 q
(9) Solubility: Methanol / acetone mixed solution, soluble in DMSO

2. Physicochemical properties of SF2876B (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₁ N ₁₄ O ₁₂ S ₆ Cl
(3) Mass spectrum (HR-FAB-MS): Measured value 1375.1899 (M + H) ⁺ , calculated value 1375.1902
(4) ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 0.79 (d, 3H), 2.07 (m, 1H), 2.24 (m, 1H), 2.65 (s, 3H), 2.68 (m, 1H), 2.71 (m 1H), 3.15 (br-dd, 1H), 3.65 (dd, 1H), 3.75 to 3.80 (m, 2H), 4.80 (ddd, 1H), 5.21 (m, 1H) , 5.38-5.44 (m, 3H), 5.88 (s, 1H), 6.06 (s, 1H), 6.46 (s, 1H), 6.63 (d, 1H), 6.80 (s, NH), 6.96 (d, 1H ), 7.08 (m, 1H), 7.22 (dd, 1H), 7.32 (s, NH), 7.53 (s, 1H), 7.77 (d, NH), 8.00 (s, 1H), 8.13 (s, 1H) , 8.35 (d, 1H), 8.49 (d, 1H), 8.53 (s, 1H), 8.58 (d, NH), 8.66 (s, 1H), 8.91 (s, NH), 9.01 (d, NH), 9.56 (s, NH), 10.10 (s, NH)
(5) ¹³ C-NMR spectrum (125 MHz, DMSO-d ₆ ) δ (ppm): 172.4 s, 171.6 s, 171.1 s, 168.0 s, 167.6 s, 167.0 s, 164.8 s, 164.4 s, 162.4 s, 161.5 s , 160.1 s, 159.8 s, 159.4 s, 158.9 s, 155.9 s, 152.9 s, 150.7 s, 150.3 s, 150.0 s, 149.6 s, 147.5 s, 147.3 s, 141.5 s, 141.0 d, 140.3 s, 140.3 s, 134.6 s, 133.6 s, 130.0 d, 130.0 d, 128.7 d, 128.5 s, 127.7 d, 127.7 d, 127.4 d, 127.1 s, 126.9 d, 126.3 d, 126.3 d, 125.2 d, 123.1 d, 118.6 d, 116.1 d, 115.1 d, 115.1 d, 112.3 t, 105.7 t, 72.1 d, 70.4 d, 57.3 d, 53.3 d, 53.1 d, 49.1 t, 49.0 d, 40 d, 38.4 t, 38.0 t, 12.0 q, 11.7 q
(6) Solubility: Methanol / acetone mixed solution, soluble in DMSO

3. Physicochemical properties of SF2876C substance (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₂ N ₁₄ O ₁₃ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1357.2233 (M + H) ⁺ , calculated value 1339.2241
(4) Specific rotation: [α] _D ²⁶ = + 67.7 ° (c = 0.388, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 207 (490), 222 / s (455), 253 / s (280), 305 (180), 344 / s (80)
[0.1N HCl-MeOH]: 208 (420), 223 (430), 253 / s (320), 305 (180), 344 / s (80)
[0.1N NaOH-MeOH]: 214 (1040), 245 / s (370), 300 (200), 342 / s (110)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3432, 2962, 1734, 1661, 1539, 1516, 1496, 1379, 1311, 1233, 1204
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 1.05 (d, 3H), 2.60 (s, 3H), 2.62 to 2.69 (m, 2H), 2.90 (dd, 1H) , 3.10 (d, 2H), 3.20 (m, 1H), 3.40 to 3.51 (m, 4H), 4.14 (dd, 1H), 4.23 (m, 1H), 4.69 (m, 1H), 4.75 (dd, 1H ), 5.08 (br-d, 1H), 5.38 to 5.43 (m, 2H), 5.55 (m, 1H), 5.85 (s, 1H), 5.87 (s, 1H), 6.09 (s, 1H), 6.43 ( s, 1H), 7.03 (d, 2H), 7.18-7.30 (m, 4H), 7.77 (s, 1H), 8.00 (s, 1H), 8.09 (s, 1H), 8.39 (d, 1H), 8.47 (s, 1H), 8.52 (d, 1H), 8.61 (s, 1H), 8.97 (d, NH), 9.40 (s, NH), 10.00 (s, NH)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 171.0 s, 171.0 s, 170.6 s, 167.3 s, 166.5 s, 164.6 s, 164.5 s, 164.0 s, 162.2 s, 161.0 s , 160.7 s, 160.7 s, 160.1 s, 158.6 s, 156.0 s, 152.3 s, 151.0 s, 150.2 s, 149.8 s, 149.4 s, 148.6 s, 147.4 s, 141.2 s, 140.8 s, 140.7 s, 140.2 d, 134.3 s, 133.3 s, 129.9 d, 129.4 d, 129.4 d, 129.4 s, 128.3 d, 127.6 d, 127.6 d, 126.9 d, 126.2 s, 126.1 d, 126.1 d, 124.7 d, 122.7 d, 118.8 d, 118.3 d, 114.9 d, 114.9 d, 111.5 t, 105.4 t, 73.7 d, 73.3 d, 58.7 t, 56.1 d, 53.9 d, 53.7 d, 48.3 d, 38.0 t, 36.5 d, 35.4 t, 11.8 q, 9.8 q
(9) Solubility: Methanol / acetone mixed solution, soluble in DMSO

4). Physicochemical properties of SF2876D substance (1) Color and properties: colorless powder (2) Molecular formula: C ₅₈ H ₅₀ N ₁₄ O ₁₃ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1327.2133 (M + H) ⁺ , calculated value 1327.2136
(4) Specific rotation: [α] _D ²⁶ = + 73.9 ° (c = 0.164, MeOH)
(5) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3410, 2922, 2853, 1661, 1534, 1516, 1493, 1421, 1307, 1231, 1173
(6) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 0.74 (d, 3H), 1.06 (d, 3H), 1.99 (dd, 1H), 2.06 (dd, 1H), 2.65 (m, 1H), 2.74 (dd, 1H), 3.00 (m, 1H), 3.78 (dd, 1H), 4.83 (ddd, 1H), 5.18 (dd, 1H), 5.31 (m, 1H), 5.39 ( d, 1H), 5.49 (dd, 1H), 5.84 (s, 1H), 5.87 (s, 1H), 6.10 (s, 1H), 6.43 (s, 1H), 6.60 (d, 2H), 6.94 (d , 2H), 7.05 (m, 1H), 7.18-7.20 (m, 3H), 7.49 (s, 1H), 7.64 (d, NH), 8.07 (s, 1H), 8.10 (s, 1H), 8.12 ( s, 1H), 8.35 (d, 1H), 8.47 (d, 1H), 8.53 (s, 1H), 8.54 (d, NH), 8.63 (s, 1H), 8.86 (d, NH x2), 9.38 ( s, NH), 10.02 (s, NH)
(7) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 172.9 s, 172.9 s, 171.1 s, 170.8 s, 167,4 s, 166.2 s, 164.5 s, 164.3 s, 162.2 s, 160.5 s, 160.0 s, 159.9 s, 159.1 s, 158.7 s, 155.7 s, 152.9 s, 150.4 s, 150.2 s, 149.8 s, 149.4 s, 148.3 s, 147 2 s, 146.9 s, 140.7 d, 139.8 s, 134.4 s, 133.3 s, 129.7 d, 129.7 d, 128.2 d, 128.1 s, 127.3 d, 127.3 d, 127.1 d, 126.7 s, 126.5 d, 126.1 d, 126.1 d, 124.8 d, 123.5 d, 122.6 d, 118.3 d, 115.7 d, 115.0 d, 1150 d, 111.4 t, 105.4 t, 71.8 d, 66.3 d, 57.3 d, 54.2 d, 52.8 d, 48.8 d, 43.3 d, 38.3 t, 37.6 t, 19.3 q, 11.1 q
(8) Solubility: Methanol / acetone mixed solution, soluble in DMSO

5). Physicochemical properties of SF2876E (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₂ N ₁₄ O ₁₂ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1341.2294 (M + H) ⁺ , calculated value 1341.2292
(4) Specific rotation: [α] _D ²⁶ = + 87.3 ° (c = 0.416, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 207 (480), 222 (440), 252 / s (280), 306 (200), 348 / s (64)
[0.1N HCl-MeOH]: 210 (400), 224 (440), 250 / s (290), 306 (200), 348 / s (64)
[0.1N NaOH-MeOH]: 214 (1040), 246 / s (360), 303 (204), 345 / s (90)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3389, 2926, 1659, 1533, 1516, 1500, 1420, 1235, 1173, 1059, 1024
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 0.90 (d, 3H), 1.45 (m, 1H), 1.75 (m, 1H), 1.90 (dd, 1H), 2.18 (m, 1H), 2.63 (dd, 1H), 2.66 (s, 3H), 2.70 (dd, 1H), 3.15 (m, 1H), 3.45 to 3.60 (m, 2H), 4.89 (ddd, 1H), 4.94 (dd, 1H), 5.18 (m 1H), 5.36 (d, 1H), 5.45 (dd, 1H), 5.84 (s, 1H), 5.87 (s, 1H), 6.10 (s, 1H), 6.43 ( s, 1H), 6.62 (d, 2H), 6.94 (d, 2H), 7.01 to 7.04 (m, 2H), 7.18 to 7.19 (m, 3H), 7.46 (s, 1H), 7.59 (d, NH) , 8.08 (s, 1H), 8.10 (s, 1H), 8.35 (d, 1H), 8.48 (d, 1H), 8.50 (s, 1H), 8.58 (d, NH), 8.63 (s, 1H), 8.80 (m, NH x2), 9.38 (s, NH), 10.03 (s, NH)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 173.4 s, 171.3 s, 171.3 s, 168.0 s, 167.4 s, 166.1 s, 164.5 s, 164.1 s, 162.2 s, 161.2 s , 160.4 s, 159.9 s, 159.1 s, 158.7 s, 155.7 s, 153.0 s, 150.5 s, 150.2 s, 149.8 s, 149.4 s, 147.2 s, 147.0 s, 141.5 s, 140.6 d, 139.8 s, 139.7 s, 134.4 s, 133.3 s, 129.7 d, 129.7 d, 128.2 d, 128.1 s, 127.3 d, 127.3 d, 127.0 d, 126.8 s, 126.3 d, 126.1 d, 126.1 d, 124.8 d, 122.5 d, 118.4 d, 115.5 d, 115.0 d, 115.0 d, 111.4 t, 105.4 t, 71.8 d, 58.2 t, 57.4 d, 57.1 d, 52.7 d, 48.7 d, 38.1 t, 37.9 t, 35.1 t, 33.8 d, 15.7 q, 11.7 q
(9) Solubility: Methanol / acetone mixed solution, soluble in DMSO

6). Physicochemical properties of SF2876F (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₂ N ₁₄ O ₁₂ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1341.2290 (M + H) ⁺ , calculated value 1341.2292
(4) Specific rotation: [α] _D ²⁶ = + 116.9 ° (c = 0.851, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 206 (460), 222 (444), 250 / s (260), 304 (180), 348 / s (60)
[0.1N HCl-MeOH]: 210 (370), 222 (410), 250 / s (270), 304 (180), 348 / s (60)
[0.1N NaOH-MeOH]: 214 (1030), 245 / s (340), 300 (190), 342 / s (80)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3410, 2983, 2940, 1660, 1534, 1516, 1497, 1424, 1312, 1231, 1175,1024
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 0.74 (d, 3H), 1.07 (d, 3H), 1.99 (m, 1H), 2.06 (m, 1H), 2.65 (s, 3H), 2.68 (m, 1H), 2.74 (m, 1H), 3.16 (dd, 1H), 3.78 (m, 1H), 4.80 (ddd, 1H), 5.19 (dd 1H), 5.24 (dd , 1H), 5.37 (d, 1H), 5.45 (dd, 1H), 5.84 (s, 1H), 5.88 (s, 1H), 6.10 (s, 1H), 6.43 (s, 1H), 6.63 (d, 2H), 6.97 (d, 2H), 7.06 to 7.08 (m, 2H), 7.19 to 7.20 (m, 3H), 7.51 (s, 1H), 7.65 (d, NH), 8.00 (s, 1H), 8.10 (s, 1H), 8.35 (d, 1H), 8.46 (d, 1H), 8.50 (s, 1H), 8.56 (d, NH), 8.62 (s, 1H), 8.82 (m, NH x2), 9.38 (s, NH), 10.02 (s, NH)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 172.8 s, 171.2 s, 170.7 s, 167.8 s, 167.5 s, 166.7 s, 164.5 s, 164.2 s, 162.2 s, 161.3 s , 160.6 s, 160.0 s, 159.2 s, 158.7 s, 155.7 s, 152.9 s, 150.5 s, 150.2 s, 149.8 s, 149.5 s, 147.4 s, 146.9 s, 141.4 s, 140.7 d, 140.0 s, 139.9 s, 134.4 s, 133.3 s, 129.7 d, 129.7 d, 128.2 d, 128.2 s, 127.3 d, 127.3 d, 127.1 d, 126.8 s, 126.4 d, 126.1 d, 126.1 d, 124.7 d, 122.6 d, 118.4 d, 115.7 d, 115.0 d, 115.0 d, 111.4 t, 105.4 t, 72.0 d, 66.3 d, 57.1 d, 54.2 d, 53.0 d, 48.6 d, 43.3 d, 38.2 t, 37.6 t, 194 q, 11.7 q, 11.0 q
(9) Solubility: Methanol / acetone mixed solution, soluble in DMSO

7). Physicochemical properties of SF2876G (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₀ N ₁₄ O ₁₂ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1339.2122 (M + H) ⁺ , calculated value 1341.2136
(4) Specific rotation: [α] _D ²⁶ = + 62.0 ° (c = 0.205, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 207 (320), 221 (304), 252 / s (176), 305 (120), 346 / s (44)
[0.1N HCl-MeOH]: 208 (240), 223 (276), 250 / s (180), 305 (120), 346 / s (44)
[0.1N NaOH-MeOH]: 213 (940), 246 / s (230), 300 (130), 343 / s (60)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3389, 2930, 1659, 1533, 1516, 1499, 1420, 1312, 1233, 1175, 1024
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 1.00 (d, 3H), 1.94 (dd, 1H), 2.27 (s, 3H), 2.65 (s, 3H), 2.70 (m, 2H), 3.12 (m, 2H), 4.79 (ddd, 1H), 5.19 to 5.22 (m, 1H), 5.30 (dd 1H), 5.37 (d, 1H), 5.45 (dd, 1H), 5.84 (s, 1H), 5.87 (s, 1H), 6.10 (s, 1H), 6.43 (s, 1H), 6.61 (d, 2H), 6.92 (d, 2H), 7.03 to 7.06 (m, 2H), 7.17-7.19 (m, 3H), 7.51 (s, 1H), 7.62 (d, NH), 8.08 (s, 1H), 8.11 (s, 1H), 8.36 (d, 1H), 8.48 (d, 1H) , 8.55 (d, NH), 8.63 (s, 1H), 8.81 (m, NH), 8.84 (d, NH), 9.38 (s, NH), 10.02 (s, NH)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 208.0 s, 172.2 s, 171.2 s, 170.9 s, 167.9 s, 167.4 s, 166.3 s, 164.4 s, 164.1 s, 162.2 s , 161.2 s, 160.3 s, 159.9 s, 159.1 s, 158.7 s, 155.7 s, 153.0 s, 150.4 s, 150.2 s, 149.8 s, 149.4 s, 147.2 s, 147.0 s, 141.5 s, 140.6 d, 139.9 s, 139.8 s, 134.4 s, 133.3 s, 129.6 d, 129.6 d, 128.2 d, 128.2 s, 127.3 d, 127.3 d, 127.0 d, 126.6 s, 126.3 d, 126.1 d, 126.1 d, 124.8 d, 122.6 d, 118.4 d, 116.2 d, 115.0 d, 115.0 d, 111.4 t, 105.4 t, 71.8 d, 57.1 d, 53.8 d, 52.7 d, 49.4 d, 48.5 d, 38.1 t, 37.5 t, 28.3 d, 13.2 q, 11.7 q
(9) Solubility: Methanol / acetone mixed solution, soluble in DMSO

8). Physicochemical properties of SF2876H substance (1) Color and properties: colorless powder (2) Molecular formula: C ₅₃ H ₄₇ N ₁₃ O ₇ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1170.2137 (M + H) ⁺ , calculated value 1170.2124
(4) Specific rotation: [α] _D ²⁶ = + 116.5 ° (c = 0.381, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 207 (380), 220 (380), 250 / s (180), 308 (150), 346 / s (50)
[0.1N HCl-MeOH]: 208 (296), 212 (340), 250 / s (180), 308 (150), 346 / s (50)
[0.1N NaOH-MeOH]: 214 (980), 246 / s (256), 305 (156), 346 / s (50)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3389, 2983, 2963, 2924, 1661, 1538, 1516, 1497, 1420, 1362, 1311, 1235, 1173, 1075, 1024
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 0.88 (d, 3H), 0.93 (t, 3H), 1.33 (m, 1H), 1.64 (m, 1H), 1.99 (m, 1H), 2.05 (dd, 1H), 2.64 (s, 3H), 2.75 to 2.81 (m, 2H), 3.2 (m, 1H), 3.35 to 3.40 (m, 2H), 4.89 to 4.98 (m , 2H), 5.29 (m, 1H), 5.53 (dd, 1H), 6.67 (d, 2H), 7.04-7.10 (m, 4H), 7.16-7.25 (m, 3H), 7.49 (s, 1H), 7.80 (d, NH), 8.08 (s, 1H), 8.15 (s, 1H), 8.43-8.44 (m, 3H), 8.49 (s, 1H), 8.74-8.80 (m, NH x 3)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 173.6 s, 171.3 s, 171.2 s, 169.3 s, 167.7 s, 166.7 s, 164.2 s, 161.9 s, 161.0 s, 160.4 s , 159.9 s, 159.1 s, 155.7 s, 153.2 s, 151.7 s, 150.3 s, 150.2 s, 149.3 s, 147.7 s, 147.0 s, 141.6 s, 140.3 d, 139.6 s, 135.2 s, 129.7 d, 129.7 d, 129.1 d, 129.1 d, 128.0 d, 128.0 d, 127.9 s, 126.8 s, 126.7 d, 126.4 d, 126.2 d, 124.3 d, 122.3 d, 118.5 d, 115.6 d, 114.9 d, 114.9 d, 56.9 d, 52.7 d, 52.2 d, 48.6 d, 41.2 t, 38.2 t, 37.9 d, 37.5 t, 25.0 t, 15.2 q, 11.6 q, 10.6 q
(9) Solubility: Methanol / acetone mixed solution, soluble in DMSO

9. Physicochemical properties of SF2876I substance (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₂ N ₁₄ O ₁₀ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1309.2386 (M + H) ⁺ , calculated value 1309.2393
(4) Specific rotation: [α] _D ²⁶ = + 103.3 ° (c = 0.549, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 207 (480), 220 (470), 250 / s (280), 305 (190), 350 / s (60)
[0.1N HCl-MeOH]: 209 (400), 222 (436), 250 / s (280), 305 (190), 350 / s (60)
[0.1N NaOH-MeOH]: 214 (1040), 244 / s (356), 303 (200), 345 / s (80)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3389, 2965, 2932, 1665, 1534, 1516, 1496, 1422, 1379, 1314, 1231, 1173, 1076, 1024
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 0.88 (d, 3H), 0.93 (t, 3H), 1.33 (m, 1H), 1.64 (m, 1H), 1.95 (m, 1H), 2.05 (m, 1H), 2.64 (s, 3H), 2.75 (m, 1H), 2.79 (m, 1H), 3.18-3.26 (m, 2H), 3.37 (dd, 1H), 4.91 (dd, 1H), 4.97 (m, 1H), 5.29 (m, 1H), 5.53 (dd, 1H), 5.84 (s, 1H), 5.88 (s, 1H), 6.10 (s, 1H), 6.44 (s, 1H), 6.67 (d, 2H), 7.07 to 7.09 (m, 4H), 7.16 to 7.25 (m, 3H), 7.49 (s, 1H), 7.80 (d, NH), 8.08 (s, 1H ), 8.17 (s, 1H), 8.36 (d, 1H), 8.48 (d, 1H), 8.50 (s, 1H), 8.63 (s, 1H), 8.75 (d, NH), 8.77 (d, NH) , 8.79 (d, NH), 9.38 (s, NH), 10.02 (s, NH)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 173.8 s, 171.5 s, 171.4 s, 169.5 s, 167.9 s, 167.6 s, 164.7 s, 164.4 s, 162.4 s, 161.2 s , 160.6 s, 160.1 s, 159.3 s, 158.9 s, 156.0 s, 153.3 s, 150.6 s, 150.4 s, 150.0 s, 149.6 s, 147.9 s, 147.2 s, 141.8 s, 140.8 d, 139.8 s, 136.4 s, 134.6 s, 133.5 s, 129.9 d, 129.9 d, 129.3 d, 129.3 d, 128.5 d, 128.3 s, 128.2 d, 128.2 d, 127.0 s, 126.6 d, 126.5 d, 124.5 d, 122.7 d, 118.6 d, 115.9 d, 115.2 d, 115.2 d, 111.6 t, 105.6 t, 57.2 d, 52.9 d, 52.4 d, 48.8 d, 41.4 t, 38.4 t, 38.1 d, 37.7 t, 25.2 t, 15.4 q, 11.8 q, 10.8 q
(9) Solubility: Methanol / acetone mixed solution, soluble in DMSO

10. Physicochemical properties of SF2876J (1) Color and properties: colorless powder (2) Molecular formula: C ₅₉ H ₅₀ N ₁₄ O ₁₀ S ₆
(3) Mass spectrum (HR-FAB-MS): Measured value 1339.2118 (M + H) ⁺ , calculated value 1339.2135
(4) Specific rotation: [α] _D ²⁶ = + 45.1 ° (c = 0.101, MeOH)
(5) UV absorption spectrum λ _max nm (E ^% _cm )
[MeOH]: 206 (380), 221 (360), 252 / s (220), 306 (140), 354 / s (36)
[0.1N HCl-MeOH]: 210 (310), 222 (340), 252 / s (220), 306 (140), 354 / s (36)
[0.1N NaOH-MeOH]: 214 (990), 245 / s (380), 302 (160), 345 / s (60)
(6) Infrared absorption spectrum ν _max cm ^-1 (KBr)
: 3482, 1719, 1655, 1534, 1516, 1500, 1418, 1367, 1312, 1233, 1026
(7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 0.68 (d, 3H), 1.29 (m, 1H), 2.34 (m, 1H), 2.60 (m, 1H), 2.76 (m, 1H), 2.76 (s, 3H), 3.26 (m, 1H), 3.91 (dd, 1H), 4.30 (m, 1H), 4.87 (dd, 1H), 5.00 (m, 1H), 5.08 ( m, 1H), 5.31 to 5.34 (m, 2H), 5.54 (dd, 1H), 5.93 (s, 1H), 6.08 (s, 1H), 6.15 (s, 1H), 6.62 (d, 2H), 6.80 (s, 1H), 6.94 (d, 4H), 7.13 to 7.24 (m, 4H), 7.46 (d, NH), 7.89 (s, 1H), 8.16 (s, 1H), 8.24 (s, 1H), 8.29 (s, 1H), 8.60 (s, 1H), 8.65 (d, NH), 9.06 (d, NH), 9.36 (d, NH), 9.78 (d, NH), 10.10 (s, NH)
(8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm): 172.8 s, 171.7 s, 171.5 s, 168.6 s, 168.3 s, 164.7 s, 163.9 s, 162.6 s, 162.0 s, 160.9 s , 159.9 s, 159.8 s, 158.9 s, 158.6 s, 155.7 s, 153.5 s, 149.9 s, 148.6 s, 148.5 s, 148.4 s, 147.1 s, 146.9 s, 142.3 d, 141.7 s, 139.7 s, 139.4 s, 133.5 s, 131.9 s, 129.7 d, 129.7 d, 128.3 d, 127.9 d, 127.1 d, 127.1 s, 126.6 s, 126.2 s, 126.2 d, 126.2 d, 125.0 d, 124.9 d, 123.5 d, 118.7 d, 117.8 t, 115.0 d, 115.0 d, 114.0 d, 103.6 t, 71.4 d, 67.5 d, 65.0 t, 57.1 d, 54.8 d, 52.2 d, 48.4 d, 41.7 d, 38.9 t, 37.7 t, 11.8 q, 9.7 q
(9) Solubility: Soluble in methanol / acetone mixed solution and DMSO.

Test example
The antibacterial activity of SF2876 substance was measured as the minimum inhibitory concentration (MIC) by the agar plate dilution method. Cation-adjusted Müller-Hinton agar medium (made by Difco, indicated as CAMHB in the table) or 2.5% horse hemolyzed blood containing SF2876 substance so that the test bacteria grown overnight in growth medium are 5 x 10 ⁴ CFU / well The added Mueller-Hinton agar medium (labeled as + LHB in the table) was inoculated and cultured at 37 ° C. for 18-20 hours. The results are shown in Table 1.

Claims (17)

A thiopeptide compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(1)
(Wherein R ₁ represents —OH, —H, ═O,
R ₂ together with -Cl, -OH, -H, R ₁ forms -O-,
R ₃ is -OH or -H,
R ₄ represents -CH ₃ or -H,
R ₅ together with didehydroalanine, —NH ₂ , or R ₂ forms a didehydroalanine ester bond (—NH—C (═CH ₂ ) CO—NHC (═CH ₂ ) CO—O—) , Indicate. ) The compound according to claim 1, wherein R ₁ and R ₂ together represent -O-, R ₃ is -OH, R ₄ is -CH ₃ , and R ₅ is didehydroalanine, or a pharmaceutically acceptable salt thereof. Salt. _2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ is —OH, R ₂ is —Cl, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine. . _2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is —OH, R ₂ is —OH, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine. . _2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ is —OH, R ₂ is —H, R ₃ is —OH, R ₄ is —H, and R ₅ is didehydroalanine. _2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is —H, R ₂ is —OH, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine. . _2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ is —OH, R ₂ is —H, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine. . _2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ is ═O, R ₂ is —H, R ₃ is —OH, R ₄ is —CH ₃ , and R ₅ is didehydroalanine. . The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is -H, R ₂ is -H, R ₃ is -H, R ₄ is -CH ₃ , and R ₅ is -NH _2. . The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is -H, R ₂ is -H, R ₃ is -H, R ₄ is -CH ₃ , and R ₅ is didehydroalanine. . A compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

(2) A compound according to claim 1, wherein the compound according to claim 1 belongs to the genus Actinomyces Nonomurae, cultivating a microorganism having the ability to produce the compound according to claim 1, and isolating the compound according to claim 1 from the culture Manufacturing method. 2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 14. A pharmaceutical composition according to claim 13, comprising a pharmaceutically acceptable carrier. 15. The pharmaceutical composition according to claim 13 or 14, which is an antibacterial agent. 13. The production method according to claim 12, wherein the microorganism belonging to the genus Actinomyces Nonomurae is Nonomuraea sp. SF2876 strain (FERM P-21494) or a mutant thereof. A Nonomuraea sp. SF2876 strain (FERM P-21494) or a mutant thereof, which has the ability to produce the compound according to claim 1.