JP2001322997A - Novel depsipeptide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a substance that is useful as an active ingredient for antifungal agents. SOLUTION: The objective substance is a novel dipeptide represented by the following formula (I) (wherein R is hydroxyl or amino group) or pharmaceutically acceptable salt and provides medicines including the dipeptide and pharmaceutically acceptable salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel depsipeptide having antifungal activity, a method for producing the same, and a medicament containing the depsipeptide as an active ingredient.

[0002]

2. Description of the Related Art Mycosis, especially deep mycosis, is a disease that tends to increase as an opportunistic infection that develops in immunodeficient patients such as AIDS. Antifungal agents are administered for the treatment of deep mycosis. In recent years, highly effective and safe antifungal agents have been clinically applied. However, at present, the number of antifungal agents that can be used clinically is limited, and it is hard to say that it is sufficient compared with the wide variety of antibiotics used for general bacterial infections. Also, unlike bacteria that are prokaryotes, fungi are the same eukaryotes as humans, so many of the cell components and metabolic systems are similar to higher animals, and antifungal agents are replaced by antibiotics. In comparison, it has many problems in terms of selective toxicity (Jpn. J. Med. Mycol., 40, 119, 1999).

At present, antifungal agents used clinically include azole drugs such as fluconazole, amphotericin B and flucytosine. Azole drugs are the most widely used antifungal drugs because of their good pharmacokinetics and high safety, but they still have problems such as their antifungal activity being bacteriostatic and resistance to Candida. Have been. Amphotericin B, a polyene compound,
Is considered to be the first-line drug against aspergillosis because of its broad antifungal spectrum and its bactericidal action, but fungal infection is a condition with reduced immune function or severe underlying disease. It often occurs in patients with disease, and it is often difficult to administer a sufficient dose in view of the side effects of this drug, such as fever, chills, renal dysfunction, and hypokalemia. Furthermore, flucytosine has the disadvantage of inducing resistance, and no drug of the same strain has been developed (Jpn. J. Med. Mycol., 40, 157, 163, 1999). Under such circumstances, there is a need for the development of new and more effective and safe antifungal agents.

[0004]

An object of the present invention is to provide a new substance which is more effective and safer as an antifungal agent. Another object of the present invention is to provide a medicine containing the above substance as an active ingredient, more specifically, a medicine used as an antifungal agent. It is a further object of the present invention to provide a method for efficiently producing the above substance.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors conducted screening for a substance having an antifungal activity as a microbial product. It has been found that antifungal active substances are contained in cultures of microorganisms belonging to the mycelium. The present inventors have further studied and succeeded in isolating a substance having an antifungal action from the culture and elucidating its structure, and confirming its antifungal action. The present invention has been completed based on these findings.

The following depsipeptides provided by the present invention have been determined to be novel depsipeptide compounds based on their physicochemical properties. As a similar compound,
Aspergillus fumigatu
Compound EK002 produced by s) has been reported (Annual Meeting of the Japanese Society of Agricultural Chemistry, 3p176D, 1999). However, the depsipeptide of the present invention differs from this known compound in physicochemical properties and is clearly distinguished.

That is, the present invention provides the following formula (I):

Embedded image Wherein R represents a hydroxyl group or an amino group, or a pharmaceutically acceptable salt thereof. More specifically, according to the present invention, the depsipeptide MB06108A substance (the substance in which R is a hydroxyl group in the above formula (I)) and the depsipeptide MB06108B substance (the substance in which R is an amino group in the formula (I)), and Acceptable salts are provided.

[0008] From another aspect, the present invention provides a medicament containing the depsipeptide represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. This medicament can be used as an antifungal agent for preventing and / or treating fungal infections. Further, according to the present invention, there is provided a use of the depsipeptide represented by the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of the above medicament, and a method for preventing and / or treating a fungal infection. , The above formula (I)
And administering to a mammal, including a human, a prophylactically and / or therapeutically effective amount of the depsipeptide represented by the formula:

[0009] From a further viewpoint, a bacterium producing the depsipeptide represented by the above formula (I) belonging to the imperfect fungi of the subphylum Ascomycetes is cultured, and the depsipeptide is collected from the culture. A method for producing a depsipeptide represented by the above formula (I), and a method for producing a depsipeptide represented by the above formula (I), which belongs to the class of incomplete fungi of the subphylum Aconitum conidiophora. The present invention provides a microorganism capable of carrying out the reaction. As a representative microorganism, 2000 (2
000) On March 3rd, the accession number “FERM P-17767” was sent to the Institute of Biotechnology and Industrial Technology, Institute of Industrial Science and Technology (1-3-1 Higashi, Tsukuba, Ibaraki, Japan, postal code 305-8566).
The present invention provides an incomplete conidia fruit strain (denoted by the depositor: P1320; hereinafter, this microorganism may be referred to as "P1320 strain") deposited under the present invention.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the depsipeptide represented by the formula (I) of the present invention, a compound in which R is a hydroxyl group is referred to as “MB061”.
08A substance "and a compound in which R is an amino group in the formula (I) was designated as" MB06108B substance "(hereinafter, this name will be used in the description of this specification). The kind of the salt of the depsipeptide of the present invention represented by the above formula (I) is not particularly limited, but a pharmaceutically acceptable salt is preferable. For example, MB0610
Since substance 8A is an acidic substance, a base addition salt can be easily produced by an ordinary method. As pharmaceutically acceptable base addition salts, for example, alkali metal salts, alkaline earth metal salts, aluminum salts, ammonium salts,
And salts obtained from organic bases that generate pharmaceutically acceptable cations such as primary to tertiary lower alkylamines.

The depsipeptide of the present invention represented by the above formula (I) belongs to the class of incomplete mycoplasma of the subphylum Conidiophora, and is obtained by culturing a microorganism capable of producing the depsipeptide. It can be produced by collecting the depsipeptide. Microorganisms that can be used in the production of the depsipeptide of the present invention are not particularly limited, as long as they belong to the incomplete mycota of the subphylum Ascomycetes, and can produce the depsipeptide. For example, the conidia fruit incomplete fungus P132
0 strains can be suitably used.

The P1320 strain is a strain belonging to the class Incomplete Mycota Conidia, which is isolated from natural soil, and has the following bacteriological properties. [Morphological properties] The colonies reach a diameter of 36 mm after culturing on Miura medium (LCA) at 24 ° C for 7 days. White, pale fluffy. After 35 days of cultivation, the brown soluble pigment is slightly produced in the medium.
After 7 days of culture at 24 ° C on a potato dextrose agar medium (PDA), the colonies reach a diameter of 33 mm. White, fluffy on the surface, grayish white on the surface after 35 days of cultivation, reddish brown on the back of the colony, and produces brown soluble pigment in the medium.

[0013] The ability to form conidia is extremely low, and only a few formations are observed in culture on Miura medium at 24 ° C for 35 days. No formation on PDA medium is observed. The conidium is formed superficially in the conidial shell and in the aerial hyphae, and is not observed in the medium. Spherical, dark brown, about 60 micrometers in diameter. At maturation, conidia are released from the conidial shell. The conidium fruit wall is a polygonal mycelial tissue. Conidia are ellipsoidal, light brown. Single cell, smooth surface. 4.2- (5.0) -6.1 × 2.1- (2.
9) -3.6 micrometers. Teleomorph was not observed.

[Physiological properties] Growth temperature range: 9-30 ° C (cultured in Miura medium for 7 days) Optimal growth temperature: 24 ° C Growth pH range: 2-10 (Miura liquid medium, 27 ° C, shaken culture for 7 days) ) Optimum growth pH: 5

[Taxonomic considerations] This strain forms light brown, one-celled conidia in spherical conidial shells. (Co
elymycetes). However, since this strain has a low fruiting body-forming ability and very few conidial shells formed on the medium, it is difficult to specify the presence or absence of a pore and the mode of conidia formation. Therefore, this strain was identified as incomplete conidia fungus P1320.

The method of culturing the above-mentioned strain P1320 is not particularly limited, but usually a culturing method under aerobic conditions, particularly a solid culturing using rice or agar medium is most suitable. Also,
Organic and inorganic substances can be appropriately added to the medium to promote the growth of bacteria and promote the production of the depsipeptide of the present invention. A suitable temperature for culturing is 20 to 30 ° C, but in many cases, culturing can be performed at around 27 to 30 ° C.

MB06108A substance by the above P1320 strain and
In the production of the MB06108B substance, the productivity varies depending on the composition of the medium used and the culturing conditions, but generally, the accumulation reaches its maximum in 10 to 20 days in the agar medium surface culture method. Usually, it is desirable to stop the cultivation when the accumulated amount of the MB06108A substance and the MB06108B substance in the culture reaches the maximum, and to isolate and purify the target substance from the culture.

The method for isolating and purifying the MB06108A and MB06108B substances produced in the culture by the above-mentioned culture method is not particularly limited. For example, MB06108A substance and MB06108B
The substance should be isolated and purified using its properties by appropriately combining ordinary separation means such as solvent extraction, ion exchange resin, adsorption or distribution column chromatography, gel filtration, dialysis, and precipitation. Is possible.

Specifically, an extract can be obtained by adding an organic solvent such as methanol, ethanol, or acetone to the culture obtained above, stirring the mixture, and centrifuging or filtering. After the organic solvent of this extract is distilled off and concentrated, an organic solvent such as n-butanol is added to the concentrate and stirred to obtain an extract containing the MB06108A substance and the MB06108B substance. The residue obtained by distilling off the organic solvent of the extract is subjected to a method such as an adsorption / desorption method using an adsorbent, a molecular partitioning method using a gel filtration agent, and a recrystallization method from an appropriate solvent to thereby provide the present invention. MB06108A and MB06108B can be purified.

From the above extract, the substance MB06108A of the present invention and
As a method of purifying each of the MB06108B substances, more specifically, after distilling off the organic solvent of the extract and concentrating it,
The concentrate is extracted with n-butanol, and the extract is concentrated under reduced pressure. The obtained concentrate is dissolved in a small amount of an organic solvent such as methanol, and chloroform / methanol, hexane / acetone, hexane / ethyl acetate, Or silica gel chromatography (eg, Wakogel C-300, manufactured by Wako Pure Chemical Industries, Ltd.) repeatedly using a solvent system such as methanol / water, or ODS chromatography (eg, Silicalgel)
60 silanized, manufactured by Merck, etc.). Also, if necessary, Sephadex LH-20
(Pharmacia Fine Chemicals), Toyopearl
The MB06108A substance and the MB06108B substance can also be purified by a method using gel filtration column chromatography such as HW-40s (manufactured by Tosoh Corporation), eluting with methanol, water or the like.

[0021] The substances MB06108A and MB06108B of the present invention have an antifungal activity and can be used as an antifungal agent as a medicament for preventing and / or treating fungal infections. The type of fungal infection to be prevented and / or treated is not particularly limited, and tinea (eg, tinea corporis, tinea cruris, tinea unguium, tinea pedis, tinea cruris, cels ulcer, tinea pea, etc.) , Candidiasis (oral candidiasis, cutaneous candidiasis,
Superficial fungal infections, such as candidal acne and chronic mucocutaneous candidiasis, or visceral mycosis (mycemia, respiratory mycosis, gastrointestinal mycosis, uromycosis, fungal meningitis) ) And deep skin fungal infections such as deep skin mycosis. The type of fungi to be prevented and / or treated is not particularly limited. For example, Trichophyton, Microsporum, Epidermophyton, Candida, Malassezia, Aspergillus, Cropcox, Sporotrix, Fungi belonging to the genus Honcecaea can be mentioned. However, the use of the medicament of the present invention is not limited to antifungal agents or the specific fungal infections described above.

As the medicament of the present invention, one or more substances selected from the group consisting of the above-mentioned substances MB06108A and MB06108B and pharmaceutically acceptable salts thereof may be used as such. Usually, one or more of the above substances as active ingredients and one of pharmaceutically acceptable carriers
It is desirable to produce and administer a pharmaceutical composition comprising one or more species. 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, and ear drops.

Various known methods can be applied to the method of producing and administering the medicament of the present invention. As the pharmaceutically acceptable carrier used for producing the above-mentioned pharmaceutical composition, an inorganic or organic pharmaceutically acceptable carrier can be used. The pharmaceutical composition is preferably formulated in solid, semi-solid or liquid form as an oral administration preparation or a parenteral administration preparation such as an external preparation, an injection or a suppository. Solid preparations for rectal administration include suppositories which contain the active ingredient of the present invention and a pharmaceutically acceptable carrier and are produced by a conventional method.

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

In addition, the solid preparations described above include, for example,
By spraying a solution of an enteric substance such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, or methacrylic acid, methyl methacrylate copolymer with an organic solvent, or an aqueous solution An enteric coating can be formed by applying an enteric coating. Solid preparations such as powders and granules can be enclosed in enteric capsules.

Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, pellets, syrups and elixirs. These preparations can be used together with the above-mentioned depsipeptide, which is an active ingredient of the medicament of the present invention, and / or a pharmaceutically acceptable salt thereof, together with a generally used pharmaceutically acceptable carrier, for example, water or liquid paraffin. However, as a carrier component other than these, an oily base such as coconut oil, fractionated coconut oil, soybean oil, and corn oil can also be contained. If necessary, pharmaceutically acceptable carriers may contain commonly used auxiliaries, fragrances, stabilizers, preservatives and the like. Liquid preparations may also be enclosed in capsules made of a material that can be absorbed by the body, such as gelatin.

As preparations for parenteral administration, injections, drops, oil solutions, ointments, lotions, tonics, sprays, suspensions, oils, emulsifiers, suppositories, transdermal absorbers, transmucosal absorbers, inhalants Preparations, eye drops, nasal drops, ear drops, inhalants and the like, which are administered as a sterile aqueous or non-aqueous solution, 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, and injectable organic acid esters such as ethyl oleate are pharmaceutically acceptable. It can be used as an acceptable carrier. Such formulations may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents. These solutions, suspensions, and emulsifiers can be sterilized by appropriate treatment such as filtration through a bacteria-retaining filter, heating, blending of a bactericide, or irradiation with ultraviolet light.
Alternatively, a sterile solid preparation containing the active ingredient can be produced and dissolved in sterile water or a sterile injectable solvent immediately before use. In addition, vegetable oils such as soybean oil and phospholipids such as lecithin, and water are added to a homogeneous solution of the active ingredient, and, for example, a fat emulsion obtained by homogenizing with a homogenizer such as a pressure injection homogenizer or an ultrasonic homogenizer is also an injection. Can be used as

As the dosage form for transdermal administration, for example, ointments,
Creams and the like. These are manufactured by a usual method. In addition to the above, in formulating the active ingredient of the present invention, surfactants, excipients, coloring agents, flavors, preservatives, stabilizers, buffers, suspending agents, isotonic agents, and other commonly used agents are used. An adjuvant 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, patient condition, treatment time and the like. In the case of the above, 0.01 to 1000 mg / Kg (body weight), preferably 0.1 to 100 mg / Kg (body weight) can be administered per adult per day as an amount of the above-mentioned active ingredient. The amount of the above active ingredient per person per day is 0.01 to 1000 mg / Kg (body weight), preferably 0.1 to 100 m
g / Kg (body weight) can be administered. In the case of oral administration, the amount of the active ingredient is 0.5 to 2 per adult per day per adult
000 mg / Kg (body weight), preferably 1 to 1000 mg / Kg (body weight)
Can be administered. However, the dose is not limited to the above-mentioned amount, but can be appropriately increased or decreased. The medicament of the present invention can be administered once to several times a day or every other day.

[0031]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, which are intended to be illustrative only and do not limit the scope of the present invention. It goes without saying that many variations or modifications not illustrated here can be used. In addition, various methods for producing the MB06108A substance and the MB06018B substance can be proposed based on the properties of the MB06108A substance and the MB06018B substance disclosed in the present specification. It is to be understood that any variations, modifications, and methods of manufacture are within the scope of the invention.

Example 1 A 500 ml Erlenmeyer flask containing 60 g of rice and 20 ml of tap water was placed in a 2 flask.
0 tubes were prepared and autoclaved at 121 ° C. for 20 minutes. The P1320 strain was inoculated with 3 loops of each loop and allowed to stand at 27 ° C. for 14 days. To the culture containing the obtained cells, 160 ml of a 50% aqueous acetone solution was added per flask, and the cells were allowed to stand for 24 hours. After that, the cells and the solid content of the medium were separated by filtration to obtain about 2.8 L of an extract.

From the extract (2.8 L) obtained above,
The acetone was distilled off under reduced pressure to obtain a concentrated solution (1.1 L).
After extracting the active ingredient from the concentrated solution with n-butanol (1.1 L), the solvent was distilled off under reduced pressure to obtain an oily substance (3.8 g).
This oily substance is applied to a silica gel column (Wakogel C-300,
Wako Pure Chemicals, 25 g) on top, chloroform, 1% methanol-chloroform, 5% methanol-chloroform,
10% methanol-chloroform, 30% methanol-chloroform, 50% methanol-chloroform, 70% methanol-chloroform, 90% methanol-chloroform, and methanol were developed as a solvent in 200 ml each. Of these developing solvents, the combined fractions of 30% methanol-chloroform, 50% methanol-chloroform, and 70% methanol-chloroform were concentrated and dried to an oily substance (2.7 g).
I got

This oily substance was applied to an ODS column (Silicalgel 60).
silanized, Merck, 25 g), and add water, 1% methanol water, 5% methanol water, 10% methanol water, 20% methanol water, 50% methanol water, 70% methanol water, and 90% methanol water to each. Each 200 ml was developed as a solvent. Among these developing solvents, the combined fractions of 20% aqueous methanol, 50% aqueous methanol, and 70% aqueous methanol were concentrated to dryness to obtain an oily substance (1.84 g).

This oily substance was added to an ODS column (Cosmo Seal 7).
5C18-OPN, Nacalai Tesque, 50 g) was placed on the top and developed with 60% aqueous methanol (400 ml), 70% aqueous methanol (500 ml), and 80% aqueous methanol (500 ml) as a solvent, and the eluate was 4.5 mL.
Dispensed in ml. Among the eluted active fractions, fraction Nos. 16-29 were concentrated to dryness, and fraction 1 (633 mg), and fraction Nos. 39-56 were concentrated to dryness, fraction 2 (117 mg), and fraction Nos. 101-125. It was concentrated to dryness to obtain fraction 3 (91.7 mg).

[0036] 59 mg of fraction 1 was treated with 50% acetonitrile-
The solution was subjected to preparative HPLC (Cosmo Seal 5C18-AR-II, 20 x 250 mm, Nacalai Tesque) using 0.1% trifluoroacetic acid as a developing solvent. The active part was collected, concentrated and dried to dryness.
It was 8A substance (16.3 mg). 80 for 45 mg of fraction 2
% Methanol water as a developing solvent for TDS for preparative ODS (Art.1.1
5389, RP-18F254s, Merck), fractions exhibiting Rf 0.48 were collected, concentrated to dryness to obtain MB06108C (12.0 mg). The physicochemical properties of this substance were measured and found to be consistent with EK002 (Agricultural Chemistry Annual Meeting, 1999, 3p176D). In fraction 3,
Preparative HPLC using 45 mg of 50% acetonitrile-0.1% trifluoroacetic acid as a developing solvent (Cosmo Seal 5C18-AR-II, 20
x 250 mm, Nacalai Tesque), the portion showing the activity was fractionated, concentrated and dried to dryness to obtain MB06108B substance (22.2 mg). The physicochemical properties of the MB06108A and MB06108B substances thus obtained were measured. The results are as follows.

1. Physicochemical properties of 06108A substance (1) Color and properties: colorless powder (2) Molecular formula: C ₄₀ H ₆₉ N ₇ O ₁₆ (3) Mass spectrum (HR-FAB-MS): measured value 904.4883
(M + H) ⁺ , calculated 904.4879 (4) Specific rotation: [α] _D ^22.5 = + 4.1 ° (c = 0.745, Me
OH) (5) UV absorption spectrum λ _max nm (E ^% _cm ) [MeOH]:
213 (80) (6) Infrared absorption spectrum ν _max cm ^-1 (KBr): 341
0, 2926, 2855, 1728, 1659, 1654, 1543, 1534, 1460,
1410, 1383, 1341, 1260, 1209, 1138, 1102, 1073, 1
055, 1034, 1003 (7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm):
0.84 (t, 3H), 1.07 (s, 3H), 1.08 (d, 6H), 1.20 (d,
3H), 1.22-1.30 (m, 22H), 2.35 (dd, 1H), 2.5 (1H, so
lvent), 2.65 (dd, 1H), 2.82 (dd, 1H), 3.45-3.50 (2
H, solvent), 3.57 (dd, 1H), 3.68 (dd, 1H), 3.78
(m, 1H), 3.80 (m, 1H), 3.69 (dd, 1H), 3.94 (dd, 1
H), 4.19 (m, 3H), 4.22 (m, 1H), 4.30 (m, 1H), 4.40
(dd, 1H), 4.23 (d, 1H), 7.28 (d, NH), 7.72 (d, N
H), 7.80 (d, NH), 7.94 (d, NH), 8.32 (t, NH), 8.48
(d, NH), 8.52 (d, NH) (8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm):
172.7 s, 172.5 s, 171.8 s, 170.4 s, 169.8 s, 169.4
s, 168.6 s, 167.7 s, 76.2 d, 72.9 s, 67.6 d, 66.9
d, 61.2 t, 60.9 t, 59.3 d, 57.9 d, 56.1 d, 55.0
d, 50.3 d, 48.4 d, 42.8 t, 37.5 t, 37.3 t, 35.2 t,
31.3 t, 29.7 t, 29.2-29.0, 28.7 t, 22.9 t, 22.8
q, 22.1 t, 20.4 q, 20.1 q, 18.0 q, 13.9 q (9) Solubility: Soluble in methanol. Poorly soluble in water and chloroform.

2. Physicochemical properties of MB06108B substance (1) Color and properties: colorless powder (2) Molecular formula: C ₄₀ H ₇₀ N ₈ O ₁₅ (3) Mass spectrum (HR-FAB-MS): Observed value 903.5024
(M + H) ⁺ , calculated value 903.5038 (4) Specific rotation: [α] _D ^22.5 = -15.4 ° (c = 1.0, MeOH) (5) Ultraviolet absorption spectrum λ _max nm (E ^% _cm ) [MeO
H]: 213 (80) (6) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3389,
2926, 2855, 1732, 1675, 1651, 1545, 1543, 1521, 14
79, 1467, 1406, 1381, 1290, 1256, 1243, 1204, 118
8, 1138, 1102, 1071, 1048, 1026, 1003 (7) ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm):
0.84 (t, 3H), 1.00 (d, 3H), 1.01 (s, 3H), 1.9 (d, 3
H), 1.2 (d, 3H), 1.22-1.45 (m, 22H), 2.35 (dd, 1
H), 2.58 (dd, 1H), 2.67 (br-d, 1H), 2.87 (dd, 1H),
3.32 (d, 1H), 3.55 (m, 1H), 3.83 (m, 1H), 3.85-
3.90 (m, 2H), 3.93 (m, 1H), 4.18 (m, 3H), 4.28-4.35
(m, 2H), 4.30-4.40 (m, 1H), 5.0 (d, 1H), 7.11 (s,
NH), 7.32 (d, NH), 7.48 (d, NH), 7.75 (s, NH), 7.
85 (s, NH), 7.98 (br-s, NH), 8.16 (m, NHx2), 8.33
(s, NH) (8) ¹³ C-NMR spectrum (100 MHz, DMSO-d ₆ ) δ (ppm):
173.3 s, 172.2 s, 171.5 s, 171.0 s, 171.0 s, 170.3
s, 170.3 s, 168.4 s, 167.8 s, 75.8 d, 72.9s, 67.3
d, 66.4 d, 61.5 t, 61.0 t, 59.3 d, 59.3 d, 58.2
d, 55.5 d, 54.6d, 49.4 d, 49.3 d, 43.1 t, 37.6 t,
37.3 t, 35.9 t, 31.3 t, 29.8 t, 29.2 t, 29.1 t, 29.
1 t, 29.0 t, 28.7 t, 23.0 t, 22.7 q, 22.1 t, 20.4
q, 20.0q, 17.2 q, 14.0 q (9) Solubility: Soluble in methanol. Poorly soluble in water and chloroform.

Test Example 1 The antifungal activity of the substances MB06108A and MB06108B was determined by the liquid culture dilution method using the minimum inhibitory concentration (MI) against various strains.
C). YNBP (Buffered yeast n
itrogen base containing 0.5% glucose) (DIFCO)
And cultured at 28 ° C. for 48 hours. Table 1 shows the results.

[0040]

[Table 1]

Formulation Example 1: Tablets Tablets containing the depsipeptide of the present invention as an active ingredient were produced according to the component composition (for one tablet) shown in Table 2 below.
The MB06108A substance, magnesium silicate and lactose obtained in the above Example 1 were mixed, kneaded with an alcohol solution in which hydroxypropyl cellulose was dissolved, then granulated to an appropriate particle size, dried and sized. Further, magnesium stearate and hydrogenated vegetable oil were added and mixed to obtain uniform granules. Then, tablets having a diameter of 7.0 mm, a weight of 150 mg and a hardness of 6 kg were produced by a rotary tableting machine.

[0042]

[Table 2]

Formulation Example 2: Granules The depsipeptide of the present invention (MB0610 obtained in Example 1 above) was prepared according to the component composition (single dose) shown in Table 3 below.
8A) was produced as an active ingredient.
After uniformly mixing each component except for hydroxypropyl cellulose in the following formulation, kneading by adding an alcohol solution in which hydroxypropyl cellulose is dissolved, granulating with an extrusion granulator, and drying to 12 mesh What passed through the sieve and remained on the 48-mesh sieve was used as granules.

[0044]

[Table 3]

[0045]

The novel depsipeptide of the present invention, MB06
Substances 108A and MB06108B and pharmaceutically acceptable salts thereof are medically problematic C. albicans and A.
It has an excellent antifungal activity against fumigatus, and is useful as an active ingredient of a medicament for preventing and / or treating fungal infections.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) C12R 1: 645) C12R 1: 645) (C12P 21/04 (C12P 21/04 C12R 1: 645) C12R 1: 645) (72) Inventor Hiroshi Nose 760, Shikaoka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Laboratory, Meiji Seika Co., Ltd. (72) Inventor Kenzo Harimaya 760, Shiokaka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Laboratory, Meiji Seika Co., Ltd. In-house (72) Inventor Masato Sugiyama 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Corporation Yokohama Research Laboratory F-term (reference) 4B064 AG37 BA09 BE09 BG01 BH02 BH03 BH06 BH07 CA05 CC03 CD22 CE07 CE08 CE10 DA02 4B065 AA58X AC14 BB26 CA24 CA44 4H045 AA10 BA35 C A15 EA29 FA73 GA01 GA22 GA40 HA02

Claims (5)

[Claims] 1. The following formula (I): (Wherein R represents a hydroxyl group or an amino group) or a pharmaceutically acceptable salt thereof. 2. A medicament comprising the depsipeptide according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. The medicament according to claim 2, which is an antifungal agent. 4. A method of culturing an incomplete conidia fungus FERM P-17767 belonging to the class of the subphylum Conidiophora conidia, wherein the depsipeptide according to claim 1 is collected from the culture. The method for producing a depsipeptide according to claim 1. 5. A conidial fungus, FERM P-17767, which belongs to the class Conidiophyllum conidiophore.