JP2018111670A - Novel compounds having activity enhancing effects on antifungal agents and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound that effectively enhances the antimycotic activity of antifungal agents and has a skeletal structure different from publicly-known pharmaceutical compounds.SOLUTION: One aspect of the present invention is a compound represented by the formula (I), a salt thereof, or solvates thereof. [n, R, R, R, R, R, Rand Rin the formula are as defined in the description and the claims]. Another aspect of the present invention is a production method for the compound represented by the formula (I), a salt thereof, or solvates thereof, and an activity enhancing agent of at least one type of antifungal agent selected from the group consisting of polyene macrolide drugs, azole drugs, candin drugs and fluoropyrimidine drugs, which include said compound, a salt thereof, or solvates thereof as an active ingredient.SELECTED DRAWING: None

Description

  The present invention relates to a novel compound having an activity enhancing action against antifungal agents and a method for producing the same. In particular, the present invention relates to a novel compound having an activity-enhancing action of at least one antifungal agent selected from the group consisting of a polyene macrolide drug, an azole drug, a candine drug and a fluoropyrimidine drug, and its production Regarding the method.

  Since the 1950s, antibiotic research and development has made rapid progress. Accordingly, antibiotics have become widespread, and various therapeutic agents for various infectious diseases have been developed. On the other hand, in recent years, phenomena such as an increase and seriousness of deep mycosis caused by fungi such as Candida, Aspergillus and Cryptococcus have been found. These phenomena involve problems such as immunodeficiency caused by leukemia, malignant lymphoma, HIV infection, etc., decreased immune function due to administration of anticancer drugs, or fungal metastasis due to large-scale use of antibiotics. It is believed that.

  At present, antifungal agents such as polyene macrolides, azoles, candins and fluoropyrimidines are used for the treatment of deep mycosis. For example, amphotericin B, which is one of polyene macrolides, has a strong antifungal activity and is therefore effective in the treatment of serious diseases. However, since this drug may cause side effects such as nephrotoxicity, a safety problem has been pointed out (Non-patent Document 1). As for flucytosine, which is one of fluoropyrimidine drugs, low safety and the presence of resistant bacteria are problematic.

  Azole drugs are generally considered to have a wide safety margin and relatively few side effects. However, since this drug has a narrow antifungal spectrum and shows a bacteriostatic mechanism of action, it is less effective against serious diseases. In addition, an increase in resistant bacteria to the drug has been pointed out (Non-patent Document 2).

  In recent years, candin drugs such as Micafungin and Caspofungin have been developed and used for the treatment of deep mycosis (Non-patent Document 3). However, since the drug has a narrow antifungal spectrum, the disease to be treated is limited to candidiasis or aspergillosis. In addition, reports of resistant bacteria against the drug are gradually increasing.

  Patent Document 1 discloses a novel FKI-4981B substance and a pharmaceutically acceptable salt thereof having an activity of enhancing the activity of at least one antifungal agent selected from a polyene macrolide drug and an azole drug. Describe. The document describes that the FKI-4981B substance can be used as an active ingredient in pharmaceutical compositions for enhancing the activity of these antifungal agents.

Japanese Patent No. 5843188

Gallis et al., Rev. Infect. Dis., 12, 309-329, 1990 Rex et al., Antimicrob. Agents Chemothe., 39, 1-8, 1995 Denning, Lancet, 362, 9330, 1142-1151, 2003

  In the case of a blood disease such as leukemia or a disease accompanied by a decrease in immunity such as HIV infection, an easily infectious state is caused. For this reason, in patients with such diseases, the incidence of fungal infections can increase as opportunistic infections. In addition, these diseases accompanied by a decrease in immunity usually tend to become serious, and thus the treatment period is often long. As a result, chemotherapy for fungal infections is often prolonged.

  There are several problems with antifungal agents that are currently used frequently in the treatment of fungal infections such as deep mycosis. For example, amphotericin B, which is one type of polyene macrolide, may cause side effects such as severe nephrotoxicity. In addition, it is known that azole drugs are highly susceptible to drug-resistant bacteria. Therefore, in order to obtain the therapeutic effect of fungal infection while avoiding these problems, a means for reducing the dose of the antifungal agent and shortening the administration period is required.

  A compound having an effect of enhancing the antifungal activity of an antifungal agent can reduce the dose of the antifungal agent and / or shorten the administration period. Therefore, by using a compound having such an action in combination with an antifungal agent, the dose of the antifungal agent can be reduced and / or the administration period can be shortened to suppress the occurrence of side effects such as nephrotoxicity. And / or the generation of drug-resistant bacteria can be suppressed. As a compound having the above action, substance FKI-4981B and pharmaceutically acceptable salts thereof are known (Patent Document 1). However, in order to develop more effective pharmaceutical compounds, there is a need for new compounds that have an effect of effectively enhancing the antifungal activity of antifungal drugs and have a skeleton structure different from known pharmaceutical compounds. It was.

  Therefore, an object of the present invention is to provide a novel compound having an action of effectively enhancing the antifungal activity of an antifungal drug and having a skeleton structure different from a known pharmaceutical compound.

  The present inventors have studied various means for solving the above problems. The present inventors have found that a new bacterium isolated from soil produces a compound having an action of effectively enhancing the antifungal activity of amphotericin B, which is one of polyene macrolides, in the culture solution. I found it. The present inventors have found that the compound in the culture solution is a novel compound having a skeleton structure different from that of known pharmaceutical compounds. The present inventors have also found that the compound can be produced by a culture means using the bacterium. Based on the above findings, the present inventors have completed the present invention.

［式中、
nは、0〜10の範囲の整数であり、
R¹、R²、R³及びR⁴は、互いに独立して、OH、置換若しくは非置換の糖基、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のアシルオキシ、カーボナート、又はカーバマートであり、
R⁵及びR⁶は、それらが結合する炭素の間で二重結合を形成するか、又は
R⁵は、OH、置換若しくは非置換の糖基、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のアシルオキシ、カーボナート、又はカーバマートであり、且つ
R⁶は、Hであり、
但し、R⁵及びR⁶が複数個存在する場合、各R⁵及びR⁶は、それぞれ別の意味を有していてよく、
R⁷は、H、OH、NR^N1R^N2、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、置換若しくは非置換のヘテロシクロアルキルアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のヘテロアリール、置換若しくは非置換のヘテロアリールアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、又は置換若しくは非置換のアシルオキシであり、
R^N1及びR^N2は、互いに独立して、H、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、置換若しくは非置換のヘテロシクロアルキルアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のヘテロアリール、又は置換若しくは非置換のヘテロアリールアルキルである。］
で表される化合物若しくはその塩、又はそれらの溶媒和物。
（2） R¹、R²、R³及びR⁴が、互いに独立して、OH、置換若しくは非置換の糖基、置換若しくは非置換のC₁〜C₆アルコキシ、置換若しくは非置換のC₃〜C₆シクロアルコキシ、置換若しくは非置換の3〜6員ヘテロシクロアルコキシ、置換若しくは非置換のC₆〜C₁₅アリールオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルキルオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルケニルオキシ、置換若しくは非置換の5〜15員のヘテロアリールオキシ、置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₅アルキルオキシ、置換若しくは非置換のC₁〜C₂₀アシル、置換若しくは非置換のC₁〜C₂₀アシルオキシ、カーボナート、又はカーバマートであり、
R⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成するか、又は
R⁵が、OH、置換若しくは非置換の糖基、置換若しくは非置換のC₁〜C₆アルコキシ、置換若しくは非置換のC₃〜C₆シクロアルコキシ、置換若しくは非置換の3〜6員ヘテロシクロアルコキシ、置換若しくは非置換のC₆〜C₁₅アリールオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルキルオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルケニルオキシ、置換若しくは非置換の5〜15員のヘテロアリールオキシ、置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₅アルキルオキシ、置換若しくは非置換のC₁〜C₂₀アシル、置換若しくは非置換のC₁〜C₂₀アシルオキシ、カーボナート、又はカーバマートであり、且つ
R⁶が、Hである、前記実施形態（1）に記載の化合物。
（3） R¹、R²、R³及びR⁴が、互いに独立して、OH、又は式（S-1）若しくは（S-2）：

で表される基であり、
R⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成するか、又は
R⁵が、OH、又は式（S-1）若しくは（S-2）で表される基であり、且つ
R⁶が、Hである、前記実施形態（1）又は（2）に記載の化合物。
（4） （A）nが、0であり、
R¹及びR²が、式（S-1）：

で表される基であり、
R³が、式（S-2）：

で表される基であり、
R⁴が、OHであり、
R⁷が、OHである、或いは；
（B）nが、0であり、
R¹が、式（S-1）で表される基であり、
R²が、式（S-2）で表される基であり、
R³及びR⁴が、OHであり、
R⁷が、OHである、或いは；
（C）nが、0であり、
R¹及びR²が、式（S-1）で表される基であり、
R³及びR⁴が、OHであり、
R⁷が、OHである、或いは；
（D）nが、0であり、
R¹が、式（S-1）で表される基であり、
R²、R³及びR⁴が、OHであり、
R⁷が、OHである、或いは；
（E）nが、1であり、
R¹が、式（S-1）で表される基であり、
R²が、式（S-2）で表される基であり、
R³及びR⁴が、OHであり、
R⁵が、OHであり、
R⁶が、Hであり、
R⁷が、OHである、或いは；
（F）nが、2であり、
R¹が、式（S-2）で表される基であり、
R²、R³及びR⁴が、OHであり、
第1のR⁵が、式（S-1）で表される基であり、
第1のR⁶が、Hであり、
第2のR⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成し、
R⁷が、OHである、或いは；
（G）nが、2であり、
R¹が、式（S-1）で表される基であり、
R²が、式（S-2）で表される基であり、
R³及びR⁴が、OHであり、
第1のR⁵が、式（S-1）で表される基であり、
第1のR⁶が、Hであり、
第2のR⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成し、
R⁷が、OHである、或いは；
（H）nが、2であり、
R¹が、式（S-1）で表される基であり、
R²、R³及びR⁴が、OHであり、
第1のR⁵が、式（S-1）で表される基であり、
第1のR⁶が、Hであり、
第2のR⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成し、
R⁷が、OHである、前記実施形態（1）〜（3）のいずれかに記載の化合物。
（5） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の製造方法であって、
式（I）で表される化合物を産生する能力を有するシュードフィアロフォラ属菌BF-0158株（NITE AP-02400）又はその変異株である微生物を培地中で培養して、式（I）で表される化合物を該培地中に蓄積させる、化合物蓄積工程；
化合物蓄積工程で得られた式（I）で表される化合物を前記微生物の培養物から精製する、化合物精製工程；
を含む、前記方法。
（6） 前記実施形態（1）〜（4）のいずれかに記載の式（I）で表される化合物を産生する能力を有するシュードフィアロフォラ属菌BF-0158株（NITE AP-02400）又はその変異株である微生物。
（7） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含む、ポリエンマクロライド系薬剤、アゾール系薬剤、キャンディン系薬剤及びフルオロピリミジン系薬剤からなる群より選択される少なくとも1種の抗真菌薬の活性増強剤。
（8） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。
（9） 1種以上の真菌感染症の予防又は治療に使用するための、前記実施形態（8）に記載の医薬。
（10） ポリエンマクロライド系薬剤、アゾール系薬剤、キャンディン系薬剤及びフルオロピリミジン系薬剤からなる群より選択される少なくとも1種の抗真菌薬をさらに含む、前記実施形態（8）又は（9）に記載の医薬。
（11） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物と、1種以上の製薬上許容される担体とを含む医薬組成物。
（12） 1種以上の真菌感染症の予防又は治療に使用するための、前記実施形態（11）に記載の医薬組成物。
（13） ポリエンマクロライド系薬剤、アゾール系薬剤、キャンディン系薬剤及びフルオロピリミジン系薬剤からなる群より選択される少なくとも1種の抗真菌薬をさらに含む、前記実施形態（11）又は（12）に記載の医薬組成物。 That is, the gist of the present invention is as follows.
(1) Formula (I):

[Where:
n is an integer in the range 0-10;
R ¹ , R ² , R ³ and R ⁴ each independently represent OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocyclo Alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or non-substituted Substituted acyl, substituted or unsubstituted acyloxy, carbonate, or carbamate,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted Arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, carbonate, or Carbamart, and
R ⁶ is H;
However, when there are a plurality of R ⁵ and R ⁶ , each R ⁵ and R ⁶ may have a different meaning,
R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, Replace Properly is unsubstituted arylalkyloxy, substituted or unsubstituted aryl alkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl alkyloxy, or substituted or unsubstituted acyloxy,
R ^N1 and R ^N2 each independently represent H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. ]
Or a salt thereof, or a solvate thereof.
(2) R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, substituted or unsubstituted sugar group, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered heterocycloalkyl alkoxy substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted of C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, 5-15 membered substituted or unsubstituted heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, an carbonate, or Kabamato,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is, OH, substituted or unsubstituted sugar group, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocyclo alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, 5 substituted or unsubstituted 15-membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ Acyloxy, carbonate or carbamate, and
The compound according to embodiment (1), wherein R ⁶ is H.
(3) R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, or formula (S-1) or (S-2):

A group represented by
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is OH or a group represented by the formula (S-1) or (S-2), and
The compound according to embodiment (1) or (2), wherein R ⁶ is H.
(4) (A) n is 0,
R ¹ and R ² are represented by formula (S-1):

A group represented by
R ³ is the formula (S-2):

A group represented by
R ⁴ is OH;
R ⁷ is OH, or
(B) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(C) n is 0,
R ¹ and R ² are a group represented by the formula (S-1),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(D) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
R ⁷ is OH, or
(E) n is 1,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁵ is OH;
R ⁶ is H,
R ⁷ is OH, or
(F) n is 2,
R ¹ is a group represented by the formula (S-2),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(G) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(H) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
The compound according to any one of the embodiments (1) to (3), wherein R ⁷ is OH.
(5) A method for producing the compound according to any one of the embodiments (1) to (4) or a salt thereof, or a solvate thereof,
Pseudofialophora BF-0158 strain (NITE AP-02400) having the ability to produce a compound represented by formula (I) or a mutant strain thereof is cultured in a medium, A compound accumulation step of accumulating the represented compound in the medium;
A compound purification step of purifying the compound represented by the formula (I) obtained in the compound accumulation step from the culture of the microorganism;
Said method.
(6) Pseudofialophora BF-0158 strain (NITE AP-02400) having the ability to produce the compound represented by formula (I) according to any one of the above embodiments (1) to (4) or The microorganism that is the mutant.
(7) A polyene macrolide drug, an azole drug, and a candine drug containing the compound or salt thereof according to any one of the embodiments (1) to (4) or a solvate thereof as an active ingredient And at least one antifungal activity enhancer selected from the group consisting of fluoropyrimidines.
(8) A medicament comprising the compound according to any one of the above embodiments (1) to (4) or a salt thereof, or a solvate thereof as an active ingredient.
(9) The medicament according to the embodiment (8) for use in the prevention or treatment of one or more fungal infections.
(10) The embodiment (8) or (9), further comprising at least one antifungal agent selected from the group consisting of a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug. The medicament according to 1.
(11) A pharmaceutical composition comprising the compound according to any one of the embodiments (1) to (4) or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers.
(12) The pharmaceutical composition according to the embodiment (11) for use in the prevention or treatment of one or more fungal infections.
(13) The embodiment (11) or (12), further comprising at least one antifungal agent selected from the group consisting of a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug. A pharmaceutical composition according to 1.

  According to the present invention, it is possible to provide a novel compound having an action of effectively enhancing the antifungal activity of an antifungal drug and having a skeleton structure different from a known pharmaceutical compound.

  Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

  Hereinafter, preferred embodiments of the present invention will be described in detail.

<1. New compound>
As used herein, “alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, “C ₁ -C ₅ alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing at least 1 and at most 5 carbon atoms. Suitable alkyls include, but are not limited to, linear or branched C, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl. it can be mentioned ₁ -C ₅ alkyl.

In the present specification, “alkenyl” means a group in which one or more CC single bonds of the alkyl are substituted with double bonds. Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 Mention may be made of straight-chain or branched C ₂ -C ₅ alkenyl such as -methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl and 1-pentenyl.

In the present specification, “alkynyl” means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls include, but are not limited to, straight chain such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 1-pentynyl. Alternatively, branched C ₂ -C ₅ alkynyl may be mentioned.

As used herein, “cycloalkyl” means an alicyclic alkyl containing the specified number of carbon atoms. For example, “C ₃ -C ₆ cycloalkyl” means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, C ₃ -C ₆ cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present specification, “cycloalkenyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with double bonds. Suitable cycloalkenyl includes, but is not limited to, C ₄ -C ₆ cycloalkenyl such as cyclobutenyl, cyclopentenyl, and cyclohexenyl.

In the present specification, “cycloalkynyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with triple bonds. Suitable cycloalkynyl includes, but is not limited to, C ₄ -C ₆ cycloalkynyl such as cyclobutynyl, cyclopentynyl and cyclohexynyl.

  In the present specification, “heterocycloalkyl” means that one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O). Means a group substituted with one or more heteroatoms. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heterocycloalkyl include, but are not limited to, eg, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Mention may be made of ˜6-membered heterocycloalkyl.

In the present specification, “cycloalkylalkyl” means a group in which one of the hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkylalkyl include, but are not limited to, may be, for example, a C ₇ -C ₁₁ cycloalkylalkyl such as cyclohexylmethyl and cyclohexenyl methyl.

As used herein, “heterocycloalkylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms has been replaced with the heterocycloalkyl. Suitable heterocycloalkylalkyls include, but are not limited to, 3-6 membered heterocycloalkyl-C ₁ -C ₅ alkyl.

In the present specification, “alkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the alkyl, alkenyl or alkynyl. Suitable alkoxy includes, but is not limited to, C ₁ -C ₅ alkoxy such as methoxy, ethoxy, propoxy, butoxy and pentoxy.

In the present specification, “cycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the above cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkoxy includes, but is not limited to, C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy and cyclopentoxy.

  In the present specification, “heterocycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heterocycloalkyl. Suitable cycloalkoxy includes, but is not limited to, for example, 3-6 membered heterocycloalkoxy.

In the present specification, “aryl” means an aromatic ring group. Suitable aryls include, but are not limited to, C ₆ -C ₁₈ aryls such as phenyl, biphenyl, terphenyl, naphthyl and anthracenyl.

In the present specification, “arylalkyl” means a group in which one of hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the aryl. Preferred arylalkyl include, but are not limited to, for example, benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, can be exemplified terphenyl methyl and C ₇ -C ₂₀ arylalkyl styryl like.

  In the present specification, “heteroaryl” means a group in which one or more carbon atoms of the aryl are each independently substituted with one or more heteroatoms selected from N, S and O. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heteroaryl include, but are not limited to, for example, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Mention may be made of 5- to 15-membered heteroaryl such as pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.

In the present specification, “heteroarylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the heteroaryl. Suitable heteroarylalkyl includes, but is not limited to, 5- to 15-membered heteroaryl-C ₁ -C ₅ alkyl such as pyridylmethyl.

In the present specification, “aryloxy” means a group in which a hydroxyl hydrogen atom is substituted with the aryl. Suitable aryloxy includes, but is not limited to, C ₆ -C ₁₅ aryloxy such as phenoxy, biphenyloxy, naphthyloxy and anthryloxy (anthracenyloxy).

In the present specification, “arylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the arylalkyl. Suitable arylalkyloxy includes, but is not limited to, C ₇ -C ₂₀ arylalkyloxy such as benzyloxy, 1-phenethyloxy, 2-phenethyloxy and styryloxy.

  In the present specification, “heteroaryloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroaryl. Suitable heteroaryloxy include, but are not limited to, furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso 5-15 such as oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy and indolyloxy Mention may be made of member heteroaryloxy.

In the present specification, “heteroarylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroarylalkyl. Preferred heteroarylalkyloxy include, without limitation, mention may be made of heteroaryl -C ₁ -C ₅ alkyloxy, for example 5 to 15 members.

In the present specification, “acyl” means a group in which a monovalent group selected from the groups described above and carbonyl are linked. Suitable acyls include, but are not limited to, C ₁ -C ₂₀ acyls including, for example, C ₁ -C ₅ aliphatic acyls such as formyl, acetyl and propionyl, and C ₇ -C ₁₂₀ aromatic acyls such as benzoyl. Can be mentioned.

  In the present specification, the “sugar group” means a monovalent group in which a hydrogen atom of one hydroxyl of a monosaccharide, oligosaccharide or polysaccharide is removed.

  The groups described above are each independently unsubstituted or can be further substituted with one or more of the monovalent groups described above.

  In the present specification, “halogen” or “halo” means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

で表される化合物若しくはその塩、又はそれらの溶媒和物に関する。 One aspect of the present invention is a compound of formula (I):

Or a salt thereof, or a solvate thereof.

  The present inventors have found that a novel fungus isolated from soil produces a compound having an action of effectively enhancing the antifungal activity of amphotericin B, which is one of polyene macrolides, in the culture solution. I found it. The inventors of the present invention also used the novel compounds BF-0158A to H (hereinafter referred to as “compound BF-0158” or simply “BF-0158”) having an activity of enhancing the antifungal activity of amphotericin B from the culture medium. To be described). Compound BF-0158s can remarkably enhance the antifungal activity of amphotericin B when administered in combination with amphotericin B, although it does not substantially exhibit antifungal activity when administered alone. The compound represented by the formula (I) of this embodiment includes natural organic compounds BF-0158 and related compounds. Therefore, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal agent.

  In formula (I), n is an integer in the range of 0-10. n is preferably an integer in the range of 0 to 5, and more preferably 0, 1 or 2. When n is a group exemplified above, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal agent.

で表される基であることがさらに好ましい。R¹、R²、R³及びR⁴が前記で例示した基である場合、本態様の式（I）で表される化合物は、抗真菌薬の抗真菌活性を効果的に増強することができる。 In the formula (I), R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted Or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl Alkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, carbonate, or carbamate. R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, substituted or unsubstituted sugar group, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C _{3 to} C _6. cycloalkoxy, 3-6 membered heterocycloalkyl alkoxy substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ ~ C ₂₀ acyl, substituted or unsubstituted C ₁ -C ₂₀ acyloxy is preferably carbonate, or Kabamato, independently of one another, more preferably OH or a substituted or unsubstituted sugar radicals, one another Independently, OH, or formula (S-1) or (S-2):

More preferably, it is a group represented by When R ¹ , R ² , R ³ and R ⁴ are the groups exemplified above, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal agent. it can.

In formula (I), R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or R ⁵ is OH, a substituted or unsubstituted sugar group, a substituted or unsubstituted alkoxy Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted hetero Aryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, carbonate, or carbamate, and R ⁶ is H. R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or R ⁵ is OH, a substituted or unsubstituted sugar group, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl oxy, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy is carbonate, or Kabamato, and R ⁶ is preferably H, the carbon to which they are attached Between It is more preferable that R ⁵ is OH or a substituted or unsubstituted sugar group, and R ⁶ is H, and a double bond is formed between the carbons to which they are bonded. Or R ⁵ is OH or a group represented by the formula (S-1) or (S-2), and R ⁶ is more preferably H. When R ⁵ and R ⁶ are the groups exemplified above, the compound represented by formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal agent.

When a plurality of R ⁵ and R ⁶ are present, each R ⁵ and R ⁶ may have a different meaning. In the present specification, when R ⁵ and R ⁶ there are a plurality, the expression "first R ^5" and R ⁵ and R ⁶ located fatty chain terminus in (I) and the "first R ^6" And R ⁵ and R ⁶ located on the carboxylic acid terminal side are sequentially referred to as “second R ⁵ ”, “second R ⁶ ”, “third R ⁵ ”, “third R ⁶ ”,. And may be described respectively. For example, when n is 2, R ⁵ and R ⁶ located on the fatty chain terminal side in the formula (I) are located on the carboxylic acid terminal side with “first R ⁵ ” and “first R ⁶ ”. R ⁵ and R ⁶ may be referred to as “second R ⁵ ” and “second R ⁶ ”, respectively.

In formula (I), R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted Or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or Unsubstituted ant Yloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted aryl alkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl alkyloxy, or substituted or unsubstituted acyloxy. R ^{7 is, H, OH, NR N1 R} N2, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocyclo alkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, 5-15 membered substituted or unsubstituted heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, Wakashi substituted C ₃ -C ₆ cycloalkoxy of unsubstituted, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl oxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy Or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, preferably OH, NR ^N1 R ^N2 , substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy , 3-6 membered heterocycloalkyl alkoxy substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or C ₇ -C ₂₀ arylalkenyl oxy substitutions, be a substituted or unsubstituted 5-15 membered heteroaryloxy, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy More preferably, it is OH. When R ⁷ is the group exemplified above, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal agent.

In formula (I), R ^N1 and R ^N2 are independently of each other H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. R ^N1 and R ^N2 are independently of each other, H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or be a heteroaryl -C ₁ -C ₅ alkyl substituted or unsubstituted 5-15 membered Preferably independent of each other , H, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, or more preferably a substituted or unsubstituted C ₂ -C ₅ alkynyl, either in H More preferably it is. When R ^N1 and R ^N2 are the groups exemplified above, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal agent.

In the formula (I), when the group is substituted, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or non-substituted Substituted alkoxy Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted hetero At least selected from the group consisting of arylalkyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, and substituted or unsubstituted amino preferably one is monovalent, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ Alkenyl, substituted or non-substituted C ₂ -C ₅ alkynyl conversion, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl substituted, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, heteroaryl -C substituted or unsubstituted 5-15 membered ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ ~C ₁₅ Aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl oxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and more preferably at least one monovalent group selected from the group consisting of substituted or unsubstituted amino, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered heterocycloalkyl alkoxy substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy of conversion, a substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, and substituted or unsubstituted More preferably, it is at least one monovalent group selected from the group consisting of substituted C ₁ -C ₂₀ acyloxy, and particularly preferably hydroxyl. When the monovalent group is substituted, the substituent can be further selected from the monovalent group.

Preferably, the compound represented by formula (I) is:
n is an integer in the range 0-10;
R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, substituted or unsubstituted sugar group, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C _{3 to} C _6. cycloalkoxy, 3-6 membered heterocycloalkyl alkoxy substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ ~ C ₂₀ acyl, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, an carbonate, or Kabamato,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or R ⁵ is OH, a substituted or unsubstituted sugar group, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl oxy, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, carbonate, or a Kabamato, and R ⁶ is a H,
R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocyclo alkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, 5-15 membered substituted or unsubstituted heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, Wakashi substituted C ₃ -C ₆ cycloalkoxy of unsubstituted, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl oxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy or a substituted or unsubstituted C ₁ -C ₂₀ acyloxy,
R ^N1 and R ^N2 are independently of each other, H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, and hetero 3-6 membered substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl,
If the group is substituted, the substituent are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or C ₃ -C ₆ cycloalkenyl unsubstituted, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered heteroaryl cycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl Substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ acyl substitution is at least one monovalent group selected from the group consisting of substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and substituted or unsubstituted amino.

More preferably, the compound represented by formula (I) is:
n is an integer ranging from 0 to 5;
R ¹ , R ² , R ³ and R ⁴ are independently of each other OH or a substituted or unsubstituted sugar group,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is OH or a substituted or unsubstituted sugar group, and
R ⁶ is H,
R ⁷ is OH, NR ^N1 R ^N2 , substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered a heteroaryloxy, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy,
R ^N1 and R ^N2 are independently of each other H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, or substituted or unsubstituted C ₂ -C ₅ alkynyl. And
If the group is substituted, the substituents are each independently selected from the group consisting of hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, It is at least one monovalent group selected from the group consisting of substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₅ alkyloxy and substituted or unsubstituted C ₁ -C ₂₀ acyloxy.

More preferably, the compound represented by formula (I) is:
n is 0, 1 or 2,
R ¹ , R ² , R ³ and R ⁴ are independently of each other OH or a group represented by the formula (S-1) or (S-2);
R ⁵ and R ⁶ form a double bond between the carbons to which they are bonded, or R ⁵ is OH or a group represented by the formula (S-1) or (S-2) And R ⁶ is H,
R ⁷ is OH, NR ^N1 R ^N2 , substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered a heteroaryloxy, or substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy,
R ^N1 and R ^N2 are independently of each other H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, or substituted or unsubstituted C ₂ -C ₅ alkynyl. And
If the group is substituted, the substituents are each independently selected from the group consisting of hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, It is at least one monovalent group selected from the group consisting of substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₅ alkyloxy and substituted or unsubstituted C ₁ -C ₂₀ acyloxy.

Particularly preferably, the compound represented by the formula (I) is
(A) n is 0,
R ¹ and R ² are a group represented by the formula (S-1),
R ³ is a group represented by the formula (S-2),
R ⁴ is OH;
R ⁷ is OH, or
(B) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(C) n is 0,
R ¹ and R ² are a group represented by the formula (S-1),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(D) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
R ⁷ is OH, or
(E) n is 1,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁵ is OH;
R ⁶ is H,
R ⁷ is OH, or
(F) n is 2,
R ¹ is a group represented by the formula (S-2),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(G) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(H) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH.

Particularly preferred compounds of the formula (I) are:
17-Hydroxy-5,9-O-dideoxyhexosyl-13-O-hexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14-tetraene Acid (BF-0158A);
13,17-Dihydroxy-5-O-deoxyhexosyl-9-O-hexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14-tetraene Acid (BF-0158B);
13,17-Dihydroxy-5,9-O-dideoxyhexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14-tetraenoic acid (BF- 0158C);
9,13,17-Trihydroxy-5-O-deoxyhexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14-tetraenoic acid (BF -0158D);
3,15,19-trihydroxy-7-O-deoxyhexosyl-11-O-hexosyl-2,4,6,8,10,12,14,16,18,20-decamethyldocosa-4, 8,12,16-tetraenoic acid (BF-0158E);
13,17,21-Trihydroxy-5-O-deoxyhexosyl-9-O-hexosyl-2,4,6,8,10,12,14,16,18,20,22-undecamethyltetra Cosa-2,6,10,14,18-pentaenoic acid (BF-0158F);
17,21-dihydroxy-5,9-O-dideoxyhexosyl-13-O-hexosyl-2,4,6,8,10,12,14,16,18,20,22-undecamethyltetracosa -2,6,10,14,18-pentaenoic acid (BF-0158G); and
13,17,21-trihydroxy-5,9-O-dideoxyhexosyl-2,4,6,8,10,12,14,16,18,20,22-undecamethyltetracosa-2, 6,10,14,18-pentaenoic acid (BF-0158H);
Selected from the group consisting of When the compound represented by the formula (I) of this embodiment is the compound, the compound can effectively enhance the antifungal activity of the antifungal agent.

  The compound represented by the formula (I) of one embodiment of the present invention includes not only the compound itself but also a salt thereof. Examples of the salt of the compound represented by the formula (I) of one embodiment of the present invention include, but are not limited to, sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion. Salts with such cations, or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, bis Methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid , Cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfur Phosphate, isethionate, salts with organic acid anions such as p- toluenesulfonic acid or naphthalenesulfonic acid. When the compound represented by the formula (I) is in the form of the salt, the antifungal activity of the antifungal agent can be effectively enhanced.

  The compound represented by the formula (I) of one embodiment of the present invention includes not only the compound itself but also a solvate of the compound or a salt thereof. Solvents that can form solvates with the compound or salt thereof include, but are not limited to, for example, lower alcohols (eg, 1-6 carbons such as methanol, ethanol or 2-propanol (isopropyl alcohol)). Alcohols with the number of atoms), higher alcohols (for example, alcohols with 7 or more carbon atoms such as 1-heptanol or 1-octanol), organics such as dimethyl sulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate A solvent or water is preferred. When the compound represented by the formula (I) or a salt thereof is in the form of a solvate with the aforementioned solvent, the antifungal activity of the antifungal agent can be effectively enhanced.

  The compound represented by the formula (I) of one embodiment of the present invention includes not only the compound itself but also a protected form thereof. In the present specification, the “protected form” means a form in which a protective group is introduced into one or more functional groups (for example, a hydroxyl group or a carboxylic acid group). In this specification, the protected form of the compound represented by each formula may be referred to as a protected derivative of the compound represented by each formula. In the present specification, a “protecting group” is a group introduced into a specific functional group in order to prevent an undesirable reaction from progressing, and is quantitatively removed under specific reaction conditions. In other reaction conditions, it means a group that is substantially stable, that is, reaction-inactive. The protecting group capable of forming a protected form of the compound is not limited. For example, in the case of a protecting group for a hydroxyl group, silyl (for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) Or tert-butyldiphenylsilyl (TBDPS)) or alkoxy (eg, methoxymethoxy (MOM) or methoxy (Me)) is a protecting group for a carboxylic acid group, an alkyl ester (eg, methyl, ethyl or isopropyl ester), Preference is given to arylalkyl esters (eg benzyl esters) or amides (eg amides with oxazolidinones), respectively. Protection and deprotection by the protecting group can be appropriately performed by those skilled in the art based on known reaction conditions. Even when the compound represented by the formula (I) of one embodiment of the present invention is a protected form by the above-described protecting group, the antifungal activity of the antifungal agent may be effectively enhanced. .

  When the compound represented by the formula (I) of one embodiment of the present invention has one or more tautomers, the compound also includes individual tautomeric forms of the compound.

  In addition, when the compound represented by the formula (I) of one embodiment of the present invention has one or more stereocenters (chiral centers), the compound includes individual enantiomers and diastereomers of the compound, and a racemate. And mixtures thereof.

  By having the above characteristics, the compound represented by the formula (I) of one embodiment of the present invention can effectively enhance the antifungal activity of the antifungal agent.

<2. Production method of novel compounds by culture means>
The present inventors have found that a novel fungus isolated from soil produces compounds BF-0158 included in the compound represented by the formula (I) of one embodiment of the present invention in the culture solution. . Therefore, another aspect of the present invention relates to a method for producing a compound represented by formula (I) according to one aspect of the present invention using a novel fungus.

  In this embodiment, the method of the present invention includes a compound accumulation step and a compound purification step. Hereinafter, each step will be described in detail.

[2-1. Compound accumulation process]
In this embodiment, the method of the present invention comprises a microorganism that is a Pseudophialophora genus BF-0158 strain (NITE AP-02400) or a mutant thereof having the ability to produce a compound represented by formula (I) Is accumulated in a medium, and the compound represented by formula (I) is accumulated in the medium.

  Pseudofiarophora sp. BF-0158 is a new fungus belonging to the genus Pseudofiarophora isolated from the soil of Shodoshima, Kagawa Prefecture, Japan. This strain has been deposited as BF-0158 at the National Institute of Technology and Technology Patent Microorganism Deposits (NITE AP-02400).

  In this step, the microorganism used for the culture is preferably Pseudofiarophora sp. BF-0158 having an ability to produce the compound represented by the formula (I) or a mutant thereof, More preferably, the strain is BF-0158. In the present invention, the mutant strain of the genus Pseudofiarophora BF-0158 means a natural mutant or an artificial mutant of the genus BF-0158 of the genus Pseudofialophora. The artificial mutant of Pseudofiarophora sp. BF-0158 can be obtained by any artificial mutant producing means usually used in the art. As long as it is a microorganism having the ability to produce the compound represented by the formula (I), not only the pseudophyllophora BF-0158 strain itself, but also a mutant strain of the pseudophyllophora BF-0158 strain, In this step, the compound represented by the formula (I) can be accumulated in the medium. Therefore, a large amount of the compound represented by formula (I) can be accumulated in the medium by using the microorganism.

  The medium used for culturing the microorganism can be appropriately selected based on the properties of the microorganism. The medium usually contains one or more carbon sources and one or more nitrogen sources, and optionally one or more inorganic salts and one or more vitamins. Examples of the carbon source include sugars such as glucose, fructose, maltose, lactose, galactose, dextrin and starch, and vegetable oils such as soybean oil. Examples of the nitrogen source include polypeptone, yeast extract, malt extract, meat extract, soy flour, cottonseed flour, corn steve liquor, casein, amino acid, urea, ammonium salt and nitrate. Inorganic salts include cations such as sodium ion, potassium ion, calcium ion, magnesium ion, iron ion, manganese ion, copper ion, cobalt ion or zinc ion, and inorganic such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid. Mention may be made of salts with acid anions. The medium used in this step is, for example, potato dextrose agar (PDA) medium (potato dextrose agar 3.9% (Becton, Dickinson and Company)), seed medium (glucose 2.0%, polypeptone 0.5%, yeast extract 0.2% , Magnesium sulfate heptahydrate 0.05%, potassium dihydrogen phosphate 0.1%, and agar 0.1%, pH 6.0) or production medium (sucrose 2.0%, trace metal (iron sulfate heptahydrate 0.1%, manganese chloride tetra Hydrate 0.1%, Zinc sulfate heptahydrate 0.1%, Copper sulfate pentahydrate 0.1%, and Cobalt chloride hexahydrate 0.1%) 1.0%, Glucose 1.0%, Sollis 0.5%, Skipjack extract 0.5%, Preferred are calcium carbonate 0.3%, magnesium sulfate heptahydrate 0.1%, potassium dihydrogen phosphate 0.1%, and agar 0.1%, pH 6.5). By culturing Pseudophyllophora sp. Strain BF-0158 having the ability to produce the compound represented by formula (I) or a mutant thereof in the medium, the medium is represented by formula (I). Compounds can be accumulated in the medium.

  The culture of the microorganism may be either solid culture or liquid culture. When culturing the microorganism on a large scale, liquid culture is preferred. In this case, it is preferable to ventilate the culture medium by shaking the culture container, stirring the culture medium with a propeller or the like, or blowing air with a pump or the like. The air introduced into the medium is preferably sterilized using a sterilization means such as a sterilization filter. By culturing the microorganism under the above conditions, the compound represented by the formula (I) can be efficiently accumulated in the medium.

  When culturing the microorganism on a large scale, the microorganism is cultured in advance in a small amount of medium (hereinafter also referred to as “seed culture”), and then the culture obtained by seed culture is planted in a large-capacity medium. It is preferable to cultivate and culture (hereinafter also referred to as “production culture”). In this case, the components of the medium used for seed culture and production culture may be the same or different. By carrying out this step by multi-stage culture including seed culture and production culture, the growth delay of microorganisms can be substantially suppressed.

  In this step, the conditions for culturing the microorganism can be appropriately set based on the properties of the microorganism. The culture temperature is usually in the range of 25-27 ° C, typically about 27 ° C. The pH of the medium is usually pH 5.5 to 6.5, typically pH 6.0. When the liquid medium is cultured by shaking, the culture period is usually 1 to 3 weeks, typically 7 to 10 days, as the total of the seed culture and production culture. By culturing the microorganism under the above conditions, the compound represented by the formula (I) can be efficiently accumulated in the medium.

[2-2. Compound accumulation process]
In this embodiment, the method of the present invention needs to include a compound purification step of purifying the compound represented by the formula (I) obtained in the compound accumulation step from the culture of the microorganism.

  In this step, as a means for purifying the compound represented by the formula (I) from the culture of the microorganism, an organic compound separation method usually used in the technical field can be used. Examples of means for purifying the compound represented by the formula (I) from the culture of microorganisms include extraction, filtration, centrifugation, adsorption, recrystallization, distillation, and various chromatography. Preferably, this step is a step of separating cells from the microorganism culture obtained in the compound accumulation step by filtration or centrifugation, a step of extracting the separated cells with a water-miscible organic solvent such as acetone, And a step of further separating the bacterial cell extract extracted with a water-miscible organic solvent by means such as solvent extraction or preparative chromatography to obtain a compound represented by the formula (I). As the preparative chromatography, various types of chromatography such as adsorption, normal phase or reverse phase distribution, or gel filtration can be applied. In the final step, the fraction obtained by preparative chromatography may be further purified by means such as recrystallization or distillation. Each step may be repeated a plurality of times under the same or different conditions as desired. By using the above means, the compound represented by the formula (I) can be purified and isolated from the culture of the microorganism.

  In the method for producing the compound of the present invention by the culture means of this embodiment, the compound represented by the formula (I) preferably has the groups (A) to (H). In this case, the compound represented by the formula (I) is a compound BF-0158 produced by Pseudophyllophora sp. BF-0158 strain. By using the method of this embodiment, the compound represented by the formula (I) corresponding to the compound compound BF-0158 can be efficiently produced.

  The compound represented by formula (I) of one embodiment of the present invention, which can be an active ingredient of a medicament, can be obtained with high purity and low cost by the method for producing the compound of the present invention by the culture means of the present embodiment having the above characteristics. Can be provided in large quantities.

  Another embodiment of the present invention is a Pseudofiarophora BF-0158 strain (NITE AP-02400) or a mutant thereof having the ability to produce a compound represented by the formula (I) of one embodiment of the present invention. It relates to a certain microorganism. In this embodiment, the compound represented by the formula (I) preferably has the groups (A) to (H). By using the microorganism of this embodiment, the compound represented by the formula (I) corresponding to the compound BF-0158 can be efficiently produced.

<3. Pharmaceutical use>
The compound represented by the formula (I) of one embodiment of the present invention has an activity of enhancing the antifungal activity of an antifungal agent. Therefore, another aspect of the present invention provides at least one antifungal agent comprising, as an active ingredient, the compound represented by the formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof. It relates to an activity enhancer. Another embodiment of the present invention relates to a pharmaceutical comprising the compound represented by the formula (I) of one embodiment of the present invention or a salt thereof, or a solvate thereof as an active ingredient.

  In each embodiment of the present invention, the at least one antifungal agent is selected from the group consisting of a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug. The at least one antifungal agent is preferably a polyene macrolide agent. The polyene macrolide is preferably amphotericin B, pimaricin, nystatin or natamycin, more preferably amphotericin B. The azole drug is preferably an imidazole compound such as miconazole, or a triazole compound such as fluconazole, itraconazole, phosphofluconazole or voriconazole. Preferably, the candin-type drug is Micafungin or Caspofungin. The fluoropyrimidine drug is preferably flucytosine. Amphotericin B, a polyene macrolide, has high antifungal activity and is useful for the treatment of severe fungal infections, but may have side effects such as nephrotoxicity. The compound represented by the formula (I) of one embodiment of the present invention has an activity of enhancing the antifungal activity of an antifungal agent such as a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug. Have. Therefore, the compound represented by the formula (I) of one embodiment of the present invention is at least one anti-cancer compound selected from the group consisting of polyene macrolide drugs, azole drugs, candin drugs, and fluoropyrimidine drugs. Administration with a fungal agent can reduce the dose of an antifungal agent that may have side effects and / or shorten the administration period. Thereby, the occurrence of side effects due to at least one antifungal agent can be substantially reduced.

  In each aspect of the invention, “administering together” means administering multiple agents simultaneously or separately (eg, consecutively at regular intervals). In the present specification, such a dosage form may be referred to as “combination administration”. Administration of the compound represented by the formula (I) of one embodiment of the present invention and at least one antifungal agent together reduces and / or administers the dose of an antifungal agent that may cause side effects. The period can be shortened. Thereby, the occurrence of side effects due to at least one antifungal agent can be substantially reduced.

  The compound represented by the formula (I) of one embodiment of the present invention has an activity of enhancing the antifungal activity of at least one antifungal agent. On the other hand, the compound represented by the formula (I) of one embodiment of the present invention may or may not have antifungal activity. The compound represented by the formula (I) of one embodiment of the present invention usually has substantially no antifungal activity per se. The compound represented by formula (I) of one embodiment of the present invention itself enhances the antifungal activity of at least one antifungal agent even when it does not substantially have antifungal activity. Therefore, the combined administration with at least one antifungal agent can reduce the dose of an antifungal agent that may cause a side effect and / or shorten the administration period. Thereby, the occurrence of side effects due to at least one antifungal agent can be substantially reduced.

The antifungal activity of the compound represented by the formula (I) of one embodiment of the present invention and at least one antifungal agent is not limited, but can be determined, for example, by the following means. Formula (I) for any assay fungi (eg, yeast fungi, filamentous fungi and zygotes) by microfluidic dilution according to the American Society for Clinical Laboratory Standards (CLSI) M27-A3 and M38-A2 methods Or at least one antifungal agent is administered. After culturing under predetermined conditions, fungal growth is measured using turbidity (for example, OD ₅₅₀ ) or colony diameter as an index, and the inhibition rate (%) is calculated from comparison with the value at the start of culturing. The minimum concentration of the compound at which the calculated inhibition rate becomes a predetermined value (for example, 90%) or more is defined as the minimum growth inhibition concentration (MIC value) of the compound. Based on the inhibition rate and MIC value thus determined, the antifungal activity of the compound represented by formula (I) of one embodiment of the present invention and at least one antifungal agent can be evaluated.

The activity of enhancing the antifungal activity of at least one antifungal agent of the compound represented by the formula (I) of one embodiment of the present invention is not limited, but is determined by, for example, the following means: Can do. Based on the above means, the MIC value when at least one antifungal agent is administered alone is determined. Then, in similar test conditions, the compound of formula (I) and at least one antifungal agent are administered together (eg simultaneously) to give the compound of formula (I) and at least one of the Determine the MIC value for coadministration of antifungal agents. Based on the following formula (M-1), the enhancement rate of the antifungal activity of at least one antifungal agent of the compound represented by formula (I) of one embodiment of the present invention is calculated. For example, when the enhancement rate is 2 times, the MIC value of at least one antifungal agent at the time of concomitant administration of the compound represented by formula (I) of one embodiment of the present invention is 1/2 of the MIC value. Based on the enhancement rate thus determined, the activity of enhancing the antifungal activity of at least one antifungal agent of the compound represented by formula (I) of one embodiment of the present invention can be evaluated. .

  In this embodiment, the at least one antifungal agent administered in combination with the compound represented by the formula (I) of one embodiment of the present invention has a MIC value determined by the above-mentioned procedure as a yeast fungus (for example, Candida・ Albicans) is usually 0.5 μg / mL. In this case, the compound represented by the formula (I) of one embodiment of the present invention is usually at least one anti-antibody at a concentration of 0.125 μg / mL or more, for example, 0.25 μg / mL or more, particularly 0.5 μg / mL or more. To enhance the antifungal activity of at least one antifungal agent, usually in combination with a fungal agent, at a rate of enhancement of more than 2 times, for example in the range of 2 to 32 times, in particular in the range of 4 to 32 times. Can do. Therefore, in the case of having an enhancement rate in the above range, the compound represented by the formula (I) of one embodiment of the present invention is an antifungal that may cause side effects when administered in combination with at least one antifungal agent. The dose of the drug can be reduced and / or the administration period can be shortened. Thereby, the occurrence of side effects due to at least one antifungal agent can be substantially reduced.

  When the compound represented by the formula (I) of one embodiment of the present invention is applied to a pharmaceutical use, the compound represented by the formula (I) is not only the compound itself but also a pharmaceutically acceptable salt of the compound. And pharmaceutically acceptable solvates thereof. Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) of one embodiment of the present invention and the pharmaceutically acceptable solvate thereof include, but are not limited to, those exemplified above. Salts or solvates are preferred. When the compound represented by the formula (I) is in the form of the above-mentioned salt or solvate, the compound is produced without substantially reducing the activity of enhancing the antifungal activity of at least one antifungal agent. It can be applied to a desired pharmaceutical use.

  When the compound represented by the formula (I) of one embodiment of the present invention is applied to a pharmaceutical use, the compound represented by the formula (I) includes not only the compound itself but also a prodrug form of the compound. . As used herein, “prodrug” means a compound that is converted into the parent drug in vivo. Examples of the prodrug form of the compound include, but are not limited to, for example, when a hydroxyl group is present, an ester of the hydroxyl group and an arbitrary carboxylic acid, an amide of the hydroxyl group and an arbitrary amine, and the like. Can be mentioned. When the compound represented by the formula (I) of one embodiment of the present invention is in the above-mentioned prodrug form, the antifungal of at least one antifungal agent of the compound represented by the formula (I) which is the parent drug The pharmacokinetics upon administration of the prodrug form to a subject can be improved without substantially reducing the activity that enhances the activity.

  When the compound represented by formula (I) of one embodiment of the present invention is applied to a pharmaceutical use, the compound may be used alone or in combination with one or more pharmaceutically acceptable ingredients. Also good. The medicament of the present invention can be formulated into various dosage forms usually used in the art depending on the desired administration method. Therefore, the medicament of this embodiment also includes a compound represented by the formula (I) of one embodiment of the present invention or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers. It can also be provided in the form of a pharmaceutical composition. In this case, the pharmaceutical composition of this embodiment may or may not contain at least one antifungal agent. In addition to the above components, the pharmaceutical composition of this embodiment comprises one or more pharmaceutically acceptable media (for example, a solvent such as sterile water or a solution such as physiological saline), an excipient, a binder, Vehicles, solubilizers, preservatives, stabilizers, bulking agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffering agents, soothing agents, antioxidants, sweeteners and A flavoring agent etc. may be included.

  The pharmaceutical dosage form containing the compound represented by the formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is not particularly limited. It may be a preparation for use in parenteral administration or a preparation for use in oral administration. In addition, the pharmaceutical dosage form of this embodiment may be a unit dosage form or a multiple dosage form. Examples of the preparation for use in parenteral administration include injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable media. Ingredients that can be mixed with injections include, but are not limited to, for example, saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol, D-mannose or sodium chloride). Vehicles such as isotonic solutions, solubilizing agents such as alcohols (eg ethanol or benzyl alcohol), polyalcohols (eg propylene glycol or polyethylene glycol) or esters (eg benzyl benzoate), polysorbate 80 ™ or poly Nonionic surfactants such as oxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, benzalkonium chloride or procaine hydrochloride A soothing agent, human serum albumin or Stabilizers such as polyethylene glycol, may be mentioned preservatives, and antioxidants, and the like. The prepared injection is usually filled in an appropriate vial (for example, an ampoule) and stored in an appropriate environment until use.

  Examples of the preparation for use in oral administration include tablets, pills, powders, capsules, microcapsules, elixirs, solutions, syrups, slurries and suspensions. The tablet may be formulated as a sugar-coated tablet with a sugar coating or a soluble coating, a gelatin-encapsulated tablet, an enteric-coated tablet, or a film-coated tablet, if desired, or as a dosage form of a double tablet or a multilayer tablet It may be formulated.

  Ingredients that can be mixed into tablets or capsules are not limited, but for example, water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, Binders such as gelatin, corn starch, gum tragacanth or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or silicic acid; dried starch, sodium alginate , Agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch or lactose; white sugar, stearin cacao Disintegration inhibitors such as water or hydrogenated oils; absorption enhancers such as quaternary ammonium salts or sodium lauryl sulfate; humectants such as glycerin or starch; starch, lactose, kaolin, bentonite or colloidal silicic acid Adsorbents such as; refined talc, stearates (eg magnesium stearate), lubricants such as boric acid powder or polyethylene glycol; sweeteners such as sucrose, lactose or saccharin; and peppermint, red oil or cherry And the like. When the preparation is a capsule, it may further contain a liquid carrier such as fats and oils.

  A pharmaceutical comprising a compound represented by formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient should be formulated as a depot preparation. You can also. In this case, the medicament of this embodiment in the form of a depot preparation can be administered, for example, subcutaneously or intramuscularly, or administered by intramuscular injection. By applying the medicament of this embodiment to a depot preparation, the compound represented by the formula (I) of one embodiment of the present invention has an activity for enhancing the antifungal activity of at least one antifungal agent over a long period of time. It can be expressed over time.

  When the compound represented by the formula (I) of one embodiment of the present invention is applied for pharmaceutical use, the compound may be provided together with at least one antifungal agent or may be provided separately. . Either case is included in embodiments of this aspect. In the case of an embodiment further including at least one antifungal agent in addition to the compound represented by formula (I) of one aspect of the present invention, that is, represented by formula (I) of one aspect of the present invention In an embodiment where the compound and at least one antifungal agent are provided together, the medicament of this aspect is a compound represented by formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof. And at least one antifungal agent can be in the form of a pharmaceutical composition. In the case of this embodiment, the medicament of this aspect includes, for example, the compound represented by formula (I) of one aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Can be provided in the form of a single formulation comprising at least one antifungal agent. In an embodiment where the compound of Formula (I) of one aspect of the present invention is provided separately from at least one antifungal agent, the medicament of this aspect is Formula (I) of one aspect of the present invention. Or a salt thereof, or a solvate thereof, in the form of a pharmaceutical composition used in combination with at least one antifungal agent. In the case of this embodiment, the medicament of this aspect includes, for example, a compound represented by the formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof, and at least one antifungal agent. It can be provided in the form of a pharmaceutical combination or kit comprising a plurality of formulations formulated separately. When in the form of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (eg sequentially). Alternatively, the medicament of this embodiment includes only the compound represented by the formula (I) of one embodiment of the present invention or a salt thereof, or a solvate thereof (that is, does not include at least one antifungal agent). It can also be provided in the form of a formulation. In any embodiment, the compound represented by the formula (I) of one aspect of the present invention and at least one antifungal agent can be administered in combination.

  The medicament comprising the compound represented by the formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is at least one antifungal agent. It can also be used in combination with one or more other drugs useful as pharmaceuticals. In this case, the medicament of this embodiment includes a compound represented by formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more kinds thereof. It becomes the form of the combined pharmaceutical containing the said other chemical | medical agent. The combination drug is a compound represented by the formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more other drugs. And a compound represented by formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. It may be in the form of a pharmaceutical composition that is used in combination with one or more of the other drugs. When the medicament of this embodiment is in the form of a combined medicament as described above, the compound represented by the formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof A pharmaceutical combination comprising a plurality of preparations, which may be provided in the form of a single formulation comprising a Japanese and one or more other drugs, and separately formulated with one or more other drugs or It may be provided in the form of a kit. When in the form of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (eg sequentially).

  The pharmaceutical comprising the compound represented by the formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is one or more fungal infections. Can be similarly prevented or treated. Examples of fungi that cause the one or more fungal infections include, but are not limited to, yeast fungi such as Candida albicans, C. parapsilosis, Candida glabrata (C. glabrata) and Cryptococcus neoformans; filamentous fungi such as Aspergillus fumigatus, A. flavas, Aspergillus niger and Aspergillus terreus (A. niger) terreu); zygotes such as Rhizopus oryzae, Rhizomucor pusillus, R. microspores, and Absidia corymbifera. Examples of the one or more fungal infections include, but are not limited to, deep mycosis, superficial mycosis, and dermatomycosis. The one or more fungal infections are preferably one or more diseases, symptoms or disorders selected from the group consisting of deep mycosis, superficial mycosis and dermatomycosis. By administering the medicament of this embodiment to a subject in need of prevention or treatment of the one or more fungal infections, the disease, symptom or disorder can be prevented or treated.

  One or more fungal infections comprising a compound represented by formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. It can be applied to various subjects in need of prevention or treatment of symptoms, diseases and / or disorders. The subject may be a human or non-human mammal (eg, warm-blooded animals such as pigs, dogs, cows, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons or chimpanzees), or reptiles (eg, It is preferably a subject or patient such as a frog, a snake or a lizard or other variable temperature animal. By administering the pharmaceutical of this embodiment to the subject, various diseases, symptoms and / or disorders that are one or more fungal infections possessed by the subject can be prevented or treated.

  As used herein, “prevention” means substantially preventing the occurrence (onset or onset) of symptoms, diseases and / or disorders. In the present specification, “treatment” means to suppress (e.g., suppress progression), relieve, repair, and / or cure a symptom, disease, and / or disorder that has occurred (onset or onset).

  The compound represented by the formula (I) of one embodiment of the present invention is a symptom, disease and / or disorder (for example, deep mycosis, superficial mycosis) which is one or more fungal infections described above. Or a subject having dermatomycosis) can be used for the prevention or treatment of the symptom, disease and / or disorder. Therefore, the medicament of this embodiment is preferably a medicament for use in the prevention or treatment of symptoms, diseases and / or disorders that are one or more fungal infections described above, and deep mycosis More preferably, it is a medicament for use in the prevention or treatment of one or more fungal infections selected from the group consisting of superficial mycosis and dermatomycosis. By using the medicament of this embodiment for the prevention or treatment of the symptoms, diseases and / or disorders that are one or more fungal infections, at least of the compound represented by formula (I) of one embodiment of the present invention, The symptom, disease and / or disorder can be prevented or treated through the activity of enhancing the antifungal activity of one antifungal agent.

  The compound represented by the formula (I) of one embodiment of the present invention is a symptom, disease and / or disorder (for example, deep mycosis, superficial mycosis) which is one or more fungal infections described above. Or a subject having dermatomycosis) can be used for the prevention or treatment of the symptom, disease and / or disorder. Therefore, another aspect of the present invention provides an effective amount of a formula of the present invention for a subject in need of prevention or treatment of symptoms, diseases and / or disorders that are one or more fungal infections as described above. The disease or symptom comprising administration of the compound represented by (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof together with at least one antifungal agent. It is a preventive or therapeutic method. The symptom, disease and / or disorder being one or more fungal infections is one or more diseases or symptoms selected from the group consisting of deep mycosis, superficial mycosis and dermatomycosis Is preferred. To a subject in need of prevention or treatment of symptoms, diseases and / or disorders that are one or more fungal infections, the compound represented by formula (I) of one embodiment of the present invention is treated with at least one anti-antibody. When administered together with a fungal agent, the compound represented by the formula (I) of one embodiment of the present invention exhibits the symptom, disease, and the like via the activity of enhancing the antifungal activity of at least one antifungal agent. And / or the disorder can be prevented or treated.

  Another aspect of the present invention is the formula (I) of one aspect of the present invention for use in the prevention or treatment of symptoms, diseases and / or disorders that are one or more fungal infections as described above. Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Another aspect of the present invention is that of one aspect of the present invention for the manufacture of a medicament for use in the prevention or treatment of symptoms, diseases and / or disorders that are one or more fungal infections as described above. Use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The symptom, disease and / or disorder being one or more fungal infections is one or more diseases or symptoms selected from the group consisting of deep mycosis, superficial mycosis and dermatomycosis Is preferred. By using the compound or pharmaceutical represented by the formula (I) of one aspect of the present invention for the prevention or treatment of the symptoms, diseases and / or disorders that are the one or more fungal infections, The symptom, disease and / or disorder can be prevented or treated through the activity of the compound represented by the formula (I) of the embodiment to enhance the antifungal activity of at least one antifungal agent.

  A pharmaceutical comprising the compound represented by the formula (I) of one embodiment of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is administered to a subject, particularly a human patient. When doing so, the exact dosage and usage (eg, dosage, frequency of administration, and / or route of administration) will depend on the subject's age, sex, symptoms to be prevented or treated, the exact state of the disease and / or disorder (eg, severe) Degree), and many factors such as the administration route, the doctor in charge should finally determine the therapeutically effective dose, the number of administrations, the administration route, and the like. Therefore, in the medicament of this embodiment, the compound represented by the formula (I) which is an active ingredient is administered to the subject in a therapeutically effective amount and frequency. For example, when the pharmaceutical of this embodiment is administered to a human patient, the dose of the compound represented by formula (I), which is an active ingredient, is usually in the range of 0.001 to 100 mg / kg body weight per administration. Yes, typically in the range of 0.01 to 10 mg / kg body weight per dose, in particular in the range of 0.1 to 10 mg / kg body weight per dose. In addition, the number of administrations of the medicament of this embodiment can be, for example, once or several times a day, or once every several days. In addition, the administration route of the medicament of this embodiment is not particularly limited, and may be administered orally, and parenterally (for example, rectal, radial mucosa, intestine, intramuscular, subcutaneous, intramedullary, intrathecal). May be administered directly or intra-ventricularly, intravenously, intravitreally, intraperitoneally, intranasally, or intraocularly). By using the medicament of this embodiment in the above-mentioned dosage and usage, the compound represented by the formula (I) of one embodiment of the present invention has an activity of enhancing the antifungal activity of at least one antifungal agent. Thus, the symptoms, diseases and / or disorders that are the one or more fungal infections can be prevented or treated.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

<I. Production of novel compounds by culture means>
[reagent]
Glycerol and calcium carbonate were purchased from Kanto Chemical Co., Inc. Agar was purchased from Shimizu Foods. Glucose, sucrose, potassium dihydrogen phosphate, polypeptone, magnesium sulfate heptahydrate, iron sulfate heptahydrate, manganese chloride tetrahydrate, zinc sulfate heptahydrate, copper sulfate pentahydrate and cobalt chloride hexa Hydrates were purchased from Wako Pure Chemical Industries. Sollis was purchased from Oriental Yeast Co., Ltd. Skipjack extract was purchased from Kyokuto Pharmaceutical Co., Ltd. Potato dextrose agar and yeast extract were purchased from Becton Dickinson.

  Acetone, ethyl acetate and methanol were purchased from Nacalai Tesque. Sodium sulfate and phosphoric acid were purchased from Kanto Chemical Co., Inc.

  Methanol-d4 was purchased from Acros. Potassium bromide was purchased from Merck.

[Used equipment]
TXY-25R-3FS from Takasaki Scientific Instruments Co., Ltd. was used for the rotary shaker (rotary shaker). Jar fermentor MBF of EEYLA was used as the jar fan mentor. A HORIBA LAQUA twin S010 was used as the pH meter. Kokusan Co., Ltd. H-700R was used for the cooling centrifuge. US-106 manufactured by SND Co., Ltd. was used as the ultrasonic device. The following equipment was used for ultra-high performance liquid chromatography (UFLC).
Pump LH-20AD (Shimadzu Corporation)
Autosampler SIL-20AC HT (Shimadzu Corporation)
UV detector SPD-M20A (Shimadzu Corporation)
Column oven CTO-20AC (Shimadzu Corporation)
Column Shim pack XR-ODS (2.0 x 75 mm) (Shimadzu Corporation)

Himac CR21F manufactured by Hitachi Koki Co., Ltd. and RPR-9-2 as its rotor were used for the high-speed cooling centrifuge. For the rotary evaporator, NNR of EEYLA was used. The constant temperature bath used was SLI-1200 from EEYLA. The following equipment was used for high performance liquid chromatography (HPLC).
Pump PU980 (JASCO Corporation)
UV detector PU970 (JASCO Corporation)
Column CAPCELL PAK C18 MGII (20 x 250 mm) (Shiseido)
Recorder SS-250F (Seconic Corporation)

  The AccuTOF LC-plus JMS-T100LP from JEOL Ltd. was used for high resolution ESI-MS measurement. Varian XL-400 was used for NMR measurement. For the measurement of specific rotation, DIP-1000 manufactured by JASCO Corporation was used. For measurement of the UV absorption spectrum, an Agilent Technologies 8453 UV-visible spectrophotometer was used. HORIBA FT-710 was used for IR spectrum measurement.

[Culture medium]
A potato dextrose agar (PDA) medium was used as a preservation medium. For seed culture, a seed medium (glucose 2.0%, polypeptone 0.5%, yeast extract 0.2%, magnesium sulfate heptahydrate 0.05%, potassium dihydrogen phosphate 0.1%, and agar 0.1%, pH 6.0) was used. For production culture, production medium (sucrose 2.0%, trace metal (iron sulfate heptahydrate 0.1%, manganese chloride tetrahydrate 0.1%, zinc sulfate heptahydrate 0.1%, copper sulfate pentahydrate 0.1% , And cobalt chloride hexahydrate 0.1%) 1.0%, glucose 1.0%, Sollis 0.5%, skipjack extract 0.5%, calcium carbonate 0.3%, magnesium sulfate heptahydrate 0.1%, potassium dihydrogen phosphate 0.1%, and Agar 0.1%, pH 6.5) was used.

[Separation of BF-0158 strain]
BF-0158 strain is a fungus isolated from soil in Shodoshima, Kagawa Prefecture, Japan. Based on the morphological characteristics, culture properties and physiological properties of the BF-0158 strain, comparison was made with known bacterial species. As a result, it was revealed that this strain is a novel strain belonging to the genus Pseudophialophora. This strain was named BF-0158 strain. This strain has been deposited as BF-0158 at the National Institute of Technology and Technology Patent Microorganism Deposits (NITE AP-02400). The bacteriological properties of BF-0158 strain are as follows.

1. Morphological features
The BF-0158 strain grew well on a medium such as a nutrient agar medium such as a PDA medium. Colonies grown on PDA medium under an aerobic condition at 27 ° C for 2 weeks were observed with a microscope. The vegetative mycelium had a septum, the surface was brown to colorless, and it was smooth and irregularly branched. Was observed, and a partially bulging shape was observed.

2. Culture properties
The BF-0158 strain colonies grown on PDA medium under an aerobic condition at 27 ° C. had a colony radius of 45 to 55 mm. The surface of the colony has a velvety shape, and radial grooves were observed. The color tone of the colony was grayish brown to gray on the front surface and dark brown to grayish brown on the back surface. A brownish water-soluble pigment was observed.

3. BLAST homology search against DB-FU10.0 and international nucleotide sequence database
The 28S rDNA-D1D2 nucleotide sequence consists of Pseudophialophora magnispora CM14RG38-1T (accession number: KP7698727) and P. eragrostis CM12M9T (accession) No .: KF689638) and a homology of 99.8%. The ITS-5.8 rDNA nucleotide sequence showed 98.8% homology with the nucleotide sequence of P. whatonensis WSF14RG66-1 (accession number: KP769834), a kind of Ascomycota. However, it was difficult to determine species level attribution.

4. Physiological properties
The optimum growth conditions for the BF-0158 strain were aerobic conditions, pH 6, and a temperature of 27 ° C. Moreover, the growth possible conditions of this strain were aerobic conditions, static culture, pH 3-10, temperature 10-30 ° C., culture period 1-3 weeks.

[Production Example I-1: Culture of BF-0158 strain]
One platinum loop of BF-0158 strain was placed in 500 μL of glycerol for storage (10% glycerol) and stored at −80 ° C. This strain was cultured under aerobic conditions at 27 ° C. on a storage medium (PDA medium). One BF-0158 strain cultured in PDA medium is inoculated into one 500-mL Erlenmeyer flask containing 100 mL of seed medium, using a platinum shaker (rotation speed: 170 rpm) at 27 ° C for 3 days. Cultured with shaking under conditions (seed culture). Then, inoculate 300 mL of the obtained seed culture solution into a 10 L jar fermenter containing 5 L of production medium, under the conditions of 27 ° C, 300 rpm, 3 L / min aeration, 68 hours. Cultured (production culture).

[Production Example I-2: Purification of a novel compound from the culture solution of BF-0158 strain]
A production culture solution (1.0 L) obtained by the production culture for 68 hours was centrifuged at 8,000 rpm for 15 minutes to separate into a supernatant and cells. The cells were extracted by adding an equal amount of acetone to the supernatant. The cells were removed by suction filtration to obtain an acetone extract. Acetone was distilled off from the extract, and the resulting aqueous layer was adjusted to pH 3 using 2 M hydrochloric acid. To this aqueous layer, an equal amount of ethyl acetate (200 mL x 2) was added for solvent extraction. The obtained ethyl acetate layer was dehydrated by adding anhydrous sodium sulfate. Thereafter, the ethyl acetate layer was concentrated to dryness under reduced pressure to obtain 404 mg of a crude extract. The obtained crude extract was dissolved in methanol to prepare a 200 mg / mL solution. This solution was subjected to HPLC (column: CAPCELL PAK C18 MGII (20 x 250 mm), mobile phase: 70% CH ₃ CN / 0.05% H ₃ PO ₄ 0-40 min isocratic conditions, flow rate: 8 mL / min, Detection wavelength: UV 210 nm, column temperature: 25 ° C) : The fraction containing the peak detected at 31 minutes, G: 33 minutes, H: 36 minutes) was repeatedly collected. After CH ₃ CN was distilled off under reduced pressure, ethyl acetate (50 mL × 2) was added to the remaining aqueous layer (50 mL) for extraction. The resulting ethyl acetate layer was dehydrated by adding anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to give BF-0158s as isolated compounds (A: 10.4 mg, B: 14.0 mg, C: 2.49 mg, D: 1.83 mg, E: 4.88 mg, F: 4.58 mg, G: 7.20 mg, H: 5.05 mg).

Based on the results of instrumental analysis by specific rotation, UV absorption spectrum, high resolution ESI-MS, IR spectrum, ¹ H-NMR, and ¹³ C-NMR, BF-0158A was converted to 17-hydroxy-5,9-O-dideoxy Xosyl-13-O-hexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14-tetraenoic acid and BF-0158B in 13,17-dihydroxy -5-O-deoxyhexosyl-9-O-hexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14-tetraenoic acid and BF- 0158C with 13,17-dihydroxy-5,9-O-dideoxyhexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14-tetraenoic acid BF-0158D is 9,13,17-trihydroxy-5-O-deoxyhexosyl-2,4,6,8,10,12,14,16,18-nonamethylicosa-2,6,10,14 -Tetraenoic acid and BF-0158E with 3,15,19-trihydroxy-7-O-deoxyhexosyl-11-O-hexosyl-2,4,6,8,10,12,14,16,18 , 20-decamethyldocosa-4,8,12,16-tetraenoic acid and BF-0158F Lihydroxy-5-O-deoxyhexosyl-9-O-hexosyl-2,4,6,8,10,12,14,16,18,20,22-undecamethyltetracosa-2,6, 10,14,18-pentaenoic acid and BF-0158G are converted to 17,21-dihydroxy-5,9-O-dideoxyhexosyl-13-O-hexosyl-2,4,6,8,10,12,14 , 16,18,20,22-Undecamethyltetracosa-2,6,10,14,18-pentaenoic acid and BF-0158H with 13,17,21-trihydroxy-5,9-O-dideoxyhe The structure of xoxosyl-2,4,6,8,10,12,14,16,18,20,22-undecamethyltetracosa-2,6,10,14,18-pentaenoic acid was determined.

[Compound BF-0158A]
White powder
[α] _D ²⁸ = -5.1 ° (c = 0.1, MeOH)
UV λ _max (MeOH) (log ε) nm; 202 (4.57)
Molecular weight; 948
Molecular formula; C ₄₇ H ₈₀ O ₁₉
HR-ESI-MS (m / z); Calculated value of the following formula: 971.5192 [M + Na] ⁺ , measured value: 971.5143 [M + Na] ⁺
IR ν _max (KBr) (cm ^-1 ); 3425, 2964, 2929, 1637, 1449, 1398, 1234, 1070
¹³ C-NMR (MeOH-d4); 171.7, 147.3, 139.2, 139.1, 136.6, 133.1, 132.4, 132.1, 129.2, 98.3, 97.5, 96.9, 90.4, 88.3, 87.4, 79.4, 78.3, 75.8, 74.6, 73.8, 73.4, 73.2, 72.8, 72.6, 72.3, 70.5, 70.3, 68.1, 62.4, 39.4, 37.0, 36.6, 35.43, 35.40, 27.3, 18.3, 17.9, 17.8, 17.7, 17.4, 16.8, 14.5, 12.9, 11.9, 11.0, 10.82, 10.79
¹ H-NMR (MeOH-d4); 6.65 (1H), 5.46 (1H), 5.36 (1H), 5.26 (1H), 5.10 (1H), 4.70 (1H), 4.40 (1H), 3.80 (2H), 3.77 (1H), 3.75 (1H), 3.73 (1H), 3.71 (1H), 3.69 (2H), 3.66 (1H), 3.64 (1H), 3.62 (1H), 3.61 (1H), 3.51 (1H), 3.35 (1H), 3.31 (2H), 3.24 (1H), 3.07 (1H), 2.81 (1H), 2.75 (2H), 2.70 (1H), 1.86 (3H), 1.63 (3H), 1.62 (3H), 1.60 (3H), 1.46 (1H), 1.44 (1H), 1.31 (3H), 1.24 (3H), 1.18 (1H), 0.98 (3H), 0.95 (3H), 0.92 (3H), 0.87 (3H), 0.81 (3H), 0.78 (3H).

[Compound BF-0158B]
White powder
[α] _D ²⁹ = -16.0 ° (c = 0.1, MeOH)
UV λ _max (MeOH) (log ε) nm; 203 (4.52)
Molecular weight; 802
Molecular formula; C ₄₁ H ₇₀ O ₁₅
HR-ESI-MS (m / z); Calculated value of the following formula: 825.4612 [M + Na] ⁺ , measured value: 825.469 [M + Na] ⁺
IR ν _max (KBr) (cm ^-1 ); 3424, 2965, 2929, 2880, 1694, 1646, 1450, 1388, 1266, 1235, 1070
¹³ C-NMR (MeOH-d4); 171.7, 147.8, 139.3, 138.3, 137.4, 133.3, 132.8, 131.9, 128.9, 98.1, 97.0, 90.3, 88.1, 84.3, 79.4, 78.1, 75.6, 73.7, 73.3, 72.9, 72.4, 70.2, 68.2, 62.6, 38.3, 37.3, 36.6, 36.4, 35.4, 27.7, 18.2, 17.8, 17.7, 17.5, 16.7, 13.8, 12.9, 11.9, 11.4, 11.0, 10.9
¹ H-NMR (MeOH-d4); 6.66 (1H), 5.36 (1H), 5.34 (1H), 5.30 (1H), 5.05 (1H), 4.52 (1H), 3.80 (2H), 3.78 (1H), 3.74 (1H), 3.71 (1H), 3.69 (1H), 3.66 (1H), 3.62 (1H), 3.60 (1H), 3.52 (1H), 3.40 (1H), 3.33 (1H), 3.24 (1H), 3.11 (1H), 2.81 (1H), 2.75 (1H), 2.64 (2H), 1.86 (3H), 1.68 (3H), 1.63 (6H), 1.51 (1H), 1.48 (1H), 1.23 (4H), 0.93 (3H), 0.92 (3H), 0.91 (3H), 0.86 (3H), 0.79 (6H).

[Compound BF-0158C]
White powder
[α] _D ²⁵ = -23.0 ° (c = 0.1, MeOH)
UV λ _max (MeOH) (log ε) nm; 202 (4.54)
Molecular weight; 786
Molecular formula; C ₄₁ H ₇₀ O ₁₄
HR-ESI-MS (m / z); Calculated value of the following formula: 809.4663 [M + Na] ⁺ , measured value: 809.4613 [M + Na] ⁺
IR ν _max (KBr) (cm ^-1 ); 3424, 2965, 2928, 1703, 1454, 1387, 1270, 1232, 1132, 1074, 1046, 983
¹³ C-NMR (MeOH-d4); 172.7, 146.1, 138.8, 138.4, 137.2, 132.9, 132.7, 132.3, 130.2, 97.5, 97.4, 87.8, 87.3, 83.8, 79.4, 74.5, 73.9, 73.0, 72.8, 72.5, 72.4, 70.49, 70.44, 38.3, 37.5, 36.9, 36.6, 35.9, 27.7, 18.1, 18.1, 17.9, 17.9, 17.8, 16.9, 13.7, 13.2, 12.0, 11.6, 11.1, 10.8
¹ H-NMR (MeOH-d4); 6.58 (1H), 5.38 (1H), 5.36 (2H), 4.74 (1H), 4.70 (1H), 3.77 (1H), 3.75 (1H), 3.73 (1H), 3.72 (2H), 3.70-3.60 (3H), 3.54 (1H), 3.31 (2H), 3.24 (1H), 2.78 (2H), 2.70-2.60 (2H), 1.86 (3H), 1.67 (3H), 1.63 (3H), 1.61 (3H), 1.55-1.40 (2H), 1.29 (3H), 1.24 (3H), 1.23 (1H), 0.93 (3H), 0.92 (3H), 0.91 (3H), 0.87 (3H) , 0.82 (3H), 0.81 (3H).

[Compound BF-0158D]
White powder
UV λ _max (MeOH) (log ε) nm; 202 (4.56)
Molecular weight; 640
Molecular formula; C ₃₅ H ₆₀ O ₁₀
HR-ESI-MS (m / z); Calculated value: 663.4084 [M + Na] ⁺ , Actual value: 663.4053 [M + Na] ⁺
IR ν _max (KBr) (cm ^-1 ); 3408, 2964, 2928, 2878, 1650, 1547, 1452, 1385, 1304, 1267, 1072, 1043
¹³ C-NMR (MeOH-d4); 171.7, 146.4, 137.9, 137.8, 137.2, 133.5, 132.8, 132.8, 130.2, 97.9, 87.7, 84.1, 84.0, 79.4, 73.9, 72.8, 72.5, 70.4, 38.2, 37.1, 37.0, 37.0, 36.7, 27.8, 18.0, 17.96, 17.86, 17.8, 16.9, 13.6, 13.2, 12.0, 11.6, 11.4, 11.2
¹ H-NMR (MeOH-d4); 6.60 (1H), 5.40 (1H), 5.36 (1H), 5.29 (1H), 4.70 (1H), 3.76 (1H), 3.73 (1H), 3.71 (1H), 3.69 (1H), 3.63 (1H), 3.56 (1H), 3.32 (1H), 3.23 (1H), 2.79 (1H), 2.70-2.60 (3H), 1.86 (3H), 1.68 (3H), 1.66 (3H ), 1.63 (3H), 1.60-1.40 (2H), 1.23 (3H), 1.22 (1H), 0.93 (3H), 0.92 (3H), 0.91 (3H), 0.87 (3H), 0.81 (3H), 0.79 (3H).

[Compound BF-0158E]
White powder
[α] _D ²⁵ = + 6.98 ° (c = 0.1, MeOH)
UV λ _max (MeOH) (log ε) nm; 201 (4.63)
Molecular weight; 860
Molecular formula; C ₄₄ H ₇₆ O ₁₆
HR-ESI-MS (m / z); Calculated value: 883.5031 [M + Na] ⁺ , Actual value: 883.4991 [M + Na] ⁺
IR ν _max (KBr) (cm ^-1 ); 3411, 2966, 2930, 2880, 1717, 1455, 1385, 1301, 1252, 1069
¹³ C-NMR (MeOH-d4); 180.2, 139.0, 138.4, 137.4, 136.2, 135.0, 133.3, 132.8, 131.9, 98.1, 96.0, 90.3, 87.0, 84.3, 81.7, 79.5, 78.1, 75.6, 74.5, 73.3, 72.7, 72.1, 69.4, 68.2, 62.4, 44.8, 38.4, 37.3, 36.6, 35.4, 35.1, 27.7, 18.2, 17.8, 17.7, 17.5, 17.3, 15.3, 13.8, 12.0, 11.3, 11.1, 11.0, 10.9
¹ H-NMR (MeOH-d4); 5.35 (2H), 5.26 (1H), 5.20 (1H), 5.09 (1H), 4.53 (1H), 4.05 (1H), 3.80 (2H), 3.77 (2H), 3.71 (1H), 3.69 (1H), 3.66-3.56 (4H), 3.40 (1H), 3.31 (1H), 3.24 (1H), 3.10 (1H), 2.74 (2H), 2.65 (2H), 2.53 (1H ), 1.68 (3H), 1.66 (3H), 1.63 (3H), 1.61 (3H), 1.55-1.40 (2H), 1.28 (3H), 1.26 (1H), 0.98 (3H), 0.93 (3H), 0.92 (3H), 0.91 (3H), 0.81-0.78 (9H).

[Compound BF-0158F]
White powder
[α] _D ²⁶ = + 5.02 ° (c = 0.1, MeOH)
UV λ _max (MeOH) (log ε) nm; 203 (4.67)
Molecular weight; 900
Molecular formula; C ₄₇ H ₈₀ O ₁₆
HR-ESI-MS (m / z); Calculated value of the following formula: 923.5344 (M + Na), Measured value: 923.5287 (M + Na)
IR ν _max (KBr) (cm ^-1 ); 3421, 2965, 2929, 2878, 1691, 1642, 1453, 1381, 1239, 1071, 1034
¹³ C-NMR (MeOH-d4); 171.7, 147.1, 139.4, 138.2, 138.0, 137.1, 133.7, 133.3, 132.9, 132.0, 128.9, 98.1, 97.0, 90.3, 88.1, 84.5, 84.2, 79.4, 78.1, 75.6, 73.8, 73.3, 72.9, 72.4, 70.2, 68.2, 62.6, 38.2, 37.0, 36.9, 36.6, 36.3, 35.4, 27.8, 18.0, 17.8, 17.7, 17.7, 17.5, 16.7, 13.6, 13.1, 12.0, 11.5, 11.2, 11.0, 10.9
¹ H-NMR (MeOH-d4); 6.62 (1H), 5.37 (1H), 5.35 (1H), 5.30 (1H), 5.28 (1H), 5.05 (1H), 4.54 (1H), 3.80 (2H), 3.78 (1H), 3.74 (1H), 3.72 (1H), 3.70 (2H), 3.66 (1H), 3.63 (1H), 3.60 (1H), 3.53 (1H), 3.41 (1H), 3.34 (1H), 3.24 (1H), 3.12 (1H), 2.77 (2H), 2.70-2.60 (3H), 1.86 (3H), 1.69 (3H), 1.67 (3H), 1.63 (3H), 1.62 (3H), 1.60-1.40 (2H), 1.23 (3H), 1.20 (1H), 0.93 (3H), 0.92 (3H), 0.91 (3H), 0.86 (3H), 0.82-0.78 (9H).

[Compound BF-0158G]
White powder
[α] _D ²⁶ = -13.8 ° (c = 0.1, MeOH)
UV λ _max (MeOH) (log ε) nm; 202 (4.68)
Molecular weight; 1046
Molecular formula; C ₅₃ H ₉₀ O ₂₀
HR-ESI-MS (m / z); Calculated value of the following formula: 1069.5923 [M + Na] ⁺ , measured value: 1069.5829 [M + Na] ⁺
IR ν _max (KBr) (cm ^-1 ); 3399, 2966, 2929, 2880, 1686, 1451, 1386, 1264, 1233, 1128, 1071, 991
¹³ C-NMR (MeOH-d4); 171.8, 147.2, 139.2, 139.2, 138.5, 137.4, 133.2, 132.8, 132.4, 132.1, 129.2, 98.0, 97.4, 96.8, 90.2, 88.3, 87.4, 84.3, 79.5, 78.1, 75.6, 74.6, 73.8, 73.3, 73.2, 72.8, 72.6, 72.3, 70.5, 70.3, 68.2, 62.5, 38.4, 37.3, 36.9, 36.6, 35.4, 35.4, 27.7, 18.2, 17.9, 17.8, 17.8, 17.8, 17.5, 16.9, 13.8, 13.0, 11.9, 11.3, 11.0, 10.9, 10.8
¹ H-NMR (MeOH-d4); 6.65 (1H), 5.36 (2H), 5.34 (1H), 5.32 (1H), 5.10 (1H), 4.70 (1H), 4.55 (1H), 3.80 (2H), 3.78 (2H), 3.73 (1H), 3.70 (4H), 3.68-3.55 (4H), 3.52 (1H), 3.40 (1H), 3.31 (2H), 3.24 (1H), 3.11 (1H), 2.86-2.70 (3H), 2.70-2.60 (2H), 1.86 (3H), 1.68 (3H), 1.63 (6H), 1.60 (3H), 1.55-1.45 (2H), 1.31 (3H), 1.24 (3H), 1.22 ( 1H), 0.93 (3H), 0.92 (3H), 0.91 (3H), 0.88 (3H), 0.82-0.78 (9H).

[Compound BF-0158H]
White powder
[α] _D ²⁶ = -18.4 ° (c = 0.1, MeOH)
UV λ _max (MeOH) (log ε) nm; 203 (4.68)
Molecular weight; 884
Molecular formula; C ₄₇ H ₈₀ O ₁₅
HR-ESI-MS (m / z); Calculated value of the following formula: 907.5395 [M + Na] ⁺ , measured value: 907.5308 [M + Na] ⁺
IR ν _max (KBr) (cm ^-1 ); 3417, 2966, 2928, 2880, 1688, 1647, 1451, 1384, 1265, 1044, 992
¹³ C-NMR (MeOH-d4); 171.7, 147.3, 138.9, 138.3, 137.8, 137.2, 133.5, 132.82, 132.77, 132.2, 129.3, 97.6, 97.5, 87.8, 87.4, 84.1, 84.0, 79.4, 74.6, 73.7, 73.0, 72.8, 72.5, 72.4, 70.5, 70.4, 38.2, 37.1, 37.0, 37.0, 36.6, 36.0, 27.8, 18.1, 18.0, 17.9, 17.9, 17.9, 17.7, 16.9, 13.6, 13.0, 12.0, 11.6, 11.4, 11.1, 10.8
¹ H-NMR (MeOH-d4); 6.65 (1H), 5.39 (1H), 5.36 (2H), 5.29 (1H), 4.76 (1H), 4.71 (1H), 3.78 (1H), 3.77 (1H), 3.74 (1H), 3.72 (2H), 3.71 (1H), 3.68-3.60 (3H), 3.52 (1H), 3.31 (2H), 3.24 (1H), 2.90-2.70 (2H), 2.70-2.60 (3H) , 1.86 (3H), 1.69 (3H), 1.67 (3H), 1.63 (3H), 1.61 (3H), 1.60-1.40 (2H), 1.29 (3H), 1.23 (3H), 1.22 (1H), 0.93 ( 3H), 0.92 (3H), 0.91 (3H), 0.87 (3H), 0.84-0.78 (9H).

<II. Pharmacological studies of new compounds>
[reagent]
RPMI 1640 powder medium was purchased from GIBCO. 3-morpholinopropanesulfonic acid (MOPS) was purchased from DOJINDO. Sodium chloride was purchased from Kanto Chemical Co., Inc. DMSO was purchased from Nacalai Tesque.

[Equipment, equipment and materials]
A YAZAWA automatic mixer was used as the vortex mixer. A Bio Tek Power Wave x340 was used to measure the absorbance. NS-4P from ASONE was used for the plate mixer. N-Biotek's NB-203 was used for the 96-well plate (As One) incubator. Olympus CK2 was used for the microscope. 150 mm bottle top filters (pore size 0.22 mm), 15 mL centrifuge tubes and 50 mL centrifuge tubes were purchased from Corning.

[Test bacteria]
The following fungi from the laboratory were used: Candida albicans ATCC 90029, C. parapsilosis ATCC 90018, C. glabrata ATCC 90030, cryptococcus Cryptococcus neoformans ATCC 90113, Aspergillus fumigatus NBRC 33022, Aspergillus flavus NBRC 6343, Aspergillus niger NBRC 105649, Aspergillus terreus A Rhizopus oryzae NBRC 4705, R. microsporus IFM 46417, and Rhizomucor pusillus NBRC 9744.

[Reagent preparation]
Amphotericin B was prepared in a 0.8 mg / mL DMSO solution. Compound BF-0158 was prepared in a 1.6 mg / mL DMSO solution. All solutions were stored at −20 ° C. after preparation. Saline (0.85% sodium chloride aqueous solution) and bamboo skewers were autoclaved (121 ° C., 15 minutes) and then stored at room temperature.

[Preparation of RPMI 1640 medium]
10.4 and 34.5 g of RPMI 1640 powder medium and MOPS were added to 900 mL of sterile distilled water, respectively, and stirred until the added components were dissolved. The solution was then adjusted to pH 7.0 with 2 M NaOH. The solution was made up to 1 L with sterilized distilled water. The fixed volume solution was sterilized by filtration using a 150 mm bottle top filter (corning). The obtained sterilized solution was stored as RPMI 1640 medium at 4 ° C.

[Test II-1: Activity evaluation test of antifungal active substance]
[Preparation of bacterial solution]
The preparation method of the inoculum of yeast fungi (Candida albicans, Candida parapsilosis, Candida glabrata and Cryptococcus neoformans) was shown below. In a sterilized 15 mL centrifuge tube (Corning), 5 mL of 0.85% sterilized physiological saline was measured. Using a sterilized bamboo skewer, five colonies (about 1 mm in diameter) of each test bacterium were collected and suspended in measured physiological saline. This was vortexed for 15 seconds using an automatic mixer (YAZAWA). 100 μL of this suspension was dispensed into a sterilized 96-well plate (As One), and OD ₅₅₀ was measured. This suspension was diluted to 0.8 McFarland (OD ₅₅₀ = 0.0548) with 0.85% sterile saline. The resulting suspension was diluted 100 times with RPMI 1640 medium. This 100-fold diluted solution was further diluted 20-fold with RPMI 1640 medium. The obtained diluted solution was used as an inoculum.

A method for preparing inoculums of filamentous fungi (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger and Aspergillus terreus) and zygomycetes (Rhizopus oryzae, Rhizopus microsporus and Rhizomucor psirus) was shown below. In a sterilized 15 mL centrifuge tube, 2 mL of 0.85% sterilized physiological saline was measured. Spores of each test bacterium were scraped with a platinum loop and suspended in the sterilized physiological saline. This was left for 5 minutes. This suspension was dispensed 100 μL into a sterilized 96-well plate, and OD ₅₅₀ was measured. This suspension was diluted with 0.85% sterile physiological saline so that the filamentous fungus had an OD ₅₅₀ = 0.0621 and the zygote had an OD ₅₅₀ = 0.0765. The resulting suspension was diluted 50-fold with RPMI 1640 medium. The obtained diluted solution was used as an inoculum.

[Evaluation of antifungal spectrum by micro liquid dilution method]
The antifungal spectrum was measured by the micro liquid dilution method according to the American Society for Clinical Laboratory Standards (CLSI) M27-A3 and M38-A2 methods (Reference Method for Broth Dilution Antifungal Succeptibity Testing of Years; Approved Standard-Third Edition, Wayne PA, 28, M27-A3 (2008), Filamentous Fungi; Approved Standard-Second Edition Wayne, PA, 28, M38-A2 (2008)). To each well of a sterilized 96-well plate, add 1.0 μL of a diluted solution of compound BF-0158 prepared in DMSO so that the final concentration of compound BF-0158 is 32, 16, 8.0… 0.063 μg / mL. Added in increments. As a control, 1.0 μL of DMSO alone was added. Each test group and control group were prepared in 8 wells. Next, yeast fungi were added to each well at a ratio of 19 μL of RPMI 1640 medium and 180 μL of inoculum. After the addition, the OD ₅₅₀ of each well was measured (this was the initial turbidity). Using a NB-203 (N-Biotek) incubator, yeast fungi inoculated into the wells of a 96-well plate at a temperature of 35 ° C. for Candida albicans, Candida parapsilosis and Candida glabrata for 24 hours, Cryptococcus neoformans was cultured for 72 hours. Subsequently, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, the OD ₅₅₀ of each well was measured (this was the terminal turbidity). Based on the following formula (M-2), the inhibition rate of each compound was calculated. The minimum concentration of the compound at which the calculated inhibition rate was 90% or more was defined as the minimum growth inhibition concentration (MIC value) of the compound.

  In the same manner as described above, the compound and control DMSO were dispensed into predetermined wells of a 96-well plate. Filamentous fungi and zygomycetes were added to predetermined wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of the inoculum. After the addition, yeast fungi inoculated into the wells of a 96-well plate were cultured using a NB-203 incubator at a temperature of 35 ° C. for 48 hours for filamentous fungi and 24 hours for zygomycetes. Each well was observed under a microscope (CK2: Olympus). As a result of observation, in each compound, the minimum concentration at which the growth of filamentous fungi or zygomycetes was completely inhibited was determined. This concentration was taken as the MIC value of the compound.

  As a result of this test, compounds BF-0158A and B were against Candida albicans at a concentration of 512 μg / mL or less, against Cryptococcus neoformans, Aspergillus fumigatus and Rhizopus oryzae at a concentration of 128 μg / mL or less. Each showed no growth inhibitory activity. Compounds BF-0158C, D, E, F, G and H showed no growth inhibitory activity against Candida albicans at a concentration of 8 μg / mL or less.

[Test II-2: Evaluation test of potentiating activity against the antifungal agent amphotericin B]
[Preparation of bacterial solution]
The Candida albicans ATCC90029 strain was spread on PDA medium with a platinum loop and cultured at 27 ° C. for 2 to 3 days. This culture was subcultured twice and grown until the colony had a diameter of 1 mm or more. In a sterilized 15 mL centrifuge tube (Corning), 5 mL of 0.85% sterilized physiological saline was measured. Using a sterilized bamboo skewer, five colonies (about 1 mm in diameter) of the grown fungi were collected and suspended in a sterilized physiological saline solution. This was vortexed for 15 seconds using an automatic mixer (YAZAWA). 100 μL of this suspension was dispensed into a sterilized 96-well plate (As One), and OD ₅₅₀ was measured. This suspension was diluted to 0.8 McFarland (OD ₅₅₀ = 0.0548) with 0.85% sterile saline. The resulting suspension was diluted 100 times with RPMI 1640 medium. This 100-fold diluted solution was further diluted 20-fold with RPMI 1640 medium. The obtained diluted solution was used as an inoculum.

  Yeast fungi (Cryptococcus neoformans) and zygote (Rhizopus oryzae) inoculum were prepared by the same procedure as in Test II-1.

[Evaluation of fungal inhibition rate by micro liquid dilution method]
The inhibition rate against the fungal Candida albicans ATCC90029 strain was measured by the micro liquid dilution method according to the NCCLS M27-A3 method and M38-A2 method (Reference Method for Broth Dilution Antifungal Succeptibity Testing of Years; Approved Standard-Third Edition, Wayne, PA, 28, M27-A3 (2008), Filamentous Fungi; Approved Standard-Second Edition Wayne, PA, 28, M38-A2 (2008)). In each well of a sterilized 96-well plate, the final concentration of compound BF-0158A and B is 512, 256, 128 or 64 μg / mL, and the final concentration of compound BF-0158C-H is 8, 4, 2 or 1 μg / mL. 1.0 μL of a diluted solution of compound BF-0158 prepared in DMSO was added so as to be mL. As a control, 1.0 μL of DMSO alone was added. Each test group and control group were prepared in 8 wells. Next, fungi were added to each well at a ratio of 19 μL RPMI 1640 medium and 180 μL inoculum. After the addition, the OD ₅₅₀ of each well was measured (this was the initial turbidity). Using a NB-203 (N-Biotek) incubator, the fungi inoculated into the wells of a 96-well plate were cultured at 35 ° C for 24 hours for Candida albicans and 72 hours for Cryptococcus neoformans. . Subsequently, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, the OD ₅₅₀ of each well was measured (this was the terminal turbidity). Based on the formula (M-1), the inhibition rate of each compound was calculated. The minimum concentration of the compound at which the calculated inhibition rate was 90% or more was defined as the MIC value of the compound.

  In the same manner as described above, the compound and control DMSO were dispensed into predetermined wells of a 96-well plate. The zygote (Rhizopus oryzae) was added to a predetermined well at a ratio of 99 μL of RPMI 1640 medium and 100 μL of the inoculum. After the addition, yeast fungi inoculated into the wells of a 96-well plate were cultured at a temperature of 35 ° C. for 24 hours using an NB-203 incubator. Each well was observed under a microscope (CK2: Olympus). As a result of observation, in each compound, the minimum concentration at which growth was completely inhibited was determined. This concentration was taken as the MIC value of the compound.

[Evaluation of amphotericin B activity enhancing effect of compounds BF-0158 by micro liquid dilution method]
In each well of a sterilized 96-well plate, the final concentration of compound BF-0158 is 8, 4, 2, 1, 0.5, 0.25 or 0.125 μg / mL, and the final concentration of amphotericin B is 1.0, 0.5, 0.25, 0.125, To each of 0.0625, 0.0313, or 0.0156 μg / mL, 1.0 μL each of a diluted solution of Compound BF-0158s and amphotericin B prepared with DMSO was added. As a control, 2.0 μL of DMSO alone was added. 1 well of each test group and 8 wells of the control group were prepared. Next, fungi were added to each well at a ratio of 18 μL of RPMI 1640 medium and 180 μL of inoculum. After the addition, the OD ₅₅₀ of each well was measured (this was the initial turbidity). Using a NB-203 (N-Biotek) incubator, fungi inoculated into the wells of a 96-well plate were cultured at a temperature of 35 ° C. for 24 hours. Subsequently, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, the OD ₅₅₀ of each well was measured (this was the terminal turbidity). Based on the formula (M-2), the inhibition rate by the combined administration of each compound and amphotericin B was calculated. The minimum concentration of amphotericin B when the calculated inhibition rate was 90% or more was defined as the MIC value of amphotericin B in the combined administration of each compound and amphotericin B. Moreover, the amphotericin B activity enhancement rate of each compound was calculated based on the following formula (M-3). The calculation of the amphotericin B activity enhancement rate of each compound was carried out by repeating the test three times.

Table 1 shows the MIC value of amphotericin B against Candida albicans upon combined administration of compound BF-0158 and amphotericin B. In the table, the column of “Compound BF-0158” indicates the concentration of Compound BF-0158 when Compound BF-0158 and Amphotericin B are administered in combination, and the column of “Amphhotericin B” indicates Compound BF-0158. The MIC value of amphotericin B at the time of combined administration of amphotericin and amphotericin B is shown respectively.

Table 2 shows the enhancement rate of amphotericin B activity of compound BF-0158 against Candida albicans when combined administration of compound BF-0158 and amphotericin B. Table 3 shows the amphotericin B activity enhancement rate of compound BF-0158 against Rhizopus oryzae, respectively. In the table, “Compound BF-0158 Concentration” column indicates the concentration of Compound BF-0158 when Compound BF-0158 and Amphotericin B are administered in combination, and “Enhancement Rate of Amphotericin B Activity of Compound BF-0158” The column in each shows the enhancement rate of nfhotericin B activity by the compounds BF-0158 at each concentration.

  As shown in Table 2, the antifungal activity of amphotericin B against Candida albicans is 1-2 times by administering 0.25 μg / mL, particularly 0.5 μg / mL or more of compound BF-0158 in combination with amphotericin B. In particular, it was enhanced 2 to 8 times. As shown in Table 3, antifungal activity of amphotericin B against Cryptococcus neoformans was enhanced 4 to 8 times by administering 0.5 μg / mL or more of compound BF-0158A or BF-0158B together with amphotericin B . In addition, as shown in Table 4, the antifungal activity of amphotericin B against Rhizopus oryzae was enhanced 2 to 8 times by administering 1 μg / mL or more of compound BF-0158A or BF-0158B together with amphotericin B It was done.

  In addition, this invention is not limited to an above-described Example, Various modifications are included. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Moreover, it is possible to add, delete, and / or replace another configuration with respect to a part of the configuration of each embodiment.

［式中、
nは、0〜10の範囲の整数であり、
R¹、R²、R³及びR⁴は、互いに独立して、OH、置換若しくは非置換の糖基、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のアシルオキシ、カーボナート、又はカーバマートであり、
R⁵及びR⁶は、それらが結合する炭素の間で二重結合を形成するか、又は
R⁵は、OH、置換若しくは非置換の糖基、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のアシルオキシ、カーボナート、又はカーバマートであり、且つ
R⁶は、Hであり、
但し、R⁵及びR⁶が複数個存在する場合、各R⁵及びR⁶は、それぞれ別の意味を有していてよく、
R⁷は、H、OH、NR^N1R^N2、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、置換若しくは非置換のヘテロシクロアルキルアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のヘテロアリール、置換若しくは非置換のヘテロアリールアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、又は置換若しくは非置換のアシルオキシであり、
R^N1及びR^N2は、互いに独立して、H、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のシクロアルキニル、置換若しくは非置換のヘテロシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、置換若しくは非置換のヘテロシクロアルキルアルキル、置換若しくは非置換のアリール、置換若しくは非置換のアリールアルキル、置換若しくは非置換のヘテロアリール、又は置換若しくは非置換のヘテロアリールアルキルである。］
で表される化合物若しくはその塩、又はそれらの溶媒和物。
（2） R¹、R²、R³及びR⁴が、互いに独立して、OH、置換若しくは非置換の糖基、置換若しくは非置換のC₁〜C₆アルコキシ、置換若しくは非置換のC₃〜C₆シクロアルコキシ、置換若しくは非置換の3〜6員ヘテロシクロアルコキシ、置換若しくは非置換のC₆〜C₁₅アリールオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルキルオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルケニルオキシ、置換若しくは非置換の5〜15員のヘテロアリールオキシ、置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₅アルキルオキシ、置換若しくは非置換のC₁〜C₂₀アシル、置換若しくは非置換のC₁〜C₂₀アシルオキシ、カーボナート、又はカーバマートであり、
R⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成するか、又は
R⁵が、OH、置換若しくは非置換の糖基、置換若しくは非置換のC₁〜C₆アルコキシ、置換若しくは非置換のC₃〜C₆シクロアルコキシ、置換若しくは非置換の3〜6員ヘテロシクロアルコキシ、置換若しくは非置換のC₆〜C₁₅アリールオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルキルオキシ、置換若しくは非置換のC₇〜C₂₀アリールアルケニルオキシ、置換若しくは非置換の5〜15員のヘテロアリールオキシ、置換若しくは非置換の5〜15員のヘテロアリール-C₁〜C₅アルキルオキシ、置換若しくは非置換のC₁〜C₂₀アシル、置換若しくは非置換のC₁〜C₂₀アシルオキシ、カーボナート、又はカーバマートであり、且つ
R⁶が、Hである、前記実施形態（1）に記載の化合物。
（3） R¹、R²、R³及びR⁴が、互いに独立して、OH、又は式（S-1）若しくは（S-2）：

で表される基であり、
R⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成するか、又は
R⁵が、OH、又は式（S-1）若しくは（S-2）で表される基であり、且つ
R⁶が、Hである、前記実施形態（1）又は（2）に記載の化合物。
（4） （A）nが、0であり、
R¹及びR²が、式（S-1）：

で表される基であり、
R³が、式（S-2）：

で表される基であり、
R⁴が、OHであり、
R⁷が、OHである、或いは；
（B）nが、0であり、
R¹が、式（S-1）で表される基であり、
R²が、式（S-2）で表される基であり、
R³及びR⁴が、OHであり、
R⁷が、OHである、或いは；
（C）nが、0であり、
R¹及びR²が、式（S-1）で表される基であり、
R³及びR⁴が、OHであり、
R⁷が、OHである、或いは；
（D）nが、0であり、
R¹が、式（S-1）で表される基であり、
R²、R³及びR⁴が、OHであり、
R⁷が、OHである、或いは；
（E）nが、1であり、
R¹が、式（S-1）で表される基であり、
R²が、式（S-2）で表される基であり、
R³及びR⁴が、OHであり、
R⁵が、OHであり、
R⁶が、Hであり、
R⁷が、OHである、或いは；
（F）nが、2であり、
R¹が、式（S-2）で表される基であり、
R²、R³及びR⁴が、OHであり、
第1のR⁵が、式（S-1）で表される基であり、
第1のR⁶が、Hであり、
第2のR⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成し、
R⁷が、OHである、或いは；
（G）nが、2であり、
R¹が、式（S-1）で表される基であり、
R²が、式（S-2）で表される基であり、
R³及びR⁴が、OHであり、
第1のR⁵が、式（S-1）で表される基であり、
第1のR⁶が、Hであり、
第2のR⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成し、
R⁷が、OHである、或いは；
（H）nが、2であり、
R¹が、式（S-1）で表される基であり、
R²、R³及びR⁴が、OHであり、
第1のR⁵が、式（S-1）で表される基であり、
第1のR⁶が、Hであり、
第2のR⁵及びR⁶が、それらが結合する炭素の間で二重結合を形成し、
R⁷が、OHである、前記実施形態（1）〜（3）のいずれかに記載の化合物。
（5） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の製造方法であって、
式（I）で表される化合物を産生する能力を有するシュードフィアロフォラ属菌BF-0158株（NITE P-02400）又はその変異株である微生物を培地中で培養して、式（I）で表される化合物を該培地中に蓄積させる、化合物蓄積工程；
化合物蓄積工程で得られた式（I）で表される化合物を前記微生物の培養物から精製する、化合物精製工程；
を含む、前記方法。
（6） 前記実施形態（1）〜（4）のいずれかに記載の式（I）で表される化合物を産生する能力を有するシュードフィアロフォラ属菌BF-0158株（NITE P-02400）又はその変異株である微生物。
（7） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含む、ポリエンマクロライド系薬剤、アゾール系薬剤、キャンディン系薬剤及びフルオロピリミジン系薬剤からなる群より選択される少なくとも1種の抗真菌薬の活性増強剤。
（8） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。
（9） 1種以上の真菌感染症の予防又は治療に使用するための、前記実施形態（8）に記載の医薬。
（10） ポリエンマクロライド系薬剤、アゾール系薬剤、キャンディン系薬剤及びフルオロピリミジン系薬剤からなる群より選択される少なくとも1種の抗真菌薬をさらに含む、前記実施形態（8）又は（9）に記載の医薬。
（11） 前記実施形態（1）〜（4）のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物と、1種以上の製薬上許容される担体とを含む医薬組成物。
（12） 1種以上の真菌感染症の予防又は治療に使用するための、前記実施形態（11）に記載の医薬組成物。
（13） ポリエンマクロライド系薬剤、アゾール系薬剤、キャンディン系薬剤及びフルオロピリミジン系薬剤からなる群より選択される少なくとも1種の抗真菌薬をさらに含む、前記実施形態（11）又は（12）に記載の医薬組成物。 That is, the gist of the present invention is as follows.
(1) Formula (I):

[Where:
n is an integer in the range 0-10;
R ¹ , R ² , R ³ and R ⁴ each independently represent OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocyclo Alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or non-substituted Substituted acyl, substituted or unsubstituted acyloxy, carbonate, or carbamate,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted Arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, carbonate, or Carbamart, and
R ⁶ is H;
However, when there are a plurality of R ⁵ and R ⁶ , each R ⁵ and R ⁶ may have a different meaning,
R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, Replace Properly is unsubstituted arylalkyloxy, substituted or unsubstituted aryl alkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl alkyloxy, or substituted or unsubstituted acyloxy,
R ^N1 and R ^N2 each independently represent H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. ]
Or a salt thereof, or a solvate thereof.
(2) R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, substituted or unsubstituted sugar group, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, 3-6 membered heterocycloalkyl alkoxy substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted of C ₇ -C ₂₀ arylalkenyl aryloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, 5-15 membered substituted or unsubstituted heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, an carbonate, or Kabamato,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is, OH, substituted or unsubstituted sugar group, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocyclo alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, 5 substituted or unsubstituted 15-membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ Acyloxy, carbonate or carbamate, and
The compound according to embodiment (1), wherein R ⁶ is H.
(3) R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, or formula (S-1) or (S-2):

A group represented by
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is OH or a group represented by the formula (S-1) or (S-2), and
The compound according to embodiment (1) or (2), wherein R ⁶ is H.
(4) (A) n is 0,
R ¹ and R ² are represented by formula (S-1):

A group represented by
R ³ is the formula (S-2):

A group represented by
R ⁴ is OH;
R ⁷ is OH, or
(B) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(C) n is 0,
R ¹ and R ² are a group represented by the formula (S-1),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(D) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
R ⁷ is OH, or
(E) n is 1,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁵ is OH;
R ⁶ is H,
R ⁷ is OH, or
(F) n is 2,
R ¹ is a group represented by the formula (S-2),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(G) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(H) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
The compound according to any one of the embodiments (1) to (3), wherein R ⁷ is OH.
(5) A method for producing the compound according to any one of the embodiments (1) to (4) or a salt thereof, or a solvate thereof,
Pseudofialophora BF-0158 strain (NITE P- 02400) having the ability to produce a compound represented by formula (I) or a mutant microorganism thereof is cultured in a medium, A compound accumulation step of accumulating the represented compound in the medium;
A compound purification step of purifying the compound represented by the formula (I) obtained in the compound accumulation step from the culture of the microorganism;
Said method.
(6) Pseudofialophora BF-0158 strain (NITE P- 02400) having the ability to produce the compound represented by formula (I) according to any one of the above embodiments (1) to (4) or The microorganism that is the mutant.
(7) A polyene macrolide drug, an azole drug, and a candine drug containing the compound or salt thereof according to any one of the embodiments (1) to (4) or a solvate thereof as an active ingredient And at least one antifungal activity enhancer selected from the group consisting of fluoropyrimidines.
(8) A medicament comprising the compound according to any one of the above embodiments (1) to (4) or a salt thereof, or a solvate thereof as an active ingredient.
(9) The medicament according to the embodiment (8) for use in the prevention or treatment of one or more fungal infections.
(10) The embodiment (8) or (9), further comprising at least one antifungal agent selected from the group consisting of a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug. The medicament according to 1.
(11) A pharmaceutical composition comprising the compound according to any one of the embodiments (1) to (4) or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers.
(12) The pharmaceutical composition according to the embodiment (11) for use in the prevention or treatment of one or more fungal infections.
(13) The embodiment (11) or (12), further comprising at least one antifungal agent selected from the group consisting of a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug. A pharmaceutical composition according to 1.

[2-1. Compound accumulation process]
In this embodiment, the method of the present invention comprises a microorganism that is a Pseudophialophora genus BF-0158 strain (NITE P- 02400) or a mutant thereof having the ability to produce a compound represented by formula (I) Is accumulated in a medium, and the compound represented by formula (I) is accumulated in the medium.

Pseudofiarophora sp. BF-0158 is a new fungus belonging to the genus Pseudofiarophora isolated from the soil of Shodoshima, Kagawa Prefecture, Japan. This strain has been deposited as BF-0158 at the National Institute of Technology and Evaluation Patent Microorganism Depositary (NITE P- 02400).

Another embodiment of the present invention is a Pseudofiarophora BF-0158 strain (NITE P- 02400) or a mutant thereof having the ability to produce the compound represented by the formula (I) of one embodiment of the present invention. It relates to a certain microorganism. In this embodiment, the compound represented by the formula (I) preferably has the groups (A) to (H). By using the microorganism of this embodiment, the compound represented by the formula (I) corresponding to the compound BF-0158 can be efficiently produced.

[Separation of BF-0158 strain]
BF-0158 strain is a fungus isolated from soil in Shodoshima, Kagawa Prefecture, Japan. Based on the morphological characteristics, culture properties and physiological properties of the BF-0158 strain, comparison was made with known bacterial species. As a result, it was revealed that this strain is a novel strain belonging to the genus Pseudophialophora. This strain was named BF-0158 strain. This strain has been deposited as BF-0158 at the National Institute of Technology and Evaluation Patent Microorganism Depositary (NITE P- 02400). The bacteriological properties of BF-0158 strain are as follows.

Claims (13)

Formula (I):

[Where:
n is an integer in the range 0-10;
R ¹ , R ² , R ³ and R ⁴ each independently represent OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocyclo Alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or non-substituted Substituted acyl, substituted or unsubstituted acyloxy, carbonate, or carbamate,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted Arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, carbonate, or Carbamart, and
R ⁶ is H;
However, when there are a plurality of R ⁵ and R ⁶ , each R ⁵ and R ⁶ may have a different meaning,
R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, Replace Properly is unsubstituted arylalkyloxy, substituted or unsubstituted aryl alkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl alkyloxy, or substituted or unsubstituted acyloxy,
R ^N1 and R ^N2 each independently represent H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. ]
Or a salt thereof, or a solvate thereof. R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, substituted or unsubstituted sugar group, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C _{3 to} C _6. cycloalkoxy, 3-6 membered heterocycloalkyl alkoxy substituted or unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ ~ C ₂₀ acyl, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, an carbonate, or Kabamato,
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is, OH, substituted or unsubstituted sugar group, a substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocyclo alkoxy, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ -C ₂₀ aryl alkenyloxy, 5 substituted or unsubstituted 15-membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ Acyloxy, carbonate or carbamate, and
The compound of claim 1, wherein R ⁶ is H. R ¹ , R ² , R ³ and R ⁴ are independently of each other OH, or a formula (S-1) or (S-2):

A group represented by
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or
R ⁵ is OH or a group represented by the formula (S-1) or (S-2), and
The compound according to claim 1 or 2, wherein R ⁶ is H. (A) n is 0,
R ¹ and R ² are represented by formula (S-1):

A group represented by
R ³ is the formula (S-2):

A group represented by
R ⁴ is OH;
R ⁷ is OH, or
(B) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(C) n is 0,
R ¹ and R ² are a group represented by the formula (S-1),
R ³ and R ⁴ are OH,
R ⁷ is OH, or
(D) n is 0,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
R ⁷ is OH, or
(E) n is 1,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
R ⁵ is OH;
R ⁶ is H,
R ⁷ is OH, or
(F) n is 2,
R ¹ is a group represented by the formula (S-2),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(G) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² is a group represented by the formula (S-2),
R ³ and R ⁴ are OH,
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, or
(H) n is 2,
R ¹ is a group represented by the formula (S-1),
R ² , R ³ and R ⁴ are OH;
The first R ⁵ is a group represented by the formula (S-1);
The first R ⁶ is H;
The second R ⁵ and R ⁶ form a double bond between the carbons to which they are attached;
R ⁷ is OH, and The compound according to any one of claims 1 to 3. A method for producing the compound according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof,
Pseudofialophora BF-0158 strain (NITE AP-02400) having the ability to produce a compound represented by formula (I) or a mutant strain thereof is cultured in a medium, A compound accumulation step of accumulating the represented compound in the medium;
A compound purification step of purifying the compound represented by the formula (I) obtained in the compound accumulation step from the culture of the microorganism;
Said method.   A microorganism which is a Pseudofialophora BF-0158 strain (NITE AP-02400) or a mutant thereof having the ability to produce the compound represented by the formula (I) according to any one of claims 1 to 4 .   A polyene macrolide drug, an azole drug, a candine drug and a fluoropyrimidine drug containing the compound or salt thereof according to any one of claims 1 to 4 or a solvate thereof as an active ingredient. An activity enhancer for at least one antifungal agent selected from the group consisting of:   A pharmaceutical comprising the compound according to any one of claims 1 to 4 or a salt thereof, or a solvate thereof as an active ingredient.   9. The medicament according to claim 8, for use in the prevention or treatment of one or more fungal infections.   10. The medicament according to claim 8 or 9, further comprising at least one antifungal drug selected from the group consisting of a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers.   12. A pharmaceutical composition according to claim 11 for use in the prevention or treatment of one or more fungal infections.   13. The pharmaceutical composition according to claim 11 or 12, further comprising at least one antifungal agent selected from the group consisting of a polyene macrolide drug, an azole drug, a candin drug, and a fluoropyrimidine drug.