JP6969770B2 - A novel compound having an activity-enhancing effect on antifungal drugs and a method for producing the same. - Google Patents

Description

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

Since the 1950s, the research and development of antibiotics has made rapid progress. Along with this, 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 aggravation of deep fungal diseases caused by fungi such as Candida, Aspergillus and Cryptococcus have been found. These phenomena are associated with problems such as immunodeficiency caused by leukemia, malignant lymphoma or HIV infection, deterioration of immune function due to administration of anticancer drugs, or bacterial replacement phenomenon due to heavy 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-seated fungal diseases. For example, amphotericin B, which is one of the polyene macrolide drugs, has strong antifungal activity and is therefore effective in treating serious diseases. However, since this drug may cause side effects such as nephrotoxicity, safety problems have been pointed out (Non-Patent Document 1). Flucytosine, which is one of the fluoropyrimidine-based drugs, also has problems such as low safety and the presence of resistant bacteria.

Azole-based drugs are generally considered to have a wide safety margin and relatively few side effects. However, this drug has a narrow antifungal spectrum and exhibits a bacteriostatic mechanism of action, and therefore has low efficacy for serious diseases. It has also been pointed out that the number of resistant bacteria to the drug is increasing (Non-Patent Document 2).

In recent years, candy-based drugs such as micafungin and caspofungin have been developed and used for the treatment of deep-seated fungal diseases (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, the number of reported cases of resistant bacteria to the drug is gradually increasing.

Patent Document 1 describes 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 polyene macrolide agents and azole agents. Describe. This 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., Vol. 12, pp. 309-329, 1990 Rex et al., Antimicrob. Agents Chemothe., Vol. 39, pp. 1-8, 1995 Denning, Lancet, Vol. 362, No. 9330, pp. 1142-1151, 2003

In the case of blood diseases such as leukemia, or diseases associated with weakened immunity such as HIV infection, an easily infected state is induced. Therefore, in patients with such diseases, the frequency of fungal infections as opportunistic infections may increase. In addition, these diseases associated with weakened immunity usually tend to become more serious, so that the treatment period is often long. As a result, chemotherapy for fungal infections is often long-term.

Currently, there are some problems with antifungal drugs that are frequently used in the treatment of fungal infections such as deep fungal diseases. For example, amphotericin B, which is one of the polyene macrolide drugs, may cause side effects such as serious nephrotoxicity. Further, it is known that drug-resistant bacteria are extremely likely to occur in azole-based drugs. Therefore, in order to obtain a therapeutic effect on fungal infections while avoiding these problems, there is a need for means for reducing the dose and shortening of the administration period of the antifungal drug.

A compound having an action of enhancing the antifungal activity of an antifungal drug may reduce the dose of the antifungal drug and / or shorten the administration period. Therefore, by using a compound having such an action in combination with an antifungal drug, the dose of the antifungal drug is reduced and / or the administration period is shortened to suppress the occurrence of side effects such as nephrotoxicity. And / or the development of drug-resistant bacteria can be suppressed. As a compound having the above-mentioned action, an FKI-4981B substance and a pharmaceutically acceptable salt thereof are known (Patent Document 1). However, in order to develop a more effective pharmaceutical compound, a novel compound having an action of effectively enhancing the antifungal activity of an antifungal drug and having a skeletal structure different from that of a known pharmaceutical compound is required. Was there.

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 skeletal structure different from that of a known pharmaceutical compound.

The present inventors have studied various means for solving the above-mentioned problems. The present inventors have stated that a novel bacterium isolated from soil produces a compound in its culture solution that has an action of effectively enhancing the antifungal activity of amphotericin B, which is one of the polyene macrolide agents. I found it. The present inventors have found that the compound in the culture solution is a novel compound having a skeletal structure different from that of known pharmaceutical compounds. In addition, the present inventors have found that the compound can be produced by a culturing means using the bacterium. The present inventors have completed the present invention based on the above findings.

［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) Equation (I):

[During the ceremony,
n is an integer in the range 0-10
R ¹ , R ² , R ³ and R ⁴ are independent of each other, 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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or non-substituted Substituted acyl, substituted or unsubstituted acyloxy, carbonate, or carbamart.
R ⁵ and R ⁶ form a double bond between the carbons to which they bind, or they form a double bond.
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 arylalkoxyoxy, 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 different meanings.
R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, Substituted or unsubstituted cycloalkoxynyl, 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, Substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R ^N1 and R ^N2 are independent 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 aryl Alkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. ]
A compound represented by, or a salt thereof, or a solvate thereof.
(2) R ¹ , R ² , R ³ and R ⁴ are independently OH, substituted or unsubstituted sugar groups, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C ₃ ~ C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted. C _{7 to} C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C _{1 to} C ₅ alkyloxy, substituted or unsubstituted C _{1 to} C ₂₀ acyl, substituted or unsubstituted C _{1 to} C ₂₀ acyloxy, carbonate, or carbamart.
R ⁵ and R ⁶ form a double bond between the carbons to which they bind, or
R ⁵ is OH, substituted or unsubstituted sugar group, 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 heterocyclo. Alkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkenyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C _{1 to} C ₅ alkyloxy, substituted or unsubstituted C _{1 to} C ₂₀ acyl, substituted or unsubstituted C _{1 to} C ₂₀ Acyloxy, carbonate, or carbamart and
The compound according to embodiment (1), wherein R ^{6 is H.}
(3) R ¹ , R ² , R ³ and R ⁴ are independent of each other, OH, or formula (S-1) or (S-2) :.

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

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

It is a group represented by
R ⁴ is OH,
R ⁷ is OH, or;
(B) n is 0,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (S-2).
R ³ and R ⁴ are OH
R ⁷ is OH, or;
(C) n is 0,
R ¹ and R ² are the groups represented by the equation (S-1).
R ³ and R ⁴ are OH
R ⁷ is OH, or;
(D) n is 0,
R ¹ is the group expressed by the equation (S-1).
R ² , R ³ and R ⁴ are OH,
R ⁷ is OH, or;
(E) n is 1,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (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 the group expressed by the equation (S-2).
R ² , R ³ and R ⁴ are OH,
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH, or;
(G) n is 2,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (S-2).
R ³ and R ⁴ are OH
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH, or;
(H) n is 2,
R ¹ is the group expressed by the equation (S-1).
R ² , R ³ and R ⁴ are OH,
The first R ⁵ is the group expressed by the equation (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 bonded,
The compound according to any one of the above-described embodiments (1) to (3), wherein R ^{7 is OH.}
(5) The method for producing a compound according to any one of the above-described embodiments (1) to (4), a salt thereof, or a solvate thereof.
Pseudophyllofora spp. BF-0158 strain (NITE P- 02400) having the ability to produce the compound represented by the formula (I) or a microorganism thereof, which is a mutant strain thereof, is cultured in a medium and the formula (I) is used. 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;
The method described above.
(6) Pseudophyllofora spp. BF-0158 strain (NITE P -02400) or a Pseudophyllofora spp. The microorganism that is the mutant strain.
(7) A polyene macrolide-based drug, an azole-based drug, or a candine-based drug containing the compound according to any one of the above embodiments (1) to (4), a salt thereof, or a solvate thereof as an active ingredient. And an activity enhancer of at least one antifungal agent selected from the group consisting of fluoropyrimidine-based agents.
(8) A pharmaceutical agent containing the compound according to any one of the above-described embodiments (1) to (4), a salt thereof, or a solvate thereof as an active ingredient.
(9) The drug according to the above 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 polyene macrolide agents, azole agents, candy agents and fluoropyrimidine agents. The medicine described in.
(11) A pharmaceutical composition comprising the compound according to any one of 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 embodiment (11), which is used for 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 polyene macrolide agents, azole agents, candy agents and fluoropyrimidine agents. The pharmaceutical composition according to.

INDUSTRIAL APPLICABILITY 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 skeletal structure different from that of a known pharmaceutical compound.

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

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

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

As used herein, "alkenyl" means a group in which one or more CC single bonds of the alkyl are substituted with double bonds. Suitable alkenyls are, but are not limited to, for example vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 - methyl-2-propenyl, 1-methyl-1-propenyl, can be mentioned C ₂ -C ₅ alkenyl straight or branched chain, such as 2-methyl-1-propenyl and 1-pentenyl.

As used herein, "alkynyl" means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls are, but are not limited to, straight chains such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 1-pentynyl. Alternatively, the branched chain C _{2 to} C ₅ alkynyl can be mentioned.

As used herein, "cycloalkyl" means an alicyclic alkyl containing a specific number of carbon atoms. For example, "C _{3 to} 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 to} C ₆ cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, "cycloalkenyl" means a group in which one or more CC single bonds of the cycloalkyl are substituted with double bonds. Suitable cycloalkenyls include, but are not limited to, C _{4 to} C ₆ cycloalkenyls such as cyclobutenyl, cyclopentenyl and cyclohexenyl.

As used herein, "cycloalkynyl" means a group in which one or more CC single bonds of the cycloalkyl are substituted with triple bonds. Suitable cycloalkynyls include, but are not limited to, C _{4 to} C ₆ cycloalkynyls such as cyclobutynyl, cyclopentynyl and cyclohexynyl.

As used herein, "heterocycloalkyl" means that one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are independently selected from nitrogen (N), sulfur (S) and oxygen (O), respectively. Means a group substituted with one or more heteroatoms to be made. In this case, the substitution with N or S includes the substitution with N-oxide or S oxide or dioxide, respectively. Suitable heterocycloalkyls include, but are not limited to, 3 such as pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. ~ 6 members of heterocycloalkyl can be mentioned.

As used herein, "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 cycloalkylalkyls include, but are not limited to, C _{7 to} C ₁₁ cycloalkylalkyls such as cyclohexylmethyl and cyclohexenylmethyl.

As used herein, "heterocycloalkylalkyl" means a group in which one of the hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the heterocycloalkyl. Suitable heterocycloalkylalkyls include, but are not limited to, for example, 3- to 6-membered heterocycloalkyl-C _{1 to} C ₅ alkyls.

As used herein, "alkoxy" means a group in which the hydrogen atom of the hydroxyl is substituted with the alkyl, alkenyl or alkynyl. Suitable alkoxys include, but are not limited to, C _{1 to} C ₅ alkoxy such as methoxy, ethoxy, propoxy, butoxy and pentoxy.

As used herein, "cycloalkoxy" means a group in which the hydrogen atom of the hydroxyl is substituted with the cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkoxys include, but are not limited to, C _{3 to} C ₆ cycloalkoxys such as cyclopropoxy, cyclobutoxy and cyclopentoxy.

As used herein, "heterocycloalkoxy" means a group in which the hydrogen atom of the hydroxyl is substituted with the heterocycloalkyl. Suitable cycloalkoxys include, but are not limited to, 3-6 member heterocycloalkoxys, for example.

As used herein, "aryl" means an aromatic ring group. Suitable aryls include, but are not limited to, C _{6 to} C ₁₈ aryls such as phenyl, biphenyl, terphenyl, naphthyl and anthrasenyl.

As used herein, "arylalkyl" means a group in which one of the hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the aryl. _{Suitable arylalkyls include, but are not limited to, C 7 to} C ₂₀ arylalkyls such as benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, terphenylmethyl and styryl.

As used herein, "heteroaryl" means a group in which one or more carbon atoms of the aryl are independently substituted with one or more heteroatoms selected from N, S and O, respectively. In this case, the substitution with N or S includes the substitution with N-oxide or S oxide or dioxide, respectively. Suitable heteroaryls are, but are not limited to, for example, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridadinyl, pyrazinyl, 5 to 15 member heteroaryls such as pyrimidinyl, quinolinyl, isoquinolinyl and indolyl can be mentioned.

As used herein, "heteroarylalkyl" means a group in which one of the hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the heteroaryl. Preferred heteroarylalkyl include, but are not limited to, may be, for example, a 5-15 membered heteroaryl -C ₁ -C ₅ alkyl pyridylmethyl and the like.

As used herein, "aryloxy" means a group in which the hydrogen atom of the hydroxyl is substituted with the aryl. _{Suitable aryl oxys include, but are not limited to, C 6 to} C ₁₅ aryl oxys such as phenoxy, biphenyl oxy, naphthyl oxy and anthryloxy (anthrasenyl oxy).

As used herein, "arylalkyloxy" means a group in which the hydrogen atom of the hydroxyl is substituted with the arylalkyl. _{Suitable arylalkyloxys include, but are not limited to, C 7 to} C ₂₀ arylalkyloxys such as benzyloxy, 1-phenethyloxy, 2-phenethyloxy and styryloxy.

As used herein, "heteroaryloxy" means a group in which the hydrogen atom of the hydroxyl is substituted with the heteroaryl. Suitable heteroaryloxys are, but are not limited to, for example, furanyloxy, thienyloxy (thiopheneyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso. 5 to 15 of oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridadinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy, indolyloxy, etc. Heteroaryloxy of the members can be mentioned.

As used herein, "heteroarylalkyloxy" means a group in which the hydrogen atom of the 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.

As used herein, "acyl" means a group in which a monovalent group selected from the groups described above and a carbonyl are linked. Suitable acyl may include, but are not limited to, for example, formyl, C ₁ -C ₅ aliphatic acyl, and C ₁ -C ₂₀ acyl includes C ₇ -C ₁₂₀ aromatic acyl benzoyl such as acetyl and propionyl Can be mentioned.

As used herein, the term "glycosyl" means a monovalent group from which the hydrogen atom of one hydroxyl group of a monosaccharide, oligosaccharide or polysaccharide has been removed.

The groups described above can be independently unsubstituted or further substituted by one or more monovalent groups described above.

As used herein, "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 the formula (I) :.

The present invention relates to a compound represented by (1) or a salt thereof, or a solvate thereof.

The present inventors have stated that a novel fungus isolated from soil produces a compound in its culture solution that has an action of effectively enhancing the antifungal activity of amphotericin B, which is one of the polyene macrolide agents. I found it. The present inventors also referred to as novel compounds BF-0158A to H (hereinafter, "Compounds BF-0158" or simply "BF-0158") having an activity of enhancing the antifungal activity of amphotericin B in the culture solution. To be described) was found. Compounds BF-0158 can significantly enhance the antifungal activity of amphotericin B when administered in combination with amphotericin B, although they do not exhibit substantially antifungal activity when administered alone. The compound represented by the formula (I) of this embodiment includes natural organic compounds BF-0158 and related compounds thereof. Therefore, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal drug.

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

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 formula (I), R ¹ , R ² , R ³ and R ⁴ are independent of each other, OH, substituted or unsubstituted sugar group, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted. Alternatively, unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl. Alkoxyoxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, carbonate, or carbamate. R ¹ , R ² , R ³ and R ⁴ are OH, substituted or unsubstituted sugar groups, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C _{3 to} C _{6 independently of each other.} Cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkoxyoxy, 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 acyls, substituted or unsubstituted C _{1 to} C ₂₀ acyloxy, carbonate, or carbamate, preferably independent of each other, more preferably OH or substituted or unsubstituted sugar groups, independent of each other. , OH, or formula (S-1) or (S-2):

It is more preferable that the group is 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 drug. 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 an 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 arylalkoxyoxy, 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 an OH, substituted or unsubstituted sugar group, substituted or unsubstituted C _{1 to} C ₆ alkoxy, Substitutable or unsubstituted C _{3 to} C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6-membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ aryl Alkoxyoxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C _{1 to} C ₅ alkyl Oxy, substituted or unsubstituted C _{1 to} C ₂₀ acyl, substituted or unsubstituted C _{1 to} C ₂₀ acyloxy, carbonate, or carbide, and R ⁶ is preferably H, the carbon to which they are attached. It is more preferred that a double bond is formed between them, or R ⁵ is an OH or substituted or unsubstituted sugar group and R ⁶ is H, and two between the carbons to which they are attached. It is more preferred that a heavy bond is formed or R ⁵ is OH, or a group represented by the formula (S-1) or (S-2), and R ^{6 is H.} When R ⁵ and R ⁶ are the groups exemplified above, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal drug.

When there are a plurality of ^{R 5} and R ^{6 , each R 5} and R ⁶ may have different meanings. 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" R 5} and R ⁶ located on the terminal side of the carboxylic acid are sequentially referred to as "second R ⁵ " and "second R ⁶ ", "third R ⁵ " and "third R ⁶ " ... , Each may be described. ^{For example, when n is 2, R 5} and R ⁶ located on the fat 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 aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy Is. R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{2 to} C ₅ alkenyl, substituted or unsubstituted C _{2 to} C ₅ alkynyl, substituted. Alternatively, unsubstituted C _{3 to} C ₆ cycloalkyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkenyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocyclo. Alkyl, substituted or unsubstituted C _{7 to} C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3 to 6 member heterocycloalkyl-C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, substituted Or unsubstituted C _{7 to} C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl-C _{1 to} C ₅ alkyl, 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 to} C ₁₅ aryloxy, substituted or unsubstituted. C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkenyloxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl. -C _{1 to} C ₅ alkyloxy, or substituted or unsubstituted C _{1 to} C ₂₀ acyloxy, preferably 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted. Or unsubstituted C _{7 to} C ₂₀ arylalkenyloxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, or substituted or unsubstituted 5 to 15 membered heteroaryl-C _{1 to} C ₅ alkyloxy. More preferably, and even more preferably 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 drug.

In formula (I), R ^N1 and R ^N2 are independent 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 independent of each other, H, substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{2 to} C ₅ alkenyl, substituted or unsubstituted C _{2 to} C ₅ alkynyl, Substituted or unsubstituted C _{3 to} C ₆ cycloalkyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkenyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkynyl, substituted or unsubstituted 3 to 6 member hetero Cycloalkyl, substituted or unsubstituted C _{7 to} C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, _{May be} substituted or unsubstituted C _{7 to} C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, or substituted or unsubstituted 5 to 15 member heteroaryl-C _{1 to} C 5 alkyl. More preferably, they are H, substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{2 to} C ₅ alkenyl, or substituted or unsubstituted C _{2 to} C ₅ alkynyl, independently of each other. It is preferable, and it is more preferable that both are H. When ^RN1 and ^RN2 are the groups exemplified above, the compound represented by the formula (I) of this embodiment can effectively enhance the antifungal activity of the antifungal drug.

When the group is substituted in formula (I), the substituents are 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 non-substituted Select from the group consisting of substituted heteroarylalkyloxys, substituted or unsubstituted alkoxycarbonyls, substituted or unsubstituted cycloalkoxycarbonyls, substituted or unsubstituted acyls, substituted or unsubstituted acyloxys, and substituted or unsubstituted aminos. It is preferably at least one monovalent group to be, preferably halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C. _{2 to} C ₅ alkenyl, substituted or unsubstituted C _{2 to} C ₅ alkynyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkenyl, substituted or unsubstituted C _3- C ₆ cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C _7- C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, substituted or unsubstituted C _{7 to} C ₂₀ aryl alkyl, substituted or unsubstituted 5 to 15 member 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 to} C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C _{1 to} C ₅ alkyloxy, substituted or unsubstituted C _{1 to} C _{From 6} alkoxycarbonyls, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxycarbonyls, substituted or unsubstituted C _{1 to} C ₂₀ acyls, substituted or unsubstituted C _{1 to} C ₂₀ acyloxys, and substituted or unsubstituted aminos. More preferably, it is at least one monovalent group selected from the group consisting of hydroxyl, substituted or unsubstituted C _{1 to} C ₆ alkoxy, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxy, substituted or non-substituted. Substituent 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy , At least one monovalent group selected from the group consisting of substituted or unsubstituted 5- to 15-membered heteroaryl-C _{1 to} C ₅ alkyloxy and substituted or unsubstituted C _{1 to} C _{20 acyloxy.} It is even more preferable, and it is particularly preferable that it is hydroxyl. When the monovalent group is substituted, the substituent can be further selected from the monovalent group.

Preferably, the compound represented by the formula (I) is
n is an integer in the range 0-10
R ¹ , R ² , R ³ and R ⁴ are independently OH, substituted or unsubstituted sugar groups, 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkoxyoxy, 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 to} C ₂₀ acyloxy, carbonate, or carbamart.
R ⁵ and R ⁶ form a double bond between the carbons to which they are attached, or R ⁵ is an OH, substituted or unsubstituted sugar group, 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ aryl. Alkoxyoxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C _{1 to} C ₅ alkyl Oxy, substituted or unsubstituted C _{1 to} C ₂₀ acyl, substituted or unsubstituted C _{1 to} C ₂₀ acyloxy, carbonate, or carbide, and R ⁶ is H.
R ⁷ is H, OH, NR ^N1 R ^N2 , substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{2 to} C ₅ alkenyl, substituted or unsubstituted C _{2 to} C ₅ alkynyl, substituted. Alternatively, unsubstituted C _{3 to} C ₆ cycloalkyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxy, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxyyl, substituted or unsubstituted 3- to 6-membered heterocyclo. Alkoxy, substituted or unsubstituted C _{7 to} C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3 to 6 member heterocycloalkyl-C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, substituted Or unsubstituted C _{7 to} C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, substituted or unsubstituted 5 to 15 membered heteroaryl-C _{1 to} C ₅ alkyl, 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 to} C ₁₅ aryloxy, substituted or unsubstituted. C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl. -C _{1 to} C ₅ alkyloxy, or substituted or unsubstituted C _{1 to} C ₂₀ acyloxy.
R ^N1 and R ^N2 are independent of each other, H, substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{2 to} C ₅ alkenyl, substituted or unsubstituted C _{2 to} C ₅ alkynyl, Substituted or unsubstituted C _{3 to} C ₆ cycloalkyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkenyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkynyl, substituted or unsubstituted 3 to 6 member hetero Cycloalkyl, substituted or unsubstituted C _{7 to} C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, Substituted or unsubstituted C _{7 to} C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 membered heteroaryl, or substituted or unsubstituted 5 to 15 membered heteroaryl-C _{1 to} 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 to} C ₅ alkoxy, substituted or unsubstituted C _{2 to} C ₅ alkoxyyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxy, substituted or unsubstituted. Unsubstituted C _3- C ₆ cycloalkoxynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C _7- C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered hetero Cycloalkyl-C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, substituted or unsubstituted C _{7 to} C ₂₀ aryl alkyl, substituted or unsubstituted 5 to 15 member heteroaryl, substituted or Unsubstituted 5 to 15-membered heteroaryl-C _{1 to} C ₅ alkyl, 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or non-substituted. Substituted 5- to 15-membered heteroaryl-C _{1 to} C ₅ alkyloxy, substituted or unsubstituted C _{1 to} C ₆ alkoxycarbonyl, substituted or unsubstituted C _{3 to} C ₆ cycloalkoxycarbonyl, substituted or unsubstituted At least one monovalent group selected from the group consisting of _{C 1 to} C ₂₀ acyls, substituted or unsubstituted C _{1 to} C _{20 acyloxys, and substituted or unsubstituted aminos.}

More preferably, the compound represented by the formula (I) is
n is an integer in the range 0-5,
R ¹ , R ² , R ³ and R ⁴ are OH or substituted or unsubstituted sugar groups independently of each other.
R ⁵ and R ⁶ form a double bond between the carbons to which they bind, or
R ⁵ is an OH or 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 members. Heteroaryloxy, or substituted or unsubstituted 5- to 15-membered heteroaryl-C _{1 to} C ₅ alkyloxy.
R ^N1 and R ^N2 are independent of each other, H, substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{2 to} C ₅ alkenyl, or substituted or unsubstituted C _{2 to} C ₅ alkynyl. And
When the groups are substituted, the substituents are independently hydroxyl, 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, At least one monovalent group selected from the group consisting of substituted or unsubstituted 5- to 15-membered heteroaryl-C _{1 to} C ₅ alkyloxy and substituted or unsubstituted C _{1 to} C _{20 acyloxy.}

More preferably, the compound represented by the formula (I) is
n is 0, 1 or 2,
R ¹ , R ² , R ³ and R ⁴ are independent groups of 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 an OH, or a group of 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 members. Heteroaryloxy, or substituted or unsubstituted 5- to 15-membered heteroaryl-C _{1 to} C ₅ alkyloxy.
R ^N1 and R ^N2 are independent of each other, H, substituted or unsubstituted C _{1 to} C ₅ alkyl, substituted or unsubstituted C _{2 to} C ₅ alkenyl, or substituted or unsubstituted C _{2 to} C ₅ alkynyl. And
When the groups are substituted, the substituents are independently hydroxyl, 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 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, At least one monovalent group selected from the group consisting of substituted or unsubstituted 5- to 15-membered heteroaryl-C _{1 to} C ₅ alkyloxy and substituted or unsubstituted C _{1 to} C _{20 acyloxy.}

Particularly preferably, the compound represented by the formula (I) is
(A) n is 0,
R ¹ and R ² are the groups represented by the equation (S-1).
R ³ is the group expressed by the equation (S-2).
R ⁴ is OH,
R ⁷ is OH, or;
(B) n is 0,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (S-2).
R ³ and R ⁴ are OH
R ⁷ is OH, or;
(C) n is 0,
R ¹ and R ² are the groups represented by the equation (S-1).
R ³ and R ⁴ are OH
R ⁷ is OH, or;
(D) n is 0,
R ¹ is the group expressed by the equation (S-1).
R ² , R ³ and R ⁴ are OH,
R ⁷ is OH, or;
(E) n is 1,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (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 the group expressed by the equation (S-2).
R ² , R ³ and R ⁴ are OH,
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH, or;
(G) n is 2,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (S-2).
R ³ and R ⁴ are OH
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH, or;
(H) n is 2,
R ¹ is the group expressed by the equation (S-1).
R ² , R ³ and R ⁴ are OH,
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH.

Particularly preferable compounds represented by the formula (I) are as follows:
17-Hydroxy-5,9-O-Dideoxyhexosyl-13-O-Hexosyl-2,4,6,8,10,12,14,16,18-Nonamethylicossa-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-Nonamethylicossa-2,6,10,14-Tetraenoic acid (BF- 0158C);
9,13,17-Trihydroxy-5-O-deoxyhexosyl-2,4,6,8,10,12,14,16,18-Nonamethylicossa-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 Kosa-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 drug.

The compound represented by the formula (I) of one aspect of the present invention includes not only the compound itself but also a salt thereof. The salt of the compound represented by the formula (I) of one aspect of the present invention is not limited, but is, for example, sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion. Salts with cations such as, 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. Methylene salicylic 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, glutamate acid, benzenesulfonic acid , Cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid or salts with organic acid anions such as naphthalenesulfonic acid are preferred. When the compound represented by the formula (I) is in the form of the salt, the antifungal activity of the antifungal drug can be effectively enhanced.

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

The compound represented by the formula (I) in one aspect of the present invention includes not only the compound itself but also a protected form thereof. As used herein, "protected form" means a form in which a protecting group is introduced into one or more functional groups (eg, a hydroxyl group or a carboxylic acid group). In the present specification, the protected form of the compound represented by each of the above formulas may be described as a protected derivative of the compound represented by each of the above formulas. Further, in the present specification, the "protecting group" is a group introduced into a specific functional group in order to prevent the undesired progress of the reaction, and is quantitatively removed under the specific reaction conditions, and the same. It means a group that is substantially stable under the reaction conditions other than the above, that is, the reaction is inactive. The protecting group capable of forming the protected form of the compound is not limited, and for example, in the case of a hydroxyl group protecting group, silyl (for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS)). Alternatively, if tert-butyldiphenylsilyl (TBDPS)), or alkoxy (eg, methoxymethoxy (MOM) or methoxy (Me)) is the protecting group for the carboxylic acid group, an alkyl ester (eg, methyl, ethyl or isopropyl ester), Arylalkyl esters (eg, benzyl esters) or amides (eg, amides with oxazolidinones) are preferred, respectively. Protection and deprotection with the protecting group can be appropriately carried out by those skilled in the art based on known reaction conditions. Even when the compound represented by the formula (I) in one aspect of the present invention is in the form of protection by the above-mentioned protecting group, it may be possible to effectively enhance the antifungal activity of the antifungal drug. ..

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

Further, when the compound represented by the formula (I) of one aspect of the present invention has one or more stereocenters (chiral centers), the compound is an individual enantiomer and diastereomer of the compound, and a racemate. Also includes mixtures thereof such as.

By having the above-mentioned characteristics, the compound represented by the formula (I) of one aspect of the present invention can effectively enhance the antifungal activity of the antifungal drug.

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

In this aspect, the method of the present invention comprises 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 is a microorganism of the genus Pseudophialophora BF-0158 strain (NITE P- 02400) having the ability to produce a compound represented by the formula (I) or a microorganism thereof. Is cultured in a medium, and the compound represented by the formula (I) is accumulated in the medium, which comprises a compound accumulation step.

The Pseudophyllofora genus BF-0158 strain is a novel fungus belonging to the genus Pseudophyllofora 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 Microorganisms Depositary (NITE P- 02400).

In this step, the microorganism used for culturing is preferably the Pseudophyllofora genus BF-0158 strain or a mutant strain thereof, which has the ability to produce the compound represented by the formula (I), and is preferably the Pseudophyllofora genus. Bacterial BF-0158 strain is more preferable. In the present invention, the mutant strain of Pseudophyllofora genus BF-0158 means a natural mutant strain or an artificial mutant strain of Pseudophyllofora genus BF-0158 strain. The artificial mutant strain of Pseudophyllofora genus BF-0158 can be obtained by any means for producing an artificial mutant strain usually used in the art. Not only the Pseudophyllofora genus BF-0158 strain itself, but also a mutant strain of the Pseudophyllofora genus BF-0158 strain as long as it is a microorganism capable of producing the compound represented by the formula (I). , The compound represented by the formula (I) can be accumulated in the medium in this step. Therefore, by using the above-mentioned microorganism, a large amount of the compound represented by the formula (I) can be accumulated in the medium.

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 and fats such as soybean oil. Examples of the nitrogen source include polypeptone, yeast extract, malt extract, meat extract, soybean flour, cottonseed flour, corn Steve liquor, casein, amino acids, urea, ammonium salts and nitrates. 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 salts such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid. Salts with acid anions can be mentioned. The medium used in this step is, for example, potato dextrose agar (PDA) medium (Becton, Dickinson and Company), seed medium (glucose 2.0%, polypeptone 0.5%, yeast extract 0.2%). , Magnesium sulphate heptahydrate 0.05%, potassium dihydrogen phosphate 0.1%, and agar 0.1%, pH 6.0), or production medium (scurose 2.0%, trace metal (iron sulphate heptahydrate 0.1%, manganese chloride tetra) Hydrate 0.1%, Zinc Sulfate Hexahydrate 0.1%, Copper Sulfate Hexohydrate 0.1%, and Cobalt Chloride Hexahydrate 0.1%) 1.0%, Glucose 1.0%, Sollis 0.5%, Katsuo Extract 0.5%, Calcium carbonate 0.3%, magnesium sulfate heptahydrate 0.1%, potassium dihydrogen phosphate 0.1%, and agar 0.1%, pH 6.5) are preferable. Represented by the formula (I) by culturing a microorganism of the genus Pseudophyllofora BF-0158 or a mutant strain thereof having the ability to produce the compound represented by the formula (I) in the medium. The compound can be accumulated in the medium.

The culture of the microorganism may be either a solid culture or a liquid culture. When culturing the microorganism on a large scale, liquid culture is preferable. In this case, it is preferable to aerate the medium by shaking the culture vessel, stirring the 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 sterilizing means such as a sterilizing 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 cultivated in a small amount of medium in advance (hereinafter, also referred to as "seed culture"), and then the culture obtained by the seed culture is planted in a large volume medium. It is preferable to culture the cells (hereinafter, also referred to as "production culture"). In this case, the components of the medium used for the seed culture and the production culture may be the same or different. By carrying out this step by a plurality of stages of culture including seed culture and production culture, it is possible to substantially suppress the delay in the growth of microorganisms.

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 5.5-6.5, typically pH 6.0. The culture period is usually 1 to 3 weeks, typically 7 to 10 days, as a total of seed culture and production culture when the liquid medium is shake-cultured. 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 aspect, the method of the present invention is required 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 microorganisms, a method for separating an organic compound usually used in the art 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 types of chromatography. Preferably, this step is a step of separating cells from the culture of microorganisms obtained in the compound accumulation step by filtration, centrifugation or the like, a step of extracting the separated cells with a water-miscible organic solvent such as acetone, and the like. And, the cell extract extracted with a water-miscible organic solvent is further separated by a means such as solvent extraction or preparative chromatography to obtain a compound represented by the formula (I). As the preparative chromatography, various chromatographies such as adsorption, normal phase or reverse phase partitioning, and 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 of the above steps may be repeated a plurality of times under the same or different conditions, if desired. By using the above means, the compound represented by the formula (I) can be purified and isolated from the culture of microorganisms.

In the method for producing a compound of the present invention by the culturing 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 the compound BF-0158 produced by the Pseudophyllofora genus 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.

By the method for producing a compound of the present invention by the culturing means of the present invention having the above characteristics, a compound represented by the formula (I) of one aspect of the present invention which can be an active ingredient of a medicine can be produced with high purity and low cost. Can be provided in large quantities.

Another aspect of the present invention is Pseudophyllofora spp. BF-0158 strain (NITE P- 02400) or a mutant strain thereof having the ability to produce the compound represented by the formula (I) of the present invention. Regarding 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 aspect of the present invention has an activity of enhancing the antifungal activity of the antifungal drug. Therefore, another aspect of the present invention is at least one antifungal agent containing the compound represented by the formula (I) of the present invention or a salt thereof, or a solvate thereof as an active ingredient. Regarding the activity enhancer of. Further, another aspect of the present invention relates to a pharmaceutical substance containing the compound represented by the formula (I) of one aspect of the present invention, a salt thereof, or a solvate thereof as an active ingredient.

In each aspect of the present invention, at least one antifungal agent is selected from the group consisting of polyene macrolide agents, azole agents, canin agents and fluoropyrimidine agents. The at least one antifungal agent is preferably a polyene macrolide agent. The polyene macrolide agent is preferably amphotericin B, pimalysin, nystatin or natamycin, and more preferably amphotericin B. The azole agent is preferably an imidazole compound such as miconazole, or a triazole compound such as fluconazole, itraconazole, phosphofluconazole or voriconazole. The candy-based drug is preferably micafungin or caspofungin. The fluoropyrimidine-based drug is preferably flucytosine. Amphotericin B, a polyene macrolide drug, has high antifungal activity and is useful for the treatment of serious fungal infections, but may show side effects such as nephrotoxicity. The compound represented by the formula (I) of one aspect of the present invention has an activity of enhancing the antifungal activity of antifungal agents such as polyene macrolide agents, azole agents, candin agents and fluoropyrimidine agents. Have. Therefore, the compound represented by the formula (I) of one aspect of the present invention is at least one antifungal selected from the group consisting of polyene macrolide agents, azole agents, canin agents and fluoropyrimidine agents. When administered with a fungal drug, the dose of antifungal drug that may have side effects can be reduced and / or the duration of administration can be shortened. This can substantially reduce the occurrence of side effects due to at least one antifungal drug.

In each aspect of the invention, "administering together" means administering a plurality of agents simultaneously or separately (eg, sequentially at regular intervals). In the present specification, such an administration form may be referred to as "combination administration". By co-administering the compound represented by the formula (I) of one aspect of the present invention and at least one antifungal drug, the dose of the antifungal drug which may have side effects is reduced and / or administered. The period can be shortened. This can substantially reduce the occurrence of side effects due to at least one antifungal drug.

The compound represented by the formula (I) of one aspect of the present invention has an activity of enhancing the antifungal activity of at least one antifungal drug. On the other hand, the compound represented by the formula (I) of one aspect of the present invention may or may not have antifungal activity by itself. The compound represented by the formula (I) in one aspect of the present invention usually does not have substantially antifungal activity by itself. The compound represented by the formula (I) of one aspect of the present invention enhances the antifungal activity of at least one antifungal agent even when it does not have substantially antifungal activity by itself. Due to its activity, the combined administration with at least one antifungal agent can reduce the dose of the antifungal agent which may have side effects and / or shorten the administration period. This can substantially reduce the occurrence of side effects due to at least one antifungal drug.

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

The activity of the compound represented by the formula (I) of one aspect of the present invention for enhancing the antifungal activity of at least one antifungal agent is not limited, but is determined by, for example, the following means. Can be done. Based on the above means, the MIC value when at least one antifungal drug is administered alone is determined. Then, under the same test conditions, the compound represented by the formula (I) and at least one antifungal agent are administered together (for example, simultaneously) with the compound represented by the formula (I) and at least one kind. Determine the MIC value for concomitant administration 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 the formula (I) of one aspect of the present invention is calculated. For example, when the enhancement rate is doubled, the MIC value of at least one antifungal drug at the time of combined administration of the compound represented by the formula (I) of one aspect of the present invention is the MIC value at the time of single administration of the antifungal drug. It becomes 1/2 of the MIC value of. Based on the enhancement rate thus determined, the activity of the compound represented by the formula (I) of one aspect of the present invention to enhance the antifungal activity of at least one antifungal agent can be evaluated. ..

In this embodiment, at least one antifungal agent administered in combination with the compound represented by the formula (I) of one aspect of the present invention has a MIC value determined by the above procedure of a yeast fungus (eg, Candida). -Albicans), usually 0.5 μg / mL. In this case, the compound represented by the formula (I) of one aspect of the present invention is usually at least one antifungal 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. When administered in combination with a fungal drug, it enhances the antifungal activity of at least one antifungal drug, usually in the range of 2-fold or more, for example 2-32-fold, especially 4-32-fold. Can be done. Therefore, when the enhancement rate is in the above range, the compound represented by the formula (I) in one aspect of the present invention may have side effects when administered in combination with at least one antifungal agent. The dose of the drug can be reduced and / or the duration of administration can be shortened. This can substantially reduce the occurrence of side effects due to at least one antifungal drug.

When the compound represented by the formula (I) of one aspect of the present invention is applied to 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 their pharmaceutically acceptable solvates. The pharmaceutically acceptable salt of the compound represented by the formula (I) in one aspect of the present invention and the pharmaceutically acceptable solvate thereof are not limited, but are exemplified above. Salts or solvates are preferred. When the compound represented by the formula (I) is in the form of the salt or solvate, the compound can be obtained without substantially reducing the activity of enhancing the antifungal activity of at least one antifungal agent. It can be applied to desired pharmaceutical applications.

When the compound represented by the formula (I) of one aspect of the present invention is applied to pharmaceutical use, the compound represented by the formula (I) includes not only the compound itself but also the prodrug form of the compound. .. As used herein, "prodrug" means a compound that is converted to a parent drug in vivo. The prodrug form of the compound is not limited, but 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, or the like can be used. Can be mentioned. When the compound represented by the formula (I) of one aspect of the present invention is in the above-mentioned prodrug form, the antifungal of at least one antifungal drug of the compound represented by the formula (I) which is the parent drug. The pharmacokinetics of a subject upon administration of the prodrug form can be improved without substantially reducing the activity that enhances the activity.

When the compound represented by the formula (I) of one aspect of the present invention is applied to pharmaceutical use, the compound may be used alone or in combination with one or more pharmaceutically acceptable ingredients. May be good. The pharmaceuticals of the present invention can be formulated into various dosage forms commonly used in the art, depending on the desired method of administration. Therefore, the pharmaceutical of this embodiment also comprises a compound represented by the formula (I) of one aspect 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 (eg, a solvent such as sterile water or a solution such as saline), an excipient, a binder, and the like. Vehicles, solubilizers, preservatives, stabilizers, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners and It may contain a flavoring agent or the like.

The dosage form of a pharmaceutical product containing the compound represented by the formula (I) of one aspect of the present invention, 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 it may be a preparation for use in oral administration. In addition, the dosage form of the pharmaceutical product of this embodiment may be a unit-dose form or a plurality of dosage forms. Examples of the pharmaceutical product for use in parenteral administration include an injection such as a sterile solution or suspension with water or other pharmaceutically acceptable medium. Ingredients that can be mixed with the injection include, but are not limited to, for example, physiological saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol, D-mannose or sodium chloride). Vehicles such as isotonic solutions containing, solubilizers 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, benzalconium chloride or prokine hydrochloride. Sodium chloride agents, stabilizers such as human serum albumin or polyethylene glycol, preservatives, antioxidants and the like can be mentioned. The prepared injection is usually filled in a suitable vial (eg, ampoule) and stored in a suitable environment until use.

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

The components that can be mixed with tablets, capsules, etc. are not limited, but are, for example, water, ethanol, propanol, simple syrup, glucose solution, carboxymethyl cellulose, cellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like. Binding agents such as gelatin, corn starch, tragant gum or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or stearic acid; dried starch, sodium alginate , Agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch or disintegrant such as lactose; sucrose, stear cocoa butter or hydrogenated oil. Disintegration inhibitors; Absorption enhancers such as quaternary ammonium salts or sodium lauryl sulfate; Moisturizers such as glycerin or starch; Adsorbents such as starch, lactose, kaolin, bentonite or colloidal stearic acid; Purified talc, Lubricators such as stearate (eg magnesium stearate), starch borate or polyethylene glycol; sweeteners such as sucrose, lactose or saccharin; and flavoring agents such as peppermint, reddish oil or cherry. Can be done. When the pharmaceutical product is a capsule, it may further contain a liquid carrier such as fat or oil.

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

When the compound represented by the formula (I) of one aspect of the present invention is applied to pharmaceutical use, the compound may be provided together with at least one antifungal agent or may be provided separately. .. Both cases are included in the embodiments of this embodiment. In the case of an embodiment further comprising at least one antifungal agent in addition to the compound represented by the formula (I) of one aspect of the present invention, that is, represented by the formula (I) of one aspect of the present invention. In the case of an embodiment in which the compound and at least one antifungal agent are provided together, the medicine of this embodiment is a compound represented by the formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof. It can be in the form of a pharmaceutical composition comprising a combination of the compound and at least one antifungal agent. In the case of the present embodiment, the pharmaceutical product of this embodiment is, for example, a compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof which is pharmaceutically acceptable. Can be provided in the form of a single formulation, which comprises at least one antifungal agent. When the compound represented by the formula (I) of one aspect of the present invention is provided separately from at least one antifungal agent, the drug of the present embodiment is the formula (I) of the present invention. It can be in the form of a pharmaceutical composition used in combination with at least one antifungal agent, which comprises at least a compound represented by the above, a salt thereof, or a solvate thereof. In the case of the present embodiment, the pharmaceutical product of the present embodiment comprises, for example, a compound represented by the formula (I) 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 containing a plurality of separately formulated formulations. In the case of a pharmaceutical combination or in the form of a kit, the respective formulations can be administered simultaneously or separately (eg, sequentially). Alternatively, the pharmaceutical product of this embodiment contains only the compound represented by the formula (I) of one aspect of the present invention or a salt thereof, or a solvate thereof (that is, does not contain at least one antifungal agent). It can also be provided in the form of a formulation. In any of the embodiments, 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.

A pharmaceutical product containing the compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a 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 that are useful as other drugs. In this case, the pharmaceutical product of this embodiment is one or more of the compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. It is in the form of a concomitant drug containing the other drug. The concomitant drug is a compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof which is pharmaceutically acceptable, and one or more of the other drugs. It may be in the form of a pharmaceutical composition comprising a combination of the above, a compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof. It may be in the form of a pharmaceutical composition used in combination with one or more of the above-mentioned other drugs, including a compound. When the pharmaceutical product of this embodiment is in the form of a concomitant pharmaceutical product as described above, the compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof. It may be provided in the form of a single preparation containing a Japanese product and one or more other drugs, or a pharmaceutical combination containing a plurality of preparations in which one or more other drugs are separately formulated. It may be provided in the form of a kit. In the case of a pharmaceutical combination or in the form of a kit, the respective formulations can be administered simultaneously or separately (eg, sequentially).

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

A drug containing the compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is a fungal infection of one or more of the above. It can be applied to various subjects in need of prevention or treatment of symptoms, diseases and / or disorders that are symptom. The subject may be a human or non-human mammal (eg, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, cloak or chimpanzee), or a reptile (eg, a reptile). It is preferably a subject or patient such as a poikilotherm (a warm-blooded animal such as a frog, a snake or a lizard). By administering the drug of this embodiment to the subject, various diseases, symptoms and / or disorders which 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 manifestation) of symptoms, diseases and / or disorders. Also, as used herein, "treatment" means suppressing (eg, suppressing progression), ameliorating, repairing and / or curing symptoms, diseases and / or disorders that have occurred (onset or manifestation).

The compound represented by the formula (I) of one aspect of the present invention is a symptom, a disease and / or a disorder (for example, deep fungal disease, superficial fungal disease) which is one or more fungal infections described above. Or it can be used for the prevention or treatment of the symptoms, diseases and / or disorders in subjects with (or dermatofungal disease). Therefore, the medicine of this embodiment is preferably a medicine for use in the prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections described above, and is a deep fungal disease. It is more preferable that it is a medicine for use in the prevention or treatment of one or more fungal infections selected from the group consisting of superficial fungal diseases and dermatophytosis. By using the drug of this embodiment for the prevention or treatment of the symptoms, diseases and / or disorders of the one or more fungal infections, at least the compound represented by the formula (I) of one aspect of the present invention. The symptoms, diseases and / or disorders 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 aspect of the present invention is a symptom, a disease and / or a disorder (for example, deep fungal disease, superficial fungal disease) which is one or more fungal infections described above. Or it can be used for the prevention or treatment of the symptoms, diseases and / or disorders in subjects with (or dermatofungal disease). Therefore, another aspect of the invention is an effective amount of a formula of the invention for a subject in need of prevention or treatment of the symptoms, diseases and / or disorders of one or more fungal infections described above. The disease or symptom comprising administering the compound represented by (I), 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 for. The symptom, disease and / or disorder of one or more fungal infections shall be one or more diseases or symptoms selected from the group consisting of deep fungal disease, superficial fungal disease and dermatomynomy disease. Is preferable. At least one antifungal compound represented by the formula (I) of one aspect of the present invention is used for a subject in need of prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections. The symptom, disease, through the activity of the compound represented by the formula (I) of one aspect of the present invention, which enhances the antifungal activity of at least one antifungal agent, when administered together with the fungal agent. And / or the disorder can be prevented or treated.

Another aspect of the invention is the formula (I) of one aspect of the invention for use in the prevention or treatment of symptoms, diseases and / or disorders of one or more fungal infections described above. The compound represented or a pharmaceutically acceptable salt thereof, or a solvate thereof which is pharmaceutically acceptable. Another aspect of the invention is one aspect of the invention for the manufacture of a pharmaceutical for use in the prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections described above. Use of a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The symptom, disease and / or disorder of one or more fungal infections shall be one or more diseases or symptoms selected from the group consisting of deep fungal disease, superficial fungal disease and dermatomynomy disease. Is preferable. 1. The symptoms, diseases and / or disorders can be prevented or treated through the activity of the compound represented by the embodiment (I) to enhance the antifungal activity of at least one antifungal agent.

A drug containing the compound represented by the formula (I) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is administered to a subject, particularly a human patient. If so, the exact dose and dosage (eg, dose, frequency and / or route of administration) will be the age, gender, symptoms, disease and / or exact condition of the disorder to be prevented or treated (eg, severe). Degree), and many factors such as the route of administration, and the doctor in charge should make the final decision in consideration of the therapeutically effective dose, number of doses, route of administration, and the like. Therefore, in the pharmaceutical of this embodiment, the compound represented by the formula (I), which is the active ingredient, is administered to the subject in a therapeutically effective amount and frequency. For example, when the drug of this embodiment is administered to a human patient, the dose of the compound represented by the formula (I), which is the active ingredient, is usually in the range of 0.001 to 100 mg / kg body weight per single dose. Yes, typically in the range of 0.01-10 mg / kg body weight per dose, especially in the range of 0.1-10 mg / kg body weight per dose. In addition, the number of administrations of the drug of this embodiment can be, for example, once or more than once a day, or once every few days. The route of administration of the drug of this embodiment is not particularly limited and may be administered orally, or parenterally (for example, intrarectal, intravitreal mucosa, intestinal, intramuscular, subcutaneous, intramedullary, intrasheath). , Direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal or intraocular) may be administered single or multiple times. By using the medicine of this embodiment in the above-mentioned dose and usage, the activity of enhancing the antifungal activity of at least one antifungal agent of the compound represented by the formula (I) of one aspect of the present invention can be obtained. Through, the symptoms, diseases and / or disorders of the one or more fungal infections can be prevented or treated.

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

<I. Production of new compounds by culturing means>
[reagent]
Glycerol and calcium carbonate were purchased from Kanto Chemical Co., Inc. Agar was purchased from Shimizu Foods Co., Ltd. Glucose, sucrose, potassium dihydrogen phosphate, polypeptone, magnesium sulfate heptahydrate, iron sulfate heptahydrate, manganese chloride tetrahydrate, zinc sulfate heptahydrate, copper sulfate pentahydrate and cobalt chloride 6 The hydrate was purchased from Wako Pure Chemical Industries, Ltd. Sollis was purchased from Oriental Yeast Co., Ltd. Skipjack extract was purchased from Far East Pharmaceutical Industry 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]
For the rotary shaking incubator (rotary shaker), TXY-25R-3FS manufactured by Takasaki Scientific Instruments Co., Ltd. was used. The Jar fermentor MBF from EYELA was used as the Jar fan mentor. HORIBA's LAQUA twin S010 was used as the pH meter. The H-700R of Kokusan Co., Ltd. was used as the cooling centrifuge. US-106 of 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)

Hitachi Koki's himac CR21F was used as the high-speed cooling centrifuge, and RPR-9-2 was used as its rotor. EYELA's NNR was used for the rotary evaporator. SLI-1200 from EYELA was used for the constant temperature bath. 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 (SEKONIC CORPORATION)

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

[Culture medium]
As the storage medium, a potato dextrose agar (PDA) medium was used. 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 seed culture. For production culture, production medium (sulose 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%, bonito 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]
The BF-0158 strain is a fungus isolated from the soil of Shodoshima, Kagawa Prefecture, Japan. Based on the morphological characteristics, culture properties and physiological properties of the BF-0158 strain, comparison with known bacterial species was performed. As a result, it was clarified 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 Microorganisms Depositary (NITE P- 02400). The mycological properties of the 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 PDA medium. When the colonies grown on PDA medium at 27 ° C and aerobic conditions for 2 weeks were observed under a microscope, the vegetative hyphae had septa, the surface was brown to colorless, and smooth and irregular branching. Was observed, and a shape with a partial bulge was observed.

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

3. BLAST homology search for DB-FU 10.0 and international sequence database
The 28S rDNA-D1D2 base sequence consists of Pseudophialophora magnispora (Pseudophialophora magnispora) CM14RG38-1T (Axon No .: KP7698727) and P. eragrostis (P. eragrostis) CM12M9T (Axon). The nucleotide sequence of No .: KF689638) and the homology rate of 99.8% were shown. In addition, the ITS-5.8 rDNA base sequence showed a homology rate of 98.8% with the base sequence of P. whatonensis WSF14RG66-1 (accession number: KP769834), which is a type of ascomycete. 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 temperature 27 ° C. The growth conditions of this strain were aerobic conditions, static culture, pH 3 to 10, temperature range of 10 to 30 ° C, and culture period of 1 to 3 weeks.

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

[Production Example I-2: Purification of a novel compound from the culture solution of the BF-0158 strain]
1.0 L of the production culture solution obtained by 68 hours of production culture was centrifuged at 8,000 rpm for 15 minutes to separate into supernatants and cells. The cells were extracted by adding the same amount of acetone as the supernatant. Bacteria were removed by suction filtration to obtain an acetone extract. Acetone was distilled off from the extract, and the obtained aqueous layer was adjusted to pH 3 with 2 M hydrochloric acid. To this aqueous layer, an equal amount of ethyl acetate (200 mL x 2 times) was added and solvent extraction was performed. Anhydrous sodium sulfate was added to the obtained ethyl acetate layer for dehydration. Then, 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, HPLC (column: CAPCELL PAK C18 MGII (20 x 250 mm), mobile _{phase: 70% CH 3 CN / 0.05} % H 3 PO 4 0~40 minutes isocratic conditions, flow rate: 8 mL / min, Purified using detection wavelength: UV 210 nm, column temperature: 25 ° C, and the following retention times (A: 14 minutes, B: 16 minutes, C: 19 minutes, D: 20 minutes, E: 22 minutes, F. The fraction containing the peak detected at: 31 minutes, G: 33 minutes, H: 36 minutes) was repeatedly fractionated. _{After distilling off CH 3} CN of the obtained fraction under reduced pressure, ethyl acetate (50 mL x 2 times) was added to the remaining aqueous layer (50 mL) for extraction. Anhydrous sodium sulfate was added to the obtained ethyl acetate layer for dehydration, and the mixture was concentrated to dryness under reduced pressure to form isolated compounds such as BF-0158 (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) were obtained.

BF-0158A to 17-hydroxy-5,9-O-dideoxy based on instrumental analysis results by specific luminosity, UV absorption spectrum, high resolution ESI-MS, IR spectrum, ¹ H-NMR, and ^{13 C-NMR.} Xosyl-13-O-Hexosyl-2,4,6,8,10,12,14,16,18-Nonamethylicossa-2,6,10,14-Tetraenoic acid and BF-0158B 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-nonamethylicossa-2,6,10,14-tetraenoic acid , BF-0158D 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 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 13,17,21-trihydroxy-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 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 13,17,21-trihydroxy-5,9-O-dideoxyhexosyl-2,4,6,8,10,12,14,16,18, The structures of 20,22-undecamethyltetracosa-2,6,10,14,18-pentaenoic acid were determined respectively.

[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 equation: 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: 825.4569 [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 of the following formula: 663.4084 [M + Na] ⁺ , Measured 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 of the following formula: 883.5031 [M + Na] ⁺ , Measured 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 equation: 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 test of new compound>
[reagent]
RPMI 1640 powder medium was purchased from GIBCO. 3-Morpholine propanesulfonic 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]
For the vortex mixer, an automatic mixer manufactured by YAZAWA was used. A Bio Tek Power Wave x340 was used to measure the absorbance. As a plate mixer, NS-4P manufactured by AS ONE Corporation was used. N-Biotek's NB-203 was used as the incubator for the 96-well plate (As One). Olympus CK2 was used as the microscope. A 150 mm bottle top filter (hole diameter 0.22 mm), a 15 mL centrifuge tube and a 50 mL centrifuge tube were purchased from Corning.

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

[Preparation of reagents]
Amphotericin B was prepared in 0.8 mg / mL DMSO solution. Compounds BF-0158 were prepared in a 1.6 mg / mL DMSO solution. Both solutions were stored at -20 ° C after preparation. Saline (0.85% aqueous sodium chloride solution) and bamboo skewers were sterilized by high-pressure steam (121 ° C, 15 minutes), and then stored at room temperature.

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

[Test II-1: Activity evaluation test of antifungal active substance]
[Preparation of bacterial solution]
The method for preparing the inoculated bacterial solution of yeast fungi (Candida albicans, Candida parapsillosis, Candida grabulata and Cryptococcus neoformans) is shown below. 5 mL of 0.85% sterile saline was measured in a sterile 15 mL centrifuge tube (Corning). Using a sterilized bamboo skewer, 5 colonies (about 1 mm in diameter) of each test bacterium were collected and suspended in the measured sterile 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 then OD ₅₅₀ was measured. The suspension was diluted to 0.5 McFarland (OD _{550 = 0.0548) with 0.85% sterile saline.} The resulting suspension was diluted 100-fold 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 solution.

The method for preparing the inoculum of filamentous fungi (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger and Aspergillus tereus) and zygomycetes (Resopas oryzae, Resopas microspores and Resomcol psilas) is shown below. 2 mL of 0.85% sterile saline was measured in a sterile 15 mL centrifuge tube. The spores of each test bacterium were scraped off with a platinum loop and suspended in the measured sterile saline solution. This was allowed to stand for 5 minutes. 100 μL of this suspension was dispensed into a sterile 96-well plate and then OD ₅₅₀ was measured. With 0.85% sterile saline, filamentous fungi OD ₅₅₀ = 0.0621, as Zygomycetes becomes OD ₅₅₀ = 0.0765, and diluting the suspension. The resulting suspension was diluted 50-fold with RPMI 1640 medium. The obtained diluted solution was used as an inoculum solution.

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

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

As a result of this test, compounds BF-0158A and B were added to Candida albicans at a concentration of 512 μg / mL or less, and to Cryptococcus neoformans, Aspergillus fumigatus and Risopath oryzae at a concentration of 128 μg / mL or less. , Each did not show growth inhibitory activity. Compounds BF-0158C, D, E, F, G and H showed no growth inhibitory activity against Candida albicans at concentrations of 8 μg / mL or less.

[Test II-2: Evaluation test of enhancing activity against the antifungal agent amphotericin B]
[Preparation of bacterial solution]
The Candida albicans ATCC90029 strain was applied to PDA medium with a loop loop and cultured at 27 ° C for 2 to 3 days. This culture was subcultured twice and grown until the colonies were at least 1 mm in diameter. 5 mL of 0.85% sterile saline was measured in a sterile 15 mL centrifuge tube (Corning). Using a sterilized bamboo skewer, five colonies of the grown bacteria (about 1 mm in diameter) were collected and suspended in the measured sterile 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 then OD ₅₅₀ was measured. The suspension was diluted to 0.5 McFarland (OD _{550 = 0.0548) with 0.85% sterile saline.} The resulting suspension was diluted 100-fold 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 solution.

Inoculum solutions of yeast fungi (Cryptococcus neoformans) and zygomycota (Risopath oryzae) were prepared in the same procedure as in Test II-1.

[Evaluation of fungal inhibition rate by trace liquid dilution method]
Inhibition rates against the fungal Candida albicans ATCC90029 strain were measured by the microsolution dilution method according to the NCCLS 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)). In each well of the sterilized 96-well plate, the final concentrations of compounds BF-0158A and B are 512, 256, 128 or 64 μg / mL, and the final concentrations of compounds BF-0158C to H are 8, 4, 2 or 1 μg / A diluted solution of compound BF-0158 prepared by DMSO was added in 1.0 μL increments so as to be mL. As a control, 1.0 μL of DMSO alone was added. Each test plot and control plot were prepared with 8 wells. The fungus was then added to each well at a ratio of 19 μL of RPMI 1640 medium and 180 μL of inoculum solution. After the addition, OD ₅₅₀ of each well was measured (this was taken as the initial turbidity). Using an NB-203 (N-Biotek) incubator, fungi inoculated into wells of 96-well plates were cultured at a temperature of 35 ° C for 24 hours for Candida albicans and 72 hours for Cryptococcus neoformans. .. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, OD ₅₅₀ of each well was measured (this was defined as terminal turbidity). The inhibition rate of each compound was calculated based on the above formula (M-1). The minimum concentration of the calculated compound having an inhibition rate of 90% or more was defined as the MIC value of the compound.

The compound and control DMSO were dispensed into predetermined wells of a 96-well plate in the same procedure as described above. Zygomycota (Resopath oryzae) was added to the given wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of inoculum solution. After the addition, the yeast fungus inoculated into the wells of the 96-well plate was 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, the minimum concentration at which growth was completely inhibited was determined for each compound. This concentration was taken as the MIC value of the compound.

[Evaluation of amphotericin B activity enhancing effect of compound BF-0158 by trace liquid dilution method]
In each well of the 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, Diluted solutions of compound BF-0158 and amphotericin B prepared by DMSO were added in an amount of 1.0 μL each to 0.0625, 0.0313 or 0.0156 μg / mL. As a control, only DMSO was added in 2.0 μL. One well was prepared for each test plot and eight wells were prepared for the control plot. The fungus was then added to each well at a ratio of 18 μL of RPMI 1640 medium and 180 μL of inoculum solution. After the addition, OD ₅₅₀ of each well was measured (this was taken as the initial turbidity). Using an NB-203 (N-Biotek) incubator, the fungi inoculated into the wells of the 96-well plate were cultured at a temperature of 35 ° C. for 24 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, OD ₅₅₀ of each well was measured (this was defined as terminal turbidity). Based on the above 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. In addition, 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 for each compound was carried out in 3 iterations.

Table 1 shows the MIC values of amphotericin B for Candida albicans when the compounds BF-0158 and amphotericin B were co-administered. In the table, the column of "Concentration of compound BF-0158" is the concentration of compound BF-0158 at the time of combined administration of compound BF-0158 and amphotericin B, and the column of "Concentration of amphotericin B" is compound BF-0158. The MIC value of amphotericin B at the time of combined administration of amphotericin B is shown.

Table 2 shows the amphotericin B activity enhancement rate of compound BF-0158 against Candida albicans when the compound BF-0158 and amphotericin B are co-administered, and the amphotericin B activity enhancement rate of compound BF-0158 against cryptococcus neoformans. Table 3 shows the amphotericin B activity enhancement rate of the compound BF-0158 with respect to lysopath oryzae, respectively. In the table, the column of "Concentration of compound BF-0158" shows the concentration of compound BF-0158 at the time of combined administration of compound BF-0158 and amphotericin B, and "concentration of amphotericin B activity of compound BF-0158". Column shows the rate of enhancement of amphotericin B activity by compounds BF-0158 at each concentration.

As shown in Table 2, the antifungal activity of amphotericin B against Candida albicans was 1-2 times higher by co-administration of compounds BF-0158 of 0.25 μg / mL, especially 0.5 μg / mL or more, with amphotericin B. In particular, it was enhanced 2 to 8 times. As shown in Table 3, the antifungal activity of amphotericin B against cryptococcus neoformans was enhanced 4- to 8-fold by co-administration of compounds BF-0158A or BF-0158B of 0.5 μg / mL or more with amphotericin B. .. In addition, as shown in Table 4, the antifungal activity of amphotericin B against amphotericin B was enhanced 2 to 8 times by co-administering the compound BF-0158A or BF-0158B of 1 μg / mL or more with amphotericin B. Was done.

The present invention is not limited to the above-described embodiment, and includes various modifications. For example, the above-described embodiment has been described in detail in order to explain the present invention in an easy-to-understand manner, and is not necessarily limited to the one including all the configurations described. In addition, it is possible to add, delete, and / or replace a part of the configuration of each embodiment with another configuration.

Claims (16)

Equation (I):

[During the ceremony,
(A) n is 0,
R ¹ and R ² are equations (S-1):

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

It is a group represented by
R ⁴ is OH,
R ⁷ is OH, or;
(B) n is 0,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (S-2).
R ³ and R ⁴ are OH
R ⁷ is OH, or;
(C) n is 0,
R ¹ and R ² are the groups represented by the equation (S-1).
R ³ and R ⁴ are OH
R ⁷ is OH, or;
(D) n is 0,
R ¹ is the group expressed by the equation (S-1).
R ² , R ³ and R ⁴ are OH,
R ⁷ is OH, or;
(E) n is 1,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (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 the group expressed by the equation (S-2).
R ² , R ³ and R ⁴ are OH,
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH, or;
(G) n is 2,
R ¹ is the group expressed by the equation (S-1).
R ² is the group expressed by the equation (S-2).
R ³ and R ⁴ are OH
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH, or;
(H) n is 2,
R ¹ is the group expressed by the equation (S-1).
R ² , R ³ and R ⁴ are OH,
The first R ⁵ is the group expressed by the equation (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 bonded,
R ⁷ is OH. ]
A compound represented by, or a salt thereof, or a solvate thereof. A method for producing a compound according to claim 1, a salt thereof, or a solvate thereof.
Pseudophyllofora spp. BF-0158 strain (NITE P-02400) having the ability to produce the compound represented by the formula (I) or a microorganism thereof, which is a mutant strain thereof, is cultured in a medium and the formula (I) is used. 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;
The method described above. A microorganism of the genus Pseudophyllofora BF-0158 strain (NITE P-02400) or a mutant strain thereof, which has the ability to produce the compound represented by the formula (I) according to claim 1. At least selected from the group consisting of polyene macrolide-based agents, azole-based agents, candin-based agents and fluoropyrimidine-based agents, which contain the compound according to claim 1 or a salt thereof, or a solvate thereof as an active ingredient. An activity enhancer for one antifungal drug. The activity enhancer for an antifungal agent according to claim 4, wherein at least one antifungal agent is a polyene macrolide-based agent. The activity enhancer for an antifungal drug according to claim 5, wherein the polyene macrolide drug is amphotericin B. At least selected from the group consisting of polyene macrolide-based agents, azole-based agents, candin-based agents and fluoropyrimidine-based agents, which contain the compound according to claim 1 or a salt thereof, or a mixture thereof as an active ingredient. A drug to enhance the activity of one antifungal drug . The pharmaceutical according to claim 7 , for use in the prevention or treatment of one or more fungal infections through an activity that enhances the activity of at least one antifungal agent. The medicine according to claim 7 or 8 , further comprising at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, candies and fluoropyrimidine agents. The drug according to any one of claims 7 to 9, wherein the at least one antifungal drug is a polyene macrolide drug. The drug according to claim 10, wherein the polyene macrolide drug is amphotericin B. Polyene macrolides, azoles, candins and fluoropyrimidines comprising the compound according to claim 1 or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers. A pharmaceutical composition for enhancing the activity of at least one antifungal drug selected from the group consisting of a series of drugs. 12. The pharmaceutical composition according to claim 12, for use in the prevention or treatment of one or more fungal infections through an activity that enhances the activity of at least one antifungal agent. The pharmaceutical composition according to claim 12 or 13 , further comprising at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, candy agents and fluoropyrimidine agents. The pharmaceutical composition according to any one of claims 12 to 14, wherein the at least one antifungal agent is a polyene macrolide agent. The pharmaceutical composition according to claim 15, wherein the polyene macrolide agent is amphotericin B.