JP7046344B2 - A novel cyclic peptide compound having an activity-enhancing effect on antifungal drugs and a method for producing the same. - Google Patents

Description

NPMD NITE P-02402

The present invention relates to a novel cyclic peptide compound having an activity-enhancing effect on an antifungal drug and a method for producing the same. In particular, the present invention is a novel cyclic peptide compound having an activity-enhancing effect of at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, candin drugs and fluoropyrimidine drugs. Regarding the manufacturing 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 a 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 can suppress the development of drug-resistant bacteria. 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 the novel bacteria isolated from the soil produce a compound in the culture solution having 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 cyclic peptide compound having a skeletal structure different from that of known pharmaceutical compounds. Further, the present inventors have found that the compound can be produced by a cultural means using the bacterium, or a synthetic means using an amino acid corresponding to the amino acid sequence of the cyclic peptide compound or 2-aminobenzoic acid (anthranilic acid). rice field. The present inventors have completed the present invention based on the above findings.

［式中、
R¹は、H、OH、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、
R²は、H、OH、ハロゲン、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、
R³は、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が、H、置換若しくは非置換のC₁～C₅アルキル、置換若しくは非置換のC₂～C₅アルケニル、置換若しくは非置換のC₂～C₅アルキニル、置換若しくは非置換のC₇～C₁₁シクロアルキルアルキル、置換若しくは非置換の3～6員のヘテロシクロアルキル-C₁～C₅アルキル、置換若しくは非置換のC₇～C₂₀アリールアルキル、又は置換若しくは非置換の5～15員のヘテロアリール-C₁～C₅アルキルであり、
R²が、OH、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、又は置換若しくは非置換のC₁～C₂₀アシルオキシであり、
R³が、H、置換若しくは非置換のC₁～C₅アルキル、置換若しくは非置換のC₂～C₅アルケニル、置換若しくは非置換のC₂～C₅アルキニル、置換若しくは非置換のC₃～C₆シクロアルキル、置換若しくは非置換のC₃～C₆シクロアルケニル、置換若しくは非置換のC₃～C₆シクロアルキニル、置換若しくは非置換の3～6員のヘテロシクロアルキル、置換若しくは非置換のC₇～C₁₁シクロアルキルアルキル、置換若しくは非置換の3～6員のヘテロシクロアルキル-C₁～C₅アルキル、置換若しくは非置換のC₆～C₁₅アリール、置換若しくは非置換のC₇～C₂₀アリールアルキル、置換若しくは非置換の5～15員のヘテロアリール、又は置換若しくは非置換の5～15員のヘテロアリール-C₁～C₅アルキルである、前記実施形態（1）に記載の化合物。
（3） R³が、プロパン-2-イルである、前記実施形態（1）又は（2）に記載の化合物。
（4） R¹が、メチルであり、
R²が、OHであり、
R³が、プロパン-2-イルである、前記実施形態（1）～（3）のいずれかに記載の化合物。
（5） 式（I-L1）：

［式中、
R¹は、H、OH、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、
R²は、H、OH、ハロゲン、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、
R³は、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。
（6） 式（I-L2）：

［式中、
R¹は、H、OH、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、
R²は、H、OH、ハロゲン、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、
R³は、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。
（7） R¹が、メチルであり、
R²が、OHであり、
R³が、プロパン-2-イルである、前記実施形態（5）又は（6）に記載の化合物。
（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ネクトリアセア（Nectriaceae）科に属する菌BF-0114株（NITE P-02402）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。
（9） 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ネクトリアセア（Nectriaceae）科に属する菌BF-0114株（NITE P-02402）又はその変異株である微生物。
（10） 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（VI）、（VII）、（VIII）及び（IX）：

［式中、R¹、R²及びR³は、前記実施形態（1）～（4）のいずれかに記載の意味を有する。］
で表される化合物若しくはその保護誘導体、又はそれらの塩若しくは溶媒和物のアミノ基及びカルボキシル基の間を連結して、式（I）で表される化合物のアミノ酸配列を有する直鎖状ペプチドを形成する、直鎖状ペプチド形成工程；
直鎖状ペプチド形成工程で得られた直鎖状ペプチドを分子内環化して、式（I）で表される化合物を得る、環化工程；
を含む、前記方法。
（11） 前記実施形態（5）～（7）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（VI）、（VII）、（VIII）及び（IX）：

［式中、R¹、R²及びR³は、前記実施形態（5）～（7）のいずれかに記載の意味を有する。］
で表される化合物若しくはその保護誘導体、又はそれらの塩若しくは溶媒和物のアミノ基及びカルボキシル基の間を連結して、式（I-L1）又は（I-L2）で表される化合物のアミノ酸配列を有する直鎖状ペプチドを形成する、直鎖状ペプチド形成工程；
を含む、前記方法。
（12） 前記実施形態（1）～（7）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。
（13） 前記実施形態（1）～（7）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。
（14） 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（13）に記載の医薬。
（15） 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（13）又は（14）に記載の医薬。
（16） 前記実施形態（1）～（7）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。
（17） 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（16）に記載の医薬組成物。
（18） 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（16）又は（17）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,
R ¹ is H, OH, 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.
R ² is H, OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted. Substituted 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. Substituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R ³ is 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 hetero It is an aryl or a substituted or unsubstituted heteroarylalkyl. ]
A compound represented by, or a salt thereof, or a solvate thereof.
(2) R ¹ is 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 ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₅ alkyl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, or substituted or unsubstituted 5 ~ 15-membered heteroaryl-C ₁ ~ C ₅ alkyl,
R ² is OH, 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 an unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ alkyloxy, or a substituted or unsubstituted C ₁ to C ₂₀ acyloxy.
R ³ is 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 heterocycloalkyl, substituted or unsubstituted. C ₇ to 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 The embodiment (1), wherein the C ₂₀ aryl alkyl is a substituted or unsubstituted 5- to 15-membered heteroaryl, or a substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ -alkyl. Compound.
(3) The compound according to the above embodiment (1) or (2), wherein R ³ is propan-2-yl.
(4) R ¹ is methyl,
R ² is OH,
The compound according to any one of the above-described embodiments (1) to (3), wherein R ³ is propan-2-yl.
(5) Equation (I-L1):

[During the ceremony,
R ¹ is H, OH, 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.
R ² is H, OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted. Substituted 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. Substituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R ³ is 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 hetero It is an aryl or a substituted or unsubstituted heteroarylalkyl. ]
A compound represented by, or a salt thereof, or a solvate thereof.
(6) Equation (I-L2):

[During the ceremony,
R ¹ is H, OH, 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.
R ² is H, OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted. Substituted 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. Substituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R ³ is 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 hetero It is an aryl or a substituted or unsubstituted heteroarylalkyl. ]
A compound represented by, or a salt thereof, or a solvate thereof.
(7) R ¹ is methyl,
R ² is OH,
The compound according to the above embodiment (5) or (6), wherein R ³ is propan-2-yl.
(8) The method for producing the compound according to any one of the above-described embodiments (1) to (4), a salt thereof, or a solvate thereof.
The BF-0114 strain (NITE P -02402) belonging to the family Nectriaceae, which has 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 ( A compound accumulation step of accumulating the compound represented by I) 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.
(9) A strain BF-0114 (NITE P- ) belonging to the family Nectriaceae, which has the ability to produce a compound represented by the formula (I) according to any one of the above embodiments (1) to (4). 02402) or a microorganism that is a mutant strain thereof.
(10) 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.
Equations (VI), (VII), (VIII) and (IX):

[In the formula, R ¹ , R ² and R ³ have the meanings described in any of the above-described embodiments (1) to (4). ]
A linear peptide having the amino acid sequence of the compound represented by the formula (I) by linking between the amino group and the carboxyl group of the compound represented by, or a protected derivative thereof, or a salt or a mixture thereof. Linear peptide forming step to form;
A cyclization step of intramolecularly cyclizing the linear peptide obtained in the linear peptide forming step to obtain a compound represented by the formula (I);
The method described above.
(11) The method for producing a compound according to any one of the above-described embodiments (5) to (7), a salt thereof, or a solvate thereof.
Equations (VI), (VII), (VIII) and (IX):

[In the formula, R ¹ , R ² and R ³ have the meanings described in any of the above-described embodiments (5) to (7). ]
The amino acid of the compound represented by the formula (I-L1) or (I-L2) by linking between the amino group and the carboxyl group of the compound represented by (I-L1) or a protected derivative thereof, or a salt or a mixture thereof. A linear peptide forming step of forming a linear peptide having a sequence;
The method described above.
(12) 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 (7), a salt thereof, or a solvate thereof as an active ingredient. And an activity enhancer of at least one antifungal drug selected from the group consisting of fluoropyrimidine-based drugs.
(13) A pharmaceutical agent containing the compound according to any one of the above-described embodiments (1) to (7), a salt thereof, or a solvate thereof as an active ingredient.
(14) The drug according to embodiment (13), which is used for the prevention or treatment of one or more fungal infections.
(15) The embodiment (13) or (14), further comprising at least one antifungal agent selected from the group consisting of a polyene macrolide agent, an azole agent, a candine agent and a fluoropyrimidine agent. The drug described in.
(16) A pharmaceutical composition comprising the compound according to any one of embodiments (1) to (7) or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers.
(17) The pharmaceutical composition according to embodiment (16), for use in the prevention or treatment of one or more fungal infections.
(18) The embodiment (16) or (17), further comprising at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, candin 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 _{-C2 to C 5 alkenyl} of linear or branched chains such as methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl and 1-pentenyl can be mentioned.

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, cyclopentinyl 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. Heterocycloalkyls of up to 6 members 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 anthracenyl.

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 indyl 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. Suitable heteroarylalkyls include, but are not limited to, 5- to 15-membered heteroaryl-C ₁ to C ₅ alkyls such as pyridylmethyl.

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. Suitable heteroarylalkyloxys include, but are not limited to, for example, 5 to 15 membered heteroaryl-C ₁ to C ₅ alkyloxys.

As used herein, "acyl" means a group in which a monovalent group selected from the groups described above and a carbonyl are linked. Suitable acyls include, but are not limited to, C ₁ to C ₅ aliphatic acyls such as formyl, acetyl and propionyl, and C ₁ to C ₂₀ aromatic _acyls such as benzoyl _. 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), (I-L1) or (I-L2) :.

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. From the culture medium, the present inventors have a novel cyclic tetrapeptide compound cyclo (L-valinyl-N-methyl-L-tyrosinyl-anthranyl-L-alanyl) having an activity of enhancing the antifungal activity of amphotericin B (L-valinyl-N-methyl-L-tyrosinyl-anthranyl-L-alanyl) ( Hereinafter, it is also referred to as “compound (1)”). Although compound (1) does not exhibit substantially antifungal activity when administered alone, it can significantly enhance the antifungal activity of amphotericin B when administered in combination with amphotericin B. The compound represented by the formula (I) of this embodiment includes a compound (1) which is a natural organic compound and a compound thereof and related compounds thereof. Further, the compounds represented by the formulas (I-L1) and (I-L2) of this embodiment include a chain tetrapeptide in which the ring-opened compound (1), which is a natural organic compound, and related compounds thereof are included. Therefore, the compounds represented by the formulas (I), (I-L1) and (I-L2) of this embodiment can effectively enhance the antifungal activity of the antifungal drug.

In formulas (I), (I-L1) and (I-L2), R ¹ is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted. Substituted cycloalkyls, substituted or unsubstituted cycloalkenyls, substituted or unsubstituted cycloalkynyls, substituted or unsubstituted heterocycloalkyls, substituted or unsubstituted cycloalkylalkyls, substituted or unsubstituted heterocycloalkylalkyls, substituteds. 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, Alternatively, it is a substituted or unsubstituted acyloxy. R ¹ is H, OH, 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 -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkynyl, substituted or unsubstituted 3-6-membered heterocycloalkyl, substituted or non-substituted Substituted C ₇ to 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 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 _{20arylalkenyloxy} , 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; 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 alkynyls, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyls, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₅ alkyl, substituted or unsubstituted. More preferably C ₇ to C ₂₀ arylalkyl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ alkyl; H, methyl, ethyl, propyl, butyl, or pentyl. Is even more preferred; methyl is particularly preferred. When R ¹ is the group exemplified above, the compounds represented by the formulas (I), (I-L1) and (I-L2) of this embodiment effectively enhance the antifungal activity of the antifungal drug. can do.

In formulas (I), (I-L1) and (I-L2), R ² is H, OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted. Alternatively, 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 heteroarylalkyl Oxy, or substituted or unsubstituted acyloxy. R ² is H, OH, halogen, 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-membered heterocycloalkyl, substituted. Or unsubstituted C ₇ to 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 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 ~ C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ ~ C _{20arylalkenyloxy} , substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ Preferably ~ C ₅ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy; OH, 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 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ to C ₅ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ Acyloxy is more preferred; OH, methoxy, ethoxy, propoxy, or butoxy is even more preferred; OH is particularly preferred. When R ² is the group exemplified above, the compounds represented by the formulas (I), (I-L1) and (I-L2) of this embodiment effectively enhance the antifungal activity of the antifungal drug. can do.

In formulas (I), (I-L1) and (I-L2), R ³ is 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 non-substituted Substituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl. R ³ is 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 heterocycloalkyl, substituted or unsubstituted. C ₇ to 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 Preferably 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; H, substituted or unsubstituted. C ₁ to C ₅ alkyl, substituted or unsubstituted C ₂ to C ₅ alkenyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ More preferably, it is a ~ C ₅ alkyl, a substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, or a substituted or unsubstituted 5 to 15 membered heteroaryl-C ₁ to C ₅ alkyl; H, methyl, or. Propan-2-yl is more preferred; propan-2-yl is particularly preferred. When R ³ is the group exemplified above, the compounds represented by the formulas (I), (I-L1) and (I-L2) of this embodiment effectively enhance the antifungal activity of the antifungal drug. can do.

When the group is substituted in the formulas (I), (I-L1) and (I-L2), the substituent is independently a 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 unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, Substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, And preferably at least one monovalent group selected from the group consisting of substituted or unsubstituted amino; 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 ~ C ₆ cycloalkenyl, substituted or unsubstituted C ₃ to C ₆ cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted. Substituted 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-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 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy to 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 C ₁ to C ₂₀ acyl, substituted or unsubstituted C ₁ to C ₂₀ acyloxy, And at least one monovalent group selected from the group consisting of substituted or unsubstituted amino; 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 At least selected from the group consisting of 5 to 15 membered heteroaryloxy, 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 more preferably one monovalent group. When the monovalent group is substituted, the substituent can be further selected from the monovalent group.

Preferably, the compounds represented by the formulas (I), (I-L1) and (I-L2) are
R ¹ is H, OH, 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 -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkynyl, substituted or unsubstituted 3-6-membered heterocycloalkyl, substituted or non-substituted Substituted C ₇ to 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 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 _{20arylalkenyloxy} , 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 ² is H, OH, halogen, 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-membered heterocycloalkyl, substituted. Or unsubstituted C ₇ to 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 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 ~ C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ ~ C _{20arylalkenyloxy} , substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ ~ C ₅ alkyloxy, or substituted or unsubstituted C ₁ ~ C ₂₀ acyloxy,
R ³ is 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 heterocycloalkyl, substituted or unsubstituted. C ₇ to 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 arylalkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, or substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ -alkyl.
When the groups are substituted, the substituents are independently 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 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 C ₃ to C ₆ cycloalkoxyyl, substituted or unsubstituted 3 to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to 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 member heteroaryloxy, substituted or unsubstituted. 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 compounds represented by the formulas (I), (I-L1) and (I-L2) are
R ¹ is 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 ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₅ -alkyl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, or substituted or unsubstituted 5 to 15-membered. Heteroaryl-C ₁ to C ₅ alkyl,
R ² is OH, 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 an unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ alkyloxy, or a substituted or unsubstituted C ₁ to C ₂₀ acyloxy.
R ³ is H, substituted or unsubstituted C ₁ to C ₅ alkyl, substituted or unsubstituted C ₂ to C ₅ alkenyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 ~ 6-membered heterocycloalkyl-C ₁ to C ₅ alkyl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, or substituted or unsubstituted 5 to 15 member heteroaryl-C ₁ to C ₅ alkyl. ,
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 compounds represented by the formulas (I), (I-L1) and (I-L2) are
R ¹ is methyl,
R ² is OH,
R ³ is propan-2-yl.

Particularly preferred compounds represented by the formulas (I), (I-L1) and (I-L2) are as follows:
Cyclo (L-valinyl-N-methyl-L-tyrosinyl-anthranil-L-alanyl) (1);
Cyclo (D-valinyl-N-methyl-L-tyrosinyl-anthranil-L-alanyl) (1-ValD);
L-valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-anthranil-L-alanine (1-L1); and
N-Methyl-O-tert-butyl-L-tyrosinyl-anthranil-L-alanyl-L-valine (1-L2);
Selected from the group consisting of. The compounds (1), (1-ValD), (1-L1) and (1-L2) are cyclic or chain tetrapeptides consisting of the amino acid sequence of SEQ ID NO: 1 or 2 or protected forms thereof. When the compound represented by the formulas (I), (I-L1) and (I-L2) of this embodiment is the compound or a protected or deprotected form thereof, the compound is the antifungal activity of the antifungal drug. Can be effectively enhanced.

In the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and the formulas (VI), (VII), (VIII) and (IX) described below. The represented compound includes not only the above-mentioned or the following compounds themselves, but also salts thereof. The salt of the above or below compound is not limited, but is, for example, a salt with a cation such as a sodium ion, a potassium ion, a calcium ion, a magnesium ion, or a substituted or unsubstituted ammonium ion, or hydrochloric acid. Inorganic acids such as hydrobromic acid, sulfuric acid, nitrate, carbonic acid or phosphoric acid, or formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid. , Propionic acid, tartrate 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, ethane Salts with organic acid anions such as sulfonic acid, isethionic acid, p-toluene sulfonic acid or naphthalene sulfonic acid are preferred. When the compounds represented by the formulas (I), (I-L1) and (I-L2) are in the form of the above salts, the antifungal activity of the antifungal drug can be effectively enhanced.

In the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and the formulas (VI), (VII), (VIII) and (IX) described below. The represented compound includes not only the compound itself described above or below, but also a solvate of the compound or a salt thereof. The solvent that can form a solvent with the above-mentioned or the following compound or a salt thereof is not limited, but is, for example, 1 to 1 such as a lower alcohol (for example, methanol, ethanol or 2-propanol (isopropyl alcohol)). Alcohols with 6 carbon atoms), higher alcohols (eg alcohols with 7 or more carbon atoms such as 1-heptanol or 1-octanol), dimethylsulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate Organic solvents such as, or water are preferred. When the compound represented by the formulas (I), (I-L1) and (I-L2) or a salt thereof is in the form of a solvate with the above solvent, the antifungal activity of the antifungal drug is effectively effective. Can be augmented.

In the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and the formulas (VI), (VII), (VIII) and (IX) described below. The represented compound includes not only the above-mentioned or the following compounds themselves, but also the protected or deprotected form thereof. In the present specification, the "protected form" is a form in which a protecting group is introduced into one or more functional groups (for example, a hydroxyl group or a carboxylic acid group), and the "deprotected form" is one or more functional groups. Each means a form in which the protecting group introduced into the group (for example, a hydroxyl group or a carboxylic acid group) is removed. In the present specification, the protected form of the compound represented by each of the above formulas, the protected derivative of the compound represented by each of the above formulas, and the deprotected form of the compound represented by each of the above formulas are represented by the above formulas. It may be described as a deprotected derivative of the compound to be used. 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, tert-butyloxy (tBu), methoxymethoxy (MOM) or methoxy (Me)) is a 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 amino-protecting groups, t-butoxycarbonyl (Boc), 2-bromobenzyloxycarbonyl. (BrZ) or 9-fluorenylmethoxycarbonyl (Fmoc) 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. The antifungal activity of an antifungal agent even when the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention are in the protected form by the above-mentioned protecting group. May be able to be effectively enhanced.

In the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and the formulas (VI), (VII), (VIII) and (IX) described below. When the compound represented has one or more tautomers, the compound described above or below also includes the form of the individual tautomers of the compound.

Further, the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and the formulas (VI), (VII), (VIII) and (IX) described below. ) Have one or more stereocenters (chiral centers), said or below compounds also include individual enantiomers and diastereomers of the compound, as well as mixtures thereof such as racemates. do.

By having the above-mentioned characteristics, the compound represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention effectively enhances the antifungal activity of the antifungal drug. Can be done.

<2. Method for producing a new compound by culturing means>
The present inventors have stated that a novel fungus isolated from soil produces a cyclic tetrapeptide compound (1) contained in the compound represented by the formula (I) of one aspect of the present invention in its culture medium. I found it. 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 belonging to the BF-0114 strain (NITE P -02402) belonging to the family Nectriaceae, which has the ability to produce a compound represented by the formula (I), or a microorganism thereof. The present invention comprises a compound accumulation step of culturing in a medium and accumulating the compound represented by the formula (I) in the medium.

The BF-0114 strain, which belongs to the family Nextriasea, is a novel fungus isolated from the soil in Minato-ku, Tokyo, Japan. This strain has been deposited as BF-0114 at the National Institute of Technology and Evaluation Patent Microorganisms Depositary (NITE P -02402).

In this step, the microorganism used for culturing is preferably the BF-0114 strain belonging to the family Nextriasea or a mutant strain thereof, which has the ability to produce the compound represented by the formula (I), and belongs to the family Nextriasea. Bacterial BF-0114 strain is more preferable. In the present invention, the mutant strain of the strain BF-0114 belonging to the family Nextriasea means a natural mutant strain or an artificial mutant strain of the strain BF-0114 belonging to the family Nextriasea. An artificial mutant strain of the BF-0114 strain belonging to the family Nextriasea can be obtained by any means for producing an artificial mutant strain usually used in the art. Not only the strain BF-0114 belonging to the family Nextriasea, but also a mutant strain of the strain BF-0114 belonging to the family Nextriasea, 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, nitrate, 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 (2.0% potato dextrose broth (PDB) (Becton)). , Dickinson (BD), 0.1% Taiyo Agar (SSK Sales) pH 6.0), or production medium (1.2% PDB (BD), 1.0% malt extract (BD), 1.0% glucose (Wako Pure Chemical Industries, Ltd.) , 0.05% Peptone (BD), 0.0016% Yunohana (hot spring shop), pH 3) Medium is preferable. By culturing the BF-0114 strain of the bacterium belonging to the family Nextriasea, which has the ability to produce the compound represented by the formula (I), or a microorganism thereof which is a mutant strain thereof, the microorganism represented by the formula (I) is cultured 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 comprises 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 the cells from the culture of the microorganism obtained in the compound accumulation step by filtration, centrifugation or the like, and extracting the separated cells with a water-miscible organic solvent such as ethanol or acetone. The step includes a step of further separating the bacterial cell extract extracted with a water-mixable organic solvent by means such as solvent extraction or preparative chromatography to obtain a compound represented by the formula (I). As the preparative chromatography, various 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) has R ¹ as methyl, R ² as OH, and R ³ as propane-2. -Preferably ill. In this case, the compound represented by the formula (I) is the compound (1) produced by the strain BF-0114 belonging to the family Nextriasea. By using the method of this embodiment, the compound represented by the formula (I) corresponding to the compound (1) 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 a strain BF-0114 (NITE P -02402) belonging to the family Nextriasea, which has the ability to produce a compound represented by the formula (I) of one aspect of the present invention, or a mutant strain thereof. Regarding a certain microorganism. In this embodiment, it is preferable that R ¹ is methyl, R ² is OH, and R ³ is propan-2-yl in the compound represented by the formula (I). By using the microorganism of this embodiment, the compound represented by the formula (I) corresponding to the compound (1) can be efficiently produced.

<3. Method for producing a new compound by synthetic means>
The present inventors have prepared the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention without using the natural compound (1) as a raw material. We have found that the corresponding amino acids can be synthesized as reaction intermediates. Therefore, another aspect of the present invention relates to a method for producing a compound represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention by synthetic means.

In one embodiment of this aspect, the method for producing the compound represented by the formula (I) of one aspect of the present invention comprises a linear peptide forming step and a cyclization step. Further, in another embodiment of the present invention, the method for producing the compounds represented by the formulas (I-L1) and (I-L2) of the present invention comprises a linear peptide forming step. Hereinafter, each step will be described in detail.

で表される化合物若しくはその保護誘導体、又はそれらの塩若しくは溶媒和物のアミノ基及びカルボキシル基の間を連結して、式（I）、（I-L1）又は（I-L2）で表される化合物のアミノ酸配列を有する直鎖状ペプチドを形成する、直鎖状ペプチド形成工程を含む。 [3-1. Linear peptide formation step]
In one aspect, the method of the invention comprises formulas (VI), (VII), (VIII) and (IX) :.

It is represented by the formula (I), (I-L1) or (I-L2) by linking between the amino group and the carboxyl group of the compound represented by (I) or a protected derivative thereof, or a salt or a mixture thereof. It comprises a linear peptide forming step of forming a linear peptide having an amino acid sequence of a compound.

In equations (VI), (VII), (VIII) and (IX), R ¹ , R ² and R ³ are synonymous with the above.

In this step, the reaction linking between the compounds represented by the formulas (VI), (VII), (VIII) and (IX) or their protected derivatives, or the amino and carboxyl groups of their salts or solvates. The conditions of the above can be appropriately set by those skilled in the art based on known reaction conditions relating to the solid phase or liquid phase synthesis of the peptide. The reaction of this step can be carried out, for example, by solid phase synthesis. In this case, for example, a resin (for example, 2-chlorotrityl chloride resin) is added to the carboxylic acid group of any one compound selected from the compounds represented by the formulas (VI), (VII), (VIII) and (IX). ), Then the formula (VI), (VI) carried on the resin based on the amino acid sequence (SEQ ID NO: 1) of the compound represented by the formula (I), (I-L1) or (I-L2). A linear peptide can be formed by sequentially linking the remaining compounds to any one compound selected from the compounds represented by VII), (VIII) and (IX).

The compound represented by the formulas (VI), (VII), (VIII) and (IX) or a protected derivative thereof used in this step may be prepared by purchasing the compound prepared in advance. As a method for protecting and / or deprotecting an amino acid, it may be prepared by itself based on the reaction conditions known in the art.

By carrying out this step under the above conditions, a linear peptide having the amino acid sequence of the compound represented by the formula (I), (I-L1) or (I-L2) can be formed.

[3-2. Cyclization process]
In one embodiment of the present invention, the method for producing the compound represented by the formula (I) of the present invention is to intramolecularly cyclize the linear peptide obtained in the linear peptide forming step. It comprises a cyclization step to obtain the compound represented by the formula (I).

In this step, the conditions of the reaction for intramolecular cyclization of the linear peptide can be appropriately set by those skilled in the art based on the known reaction conditions relating to the solid phase or liquid phase synthesis of the peptide.

The linear peptide forming step and cyclization step described above can optionally include a step of protecting and / or deprotecting the linear peptide and / or its cyclization product. In this case, the conditions for the protection and / or deprotection reaction can be appropriately set by those skilled in the art based on the reaction conditions known in the art as a method for protecting and / or deprotecting amino acids. ..

By the method for producing a compound of the present invention by the synthetic means of the present invention, the formula (I) of one aspect of the present invention is made by using the corresponding amino acid as a reaction intermediate without using the natural product compound (1) as a raw material. , (I-L1) and (I-L2) can be produced. Therefore, it is represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention which can be an active ingredient of a pharmaceutical by the method for producing a compound of the present invention by the synthetic means of the present invention. Or various compounds derived from the compound can be provided in large quantities with high purity and low cost.

<4. Pharmaceutical use>
The compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention have an activity of enhancing the antifungal activity of an antifungal drug. Therefore, another aspect of the present invention is a compound represented by the formula (I), (I-L1) or (I-L2) of the present invention, a salt thereof, or a solvate thereof. With respect to the activity enhancer of at least one antifungal drug contained as an active ingredient. Further, in another aspect of the present invention, the compound represented by the formula (I), (I-L1) or (I-L2) of the present invention, a salt thereof, or a solvate thereof is effective. Regarding medicines contained as ingredients.

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 agent 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 compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention include polyene macrolide agents, azole agents, caninic agents, fluoropyrimidine agents and the like. It has the activity of enhancing the antifungal activity of antifungal drugs. Therefore, the compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention is a polyene macrolide drug, an azole drug, a candine drug and a fluoropyrimidine drug. When administered together with at least one antifungal drug selected from the group consisting of, the dose of the antifungal drug that may have side effects can be reduced and / or the administration period 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". Antifungals that may have side effects by concomitantly administering the compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention and at least one antifungal drug. 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.

The compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention have an activity of enhancing the antifungal activity of at least one antifungal drug. On the other hand, the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention may or may not have antifungal activity by themselves. good. The compounds represented by the formulas (I), (I-L1) and (I-L2) in one embodiment of the present invention usually do not have substantially antifungal activity by themselves. The compounds represented by the formulas (I), (I-L1) and (I-L2) in one embodiment of the present invention themselves have at least substantially no antifungal activity. Since it has the activity of enhancing the antifungal activity of one antifungal drug, the combined administration with at least one antifungal drug reduces the dose of the antifungal drug which may have side effects, and / Alternatively, the administration period can be shortened. This can substantially reduce the occurrence of side effects due to at least one antifungal drug.

The antifungal activity of the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and at least one antifungal agent is not limited, but for example. , Can be determined by the following means. Formula (I) for any assay fungus (eg, yeast, filamentous fungi and zygomycetes) by the trace liquid dilution method according to the American Clinical and Laboratory Standards Institute (CLSI) M27-A3 and M38-A2 methods. , (I-L1) or (I-L2), or at least one antifungal agent. 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 MIC value thus determined, the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and at least one antifungal species. The antifungal activity of the drug can be evaluated.

The activity of the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention to enhance the antifungal activity of at least one antifungal agent is not limited. However, it can be determined by the following means, for example. 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), (I-L1) or (I-L2) and at least one antifungal drug are administered together (for example, simultaneously) to the formula (for example, simultaneously). I) Determine the MIC value when the compound represented by (I-L1) or (I-L2) and at least one antifungal drug are co-administered. Based on the following formula (M-1), the antifungal agent of at least one antifungal agent of the compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention. Calculate the rate of increase in activity. For example, when the enhancement rate is doubled, of at least one antifungal drug at the time of concomitant administration of the compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention. The MIC value is 1/2 of the MIC value when the antifungal drug is administered alone. Based on the enhancement rate thus determined, the antifungal agent of at least one antifungal agent of the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention. The activity that enhances the fungal activity can be evaluated.

In this embodiment, at least one antifungal agent to be administered in combination with the compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention is determined by the above procedure. The MIC value is usually 0.5 μg / mL for yeast fungi (eg Candida albicans). In this case, the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention are usually 2 μg / mL or more, for example 4 μg / mL or more, particularly 8 When administered in combination with at least one antifungal drug at a concentration of μg / mL or higher, at least one species is usually enhanced in the range of 2 to 16 times or more, particularly 4 to 16 times. The antifungal activity of the antifungal drug can be enhanced. Therefore, the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, when having the enhancement rate in the above range, are associated with at least one antifungal drug. The combined administration can reduce the dose of the antifungal drug that 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.

When the compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention is applied to pharmaceutical use, the formulas (I), (I-L1) and (I-L2) are applied. ) Includes not only the compound itself, but also pharmaceutically acceptable salts of the compound and solvates thereof which are pharmaceutically acceptable. The pharmaceutically acceptable salts of the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention, and their pharmaceutically acceptable solvates are limited. However, for example, the salt or solvate exemplified above is preferable. When the compounds represented by the formulas (I), (I-L1) and (I-L2) are in the form of the above salt or solvate, the activity of enhancing the antifungal activity of at least one antifungal drug. The compound can be applied to the desired pharmaceutical use without substantially reducing.

When the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention are applied to pharmaceutical use, the formulas (I), (I-L1) and (I-L2) are applied. ) 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 compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention are in the above-mentioned prodrug form, they are the parent drugs, the formulas (I), (I-L1). ) And (I-L2), the pharmacokinetics of the compound represented by (I-L2) upon administration of the prodrug form to the subject without substantially reducing the activity of enhancing the antifungal activity of at least one antifungal drug. Can be improved.

When a compound represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention is applied to pharmaceutical use, the compound may be used alone or one or more kinds. It may be used in combination with a pharmaceutically acceptable ingredient. 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 product of the present embodiment also comprises a compound represented by the formula (I), (I-L1) or (I-L2) of the present invention or a salt thereof, or a solvate thereof. It can also be provided in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier of more than one species. 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 physiological 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 active ingredient is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The dosage form of the drug contained in is not particularly limited, and may be a preparation for use in parenteral administration or 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. Painless agents, stabilizers such as human serum albumin or polyethylene glycol, preservatives, antioxidants and the like. 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, slurrys 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.

The active ingredient is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The drug contained in the above can also be formulated as a depot preparation. 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 drug of this embodiment to a depot preparation, at least one antifungal agent of the compound represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention. The activity that enhances the antifungal activity can be continuously expressed over a long period of time.

When the compound represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention is applied for pharmaceutical use, the compound is provided together with at least one antifungal agent. It may be provided 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), (I-L1) or (I-L2) of one aspect of the present invention, that is, the present invention. In the case of an embodiment in which the compound represented by the formula (I), (I-L1) or (I-L2) of one embodiment and at least one antifungal agent are provided together, the pharmaceutical product of this embodiment is: A compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention or a salt thereof, or a solvent mixture thereof is combined with at least one antifungal drug. Can be in the form of a pharmaceutical composition. In the case of the present embodiment, the pharmaceutical product of this embodiment is, for example, a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention or a pharmaceutically acceptable salt thereof. Alternatively, they can be provided in the form of a single formulation comprising a pharmaceutically acceptable solvate thereof and at least one antifungal agent. In the case of an embodiment in which the compound represented by the formula (I), (I-L1) or (I-L2) of one embodiment of the present invention is provided separately from at least one antifungal agent, the pharmaceutical product of the present embodiment. Is at least one antifungal agent containing at least a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention or a salt thereof, or a solvate thereof. Can be in the form of a pharmaceutical composition used in combination with. In the case of the present embodiment, the pharmaceutical product of the present embodiment is, for example, a compound represented by the formula (I), (I-L1) or (I-L2) of the present invention, a salt thereof, or a solvate thereof. It can be provided in the form of a pharmaceutical combination or kit containing a plurality of formulations in which the product and at least one antifungal agent are separately formulated. 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 the present embodiment contains only the compound represented by the formula (I), (I-L1) or (I-L2) of the present invention or a salt thereof, or a solvate thereof (that is,). It can also be provided in the form of a formulation (without at least one antifungal agent). In any of the embodiments, the compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention and at least one antifungal drug can be co-administered. can.

The active ingredient is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The drug contained as may be used in combination with one or more other drugs useful as a drug other than at least one antifungal drug. In this case, the drug of this embodiment is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salts thereof. It is in the form of a concomitant drug containing an acceptable solvate and one or more of the above other agents. The concomitant drug is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof. It may be in the form of a pharmaceutical composition obtained by combining a Japanese product and one or more of the above-mentioned other drugs, and may be in the form of the formula (I), (I-L1) or (I-L2) of one aspect of the present invention. It may be in the form of a pharmaceutical composition used in combination with one or more of the above-mentioned other drugs, which comprises a compound represented by the above, a pharmaceutically acceptable salt thereof, or a solvate thereof. .. 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), (I-L1) or (I-L2) of one aspect of the present invention or a pharmaceutically acceptable thereof is acceptable. May be provided in the form of a single pharmaceutical product containing the salts, or their pharmaceutically acceptable solvates, and one or more other agents, with one or more other agents separately. It may be provided in the form of a pharmaceutical combination or kit containing a plurality of 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).

The active ingredient is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The pharmaceuticals included as can prevent or treat one or more fungal infections as well. 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. terreus); 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.

The active ingredient is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Can be applied to a variety of subjects in need of prevention or treatment of the symptoms, diseases and / or disorders of one or more of the above fungal infections. 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 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 the symptoms, diseases and / or disorders that have occurred (onset or manifest).

The compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention are symptoms, diseases and / or disorders (symptoms, diseases and / or disorders which are one or more fungal infections described above. For example, it can be used for the prevention or treatment of the symptoms, diseases and / or disorders in a subject having (deep fungal disease, superficial fungal disease or dermatomynomy 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 medicine of this embodiment for the prevention or treatment of the symptoms, diseases and / or disorders of the above-mentioned one or more fungal infections, the formulas (I), (I-L1) and (I-L1) and (I-L1) of one aspect of the present invention are used. The symptoms, diseases and / or disorders can be prevented or treated through the activity of the compound represented by I-L2) to enhance the antifungal activity of at least one antifungal agent.

The compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention are symptoms, diseases and / or disorders (symptoms, diseases and / or disorders which are one or more fungal infections described above. For example, it can be used for the prevention or treatment of the symptoms, diseases and / or disorders in a subject having (deep fungal disease, superficial fungal disease or dermatomynomy 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 compounds represented by (I), (I-L1) and (I-L2), pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof are used as at least one antifungal agent. A method for preventing or treating the disease or symptom, which comprises administration together. 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. Formula (I), (I-L1) or (I-L2) of one aspect of the present invention for a subject requiring prevention or treatment of the symptoms, diseases and / or disorders which are one or more fungal infections. By administering the compound represented by the above in combination with at least one antifungal drug, the compound represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention can be obtained. , The symptoms, diseases and / or disorders can be prevented or treated through the activity of enhancing the antifungal activity of at least one antifungal drug.

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 which are one or more fungal infections described above. A compound represented by (I-L1) or (I-L2), 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. The use of a compound represented by the formula (I), (I-L1) or (I-L2), 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. The compound or drug represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention can be used to prevent symptoms, diseases and / or disorders that are one or more fungal infections. Alternatively, by use for treatment, the antifungal activity of at least one antifungal agent of the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention is enhanced. Through its activity, the symptoms, diseases and / or disorders can be prevented or treated.

The active ingredient is a compound represented by the formula (I), (I-L1) or (I-L2) of one aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent product thereof. When administering a drug containing as to a subject, especially a human patient, the exact dose and dosage (eg, dose, frequency and / or route of administration) of the subject's age, gender, symptoms to be prevented or treated, Considering the exact condition (eg, severity) of the disease and / or disorder, and many factors such as the route of administration, the doctor in charge considers the therapeutically effective dose, number of doses, route of administration, etc. Should be decided. Therefore, in the pharmaceutical of this embodiment, the compound represented by the formula (I), (I-L1) or (I-L2), 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), (I-L1) or (I-L2), which is the active ingredient, is usually a single dose. It ranges from 0.001 to 100 mg / kg body weight per dose, typically 0.01 to 10 mg / kg body weight per dose, and in particular 0.1 to 10 mg / kg body weight per dose. Is in the range of. 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 pharmaceutical product of this embodiment in the above-mentioned dose and usage, at least one of the compounds represented by the formulas (I), (I-L1) and (I-L2) of one aspect of the present invention. Through the activity of enhancing the antifungal activity of an antifungal drug, 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>
[Separation of BF-0114 strain]
The BF-0114 strain is a fungus isolated from the soil in Minato-ku, Tokyo, Japan. Based on the morphological characteristics, culture properties and physiological properties of the BF-0114 strain, comparison with known bacterial species was performed. As a result, it was clarified that this strain is a novel strain belonging to the family Nectriaceae. This strain was named BF-0114 strain. This strain has been deposited as BF-0114 at the National Institute of Technology and Evaluation Patent Microorganisms Depositary (NITE P -02402). The mycological properties of the BF-0114 strain are as follows.

1. Morphological features
The BF-0114 strain grew well on a medium such as a nutrient agar medium such as a PDA medium. Colonies grown on PDA medium at 27 ° C for 2 weeks under aerobic conditions were observed under a microscope. , Colorless conidia were observed to form in chunks.

2. Culture properties
The surface of the colonies of the BF-0114 strain grown on PDA medium at 27 ° C. and aerobic conditions for 2 weeks had a velvety shape. The color tone of the colonies was ocher to white on the front surface and dark 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 showed a homology rate of 97.4% with the base sequence of Thelonectria veuillotiana CBS26696 (Axon No .: KJ022062), which is a member of the ascomycete phylum. In addition, the ITS-5.8 rDNA base sequence showed a homology rate of 95.8% with the base sequence of Acremonium macroclavatum CBS123922 (Acremonium number: HQ897806), which is a type of ascomycete. However, it was difficult to determine the attribution from genetic analysis and simple morphological observation.

4. Physiological properties
The optimum growth conditions for the BF-0114 strain were aerobic conditions, pH 5.6 ± 0.2, and temperature 25 ° C. The growth conditions for this strain were aerobic conditions, static culture, pH 3-9, temperature 25-27 ° C, and culture period 1-3 weeks.

[Production Example I-1: Culture of BF-0114 strain]
One loopful of BF-0114 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-0114 strain cultured in PDA medium was subjected to 100 mL of seed medium (2.0% potato dextrose broth (PDB) (Becton, Dickinson (BD)), 0.1% Taiyo Agar (SSK Sales) pH 6.0). A 500 mL Erlenmeyer flask containing 1 platinum loop was inoculated and cultured with shaking using a rotary shaker (rotation speed: 210 rpm) at 27 ° C for 3 days (seed culture). Then, the obtained 5.0 mL seed culture solution was added to 25 mL of the production medium (1.2% PDB (BD), 1.0% malt extract (BD), 1.0% glucose (Wako Pure Chemical Industries, Ltd.), 0.05% peptone (BD). ), 0.0016% Yunohana (hot spring shop), pH 3) and 50 g of Italian rice were inoculated into a 1000 mL culture vessel and cultured for 21 days under the conditions of static culture at 27 ° C (production culture).

[Production Example I-2: Purification of a novel compound from the culture solution of the BF-0114 strain]
The production culture solution (25 mL × 80) obtained by the production culture for 21 days was extracted with 4.0 L of ethanol under shaking conditions (200 rpm) for 1 hour. The bacterial cell residue was removed by suction filtration to obtain an ethanol extract. Ethanol was distilled off from the extract to obtain an aqueous layer. 1.3 L of ethyl acetate was added to this aqueous layer for phase separation. Then, the ethyl acetate layer was concentrated under reduced pressure to obtain a crude extract (8.6 g). The crude extract was dissolved in a small amount of chloroform and added to a silica gel column (50 g, 3.4 × 15 cm, 0.04-0.063 mm, Merck) to 100% chloroform, 50: 1, 25: 1, 10 :. Elutions were sequentially made with 1, 5: 1 and 1: 1 (v / v) chloroform: methanol and 100% methanol solvent system (200 mL for each solvent, 2 fractions). 25: 1 (v / v) chloroform: methanol solvent elution fraction (6th fraction) (394 mg), reverse phase C-18 high performance liquid chromatography (HPLC) (20 x 250 mm; SHISEIDO CAPCELL PAK C18 , Shiseido), further purified under the following conditions (solvent: 35% -70% acetonitrile aqueous solution, linear gradient condition for 40 minutes; flow rate: 8.0 ml / min; detection: UV 210 nm). Fractions containing peaks eluted at a retention time of 16.0 minutes were collected. The obtained fraction was concentrated to dryness under reduced pressure to give compound (1) as a white powder (14.7 mg).

Based on the instrumental analysis results by specific rotation, IR absorption spectrum, UV absorption spectrum, high resolution ESI-MS, IR spectrum, ¹ H-NMR, and ¹³ C-NMR, compound (1) was converted to cyclo (L-valinyl-). The structure was determined as N-methyl-L-tyrosinyl-anthranyl-L-alanyl).

[Compound 1]
White powder
[α]^{twenty four} _D = -92.7 (C 0.5 CH₃OH)
IR (KBr) ν_max 3324, 2965, 1643, 1514, 1444, 1304 cm^-1
UV (MeOH) λ_max (log ε) 286 (3.5), 253 (sh, 4.0), 221 (sh, 4.4)
Molecular formula; C_{twenty five}H₃₀N_FourO_Five
HR-ESI-MS (m / z); Calculated value: 489.2113 [M + Na]⁺, Measured value: 489.2099 [M + Na]^+
1H and¹³C NMR data (DMSO-d₆Middle): Table 1

<II. Production of new compounds by synthetic means>
[material]
The following solid-phase synthesis was carried out using a libra tube (manufactured by Hypep Laboratory) to which a two-way stop cock was connected. The resin was inflated in dichloromethane for 30 minutes immediately before use before use.

膨順させた2-クロロトリチルクロリドレジン（50.0 mg, 78.5 μmol）に、N-α-(9-フルオレニルメトキシカルボニル)-L-アラニン（78 mg, 236 μmol）のジクロロメタン（2 mL）溶液、及びジイソプロピルエチルアミン（82 μL, 472 μmol）を加え、室温で3時間振蘯した。未反応の2-クロロトリチルクロリドを分解するため、反応液にメタノール（500 μL）を加え、さらに10分間振蘯した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）で洗浄した。次いで、レジンを、2% ジアザビシクロウンデセンのN,N-ジメチルホルムアミド溶液（2 mL）で1分間処理し、9-フルオレニルメトキシカルボニル基を除去した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）、ジクロロメタン（2 mL, 1分間×3）で洗浄した。得られたレジンに担持されたL-アラニン（2）を、次の反応にそのまま用いた。 [Production Example II-1: Production of compound (1)]
[Synthesis Example II-1-1: Support of alanine residue on solid phase]

Dichloromethane (2 mL) solution of N-α- (9-fluorenylmethoxycarbonyl) -L-alanine (78 mg, 236 μmol) in expanded 2-chlorotrityl chloride resin (50.0 mg, 78.5 μmol) , And diisopropylethylamine (82 μL, 472 μmol) were added, and the mixture was shaken at room temperature for 3 hours. In order to decompose unreacted 2-chlorotrityl chloride, methanol (500 μL) was added to the reaction solution, and the mixture was further shaken for 10 minutes. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3). The resin was then treated with 2% diazabicycloundecene in N, N-dimethylformamide (2 mL) for 1 minute to remove the 9-fluorenylmethoxycarbonyl group. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3), dichloromethane (2 mL, 1 min x 3). L-alanine (2) supported on the obtained resin was used as it was in the next reaction.

膨順させたレジン（2）（約78.5 μmol）に、N-α-(9-フルオレニルメトキシカルボニル)-アントラニル酸（85 mg, 236 μmol）及びベンゾトリアゾリルオキシトリピロリジノフォスフォニウム・ヘキサフルオロフォスフェイト（123 mg, 236 μmol）のジクロロメタン/N,N-ジメチルホルムアミド（4/1, 2 mL）溶液、次いでジイソプロピルエチルアミン（82 μL, 472 μmol）を加え、室温で1時間振蘯した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）で洗浄した。次いで、レジンを、2% ジアザビシクロウンデセンのN,N-ジメチルホルムアミド溶液（2 mL）で1分間処理し、9-フルオレニルメトキシカルボニル基を除去した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）、ジクロロメタン（2 mL, 1分間×3）で洗浄した。得られたレジンに担持されたアントラニル-L-アラニン（3）を、次の反応にそのまま用いた。 [Synthesis Example II-1-2: Condensation of anthranilic acid on a solid phase]

N-α- (9-fluorenylmethoxycarbonyl) -anthranylic acid (85 mg, 236 μmol) and benzotriazolyloxytripyrrolidinophosphonium in expanded resin (2) (approximately 78.5 μmol) -Add a solution of hexafluorophosphate (123 mg, 236 μmol) in dichloromethane / N, N-dimethylformamide (4/1, 2 mL), then diisopropylethylamine (82 μL, 472 μmol), and shake at room temperature for 1 hour. did. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3). The resin was then treated with 2% diazabicycloundecene in N, N-dimethylformamide (2 mL) for 1 minute to remove the 9-fluorenylmethoxycarbonyl group. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3), dichloromethane (2 mL, 1 min x 3). The anthranil-L-alanine (3) supported on the obtained resin was used as it was in the next reaction.

膨順させたレジン（3）（約78.5 μmol）に、N-α-(9-フルオレニルメトキシカルボニル)-N-メチル-O-tert-ブチル-L-チロシン（85 mg, 236 μmol）及びブロモトリスピロリジノフォスフォニウム・ヘキサフルオロフォスフェイト（110 mg, 236 μmol）のジクロロメタン/N,N-ジメチルホルムアミド（4/1, 2 mL）溶液、次いでジイソプロピルエチルアミン（82 μL, 472 μmol）を加え、室温で1時間振蘯した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）で洗浄した。次いで、レジンを、2% ジアザビシクロウンデセンのN,N-ジメチルホルムアミド溶液 (2 mL) で1分間処理し、9-フルオレニルメトキシカルボニル基を除去した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）、ジクロロメタン（2 mL, 1分間×3）で洗浄した。得られたレジンに担持されたN-メチル-O-tert-ブチル-L-チロシニル-アントラニル-L-アラニン（4）を、次の反応にそのまま用いた。 [Synthesis Example II-1-3: Condensation of tyrosine residues on the solid phase]

N-α- (9-fluorenylmethoxycarbonyl) -N-methyl-O-tert-butyl-L-tyrosine (85 mg, 236 μmol) and N-α- (9-fluorenylmethoxycarbonyl) -N-methyl-O-tert-butyl-L-tyrosine (85 mg, 236 μmol) and expanded resin (3) (about 78.5 μmol). Add a solution of bromotrispyrrolidinophosphonium hexafluorophosphate (110 mg, 236 μmol) in dichloromethane / N, N-dimethylformamide (4/1, 2 mL), then diisopropylethylamine (82 μL, 472 μmol). , Shake for 1 hour at room temperature. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3). The resin was then treated with 2% diazabicycloundecene in N, N-dimethylformamide (2 mL) for 1 minute to remove the 9-fluorenylmethoxycarbonyl group. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3), dichloromethane (2 mL, 1 min x 3). The N-methyl-O-tert-butyl-L-tyrosinyl-anthranil-L-alanine (4) supported on the obtained resin was used as it was in the next reaction.

膨順させたレジン（4）（約78.5 μmol）に、N-α-(9-フルオレニルメトキシカルボニル)-L-バリン（176 mg, 472 μmol）及び7-アザベンゾトリアゾリルオキシテトラメチルウロニウム・ヘキサフルオロフォスフェイト（180 mg, 472 μmol）のジクロロメタン/N,N-ジメチルホルムアミド（4/1, 2 mL）溶液、次いでジイソプロピルエチルアミン（82 μL, 472 μmol）を加え、室温で1時間振蘯した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）で洗浄した。次いで、レジンを、2% ジアザビシクロウンデセンのN,N-ジメチルホルムアミド溶液（2 mL）で1分間処理し、9-フルオレニルメトキシカルボニル基を除去した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）、N,N-ジメチルホルムアミド（2 mL, 1分間×3）、ジクロロメタン（2 mL, 1分間×3）で洗浄した。得られたレジンに担持された L-バリニル-N-メチル-O-tert-ブチル-L-チロシニル-アントラニル-L-アラニン（5）を、次の反応にそのまま用いた。 [Synthesis Example II-1-4: Condensation of valine residue on solid phase]

N-α- (9-fluorenylmethoxycarbonyl) -L-valine (176 mg, 472 μmol) and 7-azabenzotriazolyloxytetramethyl in expanded resin (4) (approximately 78.5 μmol) Dichloromethane / N, N-dimethylformamide (4/1, 2 mL) solution of uronium hexafluorophosphate (180 mg, 472 μmol) followed by diisopropylethylamine (82 μL, 472 μmol) for 1 hour at room temperature. I was shaken. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3). The resin was then treated with 2% diazabicycloundecene in N, N-dimethylformamide (2 mL) for 1 minute to remove the 9-fluorenylmethoxycarbonyl group. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3), N, N-dimethylformamide (2 mL, 1 min x 3), dichloromethane (2 mL, 1 min x 3). The L-valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-anthranil-L-alanine (5) supported on the obtained resin was used as it was in the next reaction.

膨順させたレジン（5）（約78.5 μmol）に、20% ヘキサフルオロイソプロパノールのジクロロメタン溶液 (2 mL) を加え、室温で15分間撹拌した。反応液を吸引濾過してレジンを濾別した。レジンを、ジクロロメタン（2 mL, 1分間×3）で洗浄した。得られた濾液及び洗浄液を、減圧下溜去して粗生成物を得た。粗生成物を、分取薄層クロマトグラフィー（20 cm × 20 cm, 膜厚：0.75 mm, 溶媒系：クロロホルム/メタノール＝10/1）で精製して、L-バリニル-N-メチル-O-tert-ブチル-L-チロシニル-アントラニル-L-アラニン（6）を得た（10.1 mg, 24%）。 [Synthesis Example II-1-5: Cutting out a chain tetrapeptide from a solid phase]

A dichloromethane solution (2 mL) of 20% hexafluoroisopropanol was added to the inflated resin (5) (about 78.5 μmol), and the mixture was stirred at room temperature for 15 minutes. The reaction solution was suction-filtered and the resin was filtered off. The resin was washed with dichloromethane (2 mL, 1 min x 3). The obtained filtrate and washing liquid were distilled off under reduced pressure to obtain a crude product. The crude product is purified by preparative thin layer chromatography (20 cm x 20 cm, film thickness: 0.75 mm, solvent system: chloroform / methanol = 10/1) and L-valinyl-N-methyl-O-. tert-Butyl-L-tyrosinyl-anthranyl-L-alanine (6) was obtained (10.1 mg, 24%).

[α] _D ²⁴ -26 (c = 0.55, chloroform).
IR (KBr): 2976, 2933, 1639, 1590, 1508, 1446, 1236, 1223, 1162 cm ^-1 .
ESI-MS: Calculated value of the following equation: C ₂₉ H ₄₁ N ₄ O ₆ [M + H] ⁺ 541.3037, Measured value: 541.3026.
¹ H NMR (400 MHz, chloroform-d): δ 11.99 (1H, brs), 8.57 (1H, d, J = 7.5 Hz), 7.65 (1H, d, J = 7.0 Hz), 7.36 (1H, dd, J = 8.0, 7.5 Hz), 7.04 (2H, d, J = 7.5 Hz), 7.02 (1H, dd, J = 8.0, 7.0 Hz), 6.89 (1H, d, J = 7.5 Hz), 4.24 (1H, 1H, m), 4.02-3.92 (2H, m), 3.56 (1H, dd, J = 14.0, 3.5 Hz), 3.29 (1H, dd, J = 14.0, 10.0 Hz), 2.86 (3H, s), 1.75 (1H) , m), 1.33 (9H, s), 1.25 (3H, brs), 0.97 (3H, brs), 0.85 (3H, brs).
¹³ C NMR (100 MHz, chloroform-d): δ 179.2, 170.0, 169.0, 167.2, 153.9, 139.4, 133.2, 132.4, 129.3 (× 2), 127.5, 124.4 (× 2), 124.2, 122.6, 120.2, 78.4 , 69.5, 55.3, 51.6, 39.4, 32.5, 28.9, 28.8 (× 3), 19.3, 16.6, 15.5.

鎖状テトラペプチド（6）（8.5 mg, 15.7 μmol）のN,N-ジメチルホルムアミド（3.0 mL）溶液に、7-アザベンゾトリアゾリルオキシテトラメチルウロニウム・ヘキサフルオロフォスフェイト（6.6 mg, 17.3 μmol）、次いでジイソプロピルエチルアミン（6.0 μL, 34.6 μmol）を加え、室温で24時間撹拌した。反応液を、酢酸エチル（10 mL）で希釈した。有機層を、精製水（10 mL × 3）、飽和炭酸水素ナトリウム溶液（5 mL）、及び飽和食塩水（5 mL）で順次洗浄し、硫酸ナトリウムで乾燥した。乾燥後の有機層を濾過した。濾過した有機層から、減圧下で溶媒を溜去し、粗生成物を得た。粗生成物を、分取薄層クロマトグラフィー（20 cm × 20 cm, 膜厚：0.75 mm, 溶媒系：クロロホルム/メタノール＝10/1）で精製して、無色粉末状のシクロ（L-バリニル-N-メチル-O-tert-ブチル-L-チロシニル-アントラニル-L-アラニル）（7）（7.1 mg, 87%）を得た。 [Synthesis Example II-1-6: Cyclization]

7-Azabenzotriazolyloxytetramethyluronium hexafluorophosphate (6.6 mg, 17.3) in a solution of chain tetrapeptide (6) (8.5 mg, 15.7 μmol) in N, N-dimethylformamide (3.0 mL). (Μmol), then diisopropylethylamine (6.0 μL, 34.6 μmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate (10 mL). The organic layer was washed successively with purified water (10 mL x 3), saturated sodium hydrogen carbonate solution (5 mL), and saturated brine (5 mL), and dried over sodium sulfate. The dried organic layer was filtered. The solvent was distilled off from the filtered organic layer under reduced pressure to obtain a crude product. The crude product is purified by preparative thin layer chromatography (20 cm x 20 cm, film thickness: 0.75 mm, solvent system: chloroform / methanol = 10/1) to form a colorless powdery cyclo (L-valinyl-). N-Methyl-O-tert-butyl-L-tyrosinyl-anthranyl-L-alanyl) (7) (7.1 mg, 87%) was obtained.

[α] _D ²⁶ -100 (c = 0.72, chloroform).
IR (KBr): 3327, 2974, 2930, 1643, 1567, 1445, 1299, 1236, 1162 cm ^-1 .
ESI-MS: Calculated value of the following formula: C ₂₉ H ₃₉ N ₄ O ₅ [M + H] ⁺ 523.2920, measured value: 523.2918.
¹ H NMR (400 MHz, chloroform-d): δ 9.67 (1H, s), 8.33 (1H, d, J = 8.5 Hz), 7.40 (1H, dd, J = 8.0, 7.5 Hz), 7.36 (1H, dd, J = 7.5, 1.5 Hz), 7.07 (1H, d, J = 8.0 Hz), 7.06 (2H, d, J = 8.0 Hz), 7.01 (1H, t, J = 7.5 Hz), 6.91 (2H, 2H, d, J = 8.0 Hz), 6.50 (1H, dd, J = 9.5, 3.5 Hz), 4.46 (1H, t, J = 9.5 Hz), 4.09 (1H, ddq, J = 8.0, 7.0, 2.0 Hz), 3.76 (1H, dd, J = 11.0, 4.0 Hz), 3.48 (1H, dd, J = 14.5, 3.5 Hz), 3.16 (1H, dd, J = 14.5, 11.0 Hz), 2.83 (3H, s), 1.89 (1H, m), 1.36 (3H, dd, J = 7.0, 2.0 Hz), 1.33 (9H, s), 0.85 (3H, dd, J = 7.0, 1.0 Hz), 0.83 (3H, dd, J = 7.0) , 1.0 Hz).
¹³ C NMR (100 MHz, chloroform-d): δ 172.9, 171.9, 170.4, 167.5, 154.0, 136.8, 133.4, 131.9, 129.6 (× 2), 125.9, 124.5 (× 2), 123.9, 123.0, 121.9, 78.5 , 69.6, 54.8, 53.5, 40.1, 33.0, 30.5, 28.8 (× 3), 19.3, 18.2, 16.2.

環状テトラペプチド（7）（7.1 mg, 13.6 μmol）に、トリフルオロ酢酸/トリイソプロピルシラン/ジクロロメタン（1/0.1/2, 1.0 mL）を加え、室温で15分間撹拌した。反応液から、減圧下で溶媒を溜去し、粗生成物を得た。粗生成物を、分取薄層クロマトグラフィー（20 cm × 20 cm, 膜厚：0.75 mm, 溶媒系：クロロホルム/メタノール＝10/1）で精製して、無色粉末状の化合物（1）（6.3 mg, 定量的）を得た。 [Synthesis Example II-1-7: Deprotection of tert-butyl group]

Trifluoroacetic acid / triisopropylsilane / dichloromethane (1 / 0.1 / 2, 1.0 mL) was added to the cyclic tetrapeptide (7) (7.1 mg, 13.6 μmol), and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by preparative thin layer chromatography (20 cm × 20 cm, film thickness: 0.75 mm, solvent system: chloroform / methanol = 10/1) to form a colorless powder compound (1) (6.3). mg, quantitative) was obtained.

[α] _D ²⁴ -111 (c = 0.37, methanol).
IR (KBr): 3324, 2965, 1643, 1514, 1444, 1304, 1232, 1170 cm ^-1 .
ESI-MS: Calculated value of the following formula: C ₂₅ H ₃₁ N ₄ O ₅ [M + H] ⁺ 467.2294, Measured value: 467.2288.
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ): δ 9.63 (1H, s), 8.30 (1H, d, J = 5.0 Hz), 8.29 (1H, d, J = 8.0 Hz), 7.56 (1H, s) dd, J = 7.5, 1.0 Hz), 7.51 (1H, d, J = 9.5 Hz), 7.47 (1H, ddd, J = 8.0, 7.0, 1.0 Hz), 7.12 (1H, t, J = 7.5 Hz), 6.98 (2H, d, J = 7.5 Hz), 6.65 (2H, d, J = 7.5 Hz), 4.31 (1H, dd, J = 10.0, 9.5 Hz), 4.17 (1H, dd, J = 10.5, 3.5 Hz) ), 3.93 (1H, dq, J = 7.0, 5.0 Hz), 3.17 (1H, dd, J = 13.5, 3.5 Hz), 3.00 (1H, dd, J = 13.5, 10.5 Hz), 2.79 (3H, s) , 1.95 (1H, dqq, J = 10.0, 6.5, 6.5 Hz), 1.32 (3H, d, J = 7.0 Hz), 0.81 (3H, d, J = 6.5 Hz), 0.77 (3H, d, J = 6.5 Hz) Hz).
¹³ C NMR (100 MHz, dimethyl sulfoxide-d ₆ ): δ 172.5, 170.9, 169.8, 168.0, 155.7, 136.8, 131.1, 130.1 (× 2), 128.6, 126.9, 124.4, 122.4, 119.9, 115.1 (× 2) , 67.9, 53.9, 53.2, 39.4, 32.1, 29.3, 19.2, 18.2, 15.5.

[Production Example II-2: Production of compound (1-ValD)]
In Production Example II-1, the N-α- (9-fluorenylmethoxycarbonyl) -L-valine used in Synthesis Example II-1-4 was replaced with N-α- (9-fluorenylmethoxycarbonyl). Cyclo (D-valinyl-N-methyl-L-tyrosinyl-anthranyl-L-alanyl) (1-ValD) (7.3 mg) by the same procedure as in Production Example II-1, except that it was changed to -D-valine. Got
ESI-MS: Calculated value of the following formula: C_{twenty five}H₃₀N_FourO_FiveNa [M + Na]⁺ 489.2113, measured value: 489.2102.

[Production Example II-3: Production of compound (1-L1)]
Same as Production Example II-1 except that the cyclization of Synthesis Example II-1-6 and the deprotection of the tert-butyl group of Synthesis Example II-1-7 were changed in Production Example II-1. L-Valinyl-N-methyl-O-tert-butyl-L-tyrosinyl-anthranil-L-alanine (1-L1) (10.1 mg) was obtained by the above procedure.
ESI-MS: Calculated value of the following equation: C ₂₉ H ₄₁ N ₄ O ₆ [M + H] ⁺ 541.3037, Measured value: 541.3016.

[Production Example II-4: Production of compound (1-L2)]
In Production Example II-1, the amino acid carried on the solid phase (2-chlorotrityl chlorideresin) in Synthesis Example II-1-1 was changed to N-α- (9-fluorenylmethoxycarbonyl) -L-valine. Then, N-α- (9-fluorenylmethoxycarbonyl) -L- was added to the L-valine carried on the obtained resin by the same procedure as in Synthesis Examples II-1-2 to II-1-3. Alanine, N-α- (9-fluorenylmethoxycarbonyl) -anthranylic acid, and N-α-(9-fluorenylmethoxycarbonyl) -N-methyl-O-tert-butyl-L-tyrosine are sequentially condensed. However, the procedure was the same as that of Production Example II-1, except that the cyclization of Synthesis Example II-1-6 and the deprotection of the tert-butyl group of Synthesis Example II-1-7 were not carried out. N-Methyl-O-tert-butyl-L-tyrosinyl-anthranyl-L-alanyl-L-valine (1-L2) (11.1 mg) was obtained.
ESI-MS: Calculated value of the following equation: C ₂₉ H ₄₁ N ₄ O ₆ [M + H] ⁺ 541.3037, Measured value: 541.3018.

<III. 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 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. The test compounds (1), (1-ValD), (1-L1) and (1-L2) were prepared in 1.6 mg / mL DMSO solution, respectively. 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 III-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 sterile 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. This suspension was diluted with 0.85% sterile saline to give OD ₅₅₀ = 0.0621 for filamentous fungi and OD ₅₅₀ = 0.0765 for zygomycota. 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)). To each well of the sterilized 96-well plate, 1.0 μL of diluted solution of the test compound prepared by DMSO was added so that the final concentration of the test compound was 32, 16, 8.0… 0.063 μg / mL. 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 calculated compound having an 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 zygomycota. Each well was observed under a microscope (CK2: Olympus). As a result of observation, the minimum concentration at which the growth of filamentous fungi 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, compound (1) showed no growth inhibitory activity against Candida albicans at a concentration of 512 μg / mL or less. Compounds (1-ValD), (1-L1) and (1-L2) showed no growth inhibitory activity against Candida albicans at concentrations below 32 μg / mL.

[Test III-2: Evaluation test of enhancing activity against the antifungal agent amphotericin B]
[Preparation of bacterial solution]
The Candida albicans ATCC90029 strain was coated on a 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 sterile 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.

[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)). Each well of the sterile 96-well plate will have a final concentration of compound (1), (1-ValD), (1-L1) and (1-L2) of 32, 16, 8, 4 or 2 μg / mL. As described above, 1.0 μL of the diluted solution of the test compound prepared by DMSO was added. 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, 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). 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.

[Evaluation of amphotericin B activity enhancing effect of compound BF-0114 by trace liquid dilution method]
In each well of the sterilized 96-well plate, the final concentrations of compound (1), (1-ValD), (1-L1) and (1-L2) were 32, 16, 8, 4 or 2 μg / mL. 1.0 μL each of the test compound prepared by DMSO and the diluted solution of amphotericin B was added so that the final concentration of amphotericin B was 1.0, 0.5, 0.25, 0.125, 0.0625 or 0.00313 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 test 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 test compound and amphotericin B. In addition, the amphotericin B activity enhancement rate of each test 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 2 shows the MIC values of amphotericin B when compound (1), (1-ValD), (1-L1) or (1-L2) and amphotericin B were co-administered. In the table, the column of "Test compound concentration" indicates the concentration of the test compound at the time of combined administration of compound (1), (1-ValD), (1-L1) or (1-L2) and amphotericin B. The "Amphotericin B Concentration" column shows the MIC value of amphotericin B when the test compound and amphotericin B are co-administered.

Table 3 shows the amphotericin B activity enhancement rate of the test compound when the compound (1), (1-ValD), (1-L1) or (1-L2) and amphotericin B were co-administered. In the table, the column of "Test compound concentration" indicates the concentration of the test compound at the time of combined administration of compound (1), (1-ValD), (1-L1) or (1-L2) and amphotericin B. The column "Amphotericin B activity enhancement rate of test compound" shows the amphotericin B activity enhancement rate of each concentration of the test compound.

As shown in Table 3, by administering 2 μg / mL, especially 8 μg / mL or more of the compounds (1), (1-ValD), (1-L1) or (1-L2) in combination with amphotericin B. , The antifungal activity of amphotericin B against Candida albicans was enhanced 2 to 16 times, especially 4 to 16 times.

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 (20)

Equation (I):

[During the ceremony,
R ¹ is 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 ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₅ -alkyl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, or substituted or unsubstituted 5 to 15-membered. Heteroaryl-C ₁ to C ₅ alkyl,
R ² is OH, 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 member heteroaryloxy, substituted Or an unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ alkyloxy, or a substituted or unsubstituted C ₁ to C ₂₀ acyloxy.
R ³ is propan-2-yl. ]
A compound represented by, or a salt thereof, or a solvate thereof. The compound according to claim 1, a salt thereof, or a solvate thereof, wherein R ¹ is methyl. The compound according to claim 1 or 2, or a salt thereof, or a solvate thereof, wherein R ² is OH, methoxy, ethoxy, propoxy, or butoxy. R ¹ is methyl,
R ² is OH,
The compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof, wherein R ³ is propan-2-yl. Equation (I-L1):

[During the ceremony,
R ¹ is 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 ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₅ -alkyl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, or substituted or unsubstituted 5 to 15-membered. Heteroaryl-C ₁ to C ₅ alkyl,
R ² is OH, 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 member heteroaryloxy, substituted Or an unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ alkyloxy, or a substituted or unsubstituted C ₁ to C ₂₀ acyloxy.
R ³ is propan-2-yl. ]
A compound represented by, or a salt thereof, or a solvate thereof. Equation (I-L2):

[During the ceremony,
R ¹ is 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 ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₅ -alkyl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, or substituted or unsubstituted 5 to 15-membered. Heteroaryl-C ₁ to C ₅ alkyl,
R ² is OH, 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 member heteroaryloxy, substituted Or an unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₅ alkyloxy, or a substituted or unsubstituted C ₁ to C ₂₀ acyloxy.
R ³ is propan-2-yl. ]
A compound represented by, or a salt thereof, or a solvate thereof. The compound according to claim 5 or 6, a salt thereof, or a solvate thereof, wherein R ¹ is methyl. The compound according to any one of claims 5 to 7, or a salt thereof, or a solvate thereof, wherein R ² is OH, methoxy, ethoxy, propoxy, or butoxy. R ¹ is methyl,
R ² is OH or tert-butoxy,
The compound according to claim 5 or 6, a salt thereof, or a solvate thereof, wherein R ³ is propan-2-yl. A method for producing a compound represented by the formula (I) according to claim 4, a salt thereof, or a solvate thereof.
A microorganism of BF-0114 strain (NITE P-02402) belonging to the family Nectriaceae, which has the ability to produce a compound represented by the formula (I), is cultured in a medium and represented by the formula (I). Compound accumulation step of accumulating the compound to be 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 which is a BF-0114 strain (NITE P-02402) belonging to the family Nectriaceae, which has an ability to produce a compound represented by the formula (I) according to claim 4. A method for producing a compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof.
Equations (VI), (VII), (VIII) and (IX):

[In the formula, R ¹ , R ² and R ³ have the meaning described in any one of claims 1 to 4. ]
A linear peptide having the amino acid sequence of the compound represented by the formula (I) by linking between the amino group and the carboxyl group of the compound represented by, or a protected derivative thereof, or a salt or a mixture thereof. Linear peptide forming step to form;
A cyclization step of intramolecularly cyclizing the linear peptide obtained in the linear peptide forming step to obtain a compound represented by the formula (I);
The above method. A method for producing a compound according to any one of claims 5 to 9, a salt thereof, or a solvate thereof.
Equations (VI), (VII), (VIII) and (IX):

[In the formula, R ¹ , R ² and R ³ have the meaning described in any one of claims 5 to 9. ]
The amino acid of the compound represented by the formula (I-L1) or (I-L2) by linking between the amino group and the carboxyl group of the compound represented by (I-L1) or a protected derivative thereof, or a salt or a mixture thereof. A linear peptide forming step of forming a linear peptide having a sequence;
The method described above. An agent for enhancing the activity of an antifungal drug, which is amphotericin B, containing the compound according to any one of claims 1 to 9, a salt thereof, or a solvate thereof as an active ingredient. A pharmaceutical product for enhancing the activity of an antifungal drug which is amphotericin B, which comprises the compound according to any one of claims 1 to 9 or a salt thereof, or a solvate thereof as an active ingredient. The pharmaceutical agent according to claim 15 , for use in the prevention or treatment of one or more fungal infections through the activity of enhancing the activity of an antifungal drug which is amphotericin B. The pharmaceutical product according to claim 15 or 16 , further comprising an antifungal drug that is amphotericin B. The activity of an antifungal agent which is amphotericin B, which comprises the compound according to any one of claims 1 to 9, or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers. Pharmaceutical composition for enhancing. The pharmaceutical composition according to claim 18 , for use in the prevention or treatment of one or more fungal infections through an activity that enhances the activity of an antifungal drug that is amphotericin B. The pharmaceutical composition according to claim 18 or 19 , further comprising an antifungal agent that is amphotericin B.