JP7256527B2 - NOVEL POLYTERPENOID COMPOUND HAVING ACTIVITY-ENHANCEMENT ACTIVITY FOR ANTIFUNGAL AGENT AND METHOD FOR PRODUCING THE SAME - Google Patents

Description

NPMD NITE BP-02936

TECHNICAL FIELD The present invention relates to a novel polyterpenoid compound having an activity-enhancing effect on antifungal agents and a method for producing the same. In particular, one aspect of the present invention is a novel poly(1) having an activity-enhancing effect on at least one antifungal drug selected from the group consisting of polyene macrolides, azoles, candins, and fluoropyrimidines. The present invention relates to a terpenoid compound and a method for producing the same.

Since the 1950s, antibiotic research and development has made rapid progress. Along with this, antibiotics have become widely used, 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 mycoses 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, HIV infection, etc., decreased immune function due to administration of anticancer drugs, or bacterial replacement due to heavy use of antibiotics. It is believed that.

Currently, antifungal drugs such as polyene macrolides, azoles, candins and fluoropyrimidines are used for the treatment of deep mycoses. For example, amphotericin B, a polyene macrolide, has potent antifungal activity and is 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, one of the fluoropyrimidine drugs, also poses problems of low safety and the presence of resistant bacteria.

Azole drugs are generally considered to have a wide margin of safety and relatively few side effects. However, this drug has a narrow antifungal spectrum and exhibits a bacteriostatic mechanism of action, which makes it less effective against severe disease. In addition, an increase in bacteria resistant to the drug has also been pointed out (Non-Patent Document 2).

In recent years, candin drugs such as micafungin and caspofungin have been developed and used for the treatment of deep-seated mycoses (Non-Patent Document 3). However, this drug has a narrow antifungal spectrum, and is therefore limited to treating diseases such as candidiasis or aspergillosis. In addition, the number of reported cases of resistant bacteria to the drug is gradually increasing.

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

Patent Documents 2 and 3 disclose a novel compound represented by formula (I), which has the effect of effectively enhancing the antifungal activity of antifungal drugs and has a skeleton structure different from that of known pharmaceutical compounds. At least one selected from the group consisting of polyene macrolide drugs, azole drugs, candin drugs and fluoropyrimidine drugs containing compounds or salts thereof, or solvates thereof, and said compounds as active ingredients Kinds of antifungal activity enhancers are described.

Patent No. 5843188 Japanese Patent Application Laid-Open No. 2018-111670 Japanese Patent Application Laid-Open No. 2018-118912

Gallis et al., Rev. Infect. Dis., 12, 309-329, 1990 Rex et al., Antimicrob. Agents Chemothe., 39:1-8, 1995. Denning, Lancet, Vol. 362, No. 9330, pp. 1142-1151, 2003

Hematological diseases such as leukemia, or diseases associated with a weakened immune system such as HIV infection, cause immunocompromise. For this reason, patients with such diseases may have an increased incidence of fungal infections as opportunistic infections. In addition, since these diseases accompanied by weakened immunity usually tend to be aggravated, the treatment period is often long. As a result, chemotherapy for fungal infections is also often prolonged.

There are several problems with antifungal agents that are currently frequently used in the treatment of fungal infections such as deep mycosis. For example, amphotericin B, one of the polyene macrolide drugs, may cause side effects such as severe nephrotoxicity. In addition, it is known that azole drugs are extremely susceptible to the development of drug-resistant bacteria. Therefore, there is a need for a means of reducing the dosage and duration of administration of the antifungal agents to avoid these problems and still provide therapeutic efficacy for fungal infections.

Compounds that act to enhance the antifungal activity of an antifungal agent can reduce the dosage and/or shorten the duration of administration of the antifungal agent. Therefore, by using a compound having such an action in combination with an antifungal drug, the dosage of the antifungal drug can be reduced and/or the administration period can be shortened, thereby suppressing the occurrence of side effects such as nephrotoxicity. and/or inhibit the development of drug-resistant bacteria. Various compounds such as the FKI-4981B substance and its pharmaceutically acceptable salts are known as compounds having the above action (Patent Documents 1 to 3). However, in order to develop more effective pharmaceutical compounds, there is a need for novel compounds that effectively enhance the antifungal activity of antifungal drugs and have a skeleton structure different from that of known pharmaceutical compounds. was

Therefore, an object of the present invention is to provide a novel compound that effectively enhances the antifungal activity of an antifungal agent and has a skeleton structure different from that of known pharmaceutical compounds.

The present inventors have studied various means for solving the above problems. The present inventors have found that a novel bacterium isolated from soil produces a compound in its culture solution that effectively enhances the antifungal activity of amphotericin B, a polyene macrolide drug. Found it. The present inventors have found that the compound in the culture medium is a novel compound having a skeleton structure different from known pharmaceutical compounds. In addition, the present inventors have found that the compound can be produced by a culture method using the fungus. The present inventors completed the present invention based on the above findings.

［式中、
R^1’は、水素、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カルボニル、置換若しくは非置換のシクロアルコキシカルボニル、又は置換若しくは非置換のアシルであり、
R⁶及びR⁷は、互いに独立して、ヒドロキシル、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るか、或いは
R⁶及びR⁷は、一緒になって共有結合を形成し、
R^10aは、水素であり、
R^11aは、ヒドロキシル、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るか、或いは
R^10a及びR^11aは、一緒になって共有結合を形成し、
R^14aは、水素であり、
R^15aは、ヒドロキシル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルコキシ、置換若しくは非置換のヘテロシクロアルコキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のアリールアルケニルオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、又は置換若しくは非置換のアシルオキシであり、
R^19’、R^23’、及びR^27’は、互いに独立して、水素、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カルボニル、置換若しくは非置換のシクロアルコキシカルボニル、又は置換若しくは非置換のアシルであり、
R^31a、R^34a及びR^35aは、互いに独立して、ヒドロキシル、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るか（但し、R^10a及びR^11aが、一緒になって共有結合を形成する場合、R^31a、R^34a及びR^35aがいずれもヒドロキシルであることはない）、或いは
R^31a及びR^34aは、一緒になって-O-を形成し、且つ
R^35aは、ヒドロキシル、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るか、或いは
R^31aは、ヒドロキシル、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、且つ
R^34a及びR^35aは、一緒になって共有結合を形成する。］
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） R^10aが、水素であり、且つR^11aが、ヒドロキシルであるか、或いは
R^10a及びR^11aが、一緒になって共有結合を形成する、前記実施形態（1）に記載の化合物若しくはその塩、又はそれらの溶媒和物。
（３） R^14aが、水素であり、且つR^15aが、ヒドロキシルである、前記実施形態（1）又は（2）に記載の化合物若しくはその塩、又はそれらの溶媒和物。
（４） R^19’、R^23’、及びR^27’が、互いに独立して、水素、置換若しくは非置換のC₁～C₆アルキル、置換若しくは非置換のC₂～C₆アルケニル、置換若しくは非置換のC₂～C₆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、又は置換若しくは非置換のC₃～C₆シクロアルキニルである、前記実施形態（1）～（3）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。
（５） R^31a及びR^34aが、一緒になって-O-を形成し、且つR^35aが、ヒドロキシル、置換若しくは非置換のC₁～C₆アルコキシ、又は置換若しくは非置換のC₃～C₆シクロアルコキシである、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。
（６） R^1’が、水素であり、
R⁶及びR⁷が、一緒になって共有結合を形成し、
R^10aが、水素であり、且つR^11aが、ヒドロキシルであるか、或いは
R^10a及びR^11aが、一緒になって共有結合を形成し、
R^14aが、水素であり、
R^15aが、ヒドロキシルであり、
R^19’、R^23’、及びR^27’が、いずれも水素であり、
R^31a及びR^34aが、一緒になって-O-を形成し、且つR^35aが、ヒドロキシルである、前記実施形態（1）～（5）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。
（７） 前記実施形態（1）～（6）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（Ia）で表される化合物を産生する能力を有する真菌アスペルギルス・ポリポリコラ BFM-0088株（受託番号NITE BP-02936）又はその変異株である微生物を培地中で培養して、式（Ia）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（Ia）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。
（８） 前記実施形態（1）～（6）のいずれかに記載の式（Ia）で表される化合物を産生する能力を有する真菌アスペルギルス・ポリポリコラBFM-0088株（受託番号NITE BP-02936）又はその変異株である微生物。
（９） 式（I）：

［式中、
R^1’は、水素、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カルボニル、置換若しくは非置換のシクロアルコキシカルボニル、又は置換若しくは非置換のアシルであり、
R⁶及びR⁷は、互いに独立して、ヒドロキシル、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るか、或いは、
R⁶及びR⁷は、一緒になって共有結合を形成し、
R¹⁰及びR¹¹は、互いに独立して、水素、ヒドロキシル、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るか、或いは
R¹⁰及びR¹¹は、一緒になって共有結合又は-O-を形成し、
R¹⁴は、水素であり、
R¹⁵は、ヒドロキシル、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るか、或いは、
R¹⁴及びR¹⁵は、一緒になって共有結合を形成し、
R^19’、R^23’、及びR^27’は、互いに独立して、水素、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カルボニル、置換若しくは非置換のシクロアルコキシカルボニル、又は置換若しくは非置換のアシルであり、
R³¹、R³⁴及びR³⁵は、互いに独立して、ヒドロキシル、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るか、或いは、
R³¹及びR³⁴は、一緒になって-O-を形成し、且つ
R³⁵は、ヒドロキシル、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るか、或いは
R³¹は、ヒドロキシル、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、且つ
R³⁴及びR³⁵は、一緒になって共有結合を形成する。］
で表される化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される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。
（１０） 式（I）で表される化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される溶媒和物が、前記実施形態（1）～（6）のいずれかに記載の化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される溶媒和物である、前記実施形態（9）に記載の抗真菌薬の活性増強剤。
（１１） 前記実施形態（1）～（6）のいずれかに記載の化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される溶媒和物を有効成分として含む医薬。
（１２） 1種以上の真菌感染症の予防又は治療に使用するための、前記実施形態（11）に記載の医薬。
（１３） 前記実施形態（9）又は（10）に記載の抗真菌薬の活性増強剤を有効成分として含む、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医薬。
（１４） ポリエンマクロライド系薬剤、アゾール系薬剤、キャンディン系薬剤及びフルオロピリミジン系薬剤からなる群より選択される少なくとも1種の抗真菌薬をさらに含む、前記実施形態（11）～（13）のいずれかに記載の医薬。
（１５） 前記実施形態（1）～（6）のいずれかに記載の化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される溶媒和物と、1種以上の製薬上許容される担体とを含む医薬組成物。
（１６） 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（15）に記載の医薬組成物。
（１７） 前記実施形態（9）又は（10）に記載の抗真菌薬の活性増強剤と、1種以上の製薬上許容される担体とを含む、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（15）～（17）のいずれかに記載の医薬組成物。 That is, the present invention includes the following aspects and embodiments.
(1) Formula (Ia):

[In the formula,
R ^1′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cyclo alkynyl, 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 alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl;
R ⁶ and R ⁷ are independently of each other hydroxyl, 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, or
^R6 and ^R7 together form a covalent bond,
R ^10a is hydrogen,
R ^11a is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted is substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or
R ^10a and R ^11a together form a covalent bond,
R ^14a is hydrogen,
R ^15a is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy;
R ^19′ , R ^23′ and R ^27′ are each independently hydrogen, 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 alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl and
R ^31a , R ^34a and R ^35a are independently of each other hydroxyl, 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 (provided that R when ^10a and R ^11a together form a covalent bond, none of R ^31a , R ^34a and R ^35a can be hydroxyl), or
R ^31a and R ^34a together form -O-, and
R ^35a is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted is substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or
R ^31a is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, and
R ^34a and R ^35a together form a covalent bond. ]
A compound represented by or a salt thereof, or a solvate thereof.
(2) R ^10a is hydrogen and R ^11a is hydroxyl, or
The compound or a salt thereof, or a solvate thereof according to Embodiment (1), wherein R ^10a and R ^11a together form a covalent bond.
(3) The compound or a salt thereof, or a solvate thereof according to Embodiment (1) or (2), wherein R ^14a is hydrogen and R ^15a is hydroxyl.
(4) R ^19′ , R ^23′ and R ^27′ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, or substituted or unsubstituted C ₃ -C ₆ cycloalkynyl; A compound or a salt thereof, or a solvate thereof according to any one of Embodiments (1) to (3).
(5) R ^31a and R ^34a together form -O-, and R ^35a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C The compound according to any one of Embodiments (1) to (4), a salt thereof, or a solvate thereof, which is _6- cycloalkoxy.
(6) R ^1' is hydrogen;
^R6 and ^R7 together form a covalent bond,
R ^10a is hydrogen and R ^11a is hydroxyl, or
R ^10a and R ^11a together form a covalent bond,
R ^14a is hydrogen,
R ^15a is hydroxyl,
R ^19′ , R ^23′ , and R ^27′ are all hydrogen;
The compound or salt thereof, or a salt thereof, according to any of the preceding embodiments (1) to (5), wherein R ^31a and R ^34a together form -O- and R ^35a is hydroxyl solvate of
(7) A method for producing a compound or a salt thereof, or a solvate thereof according to any one of Embodiments (1) to (6),
The fungus Aspergillus polypolichola BFM-0088 strain (accession number NITE B P-02936) having the ability to produce the compound represented by the formula (Ia) or a microorganism that is a mutant strain thereof is cultured in a medium to produce the compound represented by the formula (Ia ) in the medium, a compound accumulation step;
A compound purification step of purifying the compound represented by formula (Ia) obtained in the compound accumulation step from the culture of the microorganism;
The above method, comprising
(8) The fungus Aspergillus polypolichola BFM-0088 strain (Accession No. NITE B P-02936 ) or a microorganism that is a mutant strain thereof.
(9) Formula (I):

[In the formula,
R ^1′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cyclo alkynyl, 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 alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl;
R ⁶ and R ⁷ are independently of each other hydroxyl, 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, or
^R6 and ^R7 together form a covalent bond,
R ¹⁰ and R ¹¹ are independently of each other hydrogen, hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or is unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or
R ¹⁰ and R ¹¹ together form a covalent bond or -O-,
R ¹⁴ is hydrogen,
R ¹⁵ is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted is substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or
R ¹⁴ and R ¹⁵ together form a covalent bond,
R ^19′ , R ^23′ and R ^27′ are each independently hydrogen, 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 alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl and
R ³¹ , R ³⁴ and R ³⁵ are independently of each other hydroxyl, 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, or
R ³¹ and R ³⁴ together form -O-, and
R ³⁵ is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted is substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or
R ³¹ is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, and
^R34 and ^R35 together form a covalent bond. ]
Polyene macrolides, azoles, candins and fluoropyrimidines containing the compound represented by or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient At least one antifungal drug activity enhancer selected from the group consisting of:
(10) The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to any one of the above embodiments (1) to (6) The antifungal drug activity enhancer according to Embodiment (9), which is a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
(11) A medicament containing, as an active ingredient, the compound according to any one of Embodiments (1) to (6), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
(12) The medicament according to embodiment (11), for use in preventing or treating one or more fungal infections.
(13) A medicament for use in the prevention or treatment of one or more fungal infections, comprising the antifungal drug activity enhancer according to Embodiment (9) or (10) as an active ingredient.
(14) The above embodiments (11) to (13), further comprising at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, candin drugs, and fluoropyrimidine drugs. The medicament according to any one of
(15) the compound according to any one of the above embodiments (1) to (6) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable and a carrier.
(16) The pharmaceutical composition of embodiment (15) above for use in preventing or treating one or more fungal infections.
(17) Prevention or treatment of one or more fungal infections, comprising the antifungal drug activity enhancer according to embodiment (9) or (10) and one or more pharmaceutically acceptable carriers. A pharmaceutical composition for use in
(18) The above embodiments (15) to (17), further comprising at least one antifungal drug selected from the group consisting of polyene macrolides, azoles, candins, and fluoropyrimidines. The pharmaceutical composition according to any one of

According to each aspect of the present invention, it is possible to provide a novel compound that effectively enhances the antifungal activity of an antifungal drug and has a skeleton structure different from that of known pharmaceutical compounds.

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

Preferred embodiments of the present invention are described in detail below.

<1. Compound>
As used herein, "alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, “C ₁ -C ₆ alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing at least 1 and at most 6 carbon atoms. Suitable alkyls are straight or branched chains such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Mention may be made of branched C ₁ -C ₆ alkyl.

As used herein, "alkenyl" means a group in which one or more CC single bonds of the above alkyl are replaced with double bonds. Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 -Methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-pentenyl and 1-hexenyl, which may be linear or branched C2 _{- C6} alkenyls. .

As used herein, "alkynyl" means a group in which one or more CC single bonds of the above alkyl are replaced with triple bonds. Suitable alkynyls include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl and 1-hexynyl. and straight or branched chain C ₂ -C ₆ alkynyl.

As used herein, "cycloalkyl" means a cycloaliphatic alkyl containing the specified number of carbon atoms. For example, " _C3 - _C6 cycloalkyl" means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, C ₃ -C ₆ cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, "cycloalkenyl" means a group in which one or more CC single bonds of the above cycloalkyl are replaced with double bonds. Suitable cycloalkenyls include, but are not limited to, C ₄ -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 above cycloalkyl are replaced with triple bonds. Suitable cycloalkynyls include, but are not limited to, _C4 - _C6 cycloalkynyls such as cyclobutynyl, cyclopentynyl and cyclohexynyl.

As used herein, "heterocycloalkyl" means that one or more carbon atoms of said cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O) means a group substituted with one or more heteroatoms. In this case, substitution by N or S includes substitution of N-oxides or S by oxides or dioxides, respectively. Suitable heterocycloalkyls include, but are not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. Mention may be made of ~6-membered heterocycloalkyl.

As used herein, "cycloalkylalkyl" means a group in which one hydrogen atom of the above alkyl, alkenyl or alkynyl is replaced with the above cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkylalkyls include, but are not limited to, C ₇ -C ₁₁ cycloalkylalkyls such as cyclohexylmethyl and cyclohexenylmethyl.

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

As used herein, "alkoxy" and "alkoxyl" mean a group in which a hydrogen atom of hydroxyl is substituted with the aforementioned alkyl, alkenyl or alkynyl. Suitable alkoxy and alkoxyl are C ₁ -C ₆ alkoxy or C ₁ - _C6 alkoxyl may be mentioned.

As used herein, "cycloalkoxy" and "cycloalkoxyl" mean a group in which a hydroxyl hydrogen atom is replaced with the above cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkoxy and cycloalkoxyl are C ₃ -C ₆ cycloalkoxy or C ₃ Mention may be made of ~ _C6 cycloalkoxyl.

As used herein, "heterocycloalkoxy" and "heterocycloalkoxyl" mean a group in which a hydrogen atom of hydroxyl is substituted with the above heterocycloalkyl. Suitable heterocycloalkoxy and heterocycloalkoxyl include, but are not limited to, 3-6 membered heterocycloalkoxy or 3-6 membered heterocycloalkoxyl.

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

As used herein, "arylalkyl" means a group in which one hydrogen atom of the above alkyl, alkenyl or alkynyl is substituted with the above aryl. Suitable arylalkyls include, but are not limited to, _C7 - _C20 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 said aryl are each independently substituted with one or more heteroatoms selected from N, S and O. In this case, substitution by N or S includes substitution of N-oxides or S by oxides or dioxides, respectively. Suitable heteroaryl include, but are not limited to, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Mention may be made of 5- to 15-membered heteroaryls such as pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.

As used herein, "heteroarylalkyl" means a group in which one hydrogen atom of the above alkyl, alkenyl or alkynyl is replaced with the above heteroaryl. Suitable heteroarylalkyls include, but are not limited to, 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyls such as pyridylmethyl.

As used herein, "aryloxy" means a group in which a hydrogen atom of hydroxyl is substituted with the above aryl. Suitable aryloxy include, but are not limited to, C ₆ -C ₁₈ aryloxy such as phenoxy, biphenyloxy, naphthyloxy and anthryloxy (anthracenyloxy).

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

As used herein, "heteroaryloxy" means a group in which a hydroxyl hydrogen atom is substituted with the above heteroaryl. Suitable heteroaryloxy include, but are not limited to, furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso 5 to 15 of oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy and indolyloxy; membered heteroaryloxy.

As used herein, "heteroarylalkyloxy" means a group in which a hydroxyl hydrogen atom is substituted with the above heteroarylalkyl. Suitable heteroarylalkyloxy include, but are not limited to, 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy.

As used herein, "acyl" means a group in which a monovalent group selected from the groups described above and carbonyl are linked. Suitable acyl are C1 _- C20 acyl including, but not limited to, _C1 - _C6 aliphatic acyl such as formyl, _acetyl and propionyl, and _C7 - _C20 aromatic acyl such as benzoyl. can be mentioned.

Each of the groups described above can be independently unsubstituted or further substituted with 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 invention is a compound of formula (Ia):

The compound represented by or a salt thereof, or a solvate thereof.

で表される化合物若しくはその製薬上許容される塩、又はそれらの製薬上許容される溶媒和物を有効成分として含む抗真菌薬の活性増強剤に関する。 Another aspect of the invention is a compound of formula (I):

A compound represented by or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient for an antifungal drug activity enhancer.

The present inventors have found that a novel fungus isolated from soil produces in its culture medium a compound that effectively enhances the antifungal activity of amphotericin B, a polyene macrolide drug. Found it. The present inventors have found, from the culture solution, a known compound glysoprenin F and novel compounds glysoprenins G and H (hereinafter also simply referred to as "glysoprenins") having an activity to enhance the antifungal activity of amphotericin B. rice field. Glysoprenins F, G, and H exhibit substantially no antifungal activity when administered alone, but can significantly enhance the antifungal activity of amphotericin B when administered in combination with amphotericin B. Compounds represented by Formula (Ia) according to one aspect of the present invention include the novel natural organic compounds glysoprenin G and H, and analogous compounds thereof. In addition, the compound represented by formula (I), which is the active ingredient of the antifungal agent activity enhancer of one embodiment of the present invention, includes known or novel natural organic compounds glysoprenins and their analogues. That is, the compound represented by Formula (I) includes the compound represented by Formula (Ia). Therefore, the compound represented by formula (I), which is the active ingredient of the antifungal activity enhancer of one embodiment of the present invention, particularly the compound represented by formula (Ia) of one embodiment of the present invention, It can effectively enhance the antifungal activity of fungal drugs.

The compounds represented by formula (Ia) are novel compounds not disclosed in the prior art. The compounds represented by the formula (I), particularly the compounds represented by the formula (Ia), have a higher antifungal activity-enhancing effect than the compounds described in Patent Documents 1 to 3, for example. In addition, the compound represented by formula (I), particularly the compound represented by formula (Ia), has a polyterpenoid skeleton. Such a skeleton structure of the compound represented by the formula (I), particularly the compound represented by the formula (Ia), is an active ingredient contained in the antifungal agent activity enhancer described in Patent Documents 1 to 3, for example. It differs from the skeletal structure of the compound. Therefore, the compound represented by formula (I), which is the active ingredient of the antifungal activity enhancer of one embodiment of the present invention, particularly the compound represented by formula (Ia) of one embodiment of the present invention, has been conventionally There is a possibility that a significant therapeutic effect can be expressed in patients who cannot obtain a sufficient effect of enhancing the activity of antifungal drugs with these drugs.

In formulas (I) and (Ia), R ^1' is hydrogen, 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 substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl. R ^1′ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C _{3 -C6} cycloalkyl, substituted or unsubstituted C3 _{- C6} cycloalkenyl, substituted or unsubstituted _C3 - _C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1- _C6 alkyl, substituted or unsubstituted _C6 - _C18 aryl, _substituted or unsubstituted _{C7 -C20} arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl- _C1 - _C6 alkyl, substituted or unsubstituted C1 _{- C6} alkoxy preferably carbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₂₀ acyl; hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted _C3 - _C6 cycloalkyl, substituted or unsubstituted _C4 - _C6 cycloalkenyl, or substituted or unsubstituted _C4 - _C6 cycloalkynyl is more preferred; hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl is more preferred; hydrogen is particularly preferred. When R ^1' is the group exemplified above, the compound represented by formula (I), particularly the compound represented by formula (Ia), can effectively enhance the antifungal activity of the antifungal agent. can.

In formulas (I) and (Ia), R ⁶ and R ⁷ are independently of each other hydroxyl, 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 or ^R6 and ^R7 together form a covalent bond. R ⁶ and R ⁷ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered hetero cycloalkoxy _, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7- _C20 arylalkyloxy, substituted or unsubstituted _C7 - _C20 arylalkenyloxy, substituted or unsubstituted 5 ~15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl- _C1 - _C6 alkyloxy, or substituted or unsubstituted _C1 - _C20 acyloxy, or ^R6 and R ⁷ preferably together form a covalent bond; independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy or more preferably ^R6 and ^R7 together form a covalent bond; both are hydroxyl; alternatively ^R6 and ^R7 can together form a covalent bond. More preferred; together forming a covalent bond is particularly preferred. When R ⁶ and R ⁷ are the groups exemplified above, the compound represented by formula (I), particularly the compound represented by formula (Ia), effectively enhances the antifungal activity of the antifungal agent. be able to.

In formula (I), R ¹⁰ and R ¹¹ are independently of each other hydrogen, hydroxyl, 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 Alternatively, R ¹⁰ and R ¹¹ together form a covalent bond or -O-. R ¹⁰ and R ¹¹ are independently of each other hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy _, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7- _C20 arylalkyloxy, substituted or unsubstituted C7- _{C20 arylalkenyloxy} , substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or R ¹⁰ and R ¹¹ together preferably form a covalent bond or —O—; independently of each other, hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C more preferably ₃ - _C6 cycloalkoxy, or R ¹⁰ and R ¹¹ together form a covalent bond or -O-; R ¹⁰ is hydrogen and R ¹¹ is hydroxyl or R ¹⁰ and R ¹¹ together form a covalent bond or -O-. When R ¹⁰ and R ¹¹ are the groups exemplified above, the compound represented by formula (I) can effectively enhance the antifungal activity of the antifungal agent.

In Formula (Ia), R ^10a is hydrogen and R ^11a is hydroxyl, 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 , or R ^10a and R ^11a together form a covalent bond. R ^10a is hydrogen and R ^11a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7 _{- C20} arylalkyloxy, substituted or unsubstituted C7- _C20 arylalkenyloxy, _substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or R ^10a and Preferably, R ^11a together form a covalent bond; R ^10a is hydrogen and R ^11a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted more preferably R ^10a and R ^11a together ^form a covalent bond _; R ^10a is hydrogen and R _11a is hydroxyl , or R ^10a and R ^11a together form a covalent bond. When R ^10a and R ^11a are the groups exemplified above, the compound represented by formula (Ia) can effectively enhance the antifungal activity of an antifungal drug.

In formula (I), R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, 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 , or R ¹⁴ and R ¹⁵ together form a covalent bond. R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or _{unsubstituted} C7 _{- C20} arylalkyloxy, substituted or unsubstituted C7- _C20 arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or R ¹⁴ and R ¹⁵ preferably together form a covalent bond; R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy or more preferably R ¹⁴ and R ¹⁵ together form a covalent bond; R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl , or R ¹⁴ and R ¹⁵ together form a covalent bond. When R ¹⁴ and R ¹⁵ are the groups exemplified above, the compound represented by formula (I) can effectively enhance the antifungal activity of the antifungal agent.

In formula (Ia), R ^14a is hydrogen and R ^15a is hydroxyl, 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 ^14a is hydrogen and R ^15a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7 _{- C20} arylalkyloxy, substituted or unsubstituted C7- _C20 arylalkenyloxy, _substituted or unsubstituted preferably 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy; R ^14a is hydrogen and R ^15a is more preferably hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy; R ^14a is hydrogen and R ^15a is more preferably hydroxyl. When R ^14a and R ^15a are the groups exemplified above, the compound represented by formula (Ia) can effectively enhance the antifungal activity of the antifungal drug.

In formulas (I) and (Ia), R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, 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 hetero cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cyclo alkoxycarbonyl, or substituted or unsubstituted acyl. R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted C3 _{- C6} cycloalkyl, substituted or _{unsubstituted C3} - _C6 cycloalkenyl, substituted or unsubstituted C3- _C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl- _C1 - _C6 alkyl, substituted or unsubstituted C ₆ -C ₁₈ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₂₀ acyl; independently of each other is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C more preferably ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, or substituted or unsubstituted C ₃ -C ₆ cycloalkynyl; independently of each other, hydrogen, methyl, ethyl, propyl, More preferred are butyl, pentyl or hexyl; especially preferred are all hydrogen. When R ^19′ , R ^23′ , and R ^27′ are the groups exemplified above, the compound represented by formula (I), particularly the compound represented by formula (Ia), is an antifungal antifungal agent. Activity can be effectively enhanced.

In one embodiment of the compounds of formula (I), R ³¹ , R ³⁴ and R ³⁵ are independently of each other hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted 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. In this embodiment, R ³¹ , R ³⁴ and R ³⁵ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy _, substituted or unsubstituted C7- _C20 arylalkyloxy, substituted or unsubstituted _C7 - _C20 aryl alkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy independently of each other, more preferably hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy; both are hydroxyl is more preferred.

Alternatively, in another embodiment of the compounds represented by formula (I), R ³¹ and R ³⁴ together form -O- and R ³⁵ is hydroxyl, substituted or unsubstituted alkoxy , substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted hetero aryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy. For this embodiment, R ³¹ and R ³⁴ together form -O- and R ³⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C _{3 -C6} cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6 _{- C18} aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted preferably substituted C ₁ -C ₂₀ acyloxy; R ³¹ and R ³⁴ together form -O- and R ³⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy , or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy; R ³¹ and R ³⁴ taken together form —O—, and R ³⁵ is hydroxyl. preferable.

Alternatively, in another embodiment of the compounds represented by formula (I), R ³¹ is hydroxyl, 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 and ^R34 and ^R35 together form a covalent bond. In this embodiment, R ³¹ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy , substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted _C7 - _C20 arylalkenyloxy, substituted or unsubstituted 5-15 heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and R ³⁴ and R ³⁵ are preferably together form a covalent bond; R ³¹ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, and R ³⁴ and R ³⁵ together form a covalent bond; more preferably R ³¹ is hydroxyl and R ³⁴ and R ³⁵ together form a covalent bond.

When R ³¹ , R ³⁴ and R ³⁵ are the groups exemplified above, the compound represented by formula (I) can effectively enhance the antifungal activity of the antifungal agent.

In one embodiment of the compounds represented by formula (Ia), R ^31a , R ^34a and R ^35a are independently of each other hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted 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. However, when R ^10a and R ^11a together form a covalent bond, none of R ^31a , R ^34a and R ^35a can be hydroxyl. In this embodiment, R ^31a , R ^34a and R ^35a are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy _, substituted or unsubstituted C7- _C20 arylalkyloxy, substituted or unsubstituted _C7 - _C20 aryl alkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy independently of each other, more preferably hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy; both are hydroxyl is more preferred. However, when R ^10a and R ^11a together form a covalent bond, none of R ^31a , R ^34a and R ^35a can be hydroxyl.

Alternatively, in another embodiment of the compounds represented by formula (Ia), R ^31a and R ^34a together form -O- and R ^35a is hydroxyl, substituted or unsubstituted alkoxy , substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted hetero aryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy. For this embodiment, R ^31a and R ^34a together form -O- and R ^35a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C _{3 -C6} cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6 _{- C18} aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted substituted or unsubstituted C ₇ -C ₂₀ arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted preferably substituted C ₁ -C ₂₀ acyloxy; R ^31a and R ^34a together form -O- and R ^35a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy , or substituted or unsubstituted _C3 - _C6 cycloalkoxy; R ^31a and R ^34a together form -O-, and R ^35a is hydroxyl. preferable.

Alternatively, in another embodiment of the compounds represented by formula (Ia), R ^31a is hydroxyl, 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 and R ^34a and R ^35a together form a covalent bond. In this embodiment, R ^31a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy , substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted _C7 - _C20 arylalkenyloxy, substituted or unsubstituted 5-15 heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and R ^34a and R ^35a are preferably together form a covalent bond; R ^31a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, and R ^34a and R ^35a together form a covalent bond; more preferably R ^31a is hydroxyl and R ^34a and R ^35a together form a covalent bond.

Particularly preferably, R ^31a and R ^34a together form -O- and R ^35a is hydroxyl. When R ^31a , R ^34a and R ^35a are the groups exemplified above, the compound represented by formula (Ia) can effectively enhance the antifungal activity of the antifungal agent.

In formulas (I) and (Ia), when said groups are substituted, said substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl , substituted or 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, substituted or unsubstituted amino, and It is preferably at least one monovalent or divalent group selected from the group consisting of oxo (C=O), halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or non- substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted _C4 - _C6 cycloalkenyl, substituted or unsubstituted _C4 - _C6 cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₆ -C ₁₈ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C ₆ -C ₁₈ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ - selected from the group consisting of _C6 cycloalkoxycarbonyl, substituted or unsubstituted _C1 - _C20 acyl, substituted or unsubstituted _C1 - _C20 acyloxy, substituted or unsubstituted amino, and oxo (C=O); is more preferably at least one monovalent or divalent group such as hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, at least one monovalent group selected from the group consisting of substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy and substituted or unsubstituted C ₁ -C ₂₀ acyloxy; is more preferred, and hydroxyl is particularly preferred. Said monovalent or divalent groups are preferably unsubstituted. When the monovalent group or divalent group is substituted, the substituent is preferably further selected from the monovalent group or divalent group, and further from the unsubstituted monovalent group or divalent group. more preferably selected.

The compound represented by formula (I) includes the above-exemplified R ^1′ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ^{14 , R 15 ,} R ¹⁹ ′ , R ^23′ , R ^27′ , Compounds defined by any combination of R ³¹ , R ³⁴ and R ³⁵ can be included.

The compound represented by the formula (Ia) includes R ^1' , R ⁶ , R ⁷ , R ^10a , R ^11a , R ^14a , R ^15a , R ^19' , R ^23' and R ^27' exemplified above. , R ^31a , R ^34a and R ^35a in any combination.

Preferably, the compound of formula (I) is
R ^1′ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C _{3 -C6} cycloalkyl, substituted or unsubstituted C3 _{- C6} cycloalkenyl, substituted or unsubstituted _C3 - _C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1- _C6 alkyl, substituted or unsubstituted _C6 - _C18 aryl, _substituted or unsubstituted _{C7 -C20} arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl- _C1 - _C6 alkyl, substituted or unsubstituted C1 _{- C6} alkoxy carbonyl, substituted or unsubstituted _C3 - _C6 cycloalkoxycarbonyl, or substituted or unsubstituted C1 _{- C20} acyl;
R ⁶ and R ⁷ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered hetero cycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7 _{- C20} arylalkyloxy, substituted or unsubstituted _C7 - _C20 arylalkenyloxy, substituted or unsubstituted 5 is to 15-membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
^R6 and ^R7 together form a covalent bond;
R ¹⁰ and R ¹¹ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered hetero cycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7 _{- C20} arylalkyloxy, substituted or unsubstituted _C7 - _C20 arylalkenyloxy, substituted or unsubstituted 5 is to 15-membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
R ¹⁰ and R ¹¹ together form a covalent bond or -O-;
R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7 _{- C20} arylalkyloxy, substituted or unsubstituted C7- _C20 arylalkenyloxy, _substituted or unsubstituted is 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
R ¹⁴ and R ¹⁵ together form a covalent bond;
R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted C3 _{- C6} cycloalkyl, substituted or _{unsubstituted C3} - _C6 cycloalkenyl, substituted or unsubstituted C3- _C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl- _C1 - _C6 alkyl, substituted or unsubstituted C ₆ -C ₁₈ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₂₀ acyl;
R ³¹ , R ³⁴ and R ³⁵ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 heterocycloalkoxy _, substituted or unsubstituted _C6 - _C18 aryloxy _, substituted or unsubstituted C7- _C20 arylalkyloxy, substituted or unsubstituted C7- _C20 arylalkenyloxy, substituted or unsubstituted substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
R ³¹ and R ³⁴ together form -O-, and R ³⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted _C7 -C ₂₀ arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
R ³¹ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, _substituted or unsubstituted C7- _C20 arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and R ³⁴ and R ³⁵ together are covalently bonded; forming;
When said groups are substituted, said substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted _C3 - _C6 cycloalkyl, substituted or unsubstituted _C4 - _C6 cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered hetero Cycloalkyl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₆ -C ₁₈ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- 6-membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, _{substituted or unsubstituted C 3 -C 6 cycloalkoxycarbonyl} , substituted or unsubstituted at least one monovalent or divalent group selected from the group consisting of C1- _C20 acyl, substituted or unsubstituted _C1 - _C20 acyloxy, substituted or unsubstituted amino _, and oxo (C=O); is the base. Said monovalent or divalent groups are preferably unsubstituted. When the monovalent group or divalent group is substituted, the substituent is preferably further selected from the monovalent group or divalent group, and further from the unsubstituted monovalent group or divalent group. more preferably selected.

More preferably, the compound of formula (I) is
R ^1′ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C _{3 -C6} cycloalkyl, substituted or unsubstituted C4 _{- C6} cycloalkenyl, or substituted or unsubstituted _C4 - _C6 cycloalkynyl;
R ⁶ and R ⁷ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, or
^R6 and ^R7 together form a covalent bond;
R ¹⁰ and R ¹¹ are independently of each other hydrogen, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, or
R ¹⁰ and R ¹¹ together form a covalent bond or -O-;
R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, or
R ¹⁴ and R ¹⁵ together form a covalent bond;
R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted is _C2 - _C6 alkynyl, substituted or unsubstituted _C3 - _C6 cycloalkyl _, substituted or unsubstituted C3 _{- C6} cycloalkenyl, or substituted or unsubstituted C3- _C6 cycloalkynyl;
R ³¹ , R ³⁴ and R ³⁵ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, or
R ³¹ and R ³⁴ together form -O-, and R ³⁵ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy or
R ³¹ is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, and R ³⁴ and R ³⁵ together form a covalent bond death;
When said groups are substituted, said substituents may be halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C _{2 -C6} alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted C3 _{- C6} cycloalkyl, substituted or unsubstituted _C4 - _C6 cycloalkenyl, substituted or unsubstituted _{C4 -C6} cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl- _{C1 -C6} alkyl, substituted or unsubstituted _C6 - _C18 aryl, substituted or unsubstituted _C7 - _C20 arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5- 15-membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy , substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ At least one monovalent or divalent group selected from the group consisting of acyl, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted amino, and oxo (C═O). Said monovalent or divalent groups are preferably unsubstituted. When the monovalent group or divalent group is substituted, the substituent is preferably further selected from the monovalent group or divalent group, and further from the unsubstituted monovalent group or divalent group. more preferably selected.

More preferably, the compound of formula (I) is
R ^1' is hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
^R6 and ^R7 are both hydroxyl, or
^R6 and ^R7 together form a covalent bond;
R ¹⁰ is hydrogen and R ¹¹ is hydroxyl, or
R ¹⁰ and R ¹¹ together form a covalent bond or -O-;
R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, or
R ¹⁴ and R ¹⁵ together form a covalent bond;
R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
R ³¹ , R ³⁴ and R ³⁵ are all hydroxyl, or
R ³¹ and R ³⁴ together form -O- and R ³⁵ is hydroxyl, or
^R31 is hydroxyl and ^R34 and ^R35 together form a covalent bond.

Particularly preferably, the compound of formula (I) is
R ^1' is hydrogen;
^R6 and ^R7 are both hydroxyl, or
^R6 and ^R7 together form a covalent bond;
R ¹⁰ is hydrogen and R ¹¹ is hydroxyl, or
R ¹⁰ and R ¹¹ together form a covalent bond or -O-;
R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, or
R ¹⁴ and R ¹⁵ together form a covalent bond;
R ^19′ , R ^23′ and R ^27′ are all hydrogen;
R ³¹ , R ³⁴ and R ³⁵ are all hydroxyl, or
R ³¹ and R ³⁴ together form -O- and R ³⁵ is hydroxyl, or
^R31 is hydroxyl and ^R34 and ^R35 together form a covalent bond.

Preferably, the compound of formula (Ia) is
R ^1′ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C _{3 -C6} cycloalkyl, substituted or unsubstituted C3 _{- C6} cycloalkenyl, substituted or unsubstituted _C3 - _C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C1- _C6 alkyl, substituted or unsubstituted _C6 - _C18 aryl, _substituted or unsubstituted _{C7 -C20} arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl- _C1 - _C6 alkyl, substituted or unsubstituted C1 _{- C6} alkoxy carbonyl, substituted or unsubstituted _C3 - _C6 cycloalkoxycarbonyl, or substituted or unsubstituted C1 _{- C20} acyl;
R ⁶ and R ⁷ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered hetero cycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7 _{- C20} arylalkyloxy, substituted or unsubstituted _C7 - _C20 arylalkenyloxy, substituted or unsubstituted 5 is to 15-membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
^R6 and ^R7 together form a covalent bond;
R ^10a is hydrogen and R ^11a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted C7 _{- C20} arylalkyloxy, substituted or unsubstituted C7- _C20 arylalkenyloxy, _substituted or unsubstituted is 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
R ^10a and R ^11a together form a covalent bond;
R ^14a is hydrogen;
R ^15a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, _substituted or unsubstituted C7- _C20 arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy or substituted or unsubstituted C ₁ -C ₂₀ acyloxy;
R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted C3 _{- C6} cycloalkyl, substituted or _{unsubstituted C3} - _C6 cycloalkenyl, substituted or unsubstituted C3- _C6 cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl- _C1 - _C6 alkyl, substituted or unsubstituted C ₆ -C ₁₈ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ -C ₂₀ acyl;
R ^31a , R ^34a and R ^35a are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 heterocycloalkoxy _, substituted or unsubstituted _C6 - _C18 aryloxy _, substituted or unsubstituted C7- _C20 arylalkyloxy, substituted or unsubstituted C7- _C20 arylalkenyloxy, substituted or unsubstituted substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy (provided that when R ^10a and R ^11a together form a covalent bond, none of R ^31a , R ^34a and R ^35a can be hydroxyl), or
R ^31a and R ^34a together form -O-, and R ^35a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted _C7 -C ₂₀ arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or
R ^31a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, _substituted or unsubstituted C7- _C20 arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyloxy or substituted or unsubstituted C ₁ -C ₂₀ acyloxy, and R ^34a and R ^35a together are a covalent bond; forming;
When said groups are substituted, said substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₄ -C ₆ cycloalkenyl, substituted or unsubstituted C ₄ -C ₆ cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3-6 membered hetero Cycloalkyl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₆ -C ₁₈ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5- to 15-membered heteroaryl, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- 6-membered heterocycloalkoxy, substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, _{substituted or unsubstituted C 3 -C 6 cycloalkoxycarbonyl} , substituted or unsubstituted at least one monovalent or divalent group selected from the group consisting of C1- _C20 acyl, substituted or unsubstituted _C1 - _C20 acyloxy, substituted or unsubstituted amino _, and oxo (C=O); is the base. Said monovalent or divalent groups are preferably unsubstituted. When the monovalent group or divalent group is substituted, the substituent is preferably further selected from the monovalent group or divalent group, and further from the unsubstituted monovalent group or divalent group. more preferably selected.

More preferably, the compound of formula (Ia) is
R ^1′ is hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C _{3 -C6} cycloalkyl, substituted or unsubstituted C4 _{- C6} cycloalkenyl, or substituted or unsubstituted _C4 - _C6 cycloalkynyl;
R ⁶ and R ⁷ are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, or
^R6 and ^R7 together form a covalent bond;
R ^10a is hydrogen and R ^11a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, or
R ^10a and R ^11a together form a covalent bond;
R ^14a is hydrogen;
R ^15a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy;
R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted is _C2 - _C6 alkynyl, substituted or unsubstituted _C3 - _C6 cycloalkyl _, substituted or unsubstituted C3 _{- C6} cycloalkenyl, or substituted or unsubstituted C3- _C6 cycloalkynyl;
R ^31a , R ^34a and R ^35a are independently of each other hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy with the proviso that R ^10a and R ^11a together form a covalent bond, none of R ^31a , R ^34a and R ^35a can be hydroxyl), or
R ^31a and R ^34a together form -O-, and R ^35a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy or
R ^31a is hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, and R ^34a and R ^35a together form a covalent bond death;
When said groups are substituted, said substituents may be halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C _{2 -C6} alkenyl, substituted or unsubstituted _C2 - _C6 alkynyl, substituted or unsubstituted C3 _{- C6} cycloalkyl, substituted or unsubstituted _C4 - _C6 cycloalkenyl, substituted or unsubstituted _{C4 -C6} cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted _C7 - _C11 cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl- _{C1 -C6} alkyl, substituted or unsubstituted _C6 - _C18 aryl, substituted or unsubstituted _C7 - _C20 arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5- 15-membered heteroaryl-C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy , substituted or unsubstituted _C6 - _C18 aryloxy, substituted or unsubstituted _C7 - _C20 arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ -C ₆ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkoxycarbonyl, substituted or unsubstituted C ₁ -C ₂₀ at least one monovalent or divalent group selected from the group consisting of acyl, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted amino, and oxo (C═O). Said monovalent or divalent groups are preferably unsubstituted. When the monovalent group or divalent group is substituted, the substituent is preferably further selected from the monovalent group or divalent group, and further from the unsubstituted monovalent group or divalent group. more preferably selected.

More preferably, the compound of formula (Ia) is
R ^1' is hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
^R6 and ^R7 are both hydroxyl, or
^R6 and ^R7 together form a covalent bond;
R ^10a is hydrogen and R ^11a is hydroxyl, or
R ^10a and R ^11a together form a covalent bond;
R ^14a is hydrogen;
R ^15a is hydroxyl;
R ^19′ , R ^23′ and R ^27′ are independently of each other hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
R ^31a , R ^34a and R ^35a are all hydroxyl (provided that when R ^10a and R ^11a together form a covalent bond, R ^31a , R ^34a and R ^35a are all hydroxyl) never), or
R ^31a and R ^34a together form -O- and R ^35a is hydroxyl, or
R ^31a is hydroxyl and R ^34a and R ^35a together form a covalent bond.

Particularly preferably, the compound of formula (Ia) is
R ^1' is hydrogen;
^R6 and ^R7 together form a covalent bond;
R ^10a is hydrogen and R ^11a is hydroxyl, or
R ^10a and R ^11a together form a covalent bond;
R ^14a is hydrogen;
R ^15a is hydroxyl;
R ^19' , R ^23' and R ^27' are all hydrogen;
R ^31a and R ^34a together form -O- and R ^35a is hydroxyl.

Especially particularly preferred compounds of formula (I) are:
(2E,6E)-30-(5-(2-Hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-3,7,11,15,19,23,27-heptamethyltriacontane -2,6-diene-1,11,15,19,23,27-hexaol (compound 1; glysoprenin G);
(2E,6E,10E)-30-(5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-3,7,11,15,19,23,27-heptamethyl triacont-2,6,10-triene-1,15,19,23,27-pentaol (compound 2; glysoprenin H); and
(2E,6E,10E)-3,7,11,15,19,23,27,31,35-nonamethylhexatriacont-2,6,10-triene-1,15,19,23,27, 31,34,35-Octaol (Compound 3: Glysoprenin F);
is.

Particularly particularly preferred compounds of formula (Ia) are:
(2E,6E)-30-(5-(2-Hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-3,7,11,15,19,23,27-heptamethyltriacontane -2,6-diene-1,11,15,19,23,27-hexaol (Compound 1; Glysoprenin G); and
(2E,6E,10E)-30-(5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-3,7,11,15,19,23,27-heptamethyl triacont-2,6,10-triene-1,15,19,23,27-pentaol (compound 2; glysoprenin H);
is.

When the compound represented by formula (I), which is the active ingredient of the antifungal drug activity enhancer of one embodiment of the present invention, particularly the compound represented by formula (Ia) of one embodiment of the present invention, is the compound , the compounds can particularly effectively enhance the antifungal activity of antifungal agents.

The compounds represented by formula (I), especially the compounds represented by formula (Ia), include not only the compounds themselves but also their salts. Salts of the compounds of formula (I), particularly of the compounds of formula (Ia), include, but are not limited to, sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or non-substituted Salts with cations such as substituted ammonium ions, or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid. , succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, Salts with organic acid anions such as glutamic acid, benzenesulfonic acid, cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid or naphthalenesulfonic acid are preferred. Even when the compound represented by formula (I), especially the compound represented by formula (Ia), is in the form of the above salt, it can effectively enhance the antifungal activity of the antifungal agent. .

The compounds represented by formula (I), especially the compounds represented by formula (Ia), include not only the compounds themselves, but also solvates of the compounds or salts thereof. Solvents capable of forming solvates with the compounds or salts thereof include, but are not limited to, water or lower alcohols such as methanol, ethanol or 2-propanol (isopropyl alcohol). -6 carbon atoms), higher alcohols (e.g. alcohols with 7 or more carbon atoms such as 1-heptanol or 1-octanol), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate Organic solvents such as are preferred. Even when the compound represented by formula (I), particularly the compound represented by formula (Ia) or a salt thereof, is in the form of a solvate with the above solvent, the antifungal activity of the antifungal agent is can be effectively enhanced.

The compounds of formula (I), in particular of formula (Ia), encompass not only said compounds themselves, but also protected forms thereof. As used herein, "protected form" means a form in which a protecting group is introduced to one or more functional groups (eg, amino group, hydroxyl group or carboxylic acid group). In this specification, protected forms of the compounds represented by the above formulas are sometimes referred to as protected derivatives of the compounds represented by the above formulas. Also, as used herein, a "protecting group" is a group introduced into a specific functional group in order to prevent the progress of an undesired reaction, and is quantitatively removed under specific reaction conditions and It means a group which is substantially stable, ie, reaction inert, under reaction conditions other than . The protective group capable of forming a protected form of the compound is not limited, but for example, in the case of an amino group protective group, t-butoxycarbonyl (Boc), 2-bromobenzyloxycarbonyl (BrZ), or When 9-fluorenylmethoxycarbonyl (Fmoc) is a hydroxyl-protecting group, silyl (e.g., t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS)), or when alkoxy (e.g. methoxymethoxy (MOM) or methoxy (Me)) is a protecting group for a carboxylic acid group, an alkyl ester (e.g. methyl, ethyl or isopropyl ester), an arylalkyl ester (e.g. benzyl ester), or an amide (eg amides with oxazolidinones) are respectively preferred. Protection and deprotection with the protecting group can be appropriately carried out by those skilled in the art based on known reaction conditions. To substantially reduce the effect of enhancing the activity of an antifungal drug even when the compound represented by the formula (I), especially the compound represented by the formula (Ia), is in a form protected by the protecting group. In some cases, the compound can be used without

When a compound of formula (I), especially a compound of formula (Ia), has one or more tautomers, said compound is in the form of the individual tautomers of said compound. also includes

In addition, when a compound of formula (I), especially a compound of formula (Ia), has one or more stereocenters (chiral centers), said compound may be an individual enantiomer of said compound and Also included are diastereomers, as well as mixtures thereof such as racemates.

By having the above characteristics, the compound represented by formula (I), which is an active ingredient of the antifungal drug activity enhancer of one embodiment of the present invention, particularly represented by formula (Ia) of one embodiment of the present invention The compounds can effectively enhance the antifungal activity of antifungal agents.

<2. Method for producing novel compounds by culture means>
The present inventors have found that the novel fungus contains compounds represented by formula (I), particularly glysoprenin G (compound 1) and glysoprenin H (compound 2), which are included in compounds represented by formula (Ia), in its culture. It was found to be produced in liquid. Therefore, another aspect of the present invention relates to a process for preparing compounds of formula (I), especially compounds of formula (Ia), using novel fungi.

In this aspect, the method of the invention includes a compound accumulation step and a compound purification step. Each step will be described in detail below.

[2-1. Compound accumulation step]
In this embodiment, the method of the present invention comprises the fungus Aspergillus polyporicola strain BFM-0088 (accepted No. NITE B P-02936) or a mutant strain thereof is cultured in a medium to allow the compound represented by formula (I), particularly the compound represented by formula (Ia), to accumulate in the medium. A compound accumulation step is included.

Aspergillus polypolichola strain BFM-0088 is a fungus isolated from the soil of Tokyo Bay, Tokyo, Japan. This strain was registered as BFM-0088 on April 3, 2019 at the Patent Microorganism Depositary Center, National Institute of Technology and Evaluation (2-5-8-122 Kazusa Kamatari, Kisarazu City, Chiba Prefecture 292-0818, Japan). Room No.) under the Budapest Treaty (accession number NITE B P-02936).

In this step, the microorganism used for culturing is Aspergillus polypolichola BFM-0088 strain or its mutant strain having the ability to produce the compound represented by formula (I), particularly the compound represented by formula (Ia). Aspergillus polypolichola strain BFM-0088 is more preferred. In each aspect of the invention, mutants of Aspergillus polypolichola strain BFM-0088 refer to natural or artificial mutants of Aspergillus polypolichola strain BFM-0088. The artificial mutant strain of Aspergillus polypolichola strain BFM-0088 can be obtained by any artificial mutant production means commonly used in the art. Not only Aspergillus polypolichola strain BFM-0088 itself, but also mutant strains of Aspergillus polypolichola strain BFM-0088 produce compounds of formula (I), in particular compounds of formula (Ia). Any competent microorganism can accumulate the compound represented by formula (I), particularly the compound represented by formula (Ia), in the medium in this step. Therefore, by using the microorganism, a large amount of the compound represented by the formula (I), especially the compound represented by the formula (Ia) 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. Carbon sources include sugars such as glucose, fructose, maltose, lactose, galactose, dextrin and starch, and vegetable oils such as soybean oil. Nitrogen sources can include polypeptones, yeast extracts, malt extracts, meat extracts, soy flour, cottonseed flour, corn-steve liquor, casein, amino acids, urea, ammonium salts and nitrates. Inorganic salts include cations such as sodium ion, potassium ion, calcium ion, magnesium ion, iron ion, manganese ion, copper ion, cobalt ion or zinc ion, and inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid. Salts with acid anions may be mentioned. The medium used in this step is, for example, potato dextrose agar (PDA) medium (potato dextrose agar 3.9% (Becton Dickinson (BD))), seed medium (1.0% glucose (Fujifilm Wako Pure Chemical Industries, Ltd. company), 0.5% polypeptone ( _BD ), 0.05% _MgSO4.7H2O (Kanto Chemical Co. _, Ltd.), 0.2% yeast extract (BD), 0.1% _K2HPO4 (Kanto Chemical Co., Ltd.) and 0.1% agar ( Shimizu Foods Co., Ltd.)), or production medium (2.4% PDB (BD), 0.5% MgSO ₄ 7H ₂ O (Kanto Chemical Co., Ltd.), 0.5% K ₂ HPO ₄ (Kanto Chemical Co., Ltd.), 0.5% Mg ₃ ( _PO4 ) _2.8H2O (Kanto Kagaku Co., Ltd.) and 5 g/mL brown rice (Myojin Co., Ltd.) are preferred _. By culturing, in the medium, a microorganism that is Aspergillus polypolichola BFM-0088 strain or a mutant strain thereof having the ability to produce the compound represented by formula (I), particularly the compound represented by formula (Ia) , a compound of formula (I), in particular a compound of formula (Ia), can accumulate in the medium.

Microorganism culture may be either solid culture or liquid culture. When culturing the microorganisms on a large scale, liquid culture is preferred. In this case, it is preferable to aerate the medium by shaking the culture vessel or agitating 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 formula (I), particularly the compound represented by formula (Ia) can be efficiently accumulated in the medium.

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

In this step, the conditions for culturing the microorganism can be appropriately set based on the properties of the microorganism. The culture temperature is usually in the range of 25-27°C, typically about 27°C. The pH of the medium is usually pH 3-9, typically pH 5.6±0.2. When a liquid medium is cultured with shaking, the culture period is usually 1 day to 3 weeks, typically 3 to 17 days, in total for seed culture and production culture. By culturing the microorganism under the above conditions, the compound represented by formula (I), particularly the compound represented by formula (Ia) can be efficiently accumulated in the medium.

[2-2. Compound purification process]
In this aspect, the method of the present invention includes a compound purification step of purifying the compound represented by formula (I) obtained in the compound accumulation step, particularly the compound represented by formula (Ia), from the culture of the microorganism. including.

In this step, as a means for purifying the compound represented by formula (I), especially the compound represented by formula (Ia) from the culture of microorganisms, a separation method for organic compounds commonly used in the art can be used. can be used. Means for purifying the compound represented by formula (I), especially the compound represented by formula (Ia) from a culture of microorganisms include, for example, extraction, filtration, centrifugation, adsorption, recrystallization, distillation, and various Chromatography and the like can be mentioned. Preferably, this step includes a step of separating the cells from the microbial culture obtained in the compound accumulation step by filtration or centrifugation, a step of extracting the separated cells with an organic solvent such as ethanol or ethyl acetate, and a step of further separating the bacterial cell extract extracted with an organic solvent by a means such as solvent extraction or preparative chromatography to obtain a compound represented by formula (I), particularly a compound represented by formula (Ia) including. Various types of chromatography such as adsorption, normal phase or reverse phase partition, or gel filtration can be applied as the preparative chromatography. In the final step, the fractions obtained by preparative chromatography may be further purified by means such as recrystallization or distillation. Each of the above steps may be repeated multiple times under the same or different conditions, if desired. By using said means, compounds of formula (I), in particular compounds of formula (Ia), can be purified and isolated from cultures of microorganisms.

In the method for producing the compound of the present invention by culturing method of this embodiment, the compound represented by formula (I) contains the above-exemplified groups R ^1′ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ^19′ , R ^23′ , and R ^27′ , R ³¹ , R ³⁴ and R ³⁵ , especially the compounds of formula (Ia), the groups R ^{1 '} , ^R6 , ^R7 , ^R10a , ^R11a , ^R14a , R15a, R19 ^' , ^{R23 '} , and ^R27' , ^R31a , ^R34a and ^R35a . In this case, the compound represented by formula (I), particularly the compound represented by formula (Ia), includes glysoprenin G (compound 1) and glysoprenin H (compound 2) produced by Aspergillus polypolichola BFM-0088 strain. do. By using the method of this embodiment, compounds represented by formula (I) including glysoprenin G (compound 1) and glysoprenin H (compound 2), especially compounds represented by formula (Ia) are efficiently produced. can do.

By the method for producing the compound of the present invention by the culture method of this aspect having the above characteristics, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), which can be an active ingredient of a drug, is produced at a high concentration. It can be provided in large quantities with purity and low cost.

Another aspect of the present invention is a fungus Aspergillus polypolichola strain BFM-0088 (accession number NITE BP- 02936) or its mutants. In this embodiment, the compound represented by formula (I) has the above-exemplified groups R ^1′ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ^19′ , R ^23′ , and R ^27′ , R ³¹ , R ³⁴ and R ³⁵ , and in particular the compound represented by formula (Ia) has the above-exemplified groups R ^1′ , R ⁶ , R ⁷ , R ^10a , R It is preferred to have ^11a , ^R14a , ^R15a , R19 ^' , ^R23' and ^R27' , ^R31a , ^R34a and ^R35a . Efficient production of compounds represented by formula (I) including glysoprenin G (compound 1) and glysoprenin H (compound 2), particularly compounds represented by formula (Ia), by using the microorganism of this embodiment can do.

<3. Pharmaceutical use>
The compound represented by formula (I), which is the active ingredient of the antifungal activity enhancer of one embodiment of the present invention, particularly the compound represented by formula (Ia) of one embodiment of the present invention, is an antifungal drug It has the activity of enhancing antifungal activity. Therefore, another aspect of the present invention is a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof The present invention relates to an activity enhancer for at least one antifungal agent containing a solute as an active ingredient. In addition, when the compound represented by formula (I), particularly the compound represented by formula (Ia), is administered to a subject, the subject has a specific symptom, disease or Disorders can be prevented or treated. Therefore, another aspect of the present invention is a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof The present invention relates to a pharmaceutical or pharmaceutical composition containing a soda as an active ingredient.

In each aspect of the invention, the at least one antifungal agent is selected from the group consisting of polyene macrolides, azoles, candins and fluoropyrimidines. Preferably, the at least one antifungal agent is a polyene macrolide. The polyene macrolide drug is preferably amphotericin B, pimaricin, nystatin or natamycin, more preferably amphotericin B. The azole drug is preferably an imidazole compound such as miconazole, or a triazole compound such as fluconazole, itraconazole, phosphofluconazole or voriconazole. Preferably, the candin is micafungin or caspofungin. Preferably, the fluoropyrimidine drug is flucytosine. Amphotericin B, a polyene macrolide drug, has high antifungal activity and is useful for treating serious fungal infections, but it may show side effects such as nephrotoxicity. The compound represented by formula (I), particularly the compound represented by formula (Ia), has antifungal activity against antifungal drugs such as polyene macrolides, azoles, candins and fluoropyrimidines. It has activity to enhance Therefore, the compound represented by formula (I), particularly the compound represented by formula (Ia), is selected from the group consisting of polyene macrolides, azoles, candins and fluoropyrimidines By co-administration with at least one antifungal agent, the dosage of antifungal agents with potential side effects can be reduced and/or the duration of administration can be shortened. This can substantially reduce the incidence of side effects from the at least one antifungal agent.

In various aspects of the invention, "administering together" means administering the agents simultaneously or separately (eg, sequentially at regular intervals). Such dosage forms may be referred to herein as "combined administration." Co-administration of a compound of formula (I), particularly a compound of formula (Ia), and at least one antifungal agent reduces the potential side effects of the antifungal agent dosage. , and/or the administration period can be shortened. This can substantially reduce the incidence of side effects from the at least one antifungal agent.

The compound represented by formula (I), which is the active ingredient of the antifungal activity enhancer of one embodiment of the present invention, particularly the compound represented by formula (Ia) of one embodiment of the present invention, contains at least one It has the activity of enhancing the antifungal activity of antifungal drugs. On the other hand, compounds of formula (I), in particular compounds of formula (Ia), may or may not themselves have antifungal activity. Compounds of formula (I), in particular compounds of formula (Ia), generally do not themselves have substantial antifungal activity. Compounds of formula (I), especially compounds of formula (Ia), even if they themselves have substantially no antifungal activity, contain at least one antifungal agent. Concomitant administration with at least one antifungal drug that has antifungal activity-enhancing activity to reduce the dosage and/or shorten the duration of administration of the antifungal drug, which may have side effects can be done. This can substantially reduce the incidence of side effects from the at least one antifungal agent.

A compound represented by formula (I), which is an active ingredient of the antifungal activity enhancer of one embodiment of the present invention, particularly a compound represented by formula (Ia) of one embodiment of the present invention, and at least one The antifungal activity of an antifungal agent can be determined, for example, but not limited to, by the following means. Formula (I) against any test fungi (e.g. yeast fungi, filamentous fungi and zygomycetes) by broth microdilution according to American Clinical Laboratory Standards Institute (CLSI) methods M27-A3 and M38-A2 A compound of formula (Ia), in particular a compound of formula (Ia), or at least one antifungal agent is administered. After culturing under predetermined conditions, fungal growth is measured using turbidity (for example, OD ₅₅₀ ) or colony diameter as an indicator, and the inhibition rate (%) is calculated from the comparison with the value at the start of culturing. The minimum concentration of the compound at which the calculated inhibition rate is a predetermined value (eg, 90%) or more is defined as the minimum growth inhibitory concentration (MIC value) of the compound. Based on the inhibition rate and MIC value thus determined, the compound represented by formula (I), which is the active ingredient of the antifungal drug activity enhancer of one embodiment of the present invention, particularly one embodiment of the present invention The antifungal activity of compounds of formula (Ia) and at least one antifungal agent can be evaluated.

At least one compound represented by formula (I), which is an active ingredient of the antifungal drug activity enhancer of one embodiment of the present invention, particularly the compound represented by formula (Ia) of one embodiment of the present invention The antifungal activity-enhancing activity of an antifungal agent can be determined by, for example, but not limited to, the following means. Based on the above measures, the MIC value for the single administration of at least one antifungal agent is determined. Then, under similar test conditions, a compound of formula (I), particularly a compound of formula (Ia) of one aspect of the present invention, and at least one antifungal agent are combined (e.g. simultaneously) to determine the MIC value for co-administration of a compound of formula (I), particularly a compound of formula (Ia) of one aspect of the present invention, and at least one antifungal agent . Antifungal activity of at least one antifungal agent of a compound represented by formula (I), particularly a compound represented by formula (Ia) of one embodiment of the present invention, based on formula (M-1) below Calculate the enhancement rate of For example, when the enhancement factor is 2-fold, the MIC of at least one antifungal drug when administered in combination with a compound of formula (I), particularly a compound of formula (Ia) in one aspect of the present invention The value is 1/2 of the MIC value when the antifungal drug is administered alone. Based on the enhancement rate thus determined, the compound represented by formula (I), which is the active ingredient of the antifungal drug activity enhancer of one embodiment of the present invention, particularly the formula (Ia ) can be evaluated for the activity of enhancing the antifungal activity of at least one antifungal drug.

In this embodiment, at least one antifungal agent co-administered with a compound of formula (I), particularly a compound of formula (Ia), has a MIC value determined by the above procedure For fungi (eg Candida albicans) it is usually 1 μg/mL. In this case, the compound represented by formula (I), particularly the compound represented by formula (Ia), is usually added at a concentration of 0.25 μg/mL or more, for example 0.5 μg/mL or more, particularly 1 μg/mL or more. The antifungal effect of at least one antifungal agent, usually by a factor of 2 or more, for example in the range of 8 to 64 fold, especially in the range of 16 to 32 fold, by co-administration with at least one antifungal agent activity can be enhanced. Therefore, compounds of formula (I), especially compounds of formula (Ia), when having a potentiation rate in said range, may cause side effects when co-administered with at least one antifungal agent. Potential antifungal drug doses can be reduced and/or the duration of administration shortened. This can substantially reduce the incidence of side effects from the at least one antifungal agent.

When applying the compound represented by formula (I), especially the compound represented by formula (Ia), to pharmaceutical use, the compound represented by formula (I), particularly the compound represented by formula (Ia), is Not only the compounds themselves, but also pharmaceutically acceptable salts of the compounds and pharmaceutically acceptable solvates thereof are included. Pharmaceutically acceptable salts of compounds of formula (I), especially compounds of formula (Ia), and pharmaceutically acceptable solvates thereof, include, but are not limited to, , salts or solvates exemplified above are preferred. at least one antifungal compound of formula (I), particularly when the compound of formula (Ia) is in the form of a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the foregoing The compounds can be applied to desired pharmaceutical uses without substantially reducing the drug's antifungal-enhancing activity.

When applying the compound represented by formula (I), especially the compound represented by formula (Ia), to pharmaceutical use, the compound represented by formula (I), particularly the compound represented by formula (Ia), is It includes not only the compounds themselves, but also prodrug forms of the compounds. As used herein, "prodrug" means a compound that is converted in vivo to the parent drug. Prodrug forms of the compounds include, but are not limited to, esters of the hydroxyl group with any carboxylic acid, and amides of the hydroxyl group with any amine, if a hydroxyl group is present. For example, when an amino group is present, amides of the amino group and any carboxylic acid can be mentioned. When the compound of formula (I), especially the compound of formula (Ia), is a prodrug form as described above, the parent drug compound of formula (I), especially formula (Ia) The pharmacokinetics of the represented compounds can be improved upon administration of the prodrug form to a subject without substantially reducing the activity of enhancing the antifungal activity of at least one antifungal agent.

When a compound of formula (I), especially a compound of formula (Ia), is applied for pharmaceutical use, said compound may be used alone or in combination with one or more pharmaceutically acceptable ingredients. May be used in combination. The medicament of this aspect can be formulated into various dosage forms commonly used in the art, depending on the desired method of administration. Therefore, the medicament of this embodiment is also a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof and one or more pharmaceutically acceptable carriers. In addition to the above ingredients, the pharmaceutical composition of this embodiment contains one or more pharmaceutically acceptable vehicles (e.g., solvents such as sterile water or solutions such as physiological saline), excipients, binders, Vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, analgesics, Antioxidants, sweetening and flavoring agents and the like may also be included.

A pharmaceutical dosage form containing, as an active ingredient, a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is not particularly limited, and may be a formulation for use in parenteral administration or a formulation for use in oral administration. In addition, the dosage form of the medicament of this aspect may be a unit dosage form formulation or a multiple dosage form formulation. Formulations for parenteral administration include injections such as sterile solutions or suspensions in water or other pharmaceutically acceptable vehicles. Ingredients that can be mixed with injections include, but are not limited to, physiological saline, glucose, or other adjuvants (such as D-sorbitol, D-mannitol, D-mannose, or sodium chloride). Vehicles such as isotonic solutions containing, solubilizing agents such as alcohols (e.g. ethanol or benzyl alcohol), polyalcohols (e.g. propylene glycol or polyethylene glycol) or esters (e.g. benzyl benzoate), polysorbate 80 (trademark) or poly Non-ionic surfactants such as oxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffers or sodium acetate buffers, benzalkonium chloride or procaine hydrochloride. soothing agents, stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants. The prepared injection is usually filled into a suitable vial (for example, an ampoule) and stored under an appropriate environment until use.

Formulations for oral administration include, for example, tablets, pills, powders, capsules, soft capsules, microcapsules, elixirs, liquids, syrups, slurries and suspensions. . Tablets may optionally be formulated as sugar-coated or dissolvable-coated tablets, gelatin-coated tablets, enteric-coated tablets, orally disintegrating tablets (OD tablets), or film-coated tablets. It may be formulated as a heavy tablet or multi-layer tablet dosage form.

Ingredients that can be mixed with tablets or capsules include, but are not limited to, water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, binders such as gelatin, corn starch, gum tragacanth or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or silicic acid; dry starch, sodium alginate. , agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, disintegrating agents such as stearic acid monoglyceride, starch, lactose or polyvinylpyrrolidone; sucrose, stearin cocoa butter or hydrogenated oil Bulking agents such as corn starch, gelatin or alginic acid; Lubricants such as magnesium stearate; 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 silicic acid; lubricants such as refined talc, stearates (eg magnesium stearate), boric acid powder or polyethylene glycol; sucrose, lactose or Sweetening agents such as saccharin; and flavoring agents such as peppermint, redleaf oil or cherries, and the like. When the formulation is a capsule, it may further contain a liquid carrier such as oil.

A medicament containing a compound represented by formula (I), especially a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient is a depot preparation. It can also be formulated as In this case, the medicament of this aspect in the form of a depot formulation can be implanted, for example, subcutaneously or intramuscularly, or administered by intramuscular injection. By applying the medicament of this embodiment to a depot formulation, the activity of the compound represented by formula (I), particularly the compound represented by formula (Ia), to enhance the antifungal activity of at least one antifungal drug can be expressed continuously over a long period of time.

When applying a compound of formula (I), in particular a compound of formula (Ia), for pharmaceutical use, said compound may be provided together with at least one antifungal agent or separately may be provided. Either case is included in the embodiment of this aspect. In the case of embodiments which, in addition to the compound of formula (I), in particular the compound of formula (Ia), further comprise at least one antifungal agent, i.e. the compound of formula (I) In embodiments in which a compound of formula (Ia), particularly a compound of formula (Ia), and at least one antifungal agent are provided together, the medicament of this aspect comprises a compound of formula (I), particularly the formula ( Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in combination with at least one antifungal drug in the form of a pharmaceutical composition can. In this embodiment, the medicament of this aspect is, for example, a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable and at least one antifungal agent in the form of a single formulation. For embodiments in which a compound of formula (I), particularly a compound of formula (Ia), is provided separately from at least one antifungal agent, the medicament of this aspect is a compound of formula (I) in combination with at least one antifungal agent comprising at least a compound represented by Formula (Ia), particularly a compound represented by Formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof It can be in the form of a pharmaceutical composition. In this embodiment, the medicament of this aspect is, for example, a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable It can be provided in the form of a pharmaceutical combination or kit comprising a plurality of separately formulated formulations of the solvate and at least one antifungal agent. When in the form of a pharmaceutical combination or kit, each formulation can be administered simultaneously or separately (eg, sequentially). Alternatively, the medicament of this aspect contains only the compound represented by formula (I), particularly the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof It can also be provided in the form of a formulation that contains (ie does not contain at least one antifungal agent). In either embodiment, a compound of formula (I), particularly a compound of formula (Ia), and at least one antifungal agent may be co-administered.

A medicament containing, as an active ingredient, a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, at least one It can also be used in combination with one or more other pharmaceutically useful agents other than antifungal agents. In this case, the medicament of this embodiment is a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof , in the form of a combination drug containing one or more of the other drugs. The concomitant drug is a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more The compound represented by formula (I), especially the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, Or it may be in the form of a pharmaceutical composition, including pharmaceutically acceptable solvates thereof, used in combination with one or more of said other drugs. When the medicament of this aspect is in the form of a combination medicament as described above, the compound represented by formula (I), particularly the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or pharmaceuticals thereof Multiple formulations containing the above-acceptable solvate and one or more other drugs, which may be provided in the form of a single formulation or separately formulated with one or more other drugs may be provided in the form of a pharmaceutical combination or kit comprising When in the form of a pharmaceutical combination or kit, each formulation can be administered simultaneously or separately (eg, sequentially).

One kind of medicine containing as an active ingredient a compound represented by formula (I), especially a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof The above fungal infections can be similarly prevented or treated. Fungi that cause said one or more fungal infections include, but are not limited to, yeast fungi such as Candida albicans, C. parapsilosis, Candida glabrata (C. glabrata) and Cryptococcus neoformans; filamentous fungi such as Aspergillus fumigatus, A. flavas, A. niger and Aspergillus terreus (A. zygomycetes such as Rhizopus oryzae, Rhizomucor pusillus, R. microspores, and Absidia corymbifera. The one or more fungal infections include, but are not limited to, deep mycoses, superficial mycoses, and cutaneous mycoses. The one or more fungal infections are preferably one or more diseases, symptoms or disorders selected from the group consisting of deep mycosis, superficial mycosis and cutaneous mycosis. By administering the medicament of this embodiment to a subject in need of prevention or treatment of one or more fungal infections, the above diseases, symptoms, or disorders can be prevented or treated.

A medicament containing, as an active ingredient, a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, according to the above-mentioned 1 It can be applied to a variety of subjects in need of prevention or treatment of conditions, diseases and/or disorders that are more than one species of fungal infection. The subject may be a human or non-human mammal (e.g. warm-blooded animals such as pigs, dogs, cows, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons or chimpanzees), or reptiles (e.g. It is preferably a subject or patient, such as a cold-blooded animal such as a frog, snake or lizard. By administering the medicament of this embodiment to the subject, various diseases, symptoms and/or disorders that are one or more fungal infections that the subject has can be prevented or treated.

As used herein, "prevention" means to substantially prevent the occurrence (development or manifestation) of symptoms, diseases and/or disorders. In addition, as used herein, “treatment” means suppressing (for example, suppressing progression), relieving, repairing and/or curing a symptom, disease and/or disorder that has occurred (onset or manifested).

Compounds of formula (I), especially compounds of formula (Ia), may be used to treat one or more conditions, diseases and/or disorders that are fungal infections as described above (e.g. deep mycosis). , superficial mycosis or dermatomycosis) in the prevention or treatment of said symptoms, diseases and/or disorders. Therefore, the medicament of this embodiment is preferably a medicament for use in preventing or treating symptoms, diseases and/or disorders that are one or more of the fungal infections described above. , superficial mycosis and cutaneous mycosis. By using the medicament of this embodiment for the prevention or treatment of one or more of the symptoms, diseases and/or disorders that are fungal infections, the compounds represented by formula (I), especially Said symptoms, diseases and/or disorders can be prevented or treated through the activity of the compounds in enhancing the antifungal activity of at least one antifungal agent.

Compounds of formula (I), especially compounds of formula (Ia), may be used to treat one or more conditions, diseases and/or disorders that are fungal infections as described above (e.g. deep mycosis). , superficial mycosis or dermatomycosis) in the prevention or treatment of said symptoms, diseases and/or disorders. Therefore, another aspect of the present invention provides a subject in need of prevention or treatment of a condition, disease and/or disorder which is one or more of the fungal infections described above, in an effective amount of formula (I) administering a compound of formula (Ia), particularly a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, together with at least one antifungal agent A method for the prevention or treatment of said symptoms, diseases and/or disorders, comprising: The one or more symptoms, diseases and/or disorders that are fungal infections are one or more symptoms, diseases and/or disorders selected from the group consisting of deep mycosis, superficial mycosis and cutaneous mycosis. Disability is preferred. A compound of formula (I), particularly a compound of formula (Ia) or the present invention, to a subject in need of prevention or treatment of one or more of the conditions, diseases and/or disorders that are fungal infections. By administering the medicament of the embodiment together with at least one antifungal agent, the compound represented by formula (I), especially the compound represented by formula (Ia), of at least one antifungal agent Said conditions, diseases and/or disorders can be prevented or treated through activity that enhances antifungal activity.

Another aspect of the present invention is a compound of formula (I), in particular A compound represented by formula (Ia), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Another aspect of the present invention is one or more of the fungal infections represented by formula (I) for the manufacture of a medicament for use in the prevention or treatment of conditions, diseases and/or disorders which are fungal infections as described above. or a pharmaceutically acceptable solvate thereof, particularly a compound represented by Formula (Ia) or a pharmaceutically acceptable salt thereof. The one or more symptoms, diseases and/or disorders that are fungal infections are one or more symptoms, diseases and/or disorders selected from the group consisting of deep mycosis, superficial mycosis and cutaneous mycosis. Disability is preferred. Use of a compound represented by formula (I), particularly a compound represented by formula (Ia) or a medicament of this embodiment for the prevention or treatment of one or more of the symptoms, diseases and/or disorders that are fungal infections The symptoms, diseases and /or the disorder can be prevented or treated.

a compound represented by formula (I), particularly a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient, Especially when administered to human patients, the precise dosage and administration (e.g., dosage, frequency and/or route of administration) may depend on the subject's age, weight, sex, condition, disease and/or disorder to be prevented or treated. In view of many factors such as the exact status (e.g., severity) and route of administration, the final decision should be made by the attending physician, taking into account the therapeutically effective dose, frequency of administration, route of administration, etc. be. Therefore, in the medicament of this embodiment, the compound represented by formula (I), particularly the compound represented by formula (Ia), which is an active ingredient, is administered to a subject in a therapeutically effective amount and frequency. For example, when the medicament of this embodiment is administered to a human patient, the dose of the active ingredient, the compound represented by formula (I), particularly the compound represented by formula (Ia), is usually , in the range of 0.001 to 100 mg/kg body weight, typically in the range of 0.01 to 10 mg/kg body weight per dose, in particular 0.1 to 10 mg/kg body weight per dose Range. In addition, the administration frequency of the medicament of this aspect can be, for example, once or multiple times a day, or once every several days. In addition, the administration route of the medicament of this aspect is not particularly limited, and it may be administered orally or parenterally (e.g., rectal, transmucosal, intestinal, intramuscular, subcutaneous, intramedullary, intrathecal , directly intraventricularly, intravenously, intravitreally, intraperitoneally, intranasally or intraocularly) in single or multiple doses. The antifungal activity of at least one antifungal agent of the compound of formula (I), especially of the compound of formula (Ia), by using the medicament of this embodiment in the doses and regimens described above can be prevented or treated for one or more of the conditions, diseases and/or disorders that are fungal infections.

EXAMPLES The present invention will be described in more detail below using examples. However, the technical scope of the present invention is not limited to these examples.

<I. PRODUCTION OF NOVEL COMPOUNDS BY CULTURAL MEANS>
[Isolation of BFM-0088 strain]
The BFM-0088 strain is a fungus isolated from the soil of Tokyo Bay, Tokyo, Japan. Based on the morphological characteristics, culture properties and physiological properties of the BFM-0088 strain, comparison with known strains was performed. As a result, this strain was found to be Aspergillus polyporicola. This strain was named BFM-0088 strain. This strain was registered as Aspergillus polypolichola BFM-0088 on April 3, 2019 at the Patent Microorganism Depositary Center, National Institute of Technology and Evaluation (2-5 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, 292-0818, Japan). -8 Room 122) under the Budapest Treaty (accession number NITE B P-02936). The mycological properties of the BFM-0088 strain are as follows.

1. Morphological features
The BFM-0088 strain grew well in a medium such as a nutrient agar medium such as a PDA medium. Colonies grown on PDA medium at 27°C under aerobic conditions for 2 weeks were observed under a microscope. Formation of two whorls of aspergillum, in which metole and phialide were formed around the cyst, was observed. The conidia were phialo-type conidia, one-celled, globose to subglobose, colorless, and smooth on the surface.

2. Culture properties
The colonies of the BFM-0088 strain grown on PDA medium at 27° C. under aerobic conditions for 2 weeks had a velvety surface. The color tone of the colony was ocher to pale yellow on the surface and ocher on the back.

3. BLAST homology search against DB-FU10.0 and international nucleotide sequence databases
The 28S rDNA-D1D2 nucleotide sequence showed 100% homology with the nucleotide sequence of Aspergillus polypolichola NRRL32683 ^T (accession number EF669595), which is a kind of Ascomycota. In addition, the ITS-5.8 rDNA sequence showed 100% homology with multiple nucleotide sequences of Aspergillus polypolichola, a kind of Ascomycota. From the above, the BFM-0088 strain was identified as Aspergillus polypolichola.

4. Physiological properties
The optimal growth conditions for strain BFM-0088 were aerobic conditions, pH 5.6±0.2, and temperature 27°C. In addition, the viable conditions for this strain were aerobic conditions, static culture, pH range of 3-9, temperature range of 25-27°C, and culture period of 1-2 weeks.

[Production Example I-1: Culture of BF-0088 strain]
One platinum loop of strain BFM-0088 was added to 500 µL of glycerol for storage (10% glycerol) and stored at -80°C. This strain was cultured on a storage medium (PDA medium) at 27° C. under aerobic conditions. BFM-0088 strain cultured in PDA medium was added to 100 mL of seed medium (1.0% glucose (Fujifilm Wako Pure Chemical Industries, Ltd.), 0.5% polypeptone (Becton Dickinson (Becton Dickinson, BD)), 0.05% _MgSO4.7H2O (Kanto Chemical Co., Ltd.) _, 0.2% yeast extract (BD), 0.1% _K2HPO4 (Kanto Chemical Co., Ltd.) and 0.1% agar (Shimizu Foods Co. _, Ltd.)) A platinum loop was inoculated into a 500 mL Erlenmeyer flask containing the strain, and shake culture was performed using a rotary shaker (rotation speed: 180 rpm) at 27° C. for 3 days (seed culture). After that, 10 mL of the resulting seed culture was added to 10 mL of production medium (2.4% PDB (BD), 0.5% _MgSO4.7H2O (Kanto Kagaku)) prepared using deep ocean water (Deep _Ocean ). Co., Ltd.), 0.5% _K2HPO4 (Kanto Chemical Co., Ltd.) _, 0.5% _Mg3 ( _PO4 ) _2.8H2O (Kanto Chemical Co., Ltd.)) and ₅₀ g of brown rice (Myojin Co., Ltd.). It was inoculated into an mL-volume culture vessel and cultured at 27°C for 14 days under static culture conditions (production culture).

[Production Example I-2: Purification of novel compound from culture medium of strain BF-0088]
2 L of 70% ethanol aqueous solution was added to the production culture (for 20 culture vessels) obtained by production cultivation for 14 days in Production Example I-1, and the mixture was extracted overnight under stationary conditions. 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. To this aqueous layer was added 2 L of ethyl acetate and the phases were separated. After that, the ethyl acetate layer was concentrated under reduced pressure to obtain a crude extract (1.6 g). The crude extract was dissolved in a small amount of methanol, added to an octadecylsilyl column (3 × 15 cm, Merck), and 0%, 40%, 60%, 80% and 100% (v/v) acetonitrile aqueous solution. (200 mL each for each solvent). The 80% acetonitrile aqueous solution elution fraction (Fraction 4) (70 mg) was subjected to reversed phase C-18 high performance liquid chromatography (HPLC) (20 × 250 mm; Senshu Pack PEGASIL ODS SP100, Senshu Kagaku) as follows: Further purification was performed under the conditions (solvent: 80% acetonitrile/0.1% aqueous phosphoric acid; flow rate: 6.0 ml/min; detection: UV 210 nm). Fractions containing a peak eluting at a retention time of 14.0 minutes were collected. The resulting fractions were concentrated to dryness under reduced pressure to give Compound 1 (Glysoprenin G) as a colorless oil (3.2 mg). A fraction containing a peak eluted at a retention time of 12.0 minutes was also collected. The resulting fractions were concentrated to dryness under reduced pressure to give compound 3 (glysoprenin F) as a colorless oil (6.6 mg). Similarly, the 100% acetonitrile water elution fraction (5th fraction) (100 mg) was analyzed by reversed-phase C-18 high performance liquid chromatography (HPLC) (20 × 250 mm; Senshu Pack PEGASIL ODS SP100, Senshu Kagaku). , was further purified under the following conditions (solvent: 85% acetonitrile/0.1% aqueous phosphoric acid; flow rate: 6.0 ml/min; detection: UV 210 nm). Fractions containing a peak eluting at a retention time of 12.0 minutes were collected. The resulting fractions were concentrated to dryness under reduced pressure to give compound 2 (glysoprenin H) as a colorless oil (3.8 mg).

[Compound 1 (Glysoprenin G)]
(1) Properties: Colorless oil (2) Molecular weight: 754
Observed ESI-MS(m/z) [M+Na] ⁺ 777 (3) Molecular formula: C ₄₅ H ₈₆ O ₈
HRESI-MS (m/z) [M+Na] ⁺ calculated 777.6220, found 777.6226
(4) Ultraviolet absorption spectrum: measured in methanol solution:
λ _max (MeOH, logε): Absorption at 205 nm (4.04) (5) Infrared absorption spectrum: Measured by potassium bromide tablet method:
Characteristic absorption maximum at ν _max 3448 cm ^-1 etc. (6) Specific rotation: [α] _D ²⁵ +17.86° (c=0.1, methanol)
(7) Solubility in solvents: Soluble in methanol, chloroform, DMSO, etc. (8) Proton and carbon nuclear magnetic resonance spectra: chemical shifts of hydrogen measured with a Bruker 600 MHz nuclear magnetic resonance spectrometer in heavy chloroform. (ppm) and carbon chemical shifts (ppm) are given below:
_δH : 1.11 (3H), 1.15 (3H), 1.16 (3H), 1.17 (3Hx3), 1.19 (3H), 1.21 (3H), 1.37 (2H), 1.39 (2H), 1.40 (2Hx5), 1.45 ( 2Hx9), 1.50 (2H), 1.58 (3H), 1.65 (3H), 1.67 (1H), 1.76 (1H), 1.79 (1H), 1.84 (1H), 1.97 (2H), 2.05 (2H), 2.13( 2H), 3.70 (1H), 4.10 (2H), 5.08 (1H), 5.37 (1H) ppm
_δC : 15.8, 16.1, 18.2 (x4), 18.9, 21.9, 24.1, 25.6, 25.8, 26.5, 26.9 (x5), 27.5, 37.1, 39.4, 39.8, 41.1, 42.1, 42.2, 42.3 (x8), 59.2 71.2, 72.7 (x5), 83.2, 84.7, 124.0, 124.3, 134.9, 138.5 ppm.

As a result of detailed examination of the physicochemical properties and spectral data, Compound 1 was (2E,6E)-30-(5-(2-hydroxypropan-2-yl) having a structure represented by the following formula. -2-methyltetrahydrofuran-2-yl)-3,7,11,15,19,23,27-heptamethyltriacont-2,6-diene-1,11,15,19,23,27-hexaol The structure was determined to be

[Compound 2 (Glysoprenin H)]
(1) Properties: Colorless oil (2) Molecular weight: 736
Observed ESI-MS(m/z) [M+Na] ⁺ 759 (3) Molecular formula: C ₄₅ H ₈₄ O ₇
HRESI-MS (m/z) [M+Na] ⁺ calculated 759.6114, found 759.6102
(4) Ultraviolet absorption spectrum: measured in methanol solution:
λ _max (MeOH, logε): Absorption at 205 nm (4.06) (5) Infrared absorption spectrum: Measured by potassium bromide tablet method:
Characteristic absorption maximum at ν _max 3449 cm ^-1 etc. (6) Specific rotation: [α] _D ²⁵ +3.84° (c=0.1, methanol)
(7) Solubility in solvents: Soluble in methanol, chloroform, DMSO, etc. (8) Proton and carbon nuclear magnetic resonance spectra: chemical shifts of hydrogen measured with a Bruker 800 MHz nuclear magnetic resonance spectrometer in heavy chloroform. (ppm) and carbon chemical shifts (ppm) are given below:
_δH : 1.12 (3H), 1,17 (3Hx4), 1.20 (3H), 1.22 (3H), 1.38 (2Hx3), 1.40 (2H), 1.41 (2H), 1.42 (2H), 1.45 (2Hx7), 1.51 (2H), 1.59 (3H), 1.60 (3H), 1.67 (1H), 1.68 (3H), 1.76 (1H), 1.79 (1H), 1.84 (1H), 1.96 (2H), 1.99 (2H), 2.04 (2H), 2.08 (2H), 2.12 (2H), 3.78 (1H), 4.15 (2H), 5.10 (1Hx2), 5.41 (1H) ppm
_δC : 15.9, 16.0, 16.3, 18.2 (x3), 19.0, 22.2, 24.2, 25.6, 26.3, 6.5 (x2), 26.9, 27.0 (x2), 27.1, 27.5, 37.1, 39.6, 39.7, 40.1, 41.6 42.2, 42.4 (x6), 42.5, 59.4, 71.2, 72.8 (x4), 83.2, 84.7, 123.5, 123.9, 124.4, 134.8, 135.2, 139.6 ppm.

As a result of detailed examination of the physicochemical properties and spectral data, Compound 2 was selected as (2E,6E,10E)-30-(5-(2-hydroxypropane-2- yl)-2-methyltetrahydrofuran-2-yl)-3,7,11,15,19,23,27-heptamethyltriacont-2,6,10-triene-1,15,19,23,27- The structure was determined to be pentaol.

[Compound 3 (Glysoprenin F)]
(1) Properties: Colorless oil (2) Molecular weight: 754
Observed ESI-MS(m/z) [M+Na] ⁺ 777 (3) Molecular formula: C ₄₅ H ₈₆ O ₈
HRESI-MS (m/z) [M+Na] ⁺ calculated 777.6220, found 777.6194
(4) Ultraviolet absorption spectrum: measured in methanol solution:
λ _max (MeOH,logε): Absorption at 205 nm (1.53) (5) Infrared absorption spectrum: Measured by potassium bromide tablet method:
Characteristic absorption maximum at ν _max 3449 cm ^-1 etc. (6) Specific rotation: [α] _D ²² +1.36° (c=0.1, methanol)
(7) Solubility in solvents: Soluble in methanol, chloroform, DMSO, etc. (8) Proton and carbon nuclear magnetic resonance spectra: chemical shifts of hydrogen measured with a Bruker 800 MHz nuclear magnetic resonance spectrometer in heavy chloroform. (ppm) and carbon chemical shifts (ppm) are given below:
_δH : 1.15(3Hx3), 1.16(3Hx3), 1.21(3H), 1.30-1.50 (2Hx16H), 1.58(3H), 1.59(3H), 1.66(3H), 1.95-2.01(2Hx5), 2.00-2.12 (2Hx2), 3.33(1H), 4.12(1H), 5.10(1Hx2), 5.38(1H) ppm
_δC : 15.9, 16.0, 16.3, 18.1(x4), 22.2, 23.5, 26.2, 26.3, 26.5, 26.8(x2), 27.2(x3), 39.5, 39.6, 40.0, 41.7, 42.1(3), 42.2(x5 ), 42.3, 42.6, 59.2, 72.6, 72.8(x5), 78.9, 123.5, 123.9, 124.4, 134.8, 135.1, 139.3 ppm.

As a result of comparing the physicochemical properties and spectral data with literature values, Compound 3 was replaced with (2E,6E,10E)-3,7,11,15,19, a known compound having a structure represented by the following formula. ,23,27,31,35-nonamethylhexatriacont-2,6,10-triene-1,15,19,23,27,31,34,35-octaol.

<II. Pharmacological test of novel compounds>
[reagent]
RPMI 1640 powder medium was purchased from GIBCO. 3-morpholinopropanesulfonic acid (MOPS) was purchased from DOJINDO. Sodium chloride was purchased from Kanto Kagaku Co., Ltd. DMSO was purchased from Nacalai Tesque. Alamar Blue was purchased from Bio-Rad.

[Equipment, instruments and materials]
A YAZAWA automatic mixer was used as the vortex mixer. BioTek's Power Wave x340 was used for absorbance measurements. As a plate mixer, NS-4P manufactured by AS ONE was used. N-Biotek NB-203 was used as a culture machine for 96-well plates (As One). 150 mm bottle top filters (0.22 mm pore size), 15 mL centrifuge tubes and 50 mL centrifuge tubes were purchased from Corning.

[test bacteria]
Laboratory-owned Candida albicans ATCC 90029 and Rhizopus oryzae NBRC 4705 were used as test organisms.

[Preparation of reagent]
Amphotericin B was prepared in 0.8 mg/mL DMSO solution. Test compounds (Compounds 1 and 2) were each prepared in DMSO at 6.4 mg/mL. All solutions were stored at -20°C after preparation. Physiological saline (0.85% aqueous sodium chloride solution) and bamboo skewers were sterilized with high pressure steam (121° C., 15 minutes) and then stored at room temperature.

[Preparation of RPMI 1640 medium]
10.4 and 34.5 g of RPMI 1640 powdered medium and MOPS were added to 900 mL of distilled water and stirred until the added ingredients were dissolved. The solution was then adjusted to pH 7.0 with 2 M NaOH. Distilled water was added to bring the solution up to 1 L. The volumetric solution was filter sterilized using a 150 mm bottle top filter (Corning). The resulting sterile solution was designated as RPMI 1640 medium and stored at 4°C.

[Test II-1: Activity evaluation test of antifungal active substance]
[Preparation of bacterial solution]
A method for preparing an inoculum of Candida albicans is shown below. 5 mL of 0.85% sterile saline was measured into a sterile 15 mL centrifuge tube (Corning). Using a sterilized bamboo skewer, five colonies of Candida albicans (approximately 1 mm in diameter) were collected and suspended in a weighed sterilized physiological saline solution. This was vortexed for 15 seconds using an automatic mixer (YAZAWA). 100 μL of this suspension was dispensed into a sterilized 96-well plate (As One), and OD ₅₅₀ was measured. 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 dilution was further diluted 20-fold with RPMI 1640 medium. The resulting diluted solution was used as an inoculum solution.

A method for preparing an inoculum of Rhizopus oryzae is shown below. 2 mL of 0.85% sterile saline was measured into a sterile 15 mL centrifuge tube. Spores of Rhizopus oryzae were scraped off with a platinum loop and suspended in a weighed amount of sterile physiological saline. This was allowed to stand for 5 minutes. 100 μL of this suspension was dispensed into a sterilized 96-well plate and then OD ₅₅₀ was measured. This suspension was diluted with 0.85% sterile saline to OD ₅₅₀ =0.0765. The resulting suspension was diluted 50-fold with RPMI 1640 medium. The resulting diluted solution was used as an inoculum solution.

[Evaluation of antifungal spectrum by microdilution method]
The antifungal spectrum was measured by the broth microdilution method according to the American Institute of Clinical Laboratory Standards (CLSI) M27-A3 and M38-A2 methods (Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard - Third Edition, Wayne , PA, 28, M27-A3 (2008), Filamentous Fungi; Approved Standard-Second Edition Wayne, PA, 28, M38-A2 (2008)). To each well of a sterilized 96-well plate, 1.0 μL of test compound dilutions prepared in DMSO were added to give final test compound concentrations of 32, 16, 8.0...0.016 μg/mL. As a control, DMSO alone was added at 1.0 µL. Eight wells were prepared for each test plot and control plot. Candida albicans was then added to each well at a ratio of 19 μL RPMI 1640 medium and 180 μL inoculum. After addition, the _OD550 of each well was measured (this was taken as the initial turbidity). Using an NB-203 (N-Biotek) incubator, Candida albicans inoculated into wells of a 96-well plate was cultured at 35°C for 72 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, the OD ₅₅₀ of each well was measured (this was taken as the terminal turbidity). The inhibition rate of each compound was calculated based on the following formula (M-2). The minimum concentration of the compound at which the calculated inhibition rate was 90% or more was defined as the minimum growth inhibitory concentration (MIC value) of the compound.

Compounds and control DMSO were dispensed into predetermined wells of a 96-well plate in the same manner as described above. Rhizopus oryzae was added to designated wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of inoculum. After that, 5 μL of Alamar Blue was added. Wells to which 1 μL of DMSO was added, 194 μL of RPMI 1640 medium and 5 μL of Alamar Blue were added were used as empty wells. After the addition, using an NB-203 incubator, Rhizopus oryzae inoculated into wells of a 96-well plate was cultured at 35°C for 24 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, the OD ₅₇₀ of each well was measured. The inhibition rate of each compound was calculated based on the following formula (M-3). The minimum concentration of the compound at which the calculated inhibition rate was 80% or more was defined as the minimum growth inhibitory concentration (MIC value) of the compound.

As a result of this test, none of Compounds 1, 2 and 3 exhibited growth inhibitory activity against Candida albicans and Rhizopus oryzae at concentrations of 32 μg/mL or less.

[Test II-2: Evaluation test of enhancing activity against antifungal agent amphotericin B]
[Preparation of bacterial solution]
Inoculum solutions of Candida albicans and Rhizopus oryzae were prepared in the same manner as in Test II-1.

[Evaluation of amphotericin B activity enhancing effect of test compound by microdilution method]
The method for evaluating the amphotericin B activity-enhancing effect of the test compounds (compounds 1 and 2) on Candida albicans is shown below. Final test compound concentrations of 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.0625 µg/mL and amphotericin B final concentrations of 1.0, 0.5 in each well of a sterile 96-well plate. , 0.25, 0.125, 0.0625 or 0.0313 μg/mL of test compound and amphotericin B dilutions prepared in DMSO were added at 1.0 μL each. As a control, 2.0 μL of DMSO alone was added. 1 well for each test group and 8 wells for the control group were prepared. Candida albicans was then added to each well at a ratio of 18 μL RPMI 1640 medium and 180 μL inoculum. After addition, the _OD550 of each well was measured (this was taken as the initial turbidity). Using an NB-203 (N-Biotek) incubator, Candida albicans inoculated into wells of a 96-well plate was cultured at 35°C for 24 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, the OD ₅₅₀ of each well was measured (this was taken as the terminal turbidity). Based on the above formula (M-2), the inhibition rate by combined administration of each compound and amphotericin B was calculated. The minimum concentration of amphotericin B at which the calculated inhibition rate was 90% or more was defined as the MIC value of amphotericin B in the combined administration of each compound and amphotericin B. In addition, the amphotericin B activity enhancing rate of each test compound was calculated based on the following formula (M-4). Calculation of the amphotericin B activity enhancement rate of each test compound was repeated three times.

The method for evaluating the amphotericin B activity-enhancing effect of the test compounds (compounds 1 and 2) on Rhizopus oryzae is shown below. Dilutions of test compound and amphotericin B, and control DMSO were dispensed into predetermined wells of a 96-well plate in the same manner as described above. Rhizopus oryzae was added to designated wells at a ratio of 93 μL of RPMI 1640 medium and 100 μL of inoculum. After that, 5 μL of Alamar Blue was added. Wells to which 193 μL of RPMI 1640 medium and 5 μL of Alamar Blue were added to wells to which 2 μL of DMSO was added were used as empty wells. After the addition, using an NB-203 incubator, Rhizopus oryzae inoculated into wells of a 96-well plate was cultured at 35°C for 24 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, the OD ₅₇₀ of each well was measured. Based on the above formula (M-3), the inhibition rate by combined administration of each test compound and amphotericin B was calculated. The minimum concentration of amphotericin B at which the calculated inhibition rate was 80% 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 enhancing rate of each test compound was calculated based on the above formula (M-4). Calculation of the amphotericin B activity enhancement rate of each test compound was repeated three times.

Table 1 shows the MIC values of amphotericin B against Candida albicans when the test compound and amphotericin B are co-administered. In addition, Table 2 shows the MIC value of amphotericin B against Rhizopus oryzae when the test compound and amphotericin B are administered in combination. In the table, the "test compound concentration" column indicates the concentration of the test compound when the test compound and amphotericin B are administered in combination, and the "MIC" column indicates the MIC of amphotericin B when the test compound and amphotericin B are administered in combination. The column "enhancement rate" shows the amphotericin B activity enhancement rate by each concentration of the test compound, respectively.

As shown in Table 1, co-administration of 0.25 μg/mL, especially 0.5 μg/mL or more of compound 1, 2 or 3 with amphotericin B increased the antifungal activity of amphotericin B against Candida albicans by 2- to 64-fold. , especially 8 to 64-fold enhancement. In addition, as shown in Table 2, 0.25 μg / mL, especially 0.5 μg / mL or more of compound 1, 2 or 3 was administered in combination with amphotericin B, the antifungal activity of amphotericin B against Rhizopus oryzae increased from 2 to 2. It was enhanced 16 times, especially 4-16 times.

It should be noted that the present invention is not limited to the above-described embodiments, and includes various modifications. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the described configurations. Moreover, it is possible to add, delete and/or replace part of the configuration of each embodiment with another configuration.

Claims (13)

Formula (Ia):

[In the formula,
R ^1' is hydrogen ,
R6 ^{and R7} together form a covalent bond,
R ^10a is hydrogen and R ^11a is hydroxyl , or
R ^10a and R ^11a together form a covalent bond,
R ^14a is hydrogen,
R ^15a is hydroxyl ,
R ^19′ , R ^23′ and R ^27′ are all hydrogen ;
R ^31a and R ^34a together form -O-, and
R ^35a is hydroxyl . ]
A compound represented by or a salt thereof, or a solvate thereof. A method for producing the compound according to claim 1 , a salt thereof, or a solvate thereof,
A microorganism that is the fungus Aspergillus polypolichola BFM-0088 (Accession No. NITE P-02936 ) having the ability to produce the compound represented by formula (Ia) is cultured in a medium to obtain the compound represented by formula (Ia). a compound accumulation step of accumulating a compound in said medium;
A compound purification step of purifying the compound represented by formula (Ia) obtained in the compound accumulation step from the culture of the microorganism;
The above method, comprising A microorganism which is the fungus Aspergillus polypolichola strain BFM-0088 (accession number NITE P-02936 ) capable of producing the compound represented by formula (Ia) according to claim 1 . Formula (I):

[In the formula,
R ^1' is hydrogen ,
R6 ^{and R7} together form a covalent bond,
R ¹⁰ is hydrogen and R ¹¹ is hydroxyl , or
R ¹⁰ and R ¹¹ together form a covalent bond ,
R ¹⁴ is hydrogen,
R ¹⁵ is hydroxyl,
R ^19′ , R ^23′ and R ^27′ are all hydrogen ;
R ³¹ , R ³⁴ and R ³⁵ are all hydroxyl , or
^R31 and ^R34 together form -O- and ^R35 is hydroxyl . ]
Polyene macrolides, azoles, candins and fluoropyrimidines containing the compound represented by or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient At least one antifungal drug activity enhancer selected from the group consisting of: The compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is the compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a 5. The antifungal drug activity enhancer according to claim 4 , which is a pharmaceutically acceptable solvate. 10. A medicament comprising the compound according to claim 1 , a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. 7. A medicament according to claim 6 for use in the prevention or treatment of one or more fungal infections. 6. A medicament for use in preventing or treating one or more fungal infections, comprising the antifungal drug activity enhancer according to claim 4 or 5 as an active ingredient. 9. The method according to any one of claims 6 to 8 , further comprising at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, candin drugs and fluoropyrimidine drugs. Medicine. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable carriers. 11. A pharmaceutical composition according to claim 10 for use in preventing or treating one or more fungal infections. A pharmaceutical composition for use in preventing or treating one or more fungal infections, comprising the antifungal drug activity enhancer according to claim 4 or 5 and one or more pharmaceutically acceptable carriers. . 13. The method according to any one of claims 10 to 12 , further comprising at least one antifungal drug selected from the group consisting of polyene macrolide drugs, azole drugs, candin drugs and fluoropyrimidine drugs. pharmaceutical composition.