WO2020230833A1

WO2020230833A1 - Novel polyterpenoid compound having activity enhancing action on antifungal drug, and production method thereof

Info

Publication number: WO2020230833A1
Application number: PCT/JP2020/019174
Authority: WO
Inventors: 洋供田; 聡大手
Original assignee: 学校法人北里研究所
Priority date: 2019-05-15
Filing date: 2020-05-14
Publication date: 2020-11-19
Also published as: JP2020186206A; JP7256527B2

Abstract

The purpose of the present invention is to provide a novel compound which has the action of effectively enhancing the antifungal activity of an antifungal drug and which has a skeleton structure different from that of known pharmaceutical compounds. One embodiment of the present invention relates to the compound represented in formula (Ia) [in the formula, R^1'-R^35a are defined the same as in the specification or claims] or a salt thereof, or a solvate of these. Another embodiment of the present invention relates to: a method of manufacturing the compound, etc., represented in formula (Ia); an activity enhancer of at least one type of antifungal drug, the activity enhancer containing, as the effective ingredient, the compound represented in formula (I) [in the formula, R^1'-R³⁵ are defined the same as in the specification or claims] or a salt thereof, or a solvate of these; and a drug or pharmaceutical composition containing said compound as the effective ingredient.

Description

A novel polyterpenoid compound having an activity-enhancing effect on antifungal drugs and a method for producing the same

The present invention relates to a novel polyterpenoid compound having an activity enhancing action against an antifungal drug and a method for producing the same. In particular, one aspect of the present invention is a novel poly having an activity enhancing action of 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, research and development of antibiotics has made rapid progress. Along with this, antibiotics have become widespread and various therapeutic agents for various infectious diseases have been developed. On the other hand, in recent years, phenomena such as an increase and aggravation of deep mycosis 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., deterioration of immune function due to administration of anticancer drugs, or bacterial replacement phenomenon due to heavy use of antibiotics. It is believed that.

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

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

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

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

Patent Documents 2 and 3 are represented by the formula (I), which is a novel compound having an action of effectively enhancing the antifungal activity of an antifungal drug and having a skeletal structure different from that of a known pharmaceutical compound. At least one selected from the group consisting of polyene macrolide agents, azole agents, canin agents and fluoropyrimidine agents containing a compound or a salt thereof, a solvent product thereof, and the compound or the like as an active ingredient. Describe the activity enhancers of the species of antifungal agents.

Japanese Patent No. 5843188 JP-A-2018-111670 JP-A-2018-118912

In the case of blood diseases such as leukemia, or diseases accompanied by weakened immunity such as HIV infection, immunocompromised states are induced. Therefore, in patients with such diseases, the frequency of fungal infections as opportunistic infections can increase. In addition, these diseases associated with weakened immunity usually tend to become more serious, and therefore the treatment period is often long. As a result, chemotherapy for fungal infections is often long-term.

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

A compound having an action of enhancing the antifungal activity of an antifungal drug can reduce the dose of the antifungal drug and / or shorten the administration period. Therefore, by using a compound having such an action in combination with an antifungal drug, the dose of the antifungal drug is reduced and / or the administration period is shortened to suppress the occurrence of side effects such as nephrotoxicity. And / or the development of drug-resistant bacteria can be suppressed. As compounds having the above-mentioned action, various compounds such as FKI-4981B substance and a pharmaceutically acceptable salt thereof are known (Patent Documents 1 to 3). However, in order to develop a more effective pharmaceutical compound, a new compound having an action of effectively enhancing the antifungal activity of an antifungal drug and having a skeletal structure different from that of a known pharmaceutical compound is required. Was there.

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

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

That is, the present invention includes the following aspects and embodiments.
(1) Equation (Ia):

[During the ceremony,
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 cycloalkyl Alkinyl, 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 independent 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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or R ⁶ and R ⁷ Together to 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. Substituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or R ^10a and R ^11a are covalently bonded together. Form and
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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R ^{19 ^',} R ^{^23',} and R ^{27 'are} independently of one another, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkoxynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl , Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl And
R ^31a , R ^34a and R ^35a are independent of each other, hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted. Or is it an unsubstituted arylalkyloxy, a substituted or unsubstituted arylalkenyloxy, a substituted or unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, or a substituted or unsubstituted acyloxy (however, R). ^{If 10a} and R ^11a together form a covalent bond, then neither R ^31a , R ^34a and R ^35a are hydroxyl), or R ^31a and R ^34a together -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 aryl. Alkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or R ^31a is hydroxyl, substituted. Alternatively, unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted. Alternatively, it is an unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, or a 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) The compound according to the above embodiment (1), wherein R ^10a is hydrogen and R ^11a is a hydroxyl group, or R ^10a and R ^11a together form a covalent bond. The salt, or a solvate thereof.
(3) The compound according to the above embodiment (1) or (2) or a salt thereof, or a solvate thereof, wherein R ^14a is hydrogen and R ^15a is a hydroxyl group.
^{(4) R 19 ', R} 23', and R ^{27 ',} independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ alkenyl, substituted or With unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, or substituted or unsubstituted C ₃ to C ₆ cycloalkynyl. A compound according to any one of the above-described embodiments (1) to (3), a salt thereof, or a solvate thereof.
(5) R ^31a and R ^34a together form -O-, and R ^35a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C. ₆ The compound according to any one of the above-described embodiments (1) to (4), a salt thereof, or a solvate thereof, which is cycloalkoxy.
(6) R ^{1 'is} hydrogen,
R ⁶ and R ⁷ together form a covalent bond,
R ^10a is hydrogen and R ^11a is a hydroxyl, or R ^10a and R ^11a together form a covalent bond.
R ^14a is hydrogen,
R ^15a is the hydroxyl,
R ^19' , R ^23' , and R ^27'are all hydrogen,
The compound according to any one of the above-described embodiments (1) to (5), or a salt thereof, or a salt thereof, wherein R ^31a and R ^34a together form -O-, and R ^35a is a hydroxyl group. Solvation product.
(7) A method for producing a compound according to any one of the above-described embodiments (1) to (6), a salt thereof, or a solvate thereof.
The fungal Aspergillus polypolycola BFM-0088 strain (receipt number NITE ABP-02936) capable of producing the compound represented by the formula (Ia) or a microorganism thereof is cultured in a medium and the formula (Ia) is used. Compound accumulation step of accumulating the compound represented by the above in the medium;
A compound purification step of purifying the compound represented by the formula (Ia) obtained in the compound accumulation step from the culture of the microorganism;
The method described above.
(8) Fungal Aspergillus polypolycola BFM-0088 strain (receipt number NITE ABP-02936) having the ability to produce the compound represented by the formula (Ia) according to any one of the above embodiments (1) to (6). Or a microorganism that is a mutant strain thereof.
(9) Equation (I):

[During the ceremony,
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 cycloalkyl Alkinyl, 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 independent 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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R ⁶ and R ⁷ together form a covalent bond,
R ¹⁰ and R ¹¹ are independent 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 arylalkoxyoxy, 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. Substituted arylalkoxyoxy, 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} independently of one another, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkoxynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl , Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl And
R ³¹ , R ³⁴ and R ³⁵ are independent of each other, hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted. Alternatively, it may be unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
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. Alternatively, an unsubstituted aryloxy, a substituted or unsubstituted arylalkyloxy, a substituted or unsubstituted arylalkenyloxy, a substituted or unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, or a 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 aryl. Alkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, and R ³⁴ and R ³⁵ are together. To form a covalent bond. ]
Polyene macrolides, azoles, candins and fluoropyrimidines containing the compound represented by (1), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. An activity enhancer of at least one antifungal drug selected from the group consisting of.
(10) The compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is described in any of the above-described embodiments (1) to (6). The activity enhancer for an antifungal agent according to the above embodiment (9), which is a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof which is pharmaceutically acceptable.
(11) A drug containing the compound according to any one of the above-described embodiments (1) to (6), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.
(12) The medicament according to the above embodiment (11) for use in the prevention or treatment of one or more fungal infections.
(13) A medicament for use in the prevention or treatment of one or more fungal infections, which comprises the antifungal activity enhancer according to the embodiment (9) or (10) as an active ingredient.
(14) The embodiments (11) to (13), further comprising at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, candy agents and fluoropyrimidine agents. The drug described in any of.
(15) The compound according to any one of the above-described embodiments (1) to (6), a pharmaceutically acceptable salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable salts. A pharmaceutical composition comprising a carrier.
(16) The pharmaceutical composition according to embodiment (15), for use in the prevention or treatment of one or more fungal infections.
(17) Prevention or treatment of one or more fungal infections, including the antifungal activity enhancer according to embodiment (9) or (10) and one or more pharmaceutically acceptable carriers. Pharmaceutical composition for use in.
(18) The embodiments (15) to (17), further comprising at least one antifungal agent selected from the group consisting of polyene macrolide agents, azole agents, candy agents and fluoropyrimidine agents. The pharmaceutical composition according to any one of.
(19) An effective amount of the compound according to any one of the above-described embodiments (1) to (6) for a subject requiring prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections. Or the prevention or treatment of said symptoms, diseases and / or disorders, comprising administering the pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, together with at least one antifungal agent. Method.
(20) An effective amount of the antifungal agent according to the above embodiment (9) or (10) for a subject requiring prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections. A method for preventing or treating the above-mentioned symptoms, diseases and / or disorders, which comprises administering an activity enhancer together with at least one antifungal agent.
(21) The embodiment (19) or (20), wherein the at least one antifungal agent is selected from the group consisting of a polyene macrolide agent, an azole agent, a canin agent and a fluoropyrimidine agent. The preventive or therapeutic method described in.
(22) The compound according to any one of the above-described embodiments (1) to (6), a pharmaceutically acceptable salt thereof, or a pharmaceutical product thereof for use in the prevention or treatment of symptoms, diseases and / or disorders. Above acceptable solvates.
(23) The compound according to embodiment (22) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvent thereof, wherein the symptom, disease and / or disorder is one or more fungal infections. Japanese product.
(24) The activity enhancer of an antifungal agent according to the above embodiment (9) or (10), for use in the prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections.
(25) The compound according to any one of the above-described embodiments (1) to (6) or a pharmaceutically acceptable salt thereof for producing a drug for use in the prevention or treatment of symptoms, diseases and / or disorders. , Or the use of their pharmaceutically acceptable solvates.
(26) The use according to embodiment (25), wherein the symptom, disease and / or disorder is one or more fungal infections.
(27) The antifungal agent according to the above embodiment (9) or (10) for the manufacture of a medicament for use in the prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections. Use of activity enhancer.

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

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

This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2019-092118, which is the basis of the priority of the present application.

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

<1. Compound>
As used herein, "alkyl" means a linear or branched saturated aliphatic hydrocarbon group containing a specific number of carbon atoms. For example, "C ₁ to C ₆ alkyl" means a linear or branched saturated aliphatic hydrocarbon group containing at least one and at most six carbon atoms. Suitable alkyls are linear or fractionated, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Branch chain C ₁ to C ₆ alkyl can be mentioned.

As used herein, "alkenyl" means a group in which one or more CC single bonds of the alkyl are substituted with double bonds. Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 C ₂ -C ₆ alkenyl with straight or branched chains such as -methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-pentenyl and 1-hexenyl can be mentioned. ..

As used herein, "alkynyl" means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls are, but are not limited to, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl and 1-hexynyl. C ₂ to C ₆ alkynyls such as straight or branched chains can be mentioned.

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

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

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

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

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

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

As used herein, "alkoxy" and "alkoxyl" mean a group in which a hydrogen atom of a hydroxyl group is substituted with the alkyl, alkenyl or alkynyl. Suitable alkoxys and alkoxyls are, but are not limited to, C ₁ to C ₆ alkoxy or C such as, for example, methoxy or methoxyl, ethoxy or ethoxyl, propoxy or propoxyl, butoxy or butoxyl, pentoxy or pentoxyl, and hexoxy or hexoxyl. ₁ to C ₆ Alkoxy can be mentioned.

As used herein, "cycloalkoxy" and "cycloalkoxyl" mean a group in which a hydrogen atom of a hydroxyl group is substituted with the cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkoxys and cycloalkoxyls are, but are not limited to, C ₃ to C ₆ cycloalkoxy or C ₃ such as, for example, cyclopropoxy or cyclopropoxyl, cyclobutoxy or cyclobutoxyl and cyclopentoxy or cyclopentoxyl. ~ C ₆ cycloalkoxyl can be mentioned.

In the present specification, "heterocycloalkoxy" and "heterocycloalkoxyl" mean a group in which a hydrogen atom of a hydroxyl group is substituted with the heterocycloalkyl. Suitable heterocycloalkoxy and heterocycloalkoxyl include, but are not limited to, for example, 3- to 6-membered heterocycloalkoxy or 3- to 6-membered heterocycloalkoxy.

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

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

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

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

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

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

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

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

As used herein, "acyl" means a group in which a monovalent group selected from the groups described above and a carbonyl are linked. Suitable acyl may include, but are not limited to, such as formyl, acetyl and C ₁ ~ C ₆ aliphatic acyl, and C ₁ ~ C ₂₀ acyl includes C ₇ ~ C ₂₀ aromatic acyl of benzoyl propionyl, etc. Can be mentioned.

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

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

One aspect of the present invention is the formula (Ia) :.

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

Another aspect of the present invention is the formula (I) :.

The present invention relates to an antifungal activity enhancer containing a compound represented by (1), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

The present inventors have stated that a novel fungus isolated from soil produces a compound in its culture solution that has an action of effectively enhancing the antifungal activity of amphotericin B, which is one of polyene macrolides. I found it. The present inventors have found from the culture solution the known compounds glycoprenin F having an activity of enhancing the antifungal activity of amphotericin B, and novel compounds glycoprenins G and H (hereinafter, also simply referred to as “glycoprenins”). It was. Glysoprenins F, G and H can significantly enhance the antifungal activity of amphotericin B when administered in combination with amphotericin B, although they do not exhibit substantial antifungal activity when administered alone. The compound represented by the formula (Ia) of one aspect of the present invention includes novel natural organic compounds glycoprenins G and H, and related compounds thereof. In addition, the compound represented by the formula (I), which is the active ingredient of the activity enhancer of the antifungal agent of one aspect of the present invention, includes known or novel natural organic compounds glycoprenins and related compounds thereof. That is, the compound represented by the formula (I) includes the compound represented by the formula (Ia). Therefore, the compound represented by the formula (I), which is the active ingredient of the activity enhancer of the antifungal agent of one aspect of the present invention, particularly the compound represented by the formula (Ia) of the one aspect of the present invention is antifungal. The antifungal activity of fungal drugs can be effectively enhanced.

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

In the formula (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 arylalkyls, substituted or unsubstituted heteroaryls, substituted or unsubstituted heteroarylalkyls, substituted or unsubstituted alkoxycarbonyls, substituted or unsubstituted cycloalkoxycarbonyls, or substituted or unsubstituted acyls. 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 ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, substituted or unsubstituted C ₃ to C ₆ cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted. C ₇ to C ₁₁ cycloalkylalkyls, substituted or unsubstituted 3- to 6-membered heterocycloalkyls-C ₁ to C ₆ alkyls, substituted or unsubstituted C ₆ to C ₁₈ aryls, substituted or unsubstituted C ₇ ~ C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxy Preferably carbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ to C ₂₀ acyl; hydrogen, substituted or unsubstituted C ₁ to C ₆ alkyl, substituted or Unsubstituted C ₂ to C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₄ to C ₆ cycloalkenyl, or substituted. Alternatively, it is more preferably an unsubstituted C ₄ to C ₆ cycloalkynyl; further preferably hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl; particularly preferably hydrogen. If R ^{1 'is} a groups exemplified above, the compound represented by the formula (I), particularly compounds represented by Formula (Ia), it can be effectively enhanced antifungal activity of antifungal drugs it can.

In formulas (I) and (Ia), R ⁶ and R ⁷ are independent 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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy Or R ⁶ and R ⁷ together form a covalent bond. R ⁶ and R ⁷ are independent of each other, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 member hetero. Cycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 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 ⁶ and R ⁷ preferably form covalent bonds together; independently of each other, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy. Alternatively, R ⁶ and R ⁷ are more preferably combined to form a co-bond; either are hydroxyl, or R ⁶ and R ⁷ may be combined to form a co-bond. More preferably; they are particularly preferred to form covalent bonds together. When R ⁶ and R ⁷ are the groups exemplified above, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), effectively enhances the antifungal activity of the antifungal drug. be able to.

In formula (I), R ¹⁰ and R ¹¹ are independent 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 arylalkoxyoxy, 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 independent of each other, hydrogen, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 members. Heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted. 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, or R ¹⁰ And R ¹¹ preferably together to form a covalent bond or -O-; independent of each other, hydrogen, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C. It is more preferably ₃ to C ₆ cycloalkoxy, or R ¹⁰ and R ¹¹ together to form a covalent bond or -O-; R ¹⁰ is hydrogen and R ¹¹ is hydroxyl. Or R ¹⁰ and R ¹¹ are more preferably combined to form a covalent bond or -O-. When R ¹⁰ and R ¹¹ are the groups exemplified above, the compound represented by the 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. Whether aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy , Or R ^10a and R ^11a together to form a covalent bond. R ^10a is hydrogen, and R ^11a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 members. Heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, or R ^10a and R ^11a preferably together to form a covalent bond; R ^10a is hydrogen and R ^11a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted. It is more preferably C ₃ to C ₆ cycloalkoxy, or R ^10a and R ^11a together to form a covalent bond; is R ^10a hydrogen and R ^11a hydroxyl? Alternatively, R ^10a and R ^11a are more preferably combined to form a covalent bond. When R ^10a and R ^11a are the groups exemplified above, the compound represented by the formula (Ia) can effectively enhance the antifungal activity of the antifungal agent.

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. Whether aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy , Or R ¹⁴ and R ¹⁵ together to form a covalent bond. R ¹⁴ is hydrogen, and R ¹⁵ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 members. Heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, or R ¹⁴ and R ¹⁵ is preferably combined to form a covalent bond; R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted. It is more preferably C ₃ to C ₆ cycloalkoxy, or R ¹⁴ and R ¹⁵ together to form a covalent bond; R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl. Alternatively, R ¹⁴ and R ¹⁵ are more preferably combined to form a covalent bond. When R ¹⁴ and R ¹⁵ are the groups exemplified above, the compound represented by the 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 arylalkoxyoxy, 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 to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 members. Heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted Preferably 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy; R ^14a Is hydrogen, and R ^15a is more preferably hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to 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 the formula (Ia) can effectively enhance the antifungal activity of the antifungal agent.

In formulas (I) and (Ia), R ^19' , R ^23' , and R ^27' are independent of each other, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted. Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkoxyl, 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 one another, hydrogen, substituted or unsubstituted C ₁ ~ C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, substituted or unsubstituted C ₃ to C ₆ cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 member heteroaryl, substituted or unsubstituted 5 to 15 member heteroaryl-C ₁ to C Preferably ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ to C ₂₀ acyl; independent of each other. Then hydrogen, substituted or unsubstituted C ₁ to C ₆ alkyl, substituted or unsubstituted C ₂ to C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C. More preferably, they are ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, or substituted or unsubstituted C ₃ to C ₆ cycloalkynyl; independent of each other, hydrogen, methyl, ethyl, propyl, It is more preferably butyl, pentyl or hexyl; especially hydrogen. R ¹⁹ if ^', R ^23', and R ^{27 'are} groups exemplified above, the compound represented by formula (I), a compound particularly represented by formula (Ia), antifungal antifungals The activity can be effectively enhanced.

In one embodiment of the compound of formula (I), R ³¹ , R ³⁴ and R ³⁵ are independently hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted. Substituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy , Or substituted or unsubstituted acyloxy. In the case of this embodiment, R ³¹ , R ³⁴ and R ³⁵ are hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted, independently of each other. Unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ aryl Alkoxyoxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy. It is more preferable that it is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy independently of each other; both are hydroxyl. Is even more preferable.

Alternatively, in another embodiment of the compound of formula (I), R ³¹ and R ³⁴ together form -O-, and R ³⁵ is a hydroxyl, substituted or unsubstituted alkoxy. , Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted hetero Aryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy. In the case of this embodiment, R ³¹ and R ³⁴ together form -O-, and R ³⁵ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ ~ C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted. Substituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or non-substituted Preferred are substituted C ₁ to C ₂₀ acyloxys; R ³¹ and R ³⁴ together form -O-, and R ³⁵ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy. , Or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy; R ³¹ and R ³⁴ together form -O-, and R ³⁵ is further preferred to be hydroxyl. preferable.

Alternatively, in another embodiment of the compound of formula (I), R ³¹ is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted. Alternatively, unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted. It is acyloxy and R ³⁴ and R ³⁵ together form a covalent bond. In the case of this embodiment, R ³¹ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy. , Substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 Members of heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, and R ³⁴ and R ³⁵ are Preferably together to form a covalent bond; R ³¹ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy and R ^34. And R ³⁵ are more preferably together to form a co-bond; R ³¹ is a hydroxyl and R ³⁴ and R ³⁵ are more preferably together to form a co-bond.

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

In one embodiment of the compound of formula (Ia), R ^31a , R ^34a and R ^35a are independently hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or non-substituted. Substituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy , Or substituted or unsubstituted acyloxy. However, when R ^10a and R ^11a form a covalent bond together, none of R ^31a , R ^34a and R ^35a is a hydroxyl group. In the case of this embodiment, R ^31a , R ^34a and R ^35a are hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or substituted independently of each other. Unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ aryl Alkoxyoxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy. It is more preferable that it is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy independently of each other; both are hydroxyl. Is even more preferable. However, when R ^10a and R ^11a form a covalent bond together, none of R ^31a , R ^34a and R ^35a is a hydroxyl group.

Alternatively, in another embodiment of the compound of formula (Ia), R ^31a and R ^34a together form -O-, and R ^35a is a hydroxyl, substituted or unsubstituted alkoxy. , Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted hetero Aryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy. In the case of this embodiment, R ^31a and R ^34a together form -O-, and R ^35a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ ~ C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted. Substituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or non-substituted It is preferably substituted C ₁ to C ₂₀ acyloxy; R ^31a and R ^34a together form -O-, and R ^35a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy. , Or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy; R ^31a and R ^34a together form -O-, and R ^35a is further hydroxylated. preferable.

Alternatively, in another embodiment of the compound of formula (Ia), R ^31a is hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted. Alternatively, unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted. It is acyloxy and R ^34a and R ^35a together form a covalent bond. In the case of this embodiment, R ^31a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy. , Substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 Members of heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, and R ^34a and R ^35a are Preferably together to form a covalent bond; R ^31a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, and R ^34a. And R ^35a are more preferably together to form a co-bond; R ^31a is a hydroxyl and R ^34a and R ^35a are more preferably together to form a co-bond.

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

When the groups are substituted in formulas (I) and (Ia), the substituents are independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted. Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, Substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl , Substituted or 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), preferably halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or non-substituted. Substituted C ₁ to C ₆ alkyl, substituted or unsubstituted C ₂ to C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted. C ₄ to C ₆ cycloalkenyl, substituted or unsubstituted C ₄ to C ₆ cycloalkynyl, substituted or unsubstituted 3 to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyl, Substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ aryl alkyl, substituted or unsubstituted. 5 to 15 member heteroaryl, substituted or unsubstituted 5 to 15 member heteroaryl-C ₁ to C ₆ al Kill, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ Aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyl Oxy, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, substituted or unsubstituted C ₁ to C ₂₀ acyl, substituted or unsubstituted C ₁ to C ₂₀ More preferably at least one monovalent or divalent group selected from the group consisting of acyloxy, substituted or unsubstituted amino, and oxo (C = O), hydroxyl, substituted or unsubstituted C. ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, and substituted or unsubstituted It is more preferably at least one monovalent group selected from the group consisting of C ₁ to C ₂₀ acyloxy, and particularly preferably hydroxyl. The monovalent group or divalent group is preferably unsubstituted. When the monovalent or divalent group is substituted, the substituent is preferably further selected from the monovalent or divalent group and further from the unsubstituted monovalent or divalent group. More preferably selected.

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

The compounds represented by the formula (Ia) are 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 can include compounds defined by any combination.

Preferably, the compound represented by the 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 ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, substituted or unsubstituted C ₃ to C ₆ cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted. C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to 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 to C ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxy Carbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ to C ₂₀ acyl;
R ⁶ and R ⁷ are independent of each other, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 member hetero. Cycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 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 ⁶ and R ⁷ together form a covalent bond;
R ¹⁰ and R ¹¹ are independent of each other, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered hetero. Cycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 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 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 to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 members. Heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, or R ¹⁴ and R ¹⁵ together form a covalent bond;
R ^{19 ^',} R ^{^23',} and R ^{27 'are} independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, substituted or unsubstituted C ₃ to C ₆ cycloalkynyl, substituted or unsubstituted 3 to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 member heteroaryl, substituted or unsubstituted 5 to 15 member heteroaryl-C ₁ to C ₆ Alkynes, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyls, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyls, or substituted or unsubstituted C ₁ to C ₂₀ acyls;
R ³¹ , R ³⁴ and R ³⁵ are independent of each other, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 Member heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkenyloxy, substituted or unsubstituted. Substituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, or R. ³¹ and R ³⁴ together form -O-, and R ³⁵ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted. Alternatively, unsubstituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C _20. Arylalkenyloxy, substituted or unsubstituted 5- to 15-membered heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ Aryloxy or R ³¹ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy. , Substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkenyloxy, substituted or unsubstituted 5 to 15 Members of heteroaryloxy, substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, and R ³⁴ and R ³⁵ are Together they form a covalent bond;
When the groups are substituted, the substituents are independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkyl, substituted or Unsubstituted C ₂ to C ₆ alkoxys, substituted or unsubstituted C ₂ to C ₆ alkoxyls, substituted or unsubstituted C ₃ to C ₆ cycloalkyls, substituted or unsubstituted C ₄ to C ₆ cycloalkoxys, substituted or Unsubstituted C ₄ to C ₆ cycloalkoxyyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered hetero Cycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ aryl alkyl, substituted or unsubstituted 5 to 15 member heteroaryl, substituted or Unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted. Substituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, substituted or unsubstituted At least one monovalent or divalent group selected from the group consisting of C ₁ to C ₂₀ acyls, substituted or unsubstituted C ₁ to C ₂₀ acyloxys, substituted or unsubstituted aminos, and oxo (C = O). It is the basis. The monovalent group or divalent group is preferably unsubstituted. When the monovalent or divalent group is substituted, the substituent is preferably further selected from the monovalent or divalent group and further from the unsubstituted monovalent or divalent group. More preferably selected.

More preferably, the compound represented by the 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 ~ C ₆ cycloalkyl, substituted or unsubstituted C ₄ to C ₆ cycloalkenyl, or substituted or unsubstituted C ₄ to C ₆ cycloalkynyl;
R ⁶ and R ⁷ are independently hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, or R ⁶ and R ⁷ are Together to form a covalent bond;
R ¹⁰ and R ¹¹ are independent of each other, hydrogen, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, or R ¹⁰ and R 11. ¹¹ together form a covalent bond or -O-;
R ¹⁴ is hydrogen and R ¹⁵ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, or R ¹⁴ and R ¹⁵ Together to form a covalent bond;
R ^{19 ^',} R ^{^23',} and R ^{27 'are} independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, or substituted or unsubstituted C ₃ to C ₆ cycloalkynyl;
R ³¹ , R ³⁴ and R ³⁵ are independently hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, or R ³¹ and R ³⁴ together form -O-, and is R ³⁵ hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy? , Or R ³¹ is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, and R ³⁴ and R ³⁵ are covalently bonded together. Form;
When the group is substituted, the substituent is halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ Alkoxy, substituted or unsubstituted C ₂ to C ₆ alkoxyyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₄ to C ₆ cycloalkoxy, substituted or unsubstituted C ₄ ~ C ₆ cycloalkoxyyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ ~ C ₆ Alkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15-membered heteroaryl, substituted or unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy , Substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15 Heteroaryl-C ₁ to C ₆ alkyloxy, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, substituted or unsubstituted C ₁ to C ₂₀ At least one monovalent or divalent group selected from the group consisting of acyl, substituted or unsubstituted C ₁ to C ₂₀ acyloxy, substituted or unsubstituted amino, and oxo (C = O). The monovalent group or divalent group is preferably unsubstituted. When the monovalent or divalent group is substituted, the substituent is preferably further selected from the monovalent or divalent group and further from the unsubstituted monovalent or divalent group. More preferably selected.

More preferably, the compound represented by the formula (I) is
R ^{1 'is} hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
R ⁶ and R ⁷ are both hydroxyl groups, or R ⁶ and R ⁷ 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 a hydroxyl, or R ¹⁴ and R ¹⁵ together form a covalent bond;
R ^{19 ^',} R ^{^23',} and R ^{27 'independently} of one another are hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
R ³¹ , R ³⁴ and R ³⁵ are all hydroxyl groups, or R ³¹ and R ³⁴ together form -O-, and R ³⁵ is a hydroxyl group, or R ³¹ is , Hydroxy, and R ³⁴ and R ³⁵ together form a covalent bond.

Particularly preferably, the compound represented by the formula (I) is
R ^1'is hydrogen;
R ⁶ and R ⁷ are both hydroxyl groups, or R ⁶ and R ⁷ 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 a 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 groups, or R ³¹ and R ³⁴ together form -O-, and R ³⁵ is a hydroxyl group, or R ³¹ is , Hydroxy, and R ³⁴ and R ³⁵ together form a covalent bond.

Preferably, the compound represented by the 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 ~ C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, substituted or unsubstituted C ₃ to C ₆ cycloalkynyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted. C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to 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 to C ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxy Carbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, or substituted or unsubstituted C ₁ to C ₂₀ acyl;
R ⁶ and R ⁷ are independent of each other, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 member hetero. Cycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 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 ⁶ and R ⁷ together form a covalent bond;
R ^10a is hydrogen, and R ^11a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 members. Heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15 membered heteroaryloxy, substituted or unsubstituted 5 to 15 membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to 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 to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 member heterocycloalkoxy, substituted or unsubstituted. C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkoxyoxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, Substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy;
R ^{19 ^',} R ^{^23',} and R ^{27 'are} independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, substituted or unsubstituted C ₃ to C ₆ cycloalkynyl, substituted or unsubstituted 3 to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkyl alkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15 member heteroaryl, substituted or unsubstituted 5 to 15 member heteroaryl-C ₁ to C ₆ Alkynes, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyls, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyls, or substituted or unsubstituted C ₁ to C ₂₀ acyls;
R ^31a , R ^34a and R ^35a are hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6 independently of each other. Member heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkenyloxy, substituted or unsubstituted. Is it a substituted 5- to 15-membered heteroaryloxy, a substituted or unsubstituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, or a substituted or unsubstituted C ₁ to C ₂₀ acyloxy (provided that it is)? If R ^10a and R ^11a together form a covalent bond, then neither R ^31a , R ^34a, nor R ^35a is hydroxyl), or R ^31a and R ^34a together- O- is formed and R ^35a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocyclo. Alkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkenyloxy, substituted or unsubstituted 5 to A 15-membered heteroaryloxy, a substituted or unsubstituted 5--15-membered heteroaryl-C ₁ -C ₆ alkyloxy, or a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, or R ^31a is hydroxyl. , Substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ Aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkenyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15 members of heteroaryl-C ₁ to C ₆ alkyloxy, or substituted or unsubstituted C ₁ to C ₂₀ acyloxy, and R ^34a and R ^35a together. Form a covalent bond;
When the groups are substituted, the substituents are independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkyl, substituted or Unsubstituted C ₂ to C ₆ alkoxys, substituted or unsubstituted C ₂ to C ₆ alkoxyls, substituted or unsubstituted C ₃ to C ₆ cycloalkyls, substituted or unsubstituted C ₄ to C ₆ cycloalkoxys, substituted or Unsubstituted C ₄ to C ₆ cycloalkoxyyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered hetero Cycloalkyl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ aryl alkyl, substituted or unsubstituted 5 to 15 member heteroaryl, substituted or Unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3 to 6-membered heterocycloalkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted. Substituted 5- to 15-membered heteroaryl-C ₁ to C ₆ alkyloxy, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, substituted or unsubstituted At least one monovalent or divalent group selected from the group consisting of C ₁ to C ₂₀ acyls, substituted or unsubstituted C ₁ to C ₂₀ acyloxys, substituted or unsubstituted aminos, and oxo (C = O). It is the basis. The monovalent group or divalent group is preferably unsubstituted. When the monovalent or divalent group is substituted, the substituent is preferably further selected from the monovalent or divalent group and further from the unsubstituted monovalent or divalent group. More preferably selected.

More preferably, the compound represented by the 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 ~ C ₆ cycloalkyl, substituted or unsubstituted C ₄ to C ₆ cycloalkenyl, or substituted or unsubstituted C ₄ to C ₆ cycloalkynyl;
R ⁶ and R ⁷ are independently hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, or R ⁶ and R ⁷ are Together to form a covalent bond;
R ^10a is hydrogen and R ^11a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, or R ^10a and R ^11a. Together to form a covalent bond;
R ^14a is hydrogen;
R ^15a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy;
R ^{19 ^',} R ^{^23',} and R ^{27 'are} independently of one another, hydrogen, substituted or unsubstituted C ₁ ~ C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ alkenyl, substituted or unsubstituted C ₂ to C ₆ alkynyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₃ to C ₆ cycloalkenyl, or substituted or unsubstituted C ₃ to C ₆ cycloalkynyl;
^Whether R ^31a , R ^34a and R ^35a are hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy independently of each other (provided that R ^10a And R ^11a together to form a covalent bond, then R ^31a , R ^34a and R ^35a are not hydroxyl), or R ^31a and R ^34a together -O- And R ^35a is hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, or R ^31a is hydroxyl, substituted or non-substituted. Substituted C ₁ to C ₆ alkoxy, or substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, and R ^34a and R ^35a together form a covalent bond;
When the group is substituted, the substituent is halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ to C ₆ alkyl, substituted or unsubstituted C ₂ ~ C ₆ Alkoxy, substituted or unsubstituted C ₂ to C ₆ alkoxyyl, substituted or unsubstituted C ₃ to C ₆ cycloalkyl, substituted or unsubstituted C ₄ to C ₆ cycloalkoxy, substituted or unsubstituted C ₄ ~ C ₆ cycloalkoxyyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C ₇ to C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl-C ₁ ~ C ₆ Alkoxy, substituted or unsubstituted C ₆ to C ₁₈ aryl, substituted or unsubstituted C ₇ to C ₂₀ arylalkyl, substituted or unsubstituted 5 to 15-membered heteroaryl, substituted or unsubstituted 5 to 15-membered heteroaryl-C ₁ to C ₆ alkyl, substituted or unsubstituted C ₁ to C ₆ alkoxy, substituted or unsubstituted C ₃ to C ₆ cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkoxy , Substituted or unsubstituted C ₆ to C ₁₈ aryloxy, substituted or unsubstituted C ₇ to C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15-membered heteroaryloxy, substituted or unsubstituted 5 to 15 Heteroaryl-C ₁ to C ₆ alkyloxy, substituted or unsubstituted C ₁ to C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ to C ₆ cycloalkoxycarbonyl, substituted or unsubstituted C ₁ to C ₂₀ At least one monovalent or divalent group selected from the group consisting of acyl, substituted or unsubstituted C ₁ to C ₂₀ acyloxy, substituted or unsubstituted amino, and oxo (C = O). The monovalent group or divalent group is preferably unsubstituted. When the monovalent or divalent group is substituted, the substituent is preferably further selected from the monovalent or divalent group and further from the unsubstituted monovalent or divalent group. More preferably selected.

More preferably, the compound represented by the formula (Ia) is
R ^{1 'is} hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
R ⁶ and R ⁷ are both hydroxyl groups, or R ⁶ and R ⁷ together form a covalent bond;
R ^10a is hydrogen and R ^11a is a hydroxyl, or R ^10a and R ^11a together form a covalent bond;
R ^14a is hydrogen;
R ^15a is a hydroxyl;
R ^{19 ^',} R ^{^23',} and R ^{27 'independently} of one another are hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl;
Are R ^31a , R ^34a and R ^35a all hydroxyl (however, if R ^10a and R ^11a together form a covalent bond, then R ^31a , R ^34a and R ^35a are all hydroxyl groups? (There is no such thing), or R ^31a and R ^34a together form -O-, and R ^35a is a hydroxyl, or R ^31a is a hydroxyl and R ^34a and R ^35a. Together form a covalent bond.

Particularly preferably, the compound represented by the formula (Ia) is
R ^1'is hydrogen;
R ⁶ and R ⁷ together form a covalent bond;
R ^10a is hydrogen and R ^11a is a hydroxyl, or R ^10a and R ^11a together form a covalent bond;
R ^14a is hydrogen;
R ^15a is a hydroxyl;
R ^19' , R ^23' , and R ^27'are all hydrogen;
R ^31a and R ^34a together form -O-, and R ^35a is a hydroxyl group.

Particularly preferable compounds represented by the formula (I) are as follows:
(2E, 6E) -30-(5- (2-Hydroxypropan-2-yl) -2-methyltetra-2-yl) -3,7,11,15,19,23,27-Heptamethyltriacone -2,6-diene-1,11,15,19,23,27-hexaol (Compound 1; glycoprenin G);
(2E, 6E, 10E) -30-(5- (2-Hydroxypropan-2-yl) -2-methyltetra-2-yl) -3,7,11,15,19,23,27-Heptamethyl Triaconta-2,6,10-triene-1,15,19,23,27-pentaol (Compound 2; glycoprenin H); and (2E, 6E, 10E) -3,7,11,15,19, 23,27,31,35-Nonamethylhexatriaconta-2,6,10-Triene-1,15,19,23,27,31,34,35-Octaol (Compound 3: Glysoprenin F);
Is.

Particularly preferred compounds represented by the formula (Ia) are:
(2E, 6E) -30-(5- (2-Hydroxypropan-2-yl) -2-methyltetra-2-yl) -3,7,11,15,19,23,27-Heptamethyltriacone -2,6-diene-1,11,15,19,23,27-Hexaol (Compound 1; Glysoprenin G); and (2E, 6E, 10E) -30-(5- (2-Hydroxypropane-2) -Il) -2-methyltetra-2-yl) -3,7,11,15,19,23,27-Heptamethyltriaconta-2,6,10-Triene-1,15,19,23,27 -Pentaol (Compound 2; Glysoprenin H);
Is.

When the compound represented by the formula (I), which is the active ingredient of the activity enhancer of the antifungal agent of the present invention, particularly the compound represented by the formula (Ia) of the present invention is the compound. , The compound can particularly effectively enhance the antifungal activity of the antifungal agent.

The compound represented by the formula (I), particularly the compound represented by the formula (Ia), includes not only the compound itself but also a salt thereof. The salt of the compound represented by the formula (I), particularly the compound represented by the formula (Ia), is not limited, but is, for example, 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, nitrate, carbonic acid or phosphoric acid, or formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid. , Succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, 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 the formula (I), particularly the compound represented by the formula (Ia), is in the form of the salt, the antifungal activity of the antifungal drug can be effectively enhanced. ..

The compound represented by the formula (I), particularly the compound represented by the formula (Ia), includes not only the compound itself but also a solvate of the compound or a salt thereof. The solvent that can form a solvent mixture with the compound or a salt thereof is not limited, but is, for example, water, or a lower alcohol (for example, methanol, ethanol or 2-propanol (isopropyl alcohol)). Alcohols with up to 6 carbon atoms), higher alcohols (eg alcohols with 7 or more carbon atoms such as 1-heptanol or 1-octanol), dimethylsulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate An organic solvent such as is preferred. Even when the compound represented by the formula (I), particularly the compound represented by the formula (Ia) or a salt thereof is in the form of a solvate with the above-mentioned solvent, the antifungal activity of the antifungal drug is exhibited. Can be effectively enhanced.

The compound represented by the formula (I), particularly the compound represented by the formula (Ia), includes not only the compound itself but also a protected form thereof. As used herein, "protected form" means a form in which a protecting group is introduced into one or more functional groups (for example, an amino group, a hydroxyl group or a carboxylic acid group). In the present specification, the protected form of the compound represented by each of the above formulas may be described as a protected derivative of the compound represented by each of the above formulas. Further, in the present specification, the "protecting group" is a group introduced into a specific functional group in order to prevent the undesired progress of the reaction, and is quantitatively removed under the specific reaction conditions. It means a group that is substantially stable under the reaction conditions other than the above, that is, the reaction is inactive. The protecting group that can form the protected form of the compound is not limited, but for example, in the case of an amino group protecting group, t-butoxycarbonyl (Boc), 2-bromobenzyloxycarbonyl (BrZ), or If 9-fluorenylmethoxycarbonyl (Fmoc) is a protecting group for the hydroxyl group, silyl (eg, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS)), Alternatively, if the alkoxy (eg, methoxymethoxy (MOM) or methoxy (Me)) is a protecting group for a carboxylic acid group, an alkyl ester (eg, methyl, ethyl or isopropyl ester), an arylalkyl ester (eg, benzyl ester), or an amide. (For example, an amide with oxazolidinones) are preferable. The protection and deprotection by the protecting group can be appropriately carried out by those skilled in the art based on known reaction conditions. Even when the compound represented by the formula (I), particularly the compound represented by the formula (Ia), is in the protected form by the protecting group, the activity enhancing effect of the antifungal drug is substantially reduced. In some cases, the compound can be used.

When the compound represented by the formula (I), particularly the compound represented by the formula (Ia), has one or more tautomers, the compound is in the form of individual tautomers of the compound. Also includes.

Further, when the compound represented by the formula (I), particularly the compound represented by the formula (Ia), has one or a plurality of stereocenters (chiral centers), the compound is an individual enantiomer of the compound and It also includes diastereomers, as well as mixtures thereof such as racemates.

By having the above-mentioned characteristics, the compound represented by the formula (I) which is the active ingredient of the activity enhancer of the antifungal agent of one aspect of the present invention, particularly the compound represented by the formula (Ia) of one aspect of the present invention. The compound can effectively enhance the antifungal activity of the antifungal agent.

<2. Method for producing a new compound by culturing means>
The present inventors cultivate glycoprenin G (Compound 1) and glycoprenin H (Compound 2) contained in the compound represented by the formula (I), particularly the compound represented by the formula (Ia). It was found to be produced in liquid. Therefore, another aspect of the present invention relates to a method for producing a compound represented by the formula (I), particularly a compound represented by the formula (Ia), using a novel fungus.

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

[2-1. Compound accumulation process]
In this aspect, the method of the invention is a fungal Aspergillus polyporicola BFM-0088 strain (received) capable of producing a compound of formula (I), in particular a compound of formula (Ia). A compound in which a microorganism represented by No. NITE ABP-02936) or a mutant strain thereof is cultured in a medium to accumulate a compound represented by the formula (I), particularly a compound represented by the formula (Ia) in the medium. Includes accumulation step.

Aspergillus polypolycola BFM-0088 strain is a fungus isolated from the soil of Tokyo Bay, Tokyo, Japan. This strain was released as BFM-0088 on April 3, 2019, at the National Institute of Technology and Evaluation Patent Microorganisms Depositary Center (2-5-8 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818 122). Room No.) has been deposited internationally based on the Butapest Convention (receipt number NITE ABP-02936).

In this step, the microorganism used for culturing is Aspergillus polypolycola BFM-0088 strain or a mutant strain thereof having an ability to produce a compound represented by the formula (I), particularly a compound represented by the formula (Ia). It is preferably present, and more preferably the Aspergillus polypolycola BFM-0088 strain. In each aspect of the present invention, the mutant strain of Aspergillus polypolycola BFM-0088 strain means a natural mutant strain or an artificial mutant strain of Aspergillus polypolycola BFM-0088 strain. The artificial mutant strain of Aspergillus polypolycola BFM-0088 strain can be obtained by any means for producing an artificial mutant strain commonly used in the art. Not only the Aspergillus polypolycola BFM-0088 strain itself, but also a mutant strain of the Aspergillus polypolycola BFM-0088 strain produces a compound represented by the formula (I), particularly a compound represented by the formula (Ia). As long as it is a capable microorganism, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), can be accumulated in the medium in this step. Therefore, by using the microorganism, a large amount of the compound represented by the formula (I), particularly 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. Examples of the carbon source include sugars such as glucose, fructose, maltose, lactose, galactose, dextrin and starch, and vegetable oils and fats such as soybean oil. Examples of the nitrogen source include polypeptone, yeast extract, malt extract, meat extract, soybean flour, cottonseed flour, corn Steve liquor, casein, amino acids, urea, ammonium salts and nitrates. Inorganic salts include cations such as sodium ion, potassium ion, calcium ion, magnesium ion, iron ion, manganese ion, copper ion, cobalt ion or zinc ion, and inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid. Salts with acid anions can be mentioned. The media used in this step are, for example, potato / dextrose / agar (PDA) medium (potato / dextrose / agar 3.9% (Becton Dickinson (BD))) and seed medium (1.0% glucose (Fuji Film Wako Pure Chemical Co., Ltd.)). company), 0.5% polypeptone _{(BD), 0.05% MgSO 4} · 7H 2 O ( Kanto Chemical Co., Inc.), 0.2% yeast extract (BD), 0.1% K ₂ HPO ₄ (Kanto Chemical Co., Inc.) and 0.1% agar ( Shimizu foods Corporation)), or the production medium (2.4% PDB (BD), 0.5% MgSO 4 · 7H 2 O ( Kanto Chemical Co., _{_{Inc.), 0.5% K 2 HPO 4}} ( Kanto Chemical Co., Inc.), 0.5% Mg ₃ _{_{_{(PO 4) 2 · 8H 2}}} O ( Kanto Chemical Co., Inc.), and 5 g / mL brown rice (Myujin Ltd.)) are preferred. By culturing the Aspergillus polypolycola BFM-0088 strain or a mutant strain thereof having the ability to produce a compound represented by the formula (I), particularly a compound represented by the formula (Ia), in the medium. , The compound represented by the formula (I), particularly the compound represented by the formula (Ia) can be accumulated in the medium.

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

When culturing the microorganism on a large scale, the microorganism is cultivated in a small amount of medium in advance (hereinafter, also referred to as "seed culture"), and then the culture obtained by the seed culture is planted in a large volume medium. It is preferable to cultivate the cells (hereinafter, also referred to as "production culture"). In this case, the components of the medium used for the seed culture and the production culture may be the same or different. By carrying out this step by a plurality of stages of culture including seed culture and production culture, delay in the 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 the liquid medium is shake-cultured, the total of seed culture and production culture is usually 1 day to 3 weeks, and typically 3 to 17 days. By culturing the microorganism under the above conditions, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), can be efficiently accumulated in the medium.

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

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

In the method for producing a compound of the present invention by the culturing means of this embodiment, the compound represented by the formula (I) is the group R ^1' , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹⁴ exemplified above. , R ¹⁵ , R ^19' , R ^23' , and R ^27' , R ³¹ , R ³⁴ and R ³⁵ , and in particular the compounds represented by formula (Ia) are the groups R ¹ exemplified above. It is preferred to have ^' , R ⁶ , R ⁷ , R ^10a , R ^11a , R ^14a , R ^15a , R ^19' , R ^23' , and R ^27' , R ^31a , R ^34a and R ^35a . In this case, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), includes glycoprenin G (Compound 1) and glycoprenin H (Compound 2) produced by the Aspergillus polypolycola BFM-0088 strain. To do. By using the method of this embodiment, a compound represented by the formula (I) including glycoprenin G (Compound 1) and glycoprenin H (Compound 2), particularly a compound represented by the formula (Ia) can be efficiently produced. can do.

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

Another aspect of the present invention is the fungal Aspergillus polypolycola BFM-0088 strain (receipt number NITE ABP-02936) capable of producing a compound represented by the formula (I), particularly a compound represented by the formula (Ia). ) Or a microorganism that is a mutant strain thereof. In this embodiment, the compounds represented by the formula (I) are the groups R ^1' , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ^19' , R ^23' , exemplified above. And R ^27' , R ³¹ , R ³⁴ and R ³⁵ , and in particular the compounds represented by formula (Ia) are the groups R ^1' , R ⁶ , R ⁷ , R ^10a , R exemplified above. It is preferred to have ^11a , R ^14a , R ^15a , R ^19' , R ^23' , and R ^27' , R ^31a , R ^34a and R ^35a . By using the microorganism of this embodiment, a compound represented by the formula (I) including glycoprenin G (Compound 1) and glycoprenin H (Compound 2), particularly a compound represented by the formula (Ia) can be efficiently produced. can do.

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

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

In each aspect of the present invention, "administering together" means administering a plurality of drugs simultaneously or separately (for example, continuously at regular intervals). In the present specification, such an administration form may be referred to as "combination administration". The combined administration of the compound represented by the formula (I), particularly the compound represented by the formula (Ia) and at least one antifungal drug reduces the dose of the antifungal drug which may have side effects. And / or the administration period can be shortened. As a result, the occurrence of side effects caused by at least one antifungal drug can be substantially reduced.

The compound represented by the formula (I), which is the active ingredient of the activity enhancer of the antifungal agent of one aspect of the present invention, particularly the compound represented by the formula (Ia) of one aspect of the present invention is at least one kind. It has the activity of enhancing the antifungal activity of antifungal drugs. On the other hand, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), may or may not have antifungal activity by itself. The compound represented by the formula (I), particularly the compound represented by the formula (Ia), usually does not have substantially antifungal activity by itself. The compound of formula (I), in particular the compound of formula (Ia), is of at least one antifungal agent, even if it does not have substantially antifungal activity by itself. Since it has an activity of enhancing antifungal activity, it is necessary to reduce the dose of the antifungal drug which may have side effects and / or shorten the administration period by co-administration with at least one antifungal drug. Can be done. As a result, the occurrence of side effects caused by at least one antifungal drug can be substantially reduced.

A compound represented by the formula (I) which is an active ingredient of the activity enhancer of the antifungal agent of one aspect of the present invention, particularly a compound represented by the formula (Ia) of one aspect of the present invention, and at least one kind. The antifungal activity of an antifungal agent is, but is not limited to, determined by, for example, the following means. Formula (I) for any test fungus (eg, yeast, filamentous and zygomycosis) by the trace liquid dilution method according to the American Clinical Laboratory Standards Association (CLSI) M27-A3 and M38-A2 methods. The compound represented by, particularly the compound represented by the formula (Ia), or at least one antifungal drug is administered. After culturing under a predetermined condition, the growth of the fungus is measured using the turbidity (for example, OD ₅₅₀ ) or the colony diameter as an index, and the inhibition rate (%) is calculated by comparing with the value at the start of culturing. The minimum concentration of a compound having a calculated inhibition rate of a predetermined value (for example, 90%) or more is defined as the minimum inhibitory concentration (MIC value) of the compound. Based on the inhibition rate and MIC value thus determined, the compound represented by the formula (I), which is the active ingredient of the activity enhancer of the antifungal agent of one aspect of the present invention, particularly according to one aspect of the present invention. The antifungal activity of the compound represented by the formula (Ia) and at least one antifungal drug can be evaluated.

At least one of the compounds represented by the formula (I), which is the active ingredient of the activity enhancer of the antifungal agent of one aspect of the present invention, particularly the compound represented by the formula (Ia) of the one aspect of the present invention. The activity of enhancing the antifungal activity of the antifungal drug is, but is not limited to, determined by, for example, the following means. Based on the above means, the MIC value when at least one antifungal drug is administered alone is determined. Then, under the same test conditions, the compound represented by the formula (I), particularly the compound represented by the formula (Ia) of one aspect of the present invention, and at least one antifungal agent are put together (for example, simultaneously). To determine the MIC value when administered in combination with the compound represented by the formula (I), particularly the compound represented by the formula (Ia) of one aspect of the present invention, and at least one antifungal drug. .. Based on the following formula (M-1), the antifungal activity of at least one antifungal agent of the compound represented by the formula (I), particularly the compound represented by the formula (Ia) of one aspect of the present invention. Calculate the enhancement rate of. For example, when the enhancement rate is doubled, the MIC of at least one antifungal drug when the compound represented by the formula (I), particularly the compound represented by the formula (Ia) of one aspect of the present invention is administered in combination. 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 the formula (I) which is the active ingredient of the activity enhancer of the antifungal agent of the present invention, particularly the formula (Ia) of the embodiment of the present invention. ) 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 administered in combination with the compound represented by the formula (I), particularly the compound represented by the formula (Ia), has a MIC value determined by the above procedure being yeasty. For fungi (eg Candida albicans), usually 1 μg / mL. In this case, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), is usually at a concentration of 0.25 μg / mL or more, for example, 0.5 μg / mL or more, particularly 1 μg / mL or more. When administered in combination with at least one antifungal drug, the antifungal activity of at least one antifungal drug is usually increased by a factor of 2 or more, for example, in the range of 8 to 64 times, particularly in the range of 16 to 32 times. The activity can be enhanced. Therefore, when the enhancement rate is in the above range, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), may have side effects when administered in combination with at least one antifungal drug. The dose of the sexual antifungal drug can be reduced and / or the duration of administration can be shortened. As a result, the occurrence of side effects caused by at least one antifungal drug can be substantially reduced.

When the compound represented by the formula (I), particularly the compound represented by the formula (Ia) is applied for pharmaceutical use, the compound represented by the formula (I), particularly the compound represented by the formula (Ia) It includes not only the compounds themselves, but also pharmaceutically acceptable salts of the compounds and pharmaceutically acceptable solvates thereof. The pharmaceutically acceptable salts of the compound represented by the formula (I), particularly the compound represented by the formula (Ia), and the pharmaceutically acceptable solvates thereof are not limited, but for example. , The salts or solvates exemplified above are preferred. When the compound represented by the formula (I), particularly the compound represented by the formula (Ia), is in the form of the above-mentioned pharmaceutically acceptable salt or pharmaceutically acceptable solvate, at least one antifungal species. The compound can be applied to the desired pharmaceutical application without substantially reducing the activity of enhancing the antifungal activity of the drug.

When the compound represented by the formula (I), particularly the compound represented by the formula (Ia) is applied to pharmaceutical use, the compound represented by the formula (I), particularly the compound represented by the formula (Ia) is used. It includes not only the compound itself, but also the prodrug form of the compound. As used herein, "prodrug" means a compound that is converted to a parent drug in vivo. The prodrug form of the compound is not limited, but for example, when a hydroxyl group is present, an ester of the hydroxyl group and an arbitrary carboxylic acid, an amide of the hydroxyl group and an arbitrary amine, or the like can be used. For example, when an amino group is present, an amide of the amino group and an arbitrary carboxylic acid can be mentioned. When the compound represented by the formula (I), particularly the compound represented by the formula (Ia), is in the above-mentioned prodrug form, the compound represented by the parent drug formula (I), particularly the compound represented by the formula (Ia) The pharmacokinetics of the represented compound upon administration of the prodrug form to the subject can be improved without substantially reducing the activity of enhancing the antifungal activity of at least one antifungal agent.

When a compound represented by the formula (I), particularly a compound represented by the formula (Ia), is applied to pharmaceutical use, the compound may be used alone, and may be used as one or more pharmaceutically acceptable components. It may be used in combination. The medicament of this embodiment can be formulated in 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 the formula (I), particularly a compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. And can also be provided in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers. In addition to the above components, the pharmaceutical composition of this embodiment comprises one or more pharmaceutically acceptable media (eg, a solvent such as sterile water or a solution such as saline), an excipient, a binder, and the like. Vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegrant inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffers, soothing agents, It may contain an antioxidant, a sweetener, a flavoring agent and the like.

The dosage form of a drug containing the compound represented by the formula (I), particularly the compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient The preparation is not particularly limited, and may be a preparation for use in parenteral administration or a preparation for use in oral administration. In addition, the dosage form of the medicament of this embodiment may be a unit-dose form or a multi-dose form. Formulations for use in parenteral administration include, for example, injectables such as sterile solutions or suspensions with water or other pharmaceutically acceptable media. Ingredients that can be mixed with the injection include, but are not limited to, physiological saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol, D-mannose or sodium chloride). Vehicles such as isotonic solutions containing, solubilizers such as alcohols (eg ethanol or benzyl alcohol), polyalcohols (eg propylene glycol or polyethylene glycol) or esters (eg benzyl benzoate), polysorbitol 80 ™ or poly. Nonionic surfactants such as oxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, such as benzalconium chloride or prokine hydrochloride. Painless agents, stabilizers such as human serum albumin or polyethylene glycol, preservatives, antioxidants and the like. The prepared injection is usually filled in a suitable vial (eg, ampoule) and stored in a suitable environment until use.

Examples of preparations for use in oral administration include tablets, pills, powders, capsules, soft capsules, microcapsules, elixirs, liquids, syrups, slurries and suspensions. .. The tablets may be formulated as a dosage form of sugar-coated or soluble-coated sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, orally disintegrating tablets (OD tablets) or film-coated tablets, if desired. It may be formulated as a dosage form of a heavy tablet or a multi-layer tablet.

The components that can be mixed with tablets, capsules, etc. are not limited, but for example, water, ethanol, propanol, simple syrup, glucose solution, carboxymethyl cellulose, cellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc. Binders such as gelatin, corn starch, traganth gum or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or stearic acid; dried starch, sodium alginate , Agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose or disintegrants such as polyvinylpyrrolidone; sucrose, stearic acid butter or hydrogenated oil Disintegration inhibitors such as; swelling 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. Agents; Adsorbents such as starch, lactose, kaolin, bentonite or colloidal silicic acid; Lubricants such as purified talc, stearate (eg magnesium stearate), powder borate or polyethylene glycol; Sucrose, lactose or Sweeteners such as saccharin; and flavors such as starch, red mono oil or cherry can be mentioned. When the preparation is a capsule, it may further contain a liquid carrier such as fat.

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

When a compound represented by the formula (I), particularly a compound represented by the formula (Ia), is applied for pharmaceutical use, the compound may be provided together with at least one antifungal agent, or separately. May be provided. In either case, it is included in the embodiment of this embodiment. In the case of an embodiment that further comprises at least one antifungal agent in addition to the compound represented by the formula (I), particularly the compound represented by the formula (Ia), that is, the compound represented by the formula (I). In particular, in the case of an embodiment in which a compound represented by the formula (Ia) and at least one antifungal agent are provided together, the medicament of this embodiment is a compound represented by the formula (I), particularly the compound represented by the formula (Ia). It may be in the form of a pharmaceutical composition obtained by combining the compound represented by Ia), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and at least one antifungal agent. it can. In the case of the present embodiment, the medicament of this embodiment is, for example, a compound represented by the formula (I), particularly a compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Can be provided in the form of a single formulation comprising the solvate and at least one antifungal agent. In the embodiment in which the compound represented by the formula (I), particularly the compound represented by the formula (Ia), is provided separately from at least one antifungal agent, the medicament of this embodiment is represented by the formula (I). Combined with at least one antifungal agent comprising at least the compounds represented, in particular the compounds represented by formula (Ia) or pharmaceutically acceptable salts thereof, or their pharmaceutically acceptable solvates. It can be in the form of a pharmaceutical composition. In the case of the present embodiment, the medicament of this embodiment is, for example, a compound represented by the formula (I), particularly a compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Can be provided in the form of a pharmaceutical combination or kit comprising a plurality of formulations of the solvate and at least one antifungal agent separately formulated. In the form of drug combinations or kits, each formulation can be administered simultaneously or separately (eg, sequentially). Alternatively, the medicament of this embodiment contains only the compound represented by the formula (I), particularly the compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a solvate thereof which is pharmaceutically acceptable. It can also be provided in the form of a formulation comprising (ie, not containing at least one antifungal agent). In any of the embodiments, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), and at least one antifungal agent can be administered in combination.

At least one drug containing the compound represented by the formula (I), particularly the compound represented by the formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is at least one. It can also be used in combination with one or more other drugs that are useful as medicines other than the species of antifungal drugs. In this case, the medicament of this embodiment is a compound represented by the formula (I), particularly a compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a solvate thereof which is pharmaceutically acceptable. , In the form of a concomitant drug containing one or more of the other drugs. The concomitant drug includes one or more compounds represented by the formula (I), particularly a compound represented by the formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof which is pharmaceutically acceptable. It may be in the form of a pharmaceutical composition in combination with the above-mentioned other drug, and the compound represented by the formula (I), particularly the compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof. Alternatively, it may be in the form of a pharmaceutical composition used in combination with one or more of the other agents, including those pharmaceutically acceptable solvates. When the drug of this embodiment is in the form of a combination drug as described above, the compound represented by the formula (I), particularly the compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutical product thereof. A plurality of formulations in which one or more other agents are separately formulated, which may be provided in the form of a single formulation, which comprises the above acceptable solvate and one or more other agents. May be provided in the form of a pharmaceutical combination or kit comprising. In the form of drug combinations or kits, each formulation can be administered simultaneously or separately (eg, sequentially).

One type of drug contains a compound represented by the formula (I), particularly a compound represented by the formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The above fungal infections can be prevented or treated in the same manner. Fungi that cause one or more of the fungal infections are, but are not limited to, for example, yeast fungi such as Candida albicans, C. parapsilosis, and Candida grabulata. (C. glabrata) and Cryptococcus neoformans; filamentous fungi, such as Aspergillus fumigatus, Aspergillus flavas, A. niger and Aspergillus teleus. terreus); 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 dermatomycoses. The one or more fungal infections are preferably one or more diseases, symptoms or disorders selected from the group consisting of deep mycoses, superficial mycoses and dermatomycoses. The disease, symptom or disorder can be prevented or treated by administering the drug of this embodiment to a subject who needs the prevention or treatment of one or more of the fungal infections.

The drug containing the compound represented by the formula (I), particularly the compound represented by the formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is described in 1 above. It can be applied to a variety of subjects in need of prevention or treatment of symptoms, diseases and / or disorders that are more than a species of fungal infection. The subject is a human or non-human mammal (eg, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, cloak or orangutan), or a reptile (eg, a reptile). It is preferably a subject or patient such as a warm-blooded animal such as a frog, a snake or a lizard). By administering the medicament of this embodiment to the subject, various diseases, symptoms and / or disorders which are one or more fungal infections possessed by the subject can be prevented or treated.

As used herein, "prevention" means substantially preventing the occurrence (onset or manifestation) of symptoms, diseases and / or disorders. Also, as used herein, "treatment" means suppressing (eg, suppressing progression), ameliorating, repairing and / or curing the symptoms, diseases and / or disorders that have occurred (onset or manifest).

The compound represented by the formula (I), particularly the compound represented by the formula (Ia), is a symptom, disease and / or disorder (eg, deep mycosis) which is one or more fungal infections described above. , Superficial mycosis or dermatomycosis), and can be used for the prevention or treatment of the symptoms, diseases and / or disorders. Therefore, the medicament of this embodiment is preferably a medicament for use in the prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections described above, and deep mycosis. It is more preferable that the medicine is used for the prevention or treatment of one or more fungal infections selected from the group consisting of superficial mycosis and dermatomycosis. By using the medicament of this embodiment for the prevention or treatment of the symptoms, diseases and / or disorders which are one or more fungal infections, the compound represented by the formula (I), particularly the compound represented by the formula (Ia). The symptoms, diseases and / or disorders can be prevented or treated through the activity of the compound to enhance the antifungal activity of at least one antifungal agent.

The compound represented by the formula (I), particularly the compound represented by the formula (Ia), is a symptom, disease and / or disorder (eg, deep mycosis) which is one or more fungal infections described above. , Superficial mycosis or dermatomycosis), and can be used for the prevention or treatment of the symptoms, diseases and / or disorders. Therefore, another aspect of the invention is an effective amount of formula (I) for a subject in need of prevention or treatment of the symptoms, diseases and / or disorders of one or more fungal infections described above. The compound represented by, particularly the compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is administered together with at least one antifungal drug. It is a method for preventing or treating the above-mentioned symptoms, diseases and / or disorders, including the above. The symptoms, diseases and / or disorders that are one or more fungal infections are one or more symptoms, diseases and / or disorders selected from the group consisting of deep mycosis, superficial mycosis and dermatomycosis. It is preferably an obstacle. The compound represented by the formula (I), particularly the compound represented by the formula (Ia) or the present, for a subject requiring prevention or treatment of the symptoms, diseases and / or disorders of the one or more fungal infections. By administering the medicament of the embodiment together with at least one antifungal agent, the compound represented by the formula (I), particularly the compound represented by the formula (Ia), of the at least one antifungal agent. The symptoms, diseases and / or disorders can be prevented or treated through activity that enhances antifungal activity.

Another aspect of the invention is a compound of formula (I) for use in the prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections described above, in particular. A compound represented by the formula (Ia), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Another aspect of the invention is represented by formula (I) for the manufacture of a medicament for use in the prevention or treatment of symptoms, diseases and / or disorders which are one or more fungal infections described above. The use of a compound, particularly a compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The symptoms, diseases and / or disorders that are one or more fungal infections are one or more symptoms, diseases and / or disorders selected from the group consisting of deep mycosis, superficial mycosis and dermatomycosis. It is preferably an obstacle. Use the compound represented by the formula (I), particularly the compound represented by the formula (Ia) or the drug of this embodiment for the prevention or treatment of the symptoms, diseases and / or disorders of one or more of the above fungal infections. By doing so, through the activity of the compound represented by the formula (I), particularly the compound represented by the formula (Ia), to enhance the antifungal activity of at least one antifungal agent, the symptoms, diseases and / Or the disorder can be prevented or treated.

The subject is a drug containing a compound represented by the formula (I), particularly a compound represented by the formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. The exact dose and dosage (eg, dose, frequency of administration and / or route of administration), especially when administered to human patients, is the age, weight, gender, symptoms, diseases and / or disorders to be prevented or treated. The final decision should be made by the attending physician in consideration of the therapeutically effective dose, frequency of administration, route of administration, etc., in consideration of many factors such as the exact condition (for example, severity) of the drug and the route of administration. is there. Therefore, in the medicament of this embodiment, the compound represented by the formula (I), which is the active ingredient, particularly the compound represented by the formula (Ia) is administered to the subject in a therapeutically effective amount and frequency. For example, when the drug of this embodiment is administered to a human patient, the dose of the compound represented by the formula (I), which is the active ingredient, particularly the compound represented by the formula (Ia) is usually per single dose. , 0.001 to 100 mg / kg body weight, typically in the range of 0.01 to 10 mg / kg body weight per dose, especially 0.1 to 10 mg / kg body weight per dose. The range. In addition, the number of administrations of the drug of this embodiment can be, for example, once or more than once a day, or once every few days. The route of administration of the drug of this embodiment is not particularly limited, and may be administered orally, or parenterally (for example, intrarectal, intravitreal, intestinal, intramuscular, subcutaneous, intramedullary, intrasheath). , Directly intraventricularly, intravenously, intravitreally, intraperitoneally, intranasally or intraocularly) may be administered single or multiple times. The antifungal activity of at least one antifungal agent of the compound represented by the formula (I), particularly the compound represented by the formula (Ia), by using the medicament of this embodiment in the above-mentioned dose and usage. Through its activity of enhancing, the symptoms, diseases and / or disorders of one or more of the above fungal infections can be prevented or treated.

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

<I. Production of new compounds by culturing means>
[Separation of BFM-0088 strain]
The BFM-0088 strain is a fungus isolated from the soil of Tokyo Bay, Tokyo, Japan. Comparison with known bacterial species was performed based on the morphological characteristics, culture properties and physiological properties of the BFM-0088 strain. As a result, it was clarified that this strain is Aspergillus polyporicola. This strain was named BFM-0088 strain. This strain was named Aspergillus polypolycola BFM-0088 as of April 3, 2019, National Institute of Technology and Evaluation Patent Microorganisms Depositary Center (2-5 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818) -It has been deposited internationally in Room 122) based on the Butapest Convention (receipt number NITE ABP-02936). The mycological properties of the BFM-0088 strain are as follows.

1. Morphological characteristics The BFM-0088 strain grew well on a medium such as a nutrient agar medium such as a PDA medium. When the colonies grown on the PDA medium at 27 ° C. under aerobic conditions for 2 weeks were observed under a microscope, the tips of the conidia (stalks) upright from the vegetative hyphae swelled, and the apex was spherical to elliptical. The formation of two-wheeled aspergillum, in which metre and fialide are formed from around the ellipse, was observed. The conidia were fiaro-type conidia, which were spherical to subspherical in one cell, colorless and had a smooth surface.

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

3. BLAST homology search for DB-FU 10.0 and international nucleotide sequence database 28S rDNA-D1D2 nucleotide sequence is 100% homologous to the nucleotide sequence of Aspergillus polypolycola NRRL32683 ^T (accession number EF669595), which is a type of Ascomycota. The rate was shown. In addition, the ITS-5.8 rDNA nucleotide sequence showed a homology rate of 100% with respect to multiple nucleotide sequences of Aspergillus polypolycola, which is a type of Ascomycota. From the above, the BFM-0088 strain was identified as Aspergillus polypolycola.

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

[Production Example I-1: Culture of BF-0088 strain]
One platinum loop strain of BFM-0088 strain was collected in 500 μL of storage glycerol (10% glycerol) and stored at -80 ° C. This strain was cultured on a storage medium (PDA medium) at 27 ° C. under aerobic conditions. 100 mL seed medium (1.0% glucose (Fuji Film Wako Pure Chemical Industries, Ltd.), 0.5% polypeptone (Becton Dickinson)) prepared by preparing BFM-0088 strain cultured in PDA medium using deep ocean water (Deep Ocean). _{BD)), 0.05% MgSO 4} · 7H 2 O ( Kanto Chemical Co., Inc.), 0.2% yeast extract (BD), 0.1% K ₂ HPO ₄ (Kanto Chemical Co., Inc.) and 0.1% agar (Shimizu foods Corporation)) 1 platinum loop was inoculated into a 500 mL Erlenmeyer flask containing the medium, and cultured with shaking using a rotary shaker (rotation speed: 180 rpm) at 27 ° C. for 3 days (seed culture). Thereafter, a seed culture of the resulting 10 mL, deep sea water production medium in 10 mL of prepared using (Deep Ocean Co.) (2.4% PDB (BD) , 0.5% MgSO 4 · 7H 2 O ( Kanto Chemical _{_{Ltd.), 0.5% K 2 HPO 4}} ( Kanto Chemical Co., Inc.), containing _{_{0.5% Mg 3 (PO 4)}} 2 · 8H 2 O ( Kanto Chemical Co., Inc.)) and 50 g of brown rice (Myojin Ltd.) 1000 The cells were inoculated into a mL culture container and cultured for 14 days under the conditions of static culture at 27 ° C (production culture).

[Production Example I-2: Purification of a novel compound from the culture solution of BF-0088 strain]
To the production culture (20 culture vessels) obtained by the 14-day production culture in Production Example I-1, 2 L of a 70% ethanol aqueous solution was added, and the mixture was extracted overnight under static 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, 2 L of ethyl acetate was added for phase separation. Then, 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 and added to an octadecylsilyl column (3 x 15 cm, Merck) to add 0%, 40%, 60%, 80% and 100% (v / v) aqueous acetonitrile solution. (200 mL for each solvent) was eluted sequentially. The 80% acetonitrile aqueous solution elution fraction (4th fraction) (70 mg) was subjected to reverse phase C-18 high performance liquid chromatography (HPLC) (20 x 250 mm; Senshu Pack PEGASIL ODS SP100, Senshu Science) as follows. Further purification was performed under the conditions (solvent: 80% acetonitrile / 0.1% aqueous phosphate solution; flow velocity: 6.0 ml / min; detection: UV 210 nm). Fractions containing peaks eluted at a retention time of 14.0 minutes were collected. The obtained fraction was concentrated to dryness under reduced pressure to give compound 1 (glycoprenin G) as a colorless oil (3.2 mg). In addition, fractions containing peaks eluted at a retention time of 12.0 minutes were collected. The obtained fraction was concentrated to dryness under reduced pressure to give compound 3 (glycoprenin F) as a colorless oil (6.6 mg). Similarly, 100% acetonitrile water-eluted fraction (5th fraction) (100 mg) by reverse phase C-18 High Performance Liquid Chromatography (HPLC) (20 x 250 mm; Senshu Pack PEGASIL ODS SP100, Senshu Science). , Further purification under the following conditions (solvent: 85% acetonitrile / 0.1% aqueous phosphoric acid; flow rate: 6.0 ml / min; detection: UV 210 nm). Fractions containing peaks eluted at a retention time of 12.0 minutes were collected. The obtained fraction was concentrated to dryness under reduced pressure to give compound 2 (glycoprenin 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 value 777.6220, measured value 777.6226
(4) Ultraviolet absorption spectrum: Measured in methanol solution:
λ _max (MeOH, logε): Absorbed at 205 nm (4.04) (5) Infrared absorption spectrum: Measured by potassium bromide tablet method:
Absorption maximum characteristic of ν _max 3448 cm ^-1 etc. (6) Specific rotation: [α] _D ²⁵ + 17.86 ° (c = 0.1, methanol)
(7) Solubility in solvent: Soluble in methanol, chloroform, DMSO, etc. (8) Proton and carbon nuclear magnetic resonance spectrum: Chemical shift of hydrogen measured by Bruker's 600 MHz nuclear magnetic resonance spectrometer in deuterated chloroform. (Ppm) and chemical shift of carbon (ppm) are as shown below:
δ _H : 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
δ _C : 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 has a structure represented by the following formula (2E, 6E) -30-(5- (2-hydroxypropan-2-yl)). -2-Methyltetra-2-yl) -3,7,11,15,19,23,27-Heptamethyltriaconta-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 value 759.6114, measured value 759.6102
(4) Ultraviolet absorption spectrum: Measured in methanol solution:
λ _max (MeOH, logε): Absorbed at 205 nm (4.06) (5) Infrared absorption spectrum: Measured by potassium bromide tablet method:
Absorption maximum characteristic of ν _max 3449 cm ^-1 etc. (6) Specific rotation: [α] _D ²⁵ + 3.84 ° (c = 0.1, methanol)
(7) Solubility in solvent: Soluble in methanol, chloroform, DMSO, etc. (8) Proton and carbon nuclear magnetic resonance spectrum: Chemical shift of hydrogen measured by Bruker's 800 MHz nuclear magnetic resonance spectrometer in deuterated chloroform. (Ppm) and chemical shift of carbon (ppm) are as shown below:
δ _H : 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
δ _C : 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 has a structure represented by the following formula (2E, 6E, 10E) -30-(5- (2-hydroxypropane-2-). Il) -2-methyltetra-2-yl) -3,7,11,15,19,23,27-Heptamethyltriaconta-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 value 777.6220, measured value 777.6194
(4) Ultraviolet absorption spectrum: Measured in methanol solution:
λ _max (MeOH, logε): Absorbed at 205 nm (1.53) (5) Infrared absorption spectrum: Measured by potassium bromide tablet method:
Absorption maximum characteristic of ν _max 3449 cm ^-1 etc. (6) Specific rotation: [α] _D ²² + 1.36 ° (c = 0.1, methanol)
(7) Solubility in solvent: Soluble in methanol, chloroform, DMSO, etc. (8) Proton and carbon nuclear magnetic resonance spectrum: Chemical shift of hydrogen measured by Bruker's 800 MHz nuclear magnetic resonance spectrometer in deuterated chloroform. (Ppm) and chemical shift of carbon (ppm) are as shown below:
δ _H : 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
δ _C : 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 the literature values, compound 3 was identified as (2E, 6E, 10E) -3,7,11,15,19 of a known compound having a structure represented by the following formula. , 23,27,31,35-Nonamethylhexatriaconta-2,6,10-Triene-1,15,19,23,27,31,34,35-Octaol was identified.

<II. Pharmacological test of new compound>
[reagent]
RPMI 1640 powder medium was purchased from GIBCO. 3-Morpholine propanesulfonic acid (MOPS) was purchased from DOJINDO. Sodium chloride was purchased from Kanto Chemical Co., Inc. DMSO was purchased from Nacalai Tesque. Allermar Blue was purchased from Bio-Rad.

[Equipment, equipment and materials]
A YAZAWA automatic mixer was used as the vortex mixer. A Bio Tek Power Wave x340 was used to measure the absorbance. As a plate mixer, NS-4P manufactured by AS ONE Corporation was used. N-Biotek's NB-203 was used as the incubator for the 96-well plate (As One). The 150 mm bottle top filter (pore diameter 0.22 mm), 15 mL centrifuge tube and 50 mL centrifuge tube were purchased from Corning.

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

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

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

[Test II-1: Activity evaluation test of antifungal active substance]
[Preparation of bacterial solution]
The method for preparing the inoculated bacterial solution of Candida albicans is shown below. In a sterilized 15 mL centrifuge tube (Corning), 5 mL of 0.85% sterile saline was measured. Five Candida albicans colonies (about 1 mm in diameter) were collected using a sterilized bamboo skewer and suspended in the measured sterile saline solution. This was vortexed for 15 seconds using an automatic mixer (YAZAWA). 100 μL of this suspension was dispensed into a sterilized 96-well plate (As One), and then OD ₅₅₀ was measured. The suspension was diluted with 0.85% sterile saline to 0.5 McFarland (OD ₅₅₀ = 0.0548). 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 obtained diluted solution was used as an inoculum solution.

The method for preparing the inoculated bacterial solution of lysopath oryzae is shown below. 2 mL of 0.85% sterile saline was measured in a sterilized 15 mL centrifuge tube. The spores of lysopath oryzae were scraped off with a platinum loop and suspended in the measured sterile saline. This was allowed to stand for 5 minutes. 100 μL of this suspension was dispensed into a sterile 96-well plate and then OD ₅₅₀ was measured. The 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 obtained diluted solution was used as an inoculum solution.

[Evaluation of antifungal spectrum by trace liquid dilution method]
The antifungal spectrum was measured by the Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard --Third Edition, Wayne according to the American Clinical and Laboratory Standards Institute (CLSI) M27-A3 and M38-A2 methods. , PA, 28, M27-A3 (2008), Filamentous Fungi; Approved Standard-Second Edition Wayne, PA, 28, M38-A2 (2008)). To each well of the sterilized 96-well plate, 1.0 μL of a diluted solution of the test compound prepared by DMSO was added so that the final concentration of the test compound was 32, 16, 8.0… 0.016 μg / mL. As a control, 1.0 μL of DMSO alone was added. Each test plot and control plot were prepared with 8 wells. Candida albicans was then added to each well at a ratio of 19 μL of RPMI 1640 medium and 180 μL of inoculum solution. After the addition, the OD ₅₅₀ 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 96-well plates was cultured at a temperature of 35 ° C. for 72 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, OD ₅₅₀ of each well was measured (this was defined as terminal turbidity). The inhibition rate of each compound was calculated based on the following formula (M-2). The minimum concentration of the compound having the calculated inhibition rate of 90% or more was defined as the minimum inhibitory concentration (MIC value) of the compound.

Compound and control DMSO were dispensed into predetermined wells of a 96-well plate in the same procedure as described above. Risopath oryzae was added to the given wells at a ratio of 99 μL of RPMI 1640 medium and 100 μL of inoculum solution. Then, 5 μL of Alamar Blue was added. Wells to which RPMI 1640 medium 194 μL and Alamar Blue 5 μL were added to wells to which DMSO 1 μL was added were designated as empty wells. After the addition, the lysopath oryzae inoculated into the wells of the 96-well plate was cultured using an NB-203 incubator at a temperature of 35 ° C. for 24 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, OD 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 having the calculated inhibition rate of 80% or more was defined as the minimum inhibitory concentration (MIC value) of the compound.

As a result of this test, none of compounds 1, 2 and 3 showed growth inhibitory activity against Candida albicans and lysopath oryzae at a concentration of 32 μg / mL or less.

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

[Evaluation of amphotericin B activity enhancing effect of test compound by trace liquid dilution 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. In each well of the sterilized 96-well plate, the final concentrations of test compound were 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.0625 μg / mL, and the final concentrations of amphotericin B were 1.0 and 0.5. , 0.25, 0.125, 0.0625 or 0.0313 μg / mL, 1.0 μL each of the test compound prepared by DMSO and the diluted solution of amphotericin B was added. As a control, 2.0 μL of DMSO alone was added. One well of each test plot and eight wells of control plot were prepared. Candida albicans was then added to each well at a ratio of 18 μL of RPMI 1640 medium and 180 μL of inoculum solution. After the addition, the OD ₅₅₀ 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 96-well plates was cultured at a temperature of 35 ° C. for 24 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, OD ₅₅₀ of each well was measured (this was defined as terminal turbidity). Based on the above formula (M-2), the inhibition rate by the combined administration of each compound and amphotericin B was calculated. The minimum concentration of amphotericin B when the calculated inhibition rate was 90% or more was defined as the MIC value of amphotericin B in the combined administration of each compound and amphotericin B. In addition, the amphotericin B activity enhancement rate of each test compound was calculated based on the following formula (M-4). The 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 lysopath oryzae is shown below. In the same procedure as described above, the test compound, a diluted solution of amphotericin B, and control DMSO were dispensed into predetermined wells of a 96-well plate. Risopath oryzae was added to the given wells at a ratio of 93 μL of RPMI 1640 medium and 100 μL of inoculum solution. Then 5 μL of Alamar Blue was added. Wells to which RPMI 1640 medium 193 μL and Alamar Blue 5 μL were added to wells to which DMSO 2 μL was added were designated as empty wells. After the addition, the lysopath oryzae inoculated into the wells of the 96-well plate was cultured using an NB-203 incubator at a temperature of 35 ° C. for 24 hours. Then, using NS-4P (As One), the 96-well plate was shaken and stirred for 30 minutes. After stirring, OD ₅₇₀ of each well was measured. Based on the above formula (M-3), the inhibition rate by the combined administration of each test compound and amphotericin B was calculated. The minimum concentration of amphotericin B when the calculated inhibition rate was 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 enhancement rate of each test compound was calculated based on the above formula (M-4). The calculation of the amphotericin B activity enhancement rate of each test compound was repeated three times.

Table 1 shows the MIC value of amphotericin B when the test compound and amphotericin B were co-administered to Candida albicans. Table 2 shows the MIC value of amphotericin B when the test compound and amphotericin B were co-administered to lysopath oryzae. In the table, the column of "test compound concentration" is the concentration of the test compound when the test compound and amphotericin B are co-administered, and the column of "MIC" is the MIC of amphotericin B when the test compound and amphotericin B are co-administered. The value and the column of "enhancement rate" indicate the amphotericin B activity enhancement rate by each concentration of the test compound.

As shown in Table 1, the antifungal activity of amphotericin B against Candida albicans was increased 2-64 times by co-administration of compounds 1, 2 or 3 of 0.25 μg / mL, especially 0.5 μg / mL or more, with amphotericin B. In particular, it was enhanced 8 to 64 times. In addition, as shown in Table 2, the antifungal activity of amphotericin B against amphotericin B is increased by co-administering compounds 1, 2 or 3 of 0.25 μg / mL, especially 0.5 μg / mL or more, in combination with amphotericin B. It was increased 16 times, especially 4 to 16 times.

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

All publications, patents and patent applications cited in this specification shall be incorporated herein by reference as is.

Claims

Equation (Ia):

[During the ceremony,
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 cycloalkyl Alkinyl, 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 independent 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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or R 6 and R 7 Together to 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. Substituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or R 10a and R 11a are covalently bonded together. Form and
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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R 19 ', R 23', and R 27 'are independently of one another, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkoxynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl , Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl And
R 31a , R 34a and R 35a are independent of each other, hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted. Or is it an unsubstituted arylalkyloxy, a substituted or unsubstituted arylalkenyloxy, a substituted or unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, or a substituted or unsubstituted acyloxy (however, R). If 10a and R 11a together form a covalent bond, then neither R 31a , R 34a and R 35a are hydroxyl), or R 31a and R 34a together -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 aryl. Alkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, or R 31a is hydroxyl, substituted. Alternatively, unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkenyloxy, substituted. Alternatively, it is an unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, or a 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.
The compound according to claim 1, or a salt thereof, wherein R 10a is hydrogen and R 11a is a hydroxyl group, or R 10a and R 11a form a covalent bond together. Solvation product.
The compound according to claim 1 or 2, or a salt thereof, or a solvate thereof, wherein R 14a is hydrogen and R 15a is a hydroxyl group.
R 19 ', R 23', and R 27 ', independently of one another, hydrogen, substituted or unsubstituted C 1 ~ C 6 alkyl, substituted or unsubstituted C 2 ~ C 6 alkenyl, substituted or unsubstituted Claimed to be C 2 to C 6 alkynyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or unsubstituted C 3 to C 6 cycloalkenyl, or substituted or unsubstituted C 3 to C 6 cycloalkynyl. The compound according to any one of Items 1 to 3, a salt thereof, or a solvate thereof.
R 31a and R 34a together form -O-, and R 35a is hydroxyl, substituted or unsubstituted C 1 to C 6 alkoxy, or substituted or unsubstituted C 3 to C 6 cycloalkoxy. The compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof.
R 1'is hydrogen,
R 6 and R 7 together form a covalent bond,
R 10a is hydrogen and R 11a is a hydroxyl, or R 10a and R 11a together form a covalent bond.
R 14a is hydrogen,
R 15a is the hydroxyl,
R 19' , R 23' , and R 27'are all hydrogen,
The compound according to any one of claims 1 to 5, or a salt thereof, or a solvate thereof, wherein R 31a and R 34a together form -O-, and R 35a is a hydroxyl group. Stuff.
A method for producing a compound according to any one of claims 1 to 6, a salt thereof, or a solvate thereof.
The fungal Aspergillus polypolycola BFM-0088 strain (receipt number NITE ABP-02936) capable of producing the compound represented by the formula (Ia) or a microorganism thereof is cultured in a medium and the formula (Ia) is used. Compound accumulation step of accumulating the compound represented by (1) in the medium;
A compound purification step of purifying the compound represented by the formula (Ia) obtained in the compound accumulation step from the culture of the microorganism;
The method described above.
A fungal Aspergillus polypolycola BFM-0088 strain (receipt number NITE ABP-02936) or a mutant strain thereof having an ability to produce a compound represented by the formula (Ia) according to any one of claims 1 to 6. Microorganisms.
Equation (I):

[During the ceremony,
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 cycloalkyl Alkinyl, 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 independent 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 arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
R 6 and R 7 together form a covalent bond,
R 10 and R 11 are independent 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 arylalkoxyoxy, 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. Substituted arylalkoxyoxy, 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 independently of one another, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted cycloalkoxynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl , Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, or substituted or unsubstituted acyl And
R 31 , R 34 and R 35 are independent of each other, hydroxyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted. Alternatively, it may be unsubstituted arylalkyloxy, substituted or unsubstituted arylalkoxyoxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy.
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. Alternatively, an unsubstituted aryloxy, a substituted or unsubstituted arylalkyloxy, a substituted or unsubstituted arylalkenyloxy, a substituted or unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylalkyloxy, or a 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 aryl. Alkyloxy, substituted or unsubstituted arylalkenyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylalkyloxy, or substituted or unsubstituted acyloxy, and R 34 and R 35 are together. To form a covalent bond. ]
Polyene macrolides, azoles, candins and fluoropyrimidines containing the compound represented by (1), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. An activity enhancer of at least one antifungal drug selected from the group consisting of.
The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. The activity enhancer of the antifungal agent according to claim 9, which is a salt thereof or a solvate thereof which is pharmaceutically acceptable.
A drug containing the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
The medicament according to claim 11, for use in the prevention or treatment of one or more fungal infections.
A drug for use in the prevention or treatment of one or more fungal infections, which comprises the antifungal activity enhancer according to claim 9 or 10 as an active ingredient.
The invention according to any one of claims 11 to 13, further comprising at least one antifungal agent selected from the group consisting of a polyene macrolide agent, an azole agent, a candine agent and a fluoropyrimidine agent. Medicine.
A medicament containing the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers. Composition.
The pharmaceutical composition according to claim 15, for use in the prevention or treatment of one or more fungal infections.
A pharmaceutical composition for use in the prevention or treatment of one or more fungal infections, which comprises the activity enhancer of the antifungal agent according to claim 9 or 10 and one or more pharmaceutically acceptable carriers. ..
13. Pharmaceutical composition.