Antifungal compound and antifungal composition

Abstract

To provide a compound having an action of inhibiting the proliferation of fungi, and to provide a composition containing the same.SOLUTION: Wherein R0 is - OH, - SH, - NHR6, or a halogen atom; R6 is H or a C1 - 6 alkyl group; one of R1 and R2 is - X - R3, and the other is H or a C1 - 6 alkyl group; X is a single bond or a C1 - 6 alkylene group; is H, -, or - C (= O) H; is H or a - 6 alkyl group; wetter is H or a wetter - 6 alkyl group, or wetter and wetter, together with the C of the - isochromene ring to which they are attached, form a 5 - or 6-membered ring containing O as a ring atom; C1 R3 1H R1 R5 OR5 R2 C1 R4. An antifungal composition comprising a compound represented by formula (I): SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to antifungal compounds and compositions. [Background technology]

[0002] It is known that certain organic compounds can inhibit the growth of mold (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 51-57890 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present disclosure is to provide a compound having the effect of inhibiting the growth of mold, and a composition containing the same. [Means for solving the problem]

[0005] The present disclosure includes the following aspects. [Section 1] Formula A below: [ka] [In formula: R 0 -OH, -SH, -NHR 6 or a halogen atom, R 6 is a hydrogen atom or C 1-6 is an alkyl group, R 1 and R 2 One of them is -XR 3 and The other is a hydrogen atom or C 1-6 is an alkyl group, X is a single bond, or O or OR 4C optionally substituted by 1-6 is an alkylene group, R 3 is a hydrogen atom, -OR 5 or -C(=O)H, R 4 is a hydrogen atom or C 1-6 is an alkyl group, R 5 is a hydrogen atom or C 1-6 is an alkyl group, Alternatively, R 1 and R 2 together with the carbon atoms of the 1H-isochromene ring to which they are attached form a 5- or 6-membered ring containing O as a ring atom, However, R 0 -OH, R 1 is -C(=O)-CH2-OH, and R 2 Except when is a hydrogen atom. An antifungal composition comprising a compound represented by the formula: [Section 2] R 0 is -OH, Item 1. The antifungal composition according to item 1. [Section 3] R 0 is -OH, R 1 is a hydrogen atom or C 1-6 is an alkyl group, R 2 -XR 3 and X is a single bond, or O or OR 4 C optionally substituted by 1-6 is an alkylene group, R 3 -OR 5 or -C(=O)H, R 4 is a hydrogen atom or C 1-6 is an alkyl group, R 5 is a hydrogen atom or C 1-6 is an alkyl group, Item 1 or 2. The antifungal composition according to item 1 or 2. [Section 4] R 1 is -CH3, Item 4. The antifungal composition according to any one of Items 1 to 3. [Section 5] X is O or OR 4 C optionally substituted by 1-6 is an alkylene group, R 3 is -C(=O)H, Item 5. The antifungal composition according to any one of Items 1 to 4. [Section 6] X is a single bond, R 3 is -C(=O)H, Item 3 or 4, the antifungal composition comprising a compound. [Section 7] X is O or OR 4 C optionally substituted by 1-6 is an alkylene group, R 3 -OR 5 and R 5 is a hydrogen atom or C 1-6 is an alkyl group, Item 3 or 4. The antifungal composition according to item 3 or 4. [Section 8] X is -CH(OR 4 )- and R 3 -OR 5 and R 4 is a hydrogen atom or C 1-6 is an alkyl group, R 5 is a hydrogen atom or C 1-6 is an alkyl group, Item 3 or 4. The antifungal composition according to item 3 or 4. [Section 9] X is -CH2-, R 3 -OR 5 and R 5 is a hydrogen atom or C 1-6 is an alkyl group, Item 3 or 4. The antifungal composition according to item 3 or 4. [Section 10] R 0 is -OH, R 1 -XR 3 and R 2 is a hydrogen atom or C 1-6 is an alkyl group, X is a single bond, or O or OR 4 C optionally substituted by 1-6 is an alkylene group, R 3 -OR 5 or -C(=O)H, R 4 is a hydrogen atom or C 1-6 is an alkyl group, R 5 is a hydrogen atom or C 1-6 is an alkyl group, 10. The antifungal composition of claim 1, comprising a compound. [Section 11] R 3 -OR 5 11. The antifungal composition according to claim 10, [Section 12] R 0 is -OH, R 1 and R 2 together with the carbon atoms of the 1H-isochromene ring to which they are attached form a 5- or 6-membered ring containing O as a ring atom, The antifungal composition according to claim 1. [Section 13] Formula B below: [ka] [In formula: R 0 is -OH, R 1 is a hydrogen atom or C 1-6 is an alkyl group, R 2 -XR 3 and X is a single bond or C 1-6 is an alkylene group, R 3 is -C(OR 4 )2, or -C(=O)H, R 4 are each independently a hydrogen atom or C 1-6 is an alkyl group. A compound represented by the formula: [Section 14] R 1 is C 1-6 is an alkyl group, X is a single bond. Item 14. The compound according to item 13. [Section 15] R 3 is -C(OR 4 )2, Item 15. The compound according to item 14. [Section 16] R 3 is -C(=O)H, Item 15. The compound according to item 14. [Effects of the Invention]

[0006] According to the present disclosure, it is possible to provide a compound having the effect of inhibiting the growth of mold, and a composition containing the same. DETAILED DESCRIPTION OF THE INVENTION

[0007] As used herein, the term "hydrocarbon group" refers to a group containing carbon and hydrogen, which is obtained by removing a hydrogen atom from a hydrocarbon. Such hydrocarbon groups include, but are not limited to, C 1-20 Examples of hydrocarbon groups include aliphatic hydrocarbon groups and aromatic hydrocarbon groups. The "aliphatic hydrocarbon group" may be linear, branched, or cyclic, and may be saturated or unsaturated. The hydrocarbon group may contain one or more ring structures. The hydrocarbon group may be substituted with one or more substituents.

[0008] As used herein, the substituent of the "hydrocarbon group" is not particularly limited, but examples thereof include a halogen atom, a C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Unsaturated cycloalkyl groups, 5- to 10-membered heterocyclyl groups, 5- to 10-membered unsaturated heterocyclyl groups, C 6-10 Examples include one or more groups selected from aryl groups and 5- to 10-membered heteroaryl groups.

[0009] The antifungal composition of the present disclosure comprises a compound represented by the following formula (A): TIFF2026011126000003.tif5588[In formula: R 0 -OH, -SH, -NHR 6 or a halogen atom, R 6 is a hydrogen atom or C 1-6 is an alkyl group, R 1 and R 2 One of them is -XR 3 and The other is a hydrogen atom or C 1-6 is an alkyl group, X is a single bond, or O or OR 4 C optionally substituted by 1-6 is an alkylene group, R 3 is a hydrogen atom, -OR 5 or -C(=O)H, R 4 is a hydrogen atom or C 1-6 is an alkyl group, R 5 is a hydrogen atom or C 1-6 is an alkyl group, Alternatively, R 1 and R 2 together with the carbon atoms of the 1H-isochromene ring to which they are attached form a 5- or 6-membered ring containing O as a ring atom, However, R 0 -OH, R 1 is -C(=O)-CH2-OH, and R 2 Except when is a hydrogen atom. The compound includes compounds represented by the formula:

[0010] R 0 -OH, -SH, -NHR 6 or a halogen atom, R 6 is a hydrogen atom or C 1-6 It is an alkyl group.

[0011] The halogen atom is fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine, more preferably chlorine.

[0012] In a preferred embodiment, R 0 is —OH or —SH, more preferably —OH.

[0013] In one embodiment, R 6 is a hydrogen atom.

[0014] In another embodiment, R 6 is C 1-6 It is an alkyl group.

[0015] R 6 C in 1-6 The alkyl group may be straight or branched. 6 C in 1-6 The alkyl group is preferably C 1-4 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0016] In one aspect, R 1 and R 2 One of them is -XR 3 and The other is a hydrogen atom or C 1-6 It is an alkyl group.

[0017] In one aspect, R 1 is a hydrogen atom or C 1-6 is an alkyl group, R 2 -XR 3 is.

[0018] In another embodiment, R 1 -XR 3 and R 2 is a hydrogen atom or C 1-6 It is an alkyl group.

[0019] R 1 or R 2 C in 1-6 The alkyl group may be straight-chain or branched. 1-6 The alkyl group is preferably C 1-4 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0020] X is a single bond, or O or OR 4 C optionally substituted by 1-6 An alkylene group. Here, an alkyl group substituted with O has two hydrogen atoms on a carbon atom replaced with oxygen, forming a —C═O group.

[0021] C in X 1-6 The alkyl group may be straight-chain or branched. 1-6 The alkyl group is preferably C 1-4 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0022] In one embodiment, X is a single bond.

[0023] In one embodiment, X is C substituted by O 1-6 It is an alkylene group.

[0024] C replaced by O 1-6 The alkylene group may be linear or branched, but is preferably linear. The number of O atoms substituted may be one or more, but is preferably one. Furthermore, such C 1-6 The alkylene group may be substituted with a substituent other than O, but is preferably substituted only with O. That is, such C 1-6 The alkylene group is preferably —(CH) m1 -C(=O)-(CH2) m2 In the above formula, m1 and m2 each independently represent an integer of 0 to 5, and the sum of m1 and m2 is 5 or less, preferably 3 or less, and more preferably 2 or less. In a preferred embodiment, m1 is 0. In a more preferred embodiment, m1 is 0 and m2 is 0 or 1.

[0025] In one embodiment, C is substituted by O. 1-6 The alkylene group is -C(=O)-CH2-.

[0026] In another embodiment, X is OR 4 C replaced by 1-6 It is an alkylene group.

[0027] OR 4 C replaced by 1-6 The alkylene group may be straight-chain or branched, but is preferably straight-chain. 4 may be one or more, but is preferably one. 1-6 The alkylene group is OR 4 may be substituted with a substituent other than OR 4 It is preferred that the C is substituted only with C. 1-6 The alkylene group is preferably —(CH) m3 -CH(OR 4 )-(CH2) m4In the above formula, m3 and m4 are each an integer of 0 to 5, and the sum of m3 and m4 is 5 or less, preferably 3 or less, and more preferably 2 or less.

[0028] R 4 is a hydrogen atom or C 1-6 It is an alkyl group. 1-6 The alkyl group may be straight-chain or branched. 1-6 The alkyl group is preferably C 1-4 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0029] In one embodiment, R 4 is a hydrogen atom.

[0030] In another embodiment, R 4 is C 1-6 It is an alkyl group.

[0031] In one embodiment, OR 4 C replaced by 1-6 The alkylene group is -CH(OR 4 )-, more preferably -CH(OCH3)-.

[0032] In another embodiment, X is an unsubstituted C 1-6 It is an alkylene group.

[0033] unsubstituted C 1-6 The alkylene group may be straight-chain or branched, but is preferably straight-chain.

[0034] In one embodiment, unsubstituted C 1-6 The alkylene group is C 1-4 It is an alkylene group, preferably a dimethylene group or a methylene group, more preferably a methylene group.

[0035] Also, X is O and OR 4 may be substituted by both O and OR 4 It is preferred that only one of the following is substituted:

[0036] R 3 is a hydrogen atom, -OR 5 Or -C(=O)H.

[0037] In one embodiment, R 3 is a hydrogen atom.

[0038] In one embodiment, R 3 is -C(=O)H.

[0039] In one embodiment, R 3 -OR 5 is.

[0040] R 5 is a hydrogen atom or C 1-6 It is an alkyl group. 1-6 The alkyl group may be straight-chain or branched. 1-6 The alkyl group is preferably C 1-4 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0041] In another embodiment, R 1 and R 2 are joined together with the carbon atoms of the 1H-isochromene ring to form a 5- or 6-membered ring containing O as a ring atom. Such a 5- or 6-membered ring may have a substituent. That is, R 1 and R 2 together with the carbon atoms of the 1H-isochromene ring to which they are attached, form the following formula (A5), (A6a), or (A6b): [ka] [ka] [ka] [In formula: R 6 are each independently a hydrogen atom or an arbitrary substituent. A compound represented by the formula:

[0042] The optional substituents are not particularly limited, but include, for example, an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a halogen atom, a C group which may be substituted with one or more halogen atoms, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Unsaturated cycloalkyl groups, 5- to 10-membered heterocyclyl groups, 5- to 10-membered unsaturated heterocyclyl groups, C 6-10 and one or more groups selected from an aryl group and a 5- to 10-membered heteroaryl group. 6 is preferably a hydrogen atom.

[0043] In one embodiment, R 1 and R 2 together with the carbon atoms of the 1H-isochromene ring to which they are attached form a 6-membered ring containing O as a ring atom (ie, Formula A6a or Formula A6b).

[0044] In such embodiments, R 6 are all hydrogen atoms.

[0045] The composition of the present disclosure contains the compound represented by formula (A) above, and therefore can have high antifungal properties, such as inhibiting the growth of fungi.

[0046] The composition of the present disclosure can be applied to various articles requiring antifungal properties. For example, the composition of the present disclosure can be applied by supporting or spray coating on a filter substrate of an air conditioner or a resin part such as a drain pan or fan. Furthermore, for example, the composition of the present disclosure can be applied by supporting or spray coating on a filter substrate of an air purifier, furniture material, wall material, bathroom wall material, etc.

[0047] Next, the compounds of the present disclosure will be described.

[0048] The compounds of the present disclosure have the following formula (A): [ka] [In formula: R 0 is -OH, R 1 is a hydrogen atom or C 1-6 is an alkyl group, R 2 -XR 3 and X is a single bond or C 1-6 is an alkylene group, R 3 is -C(OR 4 )2, or -C(=O)H, R 4 are each independently a hydrogen atom or C 1-6 is an alkyl group. It is expressed as:

[0049] R 1 is a hydrogen atom or C 1-6 It is an alkyl group.

[0050] In a preferred embodiment, R 1 is C 1-6 It is an alkyl group.

[0051] R 1 C in 1-6 The alkyl group may be straight-chain or branched. 1-6 The alkyl group is preferably C 1-4 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0052] R 2 -XR 3 and X is a single bond or C 1-6It is an alkylene group.

[0053] In a preferred embodiment, X is a single bond.

[0054] R 3 is -C(OR 4 )2, or -C(=O)H.

[0055] In one embodiment, R 3 is -C(OR 4 )2.

[0056] R 4 are each independently a hydrogen atom or C 1-6 alkyl group, preferably C 1-6 It is an alkyl group.

[0057] R 4 C in 1-6 The alkyl group may be straight-chain or branched. 1-6 The alkyl group is preferably C 1-4 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0058] In another embodiment, R 3 is -C(=O)H.

[0059] The compounds of the present disclosure can be used as antifungal agents for air conditioning, as well as in medicines, agricultural chemicals, foods, etc. [Example]

[0060] The present disclosure will be described below with reference to examples, but the present disclosure is not limited to the following examples.

[0061] (Subject to evaluation for antifungal effect) In the present disclosure, the antifungal effect was evaluated against the following molds that are often detected in air conditioners. Aspergillus brasiliensis NBRC 105650 (hereinafter referred to as A. brasiliensis) Penicillium citrinum NBRC 6352 (hereinafter referred to as P. citrinum) Cladosporium sphaerospermum NBRC 6348 (hereinafter referred to as C. sphaerospermum)

[0062] (Isolation of antifungal compounds) Gloeophyllum subferrugineum (TUFC100155), which had been completely cultured on malt agar medium, was then statically cultured in malt extract medium at 25°C for 30 days. The mycelium was then removed by suction filtration, and the culture filtrate was subjected to partition extraction with an equal volume of ethyl acetate. This partition extraction procedure was repeated three times, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered through cotton, and then concentrated under reduced pressure. The resulting residue was used as the ethyl acetate extract. Approximately 2.5 g of the ethyl acetate extract was subjected to silica gel column chromatography and eluted stepwise with a mixed solvent of ethyl acetate and hexane. The fraction eluted with 25% ethyl acetate was designated the 25% fraction, and the fraction eluted with 50% ethyl acetate was designated the 50% fraction. The 25% fraction contained 693 mg of extract, and the 50% fraction contained 564 mg of extract.

[0063] <Isolation of Components A and B> The 25% fraction was again subjected to silica gel column chromatography and eluted with 43% ethyl acetate. During this elution, the eluate was analyzed by thin-layer chromatography at fixed elution volumes and fractionated into six fractions based on absorbance at 254 nm and detection with Hanessian staining solution. The first eluted fraction of the fixed elution volume was designated Fraction 1 (hereinafter referred to as Fr. 1), the next eluted fraction as Fr. 2, and fractions up to Fr. 50 were collected. The correspondence between the six fractions, Fr. 1 to Fr. 50, and the amount of extract contained in each fraction is shown in Table 1. [Table 1]

[0064] By concentrating fraction 2, 11 mg of component A was isolated, and by concentrating fraction 4, 20 mg of component B was isolated.

[0065] <Isolation of Component C> The 50% fraction was again subjected to silica gel thin-layer chromatography and eluted with 50% ethyl acetate. During this elution, the eluate was analyzed by thin-layer chromatography at fixed elution volumes and fractionated into three fractions based on absorbance at 254 nm and detection with Hanessian staining solution. The first eluted fraction of the fixed elution volume was designated Fraction 1 (hereinafter referred to as Fr. 1), the next eluted fraction as Fr. 2, and fractions up to Fr. 50 were collected. The correspondence between the three fractions, Fr. 1 to 50, and the amount of extract contained in each fraction is shown in Table 2. [Table 2]

[0066] Fraction 2 was subjected to preparative thin-layer chromatography (dichloromethane:hexane:ethyl acetate=10:2:1, developed three times) to isolate 11 mg of component C.

[0067] (Preparation of antifungal composition) An antifungal composition was prepared as a dimethyl sulfoxide (DMSO) solution of each of the components A to C isolated by the above procedure at a concentration of 500 μg / mL. The structures of components A to C are as follows: Component A: [ka] Component B: [ka] Component C: [ka]

[0068] (Anti-fungal effect evaluation 1) 10 μl of the above antifungal composition was added to 1 ml of potato sucrose liquid medium. A 5 mm square of bacteria-containing agar containing A. brasiliensis was then inoculated to prepare antifungal evaluation samples. Samples were similarly prepared for P. citrinum and C. sphaerospermum. These samples were cultured at 25°C for 2 days, and the degree of fungal growth was observed before and after culture and evaluated according to the following criteria. +: No mold growth was observed. ±: A small amount of mold growth was observed. -: Mold growth was clearly observed. The evaluation results are shown in Table 3 below. [Table 3]

[0069] (Anti-fungal effect evaluation 2) Furthermore, to confirm the antifungal effect of compositions with lower concentrations of the antifungal components, the following evaluation was performed. DMSO was added to the above-mentioned antifungal composition with a concentration of 500 μg / mL to prepare an antifungal composition with a concentration of 100 μg / mL. Next, using the same procedure as for sample preparation in Evaluation 1 above, the above-mentioned three types of fungi were inoculated for each component to prepare antifungal evaluation samples. These samples were cultured at 25°C for two days, and the degree of fungal growth before and after culture was observed and evaluated according to the same criteria as in Evaluation 1 above. The evaluation results are shown in Table 4 below. [Table 4] [Industrial Applicability]

[0070] The compositions of the present disclosure may be suitably utilized in a wide variety of applications.

Claims

1. Formula A below: 【Chemistry 1】 [In the formula: R ０ is -OH, -SH, -NHR ６ or a halogen atom, R ６ is a hydrogen atom or C １－６ is an alkyl group, R １ and R ２ One of the two is -X-R ３ and The other is a hydrogen atom or C １－６ is an alkyl group, X is a single bond, or O or OR ４ C optionally substituted by １－６ is an alkylene group, R ３ represents a hydrogen atom, -OR ５ or —C(═O)H, R ４ is a hydrogen atom or C １－６ is an alkyl group, R ５ is a hydrogen atom or C １－６ is an alkyl group, Or, R １ and R ２ together with the carbon atoms of the 1H-isochromene ring to which they are attached form a 5- or 6-membered ring containing O as a ring atom, However, R ０ -OH, R １ -C(=O)-CH ２ -OH and R ２ is a hydrogen atom.] An antifungal composition comprising a compound represented by the formula:

2. R ０ is —OH, The antifungal composition according to claim 1.

3. R ０ is —OH, R １ is a hydrogen atom or C １－６ is an alkyl group, R ２ is -X-R ３ and X is a single bond, or O or OR ４ C optionally substituted by １－６ is an alkylene group, R ３ is -OR ５ or —C(═O)H, R ４ is a hydrogen atom or C １－６ is an alkyl group, R ５ is a hydrogen atom or C １－６ is an alkyl group, The antifungal composition according to claim 1.

4. R １ is -CH ３ That is, The antifungal composition according to claim 3.

5. X is O or OR ４ C optionally substituted by １－６ is an alkylene group, R ３ is —C(═O)H, The antifungal composition according to claim 3.

6. X is a single bond, R ３ is —C(═O)H, The antifungal composition of claim 3, comprising a compound.

7. X is O or OR ４ C optionally substituted by １－６ is an alkylene group, R ３ is -OR ５ and R ５ is a hydrogen atom or C １－６ is an alkyl group, The antifungal composition according to claim 3.

8. X is —CH(OR ４ ) - and R ３ is -OR ５ and R ４ is a hydrogen atom or C １－６ is an alkyl group, R ５ is a hydrogen atom or C １－６ is an alkyl group, The antifungal composition according to claim 3.

9. X is -CH ２ - and R ３ is -OR ５ and R ５ is a hydrogen atom or C １－６ is an alkyl group, The antifungal composition according to claim 3.

10. R ０ is —OH, R １ is -X-R ３ and R ２ is a hydrogen atom or C １－６ is an alkyl group, X is a single bond, or O or OR ４ C optionally substituted by １－６ is an alkylene group, R ３ is -OR ５ or —C(═O)H, R ４ is a hydrogen atom or C １－６ is an alkyl group, R ５ is a hydrogen atom or C １－６ is an alkyl group, The antifungal composition according to claim 1.

11. R ３ is -OR ５ The antifungal composition according to claim 10, wherein

12. R ０ is —OH, R １ and R ２ together with the carbon atoms of the 1H-isochromene ring to which they are attached form a 5- or 6-membered ring containing O as a ring atom, The antifungal composition according to claim 1.

13. Formula B below: 【Chemistry 2】 [In the formula: R ０ is —OH, R １ is a hydrogen atom or C １－６ is an alkyl group, R ２ is -X-R ３ and X is a single bond or C １－６ is an alkylene group, R ３ is -C(OR ４ ) ２ or —C(═O)H, R ４ are each independently a hydrogen atom or C １－６ is an alkyl group. A compound represented by the formula:

14. R １ is C １－６ is an alkyl group, X is a single bond; The compound of claim 13.

15. R ３ is -C(OR ４ ) ２ That is, 15. The compound of claim 14.

16. R ３ is —C(═O)H, 15. The compound of claim 14.

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