JP2022128985A - α-DICARBONYL COMPOUND DECOMPOSER - Google Patents

Abstract

To provide a novel α-dicarbonyl compound decomposer and a use thereof.SOLUTION: The present invention discloses an α-dicarbonyl compound decomposer containing a compound represented by the formula (I), a salt thereof or a solvate of them; a composition for decomposing α-dicarbonyl compounds, containing a compound represented by the formula (I), a salt thereof or a solvate of them; and their uses for decomposing Maillard reaction products, suppressing AGEs formation, breaking AGEs crosslinks, anti-glycation, and/or suppressing melanin synthesis.SELECTED DRAWING: None

Description

The present invention relates to a decomposing agent for α-dicarbonyl compounds such as Maillard reaction products, saccharification intermediates, melanin synthesis intermediates, and cosmetic compositions, pharmaceutical compositions and food compositions containing the same.

Saccharification, also known as the Maillard reaction, was described in 1912 by the French scientist L. C. It is a non-enzymatic chemical reaction between amino acids and reducing sugars discovered by Maillard. In the Maillard reaction, the carbonyl group of a sugar and the amino group of an amino acid combine to form a Schiff base, which undergoes a reaction called Amadori rearrangement to form a substance called an Amadori compound. In vivo, this Amadori compound further undergoes irreversible reactions such as oxidation and dehydration to become a saccharification intermediate such as 3-deoxyglucosone (3-DG), which is an α-dicarbonyl compound. Methylglyoxal produced as a by-product of glycolysis and glyoxal produced by oxidation of lipids are also α-dicarbonyl compounds and major intermediates of saccharification. These α-dicarbonyl compounds are highly reactive, form cross-links between amino acids in proteins, and lead to advanced glycation end products (AGEs). On the other hand, it is also known that an amadori compound of protein forms an amadori dione by dehydration reaction, and then an amadori ene-dione by further dehydration to form an amadori dion crosslink with another protein having an α-dicarbonyl structure. there is The production of AGEs impairs protein function and exerts physiological and physical damages on various tissues and cells. These AGEs are involved in tissue and cell dysfunction associated with diabetes and aging (Non-Patent Document 1). For example, if collagen in the dermis is glycated, the skin loses its elasticity and wrinkles are formed. It is also known that this saccharification is involved in many diseases such as cataract and progression of Alzheimer's disease. AGEs are known to be the cause of aging and various diseases and their aggravation, and saccharification is considered to be an important factor in anti-aging.

Therefore, in recent years, in order to prevent accumulation of AGEs in the body, glycation reaction inhibitors and AGE production inhibitors have been developed and studied. For example, N-phenacylthiazolium bromide (PTB) is known as a compound that cleaves crosslinked structures involving AGEs (Non-Patent Document 2). PTB recognizes and cleaves the α-dicarbonyl structure in 1-phenyl-1,2-propanedione (PPD), which serves as a model for AGEs cross-linking (Non-Patent Document 3). It has been reported that when PTB is administered to diabetic rats, it inhibits collagen AGEs cross-linking and reduces mesenteric vascular AGEs (Non-Patent Documents 2 and 4). There are also reports that administration of a compound called ALT-711, which is a water-soluble form of PTB, to humans improved vascular stiffness and systolic blood pressure (Non-Patent Documents 3 and 5). In addition to PTB, components having such AGEs cross-linking activity have also been found in various natural components such as monoterpene alcohol contained in yuzu and ellagitannin contained in pomegranate. Recently, it has been reported that melatonin has an AGE cross-linking action (Non-Patent Document 6).

Goto S, et al., Implications of protein degradation in aging. Ann N Y Acad Sci. 2001 Apr; 928:54-64. Vasan S, et al., An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature.1996 Jul; 382(6588):275-8. Kass DA, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation. 2001 Sep;104(13):1464-70. Cooper ME, et al. The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation. Diabetologia. 2000 May;43(5):660-4. Bakris GL, et al. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens. 2004 Dec;17(12):23S-30S. Yonei Y, et al., Cleaving effect of melatonin on crosslinks in advanced glycation end products. Glycative Stress Ressearch. 2016; 3(1):38-43

There is still a need for new substances capable of decomposing α-dicarbonyl compounds such as Maillard reaction products.

［式（Ｉ）中、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され；
ｎは、１～６の整数を表し；
点線（_－－－）は、単結合又は二重結合を表し、
点線（_－－－）が単結合である場合、Ｘ_１はＣＲ_３ｃであり、Ｘ_２はＣＲ_２ｂであり、Ｒ_２ｂおよびＲ_３ｃは、それぞれ独立して、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され、
点線（_－－－）が二重結合である場合、Ｘ_１およびＸ_２は炭素原子であり；
Ｒ_３ａは、Ｃ_２－６アシル基、水素原子、およびＣ_１－６アルキル基からなる群から選択され；
（Ａ）Ｒ_３ａがＣ_２－６アシル基のとき、
Ｒ_２ａは、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され、かつ、Ｒ_３ｂは、水素原子を表すか、又は、Ｒ_２ａとＲ_３ｂとは一緒になって結合を形成し、
Ｒ_５は、Ｃ_１－６アルコキシ基を表し、かつ、
Ｒ_１、Ｒ_２ａ、Ｒ_２ｂ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基であり；
（Ｂ）Ｒ_３ａが水素原子又はＣ_１－６アルキル基のとき、
Ｒ_２ａは、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され、
Ｒ_３ｂは、水素原子又はＣ_１－６アルキル基を表し、
Ｒ_５は、水素原子、水酸基又はＣ_１－６アルコキシ基を表し、かつ
Ｒ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない。]
［２］ 式（Ｉ）中、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はＣ_１－３アルキル基を表し、
ｎは、１～３の整数を表し、
点線（_－－－）が単結合である場合、Ｘ_１はＣＲ_３ｃであり、Ｘ_２はＣＲ_２ｂであり、Ｒ_２ｂおよびＲ_３ｃは、それぞれ独立して、水素原子、水酸基、およびＣ_１－３アルキル基からなる群から選択され、
点線（_－－－）が二重結合である場合、Ｘ_１およびＸ_２は炭素原子であり；
Ｒ_３ａは、Ｃ_２－４アシル基、水素原子、又はＣ_１－３アルキル基を表し、
（Ａ）Ｒ_３ａがＣ_２－４アシル基のとき、
Ｒ_２は、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され、かつ、Ｒ_３ｂは、水素原子を表すか、又は、Ｒ_２とＲ_３ｂとは一緒になって結合を形成し、
Ｒ_５は、Ｃ_１－３アルコキシ基を表し、かつ、
Ｒ_１、Ｒ_２ａ、Ｒ_２ｂ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基であり、
（Ｂ）Ｒ_３ａが水素原子又はＣ_１－３アルキル基のとき、
Ｒ_２ａは、水素原子、水酸基、およびＣ_１－３アルキル基からなる群から選択され、
Ｒ_３ｂは、水素原子を表し、
Ｒ_５は、水素原子、水酸基又はＣ_１－３アルコキシ基を表し、かつ
Ｒ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない、請求項１に記載の分解剤。
［３］ 式（Ｉ）で表される化合物、その塩、又はこれらの溶媒和物は、下記式（Ｉａ－１）、式（Ｉａ－２）、式（Ｉａ－３）または式（Ｉｂ－１）で表される化合物、その塩、又はこれらの溶媒和物である、［１］または［２］に記載の分解剤。

［式（Ｉa－１）中、
Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である］

［式（Ｉａ－２）中、
Ｒ_１、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である］

［式（Ｉａ－３）中、
Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である］

［式（Ｉｂ－１）中、
Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、
Ｒ_３ａおよびＲ_３ｂは、それぞれ独立して、水素原子又はＣ_１－３アルキル基を表し、
Ｒ_５は、水素原子、水酸基、メトキシ基又はヒドロキシメチル基を表し、かつ
Ｒ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない。］ For example, the present invention is as follows.
[1] An α-dicarbonyl compound decomposing agent containing a compound represented by the following formula (I), a salt thereof, or a solvate thereof.

[In formula (I), R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
n represents an integer from 1 to 6;
A dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _1- is selected from the group consisting of ₆ alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _3a is selected from the group consisting of C _2-6 acyl groups, hydrogen atoms, and C _1-6 alkyl groups;
(A) when R _3a is a C _2-6 acyl group,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-6 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-6 alkyl group,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
R _3b represents a hydrogen atom or a C _1-6 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group or a C _1-6 alkoxy group, and R ₁ , R _{3a ,} R _3b , R ₄ , R ₅ , R ₆ and R ₇ are not all hydrogen atoms. ]
[2] In formula (I), R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a C _1-3 alkyl group;
n represents an integer of 1 to 3,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _{1- 3} selected from the group consisting of alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _3a represents a C _2-4 acyl group, a hydrogen atom, or a C _1-3 alkyl group;
(A) when R _3a is a C _2-4 acyl group,
R ₂ is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group, and R _3b represents a hydrogen atom, or R ₂ and R _3b together form a bond form,
R ₅ represents a C _1-3 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-3 alkyl group,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group;
R _3b represents a hydrogen atom,
R ₅ represents a hydrogen atom, a hydroxyl group or a C _1-3 alkoxy group, and R ₁ , R _3a, R _3b , R ₄ , R ₅ , R ₆ and R ₇ are not all hydrogen atoms; The decomposing agent according to claim 1.
[3] The compound represented by formula (I), a salt thereof, or a solvate thereof is represented by the following formula (Ia-1), formula (Ia-2), formula (Ia-3) or formula (Ib- The decomposing agent according to [1] or [2], which is a compound represented by 1), a salt thereof, or a solvate thereof.

[In the formula (Ia-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R _2a , R ₄ , R ₆ and R ₇ is a hydroxyl group]

[In the formula (Ia-2),
R ₁ , R _2a , R _3c , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and R ₁ , R _2a , R _3c , R ₄ and R ₆ and at least one of R ₇ is a hydroxyl group]

[In the formula (Ia-3),
R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R ₄ , R ₆ and R ₇ is a hydroxyl group ]

[In the formula (Ib-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group;
R _3a and R _3b each independently represent a hydrogen atom or a C _1-3 alkyl group;
R5 represents a hydrogen atom, a hydroxyl group, a methoxy group or a hydroxymethyl group, and _R1 , _{R3a, R3b , R4 , R5} , _R6 and _R7 are not all hydrogen atoms. ]

からなる群から選択される化合物、その塩、又はこれらの溶媒和物である、［１］～［３］のいずれかに記載の分解剤。
［５］ メイラード反応生成物分解、ＡＧＥｓ生成抑制、ＡＧＥｓ架橋分解、抗糖化、および／またはメラニン合成の抑制に使用するための、［１］～［４］のいずれかに記載の分解剤。 [4] The compound represented by formula (I), a salt thereof, or a solvate thereof is:

The decomposing agent according to any one of [1] to [3], which is a compound selected from the group consisting of, salts thereof, or solvates thereof.
[5] The decomposing agent according to any one of [1] to [4], for use in decomposing Maillard reaction products, inhibiting AGE production, decomposing AGEs crosslinks, anti-glycation, and/or inhibiting melanin synthesis.

［式（Ｉ）中、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され；
ｎは、１～６の整数を表し；
Ｒ_３ａは、Ｃ_２－６アシル基、水素原子、およびＣ_１－６アルキル基からなる群から選択され；
（Ａ）Ｒ_３ａがＣ_２－６アシル基のとき、
点線（_－－－）は、単結合又は二重結合を表し、
点線（_－－－）が単結合である場合、Ｘ_１はＣＲ_３ｃであり、Ｘ_２はＣＲ_２ｂであり、Ｒ_２ｂおよびＲ_３ｃは、それぞれ独立して、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され、
点線（_－－－）が二重結合である場合、Ｘ_１およびＸ_２は炭素原子であり；
Ｒ_２ａは、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され、かつ、Ｒ_３ｂは、水素原子を表すか、又は、Ｒ_２ａとＲ_３ｂとは一緒になって結合を形成し、
Ｒ_５は、Ｃ_１－６アルコキシ基を表し、かつ、
Ｒ_１、Ｒ_２ａ、Ｒ_２ｂ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基であり；
（Ｂ）Ｒ_３ａが水素原子又はＣ_１－６アルキル基のとき、
点線（_－－－）が二重結合であり、Ｘ_１およびＸ_２は炭素原子であり、
Ｒ_２ａは、水素原子、水酸基、およびＣ_１－６アルキル基からなる群から選択され、
Ｒ_３ｂは、水素原子又はＣ_１－６アルキル基を表し、
Ｒ_５は、水素原子、水酸基、Ｃ_１－６アルコキシ基、又はヒドロキシＣ_１－６アルキル基を表し、かつ
Ｒ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない。]
［７］ 式（Ｉ）中、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はＣ_１－３アルキル基を表し、
ｎは、１～３の整数を表し、
Ｒ_３ａは、Ｃ_２－４アシル基、水素原子、又はＣ_１－３アルキル基を表し、
（Ａ）Ｒ_３ａがＣ_２－４アシル基のとき、
点線（_－－－）は、単結合又は二重結合を表し、
点線（_－－－）が単結合である場合、Ｘ_１はＣＲ_３ｃであり、Ｘ_２はＣＲ_２ｂであり、Ｒ_２ｂおよびＲ_３ｃは、それぞれ独立して、水素原子、水酸基、およびＣ_１－３アルキル基からなる群から選択され、
点線（_－－－）が二重結合である場合、Ｘ_１およびＸ_２は炭素原子であり；
Ｒ_２ａは、水素原子、水酸基、およびＣ_１－３アルキル基からなる群から選択され、かつ、Ｒ_３ｂは、水素原子を表すか、又は、Ｒ_２ａとＲ_３ｂとは一緒になって結合を形成し、
Ｒ_５は、Ｃ_１－３アルコキシ基を表し、かつ、
Ｒ_１、Ｒ_２ａ、Ｒ_２ｂ、Ｒ_３ｃ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基であり、
（Ｂ）Ｒ_３ａが水素原子又はＣ_１－３アルキル基のとき、
点線（_－－－）が二重結合であり、Ｘ_１およびＸ_２は炭素原子であり、
Ｒ_２ａは、水素原子、水酸基、およびＣ_１－３アルキル基からなる群から選択され、
Ｒ_３ｂは、水素原子又はＣ_１－３アルキル基を表し、
Ｒ_５は、水素原子、水酸基、Ｃ_１－３アルコキシ基、又はヒドロキシＣ_１－３アルキル基を表し、かつ
Ｒ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない、［６］に記載の組成物。
［８］ 式（Ｉ）で表される化合物、その塩、又はこれらの溶媒和物は、下記式（Ｉａ－１）、式（Ｉａ－２）、式（Ｉａ－３）または式（Ｉｂ－１）で表される化合物、その塩、又はこれらの溶媒和物である、［６］または［７］に記載の組成物。

［式（Ｉa－１）中、
Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である］

［式（Ｉａ－２）中、
Ｒ_１、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である］

［式（Ｉａ－３）中、
Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である］

［式（Ｉｂ－１）中、
Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、
Ｒ_３ａおよびＲ_３ｂは、それぞれ独立して、水素原子又はＣ_１－３アルキル基を表し、
Ｒ_５は、水素原子、水酸基、メトキシ基又はヒドロキシメチル基を表し、かつ
Ｒ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない。］ [6] A composition for decomposing α-dicarbonyl compounds, containing a compound represented by the following formula (I), a salt thereof, or a solvate thereof as an active ingredient.

[In formula (I), R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
n represents an integer from 1 to 6;
R _3a is selected from the group consisting of C _2-6 acyl groups, hydrogen atoms, and C _1-6 alkyl groups;
(A) when R _3a is a C _2-6 acyl group,
A dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _1- is selected from the group consisting of ₆ alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-6 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-6 alkyl group,
the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
R _3b represents a hydrogen atom or a C _1-6 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group, or a hydroxy C _1-6 alkyl group, and all of R ₁ , R _3a, R _3b , R ₄ , R ₅ , R ₆ and R ₇ cannot be a hydrogen atom. ]
[7] In formula (I), R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a C _1-3 alkyl group;
n represents an integer of 1 to 3,
R _3a represents a C _2-4 acyl group, a hydrogen atom, or a C _1-3 alkyl group;
(A) when R _3a is a C _2-4 acyl group,
A dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _{1- 3} selected from the group consisting of alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-3 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-3 alkyl group,
the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group;
R _3b represents a hydrogen atom or a C _1-3 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group, a C _1-3 alkoxy group, or a hydroxy C _1-3 alkyl group, and all of R ₁ , R _3a, R _3b , R ₄ , R ₅ , R ₆ and R ₇ is not a hydrogen atom, the composition according to [6].
[8] The compound represented by formula (I), a salt thereof, or a solvate thereof is represented by the following formula (Ia-1), formula (Ia-2), formula (Ia-3) or formula (Ib- The composition according to [6] or [7], which is a compound represented by 1), a salt thereof, or a solvate thereof.

[In the formula (Ia-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R _2a , R ₄ , R ₆ and R ₇ is a hydroxyl group]

[In the formula (Ia-2),
R ₁ , R _2a , R _3c , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and R ₁ , R _2a , R _3c , R ₄ and R ₆ and at least one of R ₇ is a hydroxyl group]

[In the formula (Ia-3),
R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R ₄ , R ₆ and R ₇ is a hydroxyl group ]

[In the formula (Ib-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group;
R _3a and R _3b each independently represent a hydrogen atom or a C _1-3 alkyl group;
R5 represents a hydrogen atom, a hydroxyl group, a methoxy group or a hydroxymethyl group, and _R1 , _{R3a, R3b , R4 , R5} , _R6 and _R7 are not all hydrogen atoms. ]

からなる群から選択される化合物、その塩、又はこれらの溶媒和物である、［６］～［１０］のいずれかに記載の組成物。 [9] The compound represented by formula (I), a salt thereof, or a solvate thereof is the following:

The composition according to any one of [6] to [10], which is a compound selected from the group consisting of, a salt thereof, or a solvate thereof.

[10] The composition according to any one of [6] to [10] for decomposition of Maillard reaction products, suppression of AGE production, cross-linking degradation of AGEs, anti-glycation, and/or suppression of melanin synthesis.
[11] The composition according to any one of [6] to [10], which is a cosmetic composition, pharmaceutical composition or food composition.
[12] The composition according to any one of [6] to [10], which is a cosmetic composition for preventing and/or improving skin aging, or suppressing pigmentation and/or whitening skin.
[13] The pharmaceutical composition according to any one of [6] to [10], which is a pharmaceutical composition for preventing and/or treating aging-related diseases, skin aging, or diabetic complications caused by the formation of advanced glycation end products. composition.
[14] The composition according to any one of [6] to [10], which is a food composition for preventing and/or improving aging.

The present invention has one or more of the following effects. (1) The present invention provides a novel α-dicarbonyl compound decomposing agent having α-dicarbonyl bond cleaving activity.
(2) The α-dicarbonyl compound decomposing agent of the present invention can decompose α-dicarbonyl compounds, which are intermediate products of the Maillard reaction and other glycation intermediates such as methylglyoxal (MG) and glyoxal (GO). This suppresses the production of AGEs.
(3) The α-dicarbonyl compound-decomposing agent of the present invention can decompose crosslinked structures (AGEs crosslinks) related to advanced glycation end products (AGEs), which are late products of the Maillard reaction. This contributes to the decomposition and excretion of AGEs in the body, and can suppress the accumulation of AGEs in the body.
(4) The α-dicarbonyl compound decomposing agent of the present invention decomposes dopaquinone, which is an intermediate in melanin synthesis, thereby suppressing melanin synthesis.
(5) The α-dicarbonyl compound decomposing agent of the present invention can be suitably used as cosmetic compositions, pharmaceutical compositions, food compositions and the like. The cosmetic composition of one embodiment can exhibit a skin pigmentation suppressing effect and/or a skin whitening effect. The cosmetic composition of one embodiment can exert an effect of preventing and/or improving skin aging (for example, reduction of skin elasticity, collagen cross-linking that causes wrinkles and sagging, etc.). The pharmaceutical composition of one embodiment can be used to prevent and/or treat aging-related diseases caused by the formation of advanced glycation end products (AGEs). By ingesting the food composition of one embodiment, it is possible to prevent and/or improve aging.

FIG. 1 shows the relationship between the concentration of a compound and the amount of benzoic acid produced (BA amount) in each sample solution in Example 1. FIG. FIG. 2A is a photomicrograph of precipitates on the bottom of wells of the control group and the experimental group (2HMEL 0.5 mM, 2HMEL 1 mM) obtained in the melanin darkening measurement of Example 2. FIG. FIG. 2B compares the degree of blackness between the experimental group and the control group by measuring the brightness of the entire bottom surface of the well using the free software Image J from the photograph of FIG. 2A. The blackening degree of the experimental group is calculated with the control group as 100%. 3 shows the results of electrophoresis using the lysozyme/fructose saccharification reaction model in Example 3. FIG. In the figure, A shows results for the lysozyme-only system, B for the system containing lysozyme and fructose, and C for the system containing lysozyme, fructose, and 2HMEL.

Embodiments of the present invention will be described below, but the present invention is not limited to the following embodiments, and can be arbitrarily modified without departing from the scope of the invention.
The upper and lower limits of the numerical ranges described herein can be arbitrarily combined. For example, when "A to B" and "C to D" are described, the ranges of "A to D" and "C to B" are also included in the present invention as numerical ranges.
X and Y in "C _XY " indicate the number of carbon atoms. For example, “C _1-4 ” indicates 1 to 4 carbon atoms.

The meanings of the terms and the like described in this specification are explained below.
As used herein, the term "α-dicarbonyl compound" refers to a compound having at least one α-dicarbonyl moiety (also referred to as 1,2-dicarbonyl) in its molecule. α-Dicarbonyl compounds are widely present in the natural world, such as living organisms, the environment, and foods. Examples of α-dicarbonyl compounds include, but are not limited to, 3-deoxyglucosone (3-DG), which is an intermediate product in the Maillard reaction, and a process in which glucose is decomposed and metabolized by glycolysis. Methylglyoxal (MG) and glyoxal (GO) produced in , advanced glycation end products (AGEs) crosslinked products in the Maillard reaction, and dopaquinone (L-dopaquinone), which is an intermediate product in melanin synthesis, and the like.

As used herein, the term "having an α-dicarbonyl bond cleaving activity" means having the activity of cleaving the carbon-carbon bond (CC bond) of the dicarbonyl structure of an α-dicarbonyl compound. Say. In one embodiment, the “α-dicarbonyl bond cleaving activity” of a compound is cleaving the C—C bond of the dicarbonyl structure (—CO—CO—) of 1-phenyl-1,2-propanedione (PPD). can be evaluated based on the amount of benzoic acid (BA) produced by

As used herein, the term "Maillard reaction" refers to a series of non-enzymatic reactions beginning with a nucleophilic addition reaction between a carbonyl group of a reducing sugar and an amino group of an amino compound. Specifically, the Maillard reaction includes an early stage and a late stage. In the early stage, the carbonyl group and the amino group react to form a Schiff base, and after the Amadori rearrangement, form an Amadori compound. In the latter stage, the Amadori compound undergoes irreversible reactions such as oxidation, dehydration, and condensation, and through the formation of intermediates including α-dicarbonyl compounds such as 3-deoxyglucosone (3-DG), finally It is a reaction that changes to advanced glycation end products (AGEs) with various characteristics. As used herein, "Maillard reaction" means a series of these reaction processes.
As used herein, the term "Maillard reaction product" encompasses all substances produced by the Maillard reaction, including intermediates produced by the Maillard reaction and final products produced by the Maillard reaction. "Maillard reaction product decomposing agent" refers to a substance capable of decomposing Maillard reaction products. In some embodiments, "decomposing the Maillard reaction product" includes cleaving the CC bond of the α-dicarbonyl structure contained in the Maillard reaction product.

As used herein, "AGEs" is a generic term for final products of saccharification reaction and does not indicate a fixed structure. Examples of AGEs include pentosidine, pyropyridine, crossrin, carboxymethyllysine (CML), carboxyethyllysine, pyrarin, carboxymethylarginine (CMA), algpyrimidine, glyoxallysine (GOLD), methylglyoxallysine dimer (MOLD), 3- Deoxyglucosone lysine dimer (DOLD) and the like.
etc.
As used herein, "AGEs cross-linking" refers to a cross-linking structure formed within AGEs, between AGEs, or between AGEs and a compound such as a protein. Examples of crosslinked structures formed between AGEs and compounds such as proteins include, for example, structures in which collagen molecules are crosslinked by AGEs.
As used herein, "decomposing AGEs cross-links" refers to cutting cross-linked structures formed within AGEs, between AGEs, or between AGEs and compounds such as proteins. In some embodiments, AGEs crosslinks include CC bonds of α-dicarbonyl structures within AGEs, between AGEs, or between AGEs and a compound such as a protein, and "break AGEs crosslinks." includes cleaving the CC bond of the α-dicarbonyl.

As used herein, "subject" refers to an animal. Subjects include, for example, primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like, but are limited to these animals. not a thing In preferred embodiments, the subject is a mammal, most preferably a human.
The terms "effective amount" or "therapeutically effective amount" of a compound of the invention are used to elicit a biological or medical response in a subject, or to ameliorate symptoms, alleviate a condition, slow or delay disease progression, or reduce disease progression. It refers to an amount of an active compound of the invention that, for example, prevents

"Alkyl group" means a linear, branched or cyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. Specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group and hexyl group.
An "alkoxy group" is a group in which an oxygen atom (O) is attached to the end of an alkyl having the specified number of carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy groups. are mentioned.
An "acyl group" is a group in which a carbonyl group (--CO--) is attached to the end of an alkyl having the specified number of carbon atoms. Specifically, linear chains such as methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl and hexylcarbonyl A straight or branched carbonyl group can be mentioned.

本発明者らは、上記インドール骨格を有し、特定の置換基を有する本発明のインドール化合物が、α－ジカルボニル結合切断活性を有することを見出した。本発明のインドール化合物は、α－ジカルボニル化合物内のジカルボニル構造（－Ｃ（＝Ｏ）－Ｃ（＝Ｏ）－）中のＣ－Ｃ結合を切断し、α－ジカルボニル化合物を分解することができる。
幾つかの実施形態では、本発明のインドール化合物は、メイラード反応の中間産物であるα－ジカルボニル化合物を分解し、これにより、メイラード反応が抑制され、ＡＧＥｓの生成が抑制される。また、本発明のインドール化合物は、メチルグリオキサール（ＭＧ）及びグリオキサール（ＧＯ）などの他の糖化中間産物であるα－ジカルボニル化合物を分解し、これにより、これに続くメイラード反応が抑制され、ＡＧＥｓの生成が抑制される。したがって、本発明のインドール化合物は、メイラード反応抑制剤またはＡＧＥｓ生成抑制剤として機能し得る。
幾つかの実施形態では、本発明のインドール化合物は、メイラード反応の後期生成物である終末糖化産物（ＡＧＥｓ）に関連する架橋構造（ＡＧＥｓ架橋）を分解し、これにより、生体内でのＡＧＥｓ蓄積を抑制することができる。したがって、本発明のインドール化合物は、ＡＧＥｓ架橋分解剤として機能し得る。
いくつかの実施形態では、本発明のインドール化合物は、上記のとおり、ＡＧＥｓの生成を抑制および／またはＡＧＥｓ架橋を分解することができ、抗糖化剤として機能し得る。
幾つかの実施形態では、本発明のインドール化合物は、メラニン合成の中間体であるドーパキノンを分解し、これによりメラニンの合成を抑制することができる。したがって、本発明のインドール化合物は、メラニン合成抑制剤として機能し得る。 1. α-Dicarbonyl Compound Decomposing Agent One aspect of the present invention is α-dicarbonyl containing a compound represented by the following formula (I), a salt thereof, or a solvate thereof (hereinafter also referred to as an “indole compound”). It relates to a compound decomposing agent.

The present inventors have found that the indole compound of the present invention having the above indole skeleton and having specific substituents has α-dicarbonyl bond cleavage activity. The indole compound of the present invention cleaves the CC bond in the dicarbonyl structure (-C(=O)-C(=O)-) in the α-dicarbonyl compound to decompose the α-dicarbonyl compound. be able to.
In some embodiments, the indole compounds of the present invention degrade the intermediate products of the Maillard reaction, α-dicarbonyl compounds, thereby inhibiting the Maillard reaction and inhibiting the production of AGEs. In addition, the indole compound of the present invention decomposes α-dicarbonyl compounds, which are other glycation intermediates such as methylglyoxal (MG) and glyoxal (GO), thereby suppressing the subsequent Maillard reaction and AGEs. generation is suppressed. Therefore, the indole compound of the present invention can function as a Maillard reaction inhibitor or an AGE production inhibitor.
In some embodiments, the indole compounds of the present invention degrade the cross-linked structures (AGE cross-links) associated with advanced glycation end products (AGEs), which are late products of the Maillard reaction, thereby increasing the accumulation of AGEs in vivo. can be suppressed. Therefore, the indole compound of the present invention can function as an AGEs cross-linking decomposing agent.
In some embodiments, the indole compounds of the present invention can inhibit the production of AGEs and/or degrade AGEs crosslinks, and can function as anti-glycation agents, as described above.
In some embodiments, the indole compounds of the present invention can degrade dopaquinone, an intermediate in melanin synthesis, thereby inhibiting melanin synthesis. Therefore, the indole compound of the present invention can function as a melanin synthesis inhibitor.

In formula (I) above, R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group. In some embodiments, R ₁ , R ₄ , R ₆ and R ₇ are each independently a hydrogen atom, a hydroxyl group or a C _1-3 alkyl group (preferably a methyl group or an ethyl group, more preferably a methyl group ). In certain embodiments, R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group. In one embodiment, R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom or a hydroxyl group.

In the above formula (I), n represents an integer of 1-6. In some embodiments, n represents an integer from 1-3. In one embodiment, n is two.

In formula (I) above, the dotted line ( _--- ) represents a single bond or a double bond.

When the dotted line ( _--- ) is a single bond, X ₁ represents a divalent group represented by CR _3c and X ₂ represents a divalent group represented by CR _2b .
R _2b and R _3c are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group. In some embodiments, R _2b and R _3c are each independently from the group consisting of a hydrogen atom, a hydroxyl group, and a C _1-3 alkyl group (preferably a methyl or ethyl group, more preferably a methyl group) selected. In one embodiment, R _2b and R _3c are each independently selected from the group consisting of hydrogen atoms and hydroxyl groups.

When the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms.

In formula (I), R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b are Together they form a bond. In some embodiments, each R _2a is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, and a C _1-3 alkyl group (preferably a methyl or ethyl group, more preferably a methyl group) . In some embodiments, _{R2a and R3b together} form a bond.

In formula (I), R ₅ is selected from the group consisting of a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group or a hydroxyC _1-6 alkyl group. In some embodiments, each R _2a is independently a hydrogen atom, a hydroxyl group, a C _1-3 alkoxy group (preferably a methoxy or ethoxy group, more preferably a methoxy group), and a hydroxyC _1-3 alkyl is selected from the group consisting of groups (preferably hydroxymethyl or hydroxyethyl groups, more preferably hydroxymethyl groups).

In formula (I) above, R _3a is selected from the group consisting of a C _2-6 acyl group, a hydrogen atom and a C _1-6 alkyl group. In some embodiments, R _3a is a C _2-4 acyl group (preferably an acetyl group or an ethylcarbonyl group, more preferably an acetyl group), a hydrogen atom, and a C _1-3 alkyl group (preferably a methyl group or ethyl groups, more preferably methyl groups).

The compounds of the present invention have certain combinations of substituents (R ₁ , R _2a , R _2b , R _3b , R _3c , R ₄ , R ₅ , R ₆ and R ₇ ) in formula (I). Preferred combinations of substituents in formula (I) are shown below.

(A) When R _3a is a C _2-6 acyl group, the following specific substituents (R ₁ , R _2a , R _2b , R _3b , R _3c , R ₄ , R ₅ , R ₆ and R ₇ ).
(A) When R _3a is a C _2-6 acyl group In some embodiments, when R _3a is a C _2-6 acyl group, R ₁ , R _2a , R _2b , R _3c , R ₄ , At least one of _R6 and _R7 is characterized by being a hydroxyl group.
In some embodiments,
R _3a is a C _2-6 acyl group,
R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
n represents an integer of 1 to 6 dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _1- is selected from the group consisting of ₆ alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-6 alkoxy group, and at least one of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group.
In certain embodiments,
R _3a is a C _2-4 acyl group (preferably an acetyl group or an ethylcarbonyl group, more preferably an acetyl group),
R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group;
n represents an integer of 1 to 3 dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _{1- 3} selected from the group consisting of alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-3 alkoxy group (preferably a methoxy group or an ethoxy group, more preferably a methoxy group), and R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group.
In some of these embodiments, 1, 2, 3, 4 or 5 of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ are hydroxyl groups.
In some of these embodiments, one or two of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ are hydroxyl groups. In some of these embodiments, one of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group.

In the present invention, when (B) R _3a is a hydrogen atom or a C _1-6 alkyl group, the following specific substituents (R ₁ , R _2a , R _2b , R _3b , R _3c , R ₄ , R ₅ , R ₆ and R ₇ ).
(B) when R _3a is a hydrogen atom or a C _1-6 alkyl group In some embodiments,
R _3a is a hydrogen atom or a C _1-6 alkyl group,
R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
n represents an integer from 1 to 6;
the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
R _3b represents a hydrogen atom or a C _1-6 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group or a hydroxy C _1-6 alkyl group, and all of R ₁ , R _{3a ,} R _3b , R ₄ , R ₅ , R ₆ and R ₇ are It cannot be a hydrogen atom.
In certain embodiments,
R _3a is a hydrogen atom or a C _1-3 alkyl group (preferably a methyl group or an ethyl group, more preferably a methyl group),
R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group;
n represents an integer of 1 to 3, the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group (preferably a methyl or ethyl group, more preferably a methyl group);
R _3b represents a hydrogen atom or a C _1-3 alkyl group (e.g. methyl, ethyl, n-propyl and isopropyl);
R ₅ is a hydrogen atom, a hydroxyl group or a C _1-3 alkoxy group (preferably a methoxy group or ethoxy group, more preferably a methoxy group) or a hydroxyC _1-3 alkyl group (preferably a hydroxymethyl group or a hydroxyethyl group, more preferably a hydroxymethyl group), and not all of R ₁ , R _{3a ,} R _3b , R ₄ , R ₅ , R ₆ and R ₇ are hydrogen atoms.

In some embodiments, the compound represented by formula (I) above is represented by formula (Ia-1), formula (Ia-2), formula (Ia-3) or formula (Ib-1) below. be.

式（Ｉa－１）中、Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である。 幾つかの実施形態において、式（Iａ）中、Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７のうちの１つ、２つ、３つ、４つまたは５つ（例えば、１つまたは２つ；例えば、１つ）が水酸基である。
特定の実施形態において、式（Iａ－１）中、Ｒ_１、Ｒ_２ａ、Ｒ_４、およびＲ_６のうちの１つ、２つ、３つ、４つまたは５つ（例えば、１つまたは２つ；例えば、１つ）が水酸基である。
特定の実施形態において、式（Iａ－１）中、Ｒ_２ａ、Ｒ_４、およびＲ_６のうちの１つ、２つ、または３つ（例えば、１つまたは２つ；例えば、１つ）が水酸基である。
特定の実施形態において、式（Iａ－１）中、Ｒ_２ａおよびＲ_６のうちの１つまたは２（例えば、１つ）が水酸基である。 In some embodiments, the compound represented by Formula (I) above is represented by Formula (Ia-1) below.

In formula (Ia-1), R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and R ₁ , R _2a , R ₄ , At least one of _R6 and _R7 is a hydroxyl group. _In some embodiments, one, two, three, _four or _five ( _e.g. , _one or Two; eg, one) are hydroxyl groups.
In certain embodiments, one, two, three, four or five of R ₁ , R _2a , R ₄ and R ₆ in formula (Ia-1) (eg, one or two one; for example, one) is a hydroxyl group.
In certain embodiments, in formula (Ia-1), 1, 2, or 3 (eg, 1 or 2; eg, 1) of R _2a , R ₄ , and R ₆ are is a hydroxyl group.
In certain embodiments, in formula (Ia-1), one or two (eg, one) of R _2a and R ₆ is a hydroxyl group.

式（Ｉａ－２）中、Ｒ_１、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である。
特定の実施形態において、式（Iａ－２）中、Ｒ_１、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、Ｒ_６およびＲ_７のうちの１つ、２つ、３つ、４つ、５つまたは６つ（例えば、１つまたは２つ；例えば、１つ）が水酸基である。
特定の実施形態において、式（Iａ－２）中、Ｒ_２ａ、Ｒ_３ｃ、Ｒ_４、およびＲ_６のうちの１つ、２つ、または３つ（例えば、１つまたは２つ；例えば、１つ）が水酸基である。
特定の実施形態において、式（Iａ－２）中、Ｒ_２ａおよびＲ_３ｃのうちの１つまたは２つ（例えば、１つ）が水酸基である。
一実施形態において、式（Iａ－２）中、Ｒ_３ｃが水酸基である。 In some embodiments, the compound represented by Formula (I) above is represented by Formula (Ia-2) below.

In formula (Ia-2), R ₁ , R _2a , R _3c , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and R ₁ , R _2a , At least one of R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group.
In certain embodiments, one, two, three, four, five or six of R ₁ , R _2a , R _3c , R ₄ , R ₆ and R ₇ in formula (Ia-2) One (eg, one or two; eg, one) is a hydroxyl group.
In certain embodiments, one, two, or three of R _2a , R _3c , R ₄ , and R ₆ (eg, 1 or 2; ) is a hydroxyl group.
In certain embodiments, in formula (Ia-2), one or two (eg, one) of R _2a and R _3c are hydroxyl groups.
In one embodiment, in formula (Ia-2), R _3c is a hydroxyl group.

式（Ｉａ－３）中、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、かつ、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７の少なくとも１つは、水酸基である。
特定の実施形態において、式（Iａ－３）中、Ｒ_１、Ｒ_４、Ｒ_６およびＲ_７のうちの１つ、２つ、３つ、または４つ（例えば、１つまたは２つ；例えば、１つ）が水酸基である。
特定の実施形態において、式（Iａ－３）中、Ｒ_４およびＲ_６のうちの１つまたは２（例えば、１つ）が水酸基である。
一実施形態において、式（Iａ－３）中、Ｒ_６が水酸基である。 In some embodiments, the compound represented by Formula (I) above is represented by Formula (Ia-3) below.

In formula (Ia-3), R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and R ₁ , R ₄ , R ₆ and R ₇ At least one is a hydroxyl group.
In certain embodiments, in formula (Ia-3), 1, 2, 3, or 4 of R ₁ , R ₄ , R ₆ and R ₇ (eg, 1 or 2; , one) is a hydroxyl group.
In certain embodiments, in formula (Ia-3), one or two (eg, one) of R ₄ and R ₆ is a hydroxyl group.
In one embodiment, in formula (Ia-3), R ₆ is a hydroxyl group.

式（Ｉｂ－１）中、Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、Ｒ_３ａおよびＲ_３ｂは、それぞれ独立して、水素原子又はＣ_１－３アルキル基を表し、Ｒ_５は、水素原子、水酸基、メトキシ基、又はヒドロキシメチル基を表し、かつＲ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない。
特定の実施形態において、Ｒ_１、Ｒ_２ａ、Ｒ_４、Ｒ_６およびＲ_７は、それぞれ独立して、水素原子、水酸基又はメチル基を表し、Ｒ_３ａおよびＲ_３ｂは、それぞれ独立して、水素原子、メチル基、エチル基、ｎ－プロピル基、およびイソプロピル基からなる群から選択され、Ｒ_５は、水素原子、水酸基又はメトキシ基を表し、かつＲ_１、Ｒ_３ａ、Ｒ_３ｂ、Ｒ_４、Ｒ_５、Ｒ_６およびＲ_７の全てが水素原子であることはない。
特定の実施形態において、式（Iｂ－１）中、Ｒ_１、Ｒ_４、およびＲ_５のうちの１つ、２つ、または３つ（例えば、１つまたは２つ；例えば、１つ）が水素原子ではない。
一実施形態において、Ｒ_１は、メチル基である。
一実施形態において、Ｒ_５は、水酸基、メトキシ基又はヒドロキシメチル基である。
一実施形態において、Ｒ_４は、水酸基又はメチル基である。一実施形態において、Ｒ_４は、水酸基である。 In some embodiments, the compound represented by Formula (I) above is represented by Formula (Ib-1) below.

In formula (Ib-1), R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, R _3a and R _3b each independently , represents a hydrogen atom or a C _1-3 alkyl group, R ₅ represents a hydrogen atom, a hydroxyl group, a methoxy group, or a hydroxymethyl group, and R ₁ , R _3a, R _3b, R ₄ , R ₅ , R ₆ and not all of R ₇ are hydrogen atoms.
In certain embodiments, R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, R _3a and R _3b each independently represent a hydrogen is selected from the group consisting of atoms, methyl groups, ethyl groups, n-propyl groups and isopropyl groups, R ₅ represents a hydrogen atom, a hydroxyl group or a methoxy group, and R ₁ , R _3a, R _3b, R ₄ , Not all of R ₅ , R ₆ and R ₇ are hydrogen atoms.
In certain embodiments, in formula (Ib-1), one, two, or three (e.g., one or two; e.g., one) of R ₁ , R ₄ , and R ₅ are not a hydrogen atom.
In one embodiment, R ₁ is a methyl group.
_In one embodiment, R5 is a hydroxyl group, a methoxy group, or a hydroxymethyl group.
In one embodiment, _R4 is a hydroxyl group or a methyl group. In one embodiment, _R4 is a hydroxyl group.

The structures and names of specific compounds preferably used in the present invention are shown below.

Among others, compound 1 (4HMEL), compound 2 (6HMEL), compound 3 (2HMEL), compound 4 (1,2DHMEL) compound 5 (5MTP), compound 6 (5HT), compound 7 (NMTP), compound 8 (3HMEL) , Compound 9 (C6HMEL), Compound 10 (4HNINMTP), and Compound 11 (5HMNNDMTP) are preferred, and are excellent in the effect of cleaving the α-dicarbonyl bond, so Compound 1 (4HMEL) and Compound 2 (6HMEL), compound 3 (2HMEL), compound 5 (5MTP), compound 7 (NMTP) are particularly preferred.

The indole compounds are melatonin metabolites or derivatives thereof. Melatonin (MEL) is mainly synthesized in the pineal gland of the brain in vertebrates and is known as a hormone that transmits time information. MEL is made from the amino acid tryptophan (Trp) via 5-hydroxytryptophan (5HTrp), serotonin (5HT) and N-acetylserotonin (NAS). There is also a pathway in which Trp is metabolized to indoleacetic acid (IAA) via tryptamine (TP). The indole compound of formula (I) of the present invention is advantageous in terms of safety because it is a metabolite of melatonin, a hormone present in animals, plants and microorganisms, or a derivative sharing a skeleton structure with melatonin. The metabolic pathway of melatonin is shown below.

In the present invention, it is possible to use a salt of the compound represented by the above formula (I). By "salt" is meant any pharmaceutically acceptable salt thereof. As used herein, "pharmaceutically acceptable" means not raising safety concerns or toxicity concerns. "Pharmaceutically acceptable salts" are not particularly limited, and include salts with acids or salts with bases.

Examples of salts with acids include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, and phosphates, and formic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, and tartaric acid. , stearic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid.
Salts with bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, and N,N'-dibenzylethylenediamine. , organic base salts such as arginine and lysine, and ammonium salts.

In the present invention, the compound represented by formula (I) or a salt thereof may be an anhydride, or may form a solvate such as a hydrate. Solvates may be either hydrates or non-hydrates. As nonhydrates, alcohols (eg, methanol, ethanol, n-propanol), dimethylformamide, and the like can be used. Furthermore, in the present invention, the compound represented by formula (I) may be crystalline or non-crystalline, and if there are crystal polymorphs, it may be a single crystal form of any one of them. may also be a mixture.

As the indole compound of the present invention, a commercially available product may be used, or one synthesized by a known chemical synthesis method may be used.

2. Compositions A further aspect of the invention relates to compositions comprising the indole compounds of the above forms. Since the indole compound of the present invention has excellent α-dicarbonyl bond cleaving activity, it can be used for various purposes related to decomposition of α-dicarbonyl compounds. Compositions containing the indole compounds in the above forms can be suitably used as cosmetics, pharmaceuticals, quasi-drugs, food and drink, functional foods, and the like.
In some embodiments, there is provided a composition for decomposing α-dicarbonyl compounds, containing the indole compound of the above form as an active ingredient.
In some embodiments, an anti-glycation composition is provided comprising an indole compound of the form described above as an active ingredient.

The composition containing the indole compound of the present invention may contain different kinds of indole compounds represented by the above formula (I), or may contain more than one kind. Compositions of some embodiments comprise an indole compound in the form described above and one or more additives.
Additives include excipients, fragrances, colorants, emulsifiers, stabilizers, thickeners, enzymes, preservatives, lubricants, surfactants, disintegrants, disintegration inhibitors, binders, absorption enhancers. , adsorbents, anti-glycation agents, solubilizers, preservatives, flavoring agents, sweetening agents and the like. Additives can be blended as necessary within a range that does not impair the effects of the present invention.
The content of the indole compound of the present invention in the composition is not particularly limited as long as the desired effect of the present invention is exhibited, but it is 0.000025% by weight to 25% by weight, preferably 0.000025% by weight, based on the weight of the composition. 00025 to 2.5% by weight, more preferably 0.0025 to 0.25% by weight.
Some embodiments provide cosmetic, pharmaceutical, or food compositions comprising the above forms of indole compounds as active ingredients. A composition of some embodiments is a cosmetic, pharmaceutical, or food composition comprising an indole compound of the form described above and one or more additives.

(Cosmetic composition)
One aspect of the present invention provides a cosmetic composition comprising the above aspect of the indole compound.
In some embodiments, the cosmetic composition can be used for prevention and/or improvement of skin aging (eg, loss of skin elasticity, cross-linking of collagen that causes wrinkles and sagging, etc.).
Since the indole compound of the present invention has actions such as Maillard reaction suppression, AGE production suppression, and/or AGE cross-linking decomposition, collagen cross-links (bad cross-links or aging cross-links) formed in collagen molecules by saccharification or oxidation ) can be resolved. Therefore, by including the indole compound of the present invention in a cosmetic composition, the accumulation of AGEs in collagen can be suppressed, and an effect of preventing and/or improving skin aging can be exhibited. By topical application of the cosmetic composition containing the indole compound of the present invention to the skin, the effect of preventing and/or improving skin aging can be exhibited. In some embodiments, a cosmetic method for preventing and/or improving skin aging is provided by topically applying a cosmetic composition containing the indole compound of the present invention to the skin.

In some embodiments, the cosmetic composition can be used for skin anti-pigmentation and/or whitening.
The indole compound of the present invention can cleave and decompose the α-dicarbonyl bond of dopaquinone, which is an intermediate in melanin synthesis, thereby suppressing melanin synthesis. Melanin pigment present in human skin is a general term for pigments obtained by polymerizing phenolic substances. Melanin also plays a role in protecting the body from ultraviolet rays, but excessive production or uneven accumulation causes skin darkening and blemishes. Therefore, by including the indole compound of the present invention in a cosmetic composition, it is possible to suppress melanin synthesis and exhibit excellent skin pigmentation suppression and/or whitening effects. By topical application of the cosmetic composition of the present invention to the skin, the effect of suppressing pigmentation and/or whitening the skin can be exhibited. That is, some embodiments of the present invention provide a cosmetic method for suppressing pigmentation and/or whitening the skin by topically applying the cosmetic composition of the present invention to the skin.

The cosmetic composition of the invention may be provided in any dosage form suitable for topical application. For example, solutions, emulsions obtained by dispersing an oil phase in an aqueous phase, emulsions obtained by dispersing an aqueous phase in an oil phase, suspensions, lotions, liquids such as spray liquids; powders, granules, blocks, etc. It can be prepared in various desired dosage forms such as solid; semi-solid such as cream and paste; and gel. Such cosmetic compositions include facial cleansers, emulsions, creams, gels, essences (beauty liquids), basic cosmetics such as packs and masks, makeup cosmetics such as oils, foundations and lipsticks, oral cosmetics, and aromatic cosmetics. It can be used as various cosmetics such as hair cosmetics, body cosmetics and the like.
A cosmetic composition in such a dosage form can be produced according to a conventional method. In addition, the blending amount, blending method, and blending time of the indole compound of the present invention in the cosmetic composition can be appropriately selected. Furthermore, if necessary, it can be enclosed in an appropriate container such as a bottle, bag, can, spray can, spray container, box, pack, or the like.

The cosmetic composition can be prepared by appropriately adding components commonly used in cosmetics. For example, ointment base, alcohol, polyhydric alcohol, water-soluble polymer, antioxidant, pH adjuster, UV inhibitor, sequestering agent, thickener, surfactant, purified water, antiseptic, antibacterial agents, oils, higher fatty acids, fatty acid esters, moisturizers, pigments, vitamins, amino acids and the like.

The content of the indole compound of the present invention in the cosmetic composition is not particularly limited as long as the desired effect of the present invention is exhibited, and is preferably 0.000025% by weight to 25% by weight, preferably 0.000025% by weight, based on the weight of the composition. It is 0.00025 to 2.5% by weight, more preferably 0.0025 to 0.25% by weight.

The amount of the cosmetic composition to be used varies depending on the type of indole compound used in the present invention, the dosage form, the age of the subject of administration, and the like. It can be 50 mg. However, it is not limited to these doses. The daily dose may be administered in a single dose or may be divided into multiple doses.

(Pharmaceutical composition)
One aspect of the present invention provides a pharmaceutical composition comprising an indole compound of the form described above.
Although it is possible for an indole compound of the invention to be administered alone, it can be administered as a pharmaceutical composition. Some embodiments provide pharmaceutical compositions comprising the above forms of indole compounds and one or more pharmaceutically acceptable excipients. The amount of active ingredient (indole compound) combined with the excipient will generally be that amount of the compound that produces a therapeutic effect. An indole compound of the invention may be administered either concurrently with, before, or after one or more other therapeutic agents.

Although it is possible for an indole compound of the invention to be administered alone, it can be administered as a pharmaceutical composition. Some embodiments provide pharmaceutical compositions comprising the above forms of indole compounds and one or more pharmaceutically acceptable excipients. The amount of active ingredient (indole compound) combined with the excipient will generally be that amount of the compound that produces a therapeutic effect. An indole compound of the invention may be administered either simultaneously with, before, or after one or more other therapeutic agents.
The indole compound of the present invention has effects such as Maillard reaction suppression, AGE production suppression, and/or AGEs cross-linking decomposition. AGEs are known to be the cause of aging and various diseases and their aggravation, and saccharification is considered to be an important factor in anti-aging. Therefore, the indole compound of the present invention can be used to prevent and treat diseases, tissue aging, and functional decline caused by AGEs produced in vivo. In some embodiments, pharmaceutical compositions comprising the indole compounds of the present invention are used to treat aging-related diseases (e.g., cataracts, cartilage loss, arteriosclerosis, osteoporosis, Alzheimer's disease) caused by the formation of advanced glycation end products (AGEs). Dementia) can be used for prevention and/or treatment. In some embodiments, the pharmaceutical composition containing the indole compound of the present invention is useful for skin aging (skin elasticity loss, collagen cross-linking that causes wrinkles and sagging, pigmentation that causes skin dullness, etc.). ) can be used for the prevention and/or treatment of In some embodiments, pharmaceutical compositions comprising the indole compounds of the invention are used to treat diabetic complications known to involve the Maillard reaction (e.g., myocardial infarction, diabetic nephropathy, diabetic retinopathy, It can also be used for prevention and/or treatment of diabetic neuropathy.

Some embodiments prevent and/or age-related diseases (e.g., cataracts, cartilage loss, arteriosclerosis, osteoporosis, Alzheimer's disease) due to the formation of advanced glycation end products (AGEs) in a subject in need thereof. Alternatively, a method of treatment is provided comprising administering to a subject in need thereof an effective amount of an indole compound of the invention.
Some embodiments are useful in treating skin aging (skin elasticity loss, formation of wrinkles and sagging (in particular, cross-linking of collagen that causes wrinkles and sagging), pigments that cause skin dullness in subjects in need. deposits, etc.), comprising administering to a subject in need thereof an effective amount of an indole compound of the invention.
Some embodiments prevent diabetic complications (e.g., myocardial infarction, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy) known to involve the Maillard reaction in subjects in need thereof and/or methods of treatment comprising administering to a subject in need thereof an effective amount of an indole compound of the invention.

When the indole compound of the present invention is used as a pharmaceutical composition, its dosage form can be either oral or parenteral administration.
For oral administration, for example, tablets, capsules, granules, powders, syrups and the like can be used.
In the case of parenteral administration, there are injections, suppositories, eye drops, pulmonary dosage forms (e.g. nephrizers), nasal dosage forms, transdermal dosage forms (e.g. ointments, creams), etc. mentioned. Injectable dosage forms can be administered systemically or locally, for example, by intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, and the like.
In some embodiments, an indole compound of the invention, or a pharmaceutical composition comprising same, is administered orally, topically, rectally, or transdermally, by parenteral injection or inhaled to a subject.
In certain embodiments, the indole compounds of the invention, or pharmaceutical compositions comprising same, are administered transdermally. Examples of transdermal dosage forms include ointments, creams, gels, powders, sprays, pastes, lotions, solutions, patches and inhalants. Transdermal dosage forms are applied to the skin, eg, as a solution, or applied to the skin, eg, as a skin patch.
These formulations are manufactured by well-known methods using pharmaceutically acceptable additives.
Pharmaceutically acceptable excipients include commonly used excipients, fillers, extenders, binders, wetting agents, disintegrants, lubricants, surfactants, dispersants, buffers, preservatives, solubilizers. Adjuvants, preservatives, flavoring agents, soothing agents, stabilizers, tonicity agents and the like are included.

The content of the indole compound of the present invention in the pharmaceutical composition is not particularly limited as long as the desired effect of the present invention is exhibited. 0.00025 to 2.5% by weight, more preferably 0.0025 to 0.25% by weight.

When using the indole compound of the present invention as a pharmaceutical composition, the dosage varies depending on age, symptoms, administration route, administration frequency, and dosage form. The administration method is appropriately selected depending on the age and symptoms of the subject. For example, the dosage of the indole compound can be about 0.05-50 mg/kg body weight per day. However, it is not limited to these doses. The daily dose may be administered in a single dose or may be divided into multiple doses.

(Food composition)
One aspect of the present invention provides food compositions comprising an indole compound of the above aspect.

The indole compound of the present invention has effects such as Maillard reaction suppression, AGE production suppression, and/or AGEs cross-linking decomposition. AGEs are known to be the cause of aging and various diseases and their aggravation, and by ingesting the indole compound of the present invention, it is possible to prevent and/or improve aging.
One aspect of the present invention relates to food compositions for preventing and/or improving aging.
Some embodiments relate to a method of preventing and/or ameliorating aging in a subject in need thereof comprising ingesting a food composition comprising an indole compound in the form described above.

Food compositions can be ingested in any form.
The food composition is used as food, beverage or animal feed, such as general food, health food, functional food, food for specified health use, food for sick people, beauty food, or dietary supplement (supplement). be able to. The form of the food composition is not particularly limited, and examples thereof include powder, block, liquid, syrup, and jelly.

The food composition of the present invention can be obtained by mixing the indole compound of the present invention with a known food and processing it into a food composition by a conventional method. Types of foods include, for example, beverages, dairy products, seasonings, noodles, processed meat and fish foods, margarine, bread, confectionery, and the like. It may also be in the form of a liquid, powder, granules, capsules, or tablets. The food composition of the present invention has a wide variety of forms and is not limited to the above examples.
The food composition contains one or more food-acceptable additives (e.g., various nutritional supplements (amino acids, vitamins, minerals, etc.), sugars, dairy products, sweeteners, flavors, fragrances, antioxidants, agent, preservative, colorant, emulsifier, pH adjuster, organic acid, buffer, fruit juice, etc.). One embodiment provides a food composition comprising an indole compound of the above form and one or more food acceptable excipients.

The content of the indole compound of the present invention in the food composition varies depending on the presence or absence of additives, the type of food, etc., but is 0.000025% to 25% by weight, preferably 0.00025 to 2%, based on the weight of the composition. 0.5% by weight, more preferably 0.0025 to 0.25% by weight.

The intake amount of the indole compound of the present invention is not particularly limited, and can be appropriately set according to the sex, age, weight, etc. of the intake person. For example, the weight of the indole compound can be about 0.05-50 mg per kg of body weight per day. However, it is not limited to these intake amounts. Such a daily intake amount may be used once or may be divided into multiple times for use.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples, and can be arbitrarily modified without departing from the gist of the present invention.
As used herein, "room temperature" generally indicates about 10°C to about 35°C.
As used herein, the term "about" can mean ±10%.

The abbreviations used in the examples are conventional abbreviations well known to those skilled in the art. Some abbreviations are listed below.
PPD: 1-phenyl-1,2-propanedione BA: benzoic acid HPLC: high performance liquid chromatography PTB: N-phenanthylthiazolium bromide DMSO: dimethylsulfoxide PBS: phosphate buffered saline

The physical properties in the examples were measured using the following equipment.

(High Performance Liquid Chromatography (HPLC))
The HPLC is equipped with SCL-10A, LC-20AD, SIL-20A, CTO-10A, and SPD-20A (Shimadzu Corporation, Kyoto City, Kyoto Prefecture) as system controllers, pumps, autosamplers, column ovens, and UV detectors, respectively. connected and used. The column used was CAPCELL PAK C18 MG II 4.6 mm ID×250 mm (Shiseido Co., Ltd., Minato-ku, Tokyo). The eluent used was 0.5% acetic acid, 10 mM ammonium acetate/methanol (70/30). The measurement was performed with a flow rate of 1.0 mL/min, a column temperature of 40° C., and a detection wavelength of 270 nm. The obtained data were analyzed by LCsolution (Shimadzu Corporation).

[Example 1: Measurement of α-dicarbonyl bond cleavage activity]
α-dicarbonyl based on the method described in Non-Patent Document 6 (Yonei Y, et al., Cleaving effect of melatonin on crosslinks in advanced glycation end products. Glycative Stress Ressearch. 2016; 3(1):38-43) Using 1-phenyl-1,2-propanedione (PPD) having a structure, α-dicarbonyl bond by measuring benzoic acid (BA), which is a decomposition product after α-dicarbonyl structure cleavage of PPD was measured. PPD is known as an AGEs crosslinked structural model substance, and AGEs crosslinked degradation activity can be evaluated from the α-dicarbonyl bond cleavage activity measured using PPD.

ＰＰＤ、ＭＥＬ、ＮＭＴＰ、ＢＡは富士フィルム和光純薬株式会社（大阪府）から購入したＴｒｐ、５ＨＴｒｐ、５ＨＴ、ＮＡＳ、５ＭＴｒｐ、５ＭＴＰ、５ＨＩＡＡ、５ＭＴＰＬ、ＴＰ、ＩＡＡ、ＮＡＴＰ、６ＨＭＥＬはＳｉｇｍａ－Ａｌｄｒｉｃｈ（Ｓｔ．Ｌｏｕｉｓ，ＭＯ）から購入した。２ＨＭＥＬ、４ＨＭＥＬ、６ＳＭＥＬ、２ＢｒＭＥＬ、ＡＭＫはＴｏｒｏｎｔｏ Ｒｅｓｅａｒｃｈ Ｃｈｅｍｉｃａｌｓ（Ｔｏｒｏｎｔｏ，Ｃａｎａｄａ）、ＡＦＭＫはＣＡＹＭＡＮ Ｃｈｅｍｉｃａｌ Ｃｏｍｐａｎｙ（Ａｎｎ Ａｂｏｒ，ＭＩ）、ＰＴＢはＳａｎｔａ Ｃｒｕｚ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ（Ｄａｌｌａｓ，ＴＸ）から購入した。 (i) Preparation of sample solution PPD was dissolved in a 50% acetonitrile solution to prepare a PPD solution with a predetermined concentration.
PTB was used as a positive control for AGEs cross-linking activity. PTB was dissolved in a 50% DMSO solution to prepare a PTB solution with a predetermined concentration.
Various indole compounds to be tested were dissolved in 50% DMSO solutions to prepare test substance solutions of predetermined concentrations.
The PPD solution, PTB solution, and test substance solution prepared above were used for the following measurements.
Table 1 shows the structures of PTB and various indole compounds used for the measurement.

PPD, MEL, NMTP, and BA were purchased from Fujifilm Wako Pure Chemical Industries, Ltd. (Osaka Prefecture) Trp, 5HTrp, 5HT, NAS, 5MTrp, 5MTP, 5HIAA, 5MTPL, TP, IAA, NATP, and 6HMEL were purchased from Sigma-Aldrich ( (St. Louis, Mo.). 2HMEL, 4HMEL, 6SMEL, 2BrMEL, AMK were purchased from Toronto Research Chemicals (Toronto, Canada), AFMK from CAYMAN Chemical Company (Ann Abor, MI), and PTB from Santa Cruz Biotechnology (Dallas, TX).

(ii) Preparation of Calibration Curve and Examination of Reaction Time A calibration curve for PPD as a substrate and BA as a degradation product was prepared using high performance liquid chromatography (HPLC). Both peak areas increased in a concentration-dependent manner within the measurement range, and a positive correlation was obtained. In subsequent experiments on α-dicarbonyl bond scission activity, two factors, the decrease in substrate and the increase in degradation products, were measured.

Using PTB, which is known to have AGEs cross-linking activity, the reaction time suitable for measuring α-dicarbonyl bond cleavage activity was examined. 500 μL of 10 mmol/L PTB solution, 100 μL of 10 mmol/L PPD and 400 μL of phosphate buffered saline (PBS) were mixed and incubated at 37°C. At each time point, HPLC was used to measure the amount of decomposition of PPD and the amount of BA produced as substrates, and changes over time in the amount of decomposition of PPD and the amount of BA produced were observed. As a control group, a solution containing no PTB solution was used.
There was a large difference between the PTB group and the control group at 18 hours in terms of PPD degradation and BA increase, and the reaction did not progress much at 48 hours. The reaction time was 18 hours.

表２から、本発明の式（Ｉ）で表されるインドール化合物が、安息香酸生成量が大きく、ＡＧＥｓ架橋切断活性が高いことが確認される。特に、本発明の化合物は、非特許文献３で報告されたメラトニン（ＭＥＬ）をはるかに超える高い切断活性が高いことが確認された。
中でも、４ＨＭＥＬ、２ＨＭＥＬ、６ＨＭＥＬのようなインドール環が水酸基で置換された化合物（式（Ｉａ－１）の化合物）は、一層高い切断活性を示すことが確認された。特に、４ＨＭＥＬや２ＨＭＥＬは、ＰＴＢと比較しても高い切断活性を示した。
また、ＮＭＴＰ、５ＭＴＰ、５ＨＴのような式（Ｉｂ－１）で表される化合物も高い切断活性を有していた。 (iii) Measurement of α-dicarbonyl bond cleavage activity For 500 μL of test substance solution containing 10 mmol / L of various indole compounds, 100 μL of 10 mmol / L PPD solution and 400 μL of phosphate buffered saline (PBS) Mixed and incubated at 37° C. for 18 hours. At this time, the test substance concentration in the reaction solution was 5 mM. After completion of the reaction, 200 μL of 2 mol/L hydrochloric acid was added to stop the reaction, and after centrifugation for 2 minutes, the supernatant was separated using a reverse phase column using HPLC, and the amount of BA was measured using a UV detector. For 2BrMEL, the BA amount was measured by the same procedure using a test substance solution with a concentration of 1/20 (0.5 mmol/L) due to the solubility.
PTB was used as a positive control. A solution obtained by mixing 500 μL of 10 mmol/L PTB solution with 100 μL of 10 mmol/L PPD solution and 400 μL of phosphate buffered saline (PBS) was incubated at 37° C. for 18 hours in the same manner as described above, and then subjected to HPLC. was used to measure the amount of BA.
Table 2 shows the amount of benzoic acid produced when each indole compound was used. The numerical values shown in Table 2 indicate the amount of benzoic acid produced when each indole compound was used as a ratio to the amount of benzoic acid produced from PTB (100%). An increase in benzoic acid indicates that PPD was cleaved at the position of the α-dicarbonyl structure, and it can be said that the larger the amount of benzoic acid produced, the higher the AGEs cross-linking activity.

Table 2 confirms that the indole compound represented by the formula (I) of the present invention has a large amount of benzoic acid produced and a high AGEs cross-linking activity. In particular, it was confirmed that the compounds of the present invention have a high cleavage activity far exceeding that of melatonin (MEL) reported in Non-Patent Document 3.
Among them, it was confirmed that compounds in which the indole ring was substituted with a hydroxyl group (compounds of formula (Ia-1)) such as 4HMEL, 2HMEL and 6HMEL exhibit higher cleavage activity. In particular, 4HMEL and 2HMEL showed higher cleavage activity than PTB.
Compounds represented by formula (Ib-1) such as NMTP, 5MTP and 5HT also had high cleavage activity.

(iv) Investigation of dose dependence of AGEs cross-linking cleavage activity Using 4HMEL and 2HMEL as indole compounds, test substance solutions with different concentrations were prepared. Also for PTB, PTB solutions with different concentrations were prepared. These various concentrations of test substance solutions and PTB solutions were used as sample solutions. 100 μL of 10 mmol/L PPD solution and 400 μL of phosphate buffered saline (PBS) were mixed with 500 μL of each sample solution and incubated at 37° C. for 18 hours. After completion of the reaction, 200 μL of 2 mol/L hydrochloric acid was added to stop the reaction, and after centrifugation for 2 minutes, the supernatant was separated using a reverse phase column using HPLC, and the amount of BA was measured using a UV detector.

表３から、４ＨＭＥＬおよび２ＨＭＥＬは、ＰＴＢと比較してそれぞれ約１／９、約１／１９の濃度で同量の安息香酸を生成することができたことから、ＰＴＢよりも顕著に高いＡＧＥｓ架橋切断活性を有するといえる。 FIG. 1 shows the relationship between the concentration of the compound and the amount of benzoic acid produced (BA amount) in each sample solution.
From FIG. 1, it was confirmed that the amount of benzoic acid produced increased as the concentration of the indole compound increased. It is shown that there is a dose dependence between the indole compounds of the invention and the AGEs cross-linking activity.
From FIG. 1, the concentrations of 4HMEL and 2HMEL that produce the same amount of benzoic acid (0.13 μmol/mL) produced when 5 mM of PTB was used were calculated. Table 3 shows the results.

From Table 3, 4HMEL and 2HMEL were able to generate the same amount of benzoic acid at concentrations of about 1/9 and about 1/19, respectively, compared to PTB, indicating significantly higher AGEs cross-linking than PTB. It can be said that it has cleavage activity.

本実施例では、インドール化合物として２ＨＭＥＬを用い、以下の方法により、インドール化合物のメラニン合成の抑制能を評価した。 [Example 2: Evaluation of degradability of melanin intermediates (inhibition of melanin synthesis)]
Melanin is converted from tyrosine to dopa and from dopa to dopaquinone by the action of the enzyme tyrosinase, and is then formed via intermediates such as 5,6-dihydroxyindophenol. Dopaquinone, a melanin intermediate, has an α-dicarbonyl structure.

In this example, 2HMEL was used as the indole compound, and the ability of the indole compound to suppress melanin synthesis was evaluated by the following method.

(Measurement of degree of melanin darkening)
L-DOPA (Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in phosphate-buffered saline (PBS) to 1 mM, and dispensed into a 96-well plate. 2HMEL (Toronto Research Chemicals) was dissolved in DMSO and added to experimental groups to a final concentration of 1 mM or 0.5 mM, and an equal amount of DMSO to control groups. Tyrosinase (Sigma-Aldrich) was added to 100 units/mL to initiate the reaction. Incubation was carried out at 25° C. for 18 hours, after which the supernatant was gently removed. After drying sufficiently, the sediment on the bottom of the well was photographed under a stereoscopic microscope. The results are shown in Figure 2A. The brightness of the entire bottom surface of the well was measured using Image J, a free software, and the blackness of the experimental group was calculated with the control group being 100%. FIG. 2B shows a comparison of calculated blackening degrees.

A decrease in the degree of blackening was confirmed in the experimental group to which 2HMEL was added.
It is presumed that the α-dicarbonyl structure of dopaquinone, which is a melanin intermediate produced from L-DOPA, was cleaved and decomposed by 2HMEL, and melanin synthesis was suppressed.
It was confirmed that the indole compound of the present invention can suppress melanin synthesis.

[Example 3: Cross-linking scission effect on lysozyme polymer]
Using a lysozyme/fructose saccharification reaction model, the inhibitory action of 2HMEL, an indole compound, on protein crosslink formation was verified.
2HMEL was added to a PBS solution of 2 mg/mL lysozyme (Sigma-Aldrich) and 0.2 M fructose (Fujifilm Wako Pure Chemical Industries, Ltd.) to a final concentration of 6 mM, and incubated at 60° C. for 40 hours. .
Similar incubations were performed in a system of PBS solution containing only 2 mg/mL lysozyme (Sigma-Aldrich) (no addition of 2HMEL and fructose) and 2 mg/mL lysozyme (Sigma-Aldrich) with 0.2 M fructose (Fujifilm W. A system of a PBS solution (no 2HMEL added) manufactured by Kojunyaku Co., Ltd. was also tested.
The supernatant of the solution was mixed with 2× Laemmli Sample Buffer (Bio-Rad Laboratories, Inc.) at a ratio of 1:1 and subjected to SDS-PAGE using a 4-20% gradient gel. After electrophoresis, the gel was washed with distilled water and stained with Bio-Safe Coomassie G-250 Stain (Bio-Rad Laboratories, Inc.) for 1 hour.

The results are shown in FIG. In the system containing lysozyme and fructose, bands due to the presence of dimers, trimers and tetramers were confirmed. This indicates that lysozyme monomers were crosslinked to form dimers, trimers, and tetramers by saccharification reaction with fructose. On the other hand, in the system to which 2HMEL was added, the dimer, trimer and tetramer bands faded or disappeared. It is considered that the addition of 2HMEL cut the crosslinks in the lysozyme multimers and inhibited the formation of the multimers, and it can be said that 2HMEL inhibited the polymerization due to the formation of protein crosslinks.

These results also suggest that the indole compound represented by formula (I) of the present invention has an AGEs cross-linking effect and suppresses the formation of AGEs.
These results indicate that the indole compound represented by formula (I) of the present invention can be used as an AGE production inhibitor, an AGE cross-linking decomposing agent, an anti-glycation agent, or a melanin synthesis inhibitor.

The scope of the present invention is not limited to the above description, and other than the above examples can be appropriately changed and implemented without impairing the gist of the present invention. All documents and publications mentioned herein are hereby incorporated by reference in their entirety regardless of their purpose.

Claims (14)

An α-dicarbonyl compound decomposing agent comprising a compound represented by the following formula (I), a salt thereof, or a solvate thereof.

[In formula (I), R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
n represents an integer from 1 to 6;
R _3a is selected from the group consisting of C _2-6 acyl groups, hydrogen atoms, and C _1-6 alkyl groups;
(A) when R _3a is a C _2-6 acyl group,
A dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _1- is selected from the group consisting of ₆ alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-6 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-6 alkyl group,
the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
R _3b represents a hydrogen atom or a C _1-6 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group, or a hydroxy C _1-6 alkyl group, and all of R ₁ , R _3a, R _3b , R ₄ , R ₅ , R ₆ and R ₇ cannot be a hydrogen atom. ] In formula (I), R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a C _1-3 alkyl group;
n represents an integer of 1 to 3,
R _3a represents a C _2-4 acyl group, a hydrogen atom, or a C _1-3 alkyl group;
(A) when R _3a is a C _2-4 acyl group,
A dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _{1- 3} selected from the group consisting of alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-3 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-3 alkyl group,
the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group;
R _3b represents a hydrogen atom or a C _1-3 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group, a C _1-3 alkoxy group, or a hydroxy C _1-3 alkyl group, and all of R ₁ , R _3a, R _3b , R ₄ , R ₅ , R ₆ and R ₇ The decomposing agent according to claim 1, wherein is not a hydrogen atom. The compound represented by formula (I), a salt thereof, or a solvate thereof is represented by the following formula (Ia-1), formula (Ia-2), formula (Ia-3) or formula (Ib-1) 3. The decomposing agent according to claim 1 or 2, which is the represented compound, a salt thereof, or a solvate thereof.

[In the formula (Ia-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R _2a , R ₄ , R ₆ and R ₇ is a hydroxyl group]

[In the formula (Ia-2),
R ₁ , R _2a , R _3c , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and R ₁ , R _2a , R _3c , R ₄ and R ₆ and at least one of R ₇ is a hydroxyl group]

[In the formula (Ia-3),
R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R ₄ , R ₆ and R ₇ is a hydroxyl group ]

[In the formula (Ib-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group;
R _3a and R _3b each independently represent a hydrogen atom or a C _1-3 alkyl group;
R5 represents a hydrogen atom, a hydroxyl group, a methoxy group or a hydroxymethyl group, and _R1 , _{R3a, R3b , R4 , R5} , _R6 and _R7 are not all hydrogen atoms. ] Compounds represented by formula (I), salts thereof, or solvates thereof are:

The decomposing agent according to any one of claims 1 to 3, which is a compound selected from the group consisting of, a salt thereof, or a solvate thereof. 5. The decomposing agent according to any one of claims 1 to 4, which is used for decomposition of Maillard reaction products, suppression of AGE production, degradation of AGE cross-linking, anti-glycation, and/or suppression of melanin synthesis. A composition for decomposing an α-dicarbonyl compound, comprising a compound represented by the following formula (I), a salt thereof, or a solvate thereof as an active ingredient.

[In formula (I), R ₁ , R ₄ , R ₆ and R ₇ are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
n represents an integer from 1 to 6;
R _3a is selected from the group consisting of C _2-6 acyl groups, hydrogen atoms, and C _1-6 alkyl groups;
(A) when R _3a is a C _2-6 acyl group,
A dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _1- is selected from the group consisting of ₆ alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-6 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-6 alkyl group,
the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-6 alkyl group;
R _3b represents a hydrogen atom or a C _1-6 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group, or a hydroxy C _1-6 alkyl group, and all of R ₁ , R _3a, R _3b , R ₄ , R ₅ , R ₆ and R ₇ cannot be a hydrogen atom. ] In formula (I), R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a C _1-3 alkyl group;
n represents an integer of 1 to 3,
R _3a represents a C _2-4 acyl group, a hydrogen atom, or a C _1-3 alkyl group;
(A) when R _3a is a C _2-4 acyl group,
A dotted line ( _--- ) represents a single bond or a double bond,
When the dotted line ( _--- ) is a single bond, X ₁ is CR _3c , X ₂ is CR _2b , and R _2b and R _3c are each independently a hydrogen atom, a hydroxyl group, and a C _{1- 3} selected from the group consisting of alkyl groups,
when the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms;
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group, and R _3b represents a hydrogen atom, or R _2a and R _3b together form a bond form,
R ₅ represents a C _1-3 alkoxy group, and
at least one of R ₁ , R _2a , R _2b , R _3c , R _3c , R ₄ , R ₆ and R ₇ is a hydroxyl group;
(B) when R _3a is a hydrogen atom or a C _1-3 alkyl group,
the dotted line ( _--- ) is a double bond, X ₁ and X ₂ are carbon atoms,
R _2a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a C _1-3 alkyl group;
R _3b represents a hydrogen atom or a C _1-3 alkyl group,
R ₅ represents a hydrogen atom, a hydroxyl group, a C _1-3 alkoxy group, or a hydroxy C _1-3 alkyl group, and all of R ₁ , R _3a, R _3b , R ₄ , R ₅ , R ₆ and R ₇ 7. The composition of claim 6, wherein is not a hydrogen atom. The compound represented by formula (I), a salt thereof, or a solvate thereof is represented by the following formula (Ia-1), formula (Ia-2), formula (Ia-3) or formula (Ib-1) 8. The composition according to claim 6 or 7, which is a compound represented, a salt thereof, or a solvate thereof.

[In the formula (Ia-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R _2a , R ₄ , R ₆ and R ₇ is a hydroxyl group]

[In the formula (Ia-2),
R ₁ , R _2a , R _3c , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and R ₁ , R _2a , R _3c , R ₄ and R ₆ and at least one of R ₇ is a hydroxyl group]

[In the formula (Ia-3),
R ₁ , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group, and at least one of R ₁ , R ₄ , R ₆ and R ₇ is a hydroxyl group ]

[In the formula (Ib-1),
R ₁ , R _2a , R ₄ , R ₆ and R ₇ each independently represent a hydrogen atom, a hydroxyl group or a methyl group;
R _3a and R _3b each independently represent a hydrogen atom or a C _1-3 alkyl group;
R5 represents a hydrogen atom, a hydroxyl group, a methoxy group or a hydroxymethyl group, and _R1 , _{R3a, R3b , R4 , R5} , _R6 and _R7 are not all hydrogen atoms. ] Compounds represented by formula (I), salts thereof, or solvates thereof are:

The composition according to any one of claims 6 to 8, which is a compound selected from the group consisting of, salts thereof, or solvates thereof. The composition according to any one of claims 6 to 9, for degrading Maillard reaction products, inhibiting AGE production, AGE cross-linking degradation, anti-glycation, and/or inhibiting melanin synthesis. The composition according to any one of claims 6 to 10, which is a cosmetic composition, pharmaceutical composition or food composition. The composition according to any one of claims 6 to 10, which is a cosmetic composition for preventing and/or improving skin aging, or suppressing pigmentation and/or whitening skin. The composition according to any one of claims 6 to 10, which is a pharmaceutical composition for preventing and/or treating aging-related diseases, skin aging, or diabetic complications caused by the formation of advanced glycation end products. . The composition according to any one of claims 6 to 10, which is a food composition for preventing and/or improving aging.

Images