CN118812406A - A kind of amide alkylresorcinol derivative and its use as antioxidant - Google Patents

Abstract

The invention discloses a compound of formula I, a preparation method, a composition and application thereof, wherein the compound of formula I has the following structure: Wherein T is hydrogen or R ¹ to R ⁵, Q and Q' are defined as in the specification. The compound of the invention is suitable for being used as a free radical capturing agent and an antioxidant, is suitable for being used as a skin and hair brightening agent, is suitable for being used as an anti-senile plaque inhibitor, and has wide application prospect.

Description

A kind of amide alkylresorcinol derivative and its use as antioxidant

Technical Field

The present invention relates to an amide alkylresorcinol derivative, a preparation method and a composition thereof, and uses thereof in free radical scavengers and antioxidants, in particular to uses thereof in skin and hair lighteners and anti-age spot agents.

Technical Background

Skin aging issues continue to receive attention. One of the key issues is excessive pigmentation. People with age spots or freckles hope that the spots can be reduced and faded so that they are not noticeable. For skin dullness caused by sunlight, people hope to reduce the impact of sunlight on skin color. These skin pigmentation issues are closely related to the formation of melanin on the human body.

Melanin is formed by pigment-producing cells on the body surface and transferred to the keratinocytes of the stratum corneum, resulting in changes in skin color. The formation of melanin is inseparable from the oxidation process. Tyrosine, under the action of tyrosinase containing high-valent copper ions, undergoes an oxidation process to generate 3,4-dihydroxyphenylalanine (DOPA), which is further oxidized to generate dopaquinone under the action of tyrosinase, and further oxidized to 5,6-dihydroxyindole (DHI), which is further oxidized to indole-5,6-quinone, and then undergoes oxidative polymerization to generate DHI-melanin. The formation of another type of melanin, DHICA-melanin, also starts from tyrosine. After oxidation to generate DOPA and dopaquinone, it is further converted into dihydroxyindole carboxylic acid (DHICA), and then undergoes an oxidation process to generate melanin (Marco I. et al., Pigment Cell Melanoma Res. 2015, 28 (5), 520-544). The production of melanin undergoes a series of oxidations, and multiple oxidation processes are carried out under the catalysis of tyrosinase. Therefore, if the oxidation reaction in the process of melanin production can be inhibited, or the activity of tyrosinase can be inhibited, the production of melanin can be inhibited.

Existing data show that dopamine can be converted into the corresponding quinone through an oxidation process, followed by cyclization to form 5,6-dihydroxyindole (DHI), which can then continue to produce melanin. (Nicola F.D.V. et al., Adv. Funct. Mater. 2013, 23, 1331-1340; David M.H. et al., Antioxidants, 2020, 9, 1285) This process involves multiple oxidation processes, and there may be free radical polymerization pathways. Free radical inhibitors can effectively block the oxidative polymerization process of dopamine, thereby delaying or inhibiting the conversion process from dopamine to melanin. (Wang Qianying et al., Journal of Chemistry in Higher Education, 2020, 41(6), 1378-1383)

The prior art discloses a method for treating hyperpigmentation by using a skin lightening agent. Combinations of compounds including hydroquinone, arbutin, kojic acid, licorice extract, niacinamide, vitamin C and the like are widely used in the fields of skin whitening, skin bleaching or skin brightening. A widely adopted research approach is to inhibit the activity of tyrosinase involved in melanogenesis, reduce the production of melanin, inhibit skin hyperpigmentation, and achieve the effect of brightening the skin. Hydroquinone, as an effective tyrosinase inhibitor, has been proven to have skin whitening efficacy, but its use in cosmetics is limited due to its potential dermatological and systemic side effects. Arbutin (a natural product extracted from plants) is a glycosylated derivative of hydroquinone and is an effective tyrosinase inhibitor that is more stable and less toxic than hydroquinone. However, despite its great potential, arbutin is still unstable and undergoes hydrolysis under different conditions, resulting in the release of hydroquinone (Diana I.S.P.R. et al., Applied Sciences, 2022, 12(2), 775). More efficient tyrosinase inhibitors have been developed, such as 4-butylresorcinol, 4-hexylresorcinol, dimethoxytolyl-4-propylresorcinol (WO2012/129260), phenethylresorcinol (WO2004/105736) and isobutylamidothiazolylresorcinol (WO2015/090850). This series of resorcinol derivatives can inhibit the activity of tyrosinase and have significant effects on improving skin pigmentation. Topical vitamin C is an effective skin whitening agent. While inhibiting tyrosinase, vitamin C can also serve as a reducing agent for dopaquinone. In a study on the treatment of melasma, vitamin C had a worse improvement effect than hydroquinone, but had fewer side effects than hydroquinone treatment (Woolery-Lloyd, H. et al., J. Cosmet. Dermatol. 9 (1), 22-27). It can be seen that vitamin C is a safe and effective skin whitening agent. Therefore, the development of new structural compounds that inhibit tyrosinase while also having antioxidant properties can more effectively and safely inhibit the production of melanin. This is of great significance for the development of new drugs or cosmetics for treating or improving excessive skin pigmentation, developing new skin and hair brighteners, and developing new drugs or cosmetics for fighting age spots.

Summary of the invention

The present inventors have developed an amide alkylresorcinol derivative through research, which can be used as a tyrosinase inhibitor and an antioxidant to inhibit the production of melanin, especially for cosmetic or pharmaceutical applications, and more particularly as a decolorizing agent, whitening agent, bleaching agent or brightening agent, and for the treatment of pigmentation diseases, or for cosmetic uses for slowing down or improving hyperpigmentation.

In particular, the present invention provides an amidoalkylresorcinol derivative I compound that can affect the pigmentation of the skin area caused by sunlight, especially ultraviolet and visible light, and especially prevent, treat and/or reduce the pigmentation of the skin area or skin part. The compound structure of formula I is as follows:

Wherein, T is hydrogen or

Wherein, R ¹ is selected from hydrogen, optionally substituted alkyl and optionally substituted arylalkyl; R ² , R ³ , R ⁴ and R ⁵ may be the same or different, and each independently selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; R ² and R ³ may be connected to the carbon atom to which they are commonly connected to form a ring, and R ⁴ and R ⁵ may be connected to the carbon atom to which they are commonly connected to form a ring;

Q represents any one of the following groups represented by Q-1 to Q-6:

In the formula, ^R6 is selected from hydrogen, optionally substituted alkyl, hydroxyl, optionally substituted alkoxy, or optionally substituted aryl, carboxyl or a salt thereof, cyano, optionally substituted amide, or optionally substituted ester; n is selected from a natural number of 1 to 6; the ester group is preferably _-COOCH3 , _-COOCH2CH3 , -COOCH( _{CH3 ) 2} , _{-COOCH2CH2CH3} , _{-COOCH2CH2CH2CH3 ;} the _amide group is preferably _-CONH2 , -CON( _{CH3 ) 2} , -CONHCH3 _{, -CONHCH2CH3 , -CON ( CH2CH3} ) ₂ , -CONHCH _{( CH3 )2 , -CONHCH2CH2CH3 , -CONHCH2CH2CH2CH3 ;} ^{A1 and} _A2 represent CH or a nitrogen atom _; R ^{R 7} is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted aryl, R ⁸ is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylacyl-COR ⁹ , wherein R ⁹ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

Q' and Q may be the same or different, and each independently selects any one of the groups shown in Q-1 to Q-6;

or a cosmetically or pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any ratio, in particular an enantiomer or a mixture of enantiomers, more particularly a racemic mixture.

Further, compound I is a compound of formula (II), wherein R ¹ , R ² , R ³ and Q are as defined above.

Further, compound I is a compound of formula (III), wherein R ¹ to R ⁵ , Q and Q' are as defined above.

Further, compound I is a compound of formula (IIa), ^R1 and Q are as defined above, ^Z1 and ^Z2 may be the same or different, and are independently selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl. ^Z1 and ^Z2 may be connected to the carbon atom to which they are connected to form a ring, and the ring may be substituted.

Further, compound I is a compound of formula (IIIa), wherein R ¹ , Q and Q' are as defined above; Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different and are independently selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; Z ¹ and Z ² may be linked to the carbon atom to which they are commonly attached to form a ring; Z ³ and Z ⁴ may be linked to the carbon atom to which they are commonly attached to form a ring; and the ring may be substituted.

The present invention also provides a method for preparing compound I.

The present invention also provides compositions containing the compounds of the present invention or their cosmetically or pharmaceutically acceptable salts.

The present invention also provides the use of the compound of the present invention or its cosmetically or pharmaceutically acceptable salt in free radical scavengers and antioxidants.

The present invention also provides the use of the compound of the present invention or its cosmetically or pharmaceutically acceptable salt in the preparation of (a) anti-browning of skin and hair, (b) anti-age spot medicaments.

The invention also discloses a cosmetic composition containing the compound or a salt thereof.

Beneficial Effects

The compound of the present invention exhibits excellent effects in terms of anti-browning of skin and hair, anti-senile plaque, free radical capture, anti-oxidation and the like.

DETAILED DESCRIPTION

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

The endpoints and any values of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, the endpoint values of each range and the individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

"Hyperpigmentation" in the context of the present invention refers to hyperpigmentation caused by sunlight, more particularly visible light.

In the present invention, "cosmetically or pharmaceutically acceptable" means that it can be used in the preparation of cosmetic or pharmaceutical compositions and is generally non-toxic, safe and acceptable for pharmaceutical and cosmetic uses.

In the present invention, a "cosmetically or pharmaceutically acceptable salt" is a cosmetically or pharmaceutically acceptable salt as defined herein and which possesses the pharmaceutical and cosmetic properties and activities of the original compound. Such salts may be: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, and the like, but are not limited thereto, and (2) acid addition salts formed when an acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., Na ⁺ , K ^+, or Li ⁺ ), an alkaline earth metal ion (e.g., Ca2 ⁺ , or Mg2 ⁺ ), or a ) or aluminum ion replacement; or when the acid proton present in the parent compound is coordinated with an organic base or an inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., but are not limited thereto. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide, but are not limited thereto.

The term "stereoisomer" used in the present invention refers to configurational stereoisomers, which include geometric isomers and optical isomers, and conformational isomers.

Geometric isomers (also called E/Z isomers or cis-trans isomers) result from the different positions of substituents on the C=C double bond, which can have the Z or E configuration, also called the cis or trans configuration.

Optical isomers result from different positions in space of substituents or lone pairs of electrons on an atom (such as a carbon or sulfur atom) that contains four different substituents (potentially including lone pairs of electrons). Thus, the atom represents a chiral or asymmetric center. Thus, optical isomers that are not mirror images of one another are termed "diastereomers," while optical isomers that are non-superimposable mirror images of one another are termed "enantiomers."

An equimolar mixture of two enantiomers of a chiral compound is called a racemic mixture.

Halogen in the context of the present invention denotes in all cases fluorine, chlorine, bromine and iodine.

The term "alkyl" as used herein (and in other groups containing alkyl, for example the alkyl moiety of alkoxy, the alkyl moiety of arylalkyl) denotes in each case a straight-chain or branched alkyl group having usually 1 to 20 carbon atoms, frequently 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms and in particular 1 to 3 carbon atoms. Examples of _C1 - _C4 -alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl). Examples of C ₁ -C ₆ -alkyl radicals are, in addition to the radicals mentioned for C ₁ -C ₄ -alkyl radicals, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl. Examples of the C ₁ -C ₁₀ alkyl group include, in addition to the groups mentioned for the C ₁ -C ₆ alkyl group, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 1-ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl, 2-propylpentyl, nonyl, decyl, 2-propylheptyl, and 3-propylheptyl, but are not limited thereto. The alkyl group may be substituted with, but is not limited to, halogen, cyano, nitro, aryl, cycloalkyl, heterocyclic, acylamino, ester, and the like.

In the present invention, "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl, especially naphthyl, but not limited thereto. The aryl group may be substituted by an alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclic, acylamino, ester group, etc., but not limited thereto.

In the present invention, "ring" refers to "cycloalkyl" or "heterocyclyl". "Cycloalkyl" refers to a monocyclic monovalent hydrocarbon group of three to six carbon atoms, which may be saturated or contain a double bond. Cycloalkyl may be unsubstituted or substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano, but is not limited thereto. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropyl-1-yl, 1-cyanomethylcyclopropyl-1-yl, 3-fluorocyclohexyl, etc., but are not limited thereto. When the cycloalkyl contains a double bond, it may be referred to as cycloalkenyl in this article. "Heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, wherein one or two ring atoms are heteroatoms selected from N, O or S(O) _p , wherein p is an integer from 0 to 2, and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclyl ring may be optionally replaced by -CO- groups. More specifically, the term heterocyclic group includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl (piperazino), tetrahydropyranyl, thiomorpholinyl etc., but is not limited thereto. When cycloalkyl, heterocyclic group etc. are substituted, they may be substituted by alkyl, halogen, cyano, nitro, aryl, amido, ester group etc., but are not limited thereto.

The term "optionally substituted" means that the relevant group may be substituted by a substituent or may not be substituted.

When a group is substituted, the substituent may be an alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclic, acylamino, ester, alkoxy and halogen, etc., but is not limited thereto. For example, when an alkyl is substituted by a halogen, a haloalkyl is formed, but is not limited thereto.

"Alkoxy" refers to a -OR group, where R is an alkyl group as defined above, for example, methoxy, ethoxy, propoxy, or 2-propoxy, n-butoxy, isobutoxy or tert-butoxy, etc., but is not limited thereto.

"Arylalkyl" refers to a residue in which the aryl portion is attached to the parent structure through an alkyl residue. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl, and the like. "Heteroaralkyl" refers to a residue in which the heteroaryl portion is attached to the parent structure through an alkyl residue. Examples include furanylmethyl, pyridylmethyl, pyrimidinylethyl, and the like.

The acylamino group of the present invention refers to a group containing "-CONH ₂ " or "-CON", and exemplary acylamino groups include -CONH ₂ , -CON(CH ₃ ) ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CON(CH ₂ CH ₃ ) ₂ , -CONHCH(CH ₃ ) _{2 ,} -CONHCH ₂ CH ₂ CH ₃ , -CONHCH ₂ CH ₂ CH ₃ ,

And so on, but not limited to this.

The ester group of the present invention refers to a -COOR' group, wherein R' is an alkyl group. Exemplary ester groups include, for example, _-COOCH3 , _-COOCH2CH3 , _-COOCH ( _{CH3 ) 2} , _{-COOCH2CH2CH3 , -COOCH2CH2CH2CH3} , _etc. , but are _not limited _thereto .

In the present invention It represents the endpoint connected to other groups, and those skilled in the art can understand its meaning through the compound connection structure disclosed in the specification.

The statements made below with regard to the variables of the compounds of the formula I and preferred embodiments of the variables, features of the uses and methods according to the invention and features of the compositions according to the invention are valid both on their own and preferably in combination with one another.

In general, the present invention provides an amide alkyl resorcinol derivative compound of formula I,

Wherein, T is hydrogen or

Wherein, R ¹ is selected from hydrogen, optionally substituted alkyl and optionally substituted arylalkyl; R ² , R ³ , R ⁴ and R ⁵ may be the same or different, and each independently selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; R ² and R ³ may be connected to the carbon atom to which they are commonly connected to form a ring, and R ⁴ and R ⁵ may be connected to the carbon atom to which they are commonly connected to form a ring;

Q represents any one of the following groups represented by Q-1 to Q-6:

In the formula, ^R6 is selected from hydrogen, optionally substituted alkyl, hydroxyl, optionally substituted alkoxy, or optionally substituted aryl, carboxyl or a salt thereof, cyano, optionally substituted amide, or optionally substituted ester; n is selected from a natural number of _1-6 ; the ester group is preferably _-COOCH3 , _-COOCH2CH3 , -COOCH( _{CH3 ) 2} , _{-COOCH2CH2CH3} , -COOCH2CH2CH2CH3; the amide group is preferably _-CONH2 , -CON( _{CH3 ) 2 , -CONHCH3 , -CONHCH2CH3 , -CON} ⁽ _{CH2CH3 ) 2} , -CONHCH _{( CH3 ) 2} , _{-CONHCH2CH2CH3 , -CONHCH2CH2CH2CH3 ;} ^A1 and _A2 represent CH or a nitrogen atom _; R ^{R 7} is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted aryl, R ⁸ is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylacyl-COR ⁹ (R ⁹ is selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy);

Q' and Q may be the same or different, and each independently selects any one of the groups shown in Q-1 to Q-6;

or a cosmetically or pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any ratio, in particular an enantiomer or a mixture of enantiomers, more particularly a racemic mixture.

Furthermore, the present invention provides a compound of formula (II) or a salt thereof:

Wherein, R ¹ is selected from hydrogen, optionally substituted alkyl and optionally substituted arylalkyl; R ² and R ³ may be the same or different, and are independently selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; R ² and R ³ may be connected to the carbon atom to which they are commonly connected to form a ring;

Q represents any one of the following groups represented by Q-1 to Q-6:

In the formula, ^R6 is selected from hydrogen, optionally substituted alkyl, hydroxyl, optionally substituted alkoxy, or optionally substituted aryl, carboxyl or a salt thereof, cyano, optionally substituted amide, or optionally substituted ester; n is selected from a natural number of 1 to 6; the ester group is preferably _-COOCH3 , _-COOCH2CH3 , -COOCH( _{CH3 ) 2} , _{-COOCH2CH2CH3} , _{-COOCH2CH2CH2CH3 ;} the _amide group is preferably _-CONH2 , -CON( _{CH3 ) 2} , -CONHCH3 _{, -CONHCH2CH3 , -CON ( CH2CH3} ) ₂ , -CONHCH _{( CH3 )2 , -CONHCH2CH2CH3 , -CONHCH2CH2CH2CH3 ;} ^{A1 and} _A2 represent CH or a nitrogen atom _; R ^R7 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted aryl, ^R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylacyl- ^COR9 ( ^R9 is selected from hydrogen, _C1 - _C6 alkyl or _C1 - _C6 alkoxy).

Further, in some embodiments of formula (II), R ¹ is selected from H and C ₁ -C ₆ alkyl, and H and methyl are particularly preferred.

Further, in some embodiments of formula (II), Q is selected from Q-1, wherein n is 1, 2 or 3, and ^R6 is selected from hydrogen, _carboxyl or its salt, cyano, _-COOCH3 , _-COOCH2CH3 , _-CONH2 , -CON( _CH3 ) ₂ , _-CONHCH3 , particularly preferably hydrogen and carboxyl.

Further, in some embodiments of formula (II), Q is selected from Q-6, wherein ^R7 is selected from hydrogen and _C1 - _C6 alkyl, particularly preferably hydrogen and methyl, and ^R8 is selected from hydrogen and _C1 - _C6 alkyl, particularly preferably hydrogen.

In some embodiments of formula (II), preferably, R ² is selected from H and C ₁ -C ₆ alkyl, and particularly preferably one of H, methyl, ethyl, propyl and butyl.

In some embodiments of formula (II), preferably, R ³ is selected from H and C ₁ -C ₆ alkyl, and particularly preferably one of H, methyl, ethyl, propyl and butyl.

Furthermore, the present invention preferably provides compounds of formula (II) such as compounds of formula (II-1), (II-2), (II-3), (II-4), (II-5) and (II-6):

Among them, R ¹ is selected from H and C ₁ -C ₆ alkyl, and H and methyl are particularly preferred; R ² is selected from H and C ₁ -C ₆ alkyl, and one of H, methyl, ethyl, propyl and butyl is particularly preferred; R ³ is selected from H and C ₁ -C ₆ alkyl, and one of H, methyl, ethyl, propyl and butyl is particularly preferred; R ⁶ is selected from hydrogen, carboxyl or its salt, cyano, -COOCH ₃ , -COOCH ₂ CH ₃ , -CONH ₂ , -CON(CH ₃ ) ₂ , -CONHCH ₃ , and hydrogen and carboxyl are particularly preferred; R ⁷ is selected from hydrogen and C ₁ -C ₆ alkyl, and hydrogen and methyl are particularly preferred; R ⁸ is selected from hydrogen and C ₁ -C ₆ alkyl, and hydrogen is particularly preferred; A ¹ and A ² are selected from CH or nitrogen atom; n is selected from 1, 2 and 3.

Further, in some embodiments, the compound I of the present invention is preferably a compound of formula (III),

Wherein, R ¹ is selected from hydrogen, optionally substituted alkyl and optionally substituted arylalkyl; R ² , R ³ , R ⁴ and R ⁵ may be the same or different, and each independently selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; R ² and R ³ may be connected to the carbon atom to which they are commonly connected to form a ring, and R ⁴ and R ⁵ may be connected to the carbon atom to which they are commonly connected to form a ring; Q' and Q may be the same or different, and each independently selected from any one of the groups shown in Q-1 to Q-6;

In the formula, ^R6 is selected from hydrogen, optionally substituted alkyl, hydroxyl, optionally substituted alkoxy, or optionally substituted aryl, carboxyl or a salt thereof, cyano, optionally substituted amide, or optionally substituted ester; n is selected from a natural number of 1 to 6; the ester group is preferably _-COOCH3 , _-COOCH2CH3 , -COOCH( _{CH3 ) 2} , _{-COOCH2CH2CH3} , _{-COOCH2CH2CH2CH3 ;} the _amide group is preferably _-CONH2 , -CON( _{CH3 ) 2} , -CONHCH3 _{, -CONHCH2CH3 , -CON ( CH2CH3} ) ₂ , -CONHCH _{( CH3 )2 , -CONHCH2CH2CH3 , -CONHCH2CH2CH2CH3 ;} ^{A1 and} _A2 represent CH or a nitrogen atom _; R ^R7 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted aryl, ^R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylacyl- ^COR9 ( ^R9 is selected from hydrogen, _C1 - _C6 alkyl or _C1 - _C6 alkoxy).

Further, in some embodiments of formula (III), Q and Q' are selected from Q-1, n is a natural number of 1-3, and ^R6 is preferably hydrogen.

Furthermore, the present invention preferably provides a compound of formula (III) as follows:

Wherein, ^R1 is selected from H and _C1 - _C6 alkyl, and H and methyl are particularly preferred; ^R2 is selected from H and _C1 - _C6 alkyl, and one of H, methyl, ethyl, propyl and butyl are particularly preferred; ^R3 is selected from H and _C1 - _C6 alkyl, and one of H, methyl, ethyl, propyl and butyl are particularly preferred; ^R4 is selected from H and _C1 - _C6 alkyl, and one of H, methyl, ethyl, propyl and butyl are particularly preferred; ^R5 is selected from H and _C1 - _C6 alkyl, and one of H, methyl, ethyl, propyl and butyl are particularly preferred; n is selected from 1, 2 and 3, and m is selected from 1, 2 and 3.

Further, in some embodiments, the compound I of the present invention is preferably a compound of formula (IIa), Wherein, R ¹ is selected from hydrogen, optionally substituted alkyl and optionally substituted arylalkyl; Z ¹ and Z ² may be the same or different, and are independently selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; Z ¹ and Z ² may be connected to the carbon atom to which they are commonly connected to form a ring, and the ring may be substituted;

Q represents any one of the following groups represented by Q-1 to Q-6:

In the formula, ^R6 is selected from hydrogen, optionally substituted alkyl, hydroxyl, optionally substituted alkoxy, or optionally substituted aryl, carboxyl or a salt thereof, cyano, optionally substituted amide, or optionally substituted ester; n is selected from a natural number of 1 to 6; the ester group is preferably _-COOCH3 , _-COOCH2CH3 , -COOCH( _{CH3 ) 2} , _{-COOCH2CH2CH3} , _{-COOCH2CH2CH2CH3 ;} the _amide group is preferably _-CONH2 , -CON( _{CH3 ) 2} , -CONHCH3 _{, -CONHCH2CH3 , -CON ( CH2CH3} ) ₂ , -CONHCH _{( CH3 )2 , -CONHCH2CH2CH3 , -CONHCH2CH2CH2CH3 ;} ^{A1 and} _A2 represent CH or a nitrogen atom _; R ^R7 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted aryl, ^R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylacyl- ^COR9 ( ^R9 is selected from hydrogen, _C1 - _C6 alkyl or _C1 - _C6 alkoxy).

Further, in some embodiments, the compound I of the present invention is preferably a compound of formula (IIIa), Wherein, R ¹ is selected from hydrogen, optionally substituted alkyl and optionally substituted arylalkyl; Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different, and are independently selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; Z ¹ and Z ² may be connected to the carbon atom to which they are commonly connected to form a ring; Z ³ and Z ⁴ may be connected to the carbon atom to which they are commonly connected to form a ring; and the ring may be substituted;

Q' and Q may be the same or different, and each independently selects any one of the groups shown in Q-1 to Q-6:

In the formula, ^R6 is selected from hydrogen, optionally substituted alkyl, hydroxyl, optionally substituted alkoxy, or optionally substituted aryl, carboxyl or a salt thereof, cyano, optionally substituted amide, or optionally substituted ester; n is selected from a natural number of 1 to 6; the ester group is preferably _-COOCH3 , _-COOCH2CH3 , -COOCH( _{CH3 ) 2} , _{-COOCH2CH2CH3} , _{-COOCH2CH2CH2CH3 ;} the _amide group is preferably _-CONH2 , -CON( _{CH3 ) 2} , -CONHCH3 _{, -CONHCH2CH3 , -CON ( CH2CH3} ) ₂ , -CONHCH _{( CH3 )2 , -CONHCH2CH2CH3 , -CONHCH2CH2CH2CH3 ;} ^{A1 and} _A2 represent CH or a nitrogen atom _; R ^R7 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted aryl, ^R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylacyl- ^COR9 ( ^R9 is selected from hydrogen, _C1 - _C6 alkyl or _C1 - _C6 alkoxy).

Particularly preferably, the compounds of the present invention are selected from the following compounds:

N-(1-(2,4-dihydroxyphenyl)ethyl)-2-pyrrolidone;

N-(1-(2,4-dihydroxyphenyl)propyl)-2-pyrrolidone;

N-(1-(2,4-dihydroxyphenyl)ethyl)-2-piperidone;

N-(1-(2,4-dihydroxyphenyl)propyl)-2-piperidone;

N-(1-(2,4-dihydroxyphenyl)ethyl)-2-cyclohexylimine ketone;

N-(1-(2,4-dihydroxyphenyl)propyl)-2-cyclohexylidene ketone;

1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(ethyl-1,1-ylidene))bis(pyrrolidin-2-one);

1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(propan-1,1-ylidene))bis(pyrrolidin-2-one);

1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(ethyl-1,1-ylidene))bis(piperidin-2-one);

1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(propan-1,1-idene))bis(piperidin-2-one);

1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(ethyl-1,1-idene))bis(cycloheximide-2-one);

1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(propan-1,1-ylidene))bis(cycloheximide-2-one).

The present invention also provides a method for preparing the compound of formula (II), and the synthetic route is as follows:

wherein R ¹ , R ² , R ³ and Q are as defined above, wherein LG is selected from a leaving group, the leaving group is preferably one of OTs, OMs, Cl, Br, I, the base is preferably one of NaOH, KOH, Na ₂ CO ₃ , K ₂ CO ₃ , NaH, triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide or a combination thereof;

In the above reaction, the reaction temperature is 40-150°C, preferably 70-120°C;

In the above reaction, the molar ratio of the reaction materials of formula IV and H-Q is 1:1-1:1.5, preferably 1:1.01-1:1.05;

In the above reaction, the molar ratio of the reaction mixture of formula IV and the base is 1:1.0-1:4.0, preferably 1:1.0-1:3.0;

The above reaction is carried out in a solvent, and the solvent is selected from one or a combination of toluene, acetonitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, dichloroethane, etc., preferably DMF.

The present invention also provides a method for preparing the compound of formula (IIa), and the synthetic route is as follows:

wherein R ¹ , Z ¹ , Z ² and Q are as defined above;

The reaction in which H-Q is involved can be carried out under the promotion of an acid, wherein the acid is selected from one or a combination of sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, phosphoric acid, methanesulfonic acid, and trifluoromethanesulfonic acid, preferably p-toluenesulfonic acid;

The above-mentioned reduction conditions are preferably one or a combination of hydrogen/palladium carbon, hydrogen/Raney nickel, sodium borohydride, lithium aluminum hydride, zinc powder/acetic acid, zinc powder/hydrochloric acid, iron powder/acetic acid, and iron powder/hydrochloric acid, preferably hydrogen/palladium carbon or hydrogen/Raney nickel;

The reaction in which H-Q participates is carried out in a solvent, wherein the solvent is selected from one or a combination of toluene, cyclohexane, acetonitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, ethylene dichloride, etc., preferably toluene;

The reduction reaction is carried out in a solvent, and the solvent is selected from one or a combination of toluene, tetrahydrofuran, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, methanol, ethanol, etc., preferably ethanol;

In the above reduction reaction, the reaction temperature is 20-130°C, preferably 20-60°C;

In the above reaction, the reaction temperature for generating formula (VI) from formula (V) is 30-130°C, preferably 40-110°C;

In the above reaction, the molar ratio of the reaction mixture of formula (V) and H-Q is 1:1-1:1.5, preferably 1:1.01-1:1.05.

The present invention further provides a method for preparing the compounds of formula II-1, II-2, II-3, II-4, II-5 and II-6, and the synthetic route is as follows:

wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , LG and n are as defined above, and X is preferably selected from Cl, Br, I, OTs, OMs, OAc, OCOH and the like. Compound (IV) reacts with ammonia to obtain an amine compound (VII); Compound (VII) reacts with an acyl halide or anhydride with a leaving group to obtain an amide compound (VIIb), followed by an intramolecular substitution reaction to obtain a lactam compound (II-1); Compound (VII) reacts with a cyclic acid anhydride to obtain a cyclic imide compound (II-2); Compound (VII) reacts with maleic anhydride to obtain a compound (II-3); Compound (VII) reacts with maleic anhydride with a paracyclic structure to obtain a compound (II-4); Compound (VII) reacts with ortho-aromatic dicarboxylic anhydride to obtain a cyclic imide compound (II-5); Compound (IV) reacts with an amine compound R ⁸ NH ₂ to obtain a compound (VIIc), followed by a reaction with a compound R ⁷ COX to obtain an amide compound (II-6).

The present invention also provides a method for preparing a compound of formula (III), and the synthetic route is as follows:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q and Q' are as defined above, wherein LG is selected from a leaving group, and the leaving group is preferably one of OTs, OMs, Cl, Br and I;

In the above reactions, the reactions all require the promotion of a base, and the base is preferably one or a combination of NaOH, KOH, Na ₂ CO ₃ , K ₂ CO ₃ , NaH, triethylamine, sodium methoxide, sodium ethoxide, and sodium tert-butoxide;

In the above reaction, the reaction temperature is 40-150°C, preferably 70-120°C;

In the above reaction, the molar ratio of the reaction mixture of formula IVa and H-Q is 1:1-1:1.5, preferably 1:1.01-1:1.05;

In the above reaction, the molar ratio of the reaction mixture of formula IVb and H-Q' is 1:1-1:1.5, preferably 1:1.01-1:1.05;

In the above reaction, the molar ratio of the reaction mixture of formula IVa and the base is 1:1.0-1:4.0, preferably 1:1.0-1:3.0;

In the above reaction, the molar ratio of the reaction mixture of formula IVb and the base is 1:1.0-1:4.0, preferably 1:1.0-1:3.0;

The above reaction is carried out in a solvent, and the solvent is selected from one or a combination of toluene, acetonitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, dichloroethane, etc., preferably DMF.

The present invention also provides a method for preparing a compound of formula (IIIa), and the synthetic route is as follows:

wherein R ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Q and Q' are as defined above;

The above-mentioned reactions involving H-Q and H-Q' can be carried out under the promotion of acid, wherein the acid is selected from one or a combination of sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, phosphoric acid, methanesulfonic acid, and trifluoromethanesulfonic acid, preferably p-toluenesulfonic acid;

The above-mentioned reduction conditions are preferably one or a combination of hydrogen/palladium carbon, hydrogen/Raney nickel, sodium borohydride, lithium aluminum hydride, zinc powder/acetic acid, zinc powder/hydrochloric acid, iron powder/acetic acid, and iron powder/hydrochloric acid, preferably hydrogen/palladium carbon or hydrogen/Raney nickel;

The reactions involving H-Q and H-Q' are all carried out in a solvent, wherein the solvent is selected from one or a combination of toluene, cyclohexane, cyanamide, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, ethylene dichloride, etc., preferably toluene;

The reduction reaction is carried out in a solvent, and the solvent is selected from one or a combination of toluene, tetrahydrofuran, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, methanol, ethanol, etc., preferably ethanol;

In the above reduction reaction, the reaction temperature is 20-130°C, preferably 20-60°C;

In the above reactions involving H-Q and H-Q', the reaction temperature is 30-130°C, preferably 40-110°C;

In the above reaction, the molar ratio of formula (Va) to H-Q is 1:1-1:1.5, preferably 1:1.01-1:1.05;

In the above reaction, the molar ratio of formula (VIa) to H-Q' is 1:1-1:1.5, preferably 1:1.01-1:1.05.

The compounds of the present invention can be used in the preparation of drugs or cosmetics for treating, preventing and/or alleviating hyperpigmentation, especially by topical application to the skin, such as human skin.

The present invention also provides a cosmetic composition or a pharmaceutical composition containing the compound of formula (I) or a salt thereof.

Furthermore, the above-mentioned cosmetic composition can be prepared into suitable forms such as creams, emulsions, ointments, capsules, lotions, foams, gels, dispersions, suspensions, sprays, essences, facial masks, etc.

The amount of the compound of formula (I) of the present invention in the above-mentioned preparation is preferably 0.01-95% by weight, particularly preferably 0.1-50% by weight, and most preferably 0.1-10% by weight.

Further, the pharmaceutical/cosmetic composition of the present invention may also contain one or more additives, such as antioxidants, emollients, moisturizers, thickeners, fragrances, preservatives, pigments or colorants or sunscreens. These additives are conventional to those skilled in the art.

Antioxidants may be used to protect the ingredients of the composition against oxidants contained in or to be in contact with the composition. Examples of antioxidants include ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium propyl gallate, octyl gallate, dodecyl gallate, phenyl-α-naphthylamine, and tocopherols such as α-tocopherol.

Emollients are agents that soften and smooth the skin. Examples of emollients include oils and waxes (e.g., microcrystalline wax, polyethylene), triglycerides (e.g., castor oil, cocoa butter, safflower oil, corn oil, olive oil, cod liver oil, almond oil, palm oil, soybean oil), squalene, acetylated monoglycerides, ethoxylated glycerides, fatty acids, alkyl esters of fatty acids, alkenyl esters of fatty acids, fatty alcohols, fatty alcohol ethers, ether-esters, lanolin and lanolin derivatives, polyol esters, wax esters (e.g., beeswax, vegetable waxes), phospholipids and sterols, isopropyl palmitate or glyceryl stearate, in particular almond oil or fatty alcohols (e.g., cetyl alcohol, stearyl alcohol and/or myristyl alcohol).

Silicone is a particularly preferred emollient. Silicones that can be used in the present invention include, but are not limited to, dimethicone, methylcyclosiloxane, phenyl trimethicone, phenyl dimethicone, cetyl dimethicone, stearyl dimethicone, amino dimethicone, C _30-45 alkyl dimethicone, C _30-45 alkyl methyl siloxane, cetearyl methyl siloxane, dimethicone copolyol, cyclopentyl siloxane, cyclohexyl siloxane, or any combination thereof. In particular, amino dimethicone can be used as an emollient in the present invention.

Humectants are used to increase and maintain moisture in the skin. Examples of humectants include propylene glycol, butylene glycol, polyethylene glycol (PEG) (such as PEG-4 to PEG-32), glycerol (also known as glycerin), sorbitol, xylitol, maltitol, mannitol, polydextrose, hyaluronic acid and its salts (such as sodium or potassium salts), urea, aloe vera juice, honey, etc.

Thickeners are used to increase the viscosity and thickness of the composition. Examples of thickeners include lipid thickeners such as cetyl alcohol, stearyl alcohol, myristyl alcohol, carnauba wax, or stearic acid; naturally derived thickeners, such as cellulose derivatives, such as hydroxyethylcellulose, guar gum, locust bean gum, xanthan gum, or gelatin; mineral thickeners such as silicon dioxide, bentonite, or magnesium aluminum silicate; synthetic thickeners such as carbomer; ionic thickeners such as NaCl.

Examples of fragrances or flavors include peppermint, rose oil, rose water, aloe vera juice, clove oil, menthol, camphor, eucalyptus oil and other plant extracts. In order to eliminate certain odors of the composition, masking agents may be used.

Preservatives can be used to protect the composition from degradation. Examples of preservatives include phenoxyethanol, methylparaben, benzalkonium chloride, benzethonium chloride, propylparaben, benzoic acid, benzyl alcohol, and mixtures thereof. In particular, it can be phenoxyethanol, methylparaben, or mixtures thereof.

Pigments or colorants are used to change the color of the composition. In addition to the above-mentioned soluble substances, insoluble light protection dyes, especially finely dispersed metal oxides or salts, are also suitable for this purpose. For example, titanium dioxide can be selected to obtain a white composition. In clear or transparent compositions, sunscreens such as titanium oxide are used to make them opaque. Particularly suitable metal oxide examples also include zinc oxide, iron, zirconium, silicon, manganese, aluminum and cerium oxides and mixtures thereof. Silicates (talc), barium sulfate or zinc stearate can be used as examples of suitable salts. Oxides and salts are used in the form of pigments for skin care and skin protection emulsions and decorative cosmetics. In this case, the particles should have an average diameter of less than 100nm, preferably between 5 and 50nm, and particularly preferably between 15 and 30nm. They can be spherical, but particles with elliptical shapes or other shapes that are not spherical can also be used. The pigment can also be surface treated, i.e., hydrophilized or hydrophobized. A typical example is coated titanium dioxide. In this case, the appropriate hydrophobic coating agent is first silicone, especially trialkoxyoctylsilane or tripolysiloxane. So-called micro- or nano-dyes are preferably used in sunscreen formulations, preferably micronized zinc oxide.

In a preferred embodiment, the light protection dye is selected from fine titanium dioxide, zinc oxide, and fine zinc oxide. When titanium dioxide is selected as the light protection dye, it is advantageous that its total amount is 0.1 to 10.0% by weight of the preparation. When zinc oxide is selected as the light protection dye, it is advantageous that its total amount is 0.1 to 10.0% by weight of the preparation, and when one or more triazine organic pigments are selected, it is advantageous that its total amount is 0.1 to 10.0% by weight, based on the total amount of the preparation. In a preferred embodiment, the pharmaceutical or cosmetic composition according to the present invention also contains at least one skin lightening agent, for example, sclareolide.

The invention also relates to the cosmetic use of the compounds of formula (I) according to the invention, in particular as depigmenting, whitening, bleaching or lightening agents, more particularly for cosmetic use on the skin, such as human skin.

The invention also relates to the cosmetic use of a cosmetic composition according to the invention, in particular as a depigmenting, whitening, bleaching or brightening composition, more particularly intended for topical application to the skin, such as human skin.

The invention also relates to the use of a compound of formula (I) according to the invention for preparing a cosmetic composition, in particular intended for depigmenting, whitening, bleaching or lightening the skin, such as human skin.

The invention also relates to a compound of formula (I) according to the invention for use as a depigmenting, whitening, bleaching or whitening agent, more particularly for the skin, such as human skin.

The present invention also relates to a method for depigmenting, whitening, bleaching or brightening the skin, such as human skin, by applying to the skin of a person in need thereof an effective amount of a compound according to the invention or a cosmetic composition according to the invention.

The invention also relates to a compound according to the invention for use as a medicament, in particular in the treatment of pigmentation disorders, more particularly by topical application to the skin, such as human skin.

The invention also relates to a pharmaceutical composition, in particular a dermatological composition, according to the invention, for use as a medicament, especially in the treatment of pigmentation diseases, more particularly by topical application to the skin, such as human skin.

The invention also relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition, in particular a dermatological composition, especially intended for the treatment of pigmentation diseases, more particularly by topical application to the skin, such as human skin.

The invention also relates to the use of the compounds according to the invention for treating pigmentation disorders, more particularly by topical application to the skin, such as human skin.

The invention also relates to a method for treating pigmentation diseases of the skin, such as human skin, by applying to the skin of a person in need thereof an effective amount of a compound according to the invention or a pharmaceutical composition, in particular a dermatological composition, according to the invention.

The pigmentation disorder will more particularly be hyperpigmentation including moles, melasma, freckles, post-inflammatory hyperpigmentation and hyperpigmentation induced by drugs, chemicals or the sun.

The invention also relates to a compound according to the invention for use as an antioxidant, in particular for inhibiting or reducing oxidative stress, especially oxidative stress due to UV, more particularly oxidative stress in the skin.

The invention also relates to a method for inhibiting or reducing oxidative stress, especially oxidative stress due to UV, more especially oxidative stress in the skin, which comprises administering, especially topically administering, to a person in need thereof, an effective amount of a compound according to the invention.

When the composition of the present invention is applied to human skin, the combination of the compound of the present invention and the UV filter is well tolerated, does not cause redness, whitening or browning of the skin, is non-irritating, does not dry the skin, does not form a moist, flaky, powdery or sticky film, and does not cause skin cracking. These UV filters can be UV-A filters, UV-B filters, light protection dyes or mixtures thereof. UV filters are organic substances (light filters) that are liquid or crystalline at room temperature, for example, and are able to absorb ultraviolet radiation and release the absorbed energy in the form of long-wave radiation such as heat. Typically, the content of UV filters is from 0.05% to 50% by weight, preferably from 0.5% to 40% by weight.

UV filters can be oil-soluble or water-soluble.

Suitable oil-soluble substances include:

3-Benzalcamphor and its derivatives, such as 3-(4-methylbenzylidene)camphor;

4-aminobenzoic acid derivatives, preferably 4-(dimethylamino)benzoic acid 2-ethylhexyl ester, 4-(dimethylamino)benzoic acid 2-octyl ester and 4-(dimethylamino)benzoic acid pentyl ester;

Esters of cinnamic acid, preferably 2-ethylhexyl 4-methoxycinnamate, propyl 4-methoxycinnamate, isoamyl 4-methoxycinnamate, 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene);

Esters of salicylic acid, preferably 2-ethylhexyl salicylate, homosalate, menthyl salicylate;

Benzophenone derivatives, preferably 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2-hydroxy-4-methoxy-benzophenone, 2,2'-dihydroxy-4-methoxybenzophenone;

Benzyl malonate, preferably 4-methoxybenzylmalonate bis-2-ethylhexyl ester,

triazine derivatives, for example, 2,4,6-tris(p-2-ethylhexylanilino)-1,3,5-triazine and bis-octylbutyramidotriazine;

Benzoylmethane derivatives, preferably 4-tert-butyl-4'-methoxydibenzoylmethane;

·Carbonyl-containing polycyclic compounds, such as ketotricyclic (5.2.1.0) decane derivatives, etc.

Examples of suitable water-soluble substances include:

2-Phenylbenzimidazole-5-sulfonic acid and its alkali metal, alkaline earth metal, ammonium, alkylammonium, alkanol, and gluconammonium salts;

· Disodium salt of 2,2'-bis-(1,4-phenylene) 1H-benzimidazole-4,6-disulfonic acid;

Sulfonic acid derivatives of benzophenone, preferably 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and its salts;

Sulfonic acid derivatives of 3-benzylidenecamphor, preferably benzalcamphorsulfonic acid and 2-methyl-5-(2-oxo-3-bornylene)sulfonic acid and salts thereof.

Typical examples of particularly suitable UV-A light filters include derivatives of benzoylmethane, such as 4-tert-butyl-4′-methoxy-dibenzoylmethane, 2-(4-diethylamino-2-hydroxybenzoyl)-benzoic acid hexyl ester, 1-phenyl-3-(4′-isopropylphenyl)propane-1,3-dione, and enamine compounds. Of course, UV-A and UV-B filter substances can also be used in combination, for example, a combination of diphenylmethane derivatives and/or benzoylmethane derivatives 4-tert-butyl-4′-methoxy-dibenzoylmethane and cinnamic acid derivatives, preferably 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene) and/or 2-ethylhexyl 4-methoxycinnamate and/or isopentyl 4-methoxycinnamate and/or propyl 4-methoxycinnamate. The cinnamate derivatives of this type of combination can also be replaced by water-soluble filtering substances such as 2-phenylbenzimidazole-5-sulfonic acid and its alkali metal, alkaline earth metal, ammonium, alkylammonium, alkanol, gluconammonium salts and/or 4-(2-oxo-3-bornylidenemethyl)benzenesulfonic acid and 2-methyl-5-(2-oxo-3-bornylidene)sulfonic acid and its alkali metal, alkaline earth metal, ammonium, alkylammonium, alkanol, gluconammonium salts.

In a preferred embodiment, the (cosmetic or pharmaceutical) preparation according to the invention contains at least one additional UV-absorbing substance selected from the group consisting of:

Camphor benzalkonium methyl sulfate

·Terephthalene-dibornanesulfonic acid and salts

Homomenthyl salicylate

Benzal camphorsulfonic acid and salts

·2-Ethylhexyl 2-cyano-3,3-diphenylacrylate

·Ethyl p-aminobenzoate

Isoamyl p-methoxycinnamate

2-Phenylbenzimidazolesulfonic acid and its salts

·2,4,6-Tris(p-2-ethylhexylaniline)-1,3,5-triazine

·2-(2H-Benzotriazol-2-yl)-4-methyl-6-(2-methyl-3-(1,3,3,3-tetramethyl-1-(trimethylsilyl-oxy)-disiloxanyl)-propyl)phenol

·Methylene bis-benzotriazolyl tetramethylbutylphenol

·4,4'-[(6-[4-(1,1-dimethyl)-aminocarbonyl]phenylamino)-1,3,5-triazine-2,4-diyl]diimino]-bis-(benzoic acid 2-ethylhexyl ester)

·3-(4′-Methylbenzylidene)-D,L-camphor

·3-Benzalcamphor

·2-Ethylhexyl Salicylate

·2-Ethylhexyl 4-dimethylaminobenzoate

·4-Hydroxy-4-methoxybenzophenone-5-sulfonic acid and its salts

Benzalmalonate-polysiloxane

Menthyl anthranilate

· Polyacrylamide Methylbenzylidene Camphor

·2-Ethylhexyl methoxycinnamate

or a mixture thereof.

The compositions of the present invention, when applied to human skin, may be used concurrently with a skin lightening agent to enhance the reduction of hyperpigmentation. Suitable skin lightening agents for use in the present invention include: kojic acid derivatives (preferably kojic acid dipalmitate), arbutin, ascorbic acid and ascorbic acid derivatives (preferably magnesium ascorbyl phosphate), hydroquinone and hydroquinone derivatives, clarysol, amino acids (preferably cyclohexylcarbamates, N-acetyltyrosine and its derivatives, undecylenoylphenylalanine), sulfur-containing molecules (preferably glutathione, cysteine, thiourea derivatives, lipoic acid), α-hydroxy acids (preferably citric acid, lactic acid, malic acid, their salts and esters), gluconic acid, chromone derivatives (preferably aloesin), 1-aminoethylphosphinic acid, flavonoids, ellagic acid, niacinamide, thujacin and its derivatives, triterpenes (preferably maslinic acid), sterols (preferably ergosterol), benzofuranones (preferably ligustolide), 4-vinylguaiacol, 4-ethylguaiacol, zinc salts (preferably zinc chloride or zinc gluconate), diacids (preferably octadecenedioic acid and [0063] In some embodiments, the present invention may be used in combination with any of the following: a) 1,2-dihydro-1,2-dihydro-1,2-dihydro-2,4 ...

Example

The present invention will be described in detail below by way of examples. However, it is to be understood that the relevant examples are not intended to limit the scope of protection in any way.

In the following embodiments:

The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

The conversion and selectivity of the reaction were calculated by the following formula:

Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

Selectivity = actual molar amount of target product/theoretical molar amount of target product × 100%

Unless otherwise specified, all raw materials used are commercially available products, and the room temperature is 25±5°C.

Example 1

Under nitrogen protection, 2.17 g (0.01 mol) of diphenol compound, 20 ml of anhydrous dioxane, and 1.00 g (0.01 mol) of piperidone were added to a 100 ml reaction bottle, and NaH (0.03 mol) was slowly added at 0°C, and then the temperature was raised to 80°C for reaction for 3 hours. The temperature was lowered to 0°C, and a 10% aqueous acetic acid solution was slowly added to quench the reaction, and part of the solvent was evaporated under reduced pressure, and then extracted with ethyl acetate (10 ml x 3), concentrated, and separated and purified by silica gel column (eluted with ethyl acetate/petroleum ether mixed solvent), and the product was obtained after concentration and removal of the solvent, with a yield of 42%.

Example 2

Under nitrogen protection, 1.52g (0.01mol) of acetyl diphenol compound, 1.00g (0.01mol) of piperidone, 0.17g (0.001mol) of p-toluenesulfonic acid, and 30ml of toluene were added to a 100ml reaction bottle, equipped with a water separator and a condenser, and reacted at 110°C for 5 hours, and the solvent was directly evaporated, cooled to room temperature, and 20ml of ethanol and 5% Pd/C (0.0001mol) were added, and hydrogen was replaced 3 times, and reacted under the pressure of a hydrogen balloon, and reacted at 25°C for 3 hours. Filtered with diatomaceous earth, rinsed with ethanol, and the solvent was evaporated under reduced pressure, separated and purified by a silica gel column (eluted with a mixed solvent of ethyl acetate/petroleum ether), and the product was obtained after concentrating and removing the solvent, with a yield of 71%.

Example 3

In a 100ml reaction bottle, add 1.67g (0.01mol) of a diphenol compound with an amino group, triethylamine (0.015mol), and 30ml of dichloromethane, and then add 10ml of a dichloromethane solution of 4-chlorobutyryl chloride (1.41g, 0.01mol) dropwise at 0 degrees, and then continue to react at 25°C for 3 hours, then add 1.68g (0.03mol) of KOH and 0.32g (0.001mol) of tetrabutylammonium bromide, and continue to react at 25°C for 18 hours. Cool to 0°C, slowly add 10% acetic acid aqueous solution to quench the reaction, evaporate part of the solvent under reduced pressure, extract with ethyl acetate (10ml x 3), concentrate, separate and purify through a silica gel column (elution with a mixed solvent of ethyl acetate/petroleum ether), and concentrate to remove the solvent to obtain the product with a yield of 63%.

Example 4

In a 100ml reaction bottle, add 1.53g (0.01mol) of a diphenol compound with an amino group, triethylamine (0.015mol), and 30ml of dichloromethane, and add 10ml of a dichloromethane solution of acetyl chloride (0.79g, 0.01mol) dropwise at 0°C, and then continue to react at 25°C for 3 hours. Cool to 0°C, slowly add 10% acetic acid aqueous solution to quench the reaction, evaporate part of the solvent under reduced pressure, extract with ethyl acetate (10ml x 3), concentrate, and separate and purify through a silica gel column (elution with a mixed solvent of ethyl acetate/petroleum ether), and concentrate to remove the solvent to obtain the product with a yield of 87%.

Example 5

Under nitrogen protection, 1.53 g (0.01 mol) of a diphenol compound with an amino group, 1.00 g (0.01 mol) of succinic anhydride, 5 ml of acetic acid, and 20 ml of DMF were added to a 100 ml reaction bottle, and the mixture was reacted at 100°C for 6 hours. The solvent was evaporated under reduced pressure, and the mixture was separated and purified by a silica gel column (eluted with a mixed solvent of ethyl acetate/petroleum ether), and the product was obtained after concentration to remove the solvent, with a yield of 76%.

Example 6

Under nitrogen protection, 3.24 g (0.01 mol) of diphenol compound, 20 ml of anhydrous dioxane, and 0.85 g (0.01 mol) of pyrrolidone were added to a 100 ml reaction bottle, and NaH (0.05 mol) was slowly added at 0 degrees, and then the temperature was raised to 80°C for reaction for 3 hours, and then the temperature was lowered to 0°C, and 0.85 g (0.01 mol) of pyrrolidone was added, and then the temperature was raised to 80°C for further reaction for 3 hours. The temperature was lowered to 0°C, and a 10% aqueous acetic acid solution was slowly added to quench the reaction, and after part of the solvent was evaporated under reduced pressure, it was extracted with ethyl acetate (10 ml x3), concentrated, separated and purified by silica gel column (eluted with ethyl acetate/petroleum ether mixed solvent), and the product was obtained after concentration and removal of the solvent, with a yield of 30%.

Example 7

Under nitrogen protection, 1.94 g (0.01 mol) of diacetyl diphenol compound, 0.85 g (0.01 mol) of pyrrolidone, 0.17 g (0.001 mol) of p-toluenesulfonic acid and 30 ml of toluene were added to a 100 ml reaction bottle, equipped with a water separator and a condenser, and the reaction was carried out at 110°C for 3 hours. 0.85 g (0.01 mol) of pyrrolidone was added, and the reaction was carried out at 110°C for 3 hours. The solvent was directly evaporated, cooled to room temperature, 20 ml of ethanol and 5% Pd/C (0.0001 mol) were added, hydrogen was replaced 3 times, and the reaction was carried out under the pressure of a hydrogen balloon for 3 hours at 25°C. Filtered with diatomaceous earth, rinsed with ethanol, the solvent was evaporated under reduced pressure, separated and purified by a silica gel column (eluted with a mixed solvent of ethyl acetate/petroleum ether), and the product was obtained after concentrating and removing the solvent, with a yield of 62%.

The compounds in Tables 1-3 below were prepared by referring to the above examples.

Table 1: Compounds of structure II

Table 2: Structure III compounds

Table 3: NMR data of some compounds

Application test examples:

Cytotoxicity test

1) Cell seeding: cells were seeded into 96-well plates at a seeding density of 1×10 ⁴ cells/well and incubated overnight in an incubator (37° C., 5% CO ₂ ).

2) Experimental grouping: The experiment set up a zero adjustment group, a control group, a positive control group and a sample group. In the sample group, each sample was set with a different concentration gradient, and 3 replicate wells were set under each concentration gradient.

3) Solution preparation: Prepare sample working solutions of different concentrations according to the test concentration setting table.

4) Administration: Administration was performed when the cell plating rate in the 96-well plate reached 40% to 60%. 200 μL of culture medium containing 10% PBS (Gibco) was added to each well of the control group; 200 μL of culture medium containing 10% DMSO was added to each well of the positive control group; 200 μL of culture medium containing the corresponding concentration of sample was added to each well of the sample group; no cell inoculation was performed in the zero adjustment group, and only 200 μL of cell culture medium was added. After administration, the 96-well plate was placed in an incubator (37°C, 5% CO ₂ ) for incubation.

5) Detection: After the cells were incubated for 24 h, the supernatant was discarded, and MTT working solution (0.5 mg/mL) was added. The cells were incubated at 37° C. in the dark for 4 h. After the incubation, the supernatant was discarded, 100 μL DMSO was added to each well, and the OD value was read at 490 nm.

6) Calculation of relative cell viability:

Cell viability test data example:

*Control sample: Phenethyl resorcinol

The cell viability data showed that the compound structure of the present invention had lower cytotoxicity.

Melanin synthesis inhibition test

According to the cytotoxicity test data, the cell melanin synthesis inhibition test was carried out within the range allowed by cytotoxicity. The samples were grouped according to different concentrations, the detection index was melanin content, the detection model was melanocytes, and the colorimetric method was used for detection. Cells in the logarithmic growth phase were collected, and the cell density was 2×10 ⁵ /bottle inoculated into a 24-well plate. After culturing in an incubator (37°C, 5% CO2) for 24 hours, the drug was added according to the concentration requirements according to the cytotoxicity results, and untreated cells were used as blank controls, with 3 parallels set for each group. After adding the drug, continue to culture in an incubator (37°C, 5% CO2) for 48 hours, discard the supernatant, add 1mL of 1M NaOH containing 10% DMSO, and incubate in a 60°C constant temperature oven for 1 hour. After returning to room temperature, transfer 200 μL to each well to a 96-well plate, and use 1M NaOH containing 10% DMSO as a blank control. Read the absorbance value at 405nm and calculate the relative inhibition rate of cell melanin.

Results of cell melanin synthesis inhibition rate

*Note: PC sample is kojic acid.

The test results show that the compounds II-a, II-d, II-e, II-f, II-g, II-h, III-b, and III-c of the present invention have a cellular melanin synthesis inhibitory effect at a relatively low concentration (not exceeding 0.10% g/ml), and the selected II-a and II-d both exhibit a cellular melanin synthesis inhibitory effect that is superior to kojic acid, and can inhibit cellular melanin synthesis even at extremely low concentrations.

Antioxidant test

Prepare a Tris-HCl buffer solution (Tris, trishydroxymethylaminomethane) with a pH value of 9.1 and place it in a transparent glass bottle; add dopamine to the buffer solution to make the dopamine concentration in the solution 1 mg/ml; add a certain amount of the compound of the present invention to the buffer solution; after shaking evenly, open it and place it in the air, maintain the temperature at 25 degrees, and observe the change in the color of the solution.

Example of dopamine oxidative polymerization inhibition results:

The experimental results show that the compounds II-a, II-d, II-e, II-f, II-g, II-h, III-b, III-c, II-b, II-c, II-i, II-j, II-n, and III-f of the present invention all exhibited inhibitory effects on the reaction of dopamine oxidative polymerization to produce melanin at concentrations of 0.2 mg/ml, 1.0 mg/ml, and 2.0 mg/ml, especially at a concentration of 2.0 mg/ml, the inhibitory effect was more obvious. This indicates that the compounds of the present invention can be used as free radical scavengers, have antioxidant capacity, and can effectively inhibit the reaction pathway of oxidative polymerization to produce melanin.

The above results indicate that the compounds of the present invention have low cytotoxicity, strong tyrosinase inhibitory activity, strong ability to inhibit cell melanin synthesis and ability to inhibit the reaction of dopamine oxidative polymerization to produce melanin, and can inhibit the production of melanin in multiple pathways; the compounds of the present invention can be used alone or in combination as tyrosinase inhibitors, antioxidants for whitening in whitening cosmetics, and for preventing and treating human pigmentation diseases caused by excessive melanin, as skin and hair brighteners and inhibitors against age spots.

Although the present invention has been disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the definition of the claims.

Claims (12)

1. A compound represented by general formula I, Wherein, T is hydrogen or Wherein, R ¹ is selected from hydrogen, optionally substituted alkyl and optionally substituted arylalkyl; R ² , R ³ , R ⁴ and R ⁵ may be the same or different, and each independently selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; R ² and R ³ may be connected to the carbon atom to which they are commonly connected to form a ring, and R ⁴ and R ⁵ may be connected to the carbon atom to which they are commonly connected to form a ring; Q represents any one of the following groups represented by Q-1 to Q-6: In the formula, ^R6 is selected from hydrogen, optionally substituted alkyl, hydroxyl, optionally substituted alkoxy, or optionally substituted aryl, carboxyl or its salt, cyano, optionally substituted amide, optionally substituted ester, n is selected from a natural number of 1-6, ^A1 and ^A2 represent CH or a nitrogen atom, ^R7 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino, optionally substituted aryl, ^R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylacyl- ^COR9 , wherein ^R9 is selected from hydrogen, _C1 - _C6 alkyl or _C1 - _C6 alkoxy; Q' and Q may be the same or different, and each independently selects any one of the groups shown in Q-1 to Q-6; or a cosmetically or pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any ratio, in particular an enantiomer or a mixture of enantiomers, more particularly a racemic mixture. 2. The compound according to claim 1, characterized in that compound I is a compound of formula (II), wherein R ¹ , R ² , R ³ and Q are as defined in claim 1 . 3. The compound according to claim 1, characterized in that compound I is a compound of formula (III), wherein R ¹ to R ⁵ , Q and Q′ are as defined in claim 1 . 4. The compound according to claim 1, characterized in that compound I is a compound of formula (IIa), ^R1 and Q are as defined in claim 1, ^Z1 and ^Z2 may be the same or different, and are independently selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl. ^Z1 and ^Z2 may be connected to the carbon atom to which they are commonly connected to form a ring, and the ring may be substituted. 5. The compound according to claim 1, characterized in that compound I is a compound of formula (IIIa), wherein R ¹ , Q and Q' are as defined in claim 1; Z ¹ , Z ² , Z ³ and Z ⁴ may be the same or different and are independently selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; Z ¹ and Z ² may be linked to their common carbon atoms to form a ring; Z ³ and Z ⁴ may be linked to their common carbon atoms to form a ring; and the ring may be substituted. 6. The compound according to any one of claims 1 to 5, characterized in that it is selected from the following compounds: N-(1-(2,4-dihydroxyphenyl)ethyl)-2-pyrrolidone; N-(1-(2,4-dihydroxyphenyl)propyl)-2-pyrrolidone; N-(1-(2,4-dihydroxyphenyl)ethyl)-2-piperidone; N-(1-(2,4-dihydroxyphenyl)propyl)-2-piperidone; N-(1-(2,4-dihydroxyphenyl)ethyl)-2-cyclohexylimine ketone; N-(1-(2,4-dihydroxyphenyl)propyl)-2-cyclohexylimine ketone; 1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(ethyl-1,1-ylidene))bis(pyrrolidin-2-one); 1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(propan-1,1-ylidene))bis(pyrrolidin-2-one); 1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(ethyl-1,1-ylidene))bis(piperidin-2-one); 1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(propan-1,1-idene))bis(piperidin-2-one); 1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(ethyl-1,1-idene))bis(cycloheximide-2-one); 1,1'-((4,6-dihydroxy-1,3-phenylidene)bis(propan-1,1-ylidene))bis(cycloheximide-2-one). 7. A method for preparing a compound of formula (IIa), characterized in that the compound of formula (V) reacts with H-Q in the presence of an acid and then is reduced to obtain a compound of formula (IIa), and the synthetic route is as follows: wherein R ¹ , Z ¹ , Z ² and Q are as defined in claim 4 . 8. A method for preparing compound (IIIa), characterized in that the compound of formula (Va) reacts with H-Q in the presence of an acid to obtain an intermediate (VIa), (VIa) reacts with H-Q' in the presence of an acid to obtain an intermediate (VIb), and (VIb) is reduced to obtain the compound of formula (IIIa), and the synthetic route is as follows: wherein R ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Q and Q′ are as defined in claim 5 . 9. A composition comprising the compound according to any one of claims 1 to 6 or a cosmetically or pharmaceutically acceptable salt thereof. 10. Use of the compound according to any one of claims 1 to 6 or a substance mixture of multiple compounds of formula 1 as a free radical scavenger or antioxidant. 11. Use of a compound according to any one of claims 1 to 6 or a substance mixture of multiple compounds of formula 1 for preparing (a) a medicament for preventing browning of skin and hair, and (b) preventing age spots. 12. A cosmetic composition comprising the compound or a salt thereof according to any one of claims 1 to 6.