WO2008035904A1 - Method for processing 4-substituted benzoic acid derivatives having 3, 4-methylene- or 3,4-ethylenedioxybenzene moiety and the use of the same for antiaging cosmetics - Google Patents

Method for processing 4-substituted benzoic acid derivatives having 3, 4-methylene- or 3,4-ethylenedioxybenzene moiety and the use of the same for antiaging cosmetics Download PDF

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Publication number
WO2008035904A1
WO2008035904A1 PCT/KR2007/004519 KR2007004519W WO2008035904A1 WO 2008035904 A1 WO2008035904 A1 WO 2008035904A1 KR 2007004519 W KR2007004519 W KR 2007004519W WO 2008035904 A1 WO2008035904 A1 WO 2008035904A1
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Prior art keywords
benzoic acid
methylenedioxybenzene
acid derivatives
benzoate
backbone
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PCT/KR2007/004519
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French (fr)
Inventor
Jae Won You
Ho Sik Rho
Su Jong Kim
Jun Won Yun
Sung Yeon Ahn
Duck Hee Kim
Jun Oh Kim
Ih Seop Chang
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Amorepacific Corporation
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Publication of WO2008035904A1 publication Critical patent/WO2008035904A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin

Definitions

  • the present invention relates to a method for preparing 4-substituted benzoic acid derivatives, represented by the following formula 1 and having a 3,4- methylenedioxybenzene or 3 , 4 -ethylenedioxybenzene backbone, and to the use of the derivatives for antiaging cosmetics.
  • the present invention relates to a method for preparing 4 -substituted benzoic acid derivatives, which have a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone and show the effect of stimulating the production of collagen, elastin, fibrillin and glycosaminoglycan, which are the main constituents of the skin's dermis, and to the use of the derivatives for antiaging cosmetics, which have the effect of reducing skin wrinkles .
  • R 1 is -CH 2 - or -CH 2 CH 2 - ,
  • R 3 is H, Me or Et .
  • ECM extracellular matrix
  • collagen and elastin are degraded due to the expression of matrix metallo proteases, such as collagenase and elastase, resulting in a reduction in the content of collagen in the skin.
  • matrix metallo proteases such as collagenase and elastase
  • collagenase and elastase matrix metallo proteases
  • the epidermis will become rough, and a reduction in skin elasticity, which is an aging phenomenon, will occur.
  • a method known to be most effective is a method that uses retinol and retinoic acid.
  • retinoids such as retinol and retinoic acid
  • these retinoids have the positive effects of reducing skin wrinkles and skin elasticity, they also have a disadvantage in that, even when they are applied to the skin in small amounts, they irritate the skin.
  • the retinoids are unstable, such that they are readily oxidized upon exposure to air, there are many limitations on the use thereof. For this reason, studies focused on stabilizing the retinoids have been continually conducted, a problem of skin irritation, that is, a problem of safety, is not yet solved.
  • the present inventors have conducted studies on an effective antiaging composition and, as a result, have found that 4 -substituted benzoic acid derivatives having a 3 , 4 -methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone show an excellent effect of reducing wrinkles by stimulating the production of collagen, elastin, fibrillin and glycosaminoglycan (GAG) , which are the main constituents of the skin's dermis, thereby completing the present invention.
  • collagen, elastin, fibrillin and glycosaminoglycan (GAG) which are the main constituents of the skin's dermis, thereby completing the present invention.
  • Another object of the present invention is to provide the use of 4 -substituted benzoic acid derivatives, having a 3,4 -methylenedioxybenzene or 3 , 4 -ethylenedioxybenzene backbone, for antiaging cosmetics.
  • the present invention provides the use of 4-substituted benzoic acid derivatives, represented by the following formula 1 and having a 3,4- methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone, for antiaging cosmetics:
  • R 3 is H, Me or Et.
  • the 4 -substituted benzoic acid derivatives having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone are preferably contained in an amount of 0.01-20.00 wt% based on the total weight of an antiaging composition.
  • the inventive 4 -substituted benzoic acid derivatives having a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone stimulate the biosynthesis of collagen, elastin, fibrillin and glycosaminoglycan (GAG) , which are the main constituents of the skin's dermis, which have a close connection with skin wrinkles.
  • GAG glycosaminoglycan
  • the present invention provides a method for preparing 4-substituted benzoic acid derivatives, represented by the formula 1 and having a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, the method comprising the steps of: (A) preparing compound (1) from 3,4- methylenedioxybenzoic acid or 3 , 4-ethylenedioxybenzoic acid; and
  • step (B) hydroIyzing the compound (1) of step (A) in the presence with a base to prepare compound (2) .
  • This preparation method is shown in the following reaction scheme 1 :
  • the present invention provides a method for preparing 4-substituted benzoic acid derivatives, represented by the formula 1 and having a 3,4- methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone, the method comprising the steps of:
  • step (C) preparing compound (3) from 3,4- methylenedioxyacetophenone or 3, 4-ethylenedioxyacetophenone in the presence of a base,- and (D) esterifying the compounds of step (C) to prepare compound (4) .
  • This preparation method is shown in the following reaction scheme 2.
  • Ri is -CH 2 - or - CH 2 CH 2 -
  • R' is Me or Et.
  • the inventive method for preparing 4 -substituted benzoic acid derivatives represented by the formula 1 and having a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, is carried out either according to the reaction scheme 1 consisting of steps (A) and (B) or according to the reaction scheme 2 consisting of steps (C) and (D) .
  • Each step of the inventive preparation method will now be described in detail.
  • the preparation method according to the present invention comprises the following steps (A) and (B) and can be schematized by the above reaction scheme 1.
  • the step (A) of preparing the compounds (1) can be carried out using an acid halide method, an active ester method or an acid anhydride method.
  • the acid halide method is most preferable, because it shows high reaction yield and low byproduct formation.
  • thionyl chloride is added dropwise to dimethylformamide, the mixture is stirred for 30 minutes, and then 3, 4-methylenedioxybenzoic acid or 3,4- ethylenedioxybenzoic acid is added thereto, thus producing acyl chloride.
  • the equivalent ratio between thionyl chloride and 3 , 4-methylenedioxybenzoic acid or 3,4- ethylenedioxybenzoic acid is preferably 1:1.0-1:1.2. If the equivalent ratio is below 1:1.0, the amount of the desired product will be reduced, and if it exceeds 1:1.2, the production of byproducts will be increased due to unreacted thionyl chloride .
  • the acyl chloride thus produced is substituted with 4-aminobenzoate to prepare the compound (1) .
  • the equivalent ratio between 3,4- methylenedioxybenzoic acid or 3 , 4 -ethylenedioxybenzoic acid and 4-aminobenzoate is preferably 1:1.0-1:1.3. If the equivalent ratio is below 1:1.0, the amount of the desired product will be reduced, and if it exceeds 1:1.3, the purity and yield of the product in a purification step will be reduced due to unreacted amine .
  • reaction temperature in the step (A) is preferably about 10-40 "C . At a reaction temperature below ° C , the reaction rate will be remarkably reduced, and at a reaction temperature above 40 " C , the production of byproducts will be increased.
  • step (B) Step of hydrolyzing the compound (1) of step (A) with a base to prepare compound (2)
  • alkali metal hydroxide such as sodium hydroxide or potassium hydroxide
  • the reaction solvent in the step (B) water, methanol, ethanol, propanol, tetrahydrofuran or dichloromethane may be used, but a mixture of tetrahydrofuran and methanol is preferably used, because the reaction can be completed within the shortest time.
  • the mixing ratio between methanol and tetrahydrofuran is 1:1-1:5, and most preferably 1:1.
  • Another preparation method according to the present invention comprises the following steps (C) and (D) and can be schematized by the above reaction scheme 2.
  • step (C) Step of preparing compound (3) from 3,4- methylenedioxyacetophenone or 3, 4-ethylenedioxyacetophenone in the presence of a base
  • alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, sodium methoxide or sodium ethoxide
  • the reaction solvent in the step (C) water, methanol, ethanol, propanol, tetrahydrofuran or dichloromethane may be used, but a mixture of ethanol or methanol and water is preferably used, because the reaction can be completed within the shortest time.
  • the mixing ratio between methanol or ethanol and water is 1:1-10:1, and preferably 5:1.
  • the preparation of the compound (4) in the step (D) of the inventive preparation method can be carried out using various esterification reactions. However, it is preferable to carry out the reaction in the step (D) by adding acetyl chloride dropwise to an alcohol solvent for esterification, such as methanol or ethanol, to form anhydrous hydrochloric acid, because it shows high reaction yield and low byproduct formation.
  • an alcohol solvent for esterification such as methanol or ethanol
  • the inventive 4-substituted benzoic acid derivative of formula I 7 prepared according to the above-described method and having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, can be used as an active ingredient in an antiaging cosmetic composition.
  • the derivative compound is preferably contained in an amount effective for achieving an antiaging effect and a wrinkle- reducing effect, that is, in an amount of 0.01-20.0 wt% based on the total weight of the antiaging cosmetic composition.
  • the content of the derivative compound is less than 0.01 wt%, the desired effects cannot be obtained, and if it exceeds 20.00 wt%, the resulting cosmetic product can be denaturalized, it will not be easy to control the viscosity of the cosmetic formulation, and the production economy will be reduced.
  • the antiaging cosmetic composition may have a formulation selected from the group consisting of cream, lotion, toilet water, massage cream, and essence.
  • the composition of the present invention may contain other conventional components depending on the formulation thereof, and the kinds and contents of such conventional components are well known to those skilled in the art.
  • the inventive composition may contain, in addition to the 4- substituted benzoic acid derivatives having a 3,4- methylenedioxybenzene or 3 , 4-ethylenedioxybenzene backbone, other known antiaging components for the antiaging effect thereof, and the kinds and contents of such antiaging components are also well known to those skilled in the art.
  • Example I j methyl 4-(benzo[d] [1, 3] dioxol-5- carboxamido) benzoate To 9.3 mL (0.12 mol) of dimethylformamide, 7.1 mL
  • acyl chloride (0.12 mol) of thionyl chloride was added dropwise, and the mixture was stirred for 30 minutes. Then, 16.6 g (0.10 mol) of 3 , 4-methylenedioxybenzoic acid was added thereto, and the mixture was additionally stirred for 2 hours, thus preparing acyl chloride. 15.1 g (0.10 mol) of methyl 4- aminobenzoate and 19.9 ml (0.14 mol) of triethylamine were dissolved in 200 ml of dichloromethane, and to the solution, the above-prepared acyl chloride was slowly added dropwise at a temperature of about 20 ° C, and the mixture was stirred for 2 hours.
  • reaction solution was added dropwise to and diluted in 1000 ml of dichloromethane, and washed with 1000 ml of water, and then with 500 ml of IM HCl solution. Then, the solution was dried with 100 g of anhydrous manganese, and the dried material was filtered, concentrated, and crystallized from hexane, thus obtaining 23.6 g (79% yield) of the title compound.
  • Example 2 The process of Example 1 was repeated, except that ethyl 4-aminobenzoate was used instead of methyl 4- aminobenzoate, thus obtaining 25.7 g (82% yield) of the title compound as a wilte solid.
  • the concentrate was dissolved in 1500 ml of ethyl acetate, and the solution was washed with 1000 ml of water. The washed solution was filtered, concentrated, crystallized from hexane, and then filtered again, thus obtaining 26.5 g (93% yield) of the title compound as a white solid.
  • Example 4 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) -3-oxo- 1-propenyl) benzoic acid
  • Example 5 The process of Example 5 was repeated, except that ethanol was used instead of methanol, thus obtaining 30.4 g (91% yield) of the title compound as a yellow solid.
  • Example 2 The process of Example 1 was repeated, except that 3, 4-ethylenedioxybenzoic acid was used instead of 3,4- methylenedioxybenzoic acid, thus obtaining 24.7 g (80% yiled) of the title compound as a white solid.
  • Example 3 The process of Example 3 was repeated, except that 3,4-ethylenedioxybenzoic acid was used instead of 3,4- methylenedioxybenzoic acid, thus obtaining 19.7 g (78% yield) of the title compound as a white solid.
  • Example 10 4- ( (E) -3- (2 , 3-dihydrobenzo [b] [1, 4] dioxin- 7-yl) -3 -oxo-1-propenyl) benzoic acid
  • Example 4 The process of Example 4 was repeated, except that 3 , 4-ethylenedioxyacetophenone was used instead of 3,4- methylenedioxyacetophenone, thus obtaining 19.5 g (79% yield) of the title compound as a white solid.
  • Example 6 The process of Example 6 was repeated, except that 3, 4-ethylenedioxyacetophenone was used instead of 3,4- methylenedioxyacetophenone, thus obtaining 21.6 g (79% yield) of the title compound as a white solid.
  • 1H NMR (DMSOd 6 , ⁇ ) 10.51 (s, IH), 7.42 (d, IH), 7.17 (d, IH), 7.06 (dd, IH), 6.87 (d, IH), 6.65 (d, IH), 4.01 (m, 4H), 4.18 (q, IH), 1.24 (t, 3H).
  • Test Example 1 Procolagen biosynthesis Fibroblasts isolated from human skin were seeded into a 24 -well plate at a density of 10 6 cells/well and cultured to a confluency of about 90%. The cultured cells were incubated in serum-free medium for 24 hours, and then treated with 10 "4 M of each of the 4 -substituted benzoic acid derivatives (having a 3 , 4-methylenedioxybenzene or 3,4-ethylenedioxybenzene backbone), prepared in Examples 1 to 12 and dissolved in serum-free medium. The treated cells were incubated in a CO 2 incubator for 24 hours.
  • Fibroblasts isolated from human skin were seeded into a 24-well plate at a density of 10 6 cells/well and attached for 24 hours.
  • the attached cells were treated with 10 ⁇ M of each of the 4 -substituted benzoic acid derivatives (having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone) , prepared in Examples 1 to 12.
  • the media were harvested.
  • the contents of tropoelastin and fibrillin in the harvested media were measured using the ELISA kits corresponding to tropoelastin and fibrillin. The measurement results are shown in Table 2 below, in which the tropoelastin or fibrillin production of an untreated group is taken as 100% for comparison. [Table 2]
  • Fibroblasts isolated from human skin were seeded into a 24 -well plate at a density of 5 X 10 4 cells/well and cultured in media containing no phenol red, and 5% fetal bovine serum treated with charcoal. After 18 hours, the cells were treated with 10 ⁇ M of each of the 4 -substituted benzoic acid derivatives (having a 3,4- methylenedioxybenzene or 3 , 4-ethylenedioxybenzene backbone), prepared in Examples 1 to 12. After 18 hours, the amount of GAG secreted in each of the supernatants was measured. In the assay, the Blyscan Glycosaminoglycan assay kit (Biocolor, GB) was used.
  • the inventive 4 -substituted benzoic acid derivatives having a 3 , 4-methylenedioxybenzene or 3,4-ethylenedioxybenzene backbone stimulate the biosynthesis of collagen, elastin, fibrillin and glycosaminoglycan (GAG) , which are the main constituents of the skin's dermis, which have a close connection with skin wrinkles.
  • the inventive 4-substituted benzoic acid derivatives will be useful for the preparation of medical drugs and skin external preparations for antiaging and wrinkle reduction.

Abstract

The present invention relates to a method for preparing 4-substituted benzoic acid derivatives having a 3, 4-methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone, and the use of the derivatives for antiaging cosmetics. More particularly, the invention relates to a method for preparing 4-substituted benzoic acid derivatives, which have a 3, 4-methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone and show the effect of stimulating the production of collagen, elastin, fibrillin and glycosaminoglycan, which are the main constituents of the skin's dermis, and to the use of the derivatives for antiaging cosmetics, which have the effect of reducing skin wrinkles.

Description

[DESCRIPTION]
[invention Title]
Method for processing 4 -substituted benzoic acid derivatives having 3, 4 -methylene- or 3,4- ethylenedioxybenzene moiety and the use of the same for antiaging cosmetics
[Technical Field]
The present invention relates to a method for preparing 4-substituted benzoic acid derivatives, represented by the following formula 1 and having a 3,4- methylenedioxybenzene or 3 , 4 -ethylenedioxybenzene backbone, and to the use of the derivatives for antiaging cosmetics. More particularly, the present invention relates to a method for preparing 4 -substituted benzoic acid derivatives, which have a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone and show the effect of stimulating the production of collagen, elastin, fibrillin and glycosaminoglycan, which are the main constituents of the skin's dermis, and to the use of the derivatives for antiaging cosmetics, which have the effect of reducing skin wrinkles . [Formula 1]
Figure imgf000002_0001
wherein R1 is -CH2 - or -CH2CH2- ,
0 0 H and
R3 is H, Me or Et .
[Background Art] All living organisms age, and the skin also ages. Efforts to delay aging have been continually made, and thus questions about what is the nature of aging and why aging occurs have been continually addressed. Skin aging can be classified, according to the cause, into two main categories: intrinsic aging which refers to continuous changes in the structure and physiological function of the skin, which occur with increasing age; and extrinsic aging which occurs due to external stresses such as sunlight. The intrinsic aging or the extrinsic aging is accompanied with structural changes in the skin, resulting in a decrease in skin elasticity and the formation of wrinkles.
In the structural changes in the skin, which occur due to aging, the thickness of the epidermal, dermal and subcutaneous, which are the constituents of the skin, is reduced. Also, the extracellular matrix (ECM) component of dermal tissue, which plays a role in the elasticity and tension of the skin, is changed. ECM consists of two main components: elastic fiber accounting for about 2-4 % of ECM, and collagen accounting for about 70-80% of ECM. As aging progresses, the elasticity of the skin is greatly reduced due to the reduction of collagen and elastin. Such collagen and elastin are regulated by various factors. For example, collagen and elastin are degraded due to the expression of matrix metallo proteases, such as collagenase and elastase, resulting in a reduction in the content of collagen in the skin. When collagen and elastin in the dermis are reduced, the epidermis will become rough, and a reduction in skin elasticity, which is an aging phenomenon, will occur. For this reason, various studies on methods for effectively inhibiting the reduction of collagen and elastin have been conducted. A method known to be most effective is a method that uses retinol and retinoic acid. The wrinkle reduction and elasticity improvement effects of retinoids, such as retinol and retinoic acid, are well known in the literature (Dermatology therapy, 1998, 16, pp. 357-364) . Although these retinoids have the positive effects of reducing skin wrinkles and skin elasticity, they also have a disadvantage in that, even when they are applied to the skin in small amounts, they irritate the skin. Also, because the retinoids are unstable, such that they are readily oxidized upon exposure to air, there are many limitations on the use thereof. For this reason, studies focused on stabilizing the retinoids have been continually conducted, a problem of skin irritation, that is, a problem of safety, is not yet solved.
As a substitute for said method, it has been suggested to inhibit the activities of collagenase, elastase and matrix metallo protease, which enzymes degrading collagen and elastin, and studies on inhibitors capable of inhibiting the activities of such enzymes have been actively conducted. Inhibiting the activities of such enzymes is greatly helpful in antiaging, but there is a limitation in reducing wrinkles only through the inhibition of the enzymes activities. For this reason, attempts to reduce wrinkles by stimulating the production of not only collagen and elastin, that are the main constituents of the skin's dermis, but also glycoseaminoglycan (GAG), have been actively made, and interest in compounds capable of stimulating the production of collagen, elastin and glycoseaminoglycan (GAG) has increased.
Meanwhile, in the first half of the 1970s, 4- substituted benzoic acid derivatives, represented by the following formula 2 and having a 3 , 4 -methylenedioxybenzene backbone, was reported (US Patent No. 3,931,153). However, the 4 -substituted benzoic acid derivatives having a 3,4- methylenedioxybenzene backbone were partially substituted to make the structure of efficacious compounds, and studies on the efficacy of 4 -substituted benzoic acid derivatives have not been conducted. [Formula 2]
Figure imgf000005_0001
[Disclosure]
[Technical Problem]
Accordingly, the present inventors have conducted studies on an effective antiaging composition and, as a result, have found that 4 -substituted benzoic acid derivatives having a 3 , 4 -methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone show an excellent effect of reducing wrinkles by stimulating the production of collagen, elastin, fibrillin and glycosaminoglycan (GAG) , which are the main constituents of the skin's dermis, thereby completing the present invention.
Therefore, it is an object of the present invention to provide a method for preparing 4 -substituted benzoic acid derivatives having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone .
Another object of the present invention is to provide the use of 4 -substituted benzoic acid derivatives, having a 3,4 -methylenedioxybenzene or 3 , 4 -ethylenedioxybenzene backbone, for antiaging cosmetics.
[Technical Solution]
To achieve the above objects, the present invention provides the use of 4-substituted benzoic acid derivatives, represented by the following formula 1 and having a 3,4- methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone, for antiaging cosmetics:
Figure imgf000006_0001
R3 is H, Me or Et.
In the present invention, the 4 -substituted benzoic acid derivatives having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone are preferably contained in an amount of 0.01-20.00 wt% based on the total weight of an antiaging composition. [Advantageous Effects] The inventive 4 -substituted benzoic acid derivatives having a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone stimulate the biosynthesis of collagen, elastin, fibrillin and glycosaminoglycan (GAG) , which are the main constituents of the skin's dermis, which have a close connection with skin wrinkles.
[Best Mode] The present invention provides a method for preparing 4-substituted benzoic acid derivatives, represented by the formula 1 and having a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, the method comprising the steps of: (A) preparing compound (1) from 3,4- methylenedioxybenzoic acid or 3 , 4-ethylenedioxybenzoic acid; and
(B) hydroIyzing the compound (1) of step (A) in the presence with a base to prepare compound (2) . This preparation method is shown in the following reaction scheme 1 :
[Reaction Scheme 1]
Figure imgf000007_0001
In another embodiment, the present invention provides a method for preparing 4-substituted benzoic acid derivatives, represented by the formula 1 and having a 3,4- methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone, the method comprising the steps of:
(C) preparing compound (3) from 3,4- methylenedioxyacetophenone or 3, 4-ethylenedioxyacetophenone in the presence of a base,- and (D) esterifying the compounds of step (C) to prepare compound (4) . This preparation method is shown in the following reaction scheme 2.
[Reaction Scheme 2]
Figure imgf000008_0001
In the above reaction schemes 1 and 2, Ri is -CH2- or - CH2CH2-, and R' is Me or Et.
Hereinafter, the present invention will be described in further detail.
The inventive method for preparing 4 -substituted benzoic acid derivatives, represented by the formula 1 and having a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, is carried out either according to the reaction scheme 1 consisting of steps (A) and (B) or according to the reaction scheme 2 consisting of steps (C) and (D) . Each step of the inventive preparation method will now be described in detail.
The preparation method according to the present invention comprises the following steps (A) and (B) and can be schematized by the above reaction scheme 1.
(A) Step of preparing compound (1) from 3,4- methylenedioxybenzoic acid or ethylenedioxybenzoic acid
In the preparation method of the present invention, the step (A) of preparing the compounds (1) can be carried out using an acid halide method, an active ester method or an acid anhydride method. Among these methods, the acid halide method is most preferable, because it shows high reaction yield and low byproduct formation. In the acid halide method, thionyl chloride is added dropwise to dimethylformamide, the mixture is stirred for 30 minutes, and then 3, 4-methylenedioxybenzoic acid or 3,4- ethylenedioxybenzoic acid is added thereto, thus producing acyl chloride. Herein, the equivalent ratio between thionyl chloride and 3 , 4-methylenedioxybenzoic acid or 3,4- ethylenedioxybenzoic acid is preferably 1:1.0-1:1.2. If the equivalent ratio is below 1:1.0, the amount of the desired product will be reduced, and if it exceeds 1:1.2, the production of byproducts will be increased due to unreacted thionyl chloride . The acyl chloride thus produced is substituted with 4-aminobenzoate to prepare the compound (1) . Herein, the equivalent ratio between 3,4- methylenedioxybenzoic acid or 3 , 4 -ethylenedioxybenzoic acid and 4-aminobenzoate is preferably 1:1.0-1:1.3. If the equivalent ratio is below 1:1.0, the amount of the desired product will be reduced, and if it exceeds 1:1.3, the purity and yield of the product in a purification step will be reduced due to unreacted amine . As the base in the step
(A) of the inventive preparation method, pyridine or triethylamine may be used. Preferably, triethylamine is used. The reaction temperature in the step (A) is preferably about 10-40 "C . At a reaction temperature below °C , the reaction rate will be remarkably reduced, and at a reaction temperature above 40 "C , the production of byproducts will be increased.
(B) Step of hydrolyzing the compound (1) of step (A) with a base to prepare compound (2) As the base in the step (B) of the inventive preparation method, alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, may be used. As the reaction solvent in the step (B) , water, methanol, ethanol, propanol, tetrahydrofuran or dichloromethane may be used, but a mixture of tetrahydrofuran and methanol is preferably used, because the reaction can be completed within the shortest time. The mixing ratio between methanol and tetrahydrofuran is 1:1-1:5, and most preferably 1:1.
Another preparation method according to the present invention comprises the following steps (C) and (D) and can be schematized by the above reaction scheme 2.
(C) Step of preparing compound (3) from 3,4- methylenedioxyacetophenone or 3, 4-ethylenedioxyacetophenone in the presence of a base As the base in the step (C) of the inventive preparation method, alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, sodium methoxide or sodium ethoxide may be used. As the reaction solvent in the step (C) , water, methanol, ethanol, propanol, tetrahydrofuran or dichloromethane may be used, but a mixture of ethanol or methanol and water is preferably used, because the reaction can be completed within the shortest time. The mixing ratio between methanol or ethanol and water is 1:1-10:1, and preferably 5:1. (D) Step of esterifying the compound (3) of step (C) to prepare compound (4)
The preparation of the compound (4) in the step (D) of the inventive preparation method can be carried out using various esterification reactions. However, it is preferable to carry out the reaction in the step (D) by adding acetyl chloride dropwise to an alcohol solvent for esterification, such as methanol or ethanol, to form anhydrous hydrochloric acid, because it shows high reaction yield and low byproduct formation. Specific examples of the 4 -substituted benzoic acid derivatives of formula 1, which have a 3,4- methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone and are prepared according to the preparation method shown in the above reaction scheme 1 or 2 are as follows: methyl 4- (benzo [d] [1, 3] dioxol-5-carboxamido) benzoate; ethyl 4- (benzo [d] [1, 3] dioxol-5-carboxamido) benzoate;
4- (benzo [d] [1, 3] dioxol-5-carboxamido) benzoic acid;
4- ( (E) -3- (benzofd] [1,3] dioxol-6-yl) -3-oxo-l- propenyl) benzoic acid; methyl 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) -3-oxo-l- propenyl) benzoate ; and ethyl 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) -3-oxo-l- propenyl) benzoate .
Specific examples of the 4 -substituted benzoic acid derivatives of formula 1, which have a 3,4- methylenedioxybenzene or 3 , 4-ethylenedioxybenzene backbone and are prepared according to the above-described preparation method are as follows: methyl 4- (2 , 3-dihydrobenzo [b] [1, 4] dioxin-6- carboxamido) benzoate ; ethyl 4- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6- carboxamido) benzoate ;
4- (2, 3-dihydrobenzo [bj [1,4] dioxin-6- carboxamido) benzoic acid; 4- ( (E) -3- (2, 3-dihydrobenzo [b] [1, 4] dioxin-7-yl) -3-oxo- 1-propenyl) benzoic acid; methyl 4- ( (E) -3- (2, 3-dihydrobenzo [b] [1, 4] dioxin-7- yl) -3 -oxo-1-propenyl) benzoate; and ethyl 4- ( (E) -3- (2, 3-dihydrobenzo [b] [1,4] dioxin-7-yl) - 3 -oxo-1-propenyl) benzoate .
The inventive 4-substituted benzoic acid derivative of formula I7 prepared according to the above-described method and having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, can be used as an active ingredient in an antiaging cosmetic composition. The derivative compound is preferably contained in an amount effective for achieving an antiaging effect and a wrinkle- reducing effect, that is, in an amount of 0.01-20.0 wt% based on the total weight of the antiaging cosmetic composition. If the content of the derivative compound is less than 0.01 wt%, the desired effects cannot be obtained, and if it exceeds 20.00 wt%, the resulting cosmetic product can be denaturalized, it will not be easy to control the viscosity of the cosmetic formulation, and the production economy will be reduced.
The antiaging cosmetic composition may have a formulation selected from the group consisting of cream, lotion, toilet water, massage cream, and essence. Also, the composition of the present invention may contain other conventional components depending on the formulation thereof, and the kinds and contents of such conventional components are well known to those skilled in the art. The inventive composition may contain, in addition to the 4- substituted benzoic acid derivatives having a 3,4- methylenedioxybenzene or 3 , 4-ethylenedioxybenzene backbone, other known antiaging components for the antiaging effect thereof, and the kinds and contents of such antiaging components are also well known to those skilled in the art.
[Mode for Invention] Hereinafter, the inventive 4 -substituted benzoic acid derivatives having a 3 , 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone will be described in further detail with reference to the following examples and test examples. It is to be understood, however, that these examples and test examples are illustrative only, and the scope of the present invention is not limited thereto.
Example Ij methyl 4-(benzo[d] [1, 3] dioxol-5- carboxamido) benzoate To 9.3 mL (0.12 mol) of dimethylformamide, 7.1 mL
(0.12 mol) of thionyl chloride was added dropwise, and the mixture was stirred for 30 minutes. Then, 16.6 g (0.10 mol) of 3 , 4-methylenedioxybenzoic acid was added thereto, and the mixture was additionally stirred for 2 hours, thus preparing acyl chloride. 15.1 g (0.10 mol) of methyl 4- aminobenzoate and 19.9 ml (0.14 mol) of triethylamine were dissolved in 200 ml of dichloromethane, and to the solution, the above-prepared acyl chloride was slowly added dropwise at a temperature of about 20 °C, and the mixture was stirred for 2 hours. After completion of the reaction, the reaction solution was added dropwise to and diluted in 1000 ml of dichloromethane, and washed with 1000 ml of water, and then with 500 ml of IM HCl solution. Then, the solution was dried with 100 g of anhydrous manganese, and the dried material was filtered, concentrated, and crystallized from hexane, thus obtaining 23.6 g (79% yield) of the title compound.
1H NMR (DMSO-ds, δ): 10.38 (s, IH), 7.86 (m, 4H)7 7.57 (d, IH), 7.50 (s, IH), 7.05 (d, IH), 6.17 (s, 2H), 3.82 (S, 3H) .
Example 2j Ethyl 4 - (benzo [d] [ 1 , 3 ] dioxol - 5 - carboxamido) benzoate
The process of Example 1 was repeated, except that ethyl 4-aminobenzoate was used instead of methyl 4- aminobenzoate, thus obtaining 25.7 g (82% yield) of the title compound as a wilte solid.
1H NMR (DMSO-d6, δ) : 10.35 (s, IH), 7.82 (m, 4H), 7.57 (d, IH), 7.48 (s, IH), 7.05 (d, IH), 6.15 (s, 2H), 4.26 (q, 2H) , 1.36(t, 3H) .
Example 3j 4 - (benzo [d] [1 , 3] dioxol -5 - carboxamido) benzoic acid
29 . 9 g ( 0 . 10 mol ) of the methyl 4 - (benzo [d] [1, 3] dioxol-5-carboxamido) benzoate compound of Example 1 or 29.9 g (0.10 mol) of the ethyl 4- (benzo [d] [1, 3] dioxol-5-carboxamido) benzoate compound of Example 2 was dissolved in 500 ml of a mixed solvent of tetrahydrofuran and methanol (1:1), and then 30 ml of 15% potassium hydroxide was added thereto, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was neutralized with an acid and concentrated. The concentrate was dissolved in 1500 ml of ethyl acetate, and the solution was washed with 1000 ml of water. The washed solution was filtered, concentrated, crystallized from hexane, and then filtered again, thus obtaining 26.5 g (93% yield) of the title compound as a white solid.
1H NMR (DMSO-d6, δ) : 10.38 (s, IH), 7.88 (m, 4H), 7.58 (d, IH), 7.53 (s, IH), 7.03 (d, IH), 6.16 (s, 2H).
Example 4: 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) -3-oxo- 1-propenyl) benzoic acid
16.4 g (0.10 mol) of 3 , 4-methylenedioxyacetophenone and (16.4 g (0.10 mol) of methyl 4-formylbenzoate were dissolved in 300 ml of ethanol, and then 100 ml of IN HCl aqueous solution was added thereto, and the mixture was stirred for 6 hours. After completion of the reaction, IN hydrochloric acid was added to the reaction solution, until the reaction solution reached a pH of 2. The produced solid was filtered, thus obtaining 22.5 g (76% yield) of the title compound as a light yellow solid.
1H NMR (DMSO-d6, δ): 8.07 (d, IH), 7.98 (m, 4H), 7.89 (d, IH), 7.73 (d, IH), 7.14 (d, IH), 6.19 (s, 2H).
Example 5: Methyl 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6- yl) -3-oxo-l-propenyl) benzoate
7.1 mL (0.10 mol) of acetyl chloride was slowly added dripwise to 300 ml of methanol, and the mixture was stirred for 10 minutes. To the stirred solution, 29.6 g (0.10 mol) of 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) -3-oxo-l- propenyl) benzoic acid was added, and the mixture solution was refluxed for 3 hours. After completion of the reaction, about 70% of the solvent was removed by vacuum distillation, and the residue was recrystallized from hexane, thus obtaining 30.2 g (93% yield) of the title compound as a yellow solid.
1H NMR (DMSO-d6, δ): 10.46 (s, IH), 7.38 (d, IH), 7.21 (d, IH), 7.02 (dd, IH), 6.85 (d, IH), 6.60 (d, IH), 6.04 (s, 2H) , 3.87 (s, 3H) .
Example 6: Ethyl 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) - 3-oxo-l-propenyl) benzoate
The process of Example 5 was repeated, except that ethanol was used instead of methanol, thus obtaining 30.4 g (91% yield) of the title compound as a yellow solid.
1H NMR (DMSOd6, δ): 10.51 (s, IH), 7.42 (d, IH), 7.17 (d, IH), 7.06 (dd, IH), 6.87 (d, IH), 6.65 (d, IH), 5.98 (s, 2H), 4.18 (q, IH), 1.24 (t, 3H).
Example 7: Methyl 4- (2, 3-dihydrobenzo [b] [l,4]dioxin- 6-carboxamido) benzoate
The process of Example 1 was repeated, except that 3, 4-ethylenedioxybenzoic acid was used instead of 3,4- methylenedioxybenzoic acid, thus obtaining 24.7 g (80% yiled) of the title compound as a white solid.
1H NMR (DMSO-ds, δ) : 10.38 (s, IH), 7.86 (m, 4H), 7.57 (d, IH), 7.50 (s, IH), 7.05 (d, IH), 4.42 (m, 4H), 3.82 (s, 3H) .
Example 8: Ethyl 4- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6- carboxamido) benzoate
The process of Example 2 was repeated, except that
3, 4-ethylenedioxybenzoic acid was used instead of 3,4- methylenedioxybenzoic acid, thus obtaining 21.7 g (81% yiled) of the title compound as a white solid.
1H NMR (DMSO-d6, δ): 10.35 (s, IH), 7.82 (in, 4H),
7.57 (d, IH), 7.48 (s, IH), 7.05 (d, IH), 4.45 (m, 4H), 4.26 (g, 2H) , 1.36 (t, 3H) .
Example 9j 4- (2, 3-dihydrobenzo [b] [1,4] dioxin-6- carboxamido) benzoic acid
The process of Example 3 was repeated, except that 3,4-ethylenedioxybenzoic acid was used instead of 3,4- methylenedioxybenzoic acid, thus obtaining 19.7 g (78% yield) of the title compound as a white solid.
1H NMR (DMSOd6, δ): 10.38 (s, IH), 7.88 (m, 4H),
7.58 (d, IH), 7.53 (s, IH), 7.03 (d, IH), 4.44 (m, 4H).
Example 10: 4- ( (E) -3- (2 , 3-dihydrobenzo [b] [1, 4] dioxin- 7-yl) -3 -oxo-1-propenyl) benzoic acid
The process of Example 4 was repeated, except that 3 , 4-ethylenedioxyacetophenone was used instead of 3,4- methylenedioxyacetophenone, thus obtaining 19.5 g (79% yield) of the title compound as a white solid.
1H NMR (DMSOd6, δ): 8.07 (d, IH), 7.98 (m, 4H), 7.89 (d, IH), 7.73 (d, IH), 7.14 (d, IH), 4.42 (m, 4H).
Example 1I1J methyl 4- ( (E) -3- (2,3- dihydrobenzo [b] [1, 4] dioxin-7-yl) -3 -oxo-1-propenyl) benzoate
The process of Example 5 was repeated, except that
3 , 4-ethylenedioxyacetophenone was used instead of 3,4- methylenedioxyacetophenone, thus obtaining 25.7 g (81% yield) of the title compound as a white solid. 1H NMR (DMSO-dg, δ) : 10.46 (s, IH), 7.38 (d, IH), 7.21 (d, IH) , 7.02 (dd, IH) , 6.85 (d, IH) , 6.60 (d, IH) , 4.40 (m, 4H) , 3.87 (s, 3H) .
Example 12j Ethyl 4- ( (E) -3- (2,3- dihydrobenzo [b] [1, 4] dioxin-7-yl) -3 -oxo-1-property1) benzoate
The process of Example 6 was repeated, except that 3, 4-ethylenedioxyacetophenone was used instead of 3,4- methylenedioxyacetophenone, thus obtaining 21.6 g (79% yield) of the title compound as a white solid. 1H NMR (DMSOd6, δ) : 10.51 (s, IH), 7.42 (d, IH), 7.17 (d, IH), 7.06 (dd, IH), 6.87 (d, IH), 6.65 (d, IH), 4.01 (m, 4H), 4.18 (q, IH), 1.24 (t, 3H).
Test Example 1: Procolagen biosynthesis Fibroblasts isolated from human skin were seeded into a 24 -well plate at a density of 106 cells/well and cultured to a confluency of about 90%. The cultured cells were incubated in serum-free medium for 24 hours, and then treated with 10"4 M of each of the 4 -substituted benzoic acid derivatives (having a 3 , 4-methylenedioxybenzene or 3,4-ethylenedioxybenzene backbone), prepared in Examples 1 to 12 and dissolved in serum-free medium. The treated cells were incubated in a CO2 incubator for 24 hours. The supernatants of the culture media were collected, and the content of procollagen in each of the culture media was measured using the Procollagen type 1 Elisa kit. The measurement results are shown in Table 1 below, in which the collagen biosynthesis of an untreated group is taken as 100% for comparison. [Table l]
Figure imgf000019_0001
As can be seen in Table 1 above, the 4 -substituted benzoic acid derivatives having a 3, 4-methylenedioxybenzene or 3, 4-ethylenedioxybenzene backbone showed the effect of increasing collagen biosynthesis.
Test Example 2 : Measurement of production of tropoelastin and fibrillin
Fibroblasts isolated from human skin were seeded into a 24-well plate at a density of 106 cells/well and attached for 24 hours. The attached cells were treated with 10 μM of each of the 4 -substituted benzoic acid derivatives (having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone) , prepared in Examples 1 to 12. After 2 days, the media were harvested. The contents of tropoelastin and fibrillin in the harvested media were measured using the ELISA kits corresponding to tropoelastin and fibrillin. The measurement results are shown in Table 2 below, in which the tropoelastin or fibrillin production of an untreated group is taken as 100% for comparison. [Table 2]
Figure imgf000020_0001
As can be seen in Table 2 above, the 4 -substituted benzoic acid derivatives having a 3 , 4-methylenedioxybenzene or 3 , 4-ethylenedioxybenzene backbone showed the effect of increasing the production of elastin and fibrillin.
Test Example 3: Measurement of production of glycoseaminoglycan (GAG)
Fibroblasts isolated from human skin were seeded into a 24 -well plate at a density of 5 X 104 cells/well and cultured in media containing no phenol red, and 5% fetal bovine serum treated with charcoal. After 18 hours, the cells were treated with 10 μM of each of the 4 -substituted benzoic acid derivatives (having a 3,4- methylenedioxybenzene or 3 , 4-ethylenedioxybenzene backbone), prepared in Examples 1 to 12. After 18 hours, the amount of GAG secreted in each of the supernatants was measured. In the assay, the Blyscan Glycosaminoglycan assay kit (Biocolor, GB) was used. In the GAG measurement, 1,9- dimethyl methylene blue having (+) charges was bound to sulfated GAG and proteoglycan to form a precipitate, which was then dissolved and quantified. The measurement results are shown in Table 3 below, in which the GAG production of an untreated group is taken as 100% for comparison. [Table 3]
Figure imgf000021_0001
As can be seen in Table 3 above, the 4 -substituted benzoic acid derivatives having a 3 , 4-methylenedioxybenzene or 3 , 4-ethylenedioxybenzene backbone showed the effect of increasing the biosynthesis of GAG. [industrial Applicability]
As described above, the inventive 4 -substituted benzoic acid derivatives having a 3 , 4-methylenedioxybenzene or 3,4-ethylenedioxybenzene backbone stimulate the biosynthesis of collagen, elastin, fibrillin and glycosaminoglycan (GAG) , which are the main constituents of the skin's dermis, which have a close connection with skin wrinkles. Thus, the inventive 4-substituted benzoic acid derivatives will be useful for the preparation of medical drugs and skin external preparations for antiaging and wrinkle reduction.

Claims

[CLAIMS] [Claim l] An antiaging cosmetic composition, containing 4- substitited benzoic acid derivatives, represented by the following formula 1 and having a 3 , 4-methylenedioxybenzene or 3 , 4 -methylenedioxybenzene backbone : :
[Formula 1]
Figure imgf000023_0001
wherein Ri is -CH2- or -CH2CH2-,
K2 = L ^ or ^A^
H , and
R3 is H, Me or Et.
[Claim 2]
The antiaging cosmetic composition of Claim 1, wherein the 4-substitited benzoic acid derivatives of formula 1 are selected from the group consisting of the following compounds: methyl 4-(benzo[d] [1, 3] dioxol-5-carboxamido) benzoate; ethyl 4-(benzo[d] [1, 3] dioxol-5-carboxamido) benzoate; 4-(benzo[d] [1, 3] dioxol-5-carboxamido) benzoic acid;
4- ( (E) -3- (benzo[d] [1, 3] dioxol-6-yl) -3-oxo-l- propenyl) benzoic acid; methyl 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) -3-oxo-l- propenyl) benzoate ; ethyl 4- ( (E) -3- (benzo [d] [1, 3] dioxol-6-yl) -3-oxo-l- propenyl) benzoate ; methyl 4- (2 , 3-dihydrobenzo [b] [1, 4] dioxin-6- carboxamido) benzoate ; ethyl 4- (2, 3-dihydrobenzo [b] [1, 4] dioxin-6- carboxaraido) benzoate;
4- (2, 3-dihydrobenzo [b] [1,4] dioxin-6- carboxamido) benzoic acid;
4- ( (E) -3- (2 , 3-dihydrobenzo [b] [1,4] dioxin-7-yl) -3-oxo- 1-propenyl) benzoic acid; methyl 4- ( (E) -3- (2, 3-dihydrobenzo [b] [1, 4] dioxin-7- yl) -3 -oxo-1-propenyl) benzoate; and ethyl 4- ( (E) -3- (2, 3-dihydrobenzo [b] [1, 4] dioxin-7-yl) - 3 -oxo-1-propenyl) benzoate .
[Claim 3]
The antiaging cosmetic composition of Claim 1, wherein the 4 -substituted benzoic acid derivatives are contained in an amount of 0.01-20.00 wt% based on the total weight of the composition.
[Claim 4]
The antiaging cosmetic composition of Claim 1, which has a formulation selected from the group consisting of cream, lotion, toilet water, massage cream and essence.
[Claim 5]
A method for preparing 4 -substituted benzoic acid derivatives having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, wherein the method is carried out according to the following reaction scheme 1 and comprises the steps of:
(A) preparing compound (1) from 3,4- methylenedioxybenzoic acid or 3 , 4-ethylenedioxybenzoic acid; and (B) hydrolyzing the compound (1) of step (A) with a base to prepare compound (2 ) : [Reaction Scheme 1]
Figure imgf000025_0001
wherein R1 is -CH2- or -CH2CH2-, and R' is Me or Et.
[Claim 6]
A method for preparing 4-substituted benzoic acid derivatives having a 3, 4-methylenedioxybenzene or 3,4- ethylenedioxybenzene backbone, wherein the method is carried out according to the following reaction scheme 2 and comprises the steps of:
(C) preparing compound (3) from 3,4- methylenedioxyacetophenone or 3, 4-ethylenedioxyacetophenone in the presence of a base; and
(D) esterifying the compound of step (C) to prepare compound (4) :
[Reaction Scheme 2]
Figure imgf000025_0002
wherein Ri is -CH2- or -CH2CH2-, and R' is Me or Et.
[Claim 7] Use of 4-substitited benzoic acid derivatives, represented by the following formula 1 and having a 3,4- methylenedioxybenzene or 3, 4-methylenedioxybenzene backbone, for antiaging: [Formula 1]
Figure imgf000026_0001
wherein Rx is -CH, - or - CH2CH2 - ,
0 °
H , and
R3 is H, Me or Et. [Claim 8]
Use of 4-substitited benzoic acid derivatives, represented by the following formula 1 and having a 3,4- methylenedioxybenzene or 3 , 4 -methylenedioxybenzene backbone , for wrinkle reduction: [Formula 1]
Figure imgf000026_0002
wherein Ri is -CH2- or -CH2CH2-,
Figure imgf000026_0003
R3 is H, Me or Et.
PCT/KR2007/004519 2006-09-19 2007-09-18 Method for processing 4-substituted benzoic acid derivatives having 3, 4-methylene- or 3,4-ethylenedioxybenzene moiety and the use of the same for antiaging cosmetics WO2008035904A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8779001B2 (en) 2008-06-04 2014-07-15 The United States of America National Institute of Health (NIH) Stat3 inhibitors
CN111315377A (en) * 2017-08-02 2020-06-19 赫赛德生物有限公司 Composition for anti-aging or regenerating skin comprising pyrrole acid as active ingredient
CN114456143A (en) * 2022-02-23 2022-05-10 北京丰帆生物医药科技有限公司 uPA inhibitor and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931153A (en) * 1972-12-08 1976-01-06 Bayer Aktiengesellschaft Penicillins
JPH08175959A (en) * 1994-12-27 1996-07-09 Kao Corp Skin cosmetic
JPH10265340A (en) * 1997-03-26 1998-10-06 Shiseido Co Ltd Composition for head containing methylenedioxybenzene ring-aliphatic compound

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57106677A (en) 1980-12-22 1982-07-02 Kureha Chem Ind Co Ltd N-(3,4-methylenedioxybenzylidene) aminomethylcyclohexane-carboxylic acid, and salt of said carboxylic acid
JP2003095951A (en) 2001-09-25 2003-04-03 Sumitomo Pharmaceut Co Ltd Therapeutic agent for rheumatoid arthritis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931153A (en) * 1972-12-08 1976-01-06 Bayer Aktiengesellschaft Penicillins
JPH08175959A (en) * 1994-12-27 1996-07-09 Kao Corp Skin cosmetic
JPH10265340A (en) * 1997-03-26 1998-10-06 Shiseido Co Ltd Composition for head containing methylenedioxybenzene ring-aliphatic compound

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8779001B2 (en) 2008-06-04 2014-07-15 The United States of America National Institute of Health (NIH) Stat3 inhibitors
CN111315377A (en) * 2017-08-02 2020-06-19 赫赛德生物有限公司 Composition for anti-aging or regenerating skin comprising pyrrole acid as active ingredient
EP3662907A4 (en) * 2017-08-02 2021-03-31 Hesed Bio Co., Ltd. Anti-aging or skin-regenerating composition comprising piperonylic acid as effective ingredient
US11439577B2 (en) 2017-08-02 2022-09-13 Hesed Bio Co., Ltd. Anti-aging or skin-regenerating composition comprising piperonylic acid as effective ingredient
CN111315377B (en) * 2017-08-02 2024-04-02 赫赛德生物有限公司 Anti-aging or skin regenerating composition containing pyrrole acid as active ingredient
CN114456143A (en) * 2022-02-23 2022-05-10 北京丰帆生物医药科技有限公司 uPA inhibitor and preparation method and application thereof
CN114456143B (en) * 2022-02-23 2023-08-15 北京丰帆生物医药科技有限公司 uPA inhibitor and its preparation method and application

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