WO2009014343A2 - Ascorbic acid derivatives having alpha-lipoyl groups and process for preparing the same - Google Patents

Ascorbic acid derivatives having alpha-lipoyl groups and process for preparing the same Download PDF

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WO2009014343A2
WO2009014343A2 PCT/KR2008/004182 KR2008004182W WO2009014343A2 WO 2009014343 A2 WO2009014343 A2 WO 2009014343A2 KR 2008004182 W KR2008004182 W KR 2008004182W WO 2009014343 A2 WO2009014343 A2 WO 2009014343A2
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group
ascorbic acid
lipoyl
formula
compound
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PCT/KR2008/004182
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French (fr)
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WO2009014343A3 (en
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Chul Hwan Kim
Chan Jae Shin
Jin Gab Oh
Seung Hak Ko
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Biogenics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid

Definitions

  • the present invention relates to an ascorbic acid derivative having an ⁇ -lipoyl group and a process for preparing the same.
  • compositions and/or cosmetic compositions include various antioxidants.
  • a variety of compounds such as ⁇ -lipoic acid, coenzyme Q10, ⁇ -tocopherol, retinol, glutathione, ascorbic acid, butylated hydroxy toluene, genistein, quercetin, propyl gallate, epigallocatechin gallate, gallocatechin gallate, sylibin, diosmetin, kaempferol, epicatechin, and galangin are known as antioxidants.
  • Ascorbic acid which is widely used as an antioxidant has a structure similar to that of Y-lactone. Due to its structure, ascorbic acid sensitively reacts with environmental factors such as air, particularly oxygen, heat, and light to be easily decomposed.
  • a method of adding an anti-oxidizing agent a method of stabilizing ascorbic acid in a multi-lamellar emulsion, a method of stabilizing ascorbic acid in an oil in water type emulsion, and a method of inhibiting oxidization of ascorbic acid using zinc sulfate and L-tyrosine have been reported (U.S. Patent No. 4,938,969, European Patent Publication No. 533,667 B1 , etc.).
  • ascorbic acid is chemically modified into a derivative such as sodium ascorbylphosphate, magnesium ascorbyl phosphate, calcium ascorbylphosphate, ascorbic acid polypeptide, ethyl ascorbyl ether, ascorbyl dipalmitate, ascorbyl palmitate, ascorbyl glucoside, and ascorbyl ethylsilanol pectinate.
  • a derivative such as sodium ascorbylphosphate, magnesium ascorbyl phosphate, calcium ascorbylphosphate, ascorbic acid polypeptide, ethyl ascorbyl ether, ascorbyl dipalmitate, ascorbyl palmitate, ascorbyl glucoside, and ascorbyl ethylsilanol pectinate.
  • Alpha-lipoic acid which has various pharmacological effects such as improving immune function, reducing blood sugar level, and suppressing appetite in human body, is readily reduced to dihydrolipoic acid which has unpleasant odor.
  • a method of encapsulating ⁇ -lipoic acid using liposome has been introduced in order to overcome this problem, it is difficult to encapsulate a large amount of ⁇ -lipoic acid.
  • the present inventors conducted various researches in order to develop methods for improving stability of ⁇ -lipoic acid and ascorbic acid, particularly in an aqueous medium. As a result, the present inventors found that, when ascorbic acid modified into ascorbic acid derivatives having ⁇ -lipoic acid, the obtained ascorbic acid derivatives have excellent stability; and unpleasant odor formation and discoloration of each of ascorbic acid and ⁇ -lipoic acid can be significantly prevented.
  • the ascorbic acid derivatives can be dissociated into ascorbic acid and ⁇ -lipoic acid in vivo environment, for example, in stomach with acidic environment or in skin tissue, it has been found that synergistic pharmacological effects such as whitening, anti-aging, skin care, anti-wrinkle, and moisturizing can be expected through the two types of antioxidants.
  • the present invention provides an ascorbic acid derivative having ⁇ -lipoic acid.
  • the present invention also provides a process for preparing the ascorbic acid derivative.
  • an ascorbic acid derivative represented by the following Formula 1 :
  • one of the substituents R 1 to R 4 is an ⁇ -lipoyl group; one or two of the remaining substituents are, each independently, an ⁇ -lipoyl group, a Ci-C 4 alkyl group, CH3CH2 ⁇ -(CH 2 CH2 ⁇ ) m -CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a C 8 -Ci 8 acyl group; and the remaining substituents are hydrogen atoms.
  • a process for preparing an ascorbic acid derivative of Formula 1 comprising (a) reacting a compound of Formula 2 with a compound of Formula 3 and (b) deprotecting the product obtained in Step (a):
  • R-i , R 2 , R 3 , and R 4 are the same as defined in the above; two or three of the substituents R5 to Rs are hydrogen atoms, and the remaining substituents are hydroxy protecting groups; and Rg is a hydroxy group, a carbodiimidyl group, a halogen atom, a C 1 -C 4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group.
  • R 1 , R 2 , R 3 , and R 4 are the same as defined in the above;
  • R 9 is a hydroxy group, a carbodiimidyl group, a halogen atom, a CrC 4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group; and one or two of the substituents R1 0 to R13 are, each independently, an ⁇ -lipoyl group, a CrC 4 alkyl group, CH 3 CH 2 O-(CH 2 CH 2 O) 111 -CH 2 CH 2 - (wherein m is an integer of 7 to 45), a glucosyl group, or a Cs-Ci 8 acyl group, and the remaining substituents are hydrogen atoms.
  • the reacting a compound of Formula 3 with a compound of Formula 4 may be performed in the presence of one or more coupling agent selected from the group consisting of 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride; and in the presence of one or more base selected from the group consisting of dimethylaminopyridine, imidazole, pyridine, diisopropylethylamine, and triethylamine.
  • one or more coupling agent selected from the group consisting of 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride
  • one or more base selected from the group consisting of dimethylaminopyridine, imidazole, pyridine, diis
  • the ascorbic acid derivative according to the present invention contains two types of substituents including ⁇ -lipoic acid in its structure.
  • the ascorbic acid derivative has excellent stability in an aqueous medium, and thus can minimize denaturation caused by environmental factors such as temperature, light, oxygen, and water, even when being stored in an aqueous composition for a long period of time.
  • odor caused by denaturation of ⁇ -lipoic acid e.g., reduction of ⁇ -lipoic acid, can be significantly prevented.
  • the ascorbic acid derivatives can be dissociated into ascorbic acid and ⁇ -lipoic acid in vivo environment, for example, in stomach with acidic environment or in skin tissue, synergistic pharmacological effects such as whitening, anti-aging, skin care, anti-wrinkle, and moisturizing can be expected through the two types of antioxidants. Therefore, the ascorbic acid derivative according to the present invention can be usefully applied to pharmaceutical compositions and cosmetic compositions, particularly to aqueous pharmaceutical compositions and cosmetic compositions.
  • the present invention provides an ascorbic acid derivative represented by the following Formula 1 : Formula 1
  • one of the substituents Ri to R 4 is an ⁇ -lipoyl group; one or two of the remaining substituents are, each independently, an ⁇ -lipoyl group, a d-C 4 alkyl group, CH 3 CH 2 O-(CH 2 CH 2 O) ⁇ CH 2 CH 2 - (wherein m is an integer of 7 to 45), a glucosyl group, or a C 8 -C 18 acyl group; and the remaining substituents are hydrogen atoms.
  • the ascorbic acid derivative according to the present invention preferred are those wherein: two of the substituents Ri to R 4 are hydrogen atoms; one of the remaining substituents is an ⁇ -lipoyl group; and the remaining substituent is an ⁇ -lipoyl group, an ethyl group, CH 3 CH 2 O-(CH 2 CH 2 O) m -CH 2 CH 2 - (wherein m is an integer of 7 to 45), a glucosyl group, or a palmitoyl group.
  • CH 3 CH 2 O-(CH 2 CH 2 O) m -CH 2 CH 2 - refers to a polyethylene glycol group, and preferably a polyethylene glycol group having an average molecular weight of about 300 to about 2000, and preferably about 1000.
  • More preferred ascorbic acid derivative of the present invention are: L-5,6-di- ⁇ -lipoyl-ascorbic acid; L-2,3-di- ⁇ -lipoyl-ascorbic acid; L-2,6-di- ⁇ -lipoyl ascorbic acid; L- ⁇ - ⁇ -lipoyl ⁇ -glucosyl-ascorbic acid; L-6- ⁇ -lipoyl-3-polyethylene glycol-ascorbic acid; L-6- ⁇ -lipoyl-2-ethyl-ascorbic acid; L-6- ⁇ -lipoyl-3-ethyl-ascorbic acid; L-6-palmitoyl-2- ⁇ -lipoyl-ascorbic acid; L-2- ⁇ -lipoyl-3-polyethylene glycol-ascorbic acid; L-2- ⁇ -lipoyl-3-ethyl-ascorbic acid.
  • the ascorbic acid derivative according to the present invention contains two types of substituents including ⁇ -lipoic acid in its structure.
  • the ascorbic acid derivative has excellent stability in an aqueous medium, and thus can minimize denaturation caused by environmental factors such as temperature, light, oxygen, and water, even when being stored in an aqueous composition for a long period of time.
  • odor caused by denaturation of ⁇ -lipoic acid e.g., reduction of ⁇ -lipoic acid, can be significantly prevented.
  • the ascorbic acid derivatives can be dissociated into ascorbic acid and ⁇ -lipoic acid in vivo environment, for example, in stomach with acidic environment or in skin tissue, synergistic pharmacological effects such as whitening, anti-aging, skin care, anti-wrinkle, and moisturizing can be expected through the two types of antioxidants. Therefore, the ascorbic acid derivative according to the present invention can be usefully applied to pharmaceutical compositions and cosmetic compositions, particularly to aqueous pharmaceutical compositions and cosmetic compositions.
  • the present invention also provides a process for preparing an ascorbic acid derivative of Formula 1 , the method comprising (a) reacting a compound of Formula 2 with a compound of Formula 3 and (b) deprotecting the product obtained in Step (a): Formula 1
  • R 9 is a hydroxy group, a carbodiimidyl group, a halogen atom, a Ci-C 4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group.
  • both R 5 and R 6 are hydrogen atoms and both R 7 and R 8 are hydroxy protecting groups
  • both R 7 and R 8 are hydrogen atoms and both R 5 and R 6 are hydroxy protecting groups
  • both R 5 and R 8 are hydrogen atoms and both R 6 and R 7 are hydroxy protecting groups.
  • the compound of Formula 2 may be prepared by introducing a hydroxy protecting group into a desired position in ascorbic acid using a conventional method.
  • a hydroxy protecting group may be selectively introduced into a hydroxy group of position 2, position 3, or positions 5 and 6 of ascorbic acid according to Journal of Organic Chemistry 69, pp 7026, 2004 and Journal of the American Chemical Society, 102, pp 6304, 1980.
  • the hydroxy protecting group may be selected from the group consisting of a benzyl group, an isopropylidenyl group, a benzoyl group, a benzyloxycarbonyl group, an acetyl group, and a silyl group.
  • ⁇ -lipoic acid i.e., R 9 is a hydroxy group
  • R 9 is a hydroxy group
  • a group activating the carboxyl group of ⁇ -lipoic acid such as a carboimidyl group, a halogen atom, a C 1 - C 4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, or an imidazolyl group may be introduced into ⁇ -lipoic acid and then used in the reaction.
  • the reaction between the compound of Formula 2 and the compound of Formula 3 may be performed in the presence of a coupling agent, such as 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride; and in the presence of a base, such as dimethylaminopyridine, imidazole pyridine, diisopropylethylamine, and triethylamine.
  • a coupling agent such as 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride
  • a base such as dimethylaminopyridine, imidazole pyridine, diisopropylethylamine, and triethylamine.
  • the reaction may be performed in a solvent, such as dichloromethane, ethyl acetate, diethylformamide, tetrahydrofuran (THF), chloroform, and dimethyl sulfone imide, at room temperature (at about 25 " C) at atmospheric pressure.
  • a solvent such as dichloromethane, ethyl acetate, diethylformamide, tetrahydrofuran (THF), chloroform, and dimethyl sulfone imide
  • the ratio of the compound of Formula 2 to the compound of Formula 3 may be 1 : 1-1.5 equivalence ratio, and preferably 1 : 1.1-1.3 equivalence ratio, but is not limited thereto.
  • purification of the ascorbic acid derivative may be facilitated since un-reacted ascorbic acid is not remained.
  • the product prepared according to the reaction above i.e., the compound having an ⁇ -lipoyl group and a hydroxy protecting group, may be isolated by
  • Deprotection of the product prepared by the reaction between the compound of Formula 2 and the compound of Formula 3, i.e., a reaction for removing the hydroxy protecting group may be conducted using a conventional method for removing a hydroxy protecting group.
  • a reaction for removing the hydroxy protecting group may be conducted using a conventional method for removing a hydroxy protecting group.
  • the hydroxy protecting group may be removed by dissolving the product obtained from the reaction of the compound of Formula 2 and the compound of Formula 3 in methanol, tetrahydrofuran, or a mixture thereof, and hydrogenising the resultant using palladium/carbon (Pd/C).
  • the hydroxy protecting group may be removed by stirring the product obtained from the reaction of the compound of Formula 2 and the compound of Formula 3 in hydrochloric acid and methanol.
  • the obtained product may be isolated using a conventional method, e.g., concentration under reduced pressure and, if desired, a filtering process may be further included.
  • the compound of Formula 1 according to the present invention may also be prepared by reacting a compound having a single substituent, e.g., ⁇ -lipoic acid, with ⁇ -lipoic acid or its activated derivative. That is, the present invention provides a process for preparing an ascorbic acid derivative of Formula 1 , the method comprising reacting a compound of Formula 4 with a compound of Formula 3:
  • R 1 , R 2 , R 3 , and R 4 are the same as defined in the above;
  • Rg is a hydroxy group, a carbodiimidyl group, a halogen atom, a C 1 -C 4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group; and one or two of the substituents R 10 to R 13 are, each independently, an ⁇ -lipoyl group, a C 1 -C 4 alkyl group,
  • R 11 is an ⁇ -lipoyl group and R 10 , Ri 2 , and R 13 are hydrogen atoms; or one of the substituents R 10 to R 13 is an ethyl group, CH 3 CH 2 O-(CH 2 CH 2 O) m -CH 2 CH 2 - (wherein m is an integer of 7 to 45), a glucosyl group, or a palmitoyl group and the remaining substituents are hydrogen atoms.
  • the compound of Formula 4 may be prepared by introducing an ⁇ -lipoyl group into position 2, 3, 5, and/or 6 of ascorbic acid according to Journal of Organic Chemistry, V69, pp 7026-7032, 2004.
  • the reaction between the compound of Formula 3 and the compound of Formula 4 may be performed in the presence of a coupling agent, such as 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride; and in the presence of a base, such as dimethylaminopyridine, imidazole pyridine, diisopropylethylamine, and triethylamine.
  • a coupling agent such as 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride
  • a base such as dimethylaminopyridine, imidazole pyridine, diisopropylethylamine, and triethylamine.
  • the reaction may be performed in a solvent, such as dichloromethane, ethyl acetate, diethylformamide, tetrahydrofuran, chloroform, and dimethyl sulfone imide, at room temperature (at about 25 0 C) at atmospheric pressure.
  • a solvent such as dichloromethane, ethyl acetate, diethylformamide, tetrahydrofuran, chloroform, and dimethyl sulfone imide
  • the ratio of the compound of Formula 4 to the compound of Formula 3 may be 1 : 1-1.5 equivalence ratio, and preferably 1 : 1.1-1.3 equivalence ratio, but is not limited thereto.
  • purification of the ascorbic acid derivative may be facilitated since un-reacted ascorbic acid is not remained.
  • the product prepared according to the reaction above may be isolated by removing the solvent using a conventional method, for example, distillation under reduced pressure.
  • L-5,6-O-isopropylidin-ascorbic acid was prepared according to a method disclosed in Journal of the American Chemical Society, Vol. 102, No. 20, pp 6304,
  • Example 3 Preparation of L-2,6-di- ⁇ -lipoyl ascorbic acid 3 g of L-6- ⁇ -lipoyl-ascorbic acid obtained in Comparative Example 1 described below and 2.04 g of ⁇ -lipoic acid were added to 100 ml of dichloromethane. While stirring the reaction mixture, 1.89 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 500 mg of N.N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue.
  • L-6- ⁇ -lipoyl-2-ethyl-ascorbic acid (yield: 63 %) was prepared in the same manner as in Step 2 of Example 5, except that 5.0 g of L-2-ethyl-ascorbic acid was used instead of L-3-polyethylene glycol-ascorbic acid.
  • Example 9 Preparation of L-2- ⁇ -lipoyl-3-polyethylene glycol-ascorbic acid 3.0 g of L-3-polyethylene glycol-ascorbic acid prepared according to Step 1 of Example 5 and 0.58 g of ⁇ -lipoic acid were added to 50 ml of a mixed solvent of chloroform and methylene chloride (2:1 , v/v). While stirring the reaction mixture, 0.54 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 300 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature (about 25 0 C) overnight.
  • Step 1 Preparation of L-3-polyethylene glycol-ascorbic acid 5.O g of bromo ethane and 0.97 g of ascorbic acid were added to 30 ml of dimethylformamide. 0.98 g of potassium carbonate was added to the reaction mixture, which was then stirred at room temperature overnight. The resultant was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 4.06 g of L-3-ethyl-ascorbic acid (yield: 69%).
  • Example 1 and 20 g of ⁇ -lipoic acid were added to 200 ml of pyridine. While stirring the reaction mixture, a solution of 24 g of dicyclohexyl carbodiimide in 50 ml of dichloromethane was gradually added to the reaction mixture, which was then stirred at room temperature overnight. The resultant was distilled under reduced pressure, and then extracted by adding 200 ml of ethyl acetate thereto. The obtained organic layer was washed three times with a saturated aqueous solution of sodium carbonate. The resultant was concentrated under reduced pressure, and 300 ml of a mixed solvent of ether and hexane (1 :1 , v/v) was added thereto.
  • Conditions for the high performance liquid chromatography are as follows: column - ACE 5-C18 (4.6*150mm, 5 jum), mobile phase - a mixture of acetonitrile and 0.1% phosphoric acid solution (80:20), wavelength of detector - UV 224 nm, flow rate - 1 ml/min, and amount of injection - 2 ⁇ i.
  • the derivatives show at least 90% of remaining amount in an aqueous medium, thereby increasing stability thereof; and significantly reduce unpleasant odor problems.

Abstract

The present invention provides an ascorbic acid derivative having an α-lipoyl group and a process for preparing the same. The ascorbic acid derivative of the present invention has excellent stability in an aqueous medium, and thus can minimize denaturation caused by environmental factors such as temperature, light, oxygen, and water, even when being stored in an aqueous composition for a long eriod of time.

Description

[DESCRIPTION] [Invention Title]
ASCORBIC ACID DERIVATIVES HAVING ALPHA-LIPOYL GROUPS AND PROCESS FOR PREPARING THE SAME
[TECHNICAL FIELD]
The present invention relates to an ascorbic acid derivative having an α-lipoyl group and a process for preparing the same.
[BACKGROUND ART]
Pharmaceutical compositions and/or cosmetic compositions include various antioxidants. A variety of compounds such as α-lipoic acid, coenzyme Q10, α-tocopherol, retinol, glutathione, ascorbic acid, butylated hydroxy toluene, genistein, quercetin, propyl gallate, epigallocatechin gallate, gallocatechin gallate, sylibin, diosmetin, kaempferol, epicatechin, and galangin are known as antioxidants.
Ascorbic acid which is widely used as an antioxidant has a structure similar to that of Y-lactone. Due to its structure, ascorbic acid sensitively reacts with environmental factors such as air, particularly oxygen, heat, and light to be easily decomposed. In order to improve stability of ascorbic acid, a method of adding an anti-oxidizing agent, a method of stabilizing ascorbic acid in a multi-lamellar emulsion, a method of stabilizing ascorbic acid in an oil in water type emulsion, and a method of inhibiting oxidization of ascorbic acid using zinc sulfate and L-tyrosine have been reported (U.S. Patent No. 4,938,969, European Patent Publication No. 533,667 B1 , etc.). Furthermore, in order to improve stability of ascorbic acid, ascorbic acid is chemically modified into a derivative such as sodium ascorbylphosphate, magnesium ascorbyl phosphate, calcium ascorbylphosphate, ascorbic acid polypeptide, ethyl ascorbyl ether, ascorbyl dipalmitate, ascorbyl palmitate, ascorbyl glucoside, and ascorbyl ethylsilanol pectinate. However, even though the chemical structure of ascorbic acid is modified as described above, stability of ascorbic acid is not satisfactory when ascorbic acid is exposed to water, light, or air, particularly in an aqueous medium.
Alpha-lipoic acid, which has various pharmacological effects such as improving immune function, reducing blood sugar level, and suppressing appetite in human body, is readily reduced to dihydrolipoic acid which has unpleasant odor. Although a method of encapsulating α-lipoic acid using liposome has been introduced in order to overcome this problem, it is difficult to encapsulate a large amount of α-lipoic acid.
Therefore, there is a need to develop a method of improving stabilities of ascorbic acid and α-lipoic acid, in addition to preventing ascorbic acid and α-lipoic acid from unpleasant odor formation and/or discoloration.
[DETAILED DESCRIPTION OF THE INVENTION]
[TECHNICAL PROBLEM] The present inventors conducted various researches in order to develop methods for improving stability of α-lipoic acid and ascorbic acid, particularly in an aqueous medium. As a result, the present inventors found that, when ascorbic acid modified into ascorbic acid derivatives having α-lipoic acid, the obtained ascorbic acid derivatives have excellent stability; and unpleasant odor formation and discoloration of each of ascorbic acid and α-lipoic acid can be significantly prevented. Furthermore, since the ascorbic acid derivatives can be dissociated into ascorbic acid and α-lipoic acid in vivo environment, for example, in stomach with acidic environment or in skin tissue, it has been found that synergistic pharmacological effects such as whitening, anti-aging, skin care, anti-wrinkle, and moisturizing can be expected through the two types of antioxidants.
Thus, the present invention provides an ascorbic acid derivative having α-lipoic acid.
The present invention also provides a process for preparing the ascorbic acid derivative.
[TECHNICAL SOLUTION]
According to an aspect of the present invention, there is provided an ascorbic acid derivative represented by the following Formula 1 : Formula 1
Figure imgf000004_0001
wherein one of the substituents R1 to R4 is an α-lipoyl group; one or two of the remaining substituents are, each independently, an α-lipoyl group, a Ci-C4 alkyl group, CH3CH2θ-(CH2CH2θ)m-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a C8-Ci8 acyl group; and the remaining substituents are hydrogen atoms.
According to another aspect of the present invention, there is provided a process for preparing an ascorbic acid derivative of Formula 1 , the method comprising (a) reacting a compound of Formula 2 with a compound of Formula 3 and (b) deprotecting the product obtained in Step (a): Formula 1
Figure imgf000005_0001
Formula 2
Figure imgf000005_0002
Formula 3
Figure imgf000006_0001
wherein R-i , R2, R3, and R4 are the same as defined in the above; two or three of the substituents R5 to Rs are hydrogen atoms, and the remaining substituents are hydroxy protecting groups; and Rg is a hydroxy group, a carbodiimidyl group, a halogen atom, a C1-C4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group.
According to still another aspect of the present invention, there is provided a process for preparing an ascorbic acid derivative of Formula 1 , the method comprising reacting a compound of Formula 4 with a compound of Formula 3:
Formula 1
Figure imgf000006_0002
Formula 3
Figure imgf000006_0003
Formula 4
Figure imgf000007_0001
wherein R1, R2, R3, and R4 are the same as defined in the above; R9 is a hydroxy group, a carbodiimidyl group, a halogen atom, a CrC4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group; and one or two of the substituents R10 to R13 are, each independently, an α-lipoyl group, a CrC4 alkyl group, CH3CH2O-(CH2CH2O)111-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a Cs-Ci8 acyl group, and the remaining substituents are hydrogen atoms. The reacting a compound of Formula 3 with a compound of Formula 4 may be performed in the presence of one or more coupling agent selected from the group consisting of 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride; and in the presence of one or more base selected from the group consisting of dimethylaminopyridine, imidazole, pyridine, diisopropylethylamine, and triethylamine.
[ADVANTAGEOUS EFFECTS]
The ascorbic acid derivative according to the present invention contains two types of substituents including α-lipoic acid in its structure. The ascorbic acid derivative has excellent stability in an aqueous medium, and thus can minimize denaturation caused by environmental factors such as temperature, light, oxygen, and water, even when being stored in an aqueous composition for a long period of time. In particular, odor caused by denaturation of α-lipoic acid, e.g., reduction of α-lipoic acid, can be significantly prevented. In addition, since the ascorbic acid derivatives can be dissociated into ascorbic acid and α-lipoic acid in vivo environment, for example, in stomach with acidic environment or in skin tissue, synergistic pharmacological effects such as whitening, anti-aging, skin care, anti-wrinkle, and moisturizing can be expected through the two types of antioxidants. Therefore, the ascorbic acid derivative according to the present invention can be usefully applied to pharmaceutical compositions and cosmetic compositions, particularly to aqueous pharmaceutical compositions and cosmetic compositions.
[BEST MODE FOR CARRYING OUT THE INVENTION]
The present invention provides an ascorbic acid derivative represented by the following Formula 1 : Formula 1
Figure imgf000008_0001
wherein one of the substituents Ri to R4 is an α-lipoyl group; one or two of the remaining substituents are, each independently, an α-lipoyl group, a d-C4 alkyl group, CH3CH2O-(CH2CH2O)^CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a C8-C18 acyl group; and the remaining substituents are hydrogen atoms.
Among the ascorbic acid derivative according to the present invention, preferred are those wherein: two of the substituents Ri to R4 are hydrogen atoms; one of the remaining substituents is an α-lipoyl group; and the remaining substituent is an α-lipoyl group, an ethyl group, CH3CH2O-(CH2CH2O)m-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a palmitoyl group. Among the substituents, CH3CH2O-(CH2CH2O)m-CH2CH2- (wherein m is an integer of 7 to 45) refers to a polyethylene glycol group, and preferably a polyethylene glycol group having an average molecular weight of about 300 to about 2000, and preferably about 1000.
More preferred ascorbic acid derivative of the present invention are: L-5,6-di-α-lipoyl-ascorbic acid; L-2,3-di-α-lipoyl-ascorbic acid; L-2,6-di-α-lipoyl ascorbic acid; L-θ-α-lipoyl^-glucosyl-ascorbic acid; L-6-α-lipoyl-3-polyethylene glycol-ascorbic acid; L-6-α-lipoyl-2-ethyl-ascorbic acid; L-6-α-lipoyl-3-ethyl-ascorbic acid; L-6-palmitoyl-2-α-lipoyl-ascorbic acid; L-2-α-lipoyl-3-polyethylene glycol-ascorbic acid; L-2-α-lipoyl-3-ethyl-ascorbic acid.
The ascorbic acid derivative according to the present invention contains two types of substituents including α-lipoic acid in its structure. The ascorbic acid derivative has excellent stability in an aqueous medium, and thus can minimize denaturation caused by environmental factors such as temperature, light, oxygen, and water, even when being stored in an aqueous composition for a long period of time. In particular, odor caused by denaturation of α-lipoic acid, e.g., reduction of α-lipoic acid, can be significantly prevented. In addition, since the ascorbic acid derivatives can be dissociated into ascorbic acid and α-lipoic acid in vivo environment, for example, in stomach with acidic environment or in skin tissue, synergistic pharmacological effects such as whitening, anti-aging, skin care, anti-wrinkle, and moisturizing can be expected through the two types of antioxidants. Therefore, the ascorbic acid derivative according to the present invention can be usefully applied to pharmaceutical compositions and cosmetic compositions, particularly to aqueous pharmaceutical compositions and cosmetic compositions.
The present invention also provides a process for preparing an ascorbic acid derivative of Formula 1 , the method comprising (a) reacting a compound of Formula 2 with a compound of Formula 3 and (b) deprotecting the product obtained in Step (a): Formula 1
Figure imgf000010_0001
Figure imgf000010_0002
Formula 3
Figure imgf000011_0001
wherein Ri, R2, R3, and R4 are the same as defined in the above; two or three of the substituents R5 to R8 are hydrogen atoms, and the remaining substituents are hydroxy protecting groups; and R9 is a hydroxy group, a carbodiimidyl group, a halogen atom, a Ci-C4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group. Among the compound of Formula 2, preferred are those wherein: both R5 and R6 are hydrogen atoms and both R7 and R8 are hydroxy protecting groups; both R7 and R8 are hydrogen atoms and both R5 and R6 are hydroxy protecting groups; or both R5 and R8 are hydrogen atoms and both R6 and R7 are hydroxy protecting groups. The compound of Formula 2 may be prepared by introducing a hydroxy protecting group into a desired position in ascorbic acid using a conventional method. For example, a hydroxy protecting group may be selectively introduced into a hydroxy group of position 2, position 3, or positions 5 and 6 of ascorbic acid according to Journal of Organic Chemistry 69, pp 7026, 2004 and Journal of the American Chemical Society, 102, pp 6304, 1980. The hydroxy protecting group may be selected from the group consisting of a benzyl group, an isopropylidenyl group, a benzoyl group, a benzyloxycarbonyl group, an acetyl group, and a silyl group. As the compound of Formula 3, α-lipoic acid (i.e., R9 is a hydroxy group) may be directly used. Alternatively, in order to easily remove byproducts, a group activating the carboxyl group of α-lipoic acid such as a carboimidyl group, a halogen atom, a C1- C4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, or an imidazolyl group may be introduced into α-lipoic acid and then used in the reaction.
The reaction between the compound of Formula 2 and the compound of Formula 3 may be performed in the presence of a coupling agent, such as 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride; and in the presence of a base, such as dimethylaminopyridine, imidazole pyridine, diisopropylethylamine, and triethylamine. The reaction may be performed in a solvent, such as dichloromethane, ethyl acetate, diethylformamide, tetrahydrofuran (THF), chloroform, and dimethyl sulfone imide, at room temperature (at about 25 "C) at atmospheric pressure. The ratio of the compound of Formula 2 to the compound of Formula 3 may be 1 : 1-1.5 equivalence ratio, and preferably 1 : 1.1-1.3 equivalence ratio, but is not limited thereto. When the reaction is performed in the range described above, purification of the ascorbic acid derivative may be facilitated since un-reacted ascorbic acid is not remained. The product prepared according to the reaction above, i.e., the compound having an α-lipoyl group and a hydroxy protecting group, may be isolated by removing the solvent using a conventional method, for example, distillation under reduced pressure.
Deprotection of the product prepared by the reaction between the compound of Formula 2 and the compound of Formula 3, i.e., a reaction for removing the hydroxy protecting group, may be conducted using a conventional method for removing a hydroxy protecting group. For example, when a benzyl group is used as the hydroxy protecting group, the hydroxy protecting group may be removed by dissolving the product obtained from the reaction of the compound of Formula 2 and the compound of Formula 3 in methanol, tetrahydrofuran, or a mixture thereof, and hydrogenising the resultant using palladium/carbon (Pd/C). When an isopropylidenyl group is used as the hydroxy protecting group, the hydroxy protecting group may be removed by stirring the product obtained from the reaction of the compound of Formula 2 and the compound of Formula 3 in hydrochloric acid and methanol. The obtained product may be isolated using a conventional method, e.g., concentration under reduced pressure and, if desired, a filtering process may be further included.
The compound of Formula 1 according to the present invention may also be prepared by reacting a compound having a single substituent, e.g., α-lipoic acid, with α-lipoic acid or its activated derivative. That is, the present invention provides a process for preparing an ascorbic acid derivative of Formula 1 , the method comprising reacting a compound of Formula 4 with a compound of Formula 3:
Formula 1
Figure imgf000013_0001
Formula 3
Figure imgf000014_0001
Formula 4
R1
Figure imgf000014_0002
wherein R1, R2, R3, and R4 are the same as defined in the above; Rg is a hydroxy group, a carbodiimidyl group, a halogen atom, a C1-C4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group; and one or two of the substituents R10 to R13 are, each independently, an α-lipoyl group, a C1-C4 alkyl group,
CH3CH2O-(CH2CH2O)m-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a Cβ-Ciβ acyl group, and the remaining substituents are hydrogen atoms.
Among the compound of Formula 4, preferred are those wherein: R11 is an α-lipoyl group and R10, Ri2, and R13 are hydrogen atoms; or one of the substituents R10 to R13 is an ethyl group, CH3CH2O-(CH2CH2O)m-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a palmitoyl group and the remaining substituents are hydrogen atoms. The compound of Formula 4 may be prepared by introducing an α-lipoyl group into position 2, 3, 5, and/or 6 of ascorbic acid according to Journal of Organic Chemistry, V69, pp 7026-7032, 2004. The reaction between the compound of Formula 3 and the compound of Formula 4 may be performed in the presence of a coupling agent, such as 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride; and in the presence of a base, such as dimethylaminopyridine, imidazole pyridine, diisopropylethylamine, and triethylamine. The reaction may be performed in a solvent, such as dichloromethane, ethyl acetate, diethylformamide, tetrahydrofuran, chloroform, and dimethyl sulfone imide, at room temperature (at about 250C) at atmospheric pressure. The ratio of the compound of Formula 4 to the compound of Formula 3 may be 1 : 1-1.5 equivalence ratio, and preferably 1 : 1.1-1.3 equivalence ratio, but is not limited thereto. When the reaction is performed in the range described above, purification of the ascorbic acid derivative may be facilitated since un-reacted ascorbic acid is not remained. The product prepared according to the reaction above may be isolated by removing the solvent using a conventional method, for example, distillation under reduced pressure.
Hereinafter, the present invention will be described more specifically with reference to the following examples. The following examples are only for illustrative purposes and are not intended to limit the scope of the invention.
Preparation Example 1 : Preparation of ---5,6-O-isopropylidin-ascorbic acid
L-5,6-O-isopropylidin-ascorbic acid was prepared according to a method disclosed in Journal of the American Chemical Society, Vol. 102, No. 20, pp 6304,
1980. That is, 100 g of ascorbic acid was added to 50 ml of acetone. While the reaction mixture was stirred at room temperature, 10 ml of acetyl chloride was added to the mixture, which was then stirred for 3 hours. The mixture was cooled in ice bath and filtered to isolate a precipitate. The precipitate was washed with 500 ml of cold acetone and dried under reduced pressure to obtain 105 g of L-δ.e-O-isopropylidin-ascorbic acid (yield: 86%, mp: 206-208 °C). 1H NMR (400MHz, CDCL3), Chemical shift; 5.50 (1 H, d), 5.18 (1 H1 m),
4.20(2H, t), 2.52(2H, m), 2.51 (4H, t), 2.25-1.55 (12H, m)
Preparation Example 2: Preparation of 2,3-dibenzyl-ascorbic acid 50 g of L-5,6-O-isopropylidin-ascorbic acid prepared in Preparation Example
1 was added to 70 ml of dimethylformamide. 64 g of calcium carbonate was added to the reaction mixture, which was then stirred for 30 minutes. 60 ml of benzyl bromide was gradually added to the reaction mixture, which was then stirred overnight at room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent, and 300 ml of dichloromethane was added thereto. The reaction mixture was washed with water and further distilled under reduced pressure to obtain a brown solid. The obtained brown solid was added to methanol to remove un-reacted reactants and byproducts (i.e., a compound having a single benzyl group). The obtained reaction mixture was dried to obtain 65 g of L-5,6-O-isopropylidin-2,3-dibenzyl-ascorbic acid (yield: 71 %).
50 g of L-5,6-O-isopropylidin-2,3-dibenzyl-ascorbic acid obtained in the above was added to a mixed solvent of 20 ml of tetrahydrofuran (THF) and 20 ml of 1.5 N hydrochloric acid, stirred at 50 °C for 5 hours, and then distilled under reduced pressure. 300 ml of ethyl acetate was added to the obtained residue. The resultant reaction mixture was washed with water and then dried under reduced pressure to obtain 43 g of 2,3-dibenzyl-ascorbic acid (yield: 95%).
1H NMR (400MHz1 CDCL3), Chemical shift; 4.99 (1H, d), 3.81 (2H, d), 3.93 (1 H, m), 2.52(2H, m), 2.61 (4H, t), 1.73 (4H, m), 2.23-1.55 (12H, m)
Example 1: Preparation of L-5,6-di-a-lipoyl-ascorbic acid
5 g L-2,3-dibenzyl-ascorbic acid prepared obtained in Preparation Example 2 and 7.3 g of α-lipoic acid were added to 100 ml of dichloromethane. While stirring the reaction mixture, 6.76 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 500 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred overnight at room temperature. The reaction mixture was distilled under reduced pressure and 100 ml of ethyl acetate was added to the resulting residue. Then, the resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 8.5 g of L-5,6-di-α-lipoyl-2,3-dibenzyl-ascorbic acid as a solid (yield: 78%).
5 g of L-5,6-di-α-lipoyl-2,3-dibenzyl-ascorbic acid was dissolved in 50 ml of a mixture of methanol and tetrahydrofuran (THF) (1:1 , v/v), and 1 g of 5% active palladium/carbon was added to the reaction mixture, which was then stirred under a hydrogen pressure for 5 hours. The reaction mixture was filtered and the obtained filtrate was dried under reduced pressure to obtain 3.65 g of L-5,6-di-α-lipoyl-ascorbic acid (yield: 95%).
1H NMR (400MHz, CDCL3), Chemical shift ; 5.50 (1H, d), 5.18 (1H, m), 4.20(2H, t), 2.52(2H, m), 2.51 (4H, t), 2.25-1.55 (12H, m) Example 2: Preparation of L-2,3-di-α-lipoyl-ascorbic acid
3 g of L-δ^-O-isopropylidin-ascorbic acid prepared in Preparation Example 1 and 6.01 g of α-lipoic acid were added to 100 ml of dichloromethane. While stirring the reaction mixture, 5.59 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 500 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred overnight at room temperature. The reaction mixture was distilled under reduced pressure and 100 ml of ethyl acetate was added to the resulting residue. Then, the resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 6.25 g of L-5,6-0-isopropylidin-2,3-di-α-lipoyl-ascorbic acid as a solid (yield: 76 %).
3 g of L-5,6-O-isopropylidin-2,3-di-a-lipoyl-ascorbic acid was added to 5 ml of 1 N HCI and 50 ml of methanol was added to the reaction mixture, which was then stirred at room temperature for 6 hours. The reaction mixture was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 2.38 g of L-2,3-di-α-lipoyl-ascorbic acid as a solid (yield: 85%).
1H NMR (400MHz, CDCL3), Chemical shift ; 4.99 (1 H, d), 3.81 (2H, d), 3.93 (1 H, m), 2.52(2H, m), 2.61 (4H, t), 1.73 (4H, m), 2.23-1.55 (12H, m)
Example 3: Preparation of L-2,6-di-α-lipoyl ascorbic acid 3 g of L-6-α-lipoyl-ascorbic acid obtained in Comparative Example 1 described below and 2.04 g of α-lipoic acid were added to 100 ml of dichloromethane. While stirring the reaction mixture, 1.89 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 500 mg of N.N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 3.73 g of L-2,6-di-α-lipoyl-ascorbic acid as a solid (yield: 82%).
1H NMR (400MHz, CDCL3), Chemical shift; 5.2 (1 H, d), 4.44 (1 H, m), 4.23 (2H1 dd), 2.52(2H, m), 2.51-2.61 (4H, m), 1.84 (4H1 m), 1.29-2.25 (12H, m)
Example 4: Preparation of L-β-α-lipoyl^-glucosyl-ascorbic acid
5.0 g of L-ascorbic acid and 5.11 g of glucose were added to 50 ml of a mixed solvent of chloroform and dimethylformamide (2:1 , v/v). While stirring the reaction mixture, 6.12 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the mixture over the period of 30 minute. 500 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 5.95 g of L-2-glucosyl-ascorbic acid as a solid (yield: 62%). 3.0 g of L-2-glucosyl-ascorbic acid and 2.01 g of α-lipoic acid were added to 100 ml of a mixed solvent of chloroform and methylene chloride (2:1 , v/v). While stirring the reaction mixture, 1.87 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 500 mg of N.N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature overnight. 150 ml of water was slowly added to the reaction mixture, which was then extracted with 300 ml of ethyl acetate. The obtained organic layer was washed three times with water, dried over sodium sulfate, and then concentrated under reduced pressure. 300 ml of n-hexane was added to the resulting residue, and the resultant was filtered to isolate crystal. The obtained crystal was dried to obtain 3.84 g of L-6-α-lipoyl-2-glucosyl-ascorbic acid (yield: 82%). m.p.: 63-67 0C
1H NMR (400MHz, CDCI3), 9.72(1H1 s), 5.01 (1H, d), 4.24-3.99(2H, d), 4.18-4.14(1H, q), 3.95-3.87(1H, m), 3.81-3.56(2H, d), 3.63-3.57(2H, m),
3.41-3.33(1 H1 m), 2.61-2.51(2H, m), 2.54-2.50(1 H1 m), 2.26-2.24(2H, t), 1.98-1.73(2H, m), 1.68-1.29(6H, m)
Example 5: Preparation of L-6-α-lipoyl-3-polyethylene glycol-ascorbic acid
Step 1. Preparation of L-3-polyethylene glycol-ascorbic acid
5.0 g of polyethylene glycol bromide (PEG-Br) having a molecular weight of
1000 and 0.97 g of ascorbic acid were added to 30 ml of dimethylformamide.
0.98 g of potassium carbonate was added to the reaction mixture, which was then stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 4.59 g of L-3-polyethylene glycol-ascorbic acid as a solid (yield: 78%).
Step 2. Preparation of L-6-α-lipoyl-3-polyethylene glycol-ascorbic acid
3.0 g of L-3-polyethylene glycol-ascorbic acid and 0.58 g of α-lipoic acid were added to 50 ml of a mixed solvent of chloroform and methylene chloride (2:1 , v/v). While stirring the reaction mixture, 0.54 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 300 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at 50 °C overnight. The resultant was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 2.24 g of L-6-α-lipoyl-3-polyethylene glycol-ascorbic acid as a solid (yield: 74%). m.p.: 53-57 0C
1H NMR (400MHz, acetone-d6), 4.96 (1 H, d), 4.42-4.38(2H, q), 3.90 (1 H, t), 4.13-3.54(polyethylene glycol, m)3.71-3.56(3H, m), 2.60-2.55(2H, t), 2.50-2.42(1 H, m), 2.02-2.01(2H, m), 1.94-1.86(1 H, m), 1.78-1.65(4H, m), 1.62-1.47(2H, m).
Example 6: Preparation of L-6-α-lipoyl-2-ethyl-ascorbic acid
7.68 g of L-2-ethyl-ascorbic acid (yield: 82 %) was prepared in the same manner as in Step 1 of Example 5, except that 5.00 g of bromo ethane was used instead of polyethylene glycol bromide and the reaction was performed at about -100C instead of room temperature. Furthermore, 6.06 g of
L-6-α-lipoyl-2-ethyl-ascorbic acid (yield: 63 %) was prepared in the same manner as in Step 2 of Example 5, except that 5.0 g of L-2-ethyl-ascorbic acid was used instead of L-3-polyethylene glycol-ascorbic acid.
1H NMR (400MHz, acetone-d6), 4.97 (1H, d), 4.43-4.39(2H, q), 3.92 (1 H, t), 3.73-3.58(3H1 m), 3.25-3.14(2H1 m), 2.62-2.56(2H, t), 2.51-2.43(1 H, m), 2.01-2.00(2H, m), 1.95-1.85(1H, m), 1.78-1.64(4H, m), 1.61-1.49(2H, m),
1.34-1.28(3H1 1)
Example 7: Preparation of L-β-α-lipoyl-3-ethyl-ascorbic acid
8.15 g of L-3-ethyl-ascorbic acid (yield: 87 %) was prepared in the same manner as in Step 1 of Example 5, except that 5.00 g of bromo ethane was used instead of polyethylene glycol bromide. Furthermore, 6.63 g of L-θ-α-lipoyl-S-ethyl-ascorbic acid (yield: 69 %) was prepared in the same manner as in Step 2 of Example 5, except that 5.0 g of L-3-ethyl-ascorbic acid was used instead of L-3-polyethylene glycol-ascorbic acid.
1H NMR (400MHz, acetone-d6), 4.96 (1 H, d), 4.42-4.38(2H, q), 3.94 (1 H, t), 3.75-3.59(3H, m), 3.24-3.12(2H, m), 2.62-2.57(2H, t), 2.53-2.46(1 H, m), 2.04-2.01(2H, m), 1.96-1.85(1 H, m), 1.77-1.63(4H, m), 1.63-1.51 (2H, m), 1.35-1.29(3H, t)
Example 8: Preparation of L-6-palmitoyl-2-α-lipoyl-ascorbic acid
5.0 g of α-lipoic acid and 3.18 g of triethylamine were dissolved in 80 ml of methylene chloride. The reaction mixture was cooled to about -15°C and then 3.16 g of ethyl chloroformate was gradually added thereto. The reaction mixture was stirred for 1 hour while the temperature was maintained and then further stirred at room temperature for 1 hour. The reaction mixture was cooled again to about -150C . A solution of 12.05 g of L-6-palmitoyl-ascorbic acid and 3.18 g of triethylamine in 100 ml of methylene chloride was rapidly added to the reaction mixture, which was then stirred for 2 hours while gradually increasing the temperature to room temperature. The resultant was concentrated under reduced pressure. 100 ml of a mixed solvent of n-hexane and methylene chloride (2:1 , v/v) was added to the obtained obtained oily residue. The reaction mixture was cooled to -50C and then filtered. The obtained crystal was dried to obtain 10.37 g of L-6-palmitoyl-2-α-lipoyl-ascorbic acid (yield: 71%). m.p.: 129-1320C
1H NMR (400MHz, CDCI3), 4.89 (1H, s), 4.42-4.38(1 H, q), 4.36-4.22 (2H, m), 3.62-3.55(1 H, m), 3.23-3.10(2H, m), 2.65-2.61 (2H, t), 2.52-2.44(1 H1 m), 2.39-2.35(2H, t), 1.97-1.89(1 H, m), 1.79-1.43(8H1 m), 1.35-1.04(24H1 m), 0.90-0.88(3H, t)
Example 9: Preparation of L-2-α-lipoyl-3-polyethylene glycol-ascorbic acid 3.0 g of L-3-polyethylene glycol-ascorbic acid prepared according to Step 1 of Example 5 and 0.58 g of α-lipoic acid were added to 50 ml of a mixed solvent of chloroform and methylene chloride (2:1 , v/v). While stirring the reaction mixture, 0.54 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 300 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature (about 250C) overnight. The resultant was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 3.84 g of L-6-α-lipoyl-3-polyethylene glycol-ascorbic acid as a solid (yield: 76%). m.p.: 55-590C
1H NMR (400MHz, acetone-d6), 4.97 (1 H, d), 4.41 -4.37 (2H, q), 3.89 (1 H, t), 4.11-3.53(polyethylene, m)3.76-3.57(3H, m), 2.61-2.54(2H, t), 2.49-2.39(1 H, m), 2.04-2.00(2H, m), 1.93-1.85(1H1 m), 1.77-1.68(4H1 m), 1.59-1.45(2H, m).
Example 10: Preparation of L-2-α-lipoyl-3-ethyl-ascorbic acid
Step 1. Preparation of L-3-polyethylene glycol-ascorbic acid 5.O g of bromo ethane and 0.97 g of ascorbic acid were added to 30 ml of dimethylformamide. 0.98 g of potassium carbonate was added to the reaction mixture, which was then stirred at room temperature overnight. The resultant was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 4.06 g of L-3-ethyl-ascorbic acid (yield: 69%).
Step 2. Preparation of L-2-α-lipoyl-3-ethyl-ascorbic acid
3.0 g of L-3-ethyl-ascorbic acid and 0.58 g of α-lipoic acid were added to 50 ml of a mixed solvent of chloroform and methylene chloride (2:1 , v/v). While stirring the reaction mixture, 0.54 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 300 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred at room temperature (about 250C) overnight. The resultant was distilled under reduced pressure, and 100 ml of ethyl acetate was added to the resulting residue. The resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 8.84 g of L-2-α-lipoyl-3-ethyl-ascorbic acid as a solid (yield: 92%).
1H NMR (400MHz, acetone-d6), 4.96 (1H, d), 4.42-4.38(2H, q), 3.90 (1 H, t), 3.71-3.56(3H, m), 3.21-3.06(2H, m), 2.60-2.55(2H, t), 2.50-2.42(1 H, m),
2.02-2.01(2H, m), 1.94-1.86(1 H, m), 1.78-1.65(4H, m), 1.62-1.47(2H, m),
1.36-1.30(3H, t)
Comparative Example 1: Preparation of L-6-α-lipoyl-ascorbic acid L-6-α-lipoyl-ascorbic acid was prepared according to a method disclosed in
Journal of the American Chemical Society, 54, pp 308, 1977. That is, 1.76 g of ascorbic acid and 2.47 g of α-lipoic acid were added to 10 ml of anhydrous hydrogen sulfate. The reaction mixture was stirred for 30 hours, and then 250 ml of water was added thereto. The resultant was extracted by adding 300 ml of ethyl acetate thereto. The obtained organic layer was washed three times with water, dried over sodium sulfate. The resultant was concentrated under reduced pressure. 300 ml of hexane was added to the resulting residue, and the resultant was filtered. The obtained crystal was dried to obtain 2.5 g of L-6-α-lipoyl-ascorbic acid (yield: 68%). m.p.: 45-47°C 1H NMR (400MHz, CDCL3), Chemical shift; 4.9 (1 H, d), 4.44 (1 H, m), 4.32 (2H, dd), 2.52(1 H, m), 2.54 (2H, t), 1.85 (2H, m), 1.29-2.25 (6H, m)
Comparative Example 2: Preparation of L-2-α-lipoyl-ascorbic acid 18.8 g of L-5,6-O-isopropylidin-ascorbic acid prepared in Preparation
Example 1 and 20 g of α-lipoic acid were added to 200 ml of pyridine. While stirring the reaction mixture, a solution of 24 g of dicyclohexyl carbodiimide in 50 ml of dichloromethane was gradually added to the reaction mixture, which was then stirred at room temperature overnight. The resultant was distilled under reduced pressure, and then extracted by adding 200 ml of ethyl acetate thereto. The obtained organic layer was washed three times with a saturated aqueous solution of sodium carbonate. The resultant was concentrated under reduced pressure, and 300 ml of a mixed solvent of ether and hexane (1 :1 , v/v) was added thereto. The resultant was cooled to -10°C and then filtered. The filtrate was dried to obtain 32 g of L-5,6-O-isopropylidin-2-α-lipoyl-ascorbic acid (yield: 92%).
3 g of L-5,6-O-isopropylidin-2-α-lipoyl-ascorbic acid obtained in the above was added to 20 ml of a mixed solvent of dichloromethane and methanol (1 :1 , v/v). While stirring the reaction mixture, 300 mg of p-toluenesulfonic acid was added to the reaction mixture, which was then stirred at 400C for 12 hours. The resultant was concentrated under reduced pressure and then extracted by adding 100 ml of ethyl acetate thereto. The obtained organic layer was washed three times with brine and dried under reduced pressure to obtain 2 g of L-2-α-lipoyl-ascorbic acid (yield: 74%).
1H NMR (400MHz, CDCL3), Chemical shift; 5.1 (1H, d), 4.43 (1 H, m), 4.28 (2H, dd), 2.49(1H, m), 2.53 (2H, t), 1.81 (2H, m), 1.31-2.22 (6H, m) Experimental Example: Chemical stability test and sensory test
3.0 g of each of ascorbic acid derivatives prepared according to Examples 1 to 10 and Comparative Examples 1 and 2 was completely dissolved in 100 ml of a mixed solvent of distilled water and acetone (1 :1 v/v) to prepare a clear solution. The solution was stirred at 40 °C for 30 minutes to evaporate acetone to prepare a micelle solution. 10 ml of each of the micelle solutions was respectively stored at 450C for one week, two weeks, three weeks, and four weeks to measure the amount of the remaining antioxidant and to perform sensory tests. In order to identify stability of the ascorbic acid derivatives, the amount of ascorbic acid in each of the micelle solutions was measured three times using high performance liquid chromatography to calculate the mean values. Conditions for the high performance liquid chromatography are as follows: column - ACE 5-C18 (4.6*150mm, 5 jum), mobile phase - a mixture of acetonitrile and 0.1% phosphoric acid solution (80:20), wavelength of detector - UV 224 nm, flow rate - 1 ml/min, and amount of injection - 2 μi.
Sensory tests were performed as follows: 10 healthy women in late twenties estimated odor intensity of samples to calculate the mean values of average odor intensity. The odor intensity is established as in the following Table 1 .
Table 1
Figure imgf000027_0001
Figure imgf000028_0001
The results of stability test (measurement of the remaining antioxidant amount) and sensory test are shown in Tables 2 and 3.
Table 2
Figure imgf000029_0001
Figure imgf000030_0001
Table 3
Figure imgf000031_0001
Figure imgf000032_0001
Referring to Tables 2 and 3, when ascorbic acid and α-lipoic acid having discoloration and odor problems are made into the derivatives according to the present invention, the derivatives show at least 90% of remaining amount in an aqueous medium, thereby increasing stability thereof; and significantly reduce unpleasant odor problems.

Claims

[CLAIMS]
1. An ascorbic acid derivative represented by the following Formula 1 : Formula 1
Figure imgf000033_0001
wherein one of the substituents Ri to R4 is an α-lipoyl group; one or two of the remaining substituents are, each independently, an α-lipoyl group, a C1-C4 alkyl group, CH3CH2θ-(CH2CH2θ)m-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a Ca-Ci8 acyl group; and the remaining substituents are hydrogen atoms.
2. The ascorbic acid derivative of claim 1 , which is selected from the group consisting of L-5,6-di-α-lipoyl-ascorbic acid; L-2,3-di-α-lipoyl-ascorbic acid; L-2,6-di-α-lipoyl ascorbic acid; L-6-α-lipoyl-2-glucosyl-ascorbic acid; L-6-α-lipoyl-3-polyethylene glycol-ascorbic acid; L-6-α-lipoyl-2-ethyl-ascorbic acid; L-6-α-lipoyl-3-ethyl-ascorbic acid; L-6-palmitoyl-2-α-lipoyl-ascorbic acid; L-2-α-lipoyl-3-polyethylene glycol-ascorbic acid; and L-2-α-lipoyl-3-ethyl-ascorbic acid.
3. A process for preparing an ascorbic acid derivative of Formula 1 , the method comprising (a) reacting a compound of Formula 2 with a compound of Formula 3 and (b) deprotecting the product obtained in Step (a): Formula 1
Figure imgf000034_0001
Figure imgf000034_0002
Formula 3
Figure imgf000034_0003
wherein Ri, R2, R3, and R4 are the same as defined in Claim 1 ; two or three of the substituents R5 to Rs are hydrogen atoms, and the remaining substituents are hydroxy protecting groups; and R9 is a hydroxy group, a carbodiimidyl group, a halogen atom, a CrC4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group.
4. The process of claim 3, wherein both R5 and Re are hydrogen atoms and both R7 and Rs are hydroxy protecting groups; both R7 and R8 are hydrogen atoms and both R5 and R6 are hydroxy protecting groups; or both R5 and Rs are hydrogen atoms and both R& and R7 are hydroxy protecting groups.
5. The process of claim 3 or 4, wherein the hydroxy protecting group is selected from the group consisting of a benzyl group, an isopropylidenyl group, a benzoyl group, a benzyloxycarbonyl group, an acetyl group, and a silyl group.
6. A process for preparing an ascorbic acid derivative of Formula 1 , the method comprising reacting a compound of Formula 4 with a compound of Formula 3:
Figure imgf000035_0001
Formula 3
Figure imgf000036_0001
Formula 4
Figure imgf000036_0002
wherein R1, R2, R3, and R4 are the same as defined in Claim 1 ; Rg is a hydroxy group, a carbodiimidyl group, a halogen atom, a CrC4 alkoxy group, a hydroxysuccinimidyl group, an ethylcarbonyloxy group, an ethoxycarbonyloxy group, or an imidazolyl group; and one or two of the substituents Ri0 to R13 are, each independently, an α-lipoyl group, a C1-C4 alkyl group, CH3CH2θ-(CH2CH2θ)m-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a Ce-C18 acyl group, and the remaining substituents are hydrogen atoms.
7. The process of claim 6, wherein R11 is an α-lipoyl group; and R10, R-12, and R13 are hydrogen atoms.
8. The process of claim 6, wherein one of the substituents R10 to R13 is an ethyl group, CH3CH2O-(CH2CH2O)m-CH2CH2- (wherein m is an integer of 7 to 45), a glucosyl group, or a palmitoyl group; and the remaining substituents are hydrogen atoms.
9. The process of any one of claims 6 to 8, wherein the reacting a compound of Formula 3 with a compound of Formula 4 is performed in the presence of one or more coupling agent selected from the group consisting of 3-dimethyl-aminopropyl-N-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide, and ethoxy carbonyl chloride.
10. The process of any one of claims 6 to 8, wherein the reacting a compound of Formula 3 with a compound of Formula 4 is performed in the presence of one or more base selected from the group consisting of dimethylaminopyridine, imidazole, pyridine, diisopropylethylamine, and triethylamine.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019171088A1 (en) 2018-03-07 2019-09-12 National Hellenic Research Foundation Bioispired proteasome activators with antiageing activity
WO2019225035A1 (en) * 2018-05-23 2019-11-28 株式会社らいむ Compound, anti-allergy drug, and mediator release inhibitor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0869126A1 (en) * 1997-04-02 1998-10-07 Sankyo Company Limited Dithiolan derivatives, their preparation and their therapeutic effect
JP2000169371A (en) * 1998-10-02 2000-06-20 Sankyo Co Ltd Medicament containing dithiolane derivative
US6288106B1 (en) * 1999-05-25 2001-09-11 Chronorx, Llc Processes for the synthesis and use of various α-lipoic acid complexes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0869126A1 (en) * 1997-04-02 1998-10-07 Sankyo Company Limited Dithiolan derivatives, their preparation and their therapeutic effect
JP2000169371A (en) * 1998-10-02 2000-06-20 Sankyo Co Ltd Medicament containing dithiolane derivative
US6288106B1 (en) * 1999-05-25 2001-09-11 Chronorx, Llc Processes for the synthesis and use of various α-lipoic acid complexes

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019171088A1 (en) 2018-03-07 2019-09-12 National Hellenic Research Foundation Bioispired proteasome activators with antiageing activity
WO2019225035A1 (en) * 2018-05-23 2019-11-28 株式会社らいむ Compound, anti-allergy drug, and mediator release inhibitor
JP2019202955A (en) * 2018-05-23 2019-11-28 株式会社らいむ Compound, antiallergic drug, and mediator release inhibitor
US11345675B2 (en) 2018-05-23 2022-05-31 Laimu Corporation Compound, anti-allergy drug, and mediator release inhibitor
JP7140325B2 (en) 2018-05-23 2022-09-21 株式会社らいむ Compounds, antiallergic agents and mediator release inhibitors

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