KR19980042831A - Asian Acid Derivatives and Wound Treatments Containing the Same - Google Patents

Abstract

The present invention relates to an asiatic acid derivative represented by the following formula (1) and a wound healing agent containing the same as an active ingredient.

Description

Asian Acid Derivatives and Wound Treatments Containing the Same

The present invention relates to an asiatic acid derivative represented by the following formula (1) and a wound healing agent containing the same as an active ingredient.

Wherein R ₁ represents hydroxy, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy, octyloxymethyloxy which may be protected by hydrogen, acetyl or benzyl; R ₂ represents hydrogen or a hydroxy group; R ₁ and R ₂ together may form an oxo group; R ₃ represents hydroxy or hydrogen which may be protected by acetyl or benzoyl; R ₂ and R ₃ together may form an epoxy group; R ₄ represents hydroxymethyl which may be protected by acetyl or benzoyl; R ₃ may form —OC (R ₆ ) (R ₇ ) OCH ₂ — with R ₄ , where R ₆ is hydrogen, lower alkyl or phenyl having 1 to 4 carbon atoms, and R ₇ is hydrogen, carbon number Lower alkyl or phenyl of 1 to 4 and R ₆ and R ₇ may together form — (CH ₂ ) ₅ —; R ₅ represents hydrogen, lower alkyl having 1 to 4 carbon atoms, alkoxymethyl having 1 to 4 carbon atoms, octyloxymethyl, methoxyethoxymethyl, benzyloxymethyl and 2-tetrahydropyranyl.

Asiatic acid and madecassic acid and its trisaccharide, Asiaticoside, are substances extracted from Centella asiatica and first isolated by Bontems et al. In 1941 [J.E. Bontems, Bull. Sci. Pharmacol., 49, 186-91 (1941)], Polonsky et al. [J. Polonsky, Compt. Rend., 232, 1878-80 (1951); J. Polonsky, Bull. Soc. Chim., 173-80 (1953). Extracts of Centella asiatica, including asiatic acid and asiaticosides, have long been used in the treatment of skin wounds and chronic ulcers, and in the treatment of skin deformation caused by tuberculosis or leprosy [P. Boiteau, A. Buzas, E. Lederer and J. Polonsky, Bull. Soc. Chim., 31, 46-51 (1949)], pharmacological mechanisms of the treatment of skin wounds of these substances have been reported by activating cells in the Malpighean layer and inducing keratinization [May. Anne, Eur. J. Pharmacol., 4 (3), 331-9 (1968)].

Madecasol, a currently available treatment for skin diseases, is also a mixture of three compounds of asiaticoside (40%) and asiatic acid and madecassic acid (60%). Among them, asiaticoside, the trisaccharide of asiatic acid, shows the main effect. Asian acid itself has been reported to be ineffective [Kiesswetter, Wien. Med. Wochschr., 114 (7), 124-6 (1964)], which is due to differences in the absorption process of these substances in the body, and reports that demonstrate that the substance showing the actual efficacy is asiatic acid itself [L.F. Chasseaud, B.J. Fry, D.R. Hawkins, J.D. Lewis, T. Taylor ard D. E. Hathway, Arzneim-Forsch, 21 (9), 179-84 (1971), are also drawing attention to the synthesis of asiatic derivatives and their pharmacological action. However, this Asian acid has been pointed out as a problem because there are so many synthetic steps that it is difficult to presynthesize from a simple starting material.

Accordingly, the present inventors synthesized various Asian acid derivatives as starting materials, which were obtained from Centella asiatica, and completed the present invention by finding that they have excellent skin wound healing effects.

The present invention relates to an Asian acid derivative of the general formula 1 and a wound healing agent containing the same as an active ingredient.

Wherein R ₁ represents hydroxy, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy, octyloxymethyloxy which may be protected with hydrogen, acetyl or benzyl; R ₂ represents hydrogen or a hydroxy group; R ₁ and R ₂ together may form an oxo group; R ₃ represents hydroxy or hydrogen which may be protected by acetyl or benzoyl; R ₂ and R ₃ together may form an epoxy group; R ₄ represents hydroxymethyl which may be protected by acetyl or benzoyl; R ₃ may form —OC (R ₆ ) (R ₇ ) OCH ₂ — with R ₄ , where R ₆ is hydrogen, lower alkyl or phenyl having 1 to 4 carbon atoms, and R ₇ is hydrogen, carbon number Lower alkyl or phenyl of 1 to 4 and R ₆ and R ₇ may together form — (CH ₂ ) ₅ —; R ₅ represents hydrogen, lower alkyl having 1 to 4 carbon atoms, alkoxymethyl having 1 to 4 carbon atoms, octyloxymethyl, methoxyethoxymethyl, benzyloxymethyl and 2-tetrahydropyranyl.

A method for producing an asiatic acid derivative according to the present invention will be described below.

Method 1

Hydrolysis of Centella asiatica (TECA) to hydrolyze to obtain a mixture of asiatic acid and madecassic acid (2), the mixture was reacted with an acid catalyst and 2, 2-dimethoxypropane and then column chromatography 3, 23, 3, 23-O-isopropylidene asiatic acid (3) protected by a dihydroxy group is separated and the compound is treated with diazomethane to synthesize methyl 3, 23-O-isopropylidene asiatate (4). (See Scheme 1)

Method 2

Compounds of formula (5) were synthesized by protecting various ketones and aldehydes of dihydroxy groups 3 and 23 of asiatic acid (wherein R ₆ = H and R ₇ = H, dimethyl sulfoxide and trimethylsilyl chloride The compound of General formula (6) is synthesize | combined using chloromethyl octyl ether for the compound of General formula (5).

Wherein R ₆ and R ₇ are as defined above.

Method 3

In the compound (4) obtained above, -OH at position 2 was converted to an alkoxide by treatment with sodium hydride and imidazole, and then refluxed with carbon disulfide and methyl iodide treatment to obtain xanthate (7). This was treated with tributyltin hydride and a catalytic amount of AIBN to give methyl 2-deoxy-3,23-O-isopropylidene asiatate (8), which was deprotected to give methyl 2-deoxyasate (9). ). The compound (9) is hydrolyzed to obtain 2-deoxyamic acid (10). 2-deoxy-3, 23-O-isopropylidene asiatic acid (11) was synthesized from 2-deoxy asiatic acid (10), and the compound was reacted under the conditions mentioned in Method 2 to give a general formula Synthesize a compound of (see Scheme 3).

Method 4

Methyl 2-O-octyloxymethyl-3, 23-O-isopropylidene asiatate (13) is synthesized from the obtained compound (4) using Method 2 (see Scheme 4).

Method 5

An alkyl halide is reacted with the obtained compound (3) under the condition of Method 2 to synthesize a compound of formula (14). The compound of the general formula (15) is synthesized by acetylating the position 2 in the compound of the general formula (14) (see Scheme 5).

Wherein R ₅ is as defined above.

Method 6

By increasing the reaction time under the same conditions as in Method 2, ethoxymethyl 2-O-ethoxymethyl-3,23-O-isopropylidene asiatate (16) was synthesized from the obtained compound (3), and the same method was used. However, benzyloxymethyl group was introduced into COOH No. 28 using chloromethylbenzyl ether and acetylated to synthesize benzyloxymethyl 3,23-O-diacetylasiatate (17) (see Scheme 6).

Method 7

A series of novel compounds of the invention can be prepared by modifying the 2,3-hydroxy group of asiatic acid to a 2,3-epoxy group and reacting various nucleophiles to cleave the epoxy. That is, the obtained compound (4) was reacted with methanesulfonyl chloride to obtain methyl 2-O-methanesulfonyl-3, 23-O-isopropylidene asiatate (18), which was treated with PTSA to give methyl 2 -O-methanesulfonylasiatate (19) is obtained. Again, this is treated with potassium carbonate in methanol solvent to synthesize methyl 2,3-epoxyasiatate (20). Compound 20 was treated with lithium iodide trihydrate and acetic acid to synthesize methyl 2-α-iodo-2-deoxyasiatate (21) having cleaved epoxide (see Scheme 7).

Method 8

Dihydroxy groups 3 and 23 of asiatic acid were protected with methylidene using dimethyl sulfoxide and trimethylsilyl chloride to synthesize a compound of the general formula (5, R ₆ = R ₇ = H), and a general formula (5) A compound of formula (23) can be obtained by reacting a compound of formula (22) with chloromethyloctyl ether obtained by treating a compound of formula with pyridinium dichromate (PDC) (see Scheme 8).

As a result of observing the effects of wound healing by inducing experimental wounds in rats, the results of the present invention are shown to be comparable to or better than the TECA of 1% Centella asiatica. Can be.

The dosage of the compound of Formula 1 is 10-100 mg per day for adults, and the dosage may be varied depending on the age and weight of the patient as well as the severity of symptoms.

The wound treatment of the present invention may be prepared according to a conventional ointment preparation method.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited thereto.

Example 1 Mass Separation and Purification of Asian Ticoside and Asian Acid

5 g of Centella asiatica quantitative extract was isolated by direct column chromatography (silica gel, 230-400 mesh; dichloromethane: methanol = 10: 1), and 1.5 g of asiatic acid, 1.4 g of madecassic acid, and asiaticoside and madeade 2.0 g of a mixture of carsosides were obtained. The resulting mixture was dissolved in a minimum amount of 60% methanol in a water bath at 100 ° C. and then cooled at room temperature to give pure asiaticoside as acicular crystals (melting point: 230-240 ° C.).

Separately, 62 g of the extract was dissolved in methanol (700 ml), 5N-sodium hydroxide solution (50 ml) was added and heated to reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, neutralized, filtered and dried to obtain 43 g of a mixture (2) of asiatic acid and madecassic acid.

Example 2: Preparation of 3,23-O-isopropylidene asiatic acid (3)

A mixture of asiatic acid and madecassic acid (12 g) and p-toluenesulfonic acid (200 mg) were dissolved in anhydrous DMF (100 ml), 2, 2-dimethoxypropane (5 ml) was added thereto, and stirred at room temperature for 14 hours. The reaction mixture was neutralized and concentrated under reduced pressure to remove the solvent. After extraction, washing and drying, the residue was separated by column chromatography (dichloromethane: methanol = 30: 1) to obtain 8.04 g of 3,23-O-isopropylidene asian acid (3).

IR (neat): 3440, 1698, 1200 cm ^-1

Mass (EI): m / e 528 (M ⁺ ), 513 (M ⁺ -Me), 482 (M ⁺ -HCOOME), 452, 424, 407, 248,

203, 189, 133

¹ H-NMR (CDCl ₃ ): δ 0.75, 1.04, 1.06, 1.09, 1.45, 1.46 (each s, 3H),

0.85 (d, 3H, J = 6.4 Hz), 0.95 (d, 3H, J = 6.4 Hz),

2.18 (d, 1H, J = 11.2 Hz), 3.32 (d, 1H, J = 9.6 Hz), 3.46,

3.51 (ABq, 2H, J = 10.8 Hz), 3.78 (m, 1H), 5.24 (brt, 1H)

Example 3 Preparation of Methyl 3,23-O-Isopropylidene Asiatate (4)

5 g of 3,23-O-isopropylidene asiatic acid (3) was dissolved in ether, and diazomethane ether solution was slowly added dropwise at 0 ° C, and stirred at room temperature for 1 hour. The ether was concentrated under reduced pressure to remove the residue. The residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) to give 4.9 g (95%) of methyl 3,23-O-isopropylidene asiatate (4). .

IR (neat): 3466, 1724, 1201 cm ^-1

Mass (EI): m / e 542 (M ⁺ ), 527 (M ⁺ -Me), 482 (M ⁺ -HCOOME), 483, 467, 451, 407,

262, 203, 189, 133

¹ H-NMR (CDCl ₃ ): δ 0.66, 0.97, 1.00, 1.02, 1.40, 1.39 (each s, 3H),

0.79 (d, 3H, J = 6.4 Hz), 0.87 (d, 3H, J = 6.0 Hz), 2.15 (d, 1H),

3.25 (d, 1H, J = 9.6 Hz), 3.41 3.43 (ABq, 2H), 3.53 (s, 3H),

3.72 (m, 1 H), 5.18 (brt, 1 H)

Example 4: Preparation of 3,23-O-alkylidene asiatic acid (5)

① R ₆ = H, R ₇ = H

Dimethyl sulfoxide (2.5 equiv) and trimethylsilyl chloride (2.5 equiv) were added to THF, followed by stirring, and the resultant was added (2) (2.53 g, 5.18 mmol) to the resultant, followed by heating under reflux for 3 days under argon. . The solvent was evaporated under reduced pressure and purified by column chromatography (dichloromethane: methanol = 20: 1) to give 2.01 g of a light brown solid. (Yield 79.45%)

H ¹ NMR (300 MHz, CDCl ₃ ) δ 0.75, 1.05, 1.08, 1.12 (each s, 3H),

0.85 (d, 3H, J = 6.18 Hz), 0.95 (d, 3H, J = 5.76 Hz),

2.19 (d, 1H, J = 10.9 Hz), 3.04, 3.76 (ABq, 2H, J = 10.11 Hz),

3.23 (d, 1H, J = 10.23 Hz), 3.87 (dt, 1H, J = 4.26 Hz, 10.02 Hz),

4.95 (d, d, 2H, J = 5.9 Hz), 5.24 (t, 1H)

② R ₆ = H, R ₇ = CH ₃

The obtained asian acid (255 mg, 0.52 mmol) was dissolved in p-toluenesulfonic acid and dried under reduced pressure in anhydrous THF, and CH ₃ CH (OEt) ₂ (0.15 ml) was added dropwise and stirred at room temperature for 2 hours. Saturated sodium carbonate was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate, washed, and dried. Separation and purification by column chromatography (dichloromethane: methanol = 20: 1) gave 178 mg of the compound. (Yield 66.2%)

IR (neat) 2926, 1695 cm ^-1

Mass (EI) m / e 514 [M ⁺ ]

H ¹ NMR (300 MHz, CDCl ₃ ) δ 5.14 (t, 1H), 4.64 (qt, 1H, J = 4.92 Hz),

3.75 (m, 1H), 3.63, 2.97 (ABq, 2H, J = 10.1 Hz),

3.17 (d, 1H, J = 10.4 Hz), 0.98, 0.95, 0.65 (each s, 3H),

0.85 (d, 3H, J = 5,49 Hz), 0.75 (d, 3H, J = 6.39 Hz)

③ R ₆ = H, R ₇ = C ₆ H ₅

The same method as in Example 4 ② was used except that C ₆ H ₅ CH (OMe) ₂ was used instead of CH ₃ CH (OEt) ₂ (yield: 1.31%).

IR (neat) 3437, 1696 cm ^-1

Mass (EI) m / e 576 [M ⁺ ] 578

H ¹ NMR (300 MHz, CDCl ₃ ) δ 7.52 to 7.49 (m, 2H), 7.37 to 7.35 (m, 3H),

5.53 (s, 1H), 5.24 (t, 1H), 3.90, 3.30 (ABq, 2H, J = 10.11 Hz),

3.47 (d, 1H, J = 10.47 Hz), 2.18 (d, 1H, J = 11.46 Hz), 1.19, 1.09, 1.07,

0.77 (each s, 3H), 0.93 (d, 3H, J = 6.09 Hz), 0.85 (d, 3H, J = 6.33 Hz)

④ R ₆ = CH ₃ , R ₇ = C ₂ H ₅

The same method as in Example 4 ② was used except that C ₂ H ₅ COCH ₃ was used instead of CH ₃ CH (OEt) ₂ (yield: 58.96%).

IR (neat) 3436, 1694 cm ^-1

Mass (EI) m / e 542 [M ⁺ ]

H ¹ NMR (300 MHz, CDCl ₃ ) δ 5.18 (t, 1H), 3.68, 3.47 (ABq, 2H, J = 4.26 Hz),

3.48 (d, 1H, J = 7.05 Hz), 2.12 (d, 1H, J = 10.65 Hz), 0.97, 0.89,

0.69 (each s, 3H)

⑤ R ₆ = CH ₃ , R ₇ = C ₃ H ₇

The same method as in ② of Example 4 was used except that C ₃ H ₇ COCH ₃ was used instead of CH ₃ CH (OEt) ₂ (yield: 43.01%).

IR (neat) 3369, 2928, 1694 cm ^-1

Mass (EI) m / e 558 [M ⁺ +2]

H ¹ NMR (300 MHz, CDCl ₃ ) δ 5.18 (t, 1H), 3.79-3.75 (m, 1H),

3.18 (d, 1H, J = 10.23 Hz), 3.67, 2.98 (ABq, 2H, J = 9.8 Hz),

2.12 (d, 1H, J = 10.65 Hz), 1.05, 1.01, 0.98, 0.69 (each s, 3H),

0.88 (d, 3H, J = 5.55 Hz), 0.79 (d, 3H, J = 6.39 Hz)

⑥ R ₆ -R ₇ =-(CH ₂ ) _5-

The same method as in (2) of Example 4 was used except that cyclohexanone was used instead of CH ₃ CH (OEt) ₂ .

Mass (EI) m / e

H ¹ NMR (300 MHz, CDCl ₃ ) δ 0.77, 0.96, 1.07 (each s, 3H),

0.85 (d, 3H, J = 6.33 Hz), 2.18 (d, 1H, J = 11.46 Hz),

3.24 (d, 1H, J = 9.51 Hz), 3.41, 3.59 (ABq, 2H, J = 10.47 Hz),

3.76 (dt, 1H, J = 8.54 Hz), 5.23 (t, 1H)

Example 5: Preparation of octyloxymethyl 3, 23-O-alkylidene asiatate (6)

① R ₆ = H, R ₇ = H

Compound 5 (258.4 mg, 0.52 mmol) obtained in ① of Example 4 was dissolved in anhydrous dichloromethane, diisopropylethylamine (0.18 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Chloromethyloctyl ether (0.1 ml) was added dropwise at 0 ° C. and stirred for 5 minutes. Methanol was added and the residue was subjected to column chromatography (dichloromethane: methanol = 30: 1) to give 138 mg of a white solid. (Yield 41.6%)

H ¹ NMR (400 MHz, CDCl ₃ ) δ 0.76, 1.05, 1.09, 1.13 (each s, 3H),

0.88 (d, 3H, J = 5.6 Hz), 0.95 (d, 3H, J = 6.36 Hz),

2.25 (d, 1H, J = 10.8 Hz), 3.04, 3.76 (ABq, 2H, J = 10.0 Hz),

3.22 (d, 1H, J = 10.8 Hz), 3.58 (m, 2H), 4.94 (d, d, 2H, J = 6.0 Hz),

5.21, 5.24 (ABq, 2H, J = 5.88 Hz), 5.26 (t, 1H)

② R ₆ = H, R ₇ = CH ₃

The same method as in ① of Example 5 was used except that Compound 5 obtained in ② of Example 4 was used instead of Compound 5 obtained in ① of Example 4.

IR (neat) 3481, 2927, 1732 cm ^-1

Mass (EI) m / e 656 [M ⁺ ]

H ¹ NMR (300 MHz, CDCl ₃ ) δ 5.22 (t, 1H), 5.20, 5.17 (ABq, 2H, J = 6.21 Hz),

4.69 (qt, 1H, J = 4.95 Hz), 3.84-3.77 (m, 1H), 3.69,

3.03 (ABq, 2H, J = 10.07 Hz), 3.55 (m, 2H), 2.22 (d, 1H, J = 11.16 Hz),

1.05, 1.00, 0.95, 0.72 (each s, 3H), 0.84 (d, 3H, J = 2.55 Hz),

0.82 (d, 3H, J = 2.19 Hz)

③ R ₆ = H, R ₇ = C ₆ H ₅

The same method as in ① of Example 5 was used except that Compound 5 obtained in ③ of Example 4 was used instead of Compound 5 obtained in ① of Example 4 (yield: 23.8%).

IR (neat) 3697, 1730 cm ^-1

Mass (EI) m / e 719 [M ⁺ +1]

④ R ₆ = CH ₃ , R ₇ = C ₂ H ₅

The same method as in ① of Example 5 was used except that Compound 5 obtained in ④ of Example 4 was used instead of 5 of the compound obtained in ① of Example 4 (yield: 58.96%).

IR (neat) 3469, 1733 cm ^-1

Mass (EI) m / e 684 [M ⁺ ]

H ¹ NMR (300 MHz, CDCl ₃ ) δ 5.16 (t, 1H), 5.14, 5.11 (ABq, 2H, J = 6.29 Hz),

3.68 (m, 1H), 3.48 (m, 2H,), 3.24 (d, 1H, J = 9.57 Hz),

2.16 (d, 1H, J = 11.5 Hz), 1.00, 0.96, 0.91, 0.66 (each s, 3H),

0.84 (d, 1H, J = 5.55 Hz), 0.76 (d, 1H, J = 5.73 Hz)

⑤ R ₆ = CH ₃ , R ₇ = C ₃ H ₇

The same method as in ① of Example 5 was used except that Compound 5 obtained in ⑤ of Example 4 was used instead of Compound 5 obtained in ① of Example 4 (yield: 80.2%).

IR (neat) 3468, 2927, 1729 cm ^-1

Mass (EI) m / e 698 [M ⁺ ]

H ¹ NMR (400 MHz, CDCl ₃ ) δ 5.26 to 5.20 (m, 2H), 5.10 (t, 1H),

3.87 to 3.84 (m, 1H), 3.60 to 3.56 (m, 2H), 2.27 (d, 1H),

1.08, 1.07, 1.03, 0.76 (each s, 3H), 0.94 (d, 3H, J = 5.84 Hz),

0.87 (d, 3H, J = 5.4 Hz)

⑥ R ₆ -R ₇ =-(CH ₂ ) _5-

The same method as in ① of Example 5 was used except that Compound 5 obtained in 6 of Example 4 was used instead of 5 obtained in ① of Example 4 (yield: 34%).

Mass (EI) m / e 710 [M ⁺ ], 667, 596, 567, 522, 521

H ¹ NMR (400 MHz, CDCl ₃ ) δ 0.75, 0.95, 1.03 (each s, 3H),

0.87 (d, 3H, J = 5.86 Hz), 1.09 (d, 3H, J = 3.9 Hz),

2.10 (d, 1H, J = 4.40 Hz), 3.35 (d, 1H, J = 9.77 Hz),

3.48, 3.52 (ABq, 2H, J = 11.24 Hz), 3.58 (m, 2H), 3.8 (m, 1H),

5.21, 5.24 (dd, 2H, J = 5.86 Hz), 5.26 (t, 1H)

Example 6 Preparation of Methyl 3, 23-O-isopropylidene-2-O-[(methylthio) thiocarbonyl] asiatate (7)

Sodium hydride (60% inorganic oil dispersion, 18.3 mg, 0.46 mmole), imidazole (2 mg) and tetrahydrofuran (Methyl 3, 23-O-isopropylidene asiatate (4) (50 mg, 0.092 mmole) 2 ml) was added, stirred for 30 minutes, and carbon disulfide (0.2 ml, excess) was added to reflux for 2 hours. Methyl iodide (0.1 ml, excess) was added thereto, and the mixture was further heated to reflux for 1 hour. The reaction mixture was treated with water and the solvent was evaporated under reduced pressure, extraction, washing and drying followed by purification by column chromatography (hexane / ethyl acetate = 10/1) to give 56 mg (yield: 96%) of a white solid.

IR (neat): 1723, 1233, 1057 cm ^-1

¹ H NMR (CDCl ₃ ) δ 5.78 (1H, m), 5.24 (1H, bt), 3.80 (1H, d, J = 10Hz), 3.60 (3H, s),

3.54, 3.58 (2H, dd, J = 7.2 Hz), 2.51 (3H, s), 2.23 (1H, d, J = 11.2 Hz),

0.94 (3H, d, J = 5.2 Hz), 0.84 (3H, d, J = 6 Hz), 0.73, 1.09, 1.11, 1.14,

1.41, 1.45 (each 3 H, s).

Example 7 Preparation of Methyl 2-deoxy-3, 23-O-isopropylidene asiatate (8)

To the obtained xanthate compound (7) (202 mg, 0.32 mmole), a catalytic amount of AIBN and benzene (10 ml) were added, and heated and refluxed, tributyltin hydride (0.26 ml, 0.96 mmole) was added thereto and stirred for 1 hour 30 minutes. . The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 10: 1) to give 168 mg (yield: 100%) of a white solid. The product was recrystallized from hexane to give needle crystals.

IR (neat): 1724 cm ^-1

MS (EI): 527 (M ⁺ +1), 512, 407, 262, 203, 133.

¹ H NMR (CDCl ₃ ) δ 5.25 (1H, bt), 3.60 (3H, s), 3.52 (1H, t),

3.44, 3.54 (2H, dd, J = 10 Hz), 2.23 (1H, d, J = 11.2 Hz), 0.94 (3H, d, J = 5.6 Hz),

0.86 (3H, d, J = 6.4 Hz), 0.73, 0.97, 1.07, 1.09, 1.42, 1.45 (3H, s, respectively)

Example 8 Preparation of Methyl 2-deoxyasiatate (9)

To the obtained compound (8) (460 mg, 0.87 mmol), tetrahydrofuran (10 ml) and 1N hydrochloric acid solution (1 ml) were added and stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure to completely remove the residue, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 3: 2) to give 402 mg (yield: 95%) of a white solid. The crude product obtained was recrystallized from ethyl acetate to give needle crystals.

IR (neat): 3400, 1724 cm ^-1

MS (EI): 486 (M ⁺ ), 426, 262, 203, 133

Example 9 Preparation of 2-Deoxyamic Acid (10)

LiI-3H ₂ O (450 mg, 2.39 mmoles) and 2,4,6-collidine (5 ml) were added to methyl 2-deoxyamate (9) (38 mg, 0.78 mmol) and heated to reflux for 10 hours. At reflux, the flask was covered with aluminum foil to shield the light. The reaction solution was concentrated under reduced pressure to remove collidine, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give a pale yellow solid, which was recrystallized from methanol and 280 mg (yield: 76%). Needle crystals were obtained.

IR (KBr): 3436, 1693 cm ^-1

MS (EI): 472 (M ⁺ ), 426, 248, 203, 133

¹ H NMR (CDCl ₃ + pyridine-d ₅ ) δ 5.21 (1H, bt, J = 2.8 Hz, 3.6 Hz),

3.60 (1H, t, J = 7.2 Hz, 8.2 Hz), 3.36, 3.70 (2H, dd, J = 10.0 Hz),

2.21 (1Hd, J = 11.2 Hz).

Example 10 Preparation of 2-deoxy-3, 23-O-isopropylidene asiatic acid (11)

The same preparation method as in Example 2 was used except that Compound 10 was used instead of the mixture of asiatic acid and madecassic acid. (Yield: 59.9%)

IR (neat) 2928, 1697 cm ^-1

H ¹ NMR (400 MHz, CDCl ₃ ) δ 5.25 (d, 1H), 3.52 (t, 1H), 2.17 (d, 1H),

1.44, 1.40, 1.10, 1.04, 0.98, 0.78 (each s, 3H), 0.95 (d, 3H, J = 6.4 Hz),

0.87 (d, 3H, J = 6.4 Hz)

Example 11 Preparation of Octyloxymethyl 2-Deoxy-3, 23-O-isopropylidene asiatate (12, R ₅ = octyloxymethyl)

Except for using Compound 11 instead of Compound 5 in ① of Example 5, the same production method as in ① of Example 5 was used. (Yield: 53.9%)

IR (neat) 2929, 1733 cm ^-1

Mass (EI) m / e 654 [M ⁺ ]

H ¹ NMR (500 MHz, CDCl ₃ ) δ 5.17 (t, 1H), 5.14, 5.12 (ABq, 2H, J = 6.02 Hz),

3.49 to 3.48 (m, 2H), 3.46, 3.34 (ABq, 2H, J = 6.17 Hz), 2.15 (d, 1H),

1.35, 1.32, 1.01, 0.96, 0.67 (each s, 3H), 0.87 (d, 3H, J = 7.04 Hz),

Example 12 Preparation of ethyloxymethyl 2-deoxy-3, 23-O-isopropylidene asiatate (12, R ₅ = ethoxymethyl)

In Example 5 ①, the same preparation method as in ① of Example 5 was used except that Compound 11 was used instead of Compound 5 and chloromethylethyl ether was used instead of chloromethyloctyl ether. (Yield: 46%)

IR (neat) 2929, 1733 cm ^-1

Mass (EI) m / e 570 [M ⁺ ]

H ¹ NMR (500 MHz, CDCl ₃ ) δ 5.16 (t, 1H), 5.16 (s, 2H),

3.60, 3.58 (ABq, 2H, J = 1.36 Hz), 3.45-3.35 (m, 3H), 2.15 (d, 1H),

1.45, 1.38, 1.34, 1.04, 0.98, 0.70 (each s, 3H),

0.88 (d, 3H, J = 6.32 Hz), 0.79 (d, 3H, J = 2.24 Hz)

Example 13: Preparation of Tetrahydropyranyl 2-deoxy-3, 23-O-isopropylidene asiatate (12, R ₅ = 2-tetrahydropyranyl)

Compound 11 (133 mg, 0.26 mmol) and pyridinium paratoluenesulfonate (catalyst amount) were dissolved in anhydrous dichloromethane and dihydropyran (0.07 ml) was added dropwise, followed by stirring at room temperature for 40 hours. After neutralization, the solvent was evaporated under reduced pressure, extraction, washing and drying, followed by column chromatography (hexane: ethyl acetate = 8: 1) to give 73 mg of a compound (12, R ₅ = 2-tetrahydropyranyl). (Yield: 47.2%)

IR (neat) 2945, 1733 cm ^-1

H ¹ NMR (400 MHz, CDCl ₃ ) δ 5.96 (t, 1 / 2H), 5.92 (t, 1 / 2H), 5.28 (t, 1 / 2H),

5.26 (t, 1 / 2H), 3.88 (t, 1H), 3.67 (t, 1H), 3.52 (t, 2H),

3.46 (t, 2H), 1.45, 1.42, 1.11, 1.05, 0.96 (each s, 3H),

0.87 (d, 3H, J = 6.4 Hz)

Example 14 Preparation of Methyl 2-O-octyloxymethyl-3,23-O-isopropylidene asiatate (13)

Except for using the compound 4 instead of compound 5 in ① of Example 5, the same production method as in ① of Example 5 was used.

IR (neat) 2927, 1728 cm ^-1

Mass (EI) m / e 684 [M ⁺ ]

H ¹ NMR (500 MHz, CDCl ₃ ) δ 5.18 (t, 1H), 4.73, 4.62 (ABq, 2H, J = 6.72 Hz),

3.70 to 3,65 (m, 1H), 3.53 (s, 3H), 3.35 (d, 1H, J = 9.76 Hz),

1.36, 1.33, 1.02, 1.01, 0.96, 0.66 (each s, 3H),

0.87 (d, 3H, J = 6.18 Hz), 0.79 (d, 3H, J = 6.46 Hz)

Example 15 Preparation of methoxymethyl 3, 23-O-isopropylidene asiatate (14, R ₅ = methoxymethyl)

In Example 1 of Example 5, Compound 3 was used instead of Compound 5, and chloromethyl methyl ether was used instead of chloromethyl octyl ether. (Yield 19%)

mp. 104-112 ℃

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.77, 1.04, 1.08, 1.11, 1.45, 1.46 (each s, 3H),

0.87 (d, 3H, J = 6.3 Hz), 0.96 (d, 3H, J = 5.7 Hz), 2.27 (d, 1H, J = 11.1 Hz),

3.32 (d, 1H, J = 9.6 Hz), 3.45 (s, 3H), 3.47 (d, 1H, 9.6 Hz),

3.55 (d, 1H, 9 Hz), 3.79 (m, 1H), 5.17 (d, 1H, 6 Hz),

5.20 (d, 2H, J = 6 Hz), 5.28 (t, 1H, J = 3.5 Hz)

IR (KBr) cm ^-1 3500, 2950, 1740, 1450, 1380, 1065, 925, 860

[α] _o ²³ = + 10.4 ° (c = 0.2, CHCl ₃ )

Example 16 Preparation of ethoxymethyl 3, 23-O-isopropylidene asiatate (14, R ₅ = ethoxymethyl)

In Example 5 ①, Compound 3 was used instead of Compound 5, and chloromethyl ethyl ether was used instead of chloromethyl octyl ether. (Yield 46%)

IR (neat): 3468, 1734 cm ^-1

MS (EI) m / z: 586 (M ⁺ )

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.27 (t, 1H), 5.23 (s, 2H), 3.74-3.82 (m, 1H),

3.66 (q, 2H, J = 7.6 Hz), 3.53, 3.44 (ABq, 2H), 3.32 (d, 1H, J = 9.6 Hz),

2.25 (d, 1H), 1.46, 1.44, 1.10 (ABq, 2H), 1.07, 1.03,

0.76 (each s, 3H), 1.22 (t, 3H, J = 6.8 Hz), 0.95 (d, 3H, J = 5.6 Hz),

0.86 (d, 3H, J = 6.4 Hz)

Example 17 Preparation of methoxyethoxymethyl 3, 23-O-isopropylidene asiatate (14, R ₅ = methoxyethoxymethyl)

In Example 5 ① was synthesized in the same manner as in Example 5 ① except that Compound 3 was used instead of Compound 5 and methoxyethoxymethyl chloride was used instead of chloromethyl octyl ether. (Yield 25%)

mp. 76-79 ℃

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.77, 1.04, 1.08, 1.11, 1.45, 1.46 (each s, 3H),

0.86 (d, 6.3 Hz, J = 3 Hz), 0.96 (d, 3H, J = 5.7 Hz), 2.2-0.9 (m, 21H),

2.26 (d, 1H, J = 10.2 Hz), 3.32 (d, 1H, J = 9.6 Hz), 3.39 (s, 3H),

3.47 (d, J = 9.0 Hz), 3.52 (d, 1H, J = 9.0 Hz), 3.55 (t, 2H, J = 5.1 Hz),

3.77 (m, 1H), 3.77 (t, 2H, J = 5.1 Hz), 5.26 (t, 1H, J = 3.6 Hz),

5.28 (s, 2 H)

IR (KBr) cm ^-1 3500, 2950, 1725, 1450, 1380, 1070, 940, 860

[α] _o ²⁴ = + 38.7 ° (c = 0.1, CHCl ₃ )

Example 18 Preparation of methoxymethyl 2-O-acetyl-3, 23-O-isopropylidene asiatate (15, R ₅ = methoxymethyl)

The obtained compound (14) (R ₅ = methoxymethyl, 139 mg, 0.24 mmol) was dissolved in pyridine, acetic anhydride (0.04 ml, 0.38 mmol) was added thereto and stirred for 2 days. Concentration under reduced pressure, dilution, washing and drying were performed by column chromatography (dichloromethane: methanol = 30: 1) to give a white solid 75 mg. (Yield 52%)

mp. 110-115 ℃

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.77, 1.09, 1.11, 1.12, 1.41, 1.43,

2.01 (each s, 3H), 0.86 (d, 3H, J = 6.3 Hz), 0.95 (d, 3H, J = 6 Hz),

2.27 (d, 1H, J = 10.8 Hz), 3.45 (s, 3H), 3.50 (d, 1H, J = 9.6 Hz),

3.52 (d, 1H, J = 9.6 Hz), 3.56 (d, 3H, J = 9 Hz), 5.0 (m, 1H),

5.17 (d, 1H, J = 6Hz), 5.20 (d, 1H, J = 6Hz), 5.27 (t, 1H, J = 3.5Hz)

IR (KBr) cm ^-1 2950, 2740, 1450, 1240, 1080, 1025, 950, 800

[α] _o ²⁴ = + 43.6 ° (c = 0.1, CHCl ₃ )

Example 19 Preparation of ethoxymethyl 2-O-acetyl-3, 23-O-isopropylidene asiatate (15, R ₅ = ethoxymethyl)

Example 18 Compound 14 used in the (R ₅ = methoxymethyl), except that instead of the compound 14 (R ₅ = ethoxymethyl) was synthesized in the same method as in Example 18. (Yield 91%)

mp. 136-137 ℃

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.85 (d, 3H, J = 6.1 Hz), 0.95 (d, 3H, J = 5.7 Hz),

1.01, 1.06, 1.08, 1.41, 1.43, 2.01 (each s, 3H), 0.9-2.2 (m, 20H),

1.21 (t, 7.3 Hz), 2.26 (d, 1H, 11.1 Hz), 3.48 (d, 1H, J = 9 Hz),

3.53 (d, 1H, J = 9 Hz), 3.54 (d, 1H, J = 10.7 Hz), 3.66 (q, 2H, J = 7.3 Hz),

5.00 (dt, 1H, 4.3, 10.7 Hz), 5.23 (s, 2H), 5.26 (t, 1H, J = 4.2 Hz)

[α] _o ²⁴ = -0.66 ° (c = 0.34, CCl ₄ )

Example 20 Preparation of ethoxymethyl 2-O-ethoxymethyl-3, 23-O-isopropylidene asiatate (16)

Compound 3 was used instead of compound 5 of ① of Example 5 and chloromethyl ethyl ether was used instead of chloromethyl octyl ether. (Yield 19%)

mp. 68-70 ℃

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.86 (d, 3H, J = 6.3 Hz), 0.95 (d, 3H, J = 5.7 Hz),

0.80, 1.05, 1.10, 1.41, 1.51 (each s, 3H), 0.9-2.2 (m, 20H),

1.22 (t, 3H, J = 7.2 Hz), 2.26 (d, 1H, J = 11.1 Hz), 3.35 (d, 1H, J = 9 Hz),

3.39 (d, 1H, J = 9 Hz), 3.46 (d, 1H, J = 9.6 Hz), 3.60 (q, 2H, J = 7.2 Hz),

3.76 (q, 2H, J = 7.2 Hz), 3.80 (dt, 1H, 4.2, 9.6 Hz), 4.67 (s, 2H),

5.24 (s, 2H), 5.27 (t, 1H, J = 3.6 Hz)

IR (KBr) cm ^-1 2950, 1715, 1450, 1380, 1020, 925, 860

[α] _o ²⁴ = + 33.1 ° (c = 0.1, CHCl ₃ )

Example 21 Preparation of Benzyloxymethyl 3, 23-O-Diacetylasiatate (17)

Compound 3 was used instead of compound 5 of ① of Example 5 and chloromethyl benzyl ether was used instead of chloromethyl octyl ether. (Yield 45%)

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.75, 0.85, 0.99, 1.10, 2.04, 2.09 (each s, 3H),

0.89 (d, 3H, J = 6.3 Hz), 0.9-2.2 (m, 21H), 2.27 (d, 1H, J = 12.9 Hz),

3.57 (d, J = 11.7 Hz), 3.83 (d, J = 11.7 Hz), 3.90 (dt, 1H, 3.9, 10.2 Hz),

4.68 (s, 2H), 5.04 (d, 1H, J = 10.2 Hz), 5.28 (t, 1H, J = 3.6 Hz),

5.32 (s, 3H), 7.34 (s, 5H)

IR (neat) cm ^-1 2950, 2740, 1450, 1380, 1065, 925, 860, 800

[α] _o ²⁵ = + 25.25 ° (c = 0.1, CHCl ₃ )

Example 22 Preparation of Methyl 2-O-methanesulfonyl-3, 23-O-isopropylidene asiatate (18)

Methyl 3, 23-O-isopropylidene asiatic acid (4) (354.7 mg, 0.65 mmol) was dissolved in 15 ml of dichloromethane, triethyl amine (82.4 mg, 0.72 mmol) and methanesulfonyl chloride (99.2 mg, 0.98 mmole) was added and stirred at 0 ° C. for 3 hours under a stream of nitrogen. After completion of the reaction, the solvent was removed, extracted, washed, dried and column chromatography (hexane: ethyl acetate = 2: 1) yielded 380 mg (yield: 93%) of pure compound 18 as a white solid.

¹ H NMR (CDCl ₃ ) δ 5.24 (1H, m), 4.69-4.62 (1H, m), 3.60 (3H, s),

3.57 (1H, d, J = 10.5 Hz), 3.53 (1H, d, J = 10.5 Hz),

3.49 (1H, d, J = 10.5 Hz), 3.01 (3H, s), 2.26-2.20 (1H, m),

2.23 (1H, bs), 1.44 (3H, s), 1.40 (3H, s), 1.11 (3H, s),

1.09 (3H, s), 1.07 (3H, s), 0.94 (3H, d, J = 6.0 Hz),

0.85 (3H, d, J = 7.0 Hz), 0.72 (3H, s)

Example 23 Preparation of Methyl 2-O-methanesulfonylasiatate (19)

The obtained compound (18) (1.2 g, 1.92 mmol) was dissolved in 30 ml of methanol, p-toluenesulfonic acid (480 mg, 2.52 mmol) was added, and the mixture was refluxed under nitrogen stream for 10 minutes. The reaction was neutralized, extracted, washed, dried and purified by column chromatography (hexane: ethyl acetate = 1: 1) to yield 1.06 g (yield: 94%) of pure compound (19) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 5.24 (1H, m), 4.77-4.74 (1H, m), 3.69 (1H, d, J = 10.5 Hz),

3.61 (3H, s), 3.44 (1H, d, J = 10.5 Hz), 3.20 (1H, bs), 3.10 (3H, s),

1.08 (3H, s), 1.07 (3H, s), 0.95 (3H, s), 0.94 (3H, d, J = 5.1 Hz),

0.85 (3H, d, J = 6.5 Hz), 0.74 (3H, s)

Example 24 Preparation of Methyl 2,3-Epoxyasiatate (20)

The obtained compound (19) (2.78 g, 4.77 mmol) was dissolved in 60 ml of methanol, potassium carbonate (1.32 g, 9.53 mmol) was added, and stirred at room temperature for 3 days under a nitrogen stream. After completion of the reaction, the solvent was removed, extracted, washed, dried and purified by column chromatography (hexane: ethyl acetate = 2: 1) to give 2.05 g (yield: 89%) of pure compound 20 as a white solid. .

Melting Point: 230 ~ 234 ℃

IR (KBr): 3400, 2920, 1730, 1430, 1450, 1200, 1040 cm ^-1

¹ H NMR (CDCl ₃ ) δ 5.27 (1H, m), 3.60 (3H, s), 3.56 (1H, m), 3.31 (1H, m),

3.27 (1H, m), 3.11 (1H, d, J = 4.0 Hz), 1.12 (3H, s), 1.06 (3H, s),

0.96 (3H, s), 0.94 (3H, d, J = 5.1 Hz), 0.86 (3H, d, J = 6.4 Hz),

0.74 (3H, s)

Example 25 Preparation of Methyl 2β-iodo-2-deoxyasiatate (21)

Compound 20 (24.5 mg, 0.05 mmol), LiI.3H ₂ O (98 mg, 10.3 eq) was dissolved in THF (5 ml), stirred, AcOH (0.5 ml) was added and reacted at room temperature under argon for 1 day, followed by dilution with water. Then, extracted with ethyl acetate, brine, washed with 10% Na ₂ S ₂ O ₃ solution, dried, column chromatography (hexane: ethyl acetate = 3: 1) to give a colorless solid 16.5mg. (Yield 53.3%)

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.74, 0.85, 1.02, 1.08 (each s, 3H),

0.86 (d, 3H, J = 6.3 Hz), 0.94 (d, 3H, J = 5.13 Hz),

2.24 (d, 1H, J = 11.2 Hz), 3.42, 3.72 (ABq, 2H, J = 12.7 Hz),

3.60 (s, 3H), 4.57 (dt, 1H), 5.25 (t, 1H)

Mass (EI) m / e 612 [M ⁺ ], 552, 467, 407, 349

Example 26 Preparation of 3,23-O-methylidene-2-oxoasiatic acid (22)

Compound 5 (R ₆ = R ₇ = H, 1.1 g 2.2 mmol) and pyridinium dichromate (0.83 g, 2.2 mmol) were dissolved in anhydrous dichloromethane, and acetic anhydride (0.62 ml) was added dropwise, followed by heating to reflux for 2 hours. . The reaction solution was diluted with ethyl acetate, filtered and column chromatographed (dichloromethane: methanol = 20: 1) to give compound 23 (0.32 g, yield 29.2%).

¹ H NMR (300MHz, CDCl ₃ ) δ

0.75, 1.02, 1.07, 1.13 (each s, 3H), 0.95 (d, 3H, J = 5.9 Hz),

0.85 (d, 3H, J = 6.3 Hz), 2.11-2.21 (m, 2H), 2.39 (d, 1H, J = 12.7 Hz),

3.42, 3.84 (ABq, 2H, J = 10.4 Hz), 4.10 (s, 1H), 4.69,

5.20 (ABq, 2H, J = 5.9 Hz), 5.23 (t, 1H)

Example 27 Preparation of Octyloxymethyl 3,23-O-methylidene-2-oxoasiatate (23)

Except for using the compound 22 in place of compound 5 in ① of Example 5, the same production method as in ① of Example 5 was used. (Yield: 44%)

¹ H NMR (300MHz, CDCl ₃ ) δ

0.78, 1.02, 1.10, 1.14 (each s, 3H), 0.87 (d, 3H, J = 7.3 Hz),

0.95 (d, 3H, J = 5.9 Hz), 2.13, 2.40 (ABq, 2H, J = 12.7 Hz),

2.27 (d, 1H, J = 11.5 Hz), 3.42, 3.84 (ABq, 2H, J = 10.1 Hz),

3.58 (dt, 2H, J = 5.6 Hz), 4.10 (s, 1H), 4.69, 5.24 (ABq, 2H, J = 6.1 Hz),

5.20-5.25 (m, 2H), 5.25 (t, 1H)

Experimental Example 1: wound healing effect of the compound of the present invention

Preparation of the formulation: ointment

Accurately weigh 200 mg of the Asian acid derivative of the present invention into a 20 ml syringe. Accurately weigh 6 g of propylene glycol, 3 g of glycol stearate and 1 g of white petrolatum. The syringe is immersed in a water bath at 80 ° C. to completely melt the contents and stir for about 5 minutes to ensure that the active ingredients are uniformly dispersed in the three bases. Into a separate syringe, put 10g of purified water warmed to 80 ℃. Connect two syringes to a three-way connector and repeat the infusion about 20 times on both sides to equalize the contents. The homogenized contents are placed in a container and slowly solidified at room temperature.

Experiment method

In order to evaluate the wound healing effects of newly synthesized asiatic acid derivatives and asiaticosides, asiatic acid and madecassic acid isolated from natural products, experimental wounds were made in rats, which were experimental animals, and their effects were examined. Among several methods of measuring wound healing effects based on the logic that wound wounds caused by trauma or necrosis are healed by tissue regeneration, such as granulation growth, Tensile Strength is measured until tension is recovered. Due to the fact that this increases evenly, the force until both sides of the wound open under traction is measured. On the other hand, this tensile strength measurement method is known to best reflect the quality and speed of regeneration in the incision wound.

Table 1 compares the wound healing effect of Centella asiatica (TECA), a synthesized asiatic acid derivative, using the tensile strength measurement method.

Wound Healing Effects of New Asiaticoside Derivatives Test substance Tensile Strength (g ± S.E.) Change rate Compound 6 (R ₆ = H, R ₇ = H) Compound 6 (R ₆ = H, R ₇ = CH ₃ ) Compound 6 (R ₆ = H, R ₇ = C ₆ H ₅ ) Compound 6 (R ₆ = CH ₃ , R ₇ = C ₂ H ₅ ) Compound 6 (R ₆ = CH ₃ , R ₇ = C ₃ H ₇ ) Compound 6 (R ₆ R ₇ =-(CH ₂ ) _5- ) TECA 274.44 ± 35.97241.25 ± 22.32237.78 ± 22.21212.22 ± 25.23235.56 ± 26.76237.5 ± 27.66228.33 ± 15.53 20.25.74.1-7.13.24.0 Compound 12 (R ₅ = CH ₂ C ₈ H ₁₇ ) Compound 12 (R ₅ = CH ₂ OC ₂ H ₅ ) Compound 12 (R ₅ = tetrahydropyranyl) Compound 13TECA 310.00 ± 37.08 248.89 ± 22.0 236 2.22 ± 27.57 257.70 ± 27.02 256.67 ± 24.19 20.78-3.0341.120.40

As can be seen in the experimental example, the asiatic acid derivatives of the present invention have an excellent effect in the treatment of wounds.

Claims (2)

Asian acid derivative represented by the following general formula (1) or a pharmaceutically acceptable salt or ester thereof. Wherein R ₁ represents hydroxy, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy, octyloxymethyloxy which may be protected by hydrogen, acetyl or benzyl; R ₂ represents hydrogen or a hydroxy group; R ₁ and R ₂ together may form an oxo group; R ₃ represents hydroxy or hydrogen which may be protected by acetyl or benzoyl; R ₂ and R ₃ together may form an epoxy group; R ₄ represents hydroxymethyl which may be protected by acetyl or benzoyl; R ₃ may form —OC (R ₆ ) (R ₇ ) OCH ₂ — with R ₄ , where R ₆ is hydrogen, lower alkyl or phenyl having 1 to 4 carbon atoms, and R ₇ is hydrogen, carbon number Lower alkyl or phenyl of 1 to 4 and R ₆ and R ₇ may together form — (CH ₂ ) ₅ —; R ₅ represents hydrogen, lower alkyl having 1 to 4 carbon atoms, alkoxymethyl having 1 to 4 carbon atoms, octyloxymethyl, methoxyethoxymethyl, benzyloxymethyl and 2-tetrahydropyranyl. A wound treating agent containing the asiatic acid derivative of Formula 1 or a pharmaceutically acceptable salt or ester thereof according to claim 1.