WO1998023574A1 - Asiatic acid derivatives and medicines for treating wounds, which contains the same - Google Patents
Asiatic acid derivatives and medicines for treating wounds, which contains the same Download PDFInfo
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- WO1998023574A1 WO1998023574A1 PCT/KR1997/000239 KR9700239W WO9823574A1 WO 1998023574 A1 WO1998023574 A1 WO 1998023574A1 KR 9700239 W KR9700239 W KR 9700239W WO 9823574 A1 WO9823574 A1 WO 9823574A1
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- NVTZKGZZKLZPCB-VKMLPVGISA-N C[C@@H](CCC1)C2C3=CCC([C@@](C)(C[C@H]4O)C(CC5)[C@@]6(C)[C@H]4OCOC6)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O Chemical compound C[C@@H](CCC1)C2C3=CCC([C@@](C)(C[C@H]4O)C(CC5)[C@@]6(C)[C@H]4OCOC6)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O NVTZKGZZKLZPCB-VKMLPVGISA-N 0.000 description 1
- NPCNNWYCAKNOLY-IPTMXWGHSA-N C[C@@H](CCC1)C2C3=CCC([C@@](C)(C[C@H]4O)C(CC5)[C@](C)(CO)[C@H]4O)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O Chemical compound C[C@@H](CCC1)C2C3=CCC([C@@](C)(C[C@H]4O)C(CC5)[C@](C)(CO)[C@H]4O)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O NPCNNWYCAKNOLY-IPTMXWGHSA-N 0.000 description 1
- XSEAHDNVIFMMHA-WJQDSBFZSA-N C[C@H](CC1)[C@H](C)C2C3=CCC([C@@](C)(CC4=O)C(CC5)[C@@]6(C)[C@H]4OCOC6)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O Chemical compound C[C@H](CC1)[C@H](C)C2C3=CCC([C@@](C)(CC4=O)C(CC5)[C@@]6(C)[C@H]4OCOC6)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O XSEAHDNVIFMMHA-WJQDSBFZSA-N 0.000 description 1
- OCKPHHNPBFJQMS-GINBCCHESA-N C[C@H](CC1)[C@H](C)C2C3=CCC([C@]4(C)C(CC5)C(C)(C)[C@H]6O[C@H]6C4)[C@]5(C)[C@]3(C)CC[C@@]12C(OC)=O Chemical compound C[C@H](CC1)[C@H](C)C2C3=CCC([C@]4(C)C(CC5)C(C)(C)[C@H]6O[C@H]6C4)[C@]5(C)[C@]3(C)CC[C@@]12C(OC)=O OCKPHHNPBFJQMS-GINBCCHESA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
- C07D303/06—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms in which the oxirane rings are condensed with a carbocyclic ring system having three or more relevant rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J61/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one or two atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
Abstract
The present invention relates to asiatic acid derivatives represented by formula (1), and medicines for treating wounds, which contains the same as an active component.
Description
TITLE OF INVENTION
ASIATIC ACID DERIVATIVES AND MEDICINES FOR TREATING WOUND, WHICH CONTAINS THE SAME
Technical Field
The present invention relates to asiatic acid derivatives represented by following chemical formula 1 :
Asiatic acid, madecassic acid and asiaticoside(trisaccharide of asiatic acid), which are compounds extracted from Centella asiatica, were isolated firstly by Bontems in 1941 [J. E. Bontems, Bull. Sci. Pharmacol, 49, 186-91(1941)] and their structures were defined by Polonsky [J. Polonsky, Compt. Rend., 232, 1978-80(1951); J. Polonsky, Bull. Soc. Chim., 173-80(1953)]. The extracts including asiatic acid and asiaticoside from Centella asiatica have been used for treatment of hurted skin or chronic ulcer since old times, and also for treatment deformation of skin due to tuberculosis or leprosy [P. Boiteau, A. Buzas, E. Lederer and J. Polonsky, Bull. Soc. Chim., 31, 46-51(1949)]. It is reported that the mechanism of these compounds for treating hurted skin comprises activating cells of Malpighean layer and inducing keratinization. [May. Anne, Eur. J. Pharmacol, 4(3), 331-9(1968)] Madecassol, a commercially available medicine for treating skin disease, also is a mixture of three components, i.e., asiaticoside (40%) with asiatic acid and madecassic acid (60%). It is known that remedial effect mainly comes from asiaticoside, trisaccharide of asiatic acid among the three components, and it is reported that asiatic acid itself has no remedial effect. [Kiesswetter, Wien. Med. Wochschr., 114(7), 124- 6(1964)] However, there has been a report proving that the above result is due to the difference in the absorption process of there compounds in body, and the material practically showing the remedial effect is asiatic acid itself. [L. F. Chasseaud, B. J. Fry, D. R. Hawkins, J. D. Lewis, T. Taylor and D. E. Hathway, Arzneim-Forsch, 21(9), 179-84(1971)] Thus, the synthesis and remedial effect of asiatic acid becomes the center of interest. However, total synthesis of asiatic acid requires quite many synthetic steps when starting from a simple starting material, so that the synthesis involves many problems due to its complicated process and economical disadvantage.
Disclosure of the Invention
The present inventors have synthesized various asiatic acid derivatives, starting from asiatic acid obtained from Centella asiatica. They also found that the derivatives have excellent effect for treating wound and completed the present invention.
The present invention relates to asiatic acid derivatives represented by following formula 1 ,
Method 1
Titrated extracts of Centella asiatica (TECA) is hydrolyzed to obtain a mixture of asiatic acid and madecassic acid (2), and the mixture is reacted with 2,2-dimethoxypropane in the presence of acid catalyst. The reaction product is purified by column chromatography to isolate 3,23-0- isopropylidene asiatic acid (3) in which 3,23-dihydroxy group is protected. The obtained product is treated with diazomethane to synthesize methyl 3,23-O-isopropylidene asiatate (4). [See Scheme 1.]
Scheme 1
2,2-dimethoxypropane titrated extract of , (asiatic acid + Centella asiatica (TECA) madecassic acid) 2
Method 2 Two hydroxy groups at 3- and 23 -position of asiatic acid are protected with various ketone or aldehyde group to synthesize compounds represented by general formula (5). [Provided that
and R7=H, the compound is synthesized by the use of dimethyl sulfoxide and trimethylsilyl chloride.] The compound of general formula (5) is treated
with chloromethyl octyl ether to synthesize a compound represented by general formula (6). [See Scheme 2.]
Scheme 2
chloromethyloctyl ether
(wherein, Rό and R7 are the same that are defined above.)
Method 3
The hydroxy group at 2-position of compound (4) obtained above is treated with sodium hydride and imidazole, to be converted to alkoxide group. Carbon disulfide is added thereto and the mixture is heated under reflux, and then treated with methyl iodide to obtain a xanthate (7). The resultant compound is treated with tributyltin hydride and catalytic amount of AIBN to give methyl 2-deoxy-3,23-0-isopropylidene asiatate
(8), which is then deprotected to obtain methyl 2-deoxyasiatate (9). The compound (9) above is hydrolyzed to obtain 2-deoxyasiatic acid (10). From 2-deoxyasiatic acid (10), 2-deoxy-3,23-0-isopropylidene asiatic acid (11) is synthesized, which is then reacted under the condition described in Method 2, to synthesize a compound represented by general formula (12). [See Scheme 3.]
Scheme 3
Methyl 2-0-octyloxymethyl-3,23-0-isopropylidene asiatate (13) is synthesized by means of Method 2 from compound (4) obtained above . [See Scheme 4.]
Scheme 4
Method 5
The compound (3) obtained above is reacted with an alkyl halide under the conditions of Method 2, to synthesize a compound represented by general formula (14), which is acetylated at 2-position to synthesize a compound represented by general formula (15). [See Scheme 5.]
Scheme 5
From the compound (3) obtained above, ethoxymethyl 2-0- ethoxymethyl-3,23-0-isopropylidene asiatate (16) is obtained under the same conditions of Method 2 but with prolonged reaction time. By means of the same method, benzyloxymethyl group is incorporated to COOH group at 28-position by using chloromethyl benzyl ether. The resultant compound is acetylated to synthesize benzyloxymethyl 3,23-0- diacetylasiatate (17). [See Scheme 6.]
Scheme 6
chloromethylethyl ether
Method 7 2,3-Hydroxy group of asiatic acid is converted to 2,3-epoxy group, and the obtained compound is reacted with a variety of nucleophilic compound to cause ring opening of epoxy group to prepare a series of novel compounds according to the present invention. In other words, the compound (4) obtained above is reacted with methanesulfonyl
chloride to obtain methyl 2-0-methanesulfonyl-3,23-0-isopropylidene asiatate (18), which is then treated with PTSA to give methyl 2-0- methanesulfonyl asiatate (19). The obtained compound is then treated with potassium carbonate in methanol solvent to synthesize methyl 2,3- epoxyasiatate (20). The compound (20) is treated with lithium iodide trihydrate and acetic acid to synthesize methyl 2- -iodo-2-deoxyasiatate (21) of which epoxide has been opened. [See Scheme 7.]
Scheme 7
HO' HO'
19 20
Method 8
Dihydroxy group at 3- and 23 -position of asiatic acid was methylidene protected by dimethylsulfoxide and trimethylsilyl chloride to
synthesize a compound represented by general formula (5, R6=R7=H), which is then treated with pyridinium dichromate (PDC) to obtain a compound represented by general formula (22). The resultant compound is reacted with chloromethyl octyl ether to give a compound represented by general formula (23). [See Scheme 8.]
Scheme 8
chloromethyloctyl ether
The asiatic acid derivatives according to the present invention exhibited comparable to or more excellent effect than that of control
agent, 1% quantitative extract of Centella asiatica (TECA).
The dose of compound of general formula (1) is 10 to 100 mg/day for an adult. The dose usually depends on age and body weight of a patient, as well as the condition of symptoms. The medicine for treating wound according to the present invention may be formulated into an ointment by means of conventional methods.
Best Mode for Carrying out the Invention
Now, The present invention is described with reference to Examples, Experimental Examples and Formulation Example. However, it should not be noted that the present invention is restricted to those examples.
Example 1: Isolation and purification of asiaticoside and asiatic acid in large scale Quantitative extract (5 g) of Centella asiatica was directly separated by column chromatography (silica gel, 230 - 400 mesh; dichloromethane/methanol = 10/1) to obtain asiatic acid (1.5 g), madecassic acid (1.4 g) and mixture (2.0 g) of asiaticoside and madecassoside. The obtained mixture was dissolved in minimum amount of 60% methanol, in a water bath at 100 °C , and then cooled at room temperature to give pure asiaticoside as needle-like crystalline. (m.p.: 230 - 240°C )
Separately, the extract (62 g) was dissolved in methanol (700 ml), and 5N sodium hydroxide solution(50ml) was added thereto, and the resultant mixture was heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, neutralized, filtered and dried to obtain a mixture (2, 43g) of asiatic acid and madecassic acid.
Example 2: Preparation of 3,23-O-Isopropylidene asiatic acid (3) The mixture (12 g) of asiatic acid and madecassic acid, and p- toluenesulfonic acid (200 mg) were dissolved in anhydrous DMF (100
ml), and 2,2-dimethoxypropane (5 ml) was added thereto by injection. The resultant mixture was stirred at room temperature for 14 hours, and then neutralized and concentrated under reduced pressure to remove the solvent. After extracting, washing and drying, the residue was purified by column chromatography (dichloromethane:methanol = 30: 1) to obtain 8.04 g of 3,23-O-isopropylidene asiatic acid (3).
IR (neat) : 3440, 1698, 1200 cm"1
Mass (El) : m/e 528 (M+), 513 (M+-Me), 482 (M+-HCOOME), 452, 424, 407, 248, 203, 189, 133 H-NMR (CDC13) : δ 0.75, 1.04, 1.06, 1.09, 1.45, 1.46 (each s, 3H),
0.85 (d, 3H, J=6.4Hz), 0.95 (d, 3H, J=6.4Hz), 2.18 (d, 1H, J=11.2Hz), 3.32 (d, 1H, J=9.6Hz), 3.46, 3.51(ABq, 2H, J=10.8Hz), 3.78 (m, 1H), 5.24 (bit, 1H)
Example 3: Preparation of Methyl 3,23-O-isopropyIideneasiatate (4)
3,23-O-Isopropylidene asiatic acid (3) (5 g) was dissolved in ethyl ether, and ethereal solution of diazomethane was slowly added dropwise thereto at 0°C . After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to remove ether, and the residue was purified by column chromatography (hexane:ethyl acetate = 3: 1) to obtain 4.9 g of methyl 3,23-O- isopropylidene asiatate (4) (95%). IR (neat) : 3466, 1724, 1201 cm-1
Mass (El) : m/e 542 (M+), 527 (M+-Me), 482 (M+-HCOOME), 483, 467, 451, 407, 262, 203, 189, 133
'H-NMR (CDCI3) : δ 0.66, 0.97, 1.00, 1.02, 1.40, 1.39 (each s, 3H), 0.79 (d, 3H, J=6.4Hz), 0.87 (d, 3H, J=6.0Hz), 2.15 (d, 1H), 3.25 (d, lH,J=9.6Hz), 3.41 3.43 (ABq, 2H), 3.53 (s, 3H), 3.72 (m, 1H), 5.18 (brt, 1H)
Example 4: Preparation of 3,23-O-alkylidene asiatic acid (5)
Dimethyl sulfoxide (2.5 eq.) and trimethylsilyl chloride (2.5 eq.) were added to THF with stirring. Asiatic acid (2) obtained above (2.53 g, 5.18 mmol) was added thereto, and the mixture was heated under reflux and argon atmosphere for 3 days. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (dichloromethane:methanol = 20: 1) to obtain 2.01 g of pale yellow solid (yield: 79.45%). H NMR (300MHz, CDCls) δ 0.75, 1.05, 1.08, 1.12 (each s, 3H),
0.85 (d, 3H, J=6.18Hz), 0.95 (d, 3H, J=5.76Hz), 2.19 (d, 1H, J=10.9Hz), 3.04, 3.76 (ABq, 2H, J=10.11Hz), 3.23 (d, 1H, J=10.23Hz), 3.87 (dt, 1H, J=4.26Hz, 10.02Hz), 4.95 (d,d, 2H, J=5.9Hz), 5.24 (t, 1H)
© Re=H, R7=CH3
Asiatic acid (255 mg, 0.52 mmol) obtained above was dried over p- toluenesulfonic acid under reduced pressure. Then the compound was dissolved in anhydrous THF, and CH3CH(OEt)2 (0.15 ml) was added dropwise thereto, and the resultant mixture was stirred at room temperature for 2 hours. To the reaction mixture, saturated solution of sodium carbonate was added by injection, and the solvent was removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate, washed and dried, and purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain 178 mg of title compound (yield: 66.2%).
IR (neat) 2926, 1695 cm"'
Mass (El) m/e 514 [M+]
Η NMR (300MHz, CDC13) δ 5.14 (t, 1H), 4.64 (qt, 1H, J=4.92Hz), 3.75 (m, 1H), 3.63, 2.97 (ABq, 2H, J=10.1Hz),
3.17 (d, 1H, J=10.4Hz), 0.98, 0.95, 0.65 (each s, 3H), 0.85 (d, 3H, J=5,49Hz), 0.75 (d, 3H, J=6.39Hz)
IR (neat) 3437, 1696 cm"1
Mass (El) m/e 576 [M+] 578
Η NMR (300MHZ, CDC13) δ 7.52 ~ 7.49 (m, 2H), 7.37 ~ 7.35(m, 3H), 5.53(s, 1H), 5.24(t, 1H), 3.90, 3.30(ABq, 2H, J=10.11Hz),
3.47(d, 1H, J=10.47Hz), 2.18 (d, 1H, J=1 1.46Hz), 1.19, 1.09, 4.07, 0.77 (each s, 3H), 0.93 (d, 3H, J=6.09Hz), 0.85 (d, 3H, J=6.33Hz)
Excepting from substituting C2HsCOCH3 for CH3CH(OEt)2, the same procedure as Example 4(2) was performed (yield:58.96%).
IR (neat) 3436, 1694 cm"1
Mass (El) m/e 542 [M+] Η NMR (300MHZ, CDC13) δ 5.18 (t, 1H), 3.68,
3.47 (ABq, 2H, J=4.26Hz), 3.48 (d, 1H, J=7.05Hz), 2.12(d, lH,J=10.65Hz), 0.97, 0.89, 0.69 (each s, 3H)
(!5) R6=CH3, R7=C3H7 Excepting from substituting C3H7COCH3 for CH3CH(OEt)2, the same procedure as Example 4(2) was performed (yield:43.01%).
IR (neat) 3369, 2928, 1694 cm"1
Mass (El) m/e 558 [M++2]
Η NMR (300MHz, CDC13) δ 5.18 (t, 1H), 3. 79 ~ 3.75 (m, 1H),
3.18 (d, 1H, J=10.23Hz), 3.67, 2.98 (ABq, 2H, J=9.8Hz), 2.12 (d, 1H, J=10.65Hz), 1.05, 1.01, 0.98, 0.69 (each s, 3H), 0.88 (d, 3H, J=5.55Hz), 0.79 (d, 3H, J=6.39Hz)
© R6-R7=-(CH2)5-
Excepting from substituting cyclohexanone for CH3CH(OEt)2, the same procedure as Example 4(2) was performed.
Mass (El) m/e
Η NMR (300MHZ, CDC13) δ 0.77, 0.96, 1.07 (each s, 3H), 0.85 (d, 3H, J=6.33Hz), 2.18 (d, 1H, J=11.46Hz),
3.24 (d, 1H, J=9.51Hz), 3.41, 3.59 (ABq, 2H, J=10.47Hz), 3.76 (dt, 1H, J=8.54Hz), 5.23 (t, 1H)
Example 5 : Preparation of octyloxymethyl 3, 23-O-alkylidene asiatate(6)
The compound 5(258.4mg, 0.52mmol) obtained in Example 4(T) above was dissolved in anhydrous dichloromethane. Diisopropylethylamine(0.18ml) was added thereto and stirred at room temperature for 10 minutes. At 0°C , chloromethyloctyl ether(O.lml) was added dropwise thereto and stirred for 5 minutes. Methanol was added thereto and the residue was refined by column chromatography (dichloromethane:methanol=30:l) to obtain 138mg of white solid (yield: 41.6%). 'H NMR (400MHz, CDC13) δ 0.76, 1.05, 1.09, 1.13 (each s, 3H), 0.88 (d, 3H, J=5.6Hz), 0.95 (d, 3H, J=6.36Hz),
2.25 (d, 1H, J=10.8Hz), 3.04, 3.76 (ABq, 2H, J=10.0Hz), 3.22 (d, 1H, J=10.8Hz), 3.58 (m, 2H), 4.94 (d,d, 2H, J=6.0Hz), 5.21, 5.24 (ABq, 2H, J=5.88Hz), 5.26 (t, 1H)
(2) R«=H, R7=CH3
Excepting from substituting compound 5 obtained in Example 4(2) for compound 5 obtained in Example 4® above, the same procedure as Example 5® was performed. IR (neat) 3481 , 2927, 1732 cm"1
Mass (El) m/e 656 [M+]
Η NMR (300MHz, CDC13) δ 5.22 (t, 1H), 5.20,
5.17 (ABq, 2H,J=6.21Hz), 4.69 (qt, 1H, J=4.95Hz),
3.84 -3.77 (m, 1H), 3.69, 3.03(ABq, 2H, J=10.07Hz), 3.55 (m, 2H), 2.22 (d, 1H, J=11.16Hz), 1.05, 1.00, 0.95, 0.72 (each s, 3H),
0.84 (d, 3H, J=2.55Hz), 0.82 (d, 3H, J=2.19Hz)
Excepting from substituting compound 5 obtained in Example 4(3) for compound 5 obtained in Example 4® above, the same procedure as Example 5® was performed (yield:23.8%).
IR (neat) 3697, 1730 cm"' Mass (El) m/e 719 [M++l]
Excepting from substituting compound 5 obtained in Example 4© for compound 5 obtained in Example 4® above, the same procedure as Example 5® was performed (yield:58.96%).
IR (neat) 3469, 1733 cm- 1 Mass (El) m/e 684 [M+]
Η NMR (300MHz, CDC13) δ 5.16 (t, 1H), 5.14,
5.11 (ABq, 2H, J=6.29Hz), 3.68(m,lH), 3.48 (m, 2H,),
3.24 (d, 1H, J=9.57Hz), 2.16(d, 1H,J=11.5Hz), 1.00, 0.96, 0.91,
0.66 (each s, 3H), 0.84(d,lH,J=5.55Hz), 0.76(d,lH,J=5.73Hz)
(5) R^=CH3, R7=C3H
Excepting from substituting compound 5 obtained in Example 4© for compound 5 obtained in Example 4® above, the same procedure as Example 5® was performed (yield:80.2%).
IR (neat) 3468, 2927, 1729 cm"1
Mass (El) m/e 698 [M+]
Η NMR (400MHz, CDC13) δ 5.26 - 5.20 (m, 2H), 5.10 (t, 1H), 3.87 - 3.84 (m, 1H), 3.60 -3.56 (m, 2H), 2.27 (d, 1H),
1.08, 1.07, 1.03, 0.76 (each s, 3H), 0.94 (d, 3H, J=5.84Hz), 0.87 (d, 3H, J=5.4Hz)
© R6-R7 = -(CH2)5- Excepting from substituting compound 5 obtained in Example 4© for compound 5 obtained in Example 4® above, the same procedure as Example 5® was performed (yield: 34%).
Mass (El) m/e 710 [M+], 667, 596, 567, 522, 521 Η NMR (400MHz, CDC13) δ 0.75, 0.95, 1.03 (each s, 3H), 0.87 (d, 3H, J=5.86Hz), 1.09 (d, 3H, J=3.9Hz),
2.10 (d, 1H, J=4.40Hz), 3.35 (d, 1H, J=9.77Hz), 3.48, 3.52 (ABq, 2H, J=l 1.24Hz), 3.58 (m, 2H), 3.8 (m, 1H), 5.21 , 5.24 (dd, 2H, J=5.86Hz), 5.26 (t, 1H)
Example 6 : Preparation of methyl 3, 23-0-isopropylidene-2-0- [(methylthio)thiocarbonyl]asiatate(7)
Sodium hydride(60% dispersion of inorganic oil, 18.3 mg, 0.46 mmole), imidazole(2 mg) and tetrahydrofuran(2 ml) were added to methyl 3, 23-O-isopropylidene asiatate (4) (50 mg, 0.092 mmole) and the
resultant mixture was stirred for 30 minutes. Carbon disulfιde(0.2 ml, excessive amount) was added thereto and refluxed for 2 hours. Methyl iodide (0.1 ml, excessive amount) was added thereto and heated under reflux again for 1 hour. The reactant mixture was treated with water and the solvent was removed under reduced pressure. After extracting, washing and drying the residue was refined by column chromatography (hexane: ethyl acetate = 10:1) to obtain 56 mg of white solid (yield : 96%).
IR(neat) : 1723, 1233, 1057 cm'' H NMR CDCls) δ 5.78(lH,m), 5.24(lH,bt), 3.80(lH,d,J=10Hz),
3.60(3H,s), 3.54, 3.58(2H,dd,J=7.2Hz), 2.51(3H,s), 2.23(lH,d,J=11.2Hz), 0.94(3H,d, J=5.2Hz), 0.84(3H,d,J=6Hz), 0.73, 1.09, 1.11, 1.14, 1.41, 1.45 (each 3H,s).
Example 7 : Preparation of methyl 2-deoxy-3, 23-O-isopropylidene asiatate(8)
A catalytic amount of AIBN and benzene(lθml) were added to xanthate compound (7)(202mg, 0.32mmole) obtained above. Tributyltin hydride(0.26ml, 0.96mmole) was added thereto with the resultant heated under reflux and stirred for 1 hour and a half. The reactant mixture was concentrated under reduced pressure and the solvent was removed. The obtained residue was refined by column chromatography (hexane: ethyl acetate = 10:1) to obtain 168 mg of white solid (yield : 100%). The product was recrystallized with hexane to yield needle-like crystalline. IR (neat) : 1724 cm"
MS (El) : 527(M++1), 512, 407, 262, 203, 133.
Η NMR (CDC13) δ 5.25(lH,bt), 3.60(3H,s), 3.52(lH,t), 3.44, 3.54(2H,dd,J=10Hz), 2.23(lH,d,J=11.2Hz), 0.94 (3H, d, J=5.6Hz), 0.86(3H,d,J=6.4Hz), 0.73, 0.97, 1.07, 1.09, 1.42, 1.45(each 3H,s)
Example 8 : Preparation of methyl 2-deoxyasiatate(9)
Tetrahydrofuran(10 ml) and IN HC1 solution(lml) were added to compound(8) (460mg, 0.87mmole) obtained above and stirred at room temperature for 5 hours. The solvent was totally removed by distillation under reduced pressure. The obtained residue was refined by column chromatography (hexane: ethyl acetate = 3:2) to obtain 402 mg of white solid (yield : 95%). The crude product obtained was recrystallized with ethyl acetate to yield needle-like crystalline. IR (neat) : 3400, 1724 cm"1
MS (El) : 486(M+), 426, 262, 203, 133
Example 9 : Preparation of 2-deoxyasiatic acid (10)
LiI-3H20 (450mg, 2.39mmole) and 2,4,6-colidine(5ml) was added to methyl 2-deoxyasiatate (9) (38mg, 0.78mmole) and heated under reflux for 10 hours. The flask was covered with aluminium foil to block light during reflux. The reactant solution was concentrated under reduced pressure to remove collidine. The obtained residue was refined by column chromatography(dichloromethane:methanol=20: l) to obtain pale yellow solid (yield : 99%). The product obtained was recrystallized with methanol to yield 280 mg of needle-like crystalline(yield : 76%).
IR (KBr) : 3436, 1693 cm"1
MS (El) : 472(M+), 426, 248, 203, 133
H NMR CCDCla + pyridine-ds) δ 5.21(lH,bt,J=2.8Hz,3.6Hz), 3.60(lH,t,J=7.2Hz,8.2Hz), 3.36, 3.70 (2H,dd,J=10.0Hz),
2.21(lH,d,J=11.2Hz).
Example 10 : Preparation of 2-deoxy-3, 23-O-isopropylidene asiatic acid (11) Excepting from substituting compound 10 for the mixture of
asiatic acid and madecassic acid, the same procedure as Example 2 was performed (yield:59.9%).
IR (neat) 2928, 1697 cm"1
'H NMR (400MHz, CDC13) 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=6.4Hz), 0.87 (d, 3H, J=6.4Hz)
Example 11 : Preparation of octyloxymethyl 2-deoxy-3, 23-0- isopropylidene asiatate(12, R5=octyloxymethyl) Excepting from substituting compound 11 for compound 5 in
Example 5® above, the same procedure as Example 5® was performed (yield:53.9%).
IR (neat) 2929, 1733 cm"1
Mass (El) m/e 654 [M+] Η NMR (500MHz, CDC13) δ 5.17 (t, 1H), 5.14,
5.12 (ABq, 2H, J=6.02Hz), 3.49 -3.48 (m, 2H),
3.46, 3.34(ABq,2H,J=6.17Hz), 2.15 (d, 1H), 1.35, 1.32, 1.01,
0.96, 0.67 (each s, 3H), 0.87 (d, 3H, J=7.04Hz),
Example 12 : Preparation of ethyloxymethyl 2-deoxy-3, 23-0- isopropylidene asiatate(12, R5=ethoxymethyl)
Excepting from substituting compound 11 for compound 5 in Example 5® and substituting chloromethylethyl ether for chloromethyloctyl ether, the same procedure as Example 5® was performed (yield:46%).
IR (neat) 2929, 1733 cm"1
Mass (El) m/e 570 [M+]
Η NMR (500MHz, CDC13) δ 5.16 (t, 1H), 5.16 (s, 2H),
3.60, 3.58(ABq, 2H, J=1.36Hz), 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=6.32Hz), 0.79 (d, 3H, J=2.24Hz)
Example 13 : Preparation of tetrahydropyranyl 2-deoxy-3, 23-0- isopropylidene asiatate (12, Rs=2-tetrahydropyranyl)
Compound l l(133mg, 0.26mmol) and pyridinium paratoluene sulfonate(catalytic amount) were dissolved in anhydrous dichloromethane. Dihydropyrane(0.07ml) was added dropwise thereto and stirred at room temperature for 40 hours. The resultant was neutralized and the solvent was removed under reduced pressure. After extracting, washing and drying, the residue was refined by column chromatography (hexane :ethyl acetate=8: l) to 73mg of compound(12, R5=2 -tetrahydropyranyl) (yield:47.2%).
IR (neat) 2945, 1733 cm"1 Η NMR (400MHz, CDC13) 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=6.4Hz)
Example 14 : Preparation of methyl 2-0-octyloxymethyl-3,23-0- isopropylidene asiatate (13)
Excepting from substituting compound 4 for compound 5 in Example 5®, the same procedure as Example 5® was performed.
IR (neat) 2927, 1728 cm"1 Mass (El) m/e 684 [M+]
Η NMR (500MHz, CDC13) δ 5.18 (t, 1H), 4.73,
4.62 (ABq, 2H, J=6.72Hz), 3.70-3,65 (m, 1H), 3.53 (s, 3H),
3.35 (d, 1H, J=9.76Hz), 1.36, 1.33, 1.02, 1.01, 0.96,
0.66 (each s, 3H), 0.87 (d, 3H, J=6.18Hz), 0.79 (d, 3H, J=6.46Hz)
Example 15 : Preparation of methoxymethyl 3, 23-O-isopropylidene asiatate (14, R5=methoxy methyl)
Excepting from substituting compound 3 for compound 5 in Example 5® and substituting chloromethylmethyl ether for chloromethyloctyl ether, the same procedure as Example 5® was performed (yield: 19%). mp. 104-1121C
H NMR (300MHz, CDC13): δ 0.77, 1.04, 1.08, 1.11 , 1.45,
1.46(each s, 3H), 0.87 (d, 3H, J=6.3Hz), 0.96(d, 3H, J=5.7Hz), 2.27 (d, 1H, J=l 1.1Hz), 3.32 (d, 1H, J=9.6Hz), 3.45 (s, 3H), 3.47 (d,
1H, 9.6Hz), 3.55 (d, 1H, 9Hz), 3.79 (m, 1H), 5.17 (d, 1H, 6Hz), 5.20 (d, 2H, J=6Hz), 5.28 (t, 1H, J=3.5Hz)
IR (KBr) cm"' 3500, 2950, 1740, 1450, 1380, 1065, 925, 860
[ α ]o 23 = +10.4° (c=0.2, CHC13)
Example 16 : Preparation of ethoxymethyl 3, 23-O-isopropylidene asiatate (14, R5=ethoxy methyl)
Excepting from substituting compound 3 for compound 5 in Example 5® and substituting chloromethylethyl ether for chloromethyloctyl ether, the same procedure as Example 5® was performed (yield :46%).
IR (neat) : 3468, 1734 cm"1
MS (El) m/z : 586 (M+)
H NMR (400 MHz, CDC13) δ 5.27 (t,lH), 5.23 (s,2H), 3.74 - 3.82 (m,lH), 3.66 (q,2H,J=7.6Hz), 3.53, 3.44 (ABq, 2H),
3.32 (d, 1H, J=9.6Hz), 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=6.8Hz), 0.95 (d, 3H, J=5.6Hz), 0.86 (d, 3H, J=6.4Hz)
Example 17 : Preparation of methoxyethoxymethyl 3, 23-0- isopropylidene asiatate (14, R5=methoxyethoxy methyl)
Excepting from substituting compound 3 for compound 5 in Example 5® and substituting methoxyethoxymethyl chloride for chloromethyloctyl ether, the same procedure as Example 5® was performed (yield:25%). mp. 76-79 °C
H NMR (300MHz, CDC13): δ 0.77, 1.04, 1.08, 1.11, 1.45,
1.46 (each s, 3H), 0.86 (d, 6.3Hz, J=3Hz), 0.96 (d, 3H, J=5.7Hz), 2.2-0.9 (m, 21H), 2.26 (d, 1H, J=10.2Hz), 3.32 (d, 1H, J=9.6Hz),
3.39 (s, 3H), 3.47 (d, J=9.0Hz), 3.52 (d, 1H, J=9.0Hz), 3.55 (t, 2H, J=5.1Hz), 3.77 (m, 1H), 3.77 (t, 2H, J=5.1Hz),
5.26 (t, 1H, J=3.6Hz), 5.28 (s, 2H)
IR (KBr) cm"13500, 2950, 1725, 1450, 1380, 1070, 940, 860
2 [ a ]0 =+38.7 (c=0.1,CHCl3)
Example 18 : Preparation of methoxymethyl 2-0-acetyl-3, 23-0- isopropy lideneasiatate(l 5, R5=methoxy methyl)
Compound(14)(R5=methoxymethyl, 139mg, 0.24mmol) obtained above was dissolved in pyridine and stirred. Acetic anhydride(0.04ml, 0.38mmol) was added thereto and stirred for 2 days. The resultant was concentrated under reduced pressure , washed, dried and refined by column chromatography (dichloromethane:methanol=30: l) to 75mg of white solid (yield:52%). mp. 110-115 °C
H NMR (300MHz, CDCI3): δ 0.77, 1.09, 1.11, 1.12, 1.41, 1.43, 2.01 (each s, 3H), 0.86 (d, 3H, J=6.3Hz), 0.95 (d, 3H, J=6Hz),
2.27 (d, 1H, J=10.8Hz), 3.45 (s, 3H), 3.50 (d, 1H, J=9.6Hz), 3.52 (d, 1H, J=9.6Hz), 3.56 (d, 3H, J=9Hz), 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 2950, 2740, 1450, 1240, 1080, 1025, 950, 800
24
[ a ]0 =+43.6° (c=0.1,CHCl3)
Example 19 : Preparation of ethoxymethyl 2-0-acetyl-3, 23-0- isopropylideneasiatate(15, Rs=ethoxy methyl)
Excepting from substituting compound 14 (R5=ethoxymethyl) obtained for compound 14 (R5=methoxymethyl) used in Example 18, the same procedure as Example 18 was performed (yield:91%). mp. 136-137°C H NMR (300MHz, CDC13): δ 0.85 (d, 3H, J=6.1Hz), 0.95 (d, 3H, J=5.7Hz), 1.01, 1.06, 1.08, 1.41, 1.43, 2.01 (each s, 3H), 0.9-2.2 (m, 20H), 1.21 (t, 7.3Hz), 2.26 (d, 1H, 11.1Hz), 3.48 (d, 1H, J=9Hz), 3.53 (d, 1H, J=9Hz), 3.54 (d, 1H, J=10.7Hz), 3.66 (q, 2H, J=7.3Hz), 5.00 (dt, 1H, 4.3, 10.7Hz), 5.23 (s, 2H), 5.26 (t, 1H, J=4.2Hz)
2
[ a ]0 = -0.66 (c=0.34, CCI4)
Example 20 : Preparation of ethoxymethyl 2-0-ethoxymethyl-3, 23- O-isopropylideneasiatate (16) Excepting from substituting compound 3 for compound 5 obtained in Example 5® above, and substituting chloromethylethyl ether for chloromethyloctyl ether , the same procedure as Example 5® was performed (yield: 19%). mp. 68-70 °C H NMR (300MHz, CDCI3): δ 0.86 (d, 3H, J=6.3Hz),
0.95 (d, 3H, J=5.7Hz), 0.80, 1.05, 1.10, 1.41, 1.51 (each s, 3H), 0.9-2.2 (m, 20H), 1.22 (t, 3H, J=7.2Hz), 2.26 (d, 1H, J=l 1.1Hz), 3.35 (d, 1H, J=9Hz), 3.39 (d, 1H, J=9Hz), 3.46 (d, 1H, J=9.6Hz), 3.60 (q, 2H, J=7.2Hz), 3.76 (q, 2H, J=7.2Hz),
3.80 (dt, 1H, 4.2, 9.6Hz), 4.67 (s, 2H), 5.24 (s, 2H), 5.27 (t, 1H, J=3.6Hz)
IR (KBr) cm"1 2950, 1715, 1450, 1380, 1020, 925, 860 [ tf ]0 24= +33.1 ° (c=0.1, CHCl3)
Example 21 : Preparation of benzyloxymethyl 3, 23-O-diacetyl asiatate (17)
Excepting from substituting compound 3 for compound 5 obtained in Example 5® and substituting chloromethylbenzyl ether for chloromethyloctyl ether , the same procedure as Example 5® was performed and then synthesized through acetylization (yield:45%).
H NMR (300MHz, CDC13): δ 0.75, 0.85, 0.99, 1.10, 2.04, 2.09 (each s, 3H),
0.89 (d, 3H, J=6.3Hz), 0.9-2.2 (m, 21H), 2.27 (d, 1H, J=12.9Hz), 3.57 (d, J=11.7Hz), 3.83 (d, J=11.7Hz), 3.90 (dt, 1H, 3.9, 10.2Hz),
4.68 (s, 2H), 5.04 (d, 1H, J=10.2Hz), 5.28 (t, 1H, J=3.6Hz), 5.32 (s, 3H), 7.34 (s, 5H)
IR (neat) cm"1 2950, 2740, 1450, 1380, 1065, 925, 860, 800
[ ff ]0 25 = +25.25° (c=0.1, CHCl3)
Example 22 : Preparation of methyl 2-0-methanesulfonyl-3, 23-0- isopropylideneasiatate (18)
Methyl 3, 23-O-isopropylidene asiatic acid (4) (354.7mg, 0.65mmole) was dissolved in dichloromethane(15ml). Triethyl amine(82.4mg, 0.72mmole) and methanesulfonyl chloride(99.2mg, 0.98mmole) were added thereto and stirred at 0°C for 3 hours under nitrogen atmosphere. After the reaction was finished, the solvent was removed. After extracting, washing and drying, the residue was refined by column chromatography (hexane:ethyl acetate=2: l) to 380mg of pure
compound (18) as white solid (yield:93%).
H NMR (CDCI3) δ 5.24(1H, m), 4.69-4.62 (1H, m), 3.60 (3H, s), 3.57 (1H, d ,J=10.5Hz), 3.53 (1H, d, J=10.5Hz), 3.49 (1H, d, J=10.5Hz), 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=6.0Hz), 0.85 (3H, d, J=7.0Hz), 0.72(3H,s)
Example 23 : Preparation of methyl 2-O-methanesulfonyl asiatate (19)
The compound(18) (1.2g, 1.92mmole) obtained above was dissolved in methanol(30ml). p-toluenesulfonic acid(480mg, 2.52mmole) was added thereto and refluxed for 10 minutes under nitrogen atmosphere. The reactant was neutralized, extracted, washed, dried and refined by column chromatography (hexane:ethyl acetate=l :l) to obtain 1.06g of pure compound (19) as colorless oil(yield : 94%).
H NMR (CDC13) δ 5.24 (1H, m), 4.77-4.74 (1H, m),
3.69 (1H, d, J=10.5Hz), 3.61 (3H,s), 3.44 (1H, d, J=10.5Hz),
3.70 (1H, bs), 3.10 (3H, s), 1.08 (3H, s), 1.07 (3H, s), 0.95 (3H, s), 0.94 (3H, d, J=5.1Hz), 0.85 (3H, d, J=6.5Hz), 0.74 (3H, s)
Example 24 : Preparation of methyl 2,3-epoxyasiatate (20)
The compound(19) (2.78g, 4.77mmole) obtained above was dissolved in methanol(60ml). Potassium carbonate(1.32g, 9.53mmole) was added thereto and stirred at room temperature for 3 days under nitrogen atmosphere. After the reaction was finished, solvent was removed. After extracting, washing and drying, the residue was refined by column chromatography (hexane : ethyl acetate=2: l) to obtain 2.05g of pure compound (20) as white solid (yield : 89%). m.p. : 230-234 °C
IR (KBr) : 3400, 2920, 1730, 1430, 1450, 1200, 1040 cm"1
Η NMR (CDC13) δ 5.27 (lH, m), 3.60 (3H, s), 3.56 (lH, m), 3.31 (1H, m), 3.27 (lH,m), 3.11 (1H, d, J=4.0Hz), 1.12 (3H, s), 1.6 (3H, s), 0.96 (3H, s), 0.94 (3H, d, J=5.1Hz), 0.86 (3H, d, J=6.4Hz), 0.74 (3H, s)
Example 25 : Preparation of methyl 2 β -iodo-2-deoxyasiatate(21)
Compound 20(24.5mg, 0.05mmol), Lil • 3H20(98mg, 10.3eq) were dissolved in THF(5ml). AcOH(0.5ml) was added thereto with stirring, and the resultant was reacted for 1 day under argon atmosphere. The resultant was diluted with water, extracted with ethyl acetate, washed with brine and 10% Na2S2θ3 solution, dried, and refined by column chromatography(hexane: ethyl acetate = 3: 1) to obtain 16.5mg of colorless solid (yield: 53.3%). H NMR (300MHz, CDC13): δ 0.1 , 0.85, 1.02, 1.08 (each s, 3H),
0.86 (d, 3H, J=6.3Hz), 0.94 (d, 3H, J=5.13Hz), 2.24 (d, 1H, J=l 1.2Hz), 3.42, 3.72 (ABq, 2H, J=12.7Hz), 3.60 (s, 3H), 4.57 (dt, 1H), 5.25 (t, 1H)
Mass (El) m/e 612 [M+], 552, 467, 407, 349
Example 26 : Preparation of 3,23-0-methylidene-2-oxoasatic acid(22)
Compound 22(1. lg 2.2mmole) and pyridinium dichromate(0.83g, 2.2mmole) were dissolved in anhydrous dichloromethane. Acetic anhydride (0.62ml) was added thereto and heated under reflux for 2 hours. The reactant was diluted with ethyl acetate, filtrated and refined by column chromatography (dichloromethane : methanol = 20 : 1) to obtain compound 23(0.32g, yield 29.2%)
H NMR (300MHz, CDC13) δ
0.75, 1.02, 1.07, 1.13 (each s, 3H), 0.95 (d, 3H, J=5.9Hz), 0.85 (d, 3H, J=6.3Hz), 2.1 1-2.21 (m, 2H), 2.39 (d, 1H, J=12.7Hz),
3.42, 3.84 (ABq, 2H, J=10.4Hz), 4.10 (s, 1H), 4.69, 5.20 (ABq, 2H, J=5.9Hz), 5.23 (t, 1H)
Example 27 : Preparation of Octyloxymethyl 3,23-0-methylidene-2- oxoasiatate(23)
Except from substituting compound 22 for compound 5 used in Example 5®, the same procedure as Example 5® was performed(yield : 44%).
H NMR (300MHz, CDC13) δ 0.78, 1.02, 1.10, 1.14 (each s, 3H), 0.87 (d, 3H, J=7.3Hz), 0.95 (d, 3H, J=5.9Hz), 2.13,
2.40 (ABq, 2H, J=12.7Hz), 2.27 (d, 1H, J=l 1.5Hz), 3.42,
3.84 (ABq, 2H, J=10.1Hz), 3.58 (dt, 2H, J=5.6Hz), 4.10 (s, 1H),
4.69, 5.24 (ABq, 2H, J=6.1Hz), 5.20-5.25 (m, 2H), 5.25 (t, 1H)
Experimental Example 1: Effect of the compounds according to the present invention on treating wound Formulation : Ointment
The asiatic acid derivative (200 mg) according to the present invention was accurately weighed and placed in a 20 ml syringe. Propylene glycol (6 g), glycol stearate (3 g) and white petrolatum (1 g) were accurately weighed and added thereto. The content of the syringe was completely melted in a water bath at 80 °C , and stirred for about 5 minutes so that the active component could be homogeneously dispersed in three kinds of vehicles mentioned above. Separately, purified water (10g) warmed to 80 °C was placed in another syringe. The above two syringes were connected by a threeway connector, and injecting from both side was repeated about 20 times to homogenize the content. The homogenized content was put into a vessel and slowly solidified at room temperature.
Experimental method
In order to examine the effect of newly systhesized asiatic acid derivatives, asiatic acid, madecassic acid and asiaticoside isolated from natural substance on treating wound, experimental wound have been made on rats, and the results have been watched. Among several measuring processes for wound-treating effect, which are based on the logic that the wound or the lesion owing to necrosis is treated by reproduction of tissue such as granulation, measuring of tensile strength is due to the fact that the tensile strength increases constantly until the recovering site becomes open again. In the measurement, the strength up to the point when the wounded site becomes open is measured, while both sides of the wound are pulled. It is known that the measuring of tensile strength reflects the quality and rate of reproduction in case of incised wound very well. In Table 1, the effect of synthesized asiatic acid derivatives and that of titrated extracts of Centella asiatica (TECA), which is the main component of commercially available madecassol ointment, on treating wound were examined and compared, by using measurement of tensile strength.
Table 1. Effect of novel asiaticoside derivatives on treating wound
As can be seen from the Experimental Examples described above, the asiatic acid derivatives according to the present invention showed excellent effect on treating wound.
Claims
1. An asiatic acid derivative represented by general formula 1, or pharmaceutically acceptable salt or ester thereof.
(methylthio)thiocarbonyloxy, a halogen, ethoxymethyloxy or octyloxymethyloxy group; R2 represents hydrogen or hydroxy group; R] and R2 may form an oxo group; R3 represents hydroxy group which may be protected by acetyl or benzoyl group, or hydrogen; R2 and R3 may form an epoxy group; R» represents hydroxymethyl group which may be protected by acetyl or benzoyl group; R3 and R4 may form - OC(R6)(R7)OCH2- [wherein, R^ is hydrogen, a lower alkyl group having 1 to 4 carbon atoms, or phenyl group, R7 represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms or phenyl group, and R6 and R may form -(CH2)5-]; R5 represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms, an alkoxymethyl group having 1 to 4 carbon atoms, octyloxymethyl, methoxyethoxymethyl, benzyloxymethyl or 2- tetrahydropiranyl group,
2. A medicine for treating wound, which comprises an asiatic acid derivative represented by general formula 1, or pharmaceutically acceptable salt or ester thereof according to claim 1.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97913517A EP0971873A1 (en) | 1996-11-27 | 1997-11-27 | Asiatic acid derivatives and medicines for treating wounds, which contains the same |
| JP52455298A JP2001506598A (en) | 1996-11-27 | 1997-11-27 | Asiatic acid derivative and wound treating agent containing the same |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR19960058175 | 1996-11-27 | ||
| KR1996/58175 | 1996-11-27 |
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| Country | Link |
|---|---|
| EP (1) | EP0971873A1 (en) |
| JP (1) | JP2001506598A (en) |
| KR (1) | KR19980042831A (en) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000063148A1 (en) * | 1999-04-21 | 2000-10-26 | Euphar Group S.R.L. | Salts of asiatic and madecassic acid suitable for the preparation of pharmaceutical and cosmetic compositions |
| US6274559B1 (en) * | 1997-02-28 | 2001-08-14 | Dong Kook Pharmaceutical Co., Ltd. | Liver protection or treatment agents comprising asiatic acid derivatives as the active component |
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| CN102391351B (en) * | 2011-11-03 | 2013-06-19 | 沈阳化工大学 | Asiatic acid modifier with anti-tumor activity and preparation method of the same |
| CN103816164B (en) * | 2014-01-26 | 2015-07-08 | 中国人民解放军第二军医大学 | Application of asiatic acid derivative A1 in preparation of anti-depression drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06329590A (en) * | 1993-05-24 | 1994-11-29 | Kobe Steel Ltd | Triterpene compound, its production and cancer inhibition agent |
| WO1996017819A1 (en) * | 1994-12-03 | 1996-06-13 | Dong Kook Pharmaceutical Co., Ltd. | Asiatic acid derivatives, its manufacturing method and dermatological agent containing it |
-
1997
- 1997-11-27 EP EP97913517A patent/EP0971873A1/en not_active Withdrawn
- 1997-11-27 JP JP52455298A patent/JP2001506598A/en active Pending
- 1997-11-27 WO PCT/KR1997/000239 patent/WO1998023574A1/en not_active Application Discontinuation
- 1997-11-27 CN CN97180161A patent/CN1238756A/en active Pending
- 1997-11-27 KR KR1019970063417A patent/KR19980042831A/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06329590A (en) * | 1993-05-24 | 1994-11-29 | Kobe Steel Ltd | Triterpene compound, its production and cancer inhibition agent |
| WO1996017819A1 (en) * | 1994-12-03 | 1996-06-13 | Dong Kook Pharmaceutical Co., Ltd. | Asiatic acid derivatives, its manufacturing method and dermatological agent containing it |
Non-Patent Citations (7)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol. 100, No. 21, 21 May 1984, (Columbus, Ohio, USA), page 353, Abstract No. 171516k, J. SAKAKIBARA et al., "Terpenoids of Rhododendron Japonicum"; & PHYTOCHEMISTRY, 1983, 22(11), 2535-5. * |
| CHEMICAL ABSTRACTS, Vol. 102, No. 7, 18 February 1985, (Columbus, Ohio, USA), page 351, Abstract No. 59349y, T. KIKUCHI et al., "Studies on the Constituents of Medicinal and Related Plants in Sri Lanka. I. New Triterpenes from Hedyotis Lawsoniae"; & CHEM. PHARM. BULL., 1984, 32(10), 3906-11. * |
| CHEMICAL ABSTRACTS, Vol. 109, No. 15, 10 October 1998, (Columbus, Ohio, USA), page 390, Abstract No. 125856j, C. HUANG et al., "Isolation and Identification of Two New Triterpenes from Actinidia Eriantha"; & YUNNAN ZHIWU YANJIU, 1988, 10(1), 93-100. * |
| CHEMICAL ABSTRACTS, Vol. 118, No. 21, 24 May 1993, (Columbus, Ohio, USA), pages 536-537, Abstract No. 209385d, C. HUANG et al., "Isolation and Identification of a New Triterpene from Actinidia Eriantha Benth."; & TIANRAN CHANWU YANJIU YU KAIFA, 1992, 4(3), 27-30. * |
| CHEMICAL ABSTRACTS, Vol. 122, No. 15, 10 April 1995, (Columbus, Ohio, USA), page 874, Abstract No. 185527f, N. OKADA et al., "A Triterpene, Its Manufacture and Cancer Inhibitors Containing Triterpenes"; & JP,A,06 329 590. * |
| CHEMICAL ABSTRACTS, Vol. 125, No. 7, 12 August 1996, (Columbus, Ohio, USA), page 706, Abstract No. 81911x, C. FOURNEAU et al., "Triterpenes from Prunus Africana Bark"; & PHYTOCHEMISTRY, 1996, 42(5), 1391-1393. * |
| CHEMICAL ABSTRACTS, Vol. 76, No. 9, 28 February 1982, (Columbus, Ohio, USA), page 2, Abstract No. 41801z, L.F. CHASSEAUD et al., "Metabolism of Asiatic Acid, Madecassic Acid and Asiaticoside in the Rat"; & ARZNEIM.-FORSCHUNG, 1971, 21(9), 1379-84. * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6274559B1 (en) * | 1997-02-28 | 2001-08-14 | Dong Kook Pharmaceutical Co., Ltd. | Liver protection or treatment agents comprising asiatic acid derivatives as the active component |
| WO2000063148A1 (en) * | 1999-04-21 | 2000-10-26 | Euphar Group S.R.L. | Salts of asiatic and madecassic acid suitable for the preparation of pharmaceutical and cosmetic compositions |
| AU776202B2 (en) * | 1999-04-21 | 2004-09-02 | Euphar Group S.R.L. | Salts of asiatic and madecassic acid suitable for the preparation of pharmaceutical and cosmetic compositions |
| US6891063B1 (en) | 1999-04-21 | 2005-05-10 | Euphar Group S.R.L. | Salts of asiatic and madecassic acid suitable for the preparation of pharmaceutical and cosmetic compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0971873A1 (en) | 2000-01-19 |
| CN1238756A (en) | 1999-12-15 |
| KR19980042831A (en) | 1998-08-17 |
| JP2001506598A (en) | 2001-05-22 |
| WO1998023574A8 (en) | 1999-05-20 |
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