EP0971873A1 - 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 sameInfo
- Publication number
- EP0971873A1 EP0971873A1 EP97913517A EP97913517A EP0971873A1 EP 0971873 A1 EP0971873 A1 EP 0971873A1 EP 97913517 A EP97913517 A EP 97913517A EP 97913517 A EP97913517 A EP 97913517A EP 0971873 A1 EP0971873 A1 EP 0971873A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- compound
- asiatic acid
- yield
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- JXSVIVRDWWRQRT-UYDOISQJSA-N asiatic acid Chemical class C1[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C JXSVIVRDWWRQRT-UYDOISQJSA-N 0.000 title claims abstract description 44
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 208000027418 Wounds and injury Diseases 0.000 title abstract description 17
- 229940079593 drug Drugs 0.000 title abstract description 4
- 206010052428 Wound Diseases 0.000 title abstract 2
- -1 (methylthio)thiocarbonyloxy Chemical group 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003700 epoxy group Chemical group 0.000 claims description 4
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 3
- 150000002148 esters Chemical class 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 150000001875 compounds Chemical class 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000000034 method Methods 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- 229940011658 asiatic acid Drugs 0.000 description 31
- LBGFKBYMNRAMFC-PYSQTNCISA-N asiatic acid Natural products C[C@@H]1CC[C@@]2(CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@@]34C)[C@]2(C)[C@H]1C)C(=O)O LBGFKBYMNRAMFC-PYSQTNCISA-N 0.000 description 31
- CLXOLTFMHAXJST-UHFFFAOYSA-N esculentic acid Natural products C12CC=C3C4CC(C)(C(O)=O)CCC4(C(O)=O)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(CO)C CLXOLTFMHAXJST-UHFFFAOYSA-N 0.000 description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
- 229940125898 compound 5 Drugs 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 18
- 239000000203 mixture Substances 0.000 description 14
- YUMNZEWYPUBSQA-UHFFFAOYSA-N 1-(chloromethoxy)octane Chemical compound CCCCCCCCOCCl YUMNZEWYPUBSQA-UHFFFAOYSA-N 0.000 description 11
- WYQVAPGDARQUBT-FGWHUCSPSA-N Madecassol Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O)OC[C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)OC(=O)[C@]12CC[C@H]([C@@H]([C@H]1C=1[C@@]([C@@]3(CC[C@H]4[C@](C)(CO)[C@@H](O)[C@H](O)C[C@]4(C)[C@H]3CC=1)C)(C)CC2)C)C)[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O WYQVAPGDARQUBT-FGWHUCSPSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- QCYLIQBVLZBPNK-UHFFFAOYSA-N asiaticoside A Natural products O1C(C(=O)C(C)C)=CC(C)C(C2(C(OC(C)=O)CC34C5)C)C1CC2(C)C3CCC(C1(C)C)C45CCC1OC1OCC(O)C(O)C1O QCYLIQBVLZBPNK-UHFFFAOYSA-N 0.000 description 9
- PRAUVHZJPXOEIF-AOLYGAPISA-N madecassic acid Chemical compound C1[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]2[C@H](O)C[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C PRAUVHZJPXOEIF-AOLYGAPISA-N 0.000 description 9
- BUWCHLVSSFQLPN-UHFFFAOYSA-N madecassic acid Natural products CC1CCC2(CCC3(C)C(=CCC4C5(C)CC(O)C(O)C(C)(C5CCC34C)C(=O)O)C2C1C)C(=O)OC6OC(COC7OC(CO)C(OC8OC(C)C(O)C(O)C8O)C(O)C7O)C(O)C(O)C6O BUWCHLVSSFQLPN-UHFFFAOYSA-N 0.000 description 9
- 229940011656 madecassic acid Drugs 0.000 description 9
- VAIJHUIHWZDTEZ-TWXGOCSMSA-N methyl (1R,2R,4R,5R,10R,11R,14R,15S,18S,21R,22S,23S)-4-hydroxy-2,7,7,10,14,15,21,22-octamethyl-6,8-dioxahexacyclo[12.12.0.02,11.05,10.015,24.018,23]hexacos-24-ene-18-carboxylate Chemical compound O([C@H]1[C@H](O)C2)C(C)(C)OC[C@@]1(C)[C@H]1[C@@]2(C)[C@H]2CC=C3[C@@H]4[C@@H](C)[C@H](C)CC[C@]4(C(=O)OC)CC[C@@]3(C)[C@]2(C)CC1 VAIJHUIHWZDTEZ-TWXGOCSMSA-N 0.000 description 9
- 244000146462 Centella asiatica Species 0.000 description 8
- 235000004032 Centella asiatica Nutrition 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYQVAPGDARQUBT-XCWYDTOWSA-N asiaticoside Natural products O=C(O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@H](O)[C@H](O)[C@H](O[C@H]3[C@H](O)[C@H](O)[C@@H](O)[C@H](C)O3)[C@@H](CO)O2)O1)[C@@]12[C@@H]([C@@H](C)[C@H](C)CC1)C=1[C@](C)([C@@]3(C)[C@@H]([C@@]4(C)[C@H]([C@@](CO)(C)[C@@H](O)[C@H](O)C4)CC3)CC=1)CC2 WYQVAPGDARQUBT-XCWYDTOWSA-N 0.000 description 8
- 229940022757 asiaticoside Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 239000000284 extract Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 6
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 5
- NZCULBURCGAPSF-PQWKYGPVSA-N 23-hydroxyursolic acid Chemical compound C1C[C@H](O)[C@@](C)(CO)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C NZCULBURCGAPSF-PQWKYGPVSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000000246 remedial effect Effects 0.000 description 4
- 239000011369 resultant mixture Substances 0.000 description 4
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- NZCULBURCGAPSF-UHFFFAOYSA-N UNPD19956 Natural products C1CC(O)C(C)(CO)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)C(C)C5C4=CCC3C21C NZCULBURCGAPSF-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- LADPCMZCENPFGV-UHFFFAOYSA-N chloromethoxymethylbenzene Chemical compound ClCOCC1=CC=CC=C1 LADPCMZCENPFGV-UHFFFAOYSA-N 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical group O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical group CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 2
- 150000004043 trisaccharides Chemical class 0.000 description 2
- 239000012991 xanthate Substances 0.000 description 2
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical group COCCOCCl BIAAQBNMRITRDV-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical group COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
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- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
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- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
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- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
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- 125000002243 cyclohexanonyl group Chemical group *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical group C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- UMXWTWTZJKLUKQ-UHFFFAOYSA-M lithium;iodide;trihydrate Chemical compound [Li+].O.O.O.[I-] UMXWTWTZJKLUKQ-UHFFFAOYSA-M 0.000 description 1
- 229940090813 madecassoside Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229920000059 polyethylene glycol stearate Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
Definitions
- the present invention relates to asiatic acid derivatives represented by following chemical formula 1 :
- Ri represents hydrogen, hydroxy group which may be protected by acetyl or benzyl group, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy or octyloxymethyloxy group
- R 2 represents hydrogen or hydroxy group
- K ⁇ and R 2 may form an oxo group
- R 3 represents hydrogen or hydroxy group which may be protected by acetyl or benzoyl group
- R 2 and R 3 may form an epoxy group
- R 4 represents hydroxymethyl group which may be protected by acetyl or benzoyl group
- R 3 and j may form -OC(R6)(R7)OCH 2 - [wherein, R t is hydrogen, a lower alkyl group having 1 to 4 carbon atoms, or phenyl group, R 7 represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms or phenyl group, and R_s and R 7 may form -(CH
- 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.
- 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 ,
- R 2 represents hydrogen or hydroxy group which may be protected by acetyl or benzyl group, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy or octyloxymethyloxy group
- R 2 represents hydrogen or hydroxy group
- RI and R 2 may form an oxo group
- R 3 represents hydrogen or hydroxy group which may be protected by acetyl or benzoyl group
- R 2 and R 3 may form an epoxy group
- R4 represents hydroxymethyl group which may be protected by acetyl or benzoyl group
- R 3 and R4 may form -OC(R6)(R7)OCH 2 - [wherein, R ⁇ is hydrogen, a lower alkyl group having 1 to 4 carbon atoms, or phenyl group, R 7 represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms or phenyl group, and Rt and R 7 may form -(CH 2
- 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).
- 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.]
- 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).
- TECA Centella asiatica
- 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.
- 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.
- Mass (El) m/e 542 (M + ), 527 (M + -Me), 482 (M + -HCOOME), 483, 467, 451, 407, 262, 203, 189, 133
- 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%).
- Example 5® above the same procedure as Example 5® was performed (yield:53.9%).
- Example 5® 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%).
- Example 5® Excepting from substituting compound 4 for compound 5 in Example 5®, the same procedure as Example 5® was performed.
- Example 5® 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
- Example 5® 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%).
- Example 5® 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
- Example 5® 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%).
- Example 5® Except from substituting compound 22 for compound 5 used in Example 5®, the same procedure as Example 5® was performed(yield : 44%).
- 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.
- 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.
- the asiatic acid derivatives according to the present invention showed excellent effect on treating wound.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Epoxy Compounds (AREA)
- Pyrane Compounds (AREA)
- Steroid Compounds (AREA)
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 :
wherein, Ri represents hydrogen, hydroxy group which may be protected by acetyl or benzyl group, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy or octyloxymethyloxy group; R2 represents hydrogen or hydroxy group; K\ and R2 may form an oxo group; R3 represents hydrogen or hydroxy group which may be protected by acetyl or benzoyl group; R2 and R3 may form an epoxy group; R4 represents hydroxymethyl group which may be protected by acetyl or benzoyl group; R3 and j may form -OC(R6)(R7)OCH2- [wherein, Rt 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 R_s and R7 may form -(CH2)s-]; 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-tetrahydropyranyl group; and medicines for treating wound, which contains the same as an active component.
Background Art
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 ,
wherein,
represents hydrogen, hydroxy group which may be protected by acetyl or benzyl group, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy or octyloxymethyloxy group; R2 represents hydrogen or hydroxy group; RI and R2 may form an oxo group; R3 represents hydrogen or hydroxy group which may be protected by acetyl or benzoyl group; R2 and R3 may form an epoxy group; R4 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 Rt and R7 may form -(CH2)s-]; 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-tetrahydropyranyl group, and medicines for treating wound, which contains the same as an active component.
The process for preparing the asiatic acid derivatives according to the present invention is illustrated here-in-below:
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
Method 4
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
(wherein, R5 is the same that is defined above.)
Method 6
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
chloromethyl benzyl ether . acetic
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)
Excepting from substituting C6H5CH(OMe)2 for CH3CH(OEt)2, the same procedure as Example 4(2) was performed (yield:32.1%).
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.
wherein, R\ represents hydrogen, hydroxy group which may be protected by acetyl or benzyl group, methanesulfonyloxy,
(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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR9605817 | 1996-11-27 | ||
| KR19960058175 | 1996-11-27 | ||
| PCT/KR1997/000239 WO1998023574A1 (en) | 1996-11-27 | 1997-11-27 | Asiatic acid derivatives and medicines for treating wounds, which contains the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0971873A1 true EP0971873A1 (en) | 2000-01-19 |
Family
ID=19483855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP97913517A Withdrawn EP0971873A1 (en) | 1996-11-27 | 1997-11-27 | Asiatic acid derivatives and medicines for treating wounds, which contains the same |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0971873A1 (en) |
| JP (1) | JP2001506598A (en) |
| KR (1) | KR19980042831A (en) |
| CN (1) | CN1238756A (en) |
| WO (1) | WO1998023574A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100530278B1 (en) * | 1997-02-28 | 2006-04-06 | 동국제약 주식회사 | Liver protection and therapeutic agent with asiatic acid derivative |
| IT1312089B1 (en) * | 1999-04-21 | 2002-04-04 | Euphar Group Srl | SALTS OF ASIAN AND MEDACASSIC ACID FOR THE PREPARATION OF PHARMACEUTICAL AND COSMETIC COMPOSITIONS. |
| 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 the preparation of antidepressant drugs |
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|---|---|---|---|---|
| JPH06329590A (en) * | 1993-05-24 | 1994-11-29 | Kobe Steel Ltd | Triterpene compound, its production and cancer inhibition agent |
| JPH10509959A (en) * | 1994-12-03 | 1998-09-29 | ドング クック ファーマシューティカル シーオウ．，エルティーディー． | Asian acid derivative, method for producing the same, and skin treatment agent containing the same |
-
1997
- 1997-11-27 CN CN97180161A patent/CN1238756A/en active Pending
- 1997-11-27 WO PCT/KR1997/000239 patent/WO1998023574A1/en not_active Ceased
- 1997-11-27 EP EP97913517A patent/EP0971873A1/en not_active Withdrawn
- 1997-11-27 JP JP52455298A patent/JP2001506598A/en active Pending
- 1997-11-27 KR KR1019970063417A patent/KR19980042831A/en not_active Ceased
Non-Patent Citations (1)
| Title |
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| See references of WO9823574A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998023574A1 (en) | 1998-06-04 |
| WO1998023574A8 (en) | 1999-05-20 |
| CN1238756A (en) | 1999-12-15 |
| KR19980042831A (en) | 1998-08-17 |
| JP2001506598A (en) | 2001-05-22 |
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