EP0971873A1 - Derives d'acide asiatique et medicaments les contenant aux fins du traitement de plaies - Google Patents

Derives d'acide asiatique et medicaments les contenant aux fins du traitement de plaies

Info

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Withdrawn
Application number
EP97913517A
Other languages
German (de)
English (en)
Inventor
Sang Sup Jew
Hyeung Geun Park
Young Hoon Jung
Eun Hee Park
Hong Pyo Kim
Sung Ki Seo
Tae Gyu Nam
Ducky Han
Chi Hyoung Yoo
Doo Yeon Lim
Jeong Hoon Kim
Hee Man Kim
Mi Kyeong Lee
Kyung Hwa Lim
Min Jung Lim
Do Ha Kim
So Yeon Kim
Pil Jong Shim
Hee Young Beom
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dong Kook Pharmaceutical Co Ltd
Original Assignee
Dong Kook Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dong Kook Pharmaceutical Co Ltd filed Critical Dong Kook Pharmaceutical Co Ltd
Publication of EP0971873A1 publication Critical patent/EP0971873A1/fr
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • 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)
  • Steroid Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Epoxy Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

Cette invention, qui a trait à des dérivés d'acide asiatique représentés par la formule (1), porte également sur des médicaments contenant ces dérivés comme ingrédient actif aux fins du traitement de plaies.
EP97913517A 1996-11-27 1997-11-27 Derives d'acide asiatique et medicaments les contenant aux fins du traitement de plaies Withdrawn EP0971873A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR19960058175 1996-11-27
KR9605817 1996-11-27
PCT/KR1997/000239 WO1998023574A1 (fr) 1996-11-27 1997-11-27 Derives d'acide asiatique et medicaments les contenant aux fins du traitement de plaies

Publications (1)

Publication Number Publication Date
EP0971873A1 true EP0971873A1 (fr) 2000-01-19

Family

ID=19483855

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97913517A Withdrawn EP0971873A1 (fr) 1996-11-27 1997-11-27 Derives d'acide asiatique et medicaments les contenant aux fins du traitement de plaies

Country Status (5)

Country Link
EP (1) EP0971873A1 (fr)
JP (1) JP2001506598A (fr)
KR (1) KR19980042831A (fr)
CN (1) CN1238756A (fr)
WO (1) WO1998023574A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100530278B1 (ko) * 1997-02-28 2006-04-06 동국제약 주식회사 아시아트산 유도체를 유효성분으로 하는 간 보호 및치료제
IT1312089B1 (it) 1999-04-21 2002-04-04 Euphar Group Srl Sali dell'acido asiatico e medacassico atti alla preparazione dicomposizioni farmaceutiche e cosmetiche.
CN102391351B (zh) * 2011-11-03 2013-06-19 沈阳化工大学 一种具有抗肿瘤活性的积雪草酸修饰物及其制备方法
CN103816164B (zh) * 2014-01-26 2015-07-08 中国人民解放军第二军医大学 积雪草酸衍生物a1在制备抗抑郁药物中的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06329590A (ja) * 1993-05-24 1994-11-29 Kobe Steel Ltd トリテルペン化合物およびその製造方法、ならびに発癌抑制剤
CN1067976C (zh) * 1994-12-03 2001-07-04 东国制药株式会社 积雪草酸衍生物及其制备方法和包含该衍生物的皮科制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9823574A1 *

Also Published As

Publication number Publication date
KR19980042831A (ko) 1998-08-17
CN1238756A (zh) 1999-12-15
WO1998023574A1 (fr) 1998-06-04
WO1998023574A8 (fr) 1999-05-20
JP2001506598A (ja) 2001-05-22

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