Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-08-27
2001-08-14
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C514S893000, C514S894000, C536S005000
Reexamination Certificate
active
06274559
ABSTRACT:
PRIOR FOREIGN APPLICATIONS
This application is a 35 USC §371 filing of PCT/KR98/00038, filed Feb. 28, 1998 and claims priority from KR patent application number 1997/6655, filed Feb. 28, 1997.
TECHNICAL FIELD
The present invention relates to liver protection or treatment agents, which comprise asiatic acid derivatives having the following formula 1:
wherein, R
1
represents hydrogen, hydroxyl group which may be protected by acetyl or benzyl group, methyl, ethyl, methoxy, ethoxy, vinyl, ethinyl, cyano, azide, ethoxymethyloxy, octyloxymethyloxy, methanesulfonyloxy, phenylthio group or (methylthio)thiocarbonyloxy group; R
2
represents hydrogen or hydroxyl group which may be protected by acetyl or benzoyl group, methoxy or ethoxy group; R
1
and R
2
may form an oxo group; R
3
represents hydrogen, hydroxyl group which may be protected by acetyl or benzoyl group, vinyl, methyl or ethyl group; R
4
represents hydrogen, methyl, ethyl, vinyl, or hydroxyl group which may be protected by acetyl or benzoyl group; R
2
and R
4
may form an epoxy group; R
3
and R
4
may form an oxo group; R
5
represents methyl, hydroxymethyl group of which hydroxyl group may be protected by acetyl or benzoyl group, tert-butyldimethylsilyloxymethyl group, carboxylic group, carboxylic ester moiety, carboxylic amide moiety or aldehyde group; R
4
and R
5
may form —OCR
6
R
7
OCH
2
— [wherein, R
6
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
6
and R
7
may form —(CH
2
)
5
—]; R
8
represents hydrogen or methyl group; R
9
represents —CH
2
COOR or —COOR [wherein, R represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms, 2-tetrahydropyranyl, CH(OR
11
)R
10
, CH(OR
13
)CH
2
R
12
(wherein, R
10
represents hydrogen, methyl or ethyl group, R
11
represents a lower alkyl group having 1 to 4 carbon atoms, octyl, benzyl, methoxymethyl or methoxyethyl group, R
12
represents hydrogen, methyl or ethyl group, R
13
represents methyl or ethyl group, or R
12
and R
13
may form —CH
2
CH
2
CH
2
—), or glucosyl or rhamnosyl group], hydroxymethyl of which hydroxyl group may be protected by acetyl or benzoyl group, methanesulfonyloxymethyl or cyanomethyl group; R
14
and R
15
independently represent hydrogen, or both form oxo group together [provided that when R
1
is hydroxyl, R
2
is hydrogen, R
3
is hydrogen, R
4
is hydroxyl, R
5
is hydroxymethyl and R
8
is methyl, R does not represent hydrogen nor methyl, and Rio does not represent hydrogen; and provided that when R
1
is hydroxyl, R
2
is hydrogen, R
3
or R
4
may form, with R
5
—OC(R
6
)(R
7
)OCH
2
—, and R
6
is methyl, R does not represent methyl group;
or pharmaceutically acceptable salts or esters thereof, as the active component.
BACKGROUND ART
Asiatic acid, madecassic acid and asiaticoside, trisaccharide of asiatic acid, which are compounds extracted from
Centella asiatica,
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, 1878-80(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)].
DISCLOSURE OF THE INVENTION
The present inventors have already synthesized various asiatic acid derivatives represented by the formula 1 as above and filed with the Korea Industrial Property Office as a patent application (Korean patent laid-open publication No. 96-22435, Korean Patent Application No. 96-58175), and also performed intensive studies on the asiatic acid derivatives, and found the fact that the derivatives of the formula are useful for liver protection or treatment, to complete the invention.
The object of the present invention is to provide liver protection or treatment agents, which comprise asiatic acid derivatives of the formula 1 as the active component:
(wherein, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
and R
15
are the same that are defined above.)
Specific examples of the compounds of the above formula 1 include 2-oxoasiatic acid, 2-methylasiatic acid, methyl 2&agr;-acetoxyurs-12-en-23-al-3-on-28-oate, tetrahydropyranyl 3 &bgr;,23-diacetoxyurs-12-en-28-oate, ethoxymethyl 2&agr;-hydroxy-3 &bgr;,23-isopropylidendioxyurs-12-en-28-oate, methyl 2,3-&bgr;-epoxy-12-en-23-carbomethoxyurs-28-oate, methyl 2,3-&bgr;-epoxy-12-en-23-benzamidours-28-oate, 1-ethoxyethyl asiatate, 2′,3′,4′,6′-tetra-O-acetylglucosyl 2,3,23-tri-O-acetylurs-28-oate, etc.
The liver protection or treatment agents of this invention may comprise pharmaceutically acceptable salts or esters of the above active components.
The general preparation of the compounds of the formula 1 according to the present invention is presented by Korean patent laid-open publication No. 96-22435, and for the compounds of the formula 1 which can be defined as the formula 2 below, it is desirable to prepare by Method 1~8.
wherein, R
a
represents hydrogen, hydroxyl group which may be protected by acetyl or benzyl group, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy or octyloxymethyloxy group; R
b
represents hydrogen or hydroxyl group; R
a
and R
b
may form an oxo group; R
c
represents hydrogen or hydroxyl group which may be protected by acetyl or benzoyl group; R
b
and R
c
may form an epoxy group; R
d
represents hydroxymethyl group which may be protected by acetyl or benzoyl group; R
c
and R
d
may form —OC(R
f
)(R
g
)OCH
2
— [wherein, R
f
is hydrogen, a lower alkyl group having 1 to 4 carbon atoms, or phenyl group, R
g
represents hydrogen, a lower alkyl group having 1 to 4 carbon atoms or phenyl group, and R
f
and R
g
may form —(CH
2
)
5
—]; R
e
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
The preparations of asiatic acid derivatives of the formula 2 above according to the present invention are presented below.
Method 1
Titrated extracts of
Centella asiatica
(TECA) is hydrolyzed to obtain a mixture of asiatic acid and madecassic acid, 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-O-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.]
Method 2
Two hydroxyl groups at 3- and 23-position of asiatic acid are protected with various ketone or aldehyde group to synthesize compounds represented by formula 5. [Provided that R
f
═H and R
g
═H, the compound is synthesized by the use of dimethyl sulfoxide and trimethylsilyl chloride.] The compound of the formula 5 is treated with chloromethyl octyl ether to synthesize a compound represented by the formula 6. [See Scheme 2.]
(wherein, R
f
and R
g
are the same that are defined above.)
Method 3
The hydroxyl group at 2-position of the 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-O-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
Choi Hee Sung
Jew Sang Sup
Jung Young Hoon
Kim Hee Doo
Kim Hee Man
Dong Kook Pharmaceutical Co. Ltd.
Gitomer Ralph
Heslin & Rothenberg, PC
Khare Devesh
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