Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Utility Patent
1999-05-25
2001-01-02
Badio, Barbara (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Utility Patent
active
06169112
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel medical use of asiatic acid derivatives and pharmaceutical compositions containing the same. More specifically, the present invention relates to a use of asiatic acid derivatives represented by general formula 1:
wherein, R
1
represents hydrogen, hydroxy 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 hydroxy 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, hydroxy group which may be protected by acetyl or benzoyl group, vinyl, methyl or ethyl group; R
4
represents hydrogen, methyl, ethyl, vinyl, or hydroxy 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 hydroxy 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 hydroxy 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 hydroxy, R
2
is hydrogen, R
3
is hydrogen, R
4
is hydroxy, R
5
is hydroxymethyl and R
8
is methyl, R does not represent hydrogen nor methyl, and R
10
does not represent hydrogen; and provided that when R
1
is hydroxy, 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;
and pharmaceutically acceptable salts and esters thereof, for treating dementia or cognitive disorder.
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 srtuctures 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 tratment 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)].
Recently, they have been reported to have some effect on dementia and cognitive disorder by Hoechst (EP 0383 171 A2). However, as can be seen from the experimental results described in the literature above, the remedial effect for treating dementia is so weak that the research for medicines to treat dementia with much stronger effect is still requested.
DISCLOSURE OF THE INVENTION
The present inventors have already synthesized various asiatic acid derivatives represented by chemical formula 1 as above and filed with the Korea Industrial Property Office as a patent application (Korean Patent Application No. 95-46131 and 96-58175), and also performed intensive studies on the asiatic acid derivatives, and found the fact that the derivatives of formula 1 are useful for treating dementia and cognitive disorder, to complete the invention.
The object of the present invention is to provide medicines for treating dementia or cognitive disorder, which contains asiatic acid derivatives of general formula 1 as an active component:
wherein, R
1
represents hydrogen, hydroxy 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 hydroxy 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, hydroxy group which may be protected by acetyl or benzoyl group, vinyl, methyl or ethyl group; R
4
represents hydrogen, methyl, ethyl, vinyl, or hydroxy 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 hydroxy 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-tetrahydropiranyl, 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
C
2
—), or glucosyl or rhamnosyl group of which hydroxy group may be protected by acetyl or benzoyl group], hydroxymethyl of which hydroxy 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 [provided that R
1
is hydroxy, R
2
is hydrogen, R
3
is hydrogen, R
4
is hydroxy, R
5
is hydroxymethyl and R
8
is methyl, R does not represent hydrogen nor methyl, R
10
does not represent hydrogen; and provided that R
1
is hydroxy, R
2
is hydrogen, R
3
or R
4
forms, with R
5
, —OC(R
6
)(R
7
)OCH
2
—, and R
6
is methyl, R does not represent methyl group; and pharmaceutically acceptable salts and esters thereof, for treating dementia or cognitive disorder.
In other words, the present invention relates to a use of asiatic acid derivatives represented by formula 1, and pharmaceutically acceptable salts and esters thereof, for treating dementia or cognitive disorder.
The treatment according to the invention includes rapid alleviation of symptoms or preventive measures.
The general preparation of compound of general formula 1 according to the present invention is presented by Korean patent application No. 95-46131, but in case that the definiton of general formula among compounds is general formula 2 below, it is is desirable to prepare by Method 1~8.
wherein, R
a
represents hydrogen, hydroxy group which may be protected by acetyl or benzyl group, methanesulfonyloxy, (methylthio) thiocarbonyloxy, halogen, ethoxymethyloxy or octyloxymethyloxy group; R
b
represents hydrogen or hydroxy group; R
a
and R
b
may form an oxo group; R
c
represents hydrogen or hydroxy group which may be protected by acetyl or benzoyl group; R
Beom Hee Young
Han Ducky
Jew Sang Sup
Jung Ju Eun
Jung Young Hoon
Badio Barbara
Dong Kook Pharmaceutical Co. Ltd.
Heslin & Rothenberg, P.C.
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