Use of steroidal saponins for the prophylaxis or treatment...

Details Use of steroidal saponins for the prophylaxis or treatment... Use of steroidal saponins for the prophylaxis or treatment...

2000-06-05

2003-07-15

Riley, Jezia (Department: 1637)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S001000, C514S04400A

Reexamination Certificate

active

06593301

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to the steroidal saponin compounds for the propylaxis or treatment dementia, the new steroidal saponin compounds and the pharmaceutical composition containing the same.
BACKGROUND
Dementia is a frequently encountered disease in the aged people and also defined by global cognitive decline involving gradual loss of memory, reasoning, judgment, and orientation. It mainly includes Alzheimer's disease (AD), vascular dementia (VD), mixed dementia and some other types. It is reported that incidence of dementia is 3-8% in the elderly over 65, which is as high as 20% in the elderly over 80. Shanghai, China collaborated with the United States to conduct a survey of dementia recently, and the result showed that the incidence of dementia was 4.32% in the aged over 65 in Shanghai. With the improvement of society and elongation of human life span, each country all over the world is getting into aging society and the number of patients suffering dementia will rise remarkably. The dementia has been a medical and social problem to be solved.
Recently, much attention is paid to the discovery and development of drugs for treating dementia. Although there is no definitive treatment or cure for AD, different pharmacological strategies are being actively investigated. At present, cholinesterase inhibitors (tacrine, huperzine A), nootropic agents (hydergin), calcium passage inhibitor(nimodipine) and nerve growth factor represent the available approaches to symptomatic treatment of AD. Development of new effective drugs for treating dementia is therefore of great social importance and economical benefits.
Steroidal saponin is a group of oligosaccharide glycosides derived from spirostane. It is widely distributed in plants including monocotyledon and dicotyledon, especially in Dioscoreaceae, Liliaceae, Scrophulariaceae, Smilacaceae, Agavaceae and so on. For example, steroidal saponins are rich in
Dioscorea nipponica
Makino,
Dioscorea panthaica
Prain et Burk,
Allium sativum L., Anemarrhena asphodeloides Bge., Paris polyphlla, Polygonatum odoratum
(Mill) Drace,
Ophiopogon japonicus, Agave americana L
. and so on. Steroidal saponins are famous for their sapogenins which are precursors for the partial synthesis of steroidal contraceptive and hormones drugs, so sapogenins are more important than themselves. Researchers also found that some steroidal saponins can antineoplasma, decrease blood sugar, accommodate immunity, decrease cholesterol, treat cardiovascular disease and have activity of antisepsis. For example, saponin I and IV from
Paris polyphylla
have cytotoxic effect on P
388
, L-1210 and KB cells. Prototimosaponin AIII and pseudoprototimosaponin AIII from
Anemarrhena asphodeloides Bge
, taken orally exhibited hypoglycemic effects in a dose-dependent manner in streptozotocin- and alloxan-diabetic mice. Saponins from
Ophiopogon japonicus
showed immunostimulating activity on mice. The scholars in the former Soviet Union discovered that some steroidal saponins could lower cholesterol, and the activity of spirostanol saponin is higher than that of furostanol saponin. Steroidal saponin has activity of antisepsis as it can form complex with the cholesterol in bacterial cell membrane. Water soluble saponins from
Dioscorea zingiberensis
Wright can relieve cardiac angina, accommodate metabolism and treat coronary heart disease.
OBJECT OF THE INVENTION
The object of the invention is to provide a new class of pharmaceuticals for the propyhylaxis or treatment of dementia with high effective and low side action.
SUMMARY OF THE INVENTION
Through wide and deep study, the inventors have unexpectedly discovered that the steroidal saponins of formula I can dilate the cerebral basilar artery, improve cerebral circulation and metabolism, up-regulate the number of nicotinic receptor significantly, promote the proliferation of nerve cells, and scavenge free radicals. Noticeably, in the cultural experiments of two cell lines, SY-SH5Y and M10, it is discovered that the compounds of this invention can effectively up-regulate the number of nAChRs and the potency is similar to that of nicotine. Moreover, the effect is concentration-dependent. As a result, the compounds of formula I can be used to prevent or treat dementia. Completeness of this invention is based on above discoveries.
The first aspect of this invention relates to a use of steroidal saponin compounds of formula I and their stereoisomers for the propylaxis or treatment of dementia,
Wherein
R
1
is hydrogen, —OH, —O-Xyl, —O-Ara-Rha, —O-Fuc-Rha, —O-Ara-Rha,
R
2
is hydrogen, —OH, —O-Fuc, —O-Rha, or —O-Glu;
R
3
is —OH, —OCOCH
3
, —OCOC
15
H
31
, or oxo(═O), or
—O-Gal,
—O-Glu,
—O-Gal-Glu,
—O-Glu-Glu,
—O-Glu-Ara,
—O-Fuc-Glu,
—O-Rha,
—O-Rha-Glu,
—O-Glu-Glu-Glu,
—O-Glu-Rha,
—O-Man-Glu,
—O-Gal-Glu-Glu,
R
4
is hydrogen, —OH, or —OSO
3
Na,
R
5
is hydrogen, hydroxy, —O-Glu, or is absent,
R
6
is hydrogen, OH, oxo(═O), —O-Qui-Rha, or —O-Qui-Xyl;
R
12
is hydrogen, —OH, or oxo(═O);
R
14
is hydrogen, or —OH;
R
15
is hydrogen, or —OH;
R
22
is hydroxy, or O(CH
2
)
n
CH
3
, n=0~3, or is absent,
R
23
is hydrogen, or —OH;
R
27
is —CH
3
, —CH
2
OH, or ═CH
2
;
X is O, or NH;
denotes a single bond or a double bond,
Y is a direct bond or is absent,
Z is Glu or is absent,
provided that a compound of formula I wherein R
1
═R
2
═R
4
═R
6
═R
12
═R
14
═R
15
═R
23
=H, R
3
=&bgr;-OH, R
5
=&bgr;-H, X=O,
is a single bond, Y is a direct bond, R
22
is absent, Z is absent, R
27
is —CH
3
, C
25
is (S) configuration, is not included.
The second aspect of this invention relates to the novel steroidal saponins represented by formula II
Wherein
the dotted line between positions 5 and 6 deotes no double bond, 5-position is &bgr;H
C
25
is S-configuration
R′
15
is hydrogen
R′
2
is &agr;-OH or &bgr;-OH
R′
3
is —O-Gal
2
Glu, —O-Gal
2
Glu
2
Glu,
—O-Gal
4
Glu
2
Glu,
—O-Gal
4
Glu
3
Glu,
R′
22
is OH, or O(CH
2
)
n
CH
3
, n=0~3, or R′
22
is absent, at the same time the dotted line between positions 20 and 22 denotes double bond; or
R′
2
is hydrogen
R′
3
is —O-Gal-Glu,
the dotted line between positions 5 and 6 denotes no double bond, 5-position is &bgr;H,
C
25
is (S) configuration,
R′
15
is &agr;-OH or &bgr;-OH,
R′
22
is OH, or O(CH
2
)
n
CH
3
, n=0−3, or R′
22
is absent, and at the same time the dotted line between positions 20 and 22 denotes a double bond; or
R′
2
is hydrogen,
the dotted line between positions 5-6 denotes a double bond
R′
15
is hydrogen,
C
25
is R or S configration,
R′
22
is O(CH
2
)
n
CH
3
, n=0-3, or R′
22
is absent, and at the same time the dotted line between position 20-22 denotes a double bond,
R′
3
is —O-Gal,
—O-Glu,
—O-Glu
2
Rha,
—O-Glu
3
Rha,
—O-Glu
4
Rha,
—O-Glu
4
Glu,
—O-Gal
4
Glu,
The further aspect of this invention relates to the pharmaceutical composition for the propylaxis or treatment of dementia, which comprises a compound of formula I as active component and pharmaceutically acceptable carrier, excipients, or additives.
The further aspect of this invention relates to the use of a compound of formula I for the preparation of pharmaceuticals for the propylaxis or treatment of dementia.
The last aspect of this invention relates to the method of the propylaxis or treatment of dementia, which include administering a propylaxis or treatment effective amount of a compound of formula I or the pharmaceutical composition containing the same to host which need the propylaxis or treatment of dementia.


REFERENCES:
patent: 4303214 (1994-11-01), None
patent: 0054570 (1981-03-01), None
patent: WO97/31933 (1997-09-01), None
Derwent World Patent Index (WPI) abstract for DE 4303214 A1.

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