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.
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 P388, 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.
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.
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
R1 is hydrogen, xe2x80x94OH, xe2x80x94O-Xyl, xe2x80x94O-Ara-Rha, xe2x80x94O-Fuc-Rha, xe2x80x94O-Ara-Rha, 
R2 is hydrogen, xe2x80x94OH, xe2x80x94O-Fuc, xe2x80x94O-Rha, or xe2x80x94O-Glu;
R3 is xe2x80x94OH, xe2x80x94OCOCH3, xe2x80x94OCOC15H31, or oxo(xe2x95x90O), or
xe2x80x94O-Gal,
xe2x80x94O-Glu,
xe2x80x94O-Gal-Glu,
xe2x80x94O-Glu-Glu,
xe2x80x94O-Glu-Ara,
xe2x80x94O-Fuc-Glu,
xe2x80x94O-Rha,
xe2x80x94O-Rha-Glu,
xe2x80x94O-Glu-Glu-Glu, 
xe2x80x94O-Glu-Rha,
xe2x80x94O-Man-Glu,
xe2x80x94O-Gal-Glu-Glu, 
R4 is hydrogen, xe2x80x94OH, or xe2x80x94OSO3Na,
R5 is hydrogen, hydroxy, xe2x80x94O-Glu, or is absent,
R6 is hydrogen, OH, oxo(xe2x95x90O), xe2x80x94O-Qui-Rha, or xe2x80x94O-Qui-Xyl;
R12 is hydrogen, xe2x80x94OH, or oxo(xe2x95x90O);
R14 is hydrogen, or xe2x80x94OH;
R15 is hydrogen, or xe2x80x94OH;
R22 is hydroxy, or O(CH2)nCH3, n=0xcx9c3, or is absent,
R23 is hydrogen, or xe2x80x94OH;
R27 is xe2x80x94CH3, xe2x80x94CH2OH, or xe2x95x90CH2;
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 R1xe2x95x90R2xe2x95x90R4xe2x95x90R6xe2x95x90R12xe2x95x90R14xe2x95x90R15xe2x95x90R23=H, R3=xcex2-OH, R5=xcex2-H, X=O,  is a single bond, Y is a direct bond, R22 is absent, Z is absent, R27 is xe2x80x94CH3, C25 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 xcex2H
C25 is S-configuration
Rxe2x80x215 is hydrogen
Rxe2x80x22 is xcex1-OH or xcex2-OH
Rxe2x80x23 is xe2x80x94O-Gal2Glu, xe2x80x94O-Gal2Glu2Glu,
xe2x80x94O-Gal4Glu2Glu,
xe2x80x94O-Gal4Glu3Glu, 
Rxe2x80x222 is OH, or O(CH2)nCH3, n=0xcx9c3, or Rxe2x80x222 is absent, at the same time the dotted line between positions 20 and 22 denotes double bond; or
Rxe2x80x22 is hydrogen
Rxe2x80x23 is xe2x80x94O-Gal-Glu,
the dotted line between positions 5 and 6 denotes no double bond, 5-position is xcex2H,
C25 is (S) configuration,
Rxe2x80x215 is xcex1-OH or xcex2-OH,
Rxe2x80x222 is OH, or O(CH2)nCH3, n=0xe2x88x923, or Rxe2x80x222 is absent, and at the same time the dotted line between positions 20 and 22 denotes a double bond; or
Rxe2x80x22 is hydrogen,
the dotted line between positions 5-6 denotes a double bond
Rxe2x80x215 is hydrogen,
C25 is R or S configration,
Rxe2x80x222 is O(CH2)nCH3, n=0-3, or Rxe2x80x222 is absent, and at the same time the dotted line between position 20-22 denotes a double bond,
Rxe2x80x23 is xe2x80x94O-Gal,
xe2x80x94O-Glu,
xe2x80x94O-Glu2Rha,
xe2x80x94O-Glu3Rha,
xe2x80x94O-Glu4Rha,
xe2x80x94O-Glu4Glu, 
xe2x80x94O-Gal4Glu, 
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.
USPTO Backgrounds
USPTO Backgrounds