WO2006019685A2 - Composes et leur preparation pour le traitement de la maladie d'alzheimer par inhibition de la production de peptides beta-amyloides - Google Patents

Composes et leur preparation pour le traitement de la maladie d'alzheimer par inhibition de la production de peptides beta-amyloides Download PDF

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WO2006019685A2
WO2006019685A2 PCT/US2005/024533 US2005024533W WO2006019685A2 WO 2006019685 A2 WO2006019685 A2 WO 2006019685A2 US 2005024533 W US2005024533 W US 2005024533W WO 2006019685 A2 WO2006019685 A2 WO 2006019685A2
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compound
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alkyl
formula
treating
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WO2006019685A3 (fr
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Donald W. Landry
Shixian Deng
Tae-Wan Kim
Jeong Hill Park
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The Trustees Of Columbia University In The City Of New York
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Priority claimed from US10/961,346 external-priority patent/US20060014704A1/en
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Priority to EP05788885A priority Critical patent/EP1778715A2/fr
Priority to CA002573699A priority patent/CA2573699A1/fr
Priority to JP2007521534A priority patent/JP2008506686A/ja
Priority to MX2007000562A priority patent/MX2007000562A/es
Publication of WO2006019685A2 publication Critical patent/WO2006019685A2/fr
Publication of WO2006019685A3 publication Critical patent/WO2006019685A3/fr

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Definitions

  • the present invention provides novel ginsenoside compounds, compositions
  • the present invention provides methods for inhibiting beta-amyloid peptide production and methods for treating or preventing a pathological condition, particularly, neurodegeneration diseases (e.g. Alzheimer's disease), using these ginsenoside compounds.
  • a pathological condition particularly, neurodegeneration diseases (e.g. Alzheimer's disease)
  • AD Alzheimer's disease
  • Francis et al., Neuregulins and ErbB receptors in cultured neonatal astrocytes. J. Neurosci. Res., 57:487-94, 1999
  • Alzheimer's disease is the most common form of age-related dementia, and one of the most serious health problems, in the United States. Approximately 4 million Americans suffer from Alzheimer's disease, at an annual cost of at least $100 billion - making Alzheimer's disease one of the costliest disorders of aging.
  • Alzheimer's disease is about twice as common in women as in men, and accounts for more than 65% of the dementias in the elderly. Alzheimer's disease is the fourth leading cause of death in the United States. To date, a cure for Alzheimer's disease is not available, and cognitive decline is inevitable. Although the disease can last for as many as 20 years, AD patients usually live from 8 to 10 years, on average, after being diagnosed with the disease.
  • AD Alzheimer's disease
  • a ⁇ amyloid ⁇ -peptide
  • a ⁇ is produced by sequential proteolytic cleavages of amyloid precursor protein (APP) by a set of membrane-bound proteases termed ⁇ - and ⁇ - secretases (Vassar and Citron (2000) Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron 27, 419-422; John, et al. (2003) Human beta-secretase
  • APP amyloid precursor protein
  • BACE BACE inhibitors. J. Med Chem. 46, 4625-4630; Selkoe and Kopan (2003) Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev Neurosci. 26, 565-597; Medina and Dotti (2003) ripped out by presenilin-dependent gamma-secretase. Cell Signal 15, 829-841). Heterogeneous ⁇ -secretase cleavage at the C-terminal end of A ⁇ produces two major isoforms of A ⁇ , A ⁇ 40 and A ⁇ 42.
  • a ⁇ 40 is the predominant cleavage product, the less abundant, highly amyloidogenic A ⁇ 42 is believed to be one of the key pathogenic agents in AD (Selkoe (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 81, 741-66) and increased cerebrocorical A ⁇ 42 is closely related to synaptic/neuronal dysfunction associated with AD (Selkoe, Alzheimer's disease is a synaptic failure, Science 298:789-791, 2002).
  • Presenilins are required for intramembrane proteolysis of selected type-I membrane proteins, including amyloid-beta precursor protein (APP), to yield amyloid-beta protein (De Strooper et al., Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387-90, 1998; Steiner and Haass, Intramembrane proteolysis by presenilins. Nat. Rev. MoI. Cell. Biol. 1:217-24, 2000; Ebinu and Yankner, A rip tide in neuronal signal transduction.
  • APP amyloid-beta precursor protein
  • Such proteolysis may be mediated by presenilin-dependent ⁇ -secretase machinery, which is known to be highly conserved across species, including nematodes, flies, and mammals (L'Hernault and Arduengo, Mutation of a putative sperm membrane protein in Caenorhabditis elegans prevents sperm differentiation but not its associated meiotic divisions. J Cell. Biol. 119:55- 58, 1992; Levitan and Greenwald, Facilitation of lin-12-mediated signaling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene.
  • ⁇ -Secretase a high-molecular- weight, multi-protein complex harboring presenilin heterodimers and nicastrin, mediates the final step in A ⁇ production in Alzheimer's disease (Li, et al., Presenilin 1 is linked with ⁇ -secretase activity in the detergent solubilized state. Proc. Natl. Acad. ScL USA 97:6138-43, 2000; Esler, et al., Activity-dependent isolation of the presenilin- ⁇ -secretase complex reveals nicastrin and a gamma substrate. Proc. Natl. Acad. Sci. USA 99:2720-25, 2002). The stabilization of presenilin heterodimers
  • ⁇ -Secretase activity displays very loose sequence specificity near the target transmembrane cleavage site and has been shown to mediate the intramembrane cleavage of other non-APP type-I membrane substrates, including Notch (Schroeter, E.H., et al. (1998) Notch- 1 signaling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382-386; De
  • a ⁇ 42 (Weggen, et al. (2001). A subset of NSAIDs lower aniyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414, 212-216), without significantly affecting ⁇ -secretase-mediated cleavage of ErbB4 (Weggen, et al. (2003). Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain. J. Biol. Chem. 278, 30748-30754). Accordingly, small molecules which are able to selectively reduce A ⁇ 42 production (without affecting the cleavage of other ⁇ -secretase substrates) are attractive and promising as therapeutic reagents for treating AD.
  • APP amyloid precursor protein
  • FAD-associated mutations in the presenilins give rise to an increased production of a longer (42 amino acid residues), more amyloidogenic form of amyloid-beta (A ⁇ 42).
  • Deciphering the pathobiology associated with the presenilins provides a unique opportunity to elucidate a molecular basis for Alzheimer's disease. It is suspected that excess beta- amyloid production causes the neuronal degeneration underlying dementia characteristic of AD.
  • Ginseng is the common name given to the dried roots of plants of the genus
  • Panax ginseng The effects of Panax ginseng on quality of life. J Clin. Pharm. Ther. 28, 5-15; Coon and Ernst (2002). Panax ginseng: a systematic review of adverse effects and drug interactions. DrMg Saf. 25:323-44).
  • the Panax genus contains about six species native to eastern Asia and two species native to eastern North America.
  • Panax ginseng (Asian ginseng) and Panax quinquefolius L. (North American ginseng) are the two species most commonly used in nutraceutical and pharmaceutical compositions. The roots and their extracts contain a variety of substances including saponins.
  • Ginseng has been well known to have specific pharmacological effects including improvement of liver function and immune enhancement, as well as anti- arteriosclerotic, anti-thrombotic, anti-stress, anti-diabetic, anti-hypertensive and antitumor effects.
  • ginseng saponins are known to be the chemical constituents that contribute to its pharmacological effects. These compounds are triterpene glycosides named ginsenosides Rx (x is index "a” to "k” depending on its polarity). The polarity is determined by their mobility on thin-layer chromatography plates and is a function of the number of monosaccharide residues in the molecule's sugar chain.
  • ginsenosides have been isolated from white and red ginseng.
  • AU of the ginsenosides can be divided into three groups depending on their aglycons: protopanaxadiol-type ginsenosides (e.g., RbI, Rb2, Rc, Rd, (20R)Rg3, (20S)Rg3, Rh2), protopanaxatriol-type ginsenosides (e.g., Re, Rf, RgI, Rg2, RhI), and oleanolic acid- type ginsenosides (e.g., Ro).
  • protopanaxadiol-type ginsenosides e.g., RbI, Rb2, Rc, Rd, (20R)Rg3, (20S)Rg3, Rh2
  • protopanaxatriol-type ginsenosides e.g., Re, Rf, RgI, Rg2, RhI
  • Carbohydrates including glucopyranosyl, arabinopyranosyl, arabinofuranosyl and rhamnopyranosyl may also be chemically associated with a particular ginsenoside.
  • ginsenosides Processing of ginseng with steam at high temperature further enhances the content of these unique ginsenosides RkI, Rg5, (20R)Rg3 and (20S)Rg3, which appear to possess novel pharmacological activities. At least some of the beneficial qualities of ginseng can be attributed to its triterpene saponin content, a mixture of glucosides referred to collectively as ginsenosides.
  • U.S. Patent 5,776,460 discloses a processed ginseng product having enhanced pharmacological effects.
  • This ginseng product commercially known as “sun ginseng” contains increased levels of effective pharmacological components due to heat-treating of the ginseng at a high temperature for a particular period of time.
  • heat treatment of ginseng may be performed at a temperature of 120° to 180° C for 0.5 to 20 hours, and is preferably performed at a temperature of 120° to 140° C for 2 to 5 hours.
  • the heating time varies depending on the heating temperature such that lower heating temperatures require longer heating times while higher heating temperatures require comparatively shorter heating times.
  • the '460 patent also discloses that the processed ginseng product has pharmacological properties specifically including anti-oxidant activity and vasodilation activity.
  • the present invention provides compositions and methods for preventing and treating neurodegenerative diseases, such as Alzheimer's disease.
  • the present invention provides a compound having the general formula:
  • R 4 is an alkenyl, aryl, or alkyl II
  • R 5 is H or OH.
  • the alkyl I group may further contains oxygen, nitrogen, or phosphorus and the alkyl II group may further contain a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base.
  • the sugar group is selected from the group consisting of GIc, Ara(pyr), Ara(fur), Rha, and XyI. In another embodiment,
  • R 4 is selected from the group consisting of: wherein the configuration of any stereo-center is R or S; X is OR or NR, wherein R is alkyl or aryl; X' is alkyl, OR 3 or NR, wherein R is alkyl or aryl; and R' is H, alkyl, or acyl.
  • the present invention provides a composition, particularly, a pharmaceutical composition, comprising a compound having the general formula:
  • R 1 is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ -O-X, ⁇ -R 6 COO- 3
  • R 2 is selected from the group consisting of H 5 OH, OAc, and 0-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof;
  • R 3 is selected from the group consisting of H, OH, and OAc;
  • R 4 is alkenyl, aryl, or alkyl II; and
  • R 5 is H or OH.
  • the present invention also provides a method for the synthesis of a compound having formula: which comprises the steps of: a) treating a compound having formula:
  • step (c) treating the compound formed in step (a) with a reducing agent, to form a compound having formula:
  • R 1 is H or OH
  • R 2 is selected from the group consisting of H, OH, OAc, and 0-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof
  • R 3 is selected from the group consisting of H, OH, and OAc
  • R 4 is alkenyl, aryl, or alkyl.
  • the oxidizing agent is chromic anhydride and the reducing agent is NaBH 4 .
  • the present invention further provides a method for the synthesis of a compound having formula: which comprises the steps of:
  • step (b) treating the compound formed in step (a) with a reducing agent, to form a compound having formula:
  • step (c) optionally, treating the compound formed in step (b) with protected R 1 derivative, to form a compound having formula:
  • Rl is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ -O-X, Ot-R 6 COO- , P-R 6 COO-, OC-R 6 PO 3 -, and ⁇ -R 6 PO 3 -, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof, and R 6 is alkenyl, aryl, or alkyl I; R 2 is selected from the group consisting of H, OH, OAc, and 0-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof; R 3 is selected from the group consisting of H, OH, and OAc; R 4 is alkenyl, aryl, or alkyl II; and R 5 is H or OH.
  • the invention provides a method for the synthesis of a compound having formula:
  • step (b) treating the compound formed in step (a) with a protecting agent, to form a compound having formula:
  • step (c) treating the compound formed in step (b) with a reducing agent, to form a compound having formula:
  • step (d) treating the compound formed in step (c) with Ac 8 -GIc-GIc-Br, to form a compound having formula:
  • step (e) treating the compound formed in step (d) with deprotection agent, to form a compound having formula:
  • step (f) further modifying the compound formed in step (e) to form a compound having formula:
  • the starting material is obtained from a plant, such as, for example, common birch.
  • the present invention provides a method for the synthesis of a compound having formula: wherein the method comprises the step of treating a compound having formula:
  • a reducing agent such as NaBH 4 .
  • the present invention provides a method for the synthesis of a compound having formula:
  • step (b) treating the compound formed in step (a) with Ac 8 -GIc-GIc-Br, to form a compound having formula:
  • step (c) treating the compound formed in step (d) with deprotection agent, to form a compound having formula:
  • the present invention provides a method for treating or preventing a pathological condition in a subject, comprising administering a compound having the general formula:
  • Rl is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ - O-X, CC-R 6 COO-, P-R 6 COO-, U-R 6 PO 3 -, and P-R 6 PO 3 -, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof, and R 6 is alkenyl, aryl, or alkyl I; R 2 is selected from the group consisting of H, OH, OAc, and 0-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof; R 3 is selected from the group consisting of H, OH, and OAc; R 4 is alkenyl, aryl, or alkyl II; and R 5 is H or OH.
  • the pathological condition is neurodegeneration, preferably, Alzheimer's disease and A ⁇ 42-related disorder.
  • the present invention further provides a method for inhibiting ⁇ -amyloid production in subject, including inhibiting ⁇ -amyloid production in an in vitro context, comprising administering a compound having the general formula:
  • Rl is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ - 0-X, ⁇ -R 6 C00-, P-R 6 COO-, ⁇ -R ⁇ POr, and ⁇ -RePOr, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof, and R 6 is alkenyl, aryl, or alkyl
  • R 2 is selected from the group consisting of H, OH, OAc, and 0-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof;
  • R 3 is selected from the group consisting of H, OH, and OAc;
  • R 4 is alkenyl, aryl, or alkyl II; and
  • R 5 is H or OH.
  • FIG. 1 depicts sequential proteolytic processing of ⁇ -amyloid precursor protein (APP), mediated by ⁇ -: and ⁇ -secretases.
  • FIG. 2 shows the HPLC profile of (a) White Ginseng; (b) Red Ginseng; and (c)
  • FIG. 3 illustrates the general chemical formula of: (a) Rg3, (b) RkI and (c)
  • FIG. 4 shows that Rgk351, (20R)Rg3, RkI and Rg5 reduce the generation of
  • the CHO cells were treated with the indicated compounds (at 50 ⁇ g/ml) for 8 hrs.
  • a ⁇ 42 levels in the medium were measured by ELISA and normalized to intracellular full-length APP.
  • FIG. 5 shows that treatment with Rgk351, RkI and Rg5 reduced A ⁇ 42 in the medium of CHO cells expressing human APP in a dose-dependent manner.
  • FIG. 6 demonstrates that treatment of Rgk351, RkI and Rg5 preferentially reduced A ⁇ 42 (vs. A ⁇ 40) in the medium of CHO cells expressing human APP in a dose- dependent manner.
  • the relative levels of A ⁇ and A ⁇ 42 were normalized to values obtained from non-treated and vehicle-treated cells. Similar data were obtained using Neuro2a-sw (mouse Neuro2a cells expressing Swedish familial Alzheimer's disease mutant form of APP) and 293 cells expressing human APP.
  • FIG. 7 depicts an analysis of cell lysates and shows that Rgk351 , RkI and Rg5 caused the increased accumulation of APP C-terminal fragments ( ⁇ -secretase substrates), while the full-length holoAPP levels were not affected.
  • FIG. 8 demonstrates that treatment of Rgk351 and RkI reduced the A ⁇ 42 levels in CHO cells co-expressing human APP together with either wild-type presenilin 1 or familial Alzheimer-linked mutant forms of presenilin 1 (delta E9 ad L286V).
  • Rg5 on the A ⁇ 42 generation were much smaller as compared to Rgk351 and RkI.
  • FIG. 9 shows effects of RkI(Rl) and Rg5(R5) on A ⁇ 42-s ⁇ ecific ⁇ -secretase activity. Naproxen (NP) and sulindac sulfide (SS) were tested in parallel.
  • FIG. 10 depicts the effects of native ginsenosides on A ⁇ 42 production.
  • the structures of seven standard ginsenosides studied (RbI, Rb2, Rc, Rd, Re 5 RgI, and Rg2) are shown in Table 1.
  • CHO cells stably transfected with human APP695 together with either wild-type (A, CHO-APP/PS1 cells) or ⁇ E9 FAD mutant (B, CHO-APP/ ⁇ E9PS1 cells) forms of PSl were used. Cells were treated with the indicated compounds (at 50 ⁇ M) for 8 hrs.
  • Levels of secreted A ⁇ 40 and A ⁇ 42 in the medium were determined by ELISA and normalized to intracellular full-length APP.
  • average A ⁇ amounts in control samples were 320 pM for A ⁇ 40 and 79 pM for A ⁇ 42.
  • the relative levels of A ⁇ and A ⁇ 42 were normalized to values obtained from non-treated and vehicle-treated cells and are shown as % to control + s.d.). One of three representative experiments are shown.
  • FIG. 11 shows A ⁇ 42-lowering activity of several ginsenosides derived from heat- or steam-processed ginseng.
  • CHO-APP/PS1 (A) and CHO-APP/ ⁇ E9PS 1 (B) cells were treated with the indicated compounds at 50 ⁇ M for 8 hrs and the levels of secreted A ⁇ 40 and
  • Rh2 also exhibited A ⁇ 42-lowering effects although the cell viability was partially affected at 50 ⁇ M treatment (data not shown).
  • the PS1- ⁇ E9 FAD mutation diminished the A ⁇ 42 response to RkI treatment (B).
  • FIG. 12 shows treatment with Rgk351, RkI and Rg5 reduced A ⁇ 42 in the medium of CHO-APP cells in a dose-dependent manner.
  • A Dose-response of A ⁇ 42 lowering activity of RkI and Rg5. IC50 of RkI was about 20 ⁇ M.
  • B RkI preferentially lowers A ⁇ 42 (vs. A ⁇ 40) in cultured CHO-APP cells and the A ⁇ 42-inhibition pattern of RkI is similar to that of sulindac sulfide (SS). The relative levels of A ⁇ 40 and A ⁇ 42 were normalized to values obtained from non-treated and vehicle-treated cells.
  • FIG. 13 depicts an analysis of APP processing after RkI treatment. Steady- state levels of full-length APP and APP C-terminal fragments (APP-CTFs) were examined by Western blot analysis using anti-Rl antibody.
  • Rgk351 (mixture of Rg3, Rg5 and RkI), RkI and Rg5 treatment resulted in increased accumulation of APP C-terminal fragments ( ⁇ - secretase substrates) in CHO-APP cells and mouse neuroblastoma neuro2a cells stably expressing Swedish FAD mutant form (KM670/671NL) of APP (APPsw). Correlated A ⁇ 42 levels for each sample are shown in the bottom panel.
  • FIG. 14 shows that A ⁇ 42-lowering ginsenoside RkI does not significantly affect the production of intracellular domains (ICDs) from APP (A, AICD) 5 Notchl (B, NICD) or p75 neurotrophin receptor (p75NTR, p75-ICD).
  • ICDs intracellular domains
  • B AICD
  • NICD Notchl
  • p75 neurotrophin receptor p75NTR
  • p75-ICD membrane fractions isolated from 293 cells overexpressing either APP (A) 5 Notch- ⁇ E (B) or p75- ⁇ E (C) and incubated in the presence of indicated compounds: Compound E (CpdE, general ⁇ -secretase inhibitor), Rgk351, RkI and sulindac sulfide (SS).
  • AICD, NICD and p75-ICD were detected in control samples (- Incubate) or in samples treated with Cpd.E, but AICD, NICD and p75-ICD were abundantly produced in samples incubated with Rgk351, RkI and SS.
  • FIG. 15 shows that A ⁇ 42-lowering ginsenoside RkI and (20,S)Rg3 inhibits A ⁇ generation in a cell-free ⁇ -secretase assay.
  • A CHAPSO-solubilized membrane fractions were incubated with recombinant ⁇ -secretase substrates together with the indicated compounds (at 100 ⁇ M) and the levels of A ⁇ 42 and A ⁇ 40 were determined by ELISA as described (27-29).
  • B Dose-response of A ⁇ 40 and A ⁇ 42-lowering activity of RkI and
  • FIG. 16 depicts the effects of two major metabolites of ginsenosides, including
  • 20(S)- panaxatriol (PT) and 20(S)-panaxadiol (PD) are the artificial derivatives of PPT and PPPD, respectively.
  • Treatment with either PPT or PT reduced the production of A ⁇ 42 without affecting the levels of A ⁇ 42 in Neuro2a cells expressing the human Swedish mutant form of
  • FIG. 17 shows mass spectrometric analysis of A ⁇ species produced from CHO-APP cells treated with DMSO (vehicle), RkI, or (20S)Rg3. Note that treatment leads to a decrease in A ⁇ 42 species (1-42), and elevation in both A ⁇ 37 (1-37) and A ⁇ 38 (1-38). Mass spectrometric analysis of A ⁇ species were performed as previously described (Wang R, Sweeny D, Gandy SE 5 Sisodia SS. The profile of soluble amyloid ⁇ -protein in cultured cell media. J Bio. Chem. 1996; 271: 31894-31902). [0042] FIG.
  • FIG. 18 depicts analysis of secreted A ⁇ levels after treatment of CHO-APP cells with DMSO (Control 1), naproxen (Control 2), RId, or (20S)Rg3.
  • a ⁇ was immoprecipitated using 4G8 antibody (Purchased from Senetek), subjected to SDS-PAGE using Tricine/Urea gel (the protocol was supplied by Dr. Y. Ihara, University of Tokyo), and analyzed by Western blot analysis using the 6E10 antibody (Senetek). Synthetic A ⁇ 40 and A ⁇ 42 peptides were used to identify corresponding A ⁇ species.
  • FIG. 19 shows the effects of the ginsenoside RkI and (20S)Rg3 on A ⁇ 40 and
  • Treatment of RkI and Rg3 decreased the level of secreted A ⁇ 40 and A ⁇ 42.
  • Alzheimer's disease neurodegeneration and for modulating the production of amyloid-beta protein (A ⁇ ) are provided.
  • a ⁇ amyloid-beta protein
  • the present invention provides a compound having the general formula:
  • R 1 is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ -O-X, OC-R 6 COO-, ⁇ -R ⁇ COO-, OC-R 6 PO 3 -, and ⁇ -RePO 3 -, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof, and R 6 is alkenyl, aryl, or alkyl I; R 2 is selected from the group consisting of H, OH, OAc, and O-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof; R 3 is selected from the group consisting of H, OH, and OAc; R 4 is alkenyl, aryl, or alkyl II; and R 5 is H or OH.
  • the alkyl I group may further contain oxygen, nitrogen, or phosphorus and the alkyl II group may further contain a function group, such as hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base.
  • the sugar is selected from a group comprising GIc, Ara(pyr), Ara(fur), Rha, and XyI.
  • R 4 is selected from the group consisting of: [0047] wherein the configuration of any stereo-center is R or S; X is OR or NR, wherein R is alkyl or aryl; X' is alkyl, OR, NR, wherein R is alkyl or aryl; and R' is H, alkyl, or acyl.
  • the compounds are dammaranes, particularly ginsenosides and their analogues.
  • ginsenoside refers to the class of triterpene glycosides which includes, without limitation, the specific compounds RaI, Ra2, Ra3, RbI, Rb2, Rb3, Rc, Rd, Re, Rf, RgI, (20R)Rg2, (20S)Rg2, (20R)Rg3, (20S)Rg3, Rg5, Rg6, RhI,
  • the ginsenosides of the present invention may be chemically associated with carbohydrates including, but not limited to, glucopyranosyl, arabinopyranosyl, arabinofuranosyl and rhamnopyranosyl.
  • the ginsenosides of the present invention may be isolated ginsenoside compounds or isolated and further synthesized ginsenosides.
  • the isolated ginsenosides of the present invention can be further synthesized using processes including, but not necessarily limited to, heat, light, chemical, enzymatic or other synthesis processes generally known to the skilled artisan.
  • the present invention further provides a method for the synthesis of a compound having formula: wherein the method comprises the steps of:
  • step (b) treating the compound formed in step (a) with a reducing agent, to form a compound having formula:
  • Rj is H or OH
  • R 2 is selected from the group consisting of H, OH, OAc, and 0-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof
  • R 3 is selected from the group consisting of H, OH, and OAc
  • R 4 is alkenyl, aryl, or alkyl.
  • the oxidizing agent is chromic anhydride and the reducing agent is NaBH 4 .
  • the starting material i.e. the compound having formula: particularly, betulafolienetriol
  • the extracts of these plants are rich sources of betulafolienetriol and are desired starting materials for making ginsenosides because they cost significantly less than ginseng.
  • the present invention also provides a method for the synthesis of a compound having formula:
  • step (b) treating the compound formed in step (a) with a reducing agent, to form a compound having formula:
  • step (c) optionally, treating the compound formed in step (b) with protected R 1 derivative, to form a compound having formula:
  • step (d) treating the compound formed in step (c) with deprotection agent, to form a compound having formula:
  • Rl is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ -O-X, ⁇ -R 6 COO- , P-R 6 COO-, OC-R 6 PO 3 -, and ⁇ -R 6 PO 3 -, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof, and R 6 is alkenyl, aryl, or alkyl I; R 2 is selected from the group consisting of H, OH, OAc, and 0-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof; R 3 is selected from the group consisting of H, OH, and OAc; R 4 is alkenyl, aryl, or alkyl II; and R 5 is H or OH.
  • the alkyl I group may further contain oxygen, nitrogen, or phosphorus; and the alkyl II group may further contain a function group, such as hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base.
  • the oxidizing agent is chromic anhydride and the reducing agent is NaBH 4 .
  • the protected R 1 derivative is a protected R 1 halogen derivative.
  • the protected R 1 derivative may be protected by an Ac 8 - group.
  • the protected R 1 group may be deprotected using agents such as NaOMe.
  • step (b) treating the compound formed in step (a) with a protecting agent, to form a compound having formula:
  • step (c) treating the compound formed in step (b) with a reducing agent, to form a compound having formula:
  • step (d) treating the compound formed in step (c) with Ac 8 -GIc-GIc-Br, to form a compound having formula:
  • step (e) treating the compound formed in step (d) with deprotection agent, to form a compound having formula:
  • step (f) further modifying the compound formed in step (e) to form a compound having formula:
  • the oxidizing agent is chromic anhydride
  • the reducing agent is NaBH 4
  • the compound is deprotected using NaOMe.
  • the present invention also provides a method for the synthesis of a compound having formula:
  • step (b) treating the compound formed in step (a) with Ac 8 -GIc-GIc-Br, to form a compound having formula:
  • step (c) treating the compound formed in step (d) with deprotection agent, to form a compound having formula:
  • the reducing agent is NaBH 4 and the compound is deprotected using NaOMe.
  • the present invention provides ginsenoside compositions for use in modulating amyloid-beta production in a subject, treating or preventing Alzheimer's disease and treating or preventing neurodegeneration comprising a mixture of isolated or isolated and further synthesized ginsenosides, wherein one or more of the ginsenosides is selected from the group consisting of: RaI, Ra2, Ra3, RbI, Rb2, Rb3, Rc, Rd, Re 5 Rf, RgI, (20R)Rg2, (20S)Rg2, (20R)Rg3, (20S)Rg3, Rg5, Rg6, RhI, (20R)Rh2, (20S)Rh2, Rh3, Rh4, (20R)Rg3, (20S)Rg3, RkI, Rk2, Rk3, RsI, Rs2, Rs3, Rs4 5 Rs5, Rs6, Rs7, F4, protopanaxadiol (PPD), protopanaxatriol (PPT), DHPPD-I, DHPPD-II, DHPPT
  • the ginsenoside composition is Rgk351.
  • the present invention provides methods and pharmaceutical compositions for use in decreasing amyloid-beta production, comprising use of a pharmaceutically-acceptable carrier and a ginsenoside compound. Examples of acceptable pharmaceutical carriers, formulations of the pharmaceutical compositions, and methods of preparing the formulations are described herein.
  • the pharmaceutical compositions may be useful for administering the dammarane and ginsenoside compounds of the present invention to a subject to treat a variety of disorders, including neurodegeneration and/or its associated symptomology, as disclosed herein.
  • the ginsenoside compound is provided in an amount that is effective to treat the disorder (e.g., neurodegeneration) in a subject to whom the pharmaceutical composition is administered.
  • the present invention provides a method for inhibiting ⁇ -amyloid production in a subject, comprising administering a compound having the general formula: to the subject, wherein Rl is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ -
  • the term "subject” includes, for example, an animal, e.g. human, rat, mouse, rabbit, dog, sheep, and cow, as well as an in vitro system, e.g. a cultured cell, tissue, and organ.
  • the present invention also provides a method for treating neurodegeneration in a subject in need of treatment, by contacting cells (preferably, cells of the CNS) in the subject with an amount of a ginsenoside compound or composition effective to decrease amyloid-beta production in the cells, thereby treating the neurodegeneration.
  • neurodegeneration examples include, without limitation, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), Binswanger's disease, corticobasal degeneration (CBD), dementia lacking distinctive histopathology (DLDH), frontotemporal dementia (FTD), Huntington's chorea, multiple sclerosis, myasthenia gravis, Parkinson's disease, Pick's disease, and progressive supranuclear palsy (PSP).
  • the neurodegeneration is a preferred embodiment of the present invention.
  • the present invention also provides a method for treating or preventing a pathological condition, such as neurodegeneration and A ⁇ 42-related disorder, in a subject in need of treatment, comprising administering to the subject one or more ginsenoside compounds in an amount effective to treat the neurodegeneration.
  • a pathological condition such as neurodegeneration and A ⁇ 42-related disorder
  • the A ⁇ 42-related disorder may be any disorder caused by A ⁇ 42 or has a symptom of aberrant A ⁇ 42 accumulation.
  • the phrase "effective to treat the neurodegeneration” means effective to ameliorate or minimize the clinical impairment or symptoms of the neurodegeneration.
  • the neurodegeneration is Alzheimer's disease
  • the clinical impairment or symptoms of the neurodegeneration may be ameliorated or minimized by reducing the production of amyloid-beta and the development of senile plaques and neurofibrillary tangles, thereby minimizing or attenuating the progressive loss of cognitive function.
  • the amount of inhibitor effective to treat neurodegeneration in a subject in need of treatment will vary depending upon the particular factors of each case, including the type of neurodegeneration, the stage of the neurodegeneration, the subject's weight, the severity of the subject's condition, and the method of administration. This amount can be readily determined by the skilled artisan.
  • the present invention provides a method for treating or preventing neurodegeneration in a subject, comprising administering a compound having the general formula:
  • Rl is selected from the group consisting of ⁇ -OH, ⁇ -OH, ⁇ -O-X, ⁇ - O-X, CC-R 6 COO-, ⁇ -ReCOO-, ⁇ -R 6 PO 3 - s and ⁇ -RePOr, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof, and R 6 is alkenyl, aryl, or alkyl I; R 2 is selected from the group consisting of H, OH, OAc, and O-X, wherein X is a carbohydrate containing one or more sugars or acylated derivatives thereof; R 3 is selected from the group consisting of H, OH, and OAc; R 4 is alkenyl, aryl, or alkyl II; and R 5 is H or OH.
  • Alzheimer's disease is treated in a subject in need of treatment by administering to the subject a therapeutically effective amount of a ginsenoside composition, a ginsenoside or analogue or homologue thereof effective to treat the Alzheimer's disease.
  • the subject is preferably a mammal (e.g., humans, domestic animals, and commercial animals, including cows, dogs, monkeys, mice, pigs, and rats), and is most preferably a human.
  • the term analogue as used in the present invention refers to a chemical compound that is structurally similar to another and may be theoretically derivable from it, but differs slightly in composition.
  • an analogue of the ginsesnoside (20S)Rg3 is a compound that differs slightly from (20S)Rg3 (e.g., as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group), and may be derivable from (20S)Rg3.
  • the term homologue as used in the present invention refers to members of a series of compounds in which each member differs from the next member by a constant chemical unit.
  • synthesize as used in the present invention refers to formation of a particular chemical compound from its constituent parts using synthesis processes known in the art. Such synthesis processes include, for example, the use of light, heat, chemical, enzymatic or other means to form particular chemical composition.
  • terapéuticaally effective amount means the quantity of the composition according to the invention which is necessary to prevent, cure, ameliorate or at least minimize the clinical impairment, symptoms or complications associated with Alzheimer's disease in either a single or multiple dose.
  • the amount of ginsenoside effective to treat Alzheimer's disease will vary depending on the particular factors of each case, including the stage or severity of Alzheimer's disease, the subject's weight, the subject's condition and the method of administration. The skilled artisan can readily determine these amounts.
  • the clinical impairment or symptoms of Alzheimer's disease may be ameliorated or minimized by diminishing any dementia or other discomfort suffered by the subject; by extending the survival of the subject beyond that which would otherwise be expected in the absence of such treatment; or by inhibiting or preventing the progression of the Alzheimer's disease.
  • Treating Alzheimer's disease refers to treating any one or more of the conditions underlying Alzheimer's disease including, without limitation, neurodegeneration, senile plaques, neurofibrillary tangles, neurotransmitter deficits, dementia, and senility.
  • preventing Alzheimer's disease includes preventing the initiation of Alzheimer's disease, delaying the initiation of Alzheimer's disease, preventing the progression or advancement of Alzheimer's disease, slowing the progression or advancement of Alzheimer's disease, and delaying the progression or advancement of
  • ginsenosides such as (20S)Rg3, RkI and Rg5 or their analogues or homologues can also be used to prevent and treat Alzheimer's disease patients.
  • This new therapy provides a unique strategy to treat and prevent neurodegeneration and dementia associated with Alzheimer's disease by modulating the production of A ⁇ 42.
  • neurodegeneration and dementias not associated with Alzheimer's disease can also be treated or prevented using the ginsenosides of the present invention to modulate the production of A ⁇ 42.
  • the ginsenosides of the present invention include natural or synthetic functional variants, which have ginsenoside biological activity, as well as fragments of ginsenoside having ginsenoside biological activity.
  • ginsenoside biological activity refers to activity that modulates the generation of the highly amyloidogenic A ⁇ 42, the 42 -amino acid isoform of amyloid ⁇ -peptide.
  • the ginsenoside reduces the generation of A ⁇ 42 in the cells of a subject.
  • Commonly known ginsenosides and ginsenoside compositions include, but are not limited to,
  • PPD protopanaxadiol
  • PPT protopanaxatriol
  • the ginsenoside is RkI. In another embodiment of the invention, the ginsenoside is (20S)Rg3. In a further embodiment, the ginsenoside is Rg5. In still another embodiment, the ginsenoside composition is Rgk351, a mixture of (20S)Rg3, Rg5 and Rkl. [0063] Methods of preparing ginsenosides such as RkI, (20S)Rg3 and Rg5, as well as their analogues and homologues, are well known in the art. For example, U.S.
  • Patent 5,776,460 describes preparing a processed ginseng product in which a ratio of ginsenoside (Rg3 + Rg5) to (Rc + Rd + RbI + Rb2) is above 1.0.
  • the processed product disclosed in U.S. Patent 5,776,460 is prepared by heat-treating ginseng at a high temperature of 120° to 180° C for 0.5 to 20 hours.
  • the ginsenosides of the present invention may be isolated ginsenoside compounds or isolated and further synthesized ginsenoside compounds.
  • the isolated ginsenosides of the present invention can be further synthesized using processes including, but not necessarily limited to, heat, light, chemical, enzymatic or other synthesis processes generally known to the skilled artisan.
  • the ginsenoside compound is administered to a subject in combination with one or more different ginsenoside compounds.
  • Administration of a ginsenoside compound "in combination with" one or more different ginsenoside compounds refers to co-administration of the therapeutic agents. Co ⁇ administration may occur concurrently, sequentially, or alternately. Concurrent co ⁇ administration refers to administration of the different ginsenoside compounds at essentially the same time. For concurrent co-administration, the courses of treatment with the two or more different ginsenosides may be run simultaneously. For example, a single, combined formulation, containing both an amount of a particular ginsenoside compound and an amount of a second different ginsenoside compound in physical association with one another, may be administered to the subject. The single, combined formulation may consist of an oral formulation, containing amounts of both ginsenoside compounds, which may be orally administered to the subject, or a liquid mixture, containing amounts of both the ginsenoside compounds, which may be injected into the subject.
  • an amount of one particular ginsenoside compound and an amount one or more different ginsenoside compound may be administered concurrently to a subject, in separate, individual formulations. Accordingly, the method of the present invention is not limited to concurrent co-administration of the different ginsenoside compounds in physical association with one another.
  • the ginsenoside compounds also may be co-administered to a subject in separate, individual formulations that are spaced out over a period of time, so as to obtain the maximum efficacy of the combination.
  • Administration of each therapeutic agent may range in duration from a brief, rapid administration to a continuous perfusion.
  • co-administration of the ginsenoside compounds may be sequential or alternate.
  • one of the therapeutic agents is separately administered, followed by the other. For example, a full course of treatment with an Rg5 derivative may be completed, and then may be followed by a full course of treatment with an RkI derivative.
  • a foil course of treatment with RkI derivative may be completed, then followed by a full course of treatment with an Rg5 derivative.
  • partial courses of treatment with the RkI derivative may be alternated with partial courses of treatment with the Rg5 derivative, until a full treatment of each therapeutic agent has been administered.
  • the therapeutic agents of the present invention may be administered to a human or animal subject by known procedures including, but not limited to, oral administration, parenteral administration (e.g., intramuscular, intraperitoneal, intravascular, intravenous, or subcutaneous administration), and transdermal administration.
  • parenteral administration e.g., intramuscular, intraperitoneal, intravascular, intravenous, or subcutaneous administration
  • transdermal administration e.g., transdermal administration.
  • the therapeutic agents of the present invention are administered orally or intravenously.
  • the formulations of the ginsenoside may be presented as capsules, tablets, powders, granules, or as a suspension.
  • the formulations may have conventional additives, such as lactose, mannitol, corn starch, or potato starch.
  • the formulations also may be presented with binders, such as crystalline cellulose, cellulose analogues, acacia, cornstarch, or gelatins.
  • the formulations may be presented with disintegrators, such as cornstarch, potato starch, or sodium carboxymethyl cellulose.
  • the formulations also may be presented with dibasic calcium phosphate anhydrous or sodium starch glycolate.
  • the formulations may be presented with lubricants, such as talc or magnesium stearate.
  • the formulations of the ginsenoside may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the subject.
  • a sterile aqueous solution which is preferably isotonic with the blood of the subject.
  • Such formulations may be prepared by dissolving a solid active ingredient in water containing physiologically-compatible substances, such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions, so as to produce an aqueous solution, then rendering said solution sterile.
  • physiologically-compatible substances such as sodium chloride, glycine, and the like
  • the formulations may be presented in unit or multi-dose containers, such as sealed ampules or vials.
  • the formulations may be delivered by any mode of injection including, without limitation, epifascial, intracapsular, intracutaneous, intramuscular, intraorbital, intraperitoneal (particularly in the case of localized regional therapies), intraspinal, intrasternal, intravascular, intravenous, parenchymatous, or subcutaneous.
  • the formulations of the ginsenoside may be combined with skin penetration enhancers, such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, and the like, which increase the permeability of the skin to the therapeutic agent, and permit the therapeutic agent to penetrate through the skin and into the bloodstream.
  • the therapeutic agent/enhancer compositions also may be further combined with a polymeric substance, such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, and the like, to provide the composition in gel form, which may be dissolved in a solvent such as methylene chloride, evaporated to the desired viscosity, and then applied to backing material to provide a patch.
  • a polymeric substance such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, and the like
  • the dose of the ginsenoside of the present invention may also be released or delivered from an osmotic mini-pump.
  • the release rate from an elementary osmotic mini- pump may be modulated with a microporous, fast-response gel disposed in the release orifice.
  • the formulations of the ginsenoside may be further associated with a pharmaceutically-acceptable carrier, thereby comprising a pharmaceutical composition.
  • the pharmaceutically-acceptable carrier must be "acceptable” in the sense of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.
  • acceptable pharmaceutical carriers include, but are not limited to, carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc, and water, among others. Formulations of the pharmaceutical composition may conveniently be presented in unit dosage.
  • the formulations of the present invention may be prepared by methods well known in the pharmaceutical art.
  • the active compound may be brought into association with a carrier or diluent, as a suspension or solution.
  • a carrier or diluent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, g., g., g., g., g., g., g., ginsenosides their analogues and analogues, either in separate, individual formulations, or in a single, combined formulation) to a subject to treat
  • the therapeutic agents of the present invention i.e., ginsenosides their analogues and analogues, either in separate, individual formulations, or in a single, combined formulation
  • the therapeutic agents are provided in amounts that are effective to treat or prevent Alzheimer's disease in the subject. These amounts may be readily determined by the skilled artisan.
  • the effective therapeutic amounts of the ginsenoside will vary depending on the particular factors of each case, including the stage of the Alzheimer's disease, the subject's weight, the severity of the subject's condition, and the method of administration.
  • (20S)Rg3 can be administered in a dosage of about 5 ⁇ g/day to 1500 mg/day.
  • (20S)Rg3 is administered in a dosage of about 1 mg/day to 1000 mg/day.
  • Rg5 can be administered in a dosage of about 5 ⁇ g/day to 1500 mg/day, but is preferably administered in a dosage of about 1 mg/day to 1000mg/day.
  • RkI can be administered in a dosage of about 5 ⁇ g/day to 1500 mg/day, but is preferably administered in a dosage of about
  • the ginsenoside composition Rgk351 can be administered in a dosage of about 5 ⁇ g/day to 1500 mg/day, but is preferably administered in a dosage of about 1 mg/day to 1000 mg/day.
  • the appropriate effective therapeutic amounts of any particular ginsenoside compound within the listed ranges can be readily determined by the skilled artisan depending on the particular factors of each case.
  • the present invention additionally encompasses methods for preventing
  • pre-Alzheimer's disease condition refers to a condition prior to Alzheimer's disease.
  • the subject with a pre-Alzheimer's disease condition has not been diagnosed as having Alzheimer's disease, but nevertheless may exhibit some of the typical symptoms of Alzheimer's disease and/or have a medical history likely to increase the subject's risk to developing Alzheimer's disease.
  • the invention further provides methods for treating or preventing Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of ginsenoside compound.
  • ginsenosides and their analogues in treating AD were examined.
  • a number of ginsenosides were screened based on their effects on A ⁇ generation.
  • the effects of various ginsenosides on A ⁇ (e.g., A ⁇ 40 and A ⁇ 42) production was initially accessed by incubating the Chinese hamster ovary (CHO) cells expressing human
  • ginsenosides included RbI 5 Rb2, Rc, Rd, Re, Re, RgI and Rg2 and differ in their side chains and sugar moieties.
  • a ⁇ 42 generation differ at the two or three side chains attached to the common triterpene backbone known as dammarane.
  • dammarane The common structure skeleton for each group of ginsenosides is shown in the top panel. Ginsenosides that harbor A ⁇ 42-lowering activity are indicated in the far right column of the tables: A ⁇ 42-lowering activity ("Yes"), no profound effects (“No”), and non-determined (“ND”).
  • Ginsenosides that affected cell viability are indicated as "Cytotoxic.”
  • Abbreviation for carbohydrates are as follows: GIc, D- glucopyranosyl; Ara (pyr), L-arabinopyranosyl; Ara (fur), L-arabinofuranyosyl; Rha, L- rhamnopyranosyl. Table 1
  • Rg6, Rg5) on A ⁇ 40 and A ⁇ 42 generation were tested.
  • Initial screening identified three structurally related ginsenosides, RkI, (20S)Rg3, and Rg5, which selectively lowered the secretion of A ⁇ 42 ( Figure 11).
  • a ⁇ 42 levels were not affected by (20R)Rg3, RhI, and Rg6.
  • a ⁇ 40 levels were not changed by treatment with any of the ginsenosides tested.
  • the potency of A ⁇ 42-lowering activity was highest with RkI and (20S)Rg3.
  • Rg5 was a less effective A ⁇ 42 -lowering reagent as compared to RkI or (20S)Rg3 ( Figure 2).
  • RkI or sulindac sulfide ( Figure 12B). These studies provide a structure-activity relationship between the chemical structures of ginsenosides and A ⁇ 42-lowering activity, further providing the basis for designing additional A ⁇ 42-lowering analogues as well as for defining a class of compounds that harbor A ⁇ 42-lowering activity. [0083] RkI did not affect steady-state levels of full-length APP in both CHO-APP and Neuro2a-APPsw cells ( Figure 13), suggesting that the reduction of A ⁇ 42 is likely due to altered post-translation processing of APP. In contrast to the full-length form, the steady- state levels of C-terminal APP fragments were up-regulated by treatment with RkI ( Figure 13).
  • RkI may affect the g-secretase cleavage step (e.g., A ⁇ 42 cleavage), therefore causing the accumulation of APP C-terminal fragments, as has been shown for a general ⁇ -secretase inhibitor Compound E.
  • a ⁇ 42 levels in the medium of each corresponding samples are shown in the bottom panel.
  • Ginsenosides are metabolized by human intestinal bacteria after oral administration of ginseng extract (Kobayashi K., et al., Metabolism of ginsenoside by human intestinal bacteria [II] Ginseng Review 1994; 18: 10-14; Hasegawa H., et al., Main ginseng saponin metabolites formed by intestinal bacteria. Planta Med. 1996; 62: 453-457.).
  • ginsenosides including 20(S)- protopanaxatriol (PPT) and 20(S)-protopanaxadiol (PPD) on A ⁇ 42 generation were tested.
  • 20(S)-panaxatriol (PT) and 20(S)-panaxadiol (PD) are the artificial derivatives of PPT and PPPD, respectively.
  • Treatment with either PPT or PT reduced the production of A ⁇ 42 without affecting the levels of A ⁇ 42 in Neuro2a cells expressing the human Swedish mutant form of APP (Neuro2a-SW) as well as in CHO cells expressing wild-type human APP ( Figure 16).
  • a ⁇ 42-lowering natural compounds that originate from heat- processed ginseng have been identified.
  • Structure-activity defines a class of compounds that could serve as a foundation for development of effective therapeutic agents for treatment of AD.
  • ginsenoside therapy for treating AD associated neurodegeneration can be demonstrated in a murine model of AD.
  • the ginsenoside compounds (20S) Rg3, RkI, Rg5 and Rgk351 can be used to treat mice suffering from AD associated neurodegeneration.
  • Alzheimer's disease mutant form of APP can be obtained from the Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609.
  • Four groups of mice can then be studied: (1) APP mice without ginsenoside treatment (placebo); (2) Swedish mice without ginsenoside treatment (placebo); (3) APP mice + Rg5 (100 ⁇ g/ ⁇ l/day); and (4) Swedish mice + Rg5 (100 ⁇ g/ ⁇ l/day).
  • amounts of A ⁇ 42 in the serum of the mice can be measured. It is expected that the results of this study will demonstrate the general benefits of ginsenoside therapy for treating AD associated neuordegeneration.
  • APP and Swedish mice without ginsenoside treatment should have significantly higher levels of serum A ⁇ 42 and demonstrate behavior characterisitic of neurodegeneration, as compared with APP and Swedish mice receiving ginsenoside treatment.
  • Betulafolienetriol was isolated from an ethereal extract of the leaves Btula pendula, followed by chromatography on silica gel and crystallization from acetone: mp 195- 195°, lit. 197- 198° (Fischer et al (1959) Justus Liebigs Ann. Chem. 626:185).
  • the 12-C-acetyl derivative of 20(S)-protopanaxadiol (3) is prepared from betulafolienetriol by the sequence of reactions showen in Scheme 1.
  • Betulafolienetriol is oxidized to ketone 1, dammar-24-ene-12 ⁇ , 20(S)-diol-3-one, mp 197-199°, lit 196-199°, (yield: 60%), which is acetylated with acetic anhydride in pyridine to give compound 2, 12- O-Acetyl-dammar-24-ene-12 ⁇ , 20(S)-diol-3-one (yield: 100%?)

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Abstract

La présente invention concerne de nouveaux composés de ginsenoside, des compositions (par ex., des compositions pharmaceutiques) renfermant ces composés de ginsenoside ainsi que des procédés de synthèse de ces composés de ginsenoside. En outre, la présente invention concerne des méthodes destinées à inhiber la production de peptides bêta-amyloïdes et des méthodes destinées à traiter ou prévenir un état pathologique, et notamment les maladies neurodégénératives (par ex., la maladie d'Alzheimer), au moyen de ces composés de ginsenoside.
PCT/US2005/024533 2004-07-16 2005-07-11 Composes et leur preparation pour le traitement de la maladie d'alzheimer par inhibition de la production de peptides beta-amyloides WO2006019685A2 (fr)

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JP2007521534A JP2008506686A (ja) 2004-07-16 2005-07-11 ベータ−アミロイドペプチドの形成を阻害することによるアルツハイマー病治療用化合物及び製造
MX2007000562A MX2007000562A (es) 2004-07-16 2005-07-11 Compuestos y su preparacion para el tratamiento de la enfermedad de alzheimer al inhibir la produccion de peptidos beta-amiloideos.

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CN101397327B (zh) * 2007-09-29 2012-01-11 广州天安医药科技有限公司 二氢人参皂苷Rg2的应用
EP3072517A1 (fr) * 2013-11-22 2016-09-28 Fu, Li Utilisation de ginsénoside-rg3 pour préparer un médicament pour prévenir et/ou traiter la démence et médicament correspondant
CN106046098A (zh) * 2016-06-15 2016-10-26 大连大学 一种乙酰基人参皂苷Rd及其制备方法
JP2017023134A (ja) * 2015-07-27 2017-02-02 インテリジェント シンセティック バイオロジー センター ジンセノサイドｆ１を含むアミロイドプラーク除去用組成物
RU2673885C1 (ru) * 2014-12-17 2018-12-03 Ли ФУ Полиацилированные производные 20(r)-гинзенозида rg3, их получение и применение
CN113633650A (zh) * 2021-08-26 2021-11-12 哈尔滨工业大学（威海） 一种抑制淀粉样蛋白产生的稀有人参皂苷及其应用
CN115025106A (zh) * 2022-07-12 2022-09-09 昆明理工大学 人参皂苷Rk3在制备具有神经保护作用药物中的用途

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KR102375097B1 (ko) 2021-04-01 2022-03-17 주식회사 클로소사이언스 항노화 유전자 klotho의 발현을 유도하는 화합물을 포함하는 퇴행성 신경질환의 예방 또는 치료용 조성물

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CN101397327B (zh) * 2007-09-29 2012-01-11 广州天安医药科技有限公司 二氢人参皂苷Rg2的应用
EP3072517A1 (fr) * 2013-11-22 2016-09-28 Fu, Li Utilisation de ginsénoside-rg3 pour préparer un médicament pour prévenir et/ou traiter la démence et médicament correspondant
EP3072517A4 (fr) * 2013-11-22 2017-05-17 Fu, Li Utilisation de ginsénoside-rg3 pour préparer un médicament pour prévenir et/ou traiter la démence et médicament correspondant
AU2014352441B2 (en) * 2013-11-22 2017-10-12 Li Fu Use of ginsenoside-Rg3 in preparing medicine for preventing or/and treating dementia and medicine
RU2673885C1 (ru) * 2014-12-17 2018-12-03 Ли ФУ Полиацилированные производные 20(r)-гинзенозида rg3, их получение и применение
RU2695380C1 (ru) * 2014-12-17 2019-07-23 Ли ФУ Полиацилированные производные 20(r)-гинзенозида rg3, их получение и применение
JP2017023134A (ja) * 2015-07-27 2017-02-02 インテリジェント シンセティック バイオロジー センター ジンセノサイドｆ１を含むアミロイドプラーク除去用組成物
EP3130341A1 (fr) * 2015-07-27 2017-02-15 Intelligent Synthetic Biology Center Composition contenant du ginsénoside f1 permettant de retirer des plaques amyloïdes
US10307436B2 (en) 2015-07-27 2019-06-04 Intelligent Synthetic Biology Center Composition containing ginsenoside F1 for removing amyloid plaques
CN106046098A (zh) * 2016-06-15 2016-10-26 大连大学 一种乙酰基人参皂苷Rd及其制备方法
CN113633650A (zh) * 2021-08-26 2021-11-12 哈尔滨工业大学（威海） 一种抑制淀粉样蛋白产生的稀有人参皂苷及其应用
CN115025106A (zh) * 2022-07-12 2022-09-09 昆明理工大学 人参皂苷Rk3在制备具有神经保护作用药物中的用途

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