JP2008506686A - Compound for the treatment of Alzheimer's disease and production by inhibiting the formation of beta-amyloid peptide - Google Patents

Abstract

  The present invention provides novel ginsenoside compounds, compositions containing ginsenoside compounds (eg, pharmaceutical compositions), and methods for synthesizing these ginsenoside compounds. In addition, the present invention provides methods for inhibiting beta amyloid peptide production and methods for treating and preventing pathological conditions, particularly neurodegenerative diseases (eg, Alzheimer's disease) using these ginsenoside compounds.

Description

CROSS-REFERENCE TO RELATED art claims the benefit of U.S. Provisional Application No. 60 / 588,433, filed October 7, 2004 filed U.S. Application Serial No. 10 / 961,346 and July 16, 2004 To do. These applications are hereby incorporated herein in their entirety.

TECHNICAL FIELD The present invention provides novel ginsenoside compounds, compositions containing ginsenoside compounds (eg, pharmaceutical compositions), and methods for synthesizing these ginsenoside compounds. In addition, the present invention provides methods for inhibiting beta amyloid peptide production and methods for treating and preventing pathological conditions, particularly neurodegenerative diseases (eg, Alzheimer's disease) using these ginsenoside compounds.

Statement on Government Rights Part of this invention was made with government support under ROI N543467 granted to NIH. Accordingly, the United States government has certain rights in the invention.

  Alzheimer's disease (AD) is a nerve characterized by progressive, unrelenting, loss of cognitive function that ultimately leads to a state where it is impossible to maintain normal social and / or professional activity. It is a degenerative disease (Francis, et al., Neurogulins and ErbB receptors in cultured neuroastrology. J. Neurosci. Res., 57: 487-94, 1999). Alzheimer's disease is the most common form of aging-related dementia and is one of the most serious health problems in the United States. Approximately 4 million Americans suffer from Alzheimer's disease, with an annual cost of at least $ 100 billion making Alzheimer's disease one of the most costly aging disorders. Alzheimer's disease usually affects twice as many women as men and accounts for more than 65% of elderly dementia. Alzheimer's disease is the fourth leading cause of death in the United States. To date, treatment for Alzheimer's disease is not applicable and cognitive decline is inevitable. The disease can last for more than 20 years, and AD patients usually survive for an average of 8 to 10 years after being diagnosed with the disease.

  Hospitals for Alzheimer's disease consist of neurofibrillary tangles (consisting of helical filaments and tau protein paired together) and a neuritic or senile plaque (peripheral amyloid nucleus) in the cerebral cortex Axon, astrocytes, and glial cells)). Senile plaques and neurofibrils occur according to normal aging, but they are more prevalent in people with Alzheimer's disease. Specific protein abnormalities also occur in Alzheimer's disease. In particular, AD is characterized by the accumulation of amyloid β peptide (Aβ) in the amyloid plaques of the brain (Selkoe, et al., (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 81,741-66; Hardy and Selkoe (2002) .The amyloid hypothesis of Alzheimer's disease: progress and programs on the load to therapeutics. Aβ is produced by sequential proteolytic cleavage of amyloid precursor protein (APP) by a series of membrane-bound proteases called β and γ secretases (Vassar and Citron (2000) Abeta-generating enzymes: recipient advancements in beta). -And gamma-secretase research.Neuron 27,419-422; John, et al., (2003) Human beta-secretase (BASE) and BACE inhibitor.J Med.Chem.46, 4625-4630; ) Notch and Presenilin: regulated intramb lane protocol links development and degeneration. Annu. Rev Neurosci. 26, 565-597; Medina and Dotti (2003) ripped out by presenilin-dependent. Cleavage of heterologous β-secretase at the C-terminus of Aβ produces two major isoforms of Aβ, Aβ40 and Aβ42. Although Aβ40 is the major cleavage product, a smaller amount of highly amyloidogenic Aβ42 is believed to be one of the important virulence factors in AD (Selkoe (2001) Alzheimer's disease: genes, proteins, and therapy). Physiol Rev. 81, 741-66), increased cerebral cortex Aβ42 is closely associated with AD-related synaptic / neuronal dysfunction (Selkoe, Alzheimer's disease is synthetic failure, Science 298: 789-791, 2002).

  Presenilin is required for intramembrane proteolysis of selected type I membrane proteins, including amyloid β precursor protein (APP), and produces amyloid β protein (De Strooper et al., Defiency of presenilin-1 inhibits the normalm of amyloid precursor protein. Nature 391: 387-90, 1998; Steiner and Haass, Intrambrane strategy by presenilins. Nat. Rev. Mol. Cell. Biol. 1: 217inu, 2000. signal transducti N. Neuron 34: 499-502, 2002; De Strooper and Annaert, Presenilins and the intrambrane strategy of protein and di-E3: Ge Sand e3: Facts and fiction.Nat. , Notch, α-beta and Alzheimer's disease: where do the presenilins fit in? Nat. Rev. Neurosci. 3: 281-90, 2002). Such proteolysis can be mediated by a presenilin-dependent β-secretase mechanism known to be highly conserved across species including nematodes, flies, and mammals (L'Hernault and Arduengo, Mutation of a pure sperm membrane protein) in Caenorhabditis elegans prevents perm differentiation but not wits associated meiotic divisions, J. Cell. Biol. 119: 55-58, 1992; aenorhabditis elegans S182 Alzheimer's disease gene.Nature 377: 351-54,1999; Li and Greenwald, HOP-I, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP- I signalling.Proc.Natl.Acad.Sci.USA 94: 12204-209, 1997; Steiner and Haass, Intrambrane strategy by presenilins.Nat. Rev. Mol.Cell.Biol.1: 217-24, 2000; Sisodia and George-Hyslop, [gamma] -Secretase, Notch, [alpha] -beta and Alzheimer's disease: where do the presinlins. 3: 281-90, 2002).

  Γ-secretase, a high molecular weight multi-protein complex surrounding presenilin and nicastrin, mediates the final step in Aβ generation in Alzheimer's disease (Li, et al., Presenilin 1 is linked with β- secrete activity in the targeted soluble state.Proc.Natl.Acad.Sci.USA 97: 6138-43, 2000; Esler, et al. Proc. Natl.Acad.Sci.USA 99: 2720-25, 2002). Stabilization of presenilin heterodimers and other undefined nuclear components (converted from short-lived pools to long-lived pools) appears to have critical significance for γ-secretase activity (Tinakaran, et al., Evidence that levels of presenilins (PSl and PS2) are coordinarily regulated by competition for limiting cell factor. Et al. 27. J. Biol. of PALP motif at the C terminus of presenilins is obliga ory for stabilization, complex formation, and gamma-secretase activities of presenilins.J.Biol.Chem.276: 33273-281,2001). γ-secretase activity displays very loose sequence specificity near the target transmembrane cleavage site, and Notch [Schroeter, E .; H. , Et al. (1998) Notch-1 signaling requirements-induced proteolytic release of intracellular domain. Nature 393, 382-386; De Strooper, et al. (1999) Presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398: 518-522], ErbB4 [Lee, et al. (2002) Presenilin-dependent gamma-secretase-like intraframe clave of ErbB4. J. et al. Biol. Chem. 277, 6318-6323; Ni, et al. , (2001) Gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179-2181), and p75 neurotrophin receptor (p75NTR) (Jung, et al., (2003) Regulated intramembrane proteolysis of the p75 neurotrophic receptor. 278, 42161-42169) appears to mediate intramembrane cleavage of other non-APP-I type membrane substrates.

  General inhibition of β-secretase activity is expected not only to abolish Aβ production but also to inhibit normal processing of β-secretase substrates in other cells. Therefore, complete inhibition of γ-secretase activity could lead to potentially severe side effects (Doerfler, et al., Links Free in PMC Presenilin-dependent gamma-secretase activity modulo thymemptyte centm entrepreneurial pls. Acad. Sci USA 98, 9312-9317; Hadland, et al., Gamma-secretase inhibitors repress thymocyte development. Proc Natl. Acad. Sci USA 98, 7487-7491).

  A safe approach would ideally be to use reagents that can selectively reduce Aβ42 production without affecting the intramembrane proteolysis of other γ-secretase substrates. As an example, without significant influence on γ-secretase-mediated cleavage of ErbB4 (Wegen, et al. (2003). Abeta42-lowering non-sientoidal anti-inflammatory drug pre-membrane regeneration 4 receptor and signaling through the APP, intracellular domain. J. Biol. Chem. 278, 30748-30754, some non-steroidal anti-inflammatory drugs (NSAIDs) were shown to have reduced production of Aβ42 (Wegen). et al. (2001). subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity.Nature 414,212-216). Thus, small molecules that can selectively reduce Aβ42 production (without affecting other γ-secretase substrates) are attractive and promising as therapeutic agents for treating AD.

  Many cases of juvenile familial Alzheimer's disease (FAD) are caused by mutations in two related genes encoding presenilin proteins, PS1 and PS2 (Tanzi, et al., The gene defects for familial Alzheimer's disease. Neurobiol.Dis.3: 159-68, 1996; Hardy, J., Amyloid, the presenilins and Alzheimer's disease.Trends Neurosci.20: 154-59, 1997; Selkoe, D.e.z. genes, proteins, and therapy.Physiol.Rev.81: 741-66. , 2001). FAD-related mutations in presenilin result in a longer (42 amino acid residues), more amyloidogenic form of amyloid-beta (Aβ42). Analyzing the pathophysiology of presenilin offers the only opportunity to unravel the molecular basis of Alzheimer's disease. Excessive amyloid production appears to cause neurodegeneration that underlies the dementia properties of AD.

  Panax ginseng is a generic name given to the dry roots of the Panax genus plant, and has been widely used in Asia for thousands of years as a general health tonic and a drug to treat a range of diseases ( .. Cho, et al (1995) Pharmacological action of Korean ginseng In the Society for Korean Ginseng (edition): Understanding Korean Ginseng, Seoul: Hanlim Publishers, pp 35-54; Shibata S. (2001) Chemistry and cancer preventing activities of ginseng saponins and some related triterpen J Korea Med Sci 16 Suppl: S28-37; Attel, et al. (1999); Ginseng pharmacology: multiple constituents and multiple P. et al. The effects of Panax ginseng on quality of life.J.Clin.Pharm.Ther.28, 5-15; Coon and Ernst (2002) .Panx ginseng: a systematic review s.Drug Saf.25: 323-44). The Panax genus includes about 6 species native to East Asia and 2 species native to eastern North America. Panax ginseng (Asian ginseng) and American ginseng L (North American ginseng) are the two most commonly used species in dietary supplements and pharmaceutical compositions. The roots and their extracts contain various substrates including saponins.

  Carrots are known to have specific pharmacological effects including improved liver function and immune promotion, and anti-arteriosclerosis, anti-thrombosis, anti-stress, anti-diabetic, anti-term blood pressure, and anti-tumor effects. Among several types of compounds isolated from the ginseng root, ginseng saponins are known to be chemical components that contribute to their pharmacological effects. These compounds are triterpene glycosides named ginsenoside Rx, where x is an index from “a” to “k” depending on its polarity. The polarity is determined by their mobility on the thin layer chromatography plate and is a function of the number of monosaccharide residues in the sugar chain of the molecule.

  To date, at least 31 ginsenosides have been isolated from white and red carrots. All of the ginsenosides can be divided into three groups depending on their aglycone, such as protopanaxadiol type ginsenosides (eg Rb1, Rb2, Rc, Rd, (20R) Rg3, (20S) Rg3, Rh2) , Protopanaxatriol type ginsenoside (eg, Re, Rf, Rg1, Rg2, Rh1), and oleanolic acid type ginsenoside (eg, Ro). Both protopanaxadiol-type and protopanaxatriol-type ginsenosides have a triterpene skeleton known as damaran (Attel, et al. (1999) Ginseng pharmacology: multiple constituents and multiple actions. Bio16. Biochem. 85: Biochem. 85: Biochem. -1693). Rk1, Rg5, (20R) Rg3, and (20S) Rg3 are ginsenosides that are almost uniquely present in heat-treated carrots, but have not been found to exist as trace elements in untreated carrots (Kwon (2001) Liquid chromatographic determination of less polar ginsenodes in processed ginseng. J. Chromatogr. A. 921; 335-339; Park, et al. Bull.50, 538-540 Park, et al. (2002); w Dammarane glycosides from heat-processed ginseng.Arch.Pharm.Res.25,428-432; Kim, et al. (2000); Steaming of ginsengat high. 1702). Carbohydrates including glucopyranosyl, arabinopyranosyl, arabinofuranosyl, and rhamnopyranosyl can also be chemically related to certain ginsenosides.

  Treatment of ginseng with steam at high temperature further promotes the content of these intrinsic ginsenosides Rk1, Rg5, (20R) Rg3, and (20S) Rg3, which are believed to have novel pharmacological activity. At least some of the beneficial attributes of ginseng can be attributed to its triterpene saponin content, which is a mixture of ginseng collectively referred to as ginsenoside.

  US Pat. No. 5,776,460 (hereinafter “'460 patent”) discloses processed ginseng products with enhanced pharmacological effects. This ginseng product is commercially known as “sun ginseng” and contains an increased value of an effective pharmaceutical ingredient resulting from heat treatment of the ginseng at an elevated temperature for a certain period of time. Regarding what is specifically disclosed in the '460 patent, the heat treatment of ginseng can be carried out at a temperature of 120 ° -180 ° C for 0.5-20 hours, and preferably at a temperature of 120 ° -140 ° C. And can be carried out for 2 to 5 hours. The heating time varies depending on the heating temperature, such that lower temperatures require longer times, while higher temperatures require relatively short times. The '460 patent also discloses that the processed ginseng product has pharmacological properties including, in particular, antioxidant activity and vasodilator activity.

  Recently, Tae-Wan Kim et al. Demonstrated that the unique components of the heat treated ginseng product disclosed in the '460 patent significantly reduce the production of Aβ42 in cells (patent pending). In particular, the inventors have identified at least three ginsenosides, Rk1, (20S) Rg3, and Rg5, a heat-treated ginseng intrinsic component known as “Sun Ginseng”, and (20R) Rgk351, a mixture of Rg3, (20S) Rg3, Rg5, and Rk1, was found to reduce Aβ42 production in mammalian cells. Rgk351 and Rk1 most effectively reduce Aβ42 values. Furthermore, Rk1 has also been shown to inhibit Aβ42 production in a cell-free test using a partially purified γ-secretase complex, where either Rk1 exhibits either selectivity and / or activity of the γ-secretase enzyme. Suggested to adjust. Furthermore, Tae-Wan Kim et al. Have found that some ginsenosides that do not have Aβ42 reducing activity in vitro are effective in reducing Aβ42 in vivo. For example, 20 (S) -protopanaxatriol (PPT) group ginsenoside, such as Rg1, is converted to PPT after ingestion. Therefore, Rg1 generally does not have amyloid reducing activity in vitro, but Rg1 can be converted in vivo to the active amyloid reducing component PPT.

  The present invention provides compositions and methods for preventing and treating neurodegenerative diseases such as Alzheimer's disease.

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝を有する化合物を提供する。 In one embodiment, the present invention provides the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. } Is provided.

  The alkyl I group further comprises oxygen, nitrogen or phosphorus, and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. In certain embodiments, the sugar group is selected from the group consisting of Glc, Ara (pyr), Ara (fur), Rha, and Xyl.

｛式中、
立体中心の配置はＲ又はＳであり；
ＸはＯＲ又はＮＲであり、ここでＲはアルキル又はアリールであり；
Ｘ’はアルキル、ＯＲ、ＮＲであり、ここでＲはアルキル又はアリールであり；
Ｒ’はＨ、アルキル又はアシルである。｝からなる群より選択される。 In other embodiments, R ₄ is:

{Where,
The configuration of the stereocenter is R or S;
X is OR or NR, where R is alkyl or aryl;
X ′ is alkyl, OR, NR, wherein R is alkyl or aryl;
R ′ is H, alkyl or acyl. } Is selected.

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝を有する化合物を含む組成物、特に医薬組成物を提供する。 In another embodiment, the present invention provides the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. }, In particular a pharmaceutical composition is provided.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を酸化剤で処理し、
（ｂ）以下の一般式：

を有する化合物を形成し；
（ｃ）ステップ（ｂ）において形成された化合物を還元剤で処理し、以下の一般式：

｛式中、
Ｒ_１は、Ｈ又はＯＨであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；及び
Ｒ_４は、アルケニル、アリール又はアルキルＩＩである。｝を有する化合物を形成する、を含む、上記方法も提供する。 The present invention has the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Treating a compound having
(B) The following general formula:

Forming a compound having:
(C) treating the compound formed in step (b) with a reducing agent to produce the following general formula:

{Where,
R ₁ is H or OH;
R ₂ is selected from the group consisting of H, OH, OAc, and OX, wherein X is a carbohydrate comprising one or more sugars or acylated derivatives thereof;
R ₃ is selected from the group consisting of H, OH, and OAc; and R ₄ is alkenyl, aryl, or alkyl II. Are also provided.

In other embodiments, the oxidizing agent is chromic anhydride, the reducing agent is NaBH _4.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を酸化剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｂ）ステップ（ａ）において形成された化合物を還元剤で処理し、以下の一般式：

を有する化合物を形成し：
（ｃ）場合により、ステップ（ｂ）において形成された化合物を保護Ｒ_１誘導体で処理し、以下の一般式：

を有する化合物を形成し、
（ｄ）ステップ（ｃ）において形成された化合物を脱保護剤で処理し、以下の一般式：

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝を有する化合物を形成する、
を含む、上記方法をさらに提供する。 The present invention has the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a reducing agent to produce the following general formula:

Forming a compound having:
(C) Optionally treating the compound formed in step (b) with a protected R ₁ derivative to give the following general formula:

Forming a compound having
(D) treating the compound formed in step (c) with a deprotecting agent to give the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. To form a compound having
The above method is further provided.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を酸化剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｂ）ステップ（ａ）において形成された化合物を保護剤で処理し、以下の一般式：

を有する化合物を形成し：
（ｃ）ステップ（ｂ）において形成された化合物を還元剤で処理し、以下の一般式：

を有する化合物を形成し、
（ｄ）ステップ（ｃ）において形成された化合物をＡＣ_８−Ｇｌｃ−Ｇｌｃ−Ｂｒで処理し、以下の一般式：

を有する化合物を形成し；
（ｅ）ステップ（ｄ）において形成された化合物を脱保護剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｆ）ステップ（ｅ）において形成された化合物をさらに修飾し、以下の一般式：

を有する化合物を形成する、を含む、上記方法を提供する。 Furthermore, the present invention provides the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a protective agent to give the following general formula:

Forming a compound having:
(C) treating the compound formed in step (b) with a reducing agent to produce the following general formula:

Forming a compound having
(D) treating the compound formed in step (c) with AC ₈ -Glc-Glc-Br to obtain the following general formula:

Forming a compound having:
(E) treating the compound formed in step (d) with a deprotecting agent to give the following general formula:

Forming a compound having:
(F) The compound formed in step (e) is further modified to give the following general formula:

Forming a compound having:

  In certain embodiments, the starting material, betulaforienetriol, is obtained from a plant such as, for example, a common strain of birch.

を有する化合物の合成方法であって、以下のステップ：
以下の一般式：

を有する化合物を、ＮａＢＨ_４の如き還元剤で処理する、
を含む、上記方法を提供する。 In another embodiment, the present invention provides the following general formula:

A method of synthesizing a compound having the following steps:
The following general formula:

Treating a compound having a reducing agent such as NaBH ₄ with
The above method is provided.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を還元剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｂ）ステップ（ａ）において形成された化合物をＡ_Ｃ８−Ｇｌｃ−Ｇｌｃ−Ｂｒで処理し、以下の一般式：

を有する化合物を形成し：
（ｃ）ステップ（ｂ）において形成された化合物を脱保護剤で処理し、以下の一般式：

を有する化合物を形成する、
を含む、上記方法を提供する。 In another embodiment, the present invention provides the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with a reducing agent and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with A _C8 -Glc-Glc-Br;

Forming a compound having:
(C) treating the compound formed in step (b) with a deprotecting agent to give the following general formula:

Forming a compound having
The above method is provided.

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝
を有する化合物を前記対象に投与することを含む、上記方法を提供する。 Furthermore, the present invention is a method for treating or preventing a pathological condition of a subject, comprising the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 method is provided comprising administering to the subject a compound having:

  In certain embodiments, the pathological condition is neurodegeneration, preferably Alzheimer's disease, Aβ42-related disorder.

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝
を有する化合物を前記対象に投与することを含む、上記方法を提供する。 The present invention is a method for inhibiting β-amyloid production in a subject, comprising inhibiting β-amyloid production in an in vivo event, wherein the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 method is provided comprising administering to the subject a compound having:

  Still other aspects of the invention will become apparent in view of the following description.

  As used in this specification and the claims, the singular forms “a”, “an”, and “the” include the plural unless the context clearly dictates otherwise. Thus, for example, reference to “a agent” includes a plurality of such agents, reference to “the ginsenoside” includes one or more ginsenosides and their equivalents known by those skilled in the art, and the like. Mention. The entire contents of all publications, patent applications, patents, and other references cited herein are hereby incorporated by reference.

  In the context of the present invention, compounds and methods for treating Alzheimer's disease, neurodegenerative diseases and for modulating the production of amyloid-beta protein (Aβ) are provided.

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝を有する化合物を提供する。当該アルキルＩ基は、酸素、窒素又はリンをさらに含み；及び当該アルキルＩＩ基は、ヒドロキシル、エーテル、ケトン、オキシム、ヒドラゾン、イミン、及びシッフ塩基からなる群より選択される官能基をさらに含み得る。ある態様において、当該糖は、Ｇｌｃ、Ａｒａ（ｐｙｒ）、Ａｒａ（ｆｕｒ）、Ｒｈａ、及びＸｙｌからなる群より選択される。 In certain embodiments, the present invention provides the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. } Is provided. The alkyl I group further comprises oxygen, nitrogen or phosphorus; and the alkyl II group may further comprise a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. . In certain embodiments, the sugar is selected from the group consisting of Glc, Ara (pyr), Ara (fur), Rha, and Xyl.

｛式中、
立体中心の配置はＲ又はＳであり；
ＸはＯＲ又はＮＲであり、ここでＲはアルキル又はアリールであり；
Ｘ’はアルキル、ＯＲ、ＮＲであり、ここでＲはアルキル又はアリールであり；
Ｒ’はＨ、アルキル又はアシルである。｝からなる群より選択される。本明細書に使用される通り、当該化合物はダマラン、特にジンセノシド及びそれらの類似体である。本明細書に使用される「ジンセノシド」は、特定化合物、Ｒａ１、Ｒａ２、Ｒａ３、Ｒｂ１、Ｒｂ２、Ｒｂ３、Ｒｃ、Ｒｄ、Ｒｅ、Ｒｆ、Ｒｇ１、（２０Ｒ）Ｒｇ２、（２０Ｓ）Ｒｇ２、（２０Ｒ）Ｒｇ３、（２０Ｓ）Ｒｇ３、Ｒｇ５、Ｒｇ６、Ｒｈ１、（２０Ｒ）Ｒｈ２、（２０Ｓ）Ｒｈ２、Ｒｈ３、Ｒｈ４、（２０Ｒ）Ｒｇ３、（２０Ｓ）Ｒｇ３、Ｒｋ１、Ｒｋ２、Ｒｋ３、Ｒｓ１、Ｒｓ２、Ｒｓ３、Ｒｓ４、Ｒｓ５、Ｒｓ６、Ｒｓ７、Ｆ４、Ｒｇｋ３５１、プロトパナキサジオール（ＰＰＤ）、プロトパナキサトリオール（ＰＰＴ）、ＤＨＰＰＤ−Ｉ、ＤＨＰＰＤ−ＩＩ、ＤＨＰＰＴ−Ｉ、ＤＨＰＰＴ−ＩＩ、サン人参、白人参又は赤人参、又はそれらの相同体のブタノール溶解画分を非制限的に含むトリテルペングリコシドの集合を言及する。本発明のジンセノシドは、グルコピラノシル、アラビノピラノシル、アラビノフルラノシル、及びラムノピラノシルを非制限的に含む炭水化物と化学的に結合し得る。本発明のジンセノシドは単離されたジンセノシド化合物又は単離され、さらに合成されたジンセノシドとなり得る。本発明の単離されたジンセノシドは、熱、光、化学的、酵素的方法、又は当業者に通常知られる他の合成方法を非制限的に含む方法を使用してさらに合成され得る。 In other embodiments, the R ₄ is:

{Where,
The configuration of the stereocenter is R or S;
X is OR or NR, where R is alkyl or aryl;
X ′ is alkyl, OR, NR, wherein R is alkyl or aryl;
R ′ is H, alkyl or acyl. } Is selected. As used herein, the compound is damaran, particularly ginsenoside and analogs thereof. As used herein, “ginsenoside” refers to a specific compound, Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, (20R) Rg2, (20S) Rg2, (20R) Rg3, (20S) Rg3, Rg5, Rg6, Rh1, (20R) Rh2, (20S) Rh2, Rh3, Rh4, (20R) Rg3, (20S) Rg3, Rk1, Rk2, Rk3, Rs1, Rs2, Rs3, Rs4 , Rs5, Rs6, Rs7, F4, Rgk351, protopanaxadiol (PPD), protopanaxatriol (PPT), DHPPD-I, DHPPD-II, DHPPT-I, DHPPT-II, San ginseng, white ginseng or red A collection of triterpene glycosides including but not limited to butanol-soluble fractions of carrots or their homologues To 及. The ginsenosides of the present invention can be chemically conjugated to carbohydrates including, but not limited to, glucopyranosyl, arabinopyranosyl, arabinofluranosyl, and rhamnopyranosyl. The ginsenosides of the present invention can be isolated ginsenoside compounds or isolated and further synthesized ginsenosides. The isolated ginsenosides of the present invention can be further synthesized using methods including, but not limited to, thermal, light, chemical, enzymatic methods, or other synthetic methods commonly known to those skilled in the art.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を酸化剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｂ）ステップ（ａ）において形成された化合物を還元剤で処理し、以下の一般式：

｛式中、
Ｒ_１は、Ｈ又はＯＨであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩである。｝を有する化合物を形成する、
を含む、上記方法をさらに提供する。ある態様において、当該酸化剤は無水クロム酸であり、そして当該還元剤はＮａＢＨ_４である。 The present invention has the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a reducing agent to produce the following general formula:

{Where,
R ₁ is H or OH;
R ₂ is selected from the group consisting of H, OH, OAc, and OX, wherein X is a carbohydrate comprising 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. To form a compound having
The above method is further provided. In certain embodiments, the oxidizing agent is chromic anhydride and the reducing agent is NaBH ₄ .

を有する化合物であって、特にベチュラフォリエネトリオール（ｂｅｔｕｌａｆｏｌｉｅｎｅｔｒｉｏｌ）は、普通株のカバノキを非制限的に含む植物から入手され得る。これらの抽出物は、ベチュラフォリエネトリオールを豊富に含み、ジンセノシドを製造するための所望の出発物質である、なぜならば、人参よりもそれらの方が著しくコストが安いからである。 The starting material, ie the following general formula:

In particular, betulaforienetriol can be obtained from plants that include, but are not limited to, common birch. These extracts are rich in betula folienetriol and are the desired starting materials for producing ginsenoside, because they are significantly less expensive than carrots.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を酸化剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｂ）ステップ（ａ）において形成された化合物を還元剤で処理し、以下の一般式：

を有する化合物を形成し：
（ｃ）場合により、ステップ（ｂ）において形成された化合物を保護Ｒ_１誘導体で処理し、以下の一般式：

を有する化合物を形成し、
（ｄ）ステップ（ｃ）において形成された化合物を脱保護剤で処理し、以下の一般式：

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝を有する化合物を形成する、
を含む、上記方法も提供する。 The present invention has the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a reducing agent to produce the following general formula:

Forming a compound having:
(C) Optionally treating the compound formed in step (b) with a protected R ₁ derivative to give the following general formula:

Forming a compound having
(D) treating the compound formed in step (c) with a deprotecting agent to give the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. To form a compound having
The above method is also provided.

The alkyl I group can further include oxygen, nitrogen, or phosphorus; and the alkyl II group can further include a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. . In some embodiments, the oxidizing agent is chromic anhydride and the reducing agent is NaBH ₄ . In certain embodiments, the protected R ₁ derivative is a protected R ₁ halogen derivative. For example, the protected R ₁ derivative can be protected by an A _C8 -group. The protected R ₁ group can be deprotected using an agent such as NaOMe.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を酸化剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｂ）ステップ（ａ）において形成された化合物を保護剤で処理し、以下の一般式：

を有する化合物を形成し：
（ｃ）ステップ（ｂ）において形成された化合物を還元剤で処理し、以下の一般式：

を有する化合物を形成し、
（ｄ）ステップ（ｃ）において形成された化合物をＡ_Ｃ８−Ｇｌｃ−Ｇｌｃ−Ｂｒで処理し、以下の一般式：

を有する化合物を形成し；
（ｅ）ステップ（ｄ）において形成された化合物を脱保護剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｆ）ステップ（ｅ）において形成された化合物をさらに修飾し、以下の一般式：

を有する化合物を形成する、を含む、上記方法を提供する。 Furthermore, the present invention provides the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a protective agent to give the following general formula:

Forming a compound having:
(C) treating the compound formed in step (b) with a reducing agent to produce the following general formula:

Forming a compound having
(D) treating the compound formed in step (c) with A _C8 -Glc-Glc-Br to produce the following general formula:

Forming a compound having:
(E) treating the compound formed in step (d) with a deprotecting agent to give the following general formula:

Forming a compound having:
(F) The compound formed in step (e) is further modified to give the following general formula:

Forming a compound having:

を有する化合物の合成方法であって、以下のステップ：
以下の一般式：

を有する化合物をＮａＢＨ_４の如き還元剤で処理する、
を含む上記方法も提供する。 The present invention has the following general formula:

A method of synthesizing a compound having the following steps:
The following general formula:

Treating a compound having a reducing agent such as NaBH ₄ with
A method as described above is also provided.

を有する化合物の合成方法であって、以下のステップ：
（ａ）以下の一般式：

を有する化合物を還元剤で処理し、以下の一般式：

を有する化合物を形成し；
（ｂ）ステップ（ａ）において形成された化合物をＡ_Ｃ８−Ｇｌｃ−Ｇｌｃ−Ｂｒで処理し、以下の一般式：

を有する化合物を形成し：
（ｃ）ステップ（ｂ）において形成された化合物を脱保護剤で処理し、以下の一般式：

を有する化合物を形成する、
を含む、上記方法も提供する。ある態様において、当該還元剤はＮａＢＨ_４であり、当該化合物は、ＮａＯＭｅを使用して脱保護される。 The present invention has the following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with a reducing agent and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with A _C8 -Glc-Glc-Br;

Forming a compound having:
(C) treating the compound formed in step (b) with a deprotecting agent to give the following general formula:

Forming a compound having
The above method is also provided. In certain embodiments, the reducing agent is NaBH ₄ and the compound is deprotected using NaOMe.

  Furthermore, the present invention provides a ginsenoside composition for use in modulating amyloid-beta production in a subject, treating and preventing Alzheimer's disease, and treating and preventing neurodegenerative diseases Or a ginsenoside composition comprising a mixture of isolated and further synthesized ginsenosides, wherein one or more of the ginsenosides are Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, Rc, Rd, Re , Rf, Rg1, (20R) Rg2, (20S) Rg2, (20R) Rg3, (20S) Rg3, Rg5, Rg6, Rh1, (20R) Rh2, (20S) Rh2, Rh3, Rh4, (20R) Rg3, (20S) Rg3, Rk1, Rk2, Rk3, Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, F4, pre It consists of butanol-soluble fractions of topanaxadiol (PPD), protopanaxatriol (PPT), DHPPD-I, DHPPD-II, DHPPT-I, DHPPT-II, San ginseng, white ginseng or red ginseng or their homologues. Selected from the group. In certain embodiments, the ginsenoside composition is Rgk351.

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝
を有する化合物を当該対象に投与することを含む、上記方法を提供する。本明細書中に使用される用語「対象」は、例えば、ヒト、ラット、マウス、ウサギ、イヌ、ヒツジ、及びウシの如き動物、並びに培養された細胞、組織、及び器官の如き生体内系を含む。 The present invention provides methods and pharmaceutical compositions for use in reducing amyloid-beta production comprising a pharmaceutically acceptable carrier and a ginsenoside compound. Examples of acceptable pharmaceutical carriers, formulations of the pharmaceutical composition, and methods for making the formulation are described herein. The pharmaceutical composition comprises administering to the subject the damarin and ginsenoside compounds of the present invention to treat various disorders including neurodegeneration as described herein, and / or associated symptoms. Can be useful. The ginsenoside is provided in an amount sufficient to treat a disorder (eg, neurodegeneration) in a subject to which the pharmaceutical composition is administered. As noted above, those skilled in the art will readily determine this amount. In certain embodiments, the present invention is a method of treating or preventing β-amyloid production in a subject, having the general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 method is provided comprising administering to the subject a compound having: As used herein, the term “subject” refers to animals such as humans, rats, mice, rabbits, dogs, sheep, and cows, as well as in vivo systems such as cultured cells, tissues, and organs. Including.

  The present invention involves contacting a cell of interest (preferably a cell of the CNS) with an amount of ginsenoside compound or composition effective to reduce amyloid-beta production in the cell, and therefore the neurodegeneration. Is also provided for the treatment of neurodegeneration in the subject in need thereof. Examples of neurodegeneration that can be treated by the methods of the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Luguerick's disease), Vinswanger's disease, cortical basal ganglia degeneration (CBD), dementia lacking a specific histopathology (DLDH), frontotemporal dementia (FTD), Huntington's disease, multiple sclerosis, myasthenia gravis, Parkinson's disease, Pick's disease, and progressive supranuclear palsy (PSP). In a preferred embodiment of the invention, the neurodegeneration is Alzheimer's disease (AD) or sporadic Alzheimer's disease (SAD). In yet another aspect of the invention, the Alzheimer's disease is early familial Alzheimer's disease (FAD). One skilled in the art can readily determine when clinical symptoms of neurodegeneration are improved and minimized.

  The present invention treats a pathological condition, such as neurodegeneration and Aβ42-related disorders, in the subject in need of treatment, comprising administering to the subject one or more ginsenoside compounds in an effective amount to treat neurodegeneration. A method for prevention is also provided. The Aβ42-related disorder is a disorder caused by Aβ42 or may have symptoms of abnormal Aβ42 accumulation. As used herein, the phrase “effective to treat neurodegeneration” means effective to ameliorate or minimize clinical impairment or symptoms of the neurodegeneration. For example, if the neurodegeneration is Alzheimer's disease, the clinical impairment or sign of the neurodegeneration reduces the production of amyloid-beta and the development of senile plaques and neurofibrillary tangles, and thus the progression of cognitive function It can be improved or minimized by minimizing or weakening the lack of sex. An effective amount of an inhibitor for treating neurodegeneration in a subject in need of treatment is the type of neurodegeneration, the stage of the neurodegeneration, the weight of the subject, the severity of the condition of the subject, and the method of administration Will vary depending on the specific factors in each case. This amount is readily determined by those skilled in the art.

｛式中、
Ｒ_１は、α−ＯＨ、β−ＯＨ、α−Ｏ−Ｘ、β−Ｏ−Ｘ、α−Ｒ_６ＣＯＯ−、β−Ｒ_６ＣＯＯ−、α−Ｒ_６ＰＯ_３−、及びβ−Ｒ_６ＰＯ_３−からなる群より選択され、ここでＸは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり、そしてＲ_６はアルケニル、アリール又はアルキルＩであり；
Ｒ_２は、Ｈ、ＯＨ、ＯＡｃ、及びＯ−Ｘからなる群より選択され、ここで、Ｘは１又は複数の糖又はそれらのアシル化誘導体を含む炭水化物であり；
Ｒ_３は、Ｈ、ＯＨ、及びＯＡｃからなる群より選択され；
Ｒ_４は、アルケニル、アリール又はアルキルＩＩであり；及び
Ｒ_５は、Ｈ又はＯＨである。｝
を有する化合物を前記対象に投与することを含む、上記方法を提供する。 In certain embodiments, the present invention is a method of treating or preventing neurodegeneration in a subject comprising the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 method is provided comprising administering to the subject a compound having:

  In certain embodiments of the invention, Alzheimer's disease is treated in a subject in need of treatment with a therapeutically effective amount of ginsenoside composition, ginsenoside, or analogs thereof for effectively treating the subject. Treated by administering a homologue. The subject is preferably a mammal (eg, humans, farm animals, and commercial animals including cows, dogs, monkeys, mice, pigs, and rats), most preferably humans. As used herein, the term “analog” refers to a compound that is structurally similar to another compound and that is theoretically derived from the other compound, but slightly different in composition. For example, the ginsenoside (20S) Rg3 analog is a slightly different compound from (20S) Rg3 (eg, substitution of one atom by an atom of a different element or the presence of a particular functional group) It can be derived from (20S) Rg3. As used herein, the term “homolog” refers to a series of compound constituents in which each constituent differs from other constituents by a certain chemical unit. The term “synthesis” as used herein refers to the formation of a particular compound from its components using synthetic methods known in the art. Such synthetic methods include, for example, the use of light, heat, enzymatic or other means to form a particular compound.

  As used herein, the term “therapeutically effective amount” or “effective amount” refers to a clinical dysfunction, sign, or complication associated with Alzheimer's disease, either in a single dose or multiple doses. It refers to the amount of the composition of the invention necessary to prevent, treat, ameliorate, or at least minimize. The amount of ginsenoside effective to treat Alzheimer's disease will vary depending on the specific factors in each case, including the stage or severity of Alzheimer's disease, the subject's weight, the subject's condition, and the method of administration right. These amounts are readily determined by those skilled in the art. For example, clinical dysfunction or signs of Alzheimer's disease can be achieved by reducing dementia or discomfort afflicted by the subject; beyond surviving the subject despite expectation in the absence of such treatment Can be improved or minimized by prolonging; or by inhibiting or preventing the progression of the Alzheimer's disease.

  As used herein, “treating Alzheimer's disease” refers to Alzheimer's disease including, but not limited to, neurodegeneration, senile plaques, neurofibrillary tangles, neurotransmitter deficiency, dementia, and aging. It refers to treating one or more underlying symptoms. As used herein, `` preventing Alzheimer's disease '' means preventing the development of Alzheimer's disease, delaying the development of Alzheimer's disease, preventing the progression or development of Alzheimer's disease, slowing the progression or development of Alzheimer's disease, And delaying the progression or development of Alzheimer's disease.

  Prior to the present invention, the effects of damalan and ginsenoside on the production of beta amyloid protein were not known. The present invention establishes that ginsenosides such as (20S) Rg3, Rk1, and Rg5 or analogs or homologues thereof can also be used to interfere with and treat Alzheimer's disease. This new treatment provides the only strategy for treating and preventing neurodegeneration and dementia associated with Alzheimer's disease by modulating the production of Aβ42. Furthermore, neurodegeneration and dementia not associated with Alzheimer's disease can also be treated or prevented using the ginsenosides of the present invention to modulate Aβ42 production.

  The ginsenosides of the present invention include natural or synthetic functional variants having ginsenoside biological activity, as well as fragments of ginsenoside having ginsenoside biological activity. Further, as used herein, the term “ginsenoside biological activity” refers to an activity that regulates the production of highly amyloidogenic Aβ42, the 42-amino acid isoform of amyloid β-peptide. In certain embodiments of the invention, the ginsenoside reduces the production of Aβ42 in the cells of the subject. Commonly known ginsenosides and ginsenoside compositions are Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, (20R) Rg2, (20S) Rg2, (20R) Rg3, (20S) Rg3, Rg5, Rg6, Rh1, (20R) Rh2, (20S) Rh2, Rh3, Rh4, (20R) Rg3, (20S) Rg3, Rk1, Rk2, Rk3, Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, F4, Rgk351, protopanaxadiol (PPD), protopanaxatriol (PPT), DHPPD-I, DHPPD-II, DHPPT-I, DHPPT-II, San ginseng, white ginseng or red ginseng, or their It includes, but is not limited to, a butanol lysate fraction of homologues. In one embodiment of the invention, the ginsenoside is Rk1. In another aspect of the invention, the ginsenoside is (20S) Rg3. In a further embodiment, the ginsenoside is Rg5. In yet another embodiment, the ginsenoside is a mixture of (20S) Rg3, Rg5, and Rk1 that is Rgk351.

  Rk1, (20S) Rg3, and Rg5, and analogs and homologues thereof are well known in the art. For example, US Pat. No. 5,776,460 describes a processed ginseng product having a ratio of (Rg3 + Rg5) to (Rc + Rd + Rb1 + Rb2) of 1.0, the entire contents of which are incorporated herein by reference. The processed product disclosed in US Pat. No. 5,777,460 is manufactured by heat treating carrots at a high temperature of 120 ° -180 ° for 0.5-20 hours. The ginsenoside of the present invention is an isolated ginsenoside compound, or an isolated and further synthesized ginsenoside compound. The isolated ginsenosides of the present invention can be further synthesized using methods including, but not limited to, heat, light, chemical, enzymatic or other synthesis commonly known to those skilled in the art.

  In the methods of the present invention, the ginsenoside compound is administered to the subject in combination with one or more different ginsenoside compounds. “Administered to a subject in a“ combination ”with one or more different ginsenoside compounds” refers to concomitant administration of the therapeutic agent. Simultaneous combination administration refers to administration of different ginsenoside compounds at substantially the same time. For simultaneous combination administration, multiple different ginsenoside courses of treatment can be performed simultaneously. For example, a single formulation, a combined formulation, comprising both an amount of a particular ginsenoside compound and an amount of a second different ginsenoside compound in a state of being physically associated with each other, is administered to the subject. The single formulation, combined formulation may constitute an oral formulation comprising an amount of both ginsenoside compounds that can be administered orally to the subject, and a liquid mixture comprising an amount of both ginsenoside compounds that can be injected into the subject.

  It is also within the scope of the present invention that the amount of a particular ginsenoside compound and the amount of one or more different ginsenoside compounds can be administered to a subject separately, each formulation separately. Thus, the methods of the present invention are not limited to simultaneous co-administration of different ginsenoside compounds in a state where they are physically bound to each other.

  In one embodiment of the present invention, the ginsenoside compound can be co-administered to the subject separately, with each formulation separately over a period of time to achieve the maximum effect of the combination. Administration of each therapeutic agent ranges from simple and rapid administration to continuous perfusion over the duration. When taken at regular intervals in the time zone, the combined administration of the ginsenoside compounds can be sequential or alternating. For sequential combination administration, one of the therapeutic agents is administered alone, followed by the other. For example, the entire course of treatment with an Rg5 derivative can be achieved, and then the entire course of treatment with an Rk1 derivative can be performed. Alternatively, the sequential course of treatment with the Rk1 derivative can be achieved for the sequential combined administration, followed by the whole course of treatment with the Rg5 derivative. For alternating combination administration, some course of treatment with the Rk1 derivative may be replaced by some course of treatment with the Rg5 derivative until the respective entire therapeutic agent is administered.

  The therapeutic agents of the present invention (ie, ginsenosides and analogs and analogs thereof) are administered orally, parenterally (eg, intramuscularly, intraperitoneally, intravascularly, intravenously, or subcutaneously), and transdermally. Can be administered to human and animal subjects by known means including, but not limited to. Preferably, the therapeutic agent of the present invention is administered orally or intravenously.

  For oral administration, the ginsenoside formulations may be given as capsules, tablets, powders, granules, or suspensions. The formulation may have recognized additives such as lactose, mannitol, corn starch, or potato starch. The formulation can also be provided with a binder such as crystallin cellulose, cellulose analog, acacia, corn starch, or gelatin. Further, the formulation can be provided with a degradation product such as corn starch, potato starch, or carboxymethylcellulose sodium. The formulation can also be provided with anhydrous dicalcium phosphate or sodium starch glycolate. Finally, the formulation can be provided with a lubricant such as talc or starch glycolic acid.

  For parenteral administration, the ginsenoside formulation can be mixed with a sterile aqueous solution that is preferably isotonic with the blood of the subject. Such a formulation comprises dissolving a solid active ingredient in water containing a physiologically compatible substance such as sodium chloride, glycine, etc. and having a buffered pH compatible substance under physiological conditions to produce an aqueous solution. The solution is then sterilized. The formulation is provided in a single drug or in multiple drug containers such as sealed ampoules or vials. In addition, the formulations are delivered by various modes of injection, which can be on the fascia, intrathecally, intradermally, intramuscularly, intraocularly, intraperitoneally (especially for localized topical treatment), medulla Intramembrane, intrasternal, intravascular, venous, parenchymal, or subcutaneous includes.

  For transdermal administration, the ginsenoside formulation can be mixed with a skin penetration enhancer such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, etc. Increase the sex and allow the therapeutic agent to penetrate through the skin and into the bloodstream. The therapeutic / accelerator composition can be further mixed with a polymeric material such as ethyl cellulose, hydroxypropyl cellulose, ethylene / vinyl acetate, polyvinyl pyrrolidone, etc. to provide a composition in gel form and a solvent such as methylene chloride. Dissolved in and concentrated to the desired viscosity and then applied to the substrate to provide a patch.

  The ginsenoside drug of the present invention is also released or delivered from an osmotic minipump. The release rate from the simple osmotic minipump can be adjusted with a fast response gel placed in the micropore, release opening. An osmotic minipump would be useful for controlled release or targeted delivery of the therapeutic agent.

  It is within the scope of the present invention that the ginsenoside formulation further binds to a pharmaceutically acceptable carrier, thereby including 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 their recipients. Examples of acceptable pharmaceutical carriers include, but are not limited to, carboxymethylcellulose, crystallin cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose, starch, talc, and water Including. The formulation of the pharmaceutical composition is conveniently provided in a unit dose.

  The preparation of the present invention is produced by a method often used in the pharmaceutical field. For example, the active compounds can be obtained in association with a carrier or diluent such as a suspension or solution. Optionally, one or more auxiliary ingredients (eg, buffers, fragrances, surfactants, etc.) may also be added. The choice of carrier depends on the route of administration. The pharmaceutical composition may be used to treat Alzheimer's disease with a therapeutic agent of the invention (i.e., multiple ginsenosides, multiple analogs thereof, each in a separate individual dosage form, or a single agent, It is useful for administering a mixture. The therapeutic agent is provided in an amount effective to treat or prevent Alzheimer's disease in the subject. These amounts are readily determined by those skilled in the art.

  The therapeutically effective amount of ginsenoside will vary depending on the specific factors in each case, including the stage of Alzheimer's disease, the weight of the subject, the severity of the subject's condition, and the method of administration. For example, (20S) Rg3 can be administered at a dose of about 5 μg / day to 1500 mg / day. Preferably, (20S) Rg3 is administered at a dose of about 1 mg / day to 1000 mg / day. Rg5 is administered at a dose of about 5 μg / day to 1500 mg / day, but is preferably administered at a dose of 1 mg / day to 1000 mg / day. Rk1 is administered at a dose of about 5 μg / day to 1500 mg / day, but is preferably administered at a dose of 1 mg / day to 1000 mg / day. Further, the ginsenoside composition Rgk351 is administered at a dose of about 5 μg / day to 1500 mg / day, but is preferably administered at a dose of 1 mg / day to 1000 mg / day. A suitable therapeutically effective amount of a particular ginsenoside compound within the suggested range can be readily determined by one skilled in the art depending on the particular factor in each case.

  The invention further encompasses a method of preventing Alzheimer's disease in a subject with a pre- Alzheimer's disease condition, comprising administering to the subject a therapeutically effective amount of a ginsenoside compound. As used herein, the term “precondition of Alzheimer's disease” refers to a condition prior to Alzheimer's disease. Despite showing some of the typical symptoms of Alzheimer's disease and / or the history of the subject is likely to increase the subject's risk of developing Alzheimer's disease, Not diagnosed as having Alzheimer's disease.

  The present invention further provides a method for treating and preventing Alzheimer's disease in a subject comprising administering to the subject a therapeutically effective amount of a ginsenoside compound.

  The following examples are intended to illustrate the above and are intended to limit the scope of the invention as described to assist in understanding the invention and as defined in the appended claims. Should not be interpreted.

  The present invention provides that at least three ginsenoside compounds, Rk1, (20S) Rg3, and Rg5, and the mixture Rgk351 reduce the production of Aβ42 in the cell, thus treating AD and non-AD associated neuropathogenesis, And / or unexpectedly found to prevent the progression of AD and non-AD related neurological development. Rgk351 and Rk1 were most effective in reducing Aβ42 values. Furthermore, Rk1 has been shown to inhibit the Aβ42 production in a cell-free assay using a partially purified γ-secretase complex, which indicates the selectivity and / or activity of the γ-secretase enzyme. Suggested to regulate either.

Example 1
The potential effects of ginsenoside and their analogs to treat AD were tested. First, many ginsenosides were screened based on their effects on Aβ production. The effect of various ginsenosides on the production of Aβ (eg, Aβ40, and Aβ42) has been demonstrated by the Chinese hamster ovary (CHO) expressing human APP with each ginsenoside purified from untreated ginsenoside (known as “white ginseng”). ) The cells (CHO-APP cells) were first obtained by culturing. These exemplary ginsenosides included those that differ in Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg2 and their side chains and sugar components.

  Figures 1-3 show the structure of ginsenoside utilized in the study and their effect on Aβ42 production. They differ in two or three side chains attached to a common triterpene skeleton known as damaran. The common structural skeleton for each group of ginsenoside is shown in the upper part. Ginsenosides possessing Aβ42 reducing activity are shown in the rightmost column of the table: Aβ42 reducing activity (“Yes”), no effect (“No”), and indeterminate (“ND”). Ginsenosides that affect cell viability were designated as “cytotoxic”. The abbreviations for carbohydrates are as follows. Glc, D-glucopyranosyl; Ara (pyr), L-arabinopyranosyl; Ara (fur), L-arabinofuranosyl; Rha, L-rhamnopyranosyl.

  After 8 hours of culture, the medium was collected, and secreted values of Aβ40 and Aβ42 were measured by ELISA. None of the ginsenosides from the groups Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg2 showed an inhibitory effect on the production of Aβ40 and Aβ42 (FIG. 10).

  Steaming carrots at high temperature yielded additional ginsenosides with enhanced pharmacological activity, including (20S) Rg3, Rk1, and Rg5 (22-25). The effects of these heat-processed ginsenosides (eg (20S) Rg3, Rh1, Rh2, Rk1, Rg6, Rg5) on Aβ40 and Aβ42 production were then tested. Initial screening identified ginsenosides, Rk1, (20S) Rg3, and Rg5, related to three structures that selectively reduced Aβ42 secretion (FIG. 11).

  In contrast, Aβ42 values were not affected by (20R) Rg3, Rh1, and R6. The value of Aβ40 was not changed by the treatment with the ginsenoside tested. The potential for Aβ42 reducing activity was highest with Rk1 and (20S) Rg3. Rg5 was a less effective Aβ42 reduction reagent compared to Rk1 or (20S) Rg3 (FIG. 2). Secretion of Aβ40 was only affected when treated with Rk1 at very high concentrations (˜100 μM) and cell viability was not affected by treatment with Rk1 under these conditions (up to 100 μM at 8 Time processed, data not shown.) Interestingly, the PS1 delta E9FAD mutant (FIG. 11B) reduced the Aβ42 reduction response to (20S) Rg3, Rk1, and Rg5 treatment compared to PS1 wild type expressing cells (FIG. 11A).

  Furthermore, analysis revealed that Rk1 and Rg5 reduce Aβ42 in a dose-dependent manner (FIG. 12A). Overnight treatment with Rgk351, Rk1, and Rg5 also reduced Aβ42 production in CHO-APP cells (FIG. 12B). The Aβ42 reducing activity of Rk1 was similar to that of sulindac sulfide, one of the known Aβ42 reducing NSAIDs. During overnight treatment, Aβ production was also slightly affected by treatment with Rk1 or sulindac sulfide (FIG. 12B). These tests provide a structure-activity relationship between the chemical structure of ginsenoside and Aβ42 reducing activity, further designing analogs that further reduce Aβ42, and defining the types of compounds that have Aβ42 reducing activity To do.

  Rk1 did not affect the steady-state value of full-length APP in both CHO-APP cells and Neuro2a-APPsw cells (FIG. 13), which is likely due to Aβ42 reduction due to altered post-translational processing of APP. Present that. In contrast to the full-length form, treatment with Rk1 increased the constant value of the C-terminal APP fragment (FIG. 13). These data indicate that Rk1 can affect the g-secretase cleavage step (eg, Aβ42 cleavage) and thus, as shown for the general γ-secretase inhibitor Compound E, shows the accumulation of the C-terminal fragment of APP. Present what causes. The Aβ42 value in the medium of each corresponding sample is shown in the lower part.

  Since the effect of Rk1 is very selective for Aβ42 (but not Aβ40) in cell-based analysis, it involves the production of AICD generated from either Aβ40 or Aβ42 from the transmembrane cleavage site at the APP terminus. , Other γ-secretase-mediated cleavage, and γ-secretase-mediated transmembrane cleavage of Notch1 or p75 neurotrophin receptor (p75NTR) to produce Notch1 or p75NTR transmembrane domains (NICD or p75-ICD, respectively). The question of whether Rk1 has an effect was tested. Culture with Rgk351 or Rk1 did not affect cell-free production of ICD, NICD, and p75-ICD (FIG. 5). Under these conditions, Compound E effectively inhibited cell-free production of ICD, and sulindac sulfide did not affect ICD production from APP, Notch1 or p75NTR. These data indicate that Rk1 is not a general inhibitor of γ-secretase cleavage and does not affect the intramembrane cleavage of other γ-secretase substances such as Notch1 or p75NTR.

  Next, the interfering effect of Rk1 and (20S) Rg3 on Aβ production in in vitro γ-secretase analysis was tested. Rk1 and sulindac sulfide strongly inhibited in vivo Aβ42 production (FIG. 15). In contrast, naproxen, an NSAID without Aβ42 reducing activity, had no effect on Aβ42 production (FIG. 15A). Aβ42-reducing activity NSAID (Wegen, et al., Evidence that nonsteroidal anti-inflammatory drugs 3-development of 3D3A3. )), Aβ40 and Aβ42 reduced ginsenosides (eg, RkI and (20S) Rg3) are similar in cell-free γ-secretase analysis, although both compounds mainly affect Aβ42 production in cell-based assays. Inhibited both Aβ40 and Aβ42 with the efficacy of (FIG. 15B).

  Ginsenoside is 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; , Et al., Main ginseng saponin metabolites formed by intestinal bacteria. Plant Med. 1996; 62: 453-457). Therefore, the effects of two major metabolites of ginsenoside, including 20 (S) protopanaxatriol (PPT) and 20 (S) protopanaxadiol (PPD), on Aβ42 production were tested. 20 (S) -Panaxatriol (PT) and 20 (S) -Panaxadiol (PD) are artificial derivatives of PPT and PPD, respectively. Treatment with either PPT or PT does not affect the value of Aβ42 in Neuro2a cells expressing the Swedish mutant of human APP (Neuro2a-SW) as well as in CHO cells expressing wild type human APP. In addition, the production of Aβ42 was reduced (FIG. 16). PPD and PD did not give any inhibitory effect on the production of Aβ40 and Aβ42.

  In summary, heat-processed ginseng-derived Aβ42-reduced natural compounds were identified. Aβ42-reduced ginsenoside, including Rk1 and (20S) Rg3, appears to specifically modulate γ-secretase activity for Aβ42 production. Structure activity defines a class of compounds that can serve as a basis for the development of effective therapeutics for the treatment of AD.

Example 2
The benefits of ginsenoside treatment for treating AD-related neurodegeneration could be illustrated in a mouse model of AD. In particular, the ginsenoside compounds (20S) Rg3, Rk1, Rg5, and Rgk351 could be used to treat mice with AD-related neurodegeneration.

  Mice expressing human APP as well as mice expressing a Swedish familial Alzheimer's disease mutant of APP were obtained from Jackson Laboratories, 600 Main Street, Bar Harbor, Maine 04609. Four groups of mice could then be tested. (1) APP mice without ginsenoside treatment (placebo); (2) Swedish mice without ginsenoside treatment (placebo); (3) APP mice + Rg5 (100 μg / μl / day), and (4) Swedish mice + Rg5 (100 μg / μl / day). About 16 weeks after the infusion treatment, the amount of Aβ42 in the serum of the mice could be measured. It was expected that the results of this study would illustrate the general benefits of ginsenoside treatment to treat AD-related neurodegeneration. APP and Swedish mice without ginsenoside treatment had significantly higher serum Aβ42 values and demonstrated the behavioral characteristics of neurodegeneration compared to APP and Swedish mice that received ginsenoside treatment.

Example 3
The pure ginseng glycoside sapogenin is structurally similar to the chemical constituents of other plants. Bethula foliene triol (Damar-24-ene-3α, 12β, 20 (S) -triol) isolated from birch leaves differs from the pure ginseng glycoside sapogenin only in the C-3 configuration. Therefore, cheap and relatively readily available bechforienetriol constitutes the desired substrate for producing 20 (S) -protopanaxadiol and its glycosides Rg3, Rg5, and Rk1.

  Vetula foliene triol was isolated from an ether extract of birch (Btula pendula) leaves, then subjected to silica gel chromatography and crystallized from acetone: mp 195-195 °, lit. 197-198 ° (Fischer et al. (1959) Justus Liebigs Ann. Chem. 626: 185).

  The 12-O-acetyl derivative of 20 (S) -protopanaxadiol (3) was prepared from Vetula folienetriol by the series of reactions shown in Scheme 1. Vetula foliene triol was oxidized and the ketone 1, dammar-24-ene-12β, 20 (S) -diol-3-one, mp 197-199 °, lit. 196-199 °, (yield: 60%), acetylated with acetic anhydride in pyridine, and compound 2, 12-O-acetyl-damal-24-ene-12β, 20 (S) -diol-3- ON (yield: 100%?) (Nagai et al., (1973) Chem. Pharm. Bull. 9: 2061). The 1H NMR (CDC13) of Compound 2 is as follows: 0.90 (s, 3H), 0.95 (s, 3H), 1.0 (s, 6H), 1.1 (s, 3H), 1 .1 (s, 3H), 1.65 (s, 3H), 1.72 (s, 3H), 2.1 (s, 3H), 3.04 (s, 1H), 4.73 (td, 1H), 5.17 (t, 1H). Reduction of compound 2 in 2-propanol with sodium borohydride gives compound 3, 12-O-acetyl-damal-24-ene-3β, 12β, 20 (S) -triol (yield: 90%). It was. 1H NMR (CDC13) of Compound 3 is as follows: 0.78 (s, 3H), 0.86 (8, 3H), 0.95 (s, 3H), 1.0 (s, 3H), 1 .02 (s, 3H), 1.13 (s, 3H), 1.64 (s, 3H), 1.71 (s, 3H), 2.05 (s, 3H, OAc), 3.20 ( dd, 1H, H-3α), 4.73 (td, 1H, H-12α), 5.16 (t, 1H, H-24).

Condensation of compound 3 with O-acetylated-carbohydrate bromide in the presence of silver oxide and molecular sieve 4A in dichloroethane gave the form of compound 4 (yield 50%). In particular, compound 3 (1.08 g, 2 mmol), silver oxide (1.4 g, 6 mmol), α-acetobromoglucose (2.47 g, 6 mmol), molecular sieve 4A (1.0 g), and dichloroethane (20 ml). The mixture was stirred at ambient temperature until acetobromoglucose had reacted (TLC). The reaction mixture was then diluted with CHCl ₃ and filtered. The solvent was evaporated and the residue was washed with hot water to remove excess glucose derivative. Silica gel column chromatography (8: 1 n-hexane-acetone) gave compound 4 (853 mg). Glucoside 4 was deprotected to give ginsenoside Rg3, which is adjusted with Rk1 or Rg5 in two steps.

  Although the prior invention has been described in detail for purposes of clarity and understanding, various changes in form and detail may be made without departing from the true scope of the invention as set forth in the claims. This will be appreciated by those skilled in the art from the disclosure.

FIG. 1 shows the proteolytic sequence of β-amyloid precursor protein (APP) mediated by β- and γ-secretase. FIG. 2 shows the HPLC analysis results of (a) white ginseng; (b) red ginseng; and (c) Sun ginseng (heat-treated carrot). FIG. 3 shows the general chemical formulas of (a) Rg3, (b) Rk1, and (c) Rg5. FIG. 4 shows that Rgk351, (20S) Rg3, Rk1, and Rg5 reduce Aβ42 production in CHO cells stably transfected with human APP695. The CHO cells were treated with the indicated compound (at 50 μg / ml) for 8 hours. The value of Aβ42 in the medium was measured by ELISA and normalized to the intracellular full length APP. FIG. 5 shows that treatment with Rgk351, Rk1, and Rg5 reduced Aβ42 in the medium of CHO cells expressing human APP in a dose-dependent manner. FIG. 6 illustrates that treatment of Rgk351, Rk1 and Rg5 selectively reduces Aβ42 (versus Aβ40) in the medium of CHO cells expressing human APP in a dose-dependent manner. The relative values of Aβ and Aβ42 were normalized to the values obtained from untreated cells and cells treated with vehicle. Similar data was obtained using Neuro2a-sw (mouse Neuro2a cells expressing a Swedish familial Alzheimer's disease mutant of APP) and 293 cells expressing human APP. FIG. 7 shows the analysis of cell lysates, showing that Rgk351, Rk1, and Rg5 cause increased accumulation of the C-terminal fragment of APP (γ-secretase substance) but do not affect the value of full-length holoAPP. . FIG. 8 shows that treatment of Rgk351 and Rk1 reduces the value of Aβ42 in CHO cells co-expressing human APP with either wild-type presenilin 1 or a familial Alzheimer-linked mutant of presenilin 1 (Delta E9adL286V) Illustrate that. The effect of Rg5 on Aβ42 production was very small compared to Rgk351 and Rk1. FIG. 9 shows the effect of Rk1 (R1) and Rg5 (R5) on Aβ42-specific γ-secretase activity. Naproxen (NP) and sulindac sulfide (SS) were tested simultaneously. FIG. 10 shows the effect of natural ginsenoside on Aβ42. The structures of the seven standard ginsenosides tested (Rb1, Rb2, Rc, Rd, Re, Rg1 and Rg2) are shown in Table 1. CHO cells stably transfected with human APP695 were used with either wild type (A, CHO-APP / PS1 cells) or delta E9FAD mutant (B, CHO-APP / delta E9PS1 cells). Cells were treated with the indicated compound (at 50 μM) for 8 hours. Values of Aβ42 and Aβ40 secreted into the medium were measured by ELISA and normalized to intracellular full length APP. In CHO-APP / PS1 cells, the amount of Aβ in the subject sample was 320 pM for Aβ40 and 79 pM for Aβ42. Relative values of Aβ and Aβ42 were normalized to values obtained from untreated cells and vehicle-treated cells and presented as% of control + standard deviation. One of three typical tests is shown. FIG. 11 shows the Aβ42 reducing activity of several ginsenosides from ginseng treated with heat or steam. CHO-APP / PS1 (A) and CHO-APP / delta E9PS1 (B) cells were treated with the indicated compounds for 8 hours at 50 μM and secreted Aβ40 and Aβ42 values as described in FIG. It was measured. The effectiveness of Aβ42 reducing activity was in the order of Rk1> / = (20S) Rg3> Rg5> (20R) Rg3, and the effects of Rh1 and Rg6 were not significant. Rh2 also showed Aβ42 reducing activity, but cell viability was partially affected by 50 μM treatment (data not shown). The PS1-delta E9FAD mutant attenuated the Aβ42 response to Rk1 treatment (B). FIG. 12 shows that treatment of Rgk351, Rk1, and Rg5 in the medium of CHO-APP cells reduces Aβ42 in a dose-dependent manner. (A) Dose response of Aβ42 reducing activity of Rk1 and Rg5. Rk1 had an IC50 of about 20 μM. (B) Rk1 selectively reduces Aβ42 (vs. Aβ40) in cultured CHO-APP cells, and the inhibition pattern of Rk1 on Aβ42 is similar to that of sulindac sulfide (SS). Relative values for Aβ40 and Aβ42 were normalized to values obtained from untreated cells and vehicle treated cells. Similar data was obtained using Neuro2a-sw (mouse Neuro2a cells expressing a Swedish familial Alzheimer's disease variant of APP) and 293 cells expressing human APP (data not shown). . The effect of Rg5 on Aβ42 production was very small compared to Rgk351 and Rk1. FIG. 13 shows an analysis of APP processing after Rk1 treatment. Steady state values of full-length APP and APP C-terminal fragments (APP-CTFs) were tested by Western blot analysis using anti-R1 antibodies. Rgk351 (mixture of Rg3, Rg5, and Rk1), Rk1, and Rg5 treatment are CHO-APP cells and mouse neuroblasts that stably express the Swedish FAD mutant form (KM670 / 671NL) (APPsw) of APP. This results in an increased accumulation of the C-terminal fragment of APP (γ-secretase substrate) in tumor neuro2a cells. Correlated Aβ42 values for each sample are shown in the lower panel. FIG. 14 shows that ginsenoside Rk1, which reduces Aβ42, is responsible for the generation of intracellular domains (ICDs) from APP (A, AICD), Notch1 (B, NICD) or p75 neurotrophin receptors (p75NTR, p75-ICD). Indicates no significant effect. Membrane fractions were isolated from 293 cells overexpressing either APP (A), Notch-delta E (B), or p75-delta E (C) and the indicated compound: Compound E (CpdE, general A typical γ-secretase inhibitor), Rgk351, Rk1, and sulindac sulfide (SS). Very small amounts of AICD, NICD, and p75-ICD were transferred to control samples (-incubation) or Cpd. Although detected in samples treated with E, AICD, NICD, and p75-ICD were abundantly produced in samples incubated with Rgk351, Rk1, and SS. FIG. 15 shows that ginsenoside Rk1 and (20S) Rg3 that reduce Aβ42 inhibit Aβ production in a cell-free γ-secretase assay. (A) CHAPSO-dissolved membrane fraction was cultured with recombinant γ-secretase substrate together with the indicated compound (at 100 μM) and Aβ42 and Aβ40 values were measured by ELISA as described above. (B) Dose response of Aβ42 and Aβ40 reducing activity of Rk1 and (20S) Rg3 in cell-free γ-secretase assay. The IC _{50 for} Rk1 was 27 ± 3 μM for Aβ40 and 32 ± 5 for Aβ42. The IC _{50 for} (20S) Rg3 was 27 ± 4 μM for Aβ40 and 26 ± 7 for Aβ42. FIG. 16 shows the effect of two major metabolites of ginsenoside, including 20 (S) -protopanaxatriol (PPT) and 20 (S) protopanaxadiol (PPD) on Aβ42 production. 20 (S) -panaxatriol (PT) and 20 (S) panaxadiol (PD) are artificial derivatives of PPT and PPPD, respectively. Treatment with either PPT or PT reduces Aβ42 production in Neuro2a cells expressing the human Swedish mutant form of APP without affecting the value of Aβ42 (Neuro2a-SW, lower panel), as well as human The same was true for CHO cells expressing the wild type of APP (data not shown). PPD and PD did not give any inhibitory effect on Aβ40 or Aβ42 production. FIG. 17 shows mass spectrometry of Aβ species generated from CHO-APP cells treated with DMSO (vehicle), Rk1, or (20S) Rg3. Note that treatment leads to a reduction in Aβ42 species (1-42) and an increase in both Aβ37 (1-37) and Aβ38 (1-38). Mass spectrometry of Aβ species was performed as previously described (Wang R, Sweeney D, Gandy SE, Sisodia SS. The profile of solid amyloid β-protein in cultured cell media. J. Bio. : 31894-31902). FIG. 18 shows an analysis of secreted Aβ values after treatment of CHO-APP cells with DMSO (control 1), naproxen (control 2), Rk1, or (20S) Rg3. Aβ was immunoprecipitated using 4G8 antibody (purchased from Senetek) and subjected to SDS-PAGE using a tricine / urea gel (protocol provided by Dr. Y. Ihara, University of Tokyo). And analyzed by Western blot analysis using 6E10 antibody (Senetek). Synthetic Aβ40 and Aβ42 peptides were used to identify the corresponding Aβ species. FIG. 19 shows the effect of ginsenoside, Rk1, and (20S) Rg3 on Aβ40 and Aβ42 secretion in early fetal cortical neurons derived from Tg2576 transgenic mice. Treatment with RK1 and Rg3 reduced secreted Aβ40 and Aβ42 values.

Claims (51)

The following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 compound of claim 1, wherein the alkyl I group further comprises oxygen, nitrogen, or phosphorus.   The compound of claim 1, wherein the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base.   2. The compound of claim 1, wherein the sugar is selected from the group consisting of Glc, Ara (pyr), Ara (fur), Rha, and Xyl. Said R ₄ is:

{Where,
The configuration of the stereocenter is R or S;
X is OR or NR, where R is alkyl or aryl;
X ′ is alkyl, OR, NR, wherein R is alkyl or aryl; and R ′ is H, alkyl, or acyl. The compound of claim 1, wherein the compound is selected from the group consisting of: The following general formula in the treatment or prevention of pathological conditions:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. }. Use of a compound having The alkyl I group further comprises oxygen, nitrogen or phosphorus; and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. Use according to claim 6.   7. Use according to claim 6, wherein the pathological condition is neurodegeneration.   Use according to claim 8, wherein the pre-morbid state is Alzheimer's disease.   Use according to claim 6, wherein the pathological condition is an Aβ42-related disorder. The following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 further comprises oxygen, nitrogen or phosphorus; and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. The isolated compound according to claim 10. The following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 composition containing the compound which has}. The alkyl I group further comprises oxygen, nitrogen or phosphorus; and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. The composition according to claim 13. Pharmaceutically acceptable carriers and the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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 pharmaceutical composition containing the compound which has these. The alkyl I group further comprises oxygen, nitrogen or phosphorus; and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. The pharmaceutical composition according to claim 15. The following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a reducing agent to produce the following general formula:

{Where,
R ₁ is H or OH;
R ₂ is selected from the group consisting of H, OH, OAc, and OX, wherein X is a carbohydrate comprising 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. To form a compound having
Including the above method.   The method of claim 17, wherein the oxidant is chromic anhydride. The method of claim 17, wherein the reducing agent is NaBH ₄ . The following general formula:

18. The method of claim 17, wherein the compound having is obtained from a plant.   21. The method of claim 20, wherein the plant is selected from the group consisting of common strains of birch. The following general formula:

21. The method of claim 20, wherein the compound having a betula folienetriol. The following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a reducing agent to produce the following general formula:

Forming a compound having:
(C) Optionally treating the compound formed in step (b) with a protected R ₁ derivative to give the following general formula:

Forming a compound having
(D) treating the compound formed in step (c) with a deprotecting agent to give the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. To form a compound having
Including the above method. The alkyl I group further comprises oxygen, nitrogen or phosphorus; and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. 24. The method of claim 23.   24. The method of claim 23, wherein the oxidant is chromic anhydride. Wherein the reducing agent is NaBH _4, The method of claim 23. The protective _{R 1} derivative is a protected _{R 1} halogen derivatives, method of claim 23. The protective _{R 1 derivative, A C8} - is protected by a group A method according to claim 23.   30. The method of claim 28, wherein the compound is deprotected using NaOMe. The following general formula:

24. The method of claim 23, wherein the compound having: is obtained from a plant.   32. The method of claim 30, wherein the plant is selected from the group consisting of common strains of birch. The following general formula:

31. The method of claim 30, wherein the compound having a is betulaforienetriol. The following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with an oxidant and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with a protective agent to give the following general formula:

Forming a compound having:
(C) treating the compound formed in step (b) with a reducing agent to produce the following general formula:

Forming a compound having
(D) treating the compound formed in step (c) with A _C8 -Glc-Glc-Br to produce the following general formula:

Forming a compound having:
(E) treating the compound formed in step (d) with a deprotecting agent to give the following general formula:

Forming a compound having:
(F) The compound formed in step (e) is further modified to give the following general formula:

Forming a compound having
Including the above method.   34. The method of claim 33, wherein the oxidant is chromic anhydride. Wherein the reducing agent is NaBH _4, The method of claim 33.   34. The method of claim 33, wherein the compound is deprotected using NaOMe. The following general formula:

34. The method of claim 33, wherein the compound having is obtained from a plant.   38. The method of claim 37, wherein the plant is selected from the group consisting of common strains of birch. The following general formula:

A method of synthesizing a compound having the following steps:
The following general formula:

Is treated with a reducing agent and the following general formula:

Forming a compound having
Including the above method. Wherein the reducing agent is NaBH _4, The method of claim 39. The following general formula:

A method of synthesizing a compound having the following steps:
(A) The following general formula:

Is treated with a reducing agent and the following general formula:

Forming a compound having:
(B) treating the compound formed in step (a) with A _C8 -Glc-Glc-Br;

Forming a compound having:
(C) treating the compound formed in step (b) with a deprotecting agent to give the following general formula:

Forming a compound having
Including the above method. Wherein the reducing agent is NaBH _4, The method of claim 41.   42. The method of claim 41, wherein the compound is deprotected using NaOMe. A method for treating or preventing a pathological condition of a subject, having the following general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. }
Administering the compound having: to the subject. The alkyl I group further comprises oxygen, nitrogen or phosphorus; and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. 45. The method of claim 44.   45. The method of claim 44, wherein the pathological condition is neurodegeneration.   45. The method of claim 44, wherein the pathological condition is Alzheimer's disease.   45. The method of claim 44, wherein the pathological condition is an Aβ42 related disorder.   45. The method of claim 44, wherein the subject is a human. A method of inhibiting β-amyloid production in a subject, having the general formula:

{Where,
R ₁ is α-OH, β-OH, α-OX, β-OX, α-R ₆ COO—, β-R ₆ COO—, α-R ₆ PO ₃ —, and β-R. Selected from the group consisting of ₆ PO ₃ —, wherein X is a carbohydrate comprising 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 OX, wherein X is a carbohydrate comprising 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. }
Administering the compound having: to the subject. The alkyl I group further comprises oxygen, nitrogen or phosphorus; and the alkyl II group further comprises a functional group selected from the group consisting of hydroxyl, ether, ketone, oxime, hydrazone, imine, and Schiff base. 51. The method of claim 50.

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