KR101200996B1 - Novel Organic Germanium Compound - Google Patents

Abstract

The present invention relates to an organic germanium compound represented by the following formula (1) or a salt thereof.

[Formula 1]

In Formula 1, R ₁ , R ₂ and R ₃ are the same as or different from each other, and each independently a C ₁ -C ₆ linear or branched alkyl group, C ₂ -C ₆ linear or branched alkenyl group, An aryl group substituted with a C ₂ -C ₆ straight or branched alkynyl group, an aryl group, a C ₁ -C ₆ straight or branched alkyl group, or a C ₂ -C ₆ straight or branched alkenyl group an aryl group, an aryl group substituted with an alkynyl of straight or branched-chain C ₂ -C _6, and; R ₄ is monosaccharide, alcohol, L-ascorbic acid, L-ascorbic acid derivative protected by hydroxyl group at carbon position 2 of furan ring of L-ascorbic acid, or these Amine derivatives of; m is an integer from 0 to 10; X is CO or CH ₂ ; Ge is germanium. The novel organic germanium compounds of the present invention have a markedly improved water solubility and are easily absorbed into the living body and do not accumulate in tissues, and thus have no toxicity in the body and can fully exhibit the inherent efficacy of germanium. In addition, L-ascorbic acid-bound compounds show strong antioxidant activity.

Organic germanium compound, bioabsorption rate, interferon-gamma, anticancer agent, immunopotentiation, anti-inflammatory agent, L-ascorbic acid, skin condition improvement, wrinkle, whitening, atopic dermatitis, psoriasis

Description

Novel Organic Germanium Compound

The present invention relates to novel organic germanium compounds.

Germanium (atomic number 32; atomic weight 72.59; melting point 937.4 ° C; boiling point 2830 ° C) is present in various forms of organic and inorganic substances in stones, soil, plants and animals (1). It is contained about 7 ppm in the earth's crust, and is a trace element found in the United States by 0.6-1.3 mg Ge / kg in soil and 0.004-0.6 mg Ge / L in water (2, 3).

Germanium compounds are roughly classified into inorganic germanium compounds and organic germanium compounds. Generally, salts or oxides lacking the germanium-carbon bond are classified as inorganic germanium. Representative inorganic germanium, GeO ₂ (germanium dioxide) or germanium citrate lactate, has nephrotoxicity, causing acute renal failure (9-12). Toxicity of inorganic germanium is believed to be due to the accumulation of germanium in biological tissues (2, 13).

In contrast, organic germanium has a germanium-carbon bond, which is a stable group because germanium is a carbon-like group 14, and bonds are not easily broken in vivo. None (3, 9).

In the 1980s, many studies showed that organic germanium compounds had anticancer and immunomodulatory functions (15-18), and became known as immunostimulators with anticancer effects that prevent cancer and AIDS from progressing and kill cancer cells. 1-3, 14, 19). Organic germanium compounds were first synthesized variously by Mironov of Russia for the first time in the 1950s, and bis (2-carboxyethylgermanium) sesquioxide (O ₃ (GeCH ₂ CH ₂ COOH) ₂ ) was synthesized in 1966 (20, 21). Shortly after, in 1967, the same bis (2-carboxyethylgermanium) sesquioxide, (O ₃ (GeCH ₂ CH ₂ COOH) ₂ ), was synthesized at the Asai Germanium Research Institute in Tokyo, Japan (22, 23). This was named Ge-132 (9) (FIG. 1). The chemical structure and physicochemical properties of this Ge-132 compound have already been reported (24-26). Since then, many studies have been conducted on Ge-132, which has shown that Ge-132 has immunopotentiating efficacy (25, 27), interferon induction (IFN induction), increased NK cell activity, production of cytotoxic macrophages, It has been shown to exhibit various biological effects including anticancer efficacy (13, 25, 27-29).

Ongoing studies of Ge-132 resulted in strong immunopotentiating activity by Ge-132 increasing CD4 and CD8 cell function and NK cell activity and inducing the production of cytokines such as interferon-γ and interleukin-2. Has been reported to have anti-inflammatory, antiviral and anticancer effects (16, 34, 35). It has been reported to be particularly effective in treating chronic hepatitis B (36). In addition, Ge-132 activates macrophages and T cells, in particular cytotoxic T cells and NK cells, antibody-dependent cellular cytotoxicity (ADCC) by induction of interferon gamma, and peripheral mononuclear cells (peripheral mononuclear). induce 2 ′, 5′-oligoadenylate synthetase (25, 36, 38, 39). It is also known to have an antioxidant effect as one of the important physiological activities of organic germanium Ge-132. (Protective role of germanium-132 against paraquat-induced oxidative stress in the livers of senescence-accelerated mice.Yang MK, Kim YG. J. Toxicol.Environ.Health A. 1999, 58 (5): 289-97).

Despite the many beneficial physiological activities of Ge-132, Ge-132 has a poor solubility in water due to its high molecular properties and it does not completely remove the inorganic germanium GeO ₂ used as a reactant in the purification process after synthesis. (Hazard assessment of germanium supplements. Tao SH, Bolger PM. Regul. Toxicol. Pharmacol. 1997, 25 (3): 211-9.). Because of this, long-term use of Ge-132 is known to be toxic.

Free radicals include aging (53), cancer (54), atherosclerosis (55), stroke (56), rheumatoid arthritis (57), neurodegeneration (58), inflammatory diseases (59), diabetes (60), etc. It is very relevant to the invention and progression of the disease. Therefore, L-ascorbic acid, which has a strong antioxidant capacity, has been attracting attention as a substance for preventing and treating diseases caused by removing active oxygen in the living body (61). L-ascorbic acid is known to have an ultraviolet (UV) blocking effect, an antioxidant effect, to improve skin wrinkles by promoting collagen formation, to improve pigmentation such as blemishes / freckles / mushrooms, and strengthen the immune system. That is, L-ascorbic acid has a strong UV protection against ultraviolet light, particularly UV A and UV B (Darr, D. et al., 1996, Acta Derm. Venereol. (Strckh). 76: 264-268; Black, HS et al., 1975, J. Invest.Dermatol. 65: 412-414; Darr, D. et al., 1992, Brit. J. Dermatil. 127: 247-253; Murry, J. et al., 1991, J. Invest.Dermatol. 96: 587), Reactive Oxygen Species (ROS) caused by chemical contamination, smoking, especially ultraviolet (UV) in skin, blood and other tissues due to their excellent ability to accept electrons. It acts as a powerful bioantioxidant that neutralizes it. In addition, L-ascorbic acid promotes the synthesis of collagen to improve skin gloss, skin color, reduce wrinkles, increase elasticity, and inhibits tyrosinase activity and melanin formation, which are important for melanin formation. (US Pat. No. 4,983,382; Tomita, Y. et al., 1980, J. Invset. Dermatol. 75 (5); 379-382). In addition, L-ascorbic acid enhances the immune system (Nakamura, T. et al., 1997, J. Invest. Dermatol. 109: 20-24), aids phagocytosis of leukocytes, and leukocytes during infection. It is known to play a role in inhibiting infection by increasing migration and increasing biosynthesis of interferon, a virus-inhibiting substance, which also increases bioresistance against various infectious diseases. Get involved. However, ascorbic acid has low stability over time, high water solubility, but low solubility in lipids, so that the amount accumulated in the cells through the cell membrane of the skin is somewhat limited, so that ascorbic acid achieves satisfactory physiological activity. It wasn't. Therefore, a method of phosphorylating or ester-bonding hydroxyl groups of carbons 2 and 3 of ascorbic acid has been developed as a method for improving the stability of ascorbic acid, and derivatives acylated with fatty acids to increase solubility in lipids. And the like have been proposed.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have made efforts to increase the solubility of germanium in water and to synthesize organic germanium compounds which are not toxic in vivo and can exert the original effects of germanium. As a result, a novel organic germanium compound was synthesized by combining a functional group having high water solubility with germanium, and the new organic germanium compound exhibited an excellent effect of inducing interferon-gamma secretion and antioxidant activity, resulting in anti-cancer, anti-inflammatory, The present invention was completed by experimentally confirming that it can be usefully used for immunity enhancement and skin condition improvement.

Accordingly, an object of the present invention is to provide a new type of organic germanium compound having improved water solubility.

Another object of the present invention is to provide a composition for anticancer, anti-inflammatory, immune enhancing or skin condition improvement comprising the novel organic germanium compound.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides an organic germanium compound represented by the following formula (1) or a salt thereof.

[Formula 1]

In Formula 1, R ₁ , R ₂ and R ₃ are the same as or different from each other, and each independently a C ₁ -C ₆ linear or branched alkyl group, C ₂ -C ₆ linear or branched alkenyl group, An aryl group substituted with a C ₂ -C ₆ straight or branched alkynyl group, an aryl group, a C ₁ -C ₆ straight or branched alkyl group, or a C ₂ -C ₆ straight or branched alkenyl group an aryl group, an aryl group substituted with an alkynyl of straight or branched-chain C ₂ -C _6, and; R ₄ is monosaccharide, alcohol, L-ascorbic acid, L-ascorbic acid derivative protected by hydroxyl group at position 2 of furan ring of L-ascorbic acid, or Amine derivatives; m is an integer from 0 to 10; X is CO or CH ₂ ; Ge is germanium.

In Formula 1, which defines a compound of the present invention, the term “C ₁ -C ₆ straight or branched chain alkyl” means a straight or branched chain saturated hydrocarbon having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl and t-butyl.

The term “C ₂ -C ₆ straight or branched alkenyl group” means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one double bond, for example, ethenyl, propenyl , Isopropenyl, butenyl, isobutenyl, t-butenyl, n-pentenyl and n-hexenyl.

The term “C ₂ -C ₆ straight or branched alkynyl group” refers to a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one triple bond, for example, ethynyl, propy Nil, 1-butynyl, 2-butynyl.

M is an integer of 0 to 10, preferably 0 to 6, more preferably 0 to 4, even more preferably 0 to 3, most preferably 2.

In the present invention, the functional group of R ₄ of the formula (1) serves to increase the water solubility of the organic germanium compound of the present invention. In particular, the germanium L-ascorbic acid compound when R ₄ is L-ascorbic acid or a derivative thereof has a water solubility which is increased and a synergistic improvement in antioxidant activity.

According to a preferred embodiment of the present invention, the monosaccharide of R ₄ in the formula (1) is glucose (glucose), fructose (fructose), galactose (galactose), mannose (mannose), xylose (xylose) Or ribose, most preferably glucose.

According to another preferred embodiment of the present invention, the alcohol of R ₄ in Formula 1 is inositol.

According to another preferred embodiment of the present invention, the L- ascorbic acid derivative in which the hydroxyl group at the carbon position of the furan ring 2 of L-ascorbic acid of R ₄ in Chemical Formula 1 is protected is represented by the following Chemical Formulas 2a to 2d It is either a compound, More preferably, it is a compound of following formula (2a) or (2b).

[Formula 2a] [Formula 2b]

[Formula 2c] [Formula 2d]

However, in Formula 2d, R = C ₁ -C ₆ is alkyl.

By introducing a protecting group to L-ascorbic acid in the compound of the present invention, it is possible to improve the stability of L-ascorbic acid to increase antioxidant activity.

According to a more preferred embodiment of the present invention, R ₄ in the formula (1) is glucose, inositol, L- ascorbic acid, the L- ascorbic acid derivative of the formula 2a or 2b, or an amine derivative compound represented by the following formula .

Certain embodiments of the present invention are compounds selected from the following compounds:

N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (trimethyl Germanyl) propanamide;

N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Ethylgeryl) propanamide;

N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Vinylgeryl) propanamide;

N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Phenylgeryl) propanamide;

N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Benzylgeryl) propanamide;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydro Furan-3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate;

N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (trimethylgeryl) propanamide;

N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (triethylgeryl) propanamide;

N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (trivinylgeryl) propanamide;

N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (triphenylgeryl) propanamide;

N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydropran-2-yl) -2- Hydroxyethyl) -3- (tribenzylgeryl) propanamide;

N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (trimethylgeryl) propanamide;

N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (triethylgeryl) propanamide;

N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (trivinylgeryl) propanamide;

N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (triphenylgeryl) propanamide;

N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (tribenzylgeryl) propanamide;

(R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) furan-2 (5H) -one;

(R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) furan-2 (5H) -one;

(R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) furan-2 (5H) -one;

(R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) furan-2 (5H) -one;

(R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) furan-2 (5H) -one;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran-3 -Yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran-3 -Methyl methyl phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate;

(R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) furan-2 (5H) -one;

(R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) furan- 2 (5H) -one;

(R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) furan- 2 (5H) -one;

(R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) furan- 2 (5H) -one;

(R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) furan- 2 (5H) -one;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R)- 3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R ) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one;

(R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one;

(S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (trimethylgeryl) propano Eight;

(S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (triethylgeryl) prop Phanoate;

(S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (trivinylgeryl) prop Phanoate;

(S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (triphenylgeryl) prop Phanoate;

(S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (tribenzylgeryl) Propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (trimethyl Germanyl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Ethylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Vinylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Phenylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Benzylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (trimethylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (triethylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (trivinylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (triphenylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2- Yl) ethyl 3- (tribenzylgeryl) propanoate;

(S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Trimethylgeryl) propanoate;

(S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Triethylgeryl) propanoate;

(S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Trivinylgeryl) propanoate;

(S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Triphenylgeryl) propanoate;

(S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Tribenzylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (trimethylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (triethylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (trivinylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (triphenylgeryl) propanoate;

(S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tribenzylgeryl) propanoate;

N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (trimethylgeryl) propanamide;

N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (triethylgeryl) propanamide;

N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (trivinylgeryl) propanamide;

N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (triphenylgeryl) propanamide;

N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (tribenzylgeryl) propanamide;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trimethylgeryl) propoxy) furan-2 (5H) -one;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triethylgeryl) propoxy) furan-2 (5H) -one;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trivinylgeryl) propoxy) furan-2 (5H) -one;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triphenylgeryl) propoxy) furan-2 (5H) -one;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (tribenzylgeryl) propoxy) furan-2 (5H) -one;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (trimethylgeryl) propano Eight;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (triethylgeryl) prop Phanoate;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (trivinylgeryl) pro Phanoate;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (triphenylgeryl) prop Phanoate;

(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (tribenzylgeryl) pro Phanoate;

6-((3- (trimethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol;

6-((3- (triethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol;

6-((3- (trivinylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol;

6-((3- (triphenylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol;

6-((3- (tribenzylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol.

Specific preparation methods of the organic germanium compound of the present invention are described in detail in the following examples.

In addition, the present invention relates to a salt of the organic germanium compound represented by Chemical Formula 1. Salts of the compounds of the invention are preferably pharmaceutically acceptable acid addition salts or base addition salts.

Acids that can be used to prepare pharmaceutically acceptable acid addition salts of the compounds of the present invention are non-toxic acid addition salts, for example chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, acetates , Lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- Forming salts containing pharmacologically acceptable anions such as toluenesulfonate and salts of pamoate [ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] But it is not limited thereto.

Chemical bases that may be used to prepare pharmaceutically acceptable base salts of the compounds of this invention include those that form non-toxic base salts with these compounds, including, for example, alkali metal cations (eg, potassium and Sodium) and alkaline earth metal cations (such as calcium and magnesium), ammonium or water soluble amine addition salts such as N-methylglucamine- (meglumine), and lower alkanolammonium and other pharmaceutically acceptable Including but not limited to those derived from pharmaceutically acceptable cations such as base salts of organic amines.

According to another aspect of the present invention, the present invention provides a pharmaceutical composition for the treatment or prophylaxis or immuno-enhancement of cancer or inflammatory diseases comprising an organic germanium compound of formula 1 or a salt thereof as an active ingredient.

The organic germanium compound of the present invention has an increased water solubility and significantly increases the secretion of interferon-gamma in vivo and exhibits antioxidant activity, thereby improving anticancer, anti-inflammatory, immune enhancing, and skin condition improvement. It can be usefully used.

According to a preferred embodiment of the present invention, cancer to which the organic germanium compound can be applied is gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, brain cancer, prostate cancer , Bone cancer, skin cancer, thyroid cancer, parathyroid cancer or ureter cancer, and more preferably can be applied to the treatment or prevention of liver cancer.

According to a preferred embodiment of the present invention, the inflammatory disease to which the compound of the present invention can be applied is hepatitis, atopic dermatitis or psoriasis.

In addition, the organic germanium compound of the present invention has an excellent effect of inducing the secretion of interferon gamma in vivo, and has an immune enhancing effect and an antiviral effect.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the compound of Formula 1 as an active ingredient.

Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and preparations are described in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . On the other hand, the oral dosage amount of the pharmaceutical composition of the present invention is preferably 0.001-100 mg / kg (body weight) per day.

The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered by intravenous infusion, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like. In the pharmaceutical composition of the present invention, the route of administration is preferably determined depending on the type of disease to which it is applied. For example, transdermal administration is preferred when applied for the treatment of atopic dermatitis or psoriasis.

The concentration of the organic germanium compound in the composition of the present invention can be determined in consideration of the purpose of treatment, the condition of the patient, the duration of need, and the like, and is not limited to a specific range of concentration.

The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporating into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

According to another aspect of the invention, the present invention provides a cosmetic composition for use in improving the skin condition comprising an organic germanium compound of formula 1 or a salt thereof as an active ingredient.

According to a preferred embodiment of the present invention, the improvement of the skin condition is the improvement of atopic dermatitis, the improvement of psoriasis, the improvement of gum mushrooms, the improvement of skin wrinkles, the improvement of skin elasticity, or the whitening effect.

The organic germanium compound of the present invention has a strong antioxidant activity, in particular, the organic germanium compound in the form combined with L-ascorbic acid has a synergistic antioxidant activity, by this antioxidant activity wrinkle improvement of the skin, improvement of elasticity, improvement of gum mushroom And whitening effects. In addition, the effect of improving the skin condition by the compound of the present invention can also be explained by the sunscreen efficacy, collagen production promoting effect, and melanin formation inhibitory effect, which are inherent to L-ascorbic acid.

The cosmetic composition of the present invention may be prepared into any of the formulations conventionally produced in the art, and may be prepared, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, But are not limited to, cleansing, oils, powder foundations, emulsion foundations, wax foundations and sprays. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

In the case where the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. Especially, in the case of a spray, a mixture of chlorofluorohydrocarbons, propane / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives, or ethoxylated glycerol fatty acid esters.

The ingredients included in the cosmetic composition of the present invention include, in addition to the active ingredient and the carrier ingredient, ingredients conventionally used in cosmetic compositions and may contain conventional additives such as antioxidants, stabilizers, solubilizers, vitamins, . ≪ / RTI >

The amount of the compound of the present invention in the cosmetic composition of the present invention is not particularly limited and is included in an amount sufficient to achieve the improvement effect of the skin condition.

According to another aspect of the present invention, the present invention provides a functional food composition for use in the treatment or prevention of cancer or inflammatory disease, immuno-enhancement or skin condition comprising the organic germanium compound of formula (1) as an active ingredient.

According to a preferred embodiment of the present invention, the cancer is gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer , Parathyroid cancer or ureter cancer, most preferably liver cancer.

According to another preferred embodiment of the invention, the inflammatory disease is hepatitis, atopic dermatitis or psoriasis.

According to another preferred embodiment of the present invention, the improvement of the skin condition is the improvement of blemishes, the improvement of skin wrinkles, the improvement of skin elasticity, or the whitening.

The functional food composition of the present invention includes components that are ordinarily added during the manufacture of food, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, when prepared with a drink, flavoring agents or natural carbohydrates may be included as additional ingredients in addition to the extract of hawthorn as an active ingredient. For example, natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); Disaccharides (eg maltose, sucrose, etc.); oligosaccharide; Polysaccharides (eg, dextrins, cyclodextrins, etc.); And sugar alcohols (eg, xylitol, sorbitol, erythritol, and the like). As the flavoring agent, natural flavoring agents (e.g., taumartin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.

The efficacy and advantages of the novel organic germanium compound synthesized in the present invention are summarized as follows. Viii) significantly increases the induction of interferon-gamma; Ii) has a strong antioxidant effect. In particular, the compound in which the L-ascorbic acid is bound to germanium of the present invention iii) because ascorbic acid has very high water solubility, the water solubility of the germanium-ascorbic acid compound increases, so that the absorption rate in vivo increases, and 독성) synergistic antioxidant activity of germanium and L-ascorbic acid, iii) increased stability of L-ascorbic acid, iii) ultraviolet light, which is the efficacy of L-ascorbic acid itself. A blocking effect, promoting collagen production and suppressing melanin formation, skin condition improvement effect, and immune enhancing effect can be obtained.

Therefore, the organic germanium compound of the present invention is effective for anti-cancer, anti-virus, anti-inflamation, immuno-enhancing use as well as potent antioxidant activity by interferon-gamma secretion induction efficacy. It can be used to improve the skin condition.

The novel organic germanium compound of the present invention has high solubility in water due to the introduction of a functional group having water-soluble properties, thereby improving intracellular uptake, thereby exerting the inherent efficacy of the organic germanium in the cells. The organic germanium compound of the present invention induces interferon-gamma in vivo. In particular, among the compounds of the present invention, L-ascorbic acid combined with high water solubility and strong antioxidant activity has an increased intracellular absorption rate, exhibits excellent antioxidant activity in cells, and L-ascorbic acid is inherently possessed. Efficacy of immune function enhancement, sun protection, collagen production, and melanin formation can be obtained to improve skin condition.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1: Synthesis of [6-((3- (trimethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol (Compound 91)]

1-1: Preparation of 3- (trimethylgeryl) propionic acid ( Appl. Organometal. Chem , 2004, 28 , 384-393; J. Organomet. Chem , 1990, 385 , 247-253)

To a solution of trichlorogermylpropanoic acid (Gelest) (3 g, 11.90 mmol) in dry ether (11.09 mL), methylmagnesium iodide (16.6 mL, 49.9 mmol in dry ether (11.09 mL)) , 3.0 M in diethyl ether) solution was added slowly with stirring at 0 ° C. under nitrogen. The reaction mixture was refluxed for 30 minutes, cooled and poured into diluted hydrochloric acid 1N solution (10 mL; pH = 4). The ether layer was separated off, washed with water (x 2) and anhydrous MgSO ₄ Dried under reduced pressure and concentrated under reduced pressure to give a crude residue (2.811 g, 100%). The crude compound was used in the next procedure without further purification.

1-2: Preparation of 3- (trimethylgeryl) -1-propanol (see Appl. Organometal. Chem , 2005, 19 , 372-376)

3- (trimethylgeryl) propionic acid (2 g, 10.48 mmol) in diethyl ether (17.5 mL) was added to a suspension of LiAlH ₄ (954 mg, 25.16 mmol) in diethyl ether (17.5 mL) Lightly refluxed. The mixture was stirred at room temperature for 12 hours. MeOH (10 mL) was added dropwise, then water (4 mL) was added, and LAH was removed by filtration through a celite pad. The total filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel ( n- Hexane: EtOAc = 2: 1) to give an alcohol compound (1.5 g, 81%). ).

1-3: Preparation of 1-bromo-3- (trimethylgeryl) propane ( Organic Letter , 2006, 8 , 661-664)

Triphenylphosphine (9.739 g, 37.13 mmol) was added to the mixture with CBr ₄ (12.32 g, 37.13 mmol) and alcohol (2.28 g, 16. 29 mmol) in dry ether (54 mL). After stirring for 2.5 hours at room temperature, the reaction mixture was extracted with ether (x 3). The total extract was washed with water (x 3), placed in brine (x 1), dried over MgSO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel ( n- Hexane: EtOAc = 2: 1) to give the bromide compound (4.8 g, 100%).

1-4: Preparation of benzyl 2, 3, 4, 6-tetra- O -benzyl-β-D-glucopyrannoside (see Carbohydrate Research , 2005, 340 , 1213-1217; Tetrahedron Letter , 1995, 36 , 2953-2956)

50% aqueous sodium hydroxide (16.6 mL, 208.1 mmol) was added to a solution of D-glucose (15 g, 83.26 mmol) in severely stirred anhydrous DMSO (466 mL). Soon after, benzyl bromide (25 mL, 208.1 mmol) was added dropwise at room temperature and the mixture was stirred at 50 ° C. for 2 hours. Then 50% aqueous sodium hydroxide (16.6 mL, 208.1 mmol) and benzyl bromide (25 ml, 208.1 mmol) were added sequentially and the mixture was stirred at 50 ° C. for 2 hours. Then 50% aqueous sodium hydroxide (13.3 mL 166.5 mmol) and benzyl bromide (20 ml 166.5 mmol) were added as before and the mixture was stirred at 50 ° C. for 24 h. The volume ratio of DMSO and water was adjusted to about 10: 1. The reaction mixture was extracted with diethyl ether (X3). The extract was washed with water and brine, dried over MgSO ₄ , and concentrated. Recrystallization from methanol gave the product (25 g, 48%).

1-5: Preparation of benzyl 6- O -acetyl-2, 3, 4-tri- O -benzyl-β-D-glucopyrannoside ( Carbohydrate Research , 2005, 340 , 1213-1217)

Zinc chloride (22.7 g, 166.5 mmol) solution in HOAc-Ac ₂ O (1: 5 volume ratio, 85 ml) was added to benzyl 2, in HOAc-Ac ₂ O (1: 5 volume ratio, 126 ml). To a solution of 3, 4, 6-tetra- O -benzyl-β-D-glucopyrananoside (21 g, 33.3 mmol) was added via dropping funnel at 0 ° C. After stirring for 2 hours at room temperature, 500 ml of ice-water was added. The resulting white precipitate was filtered, washed with excess water and recrystallized from hexane to give the desired acetate (10 g, 53%).

1-6: Preparation of benzyl 2,3,4-tri- O -benzyl-β-D-glucopyrannoside ( Carbohydrate Research , 2005, 340 , 1213-1217)

A solution of glucosyl 6-acetate (10 g, 17.16 mmol) and potassium carbonate (11.86 g, 85.8 mmol) in methanol (57 ml) was stirred at room temperature for 2 hours. After quenching the reaction with ammonium chloride (NH ₄ Cl), the reaction mixture is extracted with ethyl acetate (x 3), washed with water (x 3) and brine (x 1) and magnesium sulfate (MgSO ₄ )). Recrystallization from ethanol gave the crude primary alcohol.

1-7: Preparation of 6-O- [3- (trimethylgeryl) propyl] -1,2,3,4-tetra-O-benzyl-β-D-glucopyrannoside (see Tetrahedron Letter , 1995 , 36 , 2953-2956).

To a solution of TBAI (386 mg, 1.05 mmol) and alcohol (2.26 g, 4.17 mmol) in DMSO (5 mL), 50% aqueous sodium hydroxide (0.59 mL, 7.32 mmol) was added followed by germanium in DMSO (3.8 mL). Bromide (500 mg, 2.09 mmol) solution was added sequentially. The resulting dark brown solution was stirred overnight at room temperature. The resulting suspension was poured into water and the aqueous layer was extracted with ether (x 3). The total organic extract was washed with water (x 3), dried over magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography ( n -Hexane: EtOAc = 3: 1) to give 6O- [3- (trimethylgeryl) propyl] -1,2,3,4 tetra-O-benzyl β D-glucopyrannoside (703 mg, 48%) was obtained.

1-8: Preparation of 6-((3- (trimethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol (see Carbohydrate Research , 2001, 330 , 309-318; Organic Letter , 2006, 8 , 3757-3760)

= + 0.727 (c=0.125, DMSO); M.P: 119.2 ℃ IR (neat): 3325, 2908, 1053cm^{-1 1}H NMR(D₂O, 300 MHz): δ = 5.16 (d, 1 H, a-isomer), 4.58 (d, 1 H, b-isomer), 3.90 (m, 1 H), 3.78 - 3.29 (m, 7 H), 3.221 (t, 1 H), 1.67 (m, 2 H), 0.67 (t, 2 H), 0.06 (s, 9 H); ¹³C NMR (DMSO, 75 MHz): δ = 96.95, 92.32, 76.79, 75.32, 73.36, 70.84, 70.75, 70.56, 70.45, 24.96, 12.44, -2.15 ppm; HRMS: m/z calcd C₁₂H₂₆GeO₆ [M+Na]⁺ 363.0941, found 363.0841 A solution of β-D-glucopyrannoside (404 mg, 0.578 mmol) in EtOAc (1.9 mL) / EtOH (3.85 mL) was added at room temperature in the presence of Pd / C (10% wt, 600 mg) and H _2. Hydrogenation was carried out in a balloon atmosphere for 2 days. The catalyst was removed by filtration through a pad of Celite and a silica gel layer and washed heavily with EtOAc (about 30 mL) and MeOH (about 10 mL). The total filtrate was evaporated in vacuo to give the crude product (201 mg, 100%). Crude residue was used in the next step without further purification:

= + 0.727 (c = 0.125, DMSO); MP: 119.2 ° C. IR (neat): 3325, 2908, 1053 cm ^{−1 1} H NMR (D ₂ O, 300 MHz): δ = 5.16 (d, 1 H, a -isomer), 4.58 (d, 1 H, b -isomer), 3.90 (m, 1 H), 3.78-3.29 (m, 7 H), 3.221 (t, 1 H), 1.67 (m, 2 H), 0.67 (t, 2 H), 0.06 (s, 9 H); ¹³ C NMR (DMSO, 75 MHz): δ = 96.95, 92.32, 76.79, 75.32, 73.36, 70.84, 70.75, 70.56, 70.45, 24.96, 12.44, -2.15 ppm; HRMS: m / z calcd C ₁₂ H ₂₆ GeO ₆ [M + Na] ⁺ 363.0941, found 363.0841

Example 2: Synthesis of [6-((3- (triethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol (Compound 92)]

3- (triethylgeryl) propionic acid was prepared according to the following scheme. Except for using the prepared 3- (triethylgeryl) propionic acid instead of 3- (trimethylgeryl) propionic acid in the same manner as in the production method described in items 1-2 to 1-8 of Example 1 [6-((3- (triethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol (Compound 92)] was prepared.

In the above scheme, RMgBr is EtMgBr (Aldrich-Sigma) as the Grignard reactant.

Example 3: Synthesis of [6-((3- (trivinylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol (Compound 93)]

[6-((3- (trivinylgeryl) propoxy) methyl) -tetrahydro by the same method as in Example 2, except that RMgBr in Example 2 is vinylmagnesium bromide (Aldrich-Sigma) -2H-pyran-2,3,4,5-tetraol (Compound 93)].

Example 4: Synthesis of [6-((3- (triphenylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol (Compound 94)]

[6-((3- (triphenylgeryl) propoxy) methyl) -tetrahydro by the same method as Example 2 except that RMgBr in Example 2 is phenylmagnesium bromide (Aldrich-Sigma) -2H-pyran-2,3,4,5-tetraol (Compound 94)] was prepared.

Example 5: Synthesis of [6-((3- (tribenzylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol (Compound 95)]

[6-((3- (tribenzylgeryl) propoxy) methyl) -tetrahydro by the same method as in Example 2, except that RMgBr in Example 2 is benzyl magnesium bromide (Aldrich-Sigma) -2H-pyran-2,3,4,5-tetraol (Compound 95)] was prepared.

Example 6: [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (trimethylgeryl) propanamide (compound 76)]

6-1: Preparation of 2,5-dioxopyrrolidin-1-yl-3- (trimethylgeryl) propanoate (see US Pat No. 6,749,832)

3- (trimethylgeryl) propionic acid (0.523 g, 2.77 mmol) was dissolved in dry dichloromethane (10 mL) and then N, N-dicyclohexylcarbodiimide (DCC) (0.63 g, 2.86 mmol) and N-hydroxysuccinimide (NHS) (0.36 g, 2.95 mmol) were added and stirred at room temperature for 16 hours. The DCC precipitate was filtered off and washed several times with dichloromethane. The filtered solution was concentrated and purified using flash column chromatography (Hexane: EA = 3: 2) on silica gel. The desired compound (0.69 g, 56.5%) was obtained as a white solid.

6-2: Preparation of N- (2,3,4,5,6-pentakis (benzyloxy) cyclohexyl) -3- (trimethylgeryl) propanamide

As reported in Elke Schoffers, Sing R. Gurung, Petra R. Kohler, Silvia Rossbach Chemical synthesis of scyllo-inosamine and catabolism studies in Sinorhizobium meliloti Bioorg.Med , Chem. (2008), 16, 7838-7842. The resulting azide derivative (0.65 g, 1.00 mmol) is dissolved in acetonitrile (15 mL) and triphenyl phosphine (0.35 g, 1.35 mmol) is acetonitrile (8 mL). ) Was added dropwise at 0 ° C. The reaction mixture solution was stirred for 1 hour and then slowly heated up to 50 ° C. After stirring for 2 hours at 50 ℃ cooled to room temperature, germanium derivative (0.25 g, 0.86 mmol) was added and stirred for 3 hours. The precipitate was removed, washed with acetonitrile several times, and the filtrate was concentrated under reduced pressure. Distilled water (20 mL) was added to the mixed solution, and extracted with dichloromethane (60 mL x 3). The organic layer was washed with 5% sodium sulfite (Na ₂ SO ₃ ) aqueous solution, dried over anhydrous magnesium sulfate (MgSO ₄ ), and the solvent was removed under reduced pressure. The yellow crude residue was purified by flash column chromatography on silica gel (Hexane: EA = 1: 2) to obtain the desired compound (0.64 g, 93%).

6-3: Preparation of N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (trimethylgeryl) propanamide ( See: Carbohydrate Research , 2001, 330 , 309-318; Organic Letter , 2006, 8 , 3757-3760)

A solution of starting material (400 mg, 0.498 mmol) in EtOAc (2 mL) EtOH (4 mL) was stirred at room temperature in the presence of Pd-C (10% wt, 500 mg) and H ₂ balloon atmosphere. Hydrogenated under 2 days. The catalyst was removed by filtration through a pad of Celite and silica gel layer and washed strongly with EtOAc (about 30 mL) -MeOH (about 10 mL). The total filtrate was evaporated in vacuo to afford the desired product (174 mg, 100%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ0.09 (s, 9H), 0.99 (t, 2H), 2.23 (t, 2H), 3.38 (m, 1H), 4.88-4.93 (m, 10H), 7.21-7.42 (m, 25H)

Example 7: [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (triethylgeryl) propanamide Synthesis of Compound 77

Grignard of Example 2 After preparing 3-(triethylgeryl) propionic acid using EtMgBr (Aldrich-Sigma) as the Grignard reactant in the reaction, the prepared 3- (triethylgeryl) propionic acid was added to 3- (trimethylgermill [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4 by the same method as the preparation method described in Example 6, except that it was used as a reactant instead of propionic acid. , 5,6-pentahydroxycyclohexyl) -3- (triethylgeryl) propanamide (Compound 77)] was prepared.

Example 8: [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (trivinylgeryl) propanamide ( Compound 78)]

As a Grignard reactant [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6 by the same method as Example 7, except that vinylmagnesium bromide (Aldrich-Sigma) was used. -Pentahydroxycyclohexyl) -3- (trivinylgeryl) propanamide (Compound 78)] was prepared.

Example 9: [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (triphenylgeryl) propanamide ( Compound 79)]

As a Grignard reactant [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6 by the same method as Example 7, except that phenylmagnesium bromide (Aldrich-Sigma) was used. -Pentahydroxycyclohexyl) -3- (triphenylgeryl) propanamide (Compound 79)] was prepared.

Example 10: [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (tribenzylgeryl) propanamide ( Compound 80)]

Except for using benzyl magnesium bromide (Aldrich-Sigma) as the Grignard reactant, [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3, 4,5,6-pentahydroxycyclohexyl) -3- (tribenzylgeryl) propanamide (Compound 80)] was prepared.

Example 11: [N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (trimethylgeryl) propanamide (Compound 1)]

11-1: Preparation of 5- (2-bromo-1-hydroxyethyl) -3,4-dihydroxyfuran-2 (5H) -one (see US Pat. No. 4043937, 1977)

HBr (6.18 mL, 34.07 mmol, 33 wt% in acetic acid) was added to L-ascorbic acid (5.0 g, 28.39 mmol) and added slowly at 50 ° C., followed by stirring for about 3 hours. Distilled water (30 mL) was added to the mixture, which was stirred at 60 ° C. for 30 minutes and distilled under reduced pressure to remove the solvent. After repeating this process once more, the mixture was dissolved in distilled water (30 mL) and extracted with ethyl acetate (150 mL x 3). The organic layer was separated, dried over anhydrous magnesium sulfate (MgSO ₄ ), distilled under reduced pressure to remove the solvent, and 30 mL of 30 mL of nitromethane was added thereto, stirred at 100 ° C. for 30 minutes, dissolved, and recrystallized at room temperature. The resulting compound was dried in vacuo to give the desired compound as a light grey-brown powder.

11-2: Preparation of 5- (2-azido-1-hydroxyethyl) -3,4-bis (benzyloxy) furan-2 (5H) -one (see Chemiker-Zeitung, 1985 , 109: 197) -202).

Starting material ascorbic acid derivative (8.32 g, 34.8 mol) was dissolved in 8 mL of distilled water, and sodium carbonate (Na ₂ CO ₃ ) (7.38 g, 69.6 mmol) dissolved in 20 mL of distilled water was slowly added dropwise to the solution. After 5 minutes, sodium azide (NaN ₃ ) (3.39 g, 52.2 mmol) was added thereto, stirred at room temperature under nitrogen for 24 hours, and then 100 mL of cation exchange resin (Dowex 50, 100-200 mesh) was added to the reaction mixture, and then After vigorously stirring, the cation exchange resin was washed down with distilled water twice the volume of the ion exchange resin. The solvent of the filtered solution was distilled off under reduced pressure, and the brown azide derivative obtained was dissolved in DMSO (65 mL), Na ₂ CO ₃ (3.69 g, 34.8 mmol) was added, followed by stirring at room temperature for 30 minutes. Benzyl bromide (4.16 mL, 34.8 mmol) was added little by little at 50 ° C. to the reaction mixture, followed by stirring at 50 ° C. for 2 hours. Again sodium carbonate (Na ₂ CO ₃ ) (3.69 g, 34.8 mmol) was added at 50 ° C., then stirred for 30 minutes, and benzyl bromide (4.16 mL, 34.8 mmol) was added. After stirring for 24 hours at 50 ℃, distilled water was added. The reaction mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure to remove the solvent. This crude residue was purified by flash column chromatography on silica gel (Hexane: EA = 3: 1) to obtain the desired compound (5.23 g, 39.4%).

11-3. Of N- (2- (3,4-bis (benzyloxy) -5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (trimethylgeryl) propanamide Manufacturing (see: Tetrahedron Lett. , 2002, 4, 6309-6311)

A solution of ascorbic acid derivative (0.79 g, 2.08 mmol) dissolved in acetonitrile (15 mL) and triphenyl phosphine (0.73 g, 2.78 mmol) in acetonitrile (8 mL) was heated to 0 ° C. Dropped at The reaction mixture was stirred for 1 hour and then slowly heated up to 50 ° C. After stirring at 50 ° C. for 2 hours and cooling to room temperature, the germanium derivative (0.40 g, 1.39 mmol) prepared by the preparation method of item 6-1 of Example 6 was added and stirred for 3 hours. The precipitate was removed, washed several times with acetonitrile, and the filtrate was concentrated by distillation under reduced pressure. Distilled water (20 mL) was added to the mixed solution, and extracted with dichloromethane (60 mL X 3). The organic layer was washed with 5% aqueous sodium sulfite (Na ₂ SO ₃ ) solution, dried over anhydrous magnesium sulfate (MgSO ₄ ), the solvent was concentrated under reduced pressure, and the yellow crude residue was subjected to flash chromatography on silica gel. Purification by chromatography, Hexane: EA = 2: 1) afforded the desired compound (0.65 g, 88.1%).

11-4: N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl)- Preparation of 3- (trimethylgeryl) propanamide ( Org. Biomol. Chem. 2005, 3, 2450-2457)

The starting germanium derivative (0.57 g, 1.08 mmol) was dissolved in anhydrous methanol (20 mL) and Pd (OH) ₂ (0.06 g) was added at room temperature and stirred for 4 h under H ₂ . Pd (OH) ₂ was filtered from the reaction mixture, washed several times with methanol, and concentrated to remove all solvents. This crude residue was recrystallized from ethylacetate / hexane to give the desired compound as a white solid (0.53 g, 85.4%). ¹ H NMR (300 MHz, D ₂ O) δ 0.14 (s, 9H), 0.98 (t, 2H), 2.35 (t, 2H), 3.50-3.56 (m, 2H), 4.13 (t, 1H), 4.88 (s, 1 H).

Example 12: [N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (triethylgeryl) propanamide (Compound 2)]

In the Grignard reaction described in Example 2, 3- (triethylgeryl) propionic acid was prepared using EtMgBr (Aldrich-Sigma) as the Grignard reactant, and 3- (triethylgeryl) propionic acid thus prepared. 2,5-dioxopyrrolidine-1- by the same method as the preparation method described in item 6-1 of Example 6, except that 3- (trimethylgeryl) propionic acid was used as a reactant. Il-3- (triethylgeryl) propanoate was prepared. Except for using 2,5-dioxopyrrolidin-1-yl-3- (triethylgeryl) propanoate prepared as a germanium derivative in the same manner as in Example 11 [N-((S ) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (triethylgeryl) propane Amide (Compound 2)] was prepared.

Example 13: [N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl ) -3- (trivinylgeryl) propanamide (Compound 3)]

3- (trivinylgeryl) propionic acid was prepared using vinylmagnesium bromide (Aldrich-Sigma) as the Grignard reactant of Example 2, and 3- (trivinylgeryl) propionic acid was prepared in 3- ( 2,5-dioxopyrrolidin-1-yl-3- by the same method as described in item 6-1 of Example 6, except that trimethylgeryl) propionic acid was used as a reactant. (Trivinylgermill) propanoate was prepared. Except for using 2,5-dioxopyrrolidin-1-yl-3- (trivinylgeryl) propanoate prepared as a germanium derivative in the same manner as in Example 11 [N-((S ) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (trivinylgeryl) propane Amide (Compound 3)] was prepared.

Example 14 [N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- ( Triphenylgermill ) Propanamide (Compound 4)]

3- (triphenylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reactant of Example 2, and 3- (trimethylgeryl) propionic acid was prepared. 2,5-dioxopyrrolidin-1-yl-3- () by the same method as described in item 6-1 of Example 6, except that it was used as a reactant instead of germanyl) propionic acid. Triphenylgeryl) propanoate was prepared. Except for using 2,5-dioxopyrrolidin-1-yl-3- (triphenylgeryl) propanoate prepared as a germanium derivative in the same manner as in Example 11 [N- ((S ) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (triphenylgeryl) propane Amide (Compound 4)] was prepared.

Example 15: [N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tribenzylgeryl) propanamide (Compound 5)]

3- (tribenzylgeryl) propionic acid was prepared using benzyl magnesium bromide (Aldrich-Sigma) as the Grignard reactant of Example 2, and 3- (tribenzylgeryl) propionic acid was prepared. 2,5-dioxopyrrolidin-1-yl-3- () by the same method as described in item 6-1 of Example 6, except that it was used as a reactant instead of germanyl) propionic acid. Tribenzylgeryl) propanoate was prepared. Except that 2,5-dioxopyrrolidin-1-yl-3- (tribenzylgeryl) propanoate thus prepared was used as the germanium derivative, by the same method as in Example 11 [N-((S ) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tribenzylgeryl) propane Amide (Compound 5)] was prepared.

Example 16: [(S) -2-((R) -3,4-Dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (trimethyl Germanyl ) propanoate (Compound 51)] ( Ultrasonic Sonochemistry 2007 , 14, 213-218).

To a solution of trimethylgermylpropanoic acid (3 g, 11.90 mmol) in concentrated sulfuric acid (10 mL) was added ascorbic acid (1.5 g, 8.5 mmol), stirred for 2 days, and poured into about 100 g of ice. After 200 mL of ethyl acetate was added and stirred, the ethyl acetate layer was separated and washed with saturated brine solution (x 5). After drying over anhydrous magnesium sulfate and concentration under reduced pressure, the desired compound was obtained (1.446 g, 49%). ¹ H NMR (300 MHz, D ₂ O) δ 0.13 (s, 9H), 0.87 (t, 2H), 2.55 (t, 2H), 4.02-4.09 (m, 2H), 4.15 (m, 1H), 4.78 (d, 1H)

Example 17: [(S) -2-((R) -3,4-Dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (tri Ethylgeryl) propanoate (Compound 52)]

3- (triethylgeryl) propionic acid was prepared using EtMgBr (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction described in Example 2. [(S) by the same method as the preparation method described in Example 16, except that 3- (triethylgeryl) propionic acid thus prepared was used as a reactant in place of 3- (trimethylgeryl) propionic acid. -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (triethylgeryl) propanoate ( Compound 52)].

Example 18: [(S) -2-((R) -3,4-Dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (tri Vinylgeryl) propanoate (Compound 53)]

[(S) -2-((R) -3,4-Dihydroxy-5-] by the same method as Example 17, except that vinyl magnesium bromide (Aldrich-Sigma) was used as the Grignard reactant. Oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (trivinylgeryl) propanoate (Compound 53)] was prepared.

Example 19: [(S) -2-((R) -3,4-Dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (tri Phenylgeryl) propanoate (Compound 54)]

[(S) -2-((R) -3,4-dihydroxy-5-] by the same method as Example 17, except that phenylmagnesium bromide (Aldrich-Sigma) was used as the Grignard reactant. Oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (triphenylgeryl) propanoate (Compound 54)].

Example 20: [(S) -2-((R) -3,4-Dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (tri Benzylgeryl) propanoate (Compound 55)]

[(S) -2-((R) -3,4-dihydroxy-5-] by the same method as Example 17, except that benzyl magnesium bromide (Aldrich-Sigma) was used as the Grignard reactant. Oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (tribenzylgeryl) propanoate (Compound 55)].

Example 21: [(R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) furan-2 (5H) -ON (Compound 26)]

21-1: Preparation of 3- (trimethylgeryl) propanal

Pyridinium dichromate (1.29 g, 3.45 mmol) was added to 3- (trimethylgeryl) propan-1-ol (0.30 g, 1.71 mmol) dissolved in anhydrous dichloromethane (3 mL) and 3 at room temperature. Stir for hours. The reaction was diluted with dichloromethane, filtered, washed several times with dichloromethane and distilled to remove all solvents. DCC remaining in the obtained crude product was dissolved in a small amount of dichloromethane and simply removed on silica gel to obtain pure 3- (trimethylgeryl) propanal.

21-2: Preparation of (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) furan-2 (5H) -one

Dry ascorbic acid amine derivative (0.50 g, 2.9 mmol) made from 3- (trimethylgeryl) propanal (0.99 g, 5.7 mmol) and the method reported in the literature ( Chemiker-Zeitung 1985, 109 , 197-202.) After dissolving in DMF (15 mL), 5% Pd / C (0.03 g) was added to the mixed solution, which was stirred for 4 hours and 30 minutes at room temperature under H ₂ . The reaction solution was filtered, washed several times with DMF, and then the solvent was removed under reduced pressure at 50 ° C. to obtain the desired compound. (1.77 g, 92.8%). ¹ H NMR (300 MHz, D ₂ O) δ 0.12 (s, 9H), 0.96 (t, 2H), 2.48 (t, 2H), 2.60-2.63 (m, 2H), 4.23-4.26 (m, 1H) , 4.90 (d, 1 H)

Example 22 [(R) -3,4-Dihydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) furan-2 (5H ) -One (compound 27)]

3- (triethylgeryl) propionic acid was prepared using EtMgBr (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction described in Example 2. 3- (triethylgeryl) -1-propanol was prepared by the same method as described in item 1-2 of Example 1, using 3- (triethylgeryl) propionic acid thus prepared as a reaction material. It was. Except for using 3- (triethylgeryl) -1-propanol thus prepared in place of 3- (trimethylgeryl) propan-1-ol by the same method as described in Example 21 [ (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) furan-2 (5H) -one (compound 27)].

Example 23: [(R) -3,4-Dihydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) furan-2 (5H ) -One (compound 28)]

3- (trivinylgeryl) propionic acid was prepared using vinylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. A 3- (trivinylgeryl) -1-propanol was prepared by the same method as described in item 1-2 of Example 1, using 3- (trivinylgeryl) propionic acid as prepared as a reactant. It was. By the same method as described in Example 21, except that 3- (trivinylgeryl) -1-propanol thus prepared was used instead of 3- (trimethylgeryl) propan-1-ol. (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) furan-2 (5H) -one (compound 28)].

Example 24: [(R) -3,4-Dihydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) furan-2 (5H ) -One (compound 29)]

3- (triphenylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. Using 3- (triphenylgeryl) propionic acid thus prepared as a reactant, 3- (triphenylgeryl) -1-propanol was prepared by the same method as described in item 1-2 of Example 1 above. Prepared. Except for using the prepared 3- (triphenylgeryl) -1-propanol in place of 3- (trimethylgeryl) propan-1-ol by the same method as the preparation method described in Example 21 [( R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) furan-2 (5H) -one (Compound 29 )].

Example 25: [(R) -3,4-Dihydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) furan-2 (5H ) -One (compound 30)]

3- (tribenzylgeryl) propionic acid was prepared using benzyl magnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. 3- (tribenzylgeryl) -1-propanol was prepared by the same method as described in item 1-2 of Example 1, using the prepared 3- (tribenzylgeryl) propionic acid as a reactant. By the same method as the preparation method described in Example 21, except that 3- (tribenzylgeryl) -1-propanol thus prepared was used instead of 3- (trimethylgeryl) propan-1-ol. [(R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) furan-2 (5H) -one ( Compound 30)].

Example 26: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trimethylgeryl) propoxy) furan-2 (5H) -On (Compound 81)]

26-1: (R) -2-((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -5-oxo-4- (3- (trimethylgeryl) Propoxy ) -2,5- Dihydrofuran -3 days Benzoate  Produce

Ascorbic acid derivatives (3.20 g, 10 mmol) synthesized as known from J. Med. Chem. 1988, 31, 793-798 were dissolved in acetone solvent (100 mL) and then potassium carbonate (K ₂ CO ₃ ) (2 g, 14.7 mmol) was added, followed by stirring at room temperature for 30 minutes. Bromogernium compound (2.50 g, 10.7 mmol) was added to the reaction mixture, which was then reacted at room temperature for 24 hours and then treated with 100 mL of water. After extraction of the product with dichloromethane, the combined organic solvents were dried over anhydrous MgSO ₄ and concentrated under reduced pressure. This crude residue was purified by flash column chromatography on silica gel (Hexane: EA = 4: 1) to obtain the desired compound (3.56 g, 74%).

26-2: (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trimethylgeryl) propoxy) furan-2 (5H)- Manufacture of

The starting germanium derivative (0.480 g, 1.00 mmol) was dissolved in 30 mL dichloromethane and then 2 mL TFA was added at O ° C. and stirred for one day. After the reaction, the solvent was completely removed under vacuum drying, dissolved in anhydrous methanol (20 mL), Pd (OH) ₂ (0.06 g) was added at room temperature, and stirred for 4 hours under H ₂ . Pd (OH) ₂ was filtered from the reaction mixture, washed several times with methanol, and concentrated to remove all solvents. Purification via flash column chromatography on silica gel (flash column chromatography, CHCl 3: MeOH = 9: 1) afforded the desired compound (0.292 g, 87%). ¹ H NMR (300 MHz, D ₂ O) δ 0.11 (s, 9H), 0.74 (t, 2H), 1.74 (m, 2H), 3.87-3.96 (m, 3H), 4.98 (d, 1H)

Example 27: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triethylgeryl) propoxy) furan-2 (5H ) -One (compound 82)]

3- (triethylgeryl) propionic acid was prepared using EtMgBr (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction described in Example 2. 1-Bromo-3- (triethylger) was prepared by the same method as described in item 1-2 and 1-3 of Example 1 using 3- (triethylgeryl) propionic acid as a starting material. Mil) propane was prepared, and by the same method as described in Example 26, except that 1-bromo-3- (triethylgeryl) propane thus prepared was used as a germanium derivative, [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triethylgeryl) propoxy) furan-2 (5H) -one (compound 82) ]of Prepared.

Example 28: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trivinylgeryl) propoxy) furan-2 (5H ) -One (compound 83)]

3- (trivinylgeryl) propionic acid was prepared using vinylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. 1-Bromo-3- (trivinylger) by the same method as described in item 1-2 and 1-3 of Example 1 using 3- (trivinylgeryl) propionic acid as a starting material Mil) propane was prepared and by the same method as described in Example 26 except that 1-bromo-3- (trivinylgeryl) propane thus prepared was used as a germanium derivative [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trivinylgeryl) propoxy) furan-2 (5H) -one (compound 83)] of Prepared.

Example 29: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triphenylgeryl) propoxy) furan-2 (5H ) -One (compound 84)]

3- (triphenylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. 1-Bromo-3- (triphenylger) by the same method as the preparation method described in items 1-2 and 1-3 of Example 1 using 3- (triphenylgeryl) propionic acid as a starting material Mil) propane was prepared. [-(R) -5-((R) was prepared by the same method as described in Example 26, except that 1-bromo-3- (triphenylgeryl) propane thus prepared was used as a germanium derivative. ) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triphenylgeryl) propoxy) furan-2 (5H) -one (compound 84)] Prepared.

Example 30: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (tribenzylgeryl) propoxy) furan-2 (5H ) -One (Compound 85)]

3- (tribenzylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. 1-Bromo-3- (tribenzylger) by the same method as the preparation method described in items 1-2 and 1-3 of Example 1 using 3- (tribenzylgeryl) propionic acid as a starting material Mil) propane was prepared and by the same method as described in Example 26, except that 1-bromo-3- (tribenzylgeryl) propane thus prepared was used as a germanium derivative, [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (tribenzylgeryl) propoxy) furan-2 (5H) -one (compound 85)] of Prepared.

Example 31: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (trimethyl Germanyl) propanoate (Compound 86)]

31-1: (R) -2-((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -5-oxo-4- (3- (trimethylgeryl) propano Preparation of yloxy) -2,5-dihydrofuran-3-yl benzoate

Ascorbic acid derivative (320 mg, 1.0 mmol) was dissolved in acetone solvent (20 mL), and potassium carbonate (K ₂ CO ₃ ) was added (0.2 g, 1.47 mmol), followed by stirring at room temperature for 30 minutes. Germanium derivative (316 mg, 1.1 mmol) was added to the reaction mixture, which was then reacted at room temperature for 24 hours, and then treated with 20 mL of water. The product was extracted with dichloromethane and the combined organic solvents were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This crude residue was purified by flash column chromatography on silica gel (Hexane: EA = 4: 1) to obtain the desired compound (384 mg, 80%).

31-2: (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (trimethylger Mil) Preparation of propanoate

The starting germanium derivative (0.494 g, 1.00 mmol) was dissolved in 30 mL dichloromethane, and then 2 mL TFA (trifluoroacetic acid, trifluoroacetic acid) was added at 0 ° C. and stirred for one day. After the reaction, the solvent was completely removed under vacuum drying, then dissolved in anhydrous methanol (20 mL), Pd (OH) ₂ (0.06 g) was added at room temperature, and stirred for 4 hours under H ₂ . Pd (OH) ₂ was filtered from the reaction mixture, washed several times with methanol, and concentrated to remove all solvents. Purification via flash column chromatography on silica gel (flash column chromatography, CHCl ₃ : MeOH = 9: 1) afforded the desired compound (0.322 g, 90%). ¹ H NMR (300 MHz, D ₂ O) δ 0.13 (s, 9H), 0.84 (t, 2H), 2.45 (t, 2H), 3.76-3.97 (m, 3H), 4.88 (d, 1H)

Example 32: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (tri Ethylgeryl) propanoate (Compound 87)]

3- (triethylgeryl) propionic acid was prepared using EtMgBr (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction described in Example 2. By the same method as described in section 6-1 of Example 6, except that 3- (triethylgeryl) propionic acid prepared was used as a reactant in place of 3- (trimethylgeryl) propionic acid. , 5-dioxopyrrolidin-1-yl-3- (triethylgeryl) propanoate was prepared and 2,5-dioxopyrrolidin-1-yl-3- (triethylgeryl [(R) -5-((R) -1,2-dihydroxyethyl) -4- by the same method as the preparation method described in Example 31 except that propanoate was used as the germanium derivative. Hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (triethylgeryl) propanoate (compound 87)] Prepared.

Example 33: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (tri Vinylgeryl) propanoate (Compound 88)]

3- (trivinylgeryl) propionic acid was prepared using vinylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. By the same method as described in item 6-1 of Example 6, except that 3- (trivinylgeryl) propionic acid prepared was used as a reactant in place of 3- (trimethylgeryl) propionic acid. , 5-dioxopyrrolidin-1-yl-3- (trivinylgeryl) propanoate was prepared and 2,5-dioxopyrrolidin-1-yl-3- (trivinylgeryl [(R) -5-((R) -1,2-dihydroxyethyl) -4- by the same method as the preparation method described in Example 31 except that propanoate was used as the germanium derivative. Hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (trivinylgeryl) propanoate (Compound 88)] Prepared.

Example 34: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (tri Phenylgeryl) propanoate (Compound 89)]

3- (triphenylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. By the same method as described in section 6-1 of Example 6, except that 3- (triphenylgeryl) propionic acid prepared was used as a reactant in place of 3- (trimethylgeryl) propionic acid. , 5-dioxopyrrolidin-1-yl-3- (triphenylgeryl) propanoate was prepared and 2,5-dioxopyrrolidin-1-yl-3- (triphenylgeryl) thus prepared [(R) -5-((R) -1,2-dihydroxyethyl) -4- by the same method as the preparation method described in Example 31 except that propanoate was used as the germanium derivative. Hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (triphenylgeryl) propanoate (Compound 89)] Prepared.

Example 35: [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (tri Benzylgeryl) propanoate (Compound 90)]

3- (tribenzylgeryl) propionic acid was prepared using benzyl magnesium bromide (Aldrich-Sigma) as the Grignard reaction in the Grignard reaction of Example 2. By the same method as the preparation method described in item 6-1 of Example 6, except that 3- (tribenzylgeryl) propionic acid prepared was used as a reactant in place of 3- (trimethylgeryl) propionic acid. , 5-dioxopyrrolidin-1-yl-3- (tribenzylgeryl) propanoate was prepared and 2,5-dioxopyrrolidin-1-yl-3- (tribenzylgeryl) thus prepared [(R) -5-((R) -1,2-dihydroxyethyl) -4- by the same method as the preparation method described in Example 31 except that propanoate was used as the germanium derivative. Hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (tribenzylgeryl) propanoate (Compound 90)] It was prepared.

Example 36 Synthesis of Organic Germanium Compounds (Compounds 6-25, 31-50, and 56-75) Combined with L-ascorbic Acid Derivatives Protected

36-1: Preparation of Organic Germanium Compounds (Compounds 6-15, 31-40 and 56-65) Coupled with L-ascorbic Acid Derivatives Incorporated with Phosphoric Acid Protecting Group (Reference: Xia, Z., Zhong, Z. Synthesis and purification of magnesium L-ascorbiate-2-phosphate Guangdong Huagong (2003), 30, 24-25)

After dissolving each of the germanium-ascorbic acid compounds (Compounds 1-5, 26-30 and 51--55) synthesized in Example 11-25 according to the ascorbic acid phosphate derivative synthesis method reported in the above reference, Pyridine was added and POCl ₃ was added slowly at 0 ° C. During the reaction, KOH was added to maintain the pH of the aqueous solution to 13, and when the reaction was terminated, separation was performed using an ion exchange resin to obtain a desired compound.

In addition, for compounds to which alkylated phosphoric acid is added, Shibayama, Hiroharu et.al.Synthesis and characterization of new ascorbic dericative: sodium isostearyl 2-O-ascorbyl phosphate, Journal of Oleo Science (2005) 54 (11), 601-608 Synthesis according to the method of).

36-2: Preparation of Organic Germanium Compounds (Compounds 16-20, 41-45 and 66-70) Combined with Ascorbic Acid Derivatives Incorporated with TBDMS Protecting Groups (Ref. Beifuss, U., Kunz, O., Auguado, GP Regioselective O-alkylation of ascorbic acid for the efficient synthesis of lipophilic antioxidants, Synlett (1999) 1, 147-149)

Following the synthesis of ascorbic acid derivatives reported in the references, 1 equivalent of sodium hydrogencarbonate was obtained for each of the germanium-ascorbic acid compounds (Compounds 1-5, 26-30 and 51-55) synthesized in Examples 11-25. After treatment with (NaHCO ₃ ) benzyl bromide (benzylbromide) to protect the oxygen three times. This compound was treated with diisopropyl ethylamine and then TfOSi (Me) ₂ C (CH ₃ ) _{3 was} added to obtain a compound protected by oxygen twice with TBDMS. This compound was dissolved in methanol, Pd (OH) ₂ was added, and then hydrogenated to remove the protecting group of oxygen three times. Subsequent separation on silica gel chromatography gave the desired compounds.

36-3: Preparation of Organic Germanium Compounds (Compounds 21-25, 46-50, and 71-75) Combined with L-Ascorbic Acid Derivatives Incorporating Glucose Protectors ( Hsieh, Hsin-Ju et al. Production of ascorbic acid glucoside by alginate-entrapped mycelia of Aspergitlus niger, Applied Microbiology and Biotechnology (2007) 77, 53-60.)

Each germanium-ascorbic acid compound synthesized in Examples 11-25 using a transglucosidase derived from alginate-entrapped mycelia of Aspergitlus niger as reported in the references (Compounds 1-5, 26) -30 and 51-55) was synthesized a germanium derivative with ascorbic acid introduced with glucose (glucose).

Compounds synthesized according to the methods of Examples 1 to 36 are summarized in the following table.

Example  37: Animal Experiment

37-1: Preparation of Organic Germanium Compound Solution

Organic germanium compound 91 [6-((3- (trimethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol synthesized in the above example for animal experiment Also referred to below as Ge-OH)], Compound 1 [N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2- Yl) -2-hydroxyethyl) -3- (trimethylgeryl) propanamide], compound 76 [N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6 -Pentahydroxycyclohexyl) -3- (trimethylgeryl) propanamide], compound 86 [(R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2- Oxo-2,5-dihydrofuran-3-yl 3- (trimethylgeryl) propanoate] was used by dissolving in sterile phosphate-buffered saline (PBS, pH 7.4) just before entering the animal experiment.

37-2: Preparation of the Mouse

Seven-week-old ICR mice (Japan SLC, Inc. Inasa Production Facility) were used for experiments after stabilization for one week in a clean animal laboratory at Chung-Ang University medical school. Female mice of 8-9 weeks old were used for the experiment, and all experiments were conducted in the clean animal laboratory. The clean animal laboratory was maintained at a temperature of 23 ° C. 1 ° C. and a humidity of 40-60% and was continuously ventilated with fresh air (14-18 times per hour). Mice were fed sterilized mouse food and water.

37-3: Administration of Organic Germanium Compounds

The organic germanium compound solution dissolved in PBS was orally administered to mice at 100 mg / kg per mouse weight.

37-4: Collection of Blood

Methods for collecting blood from mice include collection from the tail vain, collection from the orbital blood vessels, and collection through cardiac puncture, among which blood collection through the cardiac puncture is performed. The method was chosen. Other methods have limitations in drawing large amounts of blood from mice, and attempted to draw the entire amount of mouse blood through cardiac puncture.

37-5: Preparation of Serum

Blood samples obtained from mice are coagulated to obtain serum. Typically, there are two ways to obtain serum. One of them is obtained by coagulation after leaving the blood at room temperature for 2 hours, and the other is obtained by centrifugation at 2000 X g for 20 minutes after overnight at 2-8 ℃. In this experiment, serum was obtained by the former method.

37-6: Interferon-γ Analysis

Interferon-gamma (IFN-γ) analysis was performed using the Quantikine kit (Mouse IFN-γ assay) from R & D systems, and the analysis was performed according to the method instructed by the product. 50 μl of Assay Diluent RD1-21 (R & D systems, Quantikine, Mouse IFN-γ) was placed in the center of each well of the plate frame, and then the standard, control and Serum samples were placed in 50 μl each well. Mix the plate frame for 1 minute while tapping lightly. After covering the plate frame with an adhesive strip (adhesive strip) provided in the kit (kit) and incubated for 2 hours at room temperature. After the solution in each well was completely removed and washed with wash buffer, this process was repeated four more times. The plate was turned over and the remaining wash buffer was wiped off with a clean paper towel. Again, 100 μl of mouse IFN-γ conjugate was added to each well of the plate frame, covered with a new adhesive strip, and then incubated for 2 hours at room temperature. The solution was removed and washed five times as before. 100 μl of substrate solution was added to each well and incubated at room temperature for 30 minutes. At this time, care was taken not to expose to light. 100 μl of stop solution was added to each well, followed by tapping the plates to ensure complete mixing. Thereafter, the optical density of each well was measured at 450 nm using an ELISA (Enzyme-Linked Immunosorbent Assay).

Example 38: Interferon-gamma (IFN-γ) Induction Effect of Organic Germanium Compounds of the Present Invention

In order to verify the antiviral effect of the synthetic organic germanium compounds of the present invention, the organic germanium compounds [6-((3- (trimethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3, 4,5-tetraol (Compound 91, Ge-OH)] was measured the induction of IFN-γ from the serum of mice treated and compared with the results of Ge-132 treatment. In rats treated with oral Ge-132, IFN-γ was increased from 12 to 24 hours and was 326.1 pg / ml at 24 hours. In the case of mice administered orally with Ge-OH, the induction of IFN-γ at 324.6 pg / ml after 24 hours was similar to that of Ge-132. However, when treated with Ge-OH, it was observed that the amount of IFN-γ was present up to 72 hours, and the amount of induction of total IFN-γ was higher than that of Ge-132 up to 48 hours. This experimental result is the result obtained by repeating three or more times (Fig. 3).

In addition, the secretion-inducing effect of IFN-γ on Compound 1, Compound 76, Compound 86, and Compound 91 among the compounds described in the Compound Table of the present invention was measured, and the measurement results are shown in Table 1 below.

     Table 1 INF-γ secretion induction activity measurement results

상기 표 1에서 알 수 있는 바와 같이, 본 발명의 화합물 1, 화합물 76, 화합물 86, 화합물 91은 비교실험군인 Ge-132 화합물 보다 우수한 IFN-γ 유도 효과를 나타내었으며, 특히 화합물 86은 매우 우수한 IFN-γ 분비 유도 활성을 보였다.

As can be seen in Table 1, Compound 1, Compound 76, Compound 86, Compound 91 of the present invention showed a better IFN-γ inducing effect than the comparative group Ge-132 compound, in particular Compound 86 is very excellent IFN -γ secretion induction activity.

Example 39 Determination of Antioxidant Activity in Solution of Organic Germanium Compounds of the Invention

Antioxidant activity of the organic germanium compound of the present invention was measured using DPPH (1,1-diphenyl-2-picrylhydrazyl). The purple DPPH was measured using UV because it reacted with antioxidants and the color was changed and the absorbance was decreased at 517 nm. The synthesized compounds were dissolved in ethanol to a concentration of 5 ppm, and then 100 μL was mixed with DPPH solution (900 μL), and then absorbed at 517 nm after incubation at 37 ° C. for 30 minutes.

Measurement results of the antioxidant capacity of the compounds of the present invention are shown in FIG. According to the results of antioxidant activity using DPPH, the compound bound by germanium to carbon 6 of L-ascorbic acid showed that the antioxidant activity was about 2 times better than that of a single L-ascorbic acid. In addition, when the carbon 2 of L-ascorbic acid was protected with phosphoric acid, silane, and glucose to increase the stability of the compound, the antioxidant effect was not better than that of L-ascorbic acid. However, the compound having a germanium-substituted carbon compound (Compound 86-Compound 90) was found to have a good antioxidant effect (see FIG. 4).

Example 40 Measurement of Intracellular Antioxidant Activity of Organic Germanium Compounds of the Invention

Intracellular antioxidant activity of the organic germanium compound of the present invention was evaluated using DCF da (2 ', 7'-dichlorofluorescein diacetate). In this example, the antioxidant effects in the cells were measured, centering on the compounds substituted with a methyl group in germanium among the compounds of the present invention. DCF da can penetrate cells and does not have fluorescence on its own but fluoresces through oxidation. Differentiated HaCaT cells were cultured in 24 well plates at a concentration of 4.0 × 10 ⁴ cells / well for 24 hours. Compounds synthesized according to the Example were dissolved in a medium, treated in a 24-well plate to a final 5 mM, and then incubated at 37 ° C. for 3 hours. 50 μM DCF da was dissolved in HBSS solution and treated on each plate for 20 minutes. Fluorescence before and after UVB 20mJ treatment and 2 hours after UVB treatment was measured at an excitation wavelength of 485 nm and an emission wavelength of 535 nm to determine how much of the compound of the present invention reduces the amount of free radicals generated by treating UVB.

Intracellular antioxidant activity measurement results are shown in FIG. As a result of the measurement of antioxidant activity, the compound of the present invention showed better antioxidant activity than the control group, and especially, a germanium compound in which L-ascorbic acid protected with phosphoric acid and silane was bonded to carbon number 2, which was determined to have no antioxidant effect in solution. Antioxidant effect was also seen in the compound substituted with germanium for carbon 2 of L-ascorbic acid (see FIG. 5). In addition, the compound 86 was confirmed that the antioxidant effect is significantly higher than the vitamin C as well as the control.

Example 41 Evaluation of Stability of Organic Germanium Compounds of the Invention

The stability of the organic germanium compound of the present invention was evaluated as follows. Compounds synthesized according to the Examples were dissolved in 1 mL of tertiary distilled water to 10 μM, respectively, and stored at 25 ° C. and 50 ° C., respectively, to measure the change in absorbance at 254 nm to evaluate the stability of the material. The stability measurement results are shown in Table 2 below.

Table 2 Results of Stability Evaluation of Organic Germanium Compounds

As can be seen from the results shown in Table 2, the compound of the present invention showed superior stability compared to L-ascorbic acid.

Example 42 Determination of Anti-inflammatory Activity of Organic Germanium Compounds of the Invention

The anti-inflammatory activity of the organic germanium compound of the present invention was evaluated by the following method. According to the method reported in J. Invest. Dermatol. (2008) 128, 79 ?? 86), the anti-inflammatory effects of the compounds were measured using mice induced with oxazolone (Oxazolone) inflammation. After treatment with 10% oxazolone (mouse) of the depilated female mouse (mouse), 0.4% oxazolone was treated at the same site daily for 10 days to induce inflammation. Thereafter, 1% of the compounds of the present invention (Compound 1, Compound 76, Compound 86, and Compound 91) were treated twice a day in the affected area for 7 days and then the change of the affected area was measured. In addition to the visual measurement, the measurement of moisture reduction (TEWL) using a vapormeter, a measurement method reported in the literature, and the measurement of skin thickness using a caliper were performed. The measurement results are shown in Table 3 below.

   TABLE 3 Anti-inflammatory activity measurement results of organic germanium compounds

As can be seen from the results of Table 3, the result of the anti-inflammatory animal experiments induced by oxazolone showed that Compound 86 was similar to the control hydrocortisone (hydrocortisone) showing commercially effective atopic treatment.

As described above in detail certain parts of the present invention, it is apparent to those skilled in the art that these specific descriptions are merely preferred embodiments, and the scope of the present invention is not limited thereto. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

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1 is a chemical structural formula of a conventional organic germanium Ge-132 compound.

2A and 2B are structural formulas of various organic germanium compounds conventionally synthesized.

Figure 3 shows the results of measuring IFN-γ induction in mice treated with Ge-132 and Ge-OH

All. Ge-132 (-◆-) and Ge-OH (-■-) were administered orally at 12 mg intervals at a dose of 100 mg per kg of mouse. IFN-γ was induced by both Ge-132 and Ge-OH.

Figure 4 is the result of measuring the antioxidant activity in the solution of the compound of the present invention using the DPPH assay.

5 is a result of measuring the intracellular antioxidant activity of the compound of the present invention using the DCF da assay.

Claims (15)

delete delete delete delete delete The organic germanium compound or salt thereof of any of the following compounds: N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (trimethyl Germanyl) propanamide; N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Ethylgeryl) propanamide; N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Vinylgeryl) propanamide; N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Phenylgeryl) propanamide; N-((S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl) -3- (tri Benzylgeryl) propanamide; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propaneamido) ethyl) -2-oxo-2,5-dihydrofuran 3-yl methyl hydrogen phosphate; N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (trimethylgeryl) propanamide; N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (triethylgeryl) propanamide; N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (trivinylgeryl) propanamide; N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (triphenylgeryl) propanamide; N-((S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydrate Oxyethyl) -3- (tribenzylgeryl) propanamide; N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (trimethylgeryl) propanamide; N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (triethylgeryl) propanamide; N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (trivinylgeryl) propanamide; N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (triphenylgeryl) propanamide; N-((S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy -6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl) -3- (tribenzylgeryl) propanamide; (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) furan-2 (5H) -one; (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) furan-2 (5H) -one; (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) furan-2 (5H) -one; (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) furan-2 (5H) -one; (R) -3,4-dihydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) furan-2 (5H) -one; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran-3 -Yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl dihydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran-3 -Methyl methyl phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) -2-oxo-2,5-dihydrofuran- 3-yl methyl hydrogen phosphate; (R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) furan-2 (5H) -one; (R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) furan- 2 (5H) -one; (R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) furan- 2 (5H) -one; (R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) furan- 2 (5H) -one; (R) -3- (tert-butyldimethylsilyloxy) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) furan- 2 (5H) -one; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trimethylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R)- 3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triethylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (trivinylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (triphenylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one; (R) -4-hydroxy-5-((S) -1-hydroxy-2- (3- (tribenzylgeryl) propylamino) ethyl) -3-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) furan-2 (5H) -one; (S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (trimethylgeryl) propano Eight; (S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (triethylgeryl) prop Phanoate; (S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (trivinylgeryl) prop Phanoate; (S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (triphenylgeryl) prop Phanoate; (S) -2-((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3- (tribenzylgeryl) prop Phanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (trimethyl Germanyl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Ethylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Vinylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Phenylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4- (phosphonooxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tri Benzylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (trimethylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (triethylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (trivinylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (triphenylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-4- (hydroxy (methoxy) phosphoryloxy) -5-oxo-2,5-dihydrofuran-2-yl ) Ethyl 3- (tribenzylgeryl) propanoate; (S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Trimethylgeryl) propanoate; (S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Triethylgeryl) propanoate; (S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Trivinylgeryl) propanoate; (S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Triphenylgeryl) propanoate; (S) -2-((R) -4- (tert-butyldimethylsilyloxy) -3-hydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 3 -(Tribenzylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (trimethylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (triethylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (trivinylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (triphenylgeryl) propanoate; (S) -2-hydroxy-2-((R) -3-hydroxy-5-oxo-4-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (Hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) -2,5-dihydrofuran-2-yl) ethyl 3- (tribenzylgeryl) propanoate; N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (trimethylgeryl) propanamide; N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (triethylgeryl) propanamide; N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (trivinylgeryl) propanamide; N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (triphenylgeryl) propanamide; N-((1s, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclohexyl) -3- (tribenzylgeryl) propanamide; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trimethylgeryl) propoxy) furan-2 (5H) -one; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triethylgeryl) propoxy) furan-2 (5H) -one; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (trivinylgeryl) propoxy) furan-2 (5H) -one; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (triphenylgeryl) propoxy) furan-2 (5H) -one; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-3- (3- (tribenzylgeryl) propoxy) furan-2 (5H) -one; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (trimethylgeryl) propano Eight; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (triethylgeryl) prop Phanoate; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (trivinylgeryl) pro Phanoate; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (triphenylgeryl) prop Phanoate; (R) -5-((R) -1,2-dihydroxyethyl) -4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl 3- (tribenzylgeryl) pro Phanoate; 6-((3- (trimethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol; 6-((3- (triethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol; 6-((3- (trivinylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol; 6-((3- (triphenylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol; 6-((3- (tribenzylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetraol. A pharmaceutical composition for use in the treatment or prophylaxis or immunopotentiation of cancer or inflammatory disease comprising the organic germanium compound of claim 6 or a salt thereof as an active ingredient. According to claim 7, wherein the cancer is cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer Or ureter cancer. 8. The composition of claim 7, wherein the inflammatory disease is hepatitis, atopic dermatitis or psoriasis. Cosmetic composition for use in improving the skin condition comprising the organic germanium compound of claim 6 or a salt thereof as an active ingredient. The composition of claim 10, wherein the improvement of the skin condition is improvement of atopic dermatitis, improvement of psoriasis, improvement of blotch, improvement of skin wrinkles, improvement of skin elasticity, or whitening. A functional food composition for use in the treatment or prophylaxis of cancer or inflammatory diseases, immune enhancement or skin condition improvement comprising the organic germanium compound of claim 6 or a salt thereof as an active ingredient. The method of claim 12, wherein the cancer is gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer. Or ureter cancer. The composition of claim 12, wherein the inflammatory disease is hepatitis, atopic dermatitis or psoriasis. The composition of claim 12, wherein the improvement of the skin condition is an improvement of a blotch, an improvement of skin wrinkles, an improvement of skin elasticity, or a whitening.

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