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WO2011016674A2 - Nouveaux composés organiques de germanium - Google Patents

Nouveaux composés organiques de germanium Download PDF

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Publication number
WO2011016674A2
WO2011016674A2 PCT/KR2010/005114 KR2010005114W WO2011016674A2 WO 2011016674 A2 WO2011016674 A2 WO 2011016674A2 KR 2010005114 W KR2010005114 W KR 2010005114W WO 2011016674 A2 WO2011016674 A2 WO 2011016674A2
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hydroxy
oxo
dihydrofuran
ethyl
cancer
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WO2011016674A3 (fr
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함승욱
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Industry Academic Cooperation Foundation of Chung Ang University
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Industry Academic Cooperation Foundation of Chung Ang University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/30—Germanium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • the present invention relates to novel organic germanium compounds.
  • Germanium Germanium, atomic number 32; atomic weight 72.59; melting point 937.4 ° C; boiling point 2830 ° C
  • Germanium is present in various forms of organic and inorganic substances in stones, rocks, 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 on the basis of 0.6-1.3 mg Ge / kg in soil and 0.004-0.6 mg Ge / L in water (2, 3).
  • Germanium compounds are largely classified into inorganic germanium compounds and organic germanium compounds. Generally, salts or oxides that lack germanium-carbon bonds are classified as inorganic germanium. Representative inorganic germanium, Ge02 (germanium dioxide) or germanium citrate lactate, has nephrotoxicity, causing acute renal failure and death (9–12). Toxicity of inorganic germanium is believed to be due to the accumulation of germanium in biological tissues (2, 13).
  • Organic germanium on the other hand, has a germanium-carbon bond, which is stable because the germanium is a group 14, such as carbon, and maintains a stable bond and does not easily break in vivo. Almost no (3, 9).
  • Ge-132 increases potentiated CD4 and CD8 cell function and NK cell activity, and induces the production of cytokines such as interferon interleukin-2.
  • cytokines such as interferon interleukin-2.
  • Ge-132 activates macrophages and T cells, particularly cytotoxic T cells and NK cells, and antibody-dependent cellular cytotoxicity (ADCC) by induction of interferon gamma and peripheral mononuclear cells.
  • ADCC antibody-dependent cellular cytotoxicity
  • Ge-132 has high solubility in water due to its high molecular properties and does not completely remove the inorganic germanium Ge02 used as a semi-aquatic product in the purification process after synthesis. Problems have been reported (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.
  • L-ascorbic acid which has a strong antioxidant activity, has been of interest 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 / black mushrooms, and to strengthen the immune system. That is, L-ascorbic acid has a strong UV protection against ultraviolet light, especially UV A and UV B (Darr D.
  • L-ascorbic acid promotes the synthesis of collagen, thereby improving skin gloss, improving skin color, reducing wrinkles, increasing elasticity, and inhibiting tyrosinase activity and melanin formation, which are important for melanin formation. Effect (US Pat. No. 4,983,382; Tomita, Y. et al., 1980, J. Invset. Dermatol-75 (5); 379-382).
  • L-ascorbic acid enhances the immune system (Nakamura, T. et al., 1997, J. Invest-Dermatol. 109: 2 24), aids phagocytosis of leukocytes, and leukocytes during infection.
  • ascorbic acid is poor in stability over time, and has high water solubility but low solubility in lipids, so that the amount of ascorbic acid that accumulates in the cells through the cell membrane of the skin is somewhat limited, resulting in satisfactory physiological activity by ascorbic acid. It wasn't.
  • 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.
  • a novel organic germanium compound was synthesized by combining a functional group having high water solubility to germanium, and the new organic germanium compound exhibited an excellent interferon-gamma secretion inducing effect and antioxidant activity, resulting in anticancer and anti-cancer activity.
  • the present invention was completed by experimentally confirming that it can be usefully used for the purpose of inflammation, immune enhancement, and skin condition improvement.
  • 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 present invention provides an organic germanium compound represented by the following formula (1) or a salt thereof.
  • Ri, R 2 and 3 ⁇ 4 are the same as or different from each other, each independently a linear or branched alkyl group of dC 6 , a straight or branched alkenyl group of C 2 -C 6 , C 2 — C 6 Aryl group substituted with a straight or branched alkynyl group, aryl group, straight or branched chain alkyl group of CrC 6 , aryl group substituted with a straight or branched chain alkenyl group of C 2 -C 6 , c 2 -c an aryl group substituted with an alkynyl group of 6 straight-chain or branched-chain, and;
  • m is an integer from 0 to 10;
  • X is CO or CH 2 ;
  • Ge is germanium
  • linear or branched alkyl of CH ⁇ means a straight or branched chain saturated hydrocarbon of 1 to 6 carbon atoms, e.g. methyl, ethyl, ⁇ -Propyl, isopropyl, isobutyl, ⁇ -butyl and t-butyl.
  • 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-nuxenyl.
  • C 2 -C 6 straight or branched alkynyl group means 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.
  • the functional group of 3 ⁇ 4 of Formula 1 serves to increase the water solubility of the organic germanium compound of the present invention.
  • the germanium L-ascorbic acid compound when 3 ⁇ 4 is L-ascorbic acid or a derivative thereof has an increased water solubility and a synergistic improvement in antioxidant activity.
  • the monosaccharide of R4 in the formula (1) is glucose (glucose), fructose (fructose), galactose (ganactose), mannose (mannose), xylose ( xylose) or ribose, most preferably glucose.
  • the alcohol of R4 in the general formula (1) is inositol.
  • the L- ascorbic acid derivative in which the hydroxyl group at the carbon position of the furan ring of the L-ascorbic acid of R4 in the formula (1) is protected is represented by the following Chemical Formulas 2a to 2d It is any one of the compound, More preferably, it is a compound of following formula (2a) or (2b).
  • R dC 6 is alkyl.
  • the formula (1) is a glucose, inosyl, L- ascorbic acid, L- ascorbic acid derivative of the formula 2a or 2b, or an amine derivative compound represented by the following formula to be.
  • 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, bromide, iodide, nitrates, sulfates, bisulfates, phosphates, acids Phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sacrate, banjoate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • Pharmaceutically acceptable salts containing silver such as salts of nates, P-luluenesulfonates and pamoates [ie, 1, ⁇ -methylene-bis- (2-hydroxy-3-naphthoate)] It may include forming, but 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 alkanes to ammonium and other pharmaceuticals.
  • alkali metal cations eg, potassium and Sodium
  • alkaline earth metal cations such as calcium and magnesium
  • ammonium or water-soluble amine addition salts such as N-methylglucamine— (meglumine)
  • lower alkanes to ammonium and other pharmaceuticals such as basic salts of organic amines But not limited to those derived from pharmaceutically acceptable cations.
  • the present invention provides a pharmaceutical composition for use in 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 present invention provides a cancer comprising administering a pharmaceutical composition comprising an organic germanium compound of formula 1 or a salt thereof as an active ingredient to a patient in need of treatment of cancer or inflammatory disease Or a method for treating an inflammatory disease.
  • the present invention provides a method for enhancing immunity comprising the step of administering a pharmaceutical composition comprising an organic germanium compound of Formula 1 or a salt thereof as an active ingredient to a patient in need of immuno-enhancement to provide.
  • the present invention comprises the step of administering a cosmetic composition comprising an organic germanium compound of formula 1 or a salt thereof as an active ingredient to a subject in need of skin condition improvement Provides a method for improving skin condition.
  • the present invention provides the use of the organic germanium compound of formula 1 or salts thereof for the treatment or prevention of cancer or inflammatory disease.
  • the present invention provides the use of an organic germanium compound of formula 1 or a salt thereof for the manufacture of a medicament for the treatment or prevention of cancer or inflammatory diseases.
  • the present invention provides the use of the organic germanium compound of Formula 1 or a salt thereof for immunostimulation.
  • the present invention provides the use of an organic germanium compound of formula (1) or a salt thereof for the manufacture of an medicament for immunopotentiation.
  • the present invention provides the use of an organic germanium compound of formula (1) or a salt thereof for the manufacture of a medicament or cosmetic for improving the skin condition.
  • the organic germanium compound of the present invention has increased water solubility and significantly increases the secretion of interferon-gamma in vivo and exhibits antioxidant activity, thereby improving anti-cancer, anti-inflammatory, immune enhancing, and skin condition improvement. This can be useful for.
  • the 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.
  • the inflammatory disease to which the compound of the present invention can be applied is hepatitis, atopic dermatitis or psoriasis.
  • 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 composition of the present invention are commonly used in the preparation, lactose, textose, sucrose, sorbbi, manny, starch, acacia rubber, calcium phosphate, alginate, Gelatin, silicate, microcrystalline cellulose, polyvinylpyridone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil And the like, but are not limited thereto.
  • 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.
  • a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, a kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mann
  • Suitable dosages of the pharmaceutical compositions of the present invention vary depending on factors such as formulation method, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response sensitivity of the patient. Can be prescribed.
  • the oral dosage 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 injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
  • the route of administration of the pharmaceutical composition of the present invention is determined according to the type of the disease to be applied.
  • 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 period of time, etc., and is not limited to a specific range of concentration.
  • compositions of the present invention may be formulated 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. It can be made or prepared by incorporating into a multi-dose container.
  • the formulations may be in the form of solutions, suspensions or emulsions in oil or aqueous media, or may be in the form of solutions, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.
  • 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.
  • the improvement of the skin condition is the improvement of atopic dermatitis, the improvement of psoriasis, the improvement of blotch, 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, and by this antioxidant activity, wrinkle improvement of skin, improvement of elasticity, It has an improvement and whitening effect.
  • the skin condition improvement effect by the compound of the present invention can be explained by the sunscreen efficacy, collagen production promoting effect and the melanin formation inhibitory effect which is inherent in L- ascorbic acid.
  • Cosmetic compositions of the present invention may be prepared in any formulation commonly prepared in the art, for example, solutions, suspensions, emulsions, liquids Yeast, gels, creams, lotions, powders, soaps, surfactant-containing cleansing, oils, powder foundations, emulsion foundations, wax foundations, sprays, and the like, but is not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.
  • the carrier component is animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide. This can be used.
  • lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular, in the case of a spray, additionally fluorofluorohydrocarbon, Propellant such as propane / butane or dimethyl ether.
  • a solvent, a solubilizing agent or an emulsifying agent is used as the carrier component, such as water, ethanol, isopropane, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl.
  • the carrier component such as water, ethanol, isopropane, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl.
  • suspensions such as water, liquid diluents such as ethanol or propylene glycol, ethoxylated isostearyl alcohols, polyoxyethylene sorbide esters and polyoxyethylene sorbitan esters
  • microcrystalline cellulose, aluminum metahydroxy, bentonite, aga or tracant and the like can be used.
  • the carrier component may be aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, Fatty acid esters may be used for fatty acid amide ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol.
  • ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions, for example, such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings Adjuvants may be included.
  • 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.
  • the present invention provides a functional food composition for the treatment or prevention of cancer or inflammatory diseases, immune enhancement or skin condition improvement comprising the organic germanium compound of formula 1 as an active ingredient do.
  • 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.
  • the inflammatory disease is hepatitis, atopic dermatitis or psoriasis.
  • the improvement of the skin condition is the improvement of blemishes, the improvement of skin wrinkles, the improvement of skin elasticity, or the whitening.
  • Functional food compositions of the present invention include ingredients that are commonly added in the manufacture of food, and include, for example, proteins, carbohydrates, fats, nutrients and seasonings.
  • natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); Disaccharides (eg maltose, sucrose and the like); Fructose; Polysaccharides (eg, dextrins, cyclodextrins, etc.); And sugar alcohols (e.g., Xili, Sorbi, Eritri, etc.).
  • flavoring agent natural flavoring agents (e.g., taumartin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.
  • natural flavoring agents e.g., taumartin, stevia extract, etc.
  • synthetic flavoring agents e.g., saccharin, aspartame, etc.
  • the efficacy and advantages of the novel organic germanium compound synthesized in the present invention are summarized as follows. i) significantly increasing the induction of interferon-gamma; ii) has a strong antioxidant effect.
  • the compound of L-ascorbic acid bound to germanium of the present invention is iii) because the ascorbic acid has a very high water solubility, the water solubility of the germanium-ascorbic acid compound is increased to increase the absorption in vivo, iv) into the body Easily excreted, reducing toxicity in vivo, V) synergistic antioxidant activity of germanium and L-ascorbic acid, vi) increased stability of L-ascorbic acid, vii) L-ascorbic acid Its own efficacy can be obtained, such as the effect of blocking the sun, promoting the collagen production and improving the skin condition through the inhibition of melanin formation, and immune enhancing effect.
  • the organic germanium compound of the present invention is effective in anti-cancer, anti-virus, anti-inflamation, immuno-enhancing use as well as potent antioxidant activity by interferon-gamma secretion inducing efficacy. It can be used to improve skin condition.
  • the novel organic germanium compound of the present invention has a high solubility in water due to the introduction of a functional group having water-soluble properties, thereby improving the intracellular absorption rate, 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.
  • L-ascorbic acid-bonded compounds having both high water solubility and strong antioxidant activity have increased intracellular uptake and exhibit excellent antioxidant activity in cells, and L-ascorbate.
  • the effects of acid on the skin such as immune function enhancement effect, sunscreen effect, collagen production promotion and melanin formation inhibition effect can be obtained.
  • FIG. 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- ⁇ induction in mice treated with Ge-132 and Ge-OH.
  • Ge-132 (- ⁇ -) and Ge-OH (- ⁇ -) were administered orally at 12 hour intervals at a dose of lOOmg per kg of mouse.
  • IFN- ⁇ was induced by both Ge-132 and Ge_0H.
  • Figures 4a to 4c is the result of the measurement of antioxidant activeol in solution of the compound of the present invention using the DPPH assay.
  • Zinc chloride solution (22,7 g, 166.5 ⁇ l) in H0Ac-Ac20 (1: 5 volume ratio, 85 ml) was added to benzyl 2 3 in H0Ac-Ac20 (1: 5 volume ratio, 126 ml).
  • 4, 6-tetra-0-benzyl- ⁇ -D-glucopyrannoside (21 g, 33.3 mmol) solution was added via dropping funnel at 0 ° C. After stirring for 2 hours at room temperature, 500 ml of ice-water were added. The resulting white precipitate was filtered, washed with excess water and recrystallized from nucleic acid (hexane) to give the desired acetate (10 g, 53%).
  • 3- (triethylgeryl) propionic acid was prepared according to the following scheme.
  • the prepared 3— (triethylgeryl) propionic acid was used instead of 3- (trimethylgeryl) propionic acid.
  • [6 _ ((3- (triethylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2,3,4,5-tetra (Compound 92)] was prepared.
  • Example 2 is phenylmagnesium bromide (Aldrich-Sigma), by the same method as in Example 2 [6-((3- (triphenyl Germanyl) propoxy) methyl) -tetrahydro-2H-pyran-2, 3, 4, 5-tetraol (Compound 94)].
  • Example 5 Synthesis of [6-((3- (tribenzylgeryl) propoxy) methyl) -tetrahydro-2H-pyran-2, 3,4, 5-tetraol (Compound 95)]
  • Example 6 [6 — ((3- (trivanzylgeryl) propoxy) methyl) -tetra by the same method as Example 2, except that RMgBr in Example 2 is benzyl magnesium bromide (Aldrich-Sigma) Hydro-2H-pyran-2,3,4,5-tetra (compound 95)] was prepared.
  • Example 8 [N-((ls, 2R, 3S, 4r, 5R, 6S) -2,3,4,5,6-pentahydroxycyclonucleus) -3- (trivinylgeryl) propanamide (Compound 78)]
  • HBr (6.18 mL, 34.07 ⁇ l, 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.
  • the starting material ascorbic acid derivative (8.32 g, 34.8 mo 1) 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. 5 minutes later, sodium azide (NaN3) (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 1 hour. After vigorously stirring, the cation exchange resin was washed down with twice the volume of distilled water of the ion exchange resin.
  • the starting germanium derivative (0.57 g, 1.08 ⁇ l) was dissolved in anhydrous methanol (20 mL) and Pd (0H) 2 (0.06 g) was added at room temperature and stirred for 4 h under H2. Pd (0H) 2 was filtered from the reaction mixture, washed several times with methane, and concentrated to remove all solvents. This crude residue was recrystallized from ethyl acetate / nucleic acid (ethylacetate / hexane) to give the desired compound as a white solid (0.53 g, 85.4%).
  • triphenylgeryl propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction product of Example 2, and 3- (triphenylgeryl) propionic acid prepared was 3- 2,5-dioxopyrrolidinyl 1-yl-by the same method as described in item 6-1 of Example 6, except that (trimethylgeryl) propionate was used as a reaction material. 3- (triphenylgeryl) propanoate was prepared.
  • tribenzylgeryl propionic acid was prepared using benzyl magnesium bromide (Aldrich-Sigma) as the Grignard reaction product of Example 2, and 3- (tribenzylgeryl) propionic acid was prepared. 2,5-dioxopyrrolidin-1-hexyl-3- (3) by the same method as the preparation method described in item 6-1 of Example 6, except that it was used as a reaction material instead of germanyl) propionic acid. Tribenzylgeryl) propanoate was prepared.
  • Ascorbic acid 1.5 g, 8.5 mmol was added to a solution of (trimethylgermylpropanoic acid) (3 g, 11.90 mmol), stirred for 2 days, and poured into about 100 g of ice. After adding and stirring 200 mL of ethyl acetate, the ethyl acetate layer was separated and washed with saturated brine solution (X 5). After drying under anhydrous magnesium sulfate and concentration under reduced pressure, the desired compound was obtained (1.446 g, 49%).
  • Ascorbic amine derivative (0.50 g, 2.9 ⁇ ol) ol made of (Chemiker-Zeitung 1985, 109, 19 g 202.) was dissolved in dry DMF (15 mL), and 5% Pd / C (0.03 g) was added to the mixture. ) was added and stirred at room temperature under H2 for 4 hours 30 minutes. The reaction mixture was filtered and 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%).
  • 3- (triethylgeryl) propionic acid was prepared using EtMgBr (Aldrich-Sigma) as the Grignard reaction product in the Grignard reaction product described in Example 2.
  • EtMgBr Aldrich-Sigma
  • 3- (triethylgeryl) propionic acid thus prepared as a reaction material by the same method as the preparation method described in item 1-2 of Example 1 3— (Triethylgeryl) -1-propane was prepared.
  • 3- (trivinylgermyl) propionic acid was prepared using vinylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction product in the Grignard reaction system of Example 2.
  • 3- (trivinylgeryl) propionic acid thus prepared as a reaction material
  • 3- (trivinylgeryl) -1-propanol was prepared by the same method as described in item 1-2 of Example 1 above. Prepared. The same method as the preparation method described in Example 21, except that the thus prepared 3- (trivinylgeryl) -1-propanol was used in place of 3- (trimethylgeryl) propan-1-ol.
  • 3- (triphenylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction product in the Grignard reaction product of Example 2.
  • 3- (triphenylgeryl) -1-propanol by the same method as described in item 1-2 of Example 1 using 3- (triphenylgeryl) propionic acid as a reactant was prepared.
  • 3- (tribenzylgeryl) propionol was prepared using benzyl magnesium bromide ⁇ ( ⁇ -3) as the Grignard reaction product in the Grignard reaction system of Example 2.
  • 3- (tribenzylgeryl) -1—propane was prepared by the same method as described in item 1-2 of Example 1 using 3- (tribenzylgeryl) propionic acid as a reaction material.
  • 3- (tribenzylgeryl) -1-propane thus prepared in place of 3- (trimethylgeryl) propan-1-ol.
  • Example 26 [(10—3,4-dihydroxy— 5-((S) -l—hydroxy-2— (3- (tribenzyl) by the same method as the preparation method described in Example 21 except for the use Germanyl) 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) -one (compound 81)]
  • Ascorbic acid derivative (3.20 g, 10 ⁇ l) synthesized according to what is known from J. Med. Chem. 1988, 31, 793-798 was dissolved in acetone solvent (100 mL) and then potassium carbonate (K 2 C0 3 ) (2g, 14.7 ⁇ ol) was added and stirred at room temperature for 30 minutes.
  • K 2 C0 3 potassium carbonate
  • Bromogermanium compound (2.50g, 10.7 ⁇ ol) was added to the reaction mixture, followed by reaction at room temperature for 24 hours, and then treated with 100 mL water. After extraction of the product with dichloromethane, the combined organic solvents were dried over anhydrous MgSO 4 and concentrated under reduced pressure.
  • 3- (triethylgeryl) propionic acid was prepared using EtMgBr ldrich—Sigma) as a Grignard reaction product in the Grignard reaction product described in Example 2.
  • 1-bromo-3- (triethylger) was prepared by the same method as the preparation method described in items 1 ′ 2 and 1-3 of Example 1, using 3- (triethylgeryl) propionic acid as a starting material.
  • Example 28 [(R) -5-((R) -l, 2-dihydroxyethyl) -4-hydroxy-3- (3- (trivinylgeryl) propoxy) furan-2 (5H ) -One (compound 83)]
  • 3- (trivinylgeryl) propinic acid was prepared using vinylmagnesium bromide (Aldrich—Sigma) as the Grignard reaction in the Grignard reaction of Example 2.
  • vinylmagnesium bromide Aldrich—Sigma
  • the prepared 3- (trivinylgeryl) propionic acid was used as a starting material 1 1bromo-3- (tree by the same method as described in the items 1-2 and 1-3 of Example 1 Vinylgeryl) propanol, and by using the same method as described in Example 26 except that 1-bromo-3 (trivinylgeryl) propane thus prepared was used as a germanium derivative.
  • triphenylgeryl propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) ol as the Grignard reaction product of Example 2 in the Grignard reaction product.
  • 1-Bromo-3- (tri) was prepared by the same method as described in item 1-2 and 1 to 3 of Example 1, using 3- (triphenylgeryl) propionic acid as a starting material.
  • Phenylgermyl) 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.
  • 3- (tribenzylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction product in the Grignard reaction product of Example 2.
  • phenylmagnesium bromide Aldrich-Sigma
  • the prepared 3- (tribenzylgeryl) propionic acid as a starting material 1—bromo-3- (tree) by the same method as described in items 1-2 and 1-3 of Example 1 above.
  • Benzylgeryl) propane, and 1-bro [(R) -5-((R) -l, 2ndyhydride) by the same method as the preparation method described in Example 26, except that Mo-3- (tribenzylgeryl) propane was used as the germanium derivative.
  • 3_ (triethylgeryl) propionic acid was prepared using EtMgBr (Aldrich-Sigma) as the Grignard reaction product. Except for using the prepared 3- (triethylgeryl) propionic acid as a reactant in place of 3- (trimethylgeryl) propionic acid in the same method as the preparation method described in item 6-1 of Example 6 2,5-dioxopyrrolidine- 1-yl- (triethylgeryl) propanoate, and 2,5-dioxopyridinyl 1-yl-3- (tri [(R) ⁇ 5- (00-1, 2-dihydroxyethyl) by the same method as the preparation method described in Example 31, except that ethylgeryl) propanoate was used as the germanium derivative.
  • 3- (triphenylgeryl) propionic acid was prepared using phenylmagnesium bromide (Aldrich-Sigma) as the Grignard reaction product in the Grignard reaction product of Example 2. Except for using the prepared 3- (triphenylgeryl) propionic acid as a semi-aungmul in place of 3— (trimethylgeryl) propionic acid in the same manner as in the preparation method described in item 6-1 of Example 6 2,5-dioxopyridin-l-yl-3- (triphenylgeryl) propanoate was prepared, and 2,5-dioxopyridine-l-yl-3- (tri [0 -5 '((R) -l, 2-dihydroxythoxyethyl)-by the same method as Preparation 3 ⁇ 4 described in Example 31, except that phenylgeryl) propanoate was used as the germanium derivative.
  • mice Seven-week-old ICR mice (Japan SIX, Inc. Inasa Production Facility) were used for experiments after stabilization for one week in a clean animal laboratory at Jeungang University School of Medicine. Female mice of 8-9 weeks old were used for the experiment, and all experiments were conducted in the clean animal laboratory. Clean animal laboratories were maintained at a temperature of 23 ⁇ 1 ° C and a humidity of 40-60% and continued to be ventilated with fresh air (14 times 18 times / hr).
  • the solution of the organic germanium compound dissolved in PBS was orally administered to mice at 100 mg / kg per mouse weight.
  • Methods for collecting blood from mice include collection from the tail vain, collection from the orbital blood vessels, and collection through cardiac puncture, but blood collection through cardiac puncture The method was chosen. In other methods, there was a limitation in drawing a large amount of blood from the mouse, so the whole blood of the mouse was drawn through cardiac puncture.
  • Blood samples obtained from the mice are coagulated to obtain serum.
  • Interferon-gamma analysis Interferon-gamma (IFN- ⁇ ) analysis was performed using the Quantikine kit (Mouse IFN- ⁇ assay) from R & D systems, and the analysis was performed according to the instructions in the product. Inject 50 ml of Assay Diluent RDl-21 (R & D systems, Quantikine, Mouse IFN- ⁇ ) in the middle of each we ll of the plate frame. Collected serum samples were placed in each well 50 ⁇ . Plate frame was mixed for 1 minute while tapping. The plate frame was covered with an adhesive strip provided with the kit, and then incubated for 2 hours at room temperature. After the solution of each well was completely removed and washed with wash buffer, this process was repeated four more times.
  • IFN- ⁇ Interferon-gamma
  • the organic germanium compound [6-((3- (trimethylgeryl) propoxy) methyl) —tetrahydro-2H-pyran-2, 3,4,5—Tetra (Compound 91, Ge- ⁇ )] measured the induction of IFN IF ⁇ from the serum of mice and compared it with the results of Ge-132 treatment.
  • IFN- ⁇ increased from 12 h to 24 h and 326.1 pg / ml at 24 h.
  • mice administered orally with Ge- ⁇ the induction of IFN- ⁇ at 324.6 pg / ml after 24 hours was similar to that of Ge-132.
  • 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 absorbance decreased at 517 nm.
  • Synthesized compounds were dissolved in ethane to a concentration of 5ppm, lOOuL was taken and mixed with DPPH solution (900yL) and incubated at 37 ° C for 30 minutes and the absorbance was measured at 517 nm.
  • Intracellular antioxidant activity of the organic germanium compound of the present invention was evaluated using DCF da (2 ', 7'-dichlorof luorescein diacetate).
  • DCF da can penetrate cells and does not have fluorescence by itself, but fluoresces through oxidation reaction.
  • Differentiated HaCaT cells were aliquoted into 24 well plates at a concentration of 4.0 ⁇ 10 4 cells / well and incubated for 24 hours.
  • Example 42 Determination of Anti-Inflammatory Activity of the Organic Germanium Compounds of the Present Invention
  • the anti-inflammatory activity of the organic germanium compounds of the present invention was evaluated by the following method. Document U. Invest. Dermatol. (2008) 128, 79—86), using a method induced by oxazolone-induced inflammation in rats Anti-inflammatory effect was measured. After 10% oxazolone was treated to the depressed female mouse area, 0.4% oxazolone was treated on the same site daily for 10 days to induce inflammation.
  • Sesqui oxide I. Chemistry and Anticancer Properties. Journal of alternative and complementary medicine (New York, N.Y.) (2004), 10 (2): 337-44.
  • Sublet Y. Subchronic oral toxicity (six months) of carboxyethylgermanium sesquioxide in rats. Applied Organometal lie Chemistry (1992), 6 (3): 267-272.
  • Suzuki, F. Suppression of tumor growth by peritoneal macrophages isolated from mice treated with carboxyethylgermanium sesquioxide (Ge-132). Japanese journal of cancer and chemotherapy

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Abstract

La présente invention concerne des composés organiques de germanium représentés par la formule (I), ou des sels de ces composés. [Formule I] Dans cette formule, R1, R2 et R3 sont identiques ou différents et sont indépendamment un groupe alcényle en C2-C6 linéaire ou ramifié, un groupe aryle, un groupe aryle substitué par un groupe alcényle en C2-C6 linéaire ou ramifié, ou un groupe aryle substitué par un groupe alkynyle en C2-C6 linéaire ou ramifié; R4 est un monosaccharide, un alcool, un acide L-ascorbique, des dérivés d’acide L-ascorbique ayant un groupe hydroxyle protégé au niveau de l’atome de carbone en position 2 dans un noyau de furane d’acide L-ascorbique, ou un dérivé d’amine de celui-ci; m est un entier compris entre 0 et 10; X est CO ou CH2 : et GE est germanium. Les nouveaux composés organiques de germanium de l’invention marquent un progrès remarquable en termes d’hydrosolubilité, ce qui facilite leur absorption in vivo, ne présentent pas d’accumulation dans les tissus, donc pas de toxicité pour le corps, et présentent suffisamment les effets du germanium. De plus, un composé combiné avec de l’acide L-ascorbique présente une forte activité anti-oxydante.
PCT/KR2010/005114 2009-08-05 2010-08-04 Nouveaux composés organiques de germanium Ceased WO2011016674A2 (fr)

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