Isoflavone derivatives

a technology of isoflavones and derivatives, which is applied in the field of isoflavones, can solve the problems of difficult formulation of foodstuffs, low solubility of isoflavones, and insoluble water insoluble nature of isoflavones, and achieves the effect of increasing the bioavailability of isoflavones and being easy to hydrolyzed

Inactive Publication Date: 2006-11-09
VYREXIP HLDG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0011] Methods and compositions of the present invention provide increased bioavailability of isoflavones by converting a starting isoflavone into a pro-compound. This is preferably accomplished by attaching a polar (solubilizing) leaving group which can be readily hydrolyzed under physiologic conditions to produce the starting isoflavone.

Problems solved by technology

Unfortunately genistein and other isoflavones are very insoluble in water.
The insolubility of the isoflavones complicates their formulation into foodstuffs and cosmetics, many of which are aqueous-based systems.
Low solubility is also frequently an impediment to efficient bioavailability in orally administered products.
Low solubility is a particularly serious impediment to formulation of intravenous medications, which are most often delivered in aqueous media.

Method used

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Examples

Experimental program
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Effect test

example 1

Mixed Phosphate Esters of Genistein

[0028] A solution of genistein (135 mg, 0.5 mmole) and di-tert-butyl phosphoramidite (330 ul, 1.0 mmole) in DMF (1 ml) was stirred under argon while 1H-tetrazole (210 mg in 0.5 ml of DMF; 3.0 mmole) was added dropwise. After a few minutes, the solution was cooled to −20° C., then a solution of m-chloroperbenzoic acid (260 mg in 0.5 ml of methylene chloride, 1.5 mmole) was added dropwise. After warming to room temperature, the mixture was diluted threefold with ethyl acetate, then washed with 10% sodium metabisulfie and 10% sodium bicarbonate. A wash with 5% sodium carbonate removed a trace of unreacted genistein.

[0029] The ethyl acetate solution, containing the butyl esters of the genistein phosphates, was washed with 1M HCl and dried over sodium sulfate. After removal of the solvent in vacuo, the residue was treated with 30% TFA in acetic acid for 90 minutes at room temperature. The solvents were removed in vacuo, and the residue was taken up in...

example 2

Genistein-7-phosphate

[0032] a) Genistein-7-tosylate: p-Toluenesulfonyl chloride (540 mg, 2.8 mmoles) was added during 4 hours to a stirred mixture of genistein (730 mg, 2.7 mmoles) and potassium carbonate (2 g) in 25 ml of acetone. After stirring overnight , the mixture was poured into brine and extracted with ethyl acetate. The extract was evaporated under vacuum, and the residue chromatogrammed through silica gel with dichloromethane and chloroform. Crystallization from methanol yielded 920 mg (80.2% yield) of genistein-7-tosylate. The proton magnetic resonance spectrum was consistent with the expected structure.

[0033] b) 4′,5-Di(methoxymethyl)-genistein-7-tosylate: Chloromethyl methyl ether (90 ul, 1.12 mmoles) was added to a solution of genistein-7-tosylate (106 mg, 0.25 mmoles) and diisopropylethylamine (200 ul, 1.15 mmoles) in 0.6 ml of dioxane, under argon atmosphere, and stirred overnight. The mixture was poured into brine, extracted with ethyl acetate, and chromatogrammed...

example 3

Mixed Hemisuccinate Esters of Genistein

[0038] A solution of genistein (135 mg, 0.5 mmole) in 2.0 ml of pyridine was stirred at room temperature while succinic anhydride (100 mg, 1.0 mmole) was added in several portions. After stirring overnight at room temperature, the solvent was removed in vacuo. The gummy residue was taken up in water, adjusted to pH 3.0, and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with water, then evaporated to dryness in vacuo. The crude mixture of mixed hemisuccinic acid esters weighed 205 mg.

[0039] Thin layer chromatography of the product showed principally the presence of mixed mono- and disuccinate esters of genistein. The product was completely soluble in phosphate buffer at pH 7.

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Abstract

Isoflavones are modified by esterification at one or more of the C4′, C5, C6, and C7 positions to promote bioavailability, and especially to enhance solubility over the corresponding unesterified isoflavones. Preferred modifications produce a carboxylic acid hemiester or a phosphate ester which is biologically hydrolysable. Preferred starting isoflavones are genistin and daidzin, and still more preferably comprises an aglycone form such as genistein or daidzein. Esterified isoflavones may be employed therapeutically or prophylactically for a variety of conditions, provided as a dietary supplement, or added to natural or processed food-stuffs. Further preferred uses include incorporation of contemplated compounds into topical formulations, and especially cosmetic topical formulations.

Description

[0001] This application claims priority to U.S. patent application Ser. No. 10 / 371727, which was filed Feb. 20, 2003, and which is incorporated by reference herein.FIELD OF THE INVENTION [0002] The field of the invention is isoflavones. BACKGROUND OF THE INVENTION [0003] The isoflavones are a group of naturally occurring plant compounds having the aromatic heterocyclic skeleton of a flavan. Soybeans are the most common and well known source of isoflavones, and are reported to contain the isoflavones, daidzin, genistin, glycitin, 6′-O-acetyl-daidzin, 6′-O-acetyl genistin, 6′-O-malonyl daidzin, and 6′-O-malonyl genistin. (see U.S. Pat. No. 5,679,806 to Zheng et al., (October 1997) incorporated herein by reference). Isoflavones are present in processed soy foods as well, including miso and soy sauce. Legumes, lupine, fava bean, kudzu and psoralea may also be important sources. The existence of isoflavones in Pueraria has long been known, with the roots of Pueraria containing several is...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K8/49A61K8/60C07H17/07A01N43/02A01N43/16A61KA61K6/00A61K8/14A61K9/00A61K31/335A61K31/35A61K31/353A61K31/665A61K31/7048A61Q17/04A61Q19/08C07D311/36C07H15/00C07H17/00
CPCA61K8/14A61K8/602A61K31/353A61K31/665A61K31/7048A61K2800/522A61Q17/04A61Q19/08C07D311/36
Inventor HENDLER, SHELDONZIELINSKI, JAN
Owner VYREXIP HLDG
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