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WO1988008256A1 - Derives de dihydroflavonol utiles en temps qu'edulcorants - Google Patents

Derives de dihydroflavonol utiles en temps qu'edulcorants Download PDF

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Publication number
WO1988008256A1
WO1988008256A1 PCT/US1988/001202 US8801202W WO8808256A1 WO 1988008256 A1 WO1988008256 A1 WO 1988008256A1 US 8801202 W US8801202 W US 8801202W WO 8808256 A1 WO8808256 A1 WO 8808256A1
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WO
WIPO (PCT)
Prior art keywords
compound
alkyl
group
acetate
sweet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1988/001202
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English (en)
Inventor
A. Douglas Kinghorn
N. P. Dhammika Nanayakkara
Djaja D. Soejarto
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University Patents Inc
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University Patents Inc
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Filing date
Publication date
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Publication of WO1988008256A1 publication Critical patent/WO1988008256A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/30—Artificial sweetening agents

Definitions

  • sucrose is unique among sweet compounds in that it produces a sweetness which is unmasked by any other taste sensation.
  • relatively large amounts of sucrose have previously been used in sweetening of foodstuffs, and it is now generally accepted that this has been responsible as a major dietary source of dental caries.
  • T. dodoneifolia (Hook and Arnott) Cabrera (family Compositae) which was obtained in Paraguay where it is sold as a plant under the name of "Hierba dulce” for sweetening foods and beverages. While attempts to isolate the sweet constituent of this plant were not successful from the plant material at hand, seeds of T. dodoneifolia were successfully cultivated at the University of Ilionois Pharmacognosy Field Station. By bioactivity-guided fractionation, we have now shown that the sweet compound present in shoots of "Hierba dulce” is dihydroquercetin-3-acetate. Realizing that we had discovered a new class of intensely sweet compounds, which are derivatives of dihydroflavonol, we decided to continue our research with this class of compounds which has led to the present invention.
  • Tessaria dodoneifolia the plant used in our investigations, is known to be sweet, and is colloquially called, "chilca dulce" in Argentina (see E. Guerreiro, J. Kavka, and O . S. Giordano, Anales Assoc. Quim,. Argentina, 61:161-164[1973]). Only three previous chemical investigations have been conducted on this plant, and these have led to the isolation of two flavanones, additional flavonoids including dihydroquercetin-3-acetate (see J. Kavka, E. Guerreiro, and 0. S. Giordano, An. Quim. 73:305-306 [1978]), and a sesquiterpene.
  • Dihydroquercetin-3-acetate the compound we have identified as being the sweet constituent in the shoots of T. dodoneifolia, was not recognized as being sweet at the time of its isolation in 1978.
  • the compound has since been isolated from two other plant sources (F. Bohlmann, C. Zdero, M. Grenz, A. K. Dhar, H. Robinson, and R. M. King, Phytochemistry, 20:281-286[1985], and M. Grande, F. Piera, A. Cuenca, P. Torres, and I. S. Bellido, Planta Med., 414-419 [1981]), where again its sweet properties were not recognized.
  • dihydroflavonol derivatives of the present invention are compounds of the general formula
  • R 1 may be H, OH, or OC 1-4 alkyl
  • R 2 may be H, OH, or OC 1-4 alkyl
  • R 3 may be OH, OCOC 1-10 alkyl, OC 1-10 alkyl, or
  • R 4 may be H, OH, OC 1-10 alkyl
  • R 5 may be H, OH, O(CH 2 ) n CH(NH 2 )COOH, O(CH _
  • M + is a physiologically acceptable cation such as Na + , K + , or Ca ++
  • X- is a physiologically acceptable anion such as Cl-, PO 3 -3
  • n is a number from 1 to 10, wherein
  • R 5 is a sugar, e.g. glucose, rhamnose, rutinose, or neohesperidose, or other acceptable nontoxic sugar.
  • C is meant any alkyl radical having the number of carbon atoms in the subscript notation.
  • the radical when the label is defined as specifically being “C 4 alkyl” would be a butyl, isobutyl, or tertiary butyl radical.
  • the carbon designation is meant to encompass any and all of the isomeric forms of the radical defined by carbon number.
  • T. dodoneifolia Dried, ground young growing tips of T. dodoneifolia (600 g) were extracted with methanol-water (4:1, 3 x 2 liters) by percolation. The combined extracts were evaporated to dryness at 50°C to afford a gum (240 g), which was dissolved in water (4 liters) and extracted with ethyl acetate (6 x 1.5 liters). The organic layer was washed with water (2 x 500 ml), and evaporated to dryness to afford 116 g of a residue. The sweetness of the methanol-water extract of T. dodoneifolia was found to concentrate in the ethyl acetate fraction, which was determined as nonmutagenic in forward mutation assays with S. typhimurium strain TM677, and was nontoxic for mice when a 2 g/kg dose level was administered by oral intubation.
  • T. dodoneifolia flowering tip ethyl acetate extract (100 g) was adsorbed to silica gel (800 g) and transferred to a glass column (1.5 m x 15 cm) containing 2.5 kg of silica gel. Separation was achieved by elution of the column with mixtures of petroleum ether (bp 60-80°C), chloroform, and methanol, of increasing polarity. Elution of the column with chloroformmethanol (39:1) afforded a sweet fraction (6.8 g) which was crystallized from methanol-chloroform to give pale yellow needles of I (900 mg, 0.17% yield).
  • the synthetic sweet isolate, 5,7,3'-trihydroxy- 4'-methoxydihydroflavonol-3-acetate (II) exhibited the following data: mp, 182-184°C, [ ⁇ ] 25 0; UV, ⁇ max
  • R Bz methoxydihydroflavonol- 5,7,3'-Trihydroxy-4 , -meth 3-acetate
  • the first starting material (2,4-dibenzyloxy-6-methoxymethoxyacetophenone) was prepared from 2,4,6-trihydroxyacetophenone (Aldrich Chemical Co., Milwaukee, Wisconsin) according to literature procedures (M. L. Sehti, S. C. Taneja, K. L. Dhar, and C. K. Atal, Ind. J. Chem., 20B, 770-772, 1981; F. R. van Heerden, J. J. Van Zyl, G. J. H. Rail, E. V. Brandt, and D. G. Roux, Tetrahedron Lett., 661-662, 1978).
  • 3-Benzyloxy-4-methoxybenzaldehyde was prepared from isovanillin (Aldrich) by the method of R. Robinson and S. Sugasawa (J. Chem. Soc., 134, 3163-3172, 1931).
  • reaction mixture was evaporated to dryness in vacuo, and the residue was crystallized from methanol to give a yellow powder, and was further recrystallized from the same solvent as yellow needles of 5,7,3'-tribenzyloxy-4'-methoxydihydroflavonol (600 mg, 20%), with mp 196-198° C; IR, ⁇ max 3464, 3031, 2905, 1668, 1606, 1574, 1516, 1260
  • the ether layer was purified over silica gel, by elution with petroleum ether-acetone (98:2), to yield pure 3- acetoxy-5,7,3'-tri-t-butyldimethysilyloxy-4'-methoxytaxifolin (2.8 g, 87%), which was crystallized from methanol-water to give white needles, and exhibited: mp, 80-82°C, IR (KBr) ⁇ max 2931, 2860, 2680, 1680,
  • the natural compound, I and the synthetic derivative, II were nonmutagenic when tested in a forward mutation assay utilizing Salmonella typhimurium strain TM677, both in the presence and absence of a metabolic activator (S-9) from the livers of Aroclor-1254 pretreated rates. Mutagenicity was assessed for compound I over the concentration range 0.039-0.625 mg/ml and for compound I over the concentration range 0.039-0.625 mg/ml and for compound II over the range, 0.17-1.38 mg/ml. Details of the protocols used are given in Tables 1 and 2, respectively. Preliminary Safety Test Data for the Sweet Natural Product, I, and the Sweet Synthetic Derivative, II
  • the spontaneous mutant fraction i.e., average number of clones on 8-AG plates/average number of clones on plates without 8-AG
  • a compound is said to cause significant mutation if the induced mutant fraction is greater than or equal to two times the spontaneous mutant fraction.
  • the spontaneous mutant fraction i.e., average number of clones on 8-AG plates/average number of clones on plates without 8-AG
  • a compound is said to cause significant mutation if the induced mutant fraction is greater than or equal to two times the spontaneous mutant fraction.
  • a Compound II was dispersed in 1% sodium (carboxymethyl) cellulose (CMC) and mice in the test group were dosed by oral intubation at a level of 1 g/kg of body weight. Animals in the control group were treated with 1% CMC only.
  • b t Test method was used to analyze these results for any significant variation; t for day 0, -1.560, day 1, -0.532, day 3, -0.829, day 7, 0.104, day 14, -.621. Therefore, there is no significant difference between the test and control groups (0.95 confidence).
  • Synthetic compound II has been subjected to preliminary stability studies, by storage for up to two weeks in solutions at the pH levels 3, 5, and 7, and at both room temperature and at 60°C.
  • the compound was constituted at the appropriate pH in Teorell and Stenhagen's citrate-phosphate-borate buffer at a concentration of 1 mg/ml, and stability was assessed by the number of zones apparent by thin-layer chromatographic analysis at each time interval.
  • Compound II was stable at all three pH levels at ambient temperature, throughout the course of the study. At the elevated temperature, II was more stable at acid rather than neutral conditions. While no breakdown was apparent at 60°C at pH 3 after two weeks, about 5-10% of the compound decomposed at pH 7 at this temperature and time intervals storage. It may be anticipated that most of the potential uses of compound II would involve acid pH levels.
  • compound I the natural sweetener obtained from the Paraguayan plant
  • synthetic derivative II does, in being about 400 times sweeter than sucrose.
  • compound II a dihydroflavonol
  • compound II may be compared in terms of the quality of its test with three other classes of sweeteners, with which itis somewhat structurally related, namely, the dihydrochalcones (one of which has recently been approved for use as a sweetener in Belgium), and the flavans and flavanones.
  • the dihydrochalcones are limited by the long time taken for the sweetness response to become manifest, and by a lingering aftertaste.
  • the flavan and flavonone classes of sweeteners were designed to mimic structural characteristics of the sweet compound, phyllodulcin, and all compounds in these classes that were intensely sweet had unpleasant or unacceptable aftertastes.
  • Compound II appears to be superior to the known members of the dihydrochalcone, flavan, and flavanone classes of sweeteners in terms of its taste qualities.
  • the compounds according to the present invention have utility as sweetening agents for a variety of foodstuffs when added thereto in amounts sufficient to obtain the desired sweetness levels. Although such levels are arbitrary according to the perceived tastes of the user, some guidance as to the amount of compound to add in order to achieve the desired level of sweetness may be taken from comparing the sweetness of these compounds with the conventional agent, sucrose.
  • foodstuffs any material ingested for nutrition, including beverages such as sodas and coffee, powdered beverage mixes, bakery goods such as cakes, pies, and breads and miscellaneous items such as toothpastes, mouthwashes, candy, breath mints, and the like.
  • beverages such as sodas and coffee, powdered beverage mixes, bakery goods such as cakes, pies, and breads and miscellaneous items such as toothpastes, mouthwashes, candy, breath mints, and the like.
  • the compounds according to the present invention may be added to such foodstuffs either before or after preparation for ingestion, much as the commonly accepted sucrose preparations, depending upon the wishes of the individual.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Certains dérivés de dihydroflavonol sont des édulcorants très forts.
PCT/US1988/001202 1987-04-28 1988-04-18 Derives de dihydroflavonol utiles en temps qu'edulcorants Ceased WO1988008256A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4339487A 1987-04-28 1987-04-28
US043,394 1987-04-28

Publications (1)

Publication Number Publication Date
WO1988008256A1 true WO1988008256A1 (fr) 1988-11-03

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0499015A1 (fr) * 1991-02-15 1992-08-19 Fockerman, Jasmine Dérivés benzopyrannephénoliques pour utilisation comme agents bactériostatiques, antivirals et immunostimulants
EP0605261A3 (fr) * 1992-12-28 1994-08-10 San-Ei Gen F.F.I., Inc. Agent modifiant le goût et procédé pour modifier le goût
US5580545A (en) * 1992-12-28 1996-12-03 San-Ei Gen F.F.I., Inc. Taste modifier and a method of modifying taste
ES2241491A1 (es) * 2004-04-07 2005-10-16 Provital, S.A. Composicion cosmetica y/o farmaceutica, reguladora de los niveles de grasa en adipocitos y/o reguladora de la diferenciacion adipocitaria.
US8017168B2 (en) 2006-11-02 2011-09-13 The Coca-Cola Company High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith
US9101160B2 (en) 2005-11-23 2015-08-11 The Coca-Cola Company Condiments with high-potency sweetener
EP2984077A4 (fr) * 2013-03-14 2017-03-15 Chromocell Corporation Composés, compositions et procédés permettant de moduler le goût de sucré
CN111233810A (zh) * 2020-01-18 2020-06-05 安徽农业大学 一类羟基肉桂酰酯型儿茶素的制备方法和用途
WO2021043842A1 (fr) * 2019-09-05 2021-03-11 Firmenich Sa Dérivés de flavanone et leur utilisation en tant qu'exhausteurs de sucrosité
WO2023172394A1 (fr) * 2022-03-11 2023-09-14 Firmenich Incorporated Composés de flavanone et leur utilisation en tant que modificateurs d'arôme

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5449794A (en) * 1991-02-15 1995-09-12 Jasmine Fockerman Benzopyran phenol derivatives for use as antibacterial agents

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR7011M (fr) * 1968-02-28 1969-06-02
FR1578715A (fr) * 1967-07-26 1969-08-22
US3598840A (en) * 1967-07-26 1971-08-10 Sori Soc Rech Ind 3-acetoxy-flavanones and their production
US4013801A (en) * 1976-02-13 1977-03-22 Dynapol Corporation Edibles sweetened with flavanones

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1578715A (fr) * 1967-07-26 1969-08-22
US3598840A (en) * 1967-07-26 1971-08-10 Sori Soc Rech Ind 3-acetoxy-flavanones and their production
FR7011M (fr) * 1968-02-28 1969-06-02
US4013801A (en) * 1976-02-13 1977-03-22 Dynapol Corporation Edibles sweetened with flavanones

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0499015A1 (fr) * 1991-02-15 1992-08-19 Fockerman, Jasmine Dérivés benzopyrannephénoliques pour utilisation comme agents bactériostatiques, antivirals et immunostimulants
EP0605261A3 (fr) * 1992-12-28 1994-08-10 San-Ei Gen F.F.I., Inc. Agent modifiant le goût et procédé pour modifier le goût
US5580545A (en) * 1992-12-28 1996-12-03 San-Ei Gen F.F.I., Inc. Taste modifier and a method of modifying taste
ES2241491A1 (es) * 2004-04-07 2005-10-16 Provital, S.A. Composicion cosmetica y/o farmaceutica, reguladora de los niveles de grasa en adipocitos y/o reguladora de la diferenciacion adipocitaria.
ES2241491B1 (es) * 2004-04-07 2006-12-01 Provital, S.A. Composicion cosmetica y/o farmaceutica, reguladora de los niveles de grasa en adipocitos y/o reguladora de la diferenciacion adipocitaria.
US9101160B2 (en) 2005-11-23 2015-08-11 The Coca-Cola Company Condiments with high-potency sweetener
US8017168B2 (en) 2006-11-02 2011-09-13 The Coca-Cola Company High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith
EP2984077A4 (fr) * 2013-03-14 2017-03-15 Chromocell Corporation Composés, compositions et procédés permettant de moduler le goût de sucré
WO2021043842A1 (fr) * 2019-09-05 2021-03-11 Firmenich Sa Dérivés de flavanone et leur utilisation en tant qu'exhausteurs de sucrosité
CN114364265A (zh) * 2019-09-05 2022-04-15 弗门尼舍有限公司 黄烷酮衍生物及其作为甜味增强剂的用途
JP2022547292A (ja) * 2019-09-05 2022-11-11 フイルメニツヒ ソシエテ アノニム フラバノン誘導体及び甘味増強剤としてのフラバノン誘導体の使用
CN111233810A (zh) * 2020-01-18 2020-06-05 安徽农业大学 一类羟基肉桂酰酯型儿茶素的制备方法和用途
CN111233810B (zh) * 2020-01-18 2023-03-21 安徽农业大学 一类羟基肉桂酰酯型儿茶素的制备方法和用途
WO2023172394A1 (fr) * 2022-03-11 2023-09-14 Firmenich Incorporated Composés de flavanone et leur utilisation en tant que modificateurs d'arôme

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Publication number Publication date
AU1708388A (en) 1988-12-02

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