US 2003O1701.86A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0170186 A1 Geers et al. (43) Pub. Date: Sep. 11, 2003 (54) NOVEL FLAVONE GLYCOSIDE (52) U.S. Cl. .................................... 424/59; 514/27; 536/8 DERIVATIVES FOR USE IN COSMETICS, PHARMACEUTICALS AND NUTRITION (57) ABSTRACT (76) Inventors: Bernadette Geers, Duesseldorf (DE); The invention relates to flavone and isoflavone glycoside Ralf Otto, Bad Friedrichshall (DE); derivatives of general formula (I): A-C(=O)0), X Albrecht Weiss, Langenfeld (DE); Dirk O-Z-O-C(=O)-A) (I), wherein X-O-Z represents a Petersohn, Koeln (DE); Klaus Rudolf flavone or isoflavone glycoside Structure, wherein X repre Schroeder, Mettmann (DE); Kordula Sents a flavone or isoflavone parent Substance of formula Schlotmann, Duesseldorf (DE) (IIa) or (IIb), said (iso)flavone parent Substance being mono or multisubstituted and/or mono- or multireduced (hydro Correspondence Address: genated), wherein Z (Sugar) represents a mono-, di- or COGNIS CORPORATION polysaccharide which is acetally bonded to the radical X and 2500 RENAISSANCE BLVD., SUITE 200 is ester-Substituted with A n-times, A-C(=O) represent GULPH MILLS, PA 19406 ing an acyl radical on the flavone or isoflavone parent Substance, wherein A and A, independently of each other, (21) Appl. No.: 10/258,049 represent a polyunsaturated Cs-Cs-alkenyl radical with at least 4 isolated and/or at least 2 conjugated double bonds or (22) PCT Filed: Apr. 11, 2001 an arylaliphatic radical with 1-4 methylene groups between (86) PCT No.: PCT/EPO1/04151 the ester group and the aromatic ring, wherein C(=O)A represents an acyl radical on the Sugar Z, wherein n is a Publication Classification whole number (1,2,3,...) but not 0, wherein m is a whole number including 0 (0,1,2,3,...) and wherein R1,R2 and (51) Int. Cl." ....................................................... A61K 7/42 R3 represent hydroxyl groups or hydrogen atoms. US 2003/0170186 A1 Sep. 11, 2003 NOVEL FLAVONE GLYCOSIDE DERVATIVES quercetin, rutin, naringin and those mentioned above, and FOR USE IN COSMETICS, PHARMACEUTICALS also isoflavones and isoflavone glycosides (isoflavonoids) AND NUTRITION are known to be Scavengers of oxygen radicals and inhibi tors of skin proteases So that they are actively able to 0001. This invention relates to new biologically active counteract aging of the skin and Scar formation. By virtue of flavone and isoflavone glycoside derivatives corresponding their coloring properties, Some flavones, Such as quercetin, to general formula (I): are used as food colorants. At the same time, their ability to trap oxygen radicals also enables them to be used as anti 0002 of aliphatic and arylaliphatic carboxylic acids, to oxidants. Some flavonoids are inhibitors of aldose reductase processes for their production, to cosmetic and/or pharma which plays a key role in the formation of diabetes damage ceutical preparations containing these compounds and to (vascular damage, grey Star). Other flavonoids (such as hesperidin and rutin) are used therapeutically, more particu their use as additives in human nutrition and animal feeds. larly as vasodilating capillary-active agents. 0003. In the cosmetics field, the use of active substances is becoming increasingly more important. The active Sub 0009. The derivatizations carried out in accordance with stances which have already been used in cosmetics have not the invention achieve an improved effect and greater bio always been natural Substances. Much research work has availability, as previously shown with reference to the been devoted to optimizing known active Substances and to example of Salicin derivatives. producing new active Substances. 0010 Many naturally occurring alkyl and phenol gluco 0004. In the broadest sense, active substances are sub Sides Show antiviral, antimicrobial and, in Some instances, stances which-occurring or Supplied in relatively Small anti-inflammatory activity. In view of their polarity, how quantities-are able to develop Strong physiological activity. ever, their bioavailability is poor and their selectivity too Such Substances would include hormones, Vitamins, low. For example, Salicin (a glycosidic active Substance enzymes, trace elements, etc. and also pharmaceuticals from willow bark) is a nonsteroidal anti-inflammatory agent (medicaments), feed additives, fertilizers and pesticides. (NSAIA) which, after derivatization (esterifications), shows Synergism is also observed in many cases. distinctly improved activity. Recently, researcherS Suc ceeded in Synthesizing new arylaliphatic Salicin esters, Such 0005 Flavones and Isoflavones/Flavonoids and Isofla as phenylacetoyl Salicin and phenyl butyroyl Salicin, the vonoids or Flavone Glycosides and Isoflavone Glycosides esterification taking place preferentially at the primary OH 0006 Flavones are 2-phenyl-4H-1-benzopyran-4-ones in groups of the Salicin (first at the Sugar, then at the benzyl which hydroxyl groups may be present or even missing at group) in the Salicin. By virtue of the arylaliphatic group, various positions of the rings. One example of a flavone is mass transport to the point of action is improved and the apigenin of which the chemical name is 2-(p-hydroxyphe Selectivity of the effect is increased. Thus, in contrast to nyl)-4H-1-(5,7-dihydroxybenzopyran-4-one (see Römpp, unmodified salicin, these derivatives preferentially inhibit Chemie-Lexikon, 9th Edition, Vol. 2, pp. 1373/4). As the prostaglandin Synthase 2 (less danger of Side effects) (Ralf example mentioned shows, the additional hydroxyl groups T. Otto, Biotechnologische Herstellung und Charak are located at the phenyl and/or the benzopyran ring. In other terisierung neuer pharmaZeutisch aktiver Glykolipide, Dis words, flavones in the context of the present invention are sertation (1999) ISBN 3-86186-258-1). the hydrogenation, oxidation or Substitution products of 2-phenyl-4H-1-benzopyran-4-one (hydrogenation may take 0.011 PUFAs and CLAS place in the 2,3-position of the carbon Skeleton; by Substi 0012. In the field of nutrition, polyunsaturated fatty acids tution is meant the replacement of one or more hydrogen (PFAS) and conjugated linoleic acids (CLAS) belong to the atoms by hydroxy or methoxy groups). Accordingly, this group of essential fatty acids and also show a positive effect definition includes flavans, flavan-3-ols (catechols), flavan when used in the prophylaxis of arteriosclerosis. Pharma 3,4-diols (leucoanthocyanidines), flavones, flavonols and ceutical effects are also important; they are capable of flavonones in the traditional Sense. Besides apigenin, the developing anti-inflammatory activity (inhibition of pros flavones according to the invention include, for example, taglandin and leucotriene Synthesis) and also thrombolytic chrysin, galangin, fisetin, luteolin, camphor oil, quercetin, and hypotensive activity. morin, robinetin, gossypetin, taxifolin, myricetin, rhamne 0013. According to the invention, PUFA is defined as a tin, isorhamnetin, naringenin, eryodictyol, hesperetin, liq polyunsaturated fatty acid containing 16 to 26 carbon atoms, uiritigenin, catechol and epicatechol. the fatty acid containing at least four isolated and/or at least 0007. By contrast, isoflavones in the context of the two conjugated double bonds. Examples of PUFAs are the present invention are the hydrogenation, oxidation or Sub twelve octadecadienoic acids isomeric to linoleic acid (cis, Stitution products of 3-phenyl-4H-1-benzopyran-4-one cis, 9,12-octadecadienoic acid) which occur in nature and (hydrogenation may take place in the 2,3-position of the which have conjugated double bonds at carbon atoms 9 and carbon Skeleton; by Substitution is meant the replacement of 11, 10 and 12 or 11 and 13. one or more hydrogen atoms by hydroxy or methoxy groups). The isoflavones according to the invention include, 0014) These isomers of linoleic acid (for example cis, for example, daidZein, genistein, prunetin, biochanin, trans, 9,11-octadecadienoic acid, trans, cis, 10,12-octadeca orobol, Santal, pratensein, irigenin, glycitein, biochanin A dienoic acid, cis, cis, 9,11-octadecadienoic acid, trans, cis, and formononetin. 9,11-octadecadienoic acid, trans, trans, 9,11-octadecadi enoic acid, cis, cis, 10,12-octadecadienoic acid, cis, trans, 0008 Flavones and flavone glycosides (flavanoids), such 10, 12-octadecadienoic acid, trans, trans, 10,12-octadecadi as asparatin, orientin (lutexin), cisorientin (lutionaretin), iso enoic acid) can be conventionally prepared by chemical US 2003/0170186 A1 Sep. 11, 2003 isomerization of linoleic acid, these reactions leading exclu 0019 Efforts at cosmetically treating the effects of stress Sively to CLA mixtures varying widely in composition (for induced aging of the Skin have targeted the reduction of example Edenor UKD 6010, Henkel KGaA) in dependence MMP-1 activity or the increased synthesis of collagen. The upon the reaction conditions. By virtue of their conjugated use of retinic acid or retinol is Said to reduce the Synthesis double bonds, these isomeric octadecadienoic acids are also of MMP-1 in the skin or to increase the synthesis of known as conjugated linoleic acids (CLAS). collagen. However, the use of retinic acid for cosmetics is 0.015 Although numerous pharmacologically active sub not permitted in Europe because of teratogenic properties. stances which engage, for example, in the inflammation Cytotoxic effects, inadequate Stability in formulations, cascade have already been described in the literature,