WO2001079241A1 - Glycoside esters, the production and the use thereof in cosmetics, pharmaceutical products and foodstuff or animal feed - Google Patents

Glycoside esters, the production and the use thereof in cosmetics, pharmaceutical products and foodstuff or animal feed Download PDF

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Publication number
WO2001079241A1
WO2001079241A1 PCT/EP2001/004153 EP0104153W WO0179241A1 WO 2001079241 A1 WO2001079241 A1 WO 2001079241A1 EP 0104153 W EP0104153 W EP 0104153W WO 0179241 A1 WO0179241 A1 WO 0179241A1
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compounds
eis
sugar
group
radical
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PCT/EP2001/004153
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German (de)
French (fr)
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Albrecht Weiss
Ralf Otto
Bernadette Geers
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Henkel Kommanditgesellschaft Auf Aktien
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Priority to AU73939/01A priority Critical patent/AU7393901A/en
Publication of WO2001079241A1 publication Critical patent/WO2001079241A1/en

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    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/604—Alkylpolyglycosides; Derivatives thereof, e.g. esters
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/02—Monosaccharides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Glycoside esters and their production and use in cosmetics, pharmaceuticals and food or feed
  • the present invention relates to new, biologically active glycoside esters, processes for their preparation, cosmetic and / or pharmaceutical preparations containing these compounds, and food and feed containing these compounds.
  • active ingredients are becoming increasingly important in cosmetics.
  • the active ingredients that are already used in cosmetics are not always natural substances.
  • the optimization of known active ingredients and the production of new active ingredients are the subject of much research.
  • active substances are substances that - occurring or supplied in relatively small amounts - can have a great physiological effect.
  • active substances are substances that - occurring or supplied in relatively small amounts - can have a great physiological effect.
  • hormones vitamins, enzymes, trace elements etc.
  • pharmaceuticals medicinal substances
  • feed additives fertilizers
  • Glvkoside and arylaliphatic Glvkosidester The derivatizations carried out according to the invention achieve an improved effect as well as an increased bioavailability, as was shown earlier with the example of salicin derivatives.
  • salicin a glycosidic active ingredient from willow bark
  • NSAIA non-steroidal anti-inflammatory agent
  • esters such as phenylacetoyl salicin or phenylbutyroyl salicin
  • extracts of the plants of the species Ericaceae e.g. from the bearberry (Arctostaphylos uva ursi), which isolates the glycoside arbutin, which shows skin-lightening effects.
  • This glycoside has a certain biotechnological interest, because in Japan it is used in cosmetics in considerable quantities (1-2 t per year) due to its brightening effect due to the inhibition of melanin biosynthesis (inhibition of the key enzyme tyrosinase). While in the European market the preparations are used more against age spots, liver spots or freckles, in the Asian market the beauty ideal of light, flawless skin is to be achieved through full-body treatment.
  • Alkyl polyglycosides APG
  • Alkyl polyglucosides are used as phosphate-free neutraltenes Detergents and cosmetics added (based on renewable raw materials). 1-7 glucose units are glycosidically linked to a fatty alcohol (mostly 12 carbon atoms):
  • Natural oils e.g. from sunflower oil, linseed oil, olive tree oil
  • PUFAs polyunsaturated fatty acids
  • the PUFAs are part of the diet the group of essential fatty acids and also show a positive effect when used in the prophylaxis of arteriosclerosis.
  • pharmaceutical effects are also important: they can have anti-inflammatory effects (inhibition of prostaglandin or leukotriene synthesis), but also thrombolytic and hypotensive effects.
  • PUFA is defined as a polyunsaturated fatty acid with 16 to 26 carbon atoms, the fatty acid having at least four isolated and / or at least two conjugated double bonds.
  • PUFAs are the twelve octadecadienoic acids (which occur in nature) which are isomeric to linoleic acid (ice, ice, 9,12-octadecadienoic acid) and which have conjugated double bonds on the C atoms 9 and 11, 10 and 12, or 11 and 13 have.
  • linoleic acid e.g. ice, trans, 9,11-octadecadienoic acid, trans, ice, 10,12-octadecadienoic acid, ice, ice, 9,11-octadecadienoic acid, trans, ice, 9,11-octadecadienoic acid, trans, trans, 9,11-octadecadienoic acid, ice, ice, 10,12-octadecadienoic acid, ice, trans, 10,12-octadecadienoic acid, trans, trans, 10,12-octadecadienoic acid
  • CLA mixtures eg Edenor UKD 6010, Henkel KGaA
  • conjugated double bonds are also referred to as "conjugated linoleic aids" (CLAs). They are naturally obtained as a mixture mainly from milk and meat from ruminants (5 mg / g fat), in which they are synthesized by the rumen bacterium Butyrivibrio fibrisolvens.
  • CLAs conjugated linoleic aids
  • CLAs The effect of the CLAs is very versatile. They show inhibitory effects in carcinogenesis and in artherogenesis. They also show an antioxidant effect through furan formation, which plays an important role in the prevention of cancer and coronary heart diseases (CHDs).
  • CHDs cancer and coronary heart diseases
  • CLAs as a mixture of isomers follows from their competent action as anti-inflammatory agents, since, due to their structural relationship to arachidonic acid, the precursor of the inflammation mediator prostaglandin, they can competitively inhibit the desaturases required for the biosynthesis of prostaglandins. They also displace the precursors arachidonic and eicosanoic acid from the phospholipids and inhibit the conversion of arachidonic acid to eicosanoic acid and thus the conversion to prostaglandins.
  • the object on which the present invention is based was therefore to provide such substances which have few side effects, have a good action and are easy to process and apply.
  • glycosides and certain glycoside esters are e.g. known from nature.
  • esters described here, in particular PUFA and CLA esters, of unsaturated fatty acids with sugars or glycosides in which at least one of the hydroxyl groups of the sugar contains an (unsaturated one) are not known (neither from plants, microorganisms or animal cells nor synthetically produced) ) Carbon or Fatty acid is esterified.
  • esters in particular esters of unsaturated fatty acids with sugars or glycosides, have improved bioavailability, increased activity and / or a broader spectrum of activity than the known individual components (fatty acid or sugar / glycoside).
  • the ester is preferably formed by means of the primary Hydroxyl group of sugar / glycoside; however, the other OH groups on the sugar or any OH groups present in the aglycone (eg hydroxyl radical in the case of arbutin) can also be used for the esterification.
  • R is a hydrogen, a branched or straight-chain C 8 -C 2 o-alkyl bonded to the sugar via an ether bridge, an arylalkyl or a substituted or unsubstituted C ⁇ -Cio-aryl radical, in which Z (sugar) is a mono-, disaccharide or polysaccharide which is substituted n-times with ester and with Ac and if R is not hydrogen, acetal to the
  • the radical R is bound, where Ac is a polyunsaturated C 15 -C 25 acyl radical with at least 4 isolated and / or at least two conjugated double bonds or an arylaliphatic one
  • Residue with 1-4 methylene groups between ester group and aromatic ring in which m is an integer (1, 2, 3, ...) including 0, in which n is an integer (1, 2, 3, ... ), but not 0, with the proviso that Z-0-R m is not salicin, which is 2-hydroxymethylphenyl) -ß-glucopyranoside.
  • Preferred fatty acids are CLAs and stearidonic acid, particularly preferred are the octadecadienoic acids which have conjugated double bonds on the C atoms 9 and 11, 10 and 12 or 11 and 13, in particular the eis, trans, 9, 11 and the eis, eis , 9, 11-octadecadienoic acid.
  • Suitable sugars are mono-, di- and oligosaccharides, especially D-glucose, D-galactose, D-xylose, D-apiose, L-rhamnose, L-arabinose and rutinose, with D-glucose being particularly preferred.
  • glycosides (Z-0-R m ) are monosaccharides (such as those mentioned in the preceding paragraph) containing compounds, in particular arbutin, fragilin and populin, but also glycosides containing oligo- or polysaccharides, such as alkyl polyglucosides, especially APG (Henkel KGaA ).
  • esters 1 to 30 are the following esters 1 to 30, in which both m and n are 1, in which Ac, Z and R have the following meanings and in which the ester group is formed via the primary alcohol group of the sugar / glycoside (if several glucose or sugar units are present, there is esterification at the primary OH of the glucose unit, which is also glycosidically linked to, for example CH 3 - (CH 2 ) ⁇ o-CH 2 OH):
  • esters 31 to 60 which differ from the esters 1 to 30 only in that the sugar unit (s) does not consist of D-glucose, but instead of the corresponding number of D-galactose units.
  • esters 121 to 180 in analogy to the esters 61 to 120, which differ from the latter in that the second Ac residue is not on the 4-OH but on the 1-OH of the glucose or galactose Unit sits.
  • esters 181 to 240 in analogy to the esters 121 to 180, which differ from the latter in that the second Ac residue is not on the 1-OH but on the 2-OH of the glucose or galactose Unit sits.
  • esters 301 to 360 are the following esters 301 to 360 in analogy to esters 241 to 300, which differ from the latter in that the three Ac residues on the primary and the 2-OH and the 4-OH group of the Sugar are bound.
  • the modification of the fatty acids according to the invention ie the derivatization of the fatty acids in the form of the compounds of the present invention described above, improves the tolerance and the bioavailability and effect of such fatty acids for use in cosmetics, pharmacy and / or nutrition.
  • aspects of the present invention relate to the use of the compounds of the general formula (I) for the production of cosmetic and pharmaceutical preparations, their use as additives to food, nutritional supplements and animal feed. Further aspects of the present invention relate to pharmaceutical and cosmetic preparations and to food, nutritional supplements and animal feeds which contain at least one compound of the general formula (I).
  • the invention accordingly furthermore relates to a process for the preparation of the compounds of the formula (I) according to the invention, which is characterized in that a sugar Z or a glycoside Z-0-R m with an unsaturated fatty acid AcOH or with an ester, preferably a methyl or ethyl ester, this fatty acid AcOH is esterified in the presence of a lipase.
  • Suitable enzymatic catalysts for the esterification (by transesterification) of the acids and alcohol components mentioned include the hydrolases, especially the lipases such as the lipases from Candida antarctica, Candida rugosa (formerly Candida cylandracea), Geotrichum candidum, Aspergillus niger, Penicillium roqueforti, Rhizopus arrhizus and Mucor miehei.
  • a preferred lipase is the lipase (isoenzyme B) from Candida antarctica, for which there are two reasons. First, it shows a particularly high selectivity in the esterification of the acetals with the unsaturated fatty acids, although these are not among their typical substrates. Furthermore, it shows no interface activation (a crucial feature for the classification of hydrolases in the group of lipases), since it lacks an important lipase structural feature, a movable peptide chain at the active center (so-called lid).
  • region-specific means that only a certain OH group of a polyol is esterified.
  • regioselective means that a particular OH group of a polyol is preferably, but not exclusively, esterified.
  • the purification can also be carried out by a chromatographic process on silica gel, preferably with ethyl acetate / methanol or dichloromethane / methanol mixtures with small proportions of acetic acid and / or water, which can also be carried out in addition to an aqueous two-phase extraction process with organic solvents.
  • esters of formula (I) according to the invention have good bioavailability and activity, they can be used in cosmetic and pharmaceutical preparations and / or as food additives, with the result that the quality of these products is significantly improved.
  • the esters of conjugated linoleic acids (CLAs) according to the invention have an anti-inflammatory, antipyretic, anti-inflammatory and / or analgesic effect and also have antioxidative, skin-lightening or antibacterial / antiviral effects.
  • the fat depot-reducing effect of the CLAs is also evident in the compounds according to the invention.
  • the compounds of formula (I) have good bioavailability and activity, they can be used in cosmetic and pharmaceutical preparations and / or as food additives, with the result that the quality of these products is significantly improved.
  • the compounds according to the invention can be incorporated particularly well into lipophilic base formulations and can be easily formulated as stable emulsions.
  • the compounds of formula (I) according to the invention are used for the production of cosmetic and / or pharmaceutical preparations and / or food or feed.
  • the invention further relates to the use of the compounds of the formula (I) for the production of cosmetic and / or pharmaceutical preparations; the use as food supplements or additives in food preparations and in feed (e.g. for animal breeding); cosmetic and pharmaceutical preparations as well as food preparations and animal feeds containing (a) compound (s) of the formula (I).
  • the cosmetic preparations obtainable using the compounds (I) according to the invention such as hair shampoos, hair lotions, foam baths, shower baths, creams, gels, lotion, alcoholic and aqueous / alcoholic solutions, emulsions, wax / fat masses, stick preparations, powder or Ointments can also be used as further auxiliaries and additives, mild surfactants, oil bodies, emulators, superfatting agents, pearlescent waxes, consistency agents, thickeners, polymers, silicone compounds, fats, waxes, stabilizers, biogenic active substances, deodorant substances, Contain antidandruff agents, film formers, swelling agents, UV light protection factors, antioxidants, hydrotropes, preservatives, insect repellents, self-tanners, solubilizers, perfume oils, dyes, germ-inhibiting agents and the like.
  • the amount of the compounds according to the invention used in the cosmetic preparations is usually in the range from 0.01 to 5% by weight, but preferably from 0.1 to 1% by weight, based on the total amount of the preparations.
  • the compounds of the general formula (I) according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for.
  • B. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, carboxymethyl cellulose or fatty substances such as hard fat or the like suitable mixtures, work into conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or suppositories.
  • the daily dosage required to achieve a corresponding effect in pharmaceutical applications is advantageously 0.1 to 10 mg / kg body weight, preferably 0.5 to 2 mg / kg body weight.
  • the nutritional substitutes and additives, such as sports drinks, obtainable using the compounds of the formula (I) according to the invention suitably contain the compounds (s) of the formula (I) in an amount which, with a normal need for fluid intake of 1 up to 5 liters per day leads to a dosage of these compounds of 0.1 to 10 mg, preferably 0.5 to 5 mg, per kg of body weight.
  • An example of use in the food industry is for the compounds of the formula (I) as colorings and / or spices. Examples
  • reaction was carried out by means of thin layer chromatography (silica gel 60 plates with fluorescent indicator; eluent: ethyl acetate / methanol 10: 1, v / v and dichloromethane / methanol / acetic acid 95: 5: 0.1, v / v / v; visualization: UV detection as well as by means of an acetic acid /
  • ⁇ (cis-cis isomer) 14.4 (C-18), 23.8 (C-17), 25.6 (C-3) 30.1-30.7 (C-4, C-5, C-6, C-7, C- 14, C-15, C-16), 32.6 (C-13), 33.6 (C-8), 34.4 (C-2), 64.8 (C-6 '), 70.4 (C-4'), 71.8 ( C- 5 '), 73.8 (C-2'), 74.9 (C-3 '), 93.8 (C-1'), 126.8 (C-11) 129.7 (C-10), 130.2 (C-9), 131.6 (C-12), 174.8 (C-1).
  • Example 2 CLA + alkyl polyglycoside (APG) 6-0-cis-9, trans-11-octadecadienoyl-alkylglucoside 2 g APG (Henkel KGaA), 15 g Edenor UKD6010, 4.5 g molecular sieve, 10 ml t-butanol and 4.5 g immobilized lipase B from Candida antarctica were incubated for 48 hours at 60 ° C with 100 rpm using a magnetic stirrer in a 250 ml Erlenmeyer flask.
  • APG alkyl polyglycoside
  • the reaction was carried out by means of thin layer chromatography (silica gel 60 plates with fluorescence indicator; eluent: ethyl acetate 100%, visualization: UV detection and using acetic acid / sulfuric acid / anisaldehyde immersion reagent (100: 2: 1 v / v / v)).
  • the product was enriched in the hexane phase by means of an aqueous two-phase extraction, concentrated in a rotary evaporator and purified by column chromatography (silica gel F60; mobile phase: ethyl acetate / methanol (10: 1, v / v)).

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Abstract

The invention relates to the compounds of the general formula (I): Acn-O-Z-O-Rm (I), wherein R represents hydrogen, a branched or straight-chain C8-C20 alkyl group bound to the sugar moiety via an ether bridge, an arylalkyl group or a substituted or unsubstituted C6-C10 aryl group, wherein Z (sugar) represents a monosaccharide, disaccharide or polysaccharide that is n-fold substituted by Ac in the manner of an ester, and, if R is not hydrogen, is acetally bound to the group R, wherein Ac is a poly-unsaturated C15-C25 acyl group with at least 4 isolated and/or at least two conjugated double bonds or an arylaliphatic group with 1-4 methylene groups between the ester group and the aromatic ring, wherein m is an integer (1, 2, 3, ...) including 0, wherein n is an integer (1, 2, 3, ...), but different from 0, with the proviso that Z-O-Rm does not represent salicin, that is 2-(hydroxymethyl-phenyl)-β-glucopyranoside.

Description

Glykosid-Ester und ihre Herstellung sowie Verwendung in Kosmetika, Pharmazeutika und Nahrungs- bzw. Futtermitteln Glycoside esters and their production and use in cosmetics, pharmaceuticals and food or feed
Die vorliegende Erfindung betrifft neue, biologisch aktive Glykosid-Ester, Verfahren zu ihrer Herstellung, diese Verbindungen enthaltende kosmetische und/oder pharmazeutische Zubereitungen sowie diese Verbindungen enthaltende Nahrungs- und Futtermittel.The present invention relates to new, biologically active glycoside esters, processes for their preparation, cosmetic and / or pharmaceutical preparations containing these compounds, and food and feed containing these compounds.
In der Kosmetik wird die Anwendung von Wirkstoffen immer wichtiger. Bei den Wirkstoffen, die bisher bereits Anwendung in der Kosmetik finden, handelt es sich nicht immer um Naturstoffe. Die Optimierung bekannter Wirkstoffe und die Herstellung neuer Wirkstoffe sind Gegenstand vieler Forschungsarbeiten.The use of active ingredients is becoming increasingly important in cosmetics. The active ingredients that are already used in cosmetics are not always natural substances. The optimization of known active ingredients and the production of new active ingredients are the subject of much research.
Im weitesten Sinne sind Wirkstoffe solche Stoffe, die - in relativ kleinen Mengen vorkommend oder zugeführt - große physiologische Wirkung entfalten können. Hier ist an Hormone, Vitamine, Enzyme, Spurenelemente etc. zu denken, aber auch an Pharmaka (Arzneistoffe), Futterzusätze, Düngemittel undIn the broadest sense, active substances are substances that - occurring or supplied in relatively small amounts - can have a great physiological effect. Here one has to think of hormones, vitamins, enzymes, trace elements etc., but also of pharmaceuticals (medicinal substances), feed additives, fertilizers and
Schädlingsbekämpfungsmittel. Nicht selten kann man auch Synergismus beobachten.Pesticides. It is not uncommon to see synergism.
Glvkoside und arylaliphatische Glvkosidester Die erfindungsgemäß durchgeführten Derivatisierungen erzielen eine verbesserte Wirkung sowie eine erhöhte Bioverfügbarkeit, wie es bereits früher am Beispiel von Salicinderivaten gezeigt wurde.Glvkoside and arylaliphatic Glvkosidester The derivatizations carried out according to the invention achieve an improved effect as well as an increased bioavailability, as was shown earlier with the example of salicin derivatives.
Viele natürlich vorkommende Alkyl- und Phenol-Glucoside zeigen antivirale, antimikrobielle und teilweise antiinflammatorische Wirkungen. Sie sind jedoch oft aufgrund ihrer Polarität wenig bioverfügbar bzw. ihre Selektivität ist zu gering. Beispielsweise ist Salicin (ein glykosidischer Wirkstoff aus der Weidenrinde) ein nichtsteroidales antiinfiammatorisches Agenz (NSAIA), das nach Derivatisierung (Veresterungen) deutlich verbesserte Wirksamkeit zeigt. Kürzlich gelang die Synthese neuer arylaliphatischer Salicinester wie Phenylacetoyl-Salicin oder Phenylbutyroyl- Salicin, wobei die Veresterung bevorzugt an den primären OH-Gruppen des Salicins (zunächst am Zucker dann am Benzylrest) im Salicin erfolgte. Aufgrund des arylaliphatischen Restes wird der Stofftransport an den Wirkort verbessert und die Selektivität der Wirkung erhöht. So inhibieren diese Derivate im Gegensatz zu unmodifiziertem Salicin bevorzugt die Prostaglandinsynthase 2 (geringere Gefahr von Nebenwirkungen) (Ralf T. Otto, Biotechnologische Herstellung und Charakterisierung neuer pharmazeutisch aktiver Glykolipide, Dissertation (1999) ISBN 3-86186-258-1).Many naturally occurring alkyl and phenol glucosides show antiviral, antimicrobial and sometimes anti-inflammatory effects. However, due to their polarity they are often not very bioavailable or their selectivity is too low. For example, salicin (a glycosidic active ingredient from willow bark) is a non-steroidal anti-inflammatory agent (NSAIA) that shows significantly improved effectiveness after derivatization (esterification). Recently, the synthesis of new arylaliphatic salicine esters such as phenylacetoyl salicin or phenylbutyroyl salicin was successful, with the esterification preferably on the primary OH groups of the salicin (first on the sugar then on the benzyl residue) in salicin. Due to the arylaliphatic residue, the mass transfer to the site of action is improved and the selectivity of the action is increased. In contrast to unmodified salicin, these derivatives preferentially inhibit prostaglandin synthase 2 (lower risk of side effects) (Ralf T. Otto, biotechnological production and characterization of new pharmaceutically active glycolipids, dissertation (1999) ISBN 3-86186-258-1).
Darüberhinaus wurde aus Extrakten der Pflanzen der Spezies Ericaceae, z.B. aus der Bärentraube (Arctostaphylos uva ursi ), das Glykosid Arbutin isoliert, welches hautaufhellende Wirkung zeigt. Dieses Glykosid hat ein gewisses biotechnologisches Interesse, da es in Japan wegen seiner aufhellenden Wirkung bedingt durch die Inhibierung der Melaninbiosynthese (Hemmung des Schlüsselenzyms Tyrosinase) in beträchtlicher Menge (1-2 t pro Jahr) in Kosmetika verwendet wird. Während im europäischen Markt die Präparate eher gegen Altersflecken, Leber-flecken bzw. Sommersprossen eingesetzt werden, sollen im asiatischen Markt die Schönheits-ideale einer hellen makellosen Haut durch ganzkörperliche Behandlung erreicht werden.In addition, extracts of the plants of the species Ericaceae, e.g. from the bearberry (Arctostaphylos uva ursi), which isolates the glycoside arbutin, which shows skin-lightening effects. This glycoside has a certain biotechnological interest, because in Japan it is used in cosmetics in considerable quantities (1-2 t per year) due to its brightening effect due to the inhibition of melanin biosynthesis (inhibition of the key enzyme tyrosinase). While in the European market the preparations are used more against age spots, liver spots or freckles, in the Asian market the beauty ideal of light, flawless skin is to be achieved through full-body treatment.
Alkylpolvqlucoside (APG)Alkyl polyglycosides (APG)
Alkylpolyglucoside (APG), werden als Phosphat-freie Neutraltenside u.a. Waschmitteln und Kosmetika zugesetzt (auf der Basis nachwachsender Rohstoffe). 1-7 Glucose- Einheiten sind glykosidisch mit einem Fettalkohol (zumeist 12 C-Atome) verknüpft:Alkyl polyglucosides (APG) are used as phosphate-free neutraltenes Detergents and cosmetics added (based on renewable raw materials). 1-7 glucose units are glycosidically linked to a fatty alcohol (mostly 12 carbon atoms):
Figure imgf000003_0001
Figure imgf000003_0001
PUFAs und CLAsPUFAs and CLAs
Natürliche Öle (z.B. aus Sonnenblumenöl, Leinöl, Ölbaumöl) mit einem hohen Anteil an polyungesättigten Fettsäuren (englisch: polyunsaturated fatty acids, PUFAs) werden in der Kosmetik und Dermatologie eingesetzt. Die PUFAs gehören in der Ernährung zu der Gruppe der essentiellen Fettsäuren und zeigen zusätzlich eine positive Wirkung beim Einsatz in der Prophylaxe von Arteriosklerose. Daneben sind auch pharmazeutische Effekte von Bedeutung: Sie können antiinflammatorische (Hemmung der Prostaglandin- bzw. Leukotriensynthese), aber auch eine thrombolytische und hypotensive Wirkung aufweisen.Natural oils (e.g. from sunflower oil, linseed oil, olive tree oil) with a high proportion of polyunsaturated fatty acids (PUFAs) are used in cosmetics and dermatology. The PUFAs are part of the diet the group of essential fatty acids and also show a positive effect when used in the prophylaxis of arteriosclerosis. In addition, pharmaceutical effects are also important: they can have anti-inflammatory effects (inhibition of prostaglandin or leukotriene synthesis), but also thrombolytic and hypotensive effects.
Erfindungsgemäß wird PUFA definiert als eine mehrfach ungesättigte Fettsäure mit 16 bis 26 C-Atomen, wobei die Fettsäure mindestens vier isolierte und/oder mindestens zwei konjugierte Doppelbindungen aufweist. Beispiele für PUFAs sind die insgesamt zwölf zur Linolsäure (eis, eis, 9,12-Octadecadiensäure) isomeren Octadecadiensäuren (die in der Natur vorkommen), die über konjugierte Doppelbindungen an den C-Atomen 9 und 11, 10 und 12, oder 11 und 13 verfügen.According to the invention, PUFA is defined as a polyunsaturated fatty acid with 16 to 26 carbon atoms, the fatty acid having at least four isolated and / or at least two conjugated double bonds. Examples of PUFAs are the twelve octadecadienoic acids (which occur in nature) which are isomeric to linoleic acid (ice, ice, 9,12-octadecadienoic acid) and which have conjugated double bonds on the C atoms 9 and 11, 10 and 12, or 11 and 13 have.
Diese Isomeren der Linolsäure (z.B. eis, trans, 9,11-Octadecadiensäure, trans, eis, 10,12-Octade-cadiensäure, eis, eis, 9,11-Octadecadiensäure, trans, eis, 9,11- Octadecadiensäure, trans, trans, 9,11-Octadecadiensäure, eis, eis, 10,12- Octadecadiensäure, eis, trans, 10,12-Octadecadiensäure, trans, trans, 10,12- Octadecadiensäure) lassen sich auf herkömmlichem Wege mittels chemischer Isomerisierung der Linolsäure herstellen, wobei diese Reaktionen in Abhängigkeit der Reaktionsbedingungen ausschließlich zu CLA-Gemischen unterschiedlichster Zusammensetzung führen (z.B. Edenor UKD 6010, Henkel KGaA).These isomers of linoleic acid (e.g. ice, trans, 9,11-octadecadienoic acid, trans, ice, 10,12-octadecadienoic acid, ice, ice, 9,11-octadecadienoic acid, trans, ice, 9,11-octadecadienoic acid, trans, trans, 9,11-octadecadienoic acid, ice, ice, 10,12-octadecadienoic acid, ice, trans, 10,12-octadecadienoic acid, trans, trans, 10,12-octadecadienoic acid) can be prepared in a conventional manner by chemical isomerization of linoleic acid, depending on the reaction conditions, these reactions only lead to CLA mixtures of various compositions (eg Edenor UKD 6010, Henkel KGaA).
Aufgrund ihrer konjugierten Doppelbindungen werden diese isomeren Octadecadiensäuren auch als "conjugated linoleic aeids" (CLAs) bezeichnet. Natürlicherweise erhält man sie als Gemisch hauptsächlich aus Milch und Fleisch von Wiederkäuern (5 mg/g Fett), in denen sie durch das Pansenbakterium Butyrivibrio fibrisolvens synthetisiert werden.Because of their conjugated double bonds, these isomeric octadecadienoic acids are also referred to as "conjugated linoleic aids" (CLAs). They are naturally obtained as a mixture mainly from milk and meat from ruminants (5 mg / g fat), in which they are synthesized by the rumen bacterium Butyrivibrio fibrisolvens.
Die Wirkung der CLAs ist sehr vielseitig. Sie zeigen hemmende Wirkung bei der Karzinogenese und bei der Artherogenese. Sie zeigen weiterhin eine antioxidative Wirkung durch Furanbildung, die bei der Prävention von Krebs und koronaren Herzkrankheiten (KHKen) eine wichtige Rolle spielt. Die Vermehrung der Muskel- und Knochenmasse durch Fettdepot-reduzierende Eigen-schaften führt zu einer gesteigerten Nahrungsverwertung und findet Anwendung im Bereich der Nahrungsmittel- und der Futtermittelindustrie. Dieser Effekt kann auf eine gesteigerte Fettsäure-Oxidation in Muskel- und Fettzellen zurückgeführt werden.The effect of the CLAs is very versatile. They show inhibitory effects in carcinogenesis and in artherogenesis. They also show an antioxidant effect through furan formation, which plays an important role in the prevention of cancer and coronary heart diseases (CHDs). The increase in muscle and bone mass through fat-reducing properties leads to increased food utilization and is used in the area of Food and feed industries. This effect can be attributed to increased fatty acid oxidation in muscle and fat cells.
Eine weitere Anwendung dieser CLAs als Isomerengemisch folgt aus ihrer kompetenten Wirkung als antiinflammatorische Agenzien, da sie aufgrund ihrer strukturellen Verwandschaft zur Arachidonsäure, dem Vorläufer des Entzündungsmediators Prostaglandin, die zur Biosynthese der Prostaglandine benötigten Desaturasen kompetitiv hemmen können. Sie verdrängen zusätzlich die Vorläufer Arachidon- und Eicosansäure aus den Phospholipiden und hemmen die Umwandlung der Arachidonsäure in die Eicosansäure und damit die Umwandlung in die Prostaglandine.A further application of these CLAs as a mixture of isomers follows from their competent action as anti-inflammatory agents, since, due to their structural relationship to arachidonic acid, the precursor of the inflammation mediator prostaglandin, they can competitively inhibit the desaturases required for the biosynthesis of prostaglandins. They also displace the precursors arachidonic and eicosanoic acid from the phospholipids and inhibit the conversion of arachidonic acid to eicosanoic acid and thus the conversion to prostaglandins.
Obwohl in der Literatur bereits zahlreiche pharmakologisch wirksame Stoffe beschrieben sind, die beispielsweise in die Entzündungskaskade eingreifen, besteht weiterhin ein Bedarf an besser wirksamen, an Nebenwirkungen armen Wirkstoffen. Weiter besteht ein Bedarf an Wirkstoffen mit einer guten Resorbierbarkeit und einer schnellen Penetration in die Haut, die zudem gut in pharmazeutische oder kosmetische Formulierungen einarbeitbar sein müssen.Although numerous pharmacologically active substances have already been described in the literature, which intervene, for example, in the inflammatory cascade, there is still a need for more effective active substances which are low in side effects. There is also a need for active ingredients with good resorbability and rapid penetration into the skin, which must also be able to be incorporated well into pharmaceutical or cosmetic formulations.
Die Aufgabe, die der vorliegenden Erfindung zugrunde liegt, bestand also darin, solche nebenwirkungsarmen, gut wirkenden und gut zu verarbeitenden und zu applizierenden Substanzen bereitzustellen.The object on which the present invention is based was therefore to provide such substances which have few side effects, have a good action and are easy to process and apply.
Glykoside und bestimmte Glykosidester sind z.B. aus der Natur bekannt. Nicht bekannt (weder aus Pflanzen, Mikroorganismen oder tierischen Zellen noch synthetisch hergestellt) sind hingegen die hier beschriebenen Ester, insbesondere PUFA- und CLA- Ester, von ungesättigten Fettsäuren mit Zuckern oder Glykosiden, bei denen mindestens eine der Hydroxylgruppen des Zuckers mit einer (ungesättigten) Carbonbzw. Fettsäure verestert ist.Glycosides and certain glycoside esters are e.g. known from nature. On the other hand, the esters described here, in particular PUFA and CLA esters, of unsaturated fatty acids with sugars or glycosides in which at least one of the hydroxyl groups of the sugar contains an (unsaturated one) are not known (neither from plants, microorganisms or animal cells nor synthetically produced) ) Carbon or Fatty acid is esterified.
Überraschenderweise wurde von den Erfindern gefunden, daß bestimmte Ester, insbesondere Ester von ungesättigten Fettsäuren mit Zuckern oder Glykosiden eine gegenüber den bekannten Einzelkomponenten (Fettsäure bzw. Zucker/Glykosid) verbesserte biologische Verfügbarkeit, verstärkte Wirkung und/oder ein verbreitertes Wirkspektrum aufweisen. Vorzugsweise erfolgt die Esterbildung mittels der primären Hydroxylgruppe des Zuckers/Glykosids; jedoch können auch die übrigen OH-Gruppen am Zucker oder eventuell vorhandene OH-Gruppen im Aglykon (z.B. Hydroxyrest im Fall des Arbutins) zur Veresterung verwendet werden.Surprisingly, it was found by the inventors that certain esters, in particular esters of unsaturated fatty acids with sugars or glycosides, have improved bioavailability, increased activity and / or a broader spectrum of activity than the known individual components (fatty acid or sugar / glycoside). The ester is preferably formed by means of the primary Hydroxyl group of sugar / glycoside; however, the other OH groups on the sugar or any OH groups present in the aglycone (eg hydroxyl radical in the case of arbutin) can also be used for the esterification.
Durch die Bereitstellung der Verbindungen der vorliegenden Erfindung konnten dieBy providing the compounds of the present invention, the
Erfinder die gestellte Aufgabe lösen.Inventors solve the task.
Die Verbindungen der vorliegenden Erfindung sind Ester der allgemeinen Formel (I):The compounds of the present invention are esters of the general formula (I):
Acn-0-Z-0-Rm (I), worin R einen Wasserstoff-, einen über eine Etherbrucke an den Zucker gebundenen verzweigten oder geradkettigen C8-C2o-Alkyl-, einen Arylalkyl- oder einen substituierten oder unsubstituierten Cβ-Cio-Arylrest darstellt, worin Z (Zucker) für ein Mono-, Disaccharid oder Polysaccharid steht, das n-fach esterartig mit Ac substituiert und, wenn R nicht für Wasserstoff steht, acetalisch an denAc n -0-Z-0-R m (I), in which R is a hydrogen, a branched or straight-chain C 8 -C 2 o-alkyl bonded to the sugar via an ether bridge, an arylalkyl or a substituted or unsubstituted Cβ-Cio-aryl radical, in which Z (sugar) is a mono-, disaccharide or polysaccharide which is substituted n-times with ester and with Ac and if R is not hydrogen, acetal to the
Rest R gebunden ist, worin Ac einen mehrfach ungesättigten C15 - C25-Acylrest mit mindestens 4 isolierten und/oder mindestens zwei konjugierten Doppelbindungen oder einen arylaliphatischenThe radical R is bound, where Ac is a polyunsaturated C 15 -C 25 acyl radical with at least 4 isolated and / or at least two conjugated double bonds or an arylaliphatic one
Rest mit 1-4 Methylengruppen zwischen Ester-Gruppe und aromatischem Ring darstellt, worin m eine ganze Zahl (1 , 2, 3, ...) einschließlich 0 ist, worin n eine ganze Zahl (1, 2, 3, ...), nicht aber 0, ist, mit der Maßgabe, daß Z-0-Rm nicht für Salicin, das ist 2-Hydroxymethyl-phenyl)-ß- glucopyranosid, steht.Residue with 1-4 methylene groups between ester group and aromatic ring, in which m is an integer (1, 2, 3, ...) including 0, in which n is an integer (1, 2, 3, ... ), but not 0, with the proviso that Z-0-R m is not salicin, which is 2-hydroxymethylphenyl) -ß-glucopyranoside.
Bevorzugt als Fettsäuren sind CLAs und Stearidonsäure, besonders bevorzugt die Octadecadiensäuren, die über konjugierte Doppelbindungen an den C-Atomen 9 und 11 , 10 und 12 oder 11 und 13 verfügen, insbesondere die eis, trans, 9, 11- und die eis, eis, 9, 11-Octadecadiensäure.Preferred fatty acids are CLAs and stearidonic acid, particularly preferred are the octadecadienoic acids which have conjugated double bonds on the C atoms 9 and 11, 10 and 12 or 11 and 13, in particular the eis, trans, 9, 11 and the eis, eis , 9, 11-octadecadienoic acid.
Figure imgf000006_0001
Figure imgf000006_0001
Stearidonsäure (CAS 20290-75-9); 6,9,12,15-Octadecatetraenoic aeid, (6Z,9Z,12Z,15Z)- (9CI) Als Zucker kommen Mono-, Di- und Oligosaccharide, insbesondere D-Glucose, D- Galactose, D-Xylose, D-Apiose, L-Rhamnose, L-Arabinose und Rutinose, in Betracht, wobei D-Glucose besonders bevorzugt ist.Stearidonic acid (CAS 20290-75-9); 6,9,12,15-Octadecatetraenoic aeid, (6Z, 9Z, 12Z, 15Z) - (9CI) Suitable sugars are mono-, di- and oligosaccharides, especially D-glucose, D-galactose, D-xylose, D-apiose, L-rhamnose, L-arabinose and rutinose, with D-glucose being particularly preferred.
Als Glykoside (Z-0-Rm) kommen als Zuckerbestandteil Monosaccharide (wie die im vorhergehenden Absatz genannten) enthaltende Verbindungen, insbesondere Arbutin, Fragilin und Populin, aber auch Oligo- oder Polysaccharide enthaltende Glykoside wie Alkylpoly-glucoside, speziell APG (Henkel KGaA), in Betracht.The glycosides (Z-0-R m ) are monosaccharides (such as those mentioned in the preceding paragraph) containing compounds, in particular arbutin, fragilin and populin, but also glycosides containing oligo- or polysaccharides, such as alkyl polyglucosides, especially APG (Henkel KGaA ).
Geeignet im Sinne der Erfindung sind Verbindungen, bei denen der Glykosid-Anteil (Z- 0-Rm) Arbutin (d.h. m = 1), Ac der Acylrest der eis, trans, 9, 11- oder der eis, eis, 9, 11- Octadecadiensäure und n 1 ist. Gleichfalls geeignet sind solche Verbindungen, bei denen der Glykosid-Anteil (Z-0-Rm) Fragilin (d.h. m = 1), Ac der Acylrest der eis, trans, 9, 11- oder der eis, eis, 9, 11-Octadecadiensäure und n 1 ist.Suitable for the purposes of the invention are compounds in which the glycoside content (Z-0-R m ) arbutin (ie m = 1), Ac the acyl radical of the eis, trans, 9, 11- or the eis, eis, 9, 11- octadecadienoic acid and n is 1. Also suitable are those compounds in which the glycoside portion (Z-0-R m ) fragilin (ie m = 1), Ac the acyl residue of the eis, trans, 9, 11- or the eis, eis, 9, 11- Octadecadienoic acid and n is 1.
Andere vorteilhafte Verbindungen sind Ester, wobei der Glykosid-Anteil (Z-0-Rm) Arbutin (d.h. m = 1), Ac der Acylrest der eis, trans, 9, 11- oder der eis, eis, 9, 11- Octadecadiensäure und n 2 ist; Ester, wobei der Glykosid-Anteil (Z-0-Rm) Fragilin (d.h. m = 1), Ac der Acylrest der cis. rans, 9, 11- oder der eis, eis, 9, 11-Octadecadiensäure und n 2 ist; Verbindungen, bei denen der Glykosid-Anteil (Z-0-Rm) Arbutin oder Fragilin (d.h. m = 1), Ac der Acylrest der Stearidonsäure und n 1 ist; schließlich Verbindungen, wobei der Glykosid-Anteil (Z-0-Rm) Arbutin oder Fragilin (d.h. m = 1), Ac der Acylrest der Stearidonsäure und n 2 ist.Other advantageous compounds are esters, the glycoside portion (Z-0-R m ) arbutin (ie m = 1), Ac the acyl residue of eis, trans, 9, 11- or eis, eis, 9, 11-octadecadienoic acid and n is 2; Esters, the glycoside portion (Z-0-R m ) fragilin (ie m = 1), Ac the acyl residue of the cis. rans, 9, 11- or the eis, eis, 9, 11-octadecadienoic acid and n is 2; Compounds in which the glycoside portion (Z-0-R m ) is arbutin or fragilin (ie m = 1), Ac is the acyl radical of stearidonic acid and n 1; finally compounds, the glycoside portion (Z-0-R m ) arbutin or fragilin (ie m = 1), Ac the acyl residue of stearidonic acid and n 2.
Andere vorteilhafte Verbindungen sind Ester mit folgenden Parametern: wenn n = 1 , ist der einzige Rest Ac an eine primäre OH-Gruppe des Zuckers gebunden, insbesondere an diejenige primäre OH-Gruppe, die an der Zuckereinheit sitzt, an den auch R gebunden ist, wenn m ≠ 0; wenn n = 2, ist ein Rest Ac an diejenige primäre OH-Gruppe, die an der Zuckereinheit sitzt, an den auch R gebunden ist, wenn m ≠ 0, und der andere Rest Ac ist an eine weitere primäre oder an eine sekundäre OH-Gruppe des Zuckers gebunden.Other advantageous compounds are esters with the following parameters: if n = 1, the only radical Ac is bound to a primary OH group of the sugar, in particular to that primary OH group which is attached to the sugar unit to which R is also bound, if m ≠ 0; if n = 2, a radical Ac is attached to the primary OH group that is attached to the sugar unit to which R is also bound, if m ≠ 0, and the other radical Ac is attached to a further primary or to a secondary OH Group of sugar tied.
Besonders bevorzugte Verbindungen gemäß der vorliegenden Erfindung sind die folgenden Ester 1 bis 30, bei denen sowohl m als auch n 1 sind, bei denen Ac, Z und R die folgenden Bedeutungen haben und bei denen die Estergruppe über die primäre Alkoholgruppe des Zuckers/Glykosids gebildet wird (sind mehrere Glucose- bzw. Zucker-Einheiten vorhanden, liegt die Veresterung am primären OH der Glucose- Einheit vor, die auch glykosidisch verknüpft ist mit z.B. CH3-(CH2)ιo-CH2OH):Particularly preferred compounds according to the present invention are the following esters 1 to 30, in which both m and n are 1, in which Ac, Z and R have the following meanings and in which the ester group is formed via the primary alcohol group of the sugar / glycoside (if several glucose or sugar units are present, there is esterification at the primary OH of the glucose unit, which is also glycosidically linked to, for example CH 3 - (CH 2 ) ιo-CH 2 OH):
1. Ac st eis, trans, 9,11-Octadecadienoyl; Z ist D-Glucose; ist H;1. Ac st eis, trans, 9,11-octadecadienoyl; Z is D-glucose; is H;
2. Ac st eis, eis, 9,11-Octadecadienoyl; Z ist D-Glucose; R ist H;2. Ac st ice, ice, 9,11-octadecadienoyl; Z is D-glucose; R is H;
3. Ac st trans, eis, 10,12-Octadecadienoyl; Z ist D-Glucose; R ist H;3. Ac st trans, ice, 10,12-octadecadienoyl; Z is D-glucose; R is H;
4. Ac st eis, trans, 9,11-Octadecadienoyl; Z ist D-Glucose; R ist -para-C6H4-OH;4. Ac st eis, trans, 9,11-octadecadienoyl; Z is D-glucose; R is -para-C 6 H 4 -OH;
5. Ac st eis, eis, 9,11-Octadecadienoyl; Z ist D-Glucose; R ist -para-C6H -OH;5. Ac st ice, ice, 9,11-octadecadienoyl; Z is D-glucose; R is -para-C 6 H -OH;
6. Ac st trans, eis, 10,12-Octadecadienoyl; Z ist D-Glucose; R ist -para-C6H4-OH;6. Ac st trans, ice, 10,12-octadecadienoyl; Z is D-glucose; R is -para-C 6 H 4 -OH;
7. Ac st eis, trans, 9,11-Octadecadienoyl; Z ist D-Glucose; R ist (CH2)nCH3;7. Ac st eis, trans, 9,11-octadecadienoyl; Z is D-glucose; R is (CH 2 ) nCH 3 ;
8. Ac st eis, eis, 9,11-Octadecadienoyl; Z ist D-Glucose; R ist (CH2)nCH3;8. Ac st ice, ice, 9,11-octadecadienoyl; Z is D-glucose; R is (CH 2 ) nCH 3 ;
9. Ac st trans, eis, 10,12-Octadecadienoyl; Z ist D-Glucose; R ist (CH2)nCH3;9. Ac st trans, ice, 10,12-octadecadienoyl; Z is D-glucose; R is (CH 2 ) nCH 3 ;
10. Ac st eis, trans, 9,11-Octadecadienoyl; Z ist (D-Glucose)2; R ist (CH2)nCH3;10. Ac st eis, trans, 9,11-octadecadienoyl; Z is (D-glucose) 2 ; R is (CH 2 ) nCH 3 ;
11. Ac st eis, eis, 9,11-Octadecadienoyl; Z ist (D-Glucose)2; R ist (CH2)ιιCH3; 12.Ac st trans, eis, 10,12-Octadecadienoyl; Z ist (D-Glucose)2; R ist (CH2)ιιCH3; 13.Ac st eis, trans, 9,11-Octadecadienoyl; Z ist (D-Glucose)3; R ist (CH2)nCH3; 14.Ac st eis, eis, 9,11-Octadecadienoyl; Z ist (D-Glucose)3; R ist (CH2)nCH3; 15.AC st trans, eis, 10,12-Octadecadienoyl; Z ist (D-Glucose)3; R ist (CH2)nCH3; 16.Ac st eis, trans, 9,11-Octadecadienoyl; Z ist (D-Glucose)4; R ist (CH2)ιιCH3; 17.AC st eis, eis, 9,11-Octadecadienoyl; Z ist (D-Glucose)4; R ist (CH2)nCH3; 18.Ac st trans, eis, 10,12-Octadecadienoyl; Z ist (D-Glucose) ; R ist (CH2)nCH3; 19.Ac st eis, trans, 9,11-Octadecadienoyl; Z ist (D-Glucose)5; R ist (CH2)nCH3;11. Ac st eis, eis, 9,11-octadecadienoyl; Z is (D-glucose) 2 ; R is (CH 2 ) ιιCH 3 ; 12.Ac st trans, ice, 10,12-octadecadienoyl; Z is (D-glucose) 2 ; R is (CH 2 ) ιιCH 3 ; 13.Ac st eis, trans, 9,11-octadecadienoyl; Z is (D-glucose) 3 ; R is (CH2) nCH 3 ; 14.Ac st eis, eis, 9,11-octadecadienoyl; Z is (D-glucose) 3 ; R is (CH 2 ) nCH 3 ; 15.AC st trans, ice, 10,12-octadecadienoyl; Z is (D-glucose) 3 ; R is (CH 2 ) nCH 3 ; 16.Ac st eis, trans, 9,11-octadecadienoyl; Z is (D-glucose) 4 ; R is (CH 2 ) ιιCH 3 ; 17.AC st ice, ice, 9,11-octadecadienoyl; Z is (D-glucose) 4 ; R is (CH 2 ) nCH 3 ; 18.Ac st trans, ice, 10,12-octadecadienoyl; Z is (D-glucose); R is (CH 2 ) nCH 3 ; 19.Ac st eis, trans, 9,11-octadecadienoyl; Z is (D-glucose) 5 ; R is (CH 2 ) nCH 3 ;
20.Ac st eis, eis, 9,11-Octadecadienoyl; Z ist (D-Glucose)5; R ist (CH2)11CH3;20.Ac st ice, ice, 9,11-octadecadienoyl; Z is (D-glucose) 5 ; R is (CH 2 ) 11CH 3 ;
21.Ac st trans, eis, 10,12-Octadecadienoyl; Z ist (D-Glucose)5; R ist (CH2)nCH3; 22.AC st eis, trans, 9,11-Octadecadienoyl; Z ist (D-Glucose)6; R ist (CH2)nCH3;21.Ac st trans, ice, 10,12-octadecadienoyl; Z is (D-glucose) 5 ; R is (CH 2 ) nCH 3 ; 22.AC st eis, trans, 9,11-octadecadienoyl; Z is (D-glucose) 6 ; R is (CH 2 ) nCH 3 ;
23.Ac st eis, eis, 9,11-Octadecadienoyl; Z ist (D-Glucose)6; R ist (CH2)11CH3;23.Ac st eis, eis, 9,11-octadecadienoyl; Z is (D-glucose) 6 ; R is (CH 2 ) 11CH 3 ;
24.Ac st trans, eis, 10,12-Octadecadienoyl; Z ist (D-Glucose)6; R ist (CH2)nCH3;24.Ac st trans, ice, 10,12-octadecadienoyl; Z is (D-glucose) 6 ; R is (CH 2 ) nCH 3 ;
25.Ac st eis, trans, 9,11-Octadecadienoyl; Z ist (D-Glucose)7; R ist (CH2)nCH3;25.Ac st eis, trans, 9,11-octadecadienoyl; Z is (D-glucose) 7 ; R is (CH 2 ) nCH 3 ;
26.Ac st eis, eis, 9,11-Octadecadienoyl; Z ist (D-Glucose)7; R ist (CH2)nCH3;26.Ac st eis, eis, 9,11-octadecadienoyl; Z is (D-glucose) 7 ; R is (CH 2 ) nCH 3 ;
27.Ac st trans, eis, 10,12-Octadecadienoyl; Z ist (D-Glucose)7; R ist (CH2)nCH3; 28.Ac st 6,9,12,15-Octadecatetraenoyl (6Z,9Z,12Z,15Z); Z ist D-Glucose; R ist H; 29.Ac st 6,9,12, 15-Octadecatetraenoyl (6Z,9Z,12Z,15Z); Z ist D-Glucose; R ist -p-27.Ac st trans, ice, 10,12-octadecadienoyl; Z is (D-glucose) 7 ; R is (CH 2 ) nCH 3 ; 28.Ac st 6,9,12,15-octadecatetraenoyl (6Z, 9Z, 12Z, 15Z); Z is D-glucose; R is H; 29.Ac st 6,9,12, 15-octadecatetraenoyl (6Z, 9Z, 12Z, 15Z); Z is D-glucose; R is -p-
C6H4-OH; 30.Ac ist 6,9,12,15-Octadecatetraenoyl (6Z,9Z,12Z,15Z); Z ist D-Glucose; und R ist (CH2)nCH3.C 6 H 4 -OH; 30.Ac is 6,9,12,15-octadecatetraenoyl (6Z, 9Z, 12Z, 15Z); Z is D-glucose; and R is (CH 2 ) nCH 3 .
Weitere bevorzugte Verbindungen sind die Ester 31 bis 60, die sich von den Estern 1 bis 30 lediglich dadurch unterscheiden, daß die Zuckereinheit(en) nicht aus D-Glucose, sondern aus der entsprechenden Anzahl von D-Galactose-Einheiten besteht. Der EsterFurther preferred compounds are the esters 31 to 60, which differ from the esters 1 to 30 only in that the sugar unit (s) does not consist of D-glucose, but instead of the corresponding number of D-galactose units. The ester
54 ist also, um ein Beispiel zu geben, ein Analogon zum Ester 24 und somit ein Ester, bei dem Ac trans, eis, 10,12-Octadecadienoyl; Z (D-Galactose)6; R (CH2)nCH3; m und n 1 sind. Bevorzugt sind auch die folgenden Ester 61 bis 120 in Analogie zu den Estern 1 bis 60, die sich allerdings von letzteren dadurch unterscheiden, daß n = 2 und daß der zweiteTo give an example, 54 is therefore an analogue of ester 24 and thus an ester in which Ac trans, eis, 10,12-octadecadienoyl; Z (D-galactose) 6 ; R (CH 2 ) nCH3; m and n are 1. Also preferred are the following esters 61 to 120 in analogy to the esters 1 to 60, which differ from the latter in that n = 2 and that the second
Ac-Rest am 4-OH der Glucose- bzw. Galactose-Einheit sitzt.Ac residue at the 4-OH of the glucose or galactose unit.
Weiterhin bevorzugt sind die folgenden Ester 121 bis 180 in Analogie zu den Estern 61 bis 120, die sich allerdings von letzteren dadurch unterscheiden, daß der zweite Ac- Rest nicht am 4-OH, sondern am 1-OH der Glucose- bzw. Galactose-Einheit sitzt. Ebenfalls bevorzugt sind die folgenden Ester 181 bis 240 in Analogie zu den Estern 121 bis 180, die sich allerdings von letzteren dadurch unterscheiden, daß der zweite Ac-Rest nicht am 1-OH, sondern am 2-OH der Glucose- bzw. Galactose-Einheit sitzt.Further preferred are the following esters 121 to 180 in analogy to the esters 61 to 120, which differ from the latter in that the second Ac residue is not on the 4-OH but on the 1-OH of the glucose or galactose Unit sits. Likewise preferred are the following esters 181 to 240 in analogy to the esters 121 to 180, which differ from the latter in that the second Ac residue is not on the 1-OH but on the 2-OH of the glucose or galactose Unit sits.
Weitere bevorzugte Ester sind die folgenden Ester 241 bis 300 in Analogie zu den Estern 1 bis 60, die sich allerdings von letzteren dadurch unterscheiden, daß n = 3 und daß diese Verknüp-fungen an der primären (6-OH-) sowie der 1-OH- und der 4-OH- Gruppe des Zuckers erfolgen.Further preferred esters are the following esters 241 to 300 in analogy to esters 1 to 60, which differ from the latter in that n = 3 and that these linkages on the primary (6-OH-) and the 1- OH and the 4-OH group of the sugar take place.
Andere bevorzugte Ester sind die folgenden Ester 301 bis 360 in Analogie zu den Estern 241 bis 300, die sich allerdings von letzteren dadurch unterscheiden, daß die drei Ac-Reste an der primären sowie der 2-OH- und der 4-OH-Gruppe des Zuckers gebunden sind.Other preferred esters are the following esters 301 to 360 in analogy to esters 241 to 300, which differ from the latter in that the three Ac residues on the primary and the 2-OH and the 4-OH group of the Sugar are bound.
Wiederum andere bevorzugte Ester sind die folgenden Ester 361 bis 420 in Analogie zu den Estern 1 bis 60, die sich allerdings von letzteren dadurch unterscheiden, daß n = 4 und daß diese Verknüpfungen an der primären (6-OH-) sowie der 1-OH-, der 2-OH- und der 4-OH-Gruppe des Zuckers erfolgen. Durch die erfindungsgemäße Modifikation der Fettsäuren, d.h. durch die oben beschriebene Derivatisierung der Fettsäuren in Form der Verbindungen der vorliegenden Erfindung, wird die Verträglichkeit sowie die biologische Verfügbarkeit und Wirkung derartiger Fettsäuren für den Einsatz in Kosmetik, Pharmazie und/oder Ernährung verbessert.Still other preferred esters are the following esters 361 to 420 in analogy to esters 1 to 60, which differ from the latter in that n = 4 and that these linkages on the primary (6-OH-) and the 1-OH -, The 2-OH and the 4-OH group of the sugar. The modification of the fatty acids according to the invention, ie the derivatization of the fatty acids in the form of the compounds of the present invention described above, improves the tolerance and the bioavailability and effect of such fatty acids for use in cosmetics, pharmacy and / or nutrition.
Dementsprechend betreffen weitere Aspekte der vorliegenden Erfindung die Verwendung der Verbindungen der allgemeinen Formel (I) zur Herstellung von kosmetischen und pharmazeutischen Zubereitungen, ihre Verwendung als Additive zu Nahrungs-, Nahrungsergänzungs- und Futtermitteln. Weitere Aspekte der vorliegenden Erfindung betreffen pharmazeutische und kosmetische Zubereitungen sowie Nahrungs-, Nahrungsergänzungs- und Futtermittel, die wenigstens eine Verbindung der allgemeinen Formel (I) enthalten.Accordingly, further aspects of the present invention relate to the use of the compounds of the general formula (I) for the production of cosmetic and pharmaceutical preparations, their use as additives to food, nutritional supplements and animal feed. Further aspects of the present invention relate to pharmaceutical and cosmetic preparations and to food, nutritional supplements and animal feeds which contain at least one compound of the general formula (I).
Ein weiterer Gegenstand der Erfindung ist demnach ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen der Formel (I), das dadurch gekennzeichnet ist, daß ein Zucker Z bzw. ein Glykosid Z-0-Rm mit einer ungesättigten Fettsäure AcOH oder mit einem Ester, vorzugsweise einem Methyl- oder Ethylester, dieser Fettsäuren AcOH in Gegenwart einer Lipase verestert wird.The invention accordingly furthermore relates to a process for the preparation of the compounds of the formula (I) according to the invention, which is characterized in that a sugar Z or a glycoside Z-0-R m with an unsaturated fatty acid AcOH or with an ester, preferably a methyl or ethyl ester, this fatty acid AcOH is esterified in the presence of a lipase.
Zu den geeigneten enzymatischen Katalysatoren zur Veresterung (mittels Umesterung) der genannten Säuren und Alkoholkomponenten zählen die Hydrolasen, speziell die Lipasen wie die Lipasen aus Candida antarctica, Candida rugosa (ehemals Candida cylandracea), Geotrichum candidum, Aspergillus niger, Penicillium roqueforti, Rhizopus arrhizus und Mucor miehei.Suitable enzymatic catalysts for the esterification (by transesterification) of the acids and alcohol components mentioned include the hydrolases, especially the lipases such as the lipases from Candida antarctica, Candida rugosa (formerly Candida cylandracea), Geotrichum candidum, Aspergillus niger, Penicillium roqueforti, Rhizopus arrhizus and Mucor miehei.
Eine bevorzugte Lipase ist die Lipase (Isoenzym B) aus Candida antarctica, wofür es zwei Gründe gibt. Erstens zeigt sie eine besonders hohe Selektivität bei der Veresterung der Acetale mit den ungesättigten Fettsäuren, obwohl diese nicht zu ihren typischen Substraten zählen. Des weiteren zeigt sie keine Grenzflächenaktivierung (ein entscheidendes Merkmal zur Klassi-fizierung von Hydrolasen in die Gruppe der Lipasen), da ihr ein wichtiges Lipasestrukturmerk-mal, eine bewegliche Peptidkette am aktiven Zentrum (sog. lid) fehlt. Es wird also die selektive Veresterungseigenschaften einiger Enzyme (siehe Beschreibung), insbesondere Lipase aus Candida antarctica Isoenzym B, dazu genutzt, Wirksubstanzen miteinander zu verestem und so die Wirkungen zu verknüpfen und teilweise zu verbessern und gleichzeitig eine Möglichkeit zu haben, das aktivste Isomer der CLAs aus dem Gemisch zu isolieren.A preferred lipase is the lipase (isoenzyme B) from Candida antarctica, for which there are two reasons. First, it shows a particularly high selectivity in the esterification of the acetals with the unsaturated fatty acids, although these are not among their typical substrates. Furthermore, it shows no interface activation (a crucial feature for the classification of hydrolases in the group of lipases), since it lacks an important lipase structural feature, a movable peptide chain at the active center (so-called lid). The selective esterification properties of some enzymes (see description), in particular lipase from Candida antarctica isoenzyme B, are therefore used to esterify active substances with one another and thus to link and partially improve the effects, while at the same time being able to use the most active isomer of CLAs isolate from the mixture.
Gerade die gezielte Veresterung ist aber für die biologische Verfügbarkeit und Verträglichkeit der erfindungsgemäßen Substanzen entscheidend. Die chemische Synthese führt jedoch aufgrund mangelnder Regioselektivität zu groben Produktgemischen. Daher ist die hier beschriebene enzymatisehe (siehe Beispiele) milde und regioselektive Synthese von Vorteil. Erfindungsgemäß bedeutet regiospezifisch, daß nur e i n e bestimmte OH-Gruppe eines Polyols verestert wird. Entsprechend bedeutet regioselektiv, daß e i n e bestimmte OH-Gruppe eines Polyols bevorzugt, aber nicht ausschließlich, verestert wird.Targeted esterification, however, is crucial for the biological availability and compatibility of the substances according to the invention. However, chemical synthesis leads to coarse product mixtures due to a lack of regioselectivity. Therefore the mild and regioselective synthesis described here (see examples) is advantageous. According to the invention, region-specific means that only a certain OH group of a polyol is esterified. Correspondingly, regioselective means that a particular OH group of a polyol is preferably, but not exclusively, esterified.
Sind die erfindungsgemäßen Verbindungen der Formel (I) erst einmal mittels des erfindungsgemäßen Verfahrens hergestellt worden, muß in aller Regel ein Verfahren folgen, um=die gewünsche(n) Verbindung(en) aufzureinigen. Somit besteht ein weiterer Gegenstand der vorliegenden Erfindung darin, ein Verfahren zur Aufreinigung der Verbindungen der Formel (I) bereitzustellen, das dadurch gekennzeichnet ist, daß es sich um ein wäßriges Zweiphasen-Extraktionsverfahren mit organischen Lösungsmitteln handelt, mit dem die Zielverbindung selektiv von den nicht umgesetzten Fettsäuren getrennt werden kann. Vorzugsweise handelt es sich bei dem organischen Lösungsmittel um n-Hexan, Cyclohexan, THF, Dieethylether. Alternativ kann die Aufreinigung auch durch ein chromatographisches Verfahren an Kieselgel, vorzugsweise mit Ethylacetat/Methanol- oder Dichlormethan/Methanol-Gemischen mit geringen Anteilen Essigsäure und/oder Wasser erfolgen, das auch zusätzlich zu einem wäßrigen Zweiphasen-Extraktionsverfahren mit organischen Lösungsmitteln durchgeführt werden kann.Once the compounds of the formula (I) according to the invention have been prepared using the process according to the invention, a process must generally follow in order to = purify the desired compound (s). It is therefore a further object of the present invention to provide a process for the purification of the compounds of the formula (I), which is characterized in that it is an aqueous two-phase extraction process with organic solvents, by means of which the target compound is selective from those which are not implemented fatty acids can be separated. The organic solvent is preferably n-hexane, cyclohexane, THF, dieethyl ether. Alternatively, the purification can also be carried out by a chromatographic process on silica gel, preferably with ethyl acetate / methanol or dichloromethane / methanol mixtures with small proportions of acetic acid and / or water, which can also be carried out in addition to an aqueous two-phase extraction process with organic solvents.
Da die erfindungsgemäßen Ester der Formel (I) eine gute biologische Verfügbarkeit und Wirkung haben, lassen sie sich in kosmetischen und pharmazeutischen Zubereitungen und/oder als Nahrungsmittel-Zusatzstoffe verwenden mit dem Ergebnis, daß die Qualität ebendieser Produkte deutlich verbessert wird. Die erfindungsgemäßen Ester der konjugierten Linolsäuren (CLAs) weisen eine antiinflam-matorische, antipyretische, antiphlogistische und/oder analgetische Wirkung auf und haben über-dies auch antioxidative, hautaufhellende oder antibakterielle/antivirale Effekte. Die Fettdepot-reduzierende Wirkung der CLAs zeigt sich ebenfalls in den erfindungsgemäßen Verbindungen.Since the esters of formula (I) according to the invention have good bioavailability and activity, they can be used in cosmetic and pharmaceutical preparations and / or as food additives, with the result that the quality of these products is significantly improved. The esters of conjugated linoleic acids (CLAs) according to the invention have an anti-inflammatory, antipyretic, anti-inflammatory and / or analgesic effect and also have antioxidative, skin-lightening or antibacterial / antiviral effects. The fat depot-reducing effect of the CLAs is also evident in the compounds according to the invention.
Da die Verbindungen der Formel (I) eine gute biologische Verfügbarkeit und Wirkung haben, lassen sie sich in kosmetischen und pharmazeutischen Zubereitungen und/oder als Nahrungsmittel-Zusatzstoffe verwenden mit dem Ergebnis, daß die Qualität ebendieser Produkte deutlich verbessert wird.Since the compounds of formula (I) have good bioavailability and activity, they can be used in cosmetic and pharmaceutical preparations and / or as food additives, with the result that the quality of these products is significantly improved.
Darüber hinaus sind die erfindungsgemäßen Verbindungen besonders gut in lipophile Basis-rezepturen einarbeitbar und lassen sich auf einfache Weise als stabile Emulsionen formulieren.In addition, the compounds according to the invention can be incorporated particularly well into lipophilic base formulations and can be easily formulated as stable emulsions.
Dementsprechend werden die erfindungsgemäßen Verbindungen der Formel (I) zur Herstellung von kosmetischen und/oder pharmazeutischen Zubereitungen und/oder Nahrungs- bzw. Futtermitteln verwendet.Accordingly, the compounds of formula (I) according to the invention are used for the production of cosmetic and / or pharmaceutical preparations and / or food or feed.
Weitere Gegenstände der Erfindung sind danach die Verwendung der Verbindungen der Formel (I) zur Herstellung von kosmetischen und/oder pharmazeutischen Zubereitungen; die Verwendung als Nahrungsergänzungs- oder -Zusatzstoffe in Nahrungszubereitungen und in Futtermitteln (z.B. für die Tierzucht); kosmetische und pharmazeutische Zubereitungen sowie NahrungsmittelAzubereitungen und Futtermittel, die (eine) Verbindung(en) der Formel (I) enthalten.The invention further relates to the use of the compounds of the formula (I) for the production of cosmetic and / or pharmaceutical preparations; the use as food supplements or additives in food preparations and in feed (e.g. for animal breeding); cosmetic and pharmaceutical preparations as well as food preparations and animal feeds containing (a) compound (s) of the formula (I).
Die unter erfindungsgemäßer Verwendung der Verbindungen (I) erhältlichen kosmetischen Zubereitungen wie Haarshampoos, Haarlotionen, Schaumbäder, Duschbäder, Cremes, Gele, Lo-tionen, alkoholische und wäßrig/alkoholische Lösungen, Emulsionen, Wachs/Fett-Massen, Stift-präparate, Puder oder Salben, können ferner als weitere Hilfs- und Zusatzstoffe milde Tenside, Ölkörper, Emulatoren, Überfettungsmittel, Perlglanzwachse, Konsistenzgeber, Verdickungs-mittel, Polymere, Siliconverbindungen, Fette, Wachse, Stabilisatoren, biogene Wirkstoffe, Deo-wirkstoffe, Antischuppenmittel, Filmbildner, Quellmittel, UV-Lichtschutzfaktoren, Antioxidan-tien, Hydrotrope, Konservierungsmittel, Insektenrepellentien, Selbstbräuner, Solubilisatoren, Parfümöle, Farbstoffe, keimhemmende Mittel und dergleichen enthalten.The cosmetic preparations obtainable using the compounds (I) according to the invention such as hair shampoos, hair lotions, foam baths, shower baths, creams, gels, lotion, alcoholic and aqueous / alcoholic solutions, emulsions, wax / fat masses, stick preparations, powder or Ointments can also be used as further auxiliaries and additives, mild surfactants, oil bodies, emulators, superfatting agents, pearlescent waxes, consistency agents, thickeners, polymers, silicone compounds, fats, waxes, stabilizers, biogenic active substances, deodorant substances, Contain antidandruff agents, film formers, swelling agents, UV light protection factors, antioxidants, hydrotropes, preservatives, insect repellents, self-tanners, solubilizers, perfume oils, dyes, germ-inhibiting agents and the like.
Die Einsatzmenge der erfindungsgemäßen Verbindungen in den kosmetischen Zubereitungen liegt üblicherweise im Bereich von 0,01 bis 5 Gew.-%, vorzugsweise jedoch von 0,1 bis 1 Gew.-% bezogen auf die Gesamtmenge der Zubereitungen.The amount of the compounds according to the invention used in the cosmetic preparations is usually in the range from 0.01 to 5% by weight, but preferably from 0.1 to 1% by weight, based on the total amount of the preparations.
Zur Herstellung pharmazeutischer oder auch kosmetischer Zubereitungen lassen sich die erfindungsgemäßen Verbindungen der allgemeinen Formel (I), gegebenenfalls in Kombi-nation mit anderen Wirksubstanzen, zusammen mit einem oder mehreren inerten üblichen Trägerstoffen und/oder Verdünnungsmitteln, z. B. mit Maisstärke, Milchzucker, Rohrzucker, mikrokristalliner Cellulose, Magnesiumstearat, Polyvinylpyrrolidon, Zitronensäure, Weinsäu-re, Wasser, Wasser/Ethanol, Wasser/Glycerin, Wasser/Sorbit, Wasser/Polyethylenglykol, Propylenglykol, Carboxymethylcellulose oder fetthaltigen Substanzen wie Hartfett oder deren geeigneten Gemischen, in übliche galenische Zubereitungen wie Tabletten, Dragees, Kapseln, Pulver, Suspensionen, Tropfen, Ampullen, Säfte oder Zäpfchen einarbeiten.For the production of pharmaceutical or cosmetic preparations, the compounds of the general formula (I) according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for. B. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, carboxymethyl cellulose or fatty substances such as hard fat or the like suitable mixtures, work into conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or suppositories.
Die zur Erzielung einer entsprechenden Wirkung bei pharmazeutischen Anwendungen erforderliche tägliche Dosierung beträgt zweckmäßigerweise 0,1 bis 10 mg/kg Körpergewicht, vorzugsweise 0,5 bis 2 mg/kg Körpergewicht.The daily dosage required to achieve a corresponding effect in pharmaceutical applications is advantageously 0.1 to 10 mg / kg body weight, preferably 0.5 to 2 mg / kg body weight.
Die unter erfindungsgemäßer Verwendung der Verbindungen der Formel (I) erhältlichen Nah-rungsersatz- und -Zusatzstoffe wie Sportler-Drinks enthalten geeigneterweise die Verbindun-g(en) der Formel (I) in einer Menge, die bei einem üblichen Bedarf an Flüssigkeitsaufnahme von 1 bis 5 Litern pro Tag zu einer Dosierung dieser Verbindungen von an 0.1 bis 10 mg, vorzugsweise 0,5 bis 5 mg, pro kg Körpergewicht führt. Eine beispielhafte Verwendung in der Nahrungsmittelindustrie besteht für die Verbindungen der Formel (I) als Färbe- und/oder Gewürzstoffe. BeispieleThe nutritional substitutes and additives, such as sports drinks, obtainable using the compounds of the formula (I) according to the invention suitably contain the compounds (s) of the formula (I) in an amount which, with a normal need for fluid intake of 1 up to 5 liters per day leads to a dosage of these compounds of 0.1 to 10 mg, preferably 0.5 to 5 mg, per kg of body weight. An example of use in the food industry is for the compounds of the formula (I) as colorings and / or spices. Examples
Beispiel 1: CLA + GlucoseExample 1: CLA + glucose
6-O-cis-9,trans-11 -Octadecadienoyl-D-glucopyranose 19.8 g (0.1 mol) D-(+)-Glucose, 39.6 g CLA (60% konjugierte Linolsäure) (Edenor UKD 6010), 30 g Molekularsieb, 120 ml t-Butanol und 3 g immobilisierte Lipase B aus Candida antarctica wurden 48 Stunden bei 60 °C mit 400 rpm am Magnetrührer im 300 ml Erlenmeyerkolben inkubiert. Die Umsetzung wurde mittels Dünnschichtchromatographie (Kieselgel 60-Platten mit Fluoreszenzindikator; Laufmittel: Ethylacetat/Methanol 10:1 , v/v und Dichlormethan/Metha-nol/Essigsäure 95:5:0.1, v/v/v; Visualisierung: UV-Detektion sowie mittels eines Essigsäure/6-O-cis-9, trans-11-octadecadienoyl-D-glucopyranose 19.8 g (0.1 mol) D - (+) - glucose, 39.6 g CLA (60% conjugated linoleic acid) (Edenor UKD 6010), 30 g molecular sieve, 120 ml of t-butanol and 3 g of immobilized lipase B from Candida antarctica were incubated for 48 hours at 60 ° C. with 400 rpm on a magnetic stirrer in a 300 ml Erlenmeyer flask. The reaction was carried out by means of thin layer chromatography (silica gel 60 plates with fluorescent indicator; eluent: ethyl acetate / methanol 10: 1, v / v and dichloromethane / methanol / acetic acid 95: 5: 0.1, v / v / v; visualization: UV detection as well as by means of an acetic acid /
Schwefelsäure/Anisaldehyd-Tauchreagenz (100:2:1 , v/v/v)) nachgewiesen. Das Produkt wurde mit 300 ml THF extrahiert und über Säulenchromatographie (Kieselgel F60; Laufmittel: Ethylacetat/Methanol 10:1 , v/v) gereinigt. Nach Reinigung betrug die Ausbeute 43 g (37.3 %) (hochviskoses Produkt). Das Verhältnis von cis-trans-lsomer zu cis-cis-lsomer beträgt 1 :0.4. RrWert: 0.41 (Ethylacetat/Methanol 10:1)Sulfuric acid / anisaldehyde immersion reagent (100: 2: 1, v / v / v)) detected. The product was extracted with 300 ml of THF and purified by column chromatography (silica gel F60; mobile phase: ethyl acetate / methanol 10: 1, v / v). After purification, the yield was 43 g (37.3%) (highly viscous product). The ratio of cis-trans-isomer to cis-cis-isomer is 1: 0.4. RrValue: 0.41 (ethyl acetate / methanol 10: 1)
0.05 (Dichlormethan/Methanol/Essigsäure 95:5:0.1) 13C-NMR (100.6 MHz, CD3OD): δ = (cis-trans-lsomer) 14.4 (C-18), 23.8 (C-17), 25.8 (C- 3) 28.0 (C-8), 30.1-30.7 (C-4, C-5, C-6, C-7, C-14, C-15, C-16), 32.8 (C-13), 34.6 (C-2), 64.8 (C-6'), 70.4 (C-4'), 71.8 (C-5'), 73.8 (C-2'), 74.9 (C-3'), 93.8 (C-1 '), 129.7 (C-10), 130.2 (C-11), 130.5 (C-12), 131.6 (C-9), 173.6 (C-1). δ = (cis-cis Isomer) 14.4 (C-18), 23.8 (C-17), 25.6 (C-3) 30.1-30.7 (C-4, C-5, C-6, C-7, C-14, C-15, C-16), 32.6 (C-13), 33.6 (C-8), 34.4 (C-2), 64.8 (C-6'), 70.4 (C-4'), 71.8 (C- 5'), 73.8 (C-2'), 74.9 (C-3'), 93.8 (C-1 '), 126.8 (C-11) 129.7 (C-10), 130.2 (C-9), 131.6 (C-12), 174.8 (C-1).0.05 (dichloromethane / methanol / acetic acid 95: 5: 0.1) 13 C-NMR (100.6 MHz, CD 3 OD): δ = (cis-trans-isomer) 14.4 (C-18), 23.8 (C-17), 25.8 (C- 3) 28.0 (C-8), 30.1-30.7 (C-4, C-5, C-6, C-7, C-14, C-15, C-16), 32.8 (C-13 ), 34.6 (C-2), 64.8 (C-6 '), 70.4 (C-4'), 71.8 (C-5 '), 73.8 (C-2'), 74.9 (C-3 '), 93.8 (C-1 '), 129.7 (C-10), 130.2 (C-11), 130.5 (C-12), 131.6 (C-9), 173.6 (C-1). δ = (cis-cis isomer) 14.4 (C-18), 23.8 (C-17), 25.6 (C-3) 30.1-30.7 (C-4, C-5, C-6, C-7, C- 14, C-15, C-16), 32.6 (C-13), 33.6 (C-8), 34.4 (C-2), 64.8 (C-6 '), 70.4 (C-4'), 71.8 ( C- 5 '), 73.8 (C-2'), 74.9 (C-3 '), 93.8 (C-1'), 126.8 (C-11) 129.7 (C-10), 130.2 (C-9), 131.6 (C-12), 174.8 (C-1).
Beispiel 2: CLA + Alkylpolyglykosid (APG) 6-0-cis-9,trans-11 -Octadecadienoyl-alkylglucosid 2g APG (Henkel KGaA), 15g Edenor UKD6010, 4.5 g Molekularsieb, 10 ml t-Butanol und 4.5 g immobilisierte Lipase B aus Candida antarctica wurden 48 Stunden bei 60 °C mit 100 rpm am Magnetrührer im 250 ml Erlenmeyerkolben inkubiert. Die Umsetzung wurde mittels Dünn-schichtchromatographie (Kieselgel 60-Platten mit Fluoreszenzindikator; Laufmittel: Ethylacetat 100 %, Visualisierung: UV-Detektion sowie mittels Essigsäure/Schwefelsäure/Anisaldehyd-Tauchreagenz (100:2:1 v/v/v)). Das Produkt wurde über eine wäßrige Zweiphasen-Extraktion in der Hexanphase angereichert, einrotiert und über Säulenchromatographie (Kieselgel F60; Laufmittel Ethylacetat/Methanol (10:1 , v/v)) gereinigt.Example 2: CLA + alkyl polyglycoside (APG) 6-0-cis-9, trans-11-octadecadienoyl-alkylglucoside 2 g APG (Henkel KGaA), 15 g Edenor UKD6010, 4.5 g molecular sieve, 10 ml t-butanol and 4.5 g immobilized lipase B from Candida antarctica were incubated for 48 hours at 60 ° C with 100 rpm using a magnetic stirrer in a 250 ml Erlenmeyer flask. The reaction was carried out by means of thin layer chromatography (silica gel 60 plates with fluorescence indicator; eluent: ethyl acetate 100%, visualization: UV detection and using acetic acid / sulfuric acid / anisaldehyde immersion reagent (100: 2: 1 v / v / v)). The product was enriched in the hexane phase by means of an aqueous two-phase extraction, concentrated in a rotary evaporator and purified by column chromatography (silica gel F60; mobile phase: ethyl acetate / methanol (10: 1, v / v)).
Figure imgf000015_0001
Figure imgf000015_0001
RrWert: 0.74 (Ethylacetat/Methanol 10:1)RrValue: 0.74 (ethyl acetate / methanol 10: 1)
Beispiel 3: Stearidonsäureethylester + ArbutinExample 3: Stearidonic acid ethyl ester + arbutin
Arbutin
Figure imgf000015_0002
arbutin
Figure imgf000015_0002
6,9,12,15-Octadecatetraenoyl (6Z,9Z,12Z,15Z)-Arbutin 1.36 g (5 mmol) Arbutin, 40 g Stearidonsäureethylester, 4.5 g Molekularsieb, 10 ml t-Butanol und 4.5 g immobilisierte Lipase B aus Candida antarctica wurden 48 Stunden bei 60 °C mit 100 rpm am Magnetrührer im 300 ml Erlenmeyerkolben inkubiert. Die Umsetzung wurde mittels Dünnschichtchromatographie (Kieselgel 60-Platten mit Fluoreszenzindikator; Laufmittel: Ethylacetat 100 %, Visualisierung: UV-Detektion sowie mittels Essigsäure/Schwefelsäure/Anis-aldehyd-Tauchreagenz (100:2:1 , v/v/v)) nachgewiesen. Das Produkt wurde über Säulenchroma-tographie (Kieselgel F60; Laufmittel: Ethylacetat/2-Propanol 10:1 , v/v) gereinigt. RrWert: 0.35 (Ethylacetat 100 %) 6,9,12,15-octadecatetraenoyl (6Z, 9Z, 12Z, 15Z) arbutin 1.36 g (5 mmol) arbutin, 40 g ethyl stearidate, 4.5 g molecular sieve, 10 ml t-butanol and 4.5 g immobilized lipase B from Candida antarctica were incubated for 48 hours at 60 ° C. with 100 rpm on a magnetic stirrer in a 300 ml Erlenmeyer flask. The reaction was verified by thin layer chromatography (silica gel 60 plates with fluorescent indicator; eluent: ethyl acetate 100%, visualization: UV detection and by means of acetic acid / sulfuric acid / anis aldehyde immersion reagent (100: 2: 1, v / v / v)) , The product was purified by column chromatography (silica gel F60; eluent: ethyl acetate / 2-propanol 10: 1, v / v). Rr value: 0.35 (ethyl acetate 100%)

Claims

Patentansprüche claims
1. Verbindungen der allgemeinen Formel (I):1. Compounds of the general formula (I):
Acn-0-Z-0-Rm (I), worin R einen Wasserstoff-, einen über eine Etherbrucke an den Zucker gebundenen verzweigten oder geradkettigen Cβ-C∑o-Alkyl-, einen Arylalkyl- oder einen substituierten oder unsubstituierten C6-Cιo-Arylrest darstellt, worin Z (Zucker) für ein Mono-, Disaccharid oder Polysaccharid steht, das n-fach esterartig mit Ac substituiert und, wenn R nicht für Wasserstoff steht, acetalisch an den Rest R gebunden ist, worin Ac einen mehrfach ungesättigten C15 - C25-Acylrest mit mindestens 4 isolierten und/oder mindestens zwei konjugierten Doppelbindungen oder einen arylaliphatischen Rest mit 1-4 Methylengruppen zwischen Ester-Gruppe und aromatischem Ring darstellt, worin m eine ganze Zahl (1 , 2, 3, ...) einschließlich 0 ist, worin n eine ganze Zahl (1 , 2, 3, ...), nicht aber 0, ist, mit der Maßgabe, daß Z-0-Rm nicht für Salicin, das ist 2-Hydroxymethyl-phenyl)-ß- glucopyranosid, steht.Ac n -0-Z-0-R m (I) wherein R is a hydrogen, a bonded via a Etherbrucke to the sugar branched or straight chain Cβ-C Σ o-alkyl, an arylalkyl, or a substituted or unsubstituted C 6 -Cιo-aryl radical, in which Z (sugar) is a mono-, disaccharide or polysaccharide, which is substituted n-times by an ester with Ac and, if R is not hydrogen, is acetally bonded to the radical R, in which Ac is a polyunsaturated C 1 5 - C 25 acyl radical with at least 4 isolated and / or at least two conjugated double bonds or an arylaliphatic radical with 1-4 methylene groups between the ester group and aromatic ring, where m is an integer (1, 2, 3 , ...) including 0, where n is an integer (1, 2, 3, ...) but not 0, with the proviso that Z-0-R m is not for salicin, which is 2 -Hydroxymethyl-phenyl) -ß-glucopyranoside.
2. Die Verbindungen von Anspruch 1 , wobei Z ein Monosaccharid, insbesondere D- Glucose, D-Galactose, D-Xylose, D-Apiose, L-Rhamnose, L-Arabinose und Rutinose, ist.2. The compounds of claim 1, wherein Z is a monosaccharide, in particular D-glucose, D-galactose, D-xylose, D-apiose, L-rhamnose, L-arabinose and rutinose.
3. Die Verbindungen von Anspruch 1 oder 2, wobei der Glykosid-Anteil (Z-0-Rm) ein solcher ist, der als Zuckerbestandteil ein Monosaccharid, insbesondere ein Monosaccharid gemäß Anspruch 2, enthaltende Verbindungen, insbesondere Arbutin, Fragilin und Populin.3. The compounds of claim 1 or 2, wherein the glycoside portion (Z-0-R m ) is one which contains a monosaccharide, in particular a monosaccharide according to claim 2, as a sugar component, in particular arbutin, fragilin and populin.
4. Die Verbindungen von Anspruch 1 oder 2, wobei der Glykosid-Anteil (Z-0-Rm) ein solcher ist, der als Zuckerbestandteil ein Oligo- oder Polysaccharid wie Alkylpolyglucoside, speziell APG (Henkel KGaA), ist. 4. The compounds of claim 1 or 2, wherein the glycoside portion (Z-0-R m ) is one which, as a sugar component, is an oligosaccharide or polysaccharide such as alkyl polyglucoside, especially APG (Henkel KGaA).
5. Die Verbindungen von einem der vorhergehenden Ansprüche, wobei die Bindung von Ac an den Zucker über eine primäre Alkoholgruppe des Zuckers erfolgt.5. The compounds of one of the preceding claims, wherein the binding of Ac to the sugar takes place via a primary alcohol group of the sugar.
6. Die Verbindungen von einem der vorhergehenden Ansprüche, wobei der Glykosid- Anteil (Z-0-Rm) Arbutin, Populin oder Fragilin ist.6. The compounds of any one of the preceding claims, wherein the glycoside portion (Z-0-R m ) is arbutin, populin or fragilin.
7. Die Verbindungen von einem der vorhergehenden Ansprüche, wobei Ac der Acylrest einer der folgenden Fettsäuren ist: eine CLA oder Stearidonsäure, insbesondere die Octadecadiensäuren, die über konjugierte Doppelbindungen an den C-Atomen 9 und 11, 10 und 12 oder 11 und 13 verfügen, insbesondere die eis, trans, 9, 11- und die eis, eis, 9, 11-Octadecadiensäure.7. The compounds of one of the preceding claims, wherein Ac is the acyl radical of one of the following fatty acids: a CLA or stearidonic acid, in particular the octadecadienoic acids, which have conjugated double bonds on the C atoms 9 and 11, 10 and 12 or 11 and 13 , especially the eis, trans, 9, 11- and the eis, eis, 9, 11-octadecadienoic acid.
8. Die Verbindungen von einem der vorhergehenden Ansprüche, wobei der Glykosid- Anteil (Z-0-Rm) Arbutin (d.h. m = 1), wobei Ac der Acylrest der eis, trans, 9, 11- oder der eis, eis, 9, 11-Octadecadiensäure und wobei n 1 ist.8. The compounds of any one of the preceding claims, wherein the glycoside portion (Z-0-R m ) arbutin (ie m = 1), where Ac is the acyl residue of the eis, trans, 9, 11- or the eis, eis, 9, 11-octadecadienoic acid and where n is 1.
9. Die Verbindungen von einem der Ansprüche 1 bis 7, wobei der Glykosid-Anteil (Z-O- Rm) Fragulin (d.h. m = 1), wobei Ac der Acylrest der eis, trans, 9, 11- oder der eis, eis, 9, 11-Octadecadiensäure und wobei n 1 ist.9. The compounds of one of claims 1 to 7, wherein the glycoside portion (ZO-Rm) fragulin (ie m = 1), where Ac is the acyl residue of the eis, trans, 9, 11- or the eis, eis, 9 , 11-octadecadienoic acid and where n is 1.
10.Die Verbindungen von einem der Ansprüche 1 bis 7, wobei der Glykosid-Anteil (Z-O- Rm) Arbutin (d.h. m = 1), wobei Ac der Acylrest der eis, trans, 9, 1 1- oder der eis, eis, 9, 11-Octadecadiensäure und wobei n 2 ist.10.The compounds of one of claims 1 to 7, wherein the glycoside portion (ZO-Rm) arbutin (ie m = 1), where Ac is the acyl radical of the eis, trans, 9, 1 1- or the eis, eis, 9, 11-octadecadienoic acid and where n is 2.
11.Die Verbindungen von einem der Ansprüche 1 bis 7, wobei der Glykosid-Anteil (Z-O- Rm) Fragulin (d.h. m = 1), wobei Ac der Acylrest der eis, trans, 9, 11- oder der eis, eis, 9, 11-Octadecadiensäure und wobei n 2 ist.11.The compounds of one of claims 1 to 7, wherein the glycoside portion (ZO-Rm) fragulin (ie m = 1), where Ac is the acyl radical of the eis, trans, 9, 11- or the eis, eis, 9 , 11-octadecadienoic acid and where n is 2.
12. Die Verbindungen von einem der Ansprüche 1 bis 7, wobei der Glykosid-Anteil (Z-O- Rm) Arbutin oder Fragilin (d.h. m = 1), wobei Ac der Acylrest der Stearidonsäure und wobei n 1 ist. 12. The compounds of one of claims 1 to 7, wherein the glycoside portion (ZO-R m ) arbutin or fragilin (ie m = 1), where Ac is the acyl radical of stearidonic acid and where n is 1.
13.Die Verbindungen von einem der Ansprüche 1 bis 7, wobei der Glykosid-Anteil (Z-O- Rm) Arbutin oder Fragulin (d.h. m = 1), wobei Ac der Acylrest der Stearidonsäure und wobei n 2 ist.13.The compounds of any one of claims 1 to 7, wherein the glycoside portion (Z-O-Rm) is arbutin or fragulin (i.e. m = 1), where Ac is the acyl residue of stearidonic acid and where n is 2.
14.Die Verbindungen von einem der vorhergehenden Ansprüche, wobei, wenn n = 1 , der einzige Rest Ac an eine primäre OH-Gruppe des Zuckers gebunden ist, insbesondere an diejenige primäre OH-Gruppe, die an der Zuckereinheit sitzt, an den auch R gebunden ist, wenn m ≠ 0, und wobei, wenn n = 2, ein Rest Ac an diejenige primäre OH-Gruppe, die an der Zuckereinheit sitzt, an den auch R gebunden ist, wenn m ≠ 0, und der andere Rest Ac an eine weitere primäre oder an eine sekundäre OH-Gruppe des Zuckers gebunden ist.14.The compounds of any one of the preceding claims, wherein, if n = 1, the only radical Ac is bound to a primary OH group of the sugar, in particular to that primary OH group which is attached to the sugar unit to which R is bound when m ≠ 0, and where, when n = 2, one radical Ac is attached to the primary OH group which is attached to the sugar unit to which R is also bound when m ≠ 0, and the other radical Ac is attached another primary or to a secondary OH group of the sugar is bound.
15.Verfahren zur Herstellung der Verbindungen der Formel (I) von einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß ein Zucker Z bzw. ein Glykosid Z-O-Rm mit einer ungesättigten Fettsäure AcOH oder mit einem Ester, vorzugsweise einem Methyl- oder Ethylester, dieser Fettsäuren AcOH in Gegenwart einer Hydrolase verestert oder umgeestert wird.15. A process for the preparation of the compounds of formula (I) of one of the preceding claims, characterized in that a sugar Z or a glycoside ZO-Rm with an unsaturated fatty acid AcOH or with an ester, preferably a methyl or ethyl ester of this Fatty acids AcOH is esterified or transesterified in the presence of a hydrolase.
16.Das Verfahren von Anspruch 15, wobei die Hydrolase eine Lipase, insbesondere eine Lipase aus Candida rugosa (ehemals Candida cylindracea), Candida antarctica,16. The method of claim 15, wherein the hydrolase is a lipase, in particular a lipase from Candida rugosa (formerly Candida cylindracea), Candida antarctica,
Geotrichum candidum, Aspergillus niger, Penicillium roqueforti, Rhizopus arrhizus und Mucor miehei, insbesondere die Lipase (Isoenzym B) aus Candida antarctica, ist.Geotrichum candidum, Aspergillus niger, Penicillium roqueforti, Rhizopus arrhizus and Mucor miehei, in particular the lipase (isoenzyme B) from Candida antarctica.
17.Das Verfahren von Anspruch 15 oder 16, wobei sich an die Veresterungsreaktion ein Schritt zur Aufreinigung der Verbindungen der Formel (I) anschließt, der entweder ein wäßriges Zweiphasen-Extraktionsverfahren mit organischen Lösungsmitteln wie n-Hexan, Cyclohexan, THF oder Dieethylether oder ein chromatographisches Verfahren an Kieselgel, vorzugsweise mit Ethylacetat/Methanol- oder Dichlormethan/Methanol-Gemischen mit geringen Anteilen Essigsäure und/oder17. The method of claim 15 or 16, wherein the esterification reaction is followed by a step for purifying the compounds of formula (I), which is either an aqueous two-phase extraction process with organic solvents such as n-hexane, cyclohexane, THF or dieethyl ether or chromatographic method on silica gel, preferably with ethyl acetate / methanol or dichloromethane / methanol mixtures with small amounts of acetic acid and / or
Wasser, ist. Water, is.
. Kosmetische oder pharmazeutische Zusammensetzung oder Nahrungs- bzw. Nahrungsergänzungs- oder Futtermittel-Zusammensetzung, enthaltend mindestens eine der Verbindungen von einem der Ansprüche 1 bis 14. , Cosmetic or pharmaceutical composition or food or nutritional supplement or feed composition containing at least one of the compounds of one of claims 1 to 14.
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EP1550667A1 (en) * 2002-10-10 2005-07-06 National Institute of Advanced Industrial Science and Technology Tyrosinase activity controlling agents, process for producing the same and external preparations containing the same
EP1550667A4 (en) * 2002-10-10 2008-02-20 Nat Inst Of Advanced Ind Scien Tyrosinase activity controlling agents, process for producing the same and external preparations containing the same
US7754864B2 (en) 2002-10-10 2010-07-13 National Institute Of Advanced Industrial Science And Technology Tyrosinase activity controlling agent, process for producing the same and external preparation containing the same
US7547752B2 (en) 2002-10-17 2009-06-16 Unilever Home & Personal Care Usa Division Of Conopco, Inc. Scalp treatment
AU2013202828B2 (en) * 2006-10-26 2013-12-12 Xyleco, Inc. Processing biomass
US9309545B2 (en) 2008-04-30 2016-04-12 Xyleco, Inc. Processing biomass
US9745604B2 (en) 2008-04-30 2017-08-29 Xyleco, Inc. Processing biomass
US9745609B2 (en) 2008-04-30 2017-08-29 Xyleco, Inc. Processing biomass
US9803222B2 (en) 2008-04-30 2017-10-31 Xyleco, Inc. Processing biomass
US9970039B2 (en) 2008-04-30 2018-05-15 Xyleco, Inc. Processing biomass
US10047384B2 (en) 2008-04-30 2018-08-14 Xyleco, Inc. Processing biomass
US10508291B2 (en) 2008-04-30 2019-12-17 Xyleco, Inc. Processing biomass
RU2484826C1 (en) * 2012-02-17 2013-06-20 Государственное бюджетное образовательное учреждение высшего профессионального образования "Алтайский государственный медицинский университет" Министерства здравоохранения и социального развития Российской Федерации Diuretic agent

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