GELLING AGENTS BASED ON GLYCOSYL BARBITURATES

Abstract

GLYCOSYLBARBITURATE-BASED GELDING AGENTS The present invention relates to the use as a gelling agent of a compound having the following general formula (I): (I) in which: Sacc represents a monosaccharide or polysaccharide comprising up to 20 sugar units, in the form of pyranose and / or furanose and of the L and / or D series, said mono- or polysaccharide having at least one free hydroxyl group; X1+ represents a cation selected from the group consisting of: Na+, Li+, K+, +NR3R4R5R6, and R7-NH3+, R3, R4, R5 and R6, identical or different, representing a (C1-C20)alkyl group, R7 representing a (C1-C20)alkyl group, optionally including at least one unsaturation, said alkyl group optionally being substituted by at least one (C6-C10)aryl group, R2 represents in particular H or methyl, as well as its forms tautomers. Figure for the abbreviation: none

Description

Title of the invention: GELLING AGENTS GLYCOSYLBARBITURATE BASE

[0001] The present invention relates to novel gelling agents based on glycosylbarbiturates, as well as a process for preparing an organogel or oleogel using said gelling agents based on glycosylbarbiturates.

[0002] Organogelators are small organic molecules capable of gelling all kinds of organic solvents, even at relatively low mass concentrations (less than 1% by mass).

[0003] There are currently many molecules that can be used as organogelators, but these have a number of drawbacks.

[0004] Indeed, the synthesis of these organogellators requires multiple steps, as well as the use of solvents and / or toxic reagents. Furthermore, most of these organogellators are hydrophobic in nature, which makes them poorly soluble in aqueous media and therefore "leachable". For many organogellators, their chemical and enzymatic stability is a barrier to their development.

[0005] Furthermore, organogellants of a polymeric nature such as ethylcellulose also have the disadvantage of leaving a film after their application.

[0006] Finally, an organogelator is often specific to an application and organogelators have the sole function of gelling.

[0007] There is therefore currently a need for an organogelator which does not have the aforementioned drawbacks, and therefore in particular to provide an organogelator compound which can be synthesized easily and which is chemically and enzymatically stable.

[0008] The present invention therefore aims to provide an organogelator which can be synthesized in a single step and under environmentally friendly conditions, in particular in the presence of aqueous solvents, without the formation of by-products, easy purification and a quantitative yield.

[0009] The present invention also aims to provide an organogelator which is perfectly soluble in water and therefore washable at the end of application for dermal treatments, for example.

[0010] The present invention also aims to provide a chemically and enzymatically stable organogelator, and optionally with an easily adjustable gelling capacity.

[0011] Thus, the present invention relates to the use as gelling agent of a compound of the following general formula (I):

[0012] in which: - Sacc represents a monosaccharide or polysaccharide comprising up to 20 sugar units, in pyranose and / or furanose form and of L and / or D series, said mono- or polysaccharide having at least one free hydroxyl function; - Xi+ represents a cation chosen from the group consisting of: Na+, Li+, K+, + NR3R4R5R6, and R7-NH3+,

[0013] R3, R4, R5 and R6, identical or different, representing a (Ci-C2o)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Ci0)aryl group, in particular a phenyl group,

[0014] R7 representing a (C1-C20)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Cio)aryl group, in particular a phenyl group, - R2 represents H, methyl, or a (Ci-C2o)alkyl group optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Ci0)aryl group, in particular a phenyl group,

[0015] as well as its tautomeric forms.

[0016] Thus, the compounds used as gelling agents according to the invention (or organogelators) are C-glycoside derivatives which are chemically and enzymatically stable thanks to the C-glycosidic bond.

[0017] The gelling capacity of these compounds is easily modulated by acting on the nature of the positive counterion, for example by simple mixing.

[0018] The organogellators according to the invention can be used for example in cosmetic compositions or pharmaceutical or dermo-pharmaceutical compositions, but also in the agri-food sector or in the lubricants industry or for the maintenance of painting canvases.

[0019] The tautomeric form of general formula (I) is as follows:

[0020] According to the invention, the term (Ct-Cz) group means a group comprising a carbon chain which may have from t to z carbon atoms, for example Ci-C6 a carbon chain which may have from 1 to 6 carbon atoms.

[0021] According to the invention, the term "alkyl" denotes saturated, linear or branched, aliphatic hydrocarbon groups comprising, unless otherwise stated, from 1 to 20 carbon atoms. Examples that may be mentioned are methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tertbutyl or pentyl groups.

[0022] According to one embodiment, the alkyl groups according to the invention can be interrupted by at least one unsaturation.

[0023] The alkyl groups of the invention may also be substituted by at least one aryl group. According to the invention, the aryl groups are cyclic aromatic groups comprising between 6 and 10 carbon atoms. Examples of aryl groups include phenyl or naphthyl groups.

[0024] Preferably, in formula (I), R3, R4, R5 and R6, identical or different, represent a (Ci-C2o)alkyl group, or a benzyl group.

[0025] Preferably, in formula (I), R7 represents a (Ci-C2o)alkyl group.

[0026] Preferably, in formula (I), R2 represents H or methyl, preferentially methyl.

[0027] Preferably, in formula (I), Xi+ represents a cation chosen from the group consisting of: Na+, Li+ and K+, and is preferentially Na+.

[0028] According to one embodiment, in formula (I), Sacc is selected from the group consisting of D-glucose, D-galactose, D-mannose, D-xylose, D-lyxose, L-fucose, L-arabinose, L-rhamnose, D-glucuronic acid, D-galacturonic acid, D-iduronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-maltose, D-lactose, D-cellobiose, D-maltotriose, D-iduronic acid, D-glucuronic acid with a hexosamine selected from D-galactosamine, D-glucosamine, N-acetyl-D-galactosamine or N-acetyl-D-glucosamine, xylobiose and its oligomers (from xylotriose to xylohexaose).

[0029] Preferably, in formula (I), Sacc is D-glucose.

[0030] The C-glycoside derivatives of formula (I) according to the present invention can be prepared, for example, according to the methods described by Gonzales MA et al. Carbohydrate Research 1986, 158, pp58-66 and by Wulff G. et al. Carbohydrate Researchl994, 257, pp81-95.

[0031] Among the C-glycoside derivatives of formula (I) used according to the invention, the following compounds are particularly preferred:

[0032] - l,3-dimethyl-2,6-dioxo-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxy- methyl)tetrahydro-2H-pyran-2-yl]-l,2,3,6-tetrahydropyrimidin-4-olate sodium: N / A* , OH

[0033] - 2,6-dioxo-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro- 2H-pyran-2-yl]-l,2,3,6-tetrahydropyrimidin-4-olate sodium N / A* OH

[0034] - l,3-dimethyl-2,6-dioxo-5-[(2S,3R,4R,5R,6R)-3,4,5-trihydroxy-6-(hydroxy- methyl)tetrahydro-2H-pyran-2-yl]-l,2,3,6-tetraliydropyrimidin-4-olate sodium:

[0035] - 1,3-dimethyl-2,6-dioxo-5-[(2S,3R,4S,5R)-3,4,5-trihydroxytetraliydro-2H-pyran-2- yl]-l,2,3,6-tetrahydropyrimidin-4-olate sodium: N / A* OH

[0036] - 2,6-dioxo-5-[(2S,3R,4S,5R)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl]-l,2,3,6- sodium tetrahydropyrimidin-4-olate

[0037] - l,3-dimethyl-2,6-dioxo-5-[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methyl- sodium tetrahydro-2H-pyran-2-yl]-1,2,3, 6-tetrahydropyrimidin-4-olate: OH

[0038] Preferably, the compound of formula (I) according to the invention corresponds to the following formula:

[0039] Several advantages are associated with the use of this class of molecules which belongs to the C-glycoside family.

[0040] The above-mentioned preferred glycosylbarbiturate is for example obtained in a single synthesis step in water and characterized by a glucose unit linked by a C-glycosidic bond to N,N-dimethylbarbituric acid. Its purification is obtained by simple precipitation of the reaction medium with a quantitative yield, making its production easy and practical from an industrial point of view.

[0041] The starting reagents for the preparation of this molecule are commercially available.

[0042] The compounds of the invention (or glyco-gelators) gel both organic solvents of different polarities and oils and their gelling capacity can be easily modulated by the nature of the associated cationic counterion. Gelation can be induced by ultrasound, simple mixing or by a heating cycle followed by cooling to room temperature, as explained below.

[0043] According to one embodiment, the compound of formula (I) is used as a gelling agent for an organic liquid or mixture of liquids, said organic liquid being chosen from organic solvents and oils.

[0044] According to the invention, an organic liquid is a liquid with a carbon chain or comprising carbon. As indicated above, it can be an organic solvent, an oil or a mixture thereof.

[0045] According to one embodiment, the organic liquid is an organic solvent selected from the group consisting of alcohols, ketones, aliphatic, aromatic or halogenated hydrocarbons, esters, nitrogen derivatives, ethers, aliphatic carboxylic acids and their ester, amide or lipid derivatives. Preferably, the organic solvent is selected from ethanol, propanol, butanol, octanol, isopropanol, anisole, ethyl acetate, tetrahydrofuran, oleic acid, linoleic acid, palmitic acid and adipate, stearate or caprate esters.

[0046] According to one embodiment, the organic liquid is an oil chosen from vegetable or animal oils, natural or synthetic mineral oils. Preferably, the oil is chosen from rapeseed oil, lavender essential oil, palm oil, olive oil, sunflower oil, paraffin or liquefied petroleum.

[0047] Preferably, the organic liquid is an organic solvent chosen from ethanol, propanol, butanol, octanol, isopropanol, anisole, ethyl acetate and tetrahydrofuran, or an oil chosen from rapeseed oil or lavender essential oil (lavender EO).

[0048] The present invention also relates to the above-mentioned use, wherein the compound of formula (I) is used as a gelling agent for a mixture of organic liquids, preferably comprising at least one oil and at least one organic solvent.

[0049] For example, as a mixture, mention may be made of a mixture comprising lavender essential oil and ethanol, or a mixture comprising rapeseed oil, octanol and isopropanol, but also a mixture of two organic solvents such as a mixture of octanol and ethanol.

[0050] Preferably, in the context of the use as defined above, the weight content of the compound of formula (I) is from 0.1% to 10%, preferably from 1% to 5%, by weight relative to the weight of the organic liquid or mixture of organic liquids.

[0051] The present invention also relates to a process for preparing an organogel or oleogel comprising a step of bringing a compound of formula (I) into contact with an organic liquid or mixture of organic liquids, said liquid being chosen from organic solvents and oils, and being as defined above,

[0052] said compound of formula (I) corresponding to the following formula:

[0053] in which: - Sacc represents a monosaccharide or polysaccharide containing up to 20 sugar units, in pyranose and / or furanose form and of L and / or D series, said mono- or polysaccharide having at least one free hydroxyl function; - Xi+ represents a cation chosen from the group consisting of: Na+, Li+, K+, + NR3R4R5R6, and R7-NH3+,

[0054] R3, R4, R5 and R6, identical or different, representing a (Ci-C2o)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Ci0)aryl group, in particular a phenyl group,

[0055] R7 representing a (Ci-C20)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Cio)aryl group, in particular a phenyl group, - R2 represents H, methyl, or a (Ci-C20)alkyl group optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Ci0)aryl group, in particular a phenyl group,

[0056] as well as its tautomeric forms.

[0057] According to the invention, the term organogel designates a gel of an organic solvent and the term oleogel designates a gelled oil.

[0058] According to one embodiment, the method of the invention comprises the addition of an aqueous solution of the compound of formula (I) into the organic liquid or mixture of organic liquids.

[0059] Preferably, the addition step further comprises an ultrasonic treatment step or a heating or cooling step of the organic liquid or mixture of organic liquids.

[0060] According to one embodiment of the method according to the invention, the organic liquid or mixture of organic liquids comprises an additional compound chosen from dyes, odorous molecules and pharmaceutical active ingredients, such as Nile red, eucalyptol or doxorubicin. EXAMPLES

[0061] Example 1: Determination of the correct dosage for the formation of 2% (w / v) gels

[0062] 10 mg of sodium glucosylbarbiturate are weighed into a vial of approximately 1.5 ml with screw cap. 450pL of the chosen solvent is added and then the mixture is sonicated for a few seconds to disperse the powder well in the solvent (in the majority of cases, glucosylbarbiturate is not soluble in the solvent). Then water is added in portions of 2pL and between each addition the mixture is sonicated and gently shaken by hand to see if the gel forms. The sonication time varies depending on the nature of the solvent. Once the gel has formed, it is possible that it is not very homogeneous. In this case, it is necessary to be able to judge the actions to be taken to obtain the gel. Often it is necessary to: i) either add a very small amount of water, heat and let it cool, or ii) heat and let it cool while sonicating (if the glucosylbarbiturate precipitates on cooling). The mixture is then topped up with the solvent to gel up to 500pL.

[0063] Example 2: Formation of a gel by adding a solvent + water mixture to the glycobarbiturate powder

[0064] 10 mg of sodium glucosylbarbiturate is weighed, then the mixture of solvent and water is added in the correct proportions defined above in Example 1. The mixture is then either cold sonicated or heated and allowed to cool to obtain the gel.

[0065] For example, 40 pL of water must be added to 500 pL of ethanol, 60 pL of water to 440 pL of isopropanol, 45 pL of water to 455 pL of butanol, 60 pL of water to 420 pL of acetone or 35 pL of water to 480 pL of propan-1-ol.

[0066] Example 3: Formation of a gel by adding a concentrated solution of sodium glucosylbarbiturate to the solvent

[0067] The solvent is placed in a container with stirring and then the aqueous solution of sodium glucosylbarbiturate (1.47 M) is added in the proportions defined above in Example 1. The mixture is left to stir for a few seconds and then the stirring is stopped to allow the gel to form.

[0068] In this example, 80 μL of the aqueous solution of sodium glucosylbarbiturate (1.47 M) was added to 1 mL of 96% ethanol.

[0069] Example 4: Formation of a gel with oils or apolar solvents (examples: rapeseed oil, toluene, anisole, etc.)

[0070] With solvents that are immiscible with water, it is necessary to add either another solvent that allows the introduction of the little water necessary for the formation of gels (example of a mixture that can accept a little water without forming two phases: lavender EO / Ethanol), or to change the nature of the counter-ion that is at the origin of the sodium by an alkyl ammonium halide. Two ammonium salts were tested, namely cetyltrimethylammonium bromide (CTAB) and tetrabutylammonium bromide (TBAB). To find the conditions favorable to gelation, the same method as explained in Example 1 can be used. The glucosylbarbiturate and one equivalent of ammonium salt are weighed before adding the solvent and adjusting the correct amount of water.

[0071] The different results are described further in Table 1 below.

[0072] For example, 10 mg of sodium glucosylbarbiturate was mixed with either 9.4 mg of TB AB or 11 mg of CT AB. Then, 400 μL of rapeseed oil was added, then the whole was sonicated for dispersion and finally 5 μL of water was added. Sonication allows a gel to form instantly.

[0073] With 10 mg of sodium glucosylbarbiturate weighed each time and 1 molar equivalent of ammonium salt, the protocol followed for the different solvent tests in Table 1 is that detailed in Example 4.

[0074] [Tables 1] Solvent 1 pL Solvent 2 pL Solvent 3 pL h2o pL CTAB mg TB AB mg Ethanol 500 - - 40 - - Isopropanol 440 - - 60 - - 1-Butanol 155 - - 45 - - Acetone 440 - - 60 - - 1-Propanol 480 - - 35 - - Lavender EO 250 Ethanol 250 - 20 - - 1-Octanol 300 Ethanol 100 - 20 - - Rapeseed Oil 250 1-Octanol 50 Isopropanol 230 10 - - 1-Octanol 400 - - 10 - 9.4 Rapeseed Oil 400 - - 5 - 9.4 Rapeseed Oil Nile Red (THF) - 5 - 9.4 490 10 Anisole 500 - - 2 - 9.4 Ethyl acetate 490 Nile Red (THF) 10 - 20 11 - Rapeseed oil 490 Nile Red (THF) 10 - 5 11 - THF 500 - - 8 11 -

Claims

1. Claims Use as a gelling agent for an organic liquid or mixture of organic liquids of a compound of the following general formula (I): o in which:

2. - Sacc represents a monosaccharide or polysaccharide comprising up to 20 sugar units, in pyranose and / or furanose form and of L and / or D series, said mono- or polysaccharide having at least one free hydroxyl function; - Xi+ represents a cation chosen from the group consisting of: Na+, Li+, K+, +NR3R4R5R6, and R7-NH3+, R3, R4, R5 and R6, identical or different, representing a (Ci-C2o)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Cjo)aryl group, R7 representing a (Ci-C2o)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Ci0)aryl group, - R2 represents H, or a (Ci-C20)alkyl group optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Cio)aryl group, as well as its tautomeric forms. Use according to claim 1, wherein in formula (I), Sacc is selected from the group consisting of D-glucose, D-galactose, D-mannose, D-xylose, D-lyxose, L-fucose, L-arabinose, L-rhamnose, D-glucuronic acid, D-galacturonic acid, D-iduronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-maltose, D- lactose, D-cellobiose, D-maltotriose, D-iduronic acid, D-glucuronic acid with a hexosamine selected from D-galactosamine, D-glucosamine, N-acetyl-D-galactosamine or N-acetyl-D-glucosamine, xylobiose and its oligomers.

3. Use according to any one of the preceding claims, wherein the organic liquid is selected from organic solvents and oils.

4. Use according to claim 3, wherein the organic liquid is selected from the group consisting of alcohols, ketones, aliphatic, aromatic or halogenated hydrocarbons, esters, nitrogen derivatives, ethers, aliphatic carboxylic acids and their ester, amide or lipid derivatives, and is preferably selected from ethanol, propanol, butanol, octanol, isopropanol, anisole, ethyl acetate, tetrahydrofuran, oleic acid, linoleic acid, palmitic acid and adipate, stearate or caprate esters.

5. Use according to claim 4, wherein the oil is chosen from vegetable or animal oils, natural or synthetic mineral oils, and is preferably rapeseed oil, lavender essential oil, palm oil, olive oil, sunflower oil, paraffin or liquefied petroleum.

6. Use according to any one of the preceding claims, in which the content by weight of the compound of formula (I) is from 0.1% to 10%, preferably from 1% to 5%, by weight relative to the weight of the organic liquid or mixture of organic liquids.

7. Process for preparing an organogel or oleogel comprising a step of bringing a compound of formula (I) into contact with an organic liquid or mixture of organic liquids, said liquid being chosen from organic solvents and oils, said compound of formula (I) corresponding to the following formula: x, . 1 XX Saccr O in which: - Sacc represents a monosaccharide or polysaccharide comprising up to 20 sugar units, in pyranose and / or furanose form and of L and / or D series, said mono- or polysaccharide having at least one free hydroxyl function;- Xi+ represents a cation chosen from the group consisting of: Na+, Li+, K+, +NR3R4R5R6, and R7-NH3+, R3, R4, R5 and R6, identical or different, representing a (Ci-C2o)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Cio)aryl group, in particular a phenyl group, R7 representing a (Ci-C2o)alkyl group, optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Cio)aryl group, in particular a phenyl group, - R2 represents H, or a (Ci-C20)alkyl group optionally including at least one unsaturation, said alkyl group being optionally substituted by at least one (C6-Cio)aryl group, in particular a phenyl group, as well as its tautomeric forms.;

8. A method according to claim 7, comprising adding an aqueous solution of the compound of formula (I) to the organic liquid or mixture of organic liquids.

9. The method of claim 8, wherein the adding step further comprises a step of ultrasonicating or a step of heating or cooling the organic liquid or mixture of organic liquids.

10. A method according to any one of claims 7 to 9, wherein the organic liquid or mixture of organic liquids comprises an additional compound chosen from dyes, odorous molecules and pharmaceutical active ingredients.