LOW MOLECULAR WEIGHT ORGANIC GELATORS OF VEGETABLE OIL

Abstract

The present invention relates to the composition with gelling properties comprising low molecular weight gelators of Formula (1) or a salt thereof and a vegetable oil.

##STR00001##

Uses of such composition in the food, cosmetic or pharmaceutical industry are disclosed.

Claims

1. A composition with gelling properties comprising a compound of Formula (I) or a salt thereof ##STR00007## and a vegetable oil; wherein A is selected from: i) (CH.sub.2).sub.mCH.sub.3, ii) CONHCH(R.sup.1)COCH.sub.3 and iii) CONH(CH.sub.2).sub.pNHCOCONHCH(R.sup.1)COR.sup.2 B is selected from: i) NH(CH.sub.2).sub.mCOR.sup.2 and ii) R.sup.2 R.sup.1 is H, C.sub.1-C.sub.4 alkyl, phenyl, or CH.sub.2Ph; R.sup.2 is OH, NH.sub.2 or OR.sup.3; R.sup.3 is C.sub.1-C.sub.4 alkyl or CH.sub.2Ph; m is an integer from 1-34; and n is an integer from 1-22; p is an integer from 1-12; provided that when A is (CH.sub.2).sub.mCH.sub.3, then B is NH(CH.sub.2).sub.nCOR.sup.2 and when B is NH(CH.sub.2).sub.nCOR.sup.2, then A is (CH.sub.2).sub.mCH.sub.3.

2. The composition according to claim 1 wherein the composition is in the form of gel.

3. The composition according to claim 1 wherein the oil is edible oil selected from palm oil, sunflower oil, olive oil, soybean oil, linseed oil, rapeseed oil, corn oil, pumpkin seed oil, sesame oil, safflower oil, castor, peanut oil or combination thereof.

4. The composition according to claim 1 wherein the oil is base cosmetic oil selected from sweet almond oil, linseed oil, grape seed oil, avocado oil, apricot oil, olive oil, sesame oil, rapeseed oil, sunflower oil, jojoba oil, castor oil, borage seed oil, argan oil, avocado oil, calendula oil, evening primrose oil, hazelnut oil, walnut oil, peanut oil, macadamia oil, coconut oil, rose hip seed oil, wheat germ oil, St. John's wort oil, blueberry seed oil, black cumin seed, rice bran oil or combination thereof.

5. The composition according to claim 1 wherein the oil is selected from sunflower oil, olive oil, soybean oil or combination thereof.

6. The composition according to claim 1 wherein A is (CH.sub.2).sub.m-CH.sub.3 and B is NH(CH.sub.2).sub.nCOOR.sup.2.

7. The composition according to claim 6 wherein sum of n and m is 18 to 22.

8. The composition according to claim 1 wherein A is CONHCH(R.sup.1)COCH.sub.3 and B is R.sup.2.

9. The composition according to claim 1 wherein A is CONH(CH.sub.2).sub.pNHCOCONHCH(R.sup.1)COR.sup.2 and B is R.sup.2.

10. The composition of claim 6 wherein R.sup.2 is OH, NH.sub.2 or OCH.sub.3.

11. The composition of claim 6 wherein R.sup.1 is CH.sub.2Ph, Ph, CH.sub.2CH(CH.sub.3).sub.2 or CH(CH.sub.3).sub.2.

12. The composition of claim 1 wherein the composition further comprising water.

13. The composition of claim 1 wherein the composition further comprises: (a) a food; (b) a cosmetically acceptable ingredient or (c) a pharmaceutically acceptable ingredient.

14. The composition of claim 1 wherein the compound of formula (I) or a salt thereof is present in the composition in the concentration of about 0.02 to about 10 wt. % relative to the total weight of the composition.

15. A process for the preparation of the composition according to claim 1 comprising the following steps: (a) mixing the compounds of formula (I) or a salt thereof and the oil; (b) heating the mixture obtained in step (a) to a temperature until compound is completely dissolved; and (c) cooling the mixture obtained in step (b) to room temperature or below.

16. The process of claim 15 further comprising the step of mixing a food, pharmaceutically active ingredient, nutraceuticals or a cosmetic ingredient as solid or solubilised component in oil or water into the mixture during the step (b).

Description

BRIEF DESCRIPTION OF THE FIGURES

[0027] FIG. 1 shows thixotropic behaviour of sunflower gel based on gelator 22 at 0.1 wt %. (a) Gel formed from hot solution upon cooling; (b, c) Low-viscosity fluid formed by vigorous hand shaking; (d) Gel reformed after standing for 5 min at room temperature.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The following abbreviations are used in the text: [0029] DCC for N,N-dicyclohexylcabodiimide, [0030] Et.sub.3N for thriethylamine, [0031] DMAP for 4-Dimethylaminopyridine, [0032] Boc for tert-butyloxycarbonyl protecting group, [0033] Ph for phenyl.

[0034] The term C.sub.1-C.sub.4 alkyl as used herein, refers to a saturated, straight or branched-chain hydrocarbon radical containing between one and four carbon atoms. Examples of C.sub.1-C.sub.4 alley radicals include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0035] Organogelators or gelling agents represent molecules capable to self-assemble in different solvents into three-dimensional nano-network of self-assembled fibers through highly specific noncovalent interactions such as hydrogen bonding, van der Waals, p-stacking, electrostatic and charge-transfer interactions.

[0036] Organogels represent mixture of gel fibers present in solid state and liquid phase entrapped in pores between self-assembled fibers.

[0037] Organogel of the present invention or organogel of the invention as used herein refers to a composition comprising a compound of formula (I) or a salt thereof and oil as liquid phase structured into gel state.

[0038] Vegetable oils encompassed by present invention are edible oils or base cosmetic oils.

[0039] Edible oils are selected from palm oil, sunflower oil, olive oil, soybean oil, linseed oil, rapeseed oil, corn oil, pumpkin seed oil, sesame oil, safflower oil, castor, peanut oil and the like.

[0040] The cosmetic base oils are selected from sweet almond oil, linseed oil, grape seed oil, avocado oil, apricot oil, olive oil, sesame oil, rapeseed oil, sunflower oil, jojoba oil, castor oil, borage seed oil, argan oil, avocado oil, calendula oil, evening primrose oil, hazelnut oil, walnut oil, peanut oil, macadamia oil, coconut oil, rose hip seed oil, wheat germ oil, St. John's wort oil, blueberry seed oil, black cumin seed, rice bran oil and the like.

[0041] A composition according to present invention or a composition according to the invention as used herein relates to the composition comprising the compound of formula (I) or a salt thereof and a vegetable oil.

[0042] A compound of the present invention or a pound of the invention as used herein relates to the compound of formula (I) or a salt thereof.

[0043] The term thixotropy as used herein refers to the property of certain gels that are thick (viscous) under normal conditions, but flow (become thin, less viscous) over time when shaken, agitated, or otherwise stressed and then take a fixed time to return to a more viscous, gel state.

[0044] Low molecular weight organic gelators are extremely sensitive to mechanical stress and these systems irreversibly expel solvent from their gel network when subjected to flow. On removal of the external force, these systems lose its original elastic properties. On the other hand, thixotropic gels can disintegrate in solution under an external mechanical stress and can regain their elastic properties upon removal of the stress. This operation can be carried out for an infinite number of cycles. Thixotropic LMOGs represent a unique class of dynamic self-assembled supramolecular systems.

[0045] Organogels have many different functionalities in food products, including restriction of oil mobility and stabilization of emulsions, especially in case were water droplets are entrapped inside the oleogel network.

[0046] An emulsion is termed an oil/water (o/w) emulsion if the dispersed phase is a liquid (an oil) and the continuous phase is water or an aqueous solution and is termed water/oil (w/o) if the dispersed phase is water or an aqueous solution and the continuous phase is an organic liquid (an oil).

[0047] In one aspect, compounds of the present invention are organogelators of vegetable oil.

[0048] In one aspect the present invention relates to the use of a compound of the present invention as an organogelator of vegetable oil.

[0049] In one aspect the present invention relates to a composition comprising a compound of formula (I) or a salt thereof and a vegetable oil.

[0050] In one aspect suitable salt are base addition salts selected from sodium, potassium, calcium, and magnesium salt of compound of formula (I). In further aspect a salt is sodium salt of compound of formula (I).

[0051] In another aspect suitable salts are base addition salts selected from ammonium, or alkyl amonium salt of compound of formula (I). Examples of alkyl ammonium salt are methyl, ethyl, propyl, iso-propyl, n-butyl ammonium, tetra ethylammonium, tetraethylammonium, tetrabutylammonium, ethylenediammonium salt or the like.

[0052] With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom. Thus, the compounds of Formula (I) may occur as individual enantiomers, diastereoisomers or mixtures thereof. All such isomeric forms are included within the present invention, including mixtures thereof.

[0053] In the following description, the groups A, B, R.sup.1, R.sup.2, R.sup.3, m, n and p have the meaning as defined for the compounds of Formula (I) unless otherwise stated.

[0054] It will be understood that the present invention covers all combinations of aspects, suitable, convenient and preferred groups described herein.

[0055] In one aspect the present invention relates to the composition comprising a compound of formula (I) or a salt thereof and a vegetable oil wherein A is (CH.sub.2).sub.mCH.sub.3 and B is NH(CH.sub.2).sub.nCOR.sup.2. In further aspect m is an integer from 5-20. In yet further aspect n is an integer from 1-10. In yet further aspect R.sup.2 is OH, OMe or NH.sub.2. In yet further aspect R.sup.1 is -Ph, and R.sup.2 is OH. In another aspect A is (CH.sub.2).sub.mCH.sub.3, B is NH(CH.sub.2).sub.nCOR.sup.2, m and n are each 10, wherein R.sup.1 is -Ph, CH.sub.2Ph or CH(CH.sub.3).sub.2 and R.sup.2 is OH.

[0056] In one aspect the present invention relates to the composition comprising a compound of formula (I) or a salt thereof and a vegetable oil wherein A is (CH.sub.2).sub.mCH.sub.3, B is NH(CH.sub.2).sub.nCOR.sup.2 and sum of n and m is between 18 and 22. In further aspect sum of n and m is 20.

[0057] In one aspect the present invention relates to the composition comprising a compound of formula (I) or a salt thereof and a vegetable oil wherein A is CONHCH(R.sup.1)COR.sup.2 and B is R.sup.2. In further aspect R.sup.1 is CH.sub.2Ph, CH.sub.2CH(CH.sub.3).sub.2 or CH(CH.sub.3).sub.2 and R.sup.2 is OH, OCH.sub.3 or NH.sub.2. In yet further aspect R.sup.1 is CH.sub.2Ph, CH.sub.2CH(CH.sub.3).sub.2 or CH(CH.sub.3).sub.2 and R.sup.2 is OH or NH.sub.2.

[0058] In one aspect the present invention relates to the composition comprising a compound of formula (I) or a salt thereof and a vegetable oil wherein A is CONH(CH.sub.2).sub.pNHCOCONHCH(R.sup.1)COR.sup.2 and B is R.sup.2. In further aspect p is an integer from 4-10. In yet further aspect p is 6-9 wherein R.sup.1 is CH.sub.2CH(CH.sub.3).sub.2, and R.sup.2 is OCH.sub.3, OH or NH.sub.2. In yet further aspect p is 6 or 9 wherein R.sup.1 is CH.sub.2CH(CH.sub.3).sub.2, and R.sup.2 is OCH.sub.3 or OH.

[0059] In one aspect the present invention relates to the composition comprising a compound of the invention and a vegetable oil.

[0060] In further aspect the vegetable oil is edible oil.

[0061] In one further aspect the edible oil is selected from palm oil, sunflower oil, olive oil, soybean oil, linseed oil, rapeseed oil, corn oil, pumpkin seed oil, sesame oil, safflower oil, castor, peanut oil and combination thereof. In yet further aspect the edible oil is selected from sunflower oil, olive oil, soybean oil, rapeseed oil, palm oil, and combination thereof. In yet further aspect the edible oil is selected from sunflower oil, olive oil, soybean oil and combination thereof.

[0062] In one further aspect the present invention relates to the composition comprising a compound of the invention and a cosmetic base oils. In further aspect the cosmetic base oil is selected from sweet almond oil, linseed oil, grape seed oil, avocado oil, apricot oil, olive oil, sesame oil, rapeseed oil, sunflower oil, jojoba oil, castor oil, borage seed oil, argan oil, avocado ail calendula oil, evening primrose oil, hazelnut oil, walnut oil, peanut oil, macadamia oil, coconut oil, rose hip seed oil, wheat germ oil, St. John's wort oil, blueberry seed oil, black cumin seed, rice bran oil or combination thereof. In yet further aspect the cosmetic base oil is selected from almond oil, avocado oil, jojoba oil, coconut oil, rice bran oil, peanut oil.

[0063] In one aspect the present invention relates to the composition comprising a compound of the invention and a vegetable oil wherein the compound of the invention is present in the composition in the concentration at which fluid motion of the oil stops.

[0064] In one aspect the present invention relates to the composition comprising a compound of the invention and a vegetable wherein the compound of the invention is present in the composition in the concentration at which gel is forming.

[0065] In one aspect the compound of the invention is present in the composition at a concentration of about 20% or less, on a weight/weight basis. In another aspect, the compound of the invention is present in the composition at a concentration of about 10%, on a weight/weight basis. In yet another aspect, the compound of the invention is present in the composition at a concentration of about 5% or less, on a weight/weight basis. In another aspect, compound of the invention is present in the composition at a concentration of about 2%, on a weight/weight basis. In yet another aspect, the compound of the invention is present in the composition at a concentration of about 2% or less, on a weight/weight basis. In yet another aspect, the compound of the invention is present in the composition at a concentration of about 0.5% or less, on a weight/weight basis. In yet another aspect, the compound of the invention is present in the composition at a concentration of about 0.05% or less, on a weight/weight basis.

[0066] In one aspect, the compound of the invention is present in the composition in the concentration of about 0.02 to about 10 wt % relative to the total weight of the composition.

[0067] In one aspect the present invention relates to the composition comprising a compound of the invention, a vegetable oil and water. In further aspect the composition is in the form of a gelled water-in-oil emulsion or gelled oil in water emulsion.

[0068] In one aspect, the composition according to present invention forms an organogel.

[0069] In another aspect, the organogel recovers at least about 80% within less than about 10 minute, preferably within less than about 5 minute, and more preferably within less than about 1 minute after the exposure to destructive shear. In still another embodiment, the organogel recovers at least about 90% within less than about 10 minute, preferably within less than about 5 minute, and more preferably within less than about 1 minute after the exposure to destructive shear. In a further aspect, the organogel recovers at least about 95% within less than about 10 minute, preferably within less than about 5 minute, and more preferably within less than about 1 minute after the exposure to destructive shear.

[0070] In a still further aspect, the organogel recovers at least about 99% within less than about 10 minute, preferably within less than about 5 minute, and more preferably within less than about 1 minute after the exposure to destructive shear.

[0071] In one aspect, the composition according to present invention may be used in the pharmaceutical industry as vector/carriers for active substances.

[0072] In one aspect the present invention relates to the composition comprising a compound of the present invention, edible oil and the active pharmaceutical substance. In further aspect active pharmaceutical substance are provided for a sustained release.

[0073] In one aspect the present invention relates to the composition comprising a compound of the invention, edible oil and the nutraceuticals substance wherein the nutraceuticals substance refers to dietary supplement such as vitamins, minerals, fatty acids, amino acids, proteins, herbal medicine etc.

[0074] In one aspect the invention relates to a composition comprising a compound of the invention, edible oil and a food. In further aspect food is selected from shortenings and chocolates. In yet further aspect food is selected from margarine, spreads and cooked meat products.

[0075] In another aspect, the invention relates to a cosmetic composition comprising at least one cosmetically acceptable ingredient, a compound of the invention and base cosmetic oil.

[0076] In one aspect, the invention relates to a composition usable as a cleaning tool in cultural heritage conservation comprising a compound of the invention and oil.

[0077] In one aspect, the invention relates to a consumer product comprising a compound of the invention and a vegetable oil. In further aspect consumer product is lubricant. In one aspect the invention covers process for preparing the composition of the present invention comprising the following steps: [0078] (a) mixing the compounds of formula (I) or a salt thereof and the vegetable oil; [0079] (b) heating the mixture obtained in step (a) to a temperature until compound is completely dissolved; [0080] (c) cooling the mixture obtained in step (room temperature or bellow.

[0081] In one aspect the invention covers process for preparing the composition of the present invention comprising the following steps: [0082] (a) mixing the food, pharmaceutically active ingredient, nutraceuticals or a cosmetic ingredient as solid or solubilised component in oil or water and the vegetable oil; [0083] (b) heating the mixture obtained in step (a) to a temperature until compound is completely dissolved; [0084] (c) adding and mixing the compounds of formula (I) or a salt thereof solubilised in oil during step (a) or step (b) [0085] (d) cooling the mixture obtained in step (b) to room temperature or bellow.

[0086] In one aspect the invention covers process for preparing the composition of the present invention comprising the following steps: [0087] (a) mixing the compounds of formula (I) or a salt thereof and the vegetable oil; [0088] (b) heating the mixture obtained in step (a) to a temperature until compound is completely dissolved; [0089] optionally (c) mixing the food, pharmaceutically active ingredient, nutraceuticals or a cosmetic ingredient as solid or solubilised component in oil or water into the mixture during the step (b); [0090] (d) cooling the mixture obtained in step (b) to room temperature or bellow.

[0091] Further alternatively, a food, a pharmaceutically active ingredient, a nutraceuticals or a cosmetic ingredient as solid or solubilised component in oil or water may be added to the mixture after or during step (d).

[0092] In one aspect the invention covers process for preparing the composition of the present invention comprising the following steps: [0093] (a) mixing the compounds of formula (I) or a salt thereof and the vegetable oil; and optionally a food, pharmaceutically active ingredient, nutraceuticals or a cosmetic ingredient; [0094] (b) heating the mixture obtained in step (a) to a temperature until compound is completely dissolved; [0095] optionally (c) heating of water soluble ingredients in a water phase; [0096] (d) mixing of heated oil phase obtained in (b) and water phase obtained in (c); [0097] (e) cooling the mixture obtained in step (d) to room temperature or bellow.

Method of Preparation:

[0098] Compounds of Formula (I) and salts thereof may be prepared by the general methods outlined hereinafter.

[0099] Suitable addition salt of compounds of Formula (I) may be prepared starting from corresponding free acid (R.sub.2 is OH) by the use of an equivalent quantity of suitable base.

[0100] Specifically, for the preparation of sodium salt, an equivalent quantity of 1M aqueous NaOH may be used. For the preparation of ammonium salt, equivalent quantity of corresponding amine may be used.

[0101] Compounds of Formula (I)

##STR00003##

wherein [0102] A is (CH.sub.2).sub.mCH.sub.3; and [0103] B is NH(CH.sub.2).sub.nCOR.sup.2, and [0104] R.sup.2 is OH
may be prepared by saponification of corresponding ester (R.sub.2 is OCH.sub.3) with LiOH in methanol/dichloromethane solution for optically active derivatives or with KOH or NaOH in methanol for racemic ones followed by acidification.

[0105] Compound of formula (I) wherein A is (CH.sub.2).sub.mCH.sub.3 and B is NH(CH.sub.2).sub.nCOR.sup.2 and R.sup.2 is NH.sub.2, may be prepared starting from corresponding compound of formula (I) wherein R.sup.2 is OCH.sub.3 by amonolysis in conc. NH.sub.3/MeOH for 5-10 days at 0 C.

[0106] Compounds of Formula (I) wherein A is (CH.sub.2).sub.mCH.sub.3 and B is NH(CH.sub.2).sub.nCOR.sup.2 wherein n is 2-22 R.sup.2 is OR.sup.3, may be prepared by reaction of acyl chloride of formula (II)

CH.sub.3(CH.sub.2).sub.mCOCl (II)

with the compound of formula (III)

R.sup.2CO(CH.sub.2).sub.nNHCOCH(R.sup.1)NH.sub.2 (III)

wherein n is 2-22 and R.sup.2 is OR.sup.3; in dry CH.sub.2Cl.sub.2 in the presence of Et.sub.3N.

[0107] Compound of formula (III) wherein n is 2-22 may be prepared starting with corresponding amino acid of formula (IV)

NH.sub.2CH(R.sup.1)COOH (IV)

wherein amino group is protected for example with Boc protecting group, by condensation with the compound of formula (V)

NH.sub.2(CH.sub.2).sub.nCOOR.sup.3 (V)

in the presence of DCC, Et.sub.3N and DMAP in the aprotic solvent such as CH.sub.2Cl.sub.2 at room temperature followed by deprotection of amino protected group.

[0108] Reaction of condensation of compound of formula (IV) and (V) may also be carried out under activation by Ph.sub.3P, in CCl.sub.4/MeCN as solvent in the presence of Et.sub.3N.

[0109] Alternatively, compound of formula (III) may be prepared starting with amino acid of formula (IV) wherein amino group is Boc protected and wherein carboxy group is activated with succinimide ester by coupling with compound of formula (V) in the presence of Et.sub.3N in dry dioxane.

[0110] Compound of formula (V) are commercially available in case R.sup.3 is Me, tert-buthyl or benzyl, or are easily prepared starting from corresponding amino acid by introducing carboxy protecting group according to the procedure described in Protection for the Carboxyl Group. Kohlbau, H. J.; Thtirmer, R.; Voelter, W; In Synthesis of Peptides and Peptidomimetics; M. Goodman, Ed., Houben-Weyl, 4th ed., Vol. E22a; Thieme Stuttgard, 2002, pp 193-259.

[0111] Compound of formula (V) may also be prepared through esterification reaction from corresponding acid and alcohol in the presence of acidic catalyst (Noboru Ieda at al., Ind Eng. Chem. Res. 2008, 47, 8631-8638; Naowara Al-Arafi at al., E-Journal of Chemistry 2012, 9(1), 99-106; Mantri, K. Chem. Lett. 34 (2005) 11, 1502-1503).

[0112] Alternatively, compounds of Formula (I) wherein A is (CH.sub.2).sub.mCH.sub.3 and B is NH(CH.sub.2).sub.nCOR.sup.2 and R.sup.2 is OR.sup.3, may be prepared by reaction of hydrochloride salt of compound of formula (V)

NH.sub.2(CH.sub.2).sub.nCOOR.sup.3 (V)

and compound of formula (VI)

CH.sub.3(CH.sub.2).sub.mCONHCH(R.sup.1)COOH (VI)

under activation by Ph.sub.3P, in CCl.sub.4/MeCN as solvent in the presence of Et3N.

[0113] Compound of formula (VI) may be prepared starting with ester of formula

CH.sub.3(CH.sub.2).sub.mCONHCH(R.sup.1)COOCH.sub.3 (VIa)

by saponification with NaOH in methanol solution followed by acidification.

[0114] Compounds of Formula (VIa) may be prepared from ester of formula (VII)

CH.sub.3(CH.sub.2).sub.mCOOSu (VII)

with the compound of formula

HClNH.sub.2CH(R.sup.1)COOCH.sub.3 (VIII)

in dry dioxane in the presence of Et.sub.3N.

[0115] Compound of formula (VII) may be prepared starting from acid of formula (VIIa)

CH.sub.3(CH.sub.2).sub.mCOOH (VIIa)

by reaction with N-hydroxy-succinimide in the presence of DCC in dry dioxane.

[0116] Compound of formula (I) wherein A is CONHCH(R.sup.1)COCH.sub.3 and B is R.sup.2 wherein R.sup.2 is NH.sub.2, may be prepared starting from corresponding compound of formula (I) wherein R.sup.2 is OCH.sub.3 by amonolysis in conc. NH.sub.3/MeOH for 5-10 days at 0 C.

[0117] Compound of formula (I) wherein A is CONHCH(R.sup.1)COCH.sub.3 and B is R.sup.2 wherein R.sup.2 is OR.sup.3 may be prepared by condensation of oxalylchloride of formula (COCl).sub.2 with the salt of corresponding amino acid ester of formula (VIII)

NH.sub.2CH(R.sup.1)COOR.sup.3 (VIII)

in aprotic solvent such as dichloromethane in the presence of Et.sub.3N at 0 C. to room temperature overnight.

[0118] Compound of formula (VIII) are commercially available in case R.sup.3 is Me, tert-buthyl or benzyl, or are easily prepared starting from corresponding amino acid by introducing carboxy protecting group according to the procedure described in Protection for the Carboxyl Group. Kohlbau, H. J.; Thtirmer, R.; Voelter, W; In Synthesis of Peptides and Peptidomimetics; M. Goodman, Ed., Houben-Weyl, 4th ed., Vol. E22a; Thieme Stuttgard, 2002, pp 193-259.

[0119] Compound of formula (VIII) may also be prepared with condensation reaction from corresponding amino acid and alcohol in benzene in presence of acidic catalyst under reflux in a Dean-Stark apparatus.

[0120] Compound of formula (I) wherein A is CONHCH(R.sup.1)COCH.sub.3 and B is R.sup.2 wherein R.sup.2 is OH may be prepared by condensation of oxalylchloride of formula (COCl).sub.2 with the corresponding amino acid of formula (IV)

NH.sub.2CH(R.sup.1)COOH (IV)

[0121] The reaction is carried out in biphasic CH.sub.2Cl.sub.2/aqueous KOH system by adding dropwise a solution of oxalyl chloride in CH.sub.2Cl.sub.2 and aqueous KOH to a cooled (10 C.) solution of the corresponding amino acid continuing with stirring at 0 C. to a room temperature for 1 hour. The product precipitates from aqueous layer after diluting with H.sub.2O, and acidifying with formic acid.

[0122] Compound of formula (I) wherein A is CONH(CH.sub.2).sub.pNHCOCONHCH(R.sup.1)COR.sup.2 and B is R.sup.2 wherein R.sup.2 is OH may be prepared by alkaline hydrolysis (e.g. with a LiOH) of corresponding compound wherein R.sup.2 is OMe in an aprotic solvent such as dichloromethane at room temperature.

[0123] Compound of formula (I) wherein A is CONH(CH.sub.2).sub.pNHCOCONHCH(R.sup.1)COR.sup.2 and B is R.sup.2 wherein R.sup.2 is OR.sup.3 may be prepared by transforming diacid of formula (IX)

HOOCCONH(CH.sub.2).sub.pNHCOCOOH (IX)

first to corresponding dichlorides with SOCl.sub.2 in the presence of catalytic amount of DMF in dichloromethane as solvent, followed by reaction with salt of corresponding amino acid ester of formula (VIII)

NH.sub.2CH(R.sup.1)COOR.sup.3 (VIII)

in the presence of Et.sub.3N.

[0124] Compound of formula (IX) may be prepared by treating the diester of formula (X)

EtOOCCONH(CH.sub.2).sub.pNHCOCOOEt (X)

with methanolic KOH followed by acidification.

[0125] Diester of formula (X) may be prepared by condensation of diamine of formula (XI)

H.sub.2N(CH.sub.2).sub.pNH.sub.2 (XI)

with ethyl oxalylchloride of formula EtOCOCOCl in the presence of Et.sub.3N in the aprotic solvent such as dichloromethane.

[0126] Compounds of formula (II), (IV), (V), (VIIa) (VIII) and (XI) are commercially available or are easily prepared by person skilled in the art.

EXAMPLES

Example 1

6-{[2-(heptadecanoylamino)-2-phenylethanoyl]amino}hexanoic acid

Example 2

4-{[2-(nonadecanoylamino)-2-phenylethanoyl]amino}butanoic acid.

Example 3

4-{[(2R)-2-(nonadecanoylamino)-2-phenylethanoyl]amino} butanoic acid.

Example 4

Sodium 4-{[2-(nonadecanoylamino)-2-phenylethanoyl]amino}butanoate

Example 5

2-{[2-(heneicosanoylamino)-2-phenylethanoyl]amino}acetic acid

Example 6

2-{[(2R)-2-(heneicosanoylamino)-2-phenylethanoyl]amino}acetic acid

Example 7

11-{[(2S)-2-(Dodecanoylamino)-3-methylbutanoyl]amino}undecanoic acid

Example 8

11-{[(2R,S)-2-(Dodecanoylamino)-3-methylbutanoyl]amino}undecanoic acid

Example 9

11-{[(2S)-2-(Dodecanoylamino)-3-phenylpropanoyl]amino}undecanoic acid

Example 10

11-{[(2R,S)-2-(Dodecanoylamino)-3-phenylpropanoyl]amino}undecanoic acid

Example 11

11-{[(2R,S)-2-(Dodecanoylamino)-4-methylpentanoyl]amino}undecanoic acid.

[0127] ##STR00004##

TABLE-US-00001 Example R.sup.1 R.sup.2 m n stereochemistry 1 Ph OH 15 5 rac 2 Ph OH 17 3 rac 3 Ph OH 17 3 R 4 Ph O.sup.Na.sup.+ 17 3 rac 5 Ph OH 19 1 rac 6 Ph OH 19 1 R 7 CH(CH.sub.3).sub.2 OH 10 10 S 8 CH(CH.sub.3).sub.2 OH 10 10 rac 9 CH.sub.2Ph OH 10 10 S 10 CH.sub.2Ph OH 10 10 rac 11 CH.sub.2CH(CH.sub.3).sub.2 OH 10 10 rac

[0128] Compounds of Examples 1-6 were synthesised according to the procedure described in aplar at al., Chem. Eur. J. 2010, 16, 3066-3082.

[0129] Compounds of Examples 7-11 were synthesised according to the procedure described in aplar at al., Eur. J. Org. Chem. 2004, 4048-4059.

Example 12

N,N-Oxalyl-bis((S)-leucylamide)

Example 13

N,N-Oxalyl-bis((S)-leucine methyl ester)

Example 14

N,N-Oxalyl-bis((S)-valylamide)

Example 15

N,N-Oxalyl-bis((S)-ValOH)

Example 16

N,N-Oxalyl-bis((S)-phenylalanylamide)

Example 17

N,N-Oxalyl-bis((S)-PheOH)

Example 18

N,N-Oxalyl-bis[(S)-phenylalanine methyl ester)]

Example 19

()-[N,N-Oxalyl-bis(phenylglycylamide)]

Example 20

N,N-Oxalyl-bis((R)-PhgOH)

Example 21

N,N-Oxalyl-bis[(R)-phenylglycine methyl ester)]

[0130] ##STR00005##

TABLE-US-00002 Example R.sup.1 R.sup.2 stereochemistry 12 CH.sub.2CH(CH.sub.3).sub.2 NH.sub.2 S, S 13 CH.sub.2CH(CH.sub.3).sub.2 OCH.sub.3 S, S 14 CH(CH.sub.3).sub.2 NH.sub.2 S, S 15 CH(CH.sub.3).sub.2 OH S, S 16 CH.sub.2Ph NH.sub.2 S, S 17 CH.sub.2Ph OH S, S 18 CH.sub.2Ph OCH.sub.3 S, S 19 Ph NH.sub.2 rac 20 Ph OH R, R 21 Ph OMe R, R

[0131] Compounds of Examples 12-21 were synthesised according to the procedure described in Makarevi a at al., Chem. Eur. J. 2001, 7 (15), 3328 3341.

Example 22

1,6-Bis((O-leucylmethanol)-N-yloxalamido)hexane

Example 23

1,6-Bis ((leucine)-N-yloxalamido)hexane

Example 24

1,9-Bis((O-leucylmethanol)-N-yloxalamido)nonane

Example 25

1,9-Bis ((leucine)-N-yloxalamido)nonane

[0132] ##STR00006##

TABLE-US-00003 Example R.sup.1 R.sup.2 p stereochemistry 22 CH.sub.2CH(CH.sub.3).sub.2 OCH.sub.3 6 S, S 23 CH.sub.2CH(CH.sub.3).sub.2 OH 6 S, S 24 CH.sub.2CH(CH.sub.3).sub.2 OCH.sub.3 9 S, S 25 CH.sub.2CH(CH.sub.3).sub.2 OH 9 S, S

[0133] Compounds of Examples 22-25 were synthesised according to the procedure described in ijakovi Vujii at al. Chem. Eur. J. 2013, 19, 8558-8572.

[0134] The procedures and spectroscopic data of Examples 1-25 are incorporated here by references.

Determination of Gelling Properties:

[0135] All gelation experiments were performed in test tubes of 12 mm in diameter. The tested substance was placed in a test tube, and the oil was added by micro syringe in 500 L, portions. After each addition the mixture was gently heated until the substance dissolved, and was then allowed to cool spontaneously to room temperature and formation of gel checked by test tube inversion. The procedure is repeated until formation of a loose gel or dissolution is observed.

[0136] Gelation properties of prepared compounds were tested against various edible oils and the results are collected in Tables 1 and 2. Gelation efficiency of each gelator toward the specified edible oil is expressed in mL of oil that could be immobilized by trig of the gelator.

[0137] All of the prepared gels are transparent and show thermoreversible gel-to-sol transitions

[0138] In experiments sunflower oil (Zvijezda d.o.o.), soybean oil (Fluka), olive oil (Primadonna) were used.

Determination of Thixotropic Property

[0139] The formed gel was subjected to external mechanical stress (shaking) till gel is transformed into a sol state. The self-healing process (recovery to gel-state) after standing at room temperature was measured every 5 minutes by tube inversion method and visual observation.

[0140] The time of response necessary to self-heal from sol to gel state was determined at a half of the maximum gelling volume per 10 mg of tested compound (Table 1, column Recovery time (h or min)).

[0141] For example, compound 12 forms a transparent gel after a heating-cooling process in soybean oil with a critical gelation concentration (CGC) of 0.025 wt % (which corresponds to 43.3 mL expressed as maximal volume of oil that could be immobilized by 10 mg of compound 12, see Table 1). When treated with external mechanical stress, gel 12 from soybean oil lost most of its viscosity and transformed into a sol; after resting for 5 mm at room temperature, the gel completely regenerated. The self-healing process after the gel to sol transition, which was brought about by mechanical stress, can be repeated many times.

TABLE-US-00004 TABLE 1 Gelation efficiency of compounds 1, 2, 3, 6, 7, 9, 10, 12, 15, 16, 22 and 24 toward the specified edible oil expressed as the maximal volume (V.sub.max/ml) of oil that could be immobilized by 10 mg of the gelator. Thixotropic property measured at a half of the maximum gelling volume. Recovery Recovery Sunflower oil Recovery time*/ Soybean oil time/h Olive oil time/h Compound V/ml h or min V/ml or min V/ml or min 1 9.5 no 5.8 no 1.8 no 2 9.8 12 h 12 20 min 26.3 35 min 3 12.7 no 18 no 37.2 no 6 7.2 10 min 13.7 10 min 5.7 5 min 7 15.3 5 min 18.7 35 min 18.5 10 min 9 14 1.5 h 11.1 2.5 h 21.8 4 h 10 13.4 12 h 2 no 1.8 72 h 12 13.2 5 min 43.3 5 min 27.2 10 min 15 9.4 4 h 14.5 5 min 15.2 5 min 16 24.5 no 32 no 15.2 no 22 17.3 5 min 16.6 5 min 25.9 30 min 24 9 25 min 7 5 min 8.7 15 min *Self-healing properties of gels were checked by test-tube inversion every 5 minutes

TABLE-US-00005 TABLE 2 Gelation efficiency of compounds 4, 5, 8, 11, 13, 14, 17-21, 23 and 25 expressed as the maximal volume (V.sub.max/ml) of sunflower oil that could be immobilized by 10 mg of the gelator. Compound 4 5 8 11 13 14 17 18 19 20 21 23 25 V/ml 1.9 NG 3.5 NG NG 3 1.8 1.8 NG NG 2 NG 5** *NG = no gelation; **very weak gelation after 24 h