EA039502B1 - Personal care composition, compound for such composition, processes of preparing a compound and uses thereof - Google Patents

Abstract

The invention relates to a novel compound of formula 1 of the curcuminoid class and to a process of preparing it. It has been shown to have anti-inflammatory benefit and can be utilised in a wide range of personal care products, while not having the strong yellow colouration that is characteristic of many compounds of this class.

Description

The field of technology to which the invention belongs

The invention relates to a new compound and a method for its preparation. The invention further relates to a body care composition (also referred to herein as a personal care composition) that prevents or reduces inflammation. The composition may be delivered in the form of a skin, scalp, hair, or oral care product.

Prerequisites for the creation of the invention

Inflammation, the host's complex biological response to noxious stimuli, is the mechanism by which the host removes stimuli and initiates the healing process in self-protection. The host's innate immune system is the first line of non-specific defense against invading organisms. Uncontrolled inflammation can cause a variety of personal hygiene problems, including gingivitis/periodontitis (in the mouth), dandruff (on the scalp/hair), and eczema/acne (on the skin). To assist the host (eg, human or animal) to alleviate the above problems, several anti-inflammatory agents have been developed and used either by topical application or by oral administration.

Many of the foods we consume have a negative impact on our teeth and mouth. For example, acidic drinks and sweets can erode the teeth by attacking the enamel, which is the outer covering that protects the teeth. Sticky foods can accumulate between teeth and between the gums and teeth. In the absence of good oral hygiene, they can harden over time with the help of oral bacteria to form a film known as plaque.

Gingivitis is an inflammation of the gums caused by the accumulation of plaque and/or bacteria. During gingivitis, bacteria found in plaque biofilms and their respective components interact with gum tissue. After that, the innate immune response is activated, characterized by the release of pro-inflammatory cytokines. Gingivitis is a mild phase of periodontal disease and is defined as reversible inflammation. It is believed that a good oral hygiene habit, such as brushing teeth and using a mouthwash having therapeutic antimicrobial and anti-inflammatory efficacy, may be an effective method of reducing gingivitis-causing plaque in individuals.

Chronic gingivitis results in moderate bleeding from the gums during brushing. Gingivitis can progress to a more severe condition (chronic periodontitis) when the inflammatory process extends to the periodontal ligament and alveolar bone and/or has a significant systemic impact on health. Chronic periodontitis is asymptomatic until there is shifting, loosening or loss of teeth.

Dandruff is a condition experienced by many people around the world. The condition of dandruff ranges from mild symptoms such as flaky skin to severe inflammation and itching of the scalp. The main cause of dandruff is believed to be Malassezia yeast, such as Malassezia furfur, and while this may not reflect the full scientific picture of the situation, Malassezia yeast is indeed closely related to dandruff. Thus, a strategy commonly used to treat dandruff is the topical application of antifungals such as zinc pyrithione (ZnPTO), octopirox, climbazole, and ketoconazole, which are usually delivered via a shampoo. In addition, anti-inflammatory agents are also used in dandruff remedies to mitigate the side effects of this condition.

When it comes to skin, one of the problems that many people face, especially on the face, is acne. This phenomenon leads to an unpleasant cosmetic appearance. Acne, also known as acne vulgaris, is a common skin condition that affects virtually all teens and adults at some point during their lives. It has a complex etiology, including abnormal keratinization, excess sebum production, androgen function, bacterial growth, and immune hypersensitivity. Although one or more of the above processes are correlated with acne, the initiating factor and the exact sequence of events leading to the formation of acne are not completely understood. Other factors associated with acne are the presence of free radicals, followed by oxidative stress leading to cell damage. It has been observed that acne usually occurs in areas rich in sebaceous glands such as the face, neck and back. The bacteria Propionibacterium acnes (P. acnes) has also been implicated in acne.

Acne is treated in a variety of ways. Most treatments take weeks to months before noticeable changes are seen. Benzoyl peroxide, which has an antibacterial effect, is used for mild cases of acne and is also believed to prevent new acne from forming. In very severe cases of acne, antibiotics such as tetracycline, erythromycin, and clindamycin are used. Antibiotics are believed to work through several mechanisms, the most important of which is to reduce the amount of bacteria in and around the follicle. They are also thought to reduce the levels of irritating chemicals produced by white blood cells in sebum, thereby reducing the inflammatory response.

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Thus, inflammation is a process that manifests itself on the outer surface of the human or animal body in one or all of the above conditions. The present inventors have attempted to reduce the symptoms of the above conditions by developing new active substances as well as by studying combinations of active substances that exhibit synergistic anti-inflammatory effects. The present invention relates to the identification of active substances that can be obtained as derivatives of compounds found in extracts of natural materials. Natural materials from which many active substances have been extracted include ginger, turmeric, tea, grapes, tomatoes, and many others. One such active ingredient is curcumin, which has long been known to alleviate many health and cosmetic problems. The inventors of the present invention took curcumin and tried to derivatize it into new compounds in the hope of finding active substances with anti-inflammatory properties. Curcumin is an active substance extracted from the natural rhizome of turmeric. Turmeric is used as a spice in cooking and has a distinctive yellow color. It is known to have antimicrobial and anti-inflammatory properties. Curcumin has the following structure:

BUT <, OH

С ' · ’ ’ ·' ’·*' ’ ·< ' ··’ ' · o

CH- about ohm sn _:

enol form

Keto form

Although curcumin has many therapeutic properties that allow it to be used in medical and cosmetic applications, one of its drawbacks is its bright yellow color, which prevents widespread use in the manufacture of cosmetic compositions, for which visual appeal is very important. The inventors of the present invention attempted to preserve the structural and steric characteristics of the curcumin backbone while minimizing the yellowness of the synthesized compound. After extensive experimentation involving the synthesis of hundreds of such compounds, the present invention was made.

Thus, it is an object of the present invention to provide a novel anti-inflammatory active ingredient that is effective for use in personal care products.

Another object of the present invention is to provide an active ingredient that can be obtained from a compound extractable from a natural source, such as curcumin.

Another object of the present invention is to provide an active ingredient which is a derivative of curcumin and has a significantly less yellow color.

Brief description of the essence of the invention

According to a first aspect of the present invention, there is provided a compound having the chemical structure of formula 1

Formula 1

1,3-bis(2-(4-hydroxy-3-methoxyphenyl)cyclopropyl)-2,2-dimethylpropan-1,3-dione.

According to another aspect of the present invention, there is provided a method for preparing a compound according to the first aspect, comprising the following steps:

(i) protecting the phenolic hydroxyl groups of curcumin with a suitable protecting group P to give a compound of formula 2;

(ii) dimethylating a compound of formula 2 to give a compound of formula 3;

(iii) dicyclopropanation of the compound of formula 3 to obtain the compound of formula 4;

(iv) deprotection of the phenolic hydroxyl groups of the compound of formula 4 to obtain a compound of formula 1.

- 2 039502

Curcumin Formula 2

Stage 2 t

Formula 4 Formula 3

Stage 4

V

Formula 1

According to another aspect of the present invention, a personal care composition is disclosed comprising a compound of the first aspect and a cosmetically acceptable base.

According to another aspect of the present invention, a method for reducing inflammation on an external surface of a human or animal body is described, comprising the step of applying the composition of the first aspect to the desired surface.

Detailed description of the invention

Except in the examples or where expressly stated otherwise, all numbers in this specification indicating amounts of material or reaction conditions, physical properties of materials and/or applications may be understood to be preceded by the word about. All quantities are based on the weight of the final composition, unless otherwise indicated. It should be noted that in defining any ranges of values, any particular upper value may be combined with any particular lower value.

For the avoidance of doubt, the word containing is understood to mean including, but not necessarily consisting of or composed of. In other words, the listed steps or options are not exhaustive.

The disclosure of the invention, as made herein, should be considered as covering all embodiments claimed in the claims, as if they were multiple dependent on each other, regardless of the fact that the claims can be made without multiple dependence or redundancy. .

If any feature is disclosed in connection with a particular aspect of the invention (eg, a composition of the invention), it is also considered that said disclosure applies to any other aspect of the invention (eg, a method of the invention), mutatis mutandis.

An oral care composition for the purposes of the present invention means a paste, powder, liquid, chewing gum, serum or other composition for cleaning teeth or other surfaces in the oral cavity.

Toothpaste for the purposes of the present invention means a dentifrice paste or gel for use with a toothbrush. Particularly preferred are toothpastes suitable for brushing the teeth for about 2 minutes.

Mouthwash for the purposes of the present invention means a mouthrinse for use as a mouthwash. Particularly preferred are mouthwashes suitable for rinsing the mouth by shaking the mouth and/or gargling for about half a minute before spitting.

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The viscosity of the composition is a value measured at room temperature (25° C.) with a Brookfield viscometer, No. 4 spindle, at 5 rpm. Values are in centipoise (cP=mPa.s) unless otherwise noted.

By hair care composition, as the term is used herein, is meant a composition for topical application to the hair and/or scalp of mammals, in particular humans. Such a composition can generally be classified as leave-on (i.e., left on the skin) or rinse-off and includes any product applied to the human body also to enhance appearance, cleansing, odor control, or overall aesthetics. The composition of the present invention may be presented as a liquid, lotion, cream, foam, scrub, gel, or bar of soap. Non-limiting examples of such compositions include leave-in lotions, hair creams, and rinse-off shampoos, conditioners, shower gels, or bar soaps. The composition of the present invention is preferably a rinse-off composition, particularly preferably a shampoo or conditioner, and most preferably a shampoo.

Insoluble in water, as the term is used herein, refers to the solubility of a material in water at 25° C. and atmospheric pressure of 0.1% by weight or less.

By topical composition or skin care composition, as these terms are used herein, is meant a composition for topical application to the skin of mammals, in particular humans. Such a composition may be of the leave-on or rinse/rinse type. By leave-in composition is meant a composition that is applied to the desired surface of the skin and left for some time (for example, from 1 minute to 24 hours), after which it is washed or rinsed with water, usually during a normal washing procedure. By rinse-off composition is meant a composition applied to the desired skin surface for a shorter period of time, such as a few seconds or minutes, and usually containing a sufficient amount of surface-cleansing surfactants that can be washed off with plenty of water. The composition may also be formulated as a product that is applied to the human body to improve appearance, cleansing, odor control, or general aesthetics. The composition of the present invention may be in the form of a liquid, lotion, cream, foam, scrub, gel or stick and may be delivered by roll-on or using an aerosol can containing a propellant. Skin, as the term is used herein, means the skin of any part of the body, such as the neck, chest, back, forearms, armpits, arms, legs, buttocks, and scalp. When the product is applied to the armpits, it is usually referred to as a deodorant or deo product. A class of deodorants is a so-called antiperspirant (AP) product containing an AP active agent which, when applied to the axilla of an individual, provides antiperspirant and deodorant effects.

Desirably, the color of the novel compound of the present invention ranges from colorless to light yellow for optimal visual appeal and use in topical and/or skin care compositions. Visual evaluation of the color of a solid or solution sample of novel compounds compared to a solid or solution sample of curcumin provides an opportunity to determine relative color reduction and possible attractiveness. In addition, the UV-Vis spectra of the solution samples of the new compounds compared to the solution sample of curcumin allow for experimental color measurement and allow for a more direct color measurement. Thus, the use of these two simple measurement methods makes it possible to evaluate the relative color reduction of the new compounds of the invention relative to curcumin and to prioritize compounds for further development.

The present invention relates to a new compound of formula 1 below:

Formula 1

1,3-bis(2-(4-hydroxy-3-methoxyphenyl)cyclopropyl)-2,2-dimethylpropan-1,3-dione.

The Formula 1 compound has several unique and desirable properties over curcumin, including significantly improved color (light yellow for the Formula 1 compound versus orange for curcumin), greatly improved solubility in a wide range of solvents, and a lower melting point (gel for the Formula 1 compound). 1 compared to the high melting point solid (183°C) for curcumin).

Various chemical process conditions for each of steps 1-4 under which this new compound can be synthesized are given below.

In step 1, curcumin is dissolved in a system of organic solvents selected from (but not limited to) dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, isopropylacetate

- 4 039502 ta, isobutyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, methyl tert-butyl ether and mixtures thereof. The concentration of curcumin in the organic solvent may vary from 0.001 to 10M, more preferably from 0.01 to 1M. where P is a protecting group structure that is covalently attached to the oxygen atom of the phenol and further blocks or protects the phenolic hydroxyl groups from subsequent reactions in steps 2 and 3 of the chemical process, resulting in a compound of formula 1. Suitable P protecting groups used in step 1 include, but are not limited to, tetrahydropyranyl, 4methoxytetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, triphenylmethyl, alpha-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, isopropyldimethylsilyl, t- butyldimethylsilyl, tribenzylsilyl or triisopropylsilyl. The amount of protecting group reagent added may vary in the range of 2-50 eq. in relation to the number of equivalents of curcumin, more preferably is from 2 to 20 eq. A suitable catalyst (eg, acidic, such as p-toluenesulfonic acid, or weakly basic, such as imidazole), selected based on the protecting group reagent used, is added in an amount of 0.01 to 1 eq. relative to the amount of curcumin equivalents. The reaction can be carried out at a temperature in the range of 10-50°C, more preferably 15-35°C, but is not limited to these temperatures. The progress of the reaction is followed by a suitable detection method such as UV-Vis imaging, thin layer chromatography and/or high performance liquid chromatography. At the point where no further product formation is detected, the reaction mixture is worked up to allow the product to be isolated. Typically, working up a reaction mixture to isolate a compound of Formula 2 includes, but is not limited to, removing the reaction solvent under reduced pressure at 5-20° C. followed by an extraction process (e.g., dissolving the crude reaction mixture in an organic solvent and washing with aqueous buffers to removal of impurities) to isolate the crude product and final purification of the crude product by silica gel flash chromatography or crystallization using a solvent or mixed solvent system to give the pure compound of formula 2.

In step 2, the compound of formula 2 is dissolved in a system of organic solvents selected from (but not limited to) dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, t-butanol, t-amyl alcohol, acetone, 2-butanone, chloroform, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, methyl tert-butyl ether, water, glycerol, 1,2-propanediol, and mixtures thereof, to form a biphasic or monophasic system . The concentration of the compound of formula 2 in the solvent system may vary from 0.001 to 10 M, more preferably from 0.01 to 1 M. A base selected from (but not limited to) an alkali or alkaline earth metal bicarbonate, carbonate or hydroxide is added, followed by adding a methylating agent selected from (but not limited to) iodomethane, bromomethane, chloromethane, dimethyl carbonate, dimethyl dicarbonate, dimethyl sulfate, methyl fluorosulfonate, methyl methane sulfonate, methyl trifluoromethane sulfonate, and trimethyloxonium tetrafluoroborate. The amount of base reagent and methylating agent added can vary from 2 to 10 eq. in relation to the number of equivalents of the compounds of formula 2, more preferably is from 2 to 5 eq. For two-phase solvent systems, a catalyst selected from (but not limited to) quaternary ammonium salts or organic phosphonium salts is added in an amount of 0.001 to 1 eq. in relation to the number of equivalents of the compound of formula 2. The reaction can be carried out at a temperature of 10-50°C, more preferably 15-35°C, but is not limited to these temperatures. The progress of the reaction is followed by a suitable detection method such as UV-Vis imaging, thin layer chromatography and/or high performance liquid chromatography. At the point where no further product formation is detected, the reaction mixture is worked up to allow the product to be isolated. In the case of monophasic reaction solvent systems, processing the reaction mixture to isolate a compound of formula 3 includes an extraction process (e.g., dissolving the crude reaction mixture in an organic solvent and washing with aqueous buffers to remove impurities) to isolate the crude product, removing solvents under reduced pressure at 30-65° C, and final purification of the crude product by flash chromatography on silica gel or crystallization using a solvent or a mixed solvent system to give a pure compound of formula 3. In the case of two-phase reaction solvent systems, the organic layer is separated from the aqueous layer and the solvents are removed under reduced pressure at 20- 65°C followed by extraction and purification process as described above.

In step 3, a compound of formula 3 is dissolved in a system of organic solvents selected from (but not limited to) dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, or an ionic liquid

- 5 039502 (for example, 1-butyl-3-methylimidazolium hexafluorophosphate) and mixtures thereof, and the resulting solution is added to a pre-mixed mixture of trimethylsulfoxonium iodide with a base selected from (but not limited to) an alkali or alkaline earth or tertiary metal hydride or hydroxide amine base, in any of the above solvent systems. The concentration of the compound of formula 3, trimethylsulfoxonium iodide and base in the solvent system can vary from 0.001 to 5 M, more preferably from 0.01 to 1 M. The amount of trimethylsulfoxonium iodide and base reagent can vary from 2 to 5 eq. in relation to the number of equivalents of formula 3, more preferably is from 2 to 3 eq. The reaction can be performed at a temperature of 0-50°C, more preferably 10-35°C, but is not limited to these temperatures. The progress of the reaction is followed by a suitable detection method such as UV-Vis imaging, thin layer chromatography and/or high performance liquid chromatography. At the point where no further product formation is detected, the reaction mixture is worked up to allow the product to be isolated. Typically, working up a reaction mixture to isolate a compound of formula 4 involves an extraction process (e.g., dissolving the crude reaction mixture in an organic solvent and washing with aqueous buffers to remove impurities) to isolate the crude product, removing the solvents under reduced pressure at 30-65°C, and finally purifying the crude product by flash chromatography on silica gel or by crystallization using a solvent or mixed solvent system to give the pure compound of formula 4.

In step 4, the deprotection of the P group is achieved by dissolving the compound of formula 4 in an organic solvent system suitable and compatible with the conditions required to remove the protecting group P, to obtain the compound of formula 1. A non-exhaustive list of solvents that can be used in this case include ( but not limited to) chlorinated solvents (e.g. dichloromethane), alcohols (e.g. ethanol), diols (e.g. 1,2-propanediol), triols (e.g. glycerol), ethers (e.g. tetrahydrofuran, t-butyl methyl ether ), water, esters (eg ethyl acetate), dimethyl sulfoxide, dimethylformamide, acetonitrile and mixtures thereof. A suitable deprotecting agent (eg acidic such as acetic acid or weakly basic such as sodium fluoride), depending on the nature of the P group to be removed, is added in an amount of 0.01 to 5 eq. relative to the amount of curcumin equivalents. The reaction can be performed at a temperature of 0-50°C, more preferably 15-35°C, but is not limited to these values. The progress of the reaction is followed by a suitable detection method such as UV-Vis imaging, thin layer chromatography and/or high performance liquid chromatography. At the point where no further product formation is detected, the reaction mixture is worked up to allow the product to be isolated. Typically, working up a reaction mixture to isolate a compound of formula 1 includes, but is not limited to, removing the reaction solvent under reduced pressure at 20-55° C. followed by an extraction process (e.g., dissolving the crude reaction mixture in an organic solvent and washing with aqueous buffers to removal of impurities) to isolate the crude product and final purification of the crude product by flash chromatography on silica gel or crystallization using a solvent or mixed solvent system to give the pure compound of formula 1.

Once the compound has been prepared, it is usually included in an amount of 0.01 to 5%, preferably 0.1 to 3%, more preferably 0.1 to 2% by weight in the personal care composition.

The composition of the invention may be formulated to be suitable for use as an oral care or skin, scalp or hair care agent. The agent may be delivered in the form of a solid, soft solid, liquid, emulsion, microemulsion, lotion, cream, gel, or aerosol.

oral care

When the personal care composition is delivered for oral care, it includes a cosmetically acceptable base, which may be an abrasive, thickener, humectant, or orally acceptable surfactant. The agent may be delivered in the form of an ointment, gel, dentifrice, or mouthwash.

The oral care compositions preferably contain an abrasive. Gels usually contain silicon dioxide, while opaque creams usually contain calcium-based abrasives, in particular chalk.

Preferred toothpaste compositions contain 5-60% by weight of a calcium-based abrasive. In more preferred compositions, its content is 30-60 wt.% and even more preferably from 35 to 55 wt.%. Optimum compositions contain 40-55 wt.% calcium-based abrasive.

The preferred abrasive is finely ground natural chalk (FGNC), which is a form of chalk. It is obtained from limestone or marble. Fine ground natural chalk (FGNC) can also be chemically or physically modified by coating during grinding or after grinding using heat treatment. Typical coating materials include magnesium stearate or magnesium oleate. The morphology of the FGNC can also be modified during the milling process using various methods such as ball milling, pneumatic grade grinding.

- 6 039502 grinding or spiral jet grinding.

Fine ground natural chalk (FGNC) can be used as the only calcium based abrasive. However, FGNC can also be used with other calcium based abrasives for some balance of abrasiveness. Typically, the particle size of the chalk is from 1 to 60 microns, and the preferred sizes range from 1 to 15 microns. Other preferred calcium-based abrasives include dicalcium phosphate (DCP), calcium pyrophosphate and precipitated calcium carbonate (PCC), which are preferably included in an amount of 25-55 wt.%, more preferably 35-50 wt.%.

When a combination of calcium based abrasives is desired, it is preferred that the FGNC content be 35-100%, more preferably 75-100% and especially 95% to 100% of the total amount of calcium based abrasives. In such cases, the rest is most preferably PCC.

Other abrasives may also be used depending on the degree of abrasion expected. These include synthetic abrasive polishing agents such as amorphous precipitated silica and silica gels. Other abrasive agents include magnesium carbonate, sodium metaphosphate, potassium metaphosphate, zirconium silicate, potassium metaphosphate, magnesium orthophosphate, tricalcium phosphate, magnesium orthophosphate, trimagnesium phosphate, aluminum silicate, zirconium silicate, and perlite.

In a preferred embodiment, the composition contains a thickener. Thickeners that can be used in this invention include sodium carboxymethylcellulose (SCMC), hydroxyethylcellulose, methylcellulose, ethylcellulose, gum tragacanth, gum arabic, karaya gum, xanthan gum, sodium alginate, carrageenan gum, guar gum, Irish moss, starch, modified starch , silica thickeners, including silica aerogels, aluminum magnesium silicate (eg Veegum®), carbomers (crosslinked acrylates) and mixtures thereof.

Typically thickening silica, sodium carboxymethyl cellulose and/or carbomer are/are the preferred thickeners for use in the composition of the invention. When a carbomer is used, carbomers with a weight average molecular weight of at least 700,000 are desirable, preferably with a molecular weight of at least 1,200,000, and most preferably with a molecular weight of at least about 2,500,000. Mixtures of carbomers can also be used herein.

In a particularly preferred embodiment, the carbomer is Synthalen® PNC, Synthalen® KP, or a mixture thereof. It has been described as a high molecular weight and crosslinked polyacrylic acid and identified by CAS number 9063-87-0. These types of materials are available from many suppliers such as Sigma.

In another particularly preferred embodiment, the sodium carboxymethyl cellulose (SCMC) used is SCMC 9H. It is described as the sodium salt of a cellulose derivative with carboxymethyl groups linked to the hydroxy groups of the backbone glucopyranose monomers and identified by CAS number 9004-32-4. It is available from suppliers such as Alfa Chem.

Thickening silica is particularly preferred for use in gel toothpastes. Gel toothpastes typically contain up to 8.5 wt% thickening silica, while opaque toothpastes typically contain 3-4 wt% thickening silica.

When present, preferred thickening silicas include the AEROSIL T series from Degussa or the CAB-O-SIL series from Cabot Corporation, silica gels such as the SYLODENT or SYLOX series from W. R. Grace & Co, or precipitated silica such as ZEOTHIX 265 from J. M. Huber Corporation. Suitable silica thickeners also include ZEODENT 165, ZEODENT 163 and/or 167 and ZEOFREE 153, 177 and/or 265 from J. M. Huber Corporation. Other preferred thickening silicas include MFIL, MFIL-P (from Madhu Silica, India), SIDENT 22 S and AEROSIL 200 (Ex. Evonik Industries), SYLODENT and PERKASIL thickening silicas from WR Grace & Company, Tixosil 43 and 331 from Rhodia, fine synthetic fumed silica, such as those sold under the trademarks SYLOID 244, SYLOID 266 and AEROSIL D-200.

The thickener, when present, is preferably 0.01 to 10%, more preferably 0.1 to 9% and most preferably 1.5 to 8% by weight of the composition.

Suitable humectants are preferably used in the oral composition of the present invention and include, for example, glycerin, sorbitol, propylene glycol, dipropylene glycol, diglycerin, triacetin, mineral oil, polyethylene glycol (preferably PEG400), alkanediols such as butanediol and hexanediol , ethanol, pentylene glycol, or a mixture thereof. Preferred humectants are glycerol, polyethylene glycol, sorbitol, or mixtures thereof.

The humectant may be present in an amount of 10 to 90% by weight of the oral compositions. More preferably, the humectant makes up from 25 to 80% and most preferably from 45 to 70% by weight of the composition, based on the total weight of the composition, including all ranges within these limits.

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Preferably, the oral composition contains a surfactant. Preferably the composition contains at least 0.01% surfactant by weight of the composition, more preferably at least 0.1% and most preferably 0.5 to 7%. Suitable surfactants include anionic surfactants such as sodium, magnesium, ammonium or ethanolamine salts of C ₈ -C ₁₈ alkyl sulfates (eg sodium lauryl sulfate), C ₈ -C ₁₈ alkyl sulfosuccinates (eg sodium dioctyl sulfosuccinate), C ₈ -C ₁₈ alkyl sulfoacetates (such as sodium lauryl sulfoacetate), C ₈ -C ₁₈ alkyl sarcosinates (such as sodium lauryl sarcosinate), C ₈ -C ₁₈ alkyl phosphates (which may optionally contain up to 10 units of ethylene oxide and/or propylene oxide), and sulfated monoglycerides. More preferably, the surfactant contains or is an anionic surfactant. Preferred anionic surfactants are sodium lauryl sulfate and/or sodium dodecylbenzenesulfonate. Most preferably, the surfactant is sodium lauryl sulfate. Other suitable surfactants include nonionic surfactants such as optionally polyethoxylated sorbitan fatty acid esters, ethoxylated fatty acids, polyethylene glycol esters, fatty acid monoglyceride and diglyceride ethoxylates, and ethylene oxide/propylene oxide block polymers. Other suitable surfactants include amphoteric surfactants such as betaines or sulfobetaines. You can also use mixtures of any of the above substances. The most preferred surfactants are alkali metal alkyl sulfate or betaine.

Water may preferably be included in an amount of 5-95%, in particular 10-75%, especially 10-60%, even more preferably 10-45% of the total weight of the composition.

When the oral care composition of the present invention is a toothpaste or gel, it typically has a viscosity of from about 30,000 to 180,000 centipoise, preferably from 60,000 to 170,000 centipoise, and most preferably from 65,000 to 165,000 centipoise.

The oral care composition of the present invention may contain a variety of other ingredients that are standard in the art to improve physical properties and performance. These ingredients include antimicrobial agents, anticaries agents, plaque buffers, fluoride sources, vitamins, plant extracts, desensitizing agents, anticalculus agents, biological molecules, flavors, protein compounds, preservatives, opacifiers, coloring agents, pH adjusting agents, sweeteners. agents, ground abrasives, polymeric compounds, buffers and salts that adjust the pH and ionic strength of the compositions, and mixtures thereof. Such ingredients typically and collectively comprise less than 20% by weight of the composition, preferably 0.0 to 15% and most preferably 0.01 to 12% by weight of the composition, including all ranges therein.

Hair care

According to a preferred aspect of the invention, the composition can be used for hair care. This is especially helpful in preventing or relieving the symptoms of dandruff. One of the media through which the composition can be delivered is a shampoo. The composition of the invention, in particular the shampoo, is formulated with an anionic surfactant, for example an alkyl sulfate and/or ethoxylated alkyl sulfate surfactant. These anionic surfactants are preferably present in an amount of 1 to 20%, preferably 2 to 16%, even more preferably 3 to 16% by weight of the composition. Preferred alkyl sulfates are C ₈ . ₁₈ αalkyl sulfates, more preferably C ₁₂ . ₁₈ alkyl sulfates, preferably in the form of a salt with a solubilizing cation such as sodium, potassium, ammonium or substituted ammonium.

Preferred alkyl ether sulfates are those having the formula: RO(CH ₂ CH ₂ O) _n SO ₃ M; where R represents alkyl or alkenyl containing from 8 to 18 (preferably 12-18) carbon atoms; n is a number with an average value of at least more than 0.5, preferably from 1 to 3, more preferably from 2 to 3; and M is a solubilizing cation such as sodium, potassium, ammonium, or substituted ammonium. An example is sodium lauryl ether sulfate (SLES).

A preferred ethoxylated alkyl sulfate anionic surfactant is sodium lauryl ether sulfate (SLES). Especially preferred is SLES with an average degree of ethoxylation between 0.5 and 3, preferably between 1 and 3.

Shampoo compositions of the invention may contain one or more additional anionic cleansing surfactants that are cosmetically acceptable and suitable for topical application to the hair.

The composition of the invention preferably further comprises an amphoteric surfactant, preferably a betaine surfactant, preferably an alkylamidopropyl betaine surfactant, eg cocamidopropyl betaine. In a preferred embodiment, the composition contains from 0.1 to 10% by weight, preferably

- 8 039502 from 0.5 to 8 wt.%, more preferably from 1 to 5 wt.% of the surfactant betaine.

To enhance the deposition of active substances from the compositions according to the invention, especially shampoos, they usually include cationic polymers. In the present invention, it is also preferred that the composition additionally contains 0.01-2.0% of the cationic polymer. The cationic polymer is preferably guarhydroxypropyltrimonium chloride. The guar polymer predominantly contains galactomannan polymer chains. This polymer is available in various molecular weights and degrees of cationic substitution depending on how much guar has been hydrolyzed and cationized. The cationic polymer is preferably present in an amount of 0.04 to 0.5%, more preferably 0.08 to 0.25% by weight of the composition.

When conditioning effects are achieved by a composition of the invention, the composition is referred to as a hair conditioner. Generally, the most popular conditioning agents used in hair care compositions are water-insoluble oily substances such as mineral oils, natural oils such as triglycerides, and silicone polymers. The conditioning effect is achieved by the fact that the oily substance is deposited on the hair, which leads to the formation of a film that makes the hair easier to comb when it is wet and makes it more manageable when it is dry. A particularly useful conditioning agent is a silicone compound, preferably a non-volatile silicone compound. Advantageously, the compositions herein may include one or more silicones. Silicones are conditioning agents in the form of dispersed or suspended particles. They are designed to be deposited on the hair, remaining after washing the hair with water. Suitable silicone oils may include polyalkylsiloxanes, polyarylsiloxanes, polyalkylarylsiloxanes, polyethersiloxane copolymers, and mixtures thereof. Amino silicones are often made up with shampoo. Amino silicones are silicones containing at least one primary amino group, a secondary amino group, a tertiary amino group, or a quaternary ammonium group. You can also use chewing gums based on high molecular weight silicone. Another useful type are crosslinked silicone elastomers such as dimethicone/vinyl/dimethicone crosspolymers (eg Dow Corning 9040 and 9041).

The amount of silicone in the compositions in which they are present may be from about 0.1 to about 10 wt.%, preferably from about 0.1 to about 8 wt.%, more preferably from about 0.3 to about 5 wt.% based on the weight of the compositions for hair care.

The pH value of the composition is preferably 4.0 or more, more preferably in the range of 5.0-7.0.

The hair conditioning composition typically contains conditioning surfactants selected from cationic surfactants, used alone or in admixture. Cationic surfactants suitable for use in conditioner compositions according to the present invention include cetyltrimethylammonium chloride, behenyltrimethylammonium chloride, cetylpyridinium chloride, tetramethylammonium chloride, tetraethylammonium chloride, octyltrimethylammonium chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, octyldimethylbenzylammonium chloride, decyldimethylbenzyl chloride, chloride, didodecyldimethylammonium chloride, dioctadecyldimethylammonium chloride, tallow trimethylammonium chloride, dihydrogenated tallow dimethylammonium chloride (eg Arquad 2HT/75 from Akzo Nobel), cocotrimethylammonium chloride, PEG-2-oleammonium chloride and their respective hydroxides. Other suitable cationic surfactants include the CTFA designations Quaternium-5, Quaternium31 and Quaternium-18. Mixtures of any of the above materials may also be suitable. A cationic surfactant particularly suitable for use in conditioners according to the present invention is cetyltrimethylammonium chloride, available commercially, for example as GENAMIN CTAC from Hoechst Celanese. Another cationic surfactant particularly suitable for use in conditioners according to the present invention is behenyltrimethylammonium chloride, available commercially, for example as GENAMIN KDMP from Clariant. Another preferred cationic surfactant is stearamidopropyl dimethylamine.

The most preferred cationic surfactants for use in the formulation are stearamidopropyl dimethylamine, behentrimonium chloride, or stearyltrimethylammonium chloride. In conditioners according to the invention, the content of cationic surfactant is usually from 0.1 to 5%, preferably from 0.5 to 2.5% by weight of the composition.

The hair conditioning compositions of the invention may preferably also additionally contain a fatty alcohol. The combined use of fatty alcohols and cationic surfactants in conditioning compositions is believed to be particularly advantageous because it results in the formation of a lamellar phase in which the cationic surfactant is dispersed.

- 9 039502

Typical fatty alcohols contain from 8 to 22 carbon atoms, more preferably from 16 to 22. Fatty alcohols are usually compounds containing straight chain alkyl groups. Examples of suitable fatty alcohols include cetyl alcohol, stearyl alcohol, and mixtures thereof. The use of these materials is also advantageous in that they contribute to the overall conditioning properties of the compositions of the invention.

The level of fatty alcohol in conditioners of the invention is typically 0.5 to 10%, preferably 0.1 to 8%, more preferably 0.2 to 7%, most preferably 0.3 to 6% by weight of the composition. The weight ratio of cationic surfactant to fatty alcohol is preferably 1:1 to 1:10, more preferably 1:1.5 to 1:8, optimally 1:2 to 1:5.

Hair care compositions delivered as shampoos or conditioners typically contain an anti-dandruff component. The most preferred anti-dandruff agent for use in the composition of the invention is a zinc-based anti-dandruff agent, preferably zinc pyrithione. Zinc pyrithione belongs to a class of insoluble metal pyrithione that can be represented by the following general formula:

in which M is a polyvalent metal ion, n corresponds to the valency of M. In the present invention, M corresponds to zinc and n is 2. Zinc pyrithione may have any particle shape suitable for use in a topical composition. For example, zinc pyrithione may be in the form of amorphous or crystalline particles having a range of different particle sizes. The zinc pyrithione may, for example, be in the form of particles having a size distribution, wherein at least about 90% of the particles are up to 100 µm, more preferably up to 50 µm, even more preferably up to 10 µm, most preferably 5 µm or less. .

Various methods for producing small particles of metal pyrithione are described, for example, in EP-A0173259. Suitable methods for determining particle size are described in this document. The insoluble metal pyrithione may be composed of one particle shape or two or more different particle shapes.

Other suitable particle shapes for zinc pyrithione include platelets and needle-shaped particles. Zinc pyrithione plates are described in EP-A-0034385, the content of which is incorporated herein by reference. The needle-shaped particles are preferably of the type described in WO 99/66886, the content of which is incorporated herein by reference. For acicular particles, preferably at least 50% of the number of particles are acicular particles having a length of 1 to 50 µm.

The amount of metal pyrithione included in the compositions may depend on the type of composition and the particular nature of the material used. The preferred amount of pyrithione is from about 0.01% to about 1.5% by weight of the total composition, more preferably from about 0.05% to about 1.5% by weight of the total composition.

The composition according to the invention, in particular for anti-dandruff shampoos, preferably additionally contains a zinc compound. The presence of an additional zinc compound in the composition is believed to enhance the anti-dandruff efficacy of the zinc-based anti-dandruff component. Suitable zinc compounds are zinc oxide, zinc citrate, zinc malonate, zinc carbonate, or combinations thereof. The zinc compound is preferably present in an amount of 0.1 to 3%, more preferably 0.1 to 1.5% by weight of the composition.

The shampoo composition of the invention preferably further comprises a conazole fungicide. Preferably the conazole fungicide is selected from ketoconazole, climbazole or mixtures thereof. The azole fungicide is preferably included in an amount of 0.01 to 2%, more preferably 0.025 to 0.75% by weight of the composition. The presence of the conazole fungicide is believed to improve the precipitation of zinc pyrithione.

Skin care

The composition according to the invention can be used for skin care. The cosmetically acceptable base in such cases may be a liquid or solid material. Typically, the base is present in an amount of from 10% to 99.9%, more preferably from 20% to 95%, most preferably from 40% to 85% of the total weight of the composition, including all ranges within these limits. It is particularly preferred that the cosmetically acceptable carrier comprises water. Water is preferably included in an amount of 30 to 90%, more preferably 30 to 85%, most preferably 30 to 80% of the total weight of the sunscreen composition. Along with water, suitable carrier classes include

- 10 039502 silicones, polyhydric alcohols, hydrocarbons, triglycerides and thickening powders.

The skin care composition of the invention may be presented in any form, including tonics, lotions, creams, mousses, scrubs, serums or gels, which are suitable for topical application to the skin. The composition can be either a leave-on product, such as skin lotions, creams, antiperspirants, deodorants, lipsticks, foundations, mascaras, sunscreens, and sunscreen lotions, or a rinse-off product, such as shower gels and soaps. . Preferably, the composition is a skin lotion or cream.

The composition may contain an emollient oil which acts as a co-solvent. Suitable emollient oils include, for example, an alkoxylated aromatic alcohol fatty carboxylic acid ester, polyglycol or diol fatty carboxylic acid esters such as caprylic/capric triglyceride, a fatty alcohol fatty acid ester, an alkoxylated benzyl alcohol derivative, and mixtures thereof. Preferably the emollient oil is caprylic/capric triglyceride.

Typically, such compositions contain co-solvent in an amount of 0.01% to 10%, more preferably 0.1% to 8%, most preferably 1% to 6%, based on the total weight of the sunscreen composition, including all ranges therein.

The composition may further contain sunscreen agents such as inorganic sunscreens. For example, zinc oxide, titanium dioxide, iron oxide, silicon dioxide such as colloidal silicon dioxide. The amount of such sunscreen agents is preferably 0.1 to 5% of the total weight of the sunscreen composition.

The composition of the invention may contain a UV A sunscreen selected from the group consisting of a dibenzoylmethane derivative, a triazine derivative, a benzophenone derivative, and mixtures thereof. In a preferred embodiment, the UVA sunscreen comprises or is a dibenzoylmethane derivative, eg butylmethoxydibenzoylmethane (sold under the tradename Parsol 1789).

Typically, the sunscreen composition of the present invention contains from 0.1 to 15 wt.% sunscreen agent against ultraviolet radiation spectrum A, more preferably from 0.1 to 10%, most preferably from 1 to 5% based on the total weight of the composition and including all ranges within these limits.

The composition of the invention may also contain an UVB sunscreen. A suitable UVB sunscreen of the invention is selected from the group consisting of benzophenone, anthranilate, salicylate, cinnamate, camphor, benzylidenemalonate, triazone, and derivatives thereof. In a preferred embodiment, the UVB sunscreen comprises or is a cinnamate derivative, such as ethylhexylmethoxycinnamate (commercially available under the tradename Parsol MCX).

Typically, the composition contains from 0.1 to 20 wt.% sunscreen agent against ultraviolet B radiation, more preferably from 0.5 to 18 wt.%, most preferably from 1 to 15 wt.% based on the total weight of the composition and including all ranges specified within these limits.

A skin whitening component can also be included in the composition of the invention. The most preferred skin whitening ingredient is a vitamin B3 compound. The vitamin B3 compound may be niacin, nicotinic acid or niacinamide, preferably niacinamide. Niacinamide has the structure shown below:

Niacinamide is preferably present in an amount of 0.01-5%, more preferably 0.13% by weight of the composition. Suitable skin whitening ingredients other than vitamin B3 and its derivatives are kojic acid, arbutin, tranexamic acid, placenta extract, ascorbic acid and its derivatives (e.g. magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl glucoside and ascorbyl tetraisopalmitates), aloe extract, lactate ammonium, azelaic acid, citric acid esters, ellagic acid, glycolic acid, green tea extract, hydroquinone, lemon extract, linoleic acid, vitamins such as vitamin B6, vitamin B12, vitamin C, vitamin A, dicarboxylic acid, resorcinol derivatives, hydroxycarboxylic acid such as lactic acid and its salts (eg sodium lactate) or mixtures thereof. Typically, the skin whitening component is present in an amount of 0.1 to 10%, more preferably 0.2 to 5%, most preferably 0.3 to 3% of the total weight of the composition, including all ranges therein.

A separate class of skin care compositions are those known as deodorant compositions. They can be applied to the skin as a topical cosmetic, generally speaking, in one of two ways. Different consumers prefer one way or the other. In one

- 11 039502 method, sometimes called the contact method, the composition is triturated on the surface of the skin, depositing part of the composition as it is distributed. In the second method, which is sometimes referred to as the non-contact method, the composition is sprayed from a dispenser held close to the skin, often at a distance of the order of 10 to 20 cm. side wall, or internal pressure generated due to evaporation of a portion of the liquefied propellant, the dispenser being commonly referred to as an aerosol.

In general, there are two classes of contact compositions, the first class being a liquid, usually applied with a roll-on dispenser, or which can be soaked or applied to a tissue, and in the second class, the desired active ingredient is dispersed in a carrier liquid forming a continuous phase turned into a gel. In one embodiment, the carrier fluid contains a solvent for the desired active ingredient, and in the second embodiment, the active ingredient remains in the form of solid particles suspended in oil, usually in a mixture of oils.

Pencil or soft solid compositions

Many different materials have been proposed as a gelling agent for the continuous oil phase, including waxes, low molecular weight gelling agents, and polymers. Each has its own advantages, and one of the most popular classes of gelling agents includes waxes, due at least in part to their availability and ease of processing, including, in particular, waxy linear fatty alcohol gelling agents. The gel-like composition of the deodorant is applied topically to the skin by rubbing and in contact with the skin, thereby depositing a thin film on the skin.

The nature of the film depends to a large extent on the gelling agent used. Although waxy fatty alcohols have been used as a gelling agent for many years and are effective for gelling purposes, the resulting product is rather ineffective in improving the appearance of the skin, and in particular the underarm skin to which the composition has been applied. This problem has been solved by the inclusion of enhancing agents such as di- or polyhydric humectants and/or triglyceride oil.

Roll-on applicator

Liquid compositions that can be applied from a roll-on can generally be divided into two classes, namely those in which the active ingredient is suspended in a hydrophobic carrier such as volatile silicone and those in which the active ingredient is dissolved in the carrier liquid. The latter proved to be more popular. There are mainly two kinds of solvent carrier liquid, namely carriers which are predominantly alcoholic, that is, most of the solvent carrier liquid is composed of ethanol, and a second class in which the carrier liquid is mainly water. The first class was very popular because ethanol itself is a mild bactericidal agent, but its popularity waned because it caused a burning sensation, especially if the surface to which the composition was applied was damaged or cut, which easily occurs when shaving or other depilation operations.

The second class of formulations, which is an alternative to alcohol formulations, comprises a dispersion of water-insoluble or very poorly water-soluble ingredients in an aqueous solution of the active ingredient. In this document, such compositions will be referred to as emulsions. Roll-on emulsions usually contain one or more emulsifiers to maintain the distribution of water-soluble ingredients.

Aerosol compositions

Deodorant compositions can be delivered via an aerosol that contains a propellant in addition to other components described above herein. As a rule, the propellant is introduced in a mass ratio to the main composition from 95:5 to 5:95. Depending on the propellant in such aerosol compositions, the ratio of propellant to base formulation is typically at least 20:80, typically at least 30:70, especially at least 40:60 and in many formulations the weight ratio is from 90 :10 to 50:50. Sometimes a range of 70:30 to 90:10 is preferred.

The propellants in this document generally fit into one of three classes: i) low boiling gases liquefied by compression, ii) volatile ethers, and iii) compressed gases without oxidizing activity.

Class i) generally includes materials with a low boiling point, typically below -5°C, often below -15°C, and in particular alkanes and/or halogenated hydrocarbons. This class of propellant typically liquefies under pressure in an aerosol can and vaporizes to create pressure to expel the composition from the can. Examples of suitable alkanes include, in particular, propane, butane or isobutene. The second class of propellants includes highly volatile ethers, of which dimethyl ether is the most widely used. This propellant can advantageously be used in a relatively low weight ratio to base composition, eg 5:95. It can also be used in admixture with, for example, compressible/liquefiable gaseous alkanes.

- 12 039502

The third class of propellants includes compressed gases that do not have oxidative activity, and in particular carbon dioxide or nitrogen. The theoretical alternative is inert gases such as neon.

Facial skin care compositions may also contain other ingredients that are typical in the art to improve physical properties and performance. Suitable ingredients include, but are not limited to, humectants, thickeners, opacifiers, binders, dyes and pigments, pH adjusters, preservatives, optics, fragrances, viscosity modifiers, biological additives, buffering agents, conditioners, natural extracts, essential oils, and skin beneficial agents, including anti-inflammatory agents, cooling agents, antiperspirant agents, anti-aging agents, active acne supplements, antimicrobial agents, and antioxidants.

The invention provides a method for reducing inflammation on an outer surface of a human or animal body, comprising the step of applying a composition of the invention to the desired surface. In one aspect, the method is non-therapeutic in nature. Preferably it is for cosmetic purposes. The method may include applying the composition as a leave-on composition. Leave-in compositions are applied to the desired surface of the skin and left there until the person has washed the skin during a normal hygiene procedure, such as during a shower or bath. Alternatively, the composition may be a rinse-off composition when used to cleanse a body surface, and this type of composition includes a soap, a body wash or face wash composition, or a shampoo or hair conditioner composition. Alternatively, the method is for therapeutic purposes.

According to another aspect of the present invention provides the use of a compound of formula 1 to reduce or prevent the occurrence of inflammation. In one aspect, the application is non-therapeutic in nature, preferably cosmetic in nature. Alternatively, the use is therapeutic in nature.

According to yet another aspect, a compound of the invention is disclosed for reducing inflammation on the external surface of a human or animal body.

According to yet another aspect, a personal care composition of the invention is disclosed for reducing inflammation on the outer surface of a human or animal body.

According to yet another aspect, the use of a compound of the invention for the manufacture of a composition for reducing inflammation on the outer surface of the body of a human or animal is disclosed.

Further, the invention will be illustrated using the following non-limiting example.

Examples

Examples 1-3. Anti-inflammatory efficacy of a compound of formula 1 in an in vitro study using the THP-1 human monocyte cell line (THP-1 study).

The following procedure was used to test the anti-inflammatory efficacy of the active substance.

THP1-XBlue™ cells (catalog number: thpx-sp, InvivoGen) were cultured as a suspension in RPMI 1640 supplemented with 10% FBS, penicillin (10 U/ml)/streptomycin (10 μg/ml). Cells were differentiated in 24-well plates at a density of 5x105 cells/well with 100 nM PMA for 72 hours. Cells were then co-treated with pure lipopolysaccharides (LPS) from E. coli and the active ingredient. After 24 h, the supernatants were collected and the level of interleukin (IL)-6 was measured as a pro-inflammatory biomarker using enzyme-linked immunosorbent assay (ELISA).

The results of measuring the concentration of IL-6 in pg/ml are presented below in table. one.

Table 1

Examples Composition IL-6 concentration (pg/ml) Standard off one LPS 10508 485 2 10 μM compound of formula 1 5591 148 3 20 μM compound of formula 1 2996 144

Examples 4, 5 Anti-inflammatory efficacy of a compound of formula 1 using human gingival fibroblast assay.

Primary human gingival fibroblasts (HGF, catalog number 2620, ScienCell™) were cultured in complete fibroblast medium, which included 500 ml basal medium, 10 ml fetal bovine serum (FBS), 5 ml fibroblast growth supplement, and 5 ml penicillin solution /streptomycin (catalog number 2301, ScienCell™). HGF was seeded in 24-well plates at a density of 2x104 cells/well and cultured for 72 h. Cells were pre-incubated with the active substance for 2 h. After removal of the active medium, the cells were washed with PBS and further treated with heat-inactivated P. gingivalis 33277, ATCC).

- 13 039502

After 4 hours, supernatants were collected and measured for IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP) as pro-inflammatory biomarkers using ELISA.

The data are summarized in Table. 2 below.

table 2

Concentrate walkie-talkie Examples Composition IL-6 (pg/ml) Art. off IL-8 (pg/ml) Art. off MSR-1 (pg/ml) Art. off 5 Heat inactivated P. gingivalis 595 25 17100 2299 388 66 6 20 μM compound of formula 1 286 45 8321 1938 232 21

The data in the table. 1 and 2 indicate the anti-inflammatory efficacy of the compound of formula 1, which applies to a wide range of personal care products.

Example 7 Synthesis of a Compound of Formula 1

The compound of formula 1 used in the experiments above in table. 1 and 2 were synthesized using the following substances, methods and techniques.

All reagents and solvents were obtained from commercial sources (Sigma-Aldrich, EMD Chemicals) and used without further purification unless otherwise noted. The reaction was monitored using thin layer chromatography (TLC). Thin layer chromatography (TLC) was performed using 60 F254 silica gel plates (EMD Chemicals) with UV imaging (254 nm) and 4% phosphomolybdic acid (PMA) in ethanol (EtOH). Flash chromatography (FC) was performed using a Biotage SP4 system (Biotage LLC, Charlottesville, VA). High performance liquid chromatography (HPLC) was performed using a Waters 2695 separation module equipped with a Waters 2996 diode array photodetector and controlled by Empower Pro software (Waters Corp.). Separations were performed at a rate of 1 ml/min on a Restek Pinnacle DB C18 column (5 µm, 4.6x150 mm) maintained at 30°C. Samples for HPLC were prepared by dissolving the sample in mobile phase A:B (1:1) or acetonitrile (ACN) (1 mg/ml) and injecting into a 5-10 µl column. The mobile phase consisted of A=0.1% trifluoroacetic acid (TFA) in water and B=0.1% TFA in acetonitrile using a gradient elution from 95:5 A:B to 5:95 A:B (gradient, 25 min ) followed by 100% B (isocratic mode, 5 min). Liquid chromatography/mass spectrometry (LC-MS) was performed using a Finnigan Mat LCQ mass spectrometer by directly injecting samples (50 ppm) in methanol and counting total ions controlled using electric field spray ionization in (+) mode or (-) (ESI+) or (ESI-). Nuclear magnetic resonance spectroscopy (1H NMR) at 60 MHz was performed using an Eft-60 NMR spectrometer (Anasazi instruments, Inc.) and processed using WinNuts® software (Acorn NMR, Inc.). In some cases, 1H NMR spectra were recorded on an instrument with a frequency of 400 MHz. Melting points were determined using a Meltemp® apparatus (Laboratory Devices). Purity was determined by HPLC-UV/Vis. All connections were unambiguously confirmed by LC-MS and/or 1H NMR.

- 14 039502

The reaction scheme used to obtain the compound represented by formula 1 is shown below.

k _{g coe} / Mal

DMSO

I

MgBr ₂ *Et ₂ O

DCM

I ίι ίϊ I

Τ'jT A Ύ Ύ

Formula 1

The following synthetic procedure (steps 1-4) was used to prepare the compound of formula 1.

Step 1. Protection of the phenolic hydroxyl groups of curcumin to give a compound of formula 2a 1,6-diene-3,5-dione].

Pyridinium p-toluenesulfonate (PPTS) (512 mg, 2.03 mmol) was added to a solution of curcumin (5 g, 13.6 mmol) and dihydropyran (DHP) (37.2 mL, 407 mmol) in anhydrous dichloromethane (DCM) ( 300 ml) and the resulting solution was stirred at room temperature for 16 hours. At this point, TLC ((30 µl aliquot in saturated sodium carbonate (NaHCO ₃ ):methyl tert-butyl ether (MTBE) (400 µl:400 µl); elution with ethyl acetate:hexane (EA:hexane) (25:75)) showed the formation of the main product and other minor products without impurities The reaction mixture was washed with buffer at pH 5 (300 ml), dried with sodium sulfate (Na ₂ SO ₄ ), filtered and the solvents were removed under reduced pressure to give an orange oil (9.3 g) The crude product was purified by flash chromatography (FC) on silica gel eluting with EA:hexane (30:70) to give the pure product of formula 2a as a yellow oil (4, 73 g, 65%) ¹ H NMR (60 MHz, CDCl ₃ ) δ 7.64 (2H, d), 7.03-7.35 (6H, m), 6.51 (2H, d), 5 .83 (1H, s), 5.48-5.54 (2H, m), 3.62-4.30 (4H, m), 3.92 (6H, s), 1.27-2.10 (12H, m).

Step 2. Dimethylation of a compound of formula 2a to give a compound of formula 3 a [(1E,6E)1,7-bis(3-methoxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-4, 4-dimethyl-hepta-1,6-diene-3,5-dione].

Potassium carbonate (K2CO3) (3.86 g, 27.9 mmol) was added to a solution of (1E,6E)-1,7-bis-(3-methoxy-4((tetrahydro-2H-pyran-2-yl)oxy )phenyl)hepta-1,6-diene-3,5-dione (3 g, 5.59 mmol) in anhydrous dimethyl sulfoxide (DMSO) (9 ml) followed by iodomethane (MeI) (1.74 ml, 27.9 mmol) and the mixture was stirred at room temperature for 24 h. At this point, TLC ((30 µl aliquot in pH 5:EA buffer (400 µl:400 µl); eluting with EA:hexane (30:70)) showed the formation main product The mixture was stirred for an additional 24 h and partitioned between EA (100 ml) and saturated sodium chloride (NaCl) (100 ml) The organic layer was dried over Na ₂ SO ₄ , filtered and the solvents were removed under reduced pressure to give an orange oil (3.12 g) The crude product was purified by silica gel flash chromatography eluting with EA:hexane (30:70) to give the pure product of formula 3a as a yellow oil (2.14 g, 68%) 1H NMR (60 MHz, CDCl ₃ ) δ 7.70 (2H, d), 7.03-7.09 (6H, m), 6.64 (2H, d), 5.42 -5.46(2H, m), 3.62-4.20(4H, m), 3.87(6H, s), 1.45-1.94(12H, m), 1.47(6H , s).

Step 3: Di-cyclopropanation of a compound of formula 3a to give a compound of formula 4a ,2-dimethylpropan-1,3-dione].

Dimethyl sulfoxide (6 ml) was added to a mixture of trimethylsulfoxonium iodide (TMSOI) (409 mg, 1.86 mmol) and sodium hydride (NaH) (74 mg, 1.86 mmol) and stirred at room temperature until hydrogen gas evolution ceased and a clear solution (about 45 minutes).

- 15 039502

This solution was added to a solution of (1E,6E)-1,7-bis(3-methoxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-4,4-dimethylhepta-1,6- diene-3,5-dione (500 mg, 0.86 mmol) in DMSO (2 ml) and the mixture was stirred at room temperature for 2 h. At this point, TLC ((20 μl aliquot in saturated NH ₄ Cl:EA ( 400 µl:400 µl), elution with EA:hexane (30:70)) showed the formation of three main products and the absence of SM The reaction mixture was diluted with EA (50 ml) and washed with saturated NaCl (2x50 ml), dried with Na ₂ SO ₄ , filtered and the solvents were removed under reduced pressure to give a light yellow oil (514 mg) The crude product was purified by flash chromatography on silica gel (50 g) eluting with EA:hexane (25:75) to give the pure product of formula 4a as a colorless oil (78 mg, 15%) 1H NMR (60 MHz, CDCl ₃ ) δ 6.40-7.05 (6H, m), 5.24-5.30 (2H, m), 3.42-3, 96 (4H, m), 3.79 (3H, s), 3.69 (3H, s), 1.09-2.43 (20H, m), 1.44 (6H, s).

Step 4. Deprotection of the phenolic hydroxyl groups of the compound of formula 4a to give the compound of formula 1 [1,3-bis(2-(4-hydroxy-3-methoxyphenyl)cyclopropyl)-2,2-dimethylpropan-1,3-dione] .

Magnesium bromide etherate (MgBr ₂ *Et ₂ O) (91.5 mg, 0.35 mmol) was added to a solution of 1,3-bis(2-(3methoxy-4-((tetrahydro-2H-pyran-2-yl) hydroxy)phenyl)cyclopropyl)-2,2-dimethylpropane-1,3-dione (70.0 mg, 0.12 mmol) in DCM (3.5 ml) and stirred at room temperature for 25 minutes. At this point, TLC (50 µl aliquot in pH 5:EA buffer (400 µl:400 µl); eluting with EA:hexane (40:60)) showed pure formation of the major product. The reaction mixture was partitioned between pH 5 buffer (10 ml) and DCM (5 ml) and the layers were separated. The organic layer was filtered through a pad of Na ₂ SO ₄ and the solvents were removed under reduced pressure to give a pale yellow oil (68 mg). The crude product was purified by flash chromatography on silica gel (10 g) eluting with EA:hexane (40:60) to give the pure product of Formula 1 as a pale yellow gel (48 mg, 96% yield). Analysis by HPLC-UV showed a purity of 93%. Analysis by LC-MS (ESI ^- ) showed an estimated mass [MH] ^- 423.5 (100%); 1H NMR (60 MHz, CDCl ₃ ) δ 6.37-6.89 (6H, m), 5.62 (2H, s), 3.85 (6H, s), 1.91-2.61 (4H , m), 1.18-1.70 (4H, m), 1.44 (6H, s).

Example 8 UV-Vis spectra of the compound of formula 1 in comparison with curcumin.

In FIG. 1 and 2 show the UV-Vis spectrum of a compound of formula 1 and curcumin, respectively, obtained by HPLC analysis of a 1 mg/ml solution of each compound using a photodiode array detector. The absorption in the range of 210-310 nm for the compound of the invention of formula 1 is consistent with its light/pale yellow color in its solid state and in solution. In contrast, the strong absorption in the 360-480 nm range for curcumin is consistent with the observed orange color of curcumin in the solid state and in solution.

Examples 9-11. Evaluation of the color of a solution of a compound of formula 1 compared to a solution of curcumin.

Solutions of the compound of formula 1 and curcumin were prepared in ethyl acetate (200 μM) and L*a*b* color space was measured at room temperature (21°C) using a Labscan XE instrument (Hunter Associates Labs Inc., Reston, VA) and processed with using Universal Software (version 4.10).

The results (Table 3) show that the a* and b* color components of the compound of formula 1 (colorless) are significantly reduced compared to curcumin (yellow) and more closely resemble those of the vehicle (ethyl acetate), which is colorless. These results are also consistent with the visual appearance of all solutions, which shows that when going from curcumin to the compound of formula 1, the observed color decreases significantly from yellow to colorless, the latter more resembling the color of the vehicle (colorless).

Table 3

Example sample ^{a Appearance} L* a* b* nine Filler (ethyl acetate) colorless 68.79 -0.49 1.78 ten Curcumin yellow 68.53 -18.66 63.88 eleven Formula 1 colorless 68.62 -0.68 2.49

^a Solutions prepared at a concentration of 200 µM ^b Appearance of the solution

CLAIM

Claims (12)

CLAIM 1. Compound having the chemical structure of formula 1 Formula 1 1,3-bis(2-(4-hydroxy-3-methoxyphenyl)cyclopropyl)-2,2-dimethylpropan-1,3-dione. - 16 039502 2. Composition for personal care, containing: (i) a compound according to claim 1; and (ii) a cosmetically acceptable base. 3. The composition according to claim 2, presented in the form of a product for caring for the oral cavity or skin, scalp or hair. 4. Composition according to claim 3 in the form of a solid, soft solid, liquid, emulsion, microemulsion, lotion, cream, gel or aerosol. 5. A composition according to any one of claims 2 to 4 for reducing inflammation on the external surface of the human or animal body. 6. A method for obtaining a compound of formula 1 according to claim 1, including the following stages, in which: (i) protect the phenolic hydroxyl groups of curcumin with an appropriate protecting group P to give a compound of formula 2 Curcumin Formula 2 (ii) dimethylate the compound of formula 2 to obtain a compound of formula 3 ¹ HH I - - I th n Stage 2 dd U ---LD a U I I iI P P PP Formula 2 Formula 3 (iii) dicyclopropanate a compound of formula 3 to give a compound of formula 4 I It I R R R R Formula 3 Formula 4 (iv) deprotects the phenolic hydroxyl groups of a compound of formula 4 to give a compound of formula 1 Formula 4 Formula 1 where the protecting group P includes tetrahydropyranyl, 4-methoxytetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, tert-butyl, triphenylmethyl, alphanaphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl or triisopropylsilyl. 7. A method for reducing inflammation on an external surface of a human or animal body, comprising the step of applying the composition according to any of the preceding claims 2 to 5 to the desired surface. 8. The method according to claim 7, characterized in that said method is non-therapeutic. 9. Use of a compound of formula 1 according to claim 1 to reduce or prevent inflammation. 10. Use according to claim 9, characterized in that said use is for non-therapeutic purposes. 11. Use according to claim 9, wherein the compound of formula 1 is used to reduce inflammation on the external surface of the human or animal body. 12. The use of a compound of formula 1 according to claim 1 for the manufacture of a composition designed to reduce inflammation on the external surface of the human or animal body.