Topical composition based on a nicotinamide derivative

Abstract

The present invention relates to a topical composition comprising a compound of formula (I): wherein R is a cycloalkyl group having a total number of carbon atoms in the range of 4 to 6 in the cycloalkyl group.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to topical compositions, and more particularly to topical compositions for antimicrobial benefits. BACKGROUND OF THE INVENTION

[0003] People generally strive to take good care of themselves to enjoy a healthy lifestyle. Usually, this includes taking care of their outer surfaces such as skin, scalp, hair, and oral cavity. One way people strive to take care of their outer surfaces is by using topical compositions that deliver a variety of benefits such as, for example, a dandruff-free scalp, thick and strong hair, a cavity-free and odor-free oral cavity, and antimicrobial benefits, i.e., keeping the outer surface free of microorganisms such as bacteria and some fungi.

[0004] Many (if not all) of the problems people face are related to exposure to microorganisms such as bacteria and some fungi. For example, dandruff is related to fungal microorganisms. At the same time, dental caries and bad odors are also usually related to the presence of bacteria in the oral cavity. Additionally, there are bacteria that are commonly found on the surface of human skin such as, for example, Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Although these bacteria are not pathogenic when present on the skin, however, if they enter the human body via ingestion, they can become pathogenic.

[0005] Therefore, people generally want to get rid of or at least minimize exposure to harmful or potentially harmful microorganisms. One way people strive to achieve this is by applying antimicrobial compounds after an infection has set in. Another way is to leave very small amounts of compounds that induce the generation of antimicrobial peptides (AMPs) (such as, for example, psoriasin from the skin) on the outer surface such as, for example, on the skin.

[0006] AMPs form an integral part of the skin's own defense system. AMPs were initially discovered in insects and animals, and since their initial discovery, AMPs have been considered promising antimicrobial agents. AMPs are ubiquitous in nature, and they generally exhibit broad-spectrum activity against invasive bacteria, fungi, enveloped viruses, and parasites (Braff and Gallo, 2006). AMPs are generally short peptides, and it is reported that there are approximately 90 different AMPs present in humans.

[0007] Some references describing compounds such as niacinamide for generating AMPs are found in the prior art.

[0008] WO 2015 / 172801 (Unilever, 2015) discloses a new use of niacinamide for triggering the production of AMPs on the skin. This has applications in improving the immunity of the skin, scalp, and oral cavity against microbial attacks.

[0009] Despite the existing technologies, there is a general expectation for new technologies that will deliver improved antimicrobial benefits by generating AMPs, thereby enhancing the immunity of the skin, scalp, and oral cavity.

[0010] Accordingly, there is a need to provide new technologies, such as compounds that provide improved antimicrobial benefits through AMP generation and topical compositions containing such compounds.

[0011] Accordingly, an object of the present invention is to provide a topical composition containing a compound that provides improved antimicrobial benefits through AMP generation when applied to human skin.

[0012] It has been found that the compounds of formula I provide antimicrobial benefits through AMP generation when applied to human skin, thereby fulfilling one or more of the above objects. Summary of the Invention

[0013] In a first aspect, the present invention relates to a topical composition comprising 0.001 to 10% by weight of a compound of formula I,

[0014]

[0015] wherein R is a cycloalkyl group having a total number of carbon atoms in the range of 4 to 6 in the cycloalkyl group.

[0016] In a second aspect, the present invention relates to a method of disinfecting a surface, which comprises the step of applying the composition of the first aspect to the surface, wherein the surface is an outer surface of the human body.

[0017] In a third aspect, the present invention relates to the use of the composition of the first aspect for obtaining antimicrobial benefits when applied to the outer surface of the human body.

[0018] In a fourth aspect, the present invention relates to the use of the composition of the first aspect for inducing AMP generation when applied to the outer surface of the human body.

[0019] In a fifth aspect, the present invention relates to the use of a compound of formula I for obtaining antimicrobial benefits when applied to the outer surface of the human body,

[0020]

[0021] wherein R is a cycloalkyl group having a total number of carbon atoms in the range of 4 to 6 in the cycloalkyl group.

[0022] Any feature of one aspect of the present invention can be used in any other aspect of the present invention. The term "comprising" is intended to mean "including", but not necessarily "consisting of" or "constituted by". In other words, the listed steps or options need not be exhaustive. Unless in the operating and comparative examples, or otherwise expressly indicated, all numbers in this specification indicating amounts of materials or reaction conditions, physical properties of materials, and / or uses should be understood to be modified by the word "about". A numerical range expressed in the format "x to y" should be understood to include x and y. When multiple preferred ranges are described in the format "x to y" for a particular feature, it should be understood that all ranges combining different endpoints are also contemplated. Detailed Description

[0023] In a first aspect, the present invention relates to a topical composition comprising a compound of formula I:

[0024]

[0025] wherein R is a cycloalkyl group having a total number of carbon atoms in the range of 4 to 6 in the cycloalkyl group.

[0026] Examples of the compound of formula I include compounds wherein the total number of carbon atoms in the cycloalkyl group is as follows:

[0027] - 4, i.e., N-cyclobutyl nicotinamide,

[0028] - 5, i.e., N-cyclopentyl nicotinamide; and

[0029] - 6, i.e., N-cyclohexyl nicotinamide.

[0030] Preferred compounds of formula I are any one of the three compounds mentioned above. More preferred compounds of formula I are those wherein the number of carbon atoms in the cycloalkyl group is 5, i.e., N-cyclopentyl nicotinamide.

[0031] The composition comprises from 0.001 to 10% by weight, preferably from 0.002 to 8%, more preferably from 0.005 to 8%, even more preferably from 0.01 to 6%, still more preferably from 0.05 to 5%, yet more preferably from 0.1 to 4%, further more preferably from 0.5 to 3%, and most preferably from 1 to 1.5% of the compound of formula I.

[0032] Preferably, the composition further comprises at least one ingredient selected from nicotinamide, picolinamide, and isonicotinamide. Preferably, the ingredient is nicotinamide.

[0033] Nicotinamide, also known as niacinamide, is the amide form of niacin. It is a vitamin found in foods. It is also used as a food supplement. Nicotinamide has the following chemical structure:

[0034]

[0035] Pyridinecarboxamide and isonicotinamide are isomers of nicotinamide and have the following structures:

[0036]

[0037] When present, the composition comprises from 0.001 to 10%, preferably from 0.005 to 8%, more preferably from 0.01 to 6%, even more preferably from 0.05 to 5%, still more preferably from 0.1 to 4%, yet more preferably from 0.5 to 3% and still more preferably from 1 to 1.5% of nicotinamide or pyridinecarboxamide or isonicotinamide.

[0038] If more than one of these three compounds are present simultaneously, the total amount of these compounds that can be comprised in the composition is in the range from 0.001 to 10% by weight, preferably from 0.005 to 8%, more preferably from 0.01 to 6%, even more preferably from 0.05 to 5%, still more preferably from 0.1 to 4%, yet more preferably from 0.5 to 3% and still more preferably from 1 to 1.5%.

[0039] Preferred process for the synthesis of the compounds of formula I:

[0040] First, a solution of nicotinic acid is prepared in anhydrous dichloromethane (DCM). Under an inert atmosphere, at 0 °C, propylphosphonic anhydride (T3P, in ethanol), triethanolamine (TEA) and cycloalkylamine are added to this solution. The cycloalkylamine may be selected from cyclobutylamine, cyclopentylamine and cyclohexylamine. Most preferably, it is cyclopentylamine. The reaction mixture is then stirred at about 25 °C for 6 to 24 hours, more preferably for 8 to 20 hours, most preferably for 10 to 14 hours. After completion of the reaction, which is preferably monitored by thin layer chromatography (TLC), the reaction mass is preferably partitioned between DCM and water. The layers are then separated and the aqueous layer is extracted again in 10% methanol and / or DCM. The combined extracts are then washed with water, an aqueous salt solution and dried over Na2SO4. The solvent is then evaporated to dryness. Finally, the crude product is purified to obtain the pure compound of formula 1.

[0041] The composition preferably further comprises a cosmetically acceptable matrix. The cosmetically acceptable matrix is preferably in the form of a cream, a lotion, a gel or an emulsion.

[0042] The composition can be prepared using different cosmetically acceptable emulsified or non-emulsified matrices. A highly suitable matrix is a cream. Vanishing cream is particularly preferred. A vanishing cream matrix generally comprises a mixture of fatty acids and soaps. A vanishing cream matrix imparts a highly sought-after matty feel to the skin. In a vanishing cream matrix, C 12 to C 20 fatty acids are particularly preferred, and even more preferably C14 to C 18 Fatty acids. Most preferably, the fatty acid is stearic acid or palmitic acid or a mixture thereof. The fatty acid is usually hystric acid, which is substantially (usually 90 to 95% by weight) a mixture of 45% stearic acid and 55% palmitic acid. Thus, the inclusion of hystric acid and its soaps to prepare the compositions of the present invention is within the scope of the present invention. The fatty acid in the composition is preferably present in an amount of 5 to 20%, more preferably 6 to 19% and even more preferably 7 to 17% by weight of the composition. The soap in the vanishing cream matrix includes alkali metal salts of fatty acids, such as sodium salts or potassium salts, and most preferably potassium stearate. The soap in the vanishing cream matrix is usually present in an amount of 0.1 to 10% by weight, more preferably 0.1 to 3% by weight of the composition. Usually, the vanishing cream matrix topical composition is prepared by taking a desired amount of the total fatty substances and mixing them with a desired amount of potassium hydroxide. The soap is usually formed in situ during the mixing process.

[0043] Particularly suitable cosmetic acceptable matrices are matrices comprising a water-in-oil emulsion comprising a silicone oil as the continuous phase. The water-in-oil emulsion preferably comprises a crosslinked silicone elastomer blend.

[0044] The inclusion of a silicone elastomer blend in a water-in-oil emulsion can be used as a cosmetic acceptable matrix for preparing the compositions of the present invention. While silicone fluids can be used, crosslinked silicone elastomers are particularly preferred. Compared to silicone fluid polymers, the physical properties of elastomers generally depend on the amount of crosslinking rather than the molecular weight. The ability of silicone elastomers to swell makes them ideal thickeners for the oil phase. When applied to the skin or hair, the elastomers have a very smooth and soft feel. They can also be used as delivery agents for fragrances, vitamins and other additives in cosmetic compositions. Suitable silicone elastomer blends or gels that are commercially available and suitable for inclusion in the compositions of the present invention and found to provide enhanced stability are: Dow EL-8051IN silicone organo-elastomer blend [INCI name: isodecyl neopentanoate (and) dimethicone / bis-isobutyl PPG-20 crosspolymer]; EL-8050 [INCI name: isododecane (and) dimethicone / bis-isobutyl PPG 20 crosspolymer]; DC9040, DC9041, DC9045 (dimethylsiloxane crosspolymer); DC9506, DC9509 (dimethylsiloxane vinyl dimethicone crosspolymer); and Shin-Etsu KSG-15, KSG-16, KSG-17 (dimethylsiloxane vinyl dimethicone crosspolymer). Further preferably, the composition comprises 5 to 50% by weight of the silicone elastomer.

[0045] Water and / or alcohol can also be used as a cosmetically acceptable base. The alcohol can be a monohydric alcohol or a polyhydric alcohol. Monohydric alcohols are typically short-chain, which means they contain up to 6 carbons. In fact, the most common is ethanol or sometimes isopropyl alcohol. Polyhydric alcohols generally include ethylene glycol or propylene glycol, or homologues such as diethylene glycol can be used.

[0046] The cosmetically acceptable base is usually from 10 to 99.9% by weight of the composition, preferably from 50 to 99%.

[0047] Preferably, the composition further comprises a skin brightening agent. Examples of skin brightening agents that can be used in the composition include 12-hydroxy stearic acid, aloe extract, ammonium lactate, arbutin, azelaic acid, kojic acid, butylated hydroxyanisole, butylated hydroxytoluene, citrate esters, 3-diphenylpropane derivatives, 2,5-dihydroxybenzoic acid and its derivatives, ellagic acid, fennel extract, glucopyranosyl-1-ascorbic acid, gluconic acid, glycolic acid, green tea extract, hydroquinone, 4-hydroxyanisole and its derivatives, 4-hydroxybenzoic acid derivatives, hydroxycaprylic acid, lemon extract, linoleic acid, magnesium ascorbyl phosphate, mulberry root extract, 2,4-resorcinol derivatives, 3,5-resorcinol derivatives, salicylic acid, vitamins (such as vitamin B6, vitamin B12, vitamin C, vitamin A), dicarboxylic acids, resorcinol derivatives, hydroxycarboxylic acids (such as lactic acid) and their salts (such as sodium lactate), and mixtures thereof.

[0048] Preferably, the composition further comprises one or more sunscreen agents. Any sunscreen agent that can be suitably used with the base can be added. Both UVA and UVB sunscreen agents can be preferably added.

[0049] The composition of the present invention preferably comprises a UV-A sunscreen agent, which is dibenzoylmethane or its derivative. Preferred dibenzoylmethane derivatives are selected from 4-tert-butyl-4'-methoxydibenzoylmethane, 2-methyldibenzoylmethane, 4-methyldibenzoylmethane, 4-isopropyldibenzoylmethane, 4-tert-butyldibenzoylmethane, 2,4-dimethyldibenzoylmethane, 2,5-dimethyldibenzoylmethane, 4,4'-diisopropyl-dibenzoylmethane, 2-methyl-5-isopropyl-4'-methoxydibenzoylmethane, 2-methyl-5-tert-butyl-4'-methoxy-dibenzoylmethane, 2,4-dimethyl-4'-methoxydibenzoylmethane or 2,6-dimethyl-4-tert-butyl-4'-methoxy-dibenzoylmethane. The most preferred dibenzoylmethane derivative is 4-tert-butyl-4'-methoxydibenzoylmethane. The composition of the present invention preferably comprises from 0.1 to 10% by weight, more preferably from 0.2 to 5% by weight, still more preferably from 0.4 to 3% by weight of dibenzoylmethane or its derivative based on the total weight of the composition, and includes all ranges therebetween.

[0050] The composition may also preferably contain a UV-B organic sunscreen selected from the group consisting of cinnamic acid, salicylic acid, diphenylacrylic acid, and their derivatives. Illustrative non-limiting examples of commercially available UV-B sunscreens useful for inclusion in the compositions of the present invention are octisalate TM , homosalate TM , NeoHelipan TM , octocrylene TM , oxybenzone TM , or Parsol MCX TM . The UV-B sunscreen is most preferably 2-ethylhexyl 4-methoxycinnamate, which is commercially available as Parsol MCX TM . The UV-B organic sunscreen is preferably included in the composition in an amount of from 0.1 to 10% by weight of the composition, more preferably from 0.1 to 7% by weight. It has been observed that the presence of an organic UV-B sunscreen such as 2-ethylhexyl 4-methoxycinnamate causes further rapid degradation of the UV-A dibenzoylmethane sunscreen in the presence of ultraviolet radiation. The presence of rosmarinate compounds has been found to be very effective in stabilizing the composition even in the presence of a UV-B sunscreen.

[0051] Available inorganic sun-blocks are also preferably used in the present invention. These include, for example, zinc oxide, iron oxide, silica (such as pyrogenic silica), and titanium dioxide.

[0052] The composition may further contain a preservative to protect against the growth of potentially harmful microorganisms. Conventional preservatives suitable for the compositions of the present invention are alkyl esters of p-hydroxybenzoic acid. Other preservatives that have recently come into use include hydantoin derivatives, propionates, and various quaternary ammonium compounds. Particularly preferred preservatives are phenoxyethanol, methylparaben, propylparaben, imidazolidinyl urea, sodium dehydroacetate, benzyl alcohol, alkanediols, most preferably 1,2-octanediol and phenoxyethanol. The preservative should be selected taking into account the use of the composition and possible incompatibilities between the preservative and other ingredients. The preservative is preferably used in an amount of from 0.01% to 2% by weight of the composition.

[0053] Various other optional materials may be formulated into the composition. These may include: antimicrobial agents such as 2-hydroxy-4,2',4'-trichlorodiphenyl ether (triclosan), 2,6-dimethyl-4-chlorophenol, and 3,4,4'-trichlorocarbanilide; abrasive and exfoliating granules such as polyethylene and silica or alumina; cooling agents such as menthol; skin soothers such as aloe vera; and colorants.

[0054] In addition, the composition may also contain from 0 to 10% by weight of opacifiers and pearlescent agents such as ethylene glycol distearate, titanium dioxide, or 621 (styrene / acrylic ester copolymer); all of which can be used to enhance the appearance or properties of the product.

[0055] Diluents other than water that can be used in the composition can include liquid or solid emollients, solvents, humectants, thickeners, and powders. Examples of each of these types of carriers, which can be used alone or as a mixture of one or more carriers, are as follows:

[0056] Preferably, the composition contains an emollient. Examples of emollients that can be present include stearyl alcohol, glyceryl monocastor oil, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, eicosanol, behenyl alcohol, cetyl palmitate, silicone oil (such as dimethylpolysiloxane), dibutyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, cocoa butter, corn oil, cottonseed oil, olive oil, palm kernel oil, rapeseed oil, safflower oil, evening primrose oil, soybean oil, sunflower oil, avocado oil, sesame seed oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petrolatum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate.

[0057] Preferably, the composition contains a solvent such as ethanol, isopropyl alcohol, acetone, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, and mixtures thereof.

[0058] Advantageously, the composition can preferably contain ingredients such as bactericides, vitamins, anti-acne active substances; anti-wrinkle, anti-skin atrophy and skin repair active substances, skin barrier repair active substances, non-steroidal cosmetic soothing active substances, artificial tanning agents and accelerators, sebum stimulants, sebum inhibitors, antioxidants, protease inhibitors, skin tightening agents, anti-itching ingredients, hair growth inhibitors, 5-α reductase inhibitors, desquamase enhancers, anti-glycation agents, and mixtures thereof.

[0059] The composition can preferably contain powders such as, for example, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silica, sodium polyacrylate, tetraalkyl and / or trialkyl aryl ammonium montmorillonite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, pyrogenic silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and mixtures thereof.

[0060] The compositions of the present invention can comprise a wide range of other optional components. The CTFA Personal Care Ingredient Handbook (CTFA Personal Care Ingredient Handbook, 2nd Edition, 1992), the entire content of which is incorporated herein by reference, describes a wide variety of non-limiting personal care and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples include: antioxidants, binders, biologic additives, buffers, colorants, thickeners, polymers, astringents, fragrances, humectants, opacifiers, conditioners, pH adjusters, natural extracts, essential oils, skin sensates, skin soothers, and skin healers.

[0061] The composition can also comprise one or more of the following ingredients: for example, benzethonium chloride (BEC), benzalkonium chloride (BKC), chloroxylenol, zinc pyrithione (ZPT), creatine, and creatinine.

[0062] The composition is preferably in the form of a rinse-off or leave-on composition, preferably a leave-on composition.

[0063] A rinse-off composition preferably refers to a composition that is intended / required to be removed from the body by washing with a solvent (preferably water) after application of the composition, such as, for example, a hand washing composition and a face washing composition.

[0064] A leave-on composition preferably refers to a composition that does not need to be removed from the human body after application of the composition, such as, for example, a skin cream, a lotion, a hand sanitizer, and a deodorant.

[0065] When the composition is in the form of a leave-on composition, the composition can be in the form of a deodorant, a hand sanitizer, a lotion, a cream, and a body spray.

[0066] The compositions of the present invention can preferably comprise a conventional deodorant base as a cosmetically acceptable carrier. A deodorant refers to a product in a stick, roll-on, or propellant medium that can be used for personal deodorant benefits (e.g., application in the axillary area), which may or may not contain an antiperspirant active substance.

[0067] Deodorant compositions can generally be in the form of hard solids, soft solids, gels, creams, and liquids, and are dispensed using an applicator adapted to the physical properties of the composition. Deodorant compositions delivered by roll-on typically contain a liquid carrier. Such a liquid carrier can be hydrophobic or can comprise a mixture of both hydrophilic and hydrophobic liquids. They can be in the form of an emulsion or microemulsion. The liquid carrier or carrier mixture generally constitutes 30 to 95% by weight of the composition, and in many cases 40 to 80% by weight. Hydrophobic liquid carriers can generally comprise one or more materials selected from the following chemical classes: siloxanes, hydrocarbons, branched aliphatic alcohols, esters, and ethers having a melting point of no more than 25 °C and a boiling point of at least 100 °C. Hydrophilic carrier liquids useful in the compositions herein generally include water and / or mono- or polyhydric alcohols or water-miscible homologues. Monoalcohols are generally short-chain, meaning they contain at most 6 carbons, and in practice are most commonly ethanol or sometimes isopropanol. Polyhydric alcohols generally include ethylene glycol or propylene glycol, or homologues such as diethylene glycol can be used. In addition thereto, other carriers and components suitable for deodorant compositions can be added.

[0068] When the composition is in the form of a hand sanitizer, the cosmetically acceptable matrix can include alcohols and water. The most preferred alcohols are ethanol and isopropanol. Even a mixture of two or more alcohols can preferably be used in the hand sanitizer composition. The amount of alcohol is preferably 50 to 95% by weight of the hand sanitizer composition, more preferably 60 to 80% by weight, and most preferably 65 to 80% by weight.

[0069] In a second aspect, the present invention also provides a method of cleaning or disinfecting a surface, which in the case of a leave-on composition comprises the step of applying the composition of the first aspect, wherein the surface is an outer surface of the human body. If the composition is in the form of a wash-off composition, the method optionally includes an additional step of at least partially removing the composition from the surface. Preferably, the step of at least partially removing the composition is carried out within less than 5 minutes after the step of applying the composition to the outer surface of the human body. Preferably, the method is non-therapeutic.

[0070] In a third aspect, the present invention further provides the use of the composition of the first aspect for obtaining an antimicrobial benefit when applied to the outer surface of a human body. The antimicrobial benefit preferably refers to the ability to kill or at least cause a substantial reduction in common pathogenic microorganisms. Common pathogenic Gram-positive organisms include Staphylococcus spp., Streptococcus spp., and Enterococcus spp. Some of the common pathogenic Gram-negative organisms include Escherichia coli, Salmonella spp., Klebsiella spp., and Shigella spp. Escherichia coli and Salmonella spp. can cause severe gastrointestinal diseases. The composition of the present invention provides improved antimicrobial benefits when applied to the outer surface of a human body.

[0071] The composition of the present invention provides a long-term / durable antimicrobial benefit.

[0072] In a fourth aspect, the present invention also provides the use of the composition of the first aspect for inducing the generation of AMP when applied to the outer surface of a human body.

[0073] In a fifth aspect, the present invention also provides the use of a compound of formula I for obtaining an antimicrobial benefit when applied to the outer surface of a human body,

[0074]

[0075] wherein R is a cycloalkyl group having a total number of carbon atoms in the range of 4 to 6 in the cycloalkyl group.

[0076] The outer surface of a human body includes the skin, scalp, hair, and oral cavity.

[0077] It has been found that by the present invention, the compound of formula I activates keratinocytes (which are the main cells in the skin epidermis) to provide the benefits of the present invention, namely, inducing the secretion of AMP. This results in an enhanced antimicrobial protective barrier. Thus, the composition containing the compound of formula I provides protection against infection for the body by enhancing the body's own defenses. In other words, the compound of formula I primes the body surface for microbial protection. The advantage of this is that it provides durable protection against microorganisms (e.g., protection for up to 24 hours).

[0078] The use of the composition of the present invention can preferably be for hand hygiene.

[0079] The intended use of the composition can be for therapeutic or non-therapeutic purposes. However, the preferred intended use of the composition of the present invention is non-therapeutic and / or cosmetic.

[0080] The present invention also provides the use of a combination of a compound of formula I and at least one compound selected from nicotinamide, picolinamide and isonicotinamide for inducing the generation of AMP. Preferred options regarding the compositions of the present invention are equally applicable to the uses according to the present invention.

[0081] The present invention will now be demonstrated by the following non-limiting examples.

[0082] EXAMPLES

[0083] Example 1: A compound of formula I in which the total number of carbon atoms in the cycloalkyl group is 5 (i.e., N-cyclopentylnicotinamide) SYNTHESIS

[0084]

[0085] Materials:

[0086] Nicotinic acid (Sigma catalog number C115002), propylphosphonic anhydride (T3P; Aldrich, catalog number 87801), dichloromethane anhydrous (DCM; Sigma, catalog number 270997), triethanolamine, ethyl acetate, methanol, sodium sulfate anhydrous ().

[0087] Experimental procedure:

[0088] Under an inert atmosphere and at 0 °C, to a stirred solution of nicotinic acid (1 g, 8.12 mmol, 1 equivalent) in anhydrous DCM (10 vol) was added propylphosphonic anhydride (T3P) (3.87 g, 50% solution in EtOAc, 12.18 mmol, 1.5 equivalents), TEA (2.46 g, 24.3 mmol, 3 equivalents) and cyclopentylamine (0.76 g, 8.93 mmol, 1.1 equivalents). The reaction mixture was then stirred at about 25 °C for about 12 hours. After completion of the reaction as monitored by thin layer chromatography (TLC), the reaction mass was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted again in 10% MeOH / DCM. The combined extracts were washed with water and brine solution and dried (Na2SO4). The solvent was evaporated to dryness; the crude product was purified by elution on a Biotage Isolera with 50% ethyl acetate in petroleum ether (pet ether) to afford the final compound as a colorless viscous liquid (1.15 g, yield 75%), with a purity of 97.72%.

[0089] Demonstration of the in vitro experiment of treating human keratinocytes with N-cyclopentylnicotinamide, a compound of formula I, in the presence or absence of nicotinamide and then generating psoriasin (an antimicrobial peptide): The experiment was carried out using the following protocol:

[0090] Step 1: Human neonatal primary dermal keratinocytes (NHEK) cells were obtained from This experiment was conducted using the above cells that had been passaged 3 to 4 times. Then the cells were seeded (35,000 cells / well) in a 24-well plate containing keratinocyte growth medium (KGM) obtained from . Subsequently, the plate was incubated in a CO2 incubator at 37 ± 2 °C for 48 hours.

[0091] Step 2: After culturing for 48 hours, cell differentiation was induced by replacing the medium with fresh KGM supplemented with a 2 mM calcium chloride solution. Then, the cells were cultured in a CO2 incubator at 37 ± 2 °C for 48 hours.

[0092] Step 3: Subsequently, the cells were treated with N-cyclopentylnicotinamide at different concentrations (as listed in Table 1 below) using keratinocyte growth medium supplemented with a 2 mM calcium chloride solution.

[0093] Table 1:

[0094]

[0095] Step 4: After the above treatment, the cells were cultured again in a CO2 incubator at 37 ± 2 °C for 72 hours.

[0096] Step 5: After culturing for 72 hours, the cell culture supernatant from each well was collected in a sterile tube. Then, the samples were stored at -80 °C until used to test the secretion of psoriasin by standard ELISA technique using a psoriasin ELISA kit (Cat. No.: CY-8073) obtained from . In the current experiment, psoriasin was used as a marker for AMP.

[0097] Step 6: The ELISA method was performed by using 100 μL of the cell culture supernatant from each sample.

[0098] The data were expressed as fold change over the control (no treatment: Example A). The fold change in the psoriasin level in the case of the control (Example A) was considered equal to 1-fold. Any fold change in psoriasin obtained due to treatment listed in all other examples was greater than and higher than the 1-fold change obtained from the control. For example, Example C showed a fold change of 1.4-fold, which means 0.4-fold greater than and higher than the 1-fold obtained from the control. Similarly, Example 5 showed a fold change of 2.84, which means 1.84-fold greater than and higher than the 1-fold obtained from the control.

[0099] The results are summarized in Table 2 below:

[0100] Table 2:

[0101] EXAMPLES FOLD CHANGE A 1 B 0.9 C 1.4 1 <![CDATA 2.06 > 2 <![CDATA 2.84 >

[0102] It is apparent from the above table that N-cyclopentylnicotinamide provides a much better fold change in psoriasin production when compared to the control. When used at the same concentration, i.e., 200 μg / mL, N-cyclopentylnicotinamide (Example 1) provides a much better fold change in psoriasin compared to nicotinamide (Example B). When N-cyclopentylnicotinamide is used at a certain concentration, i.e., 400 μg / mL (Example 2), it provides a fold change in psoriasin as high as 2.84. On the other hand, a higher concentration of nicotinamide, i.e., 500 μg / mL (Example C) shows a fold change equal to only 1.4. Thus, N-cyclopentylnicotinamide provides improved AMP production, thereby providing improved antimicrobial benefits.

[0103] In summary, when compared to the control (untreated) and to the production of AMP by known compounds such as, for example, nicotinamide, the compounds of formula I provide improved antimicrobial benefits through AMP production when applied to human skin. Also, the combination of the compounds of formula I with a compound selected from the group consisting of nicotinamide, picolinamide, isonicotinamide, and mixtures thereof provides a synergistic production of AMP.

Claims

1. A topical composition comprising 0.001 to 10% by weight of a compound of formula I; and a cosmetically acceptable matrix in the form of a cream, gel or lotion, wherein R is a cycloalkyl group having 5 carbon atoms in total in the cycloalkyl group.

2. The topical composition according to claim 1, further comprising 0.001 to 10% by weight of at least one ingredient selected from nicotinamide, picolinamide and isonicotinamide.

3. The topical composition according to claim 2, wherein the ingredient is nicotinamide.

4. The composition according to claim 1, wherein the composition is in the form of a rinse-off composition.

5. The composition according to claim 1, wherein the composition is in the form of a leave-on composition.

6. A non-therapeutic method of disinfecting a surface, comprising the step of applying the composition according to any one of claims 1 to 5 to the surface, wherein the surface is an outer surface of the human body.

7. The non-therapeutic method according to claim 6, wherein the composition is in the form of a rinse-off composition, and wherein the method comprises an additional step of at least partially removing the composition.

8. The non-therapeutic method according to claim 7, wherein the step of at least partially removing the composition is carried out within less than 5 minutes after the step of applying the composition to the outer surface of the human body.

9. The non-therapeutic use of the composition according to any one of claims 1 to 5 for obtaining an antimicrobial benefit when applied to the outer surface of the human body.

10. The non-therapeutic use of the composition according to any one of claims 1 to 5 for inducing the secretion of antimicrobial peptides (AMPs) when applied to the outer surface of the human body.

11. The non-therapeutic use of the compound of formula 1 for obtaining an antimicrobial benefit when applied to the outer surface of the human body, wherein R is a cycloalkyl group having 5 carbon atoms in total in the cycloalkyl group.

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