WO2019059555A1 - Trimethoxy phenyl compound, and composition for promoting hair growth or restoration, containing same - Google Patents

Trimethoxy phenyl compound, and composition for promoting hair growth or restoration, containing same Download PDF

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Publication number
WO2019059555A1
WO2019059555A1 PCT/KR2018/010084 KR2018010084W WO2019059555A1 WO 2019059555 A1 WO2019059555 A1 WO 2019059555A1 KR 2018010084 W KR2018010084 W KR 2018010084W WO 2019059555 A1 WO2019059555 A1 WO 2019059555A1
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composition
hair growth
acid
compound
hair
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PCT/KR2018/010084
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French (fr)
Korean (ko)
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박필준
이태룡
조은경
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(주)아모레퍼시픽
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Publication of WO2019059555A1 publication Critical patent/WO2019059555A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat

Definitions

  • trimethoxyphenyl compound an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a composition for promoting hair growth or hair growth comprising the same.
  • a hair follicle which is a physiological organ in the body that produces hair, is an anagen phase in which hair is generated and generated hair is actively grown during postnatal development, a catagen phase in which hair is degenerated, The hair growth cycle is divided into the telogen phase, which is maintained until the hair loss, and the exogen phase, where hair loss occurs.
  • hair follicle activity is caused by dermal papilla cells, and in particular, the proliferation and differentiation of dermal papilla cells are primarily involved in the progression of the hair growth cycle and hair formation. In the growth phase where the hair grows actively, the active growth and differentiation of the papillary cells occurs actively, the growth of the hair is stopped, and the cells are killed in the regenerator, the resting period and the hair removal period where the hair loss occurs.
  • hair growth and hair loss are closely related to the proliferation and death of the dermal papilla cells. Therefore, prolonging the growth period or inhibiting apoptosis and shortening the period of regrowth, dormancy and hair loss by inducing proliferation of the dermal papilla cells will be a remedy .
  • Cell division and migration in the vicinity of the dermal papilla is closely related to the growth of the hair. In the growing phase, hair is newly generated from the dermal papilla. Cells are activated by various cytokines and hormones, Of the growth rate.
  • growth factors such as HGF, IGF-1, and VEGF are most strongly expressed in the growth phase and decrease in the regressor and dormant period, thereby inducing the proliferation of the dermal papilla cells and maintaining the growth period, It is known to help.
  • Minoxidil and finasteride which are currently approved by the FDA, suffer from side effects such as hair growth and lowering of sexual function, and the specific mechanism of action of minoxidil has not been clarified. Therefore, it is necessary to develop a biological material that promotes the proliferation of dermal papilla cells in hair follicles, increases the expression of growth factors, and has less side effects.
  • the inventors of the present invention completed the present invention by preparing a novel trimethoxyphenyl compound and experimentally confirming that the compound promotes the growth of papilla cells and increases the expression of growth factors such as IGF-1.
  • an object of the present invention is to provide a novel trimethoxyphenyl compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, and a composition for promoting hair growth or hair growth, .
  • the present invention provides a novel trimethoxyphenyl compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
  • the present invention provides a process for preparing a novel trimethoxyphenyl compound.
  • the present invention provides a composition for promoting hair growth or hair growth, comprising a trimethoxyphenyl compound as an active ingredient.
  • the novel trimethoxyphenyl compound of the present invention proliferates dermal papilla cells at a level similar to that of adiponectin secreted in the body, promotes the expression of growth factors, and by this effect inhibits hair loss and promotes hair growth , A cosmetic composition, or an external preparation for skin.
  • FIG. 1 is a schematic diagram of a composition comprising a trimethoxyphenyl compound (PAC-16742, hereinafter referred to as PAC-2) according to an embodiment of the present invention and a positive control adiponectin (APN) The results of the cytotoxicity analysis are shown.
  • PAC-16742 trimethoxyphenyl compound
  • APN positive control adiponectin
  • Figures 2a to 2d are graphs showing the expression of a hair follicle activator of a composition comprising a trimethoxyphenyl compound (PAC-16742, hereinafter referred to as PAC-2) according to an embodiment of the present invention and a positive control adiponectin (APN) (Hair growth-related gene expressions).
  • PAC-16742 trimethoxyphenyl compound
  • APN positive control adiponectin
  • FIG. 3 shows the NMR of a trimethoxyphenyl compound (PAC-16742, hereinafter referred to as PAC-2) according to an embodiment of the present invention (designated by Sample Name 742).
  • the present invention is a trimethoxyphenyl compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
  • isomers refers in particular to optical isomers (for example, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof) as well as morphological isomers (i. e., isomers differing only in the angle of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (e.g., cis-trans isomers) do.
  • optical isomers for example, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof
  • morphological isomers i. e., isomers differing only in the angle of one or more chemical bonds
  • position isomers especially tautomers
  • geometric isomers e.g., cis-trans isomers
  • essentially pure when used in reference to an enantiomer or partial isomer, means that at least about 90%, preferably at least about 95%, of a specific compound, such as an enantiomer or partial isomer, , More preferably at least about 97% or at least about 98%, even more preferably at least about 99%, even more preferably at least about 99.5% (w / w).
  • the term " pharmaceutically acceptable” refers to the approval of a government or equivalent regulatory agency that can be used on animals, and more specifically on humans, by avoiding significant toxic effects when used in conventional medicinal dosage Received, approved, or listed in pharmacopoeia or other general pharmacopoeia.
  • salt means a salt according to one aspect of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound.
  • the salt may be (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; (3-hydroxybenzoyl) benzoic acid, or an acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 4-methylbicyclo [
  • &quot means a compound to which water is bound, and is a broad concept that includes an inclusion compound having no chemical bonding force between water and the compound.
  • &quot means a higher order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent.
  • the present invention relates to a method for the treatment or prevention of hair growth or hair growth comprising a trimethoxyphenyl compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, It is a composition for promoting hair growth.
  • trimethoxyphenyl compound of Formula 1 is 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 5-hydroxy-4-oxo-4H- (3,4,5-Trimethoxy-phenyl) -acrylic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester).
  • the compound of Formula 1 is an off-white solid compound at room temperature.
  • the compound represented by Formula 1 is prepared by reacting a pyrenone derivative compound of Formula 2 with a trimethoxyphenyl ester compound of Formula 3 as shown in Reaction Scheme 1 below:
  • the compound of Formula 1 is prepared by a coupling reaction between a halogen element of a pyrazine compound and a metal of a trimethoxyphenyl ester compound.
  • X is a halogen element, wherein the halogen element may be F, Cl, Br, or I, preferably Cl.
  • the compound of formula (2) can be used by purchasing a commercially available compound or by directly preparing it.
  • it may be 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one, wherein X is Cl, which is 5-hydroxy-2- (hydroxymethyl) -4-one with thionyl chloride (SOCl 2 ).
  • trimethoxyphenyl ester compound of formula (3) is an ionized salt form of 3- (3,4,5-trimethoxy-phenyl) -acrylic acid (M +) bonded to the carboxyl group of 3- (3,4,5-trimethoxy-phenyl) -acrylic acid (3- (3,4,5-trimethoxy- have.
  • the cation (M + ) is one kind selected from the group consisting of Li + , Na + , and K + .
  • it may be an ionic compound of 3- (3,4,5-trimethoxy-phenyl) -acrylic acid (3- (3,4,5-trimethoxy-phenyl) -acrylic acid) and Na +
  • 3- (3,4,5-trimethoxy-phenyl) -acrylic acid and sodium hydroxide are dissolved together in methanol and ionized And then distilling off methanol.
  • the compound of Formula 2 may be 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one and the compound of Formula 3 may be sodium 3- (3,4,5- (3, 4, 5-trimethoxy-phenyl) -acrylic acid.
  • the trimethoxyphenyl compound of the formula (1) can be prepared through the ester linkage thereof.
  • the reaction is not particularly limited in the present invention and can be carried out under conditions that the halogen-metal bond reaction can be sufficiently performed.
  • the reaction temperature may be, for example, 0.5 to 5 hours, preferably 1 to 3 hours at 50 to 250 ° C at the reflux temperature of the solvent.
  • the solvent may be any solvent capable of sufficiently dissolving the compounds of formulas (2) and (3).
  • the solvent include N, N-dimethylformamide (DMF), tetrahydrofuran (DMSO), acetonitrile, dioxane, benzene, toluene, ether, methanol, hexane, cyclohexane, pyridine, N-methylpyrrolidone and combinations thereof, preferably DMF Can be used.
  • the solvent may be distilled and then subjected to post-treatment such as washing, drying, and purification to obtain a highly pure compound.
  • the trimethoxyphenyl compound represented by the formula (1) according to the present invention can be applied to various fields, and is preferably used as an effective ingredient of a cosmetic composition.
  • the trimethoxyphenyl compound When the trimethoxyphenyl compound is contained as an active ingredient, it promotes the growth of the papilla cells and promotes the expression of the growth factors IGF-1, VEGF, and HGF to promote hair growth.
  • the concentration of the active ingredient may be in the range of 1 to 100 [mu] M based on the total volume of the composition, and may be, for example, at least 10 [mu] M, at least 15, at least 20, at least 25, at least 30, , Or greater than or equal to 40 ⁇ M, and can be less than 90 ⁇ M, less than 80 ⁇ M, less than 70 ⁇ M, or less than 60 ⁇ M. In one embodiment herein, the concentration of the active ingredient is preferably 50 [mu] M.
  • the concentration is less than 1 ⁇ M, the effect of promoting hair growth or hair growth may be insignificant. If the concentration is more than 100 ⁇ M, cytotoxicity may occur.
  • the composition may be a pharmaceutical composition, a cosmetic composition, or an external preparation for skin.
  • the pharmaceutical composition for promoting hair growth or hair growth may be added with preservatives, stabilizers, wetting agents or emulsifying accelerators, pharmaceutical adjuvants such as salts and / or buffers for controlling osmotic pressure and other therapeutically useful substances And may be formulated into various oral or parenteral dosage forms according to conventional methods.
  • oral administration agent examples include tablets, pills, hard and soft capsules, liquids, suspensions, emulsions, syrups, powders, powders, granules, granules and pellets, , Diluents (such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), lubricants (such as silica, talc, stearic acid and magnesium or calcium salts thereof and polyethylene glycols) .
  • Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine
  • lubricants such as silica, talc, stearic acid and magnesium or calcium salts thereof and polyethylene glycols
  • the tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine, optionally mixed with starch, agar, alginic acid or its sodium salt Such as disintegrants, absorbents, coloring agents, flavoring agents, and sweetening agents.
  • the tablets may be prepared by conventional mixing, granulating or coating methods.
  • it may be a transdermal dosage form in the form of parenteral administration. For example, it may be in the form of injections, drops, ointments, lotions, gels, creams, sprays, suspensions, emulsions, suppositories, But is not limited thereto.
  • the pharmaceutical composition according to one embodiment of the present invention may be administered by parenteral, rectal, topical, transdermal, subcutaneous, and the like.
  • the pharmaceutical composition according to one embodiment of the present invention may be administered topically, for example, to the scalp.
  • the pharmaceutical composition can increase the expression of one or more of the growth factors IGF-1, VEGF, and HGF, and the pharmaceutical composition can reduce the expression of TGF-b1, a factor that is activated upon the progression of hair loss.
  • the dosage of the active ingredient is within the level of those skilled in the art, and the daily dose of the drug depends on various factors such as the degree of progress of the subject to be administered, the age of onset, age, health condition, Kg of the composition may be generally from 1 ⁇ g / kg to 100 mg / kg, for example, 0.1 mg / Kg to 20 mg / Kg, 0.5 mg / Kg to 20 mg / Kg, or 1 mg / kg to 20 mg / May be administered in a divided dose of 5 mg / kg to 10 mg / kg once or three times a day, and the dose is not limited to the scope of the present invention by any means.
  • the composition for promoting hair growth or hair growth may be a cosmetic composition, and the cosmetic composition may contain a cosmetically or dermatologically acceptable medium or base. It may be any formulation suitable for topical application, for example, as a solution, a gel, a solid, a paste anhydrous product, an emulsion obtained by dispersing an oil phase in water, a suspension, a microemulsion, a microcapsule, And in the form of non-ionic follicular dispersants, or in the form of creams, skins, lotions, powders, ointments, sprays or conical sticks. These compositions may be prepared according to conventional methods in the art. The composition according to the invention may also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.
  • the cosmetic composition according to an embodiment of the present invention is not particularly limited in its formulation, and examples thereof include softening agents, convergent lotion, nutritional lotion, nutritional cream, massage cream, essence, eye cream, eye essence, Cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil and body essence.
  • the formulation of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .
  • lactose When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component.
  • a spray in particular, / Propane or dimethyl ether.
  • a solvent, a solvent or an emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.
  • the formulation of the present invention is a suspension
  • a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc.
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc.
  • the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolenic derivatives or ethoxylated glycerol fatty acid esters.
  • the cosmetic composition according to an embodiment of the present invention may further contain ingredients included in the functional additive and the general cosmetic composition in addition to the above-described effective ingredients.
  • the functional additives may include water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymeric polysaccharides, sphingolipids and seaweed extracts.
  • the cosmetic composition of the present invention may further contain, in addition to the above-described functional additive, components contained in a general cosmetic composition as required.
  • components contained in a general cosmetic composition as required.
  • the other ingredients that can be included in the composition include humectants, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbents, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, Accelerators, coolants, antiperspirants, purified water, and the like.
  • composition for promoting hair growth or hair growth is an external preparation for skin
  • the external preparation for skin may be any kind applied to the outside of the skin, and various cosmetic formulations and medicines may be included therein have.
  • the composition for promoting hair growth or hair growth may be a food composition
  • the food composition may be in a liquid or solid form and may be in the form of tablets, capsules, soft capsules, , A drink (drink), a diet bar, a chocolate, a caramel formulation or a confectionery formulation, and the formulation is not particularly limited.
  • the food composition of the present invention may contain excipients, saccharides, fragrances, pigments, oils, proteins and the like as needed in addition to the above-mentioned effective ingredients.
  • the composition may further comprise vitamin D.
  • the composition further includes vitamin D, thereby supplying nutrients to the hair follicle.
  • the amount thereof is preferably 0.0001 to 10% by weight, particularly 0.01 to 1% by weight of the total composition.
  • the present invention provides a method for promoting hair growth or hair growth by administering an effective amount of a trimethoxyphenyl compound represented by the following formula (1) to a subject in need thereof.
  • the present invention is a use of a trimethoxyphenyl compound represented by the following formula (1) for producing a composition for promoting hair growth or hair growth.
  • the present invention is a trimethoxyphenyl compound represented by the following formula (1) for promoting hair growth or hair growth.
  • Example 1 3 - (3,4,5- Trimethoxy -Phenyl) -acrylic acid 5-hydroxy-4-oxo-4 H -Pyran-2-ylmethyl ester (3- (3,4,5- Trimethoxy -phenyl) -acrylic acid 5- hydroxy -4- oxo -4H-pyran-2-ylmethyl ester)
  • Test Example 1 Proliferation and cytotoxicity analysis
  • hSCFs Human subcutaneous fat cells
  • subcutaneous fat precursor cell differentiation medium were purchased from ZenBio Inc. (NC, USA) and cultured in a CO 2 incubator with a humidity of 5%.
  • hSCFs were incubated with 10% fetal bovine serum (FBS, PAA, Pasching, Austria), 10 ⁇ g / ml insulin (Sigma-Aldrich, MO, USA), 0.5 mM 3-isobutyl- (DEX, Sigma-Aldrich, MO, USA), 1 mM dexamethasone (Sigma-Aldrich, St. Louis, Mo., USA) (DMEM; Lonza, Md, USA) containing 1 ⁇ M troglitazone (Sigma-Aldrich, St. Louis, Mo., USA) The badge was replaced every other day.
  • HDPs Human dermal papilla cells
  • HDPs maintenance medium were purchased from Cefobio Co. (Seoul, Korea) and cultured in a CO 2 incubator with a humidity of 5% according to the manufacturer's instructions.
  • Adiponectin (APN) and drug (PAC-2) -treated hSCFs culture medium were treated with HDPs to determine cell proliferation and cytotoxicity by PAC-2.
  • HDPs viability was measured according to the manufacturer's instructions using the EZ-Cytox cell viability assay kit (MTT assay, Daeil Lab Service, South Korea).
  • MTT assay Daeil Lab Service, South Korea
  • HDPs 24 hours after incubation were treated with APN 1, 5, 10 ng / ml as a positive control and the content of hSCFs culture medium treated with PAC-2 (50 ⁇ M) 25, 50, and 100%, respectively, and treated for 24 hours and 72 hours, respectively.
  • EZ-Cytox solution (10 ⁇ ⁇ ) was added to each well and cultured at 37 ⁇ ⁇ for 2 hours. Absorbance at 450 nm was measured using a spectrophotometer (Synergy H2, BioTek., VT, USA). All experiments were performed 3 times and data were expressed as absorbance.
  • the culture medium of hSCFs treated with the compound of the present invention, PAC-2 did not show any proliferation or toxicity with respect to cell proliferation of HDPs, as in the positive control APN. Accordingly, it was confirmed that the compound of the present invention promotes the activity of hair follicle activating factors in cells, which will be described later, rather than cell proliferation, thereby exhibiting a hair growth or hair growth effect.
  • cytotoxicity was also found to be equivalent to that of the normal control, and it was confirmed that it was not harmful to human body.
  • RT-qPCR Real-time quantitative PCR
  • Each TaqMan® probe is: glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Part # 4352339E). All data are expressed as a multiple of change compared to the GAPDH control and were obtained from three independent experiments.
  • GAPDH glyceraldehyde-3-phosphate dehydrogenase
  • IGF-1 insulin-like growth factor
  • VEGF vascular endothelial growth factor
  • HGF hepatocyte growth factor
  • hepatocyte growth factor 2A-2C hepatocyte growth factor 2A-2C
  • VEGF, and HGF were 1.5-3 times more expressed than the normal control and similar (10, 25%) and superior (50%) to the positive control APN.
  • TGF-b1 transforming growth factor
  • % the expression level was lowered.

Abstract

Disclosed are: a trimethoxy phenyl compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a composition for promoting hair growth or restoration, containing the same as an active ingredient. The composition according to the present specification promotes factors for activating dermal papilla cells and hair follicles, thereby enabling hair growth or restoration to be promoted. Therefore, the composition of the present specification can be variously used, in fields such as hair loss treatment, as a pharmaceutical composition or a cosmetic composition.

Description

트리메톡시 페닐 화합물 및 그를 포함하는 발모 또는 육모 촉진용 조성물Trimethoxyphenyl compound and composition for promoting hair growth or hair growth comprising the same
본 명세서에는 트리메톡시 페닐 화합물, 이의 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물 및 그를 포함하는 발모 또는 육모 촉진용 조성물이 개시된다.Disclosed herein is a trimethoxyphenyl compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a composition for promoting hair growth or hair growth comprising the same.
사람의 모발은 일차적으로는 자외선 등의 외부 자극요인으로부터 두피를 보호하기 위한 방어 기능을 담당하며 개인의 외적 이미지를 표현하는 미적 기능을 담당한다. 그러나 현대 사회에서는 환경 오염과 강한 자외선 등의 자연적인 요인, 스트레스 및 호르몬 불균형 등의 생리학적인 요인에 의해 탈모가 빈번히 발생되고 있으며 성인 남성에 국한되던 과거와 다르게 남녀노소를 불문하고 탈모 현상이 나타남에 따라 이의 예방 및 치료를 위한 소재의 필요성이 절실해졌다. Human hair primarily acts as a defense function to protect the scalp from external stimuli such as ultraviolet rays and plays an aesthetic function expressing the external image of the individual. In modern society, however, hair loss is frequently caused by environmental factors such as environmental pollution, strong ultraviolet rays, stress, and hormonal imbalance. Unlike the past, which is confined to adult males, Therefore, the need for materials for prevention and treatment of these diseases has become urgent.
모발을 만들어내는 신체 내의 생리학적 기관인 모낭(hair follicle)은 출생 후의 발생 과정동안 모발의 생성 및 생성된 모발이 활발히 성장하는 성장기(anagen phase), 모발이 퇴화하는 퇴행기(catagen phase), 모발 탈락 때까지 유지되는 휴지기(telogen phase), 탈모가 일어나는 탈모기(exogen phase)로 나뉘는 모발성장 주기(hair cycle)를 반복하며 모발의 성장과 유지 및 탈락에 관여한다. 많은 연구에 의해 이 모낭의 활성은 모유두세포에 의해 일어나며, 특히 모유두세포의 증식 및 분화가 모발성장 주기의 진행과 모발형성에 일차적으로 관여한다. 활발히 모발이 성장하는 성장기에는 모유두세포의 활발한 증식 및 분화가 활발하게 일어나며 모발의 성장이 중단되며 탈모현상이 일어나는 퇴행기, 휴지기, 탈모기에는 이 세포가 사멸된다. A hair follicle, which is a physiological organ in the body that produces hair, is an anagen phase in which hair is generated and generated hair is actively grown during postnatal development, a catagen phase in which hair is degenerated, The hair growth cycle is divided into the telogen phase, which is maintained until the hair loss, and the exogen phase, where hair loss occurs. Many studies have shown that hair follicle activity is caused by dermal papilla cells, and in particular, the proliferation and differentiation of dermal papilla cells are primarily involved in the progression of the hair growth cycle and hair formation. In the growth phase where the hair grows actively, the active growth and differentiation of the papillary cells occurs actively, the growth of the hair is stopped, and the cells are killed in the regenerator, the resting period and the hair removal period where the hair loss occurs.
따라서 발모 및 탈모에는 모유두세포의 증식 및 사멸이 밀접하게 연관되어 있으므로 이의 증식을 유도함으로써 성장기를 길게 하거나 혹은 세포 사멸을 억제하고 퇴행기, 휴지기, 탈모기를 짧게 하는 것이 탈모를 개선, 치료 방안이 될 것으로 사료된다. 또한, 모유두 부근의 세포 분열과 이동은 머리카락의 성장과 밀접한 관련을 갖고 있는데, 성장기에서 모유두로부터 모발이 새롭게 생성되는데, 여러 가지 사이토카인, 호르몬 등에 의해서 세포가 활성화 되어 모유두로 세포의 이동이 나타나 모발의 성장에 영향을 주게 된다. Therefore, hair growth and hair loss are closely related to the proliferation and death of the dermal papilla cells. Therefore, prolonging the growth period or inhibiting apoptosis and shortening the period of regrowth, dormancy and hair loss by inducing proliferation of the dermal papilla cells will be a remedy . Cell division and migration in the vicinity of the dermal papilla is closely related to the growth of the hair. In the growing phase, hair is newly generated from the dermal papilla. Cells are activated by various cytokines and hormones, Of the growth rate.
또한, 모낭의 활성화 인자들 가운데 HGF, IGF-1, VEGF 등의 성장인자는 성장기에서 가장 강하게 발현되며, 퇴행기와 휴지기에서는 감소함으로써 모유두세포의 증식을 유도하고 성장기를 유지시킴으로서 모발이 정상적으로 유지될 수 있도록 돕는 것으로 알려져 있다. In addition, growth factors such as HGF, IGF-1, and VEGF are most strongly expressed in the growth phase and decrease in the regressor and dormant period, thereby inducing the proliferation of the dermal papilla cells and maintaining the growth period, It is known to help.
현재 FDA에서 승인된 대표적인 약물 미녹시딜(minoxidil)과 피나스테라이드(finasteride)는 전신의 발모 및 성기능 저하 등의 부작용이 따르고 미녹시딜의 구체적인 작용 기전 또한 명확하게 밝혀지지는 않은 상태이다. 따라서, 모낭에서 모유두세포의 증식을 촉진하고 성장인자의 발현을 증가시키면서 부작용 우려가 적은 생물학적 소재의 개발이 필요한 실정이다.Minoxidil and finasteride, which are currently approved by the FDA, suffer from side effects such as hair growth and lowering of sexual function, and the specific mechanism of action of minoxidil has not been clarified. Therefore, it is necessary to develop a biological material that promotes the proliferation of dermal papilla cells in hair follicles, increases the expression of growth factors, and has less side effects.
상기에서 살펴본 바와 같이, 모유두세포의 증식, 그리고 모발의 성장에 관련된 성장인자들은 정상적인 모발 유지, 탈모 억제 및 발모에 있어서 매우 중요한 인자이다. 이에 대해 본 발명자들은 신규한 트리메톡시 페닐 화합물을 제조하고, 상기 화합물이 모유두세포의 증식을 촉진시키고 IGF-1과 같은 성장인자들의 발현을 증가시킴을 실험적으로 확인함으로써 본 발명을 완성하게 되었다.As described above, growth factors related to proliferation of dermal papilla cells and growth of hair are very important factors in normal hair maintenance, hair loss suppression and hair growth. The inventors of the present invention completed the present invention by preparing a novel trimethoxyphenyl compound and experimentally confirming that the compound promotes the growth of papilla cells and increases the expression of growth factors such as IGF-1.
따라서, 본 발명의 목적은 일 측면에서 신규한 트리메톡시 페닐 화합물, 이의 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물 및 그를 유효 성분으로 포함하는 발모 또는 육모 촉진용 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel trimethoxyphenyl compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, and a composition for promoting hair growth or hair growth, .
일 측면에서, 본 발명은, 신규한 트리메톡시 페닐 화합물, 이의 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물을 제공한다.In one aspect, the present invention provides a novel trimethoxyphenyl compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
일 측면에서, 본 발명은, 신규한 트리메톡시 페닐 화합물의 제조 방법을 제공한다.In one aspect, the present invention provides a process for preparing a novel trimethoxyphenyl compound.
일 측면에서, 본 발명은, 트리메톡시 페닐 화합물을 유효 성분으로 포함하는 발모 또는 육모 촉진용 조성물을 제공한다.In one aspect, the present invention provides a composition for promoting hair growth or hair growth, comprising a trimethoxyphenyl compound as an active ingredient.
일 측면에 있어서, 본 발명의 신규한 트리메톡시 페닐 화합물은 신체 내에서 분비되는 아디포넥틴과 유사한 수준으로 모유두세포를 증식시키고, 성장인자의 발현을 촉진시키며, 이러한 효과로 탈모 억제 및 발모 치료를 목적으로 하는 발모 또는 육모 촉진용 약학 조성물, 화장료 조성물 또는 피부 외용제로서 유용하게 사용될 수 있다.In one aspect, the novel trimethoxyphenyl compound of the present invention proliferates dermal papilla cells at a level similar to that of adiponectin secreted in the body, promotes the expression of growth factors, and by this effect inhibits hair loss and promotes hair growth , A cosmetic composition, or an external preparation for skin.
도 1은 본 발명의 구현예에 따른 트리메톡시 페닐 화합물(PAC-16742, 이하 PAC-2로 표시)을 포함하는 조성물, 및 양성대조군인 아디포넥틴(adiponectin, APN)을 모유두 세포에 처리하여 증식 및 세포 독성 분석 결과를 나타낸 것이다.1 is a schematic diagram of a composition comprising a trimethoxyphenyl compound (PAC-16742, hereinafter referred to as PAC-2) according to an embodiment of the present invention and a positive control adiponectin (APN) The results of the cytotoxicity analysis are shown.
도 2a 내지 2d는 본 발명의 구현예에 따른 트리메톡시 페닐 화합물(PAC-16742, 이하 PAC-2로 표시)을 포함하는 조성물, 및 양성대조군인 아디포넥틴(adiponectin, APN)의 모낭 활성화 인자 발현 정도(Hair growth-related gene expressions)를 측정한 결과를 나타낸 것이다.Figures 2a to 2d are graphs showing the expression of a hair follicle activator of a composition comprising a trimethoxyphenyl compound (PAC-16742, hereinafter referred to as PAC-2) according to an embodiment of the present invention and a positive control adiponectin (APN) (Hair growth-related gene expressions).
도 3은 본 발명의 구현예에 따른 트리메톡시 페닐 화합물(PAC-16742, 이하 PAC-2로 표시)의 NMR 결과를 나타낸 것이다(Sample Name 742로 표시). 3 shows the NMR of a trimethoxyphenyl compound (PAC-16742, hereinafter referred to as PAC-2) according to an embodiment of the present invention (designated by Sample Name 742).
용어 정의Term Definition
본 명세서에서, 어떤 부분이 어떤 구성 요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In this specification, when a part is referred to as " including " an element, it is to be understood that it may include other elements as well, without departing from the other elements unless specifically stated otherwise.
예시적인 구현예들의 설명DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 예시적인 구현예들에서는, 본 발명은 하기 화학식 1로 표시되는 트리메톡시 페닐 화합물, 이의 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물이다.In an exemplary embodiment of the present invention, the present invention is a trimethoxyphenyl compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.
본 명세서에서 "이성질체"는 특히 광학 이성질체(optical isomers)(예를 들면, 본래 순수한 거울상 이성질체(essentially pure enantiomers), 본래 순수한 부분 입체 이성질체(essentially pure diastereomers) 또는 이들의 혼합물)뿐만 아니라, 형태 이성질체(conformation isomers)(즉, 하나 이상의 화학 결합의 그 각도만 다른 이성질체), 위치 이성질체(position isomers)(특히, 호변이성체(tautomers)) 또는 기하 이성질체(geometric isomers)(예컨대, 시스-트랜스 이성질체)를 포함한다.As used herein, the term " isomers " refers in particular to optical isomers (for example, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof) as well as morphological isomers (i. e., isomers differing only in the angle of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (e.g., cis-trans isomers) do.
본 명세서에서 "본래 순수(essentially pure)"란, 예컨대 거울상 이성질체 또는 부분 이성질체와 관련하여 사용한 경우, 거울상 이성질체 또는 부분 이성질체를 예로 들 수 있는 구체적인 화합물이 약 90% 이상, 바람직하게는 약 95% 이상, 보다 바람직하게는 약 97% 이상 또는 약 98% 이상, 보다 더 바람직하게는 약 99% 이상, 보다 더욱 더 바람직하게는 약 99.5% 이상(w/w) 존재하는 것을 의미한다.As used herein, " essentially pure ", when used in reference to an enantiomer or partial isomer, means that at least about 90%, preferably at least about 95%, of a specific compound, such as an enantiomer or partial isomer, , More preferably at least about 97% or at least about 98%, even more preferably at least about 99%, even more preferably at least about 99.5% (w / w).
본 명세서에서 "약학적으로 허용 가능"이란 통상의 의약적 복용량(medicinal dosage)으로 이용할 때 상당한 독성 효과를 피함으로써, 동물, 더 구체적으로는 인간에게 사용할 수 있다는 정부 또는 이에 준하는 규제 기구의 승인을 받을 수 있거나 승인 받거나, 또는 약전에 열거되거나 기타 일반적인 약전으로 인지되는 것을 의미한다.As used herein, the term " pharmaceutically acceptable " refers to the approval of a government or equivalent regulatory agency that can be used on animals, and more specifically on humans, by avoiding significant toxic effects when used in conventional medicinal dosage Received, approved, or listed in pharmacopoeia or other general pharmacopoeia.
본 명세서에서 "약학적으로 허용 가능한 염"은 약학적으로 허용 가능하고 모 화합물(parent compound)의 바람직한 약리 활성을 갖는 본 발명의 일측면에 따른 염을 의미한다. 상기 염은 (1) 염산, 브롬화수소산, 황산, 질산, 인산 등과 같은 무기산으로 형성되거나; 또는 아세트산, 프로파이온산, 헥사노산, 시클로펜테인프로피온산, 글라이콜산, 피루브산, 락트산, 말론산, 숙신산, 말산, 말레산, 푸마르산, 타르타르산, 시트르산, 벤조산, 3-(4-히드록시벤조일) 벤조산, 신남산, 만델산, 메테인설폰산, 에테인설폰산, 1,2-에테인-디설폰산, 2-히드록시에테인설폰산, 벤젠설폰산, 4-클로로벤젠설폰산, 2-나프탈렌설폰산, 4-톨루엔설폰산, 캄퍼설폰산, 4-메틸바이시클로 [2,2,2]-oct-2-엔-1-카르복실산, 글루코헵톤산, 3-페닐프로파이온산, 트리메틸아세트산, tert-부틸아세트산, 라우릴 황산, 글루콘산, 글루탐산, 히드록시나프토산, 살리실산, 스테아르산, 뮤콘산과 같은 유기산으로 형성되는 산 부가염(acid addition salt); 또는 (2) 모 화합물에 존재하는 산성 프로톤이 치환될 때 형성되는 염을 포함할 수 있다.As used herein, " pharmaceutically acceptable salt " means a salt according to one aspect of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. The salt may be (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; (3-hydroxybenzoyl) benzoic acid, or an acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 4-methylbicyclo [2,2,2] -oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic proton present in the parent compound is substituted.
본 명세서에서 “수화물(hydrate)”은 물이 결합되어 있는 화합물을 의미하며, 물과 화합물 사이에 화학적인 결합력이 없는 내포 화합물을 포함하는 광범위한 개념이다.As used herein, " hydrate " means a compound to which water is bound, and is a broad concept that includes an inclusion compound having no chemical bonding force between water and the compound.
본 명세서에서 “용매화물”은 용질의 분자나 이온과 용매의 분자나 이온 사이에 생긴 고차의 화합물을 의미한다.As used herein, " solvate " means a higher order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent.
본 발명의 예시적인 구현예들에서는, 본 발명은 하기 화학식 1로 표시되는 트리메톡시 페닐 화합물, 이의 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물을 유효 성분으로 포함하는 발모 또는 육모 촉진용 조성물이다. In an exemplary embodiment of the present invention, the present invention relates to a method for the treatment or prevention of hair growth or hair growth comprising a trimethoxyphenyl compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, It is a composition for promoting hair growth.
[화학식 1][Chemical Formula 1]
Figure PCTKR2018010084-appb-I000001
Figure PCTKR2018010084-appb-I000001
상기 화학식 1의 트리메톡시 페닐 화합물의 IUPAC명은 3-(3,4,5-트리메톡시-페닐)-아크릴산 5-히드록시-4-옥소-4H-피란-2-일메틸 에스테르(3-(3,4,5-Trimethoxy-phenyl)-acrylic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester)이다.The IUPAC name of the trimethoxyphenyl compound of Formula 1 is 3- (3,4,5-trimethoxy-phenyl) -acrylic acid 5-hydroxy-4-oxo-4H- (3,4,5-Trimethoxy-phenyl) -acrylic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester).
상기 화학식 1의 화합물은 상온에서 미색의 고체 화합물이다.The compound of Formula 1 is an off-white solid compound at room temperature.
상기 화학식 1로 표시되는 화합물은 하기 반응식 1로 나타낸 바와 같이 하기 화학식 2의 피라논 유도체 화합물과 화학식 3의 트리메톡시 페닐 에스테르 화합물을 반응시켜 제조한다:The compound represented by Formula 1 is prepared by reacting a pyrenone derivative compound of Formula 2 with a trimethoxyphenyl ester compound of Formula 3 as shown in Reaction Scheme 1 below:
[반응식 1][Reaction Scheme 1]
Figure PCTKR2018010084-appb-I000002
Figure PCTKR2018010084-appb-I000002
(상기 반응식 1에서, X는 할로겐 원소이고, M은 Li, Na 또는 K이다)(In the above Reaction Scheme 1, X is a halogen element and M is Li, Na or K)
상기 반응식 1을 보면, 화학식 1의 화합물은 피라논 화합물의 할로겐 원소와 트리메톡시 페닐 에스테르 화합물의 금속 간의 결합 반응에 의해 제조된다.Referring to Reaction Scheme 1, the compound of Formula 1 is prepared by a coupling reaction between a halogen element of a pyrazine compound and a metal of a trimethoxyphenyl ester compound.
이때 화학식 2의 피라논 화합물에서 X는 할로겐 원소이고, 이때 할로겐 원소는 F, Cl, Br, 또는 I일 수 있으며, 바람직하기로는 Cl이다. 이러한 화학식 2의 화합물은 시판되는 것을 구입하여 사용하거나 직접 제조하여 사용할 수 있다.Wherein X is a halogen element, wherein the halogen element may be F, Cl, Br, or I, preferably Cl. The compound of formula (2) can be used by purchasing a commercially available compound or by directly preparing it.
본 발명의 일 실시예에서 X가 Cl인 5-히드록시-2-(클로로메틸)-4H-피란-4-온일 수 있으며, 이는 5-히드록시-2-(히드록시메틸)-4H-피란-4-온을 티오닐클로라이드(SOCl2)와 반응시켜 제조할 수 있다. In one embodiment of the present invention, it may be 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one, wherein X is Cl, which is 5-hydroxy-2- (hydroxymethyl) -4-one with thionyl chloride (SOCl 2 ).
또한, 화학식 3의 트리메톡시 페닐 에스테르 화합물은 3-(3,4,5-트리메톡시-페닐)-아크릴산(3-(3,4,5-Trimethoxy-phenyl)-acrylic acid)의 이온화 염형태로서, 3-(3,4,5-트리메톡시-페닐)-아크릴산(3-(3,4,5-Trimethoxy-phenyl)-acrylic acid)의 카르복시기에 양이온(M+)이 결합한 형태로 존재할 수 있다. In addition, the trimethoxyphenyl ester compound of formula (3) is an ionized salt form of 3- (3,4,5-trimethoxy-phenyl) -acrylic acid (M +) bonded to the carboxyl group of 3- (3,4,5-trimethoxy-phenyl) -acrylic acid (3- (3,4,5-trimethoxy- have.
상기 양이온(M+)은 Li+, Na+, K+으로 구성되는 군으로부터 선택되는 1종이다. 바람직하기로는 3-(3,4,5-트리메톡시-페닐)-아크릴산(3-(3,4,5-Trimethoxy-phenyl)-acrylic acid)과 Na+의 이온결합물일 수 있는데, 이를 제조하기 위하여 일례로 3-(3,4,5-트리메톡시-페닐)-아크릴산(3-(3,4,5-Trimethoxy-phenyl)-acrylic acid)과 수산화 나트륨을 함께 메탄올에 녹여 이온화한 후 메탄올을 증류함으로써 얻을 수 있다.The cation (M + ) is one kind selected from the group consisting of Li + , Na + , and K + . Preferably, it may be an ionic compound of 3- (3,4,5-trimethoxy-phenyl) -acrylic acid (3- (3,4,5-trimethoxy-phenyl) -acrylic acid) and Na + For example, 3- (3,4,5-trimethoxy-phenyl) -acrylic acid and sodium hydroxide are dissolved together in methanol and ionized And then distilling off methanol.
본 발명의 바람직한 일 실시예에서 화학식 2의 화합물은 5-히드록시-2-(클로로메틸)-4H-피란-4-온일 수 있고, 화학식 3의 화합물은 소듐 3-(3,4,5-트리메톡시-페닐)-아크릴산(Sodium 3-(3,4,5-Trimethoxy-phenyl)-acrylic acid)일 수 있다. 또한, 이들의 에스테르 결합을 통해 화학식 1의 트리메톡시 페닐 화합물을 제조할 수 있다.In one preferred embodiment of the present invention, the compound of Formula 2 may be 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one and the compound of Formula 3 may be sodium 3- (3,4,5- (3, 4, 5-trimethoxy-phenyl) -acrylic acid. Further, the trimethoxyphenyl compound of the formula (1) can be prepared through the ester linkage thereof.
이때 반응은 본 발명에서 특별히 한정하지 않으며, 상기 할로겐-금속 결합 반응이 충분이 이루어질 수 있는 조건하에서 수행할 수 있다.At this time, the reaction is not particularly limited in the present invention and can be carried out under conditions that the halogen-metal bond reaction can be sufficiently performed.
반응 온도는 용매의 환류 온도, 일례로 50 내지 250℃에서 0.5 내지 5시간, 바람직하기로 1 내지 3시간 동안 수행할 수 있다. The reaction temperature may be, for example, 0.5 to 5 hours, preferably 1 to 3 hours at 50 to 250 ° C at the reflux temperature of the solvent.
이때 용매는 화학식 2 및 3의 화합물을 충분히 용해시킬 수 있는 것이면 어느 것이든 가능하며, 일례로 N,N-디메틸포름아미드(N,N-dimethylformamide, DMF), 테트라하이드로퓨란(THF), 디메틸술폭사이드(DMSO), 아세토니트릴, 디옥산, 벤젠, 톨루엔, 에테르, 메탄올, 헥산, 사이클로헥산, 피리딘, N-메틸피롤리돈 및 이들의 조합으로 이루어진 군에서 선택된 1종이 가능하며, 바람직하기로 DMF를 사용할 수 있다.The solvent may be any solvent capable of sufficiently dissolving the compounds of formulas (2) and (3). Examples of the solvent include N, N-dimethylformamide (DMF), tetrahydrofuran (DMSO), acetonitrile, dioxane, benzene, toluene, ether, methanol, hexane, cyclohexane, pyridine, N-methylpyrrolidone and combinations thereof, preferably DMF Can be used.
반응 후에는 상기 용매를 증류한 후 통상의 세척, 건조, 정제 등의 후처리 과정을 거쳐 고순도의 화합물을 얻을 수 있다. After the reaction, the solvent may be distilled and then subjected to post-treatment such as washing, drying, and purification to obtain a highly pure compound.
본 발명에 따른 화학식 1의 트리메톡시 페닐 화합물은 다양한 분야에 적용이 가능하며, 바람직하기로 화장료 조성물의 유효 성분으로 사용할 수 있다. 상기 트리메톡시 페닐 화합물을 유효 성분으로 포함하는 경우, 모유두세포 증식 촉진 효과가 있으며, 성장인자인 IGF-1, VEGF, 및 HGF의 발현을 촉진시켜, 모발 생성 촉진시킨다. The trimethoxyphenyl compound represented by the formula (1) according to the present invention can be applied to various fields, and is preferably used as an effective ingredient of a cosmetic composition. When the trimethoxyphenyl compound is contained as an active ingredient, it promotes the growth of the papilla cells and promotes the expression of the growth factors IGF-1, VEGF, and HGF to promote hair growth.
본 명세서에서는 특히, 후술하는 시험예에서 상기 조성물의 효과를 래트 등의 동물이 아닌, 인체 유래 모유두 세포를 대상으로 실험하여, 상기 조성물을 실제 인체에 화장료 또는 약학 조성물 등으로 적용할 경우 발모 또는 육모 촉진 효과가 있다는 것을 명백히 알 수 있다. In the present specification, in particular, in the test examples described later, when the effect of the composition is tested on dermal papilla cells derived from human rather than animals such as rats and the composition is applied to a human body as a cosmetic or pharmaceutical composition, It is evident that there is a promoting effect.
일 구현예에서, 상기 유효성분의 농도가 조성물 전체 부피를 기준으로 1 내지 100 μM일 수 있고, 예컨대, 10 μM 이상, 15 μM 이상, 20 μM 이상, 25 μM 이상, 30 μM 이상, 35 μM 이상, 또는 40 μM 이상일 수 있으며, 90 μM 이하, 80 μM 이하, 70 μM 이하, 또는 60 μM 이하일 수 있다. 본 명세서의 일 구현예에서, 바람직하게는, 상기 유효 성분의 농도는 50 μM 일 수 있다. In one embodiment, the concentration of the active ingredient may be in the range of 1 to 100 [mu] M based on the total volume of the composition, and may be, for example, at least 10 [mu] M, at least 15, at least 20, at least 25, at least 30, , Or greater than or equal to 40 μM, and can be less than 90 μM, less than 80 μM, less than 70 μM, or less than 60 μM. In one embodiment herein, the concentration of the active ingredient is preferably 50 [mu] M.
상기 농도가 1 μM 미만인 경우 발모 또는 육모 촉진 효과가 미미할 수 있고, 100 μM 초과인 경우 세포 독성이 나타날 수 있다. If the concentration is less than 1 μM, the effect of promoting hair growth or hair growth may be insignificant. If the concentration is more than 100 μM, cytotoxicity may occur.
일 구현예에서, 상기 조성물은 약학 조성물, 화장료 조성물, 또는 피부 외용제일 수 있다. In one embodiment, the composition may be a pharmaceutical composition, a cosmetic composition, or an external preparation for skin.
본 발명의 일 실시예에 따른 상기 발모 또는 육모 촉진용 약학 조성물은 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 약제학적 보조제 및 기타 치료적으로 유용한 물질을 추가로 함유할 수 있으며, 통상적인 방법에 따라 다양한 경구 투여제 또는 비경구 투여제 형태로 제형화할 수 있다.The pharmaceutical composition for promoting hair growth or hair growth according to an embodiment of the present invention may be added with preservatives, stabilizers, wetting agents or emulsifying accelerators, pharmaceutical adjuvants such as salts and / or buffers for controlling osmotic pressure and other therapeutically useful substances And may be formulated into various oral or parenteral dosage forms according to conventional methods.
상기 경구 투여제는 예를 들면, 정제, 환제, 경질 및 연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 분제, 산제, 세립제, 과립제, 펠렛제 등이 있으며, 이들 제형은 유효 성분 이외에 계면 활성제, 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로오스 및 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및 폴리에틸렌 글리콜)를 함유할 수 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로오스, 나트륨 카복시메틸셀룰로오스 및 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제, 흡수제, 착색제, 향미제, 및 감미제 등의 약제학적 첨가제를 함유할 수 있다. 상기 정제는 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다. 또한, 상기 비경구 투여 형태로 경피 투여형 제형일 수 있으며, 예를 들어 주사제, 점적제, 연고, 로션, 겔, 크림, 스프레이, 현탁제, 유제, 좌제(坐劑), 패취 등의 제형일 수 있으나, 이에 제한되는 것은 아니다.Examples of the oral administration agent include tablets, pills, hard and soft capsules, liquids, suspensions, emulsions, syrups, powders, powders, granules, granules and pellets, , Diluents (such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), lubricants (such as silica, talc, stearic acid and magnesium or calcium salts thereof and polyethylene glycols) . The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine, optionally mixed with starch, agar, alginic acid or its sodium salt Such as disintegrants, absorbents, coloring agents, flavoring agents, and sweetening agents. The tablets may be prepared by conventional mixing, granulating or coating methods. In addition, it may be a transdermal dosage form in the form of parenteral administration. For example, it may be in the form of injections, drops, ointments, lotions, gels, creams, sprays, suspensions, emulsions, suppositories, But is not limited thereto.
본 발명의 일 실시예에 따른 상기 약학 조성물은 비경구, 직장, 국소, 경피, 피하 등으로 투여될 수 있다. 본 발명의 일 실시예에 따른 약학 조성물은 예를 들어 두피에 국소 투여될 수 있다.The pharmaceutical composition according to one embodiment of the present invention may be administered by parenteral, rectal, topical, transdermal, subcutaneous, and the like. The pharmaceutical composition according to one embodiment of the present invention may be administered topically, for example, to the scalp.
상기 약학 조성물은 성장인자인 IGF-1, VEGF 및 HGF 중 하나 이상의 인자의 발현을 증가시킬 수 있고, 상기 약학 조성물은 탈모 진행시 활성화되는 인자인 TGF-b1의 발현을 감소시킬 수 있다.The pharmaceutical composition can increase the expression of one or more of the growth factors IGF-1, VEGF, and HGF, and the pharmaceutical composition can reduce the expression of TGF-b1, a factor that is activated upon the progression of hair loss.
상기 유효 성분의 투여량 결정은 당업자의 수준 내에 있으며, 약물의 1일 투여 용량은 투여하고자 하는 대상의 미만 진행 정도, 발병 시기, 연령, 건강상태, 합병증 등의 다양한 요인에 따라 달라지지만, 성인을 기준으로 할 때 일반적으로는 상기 조성물 1μg/kg 내지 100mg/kg일 수 있고, 예컨대 0.1mg/Kg 내지 20mg/Kg, 0.5mg/Kg 내지 20mg/Kg, 또는 1mg/kg 내지 20mg/kg, 바람직하게는 5mg/kg 내지 10mg/kg을 1일 1 내지 3회 분할하여 투여할 수 있으며, 상기 투여량은 어떠한 방법으로도 본 발명의 범위를 한정하는 것이 아니다.The dosage of the active ingredient is within the level of those skilled in the art, and the daily dose of the drug depends on various factors such as the degree of progress of the subject to be administered, the age of onset, age, health condition, Kg of the composition may be generally from 1 μg / kg to 100 mg / kg, for example, 0.1 mg / Kg to 20 mg / Kg, 0.5 mg / Kg to 20 mg / Kg, or 1 mg / kg to 20 mg / May be administered in a divided dose of 5 mg / kg to 10 mg / kg once or three times a day, and the dose is not limited to the scope of the present invention by any means.
본 발명의 일 실시예에 따른 상기 발모 또는 육모 촉진용 조성물은 화장료 조성물일 수 있으며, 화장료 조성물의 외형은 화장품학 또는 피부과학적으로 허용 가능한 매질 또는 기제를 함유한다. 이는 국소적용에 적합한 모든 제형으로, 예를 들면, 용액, 겔, 고체, 반죽 무수 생성물, 수상에 유상을 분산시켜 얻은 에멀젼, 현탁액, 마이 크로에멀젼, 마이크로캡슐, 미세과립구 또는, 이온형(리포좀) 및 비이온형의 소낭 분산제의 형태로, 또는 크림, 스킨, 로션, 파우더, 연고, 스프레이 또는 콘실 스틱의 형태로 제공될 수 있다. 이들 조성물은 당해 분야의 통상적인 방법에 따라 제조될 수 있다. 본 발명에 따른 조성물은 또한 포말(foam)의 형태로 또는 압축된 추진제를 더 함유한 에어로졸 조성물의 형태로도 사용될 수 있다.The composition for promoting hair growth or hair growth according to an embodiment of the present invention may be a cosmetic composition, and the cosmetic composition may contain a cosmetically or dermatologically acceptable medium or base. It may be any formulation suitable for topical application, for example, as a solution, a gel, a solid, a paste anhydrous product, an emulsion obtained by dispersing an oil phase in water, a suspension, a microemulsion, a microcapsule, And in the form of non-ionic follicular dispersants, or in the form of creams, skins, lotions, powders, ointments, sprays or conical sticks. These compositions may be prepared according to conventional methods in the art. The composition according to the invention may also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.
본 발명의 일 실시예에 따른 상기 화장료 조성물은 그 제형에 있어서 특별히 한정되는 바가 없으며, 예를 들면, 유연화장수, 수렴화장수, 영양화장수, 영양크림, 마사지크림, 에센스, 아이크림, 아이에센스, 클렌징크림, 클렌징폼, 클렌징워터, 팩, 파우더, 바디로션, 바디크림, 바디오일 및 바디에센스 등의 화장품으로 제형화될 수 있다.The cosmetic composition according to an embodiment of the present invention is not particularly limited in its formulation, and examples thereof include softening agents, convergent lotion, nutritional lotion, nutritional cream, massage cream, essence, eye cream, eye essence, Cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil and body essence.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물섬유, 식물섬유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액의 경우에는 담체 성분으로서 용매, 용매화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.In the case of the solution or emulsion of the present invention, a solvent, a solvent or an emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 리놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolenic derivatives or ethoxylated glycerol fatty acid esters.
본 발명의 일 실시예에 따른 화장료 조성물에는 상기 유효성분 이외에 기능성 첨가물 및 일반적인 화장료 조성물에 포함되는 성분이 추가로 포함될 수 있다. 상기 기능성 첨가물로는 수용성 비타민, 유용성 비타민, 고분자 펩티드, 고분자 다당, 스핑고 지질 및 해초 엑기스로 이루어진 군에서 선택된 성분을 포함할 수 있다.The cosmetic composition according to an embodiment of the present invention may further contain ingredients included in the functional additive and the general cosmetic composition in addition to the above-described effective ingredients. The functional additives may include water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymeric polysaccharides, sphingolipids and seaweed extracts.
본 발명의 화장료 조성물에는 또한, 상기 기능성 첨가물과 더불어 필요에 따라 일반적인 화장료 조성물에 포함되는 성분을 배합해도 된다. 이외에 포함되는 배합 성분으로서는 유지 성분, 보습제, 에몰리엔트제, 계면 활성제, 유기 및 무기 안료, 유기 분체, 자외선 흡수제, 방부제, 살균제, 산화 방지제, 식물 추출물, pH 조정제, 알콜, 색소, 향료, 혈행 촉진제, 냉감제, 제한(制汗)제, 정제수 등을 들 수 있다.The cosmetic composition of the present invention may further contain, in addition to the above-described functional additive, components contained in a general cosmetic composition as required. Examples of the other ingredients that can be included in the composition include humectants, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbents, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, Accelerators, coolants, antiperspirants, purified water, and the like.
더욱이, 상기 본 발명의 일 실시예에 따른 발모 또는 육모 촉진용 조성물은 피부 외용제이며, 상기 피부 외용제는 피부 외부에서 도포되는 어떠한 것이라도 포함될 수 있는 총칭으로서 다양한 제형의 화장품, 의약품이 여기에 포함될 수 있다.Further, the composition for promoting hair growth or hair growth according to an embodiment of the present invention is an external preparation for skin, and the external preparation for skin may be any kind applied to the outside of the skin, and various cosmetic formulations and medicines may be included therein have.
또한, 상기 본 발명의 일 실시예에 따른 발모 또는 육모 촉진용 조성물은 식품 조성물일 수 있으며, 상기 식품 조성물은 액상 또는 고체 상태의 제형일 수 있고, 정제, 캡슐제, 연질캡슐제, 환제, 과립제, 음료(드링크제), 다이어트바, 초콜렛, 카라멜 제형 또는 과자류 제형일 수 있으며, 그 제형이 특별히 한정되는 것은 아니다. 본 발명의 식품 조성물은 상기 유효 성분 외에도 필요에 따라 부형제, 당류, 향료, 색소, 유지류, 단백질 등을 적의 함유할 수 있다.In addition, the composition for promoting hair growth or hair growth according to an embodiment of the present invention may be a food composition, and the food composition may be in a liquid or solid form and may be in the form of tablets, capsules, soft capsules, , A drink (drink), a diet bar, a chocolate, a caramel formulation or a confectionery formulation, and the formulation is not particularly limited. The food composition of the present invention may contain excipients, saccharides, fragrances, pigments, oils, proteins and the like as needed in addition to the above-mentioned effective ingredients.
일 구현예에서, 상기 조성물은 비타민 D를 더 포함할 수 있다. 상기 조성물은 비타민 D를 더 포함함으로써, 모낭에 영양소를 공급할 수 있다. 이들의 양은 전체 조성물의 0.0001 내지 10 중량%, 특히 0.01 내지 1 중량%가 바람직하다.In one embodiment, the composition may further comprise vitamin D. The composition further includes vitamin D, thereby supplying nutrients to the hair follicle. The amount thereof is preferably 0.0001 to 10% by weight, particularly 0.01 to 1% by weight of the total composition.
본 발명의 또다른 예시적인 구현예들에서, 본 발명은 하기 화학식 1로 표시되는 트리메톡시 페닐 화합물을 이로 필요로 하는 대상에게 유효량으로 투여하여 발모 또는 육모를 촉진하는 방법이다.In another exemplary embodiment of the present invention, the present invention provides a method for promoting hair growth or hair growth by administering an effective amount of a trimethoxyphenyl compound represented by the following formula (1) to a subject in need thereof.
[화학식 1][Chemical Formula 1]
Figure PCTKR2018010084-appb-I000003
Figure PCTKR2018010084-appb-I000003
본 발명의 또다른 예시적인 구현예들에서, 본 발명은 발모 또는 육모 촉진용 조성물을 제조하기 위한, 하기 화학식 1로 표시되는 트리메톡시 페닐 화합물의 용도이다.In another exemplary embodiment of the present invention, the present invention is a use of a trimethoxyphenyl compound represented by the following formula (1) for producing a composition for promoting hair growth or hair growth.
[화학식 1][Chemical Formula 1]
Figure PCTKR2018010084-appb-I000004
Figure PCTKR2018010084-appb-I000004
본 발명의 또다른 예시적인 구현예들에서, 본 발명은 발모 또는 육모를 촉진하기 위한 하기 화학식 1로 표시되는 트리메톡시 페닐 화합물이다.In another exemplary embodiment of the present invention, the present invention is a trimethoxyphenyl compound represented by the following formula (1) for promoting hair growth or hair growth.
[화학식 1][Chemical Formula 1]
Figure PCTKR2018010084-appb-I000005
Figure PCTKR2018010084-appb-I000005
이하, 하기의 실시예를 통하여 본 발명을 보다 구체적으로 설명한다. 그러나 하기의 실시에는 본 발명에 대한 이해를 돕기 위해 예시의 목적으로만 제공된 것일 뿐, 본 발명의 범주 및 범위가 이에 한정되지 않는다.Hereinafter, the present invention will be described more specifically with reference to the following examples. However, the following embodiments are provided for illustrative purposes only in order to facilitate understanding of the present invention, and the scope and scope of the present invention are not limited thereto.
실시예Example
실시예Example 1: 31: 3 -(3,4,5-- (3,4,5- 트리메톡시Trimethoxy -페닐)-아크릴산 5-히드록시-4-옥소-4-Phenyl) -acrylic acid 5-hydroxy-4-oxo-4 HH -피란-2-일메틸 에스테르(3-(3,4,5--Pyran-2-ylmethyl ester (3- (3,4,5- TrimethoxyTrimethoxy -phenyl)-acrylic acid 5--phenyl) -acrylic acid 5- hydroxyhydroxy -4--4- oxooxo -4H-pyran-2-ylmethyl ester)의 제조-4H-pyran-2-ylmethyl ester)
하기 반응식 2에 따라 본 발명의 화학식 1의 트리메톡시 페닐 화합물인 3-(3,4,5-트리메톡시-페닐)-아크릴산 5-히드록시-4-옥소-4H-피란-2-일메틸 에스테르(3-(3,4,5-Trimethoxy-phenyl)-acrylic acid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester)를 제조하였다.(3, 4, 5-trimethoxy-phenyl) -acrylic acid 5-hydroxy-4-oxo-4H-pyran-2-yl 4-oxo-4H-pyran-2-ylmethyl ester (3- (3,4,5-Trimethoxy-phenyl) -acrylic acid 5-hydroxy-4-oxo-4-methyl ester.
[반응식 2][Reaction Scheme 2]
Figure PCTKR2018010084-appb-I000006
Figure PCTKR2018010084-appb-I000006
상기 반응식 2을 수행한 상세한 과정은 하기와 같다.The detailed procedure of the above reaction scheme 2 is as follows.
50g의 5-히드록시-2-(히드록시메틸)-4H-피란-4-온 (0.35mmol)을 N,N-디메틸포름아미드 250ml에 녹이고, 10 ℃ 빙수욕에서 냉각하여 티오닐클로라이드 50g (0.42mol)을 30분 동안 적가하였다. 상온에서 2시간 교반한 뒤 빙수 2000 ml에 반응액을 가하였다. 생성된 고체를 여과하고, 초산에틸 1000 ml에 고체 (여과물)를 녹였다. 황산마그네슘과 활성탄을 가하여 건조, 탈색을 하고 여과한 뒤, 여액을 농축하고 핵산을 가하여 결정을 얻었다. 진공 건조하여 반응 생성물인 화학식 2-1의 5-히드록시-2-(클로로메틸)-4H-피란-4-온 39.5g (70%)을 노란색 고체로 얻었다.(0.35 mmol) of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one (0.35 mmol) was dissolved in 250 ml of N, N-dimethylformamide, cooled in an ice- 0.42 mol) was added dropwise over 30 minutes. After stirring at room temperature for 2 hours, the reaction solution was added to 2000 ml of ice water. The resulting solid was filtered, and a solid (filtrate) was dissolved in 1000 ml of ethyl acetate. Magnesium sulfate and activated charcoal were added, dried, discolored and filtered, and the filtrate was concentrated and nucleic acid was added to obtain crystals. And dried under vacuum to obtain 39.5 g (70%) of 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one as a reaction product as a yellow solid.
이어서, 3-(3,4,5-트리메톡시-페닐)-아크릴산(3-(3,4,5-Trimethoxy-phenyl)-acrylic acid)(3-(2,6,6-timethyl-cyclohex-2-enyl) propenoic acid) 5g (0.026mol)과 수산화나트륨 1.3g (0.031mol)을 메탄올 40ml에 녹이고 메탄올을 증류한 후 남은 잔사를 N,N-디메틸포름아미드 70ml에 녹여 화학식 3-1의 화합물을 제조하였다.Then 3- (3,4,5-trimethoxy-phenyl) -acrylic acid (3- (3,4,5-Trimethoxy-phenyl) 2-enyl) propenoic acid and 1.3 g (0.031 mol) of sodium hydroxide were dissolved in 40 ml of methanol. The methanol was distilled off and the residue was dissolved in 70 ml of N, N-dimethylformamide, Lt; / RTI >
상기 제조된 화학식 3-1의 화합물에, 상기 제조한 화학식 2-1의 5-히드록시-2-(클로로메틸)-4H-피란-4-온 4.2g(0.026mol)을 가하고 110 ℃ 오일 욕조에서 2시간 동안 가열 교반하였다. 용매를 증류하고 잔사를 초산에틸 300ml에 녹인 후, 초산에틸 용액을 5% 염산과 증류수로 세척하고 황산마그네슘과 활성탄을 가하여 건조, 탈색을 하였다. 이어서 불용물을 여과하고 여액을 감압 하에서 증발시켜 반응 생성물 5.9g (69% 수율)을 미색 고체로 얻었다.4.2 g (0.026 mol) of 5-hydroxy-2- (chloromethyl) -4H-pyran-4-one of the above prepared formula 2-1 was added to the compound of the formula 3-1 thus prepared, Lt; / RTI > for 2 hours. The solvent was distilled off and the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, dried over magnesium sulfate and activated carbon, and discolored. The insolubles were then filtered off and the filtrate was evaporated under reduced pressure to give 5.9 g (69% yield) of the reaction product as a off-white solid.
상기 미색 고체의 NMR 결과는 도 3에 나타내었다. The NMR results of the off-white solid are shown in FIG.
시험예Test Example
시험예 1: 증식 및 세포 독성 분석Test Example 1: Proliferation and cytotoxicity analysis
세포 배양 및 분화Cell culture and differentiation
인간 피하 지방 세포(human Subcutaneous Fat cells; 이하 hSCFs)과 피하 지방 전구 세포 분화 배지를 ZenBio Inc. (NC, USA)로부터 구입하여 습도가 5 % 인 CO2 배양기에서 배양하였다. 분화를 유도하기 위해, hSCFs는 10 % 태아 소 혈청 (FBS, PAA, Pasching, 오스트리아), 10 μg/ml 인슐린(Sigma-Aldrich, MO, USA), 0.5 mM 3-이소부틸-1-메틸크산틴 (IBMX; Sigma-Aldrich, St. Louis, MO, USA) 1 μM 덱사메타손(DEX, Sigma-Aldric, MO, USA), St. Louis, MO, USA) 및 1 μM 트로글리타존 (Sigma-Aldrich, St. Louis, MO, USA)을 함유한 Dulbecco 변형 이글스 배지 (DMEM; Lonza, Md, USA)에서 14일동안 배양되었다. 배지는 격일로 교체되었다. Human subcutaneous fat cells (hSCFs) and subcutaneous fat precursor cell differentiation medium were purchased from ZenBio Inc. (NC, USA) and cultured in a CO 2 incubator with a humidity of 5%. To induce differentiation, hSCFs were incubated with 10% fetal bovine serum (FBS, PAA, Pasching, Austria), 10 μg / ml insulin (Sigma-Aldrich, MO, USA), 0.5 mM 3-isobutyl- (DEX, Sigma-Aldrich, MO, USA), 1 mM dexamethasone (Sigma-Aldrich, St. Louis, Mo., USA) (DMEM; Lonza, Md, USA) containing 1 μM troglitazone (Sigma-Aldrich, St. Louis, Mo., USA) The badge was replaced every other day.
인간의 모유두 세포(Human Dermal Papilla cells, 이하 HDPs)와 HDPs 유지 배지는 Cefobio Co. (Seoul, Korea)에서 구입하여 습도가 5 % 인 CO2 incubator에서 제조사의 지침에 따라 배양 하였다. Human dermal papilla cells (HDPs) and HDPs maintenance medium were purchased from Cefobio Co. (Seoul, Korea) and cultured in a CO 2 incubator with a humidity of 5% according to the manufacturer's instructions.
세포 증식 및 세포독성 분석Cell proliferation and cytotoxicity analysis
PAC-2에 의한 세포 증식 및 세포 독성 정도를 알기 위하여, 양성 대조군인아디포넥틴(Adiponectin, 이하 APN) 및 약물(PAC-2)이 처리된 hSCFs 배양 배지를 각각 HDPs에 처리하여 분석하였다.Adiponectin (APN) and drug (PAC-2) -treated hSCFs culture medium were treated with HDPs to determine cell proliferation and cytotoxicity by PAC-2.
HDPs 생존력은 EZ-Cytox 세포 생존능 분석 키트 (MTT assay, Daeil lab Service, South Korea)를 사용하여 제조자의 지시에 따라 측정하였다. 요약하면, 배양후 24시간이 지난 HDPs에 양성 대조군으로 APN 1, 5, 10 ng/ml를 처리하고, 실험군으로는 PAC-2 (50 μM)를 처리한 hSCFs 배양배지의 함량이 HDPs 배양 배지 부피를 기준으로 10, 25, 50, 100%가 되도록 각각 처리하여 24 시간 및 72 시간 동안 처리하였다. 그 후, EZ-Cytox 용액 (10 ㎕)을 각 웰에 첨가하고, 2 시간 동안 37 ℃에서 배양하였다. 분광 광도계 (Synergy H2, BioTek., VT, USA)를 사용하여 450 nm에서의 흡광도를 측정하였다. 모든 실험을 3 회 수행하고 데이터를 흡광도로 나타내었다.HDPs viability was measured according to the manufacturer's instructions using the EZ-Cytox cell viability assay kit (MTT assay, Daeil Lab Service, South Korea). In summary, HDPs 24 hours after incubation were treated with APN 1, 5, 10 ng / ml as a positive control and the content of hSCFs culture medium treated with PAC-2 (50 μM) 25, 50, and 100%, respectively, and treated for 24 hours and 72 hours, respectively. Then, EZ-Cytox solution (10 占 퐇) was added to each well and cultured at 37 占 폚 for 2 hours. Absorbance at 450 nm was measured using a spectrophotometer (Synergy H2, BioTek., VT, USA). All experiments were performed 3 times and data were expressed as absorbance.
실험 결과, 양성 대조군인 APN과 마찬가지로 본 발명에 따른 화합물인 PAC-2를 처리한 hSCFs 배양 배지는 HDPs의 세포 증식과 관련하여, 증식 혹은 독성을 일으킬 유의성이 나타나지 않았다. 따라서, 본 발명에 따른 화합물의 경우 세포 증식이 아닌, 후술하는 세포 내의 모낭 활성화 인자들의 활성을 촉진시켜 발모 또는 육모 효과를 나타낸다는 것을 확인할 수 있었다. As a result, the culture medium of hSCFs treated with the compound of the present invention, PAC-2, did not show any proliferation or toxicity with respect to cell proliferation of HDPs, as in the positive control APN. Accordingly, it was confirmed that the compound of the present invention promotes the activity of hair follicle activating factors in cells, which will be described later, rather than cell proliferation, thereby exhibiting a hair growth or hair growth effect.
또한, 세포 독성 또한, 정상 대조군과 동등한 수준인 것으로 보아 인체에 유해하지 않은 것을 확인하였다. In addition, the cytotoxicity was also found to be equivalent to that of the normal control, and it was confirmed that it was not harmful to human body.
시험예Test Example 2: 모낭 활성화 인자 발현(Hair growth-related gene expressions) 분석 2: Analysis of hair growth-related gene expressions
실시간 정량 PCR (Real-time quantitative PCR (RT-qPCR))Real-time quantitative PCR (RT-qPCR)
TRIzol 시약 (Life Technologies, Carlsbad, CA, USA)을 사용하여 제조사의 지침에 따라, 상기 실시예 1에서 배양된 모유두 세포로부터 총 RNA를 추출하고, RevertAid 제 1 가닥 cDNA 합성 키트 (Thermo Scientific, Pittsburgh, PA, USA)를 사용하여 상보적인 DNA (cDNAs)를 합성하기 위해, 1μg의 총 RNA를 사용하였다. 약 1 μg의 cDNA 샘플 및 각 TaqMan® 프로브 (Life Technologies, Carlsbad, CA, USA)를 Quantitect Probe PCR 키트 (Qiagen, Valencia, CA, USA)의 반응 혼합물에 희석하고, PCR을 7500 빠른 실시간 PCR 시스템(Fast real-time PCR system) (Life Technologies, Carlsbad, CA, USA)에 의해 수행하였다. 각 TaqMan® 프로브는 다음과 같다: glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Part # 4352339E)이다. 모든 데이터는 GAPDH 대조군에 비해 배수 변화로 나타내며, 세 번의 독립적인 실험에서 얻은 것이다.Total RNA was extracted from the dermal papilla cells cultured in Example 1 using TRIzol reagent (Life Technologies, Carlsbad, Calif., USA) according to the manufacturer's instructions, and the RevertAid first strand cDNA synthesis kit (Thermo Scientific, Pittsburgh, PA, USA) was used to synthesize complementary DNAs (cDNAs). About 1 μg of cDNA sample and each TaqMan® probe (Life Technologies, Carlsbad, Calif., USA) were diluted in the reaction mixture of Quantitect Probe PCR kit (Qiagen, Valencia, CA, USA) Fast real-time PCR system) (Life Technologies, Carlsbad, Calif., USA). Each TaqMan® probe is: glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Part # 4352339E). All data are expressed as a multiple of change compared to the GAPDH control and were obtained from three independent experiments.
성장인자인 IGF-1(유사인슐린 성장인자, Insuline-like growth factor), VEGF(혈관 내피 성장 인자, Vascular endothelial growth factor), HGF(간 세포 성장인자, Hepatocyte groeth factor)를 발현시키는 정도를 표시한 도 2a 내지 2c를 참조하면, IGF-1의 경우 정상 대조군(control)에 비하여 1.5-3배의 발현을 보이고, 양성대조군인 APN을 1, 10 ng/ml로 적용한 것과 비교하여, PAC-2를 처리한 hSCFs 배양배지 함량이 HDPs 배양배지의 부피(ml)를 기준으로 10%인 경우 효과가 다소 저하되었으나, 25, 50 %인 경우 비슷하거나 양성대조군보다 우수한 것으로 나타났다.The expression level of IGF-1 (insulin-like growth factor), VEGF (vascular endothelial growth factor), HGF (hepatocyte growth factor) and hepatocyte growth factor 2A-2C, the expression of IGF-1 was 1.5-3 times higher than that of the normal control, and compared with the application of the positive control APN at 1, 10 ng / ml, PAC-2 In the case of 10% based on the volume (ml) of the HDPs culture medium, the effect of the treated hSCFs culture medium was somewhat lowered, but 25% and 50% of the treated hSCFs culture medium were similar or better than the positive control.
VEGF, 및 HGF의 경우에도, 정상 대조군에 비하여 1.5-3배의 발현을 보이고, 양성 대조군인 APN과 유사하거나(10, 25%), 우수한 것(50%)으로 나타났다.VEGF, and HGF were 1.5-3 times more expressed than the normal control and similar (10, 25%) and superior (50%) to the positive control APN.
반면, 도 2d를 참조하면, 탈모 진행시 활성화되는 인자인 TGF-b1(형질전환 성장인자, Transforming growth factor)의 경우, 정상 대조군과 유사하거나 그보다 낮은 것으로 나타났으며, 특히 농도가 10% 에서 25%로 높아지는 경우 발현 정도가 낮아지는 유의미한 결과를 나타내었다.On the other hand, referring to FIG. 2d, TGF-b1 (transforming growth factor), which is a factor activated during hair loss, is similar to or lower than that of the normal control, %, The expression level was lowered.

Claims (11)

  1. 하기 화학식 1로 표시되는 트리메톡시 페닐 화합물, 이의 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물:Claims 1. A trimethoxyphenyl compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2018010084-appb-I000007
    Figure PCTKR2018010084-appb-I000007
  2. 하기 반응식 1로 표시되며,Represented by the following Reaction Scheme 1,
    하기 화학식 2의 피라논 화합물과 화학식 3의 트리메톡시 페닐 에스테르 화합물을 반응시켜 제조하는 화학식 1의 트리메톡시 페닐 화합물의 제조 방법:A process for producing a trimethoxyphenyl compound of the formula (1), which comprises reacting a pyrazine compound of the formula (2) with a trimethoxyphenyl ester compound of the formula (3)
    [반응식 1][Reaction Scheme 1]
    Figure PCTKR2018010084-appb-I000008
    Figure PCTKR2018010084-appb-I000008
    반응식 1에 있어서, X는 할로겐 원소이고, M은 Li, Na 또는 K이다.In Scheme 1, X is a halogen element and M is Li, Na or K.
  3. 하기 화학식 1로 표시되는 트리메톡시 페닐 화합물, 이의 이성질체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물을 유효 성분으로 포함하는 발모 또는 육모 촉진용 조성물:A composition for promoting hair growth or hair growth comprising an effective component of a trimethoxyphenyl compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2018010084-appb-I000009
    Figure PCTKR2018010084-appb-I000009
  4. 제3항에 있어서,The method of claim 3,
    상기 유효성분의 농도가 조성물 전체 부피를 기준으로 1 내지 100 μM인 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.Wherein the concentration of the active ingredient is 1 to 100 [mu] M based on the total volume of the composition.
  5. 제3항에 있어서, The method of claim 3,
    상기 조성물은 IGF-1, VEGF 및 HGF 중 하나 이상의 인자의 발현을 증가시키는 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.Wherein said composition increases the expression of at least one of IGF-1, VEGF and HGF.
  6. 제3항에 있어서, The method of claim 3,
    상기 조성물은 TGF-b1의 발현을 감소시키는 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.Wherein said composition decreases the expression of TGF-b1.
  7. 제3항에 있어서,The method of claim 3,
    상기 조성물은 약학 조성물인 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.A composition for promoting hair growth or hair growth, wherein the composition is a pharmaceutical composition.
  8. 제3항에 있어서,The method of claim 3,
    상기 조성물은 화장료 조성물인 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.Wherein the composition is a cosmetic composition.
  9. 제3항에 있어서,The method of claim 3,
    상기 조성물은 피부 외용제인 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.Wherein the composition is an external preparation for skin.
  10. 제3항에 있어서,The method of claim 3,
    상기 조성물은 식품 조성물인 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.A composition for promoting hair growth or hair growth, wherein the composition is a food composition.
  11. 제3항에 있어서,The method of claim 3,
    상기 조성물은 비타민 D를 더 포함하는 것을 특징으로 하는 발모 또는 육모 촉진용 조성물.Wherein the composition further comprises vitamin D.
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