KR20210076226A - A composition for prevention or treatment of hair loss comprising piperazine deravitives - Google Patents

Abstract

The present invention relates to a composition for preventing, treating or alleviating hair loss comprising a piperazine derivative or a pharmaceutically acceptable salt thereof as an active component. A compound of the present invention promotes hair growth by converting a resting state of a hair growth cycle to an anagen phase by proliferating dermal papilla cells.

Description

A composition for preventing or treating hair loss comprising a piperazine derivative {A COMPOSITION FOR PREVENTION OR TREATMENT OF HAIR LOSS COMPRISING PIPERAZINE DERAVITIVES}

The present invention relates to a composition for preventing, treating or improving hair loss comprising a piperazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The compound of the present invention promotes hair growth by converting the resting state of the hair growth cycle to the anagen phase by proliferating dermal papilla cells.

Human hair is an aggregate of about 100,000 individual hairs, and hair is produced by hair follicles. The hair follicle serves as a repository of stem cells capable of generating all the cell lines needed to reconstruct the hair follicle itself, the epithelium and the sebaceous glands. Hair follicles are composed of dermal papilla cells (DPC), hair germinal matrix cells, an outer layer of hair follicle cells, an inner layer, and a bulge. In particular, dermal papilla cells are the core cells responsible for the development and growth of hair, and are located at the bottom of the hair root, which is the subcutaneous root of the hair. In fact, when dermal papilla cells are collected from the scalp and transplanted after culturing, new hair grows. However, there are several difficulties in using dermal papilla cells as a treatment for hair loss. First, it is difficult to separate from the scalp, the culture conditions are difficult, and it is difficult to culture a sufficient amount of cells. In addition, there is a limit in that the hair regeneration ability is significantly reduced when a lot of culture.

Hair goes through a three-stage cycle of anagen, catagen, and telogen, where it grows, maintains, and falls out. In the growth period, which is the period of hair growth, in the case of adults, hair grows on average about 0.3 mm per day, grows about 1 cm per month, and it is known that it usually lasts for 3 to 7 years. In general, for 10 to 14 days after the growth phase, overall hair follicle cell apoptosis (apoptosis) occurs and hair follicles are reduced in catagen, which is a stage in which the next growth phase is prepared for an average of 3 months (telogen). The hair falls out after passing through, and the reason the length of the hair is different depending on the part is that the duration of the growth phase, which is a unique characteristic of the hair follicle, is different for each part.

As described above, since human hair has a constant hair growth cycle, a constant number of hairs is always maintained. However, as hair loss progresses, the dermal papilla present in the hair root becomes smaller, and when the dermal papilla becomes smaller, the thickness of the hair becomes thinner, and the hair growth cycle is shortened at the same time. Therefore, as hair loss progresses, the hair becomes very thin, and the hair growth cycle becomes shorter and falls out after a little growth.

It is known that factors such as genetic causes and the action of male hormones, as well as endocrine diseases, nutritional deficiency, drug use, childbirth, fever, and severe physical and mental stress such as surgery, are the causes of hair loss. Recently, as well as male pattern hair loss, due to the increase in stress caused by changes in diet, social environment, etc., the female hair loss population is also increasing, and the age is also decreasing.

Currently, the most frequently used hair loss treatments in Korea include finasteride (trade name: Propecia®), dutasteride (trade name: Avodart®), and minoxidil (minoxidil; trade name: Minoxidil® or Rogaine®). Finasteride and dutasteride are 5α-reductase inhibitors that inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT). However, this product exhibits side effects such as decreased libido, erectile dysfunction, and loss of driving and performance. Meanwhile, in the case of minoxidil, the mechanism has not yet been fully elucidated, but it is a potassium channel opener that hyperpolarizes cell membranes, and through vasodilation and potassium channel opening, provides oxygen, blood, nutrients, etc. to the hair follicles. It is believed to make hair follicles healthy by increasing supply. However, this product also has side effects such as itching, erythema, skin irritation, eye irritation, etc. at the application site, and unwanted hair growth in other parts of the body other than the head is also observed. In addition, although hair transplantation has been recently attempted for patients with severe hair loss, high cost and side effects after the procedure are pointed out as limitations.

G protein-coupled receptor (GPCR) is a structure that spans the cytoplasmic surface and the outer cell surface of the cell membrane or the cell membrane of an intracellular organ and crosses the membrane seven times. There are about 800 to 1000 receptor types in the living body, and they catalyze almost all physiological reactions in the living body. The signaling system of GPCR has been elucidated as a result of many studies. When a ligand or receptor agonist binds to a receptor, the receptor changes its structure. The restructured receptor associates with the G protein, and this contact divides the G protein into a Gα and Gβ-Gγ duplex structure. Each divided substance catalyzes the reaction of secondary messengers within a cell or organ, and various cellular reactions occur by such a chain reaction. An antagonist, a type of receptor agonist, stabilizes the inactivated form of the GPCR.

U.S. Patent No. 6,127,357 discloses a structure and a method for preparing a piperazine derivative and a pharmaceutically acceptable acid addition salt thereof, and refers to a method for treating CNS disorders such as anxiety disorder using the same. In particular, N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide is a piperazine derivative serotonin 5-HT _1A It acts as a Serotonin 5-HT _1A receptor antagonist and as a Dopamine D4 receptor agonist. The 5-HT _1A receptor is the most widely distributed of the 5-HT receptors and mediates inhibitory neurotransmission to the inhibitory G protein-coupled receptors (Gi/Go GPCRs).

However, there have been no studies on the relationship between piperazine derivatives and hair loss.

US Patent Registration No. 6,127,357 (October 3, 2000)

It is an object of the present invention to provide a composition capable of preventing, treating or improving hair loss by inducing the growth phase of the hair growth cycle through proliferation of dermal papilla cells to promote hair thickness and length growth.

The present invention provides a composition for preventing, treating or improving hair loss comprising a piperazine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula I]

In the above formula,

Ring A is cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;

R is hydrogen, hydroxy, halo, alkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkoxy, alkoxyalkyl, or —N(Ra) ₂ ;

Ra is hydrogen or alkyl.

The composition may be a pharmaceutical composition, a cosmetic composition or a food composition.

In one embodiment, the piperazine derivative or a pharmaceutically acceptable salt thereof is used to prevent, treat or improve hair loss by converting the resting state of the hair growth cycle to the anagen phase through dermal papilla cell proliferation so that the hair can grow thicker and longer. can be used

The composition of the present invention promotes hair thickness and length growth by inducing the growth phase of the hair growth cycle through dermal papilla cell proliferation, so it can be usefully used to prevent, treat or improve hair loss due to various causes, and prevent hair loss in the future Or, it may suggest a new direction for research for improvement.

1 is a graph showing the results of dermal papilla cell proliferation according to the treatment concentration of the compound of Formula II.
Figure 2 is a photograph of the hair length before and after culture according to the treatment concentration of the compound of Formula II.
3 is a graph showing the length of hair after culture according to the treatment concentration of the compound of Formula II.
4 and 5 show the degree of hair regeneration according to the application concentration of the compound of Formula II.

Hereinafter, with reference to the accompanying drawings, embodiments and examples of the present invention will be described in detail so that those of ordinary skill in the art to which the present invention pertains can easily carry out. However, the present application may be embodied in various forms and is not limited to the embodiments and examples described herein.

Throughout this specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.

The present invention is characterized in that it was discovered for the first time that the piperazine derivative represented by the formula (I) prevents or treats hair loss or promotes hair growth. In one embodiment, the present invention provides a pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula I]

In the above formula,

Ring A is cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;

R is hydrogen, hydroxy, halo, alkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkoxy, alkoxyalkyl, or —N(Ra) ₂ ;

Ra is hydrogen or alkyl.

In a preferred embodiment, ring A is cycloalkyl; R can be alkyl, halo, or alkoxy.

In a more preferred embodiment, ring A may be cyclohexyl and R may be _{-OCH 3 .}

As used herein, "pharmaceutically acceptable salt" refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. The salt is not particularly limited as long as it is pharmaceutically acceptable, and for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and the like can be used. Preferably, the pharmaceutically acceptable salt may be a maleic acid salt.

The present invention also provides a pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula II as an active ingredient. The compound of formula II has the chemical name "N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide maleate" is referred to as Also referred to herein as "a compound of formula II".

[Formula II]

.

.

"Hair loss" of the present invention, regardless of the cause, refers to a state in which there is no hair in the site where hair should normally exist, and includes alopecia areata, hereditary androgen hair loss, telogen hair loss, traumatic hair loss, hair growth wall, pressure hair loss, It may be, but is not limited to, genital hair loss, alopecia pityis, syphilitic hair loss, seborrheic hair loss, symptomatic hair loss, scarring hair loss, or congenital hair loss.

The compound of Formula I or the compound of Formula II of the present invention promotes proliferation of dermal papilla cells to induce hair growth phase, thereby exhibiting a hair loss prevention or treatment effect.

"Treatment" of the present invention is to improve hair loss symptoms by delaying or stopping hair loss by administration of the composition of the present invention, or to beneficially change hair loss symptoms such as hair growth and hair growth promotion, such as lengthening or increasing the number of hair means all actions.

The pharmaceutical composition of the present invention may be administered parenterally or orally according to a desired method, and the dosage may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, etc. Its scope is diverse. In addition, the therapeutically effective amount of the composition may vary depending on the administration method, the target site, and the condition of the patient, and when used in the human body, the dosage should be determined as an appropriate amount in consideration of both safety and efficiency.

In one embodiment, the pharmaceutical composition of the present invention is an oral dosage form such as powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, and aerosols, ointments, creams, etc., according to a conventional method, respectively. , suppositories, injections, and sterile injection solutions may be formulated and used in any form suitable for pharmaceutical preparations.

It may further include excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, diluents, etc. commonly used for the formulation. For example, excipients that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, and the like may be used, but is not limited thereto. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

The present invention also provides a cosmetic composition for preventing or improving hair loss comprising the compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the cosmetic composition may be, for example, a cosmetic for hair, the formulation thereof is not particularly limited, and may be appropriately selected according to the purpose.

For example, the cosmetic composition is formulated as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray. may be, but is not limited thereto. More specifically, it may be a cleaning agent such as shampoo, conditioner, and body cleanser, hair dressing agent such as hair tonic, gel or mousse, and a cosmetic composition for hair such as a hair conditioner or hair dye.

In one embodiment of the present invention, the cosmetic composition may contain various suitable bases and additives as necessary, and the types and amounts of these components can be easily selected by the inventor. It may contain acceptable additives as necessary, for example, may further include components such as preservatives, pigments, and additives conventional in the art.

In another embodiment, the present invention also provides a food composition for preventing or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, for example, a health functional food. The "health functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body, and "functionality" means a health purpose such as regulating nutrients or physiological action with respect to the structure and function of the human body. It means to consume for the purpose of obtaining a useful effect.

The formulation of the food composition is not particularly limited, but, for example, may be formulated as tablets, granules, powders, liquids such as drinks, caramel, gels, bars, and the like. In addition to the active ingredient, the food composition of each dosage form can be formulated without difficulty by those skilled in the art without difficulty depending on the dosage form or purpose of use of ingredients commonly used in the field.

Justice

Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Moreover, numerical values recited herein are intended to include the meaning of “about” unless explicitly stated otherwise. Definitions of residues and substituents as used herein are provided below. Unless otherwise specified, each residue has the following definitions and is used in the sense commonly understood by one of ordinary skill in the art.

"Alkyl" as used herein is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms, substituted or unsubstituted, and saturated aliphatic, which may be straight chain, branched, cyclic, or combinations thereof. includes the group. For example, an alkyl group may have 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ alkyl), 1 to 10 carbon atoms (ie, C ₁ -C ₁₀ alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C ₁ -C ₆ alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to _{C 1} -C _{6 alkyl.} Examples of suitable alkyl groups include methyl (Me, —CH ₃ ), ethyl (Et, —CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, —CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i -Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl ( t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl ( -CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH _{3 )} )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl ( -CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (- CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C( CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), and octyl (-(CH ₂ ) ₇ CH ₃ ). may be, but is not limited thereto.

Moreover, the term “alkyl” as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-tri refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as fluoroethyl, and the like.

As used herein, the term "C _xy " or "C _x -C _y ", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, includes x to y carbons in the chain. It is considered to include groups containing For example, a (C ₁ -C ₆ )alkyl group contains 1 to 6 carbon atoms in the chain.

The term "alkenyl," as used herein, has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and has one or more regions of unsaturation. , that is, a hydrocarbon with a ^{carbon-carbon sp 2 double bond.} For example, an alkenyl group has 2 to 20 carbon atoms (ie, C ₂ -C ₂₀ alkenyl), 2 to 12 carbon atoms (ie, C ₂ -C ₁₂ alkenyl), 2 to 10 carbon atoms ( ie, C ₂ -C ₁₀ alkenyl), or 2 to 6 carbon atoms (ie, C ₂ -C ₆ alkenyl). Examples of suitable alkenyl groups include vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), cyclopentenyl (-C ₅ H ₇ ), and 5-hexenyl (-CH ₂ CH ₂ CH). ₂ CH ₂ CH=CH ₂ ), but is not limited thereto.

The term "alkynyl," as used herein, has primary, secondary, tertiary and/or quaternary carbon atoms, and includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more carbon- It is a hydrocarbon with a carbon sp triple bond. For example, an alkynyl group has 2 to 20 carbon atoms (ie, C ₂ -C ₂₀ alkynyl), 2 to 12 carbon atoms (ie, C ₂ -C ₁₂ alkynyl), 2 to 10 carbon atoms ( ie, C ₂ -C ₁₀ alkynyl), or 2 to 6 carbon atoms (ie, C ₂ -C ₆ alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic _{(-C≡CH) and propargyl (-CH 2 C≡CH).}

As used herein, the term “halo” means halogen and includes chloro, fluoro, bromo, and iodo.

The term “cycloalkyl,” as used herein, refers to a non-aromatic, saturated or unsaturated, monovalent or divalent ring, which may be monocyclic, bicyclic or polycyclic and wherein each atom of the ring is carbon. A cycloalkyl group can have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be fused ring systems, spirocyclic ring systems or bridged ring systems. In exemplary cycloalkyl groups, the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In certain embodiments, cycloalkyl contains 3 to 20 atoms, or 3 to 10 atoms, or more preferably 3 to 7 atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Unless otherwise specified, cycloalkyl may be substituted by one or more substituents described herein.

As used herein, the term "heterocycloalkyl" means that the ring structure is at least one heteroatom (eg, N, O, or S), preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms. refers to a substituted or unsubstituted, monovalent or divalent, saturated or partially saturated non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, comprising do. The term "heterocycloalkyl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heterocyclic, e.g. For example the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. Bicyclic and polycyclic heterocyclic ring systems may be fused, bridged, or spiro ring systems. Substituted heterocycles include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, carbonyl groups. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like. Further exemplary heterocyclos include dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidinyl, 4- piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, Acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl , quinuclidinyl, morpholinyl, and oxazolidinyl, each of which may be substituted or unsubstituted.

As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic or polycyclic, substituted or unsubstituted 1 containing one or more heteroatoms (eg, N, O, or S) in the ring. refers to a valent or divalent aromatic group. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur and nitrogen. In polycyclic heteroaryl ring systems, the ring system has at least two cyclic rings in which at least two carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. A heteroaryl group is, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like, each of which may be substituted or unsubstituted.

As used herein, the term “aryl” includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic or polycyclic. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring. An aryl group can be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein one or more of the rings are aromatic, e.g., the other cyclic rings are cycloalkyl , cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. Aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.

"Alkoxy" as used herein refers to a group having the formula -O-alkyl, wherein the alkyl group as defined above is attached to the parent compound through an oxygen atom. The alkyl moiety of the alkoxy group may be, for example, 1 to 20 carbon atoms (ie C ₁ -C ₂₀ alkoxy), 1 to 12 carbon atoms (ie C ₁ -C ₁₂ alkoxy), 1 to 10 carbon atoms. (ie C ₁ -C ₁₀ alkoxy), or 1 to 6 carbon atoms (ie C ₁ -C ₆ alkoxy). Examples of suitable alkoxy groups include methoxy (-O-CH ₃ or -OMe), ethoxy (-OCH ₂ CH ₃ or -OEt), and t-butoxy (-OC(CH ₃ ) ₃ or -O-tBu ), but is not limited thereto.

The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula -alkyl-O-alkyl.

또는

(여기서, R₉, R₁₀ 및 R는 각각 독립적으로 수소 또는 히드로카르빌 기를 나타내거나, 또는 R₉ 및 R₁₀은 이들이 부착된 N 원자와 함께 고리 구조 내에 4 내지 8개의 원자를 갖는 헤테로사이클을 형성함)로 표시될 수 있는 잔기를 지칭하는 것으로 당업계에서 인정된다. 특정 실시양태에서, 아미노는 -NH₂이다.As used herein, the terms “amine” and “amino” refer to unsubstituted and substituted amines and salts thereof, e.g.

or

(wherein R ₉ , R ₁₀ and R each independently represent a hydrogen or a hydrocarbyl group, or R ₉ and R ₁₀ together with the N atom to which they are attached represent a heterocycle having 4 to 8 atoms in the ring structure It is recognized in the art to refer to a residue that may be represented by In certain embodiments, amino is —NH ₂ .

As used herein, the term “substituted” refers to a particular moiety of a compound of the present invention having one or more substituents. The term "substituted" with respect to alkyl, heterocycloalkyl, etc., for example "substituted alkyl" or "substituted heterocycloalkyl" means that one or more hydrogen atoms of the alkyl or heterocycloalkyl are each independently replaced by a non-hydrogen substituent. meant to be replaced.

The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[Example 1]

Measurement of proliferation of dermal papilla cells

In order to confirm the effect of the compound of the present invention on the proliferation of dermal papilla cells, cell proliferation was analyzed after treatment with the dermal papilla cells.

2x10 ³ dermal papilla cells were inoculated into a 96-well plate, and 24 hours later, the compound of Formula II was treated at concentrations of 1 nM, 10 nM, 100 nM, 1 μM, 10 μM and 50 μM, respectively, for 72 hours. Thereafter, the medium was removed and the cells were treated with a 10% CCK-8 solution for 2 hours using a CCK-8 assay kit (Dojindo, Japan), and then the absorbance was measured at 450 nm to determine the number of cells.

As a result, as shown in FIG. 1, when the dermal papilla cells were treated with the compound of Formula II, cell proliferation was increased compared to the control group not treated therewith. In particular, the proliferation of cells treated with 100 nM was increased by 20% or more compared to the control group.

From this, it was confirmed that the compound of the present invention is effective for the proliferation of dermal papilla cells.

[Example 2]

Measurement of hair growth effect

In this example, it was attempted to confirm the hair growth effect of the compound of the present invention in actual hair follicles. To this end, the length of hair grown by treating the compound of Formula II in mustache hair follicles was measured.

Observation under a dissecting microscope, anagen vibrissa follicles were carefully isolated. Add Williams E medium supplemented with 2 mM L-glutamine, 10 µg/mL insulin, 10 ng/mL hydrocortisone, 100 U/mL penicillin, and serum-free 100 µg/mL streptomycin to each well of a 48-well plate, Separated hair follicles were put one by one and incubated at _{37 °C, 5% CO 2 incubator.} Compounds of formula II were treated at concentrations of 0.1 μM, 1 μM and 10 μM. After culturing for 72 hours, individual hair follicles were photographed (Edmund Optics Ltd, UK). The length of about 8 to 10 mustache hairs grown from the hair follicles was measured and the average value thereof was obtained.

As a result, as shown in FIGS. 2 and 3, when the hair follicles were treated with the compound of Formula II, the length of the mustache hair was increased compared to the control group not treated therewith. In particular, the length of hair grown in hair follicles treated with 0.1 μM was 1.5 times or more that of the control group.

From this, it was confirmed that the compound of the present invention is effective for hair growth in actual hair follicles.

[Example 3]

Confirmation of hair growth promoting effect in experimental animals

Since it was confirmed through Examples 1 and 2 that the compound of the present invention promotes the proliferation of dermal papilla cells and is effective for hair growth, in this Example, when the compound of the present invention is actually administered in vivo, the hair cycle is in the telogen phase. It was confirmed whether it was induced to the growth phase (anagen) and exhibited an actual hair growth promoting effect. To this end, in this example, an animal experiment was performed to confirm the growth of hair, and the weight of the grown hair was measured.

After hair removal on the back of 6-week-old female C3H/HeN mice, which is a telogen-to-anagen transition model in the telogen phase of the hair growth cycle, 100 uL of the compound of Formula II was added in 0.0005% and 0.005% concentration was applied. Skin darkening, which is a sign that can confirm that the hair growth phase was induced, was monitored, and after 14 days, newly grown hair was pushed on the back and the degree of hair regeneration was examined.

As a result, as shown in FIGS. 4 and 5, it was confirmed that the hairs on the back of the rats coated with the compound of Formula II grew more and covered the back compared to the control group that did not apply the compound of Formula II. Through this, it was confirmed that the compound of Formula II plays a role in inducing the telogen hair into the anagen phase. In addition, the weight of the hair of mice coated with the compound of Formula II was increased by more than 5 times compared to the control group.

From this, it was confirmed that the compound of the present invention exhibits an actual hair growth promoting effect.

Claims (9)

A pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula I]

In the above formula,
Ring A is cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;
R is hydrogen, hydroxy, halo, alkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkoxy, alkoxyalkyl, or —N(Ra) ₂ ;
Ra is hydrogen or alkyl.
2. The compound of claim 1 wherein ring A is cycloalkyl; R is alkyl, halo, or alkoxy.
The pharmaceutical composition according to claim 1, wherein ring A is cyclohexyl and R is -OCH _{3 .}
The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is a maleic acid salt.
A pharmaceutical composition for preventing or treating hair loss comprising a compound of Formula II as an active ingredient:
[Formula II]

.
The hair loss according to any one of claims 1 to 5, wherein the hair loss is alopecia areata, hereditary androgen hair loss, telogen hair loss, traumatic hair loss, hair growth wall, pressure hair loss, anagen phase hair loss, alopecia areata, syphilitic hair loss, seborrheic hair loss , A pharmaceutical composition that is selected from the group consisting of symptomatic alopecia, scarring alopecia or congenital alopecia.
The pharmaceutical composition according to any one of claims 1 to 5, wherein the compound of Formula I or the compound of Formula II promotes proliferation of dermal papilla cells to induce hair growth phase.
A cosmetic composition for preventing or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula I]

In the above formula,
Ring A is cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;
R is hydrogen, hydroxy, halo, alkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkoxy, alkoxyalkyl, or —N(Ra) ₂ ;
Ra is hydrogen or alkyl.
A food composition for preventing or improving hair loss comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula I]

In the above formula,
Ring A is cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;
R is hydrogen, hydroxy, halo, alkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkoxy, alkoxyalkyl, or —N(Ra) ₂ ;
Ra is hydrogen or alkyl.

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