Use of compound

Abstract

Provided is the use of a compound. The compound comprises: two or more peptide bonds (Y), wherein Y is represented by formula (I); two end groups (A) respectively located at two ends of the backbone of the compound, each independently being a substituted or unsubstituted C1-6 alkyl group or a substituted or unsubstituted phenyl group; and a plurality of linking groups (X), each independently being selected from the group consisting of formula (II), formula (III), and substituted or unsubstituted formula (IV), wherein every two of the peptide bonds are separated by at least one of the linking groups.

Description

Uses of compounds

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese Patent Application No. 2025100950587, filed in China on January 21, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the field of pharmaceutical technology, specifically to the use of a compound. Background Technology

[0004] According to data from the National Health Commission, more than 250 million people in my country suffer from hair loss, meaning that one in six people is troubled by it. Of these, approximately 163 million are men and 88 million are women. Hair loss disorders include androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, and immunodeficiency alopecia. Androgenetic alopecia (AGA), also known as seborrheic alopecia, is the most common type of hair loss clinically, accounting for over 80% of hair loss patients, especially prevalent in men. The main characteristic of AGA is the gradual miniaturization of hair follicles, leading to reduced hair density, thinning hair, and ultimately, the formation of scarless bald patches. This pattern of hair loss manifests as progressively worsening hair loss on the forehead and crown in men, while in women it presents as progressive or diffuse hair loss on the crown. This severely impacts patients' quality of life, causing significant mental stress and psychological burden. Androgens play a key role in the pathogenesis of AGA. Dihydrotestosterone (DHT) is a form of androgen that acts on hair follicles in specific areas of the scalp, causing follicle degeneration and atrophy, thereby triggering hair loss.

[0005] With the increasing number of people experiencing hair loss, consumers are paying more attention to scalp care, leading to a continuous increase in demand for hair loss prevention and hair regrowth products, resulting in a booming market for topical hair loss prevention and hair regrowth products. Currently, minoxidil is a first-line topical medication for treating androgenetic alopecia, primarily stimulating hair growth by promoting scalp blood circulation and the release of hair follicle growth factors. However, it has side effects such as scalp irritation causing erythema and itching, a period of rapid hair loss in the initial stage of use, and recurrence of the condition after discontinuation. Hair transplant surgery also carries risks such as postoperative infection and low hair follicle survival rate. In addition, some emerging therapies, such as microneedling and mesotherapy, are characterized by high costs, high technical requirements, and varying effectiveness among individuals. These treatment options have many limitations, seriously affecting patient treatment effectiveness, compliance, and user experience.

[0006] Therefore, there is an urgent need to develop a low-risk, high-return drug composition or preparation for preventing hair loss and promoting hair growth. Summary of the Invention

[0007] The embodiments disclosed herein address at least one of the problems of the related art in the following aspects.

[0008] The first aspect of this disclosure provides the use of a compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs in the preparation of a medicament for the prevention, treatment, or relief of hair loss, wherein...

[0009] The compound comprises:

[0010] Two or more peptide bonds (Y), where Y is ;

[0011] The two end groups (A) located at opposite ends of the main chain of the compound are each independently a substituted or unsubstituted C group. 1-6 Alkyl or substituted or unsubstituted phenyl groups, preferably halogenated; and

[0012] Multiple linking groups (X), each X independently selected from the group consisting of: , and replaced or unreplaced ;

[0013] Each pair of peptide bonds is separated by at least one linker group.

[0014] In some embodiments, the substituent is a halogen.

[0015] In some embodiments, the hair loss disease is selected from the group consisting of: androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, and immunodeficiency alopecia.

[0016] In some embodiments, the compound further comprises one or more, preferably one to three, more preferably one ester group (B), wherein B is... .

[0017] In some embodiments, the compound comprises two to four, preferably two to three, the linking groups.

[0018] In some embodiments, the compound comprises two to four, preferably two, peptide bonds.

[0019] In some embodiments, the compound has a structure selected from the group consisting of:

[0020] AYXXBXYA, ABXXYXYA and AXXYXYA.

[0021] In some embodiments, the compound is selected from: asperphenamate, aurantiamide acetate, aurantiamide benzoate, and aurantiamide (TMC-58B).

[0022] The second aspect of this disclosure provides the use of the composition in the preparation of a medicament for the prevention, treatment, or relief of hair loss, wherein...

[0023] The composition comprises:

[0024] The compounds, stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, according to any embodiment of the first aspect of this disclosure; and

[0025] Choose any excipients that are selected from the following groups: pharmaceutically acceptable excipients, cosmetically acceptable excipients, food-acceptable excipients, and health product-acceptable excipients.

[0026] In some embodiments, the composition may also contain other medications for the prevention, treatment, or relief of hair loss.

[0027] In some embodiments, the composition is in the form of an ointment, plaster, lotion, gel, spray, skin patch, powder, granules, capsule, tablet, solution, suspension, syrup, suppository, or injection.

[0028] In some embodiments, based on the total mass of the composition, the composition comprises:

[0029] 0.0025-5% of the compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs of any embodiment of the first aspect of this disclosure.

[0030] 50-70% ethanol, and

[0031] 30-50% propylene glycol.

[0032] The third aspect of this disclosure provides a method for preventing, treating, or alleviating hair loss, comprising administering to a subject a therapeutically effective amount of a compound or stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, or a composition of any embodiment of the first aspect of this disclosure.

[0033] In some embodiments, the hair loss disease is selected from the group consisting of: androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, and immunodeficiency alopecia.

[0034] In some embodiments, the method includes administering the composition to a subject via: skin application, transdermal application, oral application, subcutaneous injection, intraperitoneal application, intravenous, intramuscular or intrathecal injection, sublingual application, buccal application, rectal insertion, vaginal insertion, ocular application, ear application, or nasal application.

[0035] Compared with related technologies, the embodiments of this disclosure achieve at least the following beneficial effects:

[0036] This disclosure presents a compound derived from a natural product that has anti-hair loss and hair growth effects, an anti-hair loss and hair growth composition containing this group of compounds as active ingredients, and a method for preparing the same. This compound is isolated and extracted from a natural product, has low toxicity and side effects, high safety, and no significant skin irritation.

[0037] As demonstrated in the specific embodiments of this disclosure, the compositions of the embodiments of this disclosure have the effects of promoting hair growth, enhancing hair quality, improving hair loss symptoms and regulating the scalp environment, and no excessive shedding phase was observed, and no recurrence of hair loss was observed after discontinuation of use. Attached Figure Description

[0038] To more clearly illustrate the technical solutions in the embodiments of this disclosure, the accompanying drawings used in the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of this disclosure. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0039] Figure 1 shows the growth of new hair after treatment with the compounds acrylamide ester, aurora amide ester, aurora amide ester benzoate, and aurora piperamide acetate in a mouse model of androgenetic alopecia (AGA). Figure 1A shows skin photographs of the test area on the back of mice from day 0 to day 18 after hair removal. Figure 1B is a bar chart of the average length of new hair in the test area of ​​mice on day 18 (taken from 5 fixed locations with evenly distributed hair, one time for each location and recorded).

[0040] To facilitate understanding of this disclosure, the implementation process of this disclosure will be further explained below with reference to specific implementation examples. These descriptions are only for further illustrating the features and advantages of this disclosure, and are not intended to limit the scope of the invention claims. Embodiments of the present invention

[0041] The present disclosure will be further described in detail below with reference to specific embodiments. The embodiments given are only for illustrating the present disclosure and are not intended to limit the scope of the present disclosure. The embodiments provided below can serve as a guide for those skilled in the art to make further improvements and do not constitute a limitation on the present disclosure in any way.

[0042] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0043] The first aspect of this disclosure provides the use of a compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs in the preparation of a medicament for the prevention, treatment, or relief of hair loss.

[0044] The compound said compound comprises:

[0045] Two or more peptide bonds (Y), where Y is ;

[0046] The two end groups (A) located at opposite ends of the main chain of the compound are each independently a substituted or unsubstituted C group. 1-6 Alkyl or substituted or unsubstituted phenyl; and

[0047] Multiple linking groups (X), each X independently selected from the group consisting of: , and replaced or unreplaced ;

[0048] Each pair of peptide bonds is separated by at least one linker group.

[0049] In some embodiments, the substituent is a halogen.

[0050] Understandably, halogens are selected from one or more of fluorine, chlorine, bromine, and iodine.

[0051] In this document, the term "alkyl" refers to a saturated hydrocarbon group, including both straight-chain and branched structures. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and hexyl (e.g., n-hexyl, isohexyl, tert-hexyl). In various embodiments, C 1-6 Alkyl groups can contain 1 to 6 carbon atoms.

[0052] In some embodiments, instead A benzene ring substituted with one or more halogens .

[0053] In some embodiments, instead A halogen is substituted at the para, ortho, or meta position on the benzene ring. .

[0054] In some embodiments, instead The benzene ring has a halogen substituent at the para position. .

[0055] In some embodiments, the hair loss disease is selected from the group consisting of: androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, and immunodeficiency alopecia.

[0056] In some embodiments, the compound further comprises one or more, preferably one to three, more preferably one ester group (B), wherein B is... .

[0057] In some embodiments, the compound comprises two to four, preferably two to three, the linking groups.

[0058] In some embodiments, the compound comprises two to four, preferably two peptide bonds.

[0059] In some embodiments, the compound has a structure selected from the group consisting of: AYXXBXYA, ABXXYXYA, and AXXYXYA.

[0060] In some embodiments, the compound is selected from: asperphenamate, aurantiamide acetate, aurantiamide benzoate, and aurantiamide (TMC-58B).

[0061] The compounds arbutin ester, auramidool ester, auramidool ester benzoate, and orange-yellow piperamide acetate are all derived from natural products and can be extracted from various edible and medicinal plants and fungi. These compounds have similar molecular structures and possess a wide range of biological activities and pharmacological effects, including anti-inflammatory, antitumor, antioxidant, antibacterial, antifibrotic, cell-protective, and immunomodulatory effects.

[0062] The inventors of this disclosure have unexpectedly discovered that compounds arbutin ester, golden amide alcohol ester, golden amide alcohol ester benzoate, and orange-yellow piperamide acetate can effectively promote hair growth, enhance hair quality, improve the scalp environment, and have good safety and long-term efficacy.

[0063] Asperphenamate:

[0064] Aspergillus ester is a dipeptide compound and a metabolite of various fungi, including Penicillium and Aspergillus. Trace amounts of aspergillus ester can also be extracted from barley (Hordeum vulgare L.) buds and Saururus chinensis (Lour.) Baill. (Saururaceae family). Related studies have shown that aspergillus ester exhibits potential applications in anti-tumor, anti-fibrotic, anti-neuroinflammatory, and hypoglycemic fields.

[0065] In some embodiments of this disclosure, arbutin esters have the structure shown in formula (I).

[0066]

[0067] Formula (I)

[0068] Aurantiamide acetate:

[0069] Aureomycinol esters are dipeptide compounds that can be isolated from various edible and medicinal plants, including *Viola phillipina* (Violacea genus), *Portulaca oleracea* (Portulaca genus), *Brassica juncea* (Brassica juncea genus), and *Potentilla griffithii var. velutina Cardot* (Potentilla griffithii var. velutina Cardot). Aureomycinol esters possess anti-inflammatory, antitumor, and antioxidant effects. Their potential mechanisms include reducing nerve damage, inflammatory responses, and promoting apoptosis, and they are widely used in research on inflammatory diseases.

[0070] In some embodiments of this disclosure, the golden amide alcohol ester has the structure shown in formula (II).

[0071]

[0072] Equation (II)

[0073] Aurantiamide benzoate:

[0074] Aureomycin benzoate is a dipeptide derivative derived from the Lamiaceae plants *Cunila spicata* and *Hyptis fasciculata*, possessing anti-inflammatory, antibacterial, antioxidant, and uric acid-lowering effects. Aureomycin benzoate is widely used in research on inflammatory diseases and has the potential to be developed into a novel xanthine oxidase inhibitor.

[0075] In some embodiments of this disclosure, the golden amide alcohol ester has the structure shown in formula (III).

[0076]

[0077] Equation (III)

[0078] Aurantiamide (TMC-58B):

[0079] Orange-yellow piperamide acetate is a dipeptide compound that can be isolated and extracted from plants such as Zanthoxylum dissitum Hemsl. (Rutaceae), Pulsatilla cernua (Thunb.) Bercht. & J. Presl (Ranunculaceae), Duhaldea cappa (Buchanan-Hamilton ex D. Don) Pruski & Anderberg (Asteraceae), and Catunaregam spinosa (Thunb.) Tirveng. (Rubiaceae). Orange-yellow piperamide acetate possesses anti-inflammatory, antioxidant, antitumor, and antiplatelet effects, and studies have shown that it has potential therapeutic effects on neurodegenerative diseases.

[0080] In some embodiments of this disclosure, orange-yellow piperamide acetate has the structure shown in formula (IV).

[0081]

[0082] Formula (IV)

[0083] In some embodiments of this disclosure, the compound is selected from the group consisting of:

[0084] , ,

[0085] .

[0086] A second aspect of this disclosure provides the use of a composition in the preparation of a medicament for the prevention, treatment, or relief of hair loss, the composition comprising:

[0087] The compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs in any of the embodiments of the first aspect above; and

[0088] Choose any excipients that are selected from the following groups: pharmaceutically acceptable excipients, cosmetically acceptable excipients, food-acceptable excipients, and health product-acceptable excipients.

[0089] In some embodiments, the composition may also contain other medications for the prevention, treatment, or relief of hair loss.

[0090] In some embodiments, the composition is in the form of an ointment, plaster, lotion, gel, spray, skin patch, powder, granules, capsule, tablet, solution, suspension, syrup, suppository, or injection.

[0091] In some embodiments, based on the total mass of the composition, the composition comprises:

[0092] 0.0025-5% of the compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs in any of the first aspects described above.

[0093] 50-70% ethanol, and

[0094] 30-50% propylene glycol.

[0095] The third aspect of this disclosure provides a method for preventing, treating, or alleviating hair loss by administering to a subject a therapeutically effective amount of a compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs from any of the embodiments of the first aspect above, or a composition from any of the embodiments of the second aspect above.

[0096] In some embodiments, the hair loss disease is selected from the group consisting of: androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, and immunodeficiency alopecia.

[0097] In some embodiments, the method includes administering the composition to a subject via: skin application, transdermal application, oral application, subcutaneous injection, intraperitoneal application, intravenous, intramuscular or intrathecal injection, sublingual application, buccal application, rectal insertion, vaginal insertion, ocular application, ear application, or nasal application.

[0098] Throughout this specification, when a section “comprises” / “contains” a component, unless otherwise expressly stated, it means that it may also include other components rather than excluding them. When permissible manufacturing and material tolerances (which are inherent in their meaning) are presented, the terms “about” or “substantially” are used in or near numerical values. These terms are intended to prevent unscrupulous infringers from improperly using the disclosure, where accurate or absolute values ​​are cited to aid in understanding embodiments of this disclosure.

[0099] Throughout the specification, the term "combination thereof" included in the Markush-type expression refers to a mixture or combination of one or more of the groups of components described in the Markush-type expression, that is, one or more of the groups of components.

[0100] The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and hindered isomers.

[0101] The term "prodrug" refers to a compound that is converted in vivo into the compound provided in the embodiments of this disclosure. Such conversion can be affected, for example, by hydrolysis of the prodrug form in the blood or by enzymatic conversion to the parent form in the blood or tissues.

[0102] The term "metabolite" refers to a product produced in the body by the metabolism of a particular compound or its salts. Metabolites of compounds can be identified using conventional techniques known in the art, and their activity can be determined using tests such as those described herein. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the applied compound. Therefore, embodiments of this disclosure include metabolites of the compounds disclosed herein, including metabolites produced by exposing the compounds disclosed herein to mammals for a sufficient period of time.

[0103] The term "pharmaceutically acceptable salt" refers to the organic or inorganic salt of the compounds disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19, which is incorporated herein by reference. Some non-limiting examples of pharmaceutically acceptable and non-toxic salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glycerophosphate, glucuronate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, picrate, neopentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salt.

[0104] The term "solvate" refers to the association or complex of one or more solvent molecules with a compound disclosed herein. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, and mixtures thereof. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0105] When the solvent is water, the term "hydrate" may be used. In one embodiment, one water molecule associates with one molecule of the compound disclosed herein, such as a hydrate. In another embodiment, more than one water molecule may associate with one molecule of the compound disclosed herein, such as a dihydrate. In yet another embodiment, fewer than one water molecule may associate with one molecule of the compound disclosed herein, such as a hemihydrate. Furthermore, all solvates of the embodiments of this disclosure retain the bioavailability of the non-hydrated forms of the compounds disclosed herein.

[0106] In this disclosure, "hair loss" refers to the absence of hair in areas where hair normally grows, specifically the loss of hair at the ends of the scalp. The causes of hair loss are not limited, and include, for example, androgenetic alopecia (seborrheic alopecia), alopecia areata, cicatricial alopecia, telogen effluvium, nutritional alopecia, drug-induced alopecia, traumatic alopecia, immunodeficiency alopecia, and folliculitis alopecia.

[0107] The term "androgenetic alopecia," also known as seborrheic alopecia or premature baldness, refers to a type of hair loss induced by excessive sebum secretion. It is often accompanied by increased dandruff, oily scalp, and significant itching. This type of hair loss typically begins at the top of the head and gradually spreads outwards, eventually potentially leading to the complete loss of hair on the forehead and crown. It primarily occurs in young adults with high sebum production. The clinical manifestations of seborrheic alopecia vary depending on gender and the severity of the condition: men mainly experience a receding hairline, forming an M-shaped pattern of baldness; the hair on the crown gradually thins and becomes thinner, potentially eventually forming a U-shaped pattern. Some patients experience oily hair, increased dandruff, and itchy scalp, or may have rashes. Women mainly experience progressive thinning and reduction of hair on the crown, with a smaller percentage experiencing diffuse hair loss.

[0108] The term "subject" refers to a person who needs treatment for a disease, and in a more specific embodiment, it refers to a mammal, such as a human or non-human primate, mouse, rat, dog, cat, horse, or cow.

[0109] In the embodiments of this disclosure, “prevention” refers to all actions involving suppressing or delaying the onset of an expected disease, “treatment” refers to all actions involving improving or beneficially altering the disease and its metabolic abnormalities by applying a composition according to the embodiments of this disclosure, and “mitigation” refers to all actions involving reducing parameters (e.g., the severity of symptoms) associated with the expected disease by applying a composition according to the embodiments of this disclosure.

[0110] In this disclosure, “application” means providing a subject with the given composition of this disclosure by any appropriate method.

[0111] The compositions according to embodiments of this disclosure are administered in a pharmaceutically effective amount. As used herein, a "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment, and an effective dose can be determined by parameters including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment and concurrent drugs, as well as other parameters well known in the medical field.

[0112] The terms "effective amount" and "effective dose" generally refer to the amount sufficient to produce the therapeutic effect, where the exact dose varies depending on the specific symptoms of the disease being treated. When the disease is hair loss, its manifestations typically include, but are not limited to, increased hair growth rate, increased hair density, improved hair quality, and improved scalp environment.

[0113] The effective amounts of the compounds arbutin ester, auramidool ester, auramidool ester benzoate, and orange-yellow piperamide acetate in the embodiments of this disclosure can depend on the species, weight, age, and individual condition of the subject, and can be determined by standard procedures such as cell culture or laboratory animals.

[0114] The compounds arbutin ester, golden amide alcohol ester, golden amide alcohol ester benzoate, and orange-yellow piperamide acetate of the present disclosure embodiments can exist in solid, semi-solid, or liquid form.

[0115] The compounds arbutin ester, golden amide alcohol ester, golden amide alcohol ester benzoate, and orange-yellow piperamide acetate contained in the embodiments of this disclosure can be prepared into powder form by additional processes such as vacuum distillation and freeze drying or spray drying for addition to various composition dosage forms.

[0116] The compounds arbutin ester, auramidool ester, auramidool ester benzoate, and orange-yellow piperamide acetate of the present disclosure embodiments can be administered to subjects via routes including but not limited to topical application and oral administration.

[0117] In the embodiments of this disclosure, a group of anti-hair loss and hair growth compositions of this disclosure may not only contain the above-mentioned compounds as active ingredients, such as arbutin ester, aurora amide alcohol ester, aurora amide alcohol ester benzoate, and orange-yellow piperamide acetate, but may also contain commonly used ingredients in anti-hair loss and hair growth compositions, such as water, diluent, antioxidant, stabilizer, solubilizer, colorant, surfactant, preservative, vitamin, and fragrance, as well as conventional additives and carriers.

[0118] The compositions of the present disclosure embodiments can be prepared into related pharmaceutical and cosmetic compositions, including dosage forms such as hair growth liquid, scalp care agent, scalp nourishing liquid, shampoo, ointment, gel, cream, patch and spray, but are not limited thereto.

[0119] The compositions according to embodiments of this disclosure also include suitable carriers, excipients, and diluents commonly used in the preparation of pharmaceutical compositions. The excipients may be one or more selected from, for example, the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film coating materials, and controlled-release additives.

[0120] The compositions according to embodiments of this disclosure can be formulated and used in the following forms according to conventional methods: powders, granules, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, lozenges, pills, capsules, hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, granules, sustained-release granules, enteric-coated granules, powders, dry extracts, liquids, suspensions, soft extracts, fluid extracts, lemonade, or topical preparations, such as aromatic waters, oils, liniments, tinctures, inhalers, elixirs, injections, infusions, sterile injections, eye drops, ointments, lotions, pastes, sprays, patches, or aerosols, and the topical preparations can be formulated as creams, gels, patches, sprays, ointments, plasters, lotions, liniments, pastes, or poultices.

[0121] The carriers, excipients, and diluents that may be included in the pharmaceutical compositions according to embodiments of the present disclosure may include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil.

[0122] In the case of formulations, commonly used diluents or excipients such as fillers, thickeners, binders, wetting agents, disintegrants, and surfactants can be used to prepare compositions according to embodiments of this disclosure.

[0123] The suspension according to embodiments of this disclosure may contain suspending agents such as gum arabic, tragacanth gum, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropyl methylcellulose (HPMC), HPMC 1828, HPMC 2906 or HPMC 2910, and may also contain surfactants, preservatives, stabilizers, colorants or fragrances if desired.

[0124] For topical application to the skin, the compounds disclosed herein can be formulated into suitable forms such as ointments, lotions, or creams, wherein the active ingredients are suspended or dissolved in one or more carriers. Carriers for ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsified wax, and water; carriers for lotions and creams include, but are not limited to: mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2... Octyldodecanool, benzyl alcohol, and water.

[0125] The compounds arbutin ester, golden amamide alcohol ester, golden amamide alcohol ester benzoate, and orange-yellow piperamide acetate of the present disclosure embodiments can be used as single compounds for treating patients or in combination with other therapeutically effective compounds, especially for patients with hair loss and people who need hair loss prevention and hair regrowth.

[0126] Those skilled in the art can select appropriate pharmaceutically tolerable excipients based on the form of the pharmaceutical and cosmetic composition, and know methods for manufacturing pharmaceutical compositions and can select appropriate methods for preparing pharmaceutical compositions based on the type of pharmaceutically tolerable excipient and the form of the pharmaceutical composition. The pharmaceutical composition may be in solid, semi-solid, or liquid form for administration to a subject via external application.

[0127] The pharmaceutical compositions of this disclosure can be administered alone or in combination with other therapeutic agents, sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking all the above parameters into consideration, it is important to achieve the maximum effect with the minimum dose without producing side effects, and such a dose can be readily determined by those skilled in the art.

[0128] The following embodiments are used to further illustrate the advantages and features of this method, and are not intended to limit this disclosure. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods, performed according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0129] The present disclosure will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the disclosure. Where specific techniques or conditions are not specified in the embodiments, they are performed in accordance with the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0130] Unless otherwise specified, the quantitative analysis experiments in the following examples are all performed in triplicate, and the results are averaged.

[0131] Example 1

[0132] Purpose:

[0133] This experiment analyzed and determined the effects of compounds arbutin ester, golden amamide alcohol ester, golden amamide alcohol ester benzoate, and orange-yellow piperamide acetate on the survival rate of mouse hair follicle stem cells.

[0134] method:

[0135] Mouse hair follicle stem cells were isolated from the raised portion of the beard follicles on the back of C57BL / 6 mice. Specifically, freshly euthanized mice were immersed in alcohol for five minutes to remove bacteria. After the beard was trimmed, the hair follicles were dissected and isolated from the raised portion of the beard follicles. The cells were washed twice with 1×PBS and treated with trypsin at 37°C for 15 minutes. Fragments and undissociated tissue in the cell suspension were removed by tryingpsin digestion and then passed through 70μm and 40μm mesh filters. The cells were seeded in DMEM medium (containing 10% fetal bovine serum (v / v), penicillin (100 U / mL), and streptomycin (100 μg / mL)) for subsequent experiments.

[0136] Cell viability experiment:

[0137] Mouse hair follicle stem cells were cultured in DMEM medium (containing 10% fetal bovine serum (v / v), penicillin (100 U / mL), and streptomycin (100 μg / mL)). The culture was carried out at a concentration of 1 × 10⁻⁶. 5 Cells were seeded per well in a 96-well plate, and different concentrations of the compounds arbutin, aurora ammonium ester, aurora ammonium ester benzoate, and aurora piperamide acetate were added. The plates were incubated at 37°C for 72 hours. Then, 10 μL of MTT reagent (5 mg / mL) was added to each well of the 96-well plate, and the plates were incubated at 37°C for 3 hours. Next, 100 μL of phosphate-buffered saline (PBS) (containing 10% sodium dodecyl sulfate (SDS), 50% N,N-dimethylformamide, pH 7.2) was added to dissolve the precipitate in the plates, and the plates were incubated overnight. The absorbance at 570 nm was measured the next day using a UV / VIS spectrophotometer. Cell viability was calculated using the formula: Cell viability (%) = (OD drug group - OD blank group) / (OD control group - OD blank group) × 100. The treatment groups consisted of cells treated with compounds (aspergillus ester, aureomaramide ester, aureomaramide ester benzoate, or aureomaramide acetate). The only difference between the control and experimental groups was the absence of these compounds. The blank group consisted of blank culture medium without cells. Results:

[0138] result:

[0139] The compounds arbutin ester, golden ammonium alcohol ester, golden ammonium alcohol ester benzoate, and orange-yellow piperamide acetate ester showed no significant toxicity to mouse hair follicle stem cells.

[0140] Example 2

[0141] Objective: This experiment compared the effects of topical compounds arbutin ester, auramidool ester, auramidool ester benzoate, and orange-yellow piperamide acetate on hair growth in mice with androgenetic alopecia (AGA).

[0142] Methods: Forty-five male C57BL / 6 mice with similar health and physiological conditions, all in the quiescent phase of hair growth, were randomly divided into four groups: control group, AGA model group, 5% minoxidil group (positive control group), 0.125% aspergillus ester group, 0.125% auramine alcohol ester group, 0.1875% auramine alcohol ester benzoate group, and 0.1875% auramine alcohol ester benzoate group. Hair removal cream was applied to the backs of all 45 mice (day 0 was the day of hair removal), exposing an equal area of ​​the back for each mouse. On day-1 (the day before hair removal), day 5, and day 13, mice in the model group, 5% minoxidil group, 0.125% aspergillate group, 0.125% auramine alcohol ester group, 0.1875% auramine alcohol ester benzoate group, and 0.1875% auramine alcohol ester acetate group were intraperitoneally injected with 0.1 mg DHT to induce the AGA model. Different doses of the compound were dissolved in a mixture of ethanol and propylene glycol according to the group. Starting from day 1, the prepared solution was evenly sprayed onto the hair removal treatment area on the back of the mice, with 200 μL of solution sprayed per mouse per day for 18 consecutive days. Mice were allowed free access to food, kept in 12-hour light-dark cycles, and fed according to their needs. Hair growth was observed and recorded. On day 18 after hair removal, the mice underwent the following procedure: Five evenly distributed fixed locations were selected on the test area of ​​the mouse's back. Hair was plucked once from each location using tweezers, and one hair was randomly selected and retained. If multiple hairs were found within a single hair follicle unit, they were also counted as one. In other words, five hair samples were obtained from the test area on the back of each mouse for hair length comparison.

[0143] result:

[0144] The results are shown in Figure 1. The compounds arbutin ester, golden amamide alcohol ester, golden amamide alcohol ester benzoate group, and orange-yellow piperamide acetate solution can promote hair growth in androgenic alopecia model mice to varying degrees.

[0145] As shown in Figure 1A, the hair growth rate and new hair density on the backs of mice treated with 5% minoxidil solution, 0.125% aspergillus ester, 0.125% auramine alcohol ester, 0.1875% auramine alcohol ester benzoate, and 0.1875% orange-yellow piperamide acetate were all higher than those in the AGA model group. After 18 days of drug treatment, the 0.125% aspergillus ester and 0.1875% orange-yellow piperamide acetate groups showed the highest new hair coverage on the backs of mice, with no significant difference compared to the control group and the 5% minoxidil solution group. The new hair growth on the backs of mice in the 0.125% auramine alcohol ester and 0.1875% auramine alcohol ester benzoate groups was slightly uneven, and the overall growth was slightly inferior to that of the 0.125% aspergillus ester and 0.1875% orange-yellow piperamide acetate groups.

[0146] From day 0 to 6, the skin on the backs of mice in all groups was predominantly pink. On day 9, except for the model group, the skin of mice in all groups gradually darkened, exhibiting a pinkish-black hue. Scattered new, fine hairs grew in the control group, the 5% minoxidil solution group, the 0.125% aspergillus ester group, and the 0.1875% orange-yellow piperamide acetate group. From day 12 to 15, the skin of mice in the model group began to darken. Except for the model group, the area of ​​new hair growth gradually increased in all groups. The 0.125% aspergillus ester group had the highest density of new hair growth, while the 0.1875% orange-yellow piperamide acetate group showed patchy new hair growth. The 0.125% golden ammonium ester group and the 0.1875% golden ammonium ester benzoate group showed varying degrees of spotty new hair growth. On day 18, the density of new hair growth in all treatment groups was higher than that in the model group. In the control group, the 5% minoxidil group, the 0.125% aspergillus ester group, and the 0.1875% orange-yellow piperamide acetate group, the newly grown hair had basically covered the entire test site, and the hair growth was uniform. The newly grown hair at the edge of the test site had basically merged with the surrounding hairless parts. The hair density of mice in the 0.125% golden ammonium ester group and the 0.1875% golden ammonium ester benzoate group was slightly lower than that in the 0.125% aspergillus ester group and the 0.1875% orange-yellow piperamide acetate group, and a clear boundary line could still be seen at the edge of the test site.

[0147] Figure 1B and Table 1 show the results compared to the model group, with the administration of 5% minoxidil solution (…). p < 0.01), 0.125% arbutin solution ( p < 0.0001), 0.125% golden amide alcohol ester solution ( p < 0.01), 0.1875% golden amyl alcohol ester benzoate solution ( p < 0.01), 0.1875% orange-yellow piperamide acetate group ( p＜0.0001）的小鼠在脱毛后的第18天，其受试区域新生毛发显示出显著地毛发长度变长，其中0.125% 曲霉酸酯组的促进毛发生长效果最佳。0.125% 曲霉酸酯（##p＜0.01）和0.1875% 橙黄胡椒酰胺乙酸酯组（##p＜0.01）的新生毛发平均长度与5% 米诺地尔组相比也存在显著性差异。

[0148] Table 1

[0149]

[0150] As can be seen from the embodiments of this disclosure, mice in each group treated with the composition solutions containing compounds arbutin ester, aurora amide alcohol ester, aurora amide alcohol ester benzoate, and orange-yellow piperamide acetate as active ingredients had shorter skin discoloration time and significantly shorter hair growth time compared to the model group mice. The mice had more uniform hair growth, higher hair regrowth efficiency, and higher coverage of new hair. They effectively controlled the adverse effects of dihydrotestosterone on hair follicles to varying degrees, with arbutin ester and orange-yellow piperamide acetate showing the most significant effects.

[0151] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this disclosure, and are not intended to limit them. Although this disclosure has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this disclosure.

[0152] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this disclosure. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0153] Although embodiments of the present disclosure have been shown and described above, it is to be understood that the above embodiments are exemplary and should not be construed as limiting the present disclosure. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present disclosure.

Claims

1. The use of a compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs in the preparation of a medicament for the prevention, treatment, or relief of hair loss, characterized in that, The compound comprises: Two or more peptide bonds (Y), where Y is ； The two end groups (A) located at opposite ends of the main chain of the compound are each independently a substituted or unsubstituted C group. 1-6 Alkyl or substituted or unsubstituted phenyl groups, preferably halogenated; and Multiple linking groups (X), each X independently selected from the group consisting of: 、 and replaced or unreplaced Preferably, the substituent is a halogen; Each pair of peptide bonds is separated by at least one linker group.

2. The use according to claim 1, characterized in that, The hair loss diseases are selected from the following groups: androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, and immunodeficiency alopecia.

3. The use according to claim 1 or 2, characterized in that, The compound further comprises one or more, preferably one to three, more preferably one ester group (B), wherein B is... ; Optionally, the compound comprises two to four, preferably two to three, of the linking groups; Optionally, the compound comprises two to four, preferably two, peptide bonds.

4. The use according to any one of claims 1 to 3, characterized in that, The compound has a structure selected from the group consisting of: AYXXBXYA, ABXXYXYA and AXXYXYA; Optionally, the compound is selected from: asperphenamate, aurantiamide acetate, aurantiamide benzoate, and aurantiamide (TMC-58B).

5. The use of the composition in the preparation of a medicament for the prevention, treatment or relief of hair loss, characterized in that, The composition comprises: The compound of any one of claims 1 to 4 or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs; and Choose any excipients that are selected from the following groups: pharmaceutically acceptable excipients, cosmetically acceptable excipients, food-acceptable excipients, and health product-acceptable excipients.

6. The use according to claim 5, characterized in that, The composition also contains other medications for the prevention, treatment or relief of hair loss.

7. The use according to claim 5 or 6, characterized in that, The composition is in the form of ointment, plaster, lotion, gel, spray, skin patch, powder, granule, capsule, tablet, solution, suspension, syrup, suppository or injection.

8. The use according to any one of claims 5 to 7, characterized in that, Based on the total mass of the composition, the composition comprises: 0.0025-5% of the compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs as described in any one of claims 1 to 4. 50-70% ethanol, and 30-50% propylene glycol.

9. A method for preventing, treating, or alleviating hair loss, characterized in that, This includes administering to a subject a therapeutically effective amount of the compound or its stereoisomers, tautomers, N-oxides, solvates, hydrates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, or the composition of any one of claims 5 to 8.

10. The method according to claim 9, characterized in that, The hair loss diseases mentioned are selected from the following groups: androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, and immunodeficiency alopecia; Optionally, the method includes administering the composition to a subject via: skin application, transdermal application, oral application, subcutaneous injection, intraperitoneal application, intravenous, intramuscular or intrathecal injection, sublingual application, buccal application, rectal insertion, vaginal insertion, ocular application, ear application, or nasal application.

Images