Use of compounds for treatment of alopecia

Abstract

The invention relates to the technical field of medicines, in particular to application of a compound. The compound comprises: two or more peptide bonds (Y), Y being # imgabs0 # two end groups (A) respectively located at both ends of the main chain 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 X being independently selected from the group consisting of # imgabs 1 # and substituted or unsubstituted # imgabs 2 # wherein at least one of the linking groups is interposed between every two of the peptide bonds.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to the use of a compound. Background Art

[0002] According to data from the National Health Commission, the number of people suffering from hair loss in China has exceeded 250 million, and on average, 1 in every 6 people is troubled by hair loss. Among them, about 163 million are men and about 88 million are women. Hair loss diseases include androgenetic alopecia, alopecia areata, cicatricial alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia, immunodeficiency alopecia, etc. Androgenetic alopecia (AGA), also known as seborrheic alopecia, is the most common hair loss disease clinically. More than 80% of hair loss patients belong to AGA or are accompanied by AGA, especially more common in men. The main feature of AGA is the gradual miniaturization of hair follicles, resulting in a decrease in hair density and thinner hair quality, and ultimately forming a scarless hair loss area. This hair loss pattern shows a gradual increase in hair loss on the forehead and the top of the head in men, while in women, it shows a gradual hair loss on the top of the head or diffuse hair loss, which seriously affects the quality of life of patients and brings great mental pressure and psychological burden to patients. Androgens play a key role in the pathogenesis of AGA. Dihydrotestosterone (DHT) is a form of androgen, which acts on hair follicles in specific areas of the scalp, leading to the degeneration and atrophy of hair follicles, thus causing hair loss.

[0003] With the increase in the number of people suffering from hair loss, consumers are becoming more and more concerned about scalp care, and the demand for anti-hair loss and hair growth products is also increasing continuously. The market demand for topical anti-hair loss and hair growth products is booming. Currently, minoxidil is the first-line topical drug for the treatment of androgenetic alopecia, mainly stimulating hair growth by promoting scalp blood circulation and the release of hair follicle growth factors, but it has side effects such as stimulating the scalp to cause erythema and itching, having an initial shedding period during use, and the condition recurring after discontinuation. Hair transplantation surgery also has risks such as postoperative infection and low hair follicle survival rate. In addition, some emerging therapies, such as microneedle therapy and mesotherapy, all show problems such as high costs, high technical requirements, and different effects for different people. These treatment options have many limitations, seriously affecting the treatment effectiveness, compliance, and use experience of patients.

[0004] Therefore, there is an urgent need to propose a drug composition or preparation for anti-hair loss and hair growth with low risk and high benefit. Summary of the Invention

[0005] The present invention solves at least one of the problems of the related technologies from the following aspects.

[0006] The use of a compound or its stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug in the preparation of a drug for preventing, treating or alleviating hair loss diseases, wherein

[0007] the compound comprises:

[0008] two or more peptide bonds (Y), where Y is

[0009] two end groups (A) respectively located at both ends of the main chain of the compound, each independently being a substituted or unsubstituted C 1-6 alkyl or a substituted or unsubstituted phenyl, preferably, the substituent is a halogen; and

[0010] a plurality of linking groups (X), each X independently selected from the group consisting of:

[0011] and a substituted or unsubstituted preferably, the substituent is a halogen;

[0012] wherein there is at least one of the linking groups between every two of the peptide bonds.

[0013] In some embodiments, the hair loss diseases are selected from the group consisting of: androgenetic alopecia, alopecia areata, cicatricial alopecia, dysnutritional alopecia, drug-induced alopecia, traumatic alopecia and immunodeficiency alopecia.

[0014] In some embodiments, the compound further comprises one or more, preferably one to three, more preferably one ester group (B), where B is

[0015] In some embodiments, the compound comprises: two to four, preferably two to three of the linking groups.

[0016] In some embodiments, the compound comprises: two to four, preferably two of the peptide bonds.

[0017] In some embodiments, the compound has a structure selected from the group consisting of:

[0018] A-Y-X-X-B-X-Y-A, A-B-X-X-Y-X-Y-A and A-X-X-Y-X-Y-A.

[0019] In some embodiments, the compound is selected from: Asperphenamate, Aurantiamide acetate, Aurantiamide benzoate, Aurantiamide, TMC-58B.

[0020] An embodiment of the second aspect of the present application provides the use of a composition in the preparation of a drug for preventing, treating or alleviating hair loss diseases, wherein

[0021] the composition comprises:

[0022] the compound of any embodiment of the first aspect of the present application or its stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug; and

[0023] optionally present excipients selected from the group consisting of: pharmaceutically acceptable excipients, cosmetically acceptable excipients, food acceptable excipients and nutraceutical acceptable excipients.

[0024] In some embodiments, the composition further comprises other drugs for preventing, treating or alleviating hair loss diseases.

[0025] In some embodiments, the composition is in the form of an ointment, plaster, lotion, gel, spray, skin patch, powder, granule, capsule, tablet, solution, suspension, syrup, suppository or injection.

[0026] In some embodiments, based on the total mass of the composition, the composition comprises:

[0027] 0.0025 - 5% of the compound of any embodiment of the first aspect of the present application or its stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug,

[0028] 50 - 70% ethanol, and

[0029] 30 - 50% propylene glycol.

[0030] An embodiment of the third aspect of the present application provides a method for preventing, treating or alleviating hair loss diseases, comprising administering to a subject a therapeutically effective amount of the compound of any embodiment of the first aspect of the present application or its stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug or the composition of any embodiment of the second aspect of the present application.

[0031] 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.

[0032] In some embodiments, the method includes administering the composition to a subject by: cutaneous administration, transdermal administration, oral administration, subcutaneous injection, intraperitoneal administration, intravenous, intramuscular or intrathecal injection, sublingual administration, buccal administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration.

[0033] Compared with the related art, the embodiments of the present invention at least achieve the following beneficial effects:

[0034] The embodiments of the present invention provide compounds with anti-hair loss and hair growth promoting effects derived from natural products, an anti-hair loss and hair growth promoting composition containing the group of compounds as an active ingredient, and a preparation method thereof. The compounds are isolated and extracted from natural products, have small toxic and side effects, high safety, and no obvious skin irritation.

[0035] As demonstrated in the specific embodiments of the present invention, the composition of the embodiments of the present invention has the effects of promoting hair growth, enhancing hair quality, improving hair loss symptoms, and regulating the scalp environment, and there is no obvious shedding period, and no recurrence of hair loss is observed after stopping use. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following will briefly introduce the drawings required for use in the embodiments. Obviously, the drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0037] Figure 1 shows the growth of new hair in a mouse model of induced androgenetic alopecia (AGA) treated with compounds aspergillic acid ester, aurantiamide acetate, aurantiamide benzoate, and piperlongumine acetate, respectively. Among them Figure 1A are skin photos of the dorsal test area of each group of mice from day 0 to day 18 after hair removal, Figure 1B is a bar graph of the average length of new hair in the test area of mice on day 18 (taken from 5 evenly distributed fixed positions of hair, taken once at each position and recorded).

[0038] To facilitate the understanding of the present invention, the following further illustrates the implementation process of the present invention with specific implementation examples. These descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention will be further described in detail below in conjunction with specific embodiments. The provided embodiments are only for clarifying the present invention and do not limit the scope of the present invention. The following provided embodiments can be used as a guide for those of ordinary skill in the art to make further improvements and do not limit the present invention in any way.

[0040] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs.

[0041] An embodiment of the first aspect of the present application provides the use of a compound or its stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug in the preparation of a drug for preventing, treating or alleviating hair loss diseases.

[0042] Wherein the compound comprises:

[0043] Two or more peptide bonds (Y), where Y is

[0044] Two end groups (A) respectively located at both ends of the main chain of the compound, each independently being a substituted or unsubstituted C 1-6 alkyl or a substituted or unsubstituted phenyl group, preferably, the substituent is a halogen; and

[0045] A plurality of linking groups (X), each X independently selected from the group consisting of:

[0046] and a substituted or unsubstituted Preferably, the substituent is a halogen;

[0047] Wherein there is at least one of the linking groups between every two of the peptide bonds.

[0048] It can be understood that the halogen is selected from one or more of fluorine, chlorine, bromine and iodine.

[0049] As used herein, the term "alkyl" refers to a saturated hydrocarbon group, including both straight-chain and branched-chain structures. Examples of alkyl include but are not limited to methyl, ethyl, propyl (such as n-propyl, isopropyl), butyl (such as n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl), hexyl (such as n-hexyl, isohexyl, tert-hexyl). In various embodiments, C 1-6 alkyl, that is, alkyl, may contain 1 to 6 carbon atoms.

[0050] As an example, the substituted is a

[0051] As an example, the substituted substituted with one halogen at the para, ortho or meta position on the benzene ring

[0052]

[0053] As an example, the substituted is substituted with one halogen at the para position on the benzene ring

[0054] In some embodiments, the hair loss disease is selected from the group consisting of: androgenetic alopecia, alopecia areata, cicatricial alopecia, traumatic alopecia, anagen effluvium, telogen effluvium, and alopecia due to immunodeficiency.

[0055] In some embodiments, the compound further comprises one or more, preferably one to three, more preferably one ester group (B), wherein B is

[0056] In some embodiments, the compound comprises: two to four, preferably two to three of the linking groups.

[0057] In some embodiments, the compound comprises: two to four, preferably two peptide bonds.

[0058] In some embodiments, the compound has a structure selected from the group consisting of: A-Y-X-X-B-X-Y-A, A-B-X-X-Y-X-Y-A, and A-X-X-Y-X-Y-A.

[0059] In some embodiments, the compound is selected from: Asperphenamate, Aurantiamide acetate, Aurantiamide benzoate, Aurantiamide, TMC-58B.

[0060] The compounds Asperphenamate, Aurantiamide acetate, Aurantiamide benzoate, and Aurantiamide, TMC-58B are all derived from natural products and can be extracted from a variety of edible, medicinal plants, and fungi. These compounds have similar molecular structures and exhibit a wide range of biological activities and pharmacological effects, including anti-inflammatory, anti-tumor, antioxidant, antibacterial, anti-fibrotic, cytoprotective, and immunomodulatory effects.

[0061] The inventors of the present application unexpectedly found that the compounds Asperphenamate, Aurantiamide acetate, Aurantiamide benzoate, and Aurantiamide, TMC-58B can effectively promote hair growth, enhance hair quality, improve the scalp environment, and have good safety and long-term efficacy.

[0062] Asperphenamate:

[0063] Aspergillate is a dipeptide compound and is a metabolite of various fungi such as Penicillium and Aspergillus. Trace amounts of aspergillate can also be extracted from plants such as the buds of Hordeum vulgare L. of the Poaceae family and Saururus chinensis (Lour.) Baill. of the Saururaceae family. Related studies have shown that aspergillate shows potential application value in the fields of anti-tumor, anti-fibrosis, anti-neuroinflammation, and blood sugar lowering.

[0064] As an example, in some embodiments of the present invention, aspergillate has the structure shown in the following formula (I).

[0065]

[0066] Aurantiamide acetate:

[0067] Aurantiamide acetate is a dipeptide compound and can be isolated from a variety of edible and medicinal plants, including Viola phillipina of the Violaceae family, Portulaca oleracea of the Portulacaceae family, Brassica juncea of the Brassicaceae family, Potentilla griffithii var. velutina Cardot of the Rosaceae family, etc. Aurantiamide acetate has anti-inflammatory, anti-tumor, antioxidant and other effects, and its potential mechanisms include reducing nerve damage, inflammatory response and promoting apoptosis, etc., and is widely used in the research of inflammatory diseases.

[0068] As an example, in some embodiments of the present invention, aurantiamide acetate has the structure shown in the following formula (II).

[0069]

[0070] Aurantiamide benzoate:

[0071] Aurantiamide benzoate is a dipeptide derivative, derived from the Lamiaceae plants Cunila spicata and Hyptis fasciculata, and has anti-inflammatory, antibacterial, antioxidant, uric acid lowering and other effects. Aurantiamide benzoate is widely used in the research of inflammatory diseases and has the potential to be developed into a new xanthine oxidase inhibitor.

[0072] As an example, in some embodiments of the present invention, the aurantiamide acetate has the structure shown in the following formula (III).

[0073]

[0074] Aurantiamide acetate (Aurantiamide, TMC-58B):

[0075] Aurantiamide acetate is a dipeptide compound that can be isolated and extracted from plants such as Zanthoxylum dissitum Hemsl. (Rutaceae, Zanthoxylum), Pulsatilla cernua (Thunb.) Bercht. & J.Presl (Ranunculaceae, Pulsatilla), Duhaldea cappa (Buchanan-Hamilton ex D.Don) Pruski & Anderberg (Asteraceae, Duhaldea), and Catunaregam spinosa (Thunb.) Tirveng. (Rubiaceae, Catunaregam). Aurantiamide acetate has anti-inflammatory, antioxidant, anti-tumor, antiplatelet and other effects, and existing studies have shown that it has potential therapeutic effects on neurodegenerative diseases.

[0076] As an example, in some embodiments of the present invention, the aurantiamide acetate has the structure shown in the following formula (IV).

[0077]

[0078] As an example, in some embodiments of the present application, the compound is selected from the group consisting of:

[0079]

[0080] The second aspect of the present application provides the use of a composition in the preparation of a drug for preventing, treating or alleviating hair loss diseases, and the composition comprises:

[0081] The compound or its stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug in any of the above-mentioned first aspect embodiments; and

[0082] Optionally present excipients selected from the group consisting of: pharmaceutically acceptable excipients, cosmetically acceptable excipients, foodologically acceptable excipients, and nutraceutically acceptable excipients.

[0083] In some embodiments, the composition further comprises other drugs for preventing, treating or alleviating hair loss diseases.

[0084] In some embodiments, the composition is in the form of an ointment, plaster, lotion, gel, spray, skin patch, powder, granule, capsule, tablet, solution, suspension, syrup, suppository or injection.

[0085] In some embodiments, based on the total mass of the composition, the composition comprises:

[0086] 0.0025 - 5% of the compound or its stereoisomer, tautomer, N - oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug in any embodiment of the first aspect above,

[0087] 50 - 70% ethanol, and

[0088] 30 - 50% propylene glycol.

[0089] An embodiment of the third aspect of the present application provides a method for preventing, treating or alleviating hair loss diseases, by administering to a subject a therapeutically effective amount of the compound or its stereoisomer, tautomer, N - oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug in any embodiment of the first aspect above, or the composition in any embodiment of the second aspect above.

[0090] In some embodiments, the hair loss diseases are selected from the group consisting of: androgenetic alopecia, alopecia areata, cicatricial alopecia, traumatic alopecia, drug - induced alopecia, traction alopecia and alopecia due to immunodeficiency.

[0091] In some embodiments, the method includes administering the composition to the subject by the following routes: cutaneous administration, transdermal administration, oral administration, subcutaneous injection, intraperitoneal administration, intravenous, intramuscular or intrathecal injection, sublingual administration, buccal administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration.

[0092] Throughout the specification, when a part "comprises" / "includes" a component, unless otherwise clearly stated, it means that it may also include other components rather than excluding components. When presenting allowable manufacturing and material tolerances (which are inherent in the meaning), the terms "about" or "substantially" are used at or near a numerical value. These terms are used to prevent unscrupulous infringers from misusing the disclosure, where the correct or absolute value is cited to aid in understanding the invention.

[0093] Throughout the specification, the term "combinations thereof" included in a Markush - type expression refers to a mixture or combination of one or more selected from the group consisting of the multiple components described in the Markush - type expression, i.e., one or more selected from the group consisting of the multiple components.

[0094] The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis / trans) isomers, atropisomers, etc.

[0095] The term "prodrug" refers to a compound that is converted in vivo to a compound provided in an embodiment of the present invention. 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.

[0096] The term "metabolite" is a product produced by the metabolism of a particular compound or its salt in vivo. Metabolites of a compound can be identified using conventional techniques known in the art and their activity can be determined using, for example, the assays described herein. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds disclosed herein, including metabolites produced by contacting a mammal with a compound disclosed herein for a sufficient period of time.

[0097] The term "pharmaceutically acceptable salt" refers to an organic or inorganic salt of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe 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 amines 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 using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 alkyl) 4Salt.

[0098] The term "solvate" refers to an 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.

[0099] When the solvent is water, the term "hydrate" may be used. In one embodiment, one water molecule is associated with one molecule of the compounds disclosed herein, such as a hydrate. In another embodiment, more than one water molecule may be associated with one molecule of the compounds disclosed herein, such as a dihydrate. In another embodiment, less than one water molecule may be associated with one molecule of the compounds disclosed herein, such as a hemihydrate. In addition, all solvates of the present invention retain the biological effectiveness of the non-hydrate forms of the compounds disclosed herein.

[0100] In the present invention, "hair loss" refers to the state of having no hair in the part where hair normally grows, specifically refers to the loss of hair at the end of the scalp. The causes of hair loss are not limited, such as androgenic alopecia (seborrheic alopecia), alopecia areata, scarring alopecia, telogen effluvium, nutritional alopecia, drug-induced alopecia, traumatic alopecia, immunodeficiency alopecia, and alopecia folliculitis.

[0101] The term "androgenic alopecia", also known as seborrheic alopecia or premature baldness, refers to a type of hair loss induced on the basis of excessive sebum secretion, often accompanied by increased dandruff, oily scalp and obvious itching. This type of hair loss usually starts from the top of the head and gradually spreads to the surrounding areas, and may eventually lead to the disappearance of the entire forehead and top of the head hair. It mainly occurs in young and middle-aged people with vigorous sebaceous gland secretion. The clinical manifestations of seborrheic alopecia vary depending on gender and condition: men mainly show a receding hairline on the forehead, forming an M-shaped hair loss; the hair on the top of the head gradually becomes sparse and thinner, and may eventually form a U-shaped hair loss. Some patients have greasy hair, increased dandruff and itchy scalp, or visible rashes; women mainly show a progressive reduction and thinning of hair on the top of the head, and a small number of them show diffuse hair loss.

[0102] The term "subject" refers to a subject in need of treatment for a disease, and more specifically, refers to a mammal, such as a human or non-human primate, mouse, rat, dog, cat, horse, or cow.

[0103] In the present invention, "prevention" refers to all actions involving the inhibition or delay of the onset of an expected disease, "treatment" refers to all actions involving the improvement or beneficial change of a disease and its metabolic abnormalities by administering a composition according to the present invention, and "alleviation" refers to all actions involving the reduction of parameters associated with an expected disease (e.g., the severity of symptoms) by administering a composition according to the present invention.

[0104] In the present invention, "administering" means providing a given composition of the present invention to a subject by any suitable method.

[0105] The compositions according to the present invention are administered in a pharmaceutically effective amount. As used herein, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose can be determined by parameters including the type and severity of the patient's disease, the drug activity, the sensitivity to the drug, the administration time, the administration route and excretion rate, the treatment duration, and the parameters of co-administered drugs, as well as other parameters well known in the medical field.

[0106] The terms "effective amount" and "effective dose" generally refer to an amount sufficient to produce the desired treatment, where the exact dose varies depending on the specific condition of the disease being treated. When the disease is hair loss, its manifestations generally include, but are not limited to, increased hair growth rate, increased hair density, enhanced hair quality, improved scalp environment, etc.

[0107] The effective amount of the compounds aspergillic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and piperlongumine acetate of the present invention can depend on the type, body weight, age, and individual condition of the subject, and can be determined by standard procedures such as cell culture or experimental animals.

[0108] The compounds aspergillic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and piperlongumine acetate of the present invention can exist in solid, semi-solid, or liquid form.

[0109] The compounds aspergillic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and piperlongumine acetate included in the present invention can be made into powder form by additional processes such as vacuum distillation and freeze drying or spray drying for addition to various composition dosage forms.

[0110] The compounds aspergillic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and piperlongumine acetate of the present invention can be administered to a subject by routes including, but not limited to, topical and oral administration.

[0111] In the embodiments of the present invention, a group of anti-hair loss and hair growth compositions of the present invention can not only contain the above-mentioned compounds aspergillic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and piperlongumine acetate as active ingredients, but also contain ingredients commonly used in anti-hair loss and hair growth composition categories. For example, it can contain conventional auxiliaries such as water, diluents, antioxidants, stabilizers, co-solvents, colorants, surfactants, preservatives, vitamins, and flavors, as well as carriers.

[0112] The compositions of the present invention can be prepared into related pharmaceutical and cosmetic compositions, including hair growth liquids, scalp care agents, scalp nourishing liquids, shampoos, ointments, gels, creams, patches, sprays and other dosage forms, but not limited thereto.

[0113] The compositions according to the present invention further comprise suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. The excipients can be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film coating materials and controlled release additives.

[0114] The compositions according to the present invention 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, spirits, tinctures, inhalants, elixirs, injections, perfusion fluids, 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 cataplasms.

[0115] The carriers, excipients and diluents that can be included in the pharmaceutical compositions according to the present invention can include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraben, propyl paraben, talc, magnesium stearate and mineral oil.

[0116] In the case of preparations, common diluents or excipients such as fillers, thickeners, binders, wetting agents, disintegrants and surfactants can be used to prepare the compositions according to the present invention.

[0117] The suspensions according to the present invention can contain suspending agents, such as gum arabic, tragacanth, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, sodium alginate, hydroxypropyl methyl cellulose (HPMC), HPMC 1828, HPMC 2906 or HPMC 2910, and if necessary, can also contain surfactants, preservatives, stabilizers, colorants or fragrances.

[0118] For topical application to the skin, the compounds disclosed herein can be formulated into suitable forms of ointments, lotions or creams, wherein the active ingredient is 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, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers for lotions and creams include, but are not limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, cetene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0119] The compounds aspergillic acid esters, aurantiamide acetates, aurantiamide benzoates, and piperlongumine acetates of the present invention can be administered as a single compound for treating a patient or in combination with other therapeutically effective compounds, particularly for patients with hair loss and those in need of preventing hair loss and promoting hair growth.

[0120] Those skilled in the art can select suitable pharmaceutically tolerable excipients according to the form of the pharmaceutical and cosmetic compositions, and know the methods for manufacturing pharmaceutical compositions and can select suitable methods for preparing pharmaceutical compositions according to the types of pharmaceutically tolerable excipients and the forms of the pharmaceutical compositions. The pharmaceutical compositions can exist in solid, semi-solid or liquid forms for administration to a subject by the topical route.

[0121] The pharmaceutical compositions of the present invention can be administered alone or in combination with other therapeutic agents, sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Considering all the above parameters, it is important to achieve the maximum effect with the minimum dose without causing side effects, and such a dose can be easily determined by those of ordinary skill in the art.

[0122] The following examples are used to further illustrate the advantages and characteristics of the method, rather than limiting the present invention. The experimental methods in the following examples are all conventional methods unless otherwise specified, and are carried out according to the techniques or conditions described in the literature in the art or according to the product specifications.

[0123] The solutions of the present invention will be explained below in conjunction with the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specifically noted in the examples regarding technical or conditions, they are carried out according to the techniques or conditions described in the literature in the art or according to the product specifications. Those reagents or instruments not indicated with the manufacturer can be obtained as conventional products through commercial purchase.

[0124] Unless otherwise specified, the quantitative analysis tests in the following examples are all set with three repeated experiments, and the results are averaged.

[0125] Example 1

[0126] Objective:

[0127] This experiment analyzed and determined the effects of kojic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and aurantiamide piperitone acetate on the survival rate of mouse hair follicle stem cells.

[0128] Methods:

[0129] Mouse hair follicle stem cells were isolated from the bulge of the back whisker follicles of C57BL / 6 mice as follows. The freshly sacrificed mice were soaked in alcohol for five minutes to remove bacteria. After cutting off the whiskers with scissors, the follicles were dissected and separated from the bulge of the whisker follicles, washed twice with 1×PBS, and treated with trypsin at 37°C for 15 minutes. The debris and undissociated tissues in the cell suspension digested by trypsin were removed sequentially through 70μm and 40μm mesh cell filters. The cells were seeded in DMEM medium (containing 10% fetal bovine serum (volume ratio), penicillin (100 U / mL), and streptomycin (100 μg / mL)), and these cells were used for subsequent experiments.

[0130] Cell survival rate experiment:

[0131] Mouse hair follicle stem cells were cultured in DMEM medium (containing 10% fetal bovine serum (volume ratio), penicillin (100 U / mL), and streptomycin (100 μg / mL)). They were seeded at 1×10 5 cells per well in a 96-well plate, and then different concentrations of kojic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and aurantiamide piperitone acetate were added respectively. The plate was incubated in a 37°C incubator for 72 hours. Then, 10 μL of MTT reagent (concentration 5 mg / mL) per well was added to the 96-well plate, and the plate was incubated in a 37°C incubator for 3 hours. Then, 100 μL of phosphate buffer (PBS) (containing 10% sodium dodecyl sulfate (SDS), 50% N,N-dimethylformamide, pH 7.2) was added to dissolve the precipitate in the well plate overnight. The next day, the absorbance at a wavelength of 570 nm was detected using a UV / VIS spectrophotometer. The formula for calculating the cell survival rate ratio is: Cell survival rate (%) = (OD of the drug-treated group - OD of the blank group) / (OD of the control group - OD of the blank group) × 100. Among them, the drug-treated group is the group treated with the compound (kojic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, or aurantiamide piperitone acetate), the difference between the control group and the experimental group is only that the above compounds are not added, and the blank group is the blank medium without cells. Results:

[0132] Results:

[0133] Kojic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and aurantiamide piperitone acetate have no obvious toxicity to mouse hair follicle stem cells.

[0134] Example 2

[0135] Objective: This experiment compared the effects of externally applied compounds kojic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and piperlongumine amide acetate on hair growth in androgenetic alopecia (AGA) model mice.

[0136] Methods: Forty-five C57BL / 6 male mice with similar health conditions and physiological conditions and all in the telogen phase of hair growth were randomly divided into a control group, an AGA model group, a 5% minoxidil group (positive drug control group), a 0.125% kojic acid ester group, a 0.125% aurantiamide acetate group, a 0.1875% aurantiamide acetate benzoate group, and a 0.1875% piperlongumine amide acetate group. The backs of the 45 mice were depilated with depilatory cream (the day of depilation was day 0), exposing the same area of the back test area for each mouse. On day -1 (i.e., one day before depilation), day 5, and day 13, the mice in the model group, 5% minoxidil group, 0.125% kojic acid ester group, 0.125% aurantiamide acetate group, 0.1875% aurantiamide acetate benzoate group, and 0.1875% piperlongumine amide acetate group were intraperitoneally injected with 0.1 mg DHT to induce the AGA model. Different doses of the compounds were dissolved in a mixed solution of ethanol and propylene glycol according to the grouping. From day 1, the prepared solution was evenly sprayed on the depilated area of the mice's backs, and the volume of the solution sprayed on each mouse per day was 200 μL, and spraying was continued for 18 days. The mice were allowed to feed freely, with a 12-hour light-dark cycle, and were adaptively raised. The hair growth situation was observed and recorded. On the 18th day after depilation, the following operations were performed on the mice: Five fixed positions were evenly selected in the test area on the backs of the mice, and the hair was plucked once at each position with forceps, and one of them was randomly selected and retained. If there were multiple hairs in one hair follicle unit, it was also recorded as one. That is, 5 hair samples were obtained from the test area on the backs of each mouse for hair length comparison.

[0137] Results:

[0138] As shown in Figure 1, the solutions of kojic acid ester, aurantiamide acetate, aurantiamide acetate benzoate, and piperlongumine amide acetate could promote hair growth in androgenetic alopecia model mice to varying degrees.

[0139] As Figure 1AAs shown, the hair growth rate and the density of new hair on the backs of mice in the 5% minoxidil solution group, 0.125% aspergillic acid ester group, 0.125% chrysotriamide alcohol ester group, 0.1875% chrysotriamide alcohol benzoate group, and 0.1875% aurantiamide acetate group were higher than those in the AGA model group. After 18 days of drug treatment, the highest coverage rates of new hair on the backs of mice in the 0.125% aspergillic acid ester group and 0.1875% aurantiamide acetate group were observed, showing no significant difference compared with the control group and the 5% minoxidil solution group. The growth of new hair on the backs of mice in the 0.125% chrysotriamide alcohol ester group and 0.1875% chrysotriamide alcohol benzoate group was slightly uneven, and the overall growth state was slightly inferior to that in the 0.125% aspergillic acid ester group and 0.1875% aurantiamide acetate group.

[0140] From day 0 to day 6, the back skin of mice in each group mainly showed a pink color. On day 9, the skin of mice in each group except the model group gradually turned black, showing a pink and black alternating state, and sporadic soft new hairs grew on the control group, 5% minoxidil solution group, 0.125% aspergillic acid ester group, and 0.1875% aurantiamide acetate group. From day 12 to day 15, the skin of mice in the model group began to turn black. The area of new hair in each group except the model group gradually expanded. Among them, the density of new hair growth in the 0.125% aspergillic acid ester group was the highest. Patchy new hair appeared in the 0.1875% aurantiamide acetate group, and spotty new hair appeared in the 0.125% chrysotriamide alcohol ester group and 0.1875% chrysotriamide alcohol benzoate group to varying degrees. On day 18, the density of new hair in each drug treatment group was higher than that in the model group. Among them, the new hair in the control group, 5% minoxidil group, 0.125% aspergillic acid ester group, and 0.1875% aurantiamide acetate group had basically covered the entire test area, the hair growth was uniform, and the new hair at the edge of the test area had basically merged with the non-depilated part around. The hair density of mice in the 0.125% chrysotriamide alcohol ester group and 0.1875% chrysotriamide alcohol benzoate group was slightly lower than that in the 0.125% aspergillic acid ester group and 0.1875% aurantiamide acetate group, and an obvious boundary line could still be seen at the edge of the test area.

[0141] Figure 1B and Table 1, compared with the model group, when given 5% minoxidil solution ( ** p < 0.01), 0.125% aspergillic acid ester solution ( **** p < 0.0001), 0.125% chrysotriamide alcohol ester solution ( ** p < 0.01), 0.1875% chrysotriamide alcohol benzoate solution ( ** p < 0.01), 0.1875% aurantiamide acetate group ( ****On the 18th day after hair removal in mice with p < 0.0001), the newly grown hair in the test area showed significantly longer hair length. Among them, the 0.125% aspergillic acid ester group had the best effect on promoting hair growth. 0.125% aspergillic acid ester ( ## p < 0.01) and the 0.1875% aurantiamide acetate group ( ## p < 0.01) also showed significant differences in the average length of newly grown hair compared with the 5% minoxidil group.

[0142] Table 1

[0143]

[0144] It can be seen from the examples of the present invention that the mice in each group treated with the composition solution containing aspergillic acid ester, chrysosplenol D, chrysosplenol D benzoate, and aurantiamide acetate as the active ingredient had a shorter skin discoloration time and a significantly shorter hair growth start time compared with the model group mice. The hair growth of the mice was uniform, and the hair growth effective rate and the coverage rate of newly grown hair were higher. To varying degrees, it effectively controlled the adverse effects of dihydrotestosterone on hair follicles. Among them, aspergillic acid ester and aurantiamide acetate had the most significant effects.

[0145] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present disclosure, not to limit them; although the present disclosure has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present disclosure.

[0146] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0147] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, replacements, and variations to the above embodiments within the scope of the present invention.

Claims

1. 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 preventing, treating or alleviating alopecia, characterized in that: The compound comprises: Two or more peptide bonds (Y), Y is The two end groups (A) located at the two ends of the main chain of the compound are each independently substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted phenyl, preferably, the substituent is halogen; and A plurality of linking groups (X), each X being independently selected from the group consisting of: and substituted or unsubstituted Preferably, the substituent is halogen; There is at least one linking group between every two peptide bonds.

2. The use according to claim 1, characterized in that The hair loss disease is selected from the group consisting of androgenic alopecia, alopecia areata, scarring 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, said compound comprises: two to four, preferably two, said 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, Aurantiamideacetate, Aurantiamide benzoate, Aurantiamide, TMC-58B.

5. Use of the composition in the preparation of a medicament for preventing, treating or alleviating alopecia, characterized in that: The composition comprises: A compound according to any one of claims 1 to 4 or a stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof; and The optional presence of excipients is selected from the group consisting of pharmaceutically acceptable excipients, cosmetically acceptable excipients, food-acceptable excipients and nutraceutical-acceptable excipients.

6. The use according to claim 5, characterized in that The composition may also contain other drugs for preventing, treating or alleviating hair loss diseases.

7. The use according to claim 5 or 6, characterized in that 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.

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 a compound as claimed in any one of claims 1 to 4 or a stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof, 50-70% ethanol, and 30-50% propylene glycol.

9. A method for preventing, treating or alleviating hair loss diseases, characterized in that: The method comprises administering to a subject a therapeutically effective amount of a compound as described in any one of claims 1 to 4 or a stereoisomer, tautomer, N-oxide, solvate, hydrate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a composition as described in any one of claims 5 to 8.

10. The method according to claim 9, characterized in that The hair loss disease is selected from the group consisting of androgenic alopecia, alopecia areata, scarring alopecia, nutritional alopecia, drug-induced alopecia, traumatic alopecia and immunodeficiency alopecia; Optionally, the method comprises administering the composition to a subject by the following routes: skin administration, transdermal administration, oral administration, subcutaneous injection, intraperitoneal administration, intravenous, intramuscular or intrathecal injection, sublingual administration, buccal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration.

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