Stimulation of hair growth

Abstract

The invention relates to stimulation of hair growth. Compositions and methods that can increase or stimulate hair growth, as well as novel chemicals that affect hair growth and hair loss.

Description

[0001] This application is a divisional application of an application with a filing date of January 8, 2021, application number 202180019260.1, and invention name “Stimulation of Hair Growth”.

[0002] Priority declaration

[0003] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 959,594, filed on January 10, 2020. The entire contents of the foregoing application are incorporated herein by reference. Technical Field

[0004] The present disclosure relates to hair care compositions and methods that can stimulate or accelerate the growth of hair. The present disclosure also relates to a novel compound, bis(trifluoromethyl)propyl squarate (CF3-SADBE), and methods of using the same. Background Art

[0005] Most mammals are covered with hair. Hair loss (also known as alopecia or baldness) is a condition involving the complete or partial loss of hair growth and affects a large proportion of the population. While desirable for some, hair loss is a cause for concern for those who wish to maintain a more youthful appearance. Currently used therapies for baldness have little success and involve significant side effects for the patient, including anti-androgen related toxicity or inflammation of the dermis. Summary of the invention

[0006] The present disclosure is based at least in part on the development of new compounds. The present disclosure is also based on the discovery of new compounds that can be used to stimulate, increase, thicken, or accelerate hair growth. The present disclosure is also based at least in part on new treatment methods for inhibiting, reducing, delaying, or treating hair loss. As described herein, hair loss can be reduced, inhibited, delayed, or treated by applying an effective amount of a composition and preparation as described herein to the scalp and / or hair follicles. As described herein, hair growth can be stimulated, increased, thickened, or accelerated by applying an effective amount of a composition and preparation as described herein to the scalp and / or hair follicles. In some cases, the compositions described herein may include bis(trifluoromethyl)propyl squarate (CF3-SADBE) or a physiologically acceptable salt thereof. In some cases, the composition includes SADBE or diphenylcyclopropenone (DPCP).

[0007] The compositions and methods described herein can be used to stimulate, increase, or accelerate hair growth. In some cases, the compositions and methods described herein exhibit less inflammation than known therapies.

[0008] In one aspect, the present disclosure provides compounds of formula (1):

[0009]

[0010] Or bis(trifluoromethyl)propyl squarate (CF3-SADBE). In some embodiments, the compound is a physiological salt of CF3-SADBE. On the other hand, the present disclosure provides a pharmaceutical composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier, consisting of a compound of formula (1) and a pharmaceutically acceptable carrier, or consisting essentially of a compound of formula (1) and a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises one or more anti-inflammatory agents. The anti-inflammatory agent may be a glucocorticoid, calcipotriol, an immunosuppressant, and / or an antihistamine. In some cases, the composition may further comprise an agent selected from minoxidil, finasteride, SADBE, DPCP, and combinations thereof. In some embodiments, the composition is formulated for topical or subcutaneous administration.

[0011] In another aspect, the present disclosure provides a pharmaceutical composition for increasing hair growth in a mammal in need thereof, comprising, consisting of, or essentially consisting of an effective amount of a compound of formula (1) and a pharmaceutically or dermatologically acceptable carrier.

[0012] In another aspect, the present disclosure provides a hair care composition for increasing hair growth in a mammal in need thereof, comprising, consisting of, or essentially consisting of an effective amount of a compound of formula (1) and a dermatologically acceptable carrier.

[0013] In another aspect, the present disclosure provides a method of increasing the percentage of hair follicles in the anagen phase and decreasing the percentage of hair follicles in the telogen phase in a subject, the method comprising, consisting of, or essentially consisting of administering to a subject in need thereof an effective amount of a compound of formula (1). In some embodiments, the subject suffers from alopecia.

[0014] In another aspect, the present disclosure provides a method of treating hair loss in a subject, the method comprising, consisting of, or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (1). In some cases, hair loss is associated with alopecia.

[0015] In another aspect, the present disclosure provides a method for stimulating hair growth, a method for increasing hair growth, and a method for inhibiting hair loss, respectively, each method comprising, consisting of, or essentially consisting of administering a therapeutically effective amount of a compound of formula (1).

[0016] In another aspect, the present disclosure provides a method for increasing hair growth in a subject, the method comprising topically applying an effective amount of a formulation to the subject's hair follicles and / or skin covering the hair follicles, consisting of, or consisting essentially of, a compound of formula (1) and an acceptable carrier, and applying the formulation once, twice, three times, or more. In another aspect, the present disclosure provides a method for promoting the transition of hair follicles to the growth phase, a method for thickening hair, and a method for reducing hair thinning, each method comprising, consisting of, or consisting essentially of applying a composition, the composition comprising, consisting of, or consisting essentially of an effective amount of formula (1), consisting of, or consisting essentially of an effective amount of formula (1).

[0017] In another aspect, the present disclosure provides a pharmaceutical composition for increasing hair growth in a mammal in need thereof, comprising, consisting of, or consisting essentially of an effective amount of SADBE and / or DPCP and a pharmaceutically or dermatologically acceptable carrier, wherein the mammal does not suffer from an autoimmune disease.

[0018] In another aspect, the present disclosure provides a method of promoting the transition of hair follicles from the telogen phase to the anagen phase, the method comprising, consisting of, or consisting essentially of administering an effective amount of SADBE and / or DPCP to a subject in need thereof, wherein the subject does not suffer from an autoimmune disease. In some embodiments, the subject suffers from alopecia.

[0019] In another aspect, the present disclosure provides a method of treating hair loss in a subject, the method comprising, consisting of, or consisting essentially of administering a therapeutically effective amount of SADBE and / or DPCP, wherein the hair loss is not associated with an autoimmune disorder. In some embodiments, the hair loss is associated with non-autoimmune alopecia.

[0020] In another aspect, the present disclosure provides a method of stimulating hair growth in a subject in need thereof, a method of increasing hair growth in a subject in need thereof, and a method of inhibiting hair loss in a subject in need thereof, each method comprising, consisting of, or essentially consisting of administering a therapeutically effective amount of SADBE and / or DPCP, wherein the subject does not suffer from an autoimmune disease.

[0021] In another aspect, the present disclosure provides a method of increasing hair growth in a subject in need thereof, the method comprising, consisting of, or consisting essentially of topically applying an effective amount of a formulation to hair follicles and / or the skin overlying the hair follicles, wherein the formulation comprises, consists of, or consists essentially of SADBE and / or DPCP and an acceptable carrier, the formulation being applied one, two, three, or more times, and the subject does not suffer from hair loss associated with an autoimmune disease.

[0022] In another aspect, the present disclosure provides a method of promoting the transition of hair follicles from the resting phase to the growth phase in a subject in need thereof, a method of thickening hair in a subject in need thereof, and a method of reducing hair thinning in a subject in need thereof, each method comprising, consisting of, or consisting essentially of administering a composition comprising, consisting of, or consisting essentially of an effective amount of SADBE or DPCP, wherein the subject does not suffer from hair loss associated with an autoimmune disease.

[0023] In some embodiments of all aspects, the hair loss disorder may include keloid acne (e.g., keloid folliculitis, keloid acne nuchal), alopecia areata (autoimmune alopecia; e.g., alopecia serpiginosa), alopecia totalis, alopecia universalis, anagen effluvium, androgenic alopecia (e.g., male and female pattern hair loss), Brocq alopecia, central centrifugal cicatricial alopecia, scarring alopecia (e.g., primary cicatricial alopecia), alopecia congenita, congenital alopecia, diffuse alopecia, discoid lupus erythematosus (DLE), anatomic cellulitis (e.g., perifolliculitis, abscedens et suffodien), "terminal" or "burn out" scarring alopecia, female pattern hair loss, folliculitis alopecia, frontal fibrosing alopecia, hair shaft abnormalities, hyperandrogenism, hypotrichosis, hereditary alopecia, lichen planus, lichen planus pilaris (e.g., diffuse), lipedema alopecia (lipedema scalp), male pattern hair loss (e.g., bitemporal), non-scarring (non-scarring) alopecia, psoriasis, psoriatic alopecia, stress (post-surgical) alopecia, seborrheic dermatitis psoriasis, telogen effluvium, temporal triangular alopecia, tinea capitis, TNF-α inhibitor-induced psoriatic alopecia, traction alopecia, trichophyton nodularis, trichotillomania, and tufted folliculitis. In some embodiments of all aspects, the alopecia associated with an autoimmune disease comprises alopecia areata. In some embodiments of all aspects, hair loss not associated with an autoimmune disease (e.g., non-autoimmune hair loss) includes keloid acne (e.g., keloid folliculitis, keloid acne nuchal), alopecia totalis, alopecia universalis, anagen effluvium, androgenic alopecia (e.g., male and female pattern hair loss), Brocq alopecia, central centrifugal cicatricial alopecia, scarring alopecia (e.g., primary cicatricial alopecia), alopecia congenita, congenital alopecia, diffuse alopecia, discoid lupus erythematosus (DLE), dissecting cellulitis (e.g., perifollicularis abscessus), " "Terminal" or "burn out" scarring alopecia, female pattern hair loss, folliculitis alopecia, frontal fibrosing alopecia, hair shaft abnormalities, hyperandrogenism, hypotrichosis, hereditary alopecia, lichen planus, lichen planus pilaris (e.g., diffuse), lipedema alopecia (lipedema of the scalp), male pattern hair loss (e.g., bitemporal), non-scarring (non-scarring) alopecia, psoriasis, psoriatic alopecia, stress (post-surgical) alopecia, seborrheic dermatitis psoriasis, telogen effluvium, temporal triangular shaped alopecia, tinea capitis, TNF-α inhibitor-induced psoriatic alopecia, traction alopecia, trichophyton nodularis, trichotillomania, and tufted folliculitis.

[0024] In some embodiments of all aspects, the compound, formulation, or composition is administered to the skin, hair, or scalp of a mammal, patient, or subject in need thereof.

[0025] In some embodiments of all aspects, the methods described herein further comprise administering an agent selected from the group consisting of minoxidil, finasteride, DPCP, SADBE, and combinations thereof.

[0026] In some embodiments, the methods described herein increase hair growth by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or 30%.

[0027] In some embodiments of all aspects, the methods described herein further comprise administering more than one steroid.

[0028] In some embodiments of all aspects, the methods described herein further comprise administering one or more agents to reduce sensitivity of the scalp or skin of a mammal (eg, a patient or subject) in need thereof.

[0029] In some embodiments of all aspects, the methods described herein further comprise administering more than one agent to modulate inflammation.

[0030] In some embodiments of all aspects, the formulations described herein further comprise one or more of an aqueous gel, an alcoholic gel, an ointment, an oil, an alcoholic or aqueous fluid, a water-in-oil emulsion, an oil-in-water emulsion, and a water-in-silicone emulsion.

[0031] In some embodiments of all aspects, the formulations described herein further comprise an acceptable auxiliary ingredient selected from the group consisting of xanthan gum, glycerin, EDTA, sodium benzoate, phenoxyethanol, 2-hydroxy fatty alcohol alkoxylate, sodium polyacrylate, polysorbate 20, BHT, disaccharide gum, ethylhexylglycerin, carbomer, butylene glycol, acrylate polymer, PEG-40 hydrogenated castor oil, methylisothiazolinone, methylchloroisothiazolinone, propylene glycol, potassium sorbate, polyglyceryl caprylate, fragrance, and water.

[0032] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. Methods and materials for use in the present disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples described are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0033] Other features and advantages of the disclosure will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1A-D Figure 1A shows the molecular structure of SADBE and DPCP. Both are contact sensitizers (haptens). Figure 1B is a schematic diagram illustrating the timeline of mouse skin with topical application of haptens to hair follicles stagnating in the telogen phase. Figure 1C is a series of pictures of mice with topical application of haptens. The red circles show the treated flanks showing anagen and hair growth. The green circles show the untreated flanks showing the telogen phase. Treatment with contact sensitizers frequently produces skin inflammation (red "*"). Figure 1D is a diagram showing relative anagen induction, which is measured by the skin pigmentation intensity (a sign of anagen) increased on the treated side as a percentage of the baseline of the untreated side (relative to).

[0035] Figure 2A-C New compounds that induce anagen and hair growth are shown. FIG. 2A shows the molecular structure of a synthetic SADBE derivative that exhibits improved anagen induction and / or reduced inflammation. FIG. 2B shows images of mice administered with SADBE, CF3-SADBE, and CCl-SADBE. CF3-SADBE shows at least as effective an induction of anagen and hair growth as SADBE, with less inflammation. CCl-SABDE produces neither inflammation nor anagen and hair growth. The red circles show treated flanks that exhibit anagen and hair growth. The green circles show untreated flanks that exhibit telogen. The dotted red circles show flanks treated with CCl-SADBE, where hair stays in telogen. (Red "*") marks inflammation in the flanks treated with SADBE. FIG. 2C is a diagram showing relative anagen induction of SADBE and its derivatives.

[0036] Figure 3A-B CF3-SADBE is shown to effectively induce anagen and hair growth, with less inflammation than SADBE. Fig. 3A is a diagram showing the following: 100mM SADBE treatment induced anagen and with significant inflammation (blue "*", blue circles) to the 14th day, while the same dose of CF3-SADBE induced anagen with less obvious inflammation (red circles). By the 17th day, strong hair growth was observed on the treated flank using two treatments. Fig. 3B is a diagram showing the relative anagen induction of the percentage of the untreated side as a baseline measured over time for the two treatments.

[0037] Figure 4A-CFigure 4A is an image showing that CF3-SADBE treatment induces resting telogen follicles to enter the anagen phase. Figure 4B is a hematoxylin and eosin (H&E) stain of CF3-SADBE treated skin showing follicles in the anagen phase (red "*"), and Figure 4C shows follicles in untreated skin maintained in the telogen phase (green "*").

[0038] Figure 5 CF3-SADBE induces anagen and hair growth earlier than SADBE with less inflammation. Treatment with CF3-SADBE induced visible anagen by day 10, whereas SADBE did not (purple arrows). SADBE also caused more pronounced inflammation at day 14 (blue "*"). By day 17, robust hair growth was observed on the treated flanks. DETAILED DESCRIPTION

[0039] Compositions for treating hair loss are not well developed; currently available treatments involve administering compositions that are of limited benefit and cause discomfort to the patient.

[0040] Hair growth composition

[0041] As described herein, a number of hapten-derived compounds have been developed. These compounds increase or stimulate hair growth. Some compounds increase hair growth while minimizing inflammation to the dermis. A compound of formula (1) was synthesized:

[0042]

[0043] Subsequently, topical delivery of the disclosed compounds showed accelerated hair growth in mice compared to the contralateral skin treated with vehicle-control in mice, all after prior shaving. In some cases, topical delivery of the novel compounds (e.g., CF3-SADBE) also showed less inflammation than known therapies. In addition, CF3-SADBE was also shown to show increased efficacy, as measured by induction of an earlier growth phase when topically delivered.

[0044] A non-limiting list of hapten derivatives that have been developed and are useful herein includes the following compounds:

[0045]

[0046] These hapten-derived compounds were designed to improve the therapeutic activity and safety of topical hair growth agents. In an attempt to improve solubility and possible skin permeability, PEG or saturated long alkyl chains were introduced to replace the dibutyl ester moiety. However, both compounds were inactive in promoting hair growth in animal models.

[0047] Then a shorter alkyl chain was introduced. Alkyl chains substituted with CF3 or CL were designed. It was speculated that the two compounds might have similar cross-linking reactivity. Surprisingly, the CF3-substituted compound was active in promoting hair growth, while the CL-substituted compound showed low activity. This suggests that the hair growth promoting activity is not simply related to the reactivity of the compound as a cross-linking agent.

[0048] Relative to known therapies, CF3-compounds (eg, CF3-SADBE or MGH-CS-4 described above) exhibit accelerated hair growth, and significantly reduced inflammation to some extent.

[0049] Synthesis of CF3-SADBE

[0050]

[0051] A solution of squaric acid (9 mmol) and alcohol (36 mmol) in toluene (9 ml) was refluxed at 100° C. for 16 hours using a Dean-Stork apparatus. After the reaction was complete, the toluene was concentrated in vacuo and the resulting solution was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution followed by brine. The volatiles were concentrated in vacuo and purified by column chromatography to produce the corresponding compound.

[0052] Use of the composition for stimulating hair growth

[0053] The compounds described herein can be used in compositions for treating hair loss, increasing hair growth, reducing hair loss, stimulating hair growth, thickening hair, or reducing thinning hair. Hair loss can be caused by a variety of conditions. Some of these conditions are associated with autoimmune diseases, while some conditions are not associated with autoimmunity.

[0054] Using CF3-SADBE and other novel compounds for increasing hair growth

[0055] As shown herein, CF3-SADBE can be used to treat hair loss and / or increase hair growth in a subject in need thereof.CF3-SADBE can be used to treat hair loss associated with an autoimmune disease (e.g., alopecia areata), or hair loss not associated with an autoimmune disease. A non-limiting list of hair loss conditions (autoimmune-related hair loss and non-autoimmune hair loss) includes keloidal acne (e.g., keloidal folliculitis, keloidal acne nuchae), alopecia areata (autoimmune hair loss; e.g., alopecia serpiginosa), alopecia totalis, alopecia universalis, anagen effluvium, androgenic alopecia (e.g., male and female pattern hair loss), Brocq alopecia, central centrifugal cicatricial alopecia, scarring alopecia (e.g., primary cicatricial alopecia), alopecia congenita, alopecia congenita, diffuse alopecia, discoid lupus erythematosus (DLE), dissecting cellulitis (e.g., burrowing folliculitis), "terminal" or "burned out" scarring alopecia, Female pattern hair loss, folliculitis alopecia, frontal fibrosing alopecia, hair shaft abnormalities, hyperandrogenism, hypotrichosis, hereditary alopecia, lichen planus, lichen planus pilaris (e.g., diffuse), lipedema alopecia (lipedema of the scalp), male pattern hair loss (e.g., bitemporal), non-cicatricial (non-scarring) alopecia, psoriasis, psoriatic alopecia, stress (post-surgical) alopecia, seborrheic dermatitis psoriasis, telogen effluvium, temporal triangular alopecia, tinea capitis, TNF-α inhibitor-induced psoriatic alopecia, traction alopecia, trichophyton nodularis, trichotillomania, and tufted folliculitis (see, e.g., Bolognia, et al., Dermatology. Elsevier Health Sciences, June 8, 2012. Pages 1163-1187. Section 11: Hair, Nails, and Mucous Membranes. 69: Alopecias). Methods of diagnosing these conditions, or identifying subjects suffering from these conditions, are known in the art; see, e.g., Bolognia, et al., Dermatology. Elsevier Health Sciences, June 8, 2012. Pages 1163-1187. Section 11: Hair, Nails, and Mucous Membranes. 69: Alopecias.

[0056] Use of SADBE or DPCP for treatment of hair loss other than autoimmune alopecia

[0057] As described herein, surprisingly, the compounds SADBE and DPCP can also be used to treat alopecia not associated with autoimmune disorders (e.g., for treating other alopecia conditions other than alopecia areata). SADBE and DPCP have been used to treat alopecia areata, an autoimmune-related alopecia. However, prior to the present disclosure, it was not known that DPCP and / or SADBE can increase hair growth in mammals that do not suffer from autoimmune diseases. As described herein, SADBE increases (e.g., promotes) hair growth in mammals that do not suffer from autoimmune diseases. In addition, DPCP shows increased hair growth in mammals that do not suffer from autoimmune diseases.

[0058] A non-limiting list of non-autoimmune related hair loss conditions includes keloid acne (e.g., keloid folliculitis, keloid acne nuchae), alopecia totalis, alopecia universalis, anagen effluvium, androgenic alopecia (e.g., male and female pattern hair loss), Brocq alopecia, central centrifugal cicatricial alopecia, scarring alopecia (e.g., primary cicatricial alopecia), alopecia congenita, alopecia congenita, diffuse alopecia, discoid lupus erythematosus (DLE), dissecting cellulitis (e.g., burrowing folliculitis), "terminal" or "burned out" scarring, Alopecia, female pattern hair loss, folliculitis alopecia, frontal fibrosing alopecia, hair shaft abnormalities, hyperandrogenism, hypotrichosis, hereditary alopecia, lichen planus, lichen planus pilaris (e.g., diffuse), lipedema alopecia (lipedema of the scalp), male pattern hair loss (e.g., bitemporal), non-cicatricial (non-scarring) alopecia, psoriasis, psoriatic alopecia, stress (post-surgical) alopecia, seborrheic dermatitis psoriasis, telogen effluvium, temporal triangular shaped alopecia, tinea capitis, TNF-alpha inhibitor induced psoriatic alopecia, traction alopecia, trichophyton nodularis, trichotillomania, and tufted folliculitis. Methods of diagnosing these conditions, or identifying subjects suffering from these conditions, are known in the art; see, e.g., Bolognia et al., Dermatology. Elsevier Health Sciences, June 8, 2012. Pages 1163-1187. Section 11: Hair, Nails, and Mucous Membranes. 69: Alopecias.

[0059] Combination therapy

[0060] In some embodiments, the methods described herein may include administering a combination therapy. A non-limiting list of therapeutic options that may be administered with the compositions and methods described herein include topical, oral, and intralesional corticosteroids (e.g., clobetasol, fluocinonide), local irritants (e.g., anthralin, tazarotene, azelaic acid, acid), topical minoxidil, topical finasteride, dutasteride, topical immunotherapy, systemic corticosteroids (e.g., pulsed), oral finasteride (e.g., type II 5α-reductase inhibitors), oral tetracyclines (e.g., doxycycline, minocycline), oral rifampin and clindamycin, TNF-α inhibitors, PPAR-γ agonists (e.g., pioglitazone hydrochloride), isotretinoin, oral zinc sulfate, oral antimalarials (e.g., hydroxychloroquine), systemic JAK / STAT pathway inhibitors (e.g., tofactinib or ruxolitinib), topical or oral photochemotherapy, excimer laser, systemic corticosteroids (e.g., long-term), and systemic cyclosporine.

[0061] Preparation and administration of the composition

[0062] The compositions of the present disclosure can be used in many different ways. For example, they can be components of dry formulations or wet solutions. They can be provided as components of injectable compositions that are injected (e.g., intradermally or subcutaneously) into bald areas (e.g., scalp). Alternatively, the compounds described herein can be components of compositions that are topically applied to bald areas or hair loss areas. This can be done for the purpose of thickening the appearance of hair. These compositions can be optionally administered in combination with any known non-toxic delivery agent and / or penetrant.

[0063] The compositions of the present disclosure can be topically administered or administered by injection. The required dose depends on the choice of route of administration; the nature of the preparation; the nature of the subject's condition; the size of the subject, the surface area of ​​treatment, age and sex; other drugs administered; and the judgment of the attending physician. In some embodiments, the appropriate dose is within the range of 0.01-500.0 mg / kg. Considering the different efficiencies of various routes of administration, it is expected that the required dose will vary greatly. The changes in these dose levels can be adjusted using standard empirical practices for optimization well known in the art. Administration can be single or multiple (e.g., 2-, 3-, 4-, 6-, 8-, 10-, 20-, 50-, 100-, 150-, or more times). The compositions of the present disclosure can also be administered in a single topical treatment. The compositions of the present disclosure can be administered in multiple topical treatments. Multiple administrations can be daily, every other day, every two weeks, weekly, every other week, monthly, or any combination thereof. The administration of the compositions described herein can be performed in one day, one week, one month, one year, or longer. Encapsulating the compound in a suitable delivery vehicle (e.g., cream, lotion, aqueous solution, or solid) can improve delivery efficiency. The required dosage also depends on the variability of the skin. Different dosages may be required due to different skin thicknesses at the hair-bearing site, number of applications, skin type, different indications (e.g., different causes of hair loss), and / or different tolerances of the subject.

[0064] The compositions of the present application can be prepared for storage by mixing the compositions of the present application with any one or more of various pharmaceutically acceptable carriers, excipients, or stabilizers known in the art. Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dosage and concentration used, and include: buffers, such as phosphates, citrates, and other non-toxic organic acids, etc.; antioxidants, such as ascorbic acid, etc.; low molecular weight (less than 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins, etc.; hydrophilic polymers, such as polyvinyl pyrrolidone, etc.; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine, etc.; monosaccharides, disaccharides, and other sugars, including glucose, mannose, or dextran, etc.; chelating agents, such as EDTA, etc.; sugar alcohols, such as mannitol, or sorbitol, etc.; salt-forming counterions, such as sodium, etc.; and / or non-ionic surfactants, such as Tweens, Pluronics, or PEG, etc.

[0065] The composition can be in any form suitable for application to the scalp and / or hair, such as solutions, suspensions, lotions, creams, gels, toners, sticks, pens, sprays, aerosols, ointments, cleansing liquid detergents and solid sticks, shampoos and hair conditioners, pastes, foams, emulsions, poultices, water-oil bilayer compositions, water-oil powder trilayer compositions, serums, powders, mousses, shaving creams, wipes, strips, patches, hydrogels, film-forming products, and disposable applicators, etc. The composition can be a shampoo, hair conditioner, or hair lotion. If a specific dermatologically acceptable carrier is present in the composition, the form of the composition can follow the specific dermatologically acceptable carrier selected. The composition can be in the form of an aqueous, aqueous-alcoholic, or oily solution; an emulsion- or serum-type-dispersion; or an emulsion (e.g., an emulsion-type emulsion of liquid or semi-liquid consistency). The composition may be in the form of a suspension or emulsion with a soft consistency of the aqueous or anhydrous cream or gel type, or alternatively, in the form of microcapsules or microparticles, or in the form of ionic and / or nonionic vesicular dispersions. The composition may be anhydrous or aqueous.

[0066] The compositions described herein may include a dermatologically acceptable carrier (also referred to herein simply as a "carrier") for the composition. The phrase "dermatologically acceptable carrier" as used herein means that the carrier is suitable for topical application to the hair / scalp, has good aesthetic properties, is compatible with the hair anti-aging agent in the composition, and does not cause any unreasonable safety or toxicity issues. A suitable carrier is selected to produce the desired product form. In addition, the solubility or dispersibility of the components can determine the form and characteristics of the carrier. In some embodiments, the carrier is present at a level of about 50 wt% to about 99 wt%, about 60 wt% to about 98 wt%, about 70 wt% to about 98 wt%, or alternatively, about 80 wt% to about 95 wt%, of the weight of the composition.

[0067] The carrier can be in various forms. Non-limiting examples include simple solutions (e.g., aqueous, organic solvents, or oil-based), emulsions, and solid forms (e.g., gels, sticks, flowable solids, or amorphous materials). In certain embodiments, the dermatologically acceptable carrier is in the form of an emulsion. Emulsions can generally be classified as having a continuous aqueous phase (e.g., oil-in-water and water-in-oil-in-water) or a continuous oil phase (e.g., water-in-oil and oil-in-water-in-oil). The oil phase of the present disclosure can include silicone oils; non-silicone oils such as hydrocarbon oils, esters, and ethers; and mixtures thereof.

[0068] The aqueous phase includes water, such as demineralized water or distilled water. Other acceptable carriers that can be used for aqueous carriers include, but are not limited to, alcohol compounds, such as ethanol, etc. According to one embodiment, the composition comprises alcohol, dipropylene glycol, and / or water.

[0069] The pH of the composition ranges from about 3.0 to about 10 (e.g., between about pH 4.0 and about pH 9.0, between about pH 5.0 and about pH 9.0, or between about pH 6.0 and about pH 8.0), which can be measured by direct pH measurement using a standard hydrogen electrode of the composition at 25° C. Thus, the pH of the composition can be, for example, in the range of about 6 to about 9.

[0070] The emulsion may further include an emulsifier. The composition may include any suitable percentage of emulsifier to fully emulsify the carrier. Based on the weight of the composition, a suitable weight range includes about 0.1wt% to about 10wt% or about 0.2wt% to about 5wt% of the emulsifier. The emulsifier may be nonionic, anionic, or cationic. Suitable emulsifiers are disclosed in, for example, U.S. Patent Nos. 3,755,560 and 4,421,769, and McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317-324 (1986), the foregoing documents being incorporated herein by reference in their entirety. Depending on the desired product form, suitable emulsions may have a wide range of viscosities. Non-limiting examples of emulsifiers include glyceryl stearate, polysorbate 60, and polysorbate 60, described by Gattefosse in the The PEG-6 / PEG-32 / glyceryl stearate mixture sold under the name of PEG-6 / PEG-32 / stearate. The emulsion may include a fat phase ranging from about 5 wt % to about 80 wt % (e.g., from about 5 wt % to about 50 wt %) of the composition. Any emulsion described herein may include one or more agents selected from the group of oils, waxes, emulsifiers, and co-emulsifiers. Examples of oils, waxes, emulsifiers, and co-emulsifiers for hair care compositions are well known in the art. Emulsifiers and co-emulsifiers may be present in the composition in a ratio ranging from 0.3 wt % to about 30 wt % (e.g., from about 0.5 wt % to about 20 wt %) of the composition. The emulsion may contain lipid vesicles.

[0071] The composition (e.g., any composition described herein) may include one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) hydrophilic gelling agents (e.g., carboxyvinyl polymers, acrylic copolymers (e.g., acrylate / alkyl acrylate copolymers), polyacrylamide, polysaccharides (e.g., hydroxypropyl cellulose), natural gums, and clays), lipophilic gelling agents (e.g., modified clays (e.g., betones), metal salts of fatty acids (e.g., aluminum stearate), and hydrophobic silica, ethyl cellulose, and polyethylene), hydrophilic or lipophilic additives, preservatives, antioxidants, solvents (e.g., ethanol, isopropanol, and propylene glycol), fragrances, fillers, odor absorbers, dyes, oils (e.g., mineral oils (e.g., liquid paraffin), vegetable oils (e.g., shea butter or sunflower oil), animal oils (e.g., squalane), synthetic oils (e.g., purcellin oil), or silicone oil), wax (e.g., cyclomethicone, beeswax, carnauba wax, or paraffin), surfactants, antimicrobial agents, metal ion chelators, water-soluble polymers, thickeners, pigments, UV protectants, humectants, antioxidants, pH adjusters, cleansers, and desiccants, for example, each of more than one agent is present in the composition, for example, at between about 0.01 wt % and about 10 wt % of the composition.

[0072] Any of the compositions provided herein may comprise at least one preservative and / or dye.

[0073] The term "subject" or "patient" is defined herein to include animals. In some embodiments, the animal is a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, and mice, etc. In some embodiments, the subject is a human. In some embodiments, the subject is a child.

[0074] Use of compounds in cosmetic compositions

[0075] The present disclosure is based, at least in part, on the development of cosmetic compositions that can be used to stimulate, increase, thicken, or accelerate hair growth. These cosmetic compositions can be used in subjects with or without alopecia. As described herein, by applying a cosmetically effective amount of the compositions and formulations described herein to the scalp and / or hair follicles, for example, temporarily, hair growth can be stimulated, increased, thickened, or accelerated. As described herein, by applying a cosmetically effective amount of the compositions and formulations described herein to the scalp and / or hair follicles, hair loss can be reduced, inhibited, delayed, or treated.

[0076] In some embodiments, the present disclosure provides a cosmetic composition comprising one or more compounds described herein and a pharmaceutically acceptable carrier. In some cases, the cosmetic composition further comprises one or more anti-inflammatory agents. The anti-inflammatory agent can be a glucocorticoid agent, a calcipotriol agent, an antihistamine and / or other immunosuppressant. The composition described herein can also comprise any hair growth agent known in the art, including, for example, minoxidil or finasteride.

[0077] The cosmetic compositions described herein may be formulated for topical or subcutaneous administration.

[0078] In some embodiments, the present disclosure provides a cosmetic composition for increasing hair growth in a mammal in need thereof, the cosmetic composition comprising an effective amount of one or more compounds described herein and a pharmaceutically or dermatologically acceptable carrier. Also described herein is a method for increasing hair growth, the method comprising topically applying an effective amount of a formulation to hair follicles and / or the skin covering the hair follicles one or more times, wherein the formulation comprises one or more compounds described herein and a cosmetically acceptable carrier. The cosmetically acceptable carrier may include one or more of the following: an aqueous gel, an alcoholic gel, an ointment, an oil, an alcoholic or aqueous fluid, a water-in-oil emulsion, an oil-in-water emulsion, and a water-in-silicone emulsion. In some cases, the compositions described herein further include a cosmetically acceptable auxiliary ingredient selected from the group consisting of xanthan gum, glycerin, EDTA, sodium benzoate, phenoxyethanol, 2-hydroxy fatty alcohol alkoxylate, sodium polyacrylate, polysorbate 20, BHT, disaccharide gum, ethylhexylglycerin, carbomer, butylene glycol, acrylate polymer, PEG-40 hydrogenated castor oil, methylisothiazolinone, methylchloroisothiazolinone, propylene glycol, potassium sorbate, polyglyceryl caprylate, fragrance, and water.

[0079] Example

[0080] The compositions and methods of the present disclosure are further described in the following examples, which do not limit the scope of the disclosure described in the claims.

[0081] Example 1: Topical application of SADBE and DPCP

[0082] To measure the effects of SABDE and DPCP (see FIG. 1a) on hair growth, 4 days before topical application of the compound (day -4), the flanks of 6 female C57BL / 6 mice aged 8 weeks were shaved. During this period, as expected from 8-week-old mice, the mice were monitored visually to confirm that there was no hair growth and that the entire shaved area was stagnant in the resting phase. On the day of application (day 0), 2% SABDE or 2% DCPC was topically applied to the shaved left flank of 3 mice using a cotton-tipped applicator, respectively (see FIG. 1b). Images were taken on the 9th and 16th days to visualize hair growth and inflammation (see FIG. 1c). Skin pigmentation intensity was quantified by ImageJ. The growth phase induction index was calculated as the change in skin pigmentation intensity (a sign of the growth phase) on the treated side relative to the untreated side (i.e., as a percentage of the untreated side) (see FIG. 1d).

[0083] The anagen induction index can be determined by any method known in the art, including, for example, histological methods (e.g., H&E, other staining, or no staining) and / or other visual morphological methods (e.g., methods for measuring biological parameters of hair growth). The value is then normalized to the specific experiment (single mouse) and displayed as relative anagen induction by the intensity of skin pigmentation (a marker of the anagen phase) on the treated side as a percentage of the baseline untreated side. Analysis of the anagen phase (or other phases) can be performed by any method known in the art, including, for example, tissue biopsy and / or morphological analysis.

[0084] Inflammation can be measured by known methods such as histological grading, visual identification, and quantification of lesions. The number, size, and extent of skin lesions present (e.g., see blue * in FIG. 3a ) can be visualized and quantified using any method known in the art, including, for example, histological methods (e.g., H&E, other stains, or no staining) and / or other visual morphological methods.

[0085] Example 2: Topical application of new compounds

[0086] To compare the effects of SABDE, CF3-SABDE or CCl-SABDE (see Figure 2a) on hair growth, three 8-week-old female C57BL / 6 mice were pre-sensitized on the chest with 2% of each compound 4 days before the first treatment and both flanks were shaved (day 0). On days 3, 5 and 7, 2% of SABDE, CF3-SABDE or CCl-SABDE was applied topically to the shaved left flank of one mouse, respectively, using a cotton-tipped applicator. Images were taken on day 17 to visualize hair growth and inflammation (see Figures 2B and 2C).

[0087] Example 3: Comparison of known and novel compounds

[0088] The effect of topical therapeutic doses of SADBE or CF3-SADBE was measured using the method described in Example 1. In Figure 3, the topical therapeutic dose used was 50 uL of 100 mM SADBE or CF3-SADBE.

[0089] Example 4: Growth phase induced by CF3-SADBE

[0090] The effect of topical treatment doses of CF3-SADBE was measured and visualized using the method described in Example 1. The overall appearance of mice treated with CF3-SADBE was imaged (see Figure 4a). CF3-SADBE was applied to the left flank at a dose of 100uL of 100mM CF3-SADBE (see Figure 4B). The right flank was not treated (see Figure 4C).

[0091] Example 5: CF3-SADBE induces growth phase earlier than SADBE and is accompanied by less inflammation

[0092] The effects of topical treatment with 100 mM CF3-SADBE on anagen induction and inflammation were measured and visualized using the methods described in Example 1. Treatment with 100 mM CF3-SADBE induced visible anagen at day 10. Treatment with 100 mM SADBE did not induce visible anagen at day 10 (see Figure 5 This indicates the enhanced efficacy of CF3-SADBE. SADBE also caused more pronounced inflammation on day 14 (see Figure 5 Blue "*"). Vigorous hair growth was observed on the treated flanks at day 17.

[0093] Other Implementations

[0094] It should be understood that although the disclosure has been described in conjunction with the detailed description of the disclosure, the foregoing description is intended to be illustrative and not intended to limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. A compound of formula (1):

2. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, further comprising one or more anti-inflammatory agents.

4. The pharmaceutical composition according to claim 3, wherein the anti-inflammatory agent is selected from the group consisting of glucocorticoids, calcipotriol, immunosuppressants, and antihistamines.

5. The pharmaceutical composition according to claim 2, further comprising an agent selected from minoxidil, finasteride, SADBE, DPCP, and a combination thereof.

6. The pharmaceutical composition of claim 2, wherein the composition is formulated for topical or subcutaneous administration.

7. A pharmaceutical composition for increasing hair growth in a mammal in need thereof, comprising an effective amount of a compound according to claim 1 and a pharmaceutically or dermatologically acceptable carrier.

8. A hair care composition for increasing hair growth in a mammal in need thereof, comprising an effective amount of a compound according to claim 1 and a dermatologically acceptable carrier.

9. Use of a compound according to claim 1 in the preparation of a medicament for increasing the percentage of hair follicles in the growth phase and reducing the percentage of hair follicles in the resting phase in a subject by the following method, the method comprising administering an effective amount of a compound according to claim 1 to a subject in need thereof.

10. The use according to claim 9, wherein the subject suffers from alopecia.

11. The use according to claim 10, wherein the hair loss disorder is selected from the group consisting of: keloidal acne, alopecia areata, alopecia totalis, alopecia universalis, anagen effluvium, androgenic alopecia, Brocq alopecia, central centrifugal cicatricial alopecia, cicatricial alopecia, alopecia congenita, congenital alopecia, diffuse alopecia, discoid lupus erythematosus (DLE), anatomic cellulitis, "terminal" or "burnt out" cicatricial alopecia, female pattern hair loss, hair follicles Inflammatory alopecia, frontal fibrosing alopecia, hair shaft abnormalities, hyperandrogenism, hypotrichosis, hereditary alopecia, lichen planus, lichen planus pilaris, limatous alopecia, male pattern hair loss, non-scarring alopecia, psoriasis, psoriatic alopecia, stress alopecia, seborrheic dermatitis psoriasis, telogen effluvium, temporal triangular shaped alopecia, tinea capitis, TNF-α inhibitor induced psoriatic alopecia, traction alopecia, trichophyton nodularis, trichotillomania, and tufted folliculitis.

12. Use of a compound according to claim 1 in the preparation of a medicament for treating hair loss in a subject by a method comprising administering a therapeutically effective amount of a compound according to claim 1 to a subject in need thereof.

13. The use according to claim 12, wherein the hair loss is associated with alopecia.

14. The use of claim 12, wherein the compound is administered to the skin, hair, or scalp of a mammal in need thereof.

15. Use of a compound according to claim 1 in the preparation of a medicament for stimulating hair growth by a method comprising administering a therapeutically effective amount of a compound according to claim 1.

16. Use of a compound according to claim 1 in the preparation of a medicament for increasing hair growth by a method comprising administering a therapeutically effective amount of a compound according to claim 1.

17. Use of the compound according to claim 1 in the preparation of a medicament for inhibiting hair loss by a method comprising administering a therapeutically effective amount of the compound according to claim 1.

18. Use of a formulation in the preparation of a medicament for increasing hair growth in a subject by the following method, the method comprising topically applying an effective amount of the formulation to the hair follicles and / or the skin covering the hair follicles of the subject, wherein the formulation comprises a compound according to claim 1 and an acceptable carrier, and the formulation is applied once, twice, three times, or more times.

19. The use according to claim 18, wherein the acceptable carrier comprises one or more of the following: aqueous gel, alcoholic gel, ointment, oil, alcoholic or aqueous fluid, water-in-oil emulsion, oil-in-water emulsion, and water-in-silicone emulsion.

20. The use according to claim 18, wherein the preparation further comprises an acceptable auxiliary ingredient selected from the group consisting of: xanthan gum, glycerin, EDTA, sodium benzoate, phenoxyethanol, 2-hydroxy fatty alcohol alkoxylate, sodium polyacrylate, polysorbate 20, BHT, disaccharide gum, ethylhexylglycerin, carbomer, butylene glycol, acrylate polymer, PEG-40 hydrogenated castor oil, methylisothiazolinone, methylchloroisothiazolinone, propylene glycol, potassium sorbate, polyglyceryl caprylate, fragrance, and water.

21. The use according to claim 18, wherein the formulation further comprises an agent selected from the group consisting of minoxidil, finasteride, DPCP, SADBE, and combinations thereof.

22. The use of claim 18, wherein the method increases hair growth by at least about 10%.

23. The use of claim 21, wherein the method increases hair growth by at least about 15%.

24. The use of claim 21, wherein the method increases hair growth by at least about 20%.

25. The use according to claim 18, further comprising administering more than one steroid.

26. The use of claim 18, further comprising administering one or more agents to reduce sensitivity of the scalp or skin of a mammal in need thereof.

27. The use of claim 18, further comprising administering one or more agents to modulate inflammation.

28. Use of a composition comprising the compound according to claim 1 in the preparation of a medicament for promoting the transition of hair follicles to the growth phase by a method comprising administering a composition comprising an effective amount of the compound according to claim 1.

29. Use of a composition comprising a compound according to claim 1 for the preparation of a medicament for thickening hair by a method comprising administering a composition comprising an effective amount of a compound according to claim 1.

30. Use of a composition comprising a compound according to claim 1 in the preparation of a medicament for reducing hair thinning by a method comprising administering a composition comprising an effective amount of a compound according to claim 1.

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