Use of steroidal compounds

Abstract

The present application provides a kind of application of the steroid compound in preparation prevention or treatment skin pigmentation related condition or anti-aging related product, the steroid compound is as shown in formula I, and has treatment, lightening and / or alleviating effect on senile plaques, freckles, chloasma and the like caused by pigmentation on the skin of mammal.(I).

Description

Technical Field

[0001] This invention belongs to the field of chemical technology, specifically relating to the application of a steroid compound in the preparation of products for the prevention or treatment of skin pigmentation-related conditions. Background Technology

[0002] Melanin is a collective term for a class of compounds found in animals, plants, and protists. In humans, melanin is formed in melanosomes, cellular structures found in cells called melanocytes, located in the epidermis, basal layer, and the lowest layer of basal cells. Melanin is transported from the keratinocytes of the epidermis to the corneocytes in the stratum corneum of the skin, giving the stratum corneum its brown pigment. Due to the presence of melanin in the stratum corneum, melanin is responsible for pigmentation in human skin. Melanin absorbs ultraviolet radiation, thus playing an important role in protecting the body (especially the skin) from damage and potential carcinogenic effects from sunlight and other environmental sources of ultraviolet radiation. When exposed to ultraviolet radiation, the body naturally increases melanin production in the exposed skin areas as a defense mechanism. This increased melanin production leads to a darkening of the exposed skin, a phenomenon commonly known as tanning. Hyperpigmentation and other uneven skin pigmentation are generally considered undesirable and unsightly. For example, acne, rashes, scratches, or injuries to the skin can cause post-inflammatory hyperpigmentation, characterized by unwanted dark spots on the face or other parts of the body. Melasma is a condition associated with hormonal changes caused by pregnancy, taking birth control pills, or menopausal changes; it is usually masked by pigmentation deposited on the surface of the epidermis or deeper in the dermis. Melasma, also known as liver spots, is a dark discoloration caused by sun damage and generally appears in older individuals. Freckles are small spots common in young people with fair skin that is easily sunburned when exposed to sunlight.

[0003] Senile spots (SS) or senile plaques (SP) are one of the most obvious signs of skin aging in mammals. They are formed by the continuous deposition of lipofuscin, a pigment produced by aging, in skin cells and sweat gland cells, gradually forming on the skin surface, especially in the elderly. Senile spots are flat, brownish-black, dark brown, or blackish-brown spots or patches of varying numbers and sizes, resembling oval shapes, that grow on the face, back of the hands, arms, and even the body surface of aging individuals. They are most commonly found on the scalp and face, followed by the back of the hands, neck, chest, back, and limbs.

[0004] The pathogenesis of age spots mainly involves four aspects. First, with age, pigment gradually accumulates in human cells, eventually depositing on the skin surface to form age spots. Second, it is caused by genetic factors, resulting in an autosomal dominant inherited skin condition, most commonly distributed on the face, especially around the nose and cheeks. Because the lesions resemble spots on a bird's pecking or sparrow eggs, they are also called freckles. Third, it is related to free radicals. With age, the amount of free radicals produced by metabolic processes in human cells gradually increases. When the body's ability to eliminate free radicals declines, these chemically active free radicals can rapidly interact with and severely damage the body. Among them, the attack of oxygen free radicals on lipid biomembranes is most closely related to the appearance of age spots. It can oxidize unsaturated fatty acids into peroxides, which can further decompose to produce large amounts of aldehydes, alcohols, and hydrocarbons. Malondialdehyde (MDA) is highly toxic and readily reacts with phospholipids and proteins to form lipofuscin, a pigment associated with aging. Fourth, it is related to physical factors such as ultraviolet radiation. Long-term, high-volume, and continuous ultraviolet radiation can cause epidermal cells to produce singlet oxygen, superoxide radicals, hydroxyl radicals, and other reactive oxygen species. These can not only damage the 8-hydroxyguanosine of DNA and cause genetic mutations, but also produce or accelerate epidermal lipid peroxidation, forming lipofuscin or age spots. In addition to sunlight, air pollution, radiation, ozone, etc., can all promote the formation of free radicals, accelerating the formation of age spots on the skin.

[0005] Currently, the main treatments for age spots include the following: First, pay attention to diet, eat more fruits and vegetables to supplement vitamin C, promote blood circulation and metabolism, regulate hormone secretion, enhance skin cell vitality, and prevent the formation of lipofuscin and age spots. Second, physical therapy, such as electrocautery, laser therapy, and methods using high-frequency current, cryotherapy, cutting, or dermabrasion. Third, chemotherapy, which uses chemical peeling agents to damage the skin surface, cause scabs, and remove the scabs to achieve the therapeutic goal, such as using 33% trichloroacetic acid solution. This method must be strictly followed according to the doctor's instructions. Fourth, biotechnology, such as superoxide dismutase (SOD) preparations and SOD complex enzyme (SOD-CCE) systems, metallothionein (MT), and activated protective proteins, which prevent the formation of lipofuscin by scavenging free radicals in the body. Fifth, traditional Chinese medicine treatment, which mainly uses single-herb and compound Chinese medicines or prepared Chinese medicines with significant antioxidant effects, free radical and metabolite scavenging effects, and the ability to increase the content of macromolecular free radical scavengers and SOD activity to remove lipofuscin.

[0006] Analysis revealed several shortcomings in the aforementioned products. For instance, while physical therapy offers noticeable and immediate results, it can easily burn the skin and leave permanent scars. Furthermore, it requires multiple sessions over extended periods and must be performed by skilled and experienced licensed physicians in professional medical institutions, and is also expensive. Chemotherapy can damage the stratum corneum of the skin, causing skin side effects. Biological and traditional Chinese medicine therapies can only temporarily inhibit or delay the formation of pigments such as melanin or lipofuscin, and cannot achieve a therapeutic effect.

[0007] Therefore, there is an urgent need in the market for a convenient and practical product that can prevent or treat skin pigmentation-related conditions. Summary of the Invention

[0008] In view of the shortcomings of the existing technology, the purpose of this invention is to provide an application of steroidal compounds in products for the prevention or treatment of pigmentation-related conditions. The steroidal compounds provided by this invention can have a good therapeutic, alleviating and preventive effect on age spots, and can greatly reduce and / or cure age spots.

[0009] To achieve this objective, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides the use of a steroidal compound in the prevention or treatment of skin pigmentation-related conditions or in anti-aging-related products, wherein the steroidal compound is a compound with the structure shown in Formula I, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound with the structure shown in Formula I.

[0011] (I)

[0012] Wherein, R is H, D (deuterium), alkyl, sulfate, phosphate, alkylsilyl, benzyl, or -C(O)-X;

[0013] X is selected from aryl, heteroaryl, cycloalkyl, heterocyclol, heteroalkyl, or alkyl;

[0014] The aryl, heteroaryl, cycloalkyl, heterocyclic, heteroalkyl, alkylsilyl, and alkyl groups described in R and X are optionally substituted by 1, 2, 3, or 4 identical or different substituents;

[0015] The substituents are selected from D, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, alkyl carbonyl, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, arylalkyl, heteroaryl, carboxyl, R. 1 R 2 NC (=O) - or R 1 R 2 NC(=NH)-NR 3 -;

[0016] R 1 R 2 and R 3 Each is independently selected from -H, -D, or alkyl groups.

[0017] In some embodiments, the steroidal compound is a compound with the structure shown in Formula II, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound with the structure shown in Formula II.

[0018] (II)

[0019] The definition of R is the same as that in equation (I).

[0020] In some implementations, R stands for H, D, C. 1-6 Alkyl, sulfate, phosphate, C 1-6 Alkylsilyl, benzyl, or -C(O)-X.

[0021] In some implementations, X is selected from C. 6-10 Aryl, C 2-9 heteroaryl, C 3-8 cycloalkyl, C 2-10 Heterocyclic group, C 1-6 Heteroalkyl or C 1-6 alkyl.

[0022] In some implementations, C as described in R and X 6-10 Aryl, C 2-9 heteroaryl, C 3-8 cycloalkyl, C 2-10 Heterocyclic group, C 1-6 Heteroalkyl, C 1-6 Alkylsilyl or C 1-6 The alkyl group may optionally be replaced by 1, 2, 3 or 4 identical or different substituents.

[0023] In some embodiments, the substituent is selected from D, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, C 1-6 alkyl carbonyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 heteroaryl, carboxyl (e.g., -COOH), R 1 R 2 NC (=O) - or R 1 R 2NC(=NH)-NR 3 -

[0024] In some implementation schemes, R 1 R 2 and R 3 Each can be independently selected from -H, -D, or -C. 1-6 alkyl.

[0025] In some embodiments, X is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, mercaptoethyl, aminomethyl, aminoethyl, aminopropyl, phenylmethyl, phenylethyl, imidazolylmethyl, carboxymethyl, carboxyethyl, methylthiomethyl, methylthioethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl 1,3-Dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaranyl, thiaranyl, homopiperazine, homopiperidinyl, oxetaneheptane, thioheptanyl, oxazine, diazaine, thiazaine, indololinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, Imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thiophenyl, 3-thiophenyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, isoquinolinyl, imidazo[1,2-a]pyridyl, pyrazol[1,5-a]pyridyl, pyrazol[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazol[4,3-b]pyridazinyl, [1,2,4]triazol[1,5-a]pyrimidinyl, [1,2,4]triazol[1,5-a]pyridyl , , , C with H2NC(=O)- substituent 1-3 Alkyl groups or C groups with H2NC(=NH)-NH- substituents 1-3 alkyl.

[0026] In some embodiments, the substituents in R and X are selected from -H, -D, halogen, hydroxyl, amino, cyano, nitro, carboxyl, C 1-6alkyl carbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 Mixed aromatic compounds.

[0027] In other embodiments, the substituents in R and X are selected from -H, -D, -F, -Cl, -Br, hydroxyl, amino, cyano, carboxyl, formyl, acetyl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiopheneyl, dihydrothiopheneyl, 1,3-dioxocyclopentyl, disulfide ring. Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaranyl, thiaranyl, homopiperazine, homopiperidinyl, oxetaneheptane, thioheptanyl, oxazate, diazayl, thiazayl, indololinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isooxazole , isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thiophenyl, 3-thiophenyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl Benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolinyl, isoquinolinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridyl.

[0028] In one specific embodiment of the present invention, X is selected from any of the following groups:

[0029] , , , , , , , , , , , , , , , , , , or .

[0030] As a specific embodiment of the present invention, the compound with the structure shown in Formula I or II is selected from any one of the following compounds:

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] In some implementations, the product is a medicine or a skin care product.

[0038] In some implementations, the skin pigmentation-related condition is selected from one or more of melasma, pregnancy mask, chloasma, age spots, café-au-lait spots, and freckles.

[0039] In some implementations, the anti-aging product is an anti-skin aging product.

[0040] In some embodiments, the product is in the form of a solution, emulsion, suspension, cream, ointment, gel, or patch.

[0041] The steroidal compounds provided by this invention can be used as unprocessed chemical drugs for treatment, or as active ingredients in pharmaceutical compositions.

[0042] In a second aspect, the present invention provides the use of the composition in the preparation of products for the prevention or treatment of skin pigmentation-related conditions or anti-aging-related conditions, the composition comprising the steroidal compound described in the first aspect, and one or more of pharmaceutically or cosmetically acceptable carriers, excipients, diluents, adjuvants or mediators.

[0043] Substances that can be used as pharmaceutically or cosmetically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts; electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solutions, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives, and antioxidants.

[0044] In some implementations, the product is a medicine or a skin care product.

[0045] In some implementations, the skin pigmentation-related condition is selected from one or more of melasma, pregnancy mask, chloasma, age spots, café-au-lait spots, and freckles.

[0046] In some implementations, the anti-aging product is an anti-skin aging product.

[0047] In some embodiments, the product is in the form of a solution, emulsion, suspension, cream, ointment, gel, or patch.

[0048] In a third aspect, the present invention provides a method for preventing or treating skin pigmentation-related conditions or for anti-aging, comprising administering to a subject a steroidal compound (a compound with the structure shown in Formula I or Formula II, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug) as described in the first aspect or a composition as described in the second aspect.

[0049] In some implementations, the skin pigmentation-related condition is selected from one or more of melasma, pregnancy mask, chloasma, age spots, café-au-lait spots, and freckles.

[0050] In some implementations, the anti-aging product is an anti-skin aging product.

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] The present invention has discovered that the steroidal compounds provided by the present invention can be used to prevent, treat, or alleviate age spots, freckles, or melasma in patients, and are convenient, practical, and have few side effects. Attached Figure Description

[0053] Figure 1 These are facial photographs taken on day 1 and day 60 after application of the composition of the present invention. Detailed Implementation

[0054] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the specific embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention.

[0055] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0056] The "stereoisomers" described in this invention refer to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, and hindered isomers, etc.

[0057] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and diastereomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0058] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0059] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0060] The term "prodrug" as used in this invention refers to the conversion of a compound into a compound represented by Formula I or Formula II in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0061] Racemic mixtures of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating their diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim, Germany, 2007).

[0062] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons. Specific examples of keto-enol tautomers are the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomers is phenol-keto tautomers. A specific example of phenol-keto tautomers is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto tautomers. Unless otherwise indicated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0063] The salts mentioned in this invention are pharmaceutically acceptable salts, and the term "pharmaceutically acceptable salts" is well known in the field, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Pharmaceutically acceptable, non-limiting examples of salts include inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, metaphosphates, sulfates, sulfites, nitrates, and perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, and thiocarboxylates, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, bis(hydroxynaphthyl) salts, salicylates, galactobionates, gluconates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, hydroxyethylsulfonates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalic acid, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, undecanoate, valerate, etc. Furthermore, pharmaceutically acceptable salts also include those obtained by means of appropriate bases, such as alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0064] Medicinal salts can form with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, gluconate, glucuronide, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactate, lacturonide, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, naphthate, naphthalenesulfonate, nicotinate, nitrates, stearate, oleate, oxalate, palmitate, pyrate, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalactonates, propionates, stearates, succinates, sulfosalicylate, tartrates, toluenesulfonates, and trifluoroacetates.

[0065] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0066] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

[0067] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0068] "Composition" means a mixture of one or more compounds, salts, or physiologically / pharmaceutically acceptable salts or prodrugs described herein with other chemical components, such as physiologically / pharmaceutical acceptable carriers or excipients. The purpose of the composition is to facilitate the administration of the compound to a living organism.

[0069] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0070] As used in this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkane" are used herein to refer to both straight-chain and branched saturated carbon chains. The term "alkane" is used herein to refer to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched saturated hydrocarbon; examples of such groups include, but are not limited to, methylene, methine, methinepropyl, etc.

[0071] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring that does not contain heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic rings of 7-12 carbon atoms. Bicyclic carbocyclic rings with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocyclic rings with 9 or 10 atoms can be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of cyclic aliphatic groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Furthermore, the "cyclic aliphatic group" or "carbocyclic", "carbocyclic group", and "cycloalkyl" may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0072] The terms “heterocyclic,” “heterocyclic group,” “heterocyclic alicyclic group,” or “heterocyclic” are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic systems in which one or more carbon atoms on the ring are independently and optionally substituted with heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, and has only one connection point to another molecule. One or more hydrogen atoms on the ring are independently and optionally substituted with one or more substituents described herein. Some of these embodiments are that the "heterocycle", "heterocyclic group", "heterocyclic alicyclic group" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2, and when the ring is a three membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2).

[0073] Heterocyclic groups can be carbonyl or heteroatomyl groups. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolyl, oxazolyl, piperazine, homopiperazine, azahexacyclic butyl, oxacyclobutyl, thiohexacyclic butyl, piperidinyl, homopiperidinyl, glycidyl, azaheptanyl, oxacycloheptanyl, thioheptanyl, 4-methoxy-piperidin-1-yl, 1, 2,3,6-Tetrahydropyridin-1-yl, oxazolidinyl, diazazidinyl, thioazolidinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazine 1,1-dioxa 2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)acetone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)acetone-4-yl, 5,6-dihydro-4H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)acetone-4-yl, 3-azabicyclo[3.1.0] [4.1.0] Hexyl, 3-azabicyclo[2.2.2] Hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazole[4,3-c]pyridin-5-yl, 3H-indolyl 2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinazinyl and N -Pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino, and those in which two carbon atoms on the ring are replaced by oxygen atoms, such as pyrimidinyl diketone. The heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)2-, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S (=O)2, carboxyalkoxy, etc.

[0074] The term "aryl" can be used alone or as a part of "aranyl," "aranalkoxy," or "aranoxyalkyl," referring to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14 membered rings, wherein at least one ring system is aromatic, and each ring system contains 3-7 membered rings with only one attachment point connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," as aromatic rings can include phenyl, naphthyl, and anthracene. Furthermore, the aryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0075] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic systems containing 5-14 membered rings, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning as described in this invention, wherein each ring system contains 3-7 membered rings and has only one attachment site connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "aromatic heterocyclic" or "heteroaromatic compound". Furthermore, the heteroaryl group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, etc.

[0076] Other embodiments include, but are not limited to, the heteroaryl group comprising, but not limited to, the following monocyclic rings: 2-furanyl, 3-furanyl, N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl N-pyrrole, 2-pyrrole, 3-pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazole The group includes, but is not limited to, the following bicyclic groups: benzimidazolyl, benzofuranyl, benzothiopheneyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), benzo[d]thiazol-2-yl, and imidazo[1,5-a]pyridin-6-yl.

[0077] The term “heteroatom” refers to one or more O, S, N, P, and Si atoms, including N, S, and P in any oxidation state; primary, secondary, tertiary amines, and quaternary ammonium salts; or in the form where the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrole), NH (e.g., NH in pyrroleyl), or NR (e.g., NR in N-substituted pyrroleyl).

[0078] The term "heteroalkyl" indicates that one or more heteroatoms may be inserted in the middle of an alkyl chain, wherein the alkyl group and the heteroatom have the meanings as described in this invention. Unless otherwise specified, the heteroalkyl group contains 1-10 carbon atoms; in other embodiments, the heteroalkyl group contains 1-8 carbon atoms; in other embodiments, the heteroalkyl group contains 1-6 carbon atoms; in other embodiments, the heteroalkyl group contains 1-4 carbon atoms; and in other embodiments, the heteroalkyl group contains 1-3 carbon atoms. Such examples include, but are not limited to, CH3OCH2-, CH3CH2OCH2-, CH3SCH2-, CH3SCH2CH2-, (CH3)2NCH2-, (CH3)2CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, etc.

[0079] The term "halogen" refers to F, Cl, Br, or I.

[0080] In this invention, "halogenated" means replacing the following group with a halogen, and the number of substitutions can be one or more.

[0081] In this invention, "hydroxyl-substituted" means that the group following it is replaced by a hydroxyl group, and the number of substitutions can be one or more.

[0082] When the term "substituted" is used between two groups in this invention, it is preceded by a substituent, such as "aryl-substituted alkyl" indicating that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" indicating that the alkyl group has an alkoxycarbonyl substituent.

[0083] When multiple groups of the present invention are used in combination, from left to right, they are in a substitution relationship, such as "arylalkyl", which means aryl-substituted alkyl, and "alkoxyalkoxy", which means alkoxy-substituted alkoxy.

[0084] As used in this invention, the term "skin" is intended to include the skin on the face, neck, chest, back, arms (including armpits), hands, legs, buttocks, and scalp.

[0085] The compounds in this invention were synthesized according to the method described in WO 2018137683.

[0086] Example 1 Tyrosinase Inhibition Test

[0087] The experimental steps are as follows:

[0088] 1) Human primary melanocytes were seeded into 6-well plates and cultured in melanocyte growth medium (MGM) with human melanocyte growth supplement for 18-24 h.

[0089] 2) Remove the original culture medium and add a culture medium containing different concentrations (1 μM, 5 μM, 10 μM, 25 μM) of compound 1 of the present invention, and incubate for 24 h;

[0090] 3) After exposure, remove the culture medium, wash twice with PBS, collect cells from each well using a cell scraper, and incubate at 10,000 rpm / min for 4 days. o Cells were collected by centrifugation at C10;

[0091] 4) Add cell lysis buffer and lyse cells using repeated freeze-thaw cycles at 10,000 rpm / min. o Centrifuge at C for 20 min to obtain the supernatant;

[0092] 5) Add the supernatant of each group to the 96-well plate, quickly add L-DOPA solution, shake, and then measure the absorbance at a wavelength of 475 nm. 37 o After reacting at C for 30 minutes, the absorbance value was measured again.

[0093] 6) Statistical methods

[0094] Graph Pad Prism was used for plotting, and results are expressed as Mean ± SD. Multiple comparisons between groups were performed using t-tests. All statistical analyses were two-tailed. p < 0.05 was considered statistically significant. , , The smaller the p-value, the more significant it is.

[0095]

[0096] The prescription composition is shown in Table 1.

[0097] The compound 1 used in step 2) is .

[0098] Conclusion: The experimental results show that the compound of the present invention has a certain inhibitory effect on tyrosinase.

[0099] Example 2: Melanonoderm Model Test

[0100] The control compound consisted of a negative control (ultrapure water), a carrier control [dimethyl sulfoxide (DMSO) in ultrapure water - final concentration 0.1%], and a positive control (2% kojic acid in ultrapure water - final concentration 700 μM). The test compound was prepared in DMSO at a concentration of 10 mM and diluted to a final concentration of 10 μM with EPI-100-LLMM medium (Mattek Corp.). Human melanin model tissue (MEL-300-B, Mattek Corp.) was equilibrated with EPI-100-NMM medium for 24 hours, followed by equilibration with EPI-100-LLMM medium for 48 hours, and then treated with the test compound and control. Following a standard protocol, the melanin model was administered the control and the test compound for a total of 12 days, and the melanin models were collected for melanin quantification, activity analysis, and macro / micro imaging analysis. For melanin quantification, tissue was suspended in phosphate-buffered saline (PBS) buffer (5 ml) for 5 minutes, removed from the PBS, and washed / rinsed with another PBS (2 ml). The tissue was treated with 1% sodium bicarbonate solution (300 μl) for 30 minutes, then the sodium bicarbonate solution was removed, and the tissue was washed / rinsed with PBS solution (2 × 2 ml). The tissue was suspended in Solvable reagent (500 μl) and incubated at 95 °C for 24 hours with melanin standards (prepared by suspending melanin in Solvable reagent to generate melanin standards of 0, 2.5, 5, 10, 25, 50, and 100 μg). All incubated samples were centrifuged at 13000 rpm for 5 minutes, and the optical density of the supernatant was read / measured at 490 nm. The amount of melanin (μg) in each tissue sample was determined from the melanin standard calibration curve. Protein concentrations in tissue samples were determined using the BCA Protein Assay Kit (Pierce), and melanin content was normalized and expressed as melanin (μg) / protein (Table 1). Tissue viability was determined using the WST-1 kit relative to negative and carrier controls after administration / feeding of the test compounds. Tissue images were examined to assess the melanin-lightening ability of the test compounds compared to negative, carrier, and positive controls, and cytotoxicity was assessed using a microscope (10x magnification).

[0101] Table 1: Melanin content after treatment with the compound

[0102]

[0103] Note: The compounds in Table 1 were prepared according to the method described in WO2018137683.

[0104] Melanoderm data showed that compound 1 and lanosterol significantly reduced melanin content, demonstrating a certain therapeutic / improving effect on pigmentation.

[0105] Example 3: Test Method for Effectiveness Testing of Age Spots

[0106] The prescription and preparation method used are shown below.

[0107] Compound 1: 10 mg

[0108] PEG400: 0.45 g

[0109] Tween 80: 0.025 g

[0110] PVP: 0.025 g

[0111] HP-β-CD: 0.475 g

[0112] Water: 8.515 mL

[0113] The specific preparation steps are as follows:

[0114] In a glass container containing compound 1, 0.45 g of PEG400, 0.025 g of Tween 80, and 0.025 g of PVP were added and heated at 45°C. o Stir for 15 minutes at C; then add 0.475 g HP-β-CD and 8.515 mL water, and stir at 45°C. o Stir for 15 minutes; finally, sonicate for 20 minutes using a Covaris ultrasonic homogenizer to obtain the above formula.

[0115] Experimental Method: Volunteers with age spots on their faces were recruited. The composition of the present invention was applied to the affected areas three times a day, morning, noon, and evening. Facial photographs were taken on day 1 and day 60 after application of the composition of the present invention.

[0116] Figure 1 (Left) A partial facial photograph taken on day 1 after application of the composition of the present invention; Figure 1 (Right) A partial facial photograph taken 60 days after application of the composition of the present invention. It can be seen that the patient's age spots were significantly improved and reduced after 60 days of application of the composition of the present invention.

[0117] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. The use of steroidal compounds in the preparation of products for the prevention or treatment of skin pigmentation-related conditions, characterized in that, The steroidal compound is a compound that is either a pharmaceutically acceptable salt of a compound that is either a steroidal compound or ... ； The skin pigmentation-related conditions are selected from one or more of the following: melasma, pregnancy mask, butterfly mask, age spot, café-au-lait spot, and freckles; The dosage form of the product is a solution, emulsion, suspension, cream, ointment, gel, or patch.

2. The application according to claim 1, characterized in that, The products are selected from pharmaceuticals and skincare products.

3. The use of the composition in the preparation of products for the prevention or treatment of skin pigmentation-related conditions, characterized in that, The composition comprises a steroidal compound or a pharmaceutically acceptable salt thereof as used in any one of claims 1-2, and a pharmaceutically or cosmetically acceptable excipient; the skin pigmentation-related condition is selected from one or more of melasma, pregnancy mask, chloasma, age spots, café-au-lait spots, and freckles.

Images