WO2023222116A1 - Utilisation d'un composé stéroïde - Google Patents

Utilisation d'un composé stéroïde Download PDF

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Publication number
WO2023222116A1
WO2023222116A1 PCT/CN2023/095320 CN2023095320W WO2023222116A1 WO 2023222116 A1 WO2023222116 A1 WO 2023222116A1 CN 2023095320 W CN2023095320 W CN 2023095320W WO 2023222116 A1 WO2023222116 A1 WO 2023222116A1
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Prior art keywords
alkyl
spots
compound
aryl
skin
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PCT/CN2023/095320
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English (en)
Chinese (zh)
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王延东
薛亚萍
于垂亮
吴美容
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广州润尔眼科生物科技有限公司
润尔眼科药物（广州）有限公司
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Publication of WO2023222116A1 publication Critical patent/WO2023222116A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention belongs to the field of chemical technology, and specifically relates to the application of a steroid compound in the preparation of products for preventing or treating skin pigmentation-related conditions.
  • Melanins are a collective name for a class of compounds found in animals, plants and protists.
  • melanin is formed in melanosomes, cellular structures found in cells called melanocytes, which are located in the lowermost layer of the epidermis, basal lamina, and basal cells.
  • melanocytes cellular structures found in cells
  • Melanin is transported to the corneocytes in the stratum corneum of the skin via keratinocytes in the epidermis, and imparts brown pigment to the stratum corneum of the skin.
  • Melanin is responsible for the pigmentation of human skin due to the presence of melanin in the stratum corneum of the skin.
  • Melanin absorbs UV radiation and thus plays an important role in protecting the human body, particularly the skin, from the damaging and potentially carcinogenic effects of sunlight and other environmental sources of UV radiation.
  • the body When exposed to UV radiation, the body naturally increases the production of melanin in the exposed areas of skin as a defense mechanism.
  • the increased production of melanin causes exposed skin to darken, a phenomenon commonly known as tanning.
  • Hyperpigmentation and other conditions of uneven skin pigmentation are often considered undesirable and unsightly. For example, the occurrence of acne, rashes, scratches, or lesions on the skin can cause post-inflammatory hyperpigmentation, characterized by the presence of unwanted dark spots on the face or other parts of the body.
  • Melasma is a condition associated with hormonal changes caused by pregnancy, birth control pills, or menopausal changes, and is often masked by pigment deposited on the surface of the epidermis or deeper in the dermis. Pigments, also known as liver spots, are dark discolorations caused by sun damage that typically appear in older individuals. Freckles are small spots common in young people with fair skin that is prone to sunburn when exposed to sunlight.
  • Senile Spenkle (SS for short) or Senile Plaques (SP for short) are one of the most intuitive features of mammalian skin aging. They are gradually formed by the continuous deposition of lipofuscin produced by aging in skin cells and sweat gland cells. It appears most frequently on the skin surface, especially on the skin surface of the elderly. Age spots are a kind of brown-black or tan or dark-brown flat spots or patches of varying numbers, uneven sizes, and oval shapes that grow on the face, back of hands, arms, and even the body surface of an aging human body. Among them, the scalp Mainly on the skin and face, followed by the back of the hands, neck, chest, back and limbs.
  • the pathogenesis of age spots mainly has four aspects. First, as age increases, pigments will gradually accumulate in human cells and continue to be deposited on the skin surface to form age spots; second, caused by factors such as genetic inheritance, Skin diseases caused by autosomal dominant inheritance are most common on the face, especially around the nose and cheeks. Because the skin lesions look like birds pecking or spots on bird eggs, they are also called freckles; thirdly , related to free radicals. As age increases, the number of free radicals produced by the metabolic process in human cells gradually increases. When the body's function of scavenging free radicals declines, these chemically active free radicals will rapidly interact with the body and Strong damage, among which the attack of oxygen free radicals on lipid biofilm is most closely related to the appearance of age spots.
  • the treatment of age spots mainly includes the following measures: 1. Pay attention to diet, eat more fruits and vegetables, supplement vitamin C, promote blood circulation and metabolism, regulate hormone secretion, enhance skin cell vitality, and prevent and treat the formation of skin lipofuscin and age spots. ; 2. Physical therapy, such as electrocautery treatment, laser treatment, and the use of high-frequency current/freezing/cutting/grinding and other methods; 3. Chemical therapy, which uses chemical peeling agents to destroy, scab, and scab the surface of the skin. Make it fall off to achieve therapeutic purposes, such as using 33% trichloroacetic acid solution.
  • the purpose of the present invention is to provide an application of a steroid compound in a product for preventing or treating pigmentation-related conditions.
  • the steroid compound provided by the present invention can effectively treat and slow down age spots. and preventive effect, which can greatly reduce and/or cure age spots.
  • the present invention adopts the following technical solutions:
  • the present invention provides an application of a steroid compound in preventing or treating skin pigmentation-related conditions or anti-aging related products.
  • the steroid compound is a compound with a structure as shown in formula I, or a compound with a structure as shown in formula I.
  • R is H, D (deuterium), alkyl, sulfate, phosphate, alkylsilyl, benzyl or -C(O)-X;
  • X is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or alkyl;
  • aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl, alkylsilyl and alkyl groups mentioned in R and X are optionally substituted by 1, 2, 3 or 4 identical or different substituents replaced;
  • R 1 , R 2 and R 3 are each independently selected from -H, -D or alkyl.
  • the steroid compound is a compound with a structure as shown in Formula II, or a stereoisomer, tautomer, nitrogen oxide, solvate, or a compound with a structure as shown in Formula II.
  • R is the same as formula (I).
  • R is H, D, C 1-6 alkyl, sulfate, phosphate, C 1-6 alkylsilyl, benzyl, or -C(O)-X.
  • X is selected from C 6-10 aryl, C 2-9 heteroaryl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 1-6 heteroalkyl, or C 1 -6 alkyl.
  • R and , C 1-6 alkylsilyl or C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 identical or different substituents.
  • R 1 , R 2 and R 3 are each independently selected from -H, -D or C 1-6 alkyl.
  • 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, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, disulfide ring Pentyl, tetrahydropyranyl, dihydr
  • the substituents described in R and C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 2-9 heteroaryl.
  • X is selected from any of the following groups:
  • the compound of the structure shown in formula I or II is selected from any one of the following compounds:
  • the product is a drug, skin care product, or nutraceutical.
  • the skin pigmentation-related condition is selected from one or more of melasma, pregnancy spots, butterfly spots, age spots, café-au-lait spots, and freckles.
  • the anti-aging product is an anti-skin aging product.
  • the product is in the form of a solution, emulsion, suspension, cream, ointment, gel, or patch.
  • the steroidal compounds provided by the present invention can be used for treatment as raw chemicals or can be provided as active ingredients of pharmaceutical compositions.
  • the present invention provides the use of a composition in the preparation of products for preventing or treating skin pigmentation-related conditions or anti-aging related products.
  • the composition includes the steroid compound described in the first aspect, and pharmaceutical or cosmetic products.
  • Substances that may serve 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; buffer substances such as phosphates; glycine; sorbate Acids; 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 silicon; magnesium trisilicate ;polyvinylpyrrolidone;polyacrylate;wax;polyethylene- Polyoxypropylene - blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and acetic acid Cellulose; gum powder; malt; gelatin; talc;
  • the product is a drug, skin care product, or nutraceutical.
  • the skin pigmentation-related condition is selected from one or more of melasma, pregnancy spots, butterfly spots, age spots, café-au-lait spots, and freckles.
  • the anti-aging product is an anti-skin aging product.
  • the product is in the form of a solution, emulsion, suspension, cream, ointment, gel, or patch.
  • the present invention provides a method for preventing or treating skin pigmentation-related conditions or anti-aging, comprising administering to a subject a steroid compound (such as the structure shown in Formula I or Formula II) as described in the first aspect.
  • a steroid compound such as the structure shown in Formula I or Formula II
  • the skin pigmentation-related condition is selected from one or more of melasma, pregnancy spots, butterfly spots, age spots, café-au-lait spots, and freckles.
  • the anti-aging product is an anti-skin aging product.
  • the present invention has the following beneficial effects:
  • the present invention finds that the steroid compound provided by the present invention can be used to prevent, treat, treat or alleviate age spots, freckles or chloasma in patients, and is convenient and practical with few side effects.
  • Figure 1 is a photograph of the face on the 1st day and the 60th day after applying the composition of the present invention.
  • Stereoisomers refer to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • the compounds of the invention can be expressed as one of the possible isomers or as a mixture thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ) exists in the form.
  • Light Chemically 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 substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.
  • Any resulting mixture of stereoisomers may 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. method and/or fractional crystallization method.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R containing an asymmetric center , S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Therefore, the individual stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.
  • prodrug used in the present invention represents a compound that is converted into a compound represented by Formula I or Formula II in the body. Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug compound of the present invention can be an ester.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonate esters. , carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form of the compound.
  • prodrug forms include phosphate esters, which are obtained by phosphorylation of the hydroxyl group of the parent.
  • phosphate esters which are obtained by phosphorylation of the hydroxyl group of the parent.
  • Any resulting racemate of the final product or intermediate may be resolved into its optical antipodes by known methods familiar to those skilled in the art, e.g., by subjecting the diastereomeric salts thereof obtained separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using chiral adsorbents.
  • 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, E.L.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • protontautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enamine Isomerization.
  • Valence tautomers involve interconversions through the reorganization of some of the bonding electrons.
  • keto-enol tautomerism is pentane-2,4-dione and tautomerism of 4-hydroxypent-3-en-2-one.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is an interconversion of the tautomers of pyridin-4-ol and pyridin-4(1H)-one. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • salts mentioned in the present invention are pharmaceutically acceptable salts, and "pharmaceutically acceptable salts" are well known in the art.
  • pharmaceutically acceptable salts include inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, and nitrates.
  • organic acid salts such as carboxylates, sulfonates, sulfinates, sulfur carboxylates, etc., specifically such as, but not limited to, methanesulfonate, ethanesulfonate, methanesulfonate, etc.
  • Acid acetate, succinate, benzoate, succinate, pamoate, salicylate, galactoate, glucoheptanoate, mandelate, 1,2 -Ethanyl disulfonate, 2-naphthalene sulfonate, carbonate, trifluoroacetate, glycolate, isethionate, oxalate, maleate, tartrate, Citrate, succinate, malonate, benzenesulfonate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate or oxalic acid, or as described in books and literature Other methods such as ion exchange are used to obtain these salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonic acid Salt, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, enanthate, caproic acid Salt, hydroiodide, 2-hydroxy-ethanesulfonate, lactouronate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamate, fruit Collate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, etc.
  • pharmaceutically acceptable salts also include salts derived from appropriate bases, such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • bases such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the formation of quaternary ammonium salts of 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, and others.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that counter counter ion formation, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates compounds and aromatic sulfonates.
  • salts can be formed with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/carbonates , bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline salt, citrate, ethylene disulfonate, fumarate, glucoheptonate, gluconate, Glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactosuronate, lauryl sulfate, malate, maleate, propylene glycol acid salt, mandelate, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate , Pamate, phosphate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts may 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.
  • Solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association of solvent molecules with water.
  • composition means one or more compounds, salts, or physiologically/pharmaceutically acceptable salts or precursors thereof as described herein.
  • a mixture of a body drug with other chemical components such as physiologically/pharmaceutically acceptable carriers or excipients.
  • the purpose of the composition is to facilitate the administration of the compound to an organism.
  • any disease or condition as used herein means ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof).
  • “treating” or “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be noticeable to the patient.
  • “treating” or “treating” refers to modulating a disease or condition physically (eg, stabilizing perceived symptoms) or physiologically (eg, stabilizing body parameters), or both.
  • “treating” or “treating” refers to preventing or delaying the onset, development, or progression of a disease or disorder.
  • alkyl as used herein means 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or A saturated linear or branched chain monovalent hydrocarbon group of 1 to 3 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2 -Butyl (-C(CH 3 ), 2-
  • alkyl and its prefix “alkyl” as used herein include both straight and branched saturated carbon chains.
  • alkylene refers to a saturated divalent hydrocarbon radical obtained by eliminating two hydrogen atoms from a linear or branched saturated hydrocarbon. Examples of such include, but are not limited to, methylene, ethylene , sub-isopropyl and so on.
  • cycloalkyl refers to a monovalent or polyvalent, nonaromatic, saturated or partially unsaturated ring and containing no heteroatoms, including a monocyclic ring of 3 to 12 carbon atoms or a monocyclic ring of 7 to 12 carbon atoms.
  • the second ring Bicyclic carbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocycles with 9 or 10 atoms It can be a bicyclic [5,6] or [6,6] system.
  • Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • 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 base, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms are independently and optionally substituted by heteroatoms having the following properties:
  • the ring may be fully saturated or contain one or more degrees of unsaturation, but is never aromatic and has only one point of attachment to other molecules.
  • Hydrogen atoms on one or more rings are independently and optionally substituted with one or more substituents described herein.
  • the "heterocycle", “heterocyclyl”, “heteroalicyclic” or “heterocyclic” group is a 3-7 membered monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , when said When the ring is a three-membered ring with only one heteroatom), or a 7-10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P optionally substituted by one or more oxygen atoms to give groups such as SO, SO 2 , PO, PO 2 ).
  • Heterocyclyl groups may be carbon or heteroatom groups.
  • Heterocyclyl also includes groups formed by combining a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl , piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-meth
  • heterocyclic groups also include, 1,1-dioxothiomorpholinyl, and pyrimidinedione groups in which two carbon atoms on the ring are replaced by oxygen atoms.
  • aryl may be used alone or as a large part of "aralkyl", “aralkoxy” or “aryloxyalkyl” to mean monocyclic, bicyclic, and bicyclic rings containing a total of 6 to 14 members.
  • a tricyclic carbocyclic ring system in which at least one ring system is aromatic and in which each ring system contains a 3- to 7-membered ring and has only one point of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term "aromatic ring”.
  • aromatic rings may include phenyl, naphthyl and anthracenyl.
  • heteroaryl refers to monocyclic, bicyclic, and tricyclic ring systems containing a total of 5 to 14 membered rings, in which at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroaryl Atoms have the meaning given herein, wherein each ring system contains a 3-7 membered ring and has only one point of attachment to the rest of the molecule.
  • heteroaryl may Used interchangeably with the term “heteroaromatic ring” or "heteroaromatic compound”.
  • the heteroaryl group includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazole- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, Pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazoly
  • heteroatom means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in heterocycles
  • N e.g. N in 3,4-dihydro-2H-pyrrolyl
  • NH e.g. NH in pyrrolidinyl
  • NR e.g. N-substituted pyrrole NR in alkyl group
  • heteroalkyl means that one or more heteroatoms may be inserted into the middle of the alkyl chain, wherein the alkyl group and the heteroatoms have the meanings described herein. Unless otherwise specified, heteroalkyl groups contain 1 to 10 carbon atoms. In other embodiments, heteroalkyl groups contain 1 to 8 carbon atoms. In other embodiments, heteroalkyl groups contain 1. -6 carbon atoms, in other embodiments the heteroalkyl group contains 1-4 carbon atoms, in other embodiments the heteroalkyl group contains 1-3 carbon atoms.
  • Such examples include, but are not limited to, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, CH 3 SCH 2 CH 2 -, (CH 3 ) 2 NCH 2 -, (CH 3 ) 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -, etc.
  • halogen refers to F, Cl, Br or I.
  • Halo as used in the present invention means substituting a subsequent group with a halogen, and the number of substitutions may be one or more.
  • Hydro-substituted in the present invention means that the following groups are replaced with hydroxyl groups, and the number of substitutions can be one or more.
  • substituted in the present invention is used between two groups, it is preceded by a substituent.
  • aryl-substituted alkyl means that the alkyl group has an aryl substituent
  • alkoxycarbonyl "Substituted alkyl” means an alkyl group having an alkoxycarbonyl substituent.
  • substitution relationship is from left to right, such as "arylalkyl”, which represents an aryl-substituted alkyl group, and "alkoxyalkoxy”, which represents an alkoxy group. Substituted alkoxy.
  • skin as used herein is intended to include the skin of the face, neck, chest, back, arms (including underarms), hands, legs, buttocks and scalp.
  • test steps are as follows:
  • MGM melanocyte growth medium
  • Graph PadPrism was used for graphing, and the results were expressed as Mean ⁇ SD. Multiple comparisons between each group were analyzed using t-test statistics. All statistical analyzes were two-tailed. p ⁇ 0.05 is considered to have significant difference, among which *p ⁇ 0.05, 0.005 ⁇ **p ⁇ 0.01, ***p ⁇ 0.001, the smaller the p value, the more significant it is.
  • the compound 1 used in step 2) is N-(2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)
  • Control compounds consisted of a negative control (ultrapure water), a vehicle control [dimethyl sulfoxide (DMSO) in ultrapure water - 0.1% final concentration] and a positive control (2% koji in ultrapure water). acid - final concentration 700 ⁇ M).
  • Test compounds of the invention were prepared in DMSO at a concentration of 10 mM and diluted with EPI-100-LLMM medium (Mattek Corp.) to a final concentration of 10 ⁇ M.
  • EPI-100-LLMM medium Melanin model human tissue (MEL-300-B, Mattek Corp.) was equilibrated with EPI-100-NMM medium for 24 hours, followed by EPI-100-LLMM medium for 48 hours, and then tested with compounds of the present invention and controls. material handling.
  • Tissue was suspended in Solvable reagent (500 ⁇ l) and incubated at 95°C with melanin standards (prepared by suspending melanin in Solvable reagent to generate 0, 2.5, 5, 10, 25, 50, and 100 ⁇ g of melanin standards). ) and incubate them together for 24 hours. All incubated samples were centrifuged at 13000 rpm for 5 minutes and the optical density of the supernatant was read/determined at 490 nm. The amount of melanin ( ⁇ g) for each tissue sample was determined from the melanin standard sample calibration curve. The protein concentration of tissue samples was determined using the BCA protein assay kit (Pierce), and the melanin content was normalized and expressed as melanin ( ⁇ g)/protein (Table 1).
  • melanin standards prepared by suspending melanin in Solvable reagent to generate 0, 2.5, 5, 10, 25, 50, and 100 ⁇ g of melanin standards.
  • Tissue viability was determined using the WST-1 kit as a result of test compound dosing/feeding relative to negative controls and vehicle controls. Tissue images were examined to assess the melanin-lightening ability of the test compounds compared to negative, vehicle and positive controls, and to assess cytotoxicity by microscopy (10x magnification).
  • Test method recruit volunteers with senile plaques on their faces, and apply the composition of the present invention to the senile plaques once a day in the morning, noon and evening. Facial photographs were taken on day 1 and day 60 of administration of the composition of the present invention.
  • Figure 1 (left) is a partial facial photo on the first day after applying the composition of the present invention
  • Figure 1 (right) is a partial facial photo on the 60th day after applying 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 administration of the composition of the present invention.

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Abstract

La présente invention concerne l'utilisation d'un composé stéroïde dans la préparation d'un produit pour la prévention ou le traitement d'états associés à la pigmentation de la peau ou de produits associés anti-vieillissement. Le composé stéroïde est représenté par la formule I et a pour effet de traiter, dessaler et soulager les plaques séniles, les taches de rousseur, le chloasma et analogues provoqués par une pigmentation sur la peau d'un mammifère.
PCT/CN2023/095320 2022-05-20 2023-05-19 Utilisation d'un composé stéroïde WO2023222116A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042846A1 (en) * 2005-08-19 2009-02-12 Bioderm Research Topical Delivery System for Phytosterols
JP2009249316A (ja) * 2008-04-03 2009-10-29 Nippon Menaade Keshohin Kk ラノスタ−８−エン誘導体およびこれらを含有する皮膚外用剤
WO2018137683A1 (fr) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Composé promédicament à base de lanostérol, procédé de préparation et utilisation associés
CN112569127A (zh) * 2020-12-30 2021-03-30 广州澳希亚实业有限公司 一种液体油性组合物及其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042846A1 (en) * 2005-08-19 2009-02-12 Bioderm Research Topical Delivery System for Phytosterols
JP2009249316A (ja) * 2008-04-03 2009-10-29 Nippon Menaade Keshohin Kk ラノスタ−８−エン誘導体およびこれらを含有する皮膚外用剤
WO2018137683A1 (fr) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Composé promédicament à base de lanostérol, procédé de préparation et utilisation associés
CN112569127A (zh) * 2020-12-30 2021-03-30 广州澳希亚实业有限公司 一种液体油性组合物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAKASHI KIKUCHI; KENSUKE WATANABE; YUICHI TOCHIGI; AYAKO YAMAMOTO; MAKOTO FUKATSU; YOICHIRO EZAKI; REIKO TANAKA; TOSHIHIRO AKIHISA: "Melanogenesis Inhibitory Activity of Sesquiterpenes from Canarium ovatum Resin in Mouse B16 Melanoma Cells", CHEMISTRY & BIODIVERSITY, HELVETICA CHIMICA ACTA, ZUERICH, CH, vol. 9, no. 8, 17 August 2012 (2012-08-17), CH , pages 1500 - 1507, XP072350130, ISSN: 1612-1872, DOI: 10.1002/cbdv.201200111 *

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