WO2023222116A1 - Use of steroid compound - Google Patents

Use of steroid compound 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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French (fr)
Chinese (zh)
Inventor
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/en

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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

The present invention provides use of a steroid compound in preparing a product for preventing or treating skin pigmentation related conditions or anti-aging related products. The steroid compound is represented by formula I and has the effects of treating, desalting and relieving senile plaques, freckles, chloasma and the like caused by pigmentation on mammalian skin.

Description

甾体化合物的应用Applications of Steroids 技术领域Technical field
本发明属于化学技术领域，具体涉及一种甾体化合物在制备预防或治疗皮肤色素沉着相关状况的产品中的应用。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.
背景技术Background technique
黑色素是在动物、植物和原生生物中发现的一类化合物的统称。在人体中，黑色素在黑素体中形成，黑素体是在称为黑色素细胞的细胞中发现的细胞结构，黑色素细胞位于表皮、基底层和基底细胞的最下层。黑色素经由表皮的角质形成细胞运送至皮肤角质层中的角化细胞(corneocyte)，并赋予皮肤角质层褐色色素。由于皮肤角质层中黑色素的存在，黑色素负责人类皮肤的色素沉着。黑色素能够吸收紫外线辐射，从而在保护人体(特别是皮肤)免受阳光及紫外线辐射的其他环境来源的损伤和潜在致癌效应中起重要作用。当暴露于紫外线辐射时，人体天然地增加暴露的皮肤区域中的黑色素的产生，作为防卫机制。黑色素的增加的产生导致暴露的皮肤颜色变深，该现象通常被称为晒黑。色素沉着过度及其他不均匀的皮肤色素沉着的病状通常被视为是不希望的和不美观的。例如，皮肤的痤疮、皮疹、抓痕或损伤的发生可以引起炎性后色素沉着过度，特征是脸部或身体其他部分上不想要的暗斑的存在。黄褐斑是与由妊娠、服用避孕药、或绝经变化引起的激素变化相关的病状，其通常被沉着在表皮表面上或真皮较深处的色素掩盖。着色斑也称为肝斑，是由日光损伤引起的深色变色，其一般出现在年龄较大的个体中。雀斑是在具有白净皮肤的年轻人中常见的小斑点，这样的皮肤当暴露于日光时易于被晒伤。Melanins are a collective name for a class of compounds found in animals, plants and protists. In the human body, 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. 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. 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.
老年斑(Senile Spenkle，简称SS)或(Senile Plaques，简称SP)是哺乳动物皮肤老化最直观的特征之一，是由衰老所产生的脂褐素不断沉积于皮肤细胞、汗腺细胞中而逐渐形成与皮肤表层，尤以老年人皮肤表面出现最多。老年斑是一种生长在衰老人体面部、手背、胳膊、甚至身体表面的一种数量不等、大小不均、形似卵圆形的棕黑色或棕褐色或黑褐色扁平斑点或斑块，其中以头皮和面部为主，其次是手背、颈部、胸部、背部和四肢等处多见。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.
老年斑的发病机制主要有四个方面，第一，随着年龄的增长，色素会在人体细胞里逐渐积聚起来，不断沉积在皮肤表面即可形成老年斑；第二，基因遗传等因素引起的，是由常染色体显性遗传性导致的皮肤病，多分布于面部、尤其是鼻与两颊周围最为常见，因皮损外观如鸟啄食，或雀卵上的的斑点，也叫雀斑；第三，与自由基有关，随着年龄的增长，人体细胞中代谢过程所产生的自由基逐渐增多，当机体清除自由基的功能下降时，这些化学性质活泼的自由基就会与机体发生迅速作用和强烈损伤，其中氧自由基对脂质生物膜的攻击与老年斑出现关系最大。它能使不饱和脂肪酸氧化成过氧化物，该过氧化物可以进一步分解，产生大量的醛类、醇类和烃类。其中丙二醛具有很强的生物毒性，极易与磷脂蛋白质等发生反应，形成老年色素即脂褐素；第四，与紫外线照射等物理因素有关，长期、大量、连续紫外线照射可使表皮细胞产生单线态氧和超氧自由基、羟自由基等活性氧，它们不仅能使DNA的8- 羟基鸟甙受损引起遗传变异，而且，它们能产生或加快表皮脂质过氧化，形成脂褐素或老年斑，除日光照射外，空气污染、辐射线、臭氧等等，都会促成自由基的形成，使皮肤加快形成老年斑。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. It can oxidize unsaturated fatty acids into peroxides, which can further decompose to produce large amounts of aldehydes, alcohols and hydrocarbons. Among them, malondialdehyde has strong biological toxicity and can easily react with phospholipids and proteins to form the senile pigment lipofuscin; fourth, it is related to physical factors such as ultraviolet irradiation. Long-term, large-scale, and continuous ultraviolet irradiation can cause epidermal cells to Generate singlet oxygen, superoxide radicals, hydroxyl radicals and other reactive oxygen species, which can not only cause DNA 8- Damage to hydroxyguanosine causes genetic variation, and they can produce or accelerate epidermal lipid peroxidation, forming lipofuscin or age spots. In addition to sunlight exposure, air pollution, radiation, ozone, etc. will all contribute to the formation of free radicals. , causing the skin to accelerate the formation of age spots.
目前对于老年斑的治疗主要有以下几种措施：一，注意饮食，平时多吃蔬菜水果，补充维生素C，促进血液循环和新陈代谢，调节激素分泌，增强皮肤细胞活力，防治皮肤脂褐素和老年斑形成；二，物理治疗，比如电灼法治疗、激光法治疗、采用高频电流作用/冷冻/切割/磨削等方法；三，化学疗法，它采用化学剥脱剂对皮肤表层加以破坏、结痂、使之脱落，以达到治疗目的，比如使用33％三氯醋酸溶液，这种方法一定要严格遵照医嘱；四，生物技术，比如超氧化物歧化酶(SOD)制剂及SOD复合酶(SOD-CCE)体系、金属硫蛋白(MT)、活化保护蛋白等，通过清除体内自由基，阻止脂褐素的形成；五，中医药治疗，中药祛除脂褐素目前主要采用具有明显抗氧化作用、自由基及其代谢产物清除作用和提高大分子自由基清除剂含量和SOD活性的单味中药和复方中药或中成药。At present, 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. This method must strictly follow the doctor's instructions; fourth, biotechnology, such as superoxide dismutase (SOD) preparations and SOD complex enzyme (SOD-CCE) ) system, metallothionein (MT), activated protective proteins, etc., prevent the formation of lipofuscin by scavenging free radicals in the body; 5. Traditional Chinese medicine treatment. Traditional Chinese medicine is currently mainly used to remove lipofuscin with obvious antioxidant effects and free radicals. Single Chinese medicine, compound Chinese medicine or Chinese patent medicine that can scavenge its metabolites and increase the content of macromolecular free radical scavengers and SOD activity.
通过分析，以上产品中还存在很多不足之处，比如物理疗法虽效果明显，立竿见影，但容易灼伤皮肤和留下永久性的疤痕，而且需要多次、长时间、且必须由熟练的经验丰富的执业医师在专业诊疗机构完成，且费用高；化学疗法会对皮肤角质层造成一定的损坏，引起皮肤副作用；生物和中医药疗法暂时也只阻止或延缓色素例如黑色素或脂褐素的形成，并不能达到治疗的效果。Through analysis, there are still many shortcomings in the above products. For example, although physical therapy has obvious and immediate effects, it is easy to burn the skin and leave permanent scars. It also requires multiple times and a long time, and must be performed by skilled and experienced practitioners. It is completed by licensed physicians in professional diagnosis and treatment institutions and is expensive; chemical therapy will cause certain damage to the stratum corneum of the skin and cause skin side effects; biological and traditional Chinese medicine therapies can only temporarily prevent or delay the formation of pigments such as melanin or lipofuscin, and The therapeutic effect cannot be achieved.
因此市面上急需一种可以预防或治疗皮肤色素沉着相关状况、且方便实用的产品。Therefore, there is an urgent need on the market for a convenient and practical product that can prevent or treat skin pigmentation-related conditions.
发明内容Contents of the invention
针对现有技术存在的不足，本发明的目的在于提供一种甾体化合物在预防或治疗色素沉着相关状况的产品中的应用，本发明提供的甾体化合物能够对老年斑有很好的治疗、减缓和预防效果，能够极大程度的减轻和/或治愈老年斑。In view of the shortcomings of the existing technology, 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.
为达此目的，本发明采用以下技术方案：To achieve this goal, the present invention adopts the following technical solutions:
第一方面，本发明提供了一种甾体化合物在预防或治疗皮肤色素沉着相关状况或者抗衰老相关产品中的应用，所述甾体化合物为如式I所示结构的化合物，或为如式I所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药；
In a first aspect, 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. Stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compound with the structure shown in I;
其中，R为H、D(氘)、烷基、硫酸基、磷酸基、烷基硅基、苄基或-C(O)-X； Wherein, R is H, D (deuterium), alkyl, sulfate, phosphate, alkylsilyl, benzyl or -C(O)-X;
X选自芳基、杂芳基、环烷基、杂环基、杂烷基或烷基；X is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or alkyl;
R和X中所述芳基、杂芳基、环烷基、杂环基、杂烷基、烷基硅基和烷基任选地被1、2、3或4个相同或不同的取代基所取代；The 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;
所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、烷基羰基、烷基、卤代烷基、环烷基、杂环基、芳基、芳基烷基、杂芳基、羧基、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-；The substituent is selected from D, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, alkylcarbonyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, Heteroaryl, carboxyl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -;
R1、R2和R3各自独立地选自-H、-D或烷基。R 1 , R 2 and R 3 are each independently selected from -H, -D or alkyl.
在一些实施方案中，所述甾体化合物为如式II所示结构的化合物，或为如式II所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药；
In some embodiments, 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. Metabolites, pharmaceutically acceptable salts or prodrugs;
其中R的定义同式(I)。The definition of R is the same as formula (I).
在一些实施方案中，R为H、D、C1-6烷基、硫酸基、磷酸基、C1-6烷基硅基、苄基或-C(O)-X。In some embodiments, R is H, D, C 1-6 alkyl, sulfate, phosphate, C 1-6 alkylsilyl, benzyl, or -C(O)-X.
在一些实施方案中，X选自C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基或C1-6烷基。In some embodiments, 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.
在一些实施方案中，R和X中所述C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基、C1-6烷基硅基或C1-6烷基任选地被1、2、3或4个相同或不同的取代基所取代。 In some embodiments , R and , C 1-6 alkylsilyl or C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 identical or different substituents.
在一些实施方案中，所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、卤代C1-6烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C6-10芳基C1-6烷基、C2-9杂芳基、羧基(例如-COOH)、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-。In some embodiments, the substituents are selected from D, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkyl, haloC 1- 6 alkyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 6-10 aryl, C 1-6 alkyl, C 2-9 heteroaryl, carboxyl ( For example -COOH), R 1 R 2 NC (=O) - or R 1 R 2 NC (=NH) -NR 3 -.
在一些实施方案中，R1、R2和R3各自独立地选自-H、-D或C1-6烷基。In some embodiments, R 1 , R 2 and R 3 are each independently selected from -H, -D or C 1-6 alkyl.
在一些实施方案中，X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑 基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、带有H2NC(＝O)-取代基的C1-3烷基或带有H2NC(＝NH)-NH-取代基的C1-3烷基。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, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxeptanyl, thieptanyl, oxazayl, diazayl, Thiaza group, indolinyl group, 1,2,3,4-tetrahydroquinolyl group, 1,2,3,4-tetrahydroisoquinolyl group, furyl group, imidazolyl group, 3-isoxazole base, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, iso Thiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2, 3-Thiodiazole base, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, Benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl, 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, [1,2,4]triazolo[1,5-a]pyridyl, C 1-3 alkyl with H 2 NC(=O)-substituent or C 1-3 alkyl with H 2 NC(=NH)-NH-substituent.
在一些实施方案中，R和X中所述取代基选自-H、-D、卤素、羟基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、C1-6卤代烷基、C3-8环烷基、C2-9杂环基、C6-10芳基或C2-9杂芳基。In some embodiments, 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.
在另外一些实施方案中，R和X中所述取代基选自-H、-D、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。In other embodiments, the substituents described in R and Ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H -Pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, Homopiperazinyl, homopiperidinyl, oxeptanyl, thieptanyl, oxazayl, diazayl, thiazepinyl, indolinyl, 1,2,3, 4-Tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl , pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, 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-thio Diazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, purine base, quinolyl, isoquinolyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazole [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.
作为本发明的一种具体实施方式，X选自如下任一基团：
As a specific embodiment of the present invention, X is selected from any of the following groups:
作为本发明的一种具体实施方式，所述式I或II所示结构的化合物选自如下化合物中的任意一种：





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





在一些实施方案中，所述产品是药物、护肤品或保健品。In some embodiments, the product is a drug, skin care product, or nutraceutical.
在一些实施方案中，所述皮肤色素沉着相关状况选自黄褐斑、妊娠斑、蝴蝶斑、老年斑、咖啡斑和雀斑中的一种或多种。In some embodiments, 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.
在一些实施方案中，所述抗衰老产品为抗皮肤衰老产品。In some embodiments, the anti-aging product is an anti-skin aging product.
在一些实施方案中，所述产品的剂型为溶液、乳液、悬浮液、霜剂、膏剂、凝胶剂或贴剂。In some embodiments, the product is in the form of a solution, emulsion, suspension, cream, ointment, gel, or patch.
本发明提供的甾体化合物可以作为未加工的化学药品用于治疗，也可以作为药物组合物的活性成分提供。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.
第二方面，本发明提供了组合物在制备预防或治疗皮肤色素沉着相关状况或者抗衰老相关产品中的应用，所述组合物包括第一方面中所述的甾体化合物，及药学上或化妆品上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种。In a second aspect, 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. One or more of the acceptable carriers, excipients, diluents, auxiliaries or vehicles.
可作为药学上或化妆品上可接受载体的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐；电解质，如硫酸鱼精蛋白；磷酸氢二钠；磷酸氢钾；氯化钠；锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯- 聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。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; 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 Compounds 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 buffered solution, and other nontoxic suitable lubricants such as sodium laurel sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings, and Flavors, preservatives and antioxidants.
在一些实施方案中，所述产品是药物、护肤品或保健品。In some embodiments, the product is a drug, skin care product, or nutraceutical.
在一些实施方案中，所述皮肤色素沉着相关状况选自黄褐斑、妊娠斑、蝴蝶斑、老年斑、咖啡斑和雀斑中的一种或多种。In some embodiments, 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.
在一些实施方案中，所述抗衰老产品为抗皮肤衰老产品。In some embodiments, the anti-aging product is an anti-skin aging product.
在一些实施方案中，所述产品的剂型为溶液、乳液、悬浮液、霜剂、膏剂、凝胶剂或贴剂。In some embodiments, the product is in the form of a solution, emulsion, suspension, cream, ointment, gel, or patch.
在第三方面，本发明提供了一种预防或者治疗皮肤色素沉着相关状况或者抗衰老方法，包括向受试者施用第一方面中所描述的甾体化合物(如式I或式II所示结构的化合物，或为如式I或式II所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药)或者第二方面中所描述的组合物。In a third aspect, 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 compound, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound with a structure as shown in Formula I or Formula II) or The composition described in two aspects.
在一些实施方案中，所述皮肤色素沉着相关状况选自黄褐斑、妊娠斑、蝴蝶斑、老年斑、咖啡斑和雀斑中的一种或多种。In some embodiments, 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.
在一些实施方案中，所述抗衰老产品为抗皮肤衰老产品。In some embodiments, the anti-aging product is an anti-skin aging product.
与现有技术相比，本发明具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
本发明发现，本发明提供的甾体化合物可以用于预防、处理、治疗或减轻患者的老年斑、雀斑或者黄褐斑等，并且方便实用，副作用小。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.
附图说明Description of the drawings
图1是施用本发明组合物第1天和第60天的面部照片。Figure 1 is a photograph of the face on the 1st day and the 60th day after applying the composition of the present invention.
具体实施方式Detailed ways
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述具体实施方式仅仅是帮助理解本发明，不应视为对本发明的具体限制。The technical solution of the present invention will be further described below through specific implementations. Those skilled in the art should understand that the specific embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which this invention belongs.
本发明所述的“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"Stereoisomers" as used in the present invention 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. .
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光 学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and methods, 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.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。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.
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise indicated, 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.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式I或式II所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.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 S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。The term "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. In the existing invention, 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. For example, if a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphate esters, which are obtained by phosphorylation of the hydroxyl group of the parent. For a complete discussion of prodrugs, please refer to the following literature: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the ACSSymposium 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 SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 ,51, 2328-2345.
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考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.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.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)。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. 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, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. 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).
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer)包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。 The term "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. For example, protontautomers (also known as 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. A specific example of keto-enol tautomerism is pentane-2,4-dione and tautomerism of 4-hydroxypent-3-en-2-one. Another example of 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.
本发明所提到的盐为药学上可接受的盐，其中“药学上可接受的盐”在所属领域是为我们所熟知的，如文献：Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66,1-19所记载的。药学上可接受的非限定性的盐例子包括与氨基基团反应形成的无机酸盐，如有盐酸盐、氢溴酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、硝酸盐、高氯酸盐，和有机酸盐，如羧酸盐、磺酸盐、亚磺酸盐、硫羧酸盐等，具体的如，但不限于，甲磺酸盐、乙磺酸盐、甲酸盐、乙酸盐、丁二酸盐、苯甲酸盐、琥珀酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、碳酸盐、三氟乙酸盐、羟基乙酸盐、羟乙基磺酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、富马酸盐、乳酸盐、乳糖酸盐或草酸，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、月桂酸盐、月桂基硫酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、十一酸盐、戊酸盐，等等。此外，药学上可接受的盐还包括通过适当的碱得到的盐，如碱金属、碱土金属、铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。The salts mentioned in the present invention are pharmaceutically acceptable salts, and "pharmaceutically acceptable salts" are well known in the art. For example, the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J .Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, and nitrates. , perchlorate, and 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. Other pharmaceutically acceptable 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. . In addition, 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. 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.
可药用的盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。Pharmaceutically acceptable 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/hydrogen phosphate/dihydrogen phosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。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.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.
“组合物”表示一种或多种本文所述化合物、盐或者其生理学上/药学上可以接受的盐或前 体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体或赋形剂。组合物的目的是促进化合物对生物体的给药。"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.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" any disease or condition as used herein, in some embodiments thereof, 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). In other embodiments, "treating" or "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be noticeable to the patient. In other embodiments, "treating" or "treating" refers to modulating a disease or condition physically (eg, stabilizing perceived symptoms) or physiologically (eg, stabilizing body parameters), or both. In other embodiments, "treating" or "treating" refers to preventing or delaying the onset, development, or progression of a disease or disorder.
本发明使用的术语“烷基”表示1-20个碳原子，或1-10个碳原子，或1-8个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代。烷基的实例包括，但并不限于，甲基(Me，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，异丙基(i-Pr，-CH(CH3)2)，正丁基(n-Bu，-CH2CH2CH2CH3)，异丁基(i-Bu，-CH2CH(CH3)2)，仲丁基(s-Bu，-CH(CH3)CH2CH3)，叔丁基(t-Bu，-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于，亚甲基，次乙基，次异丙基等等。The term "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. Examples of 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 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 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2- Methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-Methyl-2-pentyl(-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl(-C(CH 3 )(CH 2 CH 3 ) 2 ) , 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkyl" as used herein include both straight and branched saturated carbon chains. The term "alkylene" as used herein 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.
术语“环烷基”是指一价或多价，非芳香族，饱和或部分不饱和的环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个原子的双环碳环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个原子的双环碳环可以是二环[5,6]或[6,6]体系。合适的环状脂肪族基包括，但并不限于，环烷基，环烯基和环炔基。环状脂肪族基的实例包括，但绝不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基等等。并且所述“环状脂肪族基”或“碳环”、“碳环基”、“环烷基”可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，环烷基、杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O)2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O)2，羧基烷氧基等等。The term "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. 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 base, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. And the "cyclic aliphatic group" or "carbocycle", "carbocyclyl", "cycloalkyl" 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, heterocyclyl, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy radical, hydroxyl-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxyl-substituted alkyl-S (=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy, and the like.
术语“杂环”，“杂环基”，“杂脂环族”或“杂环的”在此处可交换使用，都是指单环，双环，或三环体系，其中环上一个或多个碳原子独立且任选地被杂原子所取代，所述杂原子具有如 本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，只有一个连接点连接到其他分子上去。一个或多个环上的氢原子独立且任选地被一个或多个本发明所描述的取代基所取代。其中一些实施方案是，“杂环”，“杂环基”，“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO2，PO，PO2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-10元的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO2，PO，PO2的基团)。The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and refer 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: In the meaning of the present invention, 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. In some embodiments, 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 ).
杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，噻噁烷基，噻唑烷基，噁唑烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，哌啶基，高哌啶基，环氧丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，4-甲氧基-哌啶-1-基，1,2,3,6-四氢吡啶-1-基，氧氮杂基，二氮杂基，硫氮杂基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基咪唑啉基，咪唑烷基，1,2,3,4-四氢异喹啉基，1,2,6-噻二嗪烷1,1-二氧代-2-基，4-羟基-1,4-氮杂磷烷4-氧化物-1-基，2-羟基-1-(哌嗪-1-基)乙酮-4-基，2-羟基-1-(5,6-二氢-1,2,4-三嗪-1(4H)-基)乙酮-4-基，5,6-二氢-4H-1,2,4-噁二嗪-4-基，2-羟基-1-(5,6-二氢吡啶-1(2H)-基)乙酮-4-基，3-氮杂双环[3.1.0]己基，3-氮杂双环[4.1.0]庚基，氮杂双环[2.2.2]己基，2-甲基-5,6,7,8-四氢-[1,2,4]三唑[1,5-c]嘧啶-6-基，4,5,6,7-四氢异噁唑[4,3-c]吡啶-5-基，3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基，2-氧-5-氮杂双环[2.2.2]辛烷-5-基，喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧代硫代吗啉基，和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是取代或未取代的，其中取代基可以是，但并不限于，氧代(＝O)，羟基，氨基，卤素，氰基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O)2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O)2，羧基烷氧基等等。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-methoxy-piperidin-1-yl, 1,2, 3,6-tetrahydropyridin-1-yl, oxaza base, diazepine base, thiaza base, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-di Oxypentyl, pyrazolinyl, dithialkyl, dithiazolinyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinoline base, 1,2,6-thiadiazinyl 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphine 4-oxide-1-yl, 2-hydroxy-1 -(Piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4 -yl, 5,6-dihydro-4H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethanone -4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7 ,8-tetrahydro-[1,2,4]triazole[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazole[4,3-c]pyridine- 5-yl, 3H-indolyl 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl , quinolizinyl and N-pyridyl urea. Examples of heterocyclic groups also include, 1,1-dioxothiomorpholinyl, and pyrimidinedione groups in which two carbon atoms on the ring are replaced by oxygen atoms. And the heterocyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkyl Amino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C(=O), alkyl-C(=O ), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxyl-substituted alkyl-S(=O), hydroxyl-substituted alkyl-S(=O) 2 , carboxyalkoxy Key and so on.
术语“芳基”可以单独使用或作为“芳烷基”，“芳烷氧基”或“芳氧基烷基”的一大部分，表示共含有6-14元环的单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽基。并且所述芳基可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O)2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O)2，羧基烷氧基，等等。The term "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. The term "aryl" may be used interchangeably with the term "aromatic ring". For example, aromatic rings may include phenyl, naphthyl and anthracenyl. And the aryl 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, heterocyclyl, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-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, and the like.
术语“杂芳基”表示共含有5-14元环的单环，双环，和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中杂原子具有本发明所述的含义，其中每一个环体系包含3-7元环，且只有一个附着点与分子其余部分相连。术语“杂芳基”可 以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，环烷基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)-，烷基-C(＝O)-，烷基-S(＝O)-，烷基-S(＝O)2-，羟基取代的烷基-S(＝O)-，羟基取代的烷基-S(＝O)2-，羧基烷氧基等等。The term "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. The term "heteroaryl" may Used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". And the heteroaryl 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, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-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.
另外一些实施方案是，杂芳基包括以下的单环，但并不限于这些单环：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-异噁唑基，4-异噁唑基，5-异噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，4-甲基异噁唑-5-基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，嘧啶-5-基，哒嗪基(如3-哒嗪基)，2-噻唑基，4-噻唑基，5-噻唑基，四唑基(如5-四唑基)，三唑基(如2-三唑基和5-三唑基)，2-噻吩基，3-噻吩基，吡唑基(如2-吡唑基)，异噻唑基，1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,2,3-三唑基，1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，1,3,4-噻二唑-2-基，吡嗪基，吡嗪-2-基，1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，和异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)，苯并[d]噻唑-2-基，咪唑并[1,5-a]吡啶-6-基。In other embodiments, 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-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-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-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following Bicyclic rings, but by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl) , 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzo[d]thiazole- 2-yl, imidazo[1,5-a]pyridin-6-yl.
术语“杂原子”表示一个或多个O，S，N，P和Si原子，包括N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(例如3，4-二氢-2H-吡咯基中的N)，NH(例如吡咯烷基中的NH)或NR(例如N-取代的吡咯烷基中的NR)。The term "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 The form in which the hydrogen on the nitrogen atom is substituted, for example, N (e.g. N in 3,4-dihydro-2H-pyrrolyl), NH (e.g. NH in pyrrolidinyl) or NR (e.g. N-substituted pyrrole NR in alkyl group).
术语“杂烷基”表示烷基链中间可以插入一个或多个杂原子，其中烷基基团和杂原子具有如本发明所述的含义。除非另外详细说明，杂烷基基团含有1-10个碳原子，另外一些实施方案是，杂烷基基团含有1-8个碳原子，另外一些实施方案是，杂烷基基团含有1-6个碳原子，另外一些实施方案是，杂烷基基团含有1-4个碳原子，另外一些实施方案是，杂烷基基团含有1-3个碳原子。这样的实例包括，但并不限于，CH3OCH2-，CH3CH2OCH2-，CH3SCH2-，CH3SCH2CH2-，(CH3)2NCH2-，(CH3)2CH2OCH2-，CH3OCH2CH2-，CH3CH2OCH2CH2-等。The term "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.
术语“卤素”是指F，Cl，Br或I。The term "halogen" refers to F, Cl, Br or I.
本发明所述的“卤代”表示用卤素取代其后接的基团，取代的个数可以是一个或多个。"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.
本发明所述的“羟基取代的”表示用羟基取代其后接的基团，取代的个数可以是一个或多个。"Hydroxy-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.
本发明所述的“取代的”用于两个基团之间时，则其前面为取代基，如“芳基取代的烷基”表示烷基上具有芳基取代基，“烷氧基羰基取代的烷基”表示烷基上具有烷氧基羰基取代基。When "substituted" in the present invention is used between two groups, it is preceded by a substituent. For example, "aryl-substituted alkyl" means that the alkyl group has an aryl substituent, "alkoxycarbonyl" "Substituted alkyl" means an alkyl group having an alkoxycarbonyl substituent.
当本发明多个基团联合使用时，从左到右，依次为取代关系，如“芳基烷基”，表示芳基取代的烷基，“烷氧基烷氧基”，表示烷氧基取代的烷氧基。When multiple groups are used in combination in the present invention, the 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.
如本发明所使用的术语“皮肤”意在包括面部、颈部、胸部、背部、臂部(包括腋下)、手、腿、臀部和头皮上的皮肤。 The term "skin" as used herein is intended to include the skin of the face, neck, chest, back, arms (including underarms), hands, legs, buttocks and scalp.
本发明中化合物的合成参考WO 2018137683中所记载方法获得。The synthesis of the compounds in the present invention is obtained by referring to the method described in WO 2018137683.
实施例1酪氨酸酶抑制试验Example 1 Tyrosinase Inhibition Test
试验步骤如下：The test steps are as follows:
1)将人原代黑色素细胞接种到6孔板里，在具有人黑色素细胞生长补充剂的黑色素细胞生长培养基(MGM)中生长培养18-24h；1) Inoculate primary human melanocytes into a 6-well plate and grow and culture them in melanocyte growth medium (MGM) with human melanocyte growth supplement for 18-24 hours;
2)去除原培养基，加入含不同浓度(1μM、5μM、10μM、25μM)的本发明化合物1的培养基，培养24h；2) Remove the original culture medium, add culture medium containing compound 1 of the present invention at different concentrations (1 μM, 5 μM, 10 μM, 25 μM), and culture for 24 hours;
3)暴露结束，去除培养液，用PBS清洗2次，用细胞刮收集各孔细胞，10000rpm/min，4℃离心收集细胞；3) After the exposure, remove the culture medium, wash twice with PBS, collect the cells in each well with a cell scraper, and centrifuge at 10,000 rpm/min at 4°C to collect the cells;
4)加入细胞裂解液，采用反复冻融的方式处理，裂解细胞，10000rpm/min，4℃离心20min获得上清液；4) Add cell lysis solution, freeze and thaw repeatedly, lyse cells, centrifuge at 10,000 rpm/min at 4°C for 20 min to obtain the supernatant;
5)在96孔板中加入各组上清液，迅速加入L-DOPA溶液，振荡后在475nm波长下测定吸光度值。37℃反应30min后，再次测定吸光度值；5) Add the supernatants of each group to the 96-well plate, quickly add the L-DOPA solution, shake and measure the absorbance value at 475nm wavelength. After reacting at 37°C for 30 minutes, measure the absorbance value again;
6)统计方法6)Statistical methods
应用Graph PadPrism作图，结果表示为Mean±SD。各组间多重比较采用t-test统计分析。所有的统计分析均为双尾。p<0.05被认为具有差异显著性，其中*p<0.05，0.005<**p<0.01，***p<0.001，p值越小越显著。
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.
步骤2)中采用的化合物1为 The compound 1 used in step 2) is
结论：试验结果显示本发明化合物对酪氨酸酶具有一定的抑制做作用。Conclusion: The test results show that the compound of the present invention has a certain inhibitory effect on tyrosinase.
实施例2黑色素模型(Melanoderm)测试Example 2 Melanoderm test
对照化合物由阴性对照物(超纯水)、载体对照物[超纯水中的二甲基亚砜(DMSO)-最终浓度为0.1％]和阳性对照物(超纯水中的2％的曲酸-最终浓度为700μM)组成。测试本发明化合物在DMSO中以10mM浓度制备，并用EPI-100-LLMM培养基(Mattek Corp.)稀释至10μM的最终浓度。将黑色素模型人体组织(MEL-300-B，Mattek Corp.)用EPI-100-NMM培养基平衡24小时，接下来用EPI-100-LLMM培养基平衡48小时，然后用测试本发明化合物和对照物处理。按照标准方案，用对照物和测试本发明化合物对黑色素模型进行给药，持续总共12天，收集黑色素模型用于黑色素定量、活力分析和宏观/微观成像分析。对于黑色素定量，将组织悬浮在磷酸盐缓冲盐水(PBS)缓冲液(5ml)中5分钟，从PBS中取出并用另外的PBS(2ml)洗涤/漂洗。将组织用1％碳酸氢钠溶液(300μl)处理30分钟，然后除去碳酸氢钠溶液，并用PBS 溶液(2×2ml)洗涤/漂洗。将组织悬浮于Solvable试剂(500μl)中，并在95℃下与黑色素标准样品(通过将黑色素悬浮于Solvable试剂中以生成0、2.5、5、10、25、50和100μg的黑色素标准物而制备)一起温育24小时。将所有温育的样品以13000rpm离心5分钟，在490nm读取/测定上清液的光密度。从黑色素标准样品校准曲线确定每个组织样品的黑色素的量(μg)。使用BCA蛋白质测定试剂盒(Pierce)测定组织样品的蛋白质浓度，将黑色素含量标准化并表示为黑色素(μg)/蛋白质(表1)。使用WST-1试剂盒测定相对于阴性对照物和载体对照物的测试化合物给药/供料的结果的组织活力。检查组织图像，以评估与阴性对照物、载体对照物和阳性对照物相比的测试本发明化合物的黑色素淡化能力，并通过显微镜(10倍放大)评估细胞毒性。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 μM). 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 μM. 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. Melanin models were dosed with controls and test compounds of the invention following standard protocols for a total of 12 days and collected for melanin quantification, viability analysis and macro/micro imaging analysis. For melanin quantification, tissue was suspended in phosphate buffered saline (PBS) buffer (5 ml) for 5 min, removed from PBS and washed/rinsed with additional PBS (2 ml). The tissue was treated with 1% sodium bicarbonate solution (300 μl) for 30 min, then the sodium bicarbonate solution was removed and replaced with PBS. Solution (2 x 2 ml) wash/rinse. Tissue was suspended in Solvable reagent (500 μl) 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 μg 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 (μg) 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 (μg)/protein (Table 1). 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).
表1：用化合物处理后的黑色素含量

Table 1: Melanin content after treatment with compounds

注：表1中化合物按照WO2018137683中所述方法制备所得。Note: The compounds in Table 1 were prepared according to the method described in WO2018137683.
Melanoderm数据结果显示化合物1和羊毛甾醇明显降低了黑色素含量，具有一定的治疗/改善色素沉着效果。Melanoderm data results show that compound 1 and lanosterol significantly reduce melanin content and have a certain effect in treating/improving pigmentation.
实施例3老年斑效果测试方法Example 3 Age Spot Effect Test Method
所用处方和制备方法如下所示。The recipes and preparation methods used are shown below.
化合物1：10mgCompound 1: 10mg
PEG400：0.45gPEG400: 0.45g
吐温80：0.025gTween 80: 0.025g
PVP：0.025gPVP: 0.025g
HP-β-CD：0.475gHP-β-CD: 0.475g
水：8.515mLWater: 8.515mL
具体制备步骤如下：The specific preparation steps are as follows:
在含有化合物1的玻璃容器中，加入0.45g PEG400和0.025g吐温80以及PVP 0.025g，于45℃搅拌15分钟；然后加入0.475g HP-β-CD和水8.515mL，于45℃搅拌15分钟；最后，使用Covaris超声破碎仪进行超声20分钟，获得上述处方。In the glass container containing compound 1, add 0.45g PEG400, 0.025g Tween 80 and 0.025g PVP, stir at 45°C for 15 minutes; then add 0.475g HP-β-CD and 8.515mL of water, stir at 45°C for 15 minutes minutes; finally, use the Covaris ultrasonic disrupter for 20 minutes to obtain the above prescription.
试验方法：招募面部患有老年斑的志愿者，每天早、中、晚将本发明的组合物涂抹于患老年斑处各涂抹一次。在施用本发明组合物第1天和第60天拍摄面部照片。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.
图1(左)为施用本发明组合物第1天的面部局部照片；图1(右)为施用本发明组合物第60天后的面部局部照片。可以看出，施用本发明所述的组合物60天后明显改善和减轻了患者的老年斑。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.
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。 Although the present invention has been described in detail above with general descriptions, specific embodiments and tests, it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. . Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims (12)

  1. 甾体化合物在制备预防或治疗皮肤色素沉着相关状况或者抗衰老相关产品中的应用，其特征在于，所述甾体化合物为如式(I)所示结构的化合物，或为式(I)所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药；
    The application of steroidal compounds in the preparation of products related to the prevention or treatment of skin pigmentation or anti-aging, characterized in that the steroidal compound is a compound with a structure shown in formula (I), or a compound represented by formula (I). Stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds showing the structure;
    其中，R为H、D、烷基、硫酸基、磷酸基、烷基硅基、苄基或-C(O)-X；Wherein, R is H, D, alkyl, sulfate, phosphate, alkylsilyl, benzyl or -C(O)-X;
    X选自芳基、杂芳基、环烷基、杂环基、杂烷基或烷基；X is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroalkyl or alkyl;
    R和X中所述芳基、杂芳基、环烷基、杂环基、杂烷基、烷基硅基和烷基任选地被1、2、3或4个相同或不同的取代基所取代；The 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;
    所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、烷基羰基、烷基、卤代烷基、环烷基、杂环基、芳基、芳基烷基、杂芳基、羧基、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-；The substituent is selected from D, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, alkylcarbonyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, Heteroaryl, carboxyl, R 1 R 2 NC(=O)- or R 1 R 2 NC(=NH)-NR 3 -;
    R1、R2和R3各自独立地选自H、D或烷基。R 1 , R 2 and R 3 are each independently selected from H, D or alkyl.
  2. 根据权利要求1所述的应用，其中，所述甾体化合物为如式(II)所示结构的化合物或为式(II)所示结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    The application according to claim 1, wherein the steroid compound is a compound with a structure represented by formula (II) or a stereoisomer or tautomer of a compound with a structure represented by formula (II), Nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
    其中R的定义同式(I)。The definition of R is the same as formula (I).
  3. 根据权利要求1或2所述的应用，其中，R为H、D、C1-6烷基、硫酸基、磷酸基、C1-6烷基硅基、苄基或-C(O)-X； The application according to claim 1 or 2, wherein R is H, D, C 1-6 alkyl, sulfate group, phosphate group, C 1-6 alkylsilyl, benzyl or -C(O)- X;
    X选自C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基或C1-6烷基；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和X中所述C6-10芳基、C2-9杂芳基、C3-8环烷基、C2-10杂环基、C1-6杂烷基、C1-6烷基硅基或C1-6烷基任选地被1、2、3或4个相同或不同的取代基所取代；C 6-10 aryl, C 2-9 heteroaryl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 1-6 heteroalkyl, C 1-6 alkyl mentioned in R and X Silyl or C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 identical or different substituents;
    所述取代基选自D、卤素、羟基、巯基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、卤代C1-6烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C6-10芳基C1-6烷基、C2-9杂芳基、羧基、R1R2NC(＝O)-或R1R2NC(＝NH)-NR3-；The substituent is selected from D, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3 -8 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 6-10 aryl, C 1-6 alkyl, C 2-9 heteroaryl, carboxyl, R 1 R 2 NC( =O)- or R 1 R 2 NC (=NH)-NR 3 -;
    R1、R2和R3各自独立地选自H、D或C1-6烷基。R 1 , R 2 and R 3 are each independently selected from H, D or C 1-6 alkyl.
  4. 根据权利要求1-3任一项所述的应用，其特征在于，X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、羟基甲基、羟基乙基、巯基甲基、巯基乙基、氨基甲基、氨基乙基、氨基丙基、苯基甲基、苯基乙基、咪唑基甲基、羧基甲基、羧基乙基、甲硫基甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、 带有H2NC(＝O)-取代基的C1-3烷基或带有H2NC(＝NH)-NH-取代基的C1-3烷基。The application according to any one of claims 1 to 3, characterized in that, 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, methylthio 1 ,3-dioxopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, ? Phyllinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxeptanyl, thiepane 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolyl , furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thiophene base, 3-thienyl, 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, benzofuryl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl, 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, [1,2,4]triazolo[1,5-a]pyridinyl , C 1-3 alkyl with H 2 NC(=O)-substituent or C 1-3 alkyl with H 2 NC(=NH)-NH-substituent.
  5. 根据权利要求1-4任一项所述的应用，其特征在于，所述取代基选自-D、卤素、羟基、氨基、氰基、硝基、羧基、C1-6烷基羰基、C1-6烷基、C1-6卤代烷基、C3-8环烷基、C2-9杂环基、C6-10芳基或C2-9杂芳基。The application according to any one of claims 1-4, characterized in that the substituent is selected from -D, halogen, hydroxyl, amino, cyano, nitro, carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 2-9 heteroaryl.
  6. 根据权利要求1-5任一项所述的应用，其特征在于，所述取代基选自-D、-F、-Cl、-Br、羟基、氨基、氰基、羧基、甲酰基、乙酰基、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、二氟甲基、苯基、萘基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、 四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基或[1,2,4]三唑并[1,5-a]吡啶基。The application according to any one of claims 1 to 5, characterized in that the substituent is selected from -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, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl Pyryl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiophenyl Oxalkyl, homopiperazinyl, homopiperidinyl, oxeptanyl, thieptanyl, oxazayl, diazayl, thiazepanyl, indolinyl, 1, 2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrole base, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, Tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, 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 Diazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl, 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]triazino Azolo[1,5-a]pyridyl.
  7. 根据权利要求1-6任一项所述的应用，其特征在于，X选自如下任一基团：
    The application according to any one of claims 1 to 6, characterized in that, X is selected from any of the following groups:
  8. 根据权利要求1所述的应用，其特征在于，所述式I所示结构的化合物选自如下化合物中的任意一种：





    The application according to claim 1, characterized in that the compound with the structure shown in formula I is selected from any one of the following compounds:





  9. 根据权利要求1-8任一项所述的应用，其特征在于，所述产品选自药物、保健品和护肤品；和/或The application according to any one of claims 1 to 8, characterized in that the product is selected from the group consisting of medicines, health care products and skin care products; and/or
    所述皮肤色素沉着相关状况选自黄褐斑、妊娠斑、蝴蝶斑、老年斑、咖啡斑和雀斑中的一种或多种；和/或The skin pigmentation related condition is selected from one or more of chloasma, pregnancy spots, butterfly spots, age spots, café-au-lait spots and freckles; and/or
    所述抗衰老产品为抗皮肤衰老相关产品。The anti-aging products are anti-skin aging related products.
  10. 组合物在制备预防或治疗皮肤色素沉着相关状况或抗衰老相关产品中的应用，其特 征在于，所述组合物包括权利要求1-9中任一项所述的应用中限定的甾体化合物，及药学上或化妆品上可接受的载体、赋形剂、稀释剂、辅剂或媒介物中的一种或多种，The application of the composition in the preparation of products for preventing or treating skin pigmentation related conditions or anti-aging related products, which are particularly The characteristic is that the composition includes the steroid compound defined in the application according to any one of claims 1 to 9, and a pharmaceutically or cosmetically acceptable carrier, excipient, diluent, auxiliary agent or vehicle one or more of the things,
    优选地，所述皮肤色素沉着相关状况选自黄褐斑、妊娠斑、蝴蝶斑、老年斑、咖啡斑和雀斑中的一种或多种；和/或Preferably, the skin pigmentation-related condition is selected from one or more of chloasma, pregnancy spots, butterfly spots, age spots, café-au-lait spots and freckles; and/or
    所述抗衰老产品为抗皮肤衰老产品。The anti-aging products are anti-skin aging products.
  11. 根据权利要求1-10任一项所述的应用，其中所述产品的剂型为溶液、乳液、悬浮液、霜剂、膏剂、凝胶剂或贴剂。The application according to any one of claims 1 to 10, wherein the dosage form of the product is a solution, emulsion, suspension, cream, ointment, gel or patch.
  12. 一种预防或治疗皮肤色素沉着相关状况或抗衰老的方法，包括向受试者施用权利要求1-9中任一项所述的应用中限定的甾体化合物或者权利要求10或11所述的应用中限定的组合物；A method for preventing or treating skin pigmentation-related conditions or anti-aging, comprising administering to a subject a steroidal compound defined in the use of any one of claims 1-9 or claims 10 or 11 Compositions defined in the application;
    优选地，所述皮肤色素沉着相关状况选自黄褐斑、妊娠斑、蝴蝶斑、老年斑、咖啡斑和雀斑中的一种或多种；和/或Preferably, the skin pigmentation-related condition is selected from one or more of chloasma, pregnancy spots, butterfly spots, age spots, café-au-lait spots and freckles; and/or
    所述抗衰老产品为抗皮肤衰老产品。 The anti-aging products are anti-skin aging products.
PCT/CN2023/095320 2022-05-20 2023-05-19 Use of steroid compound WO2023222116A1 (en)

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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 (en) * 2008-04-03 2009-10-29 Nippon Menaade Keshohin Kk Lanost-8-ene derivative and skin care preparation for external use comprising the same
WO2018137683A1 (en) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Lanosterol prodrug compound and preparation method therefor and use thereof
CN112569127A (en) * 2020-12-30 2021-03-30 广州澳希亚实业有限公司 Liquid oily composition and preparation method and application thereof

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 (en) * 2008-04-03 2009-10-29 Nippon Menaade Keshohin Kk Lanost-8-ene derivative and skin care preparation for external use comprising the same
WO2018137683A1 (en) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Lanosterol prodrug compound and preparation method therefor and use thereof
CN112569127A (en) * 2020-12-30 2021-03-30 广州澳希亚实业有限公司 Liquid oily composition and preparation method and application thereof

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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