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WO2024085695A1 - Nouveau dérivé d'altiratinib, son procédé de fabrication et composition le comprenant en tant que principe actif pour la prévention, le soulagement ou le traitement de la pigmentation de la peau - Google Patents

Nouveau dérivé d'altiratinib, son procédé de fabrication et composition le comprenant en tant que principe actif pour la prévention, le soulagement ou le traitement de la pigmentation de la peau Download PDF

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Publication number
WO2024085695A1
WO2024085695A1 PCT/KR2023/016293 KR2023016293W WO2024085695A1 WO 2024085695 A1 WO2024085695 A1 WO 2024085695A1 KR 2023016293 W KR2023016293 W KR 2023016293W WO 2024085695 A1 WO2024085695 A1 WO 2024085695A1
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Prior art keywords
pyridin
acetamido
altiratinib
difluorophenoxy
cyclopropanecarboxamide
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Ceased
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English (en)
Korean (ko)
Inventor
송영섭
장성은
안홍찬
이수정
이정현
김민영
박영혜
황지선
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Asan Foundation
University of Ulsan Foundation for Industry Cooperation
Daegu Gyeongbuk Medical Innovation Foundation
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Asan Foundation
University of Ulsan Foundation for Industry Cooperation
Daegu Gyeongbuk Medical Innovation Foundation
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Priority claimed from KR1020230139902A external-priority patent/KR20240055676A/ko
Application filed by Asan Foundation, University of Ulsan Foundation for Industry Cooperation, Daegu Gyeongbuk Medical Innovation Foundation filed Critical Asan Foundation
Publication of WO2024085695A1 publication Critical patent/WO2024085695A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel altiratinib derivative, a method for producing the same, and a composition for preventing, improving, or treating skin pigmentation containing the same as an active ingredient.
  • Human skin color is influenced by environmental or physiological conditions such as solar ultraviolet rays, fatigue, and stress, but is fundamentally determined by the composition and distribution of various chromophores such as melanin, hemoglobin, and carotenoid in the skin.
  • Melanin is a black-brown polymer pigment synthesized by melanocytes.
  • the tyrosinase enzyme converts tyrosine into DOPA and then undergoes a series of oxidation processes to synthesize melanin.
  • Melanosomes containing melanin transfer melanin from melanocytes to keratinocytes such as keratinoids through dendrites and distribute melanin throughout the epidermis.
  • Skin color is determined by the amount of melanin, and the greater the amount of melanin, the darker the skin color.
  • Pigmentation or hyperpigmentation is a condition in which melanin increases in the skin, nails, and mucous membranes surrounding the mouth or nasal cavity, causing the skin to turn black. It can be caused by genetic diseases, drugs, inflammation, trauma, etc. It can be caused by various causes, such as exposure to ultraviolet rays and hyperpigmented skin diseases such as melasma. Pigmentation is considered a socially important disease because it can cause mental stress and reduce quality of life.
  • the present inventors conducted research to discover a substance that can effectively suppress skin pigmentation without causing side effects to the human body.
  • a derivative of Altiratinib has a melanin production inhibition effect similar to that of Altiratinib.
  • the present invention was completed by confirming that it was similar and had significantly low cytotoxicity.
  • the object of the present invention is to provide altiratinib derivatives or salts thereof.
  • Another object of the present invention is to provide a method for producing altiratinib derivatives according to the present invention.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating pigmentation, comprising the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.
  • Another object of the present invention is to provide a cosmetic composition for preventing or improving pigmentation, comprising the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.
  • Another object of the present invention is to provide a skin care method for preventing or improving pigmentation, comprising the step of applying the cosmetic composition according to the present invention to the skin of an individual in need thereof.
  • Another object of the present invention is to provide a topically applied preparation for preventing or improving pigmentation containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.
  • Another object of the present invention is to provide a food composition for prevention or improvement containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.
  • Another object of the present invention is to provide a health functional food for prevention or improvement containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.
  • Another object of the present invention is to provide a quasi-drug composition for prevention or improvement containing the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.
  • the present invention provides an altiratinib derivative or a salt thereof represented by the following formula (1):
  • R 1 is a halogen element, or ego
  • R 2 is , , , , or ego
  • n 0, 1, or 2
  • R 3 to R 6 are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C 1 -C 5 alkoxy group, substituted or unsubstituted C 1 -C 5 alkyl group, Or a nitro group (NO 2 ),
  • a 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
  • a 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
  • the 'substituted or unsubstituted means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.
  • the altiratinib derivative may be represented by any one of the following formulas 2a to 2e, but is not limited thereto.
  • n 0, 1, or 2
  • R 3 and R 4 are each independently a halogen element, hydrogen (H), hydroxyl group (OH), methoxy (OCH 3 ), methyl (CH 3 ), ethyl (CH 2 CH 3 ), trifluoromethyl (CF 3 ), or nitro group (NO 2 ),
  • a 1 is N, CH, CMe, or CPh
  • the A 2 is O, S, NH, NMe, NEt, or CH 2.
  • n 1 or 2
  • R 5 and R 6 are each independently a halogen element, hydrogen (H), methoxy (OCH 3 ), or methyl (CH 3 ),
  • a 3 is N, CH, or CMe
  • a 4 is O, S, NH, or NMe.
  • a 5 is O, S, or NH
  • a 6 is N, or CH.
  • R 1 is a halogen element, or ego
  • the altiratinib derivative has the formula (1):
  • the R 1 is ego
  • the R 2 is , or ego,
  • the R 2 is , or It may be, but is not limited to this.
  • the altiratinib derivative may be any one selected from the group consisting of the following compounds, but is not limited thereto:
  • N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-001);
  • the present invention relates to a compound selected from the following Formula 3 or the following Formula 4 and a compound represented by the following Formula 5, in the presence of an organic solvent, using a coupling reagent, through amide coupling.
  • a manufacturing method is provided wherein the coupling reagent is at least one selected from the group consisting of TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, and DCC.
  • R is , , , , or ego
  • n 0, 1, or 2
  • R 3 to R 6 are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C 1 -C 5 alkoxy group, substituted or unsubstituted C 1 -C 5 alkyl group, Or a nitro group (NO 2 ),
  • a 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
  • a 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
  • the 'substituted or unsubstituted means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.
  • the organic solvent is dioxane, methanol, ethanol, acetonitrile, tetrahydrofuran (THF), and dimethylformamide.
  • DMF dimethyl sulfoxide
  • DCE dichloroethylene
  • the present invention provides a pharmaceutical composition for preventing or treating pigmentation, comprising the altiratinib derivative or a salt thereof according to the present invention as an active ingredient.
  • the present invention provides a method for preventing or treating pigmentation, comprising administering a pharmaceutical composition containing an altiratinib derivative or a salt thereof as an active ingredient to an individual in need thereof.
  • the present invention provides uses of altiratinib derivatives or salts thereof for preventing, improving or treating pigmentation, and/or for skin whitening.
  • the present invention provides the use of an altiratinib derivative or a salt thereof for manufacturing a medicament for treating pigmentation.
  • the pigmentation includes freckles, freckles, lentigines, age spots, moles, milk coffee spots, nevus of Ota, blue nevus, hyperpigmentation spots, hyperpigmentation after drug use, and gravidic chlorasma. ), post-inflammatory hyperpigmentation due to wounds or dermatitis, senile pigmented spots, and solar lentigines, but is not limited thereto.
  • the present invention provides a cosmetic composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.
  • the cosmetic composition includes serum, lotion, paste, patch, gel, skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutritional lotion, cream, massage cream, nutrition.
  • the present invention provides a skin care method for preventing or improving pigmentation, comprising the step of applying the composition according to the present invention to the skin of an individual in need thereof.
  • the present invention provides a topically applied preparation for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.
  • the topical application preparation may be in the form of a cream, gel, lotion, powder, powder spray, oil, roll-on formulation, ointment, foam, spray, stick, or tincture, but is limited thereto. It doesn't work.
  • the present invention provides a food composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.
  • the food composition includes a health functional food composition.
  • the present invention provides a health functional food for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.
  • the present invention provides a quasi-drug composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.
  • the present invention provides a kit for preventing or improving pigmentation, comprising a pharmaceutical composition, cosmetic composition, topical application preparation, food composition, or quasi-drug composition according to the present invention.
  • the altiratinib derivative according to the present invention had a similar or superior melanin production inhibition effect to altiratinib and had significantly low cytotoxicity. Therefore, the composition containing altiratinib derivatives or their salts according to the present invention as an active ingredient can not only be used for the prevention or treatment of pigmentation, but can also be used in various fields of skin care, such as skin whitening by improving pigmentation, etc. It is expected that it can be put to good use.
  • Figure 1 is a diagram showing the results of measuring the skin permeability of altiratinib derivative compounds ALT-002 and ALT-003 using PAMPA.
  • Figure 2 is a diagram showing the results of measuring melanin content after treatment of altiratinib derivative compounds ALT-001 to ALT-003, ALT-006, and ALT-013 on Mel-Ab, a mouse melanin cell line treated with FSK.
  • Figure 3 shows melanin content after treatment of altiratinib derivative compounds ALT-015 to ALT-017, ALT-019 to ALT-021, ALT-026, and ALT-028 on Mel-Ab, a mouse melanocyte cell line treated with FSK. This is a drawing showing the measurement results.
  • Figure 4 shows the melanin content measured after treatment of altiratinib derivative compounds ALT-001 to ALT-003, ALT-006, and ALT-013 on Mel-Ab, a mouse melanin cell line treated with FSK, compared to the control group of cells treated with only FSK. This is a drawing expressed as a percentage.
  • Figure 5 is a diagram showing the results of measuring melanin content after treatment of altiratinib derivative compounds ALT-002, ALT-003, ALT-006, and ALT-009 on B16F10, a mouse melanocyte cell line treated with FSK.
  • Figure 6 is a diagram showing the results of measuring melanin content after treating the altiratinib derivative compound ALT-022 to B16F10, a mouse melanin cell line treated with FSK.
  • Figure 7 is a diagram showing the results of measuring melanin content after treating human melanocytes with altiratinib derivative compounds ALT-002 and ALT-003.
  • Figure 8 is a diagram showing the results of measuring melanin content after treating human melanocytes with altiratinib derivative compounds ALT-024 and ALT-028.
  • Figure 9 is a diagram showing the results of treating altiratinib derivative compounds ALT-001 to ALT-014 at different concentrations to Mel-Ab, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
  • Figure 10 is a diagram showing the results of treating altiratinib derivative compounds ALT-015 to ALT-028 at different concentrations to Mel-Ab, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
  • Figure 11 is a diagram showing the results of treating altiratinib derivative compounds ALT-001 to ALT-014 at different concentrations to B16F10, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
  • Figure 12 is a diagram showing the results of treating altiratinib derivative compounds ALT-015 to ALT-028 at different concentrations to B16F10, a mouse melanocyte cell line, and confirming the degree of cell activity through apoptosis analysis.
  • Figure 13 is a diagram showing the results of treating human melanocytes with altiratinib derivative compounds ALT-001 to ALT-014 at different concentrations and then confirming the degree of cell activity through apoptosis analysis.
  • Figure 14 is a diagram showing the results of treating human melanocytes with altiratinib derivative compounds ALT-015 to ALT-028 at different concentrations and then confirming the degree of cell activity through apoptosis analysis.
  • the present inventors completed the present invention by confirming that the altiratinib derivative has significantly lower toxicity to melanocytes compared to altiratinib and effectively inhibits melanin production in melanocytes similar to altiratinib. .
  • the present invention provides an altiratinib derivative or a salt thereof represented by the following formula (1):
  • R 1 is a halogen element, or ego
  • R 2 is , , , , or ego
  • n 0, 1, or 2
  • R 3 to R 6 are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C 1 -C 5 alkoxy group, substituted or unsubstituted C 1 -C 5 alkyl group, Or a nitro group (NO 2 ),
  • a 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
  • a 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
  • the 'substituted or unsubstituted means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.
  • the altiratinib derivative may be represented by any one of the following formulas 2a to 2e, but is not limited thereto:
  • n 0, 1, or 2
  • R 3 and R 4 are each independently a halogen element, hydrogen (H), hydroxyl group (OH), methoxy (OCH 3 ), methyl (CH 3 ), ethyl (CH 2 CH 3 ), trifluoromethyl (CF 3 ), or nitro group (NO 2 ),
  • a 1 is N, CH, CMe, or CPh
  • the A 2 is O, S, NH, NMe, NEt, or CH 2.
  • n 1 or 2
  • R 5 and R 6 are each independently a halogen element, hydrogen (H), methoxy (OCH 3 ), or methyl (CH 3 ),
  • a 3 is N, CH, or CMe
  • a 4 is O, S, NH, or NMe.
  • a 5 is O, S, or NH
  • a 6 is N, or CH.
  • R 1 is a halogen element, or ego
  • the altiratinib derivative is more preferably, in Formula 1,
  • the R 1 is ego
  • the R 2 is , or ego,
  • the R 2 is , or It may be, and according to one embodiment of the present invention, the altiratinib derivative is preferably ALT-002 (Compound 7a), ALT-003 (Compound 6a), ALT-006 (Compound 9a), or ALT-013. (Compound 8c).
  • C 1 -C 5 alkyl group used in the present invention refers to a monovalent alkyl group having 1 to 5 carbon atoms. Examples of this term include functional groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-hexyl, etc.
  • the alkyl and other alkyl moiety-containing substituents described in the present invention include both straight-chain and branched forms. Substituted C 1 -C 5 alkyl means that one or more hydrogen atoms are substituted with another substituent.
  • the substituent is not limited, but may include a halogen element, N, O, S, nitrile group, nitro group, hydroxy Includes groups, carbonyl groups, ester groups, imide groups, substituted or unsubstituted aryl groups, etc.
  • halogen element used in the present invention may include fluoro (F), chloro (Cl), bromo (Br), and iodine (I).
  • C 1 -C 5 alkoxy group means the group -OR, where R means “C 1 -C 5 alkyl”.
  • Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, etc.
  • N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-001);
  • the altiratinib derivative of the present invention can be used in the form of a pharmaceutically acceptable salt.
  • the term "pharmaceutically acceptable salt” includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases, and acids formed by pharmaceutically acceptable free acids. Addition salts are useful.
  • the acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Obtained from non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Obtained from non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodine.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone or acetonitrile. It can be manufactured by ordering. It can also be prepared by evaporating the solvent or excess acid from this mixture and drying it, or by suction-filtering the precipitated salt.
  • a water-miscible organic solvent for example, methanol, ethanol, acetone or acetonitrile. It can be manufactured by ordering. It can also be prepared by evaporating the solvent or excess acid from this mixture and drying it, or by suction-filtering the precipitated salt.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts.
  • the corresponding silver salts are obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g. silver nitrate).
  • the compound of the present invention may include not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates, and solvates that can be prepared by conventional methods.
  • any one compound selected from the compound of formula 3 or the compound of formula 4 below and the compound of formula 5 below are used as a coupling reagent.
  • the coupling reagent is one or more selected from the group consisting of TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, and DCC.
  • R is , , , , or ego
  • n 0, 1, or 2
  • R 3 to R 6 are each independently a halogen atom, hydrogen (H), hydroxy group (OH), substituted or unsubstituted C 1 -C 5 alkoxy group, substituted or unsubstituted C 1 -C 5 alkyl group, Or a nitro group (NO 2 ),
  • a 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
  • a 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
  • the 'substituted or unsubstituted means substituted or unsubstituted with one or more substituents selected from the group consisting of a halogen element, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, and imide group.
  • the method for producing the altiratinib derivative may be an amide coupling reaction at room temperature for 15 to 90 hours, but is not limited thereto.
  • the altiratinib derivative according to the present invention may be synthesized through a reaction according to Scheme 1 below, and more preferably in “steps d to f: Amide Coupling”. It may be synthesized through a reaction that follows.
  • the organic solvent is dioxane, methanol, ethanol, acetonitrile, tetrahydrofuran (THF), and dimethylformamide (DMF). , dimethyl sulfoxide (DMSO), and dichloroethylene (DCE), and preferably dimethylformamide, but is not limited thereto.
  • the present invention provides, in another aspect of the present invention, a pharmaceutical composition for preventing or treating pigmentation, comprising the Altiratinib derivative or a salt thereof according to the present invention as an active ingredient,
  • the salt may preferably be a pharmaceutically acceptable salt of the altiratinib derivative.
  • Altiratinib (ALT) is a known drug known to have anticancer effects, and is registered as ID54576299 in PubChem, a chemical molecule database.
  • the structural formula of altiratinib disclosed in the database is shown in Chemical Formula 6 below.
  • pigmentation refers to any disease or disease of the skin caused by discoloration of the skin (pigmentation) or proliferation of abnormally pigmented cells, and includes “hyperpigmentation” and Can be used interchangeably.
  • Skin pigmentation includes excessive or unwanted pigmentation. Factors such as aging, environmental stress, and UV exposure can be potential causes of skin pigmentation.
  • Skin pigmentation of the present invention may be due to an increase in one or more various types of melanin biosynthesized in the skin and/or hair follicles and deposited on the hair or skin compared to the patient's basic pigmentation, and specific examples include spots, freckles, and lentigo.
  • age spots e.g., age spots, moles, milk coffee spots, nevus of Ota, blue nevus, hyperpigmentation spots, hyperpigmentation after drug use, gravidic chloasma, hyperpigmentation after inflammation due to wounds or dermatitis, senile pigmentation spots, and solar lentigines, but is not limited thereto.
  • the altiratinib derivative or a pharmaceutically acceptable salt thereof can inhibit melanin production by satisfying one or more of the following characteristics: (a) of CRTC3 (CREB Regulated Transcription Coactivator 3) Inhibits transcriptional activation function; (b) inhibiting the expression of Microphthalmia-associated transcription factor (MITF); (c) inhibiting the expression of tyrosinase, Dopachrome tautomerase (DCT), or tyrosinase related protein 1 (TRP1); or (d) inhibiting the activity of tyrosinase.
  • CRTC3 CREB Regulated Transcription Coactivator 3
  • MITF Microphthalmia-associated transcription factor
  • DCT Dopachrome tautomerase
  • TRP1 tyrosinase related protein 1
  • melanin refers to a general term for black or brown pigments present in tissues such as skin or eyes of animals.
  • melanin is an important factor in determining a person's skin color.
  • the melanin expression gene is different depending on the race, and the amount and distribution of melanocytes are adjusted accordingly to determine skin color.
  • Melanin plays a role in protecting the skin by blocking ultraviolet rays, but excessive melanin production causes skin pigmentation such as spots, freckles, and skin spots, and further participates in the etiology of skin aging and skin cancer.
  • CRTC3 CREB Regulated Transcription Coactivator 3
  • CRTC3 CREB Regulated Transcription Coactivator 3
  • inhibiting the transcriptional activation function of CRTC3 means inhibiting the expression of CRTC3 itself, inhibiting dephosphorylation of CRTC3 (i.e., promoting phosphorylation of CRTC3), and inhibiting the movement of CRTC3 into the nucleus.
  • a concept that includes both inhibiting the binding of CTRC3 to CREB and/or inhibiting the transcriptional promotion function of CRTC3's target genes.
  • MITF Microphthalmia-associated transcription factor
  • tyrosinase In the present specification, tyrosinase, DCT (Dopachrome tautomerase), and TRP1 (tyrosinase related protein 1) are proteins whose expression is promoted by MITF and are involved in melanin synthesis in melanocytes.
  • tyrosinase is an enzyme that induces melanin synthesis by oxidizing tyrosine, and increasing the expression or activity of tyrosinase further promotes melanin production.
  • the pharmaceutical composition according to the present invention is used for the treatment of patients suffering from pigmentation accompanied by mutations in one or more factors involved in melanin synthesis selected from the group consisting of CRTC3, MITF, tyrosinase, DCT, and TRP1. You can.
  • the pharmaceutical composition according to the present invention may inhibit melanin production particularly effectively in patients suffering from pigmentation accompanied by the above mutation.
  • “mutation” includes increased activity or increased expression of the factors involved in melanin synthesis.
  • the content of the altiratinib derivative or a pharmaceutically acceptable salt thereof in the composition according to the present invention can be appropriately adjusted depending on the symptoms of the disease, the degree of progression of the symptoms, the patient's condition, etc., for example, 0.0001 to 0.0001 based on the total weight of the composition. It may be 99.9% by weight, or 0.001 to 50% by weight, but is not limited thereto.
  • the content ratio is a value based on the dry amount with the solvent removed.
  • the pharmaceutical composition according to the present invention may further include appropriate carriers, excipients, and diluents commonly used in the preparation of pharmaceutical compositions.
  • the excipient may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.
  • the pharmaceutical composition according to the present invention can be prepared as powder, granules, sustained-release granules, enteric-coated granules, solutions, eye drops, ellipsis, emulsions, suspensions, spirits, troches, perfumes, and limonadese according to conventional methods.
  • Carriers, excipients, and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, and calcium. These include phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Additives to tablets, powders, granules, capsules, pills, and troches according to the present invention include corn starch, potato starch, wheat starch, lactose, white sugar, glucose, fructose, di-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, and phosphoric acid.
  • Excipients such as cellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethyl cellulose, sodium methyl cellulose, methyl cellulose, microcrystalline cellulose, dextrin.
  • binders can be used, Hydroxypropyl methyl cellulose, corn starch, agar powder, methyl cellulose, bentonite, hydroxypropyl starch, sodium carboxymethyl cellulose, sodium alginate, calcium carboxymethyl cellulose, calcium citrate, sodium lauryl sulfate, silicic anhydride, 1-hydroxy Propylcellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, Disintegrants such as amylopectin, pectin, sodium polyphosphate, ethyl cellulose
  • soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, Macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acids, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, Lubricants such as starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.
  • Additives to the liquid according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, etc. can be used.
  • a solution of white sugar, other sugars, or sweeteners, etc. may be used in the syrup according to the present invention, and if necessary, flavoring agents, colorants, preservatives, stabilizers, suspending agents, emulsifiers, thickening agents, etc. may be used.
  • Purified water can be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. can be used as needed.
  • Suspensions according to the present invention include acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. Topics may be used, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.
  • Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV solution, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV solution, ethanol, propylene glycol, non-volatile oil - sesame oil.
  • solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristic acid, and benzene benzoate;
  • Solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, Tween, nicotinic acid amide, hexamine, and dimethylacetamide;
  • Weak acids and their salts acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and buffering agents such as gums
  • Isotonic agents such as sodium chloride
  • Stabilizers such as sodium bisulfite (NaHSO 3 ) carbon dioxide gas, sodium metabisulfite (Na 2 S 2 O 5 ), sodium sulfite (Na 2 SO 3 ), nitrogen gas (N
  • Suppositories according to the present invention include cacao oil, lanolin, witepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, lecithin, Lanet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydrocote SP, S-70-XXA, S-70-XX75(S-70-XX95), Hydro Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Massaupol, Masupol-15, Neosupostal-
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the extract with at least one excipient, such as starch, calcium carbonate, and sucrose. ) or prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • the present invention provides a method for preventing or treating pigmentation, which involves administering a pharmaceutical composition containing an Altiratinib derivative or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof. to provide.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, activity of the drug, and the type of patient's disease. It can be determined based on factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art to which the present invention pertains.
  • the pharmaceutical composition of the present invention can be administered to an individual through various routes. All modes of administration are contemplated, including oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal injection, vaginal injection. It can be administered by internal insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, etc.
  • the pharmaceutical composition of the present invention is determined depending on the type of drug as the active ingredient along with various related factors such as the disease to be treated, the route of administration, the patient's age, gender, weight, and severity of the disease.
  • “individual” refers to a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cows, etc. refers to mammals of
  • administration means providing a given composition of the present invention to an individual by any suitable method. Accordingly, in the present invention, “administration” is a concept that includes not only injection or ingestion into an individual, but also application.
  • prevention refers to any action that suppresses or delays the onset of the desired disease
  • treatment refers to the improvement or improvement of the desired disease and its associated metabolic abnormalities by administration of the pharmaceutical composition according to the present invention. It refers to all actions that are beneficially changed, and “improvement” refers to all actions that reduce parameters related to the target disease, such as the degree of symptoms, by administering the composition according to the present invention.
  • the present invention provides a composition for inhibiting CRTC3 in melanocytes, comprising the altiratinib derivative or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.
  • the composition for inhibiting CRTC3 according to the present invention may be a composition for in vivo, ex vivo, and/or in vitro, but is not limited thereto.
  • the composition for inhibiting CRTC3 may be a composition for in vitro and/or ex vivo use. That is, the composition for inhibiting CRTC3 according to the present invention may be a composition used to inhibit CRTC3 in melanocytes in vitro and/or ex vivo.
  • CRTC3 inhibition is a concept that includes suppressing the expression and transcriptional activation function of CRTC3, and the meaning of suppressing the transcriptional activation function of CRTC3 is as described above. That is, the altiratinib or a pharmaceutically acceptable salt thereof may inhibit the transcriptional activation function of CRTC3 by satisfying one or more of the following characteristics: (a) promoting CRTC3 phosphorylation; or (b) inhibiting the movement of CRTC3 into the nucleus.
  • the present invention provides, in another aspect of the present invention, a cosmetic composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof according to the present invention as an active ingredient, wherein the salt is the altiratinib derivative. It may be a cosmetically acceptable salt.
  • cosmetically acceptable salt includes salts derived from cosmetically acceptable inorganic acids, organic acids, or bases. Specific examples include examples of the salts described above, including hadrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate ( Mesylate) and p-toluenesulfonate (tosylate) salts can be further mentioned.
  • the formulation of the cosmetic composition according to the present invention includes serum, lotion, paste, patch, gel, skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutritional lotion, cream, massage cream, nutritional cream, and mist. , moisture cream, hand cream, hand lotion, foundation, essence, nutritional essence, pack, soap, oil, foundation, makeup base, wax, spray, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion or It may be a body cleanser formulation.
  • the cosmetic composition of the present invention may further include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, and sphingolipids.
  • Water-soluble vitamins may be any that can be mixed into cosmetics, but examples include vitamin B1, vitamin B2, vitamin B6, pyridoxine, pyridoxine hydrochloride, vitamin B12, pantothenic acid, nicotinic acid, nicotinic acid amide, folic acid, vitamin C, and vitamin H. and their salts (thiamine hydrochloride, sodium ascorbate, etc.) or derivatives (sodium ascorbic acid-2-phosphate, magnesium ascorbic acid-2-phosphate, etc.) are also water-soluble vitamins that can be used in the present invention. Included. Water-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification from microbial cultures, enzymatic methods, or chemical synthesis.
  • Oil-soluble vitamins may be any that can be mixed into cosmetics, but examples include vitamin A, carotene, vitamin D2, vitamin D3, vitamin E (d1-alpha tocopherol, d-alpha tocopherol, d-alpha tocopherol), etc. , their derivatives (ascorbic palmitate, ascorbic stearate, ascorbic acid dipalmitate, dl-alpha tocopherol acetate, dl-alpha tocopherol nicotinic acid, vitamin E, DL-pantothenyl alcohol, D-pantothenyl alcohol, pantothenyl ethyl ether, etc.) are also included in the oil-soluble vitamins used in the present invention. Oil-soluble vitamins can be obtained by conventional methods such as microbial transformation, purification from microbial cultures, enzymatic or chemical synthesis.
  • Any polymer peptide that can be blended into cosmetics may be used, and examples include collagen, hydrolyzed collagen, gelatin, elastin, hydrolyzed elastin, and keratin.
  • High molecular weight peptides can be purified and obtained by conventional methods such as purification from microbial culture media, enzymatic methods, or chemical synthesis, or they can usually be purified and used from natural products such as dermis of pigs or cows or silk fiber of silkworms.
  • the high molecular weight polysaccharide may be anything that can be blended into cosmetics, but examples include hydroxyethyl cellulose, xanthan gum, sodium hyaluronate, chondroitin sulfate, or its salts (sodium salt, etc.).
  • chondroitin sulfate or its salt can usually be purified and used from mammals or fish.
  • the sphingolipid may be any one that can be blended into cosmetics, and examples include ceramide, phytosphingosine, and sphingolipid. Sphingolipids can usually be purified by conventional methods from mammals, fish, shellfish, yeast, or plants, or obtained by chemical synthesis.
  • the cosmetic composition of the present invention may contain other ingredients usually blended in cosmetics as needed.
  • oils and fats include oils and fats, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, disinfectants, antioxidants, plant extracts, pH adjusters, alcohol, colorants, fragrances, Examples include blood circulation promoters, cooling agents, antiperspirants, and purified water.
  • oil and fat components examples include ester-based fats and oils, hydrocarbon-based fats and oils, silicone-based fats and oils, fluorine-based fats and oils, animal fats and oils, and vegetable fats and oils.
  • Ester-based oils include glyceryl tri2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, and stearic acid.
  • octyl isononanoate hexyldecyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerol oleic acid ester, polyglycerol isostearic acid ester, Triisocetyl citrate, triisoalkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate, trioctyl citrate, dimalate Isostearyl, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succ
  • Hydrocarbon-based fats and oils include squalene, liquid paraffin, alpha-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybudene, microcrystalline wax, and petroleum jelly.
  • Silicone oils include polymethyl silicone, methylphenyl silicone, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, dimethylsiloxane/methylcetyloxysiloxane copolymer, dimethylsiloxane/methylstealoxysiloxane copolymer, and alkyl. Modified silicone oil, amino-modified silicone oil, etc. can be mentioned.
  • fluorine-based fats and oils examples include perfluoropolyether.
  • Animal or plant oils include avocado oil, almond oil, olive oil, sesame oil, rice bran oil, birdflower oil, soybean oil, corn oil, rapeseed oil, apricot oil, palm kernel oil, palm oil, castor oil, sunflower oil, and grape seed oil. , cottonseed oil, palm oil, cucumber nut oil, wheat germ oil, rice germ oil, shea butter, walnut colostrum oil, marker damia nut oil, meadow oil, egg yolk oil, beef tallow, horse oil, mink oil, orange rape oil, jojoba oil. , animal or plant oils such as candelier wax, carnaba wax, liquid lanolin, and hydrogenated castor oil.
  • Moisturizers include water-soluble low-molecular-weight moisturizers, oil-soluble molecular moisturizers, water-soluble polymers, and fat-soluble polymers.
  • fat-soluble low-molecular-weight moisturizers examples include cholesterol and cholesterol esters.
  • Water-soluble polymers include carboxyvinyl polymer, polyaspartate, tragacanth, xanthan gum, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, water-soluble chitin, chitosan, and dextrin. You can.
  • oil-soluble polymers examples include polyvinylpyrrolidone/eicosene copolymer, polyvinylpyrrolidone/hexadecene copolymer, nitrocellulose, dextrin fatty acid ester, and polymer silicone.
  • emollients include long-chain acyl glutamic acid cholesteryl ester, hydroxystearic acid cholesteryl, 12-hydroxystearic acid, stearic acid, rosin acid, and lanolin fatty acid cholesteryl ester.
  • surfactants include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Nonionic surfactants include self-emulsifying glycerin monostearate, propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, POE (polyoxyethylene) sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE.
  • Glycerin fatty acid ester POE alkyl ether, POE fatty acid ester, POE hydrogenated castor oil, POE castor oil, POE ⁇ POP (polyoxyethylene ⁇ polyoxypropylene) copolymer, POE ⁇ POP alkyl ether, polyether modified silicone, lauric acid Examples include alkanolamide, alkylamine oxide, and hydrogenated soybean phospholipid.
  • Anionic surfactants include fatty acid soap, alpha-acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate, alkyl amide sulfate, alkyl phosphate, POE alkyl phosphate, and alkyl amide phosphate.
  • alkyloyl alkyl taurine salt N-acylamino acid salt
  • POE alkyl ether carboxylate alkyl sulfosuccinate, sodium alkyl sulfoacetate, acylated hydrolyzed collagen peptide salt, perfluoroalkyl phosphate ester, etc. .
  • Cationic surfactants include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, and chloride.
  • Examples include benzalkonium, diethylaminoethylamide stearate, dimethylaminopropylamide stearate, and quaternary ammonium salts of lanolin derivatives.
  • Amphoteric surfactants include carboxy beta type, amide beta type, sulfo beta type, hydroxy sulfo beta type, amide sulfo beta type, phosphobeta type, aminocarboxylate type, imidazoline derivative type, and amide amine type. Amphoteric surfactants, etc. can be mentioned.
  • Organic and inorganic pigments include silicic acid, anhydrous silicic acid, magnesium silicate, talc, sericite, mica, kaolin, bengala, clay, bentonite, titanium-coated mica, bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium oxide, and aluminum oxide.
  • Inorganic pigments such as calcium sulfate, barium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, iron oxide, ultramarine blue, chromium oxide, chromium hydroxide, calamine and complexes thereof; Polyamide, polyester, polypropylene, polystyrene, polyurethane, vinyl resin, urea resin, phenol resin, fluorine resin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, divinylbenzene/styrene copolymer, Examples include organic pigments such as silk powder, cellulose, CI pigment yellow, and CI pigment orange, and complex pigments of these inorganic pigments and organic pigments.
  • organic powder examples include metal soap such as calcium stearate; Alkyl phosphate metal salts such as sodium zinc cetilate, zinc laurylate, and calcium laurylate; Acyl amino acid polyvalent metal salts such as N-lauroyl-beta-alanine calcium, N-lauroyl-beta-alanine zinc, and N-lauroyl glycine calcium; Amidesulfonic acid polyvalent metal salts such as N-lauroyl-taurine calcium and N-palmitoyl-taurine calcium; N such as N-epsilon-lauroyl-L-lysine, N-epsilon-palmitoylizine, N-alpha-paritoylolnithine, N-alpha-lauroylarginine, N-alpha-hydrogenated beef tallow fatty acid acylarginine, etc.
  • metal soap such as calcium stearate
  • Alkyl phosphate metal salts such as
  • N-acyl polypeptides such as N-lauroylglycylglycine
  • Alpha-amino fatty acids such as alpha-aminocaprylic acid and alpha-aminolauric acid
  • Examples include polyethylene, polypropylene, nylon, polymethyl methacrylate, polystyrene, divinylbenzene/styrene copolymer, and ethylene tetrafluoride.
  • UV absorbers include para-aminobenzoic acid, ethyl para-aminobenzoate, amyl para-aminobenzoate, octyl para-aminobenzoate, ethylene glycol salicylate, phenyl salicylate, octyl salicylate, benzyl salicylate, butylphenyl salicylate, homomenthyl salicylate, and benzyl cinnamate.
  • Disinfectants include hinokitiol, triclosan, trichlorohydroxydiphenyl ether, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zincphyllithione, benzalkonium chloride, and photosensitive.
  • Sub-No. 301, mononitroguaiacol sodium, undecirenic acid, etc. can be mentioned.
  • Antioxidants include butylhydroxyanisole, propyl gallate, and elisorbic acid.
  • pH adjusters include citric acid, sodium citrate, malic acid, sodium malate, fumal acid, sodium fumalate, succinic acid, sodium succinate, sodium hydroxide, and sodium monohydrogen phosphate.
  • alcohol include higher alcohols such as cetyl alcohol.
  • mixing ingredients that may be added are not limited to this, and any of the above ingredients can be mixed within the range that does not impair the purpose and effect of the present invention, but in an amount of 0.01-5% by weight or 0.01-3% based on the total weight. Can be formulated in % weight percentages.
  • the carrier ingredients include animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide. It can be used.
  • the formulation of the present invention is a powder or spray
  • lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder can be used as the carrier ingredient.
  • chlorofluorohydrocarbon and propane may be used as carrier ingredients.
  • May contain propellants such as butane or dimethyl ether.
  • a solvent, solvating agent or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 , 3-butyl glycol oil, glycerol aliphatic esters, polyethylene glycol or fatty acid esters of sorbitan.
  • the carrier ingredients include water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, and microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar, or tracant may be used.
  • a liquid diluent such as ethanol or propylene glycol
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester
  • microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar, or tracant may be used.
  • the carrier ingredients include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, and fatty acid amide.
  • Ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, linoline derivative, or ethoxylated glycerol fatty acid ester can be used.
  • the present invention provides a skin care method for preventing or improving pigmentation, comprising the step of applying the cosmetic composition according to the present invention to the skin of an individual in need thereof.
  • application includes all means of providing a cosmetic composition to the skin, such as administration, injection, or application.
  • the present invention provides a topically applied preparation for preventing or improving pigmentation, comprising an altiratinib derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the topical application preparations may be in the form of creams, gels, lotions, powders, powder sprays, oils, roll-on formulations, ointments, foams, sprays, sticks or tinctures.
  • the present invention provides, in another aspect of the present invention, a food composition and health functional food for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient, wherein the salt is foodologically acceptable. It may be salt.
  • foodologically acceptable salt includes salts derived from foodologically acceptable organic acids, inorganic acids, or bases.
  • the altiratinib derivative or its salt of the present invention can be added as is or used with other foods or food ingredients, and can be used appropriately according to conventional methods.
  • the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
  • the altiratinib derivative of the present invention or its salt may be added in an amount of 15% by weight or less, or 10% by weight or less, based on the raw material.
  • the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
  • foods to which the above substances can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, These include alcoholic beverages and vitamin complexes, and include all health functional foods in the conventional sense.
  • the health drink composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional drinks.
  • the above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • a sweetener natural sweeteners such as thaumatin and stevia extract or synthetic sweeteners such as saccharin and aspartame can be used.
  • the proportion of natural carbohydrates is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
  • the composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, It may contain carbonating agents used in carbonated drinks. Additionally, the composition of the present invention may contain pulp for the production of natural fruit juice, fruit juice beverages, and vegetable beverages. These ingredients can be used independently or in combination. The ratio of these additives is not very important, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
  • “health functional food” is the same term as food for special health use (FoSHU), and refers to food with high medical and medical effects that has been processed to efficiently exhibit bioregulatory functions in addition to supplying nutrients. This means that the food can be manufactured in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. to achieve useful effects in preventing or improving obesity.
  • the health functional food of the present invention can be manufactured by a method commonly used in the industry, and can be manufactured by adding raw materials and components commonly added in the industry.
  • it has the advantage of being made from food, so there are no side effects that can occur when taking the drug for a long time, and it can be highly portable.
  • the health functional food has the advantage of having better effects when consumed in the form of inner beauty food.
  • the inner beauty is a food referred to as 'edible cosmetics or beauty food'. It refers to foods that change the skin constitution to a healthy one by absorbing various ingredients that are good for the skin into the body. It refers to foods that change the skin constitution to a healthy one by selecting cosmetics that suit your skin type. You can select and consume inner beauty foods that suit each individual, considering their skin condition and lifestyle. For example, when cosmetics containing the above cosmetic composition are mixed with inner beauty food containing altilatinib derivatives or salts thereof, the effect is significantly higher compared to using only cosmetics or drugs, resulting in a more effective pigmentation prevention or improvement effect. Of course, it can have the advantage of seeing a whitening effect.
  • the present invention provides, in another aspect of the present invention, a quasi-drug composition for preventing or improving pigmentation, comprising an altiratinib derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • quasi-drug refers to products that have a milder effect than pharmaceuticals among products used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases in humans or animals.
  • quasi-drugs exclude products used for medicinal purposes and include products used to treat or prevent diseases in humans and animals, and products that have a mild or no direct effect on the human body.
  • the altiratinib derivative of the present invention or a pharmaceutically acceptable salt thereof when using the altiratinib derivative of the present invention or a pharmaceutically acceptable salt thereof as a quasi-drug additive, it can be added as is or used together with other quasi-drugs or quasi-drug components, and can be used appropriately according to conventional methods.
  • the mixing ratio with other ingredients used together can be appropriately determined depending on the purpose of use (eg, prevention, improvement or therapeutic treatment).
  • Examples of the quasi-drug composition of the present invention include, but are not limited to, scalp and hair care compositions such as masks, ointments, creams, lotions, essences, sprays, shampoos, and rinses, body cleansers, foams, and soaps.
  • scalp and hair care compositions such as masks, ointments, creams, lotions, essences, sprays, shampoos, and rinses, body cleansers, foams, and soaps.
  • the content of the altiratinib derivative of the present invention or a pharmaceutically acceptable salt thereof is not limited to the total weight of the quasi-drug composition, but is 0.001% by weight to 0.1% by weight, more preferably 0.0001% by weight to 1% by weight. can be included.
  • the present invention provides a kit for preventing or improving pigmentation, comprising a pharmaceutical composition, a composition for inhibiting CRTC3, a cosmetic composition, a topical application preparation, a food composition, or a quasi-drug composition according to the present invention.
  • Kit is intended to achieve the object of the present invention, namely, preventing, improving, or treating pigmentation; skin whitening; Alternatively, tools and/or reagents known in the art necessary for achieving skin care, etc. may be additionally included.
  • the kit further includes instructions describing a skin care method for preventing or improving pigmentation according to the present invention, or an instrument necessary for administering, applying, or absorbing the composition according to the present invention, such as a syringe. , cotton, cotton swabs, sheets, puffs, etc. may be further included.
  • active ingredient used in this specification refers to an ingredient that can exhibit the desired activity alone or in combination with a carrier that is inactive on its own.
  • Mel-Ab cells a mouse melanocyte cell line, were cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 10% FBS, 1% P/S, 100 nM TPA, and 1 nM CT.
  • DMEM Dulbecco's Modified Eagle Medium
  • 7 ⁇ 10 5 cells were seeded in a 100 mm dish and cultured at 37°C and 5% CO 2 for 6 days, and the old medium was replaced with new medium every 48 to 72 hours during the culture period. It was replaced with .
  • B16F10 another mouse melanocyte cell line, was cultured in DMEM medium containing 10% FBS and 1% P/S under the same conditions as above.
  • hMC Human primary melanocytes
  • NHM Human primary melanocytes
  • B16F10 cells were seeded in a 6-well cell culture plate at 1.2 ⁇ 10 5 cells/well. After 24 hours, the medium was replaced with DMEM containing 10% FSB and 1% AA (antibiotic antimycotic), and the drug was treated 1 hour later.
  • Mel-ab cells were seeded at 3 ⁇ 10 5 cells/well in a 6 well cell culture plate. After washing with 1 ⁇ PBS, the medium was replaced with DMEM medium containing 10% FBS and 1% AA without CT (Cefixime Tellurite) and TPA (Tissue type plasminogen activator), and treated with drugs 1 hour later.
  • hMC cells were seeded in a 6-well cell culture plate at 6.0 ⁇ 10 5 cells/well.
  • HMGS Human Melanocyte Growth Supplement
  • A.A. Human Melanocyte Growth Supplement
  • Cell viability was measured using the MTT assay. After 72 hours of drug treatment, the medium was removed and washed with PBS. Afterwards, the MTT solution dissolved in PBS was added to the medium to a concentration of 2.5 mg/ml, and cultured for 2 hours in an environment of 37°C and 5% CO 2 . The generated formazan crystals were dissolved in DMSO. Absorbance was measured at 565 nm using a microplate reader (Molecular Devices, Sunnyvale, CA, USA). Cell viability was expressed as a percentage relative to control cells without drug treatment.
  • the SKIN PAMPA Explorer Test system (Pion Inc.) was used according to the manufacturer's instructions. Incubate the membrane of the acceptor plate with hydration buffer (Pion Inc., #120706) at room temperature for 15-18 hours, dispense PRISMA HT buffer (Pion Inc., #110151) at pH 7.4 to the deep well plate, and prepare by mixing the test substances. did.
  • the acceptor plate and donor plate were separated, 150 ⁇ l of each was transferred to a UV plate, and the absorbance was measured to obtain the donor and acceptor values.
  • the transmittance value P e , 10 -6 cm/sec
  • Reagents and conditions (a) NaH, DMF, 57%; (b) cyclopropanecarboxamide, Pd 2 (dba) 3 , rac -BINAP, K 3 PO 4 , 1,4-dioxane, 100°C, 37%; (c) Zn, NH 4 Cl, MeOH, THF, 0°C, 83%; (d) acids, TBTU, i Pr 2 NEt, DMF, 6-61%; (e) acids, HATU, i Pr 2 NEt, DMF, 5-60%; (f) acids, DCC, HOBt, THF, 60°C, 8-17%; (g) 4M HCl in 1,4-dioxane, CH 2 Cl 2 , 2% (2-step yield).
  • Altiratinib began with nucleophilic aromatic substitution of phenol (Compound 1) and aryl fluoride (Compound 2).
  • Compound 4 was produced by Pd-catalyzed Suzuki coupling of aryl chloride (compound 3) and cyclopropanecarboxamide, and aniline (compound 5) was produced by nitro reduction using zinc and ammonium chloride.
  • Altiratinib derivatives were produced by amide coupling reaction between acids containing various bicyclic heterocycles and aniline (compound 5).
  • the specific synthetic route is as follows (however, compound ALT-005 is an intermediate and its synthesis is described separately below):
  • step a O-Arylation
  • step b Buchwald-Hartwig amination
  • step c Nitro Reduction
  • step d or e Amide Coupling-A
  • N,N -diisopropylethylamine as a coupling reagent in a solution of N -(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (compound 5, 1.0 equiv) in DMF.
  • step f Amide Coupling-B
  • step e amide coupling reaction of 2-(1 H -indazol-3-yl)acetic acid (17.3 mg, 0.10 mmol) was performed using HATU for 42 hours, followed by NH 2 silica gel chromatography (60% EtOAc/ n -hexane).
  • 2-oxo-1,2,3 as a coupling reagent to a solution of 4-((2-chloropyridin-4-yl)oxy)-2,5-difluoroaniline (20.0 mg, 0.08 mmol) in DMF (520.0 ⁇ L).
  • 4-tetrahydroquinoline-3-carboxylic acid (22.4 mg, 0.12 mmol), N,N -diisopropylethylamine (67.9 ⁇ L, 0.39 mmol), and TBTU (50.0 mg, 0.16 mmol) were added.
  • the reaction mixture was stirred at room temperature for 17 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride ( ⁇ 3) and brine.
  • step d amide coupling reaction of 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (18.8 mg, 0.1 mmol) using TBTU for 19 hours was followed by prep-HPLC (with 0.1% TFA). 24.0 mg (61%) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2- from 20% to 100% water/acetonitrile) oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (purity 99%, compound 9a) was obtained.
  • step d amide coupling reaction of 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (18.8 mg, 0.1 mmol) using TBTU for 88 hours was followed by prep-HPLC (with 0.1% TFA).
  • step e amide coupling reaction of 3-(1 H -indol-3-yl)propanoic acid (29.8 mg, 0.16 mmol) was performed using HATU for 18 hours, followed by NH 2 silica gel chromatography (50% EtOAc/ n -hexane).
  • step f amide coupling reaction of 1 H -benzo[ d ]imidazole-6-carboxylic acid (25.5 mg, 0.16 mmol) was performed using DCC for 18 hours, followed by silica gel chromatography (5% MeOH/CH 2 Cl 2 ).
  • the SKIN-PAMPA assay to measure the skin permeability of altiratinib derivatives was performed under pH 8.5 conditions at 25uM, the maximum concentration at which the compound does not form a precipitate.
  • ALT-002 (Compound 7a) and ALT-003 (Compound 6a) were expected to have significantly improved skin permeability compared to altiratinib at pH 8.5.
  • Hyperpigmentation of the skin is a phenomenon caused by excessive accumulation of melanin as melanin production by melanocytes in skin tissue increases. Therefore, it was confirmed whether altiratinib derivative compounds inhibit melanin synthesis in melanocytes. did.
  • Forskolin activates adenyl cyclase to induce cAMP production, and cAMP increases the expression of melanin-producing enzymes, ultimately leading to melanin production. Therefore, not only the melanin production inhibition effect of altiratinib derivative compounds in a state without stimulation of cells (without FSK treatment), but also the melanin production inhibition effect induced by FSK treatment of altiratinib derivative compounds was confirmed.
  • ALT-002 Compound 7a
  • ALT-003 Compound 6a
  • ALT-013 Compound 8c
  • ALT-024 and ALT-028 were superior to altiratinib. It was confirmed that it had a similar effect to the nib.
  • the present inventors synthesized a novel altiratinib derivative compound, and the synthesized novel altiratinib derivative compound exhibits a similar or improved effect in inhibiting melanin production as altiratinib, but has significantly lower cytotoxicity and significantly improved melanin production inhibition effect. It was confirmed that it had skin permeability. Accordingly, the present inventors confirmed the potential of the novel altiratinib derivative compound according to the present invention as a treatment for skin pigmentation.
  • ALT-002 (Compound 7a) did not show cytotoxicity even at a concentration of 10uM in both mouse melanin cell lines and human melanocytes, but showed a similar or improved effect in inhibiting melanin production as altiratinib.
  • ALT-003 (Compound 6a) and ALT-013 (Compound 8c) showed similar or improved melanogenesis inhibitory effects as altiratinib in mouse melanocyte cell lines and human melanocytes, and were more cytotoxic than ALT-002 in human melanocytes.
  • the novel altiratinib derivative compounds according to the present invention are effective in preventing or treating skin pigmentation. It is expected that it will be useful.
  • the altiratinib derivative according to the present invention had a similar melanin production inhibitory effect to altiratinib and had significantly lower cytotoxicity. Therefore, the composition containing altiratinib derivatives or their salts according to the present invention as an active ingredient can not only be used for the prevention or treatment of pigmentation, but can also be used in various fields of skin care, such as skin whitening by improving pigmentation, etc. Since it can be utilized effectively, it has industrial applicability.

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Abstract

La présente invention concerne un nouveau dérivé d'altiratinib, son procédé de fabrication, et une composition le comprenant en tant que principe actif pour la prévention, le soulagement ou le traitement de la pigmentation de la peau. Le dérivé d'altiratinib selon la présente invention s'est avéré présenter une toxicité significativement inférieure vis-à-vis des mélanocytes, par rapport à l'altimètre, tout en maintenant des effets similaires ou améliorés d'inhibition de la mélanogenèse. Par conséquent, une composition contenant le dérivé d'altiratinib selon la présente invention ou un sel de celui-ci en tant que principe actif peut non seulement être utilisée pour prévenir ou traiter la pigmentation, mais est également prévue pour trouver un large spectre d'applications dans le domaine de l'embellissement de la peau, tel que le blanchiment de la peau, par l'atténuation de la pigmentation.
PCT/KR2023/016293 2022-10-19 2023-10-19 Nouveau dérivé d'altiratinib, son procédé de fabrication et composition le comprenant en tant que principe actif pour la prévention, le soulagement ou le traitement de la pigmentation de la peau Ceased WO2024085695A1 (fr)

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KR1020230139902A KR20240055676A (ko) 2022-10-19 2023-10-18 신규 알티라티닙 유도체, 이의 제조방법, 및 이를 유효성분으로 포함하는 피부 색소침착의 예방, 개선, 또는 치료용 조성물

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011063516A (ja) * 2009-09-15 2011-03-31 Daiichi Sankyo Co Ltd アミド誘導体
KR20140097402A (ko) * 2011-11-22 2014-08-06 데시페라 파마슈티칼스, 엘엘씨. 항암 및 항증식 활성을 나타내는 피리돈 아미드 및 유사체
CN104974162A (zh) * 2014-04-09 2015-10-14 广东东阳光药业有限公司 双环吡唑酮化合物及其使用方法和用途

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JP2011063516A (ja) * 2009-09-15 2011-03-31 Daiichi Sankyo Co Ltd アミド誘導体
KR20140097402A (ko) * 2011-11-22 2014-08-06 데시페라 파마슈티칼스, 엘엘씨. 항암 및 항증식 활성을 나타내는 피리돈 아미드 및 유사체
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WANG ZHEN; SHI JIANTAO; ZHU XIANGLONG; ZHAO WENWEN; GONG YILIN; HAO XUECHEN; HOU YUNLEI; LIU YAJING; DING SHI; LIU JU; CHEN YE: "Design, synthesis and biological evaluation of novel 4-phenoxypyridine based 3-oxo-3,4-dihydroquinoxaline-2-carboxamide derivatives as potential c-Met kinase inhibitors", BIOORGANIC CHEMISTRY, ACADEMIC PRESS INC., NEW YORK, NY., US, vol. 105, 12 October 2020 (2020-10-12), US , XP086407873, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2020.104371 *
YOO HANJU, LEE HA-RI, KIM KI-HYUN, KIM MIN-AH, BANG SEUNGHYUN, KANG YOUNG-HO, KIM WOO-HYUNG, SONG YOUNGSUP, CHANG SUNG EUN: "CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders", THERANOSTICS, IVYSPRING INTERNATIONAL PUBLISHER, AU, vol. 11, no. 20, 1 January 2021 (2021-01-01), AU , pages 9918 - 9936, XP055981245, ISSN: 1838-7640, DOI: 10.7150/thno.66378 *

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