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WO2024085695A1 - Novel altiratinib derivative, manufacturing method therefor, and composition comprising same as active ingredient for prevention, alleviation, or treatment of skin pigmentation - Google Patents

Novel altiratinib derivative, manufacturing method therefor, and composition comprising same as active ingredient for prevention, alleviation, or treatment of skin pigmentation 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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WIPO (PCT)
Prior art keywords
pyridin
acetamido
altiratinib
difluorophenoxy
cyclopropanecarboxamide
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PCT/KR2023/016293
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French (fr)
Korean (ko)
Inventor
송영섭
장성은
안홍찬
이수정
이정현
김민영
박영혜
황지선
Original Assignee
재단법인 아산사회복지재단
울산대학교 산학협력단
재단법인 대구경북첨단의료산업진흥재단
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Priority claimed from KR1020230139902A external-priority patent/KR20240055676A/en
Application filed by 재단법인 아산사회복지재단, 울산대학교 산학협력단, 재단법인 대구경북첨단의료산업진흥재단 filed Critical 재단법인 아산사회복지재단
Publication of WO2024085695A1 publication Critical patent/WO2024085695A1/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
    • A61K31/33—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

The present invention relates to a novel altiratinib derivative, a manufacturing method therefor, and a composition comprising same as an active ingredient for the prevention, alleviation, or treatment of skin pigmentation. The altiratinib derivative according to the present invention has been found to exhibit significantly lower toxicity towards melanocytes, compared to altiratinib, while maintaining similar or improved effects of inhibiting melanogenesis. Therefore, a composition containing the altiratinib derivative according to the present invention or a salt thereof as an active ingredient can not only be used for preventing or treating pigmentation, but is also expected to find a broad spectrum of applications in the field of skin beautification, such as skin whitening, through the alleviation of pigmentation.

Description

신규 알티라티닙 유도체, 이의 제조방법, 및 이를 유효성분으로 포함하는 피부 색소침착의 예방, 개선, 또는 치료용 조성물Novel altiratinib derivative, method for producing the same, and composition for preventing, improving, or treating skin pigmentation containing the same as an active ingredient
본 발명은 신규 알티라티닙 유도체, 이의 제조방법, 및 이를 유효성분으로 포함하는 피부 색소침착의 예방, 개선, 또는 치료용 조성물에 관한 것이다.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.
본 발명은 2023년 10월 19일에 출원된 대한민국 특허출원 제10-2022-0135256호 및 2023년 10월 18일에 출원된 대한민국 특허출원 제10-2023-0139902호에 기초한 우선권을 주장하며, 상기 출원들의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.The present invention claims priority based on Republic of Korea Patent Application No. 10-2022-0135256 filed on October 19, 2023 and Republic of Korea Patent Application No. 10-2023-0139902 filed on October 18, 2023, and the above All contents disclosed in the specifications and drawings of the applications are incorporated into this application.
인간의 피부색은 태양 자외선, 피로, 스트레스 등의 환경 조건 또는 생리적 조건의 영향을 받으나, 근본적으로는 피부 내 멜라닌, 헤모글로빈 및 카로티노이드와 같은 다양한 발색단의 구성 및 분포에 의해 결정된다. 멜라닌(melanin)은 멜라닌세포(melanocyte)에 의해 합성되는 흑갈색의 폴리머 색소로, 티로시네이즈(tyrosinase) 효소가 티로신(tyrosine)을 DOPA로 전환시킨 후 일련의 산화과정을 일으켜 멜라닌을 합성한다. 멜라닌을 함유한 멜라닌소체(melanosome)는 수상 돌기를 통해 멜라닌세포로부터 케라틴세포(keratinoid) 등의 각질 세포로 멜라닌을 전달하여 표피 전체에 멜라닌을 분포시킨다. 멜라닌의 양에 따라 피부색이 결정되며, 멜라닌의 양이 많을수록 검은 피부색을 띤다. 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.
멜라닌은 자외선을 흡수하여 자외선의 피부 침투를 차단하는 역할을 하지만, 과도한 멜라닌 축적은 과색소침착과 같은 과색소성 피부 질환을 유발한다. 색소침착(pigmentation) 또는 과색소침착(hyperpigmentation)은 피부나 손발톱, 구강이나 비강 등을 둘러싸고 있는 점막 등에서 멜라닌이 증가하여 피부 등이 검은색을 띠게 되는 증상으로, 유전질환, 약물, 염증, 외상, 자외선 노출, 및 기미 등의 과색소성 피부 질환과 같은 다양한 원인에 의해서 발생할 수 있다. 색소침착은 정신적 스트레스를 유발하여 삶의 질을 떨어뜨릴 수 있기 때문에 사회적으로 중요한 질병으로 간주된다. Melanin absorbs ultraviolet rays and plays a role in blocking ultraviolet rays from penetrating the skin, but excessive melanin accumulation causes hyperpigmented skin diseases such as hyperpigmentation. 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.
종래 색소침착 치료를 위한 방법으로 화학 필링, 레이저 수술, 약물 요법 및 미용 시술과 같은 다양한 접근 방법이 있지만, 부작용 및 비용의 문제가 있으며, 코지산(kojic acid), 알부틴(Arbutin) 등과 같은 티로시네이즈(tyrosinase) 효소활성을 억제하는 물질 등이 약물로 사용되고 있으나 피부 자극과 세포 사멸 등 안정성의 문제가 있다. 특히, 하이드로퀴논(hydroquinone)은 단독으로 또는 다른 약물과 병용하여 피부 색소 관련 질환에서 일반적으로 사용되고 있으나, 알레르기나 암과 같은 부작용을 유발하는 것으로 알려져 있다. 따라서, 인체에 부작용을 일으키지 않으면서 색소침착을 효과적으로 예방, 개선, 및 치료할 수 있는 물질의 개발이 요구되고 있다.Conventional methods for treating pigmentation include various approaches such as chemical peeling, laser surgery, drug therapy, and cosmetic procedures, but they have side effects and cost issues, and tyrosine such as kojic acid, arbutin, etc. Substances that inhibit tyrosinase enzyme activity are used as drugs, but they have safety problems such as skin irritation and cell death. In particular, hydroquinone is commonly used alone or in combination with other drugs for diseases related to skin pigmentation, but is known to cause side effects such as allergies and cancer. Therefore, there is a need for the development of substances that can effectively prevent, improve, and treat pigmentation without causing side effects in the human body.
본 발명자들은 인체에 부작용을 유발하지 않으면서 피부의 색소침착을 효과적으로 억제할 수 있는 물질을 발굴하기 위한 연구를 수행하였으며, 그 결과 알티라티닙(Altiratinib)의 유도체가 알티라티닙과 멜라닌 생성 억제 효과는 유사하면서, 세포 독성이 현저히 낮은 것을 확인하여 본 발명을 완성하였다.The present inventors conducted research to discover a substance that can effectively suppress skin pigmentation without causing side effects to the human body. As a result, 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.
따라서, 본 발명의 목적은 알티라티닙 유도체 또는 이의 염을 제공하는 것이다.Accordingly, the object of the present invention is to provide altiratinib derivatives or salts thereof.
본 발명의 다른 목적은 본 발명에 따른 알티라티닙 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing altiratinib derivatives according to the present invention.
본 발명의 또 다른 목적은 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착(pigmentation)의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 또 다른 목적은 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 화장료 조성물 등을 제공하는 것이다.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.
본 발명의 또 다른 목적은 본 발명에 따른 화장료 조성물을 이를 필요로 하는 개체의 피부에 적용하는 단계를 포함하는, 색소침착을 예방 또는 개선하기 위한 피부 미용방법을 제공하는 것이다.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.
본 발명의 또 다른 목적은 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 색소침착 예방 또는 개선용 국소 적용 제제를 제공하는 것이다.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.
본 발명의 또 다른 목적은 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 예방 또는 개선용 식품 조성물을 제공하는 것이다.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.
본 발명의 또 다른 목적은 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 예방 또는 개선용 건강기능식품을 제공하는 것이다.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.
본 발명의 또 다른 목적은 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 예방 또는 개선용 의약외품 조성물을 제공하는 것이다.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.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art to which the present invention belongs from the description below. There will be.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 알티라티닙 유도체 또는 이의 염을 제공한다:In order to achieve the above object, the present invention provides an altiratinib derivative or a salt thereof represented by the following formula (1):
[화학식 1][Formula 1]
Figure PCTKR2023016293-appb-img-000001
Figure PCTKR2023016293-appb-img-000001
상기 화학식 1에서,In Formula 1,
R1은 할로겐 원소, 또는
Figure PCTKR2023016293-appb-img-000002
이고,R 1 is a halogen element, or
Figure PCTKR2023016293-appb-img-000002
ego,
R2는
Figure PCTKR2023016293-appb-img-000003
,
Figure PCTKR2023016293-appb-img-000004
,
Figure PCTKR2023016293-appb-img-000005
,
Figure PCTKR2023016293-appb-img-000006
, 또는
Figure PCTKR2023016293-appb-img-000007
이고,R 2 is
Figure PCTKR2023016293-appb-img-000003
,
Figure PCTKR2023016293-appb-img-000004
,
Figure PCTKR2023016293-appb-img-000005
,
Figure PCTKR2023016293-appb-img-000006
, or
Figure PCTKR2023016293-appb-img-000007
ego,
n은 0, 1, 또는 2이되,n is 0, 1, or 2,
상기 R3 내지 R6은 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 치환 또는 비치환된 C1-C5 알콕시기, 치환 또는 비치환된 C1-C5 알킬기, 또는 니트로기(NO2)이고,Wherein 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 ),
상기 A1, A3, 및 A6은 각각 독립적으로 N, CH, CMe, 또는 CPh이고,A 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
상기 A2, A4, 및 A5는 각각 독립적으로 O, S, NH, NMe, NEt, 또는 CH2이고,A 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
상기 A7 내지 A10은 각각 독립적으로 C=O, 또는 NH이고,A 7 to A 10 is each independently C=O, or NH,
상기 '치환 또는 비치환된'은 할로겐 원소, 니트릴기, 니트로기, 하이드록시기, 카보닐기, 에스테르기, 및 이미드기로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환된 것임.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.
본 발명의 일 구현예로, 상기 알티라티닙 유도체는 하기 화학식 2a 내지 2e 중 어느 하나로 표시될 수 있으나, 이에 제한되지 않는다.In one embodiment of the present invention, the altiratinib derivative may be represented by any one of the following formulas 2a to 2e, but is not limited thereto.
[화학식 2a][Formula 2a]
Figure PCTKR2023016293-appb-img-000008
Figure PCTKR2023016293-appb-img-000008
(상기 화학식 2a에서,(In Formula 2a,
n은 0, 1, 또는 2이되,n is 0, 1, or 2,
상기 R3 및 R4는 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 메톡시(OCH3), 메틸(CH3), 에틸(CH2CH3), 트리플루오로메틸(CF3), 또는 니트로기(NO2)이고,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 ),
상기 A1은 N, CH, CMe, 또는 CPh이고,Wherein A 1 is N, CH, CMe, or CPh,
상기 A2는 O, S, NH, NMe, NEt, 또는 CH2임.)The A 2 is O, S, NH, NMe, NEt, or CH 2. )
[화학식 2b][Formula 2b]
Figure PCTKR2023016293-appb-img-000009
Figure PCTKR2023016293-appb-img-000009
(상기 화학식 2b에서,(In Formula 2b,
n은 1, 또는 2이되,n is 1 or 2,
상기 R5 및 R6은 각각 독립적으로 할로겐 원소, 수소(H), 메톡시(OCH3), 또는 메틸(CH3)이고,R 5 and R 6 are each independently a halogen element, hydrogen (H), methoxy (OCH 3 ), or methyl (CH 3 ),
상기 A3은 N, CH, 또는 CMe이고,Wherein A 3 is N, CH, or CMe,
상기 A4는 O, S, NH, 또는 NMe임.)where A 4 is O, S, NH, or NMe.)
[화학식 2c][Formula 2c]
Figure PCTKR2023016293-appb-img-000010
Figure PCTKR2023016293-appb-img-000010
(상기 화학식 2c에서,(In Formula 2c,
상기 A5는 O, S, 또는 NH이고,Wherein A 5 is O, S, or NH,
상기 A6은 N, 또는 CH임.)A 6 is N, or CH.)
[화학식 2d][Formula 2d]
Figure PCTKR2023016293-appb-img-000011
Figure PCTKR2023016293-appb-img-000011
(상기 화학식 2d에서,(In Formula 2d above,
R1은 할로겐 원소, 또는
Figure PCTKR2023016293-appb-img-000012
이고,R 1 is a halogen element, or
Figure PCTKR2023016293-appb-img-000012
ego,
상기 A7 및 A8은 각각 독립적으로 C=O, 또는 NH임.)A 7 and A 8 are each independently C=O, or NH.)
[화학식 2e][Formula 2e]
Figure PCTKR2023016293-appb-img-000013
Figure PCTKR2023016293-appb-img-000013
(상기 화학식 2e에서,(In Formula 2e above,
상기 A9 및 A10은 각각 독립적으로 C=O, 또는 NH임.)A 9 and A 10 are each independently C=O, or NH.)
본 발명의 다른 구현예로, 상기 알티라티닙 유도체는 상기 화학식 1에서,In another embodiment of the present invention, the altiratinib derivative has the formula (1):
상기 R1은
Figure PCTKR2023016293-appb-img-000014
이고,The R 1 is
Figure PCTKR2023016293-appb-img-000014
ego,
ⅰ) 상기 n은 0일 때,i) When n is 0,
상기 R2는
Figure PCTKR2023016293-appb-img-000015
, 또는
Figure PCTKR2023016293-appb-img-000016
이고,The R 2 is
Figure PCTKR2023016293-appb-img-000015
, or
Figure PCTKR2023016293-appb-img-000016
ego,
ⅱ) 상기 n은 1일 때,ii) When n is 1,
상기 R2는
Figure PCTKR2023016293-appb-img-000017
, 또는
Figure PCTKR2023016293-appb-img-000018
일 수 있으나, 이에 제한되지 않는다.The R 2 is
Figure PCTKR2023016293-appb-img-000017
, or
Figure PCTKR2023016293-appb-img-000018
It may be, but is not limited to this.
본 발명의 다른 구현예로, 상기 알티라티닙 유도체는 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나일 수 있으나, 이에 제한되지 않는다:In another embodiment of the present invention, the altiratinib derivative may be any one selected from the group consisting of the following compounds, but is not limited thereto:
(1) N-(4-(4-(2-(벤조[d]이속사졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-001);(1) 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);
(2) N-(4-(4-(2-(벤조[d]옥사졸-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-002);(2) N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanca Copamide [ N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-002);
(3) N-(4-(4-(2-(1H-인다졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-003);(3) N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarcopy amide [ N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-003);
(4) N-(4-(2,5-디플루오로-4-(2-(5-플루오로-1H-인다졸-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(2,5-difluoro-4-(2-(5-fluoro-1H-indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-004);(4) N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl ) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-004);
(5) N-(4-((2-클로로피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT-005);(5) N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3- Carboxamide [ N- (4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT- 005);
(6) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT-006);(6) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-006);
(7) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1-옥소-1,2,3,4-테트라히드로이소퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide] (ALT-007);(7) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4 -tetrahydroisoquinoline-3-carboxamide] (ALT-007);
(8) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT-008);(8) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-008);
(9) N-(4-(4-(2-(1H-인돌-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-009);(9) N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-009);
(10) N-(4-(4-(2-(1H-인돌-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-010);(10) N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-010);
(11) N-(4-(4-(2-(벤조[d]이소티아졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-011);(11) N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropane Carboxamide [ N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-011);
(12) N-(4-(4-(3-(벤조[d]옥사졸-2-일)프로판아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(3-(benzo[d]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-012);(12) N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-012);
(13) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[d]티아졸-6-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]thiazole-6-carboxamide] (ALT-013);(13) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide] (ALT-013);
(14) N-(4-(4-(3-(1H-인돌-3-일)프로판아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-014);(14) N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-014);
(15) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-인덴-3-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide] (ALT-015);(15) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide [ N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indene-3-carboxamide] (ALT-015);
(16) N-(4-(2,5-디플루오로-4-(2-(3-옥소이소인돌린-1-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-016);(16) N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-016);
(17) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-인돌-6-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indole-6-carboxamide] (ALT-017);(17) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indole-6-carboxamide] (ALT-017);
(18) N-(4-(4-(2-(벤조[b]티오펜-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(4-(2-(benzo[b]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-018);(18) N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Vaxamide [ N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-018);
(19) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[b]티오펜-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[b]thiophene-6-carboxamide] (ALT-019);(19) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide] (ALT-019);
(20) N-(4-(2,5-디플루오로-4-(2-(2-옥소인돌린-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-020);(20) N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N- (4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-020);
(21) N -(4-(4-(2-(벤조푸란-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-021);(21) N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-021);
(22) N-(4-(4-(2-(벤조푸란-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)시클로프로판카르복사미드 [N-(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-022);(22) N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-022);
(23) N-(4-(4-(2-(벤조[b]티오펜-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(4-(2-(benzo[b]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-023);(23) N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-023);
(24) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-벤조[d]이미다졸-6-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-benzo[d]imidazole-6-carboxamide] (ALT-024);(24) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6- Carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide] (ALT-024) ;
(25) N-(4-(2,5-디플루오로-4-(2-(5-메톡시-1H-인다졸-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-025);(25) N -(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-methoxy-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ( ALT-025);
(26) N-(4-(4-(2-(벤조[d]티아졸-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(4-(2-(benzo[d]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-026);(26) N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-026);
(27) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조푸란-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] (ALT-027); 및(27) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide [ N- (4 -((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] (ALT-027); and
(28) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[d]옥사졸-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]oxazole-6-carboxamide] (ALT-028).(28) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide] (ALT-028).
또한, 본 발명은 유기 용매 존재 하에, 하기 화학식 3의 화합물 또는 하기 화학식 4의 화합물에서 선택되는 어느 하나의 화합물과 하기 화학식 5의 화합물을, 커플링 시약(coupling reagent)과 함께 아미드 커플링(Amide Coupling) 반응시키는 것을 특징으로 하는, 제1항에 따른 알티라티닙 유도체의 제조방법으로서,In addition, 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 method for producing the altiratinib derivative according to claim 1, characterized in that it undergoes a coupling reaction,
상기 커플링 시약은 TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, 및 DCC로 이루어진 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 제조방법을 제공한다.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.
[화학식 3][Formula 3]
Figure PCTKR2023016293-appb-img-000019
Figure PCTKR2023016293-appb-img-000019
[화학식 4][Formula 4]
Figure PCTKR2023016293-appb-img-000020
Figure PCTKR2023016293-appb-img-000020
[화학식 5][Formula 5]
Figure PCTKR2023016293-appb-img-000021
Figure PCTKR2023016293-appb-img-000021
상기 화학식 5에서,In Formula 5 above,
R은
Figure PCTKR2023016293-appb-img-000022
,
Figure PCTKR2023016293-appb-img-000023
,
Figure PCTKR2023016293-appb-img-000024
,
Figure PCTKR2023016293-appb-img-000025
, 또는
Figure PCTKR2023016293-appb-img-000026
이고,R is
Figure PCTKR2023016293-appb-img-000022
,
Figure PCTKR2023016293-appb-img-000023
,
Figure PCTKR2023016293-appb-img-000024
,
Figure PCTKR2023016293-appb-img-000025
, or
Figure PCTKR2023016293-appb-img-000026
ego,
n은 0, 1, 또는 2이되,n is 0, 1, or 2,
상기 R3 내지 R6은 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 치환 또는 비치환된 C1-C5 알콕시기, 치환 또는 비치환된 C1-C5 알킬기, 또는 니트로기(NO2)이고,Wherein 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 ),
상기 A1, A3, 및 A6은 각각 독립적으로 N, CH, CMe, 또는 CPh이고,A 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
상기 A2, A4, 및 A5는 각각 독립적으로 O, S, NH, NMe, NEt, 또는 CH2이고,A 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
상기 A7 내지 A10은 각각 독립적으로 C=O, 또는 NH이고,A 7 to A 10 is each independently C=O, or NH,
상기 '치환 또는 비치환된'은 할로겐 원소, 니트릴기, 니트로기, 하이드록시기, 카보닐기, 에스테르기, 및 이미드기로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환된 것임.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.
본 발명의 일 구현예로, 상기 유기 용매는 디옥산(dioxane), 메탄올(methanol), 에탄올(ethanol), 아세토나이트릴(acetonitrile), 테트라히드로푸란(tetrahydrofuran, THF), 다이메틸폼아마이드(dimethylformamide, DMF), 다이메틸설폭사이드(dimethyl sulfoxide, DMSO), 및 디클로로에틸렌(dichloroethylene, DCE)로 이루어진 군에서 하나 이상 선택될 수 있으나, 이에 제한되지 않는다.In one embodiment of the present invention, the organic solvent is dioxane, methanol, ethanol, acetonitrile, tetrahydrofuran (THF), and dimethylformamide. , DMF), dimethyl sulfoxide (DMSO), and dichloroethylene (DCE), but is not limited thereto.
또한, 본 발명은 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착(pigmentation)의 예방 또는 치료용 약학적 조성물을 제공한다.Additionally, 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.
또한, 본 발명은 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 색소침착의 예방 또는 치료 방법을 제공한다.Additionally, 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.
뿐만 아니라, 본 발명은 알티라티닙 유도체 또는 이의 염의 색소침착의 예방, 개선 또는 치료 용도, 및/또는 피부미백 용도를 제공한다.In addition, the present invention provides uses of altiratinib derivatives or salts thereof for preventing, improving or treating pigmentation, and/or for skin whitening.
뿐만 아니라, 본 발명은 색소침착 치료용 약제 제조를 위한 알티라티닙 유도체 또는 이의 염의 용도를 제공한다.In addition, the present invention provides the use of an altiratinib derivative or a salt thereof for manufacturing a medicament for treating pigmentation.
본 발명의 일 구현예에서, 상기 색소침착은 기미, 주근깨, 흑자, 검버섯, 점, 밀크커피 반점, 오타모반, 청색모반, 과다 색소침착 반점, 약물 사용 후의 과다 색소침착, 임신성 갈색반(gravidic chloasma), 상처 또는 피부염으로 인한 염증 후 과다 색소침착, 노인성 색소반, 및 일광흑색종(solar lentigines)으로 구성된 군으로부터 선택되는 하나 이상일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, 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.
또한, 본 발명은 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 화장료 조성물을 제공한다.Additionally, the present invention provides a cosmetic composition for preventing or improving pigmentation, comprising an altiratinib derivative or a salt thereof as an active ingredient.
본 발명의 일 구현예에서, 상기 화장료 조성물은 세럼, 화장수, 페이스트, 패치, 젤, 스킨로션, 스킨소프너, 스킨토너, 아스트린젠트, 로션, 밀크로션, 모이스쳐 로션, 영양로션, 크림, 맛사지크림, 영양크림, 미스트, 모이스쳐 크림, 핸드크림, 핸드로션, 파운데이션, 에센스, 영양에센스, 팩, 비누, 오일, 파운데이션, 메이크업 베이스, 왁스, 스프레이, 클렌징폼, 클렌징로션, 클렌징크림, 클렌징오일, 클렌징밤, 바디로션 또는 바디클렌저 제형일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, 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. Cream, 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, It may be a body lotion or body cleanser formulation, but is not limited thereto.
또한, 본 발명은 본 발명에 따른 조성물을 이를 필요로 하는 개체의 피부에 적용하는 단계를 포함하는, 색소침착을 예방 또는 개선하기 위한 피부 미용방법을 제공한다.Additionally, 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.
또한, 본 발명은 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 국소 적용 제제를 제공한다.Additionally, 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.
본 발명의 일 구현예에서, 상기 국소 적용 제제는 크림, 젤, 로션, 파우더, 파우더 스프레이, 오일, 롤-온 제형, 연고, 폼, 스프레이, 스틱 또는 팅쳐(tincture) 형태일 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, 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.
또한, 본 발명은 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 식품 조성물을 제공한다. 상기 식품조성물은 건강기능식품 조성물을 포함한다.Additionally, 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.
또한, 본 발명은 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 건강기능식품을 제공한다.In addition, 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.
또한, 본 발명은 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 의약외품 조성물을 제공한다.Additionally, 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.
또한, 본 발명은 본 발명에 따른 약학적 조성물, 화장료 조성물, 국소 적용 제제, 식품 조성물, 또는 의약외품 조성물을 포함하는, 색소침착의 예방 또는 개선용 키트를 제공한다.Additionally, 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.
본 발명에 따른 알티라티닙 유도체는 알티라티닙과 멜라닌 생성 억제 효과가 유사하거나 우수하면서 세포 독성이 현저히 낮은 것으로 확인되었다. 따라서, 본 발명에 따른 알티라티닙 유도체 또는 이들의 염을 유효성분으로 포함하는 조성물은 색소침착의 예방 또는 치료 용도로 사용할 수 있을 뿐만 아니라, 색소침착 개선 등을 통한 피부 미백 등 피부 미용 분야에 다양하게 활용될 수 있을 것으로 기대된다. It was confirmed that 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.
도 1은 알티라티닙 유도체 화합물 ALT-002 및 ALT-003의 피부 투과도를 PAMPA를 이용하여 측정한 결과를 나타낸 도면이다.Figure 1 is a diagram showing the results of measuring the skin permeability of altiratinib derivative compounds ALT-002 and ALT-003 using PAMPA.
도 2는 알티라티닙 유도체 화합물 ALT-001 내지 ALT-003, ALT-006, 및 ALT-013을 FSK 처리한 마우스 멜라닌세포주인 Mel-Ab에 처리한 후 멜라닌 함량을 측정한 결과를 나타낸 도면이다.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.
도 3은 알티라티닙 유도체 화합물 ALT-015 내지 ALT-017, ALT-019 내지 ALT-021, ALT-026, 및 ALT-028을 FSK 처리한 마우스 멜라닌세포주인 Mel-Ab에 처리한 후 멜라닌 함량을 측정한 결과를 나타낸 도면이다.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.
도 4는 알티라티닙 유도체 화합물 ALT-001 내지 ALT-003, ALT-006, 및 ALT-013을 FSK 처리한 마우스 멜라닌세포주인 Mel-Ab에 처리한 후 측정한 멜라닌 함량을 FSK만을 처리한 세포 대조군에 대한 백분율로 나타낸 도면이다.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.
도 5는 알티라티닙 유도체 화합물 ALT-002, ALT-003, ALT-006, 및 ALT-009를 FSK 처리한 마우스 멜라닌세포주인 B16F10에 처리한 후 멜라닌 함량을 측정한 결과를 나타낸 도면이다.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.
도 6은 알티라티닙 유도체 화합물 ALT-022를 FSK 처리한 마우스 멜라닌세포주인 B16F10에 처리한 후 멜라닌 함량을 측정한 결과를 나타낸 도면이다.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.
도 7은 알티라티닙 유도체 화합물 ALT-002 및 ALT-003을 인간 멜라닌세포에 처리한 후 멜라닌 함량을 측정한 결과를 나타낸 도면이다.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.
도 8은 알티라티닙 유도체 화합물 ALT-024 및 ALT-028을 인간 멜라닌세포에 처리한 후 멜라닌 함량을 측정한 결과를 나타낸 도면이다.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.
도 9는 알티라티닙 유도체 화합물 ALT-001 내지 ALT-014을 마우스 멜라닌세포주인 Mel-Ab에 농도별로 처리한 후 세포 활성 정도를 세포사멸 분석으로 확인한 결과를 나타낸 도면이다.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.
도 10은 알티라티닙 유도체 화합물 ALT-015 내지 ALT-028을 마우스 멜라닌세포주인 Mel-Ab에 농도별로 처리한 후 세포 활성 정도를 세포사멸 분석으로 확인한 결과를 나타낸 도면이다.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.
도 11은 알티라티닙 유도체 화합물 ALT-001 내지 ALT-014을 마우스 멜라닌세포주인 B16F10에 농도별로 처리한 후 세포 활성 정도를 세포사멸 분석으로 확인한 결과를 나타낸 도면이다.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.
도 12는 알티라티닙 유도체 화합물 ALT-015 내지 ALT-028을 마우스 멜라닌세포주인 B16F10에 농도별로 처리한 후 세포 활성 정도를 세포사멸 분석으로 확인한 결과를 나타낸 도면이다.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.
도 13은 알티라티닙 유도체 화합물 ALT-001 내지 ALT-014을 인간 멜라닌세포에 농도별로 처리한 후 세포 활성 정도를 세포사멸 분석으로 확인한 결과를 나타낸 도면이다.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.
도 14는 알티라티닙 유도체 화합물 ALT-015 내지 ALT-028을 인간 멜라닌세포에 농도별로 처리한 후 세포 활성 정도를 세포사멸 분석으로 확인한 결과를 나타낸 도면이다.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.
본 발명자들은 알티라티닙(Altiratinib) 유도체가 알티라티닙과 비교하여 멜라닌세포에 대한 독성이 현저히 낮으면서, 알티라티닙과 유사하게 멜라닌세포의 멜라닌 생성을 효과적으로 억제하는 것을 확인하여 본 발명을 완성하였다.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. .
이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 알티라티닙 유도체 또는 이의 염을 제공한다:The present invention provides an altiratinib derivative or a salt thereof represented by the following formula (1):
[화학식 1][Formula 1]
Figure PCTKR2023016293-appb-img-000027
Figure PCTKR2023016293-appb-img-000027
상기 화학식 1에서,In Formula 1,
R1은 할로겐 원소, 또는
Figure PCTKR2023016293-appb-img-000028
이고,R 1 is a halogen element, or
Figure PCTKR2023016293-appb-img-000028
ego,
R2는
Figure PCTKR2023016293-appb-img-000029
,
Figure PCTKR2023016293-appb-img-000030
,
Figure PCTKR2023016293-appb-img-000031
,
Figure PCTKR2023016293-appb-img-000032
, 또는
Figure PCTKR2023016293-appb-img-000033
이고,R 2 is
Figure PCTKR2023016293-appb-img-000029
,
Figure PCTKR2023016293-appb-img-000030
,
Figure PCTKR2023016293-appb-img-000031
,
Figure PCTKR2023016293-appb-img-000032
, or
Figure PCTKR2023016293-appb-img-000033
ego,
n은 0, 1, 또는 2이되,n is 0, 1, or 2,
상기 R3 내지 R6은 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 치환 또는 비치환된 C1-C5 알콕시기, 치환 또는 비치환된 C1-C5 알킬기, 또는 니트로기(NO2)이고,Wherein 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 ),
상기 A1, A3, 및 A6은 각각 독립적으로 N, CH, CMe, 또는 CPh이고,A 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
상기 A2, A4, 및 A5는 각각 독립적으로 O, S, NH, NMe, NEt, 또는 CH2이고,A 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
상기 A7 내지 A10은 각각 독립적으로 C=O, 또는 NH이고,A 7 to A 10 is each independently C=O, or NH,
상기 '치환 또는 비치환된'은 할로겐 원소, 니트릴기, 니트로기, 하이드록시기, 카보닐기, 에스테르기, 및 이미드기로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환된 것임.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.
본 발명에서, 상기 알티라티닙 유도체는 하기 화학식 2a 내지 2e 중 어느 하나로 표시될 수 있으나, 이에 제한되지 않는다:In the present invention, the altiratinib derivative may be represented by any one of the following formulas 2a to 2e, but is not limited thereto:
[화학식 2a][Formula 2a]
Figure PCTKR2023016293-appb-img-000034
Figure PCTKR2023016293-appb-img-000034
(상기 화학식 2a에서,(In Formula 2a,
n은 0, 1, 또는 2이되,n is 0, 1, or 2,
상기 R3 및 R4는 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 메톡시(OCH3), 메틸(CH3), 에틸(CH2CH3), 트리플루오로메틸(CF3), 또는 니트로기(NO2)이고,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 ),
상기 A1은 N, CH, CMe, 또는 CPh이고,Wherein A 1 is N, CH, CMe, or CPh,
상기 A2는 O, S, NH, NMe, NEt, 또는 CH2임.)The A 2 is O, S, NH, NMe, NEt, or CH 2. )
[화학식 2b][Formula 2b]
Figure PCTKR2023016293-appb-img-000035
Figure PCTKR2023016293-appb-img-000035
(상기 화학식 2b에서,(In Formula 2b,
n은 1, 또는 2이되,n is 1 or 2,
상기 R5 및 R6은 각각 독립적으로 할로겐 원소, 수소(H), 메톡시(OCH3), 또는 메틸(CH3)이고,R 5 and R 6 are each independently a halogen element, hydrogen (H), methoxy (OCH 3 ), or methyl (CH 3 ),
상기 A3은 N, CH, 또는 CMe이고,Wherein A 3 is N, CH, or CMe,
상기 A4는 O, S, NH, 또는 NMe임.)where A 4 is O, S, NH, or NMe.)
[화학식 2c][Formula 2c]
Figure PCTKR2023016293-appb-img-000036
Figure PCTKR2023016293-appb-img-000036
(상기 화학식 2c에서,(In Formula 2c,
상기 A5는 O, S, 또는 NH이고,A 5 is O, S, or NH,
상기 A6은 N, 또는 CH임.)A 6 is N, or CH.)
[화학식 2d][Formula 2d]
Figure PCTKR2023016293-appb-img-000037
Figure PCTKR2023016293-appb-img-000037
(상기 화학식 2d에서,(In Formula 2d above,
R1은 할로겐 원소, 또는
Figure PCTKR2023016293-appb-img-000038
이고,R 1 is a halogen element, or
Figure PCTKR2023016293-appb-img-000038
ego,
상기 A7 및 A8은 각각 독립적으로 C=O, 또는 NH임.)A 7 and A 8 are each independently C=O, or NH.)
[화학식 2e][Formula 2e]
Figure PCTKR2023016293-appb-img-000039
Figure PCTKR2023016293-appb-img-000039
(상기 화학식 2e에서,(In Formula 2e above,
상기 A9 및 A10은 각각 독립적으로 C=O, 또는 NH임.)A 9 and A 10 are each independently C=O, or NH.)
본 발명에서, 상기 알티라티닙 유도체는 보다 더 바람직하게는, 상기 화학식 1에서,In the present invention, the altiratinib derivative is more preferably, in Formula 1,
상기 R1은
Figure PCTKR2023016293-appb-img-000040
이고,The R 1 is
Figure PCTKR2023016293-appb-img-000040
ego,
ⅰ) 상기 n은 0일 때,i) When n is 0,
상기 R2는
Figure PCTKR2023016293-appb-img-000041
, 또는
Figure PCTKR2023016293-appb-img-000042
이고,The R 2 is
Figure PCTKR2023016293-appb-img-000041
, or
Figure PCTKR2023016293-appb-img-000042
ego,
ⅱ) 상기 n은 1일 때,ii) When n is 1,
상기 R2는
Figure PCTKR2023016293-appb-img-000043
, 또는
Figure PCTKR2023016293-appb-img-000044
일 수 있으며, 본 발명의 일 실시예에 따르면, 상기 알티라티닙 유도체는 바람직하게는 ALT-002(화합물 7a), ALT-003(화합물 6a), ALT-006(화합물 9a), 또는 ALT-013(화합물 8c)일 수 있다.The R 2 is
Figure PCTKR2023016293-appb-img-000043
, or
Figure PCTKR2023016293-appb-img-000044
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).
본 발명에서 사용된 용어 "C1-C5 알킬기"는 탄소원자수 1 내지 5의 1가 알킬기를 의미한다. 이 용어는 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, tert-부틸, n-헥실 등과 같은 기능기를 예로 들 수 있다. 본 발명에 기재된 알킬, 및 그 외 알킬 부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함한다. 치환된 C1-C5 알킬은 수소원자 중 하나 이상의 수소원자가 다른 치환기로 치환된 것을 의미하는 것으로, 치환기는 제한되지는 않으나, 할로겐 원소, N, O, S, 니트릴기, 니트로기, 하이드록시기, 카보닐기, 에스테르기, 이미드기, 치환 또는 비치환된 아릴 등을 포함한다.The term “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.
본 발명에서 사용된 용어 "할로겐 원소"는 플루오로(F), 클로로(Cl), 브로모(Br), 및 요오드(I)를 포함할 수 있다.The term “halogen element” used in the present invention may include fluoro (F), chloro (Cl), bromo (Br), and iodine (I).
본 발명에서 사용된 용어 "C1-C5 알콕시기"는 -O-R기를 의미하며, 여기서 R은 " C1-C5 알킬"을 의미한다. 바람직한 알콕시기는 예를 들면, 메톡시, 에톡시, 페녹시 등을 포함한다.As used herein, the term “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.
본 발명에 따른 화학식 1로 표시되는 알티라티닙 유도체의 바람직한 구현예는 하기와 같다:Preferred embodiments of the altiratinib derivative represented by Formula 1 according to the present invention are as follows:
(1) N-(4-(4-(2-(벤조[d]이속사졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-001);(1) 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);
(2) N-(4-(4-(2-(벤조[d]옥사졸-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-002);(2) N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanca Copamide [ N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-002);
(3) N-(4-(4-(2-(1H-인다졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-003);(3) N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarcopy amide [ N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-003);
(4) N-(4-(2,5-디플루오로-4-(2-(5-플루오로-1H-인다졸-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(2,5-difluoro-4-(2-(5-fluoro-1H-indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-004);(4) N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl ) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] (ALT-004);
(5) N-(4-((2-클로로피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT-005);(5) N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3- Carboxamide [ N- (4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT- 005);
(6) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT-006);(6) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-006);
(7) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1-옥소-1,2,3,4-테트라히드로이소퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide] (ALT-007);(7) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4 -tetrahydroisoquinoline-3-carboxamide] (ALT-007);
(8) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] (ALT-008);(8) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] (ALT-008);
(9) N-(4-(4-(2-(1H-인돌-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-009);(9) N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-009);
(10) N-(4-(4-(2-(1H-인돌-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-010);(10) N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-010);
(11) N-(4-(4-(2-(벤조[d]이소티아졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-011);(11) N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropane Carboxamide [ N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-011);
(12) N-(4-(4-(3-(벤조[d]옥사졸-2-일)프로판아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(3-(benzo[d]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-012);(12) N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-012);
(13) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[d]티아졸-6-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]thiazole-6-carboxamide] (ALT-013);(13) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide] (ALT-013);
(14) N-(4-(4-(3-(1H-인돌-3-일)프로판아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-014);(14) N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-014);
(15) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-인덴-3-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide] (ALT-015);(15) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide [ N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indene-3-carboxamide] (ALT-015);
(16) N-(4-(2,5-디플루오로-4-(2-(3-옥소이소인돌린-1-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-016);(16) N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-016);
(17) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-인돌-6-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indole-6-carboxamide] (ALT-017);(17) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H - indole-6-carboxamide] (ALT-017);
(18) N-(4-(4-(2-(벤조[b]티오펜-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(4-(2-(benzo[b]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-018);(18) N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Vaxamide [ N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-018);
(19) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[b]티오펜-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[b]thiophene-6-carboxamide] (ALT-019);(19) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide] (ALT-019);
(20) N-(4-(2,5-디플루오로-4-(2-(2-옥소인돌린-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-020);(20) N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N- (4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-020);
(21) N -(4-(4-(2-(벤조푸란-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-021);(21) N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-021);
(22) N-(4-(4-(2-(벤조푸란-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)시클로프로판카르복사미드 [N-(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-022);(22) N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-022);
(23) N-(4-(4-(2-(벤조[b]티오펜-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(4-(2-(benzo[b]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-023);(23) N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-023);
(24) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-벤조[d]이미다졸-6-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-benzo[d]imidazole-6-carboxamide] (ALT-024);(24) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6- Carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide] (ALT-024) ;
(25) N-(4-(2,5-디플루오로-4-(2-(5-메톡시-1H-인다졸-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-025);(25) N -(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-methoxy-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ( ALT-025);
(26) N-(4-(4-(2-(벤조[d]티아졸-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(4-(2-(benzo[d]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-026);(26) N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar vaxamide [ N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] (ALT-026);
(27) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조푸란-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] (ALT-027); 및(27) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide [ N- (4 -((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] (ALT-027); and
(28) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[d]옥사졸-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]oxazole-6-carboxamide] (ALT-028).(28) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide] (ALT-028).
본 발명의 상기 알티라티닙 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있다.The altiratinib derivative of the present invention can be used in the form of a pharmaceutically acceptable salt.
본 발명에서 사용되는 용어, "약학적으로 허용 가능한 염"이란 약학적으로 허용되는 무기산, 유기산, 또는 염기로부터 유도된 염을 포함하며, 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. As used in the present invention, 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.
상기 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, 베타-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 트리플루오로아세테이트, 또는 만델레이트를 포함한다.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. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodine. Ide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methylbenzoate Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycol Includes sulfonate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, trifluoroacetate, or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 상기 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.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.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염 (예, 질산은)과 반응시켜 얻는다.Additionally, 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).
또한, 본 발명의 화합물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물 및 용매화물을 모두 포함할 수 있다.In addition, 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.
또한, 본 발명은 본 발명의 다른 양태로, 유기 용매 존재 하에, 하기 화학식 3의 화합물 또는 하기 화학식 4의 화합물에서 선택되는 어느 하나의 화합물과 하기 화학식 5의 화합물을, 커플링 시약(coupling reagent)과 함께 아미드 커플링(Amide Coupling) 반응시키는 것을 특징으로 하는, 상기 알티라티닙 유도체의 제조방법으로서,In addition, in another aspect of the present invention, in the presence of an organic solvent, 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. A method for producing the altiratinib derivative, characterized in that it undergoes an amide coupling reaction with,
상기 커플링 시약은 TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, 및 DCC로 이루어진 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 제조방법을 제공한다:The coupling reagent is one or more selected from the group consisting of TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, and DCC.
[화학식 3][Formula 3]
Figure PCTKR2023016293-appb-img-000045
Figure PCTKR2023016293-appb-img-000045
[화학식 4][Formula 4]
Figure PCTKR2023016293-appb-img-000046
Figure PCTKR2023016293-appb-img-000046
[화학식 5][Formula 5]
Figure PCTKR2023016293-appb-img-000047
Figure PCTKR2023016293-appb-img-000047
상기 화학식 5에서,In Formula 5 above,
R은
Figure PCTKR2023016293-appb-img-000048
,
Figure PCTKR2023016293-appb-img-000049
,
Figure PCTKR2023016293-appb-img-000050
,
Figure PCTKR2023016293-appb-img-000051
, 또는
Figure PCTKR2023016293-appb-img-000052
이고,R is
Figure PCTKR2023016293-appb-img-000048
,
Figure PCTKR2023016293-appb-img-000049
,
Figure PCTKR2023016293-appb-img-000050
,
Figure PCTKR2023016293-appb-img-000051
, or
Figure PCTKR2023016293-appb-img-000052
ego,
n은 0, 1, 또는 2이되,n is 0, 1, or 2,
상기 R3 내지 R6은 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 치환 또는 비치환된 C1-C5 알콕시기, 치환 또는 비치환된 C1-C5 알킬기, 또는 니트로기(NO2)이고,Wherein 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 ),
상기 A1, A3, 및 A6은 각각 독립적으로 N, CH, CMe, 또는 CPh이고,A 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
상기 A2, A4, 및 A5는 각각 독립적으로 O, S, NH, NMe, NEt, 또는 CH2이고,A 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
상기 A7 내지 A10은 각각 독립적으로 C=O, 또는 NH이고,A 7 to A 10 is each independently C=O, or NH,
상기 '치환 또는 비치환된'은 할로겐 원소, 니트릴기, 니트로기, 하이드록시기, 카보닐기, 에스테르기, 및 이미드기로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환된 것임.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.
본 발명에 있어서, 상기 알티라티닙 유도체의 제조방법은 실온에서 15시간 내지 90시간 동안 아미드 커플링 반응시키는 것일 수 있으나, 이에 제한되지 않는다.In the present invention, 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.
본 발명의 일 실시예에 따르면, 본 발명에 따른 알티라티닙 유도체는 하기 반응식 1에 따른 반응으로 합성되는 것일 수 있으며, 보다 바람직하게는 "step d 내지 f: 아미드 커플링(Amide Coupling)"에 따른 반응으로 합성되는 것일 수 있다.According to one embodiment of the present invention, 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.
본 발명에 있어서, 상기 유기 용매는 디옥산(dioxane), 메탄올(methanol), 에탄올(ethanol), 아세토나이트릴(acetonitrile), 테트라히드로푸란(tetrahydrofuran, THF), 다이메틸폼아마이드(dimethylformamide, DMF), 다이메틸설폭사이드(dimethyl sulfoxide, DMSO), 및 디클로로에틸렌(dichloroethylene, DCE)로 이루어진 군에서 하나 이상 선택될 수 있으며, 바람직하게는 다이메틸폼아마이드일 수 있으나, 이에 제한되지 않는다.In the present invention, 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.
또한, 본 발명은 본 발명의 다른 양태로 본 발명에 따른 알티라티닙(Altiratinib) 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착(pigmentation)의 예방 또는 치료용 약학적 조성물을 제공하며, 본 발명에서 상기 염은 바람직하게는 상기 알티라티닙 유도체의 약학적으로 허용 가능한 염일 수 있다.In addition, 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, In the present invention, the salt may preferably be a pharmaceutically acceptable salt of the altiratinib derivative.
본 발명에 있어서, "알티라티닙(Altiratinib; ALT)"은 항암 효과가 있는 것으로 알려진 공지된 약물로, 화학 분자 데이터베이스인 PubChem에 ID54576299로 등록되어 있다. 상기 데이터베이스에 개시된 알티라티닙의 구조식은 하기 화학식 6과 같다.In the present invention, “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.
[화학식 6][Formula 6]
Figure PCTKR2023016293-appb-img-000053
Figure PCTKR2023016293-appb-img-000053
본 발명에 있어서, "색소침착(pigmentation)"은 피부의 변색(색소침착) 또는 비정상적으로 착색된 세포의 증식으로 유발된 피부의 모든 질환 또는 질병을 의미하며, "과색소침착(hyperpigmentation)"과 상호교환적으로 사용될 수 있다. 피부 색소침착은 과다하거나 원치 않는 색소 침착을 포함한다. 노화, 환경 스트레스 및 UV 노출과 같은 요인은 피부 색소침착의 잠재적인 원인이 될 수 있다. 본 발명의 피부 색소침착은 환자의 기본적인 색소 침착에 비해 피부 및/또는 모낭에서 생합성되고 모발 또는 피부에 침착된 하나 이상의 다양한 종류의 멜라닌의 증가에 기인할 수 있으며, 구체적인 예로는 기미, 주근깨, 흑자, 검버섯, 점, 밀크커피 반점, 오타모반, 청색모반, 과다 색소침착 반점, 약물 사용 후의 과다 색소침착, 임신성 갈색반(gravidic chloasma), 상처 또는 피부염으로 인한 염증 후 과다 색소침착, 노인성 색소반, 및 일광흑색종(solar lentigines)으로 구성된 군으로부터 선택되는 하나 이상일 수 있으나, 이에 제한되지 않는다.In the present invention, “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, 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.
본 발명의 일 구현예에서, 상기 알티라티닙 유도체 또는 이의 약학적으로 허용 가능한 염은 하기 특성 중 하나 이상을 만족함으로써 멜라닌 생성을 억제할 수 있다: (a) CRTC3(CREB Regulated Transcription Coactivator 3)의 전사 활성화 기능을 억제함; (b) MITF(Microphthalmia-associated transcription factor)의 발현을 억제함; (c) 티로시네이즈(tyrosinase), DCT(Dopachrome tautomerase), 또는 TRP1(tyrosinase related protein 1)의 발현을 억제함; 또는 (d) 티로시네이즈의 활성을 억제함.In one embodiment of the present invention, 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.
본 명세서에 있어서, "멜라닌(melanin)"은 동물의 피부나 눈 등의 조직에 존재하는 흑색 또는 갈색 색소를 총칭한다. 특히 멜라닌은 사람의 피부색을 결정하는 중요한 요소로써 인종에 따라서 멜라닌 발현 유전자가 다르고, 이에 따라 멜라닌 세포의 양 및 분포가 조절되어 피부색이 결정된다. 멜라닌은 자외선을 차단하여 피부를 보호하는 역할을 하지만, 과도한 멜라닌 생성은 기미, 주근깨, 피부 반점 등 피부 색소침착의 원인이 되며, 더 나아가 피부노화와 피부암 병인에 관여한다.As used herein, “melanin” refers to a general term for black or brown pigments present in tissues such as skin or eyes of animals. In particular, 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.
본 명세서에 있어서, "CRTC3(CREB Regulated Transcription Coactivator 3)"는 CREB의 전사 보조인자(transcriptional coactivator)로서, 탈인산화(dephosphorylation)되면 핵 내로 이동하여 CREB과 결합해 표적 유전자의 발현을 활성화한다. 따라서, CRTC3의 전사 활성화 기능을 억제한다는 것은 CRTC3의 발현 자체를 억제하는 것, CRTC3의 탈인산화를 억제하는 것(즉, CRTC3의 인산화를 촉진하는 것), CRTC3의 핵 내로의 이동을 저해하는 것, CTRC3의 CREB과의 결합을 저해하는 것, 및/또는 CRTC3의 표적 유전자의 전사 촉진 기능을 저해하는 것을 모두 포함하는 개념이다.In the present specification, “CRTC3 (CREB Regulated Transcription Coactivator 3)” is a transcriptional coactivator of CREB. When dephosphorylated, it moves into the nucleus and binds to CREB to activate the expression of target genes. Therefore, 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.
본 명세서에 있어서, "MITF(Microphthalmia-associated transcription factor)"는 멜라닌세포에서 멜라닌 합성을 유도하는 인자들의 유전자 발현을 촉진하는 전사인자이다. 즉, MITF의 발현이 증가하거나 기능이 활성화될수록 멜라닌 합성 유도 인자들의 발현이 촉진되어 멜라닌 생성이 유도되며, 반대로 MTIF의 발현이 감소하거나 기능이 억제될수록 멜라닌 생성은 억제된다.In the present specification, “MITF (Microphthalmia-associated transcription factor)” is a transcription factor that promotes gene expression of factors that induce melanin synthesis in melanocytes. In other words, as the expression of MITF increases or its function is activated, the expression of melanin synthesis-inducing factors is promoted to induce melanin production. Conversely, as the expression of MTIF decreases or its function is suppressed, melanin production is suppressed.
본 명세서에 있어서, 티로시네이즈(tyrosinase), DCT(Dopachrome tautomerase), 및 TRP1(tyrosinase related protein 1)는 MITF에 의해 발현이 촉진되어 멜라닌세포의 멜라닌 합성에 관여하는 단백질들이다. 특히 티로시네이즈는 티로신을 산화시켜 멜라닌 합성을 유도하는 효소로, 티로시네이즈의 발현 또는 활성 증가는 멜라닌 생성을 더욱 촉진한다. 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. In particular, tyrosinase is an enzyme that induces melanin synthesis by oxidizing tyrosine, and increasing the expression or activity of tyrosinase further promotes melanin production.
따라서, 본 발명에 따른 약학적 조성물은 CRTC3, MITF, 티로시네이즈, DCT, 및 TRP1로 이루어진 군에서 선택되는 하나 이상의 멜라닌 합성 관여 인자의 돌연변이를 수반하는 색소침착을 앓는 환자의 치료에 사용되는 것일 수 있다. 다시 말해, 본 발명에 따른 약학적 조성물은 상기 돌연변이를 수반하는 색소침착을 앓는 환자에서 특히 효과적으로 멜라닌 생성을 억제하는 것일 수 있다. 여기서 "돌연변이"란, 상기 멜라닌 합성 관여 인자들의 활성 증가 또는 발현 증가를 포함한다.Therefore, 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. In other words, the pharmaceutical composition according to the present invention may inhibit melanin production particularly effectively in patients suffering from pigmentation accompanied by the above mutation. Here, “mutation” includes increased activity or increased expression of the factors involved in melanin synthesis.
본 발명에 따른 조성물 내의 상기 알티라티닙 유도체 또는 이의 약학적으로 허용 가능한 염의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라서 적절히 조절 가능하며, 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9중량%, 또는 0.001 내지 50중량%일 수 있으나, 이에 한정되는 것은 아니다. 상기 함량비는 용매를 제거한 건조량을 기준으로 한 값이다.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.
본 발명에 따른 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 상기 부형제는 예를 들어, 희석제, 결합제, 붕해제, 활택제, 흡착제, 보습제, 필름-코팅 물질, 및 제어방출첨가제로 이루어진 군으로부터 선택된 하나 이상일 수 있다. 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.
본 발명에 따른 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 서방형 과립제, 장용과립제, 액제, 점안제, 엘실릭제, 유제, 현탁액제, 주정제, 트로키제, 방향수제, 리모나아데제, 정제, 서방형정제, 장용정제, 설하정, 경질캅셀제, 연질캅셀제, 서방캅셀제, 장용캅셀제, 환제, 틴크제, 연조엑스제, 건조엑스제, 유동엑스제, 주사제, 캡슐제, 관류액, 경고제, 로션제, 파스타제, 분무제, 흡입제, 패취제, 멸균주사용액, 또는에어로졸 등의 외용제 등의 형태로 제형화하여 사용될 수 있으며, 상기 외용제는 크림, 젤, 패치, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 또는 카타플라스마제 등의 제형을 가질 수 있다. 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. , tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, pills, tinctures, soft extracts, dry extracts, liquid extracts, injections, capsules, perfusate, It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta preparations, sprays, inhalants, patches, sterilized injection solutions, or aerosols, and the external preparations include creams, gels, patches, sprays, ointments, and warning agents. , it may have a dosage form such as lotion, liniment, pasta, or cataplasma.
본 발명에 따른 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 올리고당, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 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.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
본 발명에 따른 정제, 산제, 과립제, 캡슐제, 환제, 트로키제의 첨가제로 옥수수전분, 감자전분, 밀전분, 유당, 백당, 포도당, 과당, 디-만니톨, 침강탄산칼슘, 합성규산알루미늄, 인산일수소칼슘, 황산칼슘, 염화나트륨, 탄산수소나트륨, 정제 라놀린, 미결정셀룰로오스, 덱스트린, 알긴산나트륨, 메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 카올린, 요소, 콜로이드성실리카겔, 히드록시프로필스타치, 히드록시프로필메칠셀룰로오스(HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, 프로필렌글리콜, 카제인, 젖산칼슘, 프리모젤 등 부형제; 젤라틴, 아라비아고무, 에탄올, 한천가루, 초산프탈산셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스칼슘, 포도당, 정제수, 카제인나트륨, 글리세린, 스테아린산, 카르복시메칠셀룰로오스나트륨, 메칠셀룰로오스나트륨, 메칠셀룰로오스, 미결정셀룰로오스, 덱스트린, 히드록시셀룰로오스, 히드록시프로필스타치, 히드록시메칠셀룰로오스, 정제쉘락, 전분호, 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 폴리비닐알코올, 폴리비닐피롤리돈 등의 결합제가 사용될 수 있으며, 히드록시프로필메칠셀룰로오스, 옥수수전분, 한천가루, 메칠셀룰로오스, 벤토나이트, 히드록시프로필스타치, 카르복시메칠셀룰로오스나트륨, 알긴산나트륨, 카르복시메칠셀룰로오스칼슘, 구연산칼슘, 라우릴황산나트륨, 무수규산, 1-히드록시프로필셀룰로오스, 덱스트란, 이온교환수지, 초산폴리비닐, 포름알데히드처리 카제인 및 젤라틴, 알긴산, 아밀로오스, 구아르고무(Guar gum), 중조, 폴리비닐피롤리돈, 인산칼슘, 겔화전분, 아라비아고무, 아밀로펙틴, 펙틴, 폴리인산나트륨, 에칠셀룰로오스, 백당, 규산마그네슘알루미늄, 디-소르비톨액, 경질무수규산 등 붕해제; 스테아린산칼슘, 스테아린산마그네슘, 스테아린산, 수소화식물유(Hydrogenated vegetable oil), 탈크, 석송자, 카올린, 바셀린, 스테아린산나트륨, 카카오지, 살리실산나트륨, 살리실산마그네슘, 폴리에칠렌글리콜(PEG) 4000, PEG 6000, 유동파라핀, 수소첨가대두유(Lubri wax), 스테아린산알루미늄, 스테아린산아연, 라우릴황산나트륨, 산화마그네슘, 마크로골(Macrogol), 합성규산알루미늄, 무수규산, 고급지방산, 고급알코올, 실리콘유, 파라핀유, 폴리에칠렌글리콜지방산에테르, 전분, 염화나트륨, 초산나트륨, 올레인산나트륨, dl-로이신, 경질무수규산 등의 활택제가 사용될 수 있다.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. Calcium monohydrogen, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethyl. 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. , hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. 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, white sugar, magnesium aluminum silicate, di-sorbitol solution, light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium, kaolin, petrolatum, sodium stearate, cacao fat, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogen. Added 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.
본 발명에 따른 액제의 첨가제로는 물, 묽은 염산, 묽은 황산, 구연산나트륨, 모노스테아린산슈크로스류, 폴리옥시에칠렌소르비톨지방산에스텔류(트윈에스텔), 폴리옥시에칠렌모노알킬에텔류, 라놀린에텔류, 라놀린에스텔류, 초산, 염산, 암모니아수, 탄산암모늄, 수산화칼륨, 수산화나트륨, 프롤아민, 폴리비닐피롤리돈, 에칠셀룰로오스, 카르복시메칠셀룰로오스나트륨 등이 사용될 수 있다.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.
본 발명에 따른 시럽제에는 백당의 용액, 다른 당류 혹은 감미제 등이 사용될 수 있으며, 필요에 따라 방향제, 착색제, 보존제, 안정제, 현탁화제, 유화제, 점조제 등이 사용될 수 있다.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.
본 발명에 따른 유제에는 정제수가 사용될 수 있으며, 필요에 따라 유화제, 보존제, 안정제, 방향제 등이 사용될 수 있다.Purified water can be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. can be used as needed.
본 발명에 따른 현탁제에는 아카시아, 트라가칸타, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 미결정셀룰로오스, 알긴산나트륨, 히드록시프로필메칠셀룰로오스(HPMC), HPMC 1828, HPMC 2906, HPMC 2910 등 현탁화제가 사용될 수 있으며, 필요에 따라 계면활성제, 보존제, 안정제, 착색제, 방향제가 사용될 수 있다.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.
본 발명에 따른 주사제에는 주사용 증류수, 0.9% 염화나트륨주사액, 링겔주사액, 덱스트로스주사액, 덱스트로스+염화나트륨주사액, 피이지(PEG), 락테이티드 링겔주사액, 에탄올, 프로필렌글리콜, 비휘발성유-참기름, 면실유, 낙화생유, 콩기름, 옥수수기름, 올레인산에칠, 미리스트산 이소프로필, 안식향산벤젠과 같은 용제; 안식향산나트륨, 살리실산나트륨, 초산나트륨, 요소, 우레탄, 모노에칠아세트아마이드, 부타졸리딘, 프로필렌글리콜, 트윈류, 니정틴산아미드, 헥사민, 디메칠아세트아마이드와 같은 용해보조제; 약산 및 그 염(초산과 초산나트륨), 약염기 및 그 염(암모니아 및 초산암모니움), 유기화합물, 단백질, 알부민, 펩 톤, 검류와 같은 완충제; 염화나트륨과 같은 등장화제; 중아황산나트륨(NaHSO3) 이산화탄소가스, 메타중아황산나트륨(Na2S2O5), 아황산나트륨(Na2SO3), 질소가스(N2), 에칠렌디아민테트라초산과 같은 안정제; 소디움비설파이드 0.1%, 소디움포름알데히드 설폭실레이트, 치오우레아, 에칠렌디아민테트라초산디나트륨, 아세톤소디움비설파이트와 같은 황산화제; 벤질알코올, 클로로부탄올, 염산프로카인, 포도당, 글루콘산칼슘과 같은 무통화제; 시엠시나트륨, 알긴산나트륨, 트윈 80, 모노스테아린산알루미늄과 같은 현탁화제를 포함할 수 있다.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 2 ), and ethylenediaminetetraacetic acid; Sulfurizing agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, and acetone sodium bisulfite; Analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; It may contain suspending agents such as CMC sodium, sodium alginate, Tween 80, and aluminum monostearate.
본 발명에 따른 좌제에는 카카오지, 라놀린, 위텝솔, 폴리에틸렌글리콜, 글리세로젤라틴, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 스테아린산과 올레인산의 혼합물, 수바날(Subanal), 면실유, 낙화생유, 야자유, 카카오버터+콜레스테롤, 레시틴, 라네트왁스, 모노스테아린산글리세롤, 트윈 또는 스판, 임하우젠(Imhausen), 모놀렌(모노스테아린산프로필렌글리콜), 글리세린, 아뎁스솔리두스(Adeps solidus), 부티룸 태고-G(Buytyrum Tego-G), 세베스파마 16 (Cebes Pharma 16), 헥사라이드베이스 95, 코토마(Cotomar), 히드록코테 SP, S-70-XXA, S-70-XX75(S-70-XX95), 히드록코테(Hydrokote) 25, 히드록코테 711, 이드로포스탈 (Idropostal), 마사에스트라리움(Massa estrarium, A, AS, B, C, D, E, I, T), 마사-MF, 마수폴, 마수폴-15, 네오수포스탈-엔, 파라마운드-B, 수포시로(OSI, OSIX, A, B, C, D, H, L), 좌제기제 IV 타입 (AB, B, A, BC, BBG, E, BGF, C, D, 299), 수포스탈 (N, Es), 웨코비 (W, R, S, M ,Fs), 테제스터 트리글리세라이드 기제 (TG-95, MA, 57)와 같은 기제가 사용될 수 있다.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-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), suppositories type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecobi (W, R, S, M, Fs), Tegestor triglyceride base (TG-95, MA, 57) and The same mechanism can be used.
경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 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.
경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. 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.
또한, 본 발명은 알티라티닙(Altiratinib) 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물을 이를 필요로 하는 개체에 투여하는, 색소침착(pigmentation)의 예방 또는 치료 방법을 제공한다.In addition, 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.
본 발명에 따른 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "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.
본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 본 발명이 속하는 기술분야에 통상의 기술자에 의해 용이하게 결정될 수 있다.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.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구 복용, 피하 주사, 복강 투여, 정맥 주사, 근육 주사, 척수 주위 공간(경막내) 주사, 설하 투여, 볼점막 투여, 직장 내 삽입, 질 내 삽입, 안구 투여, 귀 투여, 비강 투여, 흡입, 입 또는 코를 통한 분무, 피부 투여, 경피 투여 등에 따라 투여될 수 있다.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.
본 발명의 약학적 조성물은 치료할 질환, 투여 경로, 환자의 연령, 성별, 체중 및 질환의 중등도 등의 여러 관련 인자와 함께 활성성분인 약물의 종류에 따라 결정된다.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.
본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간 또는 비-인간인 영장류, 생쥐 (mouse), 쥐 (rat), 개, 고양이, 말, 및 소 등의 포유류를 의미한다.In the present invention, “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
본 발명에서 "투여"란 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다. 따라서, 본 발명에서 "투여"란 개체에 주사하거나 섭취시키는 것은 물론, 도포하는 것도 포함하는 개념이다.In the present invention, “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.
본 발명에서 "예방"이란 목적하는 질환의 발병을 억제하거나 지연시키는 모든 행위를 의미하고, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 목적하는 질환과 그에 따른 대사 이상 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미하며, "개선"이란 본 발명에 따른 조성물의 투여에 의해 목적하는 질환과 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다.In the present invention, “prevention” refers to any action that suppresses or delays the onset of the desired disease, and “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.
또한, 본 발명은 본 발명의 다른 양태로 본 발명에 따른 알티라티닙 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 멜라닌세포의 CRTC3 억제용 조성물을 제공한다. 바람직하게는, 본 발명에 따른 CRTC3 억제용 조성물은 in vivo, ex vivo, 및/또는 in vitro 용 조성물일 수 있으나, 이에 한정되지 않는다. 바람직하게는, 상기 CRTC3 억제용 조성물은 in vitro 및/또는 ex vivo 용 조성물일 수 있다. 즉, 본 발명에 따른 CRTC3 억제용 조성물은 in vitro 및/또는 ex vivo에서 멜라닌세포의 CRTC3를 억제하는데 사용되는 조성물일 수 있다.In addition, in another aspect of 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. Preferably, 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. Preferably, 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.
본 발명에 있어서, "CRTC3 억제"란 CRTC3의 발현 억제 및 전사 활성화 기능 억제를 포함하는 개념이며, CRTC3의 전사 활성화 기능 억제의 의미는 상술한 바와 같다. 즉, 상기 알티라티닙 또는 이의 약학적으로 허용 가능한 염은 하기 특성 중 하나 이상을 만족함으로써 CRTC3의 전사 활성화 기능을 억제하는 것일 수 있다: (a) CRTC3 인산화를 촉진함; 또는 (b) CRTC3의 핵(nuclear) 내 이동을 억제함.In the present invention, “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.
또한, 본 발명은 본 발명의 다른 양태로 본 발명에 따른 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 화장료 조성물을 제공하며, 상기 염은 알티라티닙 유도체의 화장품학적으로 허용 가능한 염일 수 있다.In addition, 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.
본 명세서에 있어서 "화장품학적으로 허용 가능한 염"이란 화장품학적으로 허용되는 무기산, 유기산, 또는 염기로부터 유도된 염을 포함한다. 구체적인 예는 상술한 염의 예를 포함하며, 하드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트 (메실레이트) 및 p-톨루엔술포네이트 (토실레이트)염 등을 추가로 들 수 있다.As used herein, “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.
본 발명에 따른 화장료 조성물의 제형은 세럼, 화장수, 페이스트, 패치, 젤, 스킨로션, 스킨소프너, 스킨토너, 아스트린젠트, 로션, 밀크로션, 모이스쳐 로션, 영양로션, 크림, 맛사지크림, 영양크림, 미스트, 모이스쳐 크림, 핸드크림, 핸드로션, 파운데이션, 에센스, 영양에센스, 팩, 비누, 오일, 파운데이션, 메이크업 베이스, 왁스, 스프레이, 클렌징폼, 클렌징로션, 클렌징크림, 클렌징오일, 클렌징밤, 바디로션 또는 바디클렌저 제형일 수 있다.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.
본 발명의 화장료 조성물은 수용성 비타민, 유용성 비타민, 고분자 펩티드, 고분자 다당, 및 스핑고 지질로 이루어진 군에서 선택된 조성물을 더 포함할 수 있다.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.
수용성 비타민으로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 비타민 B1, 비타민 B2, 비타민 B6, 피리독신, 염산피리독신, 비타민 B12, 판토텐산, 니코틴산, 니코틴산아미드, 엽산, 비타민 C, 비타민 H 등을 들 수 있으며, 그들의 염 (티아민염산염, 아스코르빈산나트륨염 등)이나 유도체 (아스코르빈산-2-인산나트륨염, 아스코르빈산-2-인산마그네슘염 등)도 본 발명에서 사용할 수 있는 수용성 비타민에 포함된다. 수용성 비타민은 미생물 변환법, 미생물의 배양물로부터의 정제법, 효소법 또는 화학 합성법 등의 통상의 방법에 의해 수득할 수 있다.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.
유용성 비타민으로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 비타민 A, 카로틴, 비타민 D2, 비타민 D3, 비타민 E (d1-알파 토코페롤, d-알파 토코페롤, d-알파 토코페롤) 등을 들 수 있으며, 그들의 유도체 (팔미틴산아스코르빈, 스테아르산아스코르빈, 디팔미틴산아스코르빈, 아세트산dl-알파 토코페롤, 니코틴산dl-알파 토코페롤비타민 E, DL-판토테닐알코올, D-판토테닐알코올, 판토테닐에틸에테르 등) 등도 본 발명에서 사용되는 유용성 비타민에 포함된다. 유용성 비타민은 미생물 변환법, 미생물의 배양물로부터의 정제법, 효소 또는 화학 합성법 등의 통상의 방법에 의해 취득할 수 있다.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.
고분자 펩티드로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 콜라겐, 가수 분해 콜라겐, 젤라틴, 엘라스틴, 가수 분해 엘라스틴, 케라틴 등을 들 수 있다. 고분자 펩티드는 미생물의 배양액으로부터의 정제법, 효소법 또는 화학 합성법 등의 통상의 방법에 의해 정제 취득할 수 있으며, 또는 통상 돼지나 소 등의 진피, 누에의 견섬유 등의 천연물로부터 정제하여 사용할 수 있다.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.
고분자 다당으로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 히드록시에틸셀룰로오스, 크산탄검, 히알루론산나트륨, 콘드로이틴 황산 또는 그 염 (나트륨염 등) 등을 들 수 있다. 예를 들어, 콘드로이틴 황산 또는 그 염 등은 통상 포유 동물이나 어류로부터 정제하여 사용할 수 있다.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.). For example, chondroitin sulfate or its salt can usually be purified and used from mammals or fish.
스핑고 지질로서는 화장품에 배합 가능한 것이라면 어떠한 것이라도 되지만, 예를 들어 세라미드, 피토스핑고신, 스핑고당지질 등을 들 수 있다. 스핑고 지질은 통상 포유류, 어류, 패류, 효모 또는 식물 등으로부터 통상의 방법에 의해 정제하거나 화학 합성법에 의해 취득할 수 있다.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.
본 발명의 화장료 조성물에는 상기 필수 성분과 더불어 필요에 따라 통상 화장품에 배합되는 다른 성분을 배합해도 된다.In addition to the above-mentioned essential ingredients, the cosmetic composition of the present invention may contain other ingredients usually blended in cosmetics as needed.
이외에 첨가해도 되는 배합 성분으로서는 유지 성분, 보습제, 에몰리엔트제, 계면 활성제, 유기 및 무기 안료, 유기 분체, 자외선 흡수제, 방부제, 살균제, 산화 방지제, 식물 추출물, pH 조정제, 알콜, 색소, 향료, 혈행 촉진제, 냉감제, 제한(制汗)제, 정제수 등을 들 수 있다.Other ingredients that may be added 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.
유지 성분으로서는 에스테르계 유지, 탄화수소계 유지, 실리콘계 유지, 불소계 유지, 동물 유지, 식물 유지 등을 들 수 있다.Examples of oil and fat components 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.
에스테르계 유지로서는 트리2-에틸헥산산글리세릴, 2-에틸헥산산세틸, 미리스틴산이소프로필, 미리스틴산부틸, 팔미틴산이소프로필, 스테아르산에틸, 팔미틴산옥틸, 이소스테아르산이소세틸, 스테아르산부틸, 리놀레산에틸, 리놀레산이소프로필, 올레인산에틸, 미리스틴산이소세틸, 미리스틴산이소스테아릴, 팔미틴산이소스테아릴, 미리스틴산옥틸도데실, 이소스테아르산이소세틸, 세바신산디에틸, 아디핀산디이소프로필, 네오펜탄산이소알킬, 트리(카프릴, 카프린산)글리세릴, 트리2-에틸헥산산트리메틸롤프로판, 트리이소스테아르산트리메틸롤프로판, 테트라2-에틸헥산산펜타엘리슬리톨, 카프릴산세틸, 라우린산데실, 라우린산헥실, 미리스틴산데실, 미리스틴산미리스틸, 미리스틴산세틸, 스테아르산스테아릴, 올레인산데실, 리시노올레인산세틸, 라우린산이소스테아릴, 미리스틴산이소트리데실, 팔미틴산이소세틸, 스테아르산옥틸, 스테아르산이소세틸, 올레인산이소데실, 올레인산옥틸도데실, 리놀레산옥틸도데실, 이소스테아르산이소프로필, 2-에틸헥산산세토스테아릴, 2-에틸헥산산스테아릴, 이소스테아르산헥실, 디옥탄산에틸렌글리콜, 디올레인산에틸렌글리콜, 디카프린산프로필렌글리콜, 디(카프릴,카프린산)프로필렌글리콜, 디카프릴산프로필렌글리콜, 디카프린산네오펜틸글리콜, 디옥탄산네오펜틸글리콜, 트리카프릴산글리세릴, 트리운데실산글리세릴, 트리이소팔미틴산글리세릴, 트리이소스테아르산글리세릴, 네오펜탄산옥틸도데실, 옥탄산이소스테아릴, 이소노난산옥틸, 네오데칸산헥실데실, 네오데칸산옥틸도데실, 이소스테아르산이소세틸, 이소스테아르산이소스테아릴, 이소스테아르산옥틸데실, 폴리글리세린올레인산에스테르, 폴리글리세린이소스테아르산에스테르, 시트르산트리이소세틸, 시트르산트리이소알킬, 시트르산트리이소옥틸, 락트산라우릴, 락트산미리스틸, 락트산세틸, 락트산옥틸데실, 시트르산트리에틸, 시트르산아세틸트리에틸, 시트르산아세틸트리부틸, 시트르산트리옥틸, 말산디이소스테아릴, 히드록시스테아르산 2-에틸헥실, 숙신산디2-에틸헥실, 아디핀산디이소부틸, 세바신산디이소프로필, 세바신산디옥틸, 스테아르산콜레스테릴, 이소스테아르산콜레스테릴, 히드록시스테아르산콜레스테릴, 올레인산콜레스테릴, 올레인산디히드로콜레스테릴, 이소스테아르산피트스테릴, 올레인산피트스테릴, 12-스테알로일히드록시스테아르산이소세틸, 12-스테알로일히드록시스테아르산스테아릴, 12-스테알로일히드록시스테아르산이소스테아릴 등의 에스테르계 등을 들 수 있다.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. Butyl, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate, adipine. Diisopropyl acid, isoalkyl neopentanoate, tri(caprylic, capric acid)glyceryl, trimethylolpropane tri2-ethylhexanoate, trimethylolpropane triisostearate, pentaelislitol tetra2-ethylhexanoate , cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinooleate, isostear laurate. Reyl, isotridecyl myristate, isocetyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyldodecyl linoleate, isopropyl isostearate, cetoester 2-ethylhexanoate Aryl, 2-ethylhexanoate stearyl, hexyl isostearate, ethylene glycol dioctanate, ethylene glycol dioleate, propylene glycol dicapric acid, di(capryl, capric acid) propylene glycol, propylene glycol dicaprylate, dicapric acid Neopentyl glycol prinate, neopentyl glycol dioctanate, glyceryl tricaprylate, glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate. , 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 succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, Cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, phytsteryl isostearate, phytsteryl oleate, 12-stealoyl hydroxystearate isocetyl, 12-stealoyl hydride. Ester systems such as stearyl hydroxystearate and isostearyl 12-stealoylhydroxystearate can be mentioned.
탄화 수소계 유지로서는 스쿠알렌, 유동 파라핀, 알파-올레핀올리고머, 이소파라핀, 세레신, 파라핀, 유동 이소파라핀, 폴리부덴, 마이크로크리스탈린왁스, 와셀린 등의 탄화 수소계 유지 등을 들 수 있다.Hydrocarbon-based fats and oils include squalene, liquid paraffin, alpha-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybudene, microcrystalline wax, and petroleum jelly.
실리콘계 유지로서는 폴리메틸실리콘, 메틸페닐실리콘, 메틸시클로폴리실록산, 옥타메틸폴리실록산, 데카메틸폴리실록산, 도데카메틸시클로실록산, 디메틸실록산ㆍ메틸세틸옥시실록산 공중합체, 디메틸실록산ㆍ메틸스테알록시실록산 공중합체, 알킬 변성 실리콘유, 아미노 변성 실리콘유 등을 들 수 있다.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.
불소계 유지로서는 퍼플루오로폴리에테르 등을 들 수 있다.Examples of fluorine-based fats and oils include perfluoropolyether.
동물 또는 식물 유지로서는 아보카도유, 아르몬드유, 올리브유, 참깨유, 쌀겨유, 새플라워유, 대두유, 옥수수유, 유채유, 행인(杏仁)유, 팜핵유, 팜유, 피마자유, 해바라기유, 포도종자유, 면실유, 야자유, 쿠쿠이너트유, 소맥배아유, 쌀 배아유, 시아버터, 월견초유, 마커데이미아너트유, 메도홈유, 난황유, 우지(牛脂), 마유, 밍크유, 오렌지라피유, 호호바유, 캔데리러왁스, 카르나바왁스, 액상 라놀린, 경화피마자유 등의 동물 또는 식물 유지를 들 수 있다.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.
보습제로서는 수용성 저분자 보습제, 지용성 분자 보습제, 수용성 고분자, 지용성 고분자 등을 들 수 있다.Moisturizers include water-soluble low-molecular-weight moisturizers, oil-soluble molecular moisturizers, water-soluble polymers, and fat-soluble polymers.
수용성 저분자 보습제로서는 세린, 글루타민, 솔비톨, 만니톨, 피롤리돈-카르복실산나트륨, 글리세린, 프로필렌글리콜, 1,3-부틸렌글리콜, 에틸렌글리콜, 폴리에틸렌글리콜B(중합도 n = 2 이상), 폴리프로필렌글리콜(중합도 n = 2 이상), 폴리글리세린B(중합도 n = 2 이상), 락트산, 락트산염 등을 들 수 있다.Water-soluble low-molecular-weight moisturizers include serine, glutamine, sorbitol, mannitol, sodium pyrrolidone-carboxylate, glycerin, propylene glycol, 1,3-butylene glycol, ethylene glycol, polyethylene glycol B (degree of polymerization n = 2 or more), and polypropylene. Examples include glycol (degree of polymerization n = 2 or more), polyglycerin B (degree of polymerization n = 2 or more), lactic acid, lactate, etc.
지용성 저분자 보습제로서는 콜레스테롤, 콜레스테롤에스테르 등을 들 수 있다.Examples of fat-soluble low-molecular-weight moisturizers include cholesterol and cholesterol esters.
수용성 고분자로서는 카르복시비닐폴리머, 폴리아스파라긴산염, 트라가칸트, 크산탄검, 메틸셀룰로오스, 히드록시메틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 카르복시메틸셀룰로오스, 수용성 키틴, 키토산, 덱스트린 등을 들 수 있다.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.
지용성 고분자로서는 폴리비닐피롤리돈ㆍ에이코센 공중합체, 폴리비닐피롤리돈ㆍ헥사데센 공중합체, 니트로셀룰로오스, 덱스트린지방산에스테르, 고분자 실리콘 등을 들 수 있다.Examples of oil-soluble polymers include polyvinylpyrrolidone/eicosene copolymer, polyvinylpyrrolidone/hexadecene copolymer, nitrocellulose, dextrin fatty acid ester, and polymer silicone.
에몰리엔트제로서는 장쇄아실글루타민산콜레스테릴에스테르, 히드록시스테아르산콜레스테릴, 12-히드록시스테아르산, 스테아르산, 로진산, 라놀린지방산콜레스테릴에스테르 등을 들 수 있다.Examples of 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.
계면 활성제로서는 비이온성 계면 활성제, 음이온성 계면 활성제, 양이온성 계면 활성제, 양성 계면 활성제 등을 들 수 있다.Examples of surfactants include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.
비이온성 계면 활성제로서는 자기 유화형 모노스테아르산글리세린, 프로필렌글리콜지방산에스테르, 글리세린지방산에스테르, 폴리글리세린지방산에스테르, 솔비탄지방산에스테르, POE (폴리옥시에틸렌)솔비탄지방산에스테르, POE 솔비트지방산에스테르, POE 글리세린지방산에스테르, POE 알킬에테르, POE 지방산에스테르, POE 경화피마자유, POE 피마자유, POEㆍPOP (폴리옥시에틸렌ㆍ폴리옥시프로필렌) 공중합체, POEㆍPOP 알킬에테르, 폴리에테르변성실리콘, 라우린산알카놀아미드, 알킬아민옥시드, 수소첨가대두인지질 등을 들 수 있다.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, POEㆍPOP (polyoxyethyleneㆍpolyoxypropylene) copolymer, POEㆍPOP alkyl ether, polyether modified silicone, lauric acid Examples include alkanolamide, alkylamine oxide, and hydrogenated soybean phospholipid.
음이온성 계면 활성제로서는 지방산비누, 알파-아실술폰산염, 알킬술폰산염, 알킬알릴술폰산염, 알킬나프탈렌술폰산염, 알킬황산염, POE 알킬에테르황산염, 알킬아미드황산염, 알킬인산염, POE 알킬인산염, 알킬아미드인산염, 알킬로일알킬타우린염, N-아실아미노산염, POE 알킬에테르카르복실산염, 알킬술포숙신산염, 알킬술포아세트산나트륨, 아실화 가수분해 콜라겐펩티드염, 퍼플루오로알킬인산에스테르 등을 들 수 있다.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. .
양이온성 계면 활성제로서는 염화알킬트리메틸암모늄, 염화스테아릴트리메틸암모늄, 브롬화스테아릴트리메틸암모늄, 염화세토스테아릴트리메틸암모늄, 염화디스테아릴디메틸암모늄, 염화스테아릴디메틸벤질암모늄, 브롬화베헤닐트리메틸암모늄, 염화벤잘코늄, 스테아르산디에틸아미노에틸아미드, 스테아르산디메틸아미노프로필아미드, 라놀린 유도체 제 4급 암모늄염 등을 들 수 있다.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.
양성 계면 활성제로서는 카르복시베타인형, 아미드베타인형, 술포베타인형, 히드록시술포베타인형, 아미드술포베타인형, 포스포베타인형, 아미노카르복실산염형, 이미다졸린 유도체형, 아미드아민형 등의 양성 계면 활성제 등을 들 수 있다.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.
유기 및 무기 안료로서는 규산, 무수규산, 규산마그네슘, 탤크, 세리사이트, 마이카, 카올린, 벵갈라, 클레이, 벤토나이트, 티탄피막운모, 옥시염화비스무트, 산화지르코늄, 산화마그네슘, 산화아연, 산화티탄, 산화알루미늄, 황산칼슘, 황산바륨, 황산마그네슘, 탄산칼슘, 탄산마그네슘, 산화철, 군청, 산화크롬, 수산화크롬, 칼라민 및 이들의 복합체등의 무기 안료; 폴리아미드, 폴리에스테르, 폴리프로필렌, 폴리스티렌, 폴리우레탄, 비닐수지, 요소수지, 페놀수지, 불소수지, 규소수지, 아크릴수지, 멜라민수지, 에폭시수지, 폴리카보네이트수지, 디비닐벤젠ㆍ스티렌 공중합체, 실크파우더, 셀룰로오스, CI 피그먼트옐로우, CI 피그먼트오렌지 등의 유기 안료 및 이들의 무기 안료와 유기 안료의 복합 안료 등을 들 수 있다.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.
유기 분체로서는 스테아르산칼슘 등의 금속비누; 세틸린산아연나트륨, 라우릴린산아연, 라우릴린산칼슘 등의 알킬인산금속염; N-라우로일-베타-알라닌칼슘, N-라우로일-베타-알라닌아연, N-라우로일글리신칼슘 등의 아실아미노산 다가금속염; N-라우로일-타우린칼슘, N-팔미토일-타우린칼슘 등의 아미드술폰산 다가금속염; N-엡실론-라우로일-L-리진, N-엡실론-팔미토일리진, N-알파-파리토일올니틴, N-알파-라우로일아르기닌, N-알파-경화우지지방산아실아르기닌 등의 N-아실염기성아미노산; N-라우로일글리실글리신 등의 N-아실폴리펩티드; 알파-아미노카프릴산, 알파-아미노라우린산 등의 알파-아미노지방산; 폴리에틸렌, 폴리프로필렌, 나일론, 폴리메틸메타크릴레이트, 폴리스티렌, 디비닐벤젠ㆍ스티렌 공중합체, 사불화에틸렌 등을 들 수 있다.Examples of organic powder 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. -Acyl basic amino acid; 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.
자외선 흡수제로서는 파라아미노벤조산, 파라아미노벤조산에틸, 파라아미노벤조산아밀, 파라아미노벤조산옥틸, 살리실산에틸렌글리콜, 살리신산페닐, 살리신산옥틸, 살리신산벤질, 살리신산부틸페닐, 살리신산호모멘틸, 계피산벤질, 파라메톡시계피산-2-에톡시에틸, 파라메톡시계피산옥틸, 디파라메톡시계피산모노-2-에틸헥산글리세릴, 파라메톡시계피산이소프로필, 디이소프로필ㆍ디이소프로필계피산에스테르 혼합물, 우로카닌산, 우로카닌산에틸, 히드록시메톡시벤조페논, 히드록시메톡시벤조페논술폰산 및 그 염, 디히드록시메톡시벤조페논, 디히드록시메톡시벤조페논디술폰산나트륨, 디히드록시벤조페논, 테트라히드록시벤조페논, 4-tert-부틸-4'-메톡시디벤조일메탄, 2,4,6-트리아닐리노-p-(카르보-2'-에틸헥실-1'-옥시)-1,3,5-트리아진, 2-(2-히드록시-5-메틸페닐)벤조트리아졸 등을 들 수 있다.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. , paramethoxycinnamic acid-2-ethoxyethyl, paramethoxycinnamic acid octyl, diparamethoxycinnamic acid mono-2-ethylhexane glyceryl, paramethoxycinnamic acid isopropyl, diisopropylㆍdiisopropylcinnamic acid ester mixture, uro Kaninic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its salts, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone disulfonate sodium, dihydroxybenzophenone , tetrahydroxybenzophenone, 4-tert-butyl-4'-methoxydibenzoylmethane, 2,4,6-trianilino-p-(carbo-2'-ethylhexyl-1'-oxy)-1 , 3,5-triazine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, etc.
살균제로서는 히노키티올, 트리클로산, 트리클로로히드록시디페닐에테르, 크로르헥시딘글루콘산염, 페녹시에탄올, 레조르신, 이소프로필메틸페놀, 아줄렌, 살리칠산, 진크필리티온, 염화벤잘코늄, 감광소 301 호, 모노니트로과이어콜나트륨, 운데시렌산 등을 들 수 있다.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.
산화 방지제로서는 부틸히드록시아니솔, 갈릭산프로필, 엘리소르빈산 등을 들 수 있다. pH 조정제로서는 시트르산, 시트르산나트륨, 말산, 말산나트륨, 프말산, 프말산나트륨, 숙신산, 숙신산나트륨, 수산화나트륨, 인산일수소나트륨 등을 들 수 있다. 알코올로서는 세틸알코올 등의 고급 알코올을 들 수 있다.Antioxidants include butylhydroxyanisole, propyl gallate, and elisorbic acid. Examples of 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. Examples of alcohol include higher alcohols such as cetyl alcohol.
또한, 이외에 첨가해도 되는 배합 성분은 이에 한정되는 것은 아니며, 또, 상기 어느 성분도 본 발명의 목적 및 효과를 손상시키지 않는 범위 내에서 배합 가능하지만, 총중량에 대하여 0.01-5% 중량 백분율 또는 0.01-3% 중량 백분율로 배합될 수 있다.In addition, the 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.
본 발명의 제형이 로션, 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물섬유, 식물섬유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a lotion, paste, cream or gel, 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.
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When 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. In particular, when the formulation is a spray, chlorofluorohydrocarbon and propane may be used as carrier ingredients. /May contain propellants such as butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액의 경우에는 담체 성분으로서 용매, 용매화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the present invention is a solution or emulsion, 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.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, 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.
본 발명의 제형이 계면-활성제 함유 클렌징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 리놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a surfactant-containing cleansing agent, 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.
또한, 본 발명은 본 발명에 따른 화장료 조성물을 이를 필요로 하는 개체의 피부에 적용하는 단계를 포함하는, 색소침착을 예방 또는 개선하기 위한 피부 미용방법을 제공한다. 본 명세서에 있어서 "적용"이란 투여, 주사, 또는 도포 등 화장료 조성물을 피부에 제공할 수 있는 모든 수단을 포함한다.Additionally, 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. In this specification, “application” includes all means of providing a cosmetic composition to the skin, such as administration, injection, or application.
또한, 본 발명은 본 발명의 다른 양태로 알티라티닙 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 국소 적용 제제를 제공한다. 상기 국소 적용 제제는 크림, 젤, 로션, 파우더, 파우더 스프레이, 오일, 롤-온 제형, 연고, 폼, 스프레이, 스틱 또는 팅쳐(tincture) 형태일 수 있다.In addition, in another aspect of the present invention, 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.
또한, 본 발명은 본 발명의 다른 양태로 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 식품 조성물 및 건강기능식품을 제공하며, 상기 염은 식품학적으로 허용 가능한 염일 수 있다.In addition, 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.
본 명세서에서 사용된 용어, "식품학적으로 허용 가능한 염"이란 식품학적으로 허용되는 유기산, 무기산, 또는 염기로부터 유도된 염을 포함한다. As used herein, the term “foodologically acceptable salt” includes salts derived from foodologically acceptable organic acids, inorganic acids, or bases.
본 발명의 알티라티닙 유도체 또는 이의 염을 식품 첨가물로 사용할 경우, 상기 알티라티닙 유도체 또는 이의 염을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조시 본 발명의 알티라티닙 유도체 또는 이의 염은 원료에 대하여 15 중량% 이하, 또는 10 중량% 이하의 양으로 첨가될 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When using the altiratinib derivative or its salt of the present invention as a food additive, the altiratinib derivative or its salt 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). In general, when manufacturing food or beverages, 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. However, in the case of long-term intake for the purpose of health and hygiene or health control, 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.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There are no special restrictions on the types of foods above. Examples of 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.
본 발명에 따른 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당 및 과당과 같은 모노사카라이드, 말토오스 및 수크로오스와 같은 디사카라이드, 덱스트린 및 시클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨 및 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL당 일반적으로 약 0.01-0.20g, 또는 약 0.04-0.10g이다.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. As 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.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01-0.20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, 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.
본 명세서에 있어서, "건강기능식품"이란 특정보건용 식품(food for special health use, FoSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미하는데, 상기 식품은 비만의 예방 또는 개선에 유용한 효과를 얻기 위하여 정제, 캡슐, 분말, 과립, 액상, 환 등의 다양한 형태로 제조될 수 있다.In this specification, “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.
본 발명의 건강기능식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어날 수 있다.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. In addition, unlike general drugs, 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.
상기 건강기능식품은 이너뷰티 푸드(inner beauty) 형태로 섭취함으로써 더욱 우수한 효과를 갖는 장점을 가진다. 상기 이너뷰티(inner beauty)는 '먹는 화장품 또는 뷰티 푸드'로 일컬어지는 푸드로, 피부에 좋은 여러 가지 성분을 몸속으로 흡수시켜 피부 체질을 건강하게 바꾸는 식품을 지칭하며, 피부 타입에 맞는 화장품을 고르듯 피부 컨디션과 라이프스타일을 고려해 개개인에게 맞는 이너 뷰티 푸드를 선택하여 섭취할 수 있다. 예를 들면, 상기 화장료 조성물을 포함하는 화장품과 알티라티닙 유도체 또는 이의 염을 포함하는 이너뷰티 푸드를 혼용할 경우, 화장품 또는 약제만 사용하는 것에 비해 효과가 월등히 높아져 더욱 효과적인 색소침착 예방 또는 개선 효과는 물론 미백 효과를 볼 수 있는 장점을 가질 수 있다.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.
또한, 본 발명은 본 발명의 다른 양태로 알티라티닙 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 색소침착의 예방 또는 개선용 의약외품 조성물을 제공한다 In addition, 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.
본 발명에서 사용되는 용어, "의약외품"은 사람이나 동물의 질병을 진단, 치료, 개선, 경감, 처치 또는 예방할 목적으로 사용되는 물품들 중 의약품보다 작용이 경미한 물품들을 의미하는 것으로, 예를 들어 약사법에 따르면 의약외품이란 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람ㆍ동물의 질병 치료나 예방에 쓰이는 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않는 제품 등이 포함된다.The term "quasi-drug" as used in the present invention 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. For example, the Pharmaceutical Affairs Act According to the Act, 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.
본 발명의 알티라티닙 유도체 또는 이의 약학적으로 허용 가능한 염을 의약외품 첨가물로 사용하는 경우, 이를 그대로 첨가하거나 다른 의약외품 또는 의약외품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 함께 사용되는 다른 성분들과의 혼합비율은 사용 목적(예를 들어, 예방, 개선 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.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).
본 발명의 의약외품 조성물의 예로는 마스크, 연고제, 크림, 로션, 에센스, 스프레이, 샴푸, 린스 등의 두피 모발 케어 조성물, 바디 클렌저, 폼, 비누 등을 들 수 있으나, 이에 제한되는 것은 아니다.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.
본 발명의 알티라티닙 유도체 또는 이의 약학적으로 허용 가능한 염은 의약외품 조성물의 총 중량에 대하여 그 함량이 제한되는 것은 아니나, 0.001 중량% 내지 0.1 중량%, 보다 바람직하게는 0.0001 중량% 내지 1 중량%로 포함될 수 있다.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.
또한, 본 발명은 본 발명에 따른 약학적 조성물, CRTC3 억제용 조성물, 화장료 조성물, 국소 적용 제제, 식품 조성물, 또는 의약외품 조성물을 포함하는, 색소침착의 예방 또는 개선용 키트를 제공한다.In addition, 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.
본 발명에 따른 "키트"는 본 발명의 목적, 즉, 색소침착의 예방, 개선, 또는 치료; 피부미백; 또는 피부미용 등의 달성에 필요한 당 업계에 공지된 도구 및/또는 시약 등을 추가로 포함할 수 있다. 예를 들어, 상기 키트는 본 발명에 따른 색소침착을 예방 또는 개선하기 위한 피부 미용방법이 기재된 지시서를 더 포함하거나, 또는, 본 발명에 따른 조성물을 투여, 도포, 또는 흡수시키는데 필요한 기구, 예컨대 주사기, 솜, 면봉, 시트지, 퍼프 등을 더 포함할 수 있다.“Kit” according to the present invention 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. For example, 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.
본 명세서에서 사용되는 용어 "유효성분"은 단독으로 목적으로 하는 활성을 나타내거나 또는 그 자체는 활성이 없는 담체 등과 함께 목적으로 하는 활성을 나타낼 수 있는 성분을 의미한다.The term "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.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Below, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.
[실험방법][Experimental method]
1. 세포 배양1. Cell culture
마우스 멜라닌세포주인 Mel-Ab 세포는 10% FBS, 1% P/S, 100nM TPA, 및 1nM CT를 함유한 Dulbecco's Modified Eagle Medium (DMEM) 배지로 배양하였다. 실험을 위해 100mm 디쉬(dish)에 7×105개 세포를 씨딩(seeding)한 후 37℃및 5% CO2 조건에서 6일 동안 배양하였으며, 배양 기간 동안 48 내지 72시간 마다 기존 배지를 새로운 배지로 교체하였다. 다른 마우스 멜라닌세포주인 B16F10은 10% FBS 및 1% P/S를 함유한 DMEM 배지로, 위와 동일한 조건으로 배양하였다.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. For the experiment, 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.
인간 1차 멜라닌세포(human primary melanocytes; hMC, normal human melanocytes; NHM)는 인간 멜라닌세포 성장 보조제(Human Melanocyte Growth Supplement; Gibco)를 첨가한 Medium 254(Gibco) 배지에서 배양하였다. 37℃및 5% CO2 조건에서 배양하였으며, 2 내지 3일마다 배지를 교체했다. 세포의 컨플루언시(confluency)가 70% 이상에 도달하였을 때 실험을 진행하였다.Human primary melanocytes (hMC, normal human melanocytes; NHM) were cultured in Medium 254 (Gibco) supplemented with human melanocyte growth supplement (Gibco). Cultured at 37°C and 5% CO 2 conditions, the medium was replaced every 2 to 3 days. The experiment was performed when the cell confluency reached 70% or more.
2. 멜라닌 함량 측정2. Measurement of melanin content
10μM의 FSK(Forskolin)으로 1시간 전 처리 또는 전처리 하지 않은 Mel-Ab, B16F10, hMC에 알티라티닙 또는 알티라티닙 유도체 화합물을 처리하였으며, 72 시간 배양하였다. 멜라닌 함량을 측정하기 전 현미경(Olympus, Tokyo, Japan)으로 세포를 확인하여 세포의 상태를 확인 후, 세포배양액을 제거하고 PBS로 세척한 세포를 550μl의 1N NaOH에 용해시키고 100℃에서 30분 동안 가열하였다. 이후 실온에서 잠시 식힌 뒤, 5분 동안 13,000rpm에서 원심 분리 하였다. 마이크로플레이트 리더를 사용하여 405nm에서 상층액의 흡광도를 측정하였다. 세포 내 멜라닌 함량은 알티라티닙 또는 알티라티닙 유도체 화합물 및 FSK를 처리하지 않은 세포 대조군에 대한 백분율로 표시하였다.Mel-Ab, B16F10, and hMC treated with or without 10 μM FSK (Forskolin) for 1 hour were treated with altiratinib or altiratinib derivative compounds, and cultured for 72 hours. Before measuring the melanin content, check the cell condition by checking the cells under a microscope (Olympus, Tokyo, Japan). After removing the cell culture medium, the washed cells with PBS were dissolved in 550 μl of 1N NaOH and incubated at 100°C for 30 minutes. heated. After cooling for a while at room temperature, it was centrifuged at 13,000 rpm for 5 minutes. The absorbance of the supernatant was measured at 405 nm using a microplate reader. The intracellular melanin content was expressed as a percentage relative to the cell control group that was not treated with altiratinib or altiratinib derivative compound and FSK.
3. 세포독성 분석3. Cytotoxicity assay
B16F10 세포는 1.2×105 cells/well로 6 well cell culture plate에 seeding 하였다. 24시간 후, 10% FSB, 1% A.A(antibiotic antimycotic)가 포함된 DMEM 배지로 교체하고 1시간 후 약물을 처리하였다. Mel-ab 세포는 3×105 cells/well로 6 well cell culture plate에 seeding 하였다. 이후 1×PBS로 세척한 후 CT(Cefixime Tellurite) 및 TPA(Tissue type plasminogen activator)가 빠진 10% FBS, 1% A.A.가 포함된 DMEM 배지로 교체하였으며, 1시간 후 약물을 처리하였다. hMC 세포는 6.0×105 cells/well로 6 well cell culture plate에 seeding 하였다. 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.
24시간 후 HMGS(Human Melanocyte Growth Supplement) 및 1% A.A.가 포함된 Media 254 배지로 교체하였으며, 1시간 후 약물을 처리하였다. 약물 처리 후 72시간 동안 배양하였다. After 24 hours, the medium was replaced with Media 254 containing HMGS (Human Melanocyte Growth Supplement) and 1% A.A., and the drug was treated 1 hour later. After drug treatment, the cells were cultured for 72 hours.
세포 생존력은 MTT 분석을 이용하여 측정하였다. 약물 처리 72시간 후 배지를 제거하고 PBS로 세척을 하였다. 이 후 PBS에 녹인 MTT 용액을 배지에 2.5 mg/ml이 되도록 첨가하였으며, 37℃, 5% CO2 환경에서 2시간 배양하였다. 생성된 formazan crystals을 DMSO에 용해시겼다. 마이크로플레이트 리더(Molecular Devices, Sunnyvale, CA, USA)를 이용하여 565 nm에서 흡광도를 측정하였다. 세포 생존력은 약물을 처리하지 않은 세포 대조군에 대한 백분율로 표시하였다.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.
4. 인공 지질 막 투과도 분석(PAMPA; Parallel artificial membrane permeability assay) 4. Parallel artificial membrane permeability assay (PAMPA)
알티라티닙 유도체의 피부 투과도를 측정하기 위하여 SKIN PAMPA Explorer Test system(Pion Inc.)를 제조사의 설명에 따라 사용하였다. Acceptor plate의 막을 hydration buffer(Pion Inc., #120706)로 상온에서 15-18시간동안 incubation하고 Deep well plate에 pH 7.4의 PRISMA HT buffer(Pion Inc., #110151)를 분주하고 시험 물질을 섞어서 준비하였다. PRISMA HT buffer를 U.V plate에 well당 150μl씩 분주한 후 흡광도를 측정하여 blank 값을 얻고, Deep well plate에 있는 혼합물을 well당 150 μl씩 U.V plate로 분주한 후 흡광도를 측정하여 initial 값을 얻었다. Stirwell PAMPA sandwich(Pion Inc., #120657)의 donor plate에 Accetor plate의 혼합물을 200μl씩 분주하고 Acceptor plate에 PRISMA HT buffer를 200μl씩 각 well에 분주하였다. Acceptor plate와 donor plate를 합치고 25℃에서 5시간 incubation한 후 acceptor plate와 donor plate를 분리한 후 각각 150μl씩 U.V plate로 옮긴 후 흡광도를 측정하여 donor 값과 acceptor 값을 얻었다. Microplate reader를 통해 각 샘플들의 흡광도를 측정한 후 PAMPA explorer program을 이용하여 투과도 값(Pe, 10-6cm/sec)을 분석하고 Microsoft excel 프로그램을 이용하여 replicates(n=3)의 평균, 표준편차를 계산하였다.To measure the skin permeability of altiratinib derivatives, 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. After dispensing 150 μl of PRISMA HT buffer per well into a UV plate, the absorbance was measured to obtain a blank value, and the mixture in the deep well plate was dispensed into a UV plate at 150 μl per well, and then the absorbance was measured to obtain an initial value. 200 μl of the mixture from the Accetor plate was dispensed onto the donor plate of Stirwell PAMPA sandwich (Pion Inc., #120657), and 200 μl of PRISMA HT buffer was dispensed into each well of the Acceptor plate. After combining the acceptor plate and donor plate and incubating at 25°C for 5 hours, the acceptor plate and donor plate were separated, 150 μl of each was transferred to a UV plate, and the absorbance was measured to obtain the donor and acceptor values. After measuring the absorbance of each sample through a microplate reader, the transmittance value (P e , 10 -6 cm/sec) was analyzed using the PAMPA explorer program, and the average and standard of replicates (n=3) were calculated using the Microsoft Excel program. The deviation was calculated.
[실시예][Example]
실시예 1. 알티라티닙 유도체의 합성Example 1. Synthesis of altiratinib derivatives
[반응식 1][Scheme 1]
Figure PCTKR2023016293-appb-img-000054
Figure PCTKR2023016293-appb-img-000054
시약 및 조건: (a) NaH, DMF, 57%; (b) cyclopropanecarboxamide, Pd2(dba)3, rac-BINAP, K3PO4, 1,4-dioxane, 100°C, 37%; (c) Zn, NH4Cl, MeOH, THF, 0°C, 83%; (d) acids, TBTU, iPr2NEt, DMF, 6-61%; (e) acids, HATU, iPr2NEt, DMF, 5-60%; (f) acids, DCC, HOBt, THF, 60°C, 8-17%; (g) 4M HCl in 1,4-dioxane, CH2Cl2, 2% (2-step 수율).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).
알티라티닙(Altiratinib)의 합성은 페놀(화합물 1) 및 아릴 플루오라이드(화합물 2)의 친핵성 방향족 치환으로 시작하였다. 아릴 클로라이드(화합물 3)와 사이클로프로판카복사마이드의 Pd-촉매 스즈키 커플링으로 화합물 4를 생성하였고 아연 및 염화암모늄을 사용한 니트로 환원으로 아닐린(화합물 5)을 생성하였다. 다양한 바이사이클릭 헤테로사이클을 포함하는 산과 아닐린(화합물 5)의 아미드 커플링 반응으로 알티라티닙 유도체들을 생성하였다. 구체적인 합성 경로는 하기와 같다 (단, 화합물 ALT-005는 중간체로 이에 대한 합성은 하기에 별도로 기술함):The synthesis of 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-아릴화(O-Arylation)step a: O-Arylation
DMF(430.0 μL)에서 sodium hydride의 현탁액(분산액 중 60%, 40.1 mg, 1.00 mmol)에 DMF(1000.0 μL)에서 2-chloropyridin-4-ol(100.0 mg, 0.77 mmol) 용액을 0℃에서 첨가하였다. 혼합물을 30분 동안 교반하고, DMF(500.0 μL)에서 1,2,4-trifluoro-5-nitrobenzene(150.0 mg, 0.85 mmol)의 용액을 동일한 온도에서 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 감압 하에 농축하여 혼합물 중 대부분의 DMF를 제거한 다음, ethyl acetate와 10% 수성 lithium chloride 사이에 분배하였다. 형성된 침전물을 흡인 여과를 통해 제거한 다음 층을 분리하였다. 유기층을 추가의 10% 수성 lithium chloride(×2), 포화 수성 sodium bicarbonate 및 염수(brine)로 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압 농축하였다. 잔류물을 실리카겔 크로마토그래피(25% EtOAc/n-hexane)로 정제하여 125.8 mg(57%)의 황색 고체 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine(화합물 3)을 수득하였다; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 5.7 Hz, 1H), 8.06 (dd, J = 9.3, 6.8 Hz, 1H), 7.14 (dd, J = 10.3, 6.4 Hz, 1H), 6.96 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 5.7, 2.2 Hz, 1H); LCMS (ESI), m/z = 328.07 [M+1+CH3CN]+.A solution of 2-chloropyridin-4-ol (100.0 mg, 0.77 mmol) in DMF (1000.0 μL) was added to a suspension of sodium hydride (60% in dispersion, 40.1 mg, 1.00 mmol) in DMF (430.0 μL) at 0°C. . The mixture was stirred for 30 min, and a solution of 1,2,4-trifluoro-5-nitrobenzene (150.0 mg, 0.85 mmol) in DMF (500.0 μL) was added at the same temperature. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to remove most of the DMF in the mixture, and then partitioned between ethyl acetate and 10% aqueous lithium chloride. The formed precipitate was removed through suction filtration and the layers were separated. The organic layer was washed with additional 10% aqueous lithium chloride (×2), saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25% EtOAc/ n -hexane) to obtain 125.8 mg (57%) of yellow solid 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (Compound 3). Obtained; 1H NMR (400 MHz, CDCl 3 ) δ 8.39 (d, J = 5.7 Hz, 1H), 8.06 (dd, J = 9.3, 6.8 Hz, 1H), 7.14 (dd, J = 10.3, 6.4 Hz, 1H) , 6.96 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 5.7, 2.2 Hz, 1H); LCMS (ESI), m/z = 328.07 [M+1+CH 3 CN] + .
step b: Buchwald-Hartwig 아민화(amination)step b: Buchwald-Hartwig amination
Pd2(dba)3(61.3 mg, 0.07 mmol), rac-BINAP(83.0 mg, 0.13 mmol), K3PO4(592.0 mg, 2.79 mmol)의 혼합물에 1,4-dioxane(3720.0 μL)에서 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine(화합물 3, 320.0 mg, 1.12 mmol) 및 1,4-dioxane(3720.0 μL)에서 cyclopropanecarboxamide(380.0 mg, 4.47 mmol)을 첨가하였다. 반응 혼합물을 100℃로 가열하고 밤새 교반하였다. 반응 혼합물을 실온에서 냉각시키고 셀라이트 패드(Celite pad)를 통해 여과하였다. 여과액을 감압 하에 농축하고 잔류물을 실리카겔 크로마토그래피(25%에서 30% EtOAc/n-hexane)로 정제하여 150.1 mg(37%)의 황색 고체 N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)cyclopropanecarboxamide(화합물 4)를 수득하였다; 1H NMR (400 MHz, CDCl3) δ 8.26-8.22 (m, 2H), 8.02 (dd, J = 9.5, 6.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 10.7, 6.5 Hz, 1H), 6.73 (dd, J = 5.7, 2.4 Hz, 1H), 1.57-1.51 (m, 1H), 1.10-1.06 (m, 2H), 0.94-0.89 (m, 2H); LCMS (ESI), m/z = 336.08 [M+1]+.2 in 1,4-dioxane (3720.0 μL) in a mixture of Pd 2 (dba) 3 (61.3 mg, 0.07 mmol), rac -BINAP (83.0 mg, 0.13 mmol), and K 3 PO 4 (592.0 mg, 2.79 mmol). -chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (compound 3, 320.0 mg, 1.12 mmol) and cyclopropanecarboxamide (380.0 mg, 4.47 mmol) were added to 1,4-dioxane (3720.0 μL). The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (25% to 30% EtOAc/ n -hexane) to yield 150.1 mg (37%) of yellow solid N-(4-(2,5-difluoro-4). -nitrophenoxy)pyridin-2-yl)cyclopropanecarboxamide (Compound 4) was obtained; 1H NMR (400 MHz, CDCl 3 ) δ 8.26-8.22 (m, 2H), 8.02 (dd, J = 9.5, 6.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 10.7, 6.5 Hz, 1H), 6.73 (dd, J = 5.7, 2.4 Hz, 1H), 1.57-1.51 (m, 1H), 1.10-1.06 (m, 2H), 0.94-0.89 (m, 2H) ; LCMS (ESI), m/z = 336.08 [M+1] + .
step c: 니트로 환원(Nitro Reduction)step c: Nitro Reduction
메탄올(2237.0 μL) 및 THF(2237.0 μL)에서 N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)cyclopropanecarboxamide(화합물 4, 150.0 mg, 0.45 mmol)의 용액에 NH4Cl(239.0 mg, 4.47 mmol) 및 zinc dust(293.0 mg, 4.47 mmol)를 0℃에서 첨가하고 혼합물을 동일한 온도에서 30분간 교반하였다. 생성된 혼합물을 실온에서 가온하고 밤새 교반하였다. 반응 혼합물을 메탄올로 잘 세척한 셀라이트 패드를 통해 여과하였다. 여과액을 감압 하에 농축하고 잔류물을 ethyl acetate와 물 사이에 분배하였다. 유기층을 추가의 물 및 염수로 세척하고 무수 MgSO4로 건조하고 감압하에 농축하였다. 잔류물을 NH2 실리카겔 크로마토그래피(30% EtOAc/n-hexane)로 정제하여 113.0 mg(83%)의 백색 고체 N-(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(화합물 5)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.83 (s, 1H), 8.17 (d, J = 5.7 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 11.2, 7.5 Hz, 1H), 6.75-6.67 (m, 2H), 5.51 (s, 2H), 2.00-1.94 (m, 1H), 0.79-0.77 (m, 4H); LCMS (ESI), m/z = 306.11 [M+1]+.NH 4 in a solution of N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)cyclopropanecarboxamide (Compound 4, 150.0 mg, 0.45 mmol) in methanol (2237.0 μL) and THF (2237.0 μL). Cl (239.0 mg, 4.47 mmol) and zinc dust (293.0 mg, 4.47 mmol) were added at 0°C, and the mixture was stirred at the same temperature for 30 minutes. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered through a pad of Celite washed well with methanol. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with additional water and brine, dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by NH 2 silica gel chromatography (30% EtOAc/ n -hexane) to obtain 113.0 mg (83%) of a white solid, N -(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl. )cyclopropanecarboxamide (compound 5) was obtained; 1H NMR (400 MHz, DMSO -d6 ) δ 10.83 (s, 1H ), 8.17 (d, J = 5.7 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 11.2, 7.5 Hz, 1H), 6.75-6.67 (m, 2H), 5.51 (s, 2H), 2.00-1.94 (m, 1H), 0.79-0.77 (m, 4H); LCMS (ESI), m/z = 306.11 [M+1] + .
step d 또는 e: 아미드 커플링(Amide Coupling)-Astep d or e: Amide Coupling-A
DMF에 N-(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(화합물 5, 1.0 equiv)의 용액에 커플링 시약으로 산(1.2 equiv), N,N-diisopropylethylamine(DIPEA, 5.0 equiv) 및 TBTU(O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, step d)(1.2 equiv) 또는 HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, step e)(1.2 equiv)를 첨가하였다. 반응 혼합물을 실온에서 교반하였다. 반응 혼합물을 ethyl acetate로 희석하고 10% 수성 lithium chloride(×3) 및 염수로 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압 농축하였다.Acid (1.2 equiv), 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. (DIPEA, 5.0 equiv) and TBTU ( O -(benzotriazol-1-yl)- N,N,N',N' -tetramethyluronium tetrafluoroborate, step d) (1.2 equiv) or HATU (1-[Bis(dimethylamino)methylene ]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxid hexafluorophosphate, step e) (1.2 equiv) was added. The reaction mixture was stirred at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (×3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure.
step f: 아미드 커플링(Amide Coupling)-Bstep f: Amide Coupling-B
THF에 N-(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(화합물 5, 1.0 equiv)의 용액에 커플링 시약으로 산(1.2 equiv), 1-hydroxybenzotriazole (1.1 equiv) 및 DCC (N,N'-dicyclohexylcarbodiimide)(1.1 equiv)를 첨가하였다. 반응 혼합물을 60℃에서 교반하였다. 반응 혼합물을 ethyl acetate로 희석하고 10% 수성 lithium chloride(×3) 및 염수로 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압 농축하였다.A solution of N -(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (compound 5, 1.0 equiv) in THF with acid (1.2 equiv) and 1-hydroxybenzotriazole (1.1 equiv) as coupling reagents. equiv) and DCC ( N , N' -dicyclohexylcarbodiimide) (1.1 equiv) were added. The reaction mixture was stirred at 60°C. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (×3) and brine. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure.
1-1. 1-1. NN -(4-(4-(2-(benzo[-(4-(4-(2-(benzo[ dd ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(ALT-001, 화합물 6d)]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-001, Compound 6d)
[화합물 6d][Compound 6d]
Figure PCTKR2023016293-appb-img-000055
Figure PCTKR2023016293-appb-img-000055
step d를 통해 22시간 동안 TBTU를 사용한 2-(benzo[d]isoxazol-3-yl)acetic acid(17.4 mg, 0.10 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(30% EtOAc/n-hexane)로 12.6 mg(32%)의 옅은 황색 고체 N-(4-(4-(2-(benzo[d]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 95%, 화합물 6d)을 수득하였다; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.36-8.30 (m, 2H), 8.12 (d, J = 5.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.42-7.38 (m, 1H), 6.96 (dd, J = 10.5, 6.9 Hz, 1H), 6.59 (dd, J = 5.8, 2.3 Hz, 1H), 4.20 (s, 2H), 1.54-1.48 (m, 1H), 1.07-1.03 (m, 2H), 0.91-0.84 (m, 2H); LCMS (ESI), m/z = 465.22 [M+1]+.After the amide coupling reaction of 2-(benzo[ d ]isoxazol-3-yl)acetic acid (17.4 mg, 0.10 mmol) using TBTU for 22 hours through step d, NH 2 silica gel chromatography (30% EtOAc/ n - hexane) of 12.6 mg (32%) of pale yellow solid N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl) Cyclopropanecarboxamide (purity 95%, compound 6d) was obtained; 1H NMR (400 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.36-8.30 (m, 2H), 8.12 (d, J = 5.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H) , 7.75 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.42-7.38 (m, 1H), 6.96 (dd, J = 10.5, 6.9 Hz, 1H), 6.59 (dd, J = 5.8, 2.3 Hz, 1H), 4.20 (s, 2H), 1.54-1.48 (m, 1H), 1.07-1.03 (m, 2H), 0.91-0.84 (m, 2H); LCMS (ESI), m/z = 465.22 [M+1] + .
1-2. 1-2. NN -(4-(4-(2-(benzo[-(4-(4-(2-(benzo[ dd ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(ALT-002, 화합물 7a)]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-002, Compound 7a)
[화합물 7a][Compound 7a]
Figure PCTKR2023016293-appb-img-000056
Figure PCTKR2023016293-appb-img-000056
step d를 통해 76시간 동안 TBTU를 사용한 2-(benzo[d]oxazol-2-yl)acetic acid (17.4 mg, 0.10 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(30%에서 50% EtOAc/n-hexane)로 8.5 mg(27%)의 아이보리색 고체 N-(4-(4-(2-(benzo[d]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 98%, 화합물 7a)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.90 (s, 1H), 10.57 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 12.3, 7.2 Hz, 1H), 7.76-7.73 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 10.9, 7.4 Hz, 1H), 7.44-7.37 (m, 2H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 4.31 (s, 2H), 2.01-1.91 (m, 1H), 0.86-0.77 (m, 4H); LCMS (ESI), m/z = 465.16 [M+1]+.After the amide coupling reaction of 2-(benzo[ d ]oxazol-2-yl)acetic acid (17.4 mg, 0.10 mmol) using TBTU for 76 hours through step d, NH 2 silica gel chromatography (30% to 50% EtOAc) / n -hexane) of 8.5 mg (27%) of an ivory solid N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2 -yl)cyclopropanecarboxamide (purity 98%, compound 7a) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 10.90 (s, 1H), 10.57 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 12.3, 7.2 Hz, 1H), 7.76-7.73 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 10.9, 7.4 Hz, 1H), 7.44-7.37 (m, 2H), 6.77 (dd , J = 5.7, 2.4 Hz, 1H), 4.31 (s, 2H), 2.01-1.91 (m, 1H), 0.86-0.77 (m, 4H); LCMS (ESI), m/z = 465.16 [M+1] + .
1-3. 1-3. NN -(4-(4-(2-(1-(4-(4-(2-(1 HH -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(ALT-003, 화합물 6a)-indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-003, Compound 6a)
[화합물 6a][Compound 6a]
Figure PCTKR2023016293-appb-img-000057
Figure PCTKR2023016293-appb-img-000057
step e를 통해 42시간 동안 HATU를 사용한 2-(1H-indazol-3-yl)acetic acid(17.3 mg, 0.10 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(60% EtOAc/n-hexane)로 1.4 mg(5%)의 백색 고체 N-(4-(4-(2-(1H-indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 99%, 화합물 6a)를 수득하였다; 1H NMR (400 MHz, CD3OD) δ 8.19-8.12 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.44-7.40 (m, 1H), 7.25-7.16 (m, 2H), 6.70 (dd, J = 5.8, 2.4 Hz, 1H), 4.21 (s, 2H), 1.89-1.83 (m, 1H), 0.96-0.85 (m, 4H); LCMS (ESI), m/z = 464.23 [M+1]+.Through 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). ) as 1.4 mg (5%) of white solid N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 99%, compound 6a) was obtained; 1 H NMR (400 MHz, CD 3 OD) δ 8.19-8.12 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.44-7.40 (m, 1H), 7.25-7.16 (m, 2H), 6.70 (dd, J = 5.8, 2.4 Hz, 1H), 4.21 (s, 2H), 1.89-1.83 ( m, 1H), 0.96-0.85 (m, 4H); LCMS (ESI), m/z = 464.23 [M+1] + .
1-4. 1-4. NN -(4-(2,5-difluoro-4-(2-(5-fluoro-1-(4-(2,5-difluoro-4-(2-(5-fluoro-1 HH -indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide(TFA 염, ALT-004, 화합물 6b)-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (TFA salt, ALT-004, Compound 6b)
[화합물 6b][Compound 6b]
Figure PCTKR2023016293-appb-img-000058
Figure PCTKR2023016293-appb-img-000058
step d를 통해 76시간 동안 TBTU를 사용한 2-(5-fluoro-1H-indazol-3-yl)acetic acid(2-(benzo[d]oxazol-2-yl)acetic acid(19.0 mg, 0.10 mmol)의 아미드 커플링 반응 후 prep-HPLC(0.1% TFA와 함께 20% 에서 100% 물/acetonitrile)로 2.4 mg(6%)의 무색 오일 N-(4-(2,5-difluoro-4-(2-(5-fluoro-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 96%, 화합물 6b)를 수득하였다; 1H NMR (400 MHz, CD3OD) δ 8.26-8.21 (m, 2H), 7.55-7.48 (m, 2H), 7.38 (dd, J = 10.5, 7.1 Hz, 1H), 7.24 (td, J = 9.1, 2.4 Hz, 1H), 7.08-7.06 (m, 2H), 4.19 (s, 2H), 1.86-1.80 (m, 1H), 1.11-1.00 (m, 4H); LCMS (ESI), m/z = 482.08 [M+1]+.2-(5-fluoro-1 H -indazol-3-yl)acetic acid (2-(benzo[ d ]oxazol-2-yl)acetic acid (19.0 mg, 0.10 mmol) using TBTU for 76 hours through step d 2.4 mg (6%) of colorless oil N -(4-(2,5-difluoro-4-( 2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 96%, compound 6b) was obtained; 1 H NMR (400 MHz, CD 3 OD); δ 8.26-8.21 (m, 2H), 7.55-7.48 (m, 2H), 7.38 (dd, J = 10.5, 7.1 Hz, 1H), 7.24 (td, J = 9.1, 2.4 Hz, 1H), 7.08-7.06 (m, 2H), 4.19 (s, 2H), 1.86-1.80 (m, 1H), 1.11-1.00 (m, 4H); LCMS (ESI), m/z = 482.08 [M+1] + .
1-5. 1-5. NN -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (ALT-005)-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (ALT-005)
Figure PCTKR2023016293-appb-img-000059
Figure PCTKR2023016293-appb-img-000059
DMF(520.0 μL)에서 4-((2-chloropyridin-4-yl)oxy)-2,5-difluoroaniline (20.0 mg, 0.08 mmol)의 용액에 커플링 시약으로 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid(22.4 mg, 0.12 mmol), N,N-diisopropylethylamine(67.9 μL, 0.39 mmol) 및 TBTU (50.0 mg, 0.16 mmol)을 첨가하였다. 반응 혼합물을 실온에서 17시간 동안 교반하였다. 반응 혼합물을 ethyl acetate로 희석하고 10% 수성 lithium chloride(×3) 및 염수로 세척하였다. 유기층을 무수 MgSO4로 건조하고 감압 농축하였다. 조 혼합물(crude mixtrure)을 dichloromethane(5.0 mL)으로 재결정화하여 27.0 mg(79%)의 황색 고체 N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide(순도 98%, ALT-005)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.49 (s, 1H), 10.37 (s, 1H), 8.33 (d, J = 5.8 Hz, 1H), 8.26 (dd, J = 12.5, 7.2 Hz, 1H), 7.62 (dd, J = 10.9, 7.4 Hz, 1H), 7.25-7.17 (m, 3H), 7.07 (dd, J = 5.8, 2.3 Hz, 1H), 6.99-6.95 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 3.93 (dd, J = 12.1, 6.6 Hz, 1H), 3.22 (dd, J = 16.2, 12.3 Hz, 1H), 3.12 (dd, J = 16.1, 6.6 Hz, 1H); LCMS (ESI), m/z = 430.10 [M+1]+.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 μL). 4-tetrahydroquinoline-3-carboxylic acid (22.4 mg, 0.12 mmol), N,N -diisopropylethylamine (67.9 μL, 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. The organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The crude mixture was recrystallized from dichloromethane (5.0 mL) to obtain 27.0 mg (79%) of a yellow solid N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)- 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (purity 98%, ALT-005) was obtained; 1H NMR (400 MHz, DMSO- d 6 ) δ 10.49 (s, 1H), 10.37 (s, 1H), 8.33 (d, J = 5.8 Hz, 1H), 8.26 (dd, J = 12.5, 7.2 Hz, 1H), 7.62 (dd, J = 10.9, 7.4 Hz, 1H), 7.25-7.17 (m, 3H), 7.07 (dd, J = 5.8, 2.3 Hz, 1H), 6.99-6.95 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 3.93 (dd, J = 12.1, 6.6 Hz, 1H), 3.22 (dd, J = 16.2, 12.3 Hz, 1H), 3.12 (dd, J = 16.1, 6.6 Hz, 1H); LCMS (ESI), m/z = 430.10 [M+1] + .
1-6. 1-6. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide(TFA 염, ALT-006, 화합물 9a)-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (TFA salt, ALT- 006, compound 9a)
[화합물 9a][Compound 9a]
Figure PCTKR2023016293-appb-img-000060
Figure PCTKR2023016293-appb-img-000060
step d를 통해 19시간 동안 TBTU를 사용한 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid(18.8 mg, 0.1 mmol)의 아미드 커플링 반응 후 prep-HPLC(0.1% TFA와 함께 20% 에서 100% 물/acetonitrile)로 24.0 mg(61%)의 옅은 황색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide(순도 99%, 화합물 9a)를 수득하였다. 화합물 9a는 ALT-008의 TFA salt이다; 1H NMR (400 MHz, DMSO-d 6) δ 10.94 (s, 1H), 10.49 (s, 1H), 10.37 (s, 1H), 8.25-8.20 (m, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 10.9, 7.4 Hz, 1H), 7.25-7.17 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.78 (dd, J = 5.7, 2.4 Hz, 1H), 3.92 (dd, J = 12.1, 6.6 Hz, 1H), 3.24 (dd, J = 15.6, 12.5 Hz, 1H), 3.13 (dd, J = 16.0, 6.6 Hz, 1H), 2.01-1.95 (m, 1H), 0.83-0.76 (m, 4H); LCMS (ESI), m/z = 479.12 [M+1]+.Through 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. Compound 9a is the TFA salt of ALT-008; 1H NMR (400 MHz, DMSO - d6 ) δ 10.94 (s, 1H), 10.49 (s, 1H), 10.37 (s, 1H), 8.25-8.20 (m, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 10.9, 7.4 Hz, 1H), 7.25-7.17 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H) ), 6.78 (dd, J = 5.7, 2.4 Hz, 1H), 3.92 (dd, J = 12.1, 6.6 Hz, 1H), 3.24 (dd, J = 15.6, 12.5 Hz, 1H), 3.13 (dd, J = 16.0, 6.6 Hz, 1H), 2.01-1.95 (m, 1H), 0.83-0.76 (m, 4H); LCMS (ESI), m/z = 479.12 [M+1] + .
1-7. 1-7. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide(TFA 염, ALT-007, 화합물 9b)-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (TFA salt, ALT- 007, compound 9b)
[화합물 9b][Compound 9b]
Figure PCTKR2023016293-appb-img-000061
Figure PCTKR2023016293-appb-img-000061
step d를 통해 88시간 동안 TBTU를 사용한 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid(18.8 mg, 0.1 mmol)의 아미드 커플링 반응 후 prep-HPLC(0.1% TFA와 함께 20% 에서 100% 물/acetonitrile)로 2.6 mg(7%)의 옅은 황색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide(순도 97%, 화합물 9b)를 수득하였다; 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J = 6.6 Hz, 1H), 8.08 (dd, J = 12.0, 7.1 Hz, 1H), 8.00 (dd, J = 7.7, 0.9 Hz, 1H), 7.53 (td, J = 7.5, 1.3 Hz, 1H), 7.42-7.30 (m, 3H), 7.12 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 6.6, 2.5 Hz, 1H), 4.62 (t, J = 5.9 Hz, 1H), 3.51 (dd, J = 16.2, 6.1 Hz, 1H), 3.38-3.34 (m, 1H), 1.87-1.81 (m, 1H), 1.10-0.99 (m, 4H); LCMS (ESI), m/z = 479.10 [M+1]+.Through 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). 2.6 mg (7%) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1- from 20% to 100% water/acetonitrile) oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (purity 97%, compound 9b) was obtained; 1 H NMR (400 MHz, CD 3 OD) δ 8.24 (d, J = 6.6 Hz, 1H), 8.08 (dd, J = 12.0, 7.1 Hz, 1H), 8.00 (dd, J = 7.7, 0.9 Hz, 1H) ), 7.53 (td, J = 7.5, 1.3 Hz, 1H), 7.42-7.30 (m, 3H), 7.12 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 6.6, 2.5 Hz, 1H) , 4.62 (t, J = 5.9 Hz, 1H), 3.51 (dd, J = 16.2, 6.1 Hz, 1H), 3.38-3.34 (m, 1H), 1.87-1.81 (m, 1H), 1.10-0.99 (m , 4H); LCMS (ESI), m/z = 479.10 [M+1] + .
1-8. 1-8. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide(ALT-008)-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (ALT-008)
[ALT-008][ALT-008]
Figure PCTKR2023016293-appb-img-000062
Figure PCTKR2023016293-appb-img-000062
sat와 함께 5.0 mg(0.01 mmol)의 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide TFA 염(ALT-006)을 처리하였다. 수성 NaHCO3용액은 ethyl acetate와 물 사이에 분배된 잔류물을 제공하였다. 유기층을 추가의 물로 세척하고, 무수 MgSO4로 건조하고, 감압 하에 농축하여 3.4 mg(85%)의 옅은 황색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide(순도 99%, ALT-008)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.92 (s, 1H), 10.49 (s, 1H), 10.37 (s, 1H), 8.24-8.20 (m, 2H), 7.66 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 10.9, 7.4 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.97 (td, J = 7.5, 0.9 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 3.92 (dd, J = 12.1, 6.6 Hz, 1H), 3.24 (dd, J = 15.8, 12.3 Hz, 1H), 3.13 (dd, J = 16.1, 6.6 Hz, 1H), 2.01-1.92 (m, 1H), 0.83-0.76 (m, 4H); LCMS (ESI), m/z = 479.12 [M+1]+.5.0 mg (0.01 mmol) of N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- with sat Tetrahydroquinoline-3-carboxamide TFA salt (ALT-006) was treated. An aqueous NaHCO 3 solution gave the residue partitioned between ethyl acetate and water. The organic layer was washed with additional water, dried over anhydrous MgSO 4 and concentrated under reduced pressure to give 3.4 mg (85%) of a pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)- 2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (99% purity, ALT-008) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 10.92 (s, 1H), 10.49 (s, 1H), 10.37 (s, 1H), 8.24-8.20 (m, 2H), 7.66 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 10.9, 7.4 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.97 (td, J = 7.5 , 0.9 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 3.92 (dd, J = 12.1, 6.6 Hz, 1H), 3.24 (dd , J = 15.8, 12.3 Hz, 1H), 3.13 (dd, J = 16.1, 6.6 Hz, 1H), 2.01-1.92 (m, 1H), 0.83-0.76 (m, 4H); LCMS (ESI), m/z = 479.12 [M+1] + .
1-9. 1-9. NN -(4-(4-(2-(1H-indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(ALT-009, 화합물 6f)-(4-(4-(2-(1H-indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-009, Compound 6f)
[화합물 6f][Compound 6f]
Figure PCTKR2023016293-appb-img-000063
Figure PCTKR2023016293-appb-img-000063
step e를 통해 17시간 동안 HATU를 사용한 2-(1H-indol-3-yl)acetic acid (27.5 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(60% EtOAc/n-hexane)로 4 mg(6%)의 옅은 황색 고체 N-(4-(4-(2-(1H-indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 96%, 화합물 6f)를 수득하였다; 1H NMR (400 MHz, CDCl3) δ 8.39 - 8.31 (m, 3H), 8.09 (d, J = 5.8 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.23 - 7.18 (m, 1H), 6.82 (dd, J = 10.6, 6.9 Hz, 1H), 6.56 (dd, J = 5.8, 2.4 Hz, 1H), 3.95 (s, 2H), 1.54 - 1.47 (m, 1H), 1.07 - 1.02 (m, 2H), 0.89 - 0.83 (m, 2H); LCMS (ESI), m/z = 463.14 [M+1]+.After the amide coupling reaction of 2-(1 H -indol-3-yl)acetic acid (27.5 mg, 0.16 mmol) using HATU for 17 hours through step e, NH 2 silica gel chromatography (60% EtOAc/ n -hexane ) as 4 mg (6%) of pale yellow solid N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide ( Compound 6f) was obtained, purity 96%; 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 - 8.31 (m, 3H), 8.09 (d, J = 5.8 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.23 - 7.18 (m, 1H), 6.82 (dd, J = 10.6, 6.9 Hz, 1H), 6.56 (dd , J = 5.8, 2.4 Hz, 1H), 3.95 (s, 2H), 1.54 - 1.47 (m, 1H), 1.07 - 1.02 (m, 2H), 0.89 - 0.83 (m, 2H); LCMS (ESI), m/z = 463.14 [M+1] + .
1-10. 1-10. NN -(4-(4-(2-(1-(4-(4-(2-(1 HH -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(ALT-010, 화합물 7c)-indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-010, Compound 7c)
[화합물 7c][Compound 7c]
Figure PCTKR2023016293-appb-img-000064
Figure PCTKR2023016293-appb-img-000064
step e를 통해 30시간 동안 HATU를 사용한 2-(1H-indol-2-yl)acetic acid (27.5 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(85% EtOAc/n-hexane)로 22.3 mg(36%)의 옅은 갈색 고체 N-(4-(4-(2-(1H-indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 97%, 화합물 7c)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 11.00 (s, 1H), 10.90 (s, 1H), 10.25 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 12.4, 7.2 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 10.9, 7.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.97 - 6.91 (m, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 6.30 (s, 1H), 3.96 (s, 2H), 2.01 - 1.93 (m, 1H), 0.77 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 463.13 [M+1]+.After the amide coupling reaction of 2-(1 H -indol-2-yl)acetic acid (27.5 mg, 0.16 mmol) using HATU for 30 hours through step e, NH 2 silica gel chromatography (85% EtOAc/ n -hexane ) as 22.3 mg (36%) of a pale brown solid N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide ( Compound 7c) was obtained with a purity of 97%; 1H NMR (400 MHz, DMSO - d6 ) δ 11.00 (s, 1H), 10.90 (s, 1H), 10.25 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 12.4, 7.2 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 10.9, 7.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.33 ( d, J = 8.6 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.97 - 6.91 (m, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 6.30 (s, 1H), 3.96 (s, 2H), 2.01 - 1.93 (m, 1H), 0.77 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 463.13 [M+1] + .
1-11. 1-11. NN -(4-(4-(2-(benzo[-(4-(4-(2-(benzo[ dd ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide(ALT-011, 화합물 6e)]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-011, Compound 6e)
[화합물 6e][Compound 6e]
Figure PCTKR2023016293-appb-img-000065
Figure PCTKR2023016293-appb-img-000065
step e를 통해 48시간 동안 HATU를 사용한 2-(benzo[d]isothiazol-3-yl)acetic acid (30.4 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(40% EtOAc/n-hexane)로 16 mg(25%)의 옅은 황색 고체 N-(4-(4-(2-(benzo[d]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 97%, 화합물 6e)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.90 (s, 1H), 10.51 (s, 1H), 8.23 - 8.19 (m, 3H), 8.11 (dd, J = 12.4, 7.2 Hz, 1H), 7.67 - 7.51 (m, 4H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.41 (s, 2H), 2.01 - 1.93 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 481.12 [M+1]+.After the amide coupling reaction of 2-(benzo[ d ]isothiazol-3-yl)acetic acid (30.4 mg, 0.16 mmol) using HATU for 48 hours through step e, NH 2 silica gel chromatography (40% EtOAc/ n - hexane) of 16 mg (25%) of pale yellow solid N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl) Cyclopropanecarboxamide (purity 97%, compound 6e) was obtained; 1H NMR (400 MHz, DMSO- d 6 ) δ 10.90 (s, 1H), 10.51 (s, 1H), 8.23 - 8.19 (m, 3H), 8.11 (dd, J = 12.4, 7.2 Hz, 1H), 7.67 - 7.51 (m, 4H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.41 (s, 2H), 2.01 - 1.93 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 481.12 [M+1] + .
1-12. 1-12. NN -(4-(4-(3-(benzo[-(4-(4-(3-(benzo[ dd ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide(ALT-012, 화합물 7f)]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-012, Compound 7f)
[화합물 7f][Compound 7f]
Figure PCTKR2023016293-appb-img-000066
Figure PCTKR2023016293-appb-img-000066
step e를 통해 17시간 동안 HATU를 사용한 3-(benzo[d]oxazol-2-yl)propanoic acid (30.1 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(45% EtOAc/n-hexane)로 38.4 mg(60%)의 옅은 황색 고체 N-(4-(4-(3-(benzo[d]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 98%, 화합물 7f)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.90 (s, 1H), 10.21 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.09 (dd, J = 12.4, 7.2 Hz, 1H), 7.69 - 7.66 (m, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 10.9, 7.4 Hz, 1H), 7.39 - 7.30 (m, 2H), 6.74 (dd, J = 5.7, 2.4 Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 3.08 - 3.05 (m, 2H), 2.01 - 1.93 (m, 1H), 0.77 (d, J = 5.7 Hz, 4H); LCMS (ESI), m/z = 479.13 [M+1]+.After the amide coupling reaction of 3-(benzo[ d ]oxazol-2-yl)propanoic acid (30.1 mg, 0.16 mmol) using HATU for 17 hours through step e, NH 2 silica gel chromatography (45% EtOAc/ n - hexane) as a pale yellow solid, N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl) Cyclopropanecarboxamide (purity 98%, compound 7f) was obtained; 1H NMR (400 MHz, DMSO- d 6 ) δ 10.90 (s, 1H), 10.21 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.09 (dd, J = 12.4, 7.2 Hz, 1H), 7.69 - 7.66 (m, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 10.9, 7.4 Hz, 1H), 7.39 - 7.30 (m, 2H), 6.74 (dd , J = 5.7, 2.4 Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 3.08 - 3.05 (m, 2H), 2.01 - 1.93 (m, 1H), 0.77 (d, J = 5.7 Hz, 4H); LCMS (ESI), m/z = 479.13 [M+1] + .
1-13. 1-13. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ dd ]thiazole-6-carboxamide(ALT-013, 화합물 8c)]thiazole-6-carboxamide (ALT-013, Compound 8c)
[화합물 8c][Compound 8c]
Figure PCTKR2023016293-appb-img-000067
Figure PCTKR2023016293-appb-img-000067
step e를 통해 21시간 동안 HATU를 사용한 benzo[d]thiazole-6-carboxylic acid(28.2 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(35% EtOAc/n-hexane)로 6.2 mg(10%)의 황색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]thiazole-6-carboxamide(순도 96%, 화합물 8c)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.94 (s, 1H), 10.50 (s, 1H), 9.59 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.25 - 8.23 (m, 2H), 8.13 (dd, J = 8.6, 1.7 Hz, 1H), 7.90 (dd, J = 11.6, 7.1 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 10.3, 7.4 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.02 - 1.94 (m, 1H), 0.78 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 467.06 [M+1]+.After the amide coupling reaction of benzo[ d ]thiazole-6-carboxylic acid (28.2 mg, 0.16 mmol) using HATU for 21 hours through step e, 6.2 mg was obtained by NH 2 silica gel chromatography (35% EtOAc/ n -hexane). (10%) of yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide (purity 96%, Compound 8c ) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 10.94 (s, 1H), 10.50 (s, 1H), 9.59 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.25 - 8.23 ( m, 2H), 8.13 (dd, J = 8.6, 1.7 Hz, 1H), 7.90 (dd, J = 11.6, 7.1 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 10.3, 7.4 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.02 - 1.94 (m, 1H), 0.78 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 467.06 [M+1] + .
1-14. 1-14. NN -(4-(4-(3-(1-(4-(4-(3-(1 HH -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(ALT-014, 화합물 6i)-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-014, Compound 6i)
[화합물 6i][Compound 6i]
Figure PCTKR2023016293-appb-img-000068
Figure PCTKR2023016293-appb-img-000068
step e를 통해 18시간 동안 HATU를 사용한 3-(1H-indol-3-yl)propanoic acid (29.8 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(50% EtOAc/n-hexane)로 27.1 mg(42%)의 옅은 황색 고체 N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 96%, 화합물 6i)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6) δ 10.92 (s, 1H), 10.79 (s, 1H), 10.03 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.13 (dd, J = 12.4, 7.2 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.01 - 6.96 (m, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 3.04 - 3.00 (m, 2H), 2.83 - 2.79 (m, 2H), 2.00 - 1.94 (m, 1H), 0.80 - 0.75 (m, 4H); LCMS (ESI), m/z = 477.16 [M+1]+.Through 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). ) to obtain 27.1 mg (42%) of pale yellow solid N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide ( Compound 6i) was obtained with a purity of 96%; 1H NMR (400 MHz, DMSO - d6 ) δ 10.92 (s, 1H), 10.79 (s, 1H), 10.03 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.13 (dd, J = 12.4, 7.2 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.01 - 6.96 (m, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 3.04 - 3.00 (m, 2H), 2.83 - 2.79 ( m, 2H), 2.00 - 1.94 (m, 1H), 0.80 - 0.75 (m, 4H); LCMS (ESI), m/z = 477.16 [M+1] + .
1-15. 1-15. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 HH -indene-3-carboxamide (ALT-015, 화합물 9c)-indene-3-carboxamide (ALT-015, Compound 9c)
[화합물 9c][Compound 9c]
Figure PCTKR2023016293-appb-img-000069
Figure PCTKR2023016293-appb-img-000069
step e를 통해 50시간 동안 HATU를 사용한 1H-indene-3-carboxylic acid (25.2 mg, 0.16 mmol)의 아미드 커플링 반응 후 실리카겔 크로마토그래피(50% EtOAc/n-hexane)로 5.2 mg(9%)의 옅은 황색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide(순도 96%, 화합물 9c)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.95 (s, 1H), 10.23 (s, 1H), 8.24 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.89 (dd, J = 11.7, 7.1 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.62 - 7.51 (m, 3H), 7.33 (t, J = 7.0 Hz, 1H), 7.27 (td, J = 7.4, 1.1 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 3.66 (s, 2H), 1.99 - 1.96 (m, 1H), 0.78 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 448.13 [M+1]+.After the amide coupling reaction of 1 H -indene-3-carboxylic acid (25.2 mg, 0.16 mmol) using HATU for 50 hours through step e, 5.2 mg (9%) was obtained by silica gel chromatography (50% EtOAc/ n -hexane). ) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indene-3-carboxamide (purity 96%, compound 9c) Obtained; 1H NMR (400 MHz, DMSO- d 6 ) δ 10.95 (s, 1H), 10.23 (s, 1H), 8.24 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H) , 7.89 (dd, J = 11.7, 7.1 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.62 - 7.51 (m, 3H), 7.33 (t, J = 7.0 Hz, 1H), 7.27 ( td, J = 7.4, 1.1 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 3.66 (s, 2H), 1.99 - 1.96 (m, 1H), 0.78 (d, J = 6.1 Hz) , 4H); LCMS (ESI), m/z = 448.13 [M+1] + .
1-16. 1-16. NN -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-016, 화합물 6j)-(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-016, Compound 6j)
[화합물 6j][Compound 6j]
Figure PCTKR2023016293-appb-img-000070
Figure PCTKR2023016293-appb-img-000070
step f를 통해 72시간 동안 DCC를 사용한 2-(3-oxoisoindolin-1-yl)acetic acid (22.6 mg, 0.12 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(3% MeOH/CH2Cl2)로 8 mg(17%)의 옅은 황색 고체 N-(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 98%, 화합물 6j)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.94 (s, 1H), 10.16 (s, 1H), 8.75 (s, 1H), 8.26 - 8.16 (m, 2H), 7.70 - 7.59 (m, 4H), 7.59 - 7.48 (m, 2H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 5.04 - 4.97 (m, 1H), 3.02 (dd, J = 15.2, 5.5 Hz, 1H), 2.70 (dd, J = 15.2, 8.3 Hz, 1H), 2.00 - 1.94 (m, 1H), 0.77 (d, J = 5.4 Hz, 4H); LCMS (ESI), m/z = 479.10 [M+1]+.Amide coupling reaction of 2-(3-oxoisoindolin-1-yl)acetic acid (22.6 mg, 0.12 mmol) using DCC for 72 hours through step f, followed by NH 2 silica gel chromatography (3% MeOH/CH 2 Cl 2 ) as 8 mg (17%) of pale yellow solid N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide( Compound 6j) was obtained with a purity of 98%; 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.94 (s, 1H), 10.16 (s, 1H), 8.75 (s, 1H), 8.26 - 8.16 (m, 2H), 7.70 - 7.59 (m, 4H) ), 7.59 - 7.48 (m, 2H), 6.77 (dd, J = 5.7, 2.4 Hz, 1H), 5.04 - 4.97 (m, 1H), 3.02 (dd, J = 15.2, 5.5 Hz, 1H), 2.70 ( dd, J = 15.2, 8.3 Hz, 1H), 2.00 - 1.94 (m, 1H), 0.77 (d, J = 5.4 Hz, 4H); LCMS (ESI), m/z = 479.10 [M+1] + .
1-17. 1-17. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 HH -indole-6-carboxamide (ALT-017, 화합물 8g)-indole-6-carboxamide (ALT-017, compound 8g)
[화합물 8g][Compound 8g]
Figure PCTKR2023016293-appb-img-000071
Figure PCTKR2023016293-appb-img-000071
step f를 통해 72시간 동안 DCC를 사용한 1-(tert-butoxycarbonyl)-1H-indole-6-carboxylic acid (82.0 mg, 0.31 mmol)의 아미드 커플링 반응 후 prep-HPLC(0.1% TFA와 함께 20% 에서 100% 물/acetonitrile)로 혼합물로서 10.5mg(7%)의 tert-butyl 6-((4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)carbamoyl)-1H-indole-1-carboxylate(화합물 8d, 화합물 8d는 Boc protected 중간체임)를 수득하였다. in CH2Cl2(736.0μL)에 녹인 tert-butyl 6-((4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)carbamoyl)-1H-indole-1-carboxylate 혼합물(10.5 mg) 용액에 1,4-dioxane (190 μl, 0.76 mmol)에 녹인 4M HCl을 실온에서 첨가하고 혼합물을 19시간 동안 교반하였다. 용매를 감압 하에 증발시켰다. 잔류물을 NH2 실리카겔 크로마토그래피(100% EtOAc/n-hexane)로 정제하여 2.9mg(2%, 2-step 수율)의 베이지(beige)색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indole-6-carboxamide(순도 98%, 화합물 8g)를 수득하였다; 1H NMR (400 MHz, acetone-d 6)δ 10.73 (s, 1H), 9.83 (s, 1H), 9.31 (s, 1H), 8.32 (dd, J = 12.4, 7.2 Hz, 1H), 8.23 - 8.15 (m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.57 (t, J = 2.8 Hz, 1H), 7.36 (dd, J = 10.7, 7.3 Hz, 1H), 6.72 (dd, J = 5.7, 2.4 Hz, 1H), 6.61 - 6.57 (m, 1H), 1.98 - 1.94 (m, 1H), 0.91 - 0.86 (m, 2H), 0.86 - 0.79 (m, 2H); LCMS (ESI), m/z = 490.45 [M+ ACN +1]+.Amide coupling reaction of 1-( tert -butoxycarbonyl)-1 H -indole-6-carboxylic acid (82.0 mg, 0.31 mmol) using DCC for 72 hours through step f, followed by prep-HPLC (20% with 0.1% TFA) 10.5 mg (7%) of tert -butyl 6-((4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)carbamoyl as a mixture in 100% water/acetonitrile) )-1 H -indole-1-carboxylate (Compound 8d, Compound 8d is a Boc protected intermediate) was obtained. tert -butyl 6-((4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)carbamoyl)-1 H -indole- dissolved in CH 2 Cl 2 (736.0μL) 4M HCl dissolved in 1,4-dioxane (190 μl, 0.76 mmol) was added to the 1-carboxylate mixture (10.5 mg) at room temperature, and the mixture was stirred for 19 hours. The solvent was evaporated under reduced pressure. The residue was purified by NH 2 silica gel chromatography (100% EtOAc/n-hexane) to yield 2.9 mg (2%, 2-step yield) of beige solid N -(4-((2-(cyclopropanecarboxamido) pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide (purity 98%, compound 8g) was obtained; 1H NMR (400 MHz, acetone- d 6 ) δ 10.73 (s, 1H), 9.83 (s, 1H), 9.31 (s, 1H), 8.32 (dd, J = 12.4, 7.2 Hz, 1H), 8.23 - 8.15 (m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.57 (t, J = 2.8 Hz, 1H), 7.36 (dd, J = 10.7, 7.3 Hz) , 1H), 6.72 (dd, J = 5.7, 2.4 Hz, 1H), 6.61 - 6.57 (m, 1H), 1.98 - 1.94 (m, 1H), 0.91 - 0.86 (m, 2H), 0.86 - 0.79 (m , 2H); LCMS (ESI), m/z = 490.45 [M+ ACN +1] + .
1-18. 1-18. NN -(4-(4-(2-(benzo[-(4-(4-(2-(benzo[ bb ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-018, 화합물 6h)]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-018, compound 6h)
[화합물 6h][Compound 6h]
Figure PCTKR2023016293-appb-img-000072
Figure PCTKR2023016293-appb-img-000072
step e를 통해 31시간 동안 HATU를 사용한 2-(benzo[b]thiophen-3-yl)acetic acid (30.2 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(25% EtOAc/n-hexane)로 14.3 mg(22%)의 백색 고체 N-(4-(4-(2-(benzo[b]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 97%, 화합물 6h)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.93 (s, 1H), 10.40 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.12 (dd, J = 12.4, 7.2 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.57 (dd, J = 10.9, 7.4 Hz, 1H), 7.46 - 7.37 (m, 2H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.08 (s, 2H), 2.00 - 1.94 (m, 1H), 0.78 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 480.00 [M+1]+.After the amide coupling reaction of 2-(benzo[ b ]thiophen-3-yl)acetic acid (30.2 mg, 0.16 mmol) using HATU for 31 hours through step e, NH 2 silica gel chromatography (25% EtOAc/ n - hexane) of 14.3 mg (22%) of white solid N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 97%, compound 6h) was obtained; 1H NMR (400 MHz, DMSO- d 6 ) δ 10.93 (s, 1H), 10.40 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.12 (dd, J = 12.4, 7.2 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.57 (dd, J = 10.9, 7.4 Hz, 1H), 7.46 - 7.37 (m, 2H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.08 (s, 2H), 2.00 - 1.94 (m, 1H), 0.78 (d, J = 6.1 Hz, 4H); LCMS (ESI), m/z = 480.00 [M+1] + .
1-19. 1-19. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ bb ]thiophene-6-carboxamide (ALT-019, 화합물 8f)]thiophene-6-carboxamide (ALT-019, Compound 8f)
[화합물 8f][Compound 8f]
Figure PCTKR2023016293-appb-img-000073
Figure PCTKR2023016293-appb-img-000073
step e를 통해 30시간 동안 HATU를 사용한 benzo[b]thiophene-6-carboxylic acid (28.0 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(20% EtOAc/n-hexane)로 4.5 mg(7%)의 백색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[b]thiophene-6-carboxamide(순도 95%, 화합물 8f)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.93 (s, 1H), 10.39 (s, 1H), 8.68 (s, 1H), 8.25 (d, J = 5.7 Hz, 1H), 8.06 - 7.97 (m, 3H), 7.89 (dd, J = 11.7, 7.0 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.62 - 7.56 (m, 2H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.00 - 1.96 (m, 1H), 0.79 (d, J = 5.6 Hz, 4H); LCMS (ESI), m/z = 466.00 [M+1]+.After the amide coupling reaction of benzo[ b ]thiophene-6-carboxylic acid (28.0 mg, 0.16 mmol) using HATU for 30 hours through step e, 4.5 mg was obtained by NH 2 silica gel chromatography (20% EtOAc/ n -hexane). (7%) of white solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide (purity 95%, compound 8f) ) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 10.93 (s, 1H), 10.39 (s, 1H), 8.68 (s, 1H), 8.25 (d, J = 5.7 Hz, 1H), 8.06 - 7.97 ( m, 3H), 7.89 (dd, J = 11.7, 7.0 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.62 - 7.56 (m, 2H), 6.80 (dd, J = 5.7, 2.4 Hz) , 1H), 2.00 - 1.96 (m, 1H), 0.79 (d, J = 5.6 Hz, 4H); LCMS (ESI), m/z = 466.00 [M+1] + .
1-20. 1-20. NN -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-020, 화합물 6k)-(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-020, Compound 6k)
[화합물 6k][Compound 6k]
Figure PCTKR2023016293-appb-img-000074
Figure PCTKR2023016293-appb-img-000074
step f를 통해 22시간 동안 DCC를 사용한 32-(2-oxoindolin-3-yl)acetic acid (22.6 mg, 0.12 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(95% EtOAc/n-hexane)로 4 mg(8%)의 백색 고체 N-(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 98%, 화합물 6k)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.89 (s, 1H), 10.42 (s, 1H), 10.16 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.07 (dd, J = 12.3, 7.2 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 10.8, 7.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.92 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.74 (dd, J = 5.7, 2.4 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.11 (dd, J = 16.1, 4.9 Hz, 1H), 2.86 (dd, J = 16.1, 7.9 Hz, 1H), 1.97 - 1.94 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 479.00 [M+1]+.Amide coupling reaction of 32-(2-oxoindolin-3-yl)acetic acid (22.6 mg, 0.12 mmol) using DCC for 22 hours through step f, followed by NH 2 silica gel chromatography (95% EtOAc/ n -hexane) 4 mg (8%) of white solid N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 98) %, compound 6k) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 10.89 (s, 1H), 10.42 (s, 1H), 10.16 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.07 (dd, J = 12.3, 7.2 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 10.8, 7.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.92 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.74 (dd, J = 5.7, 2.4 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.11 (dd, J = 16.1, 4.9 Hz, 1H), 2.86 (dd, J = 16.1, 7.9 Hz, 1H), 1.97 - 1.94 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 479.00 [M+1] + .
1-21. 1-21. NN -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-021, 화합물 6g)-(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-021, compound 6g)
[화합물 6g][6g of compound]
Figure PCTKR2023016293-appb-img-000075
Figure PCTKR2023016293-appb-img-000075
step e를 통해 30시간 동안 HATU를 사용한 2-(benzofuran-3-yl)acetic acid (27.7 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(45% EtOAc/n-hexane)로 8.8 mg(14%)의 백색 고체 N-(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 98%, 화합물 6g)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.90 (s, 1H), 10.34 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.10 (dd, J = 12.3, 7.2 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.36 - 7.25 (m, 2H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 3.91 (s, 2H), 1.99 - 1.96 (m, 1H), 0.78 (d, J = 5.5 Hz, 4H); LCMS (ESI), m/z = 464.00 [M+1]+.After the amide coupling reaction of 2-(benzofuran-3-yl)acetic acid (27.7 mg, 0.16 mmol) using HATU for 30 hours through step e, 8.8 was obtained by NH 2 silica gel chromatography (45% EtOAc/ n -hexane). mg (14%) of white solid N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (98% purity, 6 g of compound) was obtained; 1H NMR (400 MHz, DMSO- d 6 ) δ 10.90 (s, 1H), 10.34 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.10 (dd, J = 12.3, 7.2 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.36 - 7.25 (m, 2H) ), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 3.91 (s, 2H), 1.99 - 1.96 (m, 1H), 0.78 (d, J = 5.5 Hz, 4H); LCMS (ESI), m/z = 464.00 [M+1] + .
1-221-22 NN -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-022, 화합물 7d)-(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-022, Compound 7d)
[화합물 7d][Compound 7d]
Figure PCTKR2023016293-appb-img-000076
Figure PCTKR2023016293-appb-img-000076
step e를 통해 30시간 동안 HATU를 사용한 2-(benzofuran-2-yl)acetic acid (27.7 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(35% EtOAc/n-hexane)로 6.5 mg(11%)의 옅은 황색 고체 N-(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (순도 99%, 화합물 7d)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.90 (s, 1H), 10.38 (s, 1H), 8.22 (d, J = 5.7 Hz, 1H), 8.12 (dd, J = 12.3, 7.2 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.62 - 7.52 (m, 3H), 7.30 - 7.20 (m, 2H), 6.81 (s, 1H), 6.76 (dd, J = 5.7, 2.4 Hz, 1H), 4.09 (s, 2H), 2.00 - 1.96 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 464.00 [M+1]+.Through step e, amide coupling reaction of 2-(benzofuran-2-yl)acetic acid (27.7 mg, 0.16 mmol) using HATU for 30 hours was followed by NH 2 silica gel chromatography (35% EtOAc/ n -hexane) for 6.5 mg (11%) of pale yellow solid N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 99%, compound 7d) ) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 10.90 (s, 1H), 10.38 (s, 1H), 8.22 (d, J = 5.7 Hz, 1H), 8.12 (dd, J = 12.3, 7.2 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.62 - 7.52 (m, 3H), 7.30 - 7.20 (m, 2H), 6.81 (s, 1H), 6.76 (dd, J = 5.7, 2.4 Hz) , 1H), 4.09 (s, 2H), 2.00 - 1.96 (m, 1H), 0.81 - 0.74 (m, 4H); LCMS (ESI), m/z = 464.00 [M+1] + .
1-23. 1-23. NN -(4-(4-(2-(benzo[-(4-(4-(2-(benzo[ bb ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-023, 화합물 7e)]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-023, Compound 7e)
[화합물 7e][Compound 7e]
Figure PCTKR2023016293-appb-img-000077
Figure PCTKR2023016293-appb-img-000077
step e를 통해 21시간 동안 HATU를 사용한 2-(benzo[b]thiophen-2-yl)acetic acid (30.2 mg, 0.16 mmol)의 아미드 커플링 반응 후 NH2 실리카겔 크로마토그래피(35% EtOAc/n-hexane)로 5.5mg(8%)의 황색 고체 N-(4-(4-(2-(benzo[b]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 96%, 화합물 7e)을 수득하였다; 1H NMR (400 MHz, acetone-d 6)δ 9.78 (s, 1H), 9.52 (s, 1H), 8.37 (dd, J = 12.6, 7.3 Hz, 1H), 8.17 (d, J = 5.7 Hz, 1H), 7.87 (dd, J = 13.7, 4.8 Hz, 2H), 7.83 - 7.76 (m, 1H), 7.40 - 7.27 (m, 4H), 6.69 (dd, J = 5.7, 2.4 Hz, 1H), 4.22 (s, 2H), 1.98 - 1.97 (m, 1H), 0.91 - 0.87 (m, 2H), 0.85 - 0.80 (m, 2H); LCMS (ESI), m/z = 480.00 [M+1]+.After the amide coupling reaction of 2-(benzo[ b ]thiophen-2-yl)acetic acid (30.2 mg, 0.16 mmol) using HATU for 21 hours through step e, NH 2 silica gel chromatography (35% EtOAc/ n - hexane) of 5.5 mg (8%) of yellow solid N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 96%, compound 7e) was obtained; 1H NMR (400 MHz, acetone- d 6 ) δ 9.78 (s, 1H), 9.52 (s, 1H), 8.37 (dd, J = 12.6, 7.3 Hz, 1H), 8.17 (d, J = 5.7 Hz, 1H), 7.87 (dd, J = 13.7, 4.8 Hz, 2H), 7.83 - 7.76 (m, 1H), 7.40 - 7.27 (m, 4H), 6.69 (dd, J = 5.7, 2.4 Hz, 1H), 4.22 (s, 2H), 1.98 - 1.97 (m, 1H), 0.91 - 0.87 (m, 2H), 0.85 - 0.80 (m, 2H); LCMS (ESI), m/z = 480.00 [M+1] + .
1-24. 1-24. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 HH -benzo[-benzo[ dd ]imidazole-6-carboxamide (ALT-024, 화합물 8a)]imidazole-6-carboxamide (ALT-024, Compound 8a)
[화합물 8a][Compound 8a]
Figure PCTKR2023016293-appb-img-000078
Figure PCTKR2023016293-appb-img-000078
step f를 통해 18시간 동안 DCC를 사용한 1H-benzo[d]imidazole-6-carboxylic acid (25.5 mg, 0.16 mmol)의 아미드 커플링 반응 후 실리카겔 크로마토그래피(5% MeOH/CH2Cl2)로 3.8 mg(6%)의 백색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-benzo[d]imidazole-6-carboxamide(순도 96%, 화합물 8a)를 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 12.80 (s, 1H), 10.93 (s, 1H), 10.30 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 5.7 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.74 - 7.68 (m, 2H), 7.58 (dd, J = 10.3, 7.4 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.01 - 1.97 (m, 1H), 0.82 - 0.76 (m, 4H); LCMS (ESI), m/z = 450.00 [M+1]+.Through 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 ). 3.8 mg (6%) of white solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide( Compound 8a) was obtained with a purity of 96%; 1H NMR (400 MHz, DMSO - d6 ) δ 12.80 (s, 1H), 10.93 (s, 1H), 10.30 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.25 ( d, J = 5.7 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.74 - 7.68 (m, 2H), 7.58 (dd, J = 10.3, 7.4 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.01 - 1.97 (m, 1H), 0.82 - 0.76 (m, 4H); LCMS (ESI), m/z = 450.00 [M+1] + .
1-25. 1-25. NN -(4-(2,5-difluoro-4-(2-(5-methoxy-1-(4-(2,5-difluoro-4-(2-(5-methoxy-1 HH -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-025, 화합물 6c)-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-025, Compound 6c)
[화합물 6c][Compound 6c]
Figure PCTKR2023016293-appb-img-000079
Figure PCTKR2023016293-appb-img-000079
step e를 통해 21시간 동안 HATU를 사용한 2-(5-methoxy-1H-indazol-3-yl)acetic acid (32.4 mg, 0.16 mmol)의 아미드 커플링 반응 후 실리카겔 크로마토그래피(75% EtOAc/n-hexane)로 12.8mg(19%)의 진한 주황색(da가 orange) 고체 N-(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 97%, 화합물 6c)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 12.73 (s, 1H), 10.90 (s, 1H), 10.36 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.11 (dd, J = 12.4, 7.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 10.9, 7.4 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 9.0, 2.3 Hz, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.12 (s, 2H), 3.78 (s, 3H), 2.00 - 1.94 (m, 1H), 0.81 - 0.72 (m, 4H); LCMS (ESI), m/z = 493.90 [M+1]+.After the amide coupling reaction of 2-(5-methoxy-1 H -indazol-3-yl)acetic acid (32.4 mg, 0.16 mmol) using HATU for 21 hours through step e, silica gel chromatography (75% EtOAc/ n -hexane), 12.8 mg (19%) of dark orange (da is orange) solid N -(4-(2,5-difluoro-4-(2-(5-methoxy- 1H- indazol-3-yl)) acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 97%, compound 6c) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 12.73 (s, 1H), 10.90 (s, 1H), 10.36 (s, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.11 (dd, J = 12.4, 7.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 10.9, 7.4 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.25 ( d, J = 2.0 Hz, 1H), 7.01 (dd, J = 9.0, 2.3 Hz, 1H), 6.75 (dd, J = 5.7, 2.4 Hz, 1H), 4.12 (s, 2H), 3.78 (s, 3H) ), 2.00 - 1.94 (m, 1H), 0.81 - 0.72 (m, 4H); LCMS (ESI), m/z = 493.90 [M+1] + .
1-26. 1-26. NN -(4-(4-(2-(benzo[-(4-(4-(2-(benzo[ dd ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(ALT-026, 화합물 7b)]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (ALT-026, Compound 7b)
[화합물 7b][Compound 7b]
Figure PCTKR2023016293-appb-img-000080
Figure PCTKR2023016293-appb-img-000080
step e를 통해 30시간 동안 HATU를 사용한 2-(benzo[d]thiazol-2-yl)acetic acid (30.4 mg, 0.16 mmol)의 아미드 커플링 반응 후 실리카겔 크로마토그래피(75% EtOAc/n-hexane)로 5.7 mg(9%)의 황색 고체 N-(4-(4-(2-(benzo[d]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide(순도 98%, 화합물 7b)을 수득하였다; 1H NMR (400 MHz, acetone-d 6)δ 10.12 (s, 1H), 9.80 (s, 1H), 8.40 (dd, J = 12.5, 7.3 Hz, 1H), 8.18 (d, J = 5.7 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.50 - 7.44 (m, 1H), 7.35 (dd, J = 10.9, 7.2 Hz, 1H), 6.70 (dd, J = 5.7, 2.4 Hz, 1H), 4.48 (s, 2H), 2.02 - 1.98 (m, 1H), 0.91 - 0.87 (m, 2H), 0.86 - 0.80 (m, 2H); LCMS (ESI), m/z = 481.20 [M+1]+.Amide coupling reaction of 2-(benzo[ d ]thiazol-2-yl)acetic acid (30.4 mg, 0.16 mmol) using HATU for 30 hours through step e, followed by silica gel chromatography (75% EtOAc/ n -hexane) 5.7 mg (9%) of yellow solid N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (purity 98%, compound 7b) was obtained; 1H NMR (400 MHz, acetone- d 6 ) δ 10.12 (s, 1H), 9.80 (s, 1H), 8.40 (dd, J = 12.5, 7.3 Hz, 1H), 8.18 (d, J = 5.7 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.50 - 7.44 (m, 1H), 7.35 (dd, J = 10.9, 7.2 Hz, 1H), 6.70 (dd, J = 5.7, 2.4 Hz, 1H), 4.48 (s, 2H), 2.02 - 1.98 (m, 1H) , 0.91 - 0.87 (m, 2H), 0.86 - 0.80 (m, 2H); LCMS (ESI), m/z = 481.20 [M+1] + .
1-27. 1-27. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide (ALT-027, 화합물 8e)-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide (ALT-027, Compound 8e)
[화합물 8e][Compound 8e]
Figure PCTKR2023016293-appb-img-000081
Figure PCTKR2023016293-appb-img-000081
step e를 통해 18시간 동안 HATU를 사용한 benzofuran-6-carboxylic acid (25.5 mg, 0.16 mmol)의 아미드 커플링 반응 후 실리카겔 크로마토그래피(35% EtOAc/n-hexane)로 8 mg(13%)의 백색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide(순도 95%, 화합물 8e)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.93 (s, 1H), 10.34 (s, 1H), 8.29 - 8.23 (m, 2H), 8.21 (d, J = 2.2 Hz, 1H), 7.94 - 7.81 (m, 3H), 7.71 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 10.3, 7.4 Hz, 1H), 7.10 (dd, J = 2.1, 0.8 Hz, 1H), 6.80 (dd, J = 5.7, 2.4 Hz, 1H), 2.03 - 1.95 (m, 1H), 0.79 (d, J = 5.8 Hz, 4H); LCMS (ESI), m/z = 450.00 [M+1]+.After the amide coupling reaction of benzofuran-6-carboxylic acid (25.5 mg, 0.16 mmol) using HATU for 18 hours through step e, 8 mg (13%) of white was obtained by silica gel chromatography (35% EtOAc/ n -hexane). Solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide (purity 95%, compound 8e) was obtained; 1H NMR (400 MHz, DMSO- d 6 ) δ 10.93 (s, 1H), 10.34 (s, 1H), 8.29 - 8.23 (m, 2H), 8.21 (d, J = 2.2 Hz, 1H), 7.94 - 7.81 (m, 3H), 7.71 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 10.3, 7.4 Hz, 1H), 7.10 (dd, J = 2.1, 0.8 Hz, 1H), 6.80 (dd , J = 5.7, 2.4 Hz, 1H), 2.03 - 1.95 (m, 1H), 0.79 (d, J = 5.8 Hz, 4H); LCMS (ESI), m/z = 450.00 [M+1] + .
1-28. 1-28. NN -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ dd ]oxazole-6-carboxamide(ALT-028, 화합물 8b)]oxazole-6-carboxamide (ALT-028, Compound 8b)
[화합물 8b][Compound 8b]
Figure PCTKR2023016293-appb-img-000082
Figure PCTKR2023016293-appb-img-000082
step e를 통해 30시간 동안 HATU를 사용한 benzo[d]oxazole-6-carboxylic acid (25.6 mg, 0.16 mmol)의 아미드 커플링 반응 후 실리카겔 크로마토그래피(50% EtOAc/n-hexane)로 27.8 mg(47%)의 옅은 황색 고체 N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]oxazole-6-carboxamide(순도 99%, 화합물 8b)을 수득하였다; 1H NMR (400 MHz, DMSO-d 6)δ 10.95 (s, 1H), 10.47 (s, 1H), 8.96 (s, 1H), 8.41 (d, J = 1.1 Hz, 1H), 8.25 (d, J = 5.7 Hz, 1H), 8.06 (dd, J = 8.4, 1.5 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.87 (dd, J = 11.5, 7.1 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 10.3, 7.4 Hz, 1H), 6.81 (dd, J = 5.7, 2.4 Hz, 1H), 2.02 - 1.95 (m, 1H), 0.79 (d, J = 6.2 Hz, 4H); LCMS (ESI), m/z = 451.16 [M+1]+.After the amide coupling reaction of benzo[ d ]oxazole-6-carboxylic acid (25.6 mg, 0.16 mmol) using HATU for 30 hours through step e, 27.8 mg (47 mg) was obtained by silica gel chromatography (50% EtOAc/ n -hexane). %) of pale yellow solid N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide (purity 99%, compound 8b) was obtained; 1H NMR (400 MHz, DMSO - d6 ) δ 10.95 (s, 1H), 10.47 (s, 1H), 8.96 (s, 1H), 8.41 (d, J = 1.1 Hz, 1H), 8.25 (d, J = 5.7 Hz, 1H), 8.06 (dd, J = 8.4, 1.5 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.87 (dd, J = 11.5, 7.1 Hz, 1H), 7.70 ( d, J = 2.3 Hz, 1H), 7.62 (dd, J = 10.3, 7.4 Hz, 1H), 6.81 (dd, J = 5.7, 2.4 Hz, 1H), 2.02 - 1.95 (m, 1H), 0.79 (d , J = 6.2 Hz, 4H); LCMS (ESI), m/z = 451.16 [M+1] + .
실시예 2. 알티라티닙 유도체의 피부 투과도 향상 효과 확인Example 2. Confirmation of the skin permeability improvement effect of altiratinib derivatives
알티라티닙 유도체의 피부 투과도 측정을 위한 SKIN-PAMPA assay는 표 1에 나타낸 바와 같이, 화합물이 침전을 형성하지 않는 최대 농도인 25uM로 pH 8.5 조건에서 진행하였다.As shown in Table 1, 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.
Figure PCTKR2023016293-appb-img-000083
Figure PCTKR2023016293-appb-img-000083
그 결과, 표 2 및 도 1에 나타낸 바와 같이, pH 8.5에서 ALT-002(화합물 7a) 및 ALT-003(화합물 6a)은 알티라티닙에 비해 현저히 개선된 피부투과도를 가질 것으로 예상되었다.As a result, as shown in Table 2 and Figure 1, ALT-002 (Compound 7a) and ALT-003 (Compound 6a) were expected to have significantly improved skin permeability compared to altiratinib at pH 8.5.
Figure PCTKR2023016293-appb-img-000084
Figure PCTKR2023016293-appb-img-000084
실시예 3. 알티라티닙 유도체의 멜라닌 생성 억제 효과 확인Example 3. Confirmation of melanin production inhibition effect of altiratinib derivatives
피부의 과다 색소침착은 피부 조직 내 멜라닌세포(melanocyte)에 의한 멜라닌(melanin) 생성이 증가하면서 멜라닌이 과도하게 축적되어 발생하는 현상이므로, 알티라티닙 유도체 화합물들이 멜라닌세포의 멜라닌 합성을 억제하는지 확인하였다. 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.
또한, 포스콜린(Forskolin, FSK)은 아데닐산 고리화효소(adenyl cyclase)를 활성화하여 cAMP 생산을 유도하고, cAMP는 멜라닌 생성 효소들의 발현을 증가시켜 결과적으로 멜라닌 생성이 유도된다. 따라서, 세포에 자극을 주지 않은 상태(FSK를 처리 안 한 상태)에서 알티라티닙 유도체 화합물들의 멜라닌 생성 억제 효과 뿐만 아니라 알티라티닙 유도체 화합물들의 FSK 처리로 유도된 멜라닌 생성 억제 효과도 확인하였다.In addition, Forskolin (FSK) 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.
마우스 멜라닌세포주인 Mel-Ab 세포에서 알티라티닙 유도체 화합물들의 멜라닌 생성 억제 효과를 확인한 결과를 표 3, 및 도 2 내지 도 3에, ALT-001 내지 ALT-014 알티라티닙 유도체의 멜라닌 생성 억제 효과를 FSK를 처리하지 않은 세포 대조군에 대한 백분율로 표시한 결과를 표 4 및 도 4에 나타내었다. 표 3 내지 표 4 및 도 2 내지 도 4에 나타낸 바와 같이, 알티라티닙(Altiratinib; ALT) 유도체 화합물 중 ALT-002(화합물 7a), ALT-003(화합물 6a), 및 ALT-013(화합물 8c)이 알티라티닙과 동등하거나 향상된 멜라닌 생성 억제 효과를 나타내는 것을 확인할 수 있었으며, 이는 포스콜린 즉, cAMP에 의해 유도되는 멜라닌 생성을 알티라티닙 유도체 화합물들이 억제할 수 있음을 보여준다.The results of confirming the melanin production inhibitory effect of altiratinib derivative compounds in Mel-Ab cells, a mouse melanocyte cell line, are shown in Table 3 and Figures 2 and 3. The melanin production inhibitory effect of altiratinib derivatives from ALT-001 to ALT-014. The results expressed as a percentage relative to the cell control group that was not treated with FSK are shown in Table 4 and Figure 4. As shown in Tables 3 to 4 and Figures 2 to 4, among Altiratinib (ALT) derivative compounds, ALT-002 (Compound 7a), ALT-003 (Compound 6a), and ALT-013 (Compound 8c) ) was confirmed to have an equal or improved melanin production inhibition effect than altiratinib, which shows that altiratinib derivative compounds can inhibit melanin production induced by forskolin, that is, cAMP.
Figure PCTKR2023016293-appb-img-000085
Figure PCTKR2023016293-appb-img-000085
Figure PCTKR2023016293-appb-img-000086
Figure PCTKR2023016293-appb-img-000086
또한, 다른 마우스 멜라닌세포주인 B16F10에서 알티라티닙 유도체의 멜라닌 생성 억제 효과를 확인한 결과를 표 5 및 도 5 내지 도 6에, ALT-001 내지 ALT-014 알티라티닙 유도체의 멜라닌 생성 억제 효과를 FSK를 처리하지 않은 세포 대조군에 대한 백분율로 표시한 결과를 표 6에 나타내었다. 표 5 내지 표 6 및 도 5 내지 도 6에 나타낸 바와 같이, 멜라닌 생성 억제 효과는 알티라티닙 유도체 화합물 중 ALT-002(화합물 7a) 및 ALT-003(화합물 6a)이 알티라티닙과 동등하거나 향상된 멜라닌 생성 억제 효과를 나타내는 것을 확인할 수 있었다.In addition, the results confirming the melanin production inhibition effect of altiratinib derivatives in B16F10, another mouse melanocyte cell line, are shown in Table 5 and Figures 5 to 6. The melanin production inhibition effect of altiratinib derivatives from ALT-001 to ALT-014 is shown in FSK. The results expressed as a percentage relative to the untreated cell control group are shown in Table 6. As shown in Tables 5 to 6 and Figures 5 to 6, among altiratinib derivative compounds, ALT-002 (Compound 7a) and ALT-003 (Compound 6a) have the same or improved melanin production inhibitory effect as altiratinib. It was confirmed that it had an effect of suppressing melanin production.
Figure PCTKR2023016293-appb-img-000087
Figure PCTKR2023016293-appb-img-000087
Figure PCTKR2023016293-appb-img-000088
Figure PCTKR2023016293-appb-img-000088
나아가, 마우스 멜라닌세포주에서 알티라티닙과 동등하거나 향상된 효과를 나타낸 화합물 ALT-002(화합물 7a) 및 ALT-003(화합물 6a)의 인간 1차 멜라닌세포(human primary melanocytes; hMC)에서 멜라닌 생성 억제 효과를 알티라티닙과 비교한 결과, 도 7에 나타낸 바와 같이, 알티라티닙과 유사하거나 향상된 효과를 나타내는 것을 확인할 수 있었다.Furthermore, the inhibitory effect of melanin production in human primary melanocytes (hMC) of compounds ALT-002 (Compound 7a) and ALT-003 (Compound 6a), which showed equivalent or improved effects to altiratinib in mouse melanocyte cell lines. As a result of comparing with altiratinib, it was confirmed that it showed a similar or improved effect as altiratinib, as shown in Figure 7.
또한, 알티라티닙 유도체 ALT-015 내지 ALT-028의 인간 1차 멜라닌세포에서 멜라닌 생성 억제 효과를 알티라티닙과 비교한 결과, 도 8에 나타낸 바와 같이, ALT-024 및 ALT-028가 알티라티닙과 유사한 효과를 나타내는 것을 확인할 수 있었다.In addition, as a result of comparing the melanin production inhibition effect of altiratinib derivatives ALT-015 to ALT-028 in human primary melanocytes with altiratinib, as shown in FIG. 8, ALT-024 and ALT-028 were superior to altiratinib. It was confirmed that it had a similar effect to the nib.
실시예 4. 알티라티닙 유도체의 세포 독성 확인Example 4. Confirmation of cytotoxicity of altiratinib derivatives
마우스 멜라닌세포주인 Mel-Ab 세포에 대한 알티라티닙 유도체의 세포 독성을 확인한 결과, 표 7, 도 9 및 도 10에 나타낸 바와 같이, 알티라티닙 유도체 화합물 중 ALT-002(화합물 7a), ALT-003(화합물 6a), 및 ALT-013(화합물 8c)이 알티라티닙보다 개선된 세포 독성(10uM에서 10% 이내의 독성)을 나타내는 것을 확인할 수 있었다.As a result of confirming the cytotoxicity of altiratinib derivatives against Mel-Ab cells, a mouse melanocyte cell line, as shown in Table 7 and Figures 9 and 10, among altiratinib derivative compounds, ALT-002 (Compound 7a), ALT- It was confirmed that 003 (Compound 6a) and ALT-013 (Compound 8c) showed improved cytotoxicity (toxicity within 10% at 10uM) than altiratinib.
Figure PCTKR2023016293-appb-img-000089
Figure PCTKR2023016293-appb-img-000089
또한, 다른 마우스 멜라닌세포주인 B16F10에 대한 알티라티닙 유도체의 세포 독성을 확인한 결과, 표 8, 도 11 및 도 12에 나타낸 바와 같이, 알티라티닙 유도체 화합물 중 ALT-002(화합물 7a) 및 ALT-003(화합물 6a), 및 ALT-013(화합물 8c)이 알티라티닙보다 개선된 세포 독성(10uM에서 10% 이내의 독성)을 나타내는 것을 확인할 수 있었다.In addition, as a result of confirming the cytotoxicity of altiratinib derivatives against B16F10, another mouse melanocyte cell line, as shown in Table 8 and Figures 11 and 12, among altiratinib derivative compounds, ALT-002 (Compound 7a) and ALT- It was confirmed that 003 (Compound 6a) and ALT-013 (Compound 8c) showed improved cytotoxicity (toxicity within 10% at 10uM) than altiratinib.
Figure PCTKR2023016293-appb-img-000090
Figure PCTKR2023016293-appb-img-000090
또한, 인간 1차 멜라닌세포(human primary melanocytes; hMC)에 대한 알티라티닙 유도체의 세포 독성을 확인한 결과, 표 9, 도 13 및 도 14에 나타낸 바와 같이, 알티라티닙 유도체 화합물 중 ALT-002(화합물 7a) 및 ALT-003 (화합물 6a)이 알티라티닙보다 개선된 세포 독성(10 uM에서 10% 이내의 독성)을 나타내는 것을 확인할 수 있었다.In addition, as a result of confirming the cytotoxicity of altiratinib derivatives on human primary melanocytes (hMC), as shown in Table 9 and Figures 13 and 14, among altiratinib derivative compounds, ALT-002 ( It was confirmed that Compound 7a) and ALT-003 (Compound 6a) showed improved cytotoxicity (toxicity within 10% at 10 uM) than altiratinib.
Figure PCTKR2023016293-appb-img-000091
Figure PCTKR2023016293-appb-img-000091
본 발명자들은 신규한 알티라티닙 유도체 화합물을 합성하였으며, 합성한 신규한 알티라티닙 유도체 화합물이 알티라티닙과 멜라닌 생성 억제 효과에서 유사하거나 향상된 효과를 나타내나, 세포 독성 현저히 낮으며, 현저히 개선된 피부투과도를 가지는 것을 확인하였다. 이에, 본 발명자들은 본 발명에 따른 신규한 알티라티닙 유도체 화합물의 피부 색소침착 치료제로서의 가능성을 확인하였다. 특히, 알티라티닙 유도체 중 ALT-002(화합물 7a)이 마우스 멜라닌 세포주 및 인간 멜라닌 세포 모두에서 10uM의 농도에서도 세포 독성을 나타내지 않으나, 멜라닌 생성 억제 효과는 알티라티닙과 유사하거나 향상된 효과를 나타냈으며, ALT-003(화합물 6a) 및 ALT-013(화합물 8c)은 마우스 멜라닌 세포주 및 인간 멜라닌 세포에서 알티라티닙과 유사하거나 향상된 멜라닌 생성 억제 효과를 나타냈으며, 인간 멜라닌 세포에서 ALT-002보다는 세포 독성이 강하나 알티라티닙(10uM에서 88% 독성)보다는 훨씬 낮은 독성 (10uM에서 30% 독성)을 나타내는 것을 확인하였는바, 본 발명에 따른 신규한 알티라티닙 유도체 화합물들이 피부 색소침착의 예방 또는 치료에 유용하게 활용될 것으로 기대된다.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. In particular, among altiratinib derivatives, 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. It was confirmed that this strong but much lower toxicity (30% toxicity at 10uM) than altiratinib (88% toxicity at 10uM), 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.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.
본 발명에 따른 알티라티닙 유도체는 알티라티닙과 멜라닌 생성 억제 효과는 유사하면서 세포 독성이 현저히 낮은 것으로 확인되었다. 따라서, 본 발명에 따른 알티라티닙 유도체 또는 이들의 염을 유효성분으로 포함하는 조성물은 색소침착의 예방 또는 치료 용도로 사용할 수 있을 뿐만 아니라, 색소침착 개선 등을 통한 피부 미백 등 피부 미용 분야에 다양하게 활용될 수 있으므로 산업상 이용가능성이 있다. It was confirmed that 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.

Claims (19)

  1. 하기 화학식 1로 표시되는 알티라티닙 유도체 또는 이의 염:Altiratinib derivative or salt thereof represented by the following formula (1):
    [화학식 1][Formula 1]
    Figure PCTKR2023016293-appb-img-000092
    Figure PCTKR2023016293-appb-img-000092
    상기 화학식 1에서,In Formula 1,
    R1은 할로겐 원소, 또는
    Figure PCTKR2023016293-appb-img-000093
    이고,    R 1 is a halogen element, or
    Figure PCTKR2023016293-appb-img-000093
    ego,
    R2는
    Figure PCTKR2023016293-appb-img-000094
    ,
    Figure PCTKR2023016293-appb-img-000095
    ,
    Figure PCTKR2023016293-appb-img-000096
    ,
    Figure PCTKR2023016293-appb-img-000097
    , 또는
    Figure PCTKR2023016293-appb-img-000098
    이고,    R 2 is
    Figure PCTKR2023016293-appb-img-000094
    ,
    Figure PCTKR2023016293-appb-img-000095
    ,
    Figure PCTKR2023016293-appb-img-000096
    ,
    Figure PCTKR2023016293-appb-img-000097
    , or
    Figure PCTKR2023016293-appb-img-000098
    ego,
    n은 0, 1, 또는 2이되,n is 0, 1, or 2,
    상기 R3 내지 R6은 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 치환 또는 비치환된 C1-C5 알콕시기, 치환 또는 비치환된 C1-C5 알킬기, 또는 니트로기(NO2)이고,Wherein 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 ),
    상기 A1, A3, 및 A6은 각각 독립적으로 N, CH, CMe, 또는 CPh이고,A 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
    상기 A2, A4, 및 A5는 각각 독립적으로 O, S, NH, NMe, NEt, 또는 CH2이고,A 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
    상기 A7 내지 A10은 각각 독립적으로 C=O, 또는 NH이고,A 7 to A 10 is each independently C=O, or NH,
    상기 '치환 또는 비치환된'은 할로겐 원소, 니트릴기, 니트로기, 하이드록시기, 카보닐기, 에스테르기, 및 이미드기로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환된 것임.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.
  2. 제1항에 있어서,According to paragraph 1,
    상기 알티라티닙 유도체는 하기 화학식 2a 내지 2e 중 어느 하나로 표시되는 것을 특징으로 하는, 알티라티닙 유도체 또는 이의 염:The altiratinib derivative is an altiratinib derivative or a salt thereof, characterized in that it is represented by any one of the following formulas 2a to 2e:
    [화학식 2a][Formula 2a]
    Figure PCTKR2023016293-appb-img-000099
    Figure PCTKR2023016293-appb-img-000099
    (상기 화학식 2a에서,(In Formula 2a,
    n은 0, 1, 또는 2이되,n is 0, 1, or 2,
    상기 R3 및 R4는 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 메톡시(OCH3), 메틸(CH3), 에틸(CH2CH3), 트리플루오로메틸(CF3), 또는 니트로기(NO2)이고,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 ),
    상기 A1은 N, CH, CMe, 또는 CPh이고,Wherein A 1 is N, CH, CMe, or CPh,
    상기 A2는 O, S, NH, NMe, NEt, 또는 CH2임.)The A 2 is O, S, NH, NMe, NEt, or CH 2. )
    [화학식 2b][Formula 2b]
    Figure PCTKR2023016293-appb-img-000100
    Figure PCTKR2023016293-appb-img-000100
    (상기 화학식 2b에서,(In Formula 2b,
    n은 1, 또는 2이되,n is 1 or 2,
    상기 R5 및 R6은 각각 독립적으로 할로겐 원소, 수소(H), 메톡시(OCH3), 또는 메틸(CH3)이고,R 5 and R 6 are each independently a halogen element, hydrogen (H), methoxy (OCH 3 ), or methyl (CH 3 ),
    상기 A3은 N, CH, 또는 CMe이고,Wherein A 3 is N, CH, or CMe,
    상기 A4는 O, S, NH, 또는 NMe임.)where A 4 is O, S, NH, or NMe.)
    [화학식 2c][Formula 2c]
    Figure PCTKR2023016293-appb-img-000101
    Figure PCTKR2023016293-appb-img-000101
    (상기 화학식 2c에서,(In Formula 2c,
    상기 A5는 O, S, 또는 NH이고,A 5 is O, S, or NH,
    상기 A6은 N, 또는 CH임.)A 6 is N, or CH.)
    [화학식 2d][Formula 2d]
    Figure PCTKR2023016293-appb-img-000102
    Figure PCTKR2023016293-appb-img-000102
    (상기 화학식 2d에서,(In Formula 2d above,
    R1은 할로겐 원소, 또는
    Figure PCTKR2023016293-appb-img-000103
    이고,    R 1 is a halogen element, or
    Figure PCTKR2023016293-appb-img-000103
    ego,
    상기 A7 및 A8은 각각 독립적으로 C=O, 또는 NH임.)A 7 and A 8 are each independently C=O, or NH.)
    [화학식 2e][Formula 2e]
    Figure PCTKR2023016293-appb-img-000104
    Figure PCTKR2023016293-appb-img-000104
    (상기 화학식 2e에서,(In Formula 2e,
    상기 A9 및 A10은 각각 독립적으로 C=O, 또는 NH임.)A 9 and A 10 are each independently C=O, or NH.)
  3. 제1항에 있어서,According to paragraph 1,
    상기 알티라티닙 유도체는 The altiratinib derivative is
    상기 화학식 1에서,In Formula 1,
    상기 R1은
    Figure PCTKR2023016293-appb-img-000105
    이고,    The R 1 is
    Figure PCTKR2023016293-appb-img-000105
    ego,
    ⅰ) 상기 n은 0일 때,i) When n is 0,
    상기 R2는
    Figure PCTKR2023016293-appb-img-000106
    , 또는
    Figure PCTKR2023016293-appb-img-000107
    이고,    The R 2 is
    Figure PCTKR2023016293-appb-img-000106
    , or
    Figure PCTKR2023016293-appb-img-000107
    ego,
    ⅱ) 상기 n은 1일 때,ii) When n is 1,
    상기 R2는
    Figure PCTKR2023016293-appb-img-000108
    , 또는
    Figure PCTKR2023016293-appb-img-000109
    인 것을 특징으로 하는, 알티라티닙 유도체 또는 이의 염.    The R 2 is
    Figure PCTKR2023016293-appb-img-000108
    , or
    Figure PCTKR2023016293-appb-img-000109
    An altiratinib derivative or salt thereof, characterized in that.
  4. 제1항에 있어서,According to paragraph 1,
    상기 알티라티닙 유도체는 하기 화합물들로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, 알티라티닙 유도체 또는 이의 염:The altiratinib derivative is characterized in that it is any one selected from the group consisting of the following compounds:
    (1) N-(4-(4-(2-(벤조[d]이속사졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy) pyridin-2-yl)cyclopropanecarboxamide];(1) N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Carboxamide [ N -(4-(4-(2-(benzo[ d ]isoxazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
    (2) N-(4-(4-(2-(벤조[d]옥사졸-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];(2) N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanca Copamide [ N -(4-(4-(2-(benzo[ d ]oxazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
    (3) N-(4-(4-(2-(1H-인다졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];(3) N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarcopy amide [ N -(4-(4-(2-(1 H -indazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
    (4) N-(4-(2,5-디플루오로-4-(2-(5-플루오로-1H-인다졸-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(2,5-difluoro-4-(2-(5-fluoro-1H-indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide];(4) N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl ) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-fluoro-1 H -indazol-3-yl)acetamido)phenoxy) pyridin-2-yl)cyclopropanecarboxamide] ;
    (5) N-(4-((2-클로로피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide];(5) N -(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3- Carboxamide [ N- (4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide];
    (6) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide] ;(6) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide] ;
    (7) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1-옥소-1,2,3,4-테트라히드로이소퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide] ;(7) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-oxo-1,2,3,4 -tetrahydroisoquinoline-3-carboxamide] ;
    (8) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-2-옥소-1,2,3,4-테트라히드로퀴놀린-3-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide];(8) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- Tetrahydroquinoline-3-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-2-oxo-1,2,3,4- tetrahydroquinoline-3-carboxamide];
    (9) N-(4-(4-(2-(1H-인돌-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];(9) N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
    (10) N-(4-(4-(2-(1H-인돌-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(1H-indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(10) N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(1 H -indol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (11) N-(4-(4-(2-(벤조[d]이소티아졸-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(2-(benzo[d]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(11) N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropane Carboxamide [ N -(4-(4-(2-(benzo[ d ]isothiazol-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (12) N-(4-(4-(3-(벤조[d]옥사졸-2-일)프로판아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(3-(benzo[d]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(12) N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(3-(benzo[ d ]oxazol-2-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (13) N-(4-((2-(사이클로프로판카복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[d]티아졸-6-카복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]thiazole-6-carboxamide] ;(13) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]thiazole-6-carboxamide] ;
    (14) N-(4-(4-(3-(1H-인돌-3-일)프로판아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카복사마이드 [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(14) N -(4-(4-(3-(1 H -indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [N-(4-(4-(3-(1H-indol-3-yl)propanamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (15) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-인덴-3-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide] ;(15) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indene-3-carboxamide [ N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indene-3-carboxamide] ;
    (16) N-(4-(2,5-디플루오로-4-(2-(3-옥소이소인돌린-1-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(16) N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N -(4-(2,5-difluoro-4-(2-(3-oxoisoindolin-1-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (17) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-인돌-6-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-indole-6-carboxamide] ;(17) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -indole-6-carboxamide] ;
    (18) N-(4-(4-(2-(벤조[b]티오펜-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(4-(2-(benzo[b]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(18) N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Carboxamide [ N -(4-(4-(2-(benzo[ b ]thiophen-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide];
    (19) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[b]티오펜-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[b]thiophene-6-carboxamide] ;(19) N- (4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ b ]thiophene-6-carboxamide] ;
    (20) N-(4-(2,5-디플루오로-4-(2-(2-옥소인돌린-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(20) N -(4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxylic amide [ N- (4-(2,5-difluoro-4-(2-(2-oxoindolin-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide];
    (21) N -(4-(4-(2-(벤조푸란-3-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(21) N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-3-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (22) N-(4-(4-(2-(벤조푸란-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)시클로프로판카르복사미드 [N-(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(22) N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide [ N -(4-(4-(2-(benzofuran-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (23) N-(4-(4-(2-(벤조[b]티오펜-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(4-(2-(benzo[b]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(23) N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Copamide [ N -(4-(4-(2-(benzo[ b ]thiophen-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (24) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)-1H-벤조[d]이미다졸-6-카르복사마이드[N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1H-benzo[d]imidazole-6-carboxamide] ;(24) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6- Carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1 H -benzo[ d ]imidazole-6-carboxamide] ;
    (25) N-(4-(2,5-디플루오로-4-(2-(5-메톡시-1H-인다졸-3-일)아세트아미도)페녹시)피리딘-2-일)사이클로프로판카르복사마이드 [N-(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(25) N -(4-(2,5-difluoro-4-(2-(5-methoxy-1H-indazol-3-yl)acetamido)phenoxy)pyridin-2-yl) Cyclopropanecarboxamide [ N -(4-(2,5-difluoro-4-(2-(5-methoxy-1 H -indazol-3-yl)acetamido)phenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (26) N-(4-(4-(2-(벤조[d]티아졸-2-일)아세트아미도)-2,5-디플루오로페녹시)피리딘-2-일)사이클로프로판카르복사마이드[N-(4-(4-(2-(benzo[d]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;(26) N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropancar Carboxamide [ N -(4-(4-(2-(benzo[ d ]thiazol-2-yl)acetamido)-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide] ;
    (27) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조푸란-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] ; 및(27) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide [ N- (4 -((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzofuran-6-carboxamide] ; and
    (28) N-(4-((2-(사이클로프로판카르복사미도)피리딘-4-일)옥시)-2,5-디플루오로페닐)벤조[d]옥사졸-6-카르복사마이드 [N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[d]oxazole-6-carboxamide].(28) N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide [ N -(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)benzo[ d ]oxazole-6-carboxamide].
  5. 유기 용매 존재 하에, 하기 화학식 3의 화합물 또는 하기 화학식 4의 화합물에서 선택되는 어느 하나의 화합물과 하기 화학식 5의 화합물을, 커플링 시약(coupling reagent)과 함께 아미드 커플링(Amide Coupling) 반응시키는 것을 특징으로 하는, 제1항에 따른 알티라티닙 유도체의 제조방법으로서,In the presence of an organic solvent, an amide coupling reaction is performed between a compound selected from a compound of formula 3 or a compound of formula 4 below and a compound of formula 5 below with a coupling reagent. A method for producing the altiratinib derivative according to claim 1, characterized in that,
    상기 커플링 시약은 TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, 및 DCC로 이루어진 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 제조방법:A manufacturing method characterized in that the coupling reagent is at least one selected from the group consisting of TBTU, HATU, DIPEA, 1-hydroxybenzotriazole, and DCC:
    [화학식 3][Formula 3]
    Figure PCTKR2023016293-appb-img-000110
    Figure PCTKR2023016293-appb-img-000110
    [화학식 4][Formula 4]
    Figure PCTKR2023016293-appb-img-000111
    Figure PCTKR2023016293-appb-img-000111
    [화학식 5][Formula 5]
    Figure PCTKR2023016293-appb-img-000112
    Figure PCTKR2023016293-appb-img-000112
    상기 화학식 5에서,In Formula 5 above,
    R은
    Figure PCTKR2023016293-appb-img-000113
    ,
    Figure PCTKR2023016293-appb-img-000114
    ,
    Figure PCTKR2023016293-appb-img-000115
    ,
    Figure PCTKR2023016293-appb-img-000116
    , 또는
    Figure PCTKR2023016293-appb-img-000117
    이고,    R is
    Figure PCTKR2023016293-appb-img-000113
    ,
    Figure PCTKR2023016293-appb-img-000114
    ,
    Figure PCTKR2023016293-appb-img-000115
    ,
    Figure PCTKR2023016293-appb-img-000116
    , or
    Figure PCTKR2023016293-appb-img-000117
    ego,
    n은 0, 1, 또는 2이되,n is 0, 1, or 2,
    상기 R3 내지 R6은 각각 독립적으로 할로겐 원소, 수소(H), 하이드록시기(OH), 치환 또는 비치환된 C1-C5 알콕시기, 치환 또는 비치환된 C1-C5 알킬기, 또는 니트로기(NO2)이고,Wherein 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 ),
    상기 A1, A3, 및 A6은 각각 독립적으로 N, CH, CMe, 또는 CPh이고,A 1 , A 3 , and A 6 are each independently N, CH, CMe, or CPh,
    상기 A2, A4, 및 A5는 각각 독립적으로 O, S, NH, NMe, NEt, 또는 CH2이고,A 2 , A 4 , and A 5 are each independently O, S, NH, NMe, NEt, or CH 2 ,
    상기 A7 내지 A10은 각각 독립적으로 C=O, 또는 NH이고,A 7 to A 10 is each independently C=O, or NH,
    상기 '치환 또는 비치환된'은 할로겐 원소, 니트릴기, 니트로기, 하이드록시기, 카보닐기, 에스테르기, 및 이미드기로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환된 것임.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.
  6. 제5항에 있어서,According to clause 5,
    상기 유기 용매는 디옥산(dioxane), 메탄올(methanol), 에탄올(ethanol), 아세토나이트릴(acetonitrile), 테트라히드로푸란(tetrahydrofuran, THF), 다이메틸폼아마이드(dimethylformamide, DMF), 다이메틸설폭사이드(dimethyl sulfoxide, DMSO), 및 디클로로에틸렌(dichloroethylene, DCE)로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는, 제조방법.The organic solvent is dioxane, methanol, ethanol, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethyl sulfoxide. A manufacturing method, characterized in that at least one selected from the group consisting of (dimethyl sulfoxide, DMSO), and dichloroethylene (DCE).
  7. 제1항의 화학식 1의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 색소침착(pigmentation)의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
  8. 제7항에 있어서,In clause 7,
    상기 색소침착은 기미, 주근깨, 흑자, 검버섯, 점, 밀크커피 반점, 오타모반, 청색모반, 과다 색소침착 반점, 약물 사용 후의 과다 색소침착, 임신성 갈색반(gravidic chloasma), 상처 또는 피부염으로 인한 염증 후 과다 색소침착, 노인성 색소반, 및 일광흑색종(solar lentigines)으로 구성된 군으로부터 선택되는 하나 이상인 것을 특징으로 하는, 약학적 조성물.The pigmentation includes freckles, freckles, lentigines, age spots, moles, milk coffee spots, nevus of Ota, blue nevus, hyperpigmentation spots, hyperpigmentation after drug use, gravidic chlorasma, inflammation due to wounds or dermatitis. A pharmaceutical composition, characterized in that it is one or more selected from the group consisting of post-natal hyperpigmentation, senile pigmentation, and solar lentigines.
  9. 제1항의 화학식 1의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 색소침착(pigmentation)의 예방 또는 개선용 화장료 조성물.A cosmetic composition for preventing or improving pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
  10. 제9항에 있어서,According to clause 9,
    상기 화장료 조성물은 세럼, 화장수, 페이스트, 패치, 젤, 스킨로션, 스킨소프너, 스킨토너, 아스트린젠트, 로션, 밀크로션, 모이스쳐 로션, 영양로션, 크림, 맛사지크림, 영양크림, 미스트, 모이스쳐 크림, 핸드크림, 핸드로션, 파운데이션, 에센스, 영양에센스, 팩, 비누, 오일, 파운데이션, 메이크업 베이스, 왁스, 스프레이, 클렌징폼, 클렌징로션, 클렌징크림, 클렌징오일, 클렌징밤, 바디로션 또는 바디클렌저 제형인 것을 특징으로 하는, 화장료 조성물.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, nutritional cream, 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 body cleanser formulation. Characterized by a cosmetic composition.
  11. 제9항에 따른 화장료 조성물을 이를 필요로 하는 개체의 피부에 적용하는 단계를 포함하는, 색소침착을 예방 또는 개선하기 위한 피부 미용방법.A skin care method for preventing or improving pigmentation, comprising the step of applying the cosmetic composition according to claim 9 to the skin of an individual in need thereof.
  12. 제1항의 화학식 1의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 색소침착(pigmentation)의 예방 또는 개선용 국소 적용 제제.A topically applied preparation for preventing or improving pigmentation comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
  13. 제12항에 있어서,According to clause 12,
    상기 국소 적용 제제는 크림, 젤, 로션, 파우더, 파우더 스프레이, 오일, 롤-온 제형, 연고, 폼, 스프레이, 스틱 또는 팅쳐(tincture) 형태인 것을 특징으로 하는, 국소 적용 제제.The topical application preparation is characterized in that it is in the form of a cream, gel, lotion, powder, powder spray, oil, roll-on formulation, ointment, foam, spray, stick or tincture.
  14. 제1항의 화학식 1의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 색소침착(pigmentation)의 예방 또는 개선용 식품 조성물.A food composition for preventing or improving pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
  15. 제1항의 화학식 1의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 색소침착(pigmentation)의 예방 또는 개선용 건강기능식품.A health functional food for preventing or improving pigmentation containing the altiratinib derivative of formula 1 of claim 1 or a salt thereof as an active ingredient.
  16. 제1항의 화학식 1의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 색소침착(pigmentation)의 예방 또는 개선용 의약외품 조성물.A quasi-drug composition for preventing or improving pigmentation, comprising the altiratinib derivative of Formula 1 of claim 1 or a salt thereof as an active ingredient.
  17. 제1항의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 색소침착의 예방 또는 치료 방법.A method for preventing or treating pigmentation, comprising administering a composition containing the altiratinib derivative of claim 1 or a salt thereof as an active ingredient to an individual in need thereof.
  18. 제1항의 알티라티닙 유도체 또는 이의 염을 유효성분으로 포함하는 조성물의 색소침착의 예방, 개선 또는 치료 용도. Use of a composition containing the altiratinib derivative of claim 1 or a salt thereof as an active ingredient to prevent, improve, or treat pigmentation.
  19. 색소침착 치료용 약제 제조를 위한 제1항의 알티라티닙 유도체 또는 이의 염의 용도.Use of the altiratinib derivative or salt thereof of claim 1 for manufacturing a drug for treating pigmentation.
PCT/KR2023/016293 2022-10-19 2023-10-19 Novel altiratinib derivative, manufacturing method therefor, and composition comprising same as active ingredient for prevention, alleviation, or treatment of skin pigmentation WO2024085695A1 (en)

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